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Which substance use is associated with Brodifacoum poisoning?

Brodifacoum poisoning was linked to marijuana use.

[32771937, 30022308, 9111096, 30280655, 31579608, 32300441, 32659068, 33132381]

A 50-year-old man was admitted to the emergency department with abrupt massive epistaxis. An accurate anamnesis and physical evaluation could not reveal any other anomalies, while coagulation tests showed potentially life threatening prolonged prothrombin time, with activated partial thromboplastin and thrombin time, with fibrinogen and antithrombin III within limits. Despite the prompt pharmacological and compressive local treatment, bleeding continued and the patient was therefore hospitalized. Highly specific coagulation and toxicological testing-among others high-performance liquid chromatography assessment on plasma-were performed, leading to the unexpected identification of brodifacoum. Police and criminal justice authorities revealed the source of exposure to brodifacoum after several months of investigation, residing in his everyday life. Brodifacoum is a long-lasting anticoagulant, acting as a vitamin K antagonist, and belongs to the family of superwarfarins. Brodifacoum use is authorized as rodenticide in many countries worldwide, but has been reported as cause of severe coagulopathies in humans, both intentional or involuntary, even consumed as a contaminant of herbal drugs, such as cannabis. The original contribution of this case to the knowledges of human brodifacoum intoxication resides in the multidisciplinary approach and the collaborative interplay of clinical and toxicology experts as well as judicial authorities. Synthetic marijuana is a dangerous substance due to its potency, ever-changing composition, and unpredictable side effects. Recently, brodifacoum-contaminated synthetic marijuana has led to multiple deaths and morbidity throughout the USA from severe coagulopathy associated with use of this strain of the drug (brodifacoum is a rodenticide and potent Vitamin K antagonist/anticoagulant). We describe the clinical and radiologic findings in two patients who were diagnosed with, and treated for, ingestion of this new strain of synthetic marijuana. The radiologic manifestations were most notable for hemorrhagic pyelitis/ureteritis. Both patients required hospitalization with Vitamin K supplementation. The radiologic and clinical pictures in these patients are important for radiologists to recognize in order to help guide appropriate patient management. We report the case of a 17-year-old boy with a significant history of drug and alcohol abuse, which included smoking marijuana mixed with brodifacoum. As a consequence, the patient developed a prolonged coagulopathy that persisted for more than 1 year. To our knowledge, this is the first case reported in the literature in which super-warfarin intoxication has been associated with marijuana smoking. This report should increase the awareness of pathologists and clinicians when examining a patient with a history of drug abuse who exhibits persistent vitamin K1-dependent coagulopathy. BACKGROUND: In March and April 2018, more than 150 patients presented to hospitals in Illinois with coagulopathy and bleeding diathesis. Area physicians and public health organizations identified an association between coagulopathy and synthetic cannabinoid use. Preliminary tests of patient serum samples and drug samples revealed that brodifacoum, an anticoagulant, was the likely adulterant. METHODS: We reviewed physician-reported data from patients admitted to Saint Francis Medical Center in Peoria, Illinois, between March 28 and April 21, 2018, and included in a case series adult patients who met the criteria used to diagnose synthetic cannabinoid-associated coagulopathy. A confirmatory anticoagulant poisoning panel was ordered at the discretion of the treating physician. RESULTS: A total of 34 patients were identified as having synthetic cannabinoid-associated coagulopathy during 45 hospitalizations. Confirmatory anticoagulant testing was performed in 15 of the 34 patients, and superwarfarin poisoning was confirmed in the 15 patients tested. Anticoagulant tests were positive for brodifacoum in 15 patients (100%), difenacoum in 5 (33%), bromadiolone in 2 (13%), and warfarin in 1 (7%). Common symptoms at presentation included gross hematuria in 19 patients (56%) and abdominal pain in 16 (47%). Computed tomography was performed to evaluate abdominal pain and revealed renal abnormalities in 12 patients. Vitamin K1 (phytonadione) was administered orally in all 34 patients and was also administered intravenously in 23 (68%). Red-cell transfusion was performed in 5 patients (15%), and fresh-frozen plasma infusion in 19 (56%). Four-factor prothrombin complex concentrate was used in 1 patient. One patient died from complications of spontaneous intracranial hemorrhage. CONCLUSIONS: Our data indicate that superwarfarin adulterants of synthetic cannabinoids can lead to clinically significant coagulopathy. In our series, in most of the cases in which the patient presented with bleeding diathesis, symptoms were controlled with the use of vitamin K1 replacement therapy. The specific synthetic cannabinoid compounds are not known. Recent evidence demonstrates a rising epidemic of unintentional brodifacoum poisoning associated with synthetic cannabinoid use. Synthetic cannabinoid use is on the rise because of its inexpensiveness as well as difficulty to screen and regulate. We present a rare case of severe coagulopathy and cardiac arrest secondary to synthetic cannabinoid use complicated by brodifacoum toxicity. INTRODUCTION: Recent outbreaks of brodifacoum-induced coagulopathy resulting from the use of synthetic cannabinoids represents a growing public health concern. Brodifacoum is a commonly used and commercially available rodenticide that has anticoagulant properties. As new, unregulated synthetic cannabinoids enter the market, the potential for further outbreaks continues to rise. CASE PRESENTATION: We report a case of severe bleeding secondary to inhalation of synthetic cannabinoids contaminated with brodifacoum. The patient had been evaluated for several months of ongoing, unexplained vaginal bleeding and developed hematemesis and rectal bleeding 2 weeks after her last reported use. DISCUSSION: There have been previous reports of hemorrhage after exposure to synthetic marijuana in rare cases, including an outbreak of severe bleeding and reported synthetic marijuana use in the Midwestern region of the United States in 2018. CONCLUSION: While hemorrhaging after exposure to synthetic cannabinoids has been reported previously, we use this case to increase awareness of the potentially deadly exposures to brodifacoum from synthetic cannabinoids use in Wisconsin. By increasing awareness, emergency department physicians and state agencies can collaborate more effectively when responding in these cases.

What is Alphafold?

AlphaFold is a novel machine learning approach that incorporates physical and biological knowledge about protein structure, leveraging multi-sequence alignments, into the design of the deep learning algorithm.

[34586808, 34469019, 34265844]

Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous experimental effort1-4, the structures of around 100,000 unique proteins have been determined5, but this represents a small fraction of the billions of known protein sequences6,7. Structural coverage is bottlenecked by the months to years of painstaking effort required to determine a single protein structure. Accurate computational approaches are needed to address this gap and to enable large-scale structural bioinformatics. Predicting the three-dimensional structure that a protein will adopt based solely on its amino acid sequence-the structure prediction component of the 'protein folding problem'8-has been an important open research problem for more than 50 years9. Despite recent progress10-14, existing methods fall far short of atomic accuracy, especially when no homologous structure is available. Here we provide the first computational method that can regularly predict protein structures with atomic accuracy even in cases in which no similar structure is known. We validated an entirely redesigned version of our neural network-based model, AlphaFold, in the challenging 14th Critical Assessment of protein Structure Prediction (CASP14)15, demonstrating accuracy competitive with experimental structures in a majority of cases and greatly outperforming other methods. Underpinning the latest version of AlphaFold is a novel machine learning approach that incorporates physical and biological knowledge about protein structure, leveraging multi-sequence alignments, into the design of the deep learning algorithm.

List diseases that are repeat expansion disorders (REDs).

The expansion of Short tandem repeats underlies the pathogenesis of multiple neurological disorders, including Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, fragile X-associated tremor/ataxia syndrome, and myotonic dystrophies, known as repeat expansion disorders (REDs).

[25726753, 32695777, 8908515, 32589669, 29325606, 26420841, 32619224, 9302257, 19710035, 25886163, 14526165, 8900536, 10766906, 34502075, 34054431]

The fragile X-related disorders (FXDs) are members of the group of diseases known as the repeat expansion diseases. The FXDs result from expansion of an unstable CGG/CCG repeat tract in the 5' UTR of the FMR1 gene. Contractions are also seen, albeit at lower frequency. We have previously shown that ERCC6/CSB plays an auxiliary role in promoting germ line and somatic expansions in a mouse model of the FXDs. However, work in model systems of other repeat expansion diseases has suggested that CSB may protect against expansions by promoting contractions. Since FXD mice normally have such a high expansion frequency, it is possible that such a protective effect would have been masked. We thus examined the effect of the loss of CSB in an Msh2(+/-) background where the germ line expansion frequency is reduced and in an Msh2(-/-) background where expansions do not occur, but contractions do. Our data show that in addition to promoting repeat expansion, CSB does in fact protect the genome from germ line expansions in the FXD mouse model. However, it likely does so not by promoting contractions but by promoting an error-free process that preserves the parental allele. The Fragile-X related disorders (FXDs) are Repeat Expansion Diseases (REDs) that result from expansion of a CGG-repeat tract located at the 5' end of the FMR1 gene. While expansion affects transmission risk and can also affect disease risk and severity, the underlying molecular mechanism responsible is unknown. Despite the fact that expanded alleles can be seen both in humans and mouse models in vivo, existing patient-derived cells do not show significant repeat expansions even after extended periods in culture. In order to develop a good tissue culture model for studying expansions we tested whether mouse embryonic stem cells (mESCs) carrying an expanded CGG repeat tract in the endogenous Fmr1 gene are permissive for expansion. We show here that these mESCs have a very high frequency of expansion that allows changes in the repeat number to be seen within a matter of days. CRISPR-Cas9 gene editing of these cells suggests that this may be due in part to the fact that non-homologous end-joining (NHEJ), which is able to protect against expansions in some cell types, is not effective in mESCs. CRISPR-Cas9 gene editing also shows that these expansions are MSH2-dependent, consistent with those seen in vivo. While comparable human Genome Wide Association (GWA) studies are not available for the FXDs, such studies have implicated MSH2 in expansion in other REDs. The shared unusual requirement for MSH2 for this type of microsatellite instability suggests that this new cell-based system is relevant for understanding the mechanism responsible for this peculiar type of mutation in humans. The high frequency of expansions and the ease of gene editing these cells should expedite the identification of factors that affect expansion risk. Additionally, we found that, as with cells from human premutation (PM) carriers, these cell lines have elevated mitochondrial copy numbers and Fmr1 hyperexpression, that we show here is O2-sensitive. Thus, this new stem cell model should facilitate studies of both repeat expansion and the consequences of expansion during early embryonic development. Expansion of a CGG-repeat tract in the 5' untranslated region of the FMR1 gene causes the fragile X-related disorders (FXDs; aka the FMR1 disorders). The expansion mechanism is likely shared by the 35+ other diseases resulting from expansion of a disease-specific microsatellite, but many steps in this process are unknown. We have shown previously that expansion is dependent upon functional mismatch repair proteins, including an absolute requirement for MutLγ, one of the three MutL heterodimeric complexes found in mammalian cells. We demonstrate here that both MutLα and MutLβ, the two other MutL complexes present in mammalian cells, are also required for most, if not all, expansions in a mouse embryonic stem cell model of the FXDs. A role for MutLα and MutLβ is consistent with human GWA studies implicating these complexes as modifiers of expansion risk in other Repeat Expansion Diseases. The requirement for all three complexes suggests a novel model in which these complexes co-operate to generate expansions. It also suggests that the PMS1 subunit of MutLβ may be a reasonable therapeutic target in those diseases in which somatic expansion is an important disease modifier. Fragile X-associated disorders are Repeat Expansion Diseases that result from expansion of a CGG/CCG-repeat in the FMR1 gene. Contractions of the repeat tract also occur, albeit at lower frequency. However, these contractions can potentially modulate disease symptoms or generate an allele with repeat numbers in the normal range. Little is known about the expansion mechanism and even less about contractions. We have previously demonstrated that the mismatch repair (MMR) protein MSH2 is required for expansions in a mouse model of these disorders. Here, we show that MSH3, the MSH2-binding partner in the MutSβ complex, is required for 98% of germ line expansions and all somatic expansions in this model. In addition, we provide evidence for two different contraction mechanisms that operate in the mouse model, a MutSβ-independent one that generates small contractions and a MutSβ-dependent one that generates larger ones. We also show that MutSβ complexes formed with the repeats have altered kinetics of ATP hydrolysis relative to complexes with bona fide MMR substrates and that MutSβ increases the stability of the CCG-hairpins at physiological temperatures. These data may have important implications for our understanding of the mechanism(s) of repeat instability and for the role of MMR proteins in this process. Expansion of a tandem repeat tract is responsible for the Repeat Expansion diseases, a group of more than 20 human genetic disorders that includes those like Fragile X (FX) syndrome that result from repeat expansion in the FMR1 gene. We have previously shown that the ATM and Rad3-related (ATR) checkpoint kinase protects the genome against one type of repeat expansion in a FX premutation mouse model. By crossing the FX premutation mice to Ataxia Telangiectasia-Mutated (Atm) mutant mice, we show here that ATM also prevents repeat expansion. However, our data suggest that the ATM-sensitive mechanism is different from the ATR-sensitive one. Specifically, the effect of the ATM deficiency is more marked when the premutation allele is paternally transmitted and expansions occur more frequently in male offspring regardless of the Atm genotype of the offspring. The gender effect is most consistent with a repair event occurring in the early embryo that is more efficient in females, perhaps as a result of the action of an X-linked DNA repair gene. Our data thus support the hypothesis that two different mechanisms of FX repeat expansion exist, an ATR-sensitive mechanism seen on maternal transmission and an ATM-sensitive mechanism that shows a male expansion bias. The Fragile X-related disorders (FXDs) are members of the Repeat Expansion Diseases, a group of human genetic conditions resulting from expansion of a specific tandem repeat. The FXDs result from expansion of a CGG/CCG repeat tract in the 5' UTR of the FMR1 gene. While expansion in a FXD mouse model is known to require some mismatch repair (MMR) proteins, our previous work and work in mouse models of another Repeat Expansion Disease show that early events in the base excision repair (BER) pathway play a role in the expansion process. One model for repeat expansion proposes that a non-canonical MMR process makes use of the nicks generated early in BER to load the MMR machinery that then generates expansions. However, we show here that heterozygosity for a Y265C mutation in Polβ, a key polymerase in the BER pathway, is enough to significantly reduce both the number of expansions seen in paternal gametes and the extent of somatic expansion in some tissues of the FXD mouse. These data suggest that events in the BER pathway downstream of the generation of nicks are also important for repeat expansion. Somewhat surprisingly, while the number of expansions is smaller, the average size of the residual expansions is larger than that seen in WT animals. This may have interesting implications for the mechanism by which BER generates expansions. Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded (CAG)n repeat on the huntingtin gene. It is characterised by motor, psychiatric and cognitive disturbances. Diagnosis can be confirmed by direct genetic testing, which is highly sensitive and specific and is now considered definitive. This study focused on 21 patients presenting with a clinical phenotype showing strong similarity to HD, but who do not have an expanded CAG in the huntingtin gene. However, other possible diagnoses could be evoked for most of them. Seven patients (3.5% of our cohort) could be considered as phenocopies of HD with no alternative diagnosis. Samples were screened for other triplet repeat diseases with similar presentation (DRPLA, SCA-1, SCA-2, SCA-3, SCA-6, and SCA-7) and were all negative. The repeat expansion detection technique (RED) was used to detect uncloned CAG repeat expansions and samples were also analysed by polymerase chain reaction for expansions of the polymorphic CAG-ERDA-1 and CTG18.1 trinucleotide repeats. RED expansion (>40 repeats) was detected in only one patient. The results suggest that unstable CAG/CTG repeat expansions corresponding to known or unknown sequences are not involved in the aetiology of HD-like disorders. It is hypothesised that some of these phenocopies could correspond to mutations in other unidentified genes with other unstable repeats (different from CAG) or in unknown genes with other mutations. Fragile X-related disorders (FXDs), also known as FMR1 disorders, are examples of repeat expansion diseases (REDs), clinical conditions that arise from an increase in the number of repeats in a disease-specific microsatellite. In the case of FXDs, the repeat unit is CGG/CCG and the repeat tract is located in the 5' UTR of the X-linked FMR1 gene. Expansion can result in neurodegeneration, ovarian dysfunction, or intellectual disability depending on the number of repeats in the expanded allele. A growing body of evidence suggests that the mutational mechanisms responsible for many REDs share several common features. It is also increasingly apparent that in some of these diseases the pathologic consequences of expansion may arise in similar ways. It has long been known that many of the disease-associated repeats form unusual DNA and RNA structures. This review will focus on what is known about these structures, the proteins with which they interact, and how they may be related to the causative mutation and disease pathology in the FMR1 disorders.

What is bb21217?

BB21217 is a chimeric antigen receptor (CAR)-modified T-cell therapy used to target B-cell maturation antigen (BCMA) in the treatment of multiple myeloma.

[32055000, 34256819]

Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM. BACKGROUND: CPX-351 (United States: Vyxeos®; Europe: Vyxeos® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In a pivotal phase 3 study that evaluated 309 patients aged 60 to 75 years with newly diagnosed high-risk/secondary acute myeloid leukemia, CPX-351 significantly improved median overall survival versus conventional 7 + 3 chemotherapy (cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a comparable safety profile. A Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of the phase 3 study was performed to compare survival quality between patients receiving CPX-351 versus conventional 7 + 3 after 5 years of follow-up. METHODS: Patients were randomized 1:1 between December 20, 2012 and November 11, 2014 to receive induction with CPX-351 or 7 + 3. Survival time for each patient was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity or prior to remission), TWiST (time in remission without relapse or grade 3 or 4 toxicity), and REL (time after relapse). Within each treatment arm, Q-TWiST was calculated by adding the mean time spent in each health state weighted by its respective quality-of-life, represented by health utility. The relative Q-TWiST gain, calculated as the difference in Q-TWiST between treatment arms divided by the mean survival of the 7 + 3 control arm, was determined in order to evaluate results in the context of other Q-TWiST analyses. RESULTS: The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6% in the base case scenario and 39.8% among responding patients. Across various sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to 57.6%, remaining well above the standard clinically important difference threshold of 15% for oncology. CONCLUSIONS: This post hoc analysis demonstrates that CPX-351 improved quality-adjusted survival, further supporting the clinical benefit in patients with newly diagnosed high-risk/secondary acute myeloid leukemia. Trial registration This trial was registered on September 28, 2012 at www.clinicaltrials.gov as NCT01696084 ( https://clinicaltrials.gov/ct2/show/NCT01696084 ) and is complete.

Describe the syndrome that is caused by biallelic variants in HPDL

Biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

[33970200]

Author information: (1)Friedrich-Baur-Institute, Department of Neurology, LMU Munich, Munich, Germany. (2)Department of Neuromuscular Disorders, Institute of Neurology, University College London, London, UK. (3)Department of Biochemistry, National Defense Medical Center, Neihu, Taipei, Taiwan. (4)Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. (5)Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. (6)Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. (7)Molecular Medicine Unit, IRCCS Fondazione Stella Maris, Pisa, Italy. (8)Department of Pediatrics, College of Medicine, Qassim University, Qassim, Saudi Arabia. (9)Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affliated Hospital of Zhengzhou University, Zhengzhou, China. (10)Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden. (11)Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. (12)DNA Laboratory, Department of Paediatric Neurology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic. (13)Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (14)Barrow Neurological Institute, Phoenix Children's Hospital and University of Arizona College of Medicine, Phoenix, USA. (15)Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria. (16)Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria. (17)Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, USA. (18)Neurology Department, Massachusetts General Hospital, Boston, USA. (19)Mitochondrial Medicine Frontier Program, Children's Hospital of Philadelphia, Philadelphia, USA. (20)Institute of Human Genetics, Technische Universität Mänchen, Munich, Germany. (21)Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerpen, Belgium. (22)Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium. (23)Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerpen, Belgium. (24)Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerpen, Belgium. (25)Genetics Division, Department of Pediatrics, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia. (26)Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands. (27)Polikliniek Neurologie Enschede, Medisch Spectrum Twente, Enschede, The Netherlands. (28)Medizinische Genetik Mainz, Limbach Genetics, Mainz, Germany. (29)Department of Medicine, Nephrology, University Hospital Freiburg, Germany. (30)Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. (31)Department of Genetics, Washington University School of Medicine, St. Louis, USA. (32)Department of Genetics, Yale University School of Medicine, New Haven, USA. (33)Yale Center for Genome Analysis, Yale University, New Haven, USA. (34)Department of Neurology and Psychiatry, Assiut University Hospital, Assiut, Egypt. (35)Development and Behavioural Paediatrics Department, Institute of Child Health and The Children Hospital, Lahore, Pakistan. (36)Oxford Regional Clinical Genetics Service, Northampton General Hospital, Northampton, UK. (37)NIHR Oxford BRC, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. (38)The National Hospital for Neurology and Neurosurgery, London, UK. (39)Unité Fonctionnelle 6254 d'Innovation en Diagnostique Génomique des Maladies Rares, Pôle de Biologie, CHU Dijon Bourgogne, Dijon, France. (40)Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. (41)Rare Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy. (42)Genetics and Genomics of Rare Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy. (43)Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy. (44)Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy. (45)Pediatric Neurology and Neuromuscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy. (46)Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China. (47)Department of Pediatric Neurology, Osaka Women's and Children's Hospital, Osaka, Japan. (48)Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan. (49)Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. (50)Institute of Medical Genomics, International University of Health and Welfare, Chiba, Japan. (51)Department of Clinical Genetics, CHRU Nancy, UMR_S INSERM N-GERE 1256, Université de Lorraine - Faculté de Médecine, Nancy, France. (52)Department of Neuroradiology, CHRU Nancy, Nancy, France. (53)Department of Medical Genetics, Le Havre Hospital, Le Havre, France. (54)Department of Pediatric Neurology, University Children's Hospital Tübingen, Tübingen, Germany. (55)Roberts Individualized Medical Genetics Center, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, USA. (56)Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. (57)Department of Pediatrics, Naval Medical Center San Diego, San Diego, USA. (58)Department of Pediatrics, Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, USA. (59)Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, USA. (60)GeneDx, Gaithersburg, USA. (61)Department of Pediatric Neurology, Akdeniz University Hospital, Antalya, Turkey. (62)Department of Pediatric Neurology, Izmir Katip Celebi University, Izmir, Turkey. (63)Center for Medical Genetics, Hanusch Hospital, Vienna, Austria. (64)Medical School, Sigmund Freud Private University, Vienna, Austria. (65)Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany. (66)German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany. (67)Cologne Center for Genomics, Faculty of Medicine and Cologne University Hospital, University of Cologne, Cologne, Germany. (68)Department of Paediatric Neurology, Liberec Hospital, Liberec, Czech Republic. (69)Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran. (70)Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA. (71)Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. (72)Department of Orthopaedics and Traumatology, Medical University of Vienna, Vienna, Austria. (73)Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. (74)Department of Pediatrics, Genetic Unit, Armed Forces Hospital, Khamis Mushayt, Saudi Arabia. (75)Hasti Genetic Counseling Center of Welfare Organization of Southern Khorasan, Birjand, Iran. (76)Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. (77)genetikum, Center for Human Genetics, Neu-Ulm, Germany. (78)Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Freibug, Germany. (79)Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, USA. (80)Center for the Undiagnosed Patient, Cedars-Sinai Medical Center, Los Angeles, USA.

Which receptor is targeted by Spesolimab?

Spesolimab is a novel anti-interleukin-36 receptor antibody.

[33661508, 33919434, 34085329, 33785490, 34678325, 34626330, 32884319]

The registration of the tumour necrosis factor-α inhibitor adalimumab in 2015 was a major step forward in the treatment of hidradenitis suppurativa/acne inversa (HS). However, it soon became evident that the effectiveness of adalimumab in daily practice was highly variable. A significant unmet medical need of HS patients remained, and the search for novel therapeutic targets was intensified. During the 10th European Hidradenitis Suppurativa Foundation (EHSF) e.V. Conference, reknown international HS investigators virtually presented and discussed the published data on these potential target molecules for future HS treatment. This article addresses the most promising molecules currently under investigation from a pathophysiological and clinical point of view. With phase III trials ongoing, the anti- interleukin (IL)-17 biologics bimekizumab and secukinumab are in the most advanced stage of clinical development showing promising results. In addition, targeting IL-1α with bermekimab has shown encouraging results in two clinical trials. Directing treatment at neutrophil recruitment and activation by targeting IL-36 with spesolimab fits well in the pathogenic concept of HS and clinical phase II trial results are pending. In contrast to in situ evidence, Complement 5a (C5a) and C5a receptor blockade have only shown greater clinical benefit in patients with severe HS. Inhibition of Janus kinase (JAK) 1 signalling in HS showed clinical efficacy only in the highest dosage, highlighting that careful surveillance of the balance between safety and efficacy of JAK inhibition is warranted. Overall, clinical efficacies of all novel treatments reported so far are modest. To guide drug development, more and better-defined translational data on the pathogenesis of this severe and enigmatic inflammatory skin disease are required. BACKGROUND: The IL-36 pathway plays a key role in the pathogenesis of generalized pustular psoriasis (GPP). In a proof-of-concept clinical trial, treatment with spesolimab, an anti-IL-36 receptor antibody, resulted in rapid skin and pustular clearance in patients presenting with GPP flares. OBJECTIVE: We sought to compare the molecular profiles of lesional and nonlesional skin from patients with GPP or palmoplantar pustulosis (PPP) with skin from healthy volunteers, and to investigate the molecular changes after spesolimab treatment in the skin and blood of patients with GPP flares. METHODS: Pre- and post-treatment skin and blood samples were collected from patients with GPP who participated in a single-arm, phase I study (n = 7). Skin biopsies from patients with PPP (n = 8) and healthy volunteers (n = 16) were obtained for comparison at baseline. Biomarkers were assessed by RNA-sequencing, histopathology, and immunohistochemistry. RESULTS: In GPP and PPP lesions, 1287 transcripts were commonly upregulated or downregulated. Selected transcripts from the IL-36 signaling pathway were upregulated in untreated GPP and PPP lesions. In patients with GPP, IL-36 pathway-related signatures, TH1/TH17 and innate inflammation signaling, neutrophilic mediators, and keratinocyte-driven inflammation pathways were downregulated by spesolimab as early as week 1. Spesolimab also decreased related serum biomarkers and cell populations in the skin lesions from patients with GPP, including CD3+ T, CD11c+, and IL-36γ+ cells and lipocalin-2-expressing cells. CONCLUSIONS: In patients with GPP, spesolimab showed rapid modulation of commonly dysregulated molecular pathways in GPP and PPP, which may be associated with improved clinical outcomes. Pustular psoriasis is an unusual form of psoriasis that frequently presents clinical challenges for dermatologists. The condition presents with pustules on an erythematous background and has two distinct subtypes: localized disease on the palms and soles, called palmoplantar pustulosis (PPP), and generalized pustular psoriasis (GPP). The involvement of the fingers, toes, and nails is defined as a separate localized variant, acrodermatitis continua of Hallopeau, and is now thought to be a subset of PPP. The rarity of pustular psoriasis frequently makes the correct diagnosis problematic. In addition, treatment is limited by a relative lack of evidence-based therapeutic options. Current management is often based on existing therapies for standard plaque psoriasis. However, there remains a need for treatments with high, sustained efficacy and a rapid onset of action in pustular psoriasis. Recent advances in understanding of the pathogenesis of pustular psoriasis have provided insights into potential therapies. Treatment of pustular psoriasis is generally determined by the extent and severity of disease, and recent years have seen an increasing use of newer agents, including biologic therapies. Current classes of biologic therapies with US Food and Drug Administration and European Medicines Agency approval for treatment of moderate-to-severe plaque psoriasis in the USA (and elsewhere) include tumor necrosis factor alpha inhibitors (adalimumab, certolizumab pegol, etanercept, infliximab), interleukin (IL)-17 inhibitors (brodalumab, ixekizumab, secukinumab), an IL-12/23 inhibitor (ustekinumab), and IL-23 inhibitors (guselkumab, risankizumab, tildrakizumab). Recently, specific inhibitors of the IL-36 pathway have been evaluated in GPP and PPP, including spesolimab, an IL-36 receptor inhibitor which has shown promising results in GPP. The emerging drugs for pustular psoriasis offer the possibility of rapid and effective treatment with lower toxicities than existing therapies. Further research into agents acting on the IL-36 pathway and other targeted therapies has the potential to transform the future treatment of patients with pustular psoriasis. This article reviews the clinical features of PPP and GPP, and current understanding of the genetics and immunopathology of these conditions; it also provides an update on emerging treatments.

Is NfL (neurofilament light chain) a biomarker of neurodegeneration?

Yes, Neurofilament light chain (NfL) has recently been proposed as a promising biomarker in frontotemporal dementia (FTD).

[32306372, 34480363, 34556565, 34375485, 34519102]

Frontotemporal dementia (FTD) is the second most frequent dementia, after Alzheimer's, in patients under the age of 65. It encompasses clinical entities characterized by behavioral, language, and executive control dysfunction. Neurofilament light chain (NfL) is a new, non-disease specific, widely studied biomarker indicative of axonal injury and degeneration. Various studies have previously explored the role of NfL in the diagnostic process, monitoring, and prognosis of dementia. The current systematic review and meta-analysis include all the available data concerning the role of NfL in frontotemporal dementia and its use as a potential biomarker in differentiating patients with FTD from (a) healthy individuals, (b) Alzheimer's dementia, (c) Dementia with Lewy bodies, (d) Motor Neuron disease, (e) Parkinsonian syndromes, and (f) psychiatric disorders. We also analyze the utility of NfL in distinguishing specific FTD subgroups. Neurofilament light chain has a potential role in differentiating patients with frontotemporal dementia from healthy controls, patients with Alzheimer's dementia, and psychiatric disorders. Higher NfL levels were also noted in patients with semantic primary progressive aphasia (PPA) when compared with behavioral FTD and non-fluent PPA patients. Further studies exploring the use of NfL in frontotemporal dementia are needed. BACKGROUND: Neurofilament light chain protein (NfL) is a promising biomarker of neurodegeneration. OBJECTIVES: To determine whether plasma and CSF NfL (1) associate with motor or cognitive status in Parkinson's disease (PD) and (2) predict future motor or cognitive decline in PD. METHODS: Six hundred and fifteen participants with neurodegenerative diseases, including 152 PD and 200 healthy control participants, provided a plasma and/or cerebrospinal fluid (CSF) NfL sample. Diagnostic groups were compared using the Kruskal-Wallis rank test. Within PD, cross-sectional associations between NfL and Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) and Mattis Dementia Rating Scale (DRS-2) scores were assessed by linear regression; longitudinal analyses were performed using linear mixed-effects models and Cox regression. RESULTS: Plasma and CSF NfL levels correlated substantially (Spearman r = 0.64, P < 0.001); NfL was highest in neurocognitive disorders. PD participants with high plasma NfL were more likely to develop incident cognitive impairment (HR 5.34, P = 0.005). CONCLUSIONS: Plasma NfL is a useful prognostic biomarker for PD, predicting clinical conversion to mild cognitive impairment or dementia. © 2021 International Parkinson and Movement Disorder Society. Author information: (1)From the Barcelonaβeta Brain Research Center (BBRC) (M.M.-A., M.S., G.O., G.S., C.F., J.D.G., N.V.-T., E.M.A.-U., O.G.-R., A.S.-V., G.S.-B., J.M.G.-d-E., C.M., K.F., J.L.M., M.S.-C.), Pasqual Maragall Foundation; IMIM (Hospital del Mar Medical Research Institute) (M.M.-A., M.S., G.O., G.S., C.F., J.D.G., E.M.A.-U., O.G.-R., A.S.-V., G.S.-B., J.M.G.-d-E., C.M., M.S.-C.), Barcelona; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES) (M.M.-A., G.O., E.M.A.-U., O.G.-R., G.S.-B., C.M., K.F., M.S.-C.), Madrid; Universitat Pompeu Fabra (M.M.-A., M.S.), Barcelona, Spain; Department of Psychiatry and Neurochemistry (A.B., N.J.A., H.K., H.Z., K.B.), Institute of Neuroscience and Physiology, University of Gothenburg; Clinical Neurochemistry Laboratory (A.B., H.K., H.Z., K.B.), Sahlgrenska University Hospital, Mölndal; Wallenberg Centre for Molecular and Translational Medicine (A.B., N.J.A., H.K.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Sweden; King's College London (N.J.A.), Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute; NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation (N.J.A.), London, UK; Centro de Investigación Biomédica en Red de Bioingeniería (C.F., J.D.G., A.N.-B., A.P.), Biomateriales y Nanomedicina (CIBER-BBN), Madrid; Centre for Genomic Regulation (CRG) (N.V.-T.), Barcelona Institute for Science and Technology; Department of Clinical Genetics (N.V.-T.), Erasmus MC, University Medical Center Rotterdam, the Netherlands; Servei de Neurologia (O.G.-R., M.S.-C.), Hospital del Mar; Servei de Medicina Nuclear (A.N.-B., A.P.), Hospital Clínic, Barcelona, Spain; Roche Diagnostics GmbH (G.K.), Penzberg, Germany; Roche Diagnostics International Ltd (I.S.), Rotkreuz, Switzerland; UK Dementia Research Institute at UCL (H.Z.), London; Department of Neurodegenerative Disease (H.Z.), UCL Queen Square Institute of Neurology, London, UK; and H. Lundbeck A/S (J.L.M.), Copenhagen, Denmark. (2)From the Barcelonaβeta Brain Research Center (BBRC) (M.M.-A., M.S., G.O., G.S., C.F., J.D.G., N.V.-T., E.M.A.-U., O.G.-R., A.S.-V., G.S.-B., J.M.G.-d-E., C.M., K.F., J.L.M., M.S.-C.), Pasqual Maragall Foundation; IMIM (Hospital del Mar Medical Research Institute) (M.M.-A., M.S., G.O., G.S., C.F., J.D.G., E.M.A.-U., O.G.-R., A.S.-V., G.S.-B., J.M.G.-d-E., C.M., M.S.-C.), Barcelona; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES) (M.M.-A., G.O., E.M.A.-U., O.G.-R., G.S.-B., C.M., K.F., M.S.-C.), Madrid; Universitat Pompeu Fabra (M.M.-A., M.S.), Barcelona, Spain; Department of Psychiatry and Neurochemistry (A.B., N.J.A., H.K., H.Z., K.B.), Institute of Neuroscience and Physiology, University of Gothenburg; Clinical Neurochemistry Laboratory (A.B., H.K., H.Z., K.B.), Sahlgrenska University Hospital, Mölndal; Wallenberg Centre for Molecular and Translational Medicine (A.B., N.J.A., H.K.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Sweden; King's College London (N.J.A.), Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute; NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation (N.J.A.), London, UK; Centro de Investigación Biomédica en Red de Bioingeniería (C.F., J.D.G., A.N.-B., A.P.), Biomateriales y Nanomedicina (CIBER-BBN), Madrid; Centre for Genomic Regulation (CRG) (N.V.-T.), Barcelona Institute for Science and Technology; Department of Clinical Genetics (N.V.-T.), Erasmus MC, University Medical Center Rotterdam, the Netherlands; Servei de Neurologia (O.G.-R., M.S.-C.), Hospital del Mar; Servei de Medicina Nuclear (A.N.-B., A.P.), Hospital Clínic, Barcelona, Spain; Roche Diagnostics GmbH (G.K.), Penzberg, Germany; Roche Diagnostics International Ltd (I.S.), Rotkreuz, Switzerland; UK Dementia Research Institute at UCL (H.Z.), London; Department of Neurodegenerative Disease (H.Z.), UCL Queen Square Institute of Neurology, London, UK; and H. Lundbeck A/S (J.L.M.), Copenhagen, Denmark. msuarez@barcelonabeta.org. BACKGROUND AND PURPOSE: Neurofilament light chain (NfL) has recently been proposed as a promising biomarker in frontotemporal dementia (FTD). We investigated the correlation of both cerebrospinal fluid (CSF) and serum NfL with detailed neuropsychological data and cognitive decline in a cohort of sporadic and familial FTD. METHODS: CSF and serum NfL, as well as conventional CSF Alzheimer's disease (AD) biomarkers (Aβ42, t-Tau, p-Tau181), were determined in 63 FTD patients (30 sporadic-FTD, 20 with progranulin (GRN) mutations [FTD-GRN], 13 with chromosome 9 open reading frame 72 [C9orf72] expansions [C9orf72-FTD]), 37 AD patients, and 31 neurologic controls. Serum NfL was also quantified in 37 healthy individuals. Correlations between baseline CSF and serum NfL levels, standardized neuropsychological tests, and the rate of cognitive decline in FTD patients were assessed. RESULTS: CSF and serum NfL presented with significantly higher levels in FTD than in AD patients and both control groups. Within FTD subtypes, genetic cases, and particularly FTD-GRN, had higher CSF and serum NfL levels. Significant correlations between NfL levels and overall cognitive function, abstract reasoning (CSF and serum), executive functions, memory, and language (serum) were found. A relationship between increased baseline CSF and serum NfL and a decay in cognitive performance over time was also observed. CONCLUSIONS: Our findings highlight the potential of serum NfL as a useful surrogate end point of disease severity in upcoming targeted treatments. BACKGROUND: No comprehensive meta-analysis has ever been performed to assess the value of neurofilament light chain (NfL) as a biomarker in genetic ataxia. OBJECTIVE: We conducted a meta-analysis to summarize NfL concentration and evaluate its utility as a biomarker in genetic ataxia. METHODS: Studies were included if they reported NfL concentration of genetic ataxia. We used log (mean ± SD) NfL to describe mean raw value of NfL. The effect size of NfL between genetic ataxia and healthy controls (HC) was expressed by mean difference. Correlation between NfL and disease severity was calculated. RESULTS: We identified 11 studies of 624 HC and 1006 patients, here referred to as spinocerebellar ataxia (SCA1, 2, 3, 6, and 7), Friedreich ataxia (FRDA), and ataxia telangiectasia (A-T). The concentration of blood NfL (bNfL) elevated with proximity to expected onset, and progressively increased from asymptomatic to preclinical to clinical stage in SCA3. Compared with HC, bNfL levels were significantly higher in SCA1, 2, 3, and 7, FRDA, as well as A-T, and the difference increased with the advancing disease in SCA3. bNfL levels correlated with disease severity in SCA3. There was a significant correlation between bNfL and longitudinal progression in SCA3. Additionally, bNfL increased with age in HC, yet this is probably masked by higher disease-related effects on bNfL in genetic ataxia. CONCLUSIONS: bNfL can be used as a potential biomarker to predict disease onset, severity, and progression of genetic ataxia. Reference-value setting of bNfL should be divided according to age. © 2021 International Parkinson and Movement Disorder Society.

Is Epistaxis associated with dental implant placement?

Epistaxis is a frequent complication associated with dental implant placement.

[30719578, 24155599]

BACKGROUND: After tooth loss, the posterior maxilla is usually characterized by limited bone height secondary to pneumatization of the maxillary sinus and/or collapse of the alveolar ridge that preclude in many instances the installation of dental implants. In order to compensate for the lack of bone height, several treatment options have been proposed. These treatment alternatives aimed at the installation of dental implants with or without the utilization of bone grafting materials avoiding the perforation of the Schneiderian membrane. Nevertheless, membrane perforations represent the most common complication among these procedures. Consequently, the present review aimed at the elucidation of the relevance of this phenomenon on implant survival and complications. MATERIAL AND METHODS: Electronic and manual literature searches were performed by two independent reviewers in several databases, including MEDLINE, EMBASE, and Cochrane Oral Health Group Trials Register, for articles up to January 2018 reporting outcome of implant placement perforating the sinus floor without regenerative procedure (lateral sinus lift or transalveolar technique) and graft material. The intrusion of the implants can occur during drilling or implant placement, with and without punch out Schneiderian. Only studies with at least 6 months of follow-up were included in the qualitative assessment. RESULTS: Eight studies provided information on the survival rate, with a global sample of 493 implants, being the weighted mean survival rate 95.6% (IC 95%), after 52.7 months of follow-up. The level of implant penetration (≤ 4 mm or > 4 mm) did not report statistically significant differences in survival rate (p = 0.403). Seven studies provided information on the rate of clinical complications, being the mean complication rate 3.4% (IC 95%). The most frequent clinical complication was epistaxis, without finding significant differences according to the level of penetration. Five studies provide information on the radiographic complication; the most common complication was thickening of the Schneiderian membrane. The weighted complication rate was 14.8% (IC 95%), and penetration level affects the rate of radiological complications, being these of 5.29% in implant penetrating ≤4 mm and 29.3% in implant penetrating > 4 mm, without reaching statistical significant difference (p = 0.301). CONCLUSION: The overall survival rate of the implants into the sinus cavity was 95.6%, without statistical differences according to the level of penetration. The clinical and radiological complications were 3.4% and 14.8% respectively. The most frequent clinical complication was the epistaxis, and the radiological complication was thickening of the Schneiderian membrane, without reaching statistical significant difference according to the level of implant penetration inside the sinus. BACKGROUND: To assess the survival rate of implants placed in the posterior maxilla by intentionally perforating the Schneiderian membrane and protruding the implant up to 3mm beyond the sinus floor in cases of reduced crestal bone height (CBH). MATERIALS & METHODS: 56 patients with reduced CBH received 63 implants in the posterior maxilla. All implants intentionally penetrated the Schneiderian membrane and engaged the sinus floor cortical bone. All patients were followed up and implant survival was assessed at the end of one year post implant restoration. RESULTS: Out of 63 implants, there was only one failure (98.4% Survival rate) after a follow up period of one year. 7 patients experienced mild epistaxis during the immediate post-operative period with no associated implant loss. One patient developed sinusitis secondary to the surgical procedure, which was treated by antibiotic therapy and the patient improved clinically with no associated implant loss. CONCLUSION: An intentional perforation of the Schneiderian membrane using a 2mm twist drill at the time of implant placement and protrusion of the implant up to 3mm beyond the sinus floor does not alter the stability and outcome of dental implants, one year post-restoration. This could be associated with minor complications ranging from epistaxis to sinusitis, which are manageable. How to cite this article: Nooh N. Effect of Schneiderian Membrane Perforation on Posterior Maxillary Implant Survival. J Int Oral Health 2013; 5(3):28-34.

Is Daprodustat effective for anemia?

Yes. Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor for the treatment of anemia of chronic kidney disease.

[33561857, 33744933, 32250021, 33628028, 33597868, 34739196, 27978511, 33964183, 34739194, 31306555, 34713596, 31640478]

BACKGROUND: Daprodustat is an oral agent that stimulates erythropoiesis by inhibiting the prolyl hydroxylases which mark hypoxia-inducible factor for degradation through hydroxylation. Its safety and efficacy (noninferiority) were assessed in this 52-week, open-label study. METHODS: Japanese patients not on dialysis (ND) (N = 299) with anemia of CKD (stages G3, G4, and G5) with iron parameters of ferritin >100 ng/mL or transferrin saturation >20% at screening were randomized to daprodustat or epoetin beta pegol (continuous erythropoietin receptor activator [CERA], also known as methoxy polyethylene glycol-epoetin beta). After initiation of the study, the daprodustat starting dose for erythropoiesis-stimulating agent (ESA)-naïve participants was revised, and daprodustat was started at 2 or 4 mg once daily depending on baseline hemoglobin. ESA users switched to daprodustat 4 mg once daily. CERA was started at 25 μg every 2 weeks for ESA-naïve patients and 25-250 μg every 4 weeks for ESA users based on previous ESA dose. In both treatment groups, dose was adjusted every 4 weeks based on hemoglobin level and changed according to a prespecified algorithm. The primary endpoint was mean hemoglobin level during weeks 40-52 in the intention-to-treat (ITT) population. ESA-naïve patients who entered before the protocol amendment revising the daprodustat starting dose were excluded from the ITT population. RESULTS: Mean hemoglobin levels during weeks 40-52 were 12.0 g/dL in the daprodustat group (n = 108; 95% confidence interval [CI], 11.8-12.1) and 11.9 g/dL for CERA (n = 109; 95% CI 11.7-12.0); the difference between the groups was 0.1 g/dL (95% CI -0.1 to 0.3 g/dL). The lower limit of the 95% CI of the difference was greater than the prespecified margin of -1.0 g/dL. The mean hemoglobin level was within the target range (11.0-13.0 g/dL) during weeks 40-52 for 92% of participants in both groups. There was no meaningful difference in the frequencies of adverse events. CONCLUSIONS: Oral daprodustat was noninferior to CERA in achieving and maintaining target hemoglobin levels in Japanese ND patients. Daprodustat was well tolerated, with no new safety concerns identified. BACKGROUND: The Anemia Studies in chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Dialysis (ASCEND-D) trial will test the hypothesis that daprodustat is noninferior to comparator epoetin alfa or darbepoetin alfa for two co-primary endpoints: hemoglobin (Hb) efficacy and cardiovascular (CV) safety. METHODS: We report the trial design, key demographic, clinical and laboratory findings, and baseline therapies of 2964 patients randomized in the open-label (sponsor-blinded) active-controlled, parallel-group, randomized ASCEND-D clinical trial. We also compare baseline characteristics of ASCEND-D patients with patients who are on dialysis (CKD G5D) enrolled in other large CV outcome trials (CVOTs) and in the most relevant registries. RESULTS: The median age of patients was 58 years, 43% were female; 67% were White and 16% were Black. The median Hb at baseline was 10.4 g/dL. Among randomized patients, 89% were receiving hemodialysis and 11% peritoneal dialysis. Among key comorbidities, 42% reported a history of diabetes mellitus and 45% a history of CV disease. Median blood pressure was 134/74 mmHg. The median weekly dose of epoetin was 5751 units. Intravenous and oral iron uses were noted in 64 and 11% of patients, respectively. Baseline demographics were similar to patients with CKD G5D enrolled in other CVOTs and renal patient registries. CONCLUSIONS: ASCEND-D will evaluate the efficacy and safety of daprodustat compared with epoetin alfa or darbepoetin alfa in the treatment of patients with anemia with CKD G5D.This trial is registered with ClinicalTrials.gov: NCT02879305. EudraCT Number: 2016-000541-31; Sponsor Protocol Number: 200807. Daprodustat is a prolyl hydroxylase inhibitor that stimulates erythropoiesis in a manner similar to the natural response to hypoxia, whereby inhibition of hypoxia inducible factor (HIF) prolyl-4-hydroxylases by daprodustat ultimately results in increased levels of HIF-responsive genes. Daprodustat is under development as an emerging new class of agents for the treatment of anemia associated with chronic kidney disease (CKD). This was a single-center, single-dose, open-label, randomized, 2-way crossover study in healthy Japanese male participants consisting of 2 parts. The primary objective was to evaluate the bioequivalence (BE) between daprodustat tablet strengths (part 1) and to evaluate the food effect on the pharmacokinetics (PK) of daprodustat (part 2). A total of 64 healthy Japanese male participants were enrolled; 52 participants were included in part 1 and 12 in part 2. BE was demonstrated between the daprodustat 2-mg tablet and the daprodustat 4-mg tablet. A standard CKD meal did not have a large effect on the PK parameters of daprodustat after a single oral dose of daprodustat 4 mg. Administration of single oral doses of daprodustat 4 mg was generally well tolerated in the healthy Japanese participants, and no new safety signals were identified without regard to food. Anemia is a major complication of chronic kidney disease (CKD), which mainly results from appropriate erythropoietin production impairment. Prolyl hydroxylase domain (PHD) inhibitors are currently being developed and approved in some countries as a new treatment for CKD patients with anemia due to the stabilization of intracellular hypoxia-inducible factor (HIF) 1α and HIF2α by PHD inhibition. Daprodustat is one of the orally administrated small-molecule HIF-PH inhibitors, leading to an increase in erythropoietin production, which is regulated by HIF. Also, daprodustat is expected to improve iron metabolism. Recently, several clinical trials showed its efficacy and safety in both hemodialysis- and non-hemodialysis- dependent CKD patients. In addition, some international Phase 3 studies are underway to confirm these effects and reveal the safety profile. This article summarizes the development process and results of each clinical trial. Objective: Daprodustat is a novel oral agent in treating anemia of chronic kidney disease (CKD), and several clinical trials have been conducted to compare daprodustat with recombinant human erythropoietin (rhEPO) or placebo. Our systematic review aimed to investigate the efficacy and safety of daprodustat for anemia treatment in both dialysis-dependent (DD) and non-dialysis-dependent (NDD) patients. Methods: Six databases were searched for randomized controlled trials (RCTs) reporting daprodustat vs. rhEPO or placebo for anemia patients in CKD. The outcome indicators were focused on hemoglobin (Hb), ferritin, transferrin saturation (TSAT), total iron-binding capacity (TIBC), vascular endothelial growth factor (VEGF), and serious adverse events (SAEs). Results: Eight eligible studies with 1,516 participants were included. For both NDD and DD patients, changes in Hb levels from baseline were significantly higher in daprodustat group than that in the placebo (mean difference (MD) = 1.73, [95% confidence interval (CI), 0.34 to 3.12], p = 0.01; MD = 1.88, [95% CI, 0.68 to 3.09], p = 0.002; respectively), and there was no significant difference between daprodustat and rhEPO group (MD = 0.05, [95% CI, -0.49 to 0.59], p = 0.86; MD = 0.12, [95% CI, -0.28 to 0.52], p = 0.55; respectively). The indexes of iron metabolism were improved significantly in the daprodustat group compared to placebo- or rhEPO-treated patients, while there was no similar change in terms of TSAT for DD patients. Furthermore, no trend of increasing plasma VEGF was observed in daprodustat-treated subjects. As for safety, there was no significant difference in the incidence of SAEs between daprodustat and placebo treatment, while the incidence of SAEs in the daprodustat group was significantly lower than that in the rhEPO group. Conclusion: Daprodustat was efficacious and well tolerated for anemia in both NDD and DD patients in the short term based on current RCTs. And daprodustat may become an effective alternative for treatment of anemia with CKD. Since the application of daprodustat is still under exploration, future researches should consider the limitations of our study to evaluate the value of daprodustat. Collaborators: Cuadrado J, Ulla M, Alvarisqueta A, Cusumano C, Najun Zarazaga C, Vallejos A, Santos J, Vasquez N, Ramirez N, Guinsburg M, Resk J, Marín I, Guinsburg A, Laham G, Alberdi C, Maurich M, Douthat W, Talaulikar G, Packham D, Gray N, Roger S, Mather A, Australia A, Murali K, Pedagogos E, Komala M, Badve SV, Boudville N, Ritchie A, Wilson S, Suranyi M, Van Viem B, Warling X, De Meester J, De Keyzer K, Claes K, Maes B, Vandewiele B, Debelle F, Demoulin N, Vanuytsel J, Hernandes F, Deboni LM, Bruno R, Canziani ME, Riella M, Bastos M, Noronha I, Piovesan F, Carvalho N, Contieri F, Sato V, Paschoalin R, Hernandes M, Ramalho R, Pecoits-Filho R, Lorenzoni dAvila D, Prompt C, Capanema Silva G, Rangelov R, Yanakieva T, Boyadzhieva S, Shikov P, Bakardzhiev T, Iliev V, Nikolov D, Vasileva A, Nikolova M, Staykova S, Hristozov V, Aggarwal N, McMahon A, Chow S, Cournoyer S, Wong G, Zidel B, Tennankore K, Muirhead N, Mac-Way F, Mesa L, Garcia Padilla P, Gelvez J, Carvajal JN, Cadena Bonfanti A, Vlasak J, Jirovec M, Saudek F, Kovar R, Oplustilova A, Honova V, Sevcik J, Hagstrup Christensen J, Juul-Sandberg R, Aarup M, Mose FH, Rosenberg M, Massy Z, Belmouaz M, Henri P, Legrand E, Chantrel F, Le Quintrec M, Urena-Torres PA, Heng AE, Juillard L, Strutz F, Marsen T, Krüger T, Gabriels G, Lüders S, Goumenos D, Ntounousi E, Liakopoulos V, Gouva C, Stylianou K, Dafnis E, Stefanidis I, Papadopoulou D, Papagianni A, Kaperonis N, Vlahakos D, Georgoulidou A, Mavromatidi K, Patsialas S, Passadakis P, Andrikos E, Bamichas G, Moutafis S, Chatzigiannakos D, Spaia S, Cheung SF, Chan TMD, Fung S, Tong M, Zsom M, Major L, Ladanyi E, Molnar M, Gurzo M, Csiky B, Bhalla AK, Ahlawat R, Gang S, Mali M, Jeloka T, Khandekar A, Kumar C D, Parthasarathy R, Abraham G, Sajgure A, Prabhu A R, Aggarwal M, Agrawal D, Eswarappa M, Sreelatha M, Kumar Saha T, George J, Chakravarthi R, Narula A, Chhabra GD, Bhalla D, Goplani K, Jain A, Kher V, Sahay M, Prasad N, Ramachandran R, Berar Yanay N, Beberashvili I, Hassan K, Armaly Z, Farber E, Yagil Y, Benchetrit S, Manunta P, Scarpioni R, Pani A, Esposito C, Romano P, Kim S, Joo KW, Kim HW, Shin DH, Han SY, Yoon SA, Han BG, Lim CS, Yang CW, Shin SK, Lee SH, Park MY, Kwon YJ, Shin SJ, Kim YG, Han S, Park I, Jeong KH, Lee S, Chang JH, Kim SJ, Kim YW, Kim SH, Lee KY, Loh CL, Ching CH, Abdullah R, Ong LM, Fatnoon Nik Ahmad NN, Ng KP, Lee LY, Morales LS, Nevarez Ruiz LA, Monteon Ramos F, Burgos Soto MA, Rodriguez Ruiz E, Orozco Castellanos R, Herrera L, Elizondo Moreno E, Chew Wong A, Orea Rodríguez O, Mayorga Madrigal H, García de León Guerrero M, Venegas Carrillo LA, Hernandez Diaz JC, Bazzoni Ruiz AE, Tamayo J, Bochicchio Riccardelli T, Ramos Ibarra DR, Leyva Campillo SA, Dehesa López E, Irizar Santana SS, Vervloet M, van den Dorpel M, de Boer JD, Rabindranath K, Schollum J, Hood C, Hutchison C, Maher E, Ang E, Isidto R, Solimen D, Mondano-Yap Y, AngelineGumba M, Afaga A, Nazareth MG, Vergara Lim-Dy MF, Perez R, Nowicki M, Sokalski A, Naumnik B, Wroblewski K, Chmielarska I, Górecki P, Jaroszynski A, Wiecek A, Lizakowski S, Nolasco F, Rodrigues B, Figueiredo N, Birne R, Santos P, Santos C, Bob FR, Bako G, Bobeica R, Ismail G, Tuta LA, Petrica L, Peride I, Eremeeva L, Novoseltsev I, Gerasimchuk R, Zemchenkov A, Smolyarchuk E, Shutov A, Staroselskiy K, Antropenko N, Yakushin S, Smakotina S, Federation F, Vasilevskaya O, Borsukov A, Apartsin K, Perlin D, Wong J, Weng W, Lau WLT, Liu AYL, Rayner B, Urbach D, Malan D, Prozesky H, Díaz Rodríguez C, de Arriba de la Fuente G, Agraz Pamplona I, Ambrós JT, Cases A, Santos JP, Diaz Gomez JM, Bover Sanjuan J, Cigarran Guldris S, Labrador Gomez PJ, Graterol Torres F, Bonal Bastons J, Portoles Pérez J, Calabia Martinez J, Nieto Iglesias J, Salgueira M, Calls Ginesta J, Barany P, Supranaviciene L, Lee CT, Wu CJ, Sue YM, Wu V, Wu IW, Peng YS, Huang WH, Wang MC, Chen HC, Prasithsirikul W, Noppakun K, Vareesangthip K, Traitanon O, Supasyndh O, Praditpornsilpa K, Anutrakulchai S, Ates K, Tokgoz B, Ustundag S, Karayaylali I, Karadag S, Ozturk S, Suleymanlar G, Ecder ST, Koc M, Zub L, Martynyuk L, Kolesnyk M, Dudar I, Korneyeva S, Prylypko M, Legun O, Ovska O, Bilyk S, Topchiy I, Stepanenko O, Katerenchuk I, Kostynenko T, Doretskii V, Tereshchenko N, Kolomiichuk N, Kalra P, Bhandari S, Mitra S, Ahmed A, Shah S, Ramakrishna B, Dasgupta I, Yaqoob M, Mooney A, Jones C, Mason P, Pritchard N, El Kossi M, Wroe C, Tez D, Leung J, Fraser D, Power A, Sharma A, Wheeler D, Sridharan S, Chuang P, El-Shahawy M, Rastogi A, Velar A, Wooldridge T, Zeig S, Donner B, Galperin E, Ross D, Steer D, Horeish A, Suchinda P, Linfert D, Kopyt N, Hendon K, Ayodeji O, Perez J, Reddy P, Alappan R, Shakeel M, Casey M, Gonzalez C, Mulloy L, Tietjen D, Mehta A, Betts J, Galvez O, Martin E, Baranski J, Khawar O, Fischbach B, Gandhi N, Kotzker W, Bernardo M, Narayanan M, Sun C, Silva A, Yan J, Kanade P, Carvalho C, Zaw Y, Cortez A, Berenji R, Lee S, Joshi S, Nazeer I, Belz M, Ghanekar H, Abramowitz M, Bala Subramanian V, Atta M, Oo T, Flack J, Greenwood G, Steed L, Kantor S, Fadia A, Ruiz J, Saggi S, Assefi A, Comunale R, Shafik S, Kronfli S, Al-Saghir F, Crawford P, Ortiz-Butcher C, Porter I, Dev D, Rajan J, O'Shaughnessy A, Calhoun W, Arfeen S, Schlessinger F, Kamyar A, Reichel R, Kalirao P, Jones A, Nica R, Scott D, Campbell R, Kaveh K, Ghossein C, Pedraza F, Tran TH, Belledonne M, Jacobs A, Gutierrez O, Behara V, Sloan L, Dixon B, Coyne D, Brezina B, Buridi A, Garver R, Said-Hernandez N, Obhrai J, Posada J, Patrikyan A, Arora A, Vaz A, Guadiz R, Troyan B, Ukponmwan O, Vernace M, Arencibia F, Yablon Z, Cheung A, Ali N, Shafi T, Othersen J, Luscy C, Fernandez J, Kalim S, Islam S, Vaghela M, Dukes C, Nieto J, Reyes K, Fluck P, Friedenberg K, Drawz P, Weissman P, Hernandez L, Somerman D, Ayesu K, Kovesdy C, Demko T, Jere C, Ramon P, Agha I, Pergola P, Okechukwu C, Kapoor A, Lohiya P, Amberker D, Danda R, Sikora M, Raissi S, Nguyen B, Ta D, Do T, Ha A, Nguyen T, Huynh T, Minh D. BACKGROUND: Daprodustat (GSK1278863) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for treatment of anemia associated with chronic kidney disease (CKD). The effect of daprodustat in Japanese CKD patients with anemia has not been previously investigated. METHODS: We evaluated the relationship between daprodustat dose and hemoglobin response in Japanese patients on hemodialysis (HD) with anemia in a 4-week, phase II, double-blind, placebo-controlled study. After interrupting their erythropoiesis-stimulating agent for between 2 and 8 weeks, subjects with hemoglobin 8.5-10.5 g/dL were randomized to placebo or daprodustat 4, 6, 8, or 10 mg orally once daily. Hemoglobin, erythropoietin (EPO), and vascular endothelial growth factor (VEGF) levels during therapy were evaluated. RESULTS: Eighty-six of 97 randomized subjects completed the study. Mean baseline hemoglobin ranged from 9.68 to 9.92 g/dL across groups. After 4-week administration, mean hemoglobin changes were -0.28, -0.01, 0.54, and 0.97 g/dL in the 4, 6, 8, and 10 mg groups, respectively, as compared to -1.41 g/dL for placebo. Dose-dependent increase in plasma EPO concentration were observed up to 8 mg, with the 10 mg dose responses being similar to 8 mg. Plasma VEGF concentrations were minimally changed, even though 5 subjects treated with 6-10 mg reached EPO >500 mIU/mL. CONCLUSION: Daprodustat 4-10 mg once-daily produced dose-dependent increase in hemoglobin relative to placebo in Japanese HD subjects. The doses evaluated in the study have moderately increased endogenous EPO without changes in circulating VEGF levels. Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor for the treatment of anemia of chronic kidney disease. This phase 3 study evaluated the efficacy and safety of daprodustat in an uncontrolled cohort of 56 Japanese peritoneal dialysis patients with anemia over 52 weeks. Subjects received daprodustat 4 mg orally once daily for 4 weeks and the dose was subsequently adjusted every 4 weeks. Mean baseline hemoglobin was 10.9 g/dL (95% CI 10.59, 11.12). Mean hemoglobin reached the target range (11.0-13.0 g/dL) at week 12 and was maintained until week 52. Mean hemoglobin during weeks 40-52 was 12.1 g/dL (95% CI 12.0, 12.2). The most frequent adverse events included nasopharyngitis (29%), catheter-site infection (18%), peritonitis (16%), diarrhea (14%), and nausea (11%). No deaths were reported. Once-daily oral daprodustat treatment was generally well tolerated and mean hemoglobin was achieved and maintained within the target range in Japanese peritoneal dialysis participants. Collaborators: Guinsburg M, Cusumano C, Santos J, Guinsburg A, Najun Zarazaga C, Marín I, Bevione P, Ramirez N, Laham G, Valtuille R, Douthat W, Rosa Diez G, Hawley C, Lee V, Kerr PG, Gray N, Mather A, Badve SV, Jesudason S, Pedagogos E, Komala M, Foote C, Ratanjee S, Irish A, Suranyi M, Prager R, Wiesholzer M, Rosenkranz A, Bovy C, Warling X, De Keyzer K, Maes B, Claes K, Cornelis T, Vandewiele B, Debelle F, Morelle J, Hernandes F, Bruno R, Deboni LM, Noronha I, Carvalho N, Canziani ME, Piovesan F, Sato V, Riella M, Paschoalin R, Ramalho R, Pecoits-Filho R, Lorenzoni dAvila D, Lotaif LD, Prompt C, Capanema Silva G, Yanakieva T, Rangelov R, Kirov B, Vasileva A, Bakardzhiev T, Boyadzhieva S, Georgiev I, Paunova P, Karagyozova R, Kambova L, Iliev V, Nikolov D, Shikov P, Atanasova-Ashikova K, Angelova A, Hercz G, McMahon A, Muirhead N, Jirovec M, Vlasak J, Stilec R, Bucek P, Oplustilova A, Parikova A, Tesar V, Mokrejsova M, Sevcik J, Hagstrup Christensen J, Juul-Sandberg R, Aarup M, Mose FH, Rosenberg M, Lilienthal K, Kõlvald K, Rieu P, Belmouaz M, Francois M, Vilaine E, Henri P, Legrand E, Chantrel F, Kraemer-Guth A, Schulte K, Feldkamp T, Strutz F, Kraemer B, Benck U, Krüger T, Rath T, Radermacher J, Lüders S, Kupka J, Goumenos D, Ntounousi E, Passadakis P, Stefanidis I, Stylianou K, Liakopoulos V, Papagianni A, Gouva C, Georgoulidou A, Mavromatidis K, Papadopoulou D, Petras D, Patsialas S, Andrikos E, Major L, Csiky B, Molnar M, Rikker C, Ladanyi E, Keresztesi S, Bhalla AK, Gang S, Mali M, Jeloka T, Almeida A, Kumar C D, Khandekar A, Aggarwal M, Eswarappa M, Saha TK, Sreelatha M, Agrawal D, George J, Chakravarthi R, Parthasarathy R, Abraham G, Narula A, Jasuja S, Gesualdo L, Roccatello D, Cozzolino M, Moriero E, Bolignano D, Scarpioni R, Russo D, Esposito C, Pani A, Cavalli A, Mallamaci F, Romano P, Pieruzzi F, Pedrini L, Kim S, Han SY, Shin SK, Kim KM, Chung W, Park HC, Han S, Lee JP, Han BG, Lee YK, Song HC, Oh DJ, Koh ES, Lee S, Kim SJ, Kim HW, Lee SH, Shin DH, Jo YI, Loh CL, Liu WJ, Abdullah R, Ong LM, Wong HS, Ng KP, Monteon Ramos F, Rodríguez OO, Chew Wong A, Rodriguez Ruiz E, Herrera L, Orozco Castellanos R, Mayorga Madrigal H, García de León Guerrero M, Hernandez Diaz JC, Correa-Rotter R, Perez Grovas Garza H, Leyva Campillo SA, Melo Sanchez MG, van den Dorpel M, Vervloet M, de Boer JD, Hood C, Rabindranath K, Hutchison C, Wolff M, Bækken M, Nowicki M, Wroblewski K, Kaniewski M, Kozminski P, Lewanski R, Rajca D, Kopecka-Mechlinska L, Chmielarska I, Brzósko S, Wyszynska A, Górecki P, Komorowski G, Piorecki M, Jaroszynski A, Azevedo P, Bernardo I, Ferreira A, Cruz J, Branco P, Santos C, Sousa H, Gil C, Oliveira C, Ponce P, Castro R, Berca S, Ismail G, Stirbu O, Olariu N, Khrustaleva E, Novoseltsev I, Vasilyeva G, Eremeeva L, Antropenko N, Fedotova L, Timokhovskaya G, Zemchenkov A, Selutin A, Apartsin K, Vasilevskaya O, Staroselskiy K, Perlin D, Wong J, Weng W, Lau TWL, Swanepoel C, Prozesky H, Loreto M, Santos Herrera M, Díaz Rodríguez C, García Maset R, de Arriba de la Fuente G, González Parra E, Martínez Ocaña JC, Gascó Company JM, Santos JP, Bastons JB, Del Carmen Vozmediano Poyatos M, Calabia Martinez J, Salgueira M, Portoles Pérez J, Martinez Campos E, Abad S, Herrero Calvo JA, Calls Ginesta J, Linde T, Supranaviciene L, Lee CT, Huang JW, Sue YM, Wu IW, Peng YS, Huang WH, Wang MC, Hsu YH, Lin CY, Chen HC, Ates K, Karayaylali I, Ustundag S, Tokgoz B, Suleymanlar G, Ozkurt S, Martynyuk L, Kolesnyk M, Ovska O, Dudar I, Korneyeva S, Prylypko M, Legun O, Fomenko G, Bilyk S, Stepanenko O, Kostynenko T, Kolomiichuk N, Kalra P, Bhandari S, Ahmed A, Ramakrishna B, Dasgupta I, McCafferty K, Shah S, Mason P, El Kossi M, Patel R, Sridharan S, Provenzano C, Raissi S, Suri A, El-Shahawy M, Gandhi K, Fadda G, Hendon K, Rastogi A, Khawar O, Horeish A, Darwish R, Aiello J, Galperin E, Velar A, Zeig S, Steer D, Kopyt N, Lehrner L, Suchinda P, Hon G, Polack D, Wooldridge T, Martin E, Linfert D, Casey M, Reddy P, Daswani A, Tietjen D, Sekkarie M, Masani N, Sun C, Awad A, Ayodeji O, Baranski J, Minasian R, Levine M, Kleinman K, Joshi S, Kambhampati G, Lee J, Alappan R, Adaimy M, Mulloy L, Desai A, Silva A, Bernardo M, Lynn R, Yan J, Greenwood G, Shemin D, Carvalho C, Nazeer I, Aqeel A, Joshi S, Lanier D Jr, Abramowitz M, Berenji R, Kumar N, Rubin O, Gonzalez J, Bhat P, Wright S, Kant K, Shakeel M, Rodriguez A, Assefi A, Calhoun W, Sun A, Maasarani E, Gandhi N, Arfeen S, Al-Saghir F, Brar H, Myrie K, Broumand V, Campbell R, Dev D, Porter I, Ranjan R, Kamyar A, Reichel R, Schlessinger F, O'Shaughnessy A, Niu PC, Rivers D, Erinle A, Szewc R, Kaveh K, Lu CM, Rajan J, Jacobs A, Weisinger-Hirsh J, Sloan L, Dixon B, Brezina B, Coyne D, Saggi S, Sawhney A, Charytan C, Buridi A, Cuellar J, Bleyer A, Said-Hernandez N, Obhrai J, Chowdhury P, Arora A, Durham W, Ansari N, Kupor L, Bhadra S, Guadiz R, Arias C, Ukponmwan O, Cheung A, Ali N, Anaheim D, Lapsia V, Fernandez J, Luscy C, Vaghela M, Nieto J, Lee SM, Gandhi D, Posada J. Daprodustat (GSK1278863) is a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor in development for treatment of anemia of chronic kidney disease. Daprodustat's biological activity simulates components of the natural response to hypoxia; inhibition of PHDs results in HIF stabilization and modulation of HIF-controlled gene products, including erythropoietin. The carcinogenic potential of daprodustat was evaluated in 2-year carcinogenicity studies in Sprague-Dawley rats and CD-1 mice, where once-daily doses were administered. The mouse study also included evaluation of daprodustat's 3 major circulating human metabolites. There were no neoplastic findings that were considered treatment related in either study. Exaggerated pharmacology resulted in significantly increased red cell mass and subsequent multiorgan congestion and secondary non-neoplastic effects in both species, similar to those observed in chronic toxicity studies. In rats, these included aortic thrombosis and an exacerbation of spontaneous rodent cardiomyopathy, which contributed to a statistically significant decrease in survival in high-dose males (group terminated in week 94). Survival was not impacted in mice at any dose. Systemic exposures (area under the plasma concentration-time curve) to daprodustat at the high doses in rats and mice exceed predicted maximal human clinical exposure by ≥143-fold. These results suggest that daprodustat and metabolites do not pose a carcinogenic risk at clinical doses.

Where is the the protein perforin localized?

Perforin are stored inside the leukocytes in secretory granules.

[33410220, 33467515, 33884612, 33710487]

Severe malaria caused by Plasmodium falciparum poses a major global health problem with high morbidity and mortality. P. falciparum harbors a family of pore-forming proteins (PFPs), known as perforin like proteins (PLPs), which are structurally equivalent to prokaryotic PFPs. These PLPs are secreted from the parasites and, they contribute to disease pathogenesis by interacting with host cells. The severe malaria pathogenesis is associated with the dysfunction of various barrier cells, including endothelial cells (EC). Several factors, including PLPs secreted by parasites, contribute to the host cell dysfunction. Herein, we have tested the hypothesis that PLPs mediate dysfunction of barrier cells and might have a role in disease pathogenesis. We analyzed various dysfunctions in barrier cells following rPLP2 exposure and demonstrate that it causes an increase in intracellular Ca2+ levels. Additionally, rPLP2 exposed barrier cells displayed features of cell death, including Annexin/PI positivity, depolarized the mitochondrial membrane potential, and ROS generation. We have further performed the time-lapse video microscopy of barrier cells and found that the treatment of rPLP2 triggers their membrane blebbing. The cytoplasmic localization of HMGB1, a marker of necrosis, further confirmed the necrotic type of cell death. This study highlights the role of parasite factor PLP in endothelial dysfunction and provides a rationale for the design of adjunct therapies against severe malaria. As part of the adaptive immune system, T cells are vital for the eradication of infected and malignantly transformed cells. To perform their protective function, T cells produce effector molecules that are either directly cytotoxic, such as granzymes, perforin, interferon-γ and tumour necrosis factor α, or attract and stimulate (immune) cells, such as interleukin-2. As these molecules can also induce immunopathology, tight control of their production is required. Indeed, inflammatory cytokine production is regulated on multiple levels. Firstly, locus accessibility and transcription factor availability and activity determine the amount of mRNA produced. Secondly, post-transcriptional mechanisms, influencing mRNA splicing/codon usage, stability, decay, localization and translation rate subsequently determine the amount of protein that is produced. In the immune suppressive environments of tumours, T cells gradually lose the capacity to produce effector molecules, resulting in tumour immune escape. Recently, the role of post-transcriptional regulation in fine-tuning T-cell effector function has become more appreciated. Furthermore, several groups have shown that exhausted or dysfunctional T cells from cancer patients or murine models possess mRNA for inflammatory mediators, but fail to produce effector molecules, hinting that post-transcriptional events also play a role in hampering tumour-infiltrating lymphocyte effector function. Here, the post-transcriptional regulatory events governing T-cell cytokine production are reviewed, with a specific focus on the importance of post-transcriptional regulation in anti-tumour responses. Furthermore, potential approaches to circumvent tumour-mediated dampening of T-cell effector function through the (dis)engagement of post-transcriptional events are explored, such as CRISPR/Cas9-mediated genome editing or chimeric antigen receptors. BACKGROUND: Uranium mining and processing are an ancient occupation, recognized as being grueling and accountable for injury and disease. Uranium (U) is a radioactive heavy metal used in many industrial applications. It increases the micronuclei frequencies as well as chromosomal aberration and sister chromatid exchange in peripheral blood lymphocytes. Granzyme B and perforin are stored inside the leukocytes in secretory granules. These proteins are released outside the cells by a cell-to-cell contact under specific conditions for inducing apoptosis. So, this study investigated the potential health hazards with prominence on the biological effects of radiation exposure. METHODS: A cross-sectional analytic research was conducted on Egyptian male mining field workers. Leucocytes' genotoxicity was evaluated using DNA fragmentation assay and comet assay. Furthermore, flow cytometric analysis of Granzyme B protein was done. RESULTS: A significant increase in dead cells after dual acridine orange/ethidium bromide (AO/EB) fluorescent staining in radiation-exposed groups was noticed compared to control groups. Moreover, a significant increase in the fragmented DNA was evident in exposed groups relative to the control one. Granzyme B protein levels showed a significant increase concerning control. CONCLUSION: A wide variety of adverse human health risks are considered a potential risk to Egyptian uranium miners. For employers working in both mining and processing fields, the most common molecular shift highlighted was the leucocyte damage in blood samples. To preserve the health of all employees, health education and administration of effective hazard management procedures are necessary.

Which disease is associated with X-linked recessive TLR7 deficiency?

X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years.

[34413140]

Collaborators: Abel L, Aiuti A, Al-Muhsen S, Al-Mulla F, Anderson MS, Andreakos E, Arias AA, Feldman HB, Belot A, Biggs CM, Bogunovic D, Bolze A, Bondarenko A, Bousfiha AA, Brodin P, Bryceson Y, Bustamante CD, Butte MJ, Casari G, Chakravorty S, Christodoulou J, Condino-Neto A, Constantinescu SN, Cooper MA, Dalgard CL, Desai M, Drolet BA, El Baghdadi J, Espinosa-Padilla S, Fellay J, Flores C, Franco JL, Froidure A, Gregersen PK, Haerynck F, Hagin D, Halwani R, Hammarström L, Heath JR, Henrickson SE, Hsieh EWY, Husebye E, Imai K, Itan Y, Jarvis ED, Karamitros T, Kisand K, Ku CL, Lau YL, Ling Y, Lucas CL, Maniatis T, Mansouri D, Maródi L, Meyts I, Milner JD, Mironska K, Mogensen TH, Morio T, Ng LFP, Notarangelo LD, Novelli A, Novelli G, O'Farrelly C, Okada S, Ozcelik T, Pan-Hammarström Q, de Diego RP, Planas AM, Prando C, Pujol A, Quintana-Murci L, Renia L, Resnick I, Rodríguez-Gallego C, Sancho-Shimizu V, Sediva A, Seppänen MRJ, Shahrooei M, Shcherbina A, Slaby O, Snow AL, Soler-Palacín P, Spaan AN, Tancevski I, Tangye SG, Abou Tayoun A, Ramaswamy S, Turvey SE, Uddin KMF, Uddin MJ, van de Beek D, Vinh DC, von Bernuth H, Zatz M, Zawadzki P, Su HC, Casanova JL, Foti G, Bellani G, Citerio G, Contro E, Pesci A, Valsecchi MG, Cazzaniga M, Abad J, Accordino G, Achille C, Aguilera-Albesa S, Aguiló-Cucurull A, Aiuti A, Özkan EA, Darazam IA, Roblero Albisures JA, Aldave JC, Ramos MA, Khan TA, Aliberti A, Nadji SA, Alkan G, AlKhater SA, Allardet-Servent J, Allende LM, Alonso-Arias R, Alshahrani MS, Alsina L, Alyanakian MA, Borrero BA, Amoura Z, Antolí A, Arrestier R, Aubart M, Auguet T, Avramenko I, Aytekin G, Azot A, Bahram S, Bajolle F, Baldanti F, Baldolli A, Ballester M, Feldman HB, Barrou B, Barzagh F, Basso S, Bayhan GI, Belot A, Bezrodnik L, Bilbao A, Blanchard-Rohner G, Blanco I, Blandinières A, Blázquez-Gamero D, Bleibtreu A, Bloomfield M, Bolivar-Prados M, Bondarenko A, Borghesi A, Borie R, Botdhlo-Nevers E, Bousfiha AA, Bousquet A, Boutolleau D, Bouvattier C, Boyarchuk O, Bravais J, Briones ML, Brunner ME, Bruno R, Bueno MRP, Bukhari H, Bustamante J, Cáceres Agra JJ, Capra R, Carapito R, Carrabba M, Casari G, Casasnovas C, Caseris M, Cassaniti I, Castelle M, Castelli F, de Vera MC, Castro MV, Catherinot E, Celik JB, Ceschi A, Chalumeau M, Charbit B, Cheng MP, Clavé P, Clotet B, Codina A, Cohen Y, Colobran R, Comarmond C, Combes A, Comoli P, Corsico AG, Coşkuner T, Cvetkovski A, Cyrus C, Dalmau D, Danion F, Darley DR, Das V, Dauby N, Dauger S, De Munter P, de Pontual L, Dehban A, Delplancq G, Demoule A, Desguerre I, Di Sabatino A, Diehl JL, Dobbelaere S, Domínguez-Garrido E, Dubost C, Ekwall O, Bozdemir ŞE, Elnagdy MH, Emiroglu M, Endo A, Erdeniz EH, Aytekin SE, Lasa MPE, Euvrard R, Fabio G, Faivre L, Falck A, Fartoukh M, Faure M, Arquero MF, Ferrer R, Ferreres J, Flores C, Francois B, Fumadó V, Fung KSC, Fusco F, Gagro A, Solis BG, Gaussem P, Gayretli Z, Gil-Herrera J, Gilardin L, Gatineau AG, Girona-Alarcón M, Cifuentes Godínez KA, Goffard JC, Gonzales N, Gonzalez-Granado LI, González-Montelongo R, Guerder A, Gülhan B, Gumucio VD, Hanitsch LG, Gunst J, Gut M, Hadjadj J, Haerynck F, Halwani R, Hammarström L, Hancerli S, Hariyan T, Hatipoglu N, Heppekcan D, Hernandez-Brito E, Ho PK, Holanda-Peña MS, Horcajada JP, Hraiech S, Humbert L, Hung IFN, Iglesias AD, Íñigo-Campos A, Jamme M, Arranz MJ, Jimeno MT, Jordan I, Kanık-Yüksek S, Kara Y, Karahan A, Karbuz A, Yasar KK, Kasapcopur O, Kashimada K, Keles S, Demirkol YK, Kido Y, Kizil C, Kılıç AO, Klocperk A, Koutsoukou A, Król ZJ, Ksouri H, Kuentz P, Kwan AMC, Kwan YWM, Kwok JSY, Lagier JC, Lam DSY, Lampropoulou V, Lanternier F, Lau YL, Le Bourgeois F, Leo YS, Lopez RL, Leung D, Levin M, Levy M, Lévy R, Li Z, Lilleri D, Bolanos Lima EJA, Linglart A, López-Collazo E, Lorenzo-Salazar JM, Louapre C, Lubetzki C, Lung KC, Luyt CE, Lye DC, Magnone C, Mansouri D, Marchioni E, Marioli C, Marjani M, Marques L, Pereira JM, Martín-Nalda A, Pueyo DM, Martinez-Picado J, Marzana I, Mata-Martínez C, Mathian A, Matos LR, Matthews GV, Mayaux J, McLaughlin-Garcia R, Meersseman P, Mège JL, Mekontso-Dessap A, Melki I, Meloni F, Meritet JF, Merlani P, Akcan ÖM, Meyts I, Mezidi M, Migeotte I, Millereux M, Million M, Mirault T, Mircher C, Mirsaeidi M, Mizoguchi Y, Modi BP, Mojoli F, Moncomble E, Melián AM, Martinez AM, Morandeira F, Morange PE, Mordacq C, Morelle G, Mouly SJ, Muñoz-Barrera A, Nafati C, Nagashima S, Nakagama Y, Neven B, Neves JF, Ng LF, Ng YY, Nielly H, Medina YN, Cuadros EN, Ocejo-Vinyals JG, Okamoto K, Oualha M, Ouedrani A, Özçelik T, Ozkaya-Parlakay A, Pagani M, Pan-Hammarström Q, Papadaki M, Parizot C, Parola P, Pascreau T, Paul S, Paz-Artal E, Pedraza S, González Pellecer NC, Pellegrini S, de Diego RP, Pérez-Fernández XL, Philippe A, Philippot Q, Picod A, de Chambrun MP, Piralla A, Planas-Serra L, Ploin D, Poissy J, Poncelet G, Poulakou G, Pouletty MS, Pourshahnazari P, Qiu-Chen JL, Quentric P, Rambaud T, Raoult D, Raoult V, Rebillat AS, Redin C, Resmini L, Ricart P, Richard JC, Rigo-Bonnin R, Rivet N, Rivière JG, Rocamora-Blanch G, Rodero MP, Rodrigo C, Rodriguez LA, Rodriguez-Gallego C, Rodriguez-Palmero A, Romero CS, Rothenbuhler A, Roux D, Rovina N, Rozenberg F, Ruch Y, Ruiz M, Ruiz Del Prado MY, Ruiz-Rodriguez JC, Sabater-Riera J, Saks K, Salagianni M, Sanchez O, Sánchez-Montalvá A, Sánchez-Ramón S, Schidlowski L, Schluter A, Schmidt J, Schmidt M, Schuetz C, Schweitzer CE, Scolari F, Sediva A, Seijo L, Seminario AG, Sene D, Seng P, Senoglu S, Seppänen M, Llovich AS, Shahrooei M, Shcherbina A, Siguret V, Siouti E, Smadja DM, Smith N, Sobh A, Solanich X, Solé-Violán J, Soler C, Soler-Palacín P, Sözeri B, Stella GM, Stepanovskiy Y, Stoclin A, Taccone F, Tandjaoui-Lambiotte Y, Taupin JL, Tavernier SJ, Tello LV, Terrier B, Thiery G, Thorball C, Thorn K, Thumerelle C, Tipu I, Tolstrup M, Tomasoni G, Toubiana J, Alvarez JT, Triantafyllia V, Trouillet-Assant S, Troya J, Tsang OTY, Tserel L, Tso EYK, Tucci A, Tüter Öz ŞK, Ursini MV, Utsumi T, Uzunhan Y, Vabres P, Valencia-Ramos J, Van Den Rym AM, Vandernoot I, Velez-Santamaria V, Zuniga Veliz SP, Vidigal MC, Viel S, Vilain C, Vilaire-Meunier ME, Villar-García J, Vincent A, Vogt G, Voiriot G, Volokha A, Vuotto F, Wauters E, Wauters J, Wu AKL, Wu TC, Yahşi A, Yesilbas O, Yildiz M, Young BE, Yükselmiş U, Zatz M, Zecca M, Zuccaro V, Jens VP, Lambrecht BN, Eva VB, Cédric B, Levi H, Eric H, Bauters F, De Clercq J, Cathérine H, Slabbynck H, Leslie N, Florkin B, Boulanger C, Vanderlinden D, Annereau JP, Briseño-Roa L, Gribouval O, Pelet A, Abel L, Andrejak C, Angoulvant F, Bachelet D, Bartoli M, Basmaci R, Behilill S, Beluze M, Benkerrou D, Bhavsar K, Bouadma L, Bouchez S, Bouscambert M, Cervantes-Gonzalez M, Chair A, Chirouze C, Coelho A, Couffignal C, Couffin-Cadiergues S, d'Ortenzio E, Debray MP, Deconinck L, Deplanque D, Descamps D, Desvallée M, Diallo A, Diouf A, Dorival C, Dubos F, Duval X, Elharrar B, Eloy P, Enouf V, Esperou H, Esposito-Farese M, Etienne M, Devouge EF, Gault N, Gaymard A, Ghosn J, Gigante T, Gilg M, Guedj J, Hoctin A, Hoffmann I, Houas I, Hulot JS, Jaafoura S, Kafif O, Kaguelidou F, Kali S, Khalil A, Khan C, Laouénan C, Laribi S, Le M, Le Hingrat Q, Le Mestre S, Le Nagard H, Lescure FX, Letrou S, Levy Y, Lina B, Lingas G, Lucet JC, Malvy D, Mambert M, Mentré F, Meziane A, Mouquet H, Mullaert J, Neant N, Nguyen D, Noret M, Nseir S, Papadopoulos A, Paul C, Peiffer-Smadja N, Perpoint T, Petrov-Sanchez V, Peytavin G, Pham H, Picone O, Piquard V, Puéchal O, Rabaud C, Rosa-Calatrava M, Rossignol B, Rossignol P, Roy C, Schneider M, Su R, Tardivon C, Tellier MC, Téoulé F, Terrier O, Timsit JF, Tual C, Tubiana S, Van Der Werf S, Vanel N, Veislinger A, Visseaux B, Wiedemann A, Yazdanpanah Y, Alavoine L, Behillil S, Burdet C, Charpentier C, Dechanet A, Descamps D, Duval X, Ecobichon JL, Enouf V, Frezouls W, Houhou N, Kafif O, Lehacaut J, Letrou S, Lina B, Lucet JC, Manchon P, Nouroudine M, Piquard V, Quintin C, Thy M, Tubiana S, van der Werf S, Vignali V, Visseaux B, Yazdanpanah Y, Chahine A, Waucquier N, Migaud MC, Deplanque D, Djossou F, Mergeay-Fabre M, Lucarelli A, Demar M, Bruneau L, Gérardin P, Maillot A, Payet C, Laviolle B, Laine F, Paris C, Desille-Dugast M, Fouchard J, Malvy D, Nguyen D, Pistone T, Perreau P, Gissot V, Le Goas C, Montagne S, Richard L, Chirouze C, Bouiller K, Desmarets M, Meunier A, Lefévre B, Jeulin H, Legrand K, Lomazzi S, Tardy B, Gagneux-Brunon A, Bertholon F, Botelho-Nevers E, Kouakam C, Leturque N, Roufai L, Amat K, Couffin-Cadiergues S, Espérou H, Hendou S, van Agtmael M, Algera AG, Appelman B, van Baarle F, Bax D, Beudel M, Bogaard HJ, Bomers M, Bonta P, Bos L, Botta M, de Brabander J, de Bree G, de Bruin S, Buis DTP, Bugiani M, Bulle E, Chouchane O, Cloherty A, Dijkstra M, Dongelmans DA, Dujardin RWG, Elbers P, Fleuren L, Geerlings S, Geijtenbeek T, Girbes A, Goorhuis B, Grobusch MP, Hafkamp F, Hagens L, Hamann J, Harris V, Hemke R, Hermans SM, Heunks L, Hollmann M, Horn J, Hovius JW, de Jong MD, Koning R, Lim EHT, van Mourik N, Nellen J, Nossent EJ, Paulus F, Peters E, Pina-Fuentes DAI, van der Poll T, Preckel B, Prins JM, Raasveld J, Reijnders T, de Rotte MCFJ, Schinkel M, Schultz MJ, Schrauwen FAP, Schuurmans A, Schuurmans J, Sigaloff K, Slim MA, Smeele P, Smit M, Stijnis CS, Stilma W, Teunissen C, Thoral P, Tsonas AM, Tuinman PR, van der Valk M, Veelo D, Volleman C, de Vries H, Vught LA, van Vugt M, Wouters D, Zwinderman AHK, Brouwer MC, Wiersinga WJ, Vlaar APJ, van de Beek D, Tompkins MF, Alba C, Snow AL, Hupalo DN, Rosenberger J, Sukumar G, Wilkerson MD, Zhang X, Lack J, Oler AJ, Dobbs K, Delmonte OM, Danielson JJ, Biondi A, Bettini LR, D'Angio M, Beretta I, Imberti L, Sottini A, Quaresima V, Quiros-Roldan E, Rossi C.

Is Benralizumab effective for Chronic Spontaneous Urticaria?

Yes, the anti-IL-5 antibody benralizumab has been reported to reduce Chronic Spontaneous Urticaria symptoms.

[32224275, 33685605, 31446134, 30015639]

Guidelines for the treatment of chronic spontaneous urticaria (CSU) recommend the use of the IgE-targeted biologic omalizumab in patients with antihistamine-refractory disease. The rationale for this is supported by the key role of IgE and its high-affinity receptor, FcεRI, in the degranulation of skin mast cells that drives the development of the signs and symptoms of CSU, itchy wheals, and angioedema. Here, we review the current understanding of the pathogenesis of CSU and its autoimmune endotypes. We describe the mechanisms of action of omalizumab, the only biologic currently approved for CSU, its efficacy and ways to improve it, biomarkers for treatment response, and strategies for its discontinuation. We provide information on the effects of the off-label use, in CSU, of biologics licensed for the treatment of other diseases, including dupilumab, benralizumab, mepolizumab, reslizumab, and secukinumab. Finally, we discuss targets for novel biologics and where we stand with their clinical development. These include IgE/ligelizumab, IgE/GI-310, thymic stromal lymphopoietin/tezepelumab, C5a receptor/avdoralimab, sialic acid-binding Ig-like lectin 8/lirentelimab, CD200R/LY3454738, and KIT/CDX-0159. Our aim is to provide updated information and guidance on the use of biologics in the treatment of patients with CSU, now and in the near future. PURPOSE OF REVIEW: Symptomatic management of chronic spontaneous urticaria (CSU) basically depends on second-generation H1 antihistamines and omalizumab. Omalizumab is a game changer in the management, but still there is a need for new targets and new biologics targeting new pathways in the treatment which will provide long-lasting remission, which will be given orally and which will be cheaper. This review will focus on new biologics that are underway of production or are already under use for different disorders but could be beneficial for the treatment of Chronic urticaria. RECENT FINDINGS: In this review, the treatment targets are classified according to the cells which are involved in the pathogenesis of CSU. Those are mast cells/basophils, B cells, T cells and eosinophils. The treatments that are under clinical trials for CSU are anti-IgE treatments such as ligelizumab, molecules targeting intracellular signaling pathways such as spleen tyrosine kinase inhibitors, surface inhibitory molecules such as siglec-8, anti-IL-1s such as canakinumab, Bruton kinase (BTK) inhibitors such as GDC-0853 and anti-IL-5s such as benralizumab and mepolizumab. SUMMARY: The ongoing clinical trials on new targets of treatment hold new hopes not only for a better care of the disease but also a better understanding of the pathomechanisms lying underneath.

Do RNA binding Proteins that bind to adenine uridine (AU)-rich elements (AREs) in the 5' untranslated region (UTR) of mRNAs (AU-RBPs) regulate the DNA Damage Response?

RNA Binding Proteins (RBPs) that bind to adenine uridine (AU)-rich elements (AREs) in the 3' untranslated region (UTR) of mRNAs (AU-RBPs) have emerged as key players in regulating the DNA Damage Response (DDR) and preserving genome integrity.

[11280780, 33271327, 32491174, 21457063, 23946796, 29168431, 12900401, 21729330, 25680182, 29109951, 24423872, 27634883, 11103939, 25483082, 21161418, 32655569, 20881234, 19520857, 15358174, 24692066, 23383270, 17878526, 27592685, 12762222, 22626558]

Tumors of the central nervous system (CNS) often have sustained expression of labile genes, including angiogenic growth factors and immunosuppressive cytokines, which promote tumor progression. Stabilization of the RNA transcripts for these genes, such as vascular endothelial growth factor (VEGF), is an important molecular pathway for this up-regulation. HuR, a member of the Elav family of RNA-binding proteins, has been implicated in this pathway through its binding to adenine and uridine (AU)-rich stability elements (ARE) located in the 3' untranslated regions (3'-UTRs) of the mRNA. Whereas three of the Elav family members (Hel-N1, HuC, and HuD) are restricted to young and mature neurons, HuR is more broadly expressed, including proliferating cells of the developing CNS. Because RNA stabilization of labile genes may promote tumor growth, we analyzed and compared the expression pattern of HuR in 35 freshly resected and cultured CNS tumors to determine whether there was any correlation with tumor grade or histological type. We found that HuR mRNA was consistently expressed in all of the tumors, regardless of cell origin or degree of malignancy. Using a novel HuR-specific polyclonal antibody, we found that strong HuR protein expression was limited to high-grade malignancies (glioblastoma multiforme and medulloblastoma). Within the glioblastoma multiforme, prominent HuR expression was also detected in perinecrotic areas in which angiogenic growth factors are up-regulated. To further define its role as a potential RNA stabilizer, we analyzed whether HuR could bind to the stability motifs within the 3'-UTRs of cytokines and growth factors linked to brain tumor progression. We used a novel ELISA-based RNA binding assay and focused on the 3'-UTRs of angiogenic factors VEGF, COX-2, and (interleukin) IL-8 as well as the immunomodulating factors IL-6, transforming growth factor (TGF)-beta and tumor necrosis factor (TNF)-alpha as potential RNA ligands. Our results indicated overall a very high binding affinity to these RNA targets. A comparison of these ligands revealed a hierarchy of binding affinities with the angiogenic factors, and TGF-beta showing the highest (Kd of 1.8-3.4 nM), and TNF-alpha the lowest (Kd of 18.3 nM). The expression pattern of HuR, coupled with the RNA binding data, strongly suggests a role for this protein in the posttranscriptional regulation of these genes in CNS tumors. Nucleolin (NCL) is an abundant stress-responsive, RNA-binding phosphoprotein that controls gene expression by regulating either mRNA stability and/or translation. NCL binds to the AU-rich element (ARE) in the 3'UTR of target mRNAs, mediates miRNA functions in the nearby target sequences, and regulates mRNA deadenylation. However, the mechanism by which NCL phosphorylation affects these functions and the identity of the deadenylase involved, remain largely unexplored. Earlier we demonstrated that NCL phosphorylation is vital for cell cycle progression and proliferation, whereas phosphorylation-deficient NCL at six consensus CK2 sites confers dominant-negative effect on proliferation by increasing p53 expression, possibly mimicking cellular DNA damage conditions. In this study, we show that NCL phosphorylation at those CK2 consensus sites in the N-terminus is necessary to induce deadenylation upon oncogenic stimuli and UV stress. NCL-WT, but not hypophosphorylated NCL-6/S*A, activates poly (A)-specific ribonuclease (PARN) deadenylase activity. We further demonstrate that NCL interacts directly with PARN, and under non-stress conditions also forms (a) complex (es) with factors that regulate deadenylation, such as p53 and the ARE-binding protein HuR. Upon UV stress, the interaction of hypophosphorylated NCL-6/S*A with these proteins is favored. As an RNA-binding protein, NCL interacts with PARN deadenylase substrates such as TP53 and BCL2 mRNAs, playing a role in their downregulation under non-stress conditions. For the first time, we show that NCL phosphorylation offers specificity to its protein-protein, protein-RNA interactions, resulting in the PARN deadenylase regulation, and hence gene expression, during cellular stress responses. Hu proteins have been shown to bind to AU-rich elements (AREs) in the 3'-untranslated region of unstable mRNAs. They can thereby inhibit the decay of labile transcripts by antagonizing destabilizing proteins that target these AU-rich sequences. Here we examine the sequence preferences of HuD to elucidate its possible role in counteracting mRNA decay. Using repeats of the prototype destabilizing sequence UU(AUUU)nAUU, we show that all three HuD RNA-binding domains participate in binding to AU-tracts that can be as short as 13 residues, depending on the position of the remaining As. Removal of the A residues, resulting in a poly(U)-tract, increased the affinity of HuD for RNA, suggesting that the presence of As in destabilizing elements might favor the recruitment of other proteins and/or prevent HuD from binding too tightly to AREs. In vitro selection experiments with randomized RNAs confirmed the preference of HuD for poly(U). RNA binding analysis of the related protein HuB showed a similar preference for poly(U). In contrast, tristetraprolin, an mRNA destabilizing protein, strongly prefers AU-rich RNA. Many labile mRNAs contain U-tracts in or near their AREs. Individual AREs may thus differentially affect mRNA half-life by recruiting a unique complement of stabilizing and destabilizing factors. mRNA metabolism is tightly orchestrated by highly-regulated RNA Binding Proteins (RBPs) that determine mRNA fate, thereby influencing multiple cellular functions across biological contexts. Here, we review the interplay between six well-known RBPs (TTP, AUF-1, KSRP, HuR, TIA-1, and TIAR) that recognize AU-rich elements (AREs) at the 3' untranslated regions of mRNAs, namely ARE-RBPs. Examples of the links between their cross-regulations and modulation of their targets are analyzed during mRNA processing, turnover, localization, and translational control. Furthermore, ARE recognition can be self-regulated by several factors that lead to the prevalence of one RBP over another. Consequently, we examine the factors that modulate the dynamics of those protein-RNA transient interactions to better understand the final consequences of the regulation mediated by ARE-RBPs. For instance, factors controlling the RBP isoforms, their conformational state or their post-translational modifications (PTMs) can strongly determine the fate of the protein-RNA complexes. Moreover, mRNA specific sequence and secondary structure or subtle environmental changes are also key determinants to take into account. To sum up, the whole understanding of such a fine tuned regulation is a challenge for future research and requires the integration of all the available structural and functional data by in vivo, in vitro and in silico approaches. In the present study, we investigated the 3' untranslated region (UTR) of the mouse core clock gene cryptochrome 1 (Cry1) at the post-transcriptional level, particularly its translational regulation. Interestingly, the 3'UTR of Cry1 mRNA decreased its mRNA levels but increased protein amounts. The 3'UTR is widely known to function as a cis-acting element of mRNA degradation. The 3'UTR also provides a binding site for microRNA and mainly suppresses translation of target mRNAs. We found that AU-rich element RNA binding protein 1 (AUF1) directly binds to the Cry1 3'UTR and regulates translation of Cry1 mRNA. AUF1 interacted with eukaryotic translation initiation factor 3 subunit B and also directly associated with ribosomal protein S3 or ribosomal protein S14, resulting in translation of Cry1 mRNA in a 3'UTR-dependent manner. Expression of cytoplasmic AUF1 and binding of AUF1 to the Cry1 3'UTR were parallel to the circadian CRY1 protein profile. Our results suggest that the 3'UTR of Cry1 is important for its rhythmic translation, and AUF1 bound to the 3'UTR facilitates interaction with the 5' end of mRNA by interacting with translation initiation factors and recruiting the 40S ribosomal subunit to initiate translation of Cry1 mRNA. BRCA1 tumor suppressor regulates crucial cellular processes involved in DNA damage repair and cell cycle control. We showed that expression of BCR-ABL1 correlates with decreased level of BRCA1 protein, which promoted aberrant mitoses and aneuploidy as well as altered DNA damage response. Using polysome profiling and luciferase-BRCA1 3'UTR reporter system here we demonstrate that downregulation of BRCA1 protein in CML is caused by inhibition of BRCA1 mRNA translation, but not by increased protein degradation or reduction of mRNA level and half-life. We investigated 2 mRNA-binding proteins - HuR and TIAR showing specificity to AU-Rich Element (ARE) sites in 3'UTR of mRNA. BCR-ABL1 promoted cytosolic localization of TIAR and HuR, their binding to BRCA1 mRNA and formation of the TIAR-HuR complex. HuR protein positively regulated BRCA1 mRNA stability and translation, conversely TIAR negatively regulated BRCA1 translation and was found localized predominantly in the cytosolic stress granules in CML cells. TIAR-dependent downregulation of BRCA1 protein level was a result of ER stress, which is activated in BCR-ABL1 expressing cells, as we previously shown. Silencing of TIAR in CML cells strongly elevated BRCA1 level. Altogether, we determined that TIAR-mediated repression of BRCA1 mRNA translation is responsible for downregulation of BRCA1 protein level in BCR-ABL1 -positive leukemia cells. This mechanism may contribute to genomic instability and provide justification for targeting PARP1 and/or RAD52 to induce synthetic lethality in "BRCAness" CML and BCR-ABL1 -positive ALL cells. Thrombospondin-1 (TSP-1) is a matricellular protein that participates in numerous normal and pathological tissue processes and is rapidly modulated by different stimuli. The presence of 8 highly-conserved AU rich elements (AREs) within the 3'-untranslated region (3'UTR) of the TSP-1 mRNA suggests that post-transcriptional regulation is likely to represent one mechanism by which TSP-1 gene expression is regulated. We investigated the roles of these AREs, and proteins which bind to them, in the control of TSP-1 mRNA stability. The endogenous TSP-1 mRNA half-life is approximately 2.0 hours in HEK293 cells. Luciferase reporter mRNAs containing the TSP-1 3'UTR show a similar rate of decay, suggesting that the 3'UTR influences the decay rate. Site-directed mutagenesis of individual and adjacent AREs prolonged reporter mRNA halflife to between 2.2 and 4.4 hours. Mutation of all AREs increased mRNA half life to 8.8 hours, suggesting that all AREs have some effect, but that specific AREs may have key roles in stability regulation. A labeled RNA oligonucleotide derived from the most influential ARE was utilized to purify TSP-1 ARE-binding proteins. The AU-binding protein AUF1 was shown to associate with this motif. These studies reveal that AREs in the 3'UTR control TSP-1 mRNA stability and that the RNA binding protein AUF1 participates in this control. These studies suggest that ARE-dependent control of TSP-1 mRNA stability may represent an important component in the control of TSP-1 gene expression. The zinc finger protein 36-like 2, ZFP36L2, is a member of a small family of RNA-binding proteins composed by ZFP36 (also known as tristetraprolin, TTP), ZFP36L1 and ZFP36L2 in humans, with corresponding murine orthologs. These proteins bind to adenine uridine-rich element (ARE) in the 3'untranslated region of target messenger RNA and stimulate target degradation. ZFP36 functions as an anti-inflammatory modulator in murine models of inflammatory diseases by down-regulating the production of inflammatory cytokines such as tumor necrosis factor-α. However, how ZFP36L1 and ZFP36L2 alter the function of CD4+ T cells is not completely understood. We addressed this issue by searching for the target genes of ZFP36L2 by comprehensive transcriptome analysis. We observed that ZFP36L2 is highly expressed in naïve CD4+ T cells; however, when CD4+ T cells are stimulated through their T cell receptors, ZFP36L2 expression is rapidly reduced in both humans and mice. Among CD4+ T cell populations, the expression levels of ZFP36L2 in regulatory T cells (Tregs) were significantly lower than those in naïve or effector CD4+ T cells. RNA-sequence analysis revealed that the forced expression of ZFP36L2 decreased Ikzf2 (encoding Helios) expression in Foxp3+ Tregs and inhibited the ability of induced Tregs (iTregs). ZFP36L2 directly bound to and destabilized the 3'untranslated region of Ikzf2 mRNA, which contains AU-rich elements. These results indicate that ZFP36L2 reduces the expression of Ikzf2 and suppresses iTreg function, raising the interesting possibility that the inhibition of ZFP36L2 in iTregs could be a therapeutic strategy for autoimmune diseases. Regulator of G protein signaling 4 (RGS4) regulates the strength and duration of G protein signaling and plays an important role in smooth muscle contraction, cardiac development, and psychiatric disorders. Little is known about the posttranscriptional regulation of RGS4 expression. We cloned the full-length cDNA of rabbit RGS4, which contains a long 3'-untranslated region (UTR) with several AU-rich elements (AREs). We determined whether RGS4 mRNA stability is mediated by the RNA-binding protein human antigen R (HuR) and contributes to IL-1β-induced upregulation of RGS4 expression. We show that IL-1β treatment in colonic smooth muscle cells doubled the half-life of RGS4 mRNA. Addition of RGS4 3'-UTR to the downstream of Renilla luciferase reporter induced dramatic reduction in the enzyme activity and mRNA expression of luciferase, which was attenuated by the site-directed mutation of the two 3'-most ARE sites. IL-1β increased luciferase mRNA stability in a UTR-dependent manner. Knockdown of HuR significantly aggravated UTR-mediated instability of luciferase and inhibited IL-1β-induced upregulation of RGS4 mRNA. In addition, IL-1β increased cytosolic translocation and RGS4 mRNA binding of HuR. These findings suggest that 3'-most ARE sites within RGS4 3'-UTR are essential for the instability of RGS4 mRNA and IL-1β promotes the stability of RGS4 mRNA through HuR. Hu proteins are RNA-binding proteins that are implicated in the control of stabilization, nuclear export, and/or translation of specific mRNAs with AU-rich elements (AREs) in the 3'-untranslated region. Three neuron-specific Hu proteins (HuD, HuB, and HuC), but not a ubiquitously expressed Hu protein HuR, have an activity to induce neurite outgrowth when they are overexpressed in a rat neuronal cell line PC12. Here we show that TAP/NXF1, the primary export receptor for the bulk mRNA, is a specific binding partner for HuD. In vitro binding experiments using recombinant proteins revealed that the interaction between TAP and HuD is direct and that HuD can form a ternary complex together with both TAP and RNA. Interestingly, HuR does not interact with TAP. These results suggest that HuD acts as a novel adaptor protein to recruit TAP for efficient export of ARE-containing mRNAs in neuronal cells. CXCR4 is a chemokine receptor that is overexpressed in certain cancer types and involved in migration toward distant organs. The molecular mechanisms underlying CXCR4 expression in invasive cancer, particularly posttranscriptional regulation, are poorly understood. Here, we find that CXCR4 harbors AU-rich elements (AREs) in the 3'-untranslated region (3'-UTR) that bind and respond to the RNA-binding proteins, tristetraprolin (TTP/ZFP36) and HuR (ELAVL1). Different experimental approaches, including RNA immunoprecipitation, 3'-UTR reporter, RNA shift and messenger RNA (mRNA) half-life studies confirmed functionality of the CXCR4 ARE. Wild-type TTP, but not the zinc finger mutant, C124R, was able to bind CXCR4 mRNA and ARE. In the invasive breast cancer phenotype, aberrant expression of CXCR4 is linked to both TTP deficiency and HuR overexpression. HuR silencing led to decreased CXCR4 mRNA stability and expression, and significant reduction in migration of the cells toward the CXCR4 ligand, CXCL12. Derepression of TTP using miR-29a inhibitor led to significant reduction in CXCR4 mRNA stability, expression and migration capability of the cells. The study shows that CXCR4 is regulated by ARE-dependent posttranscriptional mechanisms that involve TTP and HuR, and that aberration in this pathway helps cancer cells migrate toward the CXCR4 ligand. Targeting posttranscriptional control of CXCR4 expression may constitute an alternative approach in cancer therapy. Complex regulation of brain-derived neurotrophic factor (BDNF) governs its intricate functions in brain development and neuronal plasticity. Besides tight transcriptional control from multiple distinct promoters, alternative 3'end processing of the BDNF transcripts generates either a long or a short 3'untranslated region (3'UTR). Previous reports indicate that distinct RNA sequence in the BDNF 3'UTRs differentially regulates BDNF production in the brain to accommodate neuronal activity changes, conceivably through differential interactions with undefined trans-acting factors that regulate stability and translation of these BDNF mRNA isoforms. In this study, we report that the neuronal RNA-binding protein (RBP) HuD interacts with a highly conserved AU-rich element (ARE) specifically located in the BDNF long 3'UTR. Such interaction is necessary and sufficient for selective stabilization of mRNAs that contain the BDNF long 3'UTR in vitro and in vivo. Moreover, in a HuD transgenic mouse model, the BDNF long 3'UTR mRNA is increased in the hippocampal dentate granule cells (DGCs), leading to elevated expression of BDNF protein that is transported and stored in the mossy fiber (MF) terminals. Our results identify HuD as the first trans-acting factor that enhances BDNF expression specifically through the long 3'UTR and a novel mechanism that regulates BDNF protein production in selected neuronal populations by HuD abundance. BACKGROUND: There is often a poor correlation observed between protein and RNA in eukaryotic systems, supporting the emerging pardigm that many of the abnormalities in a cancer cell's proteome may be achieved by differential recruitment of mRNAs to polysomes referred to as the translational profile. The MCT-1 oncogene product has recently been shown to interact with the cap complex and to modulate the translational profile of cell lines when MCT-1 was highly expressed. The MCT-1 protein modifies mRNA translational profiles through its interaction with DENR/DRP, a protein containing an SUI1 domain involved in recognition of the translation initiation codon. It has been shown previously that the protein levels of DENR/DRP go up in parallel with increasing cell density, however the mechanism(s) underlying this increase is poorly understood at present. The 3'-untranslated region (3'UTR) of DENR/DRP was found to have a high number of uracyl (U)- and adenine (A)-rich sequences (AREs). Many RNA-binding proteins (RBPs) have been shown to recognize and bind to mRNAs that contains AREs generally present in the 3'UTR of mRNAs. RBPs binding to AREs such as AUF1, BRF1, KSRP, and TTP are known to regulate mRNA turnover, while TIAR and TIA-1 influence mRNA translation. MATERIALS AND METHODS: We assessed the association of several ARE binding proteins with DENR/DRP mRNA by reverse transcription of the RNA obtained after immunoprecipitation of cell lysates from HEK 293 cells growing at varying levels of cell density. HEK 293 cells were transfected with an AUF1 silencing vector (shRNA), and protein levels of DENR/DRP were analyzed by Western blotting. RESULTS: We demonstrated that both HuR and AUF1 bind to discrete regions of DENR/DRP mRNA and that AUF1 silencing increases DENR/DRP protein levels. CONCLUSION: Our data established a cell density-dependent interaction of AUF1 protein with DENR/DRP mRNA that modulates DENR/DRP protein levels. Tumor suppressor protein p53 plays a crucial role in maintaining genomic integrity in response to DNA damage. Regulation of translation of p53 mRNA is a major mode of regulation of p53 expression under genotoxic stress. The AU/U-rich element-binding protein HuR has been shown to bind to p53 mRNA 3'UTR and enhance translation in response to DNA-damaging UVC radiation. On the other hand, the microRNA miR-125b is reported to repress p53 expression and stress-induced apoptosis. Here, we show that UVC radiation causes an increase in miR-125b level in a biphasic manner, as well as nuclear cytoplasmic translocation of HuR. Binding of HuR to the p53 mRNA 3'UTR, especially at a site adjacent to the miR-125b target site, causes dissociation of the p53 mRNA from the RNA-induced silencing complex (RISC) and inhibits the miR-125b-mediated translation repression of p53. HuR prevents the oncogenic effect of miR-125b by reversing the decrease in apoptosis and increase in cell proliferation caused by the overexpression of miR-125b. The antagonistic interplay between miR-125b and HuR might play an important role in fine-tuning p53 gene expression at the post-transcriptional level, and thereby regulate the cellular response to genotoxic stress. Two different mechanisms have been well known to regulate the amounts of various transcripts in response to internal and external environmental stimuli. First, by binding of activated transcription factors to DNA regulatory regions including the cAMP response element, hormone response element, and activator protein-1 region upstream in various genes, the rate of transcription from DNA to mRNA is regulated. Secondly, the degradation of some mRNAs related to immune responses has been reported to be regulated by binding of RNA-binding proteins to adenylate uridylate-rich elements (AU-rich elements, AREs) located in the 3'-untranslated region (3'-UTR). The original study identifying the existence of a common regulatory nucleotide sequence in the 3'-UTR of inflammatory mediator transcripts pointed out that the AREs are characteristic of immune-related functional proteins. The number of transcripts containing AREs in the 3'-UTR has increased and several neuronal proteins including beta 2-adrenergic receptor, nerve growth factor, tyrosine hydroxylase, and nitric-oxide synthase II, have been reported to have AREs. We here reviewed the recent advances in the neuropsychopharmacological understanding of post-transcriptional regulation by RNA-binding protein and also pointed out the importance of this regulation in future studies using various stress paradigms. BACKGROUND: Bile salts increase intestinal mucosal proliferation through an increase in c-Myc, a transcription factor that controls the expression of numerous translation regulatory proteins. HuR is an RNA-binding protein that regulates translation of target mRNAs. RNA-binding proteins can control mRNA stability by binding to AU- and U-rich elements located in the 3'-untranslated regions (3'-UTRs) of target mRNAs. AIM: To determine how bile salt-induced c-Myc stimulates enterocyte proliferation. METHODS: Enterocyte proliferation was measured both in vivo using C57Bl6 mice and in vitro using IEC-6 cells after taurodeoxycholate (TDCA) supplementation. HuR and c-Myc protein expression was determined by immunoblot. c-Myc mRNA expression was determined by PCR. HuR expression was inhibited using specific small interfering RNA. HuR binding to c-Myc mRNA was determined by immunoprecipitation. RESULTS: TDCA increased enterocyte proliferation in vivo and in vitro. TDCA stimulates translocation of HuR from the nucleus to the cytoplasm. Cytoplasmic HuR regulates c-Myc translation by HuR binding to the 3'-UTR of c-Myc mRNA. Increased TDCA-induced c-Myc increases enterocyte proliferation. CONCLUSIONS: Bile salts have beneficial effects on the intestinal epithelial mucosa, which are important in maintaining intestinal mucosal integrity and function. These data further support an important beneficial role of bile salts in regulation of mucosal growth and repair. Decreased enterocyte exposure to luminal bile salts, as occurs during critical illness, liver failure, starvation, and intestinal injury, may have a detrimental effect on mucosal integrity.

Which drugs are included in the CAPIRI regimen?

CAPIRI regimen includes capecitabine plus irinotecan.

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BACKGROUND: To determine the efficacy and tolerability of capecitabine combined with oxaliplatin (CAPOX) or irinotecan (CAPIRI) as first-line treatment in patients with advanced/metastatic colorectal cancer aged > or =70 years. PATIENTS AND METHODS: Patients aged > or =70 years were randomly assigned to receive CAPOX [oxaliplatin 65 mg/m(2) intravenously (i.v.) days 1 and 8 and capecitabine 1000 mg/m(2) orally b.i.d. days 1-14; q21d] or CAPIRI (irinotecan 80 mg/m(2) i.v. days 1 and 8 and capecitabine 1000 mg/m(2) orally b.i.d. days 1-14; q21d). The primary study end point was overall response rate (ORR). RESULTS: Ninety-four patients were enrolled. In an intent-to-treat analysis, 2 complete responses (CRs) and 16 partial responses (PRs) were reported with CAPOX (ORR 38%), and 2 CRs and 15 PRs with CAPIRI (ORR 36%; P = 0.831). Median time to progression was 8 months for CAPOX and 7 months for CAPIRI (P = 0.195), with median survival times of 19.3 months and 14.0 months (P = 0.165), respectively. Global health status was improved in 45% and in 21% of patients in the CAPOX and CAPIRI arms, respectively. The most common treatment-related grade 3-4 adverse events in CAPIRI versus CAPOX patients were diarrhea (32% versus 15%; P = 0.052) and neutropenia (23% versus 6%; P = 0.021). CONCLUSION: CAPOX and CAPIRI had similar efficacy in elderly patients, although CAPOX seemed to be better tolerated. ABT-751 is an orally bioavailable sulfonamide with antimitotic properties. A nonrandomized phase 1 dose-escalation study of ABT-751 in combination with CAPIRI (capecitabine and irinotecan) and bevacizumab was conducted to define the maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics in patients with advanced colorectal cancer. Patients were treated with ABT-751 daily for 7 days (alone) and then began 21-day cycles of treatment with ABT-751 daily and capecitabine twice daily for 14 days plus irinotecan on day 1 intravenously. Bevacizumab was added as standard of care at 7.5 mg/kg on day 1 after the first 2 dose levels. Because of intolerance to the regimen, a reduced dose of ABT-751 was also explored with reduced-dose and full-dose CAPIRI with bevacizumab. ABT-751 and irinotecan pharmacokinetics, ABT-751 glucuronidation, and protein binding were explored. Twenty-four patients were treated over 5 dose levels. The maximum tolerated dose was ABT-751 125 mg combined with full-dose CAPIRI and bevacizumab 7.5 mg/kg on day 1. DLTs were hypokalemia, elevated liver tests, and febrile neutropenia. ABT-751 is metabolized by UGT1A8 and to a lesser extent UGT1A4 and UGT1A1. Irinotecan and APC exposure were increased, SN-38 exposure was similar, and SN-38 glucuronide exposure was decreased. Clinically relevant alterations in ABT-751 and irinotecan pharmacokinetics were not observed. Despite modest efficacy, the combination of ABT-751, CAPIRI, and bevacizumab will not be studied further in colorectal cancer. BACKGROUND: First-line treatment with FOLFOXIRI plus bevacizumab (BEV) is highly effective and regarded as one of the standards-of-care for patients with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea as side effects. AXEPT, an Asian phase III study, showed that modified CAPIRI+BEV [capecitabine (CAP: 1600 mg/m2), irinotecan (IRI: 200 mg/m2), and BEV (7.5 mg/m2)] was non-inferior to FOLFIRI+BEV as a second-line therapy for mCRC patients and was associated with a lower incidence of hematologic toxicities. Thus, a reduced dose of the CAP and IRI regimen in combination with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) may be more feasible than FOLFOXIRI+BEV, without compromising efficacy. METHODS: QUATTRO-II is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses of OX and IRI will be investigated as a safety lead-in. In Step 2, patients will be randomized to the recommended dose of either CAPOXIRI+BEV or FOLFOXIRI+BEV. Induction triplet chemotherapy plus BEV treatments will be administered for up to 4 months followed by fluoropyrimidine plus BEV maintenance. The primary endpoint is progression-free survival (PFS). The similarity in PFS between the two arms will be evaluated by observing whether the point estimate of hazard ratio (HR) for PFS falls between 0.80 and 1.25. Ensuring a 70% probability that the observed HR will be "0.8 < HR < 1.25" under the assumption of the true HR of 1.0, and 100 patients will be evaluated during the 3-year study period. Secondary endpoints include overall survival, overall response rate, safety, and patient reported outcome (PRO) (FACT/GOG-Ntx4). DISCUSSION: Considering the lower incidence of hematologic toxicities with modified CAPIRI+BEV than with FOLFIRI+BEV, CAPOXIRI+BEV may be a promising treatment option if sufficient efficacy and lower hematologic toxicities are indicated in this study. Additionally, a lower incidence of peripheral sensory neuropathy (PSN) reported following CAPEOX treatment compared to that after FOLFOX in ACHIEVE, an adjuvant phase III trial, suggest that CAPOXIRI+BEV can mitigate OX-induced PSN. TRIAL REGISTRATION: Clinicaltrials.gov NCT04097444 . Registered September 20, 2019, https://clinicaltrials.gov/ct2/show/study/NCT04097444 / Japan Registry of Clinical Trials jRCTs041190072. Registered October 9, 2019. AIM: To investigate the efficacy and safety of cape-citabine plus irinotecan +/- bevacizumab in advanced or metastatic colorectal cancer patients. METHODS: Forty six patients with previously untreated, locally-advanced or metastatic colorectal cancer (mCRC) were recruited between 2001-2006 in a prospective open-label phase II trial, in German community-based outpatient clinics. Patients received a standard capecitabine plus irinotecan (CAPIRI) or CAPIRI plus bevacizumab (CAPIRI-BEV) regimen every 3 wk. Dose reductions were mandatory from the first cycle in cases of > grade 2 toxicity. The treatment choice of bevacizumab was at the discretion of the physician. The primary endpoints were response and toxicity and secondary endpoints included progression-free survival and overall survival. RESULTS: In the CAPIRI group vs the CAPRI-Bev group there were more female than male patients (47% vs 24%), and more patients had colon as the primary tumor site (58.8% vs 48.2%) with fewer patients having sigmoid colon as primary tumor site (5.9% vs 20.7%). Grade 3/4 toxicity was higher with CAPIRI than CAPIRI-Bev: 82% vs 58.6%. Partial response rates were 29.4% and 34.5%, and tumor control rates were 70.6% and 75.9%, respectively. No complete responses were observed. The median progression-free survival was 11.4 mo and 12.8 mo for CAPIRI and CAPIRI-Bev, respectively. The median overall survival for CAPIRI was 15 mo (458 d) and for CAPIRI-Bev 24 mo (733 d). These differences were not statistically different. In the CAPIRI-Bev, group, two patients underwent a full secondary tumor resection after treatment, whereas in the CAPIRI group no cases underwent this procedure. CONCLUSION: Both regimens were well tolerated and offered effective tumor growth control in this outpatient setting. Severe gastrointestinal toxicities and thromboembolic events were rare and if observed were never fatal. PURPOSE: The AIO KRK-0104 randomized phase II trial investigated the efficacy and safety of cetuximab combined with capecitabine and irinotecan (CAPIRI) or capecitabine and oxaliplatin (CAPOX) in the first-line treatment of metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: A total of 185 patients with mCRC were randomly assigned to cetuximab (400 mg/m(2) day 1, followed by 250 mg/m(2) weekly) plus CAPIRI (irinotecan 200 mg/m(2), day 1; capecitabine 800 mg/m(2) twice daily days 1 through 14, every 3 weeks; or cetuximab plus CAPOX (oxaliplatin 130 mg/m(2) day 1; capecitabine 1,000 mg/m(2) twice daily day 1 through 14, every 3 weeks). The primary study end point was objective response rate (ORR). RESULTS: In the intention-to-treat patient population (n = 177), ORR was 46% (95% CI, 35 to 57) for CAPIRI plus cetuximab versus 48% (95% CI, 37 to 59) for CAPOX plus cetuximab. Analysis of the KRAS gene mutation status was performed in 81.4% of the intention to treat population. Patients with KRAS wild-type in the CAPIRI plus cetuximab arm showed an ORR of 50.0%, a PFS of 6.2 months and an OS of 21.1 months. In the CAPOX plus cetuximab arm, an ORR of 44.9%, a PFS of 7.1 months and an OS of 23.5 months were observed. While ORR and PFS were comparable in KRAS wild-type and mutant subgroups, a trend toward longer survival was associated with KRAS wild-type. Both regimens had manageable toxicity profiles and were safe. CONCLUSION: This randomized trial demonstrates that the addition of cetuximab to CAPIRI or CAPOX is effective and safe in first-line treatment of mCRC. In the analyzed regimens, ORR and PFS did not differ according to KRAS gene mutation status. We sought to evaluate the efficacy and safety data of a combination regimen using weekly irinotecan in combination with capecitabine and concurrent radiotherapy (CapIri-RT) as neoadjuvant treatment in rectal cancer in a phase-II trial. Patients with rectal cancer clinical stages T3/4 Nx or N+ were recruited to receive irinotecan (50 mg m(-2) weekly) and capecitabine (500 mg m(-2) bid days 1-38) with a concurrent RT dose of 50.4 Gy. Surgery was scheduled 4-6 weeks after the completion of chemoradiation. A total of 36 patients (median age 62 years; m/f: 27:9) including three patients with local recurrence were enclosed onto the trial. The median distance of the tumour from the anal verge was 5 cm. The main toxicity observed was (NCI-CTC grades 1/2/3/4 (n)): Anaemia 23/9/-/-; leucocytopenia 12/7/7/2, diarrhoea 13/15/4/-, nausea/vomiting 9/10/2/-, and increased activity of transaminases 3/3/1/-. One patient had a reversible episode of ventricular fibrillation during chemoradiation, most probably caused by capecitabine. The relative dose intensity was (median/mean (%)): irinotecan 95/91, capecitabine 100/92). Thirty-four patients underwent surgery (anterior resection n=25; abdomino-perineal resection n=6; Hartmann's procedure n=3). R0-resection was accomplished in all patients. Two patients died in the postoperative course from septic complications. Pathological complete remission was observed in five out of 34 resected patients (15%), and nine patients showed microfoci of residual tumour (26%). After a median follow-up of 28 months one patient had developed a local recurrence, and five patients distant metastases. Three-year overall survival for all patients with surgery (excluding three patients treated for local relapse or with primary metastatic disease) was 80%. In summary, preoperative chemoradiation with CapIri-RT exhibits promising efficacy whereas showing managable toxicity. The local recurrence and distant failure rates observed after a median 28 months are low compared with standard 5-fluorouracil based therapy. Colorectal cancer (CRC) is a worldwide public health problem, with nearly 800,000 new cases diagnosed each year, resulting in approximately 500,000 deaths. When advanced metastatic disease is diagnosed, CRC is associated with a poor prognosis, and 5-year survival rates are in the range of 5%-8%. Chemotherapy has been the mainstay approach for patients with advanced CRC. For nearly 40 years, the main drug used for this disease was the fluoropyrimidine 5-fluorouracil (5-FU). Significant advances have been made in chemotherapy treatment options for patients with metastatic disease, such that improvements in 2-year survival are now being reported with median survival rates of 21 months to 24 months. Over the past 10 years, 3 new cytotoxic chemotherapy agents have been approved by the FDA for metastatic CRC. These compounds include the topoisomerase I inhibitor irinotecan, the third-generation platinum analogue oxaliplatin, and the oral fluoropyrimidine capecitabine. Since 2004, 3 novel biologic agents have been approved by the FDA, and they include the anti-epidermal growth factor receptor antibodies cetuximab and panitumumab and the anti-vascular endothelial growth factor bevacizumab. The oral fluoropyrimidine capecitabine has been effectively and safely combined with irinotecan (CAPIRI) and/or oxaliplatin (CAPOX). Three randomized phase III studies have now shown that CAPOX is equivalent to FOLFOX (5-FU/leucovorin/oxaliplatin)-based regimens. Significant interest has centered around combining capecitabine-based cytotoxic regimens with the biologic agents, and specifically, bevacizumab and cetuximab. This review will update the current status of these capecitabine-based combination regimens. BACKGROUND: Triweekly capecitabine plus irinotecan (CAPIRI) was not a replacement for fluorouracil, leucovorin, and irinotecan (FOLFIRI) in the treatment of metastatic colorectal cancer (mCRC) because of the potential for greater toxicity. Recently, it has reported that mCAPIRI is well tolerated and non-inferior to FOLFIRI. In this study, we conducted a multicenter phase II trial to assess the efficacy and safety of biweekly CAPIRI plus bevacizumab as second-line chemotherapy for mCRC with reduced toxicity and preserved efficacy. METHODS: Patients with mCRC who had received prior chemotherapy, including oxaliplatin-based regimens, were eligible for this study. The treatment protocol administered capecitabine at 1000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous irinotecan at 150 mg/m2 on day 1, and bevacizumab at 10 mg/kg on day 1 every 2 weeks. Primary endpoints for this study were progression-free survival (PFS) and safety. Secondary endpoints were overall survival (OS), time to treatment failure, response rate (RR), and disease control rate (DCR). RESULTS: Fifty-one patients were enrolled in this study. Median PFS was 5.5 months [95% confidence interval (CI) 4.23-7.40 months], and median OS was 13.5 months (95% CI 11.57-20.23 months). The RR was 14.6% (95% CI 6.5-28.4%), and the DCR was 66.7% (95% CI 51.5-79.2%). Hypertension was the most common Grade 3 adverse event (27.5%), followed by neutropenia (17.6%). Only two patients suffered from grade 3 hand-foot syndrome. CONCLUSIONS: In mCRC patients, biweekly CAPIRI + bevacizumab appears effective and feasible as a second-line chemotherapy with relatively low toxicities, and has potential as a useful substitute for FOLFIRI + bevacizumab. Diversity in colorectal cancer biology is associated with variable responses to standard chemotherapy. We aimed to identify and validate DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of metastatic CRC patients. Candidate genes were selected from 389 genes involved in DNA Damage Repair by correlation analyses between gene methylation status and drug response in 32 cell lines. A large series of samples (n=818) from two phase III clinical trials was used to evaluate these candidate genes by correlating methylation status to progression-free survival after treatment with first-line single-agent fluorouracil (Capecitabine or 5-fluorouracil) or combination chemotherapy (Capecitabine or 5-fluorouracil plus irinotecan (CAPIRI/FOLFIRI)). In the discovery (n=185) and initial validation set (n=166), patients with methylated Decoy Receptor 1 (DCR1) did not benefit from CAPIRI over Capecitabine treatment (discovery set: HR=1.2 (95%CI 0.7-1.9, p=0.6), validation set: HR=0.9 (95%CI 0.6-1.4, p=0.5)), whereas patients with unmethylated DCR1 did (discovery set: HR=0.4 (95%CI 0.3-0.6, p=0.00001), validation set: HR=0.5 (95%CI 0.3-0.7, p=0.0008)). These results could not be replicated in the external data set (n=467), where a similar effect size was found in patients with methylated and unmethylated DCR1 for FOLFIRI over 5FU treatment (methylated DCR1: HR=0.7 (95%CI 0.5-0.9, p=0.01), unmethylated DCR1: HR=0.8 (95%CI 0.6-1.2, p=0.4)). In conclusion, DCR1 promoter hypermethylation status is a potential predictive biomarker for response to treatment with irinotecan, when combined with capecitabine. This finding could not be replicated in an external validation set, in which irinotecan was combined with 5FU. These results underline the challenge and importance of extensive clinical evaluation of candidate biomarkers in multiple trials. BACKGROUND: This study investigated the local effect and acute toxicity of irinotecan and capecitabine with concurrent intensity-modulated radiation therapy (IMRT) for the treatment of recurrent rectal cancer without prior pelvic irradiation. METHODS: Seventy-one patients diagnosed with recurrent rectal cancer who did not previously receive pelvic irradiation were treated in our hospital from October 2009 to July 2012. Radiotherapy was delivered to the pelvis, and IMRT of 45 Gy (1.8 Gy per fraction), followed by a boost of 10 Gy to 16 Gy (2 Gy per fraction), was delivered to the recurrent sites. The concurrent chemotherapy regimen was 50 mg/m(2) irinotecan weekly and 625 mg/m(2) capecitabine twice daily (Mon-Fri). Radical surgery was recommended for medically fit patients without extra-pelvic metastases. The patients were followed up every 3 months. Tumor response was evaluated using CT/MRIs according to the RECIST criteria or postoperative pathological findings. NCI-CTC 3.0 was used to score the toxicities. RESULTS: Forty-eight patients (67.6%) had confirmed recurrent rectal cancer without extra pelvic metastases, and 23 patients (32.4%) had extra pelvic metastases. Fourteen patients (19.7%) underwent radical resections (R0) post-chemoradiation. A pathologic complete response was observed in 7 of 14 patients. A clinical complete response was observed in 4 patients (5.6%), and a partial response was observed in 22 patients (31.0%). Only 5 patients (7.0%) showed progressive disease during or shortly after treatment. Of 53 symptomatic patients, clinical complete and partial symptom relief with chemoradiation was achieved in 56.6% and 32.1% of patients, respectively. Only 2 patients (2.8%) experienced grade 4 leukopenia. The most common grade 3 toxicity was diarrhea (16 [22.5%] patients). The median follow-up was 31 months. The cumulative local progression-free survival rate was 74.2% and 33.9% at 1 and 3 years after chemoradiation, respectively. The cumulative total survival rate was 80.1% and 36.5% at 1 and 3 years after chemoradiation, respectively. CONCLUSIONS: This study revealed that concurrent irinotecan and capecitabine with IMRT significantly relieves local symptoms and exhibits promising efficacy with manageable toxicities in recurrent rectal cancer without prior pelvic irradiation. Improving the rate of R0 resections will be investigated in a future study. BACKGROUND: To compare the efficacy and safety of CAPIRI+bevacizumab (Bev) in comparison with FOLFIRI+Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC). METHODS: Patients were randomised to receive either FOLFIRI plus Bev 5 mg kg(-1) every 2 weeks (Arm-A) or CAPIRI plus Bev 7.5 mg kg(-1) every 3 weeks (Arm-B). RESULTS: Three hundred thirty-three patients (Arm-A=167; Arm-B=166) were enrolled into the study. No difference was observed in median progression-free survival (PFS) (10.0 and 8.9 months; P=0.64), overall survival (25.7 and 27.5 months; P=0.55) or response rates (45.5 and 39.8.7%; P=0.32) for FOLFIRI-Bev and CAPIRI-Bev, respectively. Patients treated with CAPIRI-Bev presented significantly higher incidence of diarrhoea (P=0.005), febrile neutropenia (P=0.003) and hand-foot skin reactions (P=0.02) compared with patients treated with FOLFIRI-Bev. Treatment delays (P=0.05), dose reduction (P<0.001) and treatment discontinuation owing to toxicity (P=0.01) occurred more frequently in the CAPIRI-Bev arm. CONCLUSION: The PFS of FOLFIRI-BEV is not superior to that observed with the CAPIRI-Bev regimen. CAPIRI-Bev has a less favourable toxicity profile, requiring dose reductions, in order to be considered as an option in first-line treatment of patients with mCRC. PURPOSE: The aim of this randomized, multicenter, noncomparative, phase II trial was to investigate the efficacy and safety of two potential first-line treatments, capecitabine and oxaliplatin (CapOX) plus bevacizumab (BEV) and capecitabine and irinotecan (CapIRI) plus bevacizumab, in Japanese patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with untreated mCRC were randomly assigned to receive either CapOX plus bevacizumab (CapOX/BEV arm: bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 2,000 mg/m2 on days 1-14, every 3 weeks) or CapIRI plus bevacizumab (CapIRI/BEV arm: bevacizumab 7.5 mg/kg and irinotecan 200 mg/m2 on day 1 and capecitabine 1,600 mg/m2 on days 1-14, every 3 weeks). The primary endpoint was overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 107 patients were enrolled. The intent-to-treat population comprised 54 patients in the CapOX/BEV arm and 53 patients in the CapIRI/BEV arm. The median follow-up period was 35.5 months. ORR was 56% in the CapOX/BEV arm and 55% in the CapIRI/BEV arm. Median PFS and OS were 12.4 and 26.7 months in the CapOX/BEV arm and 11.5 and 28.7 months in the CapIRI/BEV arm, respectively. The frequencies of hematological and nonhematological adverse events above grade 3 were 13% and 30% in the CapOX/BEV arm and 25% and 23% in the CapIRI/BEV arm, respectively. CONCLUSION: CapOX plus bevacizumab and CapIRI plus bevacizumab are equally effective and feasible as the first-line treatments in Japanese patients with mCRC. IMPLICATIONS FOR PRACTICE: The CCOG-1201 study was designed to evaluate the efficacy and safety of capecitabine and oxaliplatin plus bevacizumab and capecitabine and irinotecan plus bevacizumab as a first-line treatment in Japanese patients with metastatic colorectal cancer. This article reports on the trial and efforts to define the role of these regimens, including the effect of KRAS status and UGT1A1 polymorphisms in metastatic colorectal cancer. PURPOSE: To establish the feasibility and efficacy of capecitabine in combination with weekly irinotecan (CAPIRI) with concurrent pelvic radiotherapy (RT) in patients with locally advanced rectal cancer. PATIENTS AND METHODS: Nineteen patients with rectal cancer clinical stage T3-4, Nx received weekly irinotecan 50 mg/m(2) (days 1, 8, 15, 22, 29) and two doses of capecitabine (days 1 through 38; dose level [DL] I, 500 mg/m(2) bid; DL II, 625 mg/m(2) bid) according to phase I methodology. Three-dimensional conformal RT was given to a dose of 50.4 Gy (45 Gy + 5.4 Gy). RESULTS: On DL I, no dose-limiting toxicities occurred, whereas diarrhea grade 3 affected three of seven patients on DL II. Twelve patients were treated on DL I and received a median relative dose-intensity of 100% for both drugs. Grade 3 or 4 adverse events were observed in only one of these patients (asthenia grade 3). All patients underwent surgery and R0 resection was achieved in all patients. Pathologic complete remission was observed in four patients and another five patients had only microfoci of residual tumor. CONCLUSION: Preoperative chemoradiotherapy with CAPIRI is feasible and well tolerated. The preliminary efficacy is good, and the tolerability is at least comparable with data for fluorouracil plus irinotecan chemoradiotherapy. Larger phase II trials of the CAPIRI-RT schedule clearly are warranted.

What is the p-crAssphage?

CrAssphage is the most abundant human-associated virus and the founding member of a large group of bacteriophages, discovered in animal-associated and environmental metagenomes, that infect bacteria of the phylum Bacteroidetes.

[33137401, 33715349, 33594055]

Recently, crAssphage has been proposed as a human-specific marker for tracking fecal contamination. However, its performance has always been validated in a limited number of host samples, which may obscure our understanding of its utility. Furthermore, few studies have quantified confidence of fecal contamination when using crAssphage. Here, we evaluate the performance and confidence of crAssphage by analyzing a large panel of metagenomic data sets combined with Bayesian analyses. Results demonstrate that crAssphage exhibits superior performance with high host sensitivity and specificity, indicating its suitability for tracking human fecal sources. With the marker, a high confidence (>90%) can be obtained and particularly, multiple samples with positive results provide a near certainty of confidence. The application of crAssphage in the sediments of three Chinese urban rivers shows a high confidence of >97% of human fecal contamination, suggesting the serious challenge of sewage pollution in these environments. Additionally, significant correlation is observed between crAssphage and antibiotic resistance genes (ARGs), expanding the utilization of crAssphage for pollution management of ARGs. This study highlights the benefit of using metagenomic-based analysis for evaluating the performance and confidence of microbial source tracking markers in the coming era of big data with increasing resources in available metagenomic data. CrAssphage is the most abundant human-associated virus and the founding member of a large group of bacteriophages, discovered in animal-associated and environmental metagenomes, that infect bacteria of the phylum Bacteroidetes. We analyze 4907 Circular Metagenome Assembled Genomes (cMAGs) of putative viruses from human gut microbiomes and identify nearly 600 genomes of crAss-like phages that account for nearly 87% of the DNA reads mapped to these cMAGs. Phylogenetic analysis of conserved genes demonstrates the monophyly of crAss-like phages, a putative virus order, and of 5 branches, potential families within that order, two of which have not been identified previously. The phage genomes in one of these families are almost twofold larger than the crAssphage genome (145-192 kilobases), with high density of self-splicing introns and inteins. Many crAss-like phages encode suppressor tRNAs that enable read-through of UGA or UAG stop-codons, mostly, in late phage genes. A distinct feature of the crAss-like phages is the recurrent switch of the phage DNA polymerase type between A and B families. Thus, comparative genomic analysis of the expanded assemblage of crAss-like phages reveals aspects of genome architecture and expression as well as phage biology that were not apparent from the previous work on phage genomics.

What is the function of Circular RNA (circRNA)?

Circular RNAs (circRNAs) are a class of conserved, endogenous non-coding RNAs that are involved in transcriptional and post-transcriptional gene regulation as well as the pathogenesis of diseases. including cancer

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Circular RNAs (circRNAs) are noncoding RNAs that form covalently closed loop structures. CircRNAs are dysregulated in cancer and play key roles in tumorigenesis, diagnosis, and tumor therapy. CircRNAs function as competing endogenous RNAs or microRNA sponges that regulate transcription and splicing, binding to proteins, and translation. CircRNAs may serve as novel biomarkers for cancer diagnosis, and they show potential as therapeutic targets in cancers including breast cancer (BC). In women, BC is the most common malignant tumor worldwide and the second leading cause of cancer death. Although evidence indicates that circRNAs play a critical role in BC, the mechanisms regulating the function of circRNAs in BC remain poorly understood. Here, we provide literature review aiming to clarify the role of circRNAs in BC and summarize the latest research. We provide a systematic overview of the biogenesis and biological functions of circRNAs, elaborate on the functional roles of circRNAs in BC, and highlight the value of circRNAs as diagnostic and therapeutic targets in BC. Circular RNAs (circRNAs) are a novel type of universal and diverse endogenous noncoding RNAs (ncRNAs) and they form a covalently closed continuous loop without 5' or 3' tails unlike linear RNAs. Most circRNAs are presented with characteristics of abundance, stability, conservatism, and often exhibiting tissue/developmental-stage-specific expression. CircRNAs are generated either from exons or introns by back splicing or lariat introns. CircRNAs play important roles as miRNA sponges, gene transcription and expression regulators, RNA-binding protein (RBP) sponges and protein/peptide translators. Emerging evidence revealed the function of circRNAs in cancer and may potentially serve as a required novel biomarker and therapeutic target for cancer treatment. In this review, we discuss about the origins, characteristics and functions of circRNA and how they work as miRNA sponges, gene transcription and expression regulators, RBP sponges in cancer as well as current research methods of circRNAs, providing evidence for the significance of circRNAs in cancer diagnosis and clinical treatment. AIMS: Circular RNA (circRNA) is a newly validated class of single-stranded RNA, ubiquitously expressed in mammalian tissues and possessing key functions including acting as microRNA sponges and as transcriptional regulators by binding to RNA-binding proteins. While independent studies confirm the expression of circRNA in various tissue types, genome-wide circRNA expression in the heart has yet to be described in detail. METHODS AND RESULTS: We performed deep RNA-sequencing on ribosomal-depleted RNA isolated from 12 human hearts, 25 mouse hearts and across a 28-day differentiation time-course of human embryonic stem cell-derived cardiomyocytes. Using purpose-designed bioinformatics tools, we uncovered a total of 15 318 and 3017 cardiac circRNA within human and mouse, respectively. Their abundance generally correlates with the abundance of their cognate linear RNA, but selected circRNAs exist at disproportionately higher abundance. Top highly expressed circRNA corresponded to key cardiac genes including Titin (TTN), RYR2, and DMD. The most abundant cardiac-expressed circRNA is a cytoplasmic localized single-exon circSLC8A1-1. The longest human transcript TTN alone generates up to 415 different exonic circRNA isoforms, the majority (83%) of which originates from the I-band domain. Finally, we confirmed the expression of selected cardiac circRNA by RT-PCR, Sanger sequencing and single molecule RNA-fluorescence in situ hybridization. CONCLUSIONS: Our data provide a detailed circRNA expression landscape in hearts. There is a high-abundance of specific cardiac-expressed circRNA. These findings open up a new avenue for future investigation into this emerging class of RNA. Circular RNA (circRNA) participates in regulation of gene transcription, while estrogen receptor alpha (ERα) and quercetin (QUE) positively regulate bone formation, but little is known about the correlation among circRNA, ERα and QUE. In this experiment, we created an ERα-deficient rBMSC model treated with QUE and evaluated the effects of ERα or QUE on rBMSCs, then analyzed differentially-expressed circRNAs by RNA-Seq and bioinformatics. The results showed that ERα deficiency constrained osteogenic differentiation and stimulated adipocytic differentiation of rBMSCs, while QUE abrogated those effects. We identified 136 differentially-expressed circRNAs in the Lv-shERα group and 120 differentially-expressed circRNAs in the Lv-shERα + QUE group. Thirty-two circRNAs retroregulated by ERα and QUE were involved in Rap1 and Wnt signaling, and four of them together sponged miR-326-5p, the target genes of which are osteogenic and adipogenic differentiation factors. Further study showed that over-expressed miR-326-5p could stimulate osteogenic differentiation, while attenuating adipogenic differentiation of rBMSCs. Therefore, we concluded that ERα and QUE might regulate the differentiation of rBMSCs through the circRNA-miR-326-5p-mRNA axis. Circular RNAs (circRNAs) are a new class of non-coding RNAs formed by covalently closed loops through backsplicing. Recent methodologies have enabled in-depth characterization of circRNAs for identification and potential functions. CircRNAs play important roles in various biological functions as microRNA sponges, transcriptional regulators and combining with RNA binding proteins. Recent studies indicated that some cytoplasmic circRNAs can be effectively translated into detectable peptides, which enlightened us on the importance of circRNAs in cellular physiology function. Internal Ribosome Entry site (IRES)- and N6-methyladenosines (m6A)-mediated cap-independent translation initiation have been suggested to be potential mechanism for circRNA translation. To date, several translated circRNAs have been uncovered to play pivotal roles in human cancers. In this review, we introduced the properties and functions of circRNAs, and characterized the possible mechanism of translation initiation and complexity of the translation ability of circRNAs. We summarized the emerging functions of circRNA-encoded proteins in human cancer. The works on circRNA translation will open a hidden human proteome, and enhance us to understand the importance of circRNAs in human cancer, which has been poorly explored so far. BACKGROUND: Circular RNA (circRNA) plays an important role in regulating cell biological function and has been shown to be involved in cancer progression, including oral squamous cell carcinoma (OSCC). Circ-KIAA0907 has been found to play an anti-cancer role in OSCC, so it is worth exploring more functions and new mechanisms of circ-KIAA0907 in OSCC progression. METHODS: Quantitative real-time PCR (qRT-PCR) was used to detect the expression of circ-KIAA0907, microRNA (miR)-96-5p, and unc-13 homolog C (UNC13C). Transwell assay, flow cytometry, and colony formation assay were employed to measure the migration, invasion, apoptosis, and radiosensitivity of cells. Besides, glucose uptake, lactate production, and extracellular acidification rate (ECAR) were determined to evaluate the glycolysis ability of cells. Dual-luciferase reporter assay and RIP assay were performed to confirm the interactions among circ-KIAA0907, miR-96-5p, and UNC13C. And RNA pull-down assay was used to verify the binding degree of miR-96-5p to its targets. Moreover, UNC13C protein level was examined using western blot (WB) analysis. OSCC xenograft models were constructed to perform in vivo experiments. RESULTS: Circ-KIAA0907 was a stability circRNA with lowly expression in OSCC. Overexpressed circ-KIAA0907 could inhibit migration, invasion, and glycolysis, while promoting apoptosis and radiosensitivity in OSCC cells. In the terms of mechanism, circ-KIAA0907 could sponge miR-96-5p to regulate UNC13C expression. MiR-96-5p overexpression could reverse the inhibitory effect of circ-KIAA0907 on OSCC progression, and UNC13C knockdown also could overturn the suppressive effect of miR-96-5p inhibitor on OSCC progression. Animal experiments revealed that circ-KIAA0907 could reduce the tumor growth of OSCC by regulating the miR-96-5p/UNC13C axis. CONCLUSION: Our study suggests that circ-KIAA0907 restrains OSCC progression via the miR-96-5p/UNC13C axis, indicating that it may be a potential target for OSCC treatment. Circular RNAs (circRNAs) are a novel class of regulatory RNAs that despite being relatively abundant have only recently begun to be explored. There are many thousands of genes that appear capable of producing circRNAs, however the function of all but a handful remain to be determined. What is emerging about these highly conserved molecules is that they play important roles in biology and cancer biology in particular. The most explored function of circRNAs is as master regulators of gene expression that act to sequester or ´sponge´ other gene expression regulators, in particular miRNAs. They have also been demonstrated to function via direct modulation of transcription, and by interfering with splicing mechanisms. Although generally expressed in low abundance when compared to their linear counterparts, they are often expressed in a tissue- and developmental stage- specific manner. Coupled with their remarkable resistance to RNAse activity due to a covalent closed cyclic structure, circRNAs show great promise as novel biomarkers of cancer and other diseases. In this review we consider the current state of knowledge regarding these molecules, their synthesis, function, and association with cancer. We will also review some of the challenges that remain to be resolved if this emerging class of RNAs are really to become useful in the clinic. Circular RNAs (circRNA) have been reported as regulators involved in hepatocellular carcinoma (HCC), but their mechanism of activity remains unknown. This study performed quantitative reverse-transcription polymerase chain reaction to determine if circNFATC3 was downregulated in 46 paired HCC tissues and cell lines. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, apoptotic, and transwell assay proved that circNFATC3 can inhibit hepatoma cell proliferation, apoptosis, and migration/invasion in vitro. Mouse xenograft assay demonstrated that circNFATC3 suppressed tumor size and weight and reduced lung metastasis in vivo, and vice versa. The RNA-seq results showed that NFATC3 itself was the most significantly differentially expressed gene when circNFATC3 was manipulated, and bioinformatics and luciferase reporter assays verified circNFATC3 regulated the expression of NFATC3 by interacting with the hsa-miR-548I. Additionally, it was also indicated that the level of NFATC3 was downregulated in HCC patients also and was significantly correlated with the staging and prognosis of HCC. Moreover, both circNFATC3 and NFATC3 were shown to inhibit the phosphorylation of JNK, c-Jun, AKT, and mTOR signaling pathways. Overall, the circNFATC3 can sponge miR-548I to protect NFATC3 itself, then it regulates hepatoma cell function via the JNK, c-Jun, AKT, and mTOR signaling pathways, and the circNFATC3 can be a tumor-repressor on HCC. Circular RNA (circRNA) is a highly stable, single-stranded, closed-loop RNA that works as RNA or as a protein decoy to regulate gene expression. In humans, thousands of circRNA transcriptional products precisely express in specific developmental stages, tissues and cell types. Due to their stability and specificity, circRNAs are ideal biomarkers for cancer diagnosis and prognosis. To provide an integrated and standardized circRNA expression profile for human cancers, we performed extensive data curation across 11 technical platforms, collecting 48 expression profile data sets for 18 cancer types and amassing 860 751 expression records. We also identified 189 193 differential expression signatures that are significantly different between normal and cancer samples. All the pre-calculated expression analysis results are organized into 132 plain text files for bulk download. Our online interface, circExp, provides data browsing and search functions. For each data set, a dynamic expression heatmap provides a profile overview. Based on the processed data, we found that 52 circRNAs were consistently and differentially expressed in 20 or more processed analyses. By mapping those circRNAs to their parent protein-coding genes, we found that they may have profoundly affected the survival of 10 797 patients in the The Cancer Genome Atlas pan-cancer data set. In sum, we developed circExp and demonstrated that it is useful to identify circRNAs that have potential diagnostic and prognostic significance for a variety of cancer types. In this online and reusable database, found at http://soft.bioinfo-minzhao.org/circexp, we have provided pre-calculated expression data about circRNAs and their parental genes, as well as data browsing and searching functions. Database URL: http://soft.bioinfominzhao.org/circexp/. Circular RNAs (circRNAs) are a type of single-stranded RNA molecules that normally do not encode proteins. circRNAs are involved in many physiological processes as well as the pathogenesis of diseases. Cardiac fibrosis is increasingly recognized as a pathological force in advanced heart diseases. A growing number of studies have reported that the occurrence and development of cardiac fibrosis is closely associated with the regulation of circRNAs. This review summarizes the current understanding of circRNA biogenesis and function and will highlight the recent updates regarding the involvement of circRNAs in cardiac fibrosis, and their potential as emerging biomarkers and therapeutic targets. Circular RNA (or circRNA) is a type of single-stranded covalently closed circular RNA molecule and play important roles in diverse biological pathways. A comprehensive functionally annotated circRNA database will help to understand the circRNAs and their functions. CircFunBase is such a web-accessible database that aims to provide a high-quality functional circRNA resource including experimentally validated and computationally predicted functions. CircFunBase provides visualized circRNA-miRNA interaction networks. In addition, a genome browser is provided to visualize the genome context of circRNA. In this chapter, we illustrate examples of searching for circRNA and getting detailed information of circRNA. Moreover, other circRNA related databases are outlined. Circular RNAs (circRNAs) are found across eukaryotes and can function in post-transcriptional gene regulation. Their biogenesis through a circle-forming backsplicing reaction is facilitated by reverse-complementary repetitive sequences promoting pre-mRNA folding. Orthologous genes from which circRNAs arise, overall contain more strongly conserved splice sites and exons than other genes, yet it remains unclear to what extent this conservation reflects purifying selection acting on the circRNAs themselves. Our analyses of circRNA repertoires from five species representing three mammalian lineages (marsupials, eutherians: rodents, primates) reveal that surprisingly few circRNAs arise from orthologous exonic loci across all species. Even the circRNAs from orthologous loci are associated with young, recently active and species-specific transposable elements, rather than with common, ancient transposon integration events. These observations suggest that many circRNAs emerged convergently during evolution - as a byproduct of splicing in orthologs prone to transposon insertion. Overall, our findings argue against widespread functional circRNA conservation. Circular (circ)RNAs, naturally formed endogenous non-coding RNAs, have received extensive attention in recent years due to their special loop structures and specific function. circRNAs are formed with covalently closed continuous loops and are mainly generated by back-splicing processes or lariat introns from exons and/or introns. Usually, circRNAs are stable, abundant, and evolutionarily conserved in the cytoplasm. circRNAs often exhibit abnormal expression in different diseases, notably in human cancers, and the presence of abundant circRNAs in serum, saliva and exosomes renders them potential diagnostic or predictive biomarkers for diseases, including multiple types of cancer. Presently, certain circRNAs have been reported to function as microRNA sponges and RNA-binding protein sponges to regulate downstream gene transcription, which suggests a potential for circRNAs in cancer diagnosis, prognosis and clinical therapy. The present study assessed the latest advances in the study of circRNAs in cancer, summarized the functions of circRNAs in different types of cancer, highlighted the competing endogenous RNA function of circRNAs in the occurrence and development of human malignancies, and provided evidence for the future application of circRNAs in the diagnosis, prognosis and treatment of multiple types of cancer. Circular RNAs (circRNAs) are currently classed as non-coding RNA (ncRNA) that, unlike linear RNAs, form covalently closed continuous loops and act as gene regulators in mammals. They were originally thought to represent errors in splicing and considered to be of low abundance, however, there is now an increased appreciation of their important function in gene regulation. circRNAs are differentially generated by backsplicing of exons or from lariat introns. Unlike linear RNA, the 3' and 5' ends normally present in an RNA molecule have been joined together by covalent bonds leading to circularization. Interestingly, they have been found to be abundant, evolutionally conserved and relatively stable in the cytoplasm. These features confer numerous potential functions to circRNAs, such as acting as miRNA sponges, or binding to RNA-associated proteins to form RNA-protein complexes that regulate gene transcription. It has been proposed that circRNA regulate gene expression at the transcriptional or post-transcriptional level by interacting with miRNAs and that circRNAs may have a role in regulating miRNA function in cancer initiation and progression. circRNAs appear to be more often downregulated in tumor tissue compared to normal tissue and this may be due to (i) errors in the back-splice machinery in malignant tissues, (ii) degradation of circRNAs by deregulated miRNAs in tumor tissue, or (iii) increasing cell proliferation leading to a reduction of circRNAs. circRNAs have been identified in exosomes and more recently, chromosomal translocations in cancer have been shown to generate aberrant fusion-circRNAs associated with resistance to drug treatments. In addition, though originally thought to be non-coding, there is now increasing evidence to suggest that select circRNAs can be translated into functional proteins. Although much remains to be elucidated about circRNA biology and mechanisms of gene regulation, these ncRNAs are quickly emerging as potential disease biomarkers and therapeutic targets in cancer. Circular RNAs (circRNAs) are covalently closed RNA molecules that have been linked to various diseases, including cancer. However, a precise function and working mechanism are lacking for the larger majority. Following many different experimental and computational approaches to identify circRNAs, multiple circRNA databases were developed as well. Unfortunately, there are several major issues with the current circRNA databases, which substantially hamper progression in the field. First, as the overlap in content is limited, a true reference set of circRNAs is lacking. This results from the low abundance and highly specific expression of circRNAs, and varying sequencing methods, data-analysis pipelines, and circRNA detection tools. A second major issue is the use of ambiguous nomenclature. Thus, redundant or even conflicting names for circRNAs across different databases contribute to the reproducibility crisis. Third, circRNA databases, in essence, rely on the position of the circRNA back-splice junction, whereas alternative splicing could result in circRNAs with different length and sequence. To uniquely identify a circRNA molecule, the full circular sequence is required. Fourth, circRNA databases annotate circRNAs' microRNA binding and protein-coding potential, but these annotations are generally based on presumed circRNA sequences. Finally, several databases are not regularly updated, contain incomplete data or suffer from connectivity issues. In this review, we present a comprehensive overview of the current circRNA databases and their content, features, and usability. In addition to discussing the current issues regarding circRNA databases, we come with important suggestions to streamline further research in this growing field. Colorectal cancer (CRC) is the 3rd most common type of cancer worldwide. Late detection plays role in one-third of annual mortality due to CRC. Therefore, it is essential to find a precise and optimal diagnostic and prognostic biomarker for the identification and treatment of colorectal tumorigenesis. Covalently closed, circular RNAs (circRNAs) are a class of non-coding RNAs, which can have the same function as microRNA (miRNA) sponges, as regulators of splicing and transcription, and as interactors with RNA-binding proteins (RBPs). Therefore, circRNAs have been investigated as specific targets for diagnostic and prognostic detection of CRC. These non-coding RNAs are also linked to metastasis, proliferation, differentiation, migration, angiogenesis, apoptosis, and drug resistance, illustrating the importance of understanding their involvement in the molecular mechanisms of development and progression of CRC. In this review, we present a detailed summary of recent findings relating to the dysregulation of circRNAs and their potential role in CRC. Circular RNAs (circRNAs) are a class of conserved, endogenous non-coding RNAs that are involved in transcriptional and post-transcriptional gene regulation and are highly enriched in the nervous system. They participate in the survival and differentiation of multiple nerve cells, and may even promote the recovery of neurological function after stroke. However, their role in the inflammatory response after spinal cord injury remains unclear. In the present study, we established a mouse model of T9 spinal cord injury using the modified Allen's impact method, and identified 16,013 circRNAs and 960 miRNAs that were differentially expressed after spinal cord injury. Of these, the expression levels of circPrkcsh were significantly different between injured and sham-treated mice. We then treated astrocytes with tumor necrosis factor-α in vitro to simulate the inflammatory response after spinal cord injury. Our results revealed an elevated expression of circPrkcsh with a concurrent decrease in miR-488 expression in injured cells. We also found that circPrkcsh regulated the expression of the inflammation-related gene Ccl2. Furthermore, in tumor necrosis factor-α-treated astrocytes, circPrkcsh knockdown decreased the expression of Ccl2 by upregulating miR-488 expression, and reduced the secretion of inflammatory cytokines in vitro. These findings suggest that differentially expressed circRNAs participate in the inflammatory response after spinal cord injury and act as the regulators of certain microRNAs. Furthermore, circPrkcsh may be used as an miR-488 sponge to regulate Ccl2 expression, which might provide a new potential therapy for SCI. The study was approved by the Animal Ethics Committee of Shandong University of China (approval No. KYLL-20170303) on March 3, 2017. Author information: (1)Department of Orthopedics, The Second Hospital of Jilin University, Ziqiang Street 218, Changchun, Jilin 130041, China; Research Centre of the Second Hospital of Jilin University, Ziqiang Street 218, Changchun, Jilin 130041, China; The Engineering Research Centre of Molecular Diagnosis and Cell Treatment for Metabolic Bone Diseases of Jilin Province, Ziqiang Street 218, Changchun, Jilin 130041, China. Electronic address: chen199001207@163.com. (2)Department of Orthopedics, The Second Hospital of Jilin University, Ziqiang Street 218, Changchun, Jilin 130041, China; Research Centre of the Second Hospital of Jilin University, Ziqiang Street 218, Changchun, Jilin 130041, China; The Engineering Research Centre of Molecular Diagnosis and Cell Treatment for Metabolic Bone Diseases of Jilin Province, Ziqiang Street 218, Changchun, Jilin 130041, China. (3)Research Centre of the Second Hospital of Jilin University, Ziqiang Street 218, Changchun, Jilin 130041, China; The Engineering Research Centre of Molecular Diagnosis and Cell Treatment for Metabolic Bone Diseases of Jilin Province, Ziqiang Street 218, Changchun, Jilin 130041, China. Electronic address: yangqw@jlu.edu.cn. (4)Department of Orthopedics, The Second Hospital of Jilin University, Ziqiang Street 218, Changchun, Jilin 130041, China; The Engineering Research Centre of Molecular Diagnosis and Cell Treatment for Metabolic Bone Diseases of Jilin Province, Ziqiang Street 218, Changchun, Jilin 130041, China. Electronic address: lyz18@mails.jlu.edu.cn. (5)Department of Orthopedics, The Second Hospital of Jilin University, Ziqiang Street 218, Changchun, Jilin 130041, China; The Engineering Research Centre of Molecular Diagnosis and Cell Treatment for Metabolic Bone Diseases of Jilin Province, Ziqiang Street 218, Changchun, Jilin 130041, China. Electronic address: songyangjlu@foxmail.com. Circular RNA (circRNA) is a type of noncoding RNA that can interact with miRNAs to regulate gene expression. However, little is known concerning circRNA, which is crucial in the pathogenesis of lung cancer. To date, limited studies have explored the role of circ_0044516 in lung cancer progression. Recently, we observed that circ_0044516 expression levels were obviously elevated in lung cancer tissues and cells. A549 and SPCA1 cells were transfected with circ_0044516 siRNA. We observed that knockdown of circ_0044516 dramatically repressed cell proliferation, increased cell apoptosis, and repressed the cell cycle. Moreover, A549 and SPCA1 cell migration and invasion abilities were greatly repressed by circ_0044516 siRNA. Due to accumulating evidence demonstrating the vital role of cancer stem cells, their mechanism of involvement has drawn increasing attention in tumor progression and metastasis research. We also found that cancer stem cell properties were restrained by silencing circ_0044516 in A549 and SPC-A1 cells. Moreover, in vivo xenograft experiments showed that circ_0044516 downregulation reduced tumor growth. Mechanistically, in lung cancer and using bioinformatics, we demonstrated that circ_0044516 sponges miR-136 targeting MAT2A. Furthermore, rescue assays were carried out to identify that circ_0044516 modulates cell proliferation, invasion, and stemness by regulating miR-136 and MAT2A in lung cancer. In summary, our study revealed that the circ_0044516/miR-136/MAT2A axis is involved in lung cancer progression. Our findings may provide novel targets for diagnosis and therapeutic intervention in lung cancer patients.

Which disease is treated with Emapalumab?

Emapalumab is a human monoclonal antibody directed against interferon-γ (IFN-γ) that was approved by the Food and Drug Administration for primary hemophagocytic lymphohistiocytosis (HLH).

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INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening hyperinflammatory syndrome. Standard treatment is based on immunosuppressive, cytotoxic drugs and hematopoietic stem cell transplantation (HSCT) in primary HLH. Interferon-gamma (IFN-γ) plays a key pathogenic role. Emapalumab, a monoclonal antibody directed against IFN-γ, is the first target therapy approved for primary HLH with refractory, recurrent or progressive disease or intolerance to conventional therapy. AREAS COVERED: We reviewed the pharmacological characteristics, safety, efficacy and clinical uses of emapalumab. We summarized the results of current standard treatment based on chemo-immunosuppressive protocols and outlined the alternative options available. EXPERT OPINION: Emapalumab is an effective treatment for HLH with a good safety profile. Its efficacy was demonstrated in a phase II/III study on primary HLH pediatric patients with refractory, relapsing HLH or intolerance to first-line treatment. The use of emapalumab allowed most patients to proceed to HSCT, with a high estimated probability of survival 12 months after transplantation. The outcomes in patients who underwent transplantation compare favorably with those reported previously with either myeloablative or reduced-intensity conditioning regimens. The potential role of emapalumab in the treatment of secondary HLH and as a prevention of graft failure after HSCT deserves to be further assessed. Emapalumab, a fully human anti-IFNγ monoclonal antibody, has been approved in the US as second-line treatment of primary hemophagocytic lymphohistiocytosis (HLH) patients and has shown promise in patients with graft failure (GF) requiring a second allogeneic hematopoietic stem cell transplantation (HSCT). The blockade of IFNγ activity may increase the risk of severe infections, including fatal mycobacteriosis. We report a case of secondary HLH-related GF in the context of HLA-haploidentical HSCT successfully treated with emapalumab in the presence of concomitant life-threatening infections, including disseminated tuberculosis (TB). A 4 years old girl with Adenosine Deaminase-Severe Combined Immunodeficiency complicated by disseminated TB came to our attention for ex-vivo hematopoietic stem cell-gene therapy. After engraftment failure of gene corrected cells, she received two HLA-haploidentical T-cell depleted HSCT from the father, both failed due to GF related to concomitant multiple infections and secondary HLH. Emapalumab administration allowed to control HLH, as well as to prevent GF after a third haplo-HSCT from the mother. Remarkably, all infections improved with antimicrobial medications and disseminated TB did not show any reactivation. This seminal case supports emapalumab use for treatment of secondary HLH and prevention of GF in patients undergoing haplo-HSCT even in the presence of multiple infections, including TB. Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune system activation driven mainly by high levels of interferon gamma. The clinical presentation of HLH can have considerable overlap with other inflammatory conditions. We present a cohort of patients with therapy refractory HLH referred to our center who were found to have a simultaneous presentation of complement-mediated thrombotic microangiopathy (TMA). Twenty-three patients had therapy refractory HLH (13 primary, 4 EVB-HLH, 6 HLH without known trigger). Sixteen (69.6%) met high-risk TMA criteria. Renal failure requiring renal replacement therapy, severe hypertension, serositis, and gastrointestinal bleeding were documented only in patients with HLH who had concomitant complement-mediated TMA. Patients with HLH and without TMA required ventilator support mainly due to CNS symptoms, while those with HLH and TMA had respiratory failure predominantly associated with pulmonary hypertension, a known presentation of pulmonary TMA. Ten patients received eculizumab for complement-mediated TMA management while being treated for HLH. All patients who received the complement blocker eculizumab in addition to the interferon gamma blocker emapalumab had complete resolution of their TMA and survived. Our observations suggest co-activation of both interferon and complement pathways as a potential culprit in the evolution of thrombotic microangiopathy in patients with inflammatory disorders like refractory HLH and may offer novel therapeutic approaches for these critically ill patients. TMA should be considered in children with HLH and multi-organ failure, as an early institution of a brief course of complement blocking therapy in addition to HLH-targeted therapy may improve clinical outcomes in these patients. Primary (familial/hereditary) and secondary (non-familial/hereditary) hemophagocytic lymphohistiocytosis (HLH) are hyperinflammatory and hypercytokinemic syndromes. Secondary HLH includes infection- (eg viral/bacterial/fungal/parasitic) and non-infection- (eg collagen disease or malignancy) related diseases. Viral HLH is the major type among all age groups. Secondary viral HLH and primary HLH must be differentiated carefully because primary HLH can be associated with viral infection(s), and the outcome is dismal without a timely diagnosis and hematopoietic stem cell transplantation (HSCT). Epstein-Barr virus (EBV)-related HLH (EBV-HLH) is the most common type of viral HLH in childhood. For non-EBV-HLH, appropriate treatment of viral infection, followed by immunomodulatory agent(s) such as corticosteroids, intravenous immunoglobulin or cyclosporine A, is usually successful; however, recent SARS-CoV-2-related HLH may become life-threatening. EBV-HLH may occur heterogeneously associated with the primary infection, with chronic active EBV infection or with underlying primary HLH. Although immunomodulatory agent(s) are effective in the majority of EBV-HLH cases, management differs from that of non-EBV-HLH because severe and refractory cases may require etoposide-containing HLH-1994/2004 regimens or other experimental agents. The novel agent, emapalumab (an anti-IFN-γ monoclonal antibody) can be used to treat EBV-HLH cases to avoid the risk of secondary malignancy due to etoposide. Finally, HSCT is required for refractory EBV-HLH cases and can also be curative in some other cases. BACKGROUND: Primary hemophagocytic lymphohistiocytosis is a rare syndrome characterized by immune dysregulation and hyperinflammation. It typically manifests in infancy and is associated with high mortality. METHODS: We investigated the efficacy and safety of emapalumab (a human anti-interferon-γ antibody), administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving patients who had received conventional therapy before enrollment (previously treated patients) and previously untreated patients who were 18 years of age or younger and had primary hemophagocytic lymphohistiocytosis. The patients could enter a long-term follow-up study until 1 year after allogeneic hematopoietic stem-cell transplantation or until 1 year after the last dose of emapalumab, if transplantation was not performed. The planned 8-week treatment period could be shortened or extended if needed according to the timing of transplantation. The primary efficacy end point was the overall response, which was assessed in the previously treated patients according to objective clinical and laboratory criteria. RESULTS: At the cutoff date of July 20, 2017, a total of 34 patients (27 previously treated patients and 7 previously untreated patients) had received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40% (P = 0.02 and P = 0.005, respectively). In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis. CONCLUSIONS: Emapalumab was an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis. (Funded by NovImmune and the European Commission; NI-0501-04 and NI-0501-05 ClinicalTrials.gov numbers, NCT01818492 and NCT02069899.). Emapalumab-Izsg (hereafter referred to as emapalumab) [Gamifant®] is a monoclonal antibody directed against interferon gamma that is available as an intravenous infusion. Emapalumab is being developed by Novimmune and Swedish Orphan Biovitrum for the treatment of haemophagocytic lymphohistiocytosis (HLH). In November 2018, emapalumab received its first global approval in the USA, for the treatment of paediatric (newborn and older) and adult patients with primary HLH, who have refractory, recurrent or progressive disease or intolerance to conventional HLH therapy. Emapalumab is under regulatory review in the EU for the treatment of primary HLH. This article summarizes the milestones in the development of emapalumab leading to this first global approval for HLH in the USA. Emapalumab-Igsz (Gamifant) is a human monoclonal antibody directed against interferon-γ (IFN-γ), and the first Food and Drug Administration (FDA)-approved therapy for primary hemophagocytic lymphohistiocytosis (HLH). HLH is a disorder characterized by hypercytokinemia in the setting of unbridled immune activation, and emapalumab represents the first therapeutic developed to address the underlying pathophysiology of HLH. Emapalumab is approved for treatment of primary HLH that is refractory, recurrent, progressing or intolerant to current HLH treatments in both adult and pediatric patients. FDA approval was based on the results of a phase II/III clinical trial evaluating the safety and efficacy of emapalumab in 34 pediatric patients with primary HLH, 27 of whom were refractory to current therapies. Additional studies of emapalumab are currently ongoing in adults and other pediatric populations. Here, we will review the pharmacology, safety and efficacy of emapalumab for the treatment of HLH. Emapalumab is a fully human immunoglobulin G1 monoclonal antibody directed against interferon-γ (IFN-γ), which in November 2018 received the first global approval for the treatment of pediatric and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance to HLH therapy. This review will highlight the pathophysiology of primary HLH, the therapeutic rationale for use of IFN-γ-targeting therapy, and potential limitations to its broader use in the treatment of HLH. Interferon-gamma (IFN-γ) plays a key role in the pathophysiology of hemophagocytic lymphohistiocytosis (HLH), and available evidence also points to a role in other conditions, including aplastic anemia (AA) and graft failure following allogeneic hematopoietic stem cell transplantation. Recently, the therapeutic potential of IFN-γ inhibition has been documented; emapalumab, an anti-IFN-γ monoclonal antibody, has been approved in the United States for treatment of primary HLH that is refractory, recurrent or progressive, or in patients with intolerance to conventional therapy. Moreover, ruxolitinib, an inhibitor of JAK/STAT intracellular signaling, is currently being investigated for treating HLH. In AA, IFN-γ inhibits hematopoiesis by disrupting the interaction between thrombopoietin and its receptor, c-MPL. Eltrombopag, a small-molecule agonist of c-MPL, acts at a different binding site to IFN-γ and is thus able to circumvent its inhibitory effects. Ongoing trials will elucidate the role of IFN-γ neutralization in secondary HLH and future studies could explore this strategy in controlling hyperinflammation due to CAR T cells. Primary Hemophagocytic lymphohistiocytosis (pHLH) is a rare, life-threatening, hyperinflammatory disorder, characterized by uncontrolled activation of the immune system. Mutations affecting several genes coding for proteins involved in the cytotoxicity machinery of both natural killer (NK) and T cells have been found to be responsible for the development of pHLH. So far, front-line treatment, established on the results of large international trials, is based on the use of glucocorticoids, etoposide ± cyclosporine, followed by allogeneic hematopoietic stem cell transplantation (HSCT), the sole curative treatment for the genetic forms of the disease. However, despite major efforts to improve the outcome of pHLH, many patients still experience unfavorable outcomes, as well as severe toxicities; moreover, treatment-refractory or relapsing disease is a major challenge for pediatricians/hematologists. In this article, we review the epidemiology, etiology and pathophysiology of pHLH, with a particular focus on different cytokines at the origin of the disease. The central role of interferon-γ (IFNγ) in the development and maintenance of hyperinflammation is analyzed. The value of emapalumab, a novel IFNγ-neutralizing monoclonal antibody is discussed. Available data support the use of emapalumab for treatment of pHLH patients with refractory, recurrent or progressive disease, or intolerance to conventional therapy, recently, leading to FDA approval of the drug for these indications. Additional data are needed to define the role of emapalumab in front-line treatment or in combination with other drugs.

Do we find bacteriophages in the gut?

yes, Bacterial viruses (bacteriophages, phages) of the gut have increasingly become a focus in microbiome studies, with an understanding that they are likely key players in health and disease.

[33171009, 34560321, 33465423, 33137401, 33176253]

We are surrounded by microbes, mostly bacteria and their viruses or phages, on the inside and outside of our bodies. These bacteria in constant interactions with phages are regulating multiple functions critical to our health. Luckily, they are amenable, but we need precise tools for their safe manipulation and improving human health. Here, we argue that recent advances in single-cell technologies, culturomics and synthetic biology offer exciting opportunities to create these tools as well as revealing specific phages-bacteria interactions in the body. Since the outset of the coronavirus disease 2019 (COVID-19) pandemic, the gut microbiome in COVID-19 has garnered substantial interest, given its significant roles in human health and pathophysiology. Accumulating evidence is unveiling that the gut microbiome is broadly altered in COVID-19, including the bacterial microbiome, mycobiome, and virome. Overall, the gut microbial ecological network is significantly weakened and becomes sparse in patients with COVID-19, together with a decrease in gut microbiome diversity. Beyond the existence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the gut microbiome of patients with COVID-19 is also characterized by enrichment of opportunistic bacteria, fungi, and eukaryotic viruses, which are also associated with disease severity and presentation. Meanwhile, a multitude of symbiotic bacteria and bacteriophages are decreased in abundance in patients with COVID-19. Such gut microbiome features persist in a significant subset of patients with COVID-19 even after disease resolution, coinciding with 'long COVID' (also known as post-acute sequelae of COVID-19). The broadly-altered gut microbiome is largely a consequence of SARS-CoV-2infection and its downstream detrimental effects on the systemic host immunity and the gut milieu. The impaired host immunity and distorted gut microbial ecology, particularly loss of low-abundance beneficial bacteria and blooms of opportunistic fungi including Candida, may hinder the reassembly of the gut microbiome post COVID-19. Future investigation is necessary to fully understand the role of the gut microbiome in host immunity against SARS-CoV-2 infection, as well as the long-term effect of COVID-19 on the gut microbiome in relation to the host health after the pandemic. Bacterial viruses (bacteriophages, phages) of the gut have increasingly become a focus in microbiome studies, with an understanding that they are likely key players in health and disease. However, characterization of the virome remains largely based on bioinformatic approaches, with the impact of these viromes inferred based on a century of knowledge from aerobic phage work. Studying the phages infecting anaerobes is difficult, as they are often technically demanding to isolate and propagate. In this review, we primarily discuss the phages infecting three well-studied anaerobes in the gut: Bifidobacterium, Clostridia and Bacteroides, with a particular focus on the challenges in isolating and characterizing these phages. We contrast the lessons learned from these to other anaerobic work on phages infecting facultative anaerobes of the gut: Enterococcus and Lactobacillus. Phages from the gut do appear to adhere to the lessons learned from aerobic work, but the additional challenges of working on them has required ingenious new approaches to enable their study. This, in turn, has uncovered remarkable biology likely underpinning phage-host relationships in many stable environments. The concept of (bacterio)phage therapy is simple; target the phage to the bacterial pathogen causing disease. As phages are natural killers of bacteria, one could expect this to be an easy task. However, when it comes to phage therapy within the gut, it might not be quite that simple. Already without exogenous intervention, a multitude of phage-bacterial interactions occur within the human gut, some of which might play a direct role in disease progression. In this perspective, we aim to summarise the current understanding of phages within our gut, moving from infancy, adulthood, and then into disease progression. We then highlight recent advances in phage-based interventions, both conventional phage therapy and the progressing field of whole virome transplant.

What is the function of the protein encoded by PUMILIO1?

Pumilio1 (Pum1) has been shown to play key roles in translational regulation of target mRNAs in many systems of diverse organisms.

[32437472, 21397187, 34531333, 17024422, 34705895, 25768905, 33508364, 30289101, 16954190, 31897787, 21098481, 30256721, 25896760, 29490074, 34541851]

Posttranscriptional regulation plays a fundamental role in the biology of embryonic stem cells (ESCs). Many studies have demonstrated that multiple mRNAs are coregulated by one or more RNA-binding proteins (RBPs) that orchestrate mRNA expression. A family of RBPs, which is known as the Pumilio-FBF (PUF) family, is highly conserved among different species and has been associated with the undifferentiated and differentiated states of different cell lines. In humans, two homologs of the PUF family have been found: Pumilio 1 (PUM1) and Pumilio 2 (PUM2). To understand the role of these proteins in human ESCs (hESCs), we first assessed the influence of the silencing of PUM1 and PUM2 on pluripotency genes and found that the knockdown of Pumilio genes significantly decreased the OCT4 and NANOG mRNA levels and reduced the amount of nuclear OCT4, which suggests that Pumilio proteins play a role in the maintenance of pluripotency in hESCs. Furthermore, we observed that PUM1-and-PUM2-silenced hESCs exhibited improved efficiency of in vitro cardiomyogenic differentiation. Through an in silico analysis, we identified mRNA targets of PUM1 and PUM2 that are expressed at the early stages of cardiomyogenesis, and further investigation will determine whether these target mRNAs are active and involved in the progression of cardiomyogenesis. Our findings contribute to the understanding of the role of Pumilio proteins in hESC maintenance and differentiation. Human PUMILIO1 (PUM1) and PUMILIO2 (PUM2) are members of the PUMILIO/FBF (PUF) family that regulate specific target mRNAs posttranscriptionally. Recent studies have identified mRNA targets associated with human PUM1 and PUM2. Here, we explore the structural basis of natural target RNA recognition by human PUF proteins through crystal structures of the RNA-binding domains of PUM1 and PUM2 in complex with four cognate RNA sequences, including sequences from p38α and erk2 MAP kinase mRNAs. We observe three distinct modes of RNA binding around the fifth RNA base, two of which are different from the prototypical 1 repeat:1 RNA base binding mode previously identified with model RNA sequences. RNA-binding affinities of PUM1 and PUM2 are not affected dramatically by the different binding modes in vitro. However, these modes of binding create structurally variable recognition surfaces that suggest a mechanism in vivo for recruitment of downstream effector proteins defined by the PUF:RNA complex. Posttranscriptional regulation of cancer gene expression programs plays a vital role in carcinogenesis; identifying the critical regulators of tumorigenesis and their molecular targets may provide novel strategies for cancer diagnosis and therapeutics. Highly conserved RNA-binding protein Pumilio-1 (PUM1) regulates mouse growth and cell proliferation, propelling us to examine its role in cancer. We found human PUM1 is highly expressed in a diverse group of cancer, including prostate cancer; enhanced PUM1 expression is also correlated with reduced survival among prostate cancer patients. Detailed expression analysis in twenty prostate cancer tissues showed enhanced expression of PUM1 at mRNA and protein levels. Knockdown of PUM1 reduced prostate cancer cell proliferation and colony formation, and subcutaneous injection of PUM1 knockdown cells led to reduced tumor size. Downregulation of PUM1 in prostate cancer cells consistently elevated cyclin-dependent kinase inhibitor 1B (CDKN1B) protein expression through increased translation but did not impact its mRNA level, while overexpression of PUM1 reduced CDKN1B protein level. Our finding established a critical role of PUM1 mediated translational control, particularly the PUM1-CDKN1B axis, in prostate cancer cell growth and tumorigenesis. We proposed that PUM1-CDKN1B regulatory axis may represent a novel mechanism for the loss of CDKN1B protein expression in diverse cancers and potential targets for therapeutics development. Author information: (1)Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA. (2)Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. (3)Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA. (4)Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA. (5)Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA. (6)Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. (7)Institute for Translational Neuroscience, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA. (8)Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA. (9)Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: hzoghbi@bcm.edu. Colon cancer is the third leading cause of death worldwide and sixth in India, where it is the cause of 5.8% of the total deaths. Pumilio-1 (PUM1) is an RNA binding protein whose regulatory role is by binding to the consensus 5'UGUANAUA3' sequence on the 3'UTR of the mRNA targets and post-transcriptionally repressing their expression. This study is the first of its kind to report the expression or function of PUM1 in colon cancer. We found that PUM1 mRNA expression is high in primary and metastatic colon cancer cell lines when compared to the normal colon cell line. Immunohistochemistry analysis showed similar trend wherein compared to the normal colon tissue, PUM1 was found to be overexpressed in both adenocarcinoma and in metastatic carcinoma. This confirms the role of PUM1 in colon cancer progression. PUM1 overexpression study in HCT116 revealed that cells transfected with PUM1 plasmid show an increased rate of proliferation, migration and colony formation. Overexpressing PUM1 increases the number and size of spheroids indicating the role of PUM1 in maintaining cancer stem cells. Overall, this is the first study that has shown the role of PUM1 in colon cancer development. SummaryTranslational regulation of mRNAs is crucial for promoting various cellular and developmental processes. Pumilio1 (Pum1) has been shown to play key roles in translational regulation of target mRNAs in many systems of diverse organisms. In zebrafish immature oocytes, Pum1 was shown to bind to cyclin B1 mRNA and promote the formation of cyclin B1 RNA granules. This Pum1-mediated RNA granule formation seemed critical to determine the timing of translational activation of cyclin B1 mRNA during oocyte maturation, leading to activation of maturation/M-phase-promoting factor (MPF) at the appropriate timing. Despite its fundamental importance, the mechanisms of translational regulation by Pum1 remain elusive. In this study, we examined the phosphorylation of Pum1 as a first step to understand the mechanisms of Pum1-mediated translation. SDS-PAGE analyses and phosphatase treatments showed that Pum1 was phosphorylated at multiple sites during oocyte maturation. This phosphorylation began in an early period after induction of oocyte maturation, which preceded the polyadenylation of cyclin B1 mRNA. Interestingly, depolymerization of actin filaments in immature oocytes caused phosphorylation of Pum1, disassembly of cyclin B1 RNA granules, and polyadenylation of cyclin B1 mRNA but not translational activation of the mRNA. Overexpression of the Pum1 N-terminus prevented the phosphorylation of Pum1, disassembly of cyclin B1 RNA granules, and translational activation of the mRNA even after induction of oocyte maturation. These results suggest that Pum1 phosphorylation in the early period of oocyte maturation is one of the key processes for promoting the disassembly of cyclin B1 RNA granules and translational activation of target mRNA. Puf proteins bind RNA sequence specifically and regulate translation and stability of target mRNAs. A "code" for RNA recognition has been deduced from crystal structures of the Puf protein, human Pumilio1, where each of eight repeats binds an RNA base via a combination of three side chains at conserved positions. Here, we report the creation of seven soluble mutant proteins with predictably altered sequence specificity, including one that binds tightly to adenosine-uracil-rich element RNA. These data show that Pumilio1 can be used as a scaffold to engineer RNA-binding proteins with designed sequence specificity. The elimination of schistosomiasis, a parasitic disease caused by Schistosoma and a major source of morbidity and mortality in developing countries, faces serious challenges. Although the pumilio protein regulates the reproductive organ development in many species, its role in Schistosoma japonicum is unknown. Thus, this study investigated the function of pumilio in S. japonicum reproduction. The complete coding sequences of S. japonicum Pumilio1 (SjPum1) and SjPum2 genes were cloned and characterized. The full-length open-reading frame SjPum1 (2613 nucleotides) and SjPum2 (4479 nucleotides) genes were obtained. Bioinformatics analysis showed that those genes belonged to the PUF (pumilio and FBF) family. Quantitative polymerase chain reaction analyses revealed that SjPum1 and SjPum2 were differentially expressed throughout the S. japonicum life cycle and were highly expressed in reproductive organs. In situ hybridization results showed that mRNA expression of SjPum2 was higher than that of SjPum1 in the ovary and testis. Knocking down SjPum2 using RNA interference techniques to explore potential reproductive functions showed that compared with the control (untransfected or scrambled mRNA-transfected) worms, the morphology of both male and female reproductive organs was altered, the number of eggs produced by paired females was significantly decreased, and the transcription levels of caspase 3 and caspase 7 genes related to apoptosis were significantly increased. The transcription level of Nanos1 gene which related to reproduction was also significantly increased. Therefore, SjPum2 may play a role in the reproductive development of S. japonicum. Pumilio is a member of the highly conserved PUF family of RNA-binding proteins that function as a developmental regulator in diverse animal species. Two Pumilio genes, Pum1 and Pum2, have been identified in mammals and are found to be involved in sperm development, neuron development as well as human diseases such as neurodegeneration. Generation of animal models disrupting different parts of Pum protein could help to further dissect their physiological function. Here we described characterization and analysis of a mouse line possessing a gene trap mutation of the Pumilio1 (Pum1) gene. Mice homozygous for the mutation (Pum1(XE002)) cannot be recovered in the adult offspring, at birth or at different time points of embryonic development (E18, E14, E12). Careful analysis of preimplantation embryos showed that no homozygous blastocysts could be detected on day 3.5 of gestation. 96-hr in vitro culture of 1-cell embryos either by natural mating or in vitro fertilization between heterozygotes failed to uncover any homozygous blastocysts, suggesting an early loss of homozygous preimplantation embryos. The lack of Pum1 gene trap homozygotes suggests a role of Pum1 in very early embryonic development or fertilization. This novel animal model affecting the beginning of embryonic development could help to understand not only the genetic mechanism underlying preimplantation embryonic development but also the translational regulation in development and diseases. Human Pumilio (hPUM) is a structurally well-analyzed RNA-binding protein that has been used recently for artificial RNA binding. Structural analysis revealed that amino acids at positions 12, 13, and 16 in the repeats from R1 to R8 each contact one specific RNA base in the eight-nucleotide RNA target. The functions of the N- and C-terminal flanking repeats R1' and R8', however, remain unclear. Here, we report how the repeats contribute to overall RNA binding. We first prepared three mutants in which R1' and/or R8' were deleted and then analyzed RNA binding using gel shift assays. The assays showed that all deletion mutants bound to their target less than the original hPUM, but that R1' contributed more than R8', unlike Drosophila PUM. We next investigated which amino acid residues of R1' or R8' were responsible for RNA binding. With detailed analysis of the protein tertiary structure, we found a hydrophobic core in each of the repeats. We therefore mutated all hydrophobic amino residues in each core to alanine. The gel shift assays with the resulting mutants revealed that both hydrophobic cores contributed to the RNA binding: especially the hydrophobic core of R1' had a significant influence. In the present study, we demonstrated that the flanking R1' and R8' repeats are indispensable for RNA binding of hPUM and suggest that hydrophobic R1'-R1 interactions may stabilize the whole hPUM structure.

What is the prevalence of the inactivating AKT variant p.Pro50Thr in the Finnish population?

1.1% frequency

[28341696]

Author information: (1)Program in Medical and Population Genetics, Broad Institute, Cambridge, MA. (2)Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, MA. (3)Department of Medicine, Harvard Medical School, Boston, MA. (4)Human Genetics Center, The University of Texas MD Anderson Cancer Center and The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences, Houston, TX. (5)Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC. (6)Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI. (7)Saw Swee Hock School of Public Health, National University of Singapore, Singapore. (8)Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA. (9)Department of Genetics, Harvard Medical School, Boston, MA. (10)23andMe, Mountain View, CA. (11)The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. (12)Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K. (13)School of Computer Science, McGill University, Montreal, Canada. (14)McGill University and Génome Québec Innovation Centre, Montreal, Canada. (15)Divisions of Endocrinology and Genetics and Genomics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA. (16)Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. (17)Department of Twin Research & Genetic Epidemiology, King's College London, London, U.K. (18)Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland. (19)Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland. (20)Wellcome Trust Sanger Institute, Hinxton, U.K. (21)Norwegian Centre for Mental Disorders Research and KG Jebsen Center for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. (22)Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC. (23)Department of Molecular Biology, Massachusetts General Hospital, Boston, MA. (24)Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL. (25)Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. (26)Department of Pediatrics, University of California, San Diego, La Jolla, CA. (27)Chronic Disease Epidemiology Unit, Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland. (28)Diabetes and Endocrinology Unit, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Malmö, Sweden. (29)Genetics of Complex Traits, University of Exeter Medical School, Exeter, U.K. (30)MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, U.K. (31)Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K. (32)Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K. (33)Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland. (34)Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland. (35)Folkhälsan Research Center, Helsinki, Finland. (36)Vaasa Central Hospital, Vaasa, Finland. (37)Department of Health, National Institute for Health and Welfare, Helsinki, Finland. (38)Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere School of Medicine, Tampere, Finland. (39)Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. (40)Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland. (41)Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. (42)Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, IN. (43)Department of Medicine, Indiana University School of Medicine, Indianapolis, IN. (44)Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA. (45)Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA. (46)Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA. (47)High-Throughput Genomics, Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K. (48)National Human Genome Research Institute, National Institutes of Health, Bethesda, MD. (49)Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. (50)German Center for Diabetes Research (DZD), Neuherberg, Germany. (51)Institute of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising, Germany. (52)Department of Psychiatry, Icahn Institute for Genomics & Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY. (53)Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. (54)Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA. (55)Institute of Human Genetics, Technische Universität München, Neuherberg, Germany. (56)Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland. (57)Department of Regional Health Research, University of Southern Denmark, Odense, Denmark. (58)Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark. (59)Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark. (60)Department of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland. (61)Kuopio Research Institute of Exercise Medicine, Kuopio, Finland. (62)Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland. (63)Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, U.K. (64)Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden. (65)Department of Clinical Sciences, Lund University Diabetes Centre, and Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden. (66)Department of Nutrition, Harvard School of Public Health, Boston, MA. (67)Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden. (68)Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX. (69)Department of Medicine, The University of Texas Health Science Center, San Antonio, TX. (70)Research and Development Service, South Texas Veterans Health Care System, San Antonio, TX. (71)Department of Pediatrics, The University of Texas Health Science Center, San Antonio, TX. (72)Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden. (73)Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC. (74)Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC. (75)Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC. (76)Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC. (77)Division of Endocrinology, Boston Children's Hospital, Boston, MA. (78)Estonian Genome Center, University of Tartu, Tartu, Estonia. (79)Program in Personalized and Genomic Medicine, Department of Medicine, University of Maryland, Baltimore, MD. (80)Departments of Medicine and Genetics, Albert Einstein College of Medicine, New York, NY. (81)Faculty of Natural Sciences, University of Haifa, Haifa, Israel. (82)Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. (83)Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. (84)Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. (85)Department of Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany. (86)Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Partner Site Munich Heart Alliance, Munich, Germany. (87)Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany. (88)German Center for Diabetes Research, Partner Düsseldorf, Germany. (89)Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany. (90)Department of Epidemiology, Harvard School of Public Health, Boston, MA. (91)Department of Biostatistics, Harvard School of Public Health, Boston, MA. (92)Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. (93)Hannover Unified Biobank, Hannover Medical School, Hannover, Germany. (94)Institute of Human Genetics, Hannover Medical School, Hannover, Germany. (95)Geriatrics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden. (96)Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS. (97)Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS. (98)Department of Medicine, University of Mississippi Medical Center, Jackson, MS. (99)College of Public Services, Jackson State University, Jackson, MS. (100)Pirkanmaa Hospital District, Tampere, Finland. (101)Department of Epidemiology and Biostatistics, Imperial College London, London, U.K. (102)Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, London, U.K. (103)Department of Cardiology, Ealing Hospital NHS Trust, Southall, U.K. (104)Institute of Health Sciences, University of Oulu, Oulu, Finland. (105)Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Singapore. (106)Imperial College Healthcare NHS Trust, Imperial College London, London, U.K. (107)Department of Biomedical Science, Hallym University, Chuncheon, Republic of Korea. (108)Ministry of Health and Welfare, Seoul, Republic of Korea. (109)Center for Genome Science, Korea National Research Institute of Health, Chungcheongbuk-do, Republic of Korea. (110)Vaasa Health Care Center, Vaasa, Finland. (111)Department of Primary Health Care, Vaasa Central Hospital, Vaasa, Finland. (112)Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY. (113)Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. (114)Hypertension and Cardiovascular Disease, Department of Clinical Sciences, Lund University, Malmö, Sweden. (115)Diabetes and Cardiovascular Disease-Genetic Epidemiology, Department of Clinical Sciences, Lund University, Malmö, Sweden. (116)Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX. (117)Cardiovascular Division, Baylor College of Medicine, Houston, TX. (118)Singapore Eye Research Institute, Singapore National Eye Centre, Singapore. (119)Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. (120)Division of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore. (121)Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. (122)Office of Clinical Sciences, Centre for Quantitative Medicine, Duke-NUS Graduate Medical School Singapore, Singapore. (123)Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. (124)Cardiovascular & Metabolic Disorders Program, Duke-NUS Graduate Medical School Singapore, Singapore. (125)Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark. (126)Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark. (127)Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. (128)Department of Social Services and Health Care, Jakobstad, Finland. (129)Department of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland. (130)Steno Diabetes Center, Gentofte, Denmark. (131)Section of General Practice, Department of Public Health, Aarhus University, Aarhus, Denmark. (132)William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K. (133)Department of Haematology, University of Cambridge, Cambridge, U.K. (134)Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, U.K. (135)Department of Primary Care Health Sciences, University of Oxford, Oxford, U.K. (136)Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, U.K. (137)Institute of Cellular Medicine, University of Newcastle, Newcastle, U.K. (138)University of Exeter Medical School, Exeter, U.K. (139)Internal Medicine, Institute of Clinical Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. (140)Functional Genomics Unit, CSIR-Institute of Genomics & Integrative Biology, New Delhi, India. (141)Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China. (142)Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China. (143)Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China. (144)CSIR-Centre for Cellular & Molecular Biology, Hyderabad, India. (145)Department of Statistics, University of Oxford, Oxford, U.K. (146)Centre for Chronic Disease Control, New Delhi, India. (147)MRC-PHE Centre for Environment & Health, Imperial College London, London, U.K. (148)Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, CO. (149)Genomics and Molecular Physiology, CNRS Institut de Biologie de Lille, Lille, France. (150)Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. (151)Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Republic of Korea. (152)Department of Statistics, Seoul National University, Seoul, Republic of Korea. (153)Institute of Public Health, Department of Public Health and Primary Care, University of Cambridge, Cambridge, U.K. (154)Department of Human Genetics, McGill University, Montreal, Canada. (155)Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, Canada. (156)Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India. (157)Life Sciences Institute, National University of Singapore, Singapore. (158)Department of Statistics and Applied Probability, National University of Singapore, Singapore. (159)Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA. (160)Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA. (161)Diabetes & Obesity Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA. (162)Department of Medicine and Abdominal Center, Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. (163)Minerva Foundation Institute for Medical Research, Helsinki, Finland. (164)Institute of Clinical Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland. (165)Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland. (166)Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland. (167)Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, U.K. (168)Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, U.K. (169)Division for Molecular Medicine, Clinical Research Centre, Ninewells Hospital and Medical School, Dundee, U.K. (170)Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA. (171)Department of Medical Sciences, Uppsala University, Uppsala, Sweden. (172)Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA. (173)Center for Vascular Prevention, Danube University Krems, Krems, Austria. (174)Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia. (175)Dasman Diabetes Institute, Dasman, Kuwait. (176)Faculty of Medicine, University of Aalborg, Aalborg, Denmark. (177)Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. (178)Kuopio University Hospital, Kuopio, Finland. (179)Departments of Medicine and Human Genetics, The University of Chicago, Chicago, IL. (180)Department of Laboratory Medicine, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA. (181)Blood Systems Research Institute, San Francisco, CA. (182)Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS. (183)Department of Biostatistics, Boston University School of Public Health, Boston, MA. (184)Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA. (185)Hjelt Institute, University of Helsinki, Helsinki, Finland. (186)Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA. (187)Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA. (188)Department of Biostatistics, University of Liverpool, Liverpool, U.K. (189)Department of Biology, Massachusetts Institute of Technology, Cambridge, MA. (190)Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, U.K.

Which mutations are inhibited by Ripretinib?

Ripretinib is a novel switch-control kinase inhibitor designed to inhibit a wide range of KIT and PDGFRA mutations.

[33473249, 32859585, 33947686, 34503977, 32511981, 32804590, 34391056, 33948116, 33876372, 31085175, 31755321, 31033566, 32578014]

Gastrointestinal stromal tumor (GIST) represents a paradigm for clinically effective targeted inhibition of oncogenic driver mutations in cancer. Five drugs are currently positioned as the standard of care for the treatment of advanced or metastatic GIST patients. This is the result of continuous, deep understanding of KIT and PDGFRA GIST oncogenic drivers as well as the resistance mechanisms associated to tumor progression. However, the complexity of GIST molecular heterogeneity is an evolving field, and critical questions remain open. Specifically, the clinical benefit of approved and/or investigated targeted agents is strikingly modest at advanced stages of the disease when compared with the activity of first-line imatinib. Ripretinib is a novel switch-pocket inhibitor with broad activity against KIT and PDGFRA oncoproteins and has recently demonstrated antitumoral activity across phase I to phase III clinical trials. Therefore, ripretinib has emerged as a new standard of care for advanced, multi-resistant GIST patients. Based on this data, the Food and Drug Administration has granted in 2020 the approval of ripretinib for GIST patients after progression to imatinib, sunitinib and regorafenib. This, in turn, constitutes a major breakthrough in sarcoma drug development, as there have not been new treatment approvals in GIST for nearly a decade. Herein, we provide a critical review on the preclinical and clinical development of ripretinib in GIST. Furthermore, we seek to assess the biological and clinical impact of this new standard of care on the course of the disease, aiming to provide an insight on future treatments strategies for the next coming years. 1. The majority of gastrointestinal stromal tumors (GIST) harbor constitutively activating mutations in KIT tyrosine kinase. Imatinib, sunitinib, and regorafenib are available as first-, second-, and third-line targeted therapies, respectively, for metastatic or unresectable KIT-driven GIST. Treatment of patients with GIST with KIT kinase inhibitors generally leads to a partial response or stable disease but most patients eventually progress by developing secondary resistance mutations in KIT. Tumor heterogeneity for secondary resistant KIT mutations within the same patient adds further complexity to GIST treatment. Several other mechanisms converge and reactivate the MAPK pathway upon KIT/PDGFRA-targeted inhibition, generating treatment adaptation and impairing cytotoxicity. To address the multiple potential pathways of drug resistance in GIST, the KIT/PDGFRA inhibitor ripretinib was combined with MEK inhibitors in cell lines and mouse models. Ripretinib potently inhibits a broad spectrum of primary and drug-resistant KIT/PDGFRA mutants and is approved by the FDA for the treatment of adult patients with advanced GIST who have received previous treatment with 3 or more kinase inhibitors, including imatinib. Here we show that ripretinib treatment in combination with MEK inhibitors is effective at inducing and enhancing the apoptotic response and preventing growth of resistant colonies in both imatinib-sensitive and -resistant GIST cell lines, even after long-term removal of drugs. The effect was also observed in systemic mastocytosis (SM) cells, wherein the primary drug-resistant KIT D816V is the driver mutation. Our results show that the combination of KIT and MEK inhibition has the potential to induce cytocidal responses in GIST and SM cells. PURPOSE: Most patients with gastrointestinal stromal tumor (GIST) have activating mutations in KIT/PDGFRA and are initially responsive to tyrosine kinase inhibitors (TKI). The acquisition of secondary mutations leads to refractory/relapsed disease. This study reports the results of an analysis from the phase III INVICTUS study (NCT03353753) characterizing the genomic heterogeneity of tumors from patients with advanced GIST and evaluating ripretinib efficacy across KIT/PDGFRA mutation subgroups. PATIENTS AND METHODS: Tumor tissue and liquid biopsy samples that captured circulating tumor DNA were collected prior to study enrollment and sequenced using next-generation sequencing. Subgroups were determined by KIT/PDGFRA mutations and correlation of clinical outcomes and KIT/PDGFRA mutational status was assessed. RESULTS: Overall, 129 patients enrolled (ripretinib 150 mg once daily, n = 85; placebo, n = 44). The most common primary mutation subgroup detected by combined tissue and liquid biopsies were in KIT exon 11 (ripretinib, 61.2%; placebo, 77.3%) and KIT exon 9 (ripretinib, 18.8%; placebo, 15.9%). Patients receiving ripretinib demonstrated progression-free survival (PFS) benefit versus placebo regardless of mutation status (HR 0.16) and in all assessed subgroups in Kaplan-Meier PFS analysis (exon 11, P < 0.0001; exon 9, P = 0.0023; exon 13, P < 0.0001; exon 17, P < 0.0001). Among patients with wild-type KIT/PDGFRA by tumor tissue, PFS ranged from 2 to 23 months for ripretinib versus 0.9 to 10.1 months for placebo. CONCLUSIONS: Ripretinib provided clinically meaningful activity across mutation subgroups in patients with advanced GIST, demonstrating that ripretinib inhibits a broad range of KIT/PDGFRA mutations in patients with advanced GIST who were previously treated with three or more TKIs. BACKGROUND: Resistance to approved inhibitors of KIT proto-oncogene, receptor tyrosine kinase (KIT), and platelet-derived growth factor receptor α (PDGFRA) is a clinical challenge for patients with advanced gastrointestinal stromal tumours. We compared the efficacy and safety of ripretinib, a switch-control tyrosine kinase inhibitor active against a broad spectrum of KIT and PDGFRA mutations, with placebo in patients with previously treated, advanced gastrointestinal stromal tumours. METHODS: In this double-blind, randomised, placebo-controlled, phase 3 study, we enrolled adult patients in 29 specialised hospitals in 12 countries. We included patients aged 18 years or older who had advanced gastrointestinal stromal tumours with progression on at least imatinib, sunitinib, and regorafenib or documented intolerance to any of these treatments despite dose modifications, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Eligible patients were randomly assigned (2:1) to receive either oral ripretinib 150 mg once daily (ripretenib group) or placebo once daily (placebo group). Randomisation was done via an interactive response system using randomly permuted block sizes of six and stratified according to number of previous therapies and ECOG performance status. Patients, investigators, research staff, and the sponsor study team were masked to a patient's treatment allocation until the blinded independent central review (BICR) showed progressive disease for the patient. The primary endpoint was progression-free survival, assessed by BICR. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of study drug. Patients randomly assigned to placebo were permitted to cross over to ripretinib 150 mg at the time of disease progression. The INVICTUS study is registered with ClinicalTrials.gov, number NCT03353753, and with WHO International Clinical Trials Registry Platform, number EUCTR2017-002446-76-ES; follow-up is ongoing. FINDINGS: Between Feb 27, 2018, and Nov 16, 2018, 129 of 154 assessed patients were randomly assigned to receive either ripretinib (n=85) or placebo (n=44). At data cutoff (May 31, 2019), at a median follow-up of 6·3 months (IQR 3·2-8·2) in the ripretinib group and 1·6 months (1·1-2·7) in the placebo group, 51 patients in the ripretinib group and 37 in the placebo group had had progression-free survival events. In the double-blind period, median progression-free survival was 6·3 months (95% CI 4·6-6·9) with ripretinib compared with 1·0 months (0·9-1·7) with placebo (hazard ratio 0·15, 95% CI 0·09-0·25; p<0·0001). The most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events in the ripretinib group (n=85) included lipase increase (four [5%]), hypertension (three [4%]), fatigue (two [2%]), and hypophosphataemia (two (2%]); in the placebo group (n=43), the most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events were anaemia (three [7%]), fatigue (one [2%]), diarrhoea (one [2%]), decreased appetite (one [2%]), dehydration (one [2%]), hyperkalaemia (one [2%]), acute kidney injury (one [2%]), and pulmonary oedema (one [2%]). Treatment-related serious adverse events were reported in eight (9%) of 85 patients who received ripretinib and three (7%) of 43 patients who received placebo. Treatment-related deaths occurred in one patient in the placebo group (septic shock and pulmonary oedema) and one patient in the ripretinib group (cause of death unknown; the patient died during sleep). INTERPRETATION: Ripretinib significantly improved median progression-free survival compared with placebo and had an acceptable safety profile in patients with advanced gastrointestinal stromal tumours who were resistant to approved treatments. FUNDING: Deciphera Pharmaceuticals. PURPOSE: In advanced gastrointestinal stromal tumor (GIST), there is an unmet need for therapies that target both primary and secondary mutations of pathogenic KIT/PDGFRA oncoproteins. Ripretinib is a novel switch-control kinase inhibitor designed to inhibit a wide range of KIT and PDGFRA mutations. PATIENTS AND METHODS: This first-in-human, to our knowledge, phase I study of ripretinib (ClinicalTrials.gov identifier: NCT02571036) included a dose-escalation phase and subsequent expansion phase at the recommended phase II dose (RP2D). Eligible patients included those with advanced GIST, intolerant to or experienced progression on ≥ 1 line of systemic therapy, and other advanced malignancies. Safety, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), and preliminary antitumor activity were evaluated. RESULTS: At data cutoff (August 31, 2019), 258 patients (n = 184 GIST) were enrolled, with 68 patients in the dose-escalation phase. Three DLTs were reported: grade 3 lipase increase (n = 2; 100 mg and 200 mg twice a day) and grade 4 increased creatine phosphokinase (n = 1; 150 mg once daily). MTD was not reached (maximum dose evaluated, 200 mg twice a day); 150 mg once daily was established as the RP2D. The most frequent (> 30%) treatment-emergent adverse events in patients with GIST receiving ripretinib 150 mg once daily (n = 142) were alopecia (n = 88 [62.0%]), fatigue (n = 78 [54.9%]), myalgia (n = 69 [48.6%]), nausea (n = 65 [45.8%]), palmar-plantar erythrodysesthesia (n = 62 [43.7%]), constipation (n = 56 [39.4%]), decreased appetite (n = 48 [33.8%]), and diarrhea (n = 47 [33.1%]). Objective response rate (confirmed) of 11.3% (n = 16/142) ranging from 7.2% (n = 6/83; fourth line or greater) to 19.4% (n = 6/31; second line) and median progression-free survival ranging from 5.5 months (fourth line or greater) to 10.7 months (second line), on the basis of investigator assessment, were observed. CONCLUSION: Ripretinib is a well-tolerated, novel inhibitor of KIT and PDGFRA mutant kinases with promising activity in patients with refractory advanced GIST. Conflict of interest statement: Conflict of interest statement The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: S.G. serves in an advisory/consultancy role for AstraZeneca, Bayer, Blueprint Medicines, Daiichi Sankyo, Deciphera Pharmaceuticals, Eli Lilly and Exelixis; has a leadership role in Alliance Foundation; receives licensing royalties from Wolters Kluwer Health and is a shareholder/stockholder of Abbott Laboratories and Allergan, and her institution receives research support from Bayer, Blueprint Medicines, Deciphera Pharmaceuticals, Novartis and Pfizer. P.C. serves in an advisory role for Deciphera Pharmaceuticals, Exelixis and Zailab; has received grant funding from Deciphera Pharmaceuticals, Exelixis, Novartis and Array and has licensing royalties and owns stock in ORIC. M.C.H. serves in a consultancy role for Blueprint Medicines, Deciphera Pharmaceuticals and Novartis; receives royalties from Novartis; receives grant funding from Blueprint Medicines and Deciphera Pharmaceuticals and has received travel, accommodations, and expenses from Blueprint Medicines and Deciphera Pharmaceuticals. M.v.M. serves in an advisory/consultancy role for Blueprint Medicines, Deciphera Pharmaceuticals and Exelexis and has received travel/accommodation expenses from Deciphera Pharmaceuticals and NCCN, and her institution has received funding from Arog, ASCO, Blueprint Medicines, Deciphera Pharmaceuticals, Gradalis, Genmab, Novartis and Solarius. R.L.J. has received honoraria and serves in an advisory role for Adaptimmune Therapeutics, Athenex, Bayer, Boehringer Ingelheim, Blueprint Medicines, Clinigen Group, Daiichi Sankyo, Deciphera Pharmaceuticals, Eisai, Epizyme, Immune Design, Eli Lilly, Merck, PharmaMar, UpToDate; serves in an advisory role for Boehringer Ingelheim and Tracon and has received funding from MSD. K.G. serves in an advisory role for Daiichi Sankyo and Foundation Medicine, and her institution has received grant funding from Deciphera Pharmaceuticals. J.T. serves in an advisory/consultancy role for Blueprint Medicines, Deciphera Pharmaceuticals, Daiichi Sankyo, Epizyme and Agios, and his institution has received grant funding from Advenchen, Agios, Blueprint Medicines, Deciphera Pharmaceuticals, and Plexxikon. H.G. institution has received grant funding from Daiichi Sankyo, Five Prime, Novartis, Deciphera Pharmaceuticals, Eli Lilly, Roche, Eisai, Debio, Boehringer Ingelheim, Pfizer, Amgen and TEVA. A.A.R. institution has received grant funding from Deciphera Pharmaceuticals. M.S.G. serves in an advisory/consultancy role for Agenus, Daiichi Sankyo, Deciphera Pharmaceuticals, ImaginAB, Imaging Endpoints, RedHill Biopharma, Salarius and Tracon, and has a leadership role in CareMission; his institution has received grant funding from AbbVie, Aeglea, Agenus, Amgen, Arcus, Astex, BeiGene, Blueprint Medicines, Bristol Meyers Squibb, Calithera, CellDex, Corcept, Clovis, Daiichi Sankyo, Deciphera Pharmaceuticals, Eli Lilly, Endocyte, Five Prime, Fujifilm Pharma, Genocea, ImaginAB, Medimmune, Merck, Neon, Plexxikon, RedHill Biopharma, Revolution Medicine, Roche/Genentech, Salarius, Seattle Genetics, Serono, Syndax, SynDevRx, Tesaro, Tolero, Tracon, and Veru, and he owns stock in Medelis. N.S. serves in an advisory role for Bayer, Blueprint Medicines and Deciphera Pharmaceuticals; has stocks in Pfizer and has received grant funding from Ascentage, AstraZeneca, Daiichi Sankyo, Deciphera Pharmaceuticals, GSK and Karyopharm. J.J. is employed by Deciphera Pharmaceuticals. J.M. is employed by Deciphera Pharmaceuticals and owns stock in Deciphera Pharmaceuticals. K.S. is employed by Deciphera Pharmaceuticals and owns stock in Alberio, Alnylam, AstraZeneca, Immunogen, Karyopharm, Deciphera Pharmaceuticals, and Spectrum. Y.S. is employed by Deciphera Pharmaceuticals. R.R-S. is employed by Deciphera Pharmaceuticals and owns stock in Deciphera Pharmaceuticals and Immunogen. F.J. serves in an advisory role for Asana, Baush Health, Cardiff Oncology, Deciphera, Guardant Health, Ideaya, IFM Therapeutics, Immunomet, Illumina, Jazz Pharmaceuticals, Novartis, PureTech Health, Sotio and Synlogic and has stocks in Cardiff Oncology, and his institution receives funding from Agios, Asana, Astellas, Astex, Bayer, Bicara, BioMed Valley Discoveries, Bioxcel, Bristol Myers Squibb, Deciphera, Fujifilm Pharma, Genentech, Ideaya, JS InnoPharm, Eli Lilly, Merck, Novartis, Novellus, Plexxikon, Proximagen, Sanofi, Sotio, SpringBank Pharmaceuticals, SQZ Biotechnologies, Synlogic, Synthorx and Symphogen. Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal (GI) tract yet represent the most common GI sarcomas. Most GISTs are driven by activating mutations of the KIT and/or PDGFRA genes. Prior to the development of tyrosine kinase inhibitors (TKIs), GISTs were associated with a poor prognosis because conventional cytotoxic chemotherapy was relatively ineffective. However, TKIs that inhibit the most common driver mutations in KIT or PDGFRA have revolutionized the treatment of GISTs over the past two decades. Notwithstanding, ongoing management challenges relate to the development of secondary mutations in these genes, resulting in tumor progression. Due to both the intra- and inter-patient heterogeneity of these secondary mutations in GISTs, optimal treatment requires an agent that blocks as many mutant genes as possible. Ripretinib - a novel switch-control TKI - inhibits many of the most common primary and secondary activating KIT and PDGFRA mutants involved in GIST progression through a dual mechanism of action. In the pivotal INVICTUS phase III trial, patients with advanced GIST that had progressed on at least imatinib, sunitinib, and regorafenib and who received ripretinib experienced significantly longer progression-free survival (primary endpoint) as well as prolongation of overall survival, compared with those receiving placebo. Treatment with ripretinib was associated with durable improvements in quality-of-life indices and a manageable toxicity profile. The most frequent side effects were common to the class of TKIs used in the management of GIST. These results led to the approval of ripretinib for treatment of advanced GIST in adults who have received three or more TKIs, including imatinib. Ripretinib is also under investigation in the second-line treatment of advanced GIST in a phase III trial (INTRIGUE) comparing ripretinib with sunitinib in patients with advanced GIST after treatment with imatinib. PLAIN LANGUAGE SUMMARY: Use of ripretinib for the treatment of gastrointestinal stromal tumors (GISTs) Gastrointestinal stromal tumors (GISTs) are a rare type of tumor most commonly located in the stomach and small intestine but can develop anywhere throughout the gastrointestinal tract. The symptoms of GISTs vary in extent depending on location of the primary tumor and include a feeling of fullness, abdominal pain, intestinal bleeding, and fatigue. Since these symptoms are nonspecific, making a diagnosis can be challenging. Most GISTs carry initial mutations in genes that control specific enzymes called tyrosine kinases. Historically, treatment of GISTs was limited because traditional chemotherapy is ineffective against these tumors. However, with the introduction of drugs that inhibit tyrosine kinases [i.e., tyrosine kinase inhibitors (TKIs)], survival has been extended substantially. However, many GISTs go on to develop secondary mutations that render them resistant to a given TKI. Prior to the approval of ripretinib, four TKIs were available for the treatment of GIST: imatinib; sunitinib; regorafenib; and, recently, avapritinib. Each drug is used until resistance develops or patients are unable to tolerate the side effects of treatment, after which the next drug is started. Ripretinib was recently approved by the FDA as the fourth drug in the usual treatment sequence recommended for patients with advanced GIST who have progressed (or are treatment intolerant) after receiving three or more TKIs, including imatinib. Approval of ripretinib was based on the results of the INVICTUS trial, which demonstrated that the drug significantly improves the time patients have without progression of the disease or death compared with placebo. The most common side effects related to ripretinib were hair loss, muscle pain, nausea, fatigue, hand-foot syndrome, and diarrhea, although most events were not very severe. Ripretinib is being further studied as the second TKI used in patients with GIST who have progressed on or could not tolerate first-line treatment with imatinib. Gastrointestinal stromal tumors (GIST) are rare neoplasms arising from the interstitial cell of Cajal in the gastrointestinal tract. Two thirds of GIST in adult patients have c-Kit mutation and smaller fractions have platelet derived growth factor receptor alpha (PDGFRA) mutation. Surgery is the only curative treatment for localized disease. Imatinib improves survival when used adjuvantly and in advanced disease. Several targeted therapies have also improved survival in GIST patients after progression on imatinib including sunitinib and regorafenib. Recently, United States Federal and Drug Administration (FDA) approved two new tyrosine kinase inhibitors for the treatment of heavily pretreated advanced/unresectable GIST including avapritinib (a selective inhibitor for PDGFRA exon 18 mutation including D842V mutations) and ripretinib (a broad-spectrum kinase inhibitor of c-Kit and PDGFRA). In this article, we will provide a comprehensive review of GIST including the current standard of care treatment and exploring future paradigm shifts in therapy. Ripretinib (DCC-2618) was designed to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloproliferative neoplasms, particularly in gastrointestinal stromal tumors (GISTs), in which the heterogeneity of drug-resistant KIT mutations is a major challenge. Ripretinib is a "switch-control" kinase inhibitor that forces the activation loop (or activation "switch") into an inactive conformation. Ripretinib inhibits all tested KIT and PDGFRA mutants, and notably is a type II kinase inhibitor demonstrated to broadly inhibit activation loop mutations in KIT and PDGFRA, previously thought only achievable with type I inhibitors. Ripretinib shows efficacy in preclinical cancer models, and preliminary clinical data provide proof-of-concept that ripretinib inhibits a wide range of KIT mutants in patients with drug-resistant GISTs. Author information: (1)The University of Toledo College of Medicine & Life Sciences, Toledo, OH 43606, USA. (2)ProMedica Health System, Toledo, OH 43606, USA. (3)West German Cancer Center, Deparment of Medical Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. (4)Centre Léon Bérard, Unicancer, LYRICAN and Université Claude Bernard Lyon 1, Lyon, France. (5)Leiden University Medical Center, Leiden, The Netherlands. (6)Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (7)University Hospitals Leuven, Department of General Medical Oncology, Leuven Cancer Institute, Leuven, Belgium. (8)Fox Chase Cancer Center, Philadelphia, PA 19111, USA. (9)Department of Epidemiology & Preventive Medicine, School of Public Health & Preventive Medicine, Monash University & Department of Medical Oncology Alfred Health, Melbourne, Australia. (10)Deciphera Pharmaceuticals, LLC, Waltham, MA 02451, USA. (11)Portland VA Health Care System & OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA. Ripretinib (QINLOCK™) is a novel type II tyrosine switch control inhibitor being developed by Deciphera Pharmaceuticals for the treatment of KIT proto-oncogene receptor tyrosine kinase (KIT)-driven and/or platelet derived growth factor receptor A (PDGFRA)-driven cancers, including gastrointestinal stromal tumour (GIST). Ripretinib inhibits KIT and PDGFRA kinase, including wild-type, primary and secondary mutations, as well as other kinases, such as PDGFRB, TIE2, VEGFR2 and BRAF. In May 2020, oral ripretinib received its first approval in the USA for the treatment of adult patients with advanced GIST who have received prior treatment with ≥ 3 kinase inhibitors, including imatinib. The US FDA, Health Canada and the Australian Therapeutic Goods Administration collaborated on the review of the ripretinib new drug application in this indication as part of Project Orbis; regulatory review in Australia and Canada is ongoing. Clinical development for GIST, solid tumours and systemic mastocytosis is underway in several countries worldwide. This article summarizes the milestones in the development of ripretinib leading to this first approval for the treatment of advanced GIST.

What is known about the PYHIN proteins?

The human PYHIN proteins, AIM2, IFI16, IFIX, and MNDA, are critical regulators of immune response, transcription, apoptosis, and cell cycle. Absent in melanoma 2 (AIM2) is a member of the PYHIN (pyrin and HIN domain-containing protein) family with important roles in sensing double-stranded DNA (dsDNA) and assembling the AIM2 inflammasome, which has wide-ranging, pro-inflammatory and pro-pyroptotic properties.

[25665578, 32946794, 28931603, 29120406, 32760121]

Absent in melanoma 2 (AIM2) is a member of the PYHIN (pyrin and HIN domain-containing protein) family with important roles in sensing double-stranded DNA (dsDNA) and assembling the AIM2 inflammasome, which has wide-ranging, pro-inflammatory and pro-pyroptotic properties. The AIM2 inflammasome can become activated in atherosclerotic plaque, abdominal aortic aneurysm wall and injured myocardium, and its activation is tightly regulated by a variety of atherogenic factors. Activation of the AIM2 inflammasome has close links to the progression of several cardiovascular diseases. This review will summarize the current knowledge of AIM2 biology, providing the latest insights into the mechanisms and contributions of atherogenic factors to AIM2 inflammasome activation. In addition, we will also explore crosstalk between AIM2 and the pathologies of atherosclerosis, abdominal aortic aneurysm, myocardial infarction and heart failure. A better understanding of the pathological roles of AIM2 in these disorders will be helpful in developing novel therapeutic approaches. Pattern recognition receptors such as nucleotide-binding oligomerization domain (NOD)-containing protein receptors (NLRs) and the pyrin and hematopoitic interferon-inducible nuclear protein (HIN) domain (PYHIN) receptors initiate the inflammatory response following cell stress or pathogenic challenge. When activated, some of these receptors oligomerize to form the structural backbone of a signalling platform known as an inflammasome. Inflammasomes promote the activation of caspase-1 and the maturation of the proinflammatory cytokines, interleukin (IL)-1β and IL-18. The gut dysregulation of the inflammasome complex is thought to be a contributing factor in the development of inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD). The importance of inflammasomes to intestinal health has been emphasized by various inflammasome-deficient mice in dextran sulphate sodium (DSS) models of intestinal inflammation and by the identification of novel potential candidate genes in population-based human studies. In this review, we summarise the most recent findings with regard to the formation, sensing, and regulation of the inflammasome complex and highlight their importance in maintaining intestinal health.

What class of drugs is commonly associated with Drug-induced interstitial lung disease (DIILD)?

[' Numerous agents including cytotoxic and noncytotoxic drugs have the potential to cause pulmonary toxicity.']

[1327232, 22189216, 20298401, 31963908, 22896776, 2185802, 31584970, 32598798, 10992015, 34177523, 29631763, 28050004, 30521972, 30326612, 24231065, 17545850, 8765915, 32874590]

The problem of the drug induced pulmonary toxicity (cytotoxic and non-cytotoxic drugs) is discussed. This domain of modern pathology is in continuous development, although yet insufficiently delineated. The essential pathogenic mechanisms are presented as well as the main histopathological lesions (i.e., interstitial pneumonia and pulmonary fibrosis). The usual lesional aspects specific to certain drugs are also reviewed. For the principal chemical substances in this category, the clinical and radiological aspects are given, also the various treatment indicated, the evolution and the prognosis of the drugs induced pulmonary disease. A number of anticancer drugs, especially molecularly-targeted drugs, have been developed every year. Drug-induced interstitial lung disease(DILD)is a common adverse event associated with molecularly-targeted drugs, and it is therefore important to obtain information about the DILD risks of each drug. Recently, all-case surveillance of new drugs have been carried out frequently as post-marketing surveillance. This allows one to understand the accurate status of DILD, such as its incidence rate and prognosis. The diagnosis of DILD is often difficult because there is no specific diagnostic approach. It is necessary to distinguish DILD from various other diseases including infectious disease, cancer progression, congestive heart failure, etc. Among those, respiratory infection is an important disease in the differential diagnosis of DILD, because patients receiving anticancer drugs are likely to be susceptible to infection. As for the treatment of DILD, the general rule is the discontinuation of the offending drug, and if necessary, the administration of corticosteroid is indicated. However, an exceptional treatment is required for DILD caused by mTOR inhibitor, for which we must take account of the adequate management. With an increasing number of therapeutic drugs, the list of drugs that is responsible for severe pulmonary disease also grows. Many drugs have been associated with pulmonary complications of various types, including interstitial inflammation and fibrosis, bronchospasm, pulmonary edema, and pleural effusions. Drug-induced interstitial lung disease (DILD) can be caused by chemotherapeutic agents, antibiotics, antiarrhythmic drugs, and immunosuppressive agents. There are no distinct physiologic, radiographic or pathologic patterns of DILD, and the diagnosis is usually made when a patient with interstitial lung disease (ILD) is exposed to a medication known to result in lung disease. Other causes of ILD must be excluded. Treatment is avoidance of further exposure and systemic corticosteroids in patients with progressive or disabling disease. Cytotoxic agents may cause interstitial or eosinophilic pneumonitis, alveolar proteinosis, pulmonary venous occlusive disease, pulmonary fibrosis, pneumothorax, or pulmonary oedema. These agents may also potentiate lung injury caused by radiotherapy or high oxygen fractions in inspired air. Clinical and roentgenological features of lung damage induced by cytotoxic drugs are usually non-specific, and differential diagnoses include progression of the malignant disease and a plethora of opportunistic infections. Monitoring of blood gases and carbon monoxide transfer factor may facilitate early detection of drug induced lung injury. Fiberoptic bronchoscopy, bronchoalveolar lavage, transbronchial biopsy, or open lung biopsy may be necessary for reliable diagnosis. Early detection of lung damage and immediate withdrawal of the responsible agent(s) are essential. Steroids may be of therapeutic value in some patients. Treatment of patients often includes the administration of medications and sometimes radiation. While the intent is to treat an underlying condition, in some cases, adverse effects occur due to these agents. Most of these adverse effects are mild, however, some can be severe and life-threatening. Furthermore, while these effects are often reversible upon cessation of exposure, especially if the inciting agent is recognized and withdrawn early, others might be permanent or even progressing. Most common histopathologic findings in drug-induced interstitial lung disease include nonspecific interstitial pneumonia (cellular and/or fibrotic), organizing pneumonia with or without bronchiolitis, eosinophilic pneumonia, pulmonary edema, diffuse alveolar damage, hypersensitivity pneumonitis, granulomatous interstitial lung disease, chronic bronchiolitis, and pulmonary hemorrhage. Pulmonary vascular changes or constrictive bronchiolitis can also occur. Drugs that are more commonly associated with lung toxicity include nitrofurantoin, amiodarone, and chemotherapeutic agents such as bleomycin and methotrexate. More recently introduced immune modulating agents including rituximab and immune checkpoint inhibitors such as anti-CTLA4, anti-PD-1 and anti-PD-L1 agents have also been associated with adverse effects in the lung. Radiation therapy to the chest can trigger acute or chronic lung toxicity. While newer radiation techniques are aimed to decrease and minimize side effects other risk factors such as additional chemotherapy, oxygen, and older age may be rising. Foreign substances such as talc, hydrogel, and medical devices such as hydrophilic polymer coated catheter may rarely also lead to pulmonary complications. It is important that clinicians and pathologists are aware of these potential adverse effects of drugs, radiation and medical devices and raise the possibility of drug-induced lung toxicity after exclusion of other differential diagnoses. It is the role of the clinician to provide the pathologist with an appropriate drug history. Early intervention to a drug-induced lung toxicity might prevent progression of side effects and permanent changes. Although pneumothorax has been reported to be a major pulmonary adverse event in patients treated with pazopanib, a multikinase inhibitor, drug-induced interstitial lung disease (DILD) has not been reported. A 74-year-old Japanese man who received pazopanib for the treatment of femoral leiomyosarcoma and lung metastasis presented with dyspnea and fatigue. He had mild interstitial pneumonia when pazopanib treatment was initiated. Chest computed tomography revealed progressive bilateral ground-glass opacity (GGO) and traction bronchiectasis. We diagnosed DILD due to pazopanib. The patient's pazopanib treatment was interrupted and a steroid was administered. The symptoms and GGO were improved with treatment. Physicians should be aware of DILD due to pazopanib in patients with pre-existing interstitial lung disease. Author information: (1)Arthritis Research UK Centre for Epidemiology, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PL, UK. sarah.skeoch@manchester.ac.uk. (2)Royal National Hospital for Rheumatic Diseases, Royal United Hospitals Bath NHS Foundation Trust, Bath BA1 1RL, UK. sarah.skeoch@manchester.ac.uk. (3)Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK. nickweatherley@doctors.org.uk. (4)Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK. A.J.Swift@sheffield.ac.uk. (5)Arthritis Research UK Centre for Epidemiology, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PL, UK. Alexander.Oldroyd@manchester.ac.uk. (6)Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK. c.johns@sheffield.ac.uk. (7)North West Lung Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M6 8HD, UK. conalhayton@doctors.org.uk. (8)Leeds Institute of Rheumatic and Musculoskeletal Medicine, NIHR Leeds Biomedical Research Centre, University of Leeds, Leeds LS2 9JT, UK. A.Giollo@leeds.ac.uk. (9)Rheumatology Unit, Department of Medicine, University of Verona, 37134 Verona, Italy. A.Giollo@leeds.ac.uk. (10)Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK. J.M.Wild@sheffield.ac.uk. (11)Bioxydyn Limited, Rutherford House, Manchester Science Park, Manchester M15 6SZ, UK. john.waterton@manchester.ac.uk. (12)Centre for Imaging Sciences, Division of Informatics Imaging & Data Sciences, School of Health Sciences, Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PL, UK. john.waterton@manchester.ac.uk. (13)Leeds Institute of Rheumatic and Musculoskeletal Medicine, NIHR Leeds Biomedical Research Centre, University of Leeds, Leeds LS2 9JT, UK. M.Buch@leeds.ac.uk. (14)Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PL, UK. Kim.Linton@manchester.ac.uk. (15)Arthritis Research UK Centre for Epidemiology, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PL, UK. Ian.Bruce@manchester.ac.uk. (16)The Kellgren Centre for Rheumatology, NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M6 8HD, UK. Ian.Bruce@manchester.ac.uk. (17)North West Lung Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M6 8HD, UK. Colm.Leonard@nice.org. (18)Academic Directorate of Respiratory Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK. Stephen.Bianchi@sth.nhs.uk. (19)North West Lung Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M6 8HD, UK. nazia.chaudhuri@nhs.net.

What pathological phenotype could potentially concomitant pomegranate juice and rosuvastatin use cause?

Concomitant use of rosuvastatin and pomegranate juice has been hypothesized to be associated with the development of rhabdomyolysis in a case report.

[16923466]

This 48-year-old man with possible underlying myopathy was successfully treated with ezetimibe 10 mg/day and rosuvastatin 5 mg every other day for 17 months. Three weeks before presentation, he began drinking pomegranate juice (200 ml twice weekly). He presented urgently with thigh pain and an elevated serum creatine kinase level (138,030 U/L, normal < 200 U/L). In conclusion, because both grapefruit and pomegranate juice are known to inhibit intestinal cytochrome P450 3A4, this report suggests that pomegranate juice may increase the risk of rhabdomyolysis during rosuvastatin treatment, despite the fact that rosuvastatin is not known to be metabolized by hepatic P450 3A4.

Is tirabrutinib effective for lymphoma?

Yes, tirabrutinib appears to be effective for lymphoma. It was approved in Japan for the treatment of recurrent or refractory primary central nervous system lymphoma.

[33902692, 34615748, 32382949, 32583848, 33851691, 30815927]

Tirabrutinib (ONO/GS-4059; Ono Pharmaceutical) is a newly developed drug that selectively and irreversibly inhibits Bruton's tyrosine kinase (BTK) and has been approved in Japan for treating relapsed/refractory primary central nervous system lymphoma (PCNSL). However, its therapeutic effect is yet to be verified at the pathological level in human patients. A 64-year-old patient with recurrent PCNSL enrolled in the phase I/II clinical trial of tirabrutinib, a second-generation BTK inhibitor designed for treating relapsed/refractory PCNSL. The left cerebellum lesions on magnetic resonance imaging disappeared one month after tirabrutinib treatment. The patient died because of suspected pneumocystis pneumonia and acute exacerbation of interstitial pneumonia 43 days after starting tirabrutinib. An autopsy confirmed no viable tumor cells in the entire brain, including the left cerebellum lesion, confirming complete obliteration of tumor cells by tirabrutinib. This letter pathologically confirms the effect of tirabrutinib on relapsed/refractory PCNSL for the first time in humans.Trial registration: JapicCTI-173646. Registered 14 July 2017, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-173646. Management of primary central nervous system lymphoma (PCNSL) includes induction and consolidation therapies in newly diagnosed patients, as well as second-line therapy in relapsed or refractory patients. The current standard-of-care induction therapy involves methotrexate (MTX)-based multi-agent immunochemotherapy with rituximab, methotrexate, procarbazine, and vincristine. Deferral or dose reduction of radiation therapy is considered in consolidation therapy, especially in elderly patients who carry a high risk of radiation-induced delayed neurotoxicity. Since elderly patients comprise the main population of PCNSL, minimally toxic treatments that are effective and feasible for them are strongly needed. For second-line therapy, rechallenge using MTX-based chemotherapy (in patients with a prior durable response to MTX-based chemotherapy) or radiation therapy is considered. Bruton's tyrosine kinase inhibitor tirabrutinib (for relapsed and refractory PCNSL) and high-dose chemotherapy with autologous stem cell transplantation support using thiotepa and busulfan (BuTT) were approved by the Japanese Ministry of Health and Welfare in March 2020 and has recently become available for clinical practice. While these novel treatments seem promising, the optimal use of these treatments along with the standard-of-care therapy of PCNSL should be defined and investigated in clinical trials. Tirabrutinib (Velexbru®) is an orally administered, small molecule, Bruton's tyrosine kinase (BTK) inhibitor being developed by Ono Pharmaceutical and its licensee Gilead Sciences for the treatment of autoimmune disorders and haematological malignancies. Tirabrutinib irreversibly and covalently binds to BTK in B cells and inhibits aberrant B cell receptor signalling in B cell-related cancers and autoimmune diseases. In March 2020, oral tirabrutinib was approved in Japan for the treatment of recurrent or refractory primary central nervous system lymphoma. Tirabrutinib is also under regulatory review in Japan for the treatment of Waldenström's macroglobulinemia and lymphoplasmacytic lymphoma. Clinical development is underway in the USA, Europe and Japan for autoimmune disorders, chronic lymphocytic leukaemia, B cell lymphoma, Sjogren's syndrome, pemphigus and rheumatoid arthritis. This article summarizes the milestones in the development of tirabrutinib leading to the first approval of tirabrutinib for the treatment of recurrent or refractory primary central nervous system lymphoma in Japan. BACKGROUND: The safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton's tyrosine kinase inhibitor, were evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL). METHODS: Patients with relapsed/refractory PCNSL, Karnofsky performance status ≥70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) within 28 days using a 3 + 3 dose escalation design and with 480 mg q.d. under fasted conditions in phase II. RESULTS: Forty-four patients were enrolled; 20, 7, and 17 received tirabrutinib at 320, 480, and 480 mg under fasted conditions, respectively. No DLTs were observed, and the maximum tolerated dose was not reached at 480 mg. Common grade ≥3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg q.d. had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). Independent review committee assessed overall response rate (ORR) at 64%: 60% with 5 complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100% with 4 CR/CRu at 480 mg, and 53% with 6 CR/CRu at 480 mg under fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1, and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. Median overall survival was not reached. ORR was similar among patients harboring CARD11, MYD88, and CD79B mutations, and corresponding wild types. CONCLUSION: These data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL. TRIAL REGISTRATION: JapicCTI-173646. Bruton tyrosine kinase (BTK) plays an important role in the B-cell receptor (BCR) signaling pathway by mediating proliferation, migration and adhesion in B-cell malignancies. Therefore, the components of BCR signaling, especially BTK, are considered to be attractive therapeutic targets. Ibrutinib, a first-in-class BTK inhibitor, has been approved for the treatment of several types of B-cell malignancies worldwide. However, ibrutinib has off-target activities on non-BTK kinase that are related to adverse effects or might translate into clinical limitations. To overcome these limitations, more specific BTK inhibitors are needed. Tirabrutinib hydrochloride (tirabrutinib) is a potent, highly selective, irreversible oral inhibitor of BTK. Tirabrutinib irreversibly and covalently binds to BTK in B cells and has demonstrated effective in vitro cytotoxicity in many types of B-cell malignancies and in vivo antitumor activity in mouse models. Here, we provide a comprehensive review of the preclinical and clinical activity of tirabrutinib, a drug approved in Japan for relapsed or refractory primary central nervous system lymphoma and all lines of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma. Conflict of interest statement: W. Munakata has received grants from Ono Pharmaceutical Co., Ltd. K. Ando has received grants from Ono Pharmaceutical Co., Ltd. K. Hatake has received grants from Ono Pharmaceutical Co., Ltd. and Chugai Pharmaceutical Co., Ltd. N. Fukuhara has received grants from Ono Pharmaceutical Co., Ltd. T. Kinoshita has received grants and/or personal fees from Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Solasia Pharma K.K., Ono Pharmaceutical Co., Ltd., Gilead Sciences, Inc., MSD, Zenyaku Kogyo, Bristol‐Myers Squibb, Kyowa Hakko Kirin Co., Ltd., Eisai Co., Ltd., and Janssen Pharmaceutica. S. Fukuhara has received grants from Ono Pharmaceutical Co., Ltd. Y. Shirasugi has received personal fees from Novartis. M. Yokoyama has received grants from Ono Pharmaceutical Co., Ltd. and personal fees from Chugai Pharmaceutical Co., Ltd. S. Ichikawa has received grants from Ono Pharmaceutical Co., Ltd. K. Ohmachi has received grants from Ono Pharmaceutical Co., Ltd. and personal fees from Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., Pfizer Inc., Takeda Pharmaceutical Co., Ltd., and Meiji Seika Pharma Co., Ltd. N. Gion is an employee of Ono Pharmaceutical Co., Ltd., and has received personal fees. A. Aoi is an employee of Ono Pharmaceutical Co., Ltd., and has received personal fees. K. Tobinai has received grants and/or personal fees from Ono Pharmaceutical Co., Ltd., Celgene, Zenyaku Kogyo, HUYA Bioscience International LLC, Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mundipharma, Janssen Pharmaceutical, Kyowa Hakko Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., GlaxoSmithKline, and AbbVie Inc.

Is covid-19 induced anosmia caused by disruption of nuclear architecture?

Yes. Disruption of nuclear architecture is a cause of COVID-19 induced anosmia.

[33594368]

Author information: (1)Mortimer B. Zuckerman Mind, Brain and Behavior Institute, Columbia University, New York, NY 10027, USA. (2)Department of Genetics and Development, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA. (3)Department of Microbiology, Icahn School of Medicine at Mt. Sinai, New York, NY, 10029, USA. (4)Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mt. Sinai, New York, NY, 10029, USA. (5)Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, New York, NY, 10029, USA. (6)Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mt. Sinai, New York, NY, 10029, USA. (7)Baylor Genetics, 2450 Holcombe Blvd, Houston, TX, 77021, USA. (8)Department of Biological Sciences, Columbia University New York, NY, 10027, USA. (9)Department of Cell Biology and Human Anatomy, School of Medicine, University of California at Davis, Davis, CA 95616, USA. (10)Department of Pathology and Cell Biology, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA. (11)Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, 10029, USA. (12)Department of Otolaryngology- Head and Neck Surgery, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.

What is the mechanism of action of Toripalimab?

Toripalimab is IgG4 monoclonal antibody targeting PD-1, which has been approved for treatment of patients with metastatic melanoma after previous systemic therapy.

[32487680, 30805896, 34532490, 32406293, 32224416, 32589350, 34603452, 32874831, 31403867, 32943323, 31236579, 30892132, 34521188, 34504425, 34632814, 32445174, 33492986, 34678907, 34894461]

Toripalimab, a recombinant, humanized programmed death receptor-1 (PD-1) monoclonal antibody that binds to PD-1 and prevents binding of PD-1 with programmed death ligands 1 (PD-L1) and 2 (PD-L2), is being developed by Shanghai Junshi Bioscience Co., Ltd in China for the treatment of various cancers. In December 2018, based on positive efficacy results of a phase 2 trial and safety data from several clinical studies, toripalimab received conditional approval in China for the treatment of unresectable or metastatic melanoma that has failed previous systemic therapy. This article summarizes the milestones in the development of toripalimab leading to this first global approval for the treatment of unresectable or metastatic melanoma. Patients diagnosed with advanced adenoid cystic carcinoma (ACC) with metastasis to the lung generally have poor prognosis when they exhibit resistance to conventional therapies. Programmed cell-death protein 1 (PD-1) inhibitors, a type of Immune checkpoint inhibitors (ICI), have shown good response in the treatment of various types of malignant tumors; however, objective response rates of monotherapy for advanced ACC are low. Anlotinib, a novel, orally managed tyrosine kinase inhibitor, that targets vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and c-kit, has appeared great adequacy in treating numerous sorts of malignant tumors, particularly tumors with lung metastases. Here, we have presented a case of refractory ACC with lung metastases that was reduced after combinatorial treatment using the immune checkpoint inhibitor (ICI) toripalimab and anti-angiogenesis agent anlotinib. The patient achieved a reduction in lung metastases by chest computed tomography (CT) examination, with an outcome of stable disease (SD) of 5 months, a significant decrease in the levels of peripheral blood cytokines interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α), as well as good tolerance without noteworthy unfavorable reactions, indicating that the combined therapy of toripalimab and anlotinib may be utilized in the management of advanced ACC. INTRODUCTION: Immune therapies have dramatically changed the treatment landscape for melanoma in the past decade. Ipilimumab, nivolumab, and pembrolizumab have been approved by U.S. Food and Drug Administration for the treatment of metastatic melanoma sequentially. Toripalimab, a humanized IgG4 monoclonal antibody against programmed cell death protein-1 (PD-1), was approved by National Medical Product Administration in China in 2018 as second-line therapy for metastatic melanoma. AREAS COVERED: This is a comprehensive review of the literature and studies of toripalimab in melanoma, including clinical trials and translational research. EXPERT OPINION: Toripalimab is not inferior to pembrolizumab as a second-line therapy for metastatic melanoma. Prospective validated predictive markers are lacking. Programmed cell death ligand 1 expression and tumor mutational burden are two common recognized biomarkers, but the predictability of these markers requires additional improvement. A number of studies have confirmed that PD-1 inhibitors, including toripalimab, are not as effective in mucosal and acral melanomas as in non-acral cutaneous subtype. Toripalimab in combination with tyrosine kinase inhibitor axitinib has shown a promising result for metastatic mucosal melanoma. It is crucial to explore the mechanisms underlying the varying biological behavior of melanoma subtypes, which may also provide clues of innate and acquired resistance to PD-1 blockade. BACKGROUND: Several programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) antibodies have been approved for cancer treatment worldwide. Their pharmacokinetic and pharmacodynamic characteristics have been reported mainly in western countries, but related data in Chinese patients are limited. This study was conducted to investigate the safety, efficacy, pharmacokinetics, and pharmacodynamics of an anti-PD-1 antibody, toripalimab, in Chinese patients. METHODS: A single-center phase I study was conducted in Sun Yat-sen University Cancer Center. Eligible patients were adults with histologically confirmed, treatment-refractory, advanced, solitary malignant tumors. Toripalimab was intravenously infused every 2 weeks in dose-escalating cohorts at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg. The study followed standard 3 + 3 design. RESULTS: Between 15th March 2016 and 27th September 2016, 25 patients were enrolled, of whom 3 (12.0%), 7 (28.0%), 6 (24.0%), 6 (24.0%), 3 (12.0%) received 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg toripalimab, respectively. After a median follow-up time of 5.0 months (range: 1.5-19.8 months), we observed that the commonest treatment-related adverse events (TRAEs) were fatigue (64.0%) and rash (24.0%). No grade 3 or higher TRAEs were observed. No dose-limiting toxicity, treatment-related serious adverse events (SAEs), or treatment-related death occurred. Objective response rate was 12.5%. The half-life of toripalimab was 150-222 h after a single dose infusion. Most patients, including those from the 0.3 mg/kg group, maintained complete PD-1 receptor occupancy (> 80%) on activated T cells since receiving the first dose of toripalimab. CONCLUSIONS: Toripalimab is a promising anti-PD-1 antibody, which was well tolerated and demonstrated anti-tumor activity in treatment-refractory advanced solitary malignant tumors. Further exploration in various tumors and combination therapies is warranted. BACKGROUND: The most effective treatment of immune checkpoint inhibitors (ICIs) is restricted in microsatellite instability (MSI-H) subsets of advanced colorectal cancer, but MSI-H only accounts for 4-5% among them. ICIs are completely ineffective in advanced colorectal cancer patients with microsatellite stable (MSS), according to literatures published. Regorafenib is a novel tyrosine kinase inhibitor (TKIs) that could normalize tumor blood vessels by inhibiting vascular endothelial growth factor receptor and its downstream, thus improving cytotoxic T cell infiltration in tumor microenvironment, which has a synergistic effect with ICIs. Toripalimab is a type of anti-PD-1 monoclonal antibody produced by Junshi Biosciences in China. Herein, we aimed to explore the efficacy and safety of regorafenib combined with toripalimab in the third-line and beyond treatment of advanced colorectal cancer. METHODS: We evaluated the outcomes of MSS patients with advanced colorectal cancer who received regorafenib combined with toripalimab in the Second Affiliated Hospital of Nanchang University from June 2019 to January 2021. These patients had previously received at least second-line treatment; the regimens were oxaliplatin and irinotecan-based chemotherapy and/or accompanied with bevacizumab or cetuximab. Thirty-three patients were treated orally with regorafenib 80 mg or 120 mg once daily for 21 days, 28 days as a cycle, combined with intravenous toripalimab until disease progression or intolerant to adverse reactions. We used the Kaplan-Meier method to estimate the rate of progression-free survival (PFS) and log-rank method to do a statistical test of the survival curve. The Cox regression model was used to analyze the influence of multiple factors on PFS. The primary endpoints were objective remission rate (ORR) and disease control rate (DCR). The secondary endpoints were the incidence of adverse reactions and median progression-free survival (mPFS). RESULTS: The evaluation of treatment effects was assessed according to RECIST 1.1. Four patients (12.12%) got partial response, twelve patients (36.36%) experienced stable disease, and seventeen patients (51.52%) suffered progressive disease. ORR was 12.12% and DCR was 48.48%. mPFS was 113 days (95% CI: 0-272.1). In univariate analysis, patients who had previously received second-line treatment were significantly better than those who had received third-line or more treatment (p=0.005). Lung metastasis was a negative factor in combined therapy (p=0.032). Five patients without previous treatment of bevacizumab were effective. Previous treatment without bevacizumab showed a trend of effective when combination therapy (p=0.034). It was also a positive factor that the Eastern Cooperative Oncology Group performance status (ECOG) score was 0 (p=0.034). Multivariable Cox regression analysis showed the number of previous chemotherapy lines and excision of primary lesions were independent prognostic factors. The most common treatment-related adverse reactions were hand-foot syndrome (33.33%), liver dysfunction (27.27), hypothyroidism (24.24%), fever (24.24%), fatigue (21.21%), leukopenia (15.15%), hypertension (12.12%), platelet count decreased (6.06%), diarrhea (3.03%), and myocarditis (3.03%); one patient stopped treatment as myocarditis. The incidence of grade 3/4 adverse reactions was 9.09%. CONCLUSIONS: Regorafenib combined with toripalimab has a promising effect in the third-line and beyond treatment of advanced colorectal cancer. In the early use of combination therapy, excision of primary lesions can have a positive impact in regorafenib and toripalimab combination. This treatment-related adverse reactions are tolerant in combined therapy. PURPOSE: Metastatic mucosal melanoma responds poorly to anti-programmed cell death-1 (PD-1) monotherapy. Vascular endothelial growth factor (VEGF) has been shown to play an important immunosuppressive role in the tumor microenvironment. The combination of VEGF inhibition and PD-1 blockade provides therapeutic opportunities for patients refractory to either therapy alone. PATIENTS AND METHODS: We conducted a single-center, phase IB trial evaluating the safety and preliminary efficacy of toripalimab, a humanized immunoglobulin G4 monoclonal antibody against PD-1 in combination with the VEGF receptor inhibitor axitinib in patients with advanced melanoma, including patients with chemotherapy-naïve mucosal melanomas (88%). Patients received toripalimab at 1 or 3 mg/kg via intravenous infusion every 2 weeks, in combination with axitinib 5 mg orally twice a day, in a dose-escalation and cohort-expansion study until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. The primary objective was safety. Secondary objectives included efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and tumor tissue biomarkers. RESULTS: Thirty-three patients were enrolled. No dose-limiting toxicities were observed. Ninety-seven percent of patients experienced treatment-related adverse events (TRAEs). The most common TRAEs were mild (grade 1 or 2) and included diarrhea, proteinuria, hand and foot syndrome, fatigue, AST or ALT elevation, hypertension, hypo- or hyperthyroidism, and rash. Grade 3 or greater TRAEs occurred in 39.4% of patients. By the cutoff date, among 29 patients with chemotherapy-naïve mucosal melanoma, 14 patients (48.3%; 95% CI, 29.4% to 67.5%) achieved objective response, and the median progression-free survival time was 7.5 months (95% CI, 3.7 months to not reached) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CONCLUSION: The combination of toripalimab plus axitinib was tolerable and showed promising antitumor activity in patients with treatment-naïve metastatic mucosal melanoma. Patients enrolled in this study were all Asian, and this combination therapy must be validated in a randomized phase III trial that includes a non-Asian population before it can become a standard of care. INTRODUCTION: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung carcinoma (NSCLC), which characterized by insensitive to conventional radiotherapy and chemotherapy and poor prognosis. Except MET exon 14 alterations and other oncogene mutations, PSC commonly harbor high tumor mutational burden (TMB) and high level of PD-L1, which provide new therapeutic opportunities. Toripalimab (JS001) is IgG4 monoclonal antibody targeting PD-1, which has been approved for treatment of patients with metastatic melanoma after previous systemic therapy. PD-1 combined with radiotherapy has been tried in several cancer types. CASE PRESENTATION: We reported a case of a PSC patient with PD-L1 overexpression responding to toripalimab and after progression the patients also benefits from toripalimab combined with local radiotherapy, which provides a promising option for PSC patients. CONCLUSION: This case provides the evidence of the effective role of toripalimab and PD-1 combined with local radiotherapy in PSC patients, which was the first application as far as we know. Author information: (1)State Key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou. (2)Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou. (3)Laboratory of Carcinogenesis & Translational Research for the Ministry of National Education, Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing. (4)Department of Medical Oncology, Chinese PLA General Hospital & Chinese PLA Medical Academy, Beijing. (5)Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan. (6)The State Key Laboratory of Biotherapy, Department of Abdominal Cancer, West China Medical School, Cancer Center, West China Hospital, Sichuan University, Chengdu. (7)Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou. (8)Department of Medical Oncology, Linyi Cancer Hospital, Linyi. (9)Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai. (10)Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou. (11)Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin. (12)Department of Oncology, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing. (13)Department of Gastrointestinal Oncology, Tianjin Cancer Hospital, Tianjin. (14)Department of Medical Oncology, The First Hospital of China Medical University, Shenyang. (15)Department of Medical Oncology, The First Hospital of Jilin University, Changchun. (16)Department of Oncology, Jiangsu Provincial Hospital, Nanjing. (17)Digestive Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou. (18)Department of Medical Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai. (19)State Key Laboratory of Oncology in South China, Department of Ultrasonography, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou. (20)Shanghai Junshi Biosciences Co., Ltd, Shanghai, China. (21)State Key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou. Electronic address: xurh@sysucc.org.cn. Monoclonal antibody (mAb)-based blockade of programmed cell death 1 (PD-1) or its ligand to enable antitumor T-cell immunity has been successful in treating multiple tumors. However, the structural basis of the binding mechanisms of the mAbs and PD-1 and the effects of glycosylation of PD-1 on mAb interaction are not well understood. Here, we report the complex structure of PD-1 with toripalimab, a mAb that is approved by China National Medical Products Administration as a second-line treatment for melanoma and is under multiple Phase 1-Phase 3 clinical trials in both China and the US. Our analysis reveals that toripalimab mainly binds to the FG loop of PD-1 with an unconventionally long complementarity-determining region 3 loop of the heavy chain, which is distinct from the known binding epitopes of anti-PD-1 mAbs with structural evidences. The glycan modifications of PD-1 could be observed in three potential N-linked glycosylation sites, while no substantial influences were detected to the binding of toripalimab. These findings benefit our understanding of the binding mechanisms of toripalimab to PD-1 and shed light for future development of biologics targeting PD-1. Atomic coordinates have been deposited in the Protein Data Bank under accession code 6JBT. BACKGROUND: Lung cancer is the leading cause of cancer-related death, of which non-small cell lung cancer (NSCLC) is the most common type. Immune checkpoint inhibitors (ICIs) have now become one of the main treatments for advanced NSCLC. This paper retrospectively investigated the effect of peripheral blood inflammatory indexes on the efficacy of immunotherapy and survival of patients with advanced non-small cell lung cancer, in order to find strategies to guide immunotherapy in NSCLC. METHODS: Patients with advanced non-small cell lung cancer who were hospitalized in The Affiliated Cancer Hospital of Nanjing Medical University from October 2018 to August 2019 were selected to receive anti-PD-1 (pembrolizumab, sintilimab or toripalimab) monotherapy or combination regimens. And were followed up until 10 December 2020, and the efficacy was evaluated according to RECIST1.1 criteria. Progression-free survival (PFS) and overall survival (OS) were followed up for survival analysis. A clinical prediction model was constructed to analyze the predictive value of neutrophil-to-lymphocyte ratio (NLR) based on NLR data at three different time points: before treatment, 6 weeks after treatment and 12 weeks after treatment (0w, 6w and 12w), and the accuracy of the model was verified. RESULTS: 173 patients were finally included, all of whom received the above treatment regimen, were followed up for a median of 19.7 months. The objective response rate (ORR) was 27.7% (48/173), the disease control rate (DCR) was 89.6% (155/173), the median PFS was 8.3 months (7.491-9.109) and the median OS was 15.5 months (14.087-16.913). The chi-square test and logistic multi-factor analysis showed that NLR6w was associated with ORR and NLR12w was associated with ORR and DCR. Further Cox regression analysis showed that NLR6w and NLR12w affected PFS and NLR0w, NLR6w and NLR12w were associated with OS. CONCLUSIONS: In patients with advanced non-small cell lung cancer, NLR values at different time points are valid predictors of response to immunotherapy, and NLR <3 is often associated with a good prognosis. Background: Anti-programmed cell death protein 1 (PD-1) has been successfully used in carcinomas treatment. However, it causes significant adverse effects (AEs), including cutaneous reactions, particularly the life-threatening severe bullous skin reactions (SBSR) and toxic epidermal necrolysis (TEN). Case summary: Herein, we described for the first time a case report of SBSR induced by anti-PD-1 therapy in a cervical cancer patient. In addition, we revised existing literature on anti-PD-1 induced cutaneous reactions. We reported a cervical cancer patient who was treated with four successive cycles of Sintilimab and Toripalimab injections and developed systemic rashes, bullae, and epidermal desquamation, which worsened and led to infection, eventually causing death after being unresponsive to aggressive treatments. Conclusion: Anti-PD-1 antibodies commonly cause skin toxicity effects, some of which may be deadly. Therefore, healthcare providers should observe early symptoms and administer proper treatment to prevent aggravation of symptoms. Anti-PD-1/PD-L1 monoclonal antibodies result in a unique spectrum of side effects, widely known as immune-related adverse events. Toripalimab is an anti-PD-1 monoclonal antibody used for the treatment of some cancers. Here we report the first case, to our knowledge, of oral lichenoid drug reaction triggered by toripalimab. A 78-year-old man who was diagnosed with systemic metastatic prostate cancer presented with ulcers on the lower lip after the fifth cycle of toripalimab. We diagnosed him with oral lichenoid drug reaction based on clinical manifestation, histopathological findings and the history of anti-PD-1 therapy. The patient responded well to oral corticosteroids combined with helium-neon laser therapy. The anti-PD-1 therapy was not restarted because of stable disease, and the eruptions did not recur. Toripalimab is a monoclonal antibody targeting programmed cell death protein 1 (PD-1). It has recently been approved as an immune checkpoint inhibitor in second-line therapies in patients with unresectable or metastatic melanoma; however, it may be associated with various immune-related adverse events (irAEs). Here we report a case of toripalimab-induced dermatomyositis in a patient receiving treatment for metastatic melanoma. The symptoms were relieved by discontinuing toripalimab and administering once-daily intravenous methylprednisolone 1 mg/kg. We suggest that this case serves a warning to clinicians of the need to be aware of the possiblilty of toripalimab-induced dermatomyositis. Early recognition and treatment may prevent progression and improve prognosis of this irAE. PURPOSE: As yet, no checkpoint inhibitor has been approved to treat nasopharyngeal carcinoma (NPC). This study was aimed to evaluate the antitumor activity, safety, and biomarkers of toripalimab, a new programmed death-1 (PD-1) inhibitor for recurrent or metastatic NPC (RM-NPC) refractory to standard chemotherapy. PATIENTS AND METHODS: In this single-arm, multicenter phase II study, patients with RM-NPC received 3 mg/kg toripalimab once every 2 weeks via intravenous infusion until confirmed disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). The secondary end points included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: Among all 190 patients, the ORR was 20.5% with median DOR 12.8 months, median PFS 1.9 months, and median OS 17.4 months. Among 92 patients who failed at least two lines of systemic chemotherapy, the ORR was 23.9%. The ORRs were 27.1% and 19.4% in PD-L1+ and PD-L1- patients, respectively (P = .31). Patients with ≥ 50% decrease of plasma Epstein-Barr virus (EBV) DNA copy number on day 28 had significantly better ORR than those with < 50% decrease, 48.3% versus 5.7% (P = .0001). Tumor mutational burden had a median value of 0.95 muts/mega-base in the cohort and had no predictive value for response. Whole-exome sequencing results from 174 patients revealed that the patients with genomic amplification in 11q13 region or ETV6 genomic alterations had poor responses to toripalimab. CONCLUSION: The POLARIS-02 study demonstrated a manageable safety profile and durable clinical response of toripalimab in patients with chemorefractory metastatic NPC. An early decrease in plasma EBV DNA copy number correlated with favorable response. RATIONALE: The targeting of signal transduction through programmed cell death receptor-1 (PD-1) and its ligand programmed cell death-ligand 1 (PD-L1) in patients with non-small cell lung cancer (NSCLC) has been widely applied in clinical research. However, the subtypes and treatment patterns that predict responses to PD-1/PD-L1 inhibitors are not fully understood. Biomarkers, such as PD-L1 expression, tumor mutation load, and DNA mismatch repair defects, have been used to screen patients who respond to PD-1/PD-L1 inhibitors, but the appropriate treatment mode requires further investigation. Immune checkpoint inhibitors combined with radiotherapy provide benefits from remote effects, especially in NSCLC patients with increased PD-L1 expression. PATIENT CONCERNS: We report a 64-year-old man who presented with left back pain for 40 days. A computed tomography scan showed a mass in the right upper lobe of the lung, with metastases in the right hilar and mediastinal lymph nodes. DIAGNOSIS: NSCLC-not otherwise specified was diagnosed by computed tomography-guided lung biopsy. INTERVENTIONS: After the failure of first-line chemotherapy, next-generation sequencing was performed for comprehensive gene analysis, and PD-L1 expression levels were evaluated by immunohistochemistry. The patient was treated with toripalimab (a PD-1 inhibitor) concurrently with radiotherapy for bone metastases. OUTCOMES: The detection results showed a high tumor mutation burden and increased PD-L1 expression. On the basis of these findings, the patient received toripalimab (PD-1 inhibitor) combined with radiotherapy for bone metastases. Partial response was achieved after 3 cycles, and the patient showed stable disease at the end of the sixth and ninth cycles of toripalimab. The patient was followed up for 26 months. At present, the patient is receiving toripalimab maintenance treatment, which has been well-tolerated without adverse events. LESSON: Toripalimab combined with radiotherapy may exert a synergistic anti-tumor effect through remote effects in advanced or metastatic NSCLC with high PD-L1 expression. However, the specific treatment mode requires further confirmation by the investigation of additional cases. Toripalimab, a humanized IgG4 monoclonal antibody (mAb) against programmed death receptor-1, is being extensively studied to treat various malignancies. At present, there is no complete methodology reported for quantifying toripalimab, except for an electrochemiluminescence immunoassay (ECLIA) mentioned in several clinical studies. Therefore, a sensitive and robust ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed to accurately detect toripalimab levels, compared with the ECLIA. Plasma samples were pretreated by a five-step process, encompassing denaturation, reduction, alkylation, enzymatic hydrolysis and quenching. And a unique, sensitive and stable enzymatic peptide (ASGYTFTDYEMHWVR) selected as surrogate of toripalimab was eluted and monitored by UPLC-MS/MS system with the linear range of 5.0375-201.5 μg/mL. After fully validated, the UPLC-MS/MS method was applied to determine 77 plasma samples from 29 patients in a phase I clinical trial, and compared with ECLIA based on 56 samples. Wilcoxon paired samples test showed toripalimab levels by UPLC-MS/MS were significantly higher than that by ECLIA (p < 0.001), though a strong correlation was observed (r = 0.96). Moreover, Passing-Bablok regression analysis exhibited constant and proportional biases: UPLC-MS/MS = 2.25 + 1.21 * ECLIA. This discrepancy could be mainly attributed to different forms determined: total mAb for UPLC-MS/MS and free mAb for ECLIA, respectively. As a result, this UPLC-MS/MS method may be complementary to ECLIA to monitor different forms of toripalimab. Beyond that, it can be easily modified to simultaneously quantitate multiple-analyte with a small volume of plasma.

Is taxilin a cancer marker?

Yes, α-Taxilin, a binding partner of the syntaxin family, is a candidate tumor marker.

[24091795, 21042709, 32377534, 28789367]

The membrane traffic system has been recognized to be involved in carcinogenesis and tumor progression in several types of tumors. α-taxilin is a newly identified membrane traffic-related molecule, and its up-regulation has been reported in embryonic and malignant tissues of neural origin. In the present study, we analyzed the expression of α-taxilin in relation to clinicopathological features of hepatocellular carcinomas (HCC) and proliferative activity of the tumor determined by proliferating cell nuclear antigen labeling index (PCNA-LI). Twenty-nine surgically resected nodules of HCC (8 well-, 11 moderately-, and 10 poorly-differentiated) were studied. Fifteen cases showed 'strong staining', while 14 cases showed 'weak staining' for α-taxilin. A significantly higher expression of α-taxilin was observed in less-differentiated (p=0.005), and more invasive (p=0.016) HCCs. The 'strong staining' group showed significantly higher PCNA-LI than the 'weak staining' group (the medians of PCNA-LI were 59.4% vs. 14.4%, p<0.0001). We also evaluated the expression of α-taxilin in hepatoma cell lines (PLC/PRF/5, Hep G2 and HuH-6) in association with cell proliferation. The expression levels of α-taxilin protein were correlated with their growth rates. In conclusion, the expression of the α-taxilin protein was related with an increased proliferative activity and a less-differentiated histological grade of HCC. α-taxilin may be involved in cell proliferation of HCC, and its expression can be a marker of malignant potential of HCC. Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease affecting the joints and surrounding tissue. Identification of novel proteins associated with the progression of a disease is a prerequisite for understanding the pathogenesis of RA. The present study was undertaken to identify the potential biomarkers from a less explored biological sample such as synovial fluid (SF) cells which is specific for RA and to analyze their functional aspects using proteomic approach. Two-dimensional gel electrophoresis (2-DE) was performed using synovial fluid cells of RA and osteoarthritis (OA) patients, and 7 differentially expressed proteins were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS/MS). Αlpha-Taxilin (α-Taxilin) has been found as one of the novel, significantly up regulated protein in RA. It has been validated in the synovium, synovial fluid (SF), SF cells, and plasma samples by Western blot, enzyme-linked immunosorbent assay (ELISA), fluorescence-activated cell sorting (FACS), immunohistochemistry (IHC), and real-time PCR. The identification of autoantibody against α-Taxilin and in silico studies has further helped us to understand its involvement in disease mechanism. The present study will therefore provide knowledge towards the etiology of RA that pave the way for suitable prognostic marker identification along with other clinical parameters. α-taxilin is a binding partner of syntaxins, which are the central coordinators of membrane traffic. Expression of α-taxilin has been implicated in the development of human glioblastoma, hepatocellular carcinoma and renal cell carcinoma. In the present study, the clinical significance of α-taxilin expression in colorectal cancer (CRC) was investigated. A total of 20 cases of colorectal intramucosal adenocarcinoma (IMA) with adenoma were analyzed using immunohistochemical analysis. The results demonstrated that α-taxilin expression was significantly associated with Ki-67 indices in adenoma and IMA. The patients expressed equally high levels of α-taxilin in the upper third of the intramucosal glands. These results suggest that α-taxilin expression is significantly associated with the proliferative activity of CRC, but that its overexpression alone is not a biomarker of malignancy. Next, α-taxilin expression was investigated in 57 advanced CRCs and its association with prognosis was determined. Well-differentiated and/or moderately differentiated adenocarcinomas in the left-sided colon with anatomic stage II and/or III were analyzed. α-taxilin expression levels were high on the surface of nearly all tumors, but variable at the deep advancing edge. α-taxilin levels at the advancing edge were not significantly associated with local invasiveness or prognosis. In conclusion, α-taxilin is a cell proliferation marker in colorectal epithelial neoplasms but cannot be a marker of malignancy or prognosis of CRCs.

What are the symptoms of an incidental durotomy (ID).

Incidental durotomy can cause postural headaches, nausea, vomiting, dizziness, photophobia, tinnitus, and vertigo. Meningitis is a rare complication reported to occur with a frequency of 0.18%

[10528385, 15260094]

STUDY DESIGN: A retrospective review of 20 patients with incidental durotomy treated without mandatory bed rest. OBJECTIVES: To determine whether patients with incidental durotomy can be treated effectively without multiple days of bed rest. SUMMARY OF BACKGROUND DATA: Incidental durotomy can cause postural headaches, nausea, vomiting, dizziness, photophobia, tinnitus, and vertigo. These symptoms are believed to result from a decrease in cerebrospinal fluid pressure, leading to traction on the supporting structures of the brain. Traditional management includes bed rest for up to 7 days to eliminate traction and reduce hydrostatic pressure during the healing process. METHODS: Twenty incidental durotomies were repaired intraoperatively with dural stitches and fibrin glue. Patients were allowed to ambulate according to the natural course after surgery without mandatory bed rest. Symptoms were monitored closely for 1 week, and long-term follow-up assessments were obtained at a minimum of 10 months. RESULTS: Of the 20 patients in this study, 75% had no symptoms after repair of the incidental durotomy. Each of the dural tears was 1-3 mm in length. Two patients reported headache, two reported nausea, and one reported tinnitus; no patients experienced vomiting. One patient (5%) had stitch loosening requiring revision surgery. There were no additional serious complications. CONCLUSIONS: This study has shown that the majority of patients with incidental durotomy can be treated effectively with dural stitches and fibrin glue. Patients can be permitted to ambulate immediately after surgery but should be cautioned to lay flat if they develop symptoms. This will reduce the costs related to the hospital stay and missed work. Despite the frequency of dural tears in spinal surgery, meningitis is a rare complication reported to occur with a frequency of 0.18%. To the best of our knowledge, no case of Acinetobacter baumanii meningitis has been reported in the literature after a dural tear secondary to lumbar spine discectomy. This case highlights the importance of repairing all dural tears and commencing antibiotics that cover uncommon bacteria in those who develop symptoms of meningitis in this setting.

Is PCAT6 a microRNA?

No, PCAT6 is a long noncoding RNA.

[34620745]

Breast cancer is an aggressive malignancy with high morbidity in females worldwide. Extensive studies reveal that long noncoding RNAs (lncRNAs) are abnormally expressed and act as key regulators in various cancers, including breast cancer. In this work, we investigated the role and regulatory mechanism of lncRNA prostate cancer-associated transcript 6 (PCAT6) in breast cancer progression. Our findings revealed that PCAT6 was overexpressed in breast cancer tissues and cell lines. Furthermore, elevation of PCAT6 reflected an adverse prognosis of patients. Functional experiments indicated that PCAT6 knockdown hampered cell proliferation, facilitated apoptosis and cell cycle arrest in vitro, and inhibited tumor growth in vivo. We also found that the transcription factor SP1 could bind to the PCAT6 promoter and promoted its expression. Subsequently, it was verified that PCAT6 was a molecular sponge for microRNA-326 (miR-326), and the leucine-rich repeat containing the eight family member E (LRRC8E) was a direct target of miR-326. Rescue assays revealed that LRRC8E overexpression attenuated the suppressive effect of PCAT6 knockdown on cellular progression of breast cancer. In summary, this study demonstrated that SP1-activated PCAT6 promoted the malignant behaviors of breast cancer cells by regulating the miR-326/LRRC8E axis.

Which enzyme is inhibited by Aramchol?

Arachidyl amido cholanoic acid (Aramchol) is a potent downregulator of hepatic stearoyl-CoA desaturase 1 (SCD1) protein expression.

[32982112, 21044742, 34151243, 31013363, 31931543, 34621052, 29159325]

BACKGROUND: Arachidyl amido cholanoic acid (Aramchol) is a potent downregulator of hepatic stearoyl-CoA desaturase 1 (SCD1) protein expression that reduces liver triglycerides and fibrosis in animal models of steatohepatitis. In a phase IIb clinical trial in patients with nonalcoholic steatohepatitis (NASH), 52 wk of treatment with Aramchol reduced blood levels of glycated hemoglobin A1c, an indicator of glycemic control. AIM: To assess lipid and glucose metabolism in mouse hepatocytes and in a NASH mouse model [induced with a 0.1% methionine and choline deficient diet (0.1MCD)] after treatment with Aramchol. METHODS: Isolated primary mouse hepatocytes were incubated with 20 μmol/L Aramchol or vehicle for 48 h. Subsequently, analyses were performed including Western blot, proteomics by mass spectrometry, and fluxomic analysis with 13C-uniformly labeled glucose. For the in vivo part of the study, male C57BL/6J mice were randomly fed a control or 0.1MCD for 4 wk and received 1 or 5 mg/kg/d Aramchol or vehicle by intragastric gavage for the last 2 wk. Liver metabolomics were assessed using ultra-high-performance liquid chromatography-time of flight-MS for the determination of glucose metabolism-related metabolites. RESULTS: Combination of proteomics and Western blot analyses showed increased AMPK activity while the activity of nutrient sensor mTORC1 was decreased by Aramchol in hepatocytes. This translated into changes in the content of their downstream targets including proteins involved in fatty acid (FA) synthesis and oxidation [P-ACCα/β(S79), SCD1, CPT1A/B, HADHA, and HADHB], oxidative phosphorylation (NDUFA9, NDUFB11, NDUFS1, NDUFV1, ETFDH, and UQCRC2), tricarboxylic acid (TCA) cycle (MDH2, SUCLA2, and SUCLG2), and ribosome (P-p70S6K[T389] and P-S6[S235/S236]). Flux experiments with 13C-uniformely labeled glucose showed that TCA cycle cataplerosis was reduced by Aramchol in hepatocytes, as indicated by the increase in the number of rounds that malate remained in the TCA cycle. Finally, liver metabolomic analysis showed that glucose homeostasis was improved by Aramchol in 0.1MCD fed mice in a dose-dependent manner, showing normalization of glucose, G6P, F6P, UDP-glucose, and Rbl5P/Xyl5P. CONCLUSION: Aramchol exerts its effect on glucose and lipid metabolism in NASH through activation of AMPK and inhibition of mTORC1, which in turn activate FA β-oxidation and oxidative phosphorylation. BACKGROUND AND AIMS: Suppression of stearoyl-coenzyme A desaturase (SCD) activity leads to reduction of obesity, fatty liver as well as of insulin resistance. It was, however, recently reported to enhance atherogenesis. The aim of the present study was to investigate whether inhibition of SCD by Aramchol, a fatty acid bile conjugate with known hypocholesterolemic effects, will affect atherogenesis and how. METHODS: Aramchol was tested in vitro in cultured cells and in vivo in rodents. RESULTS: Aramchol, at very low concentrations, reduced SCD activity in liver microsomes of mice. Aramchol enhanced cholesterol efflux from macrophages more than twofold. In vivo it increased fecal sterol output and decreased markedly plasma cholesterol levels in mice. In ApoE(-/-), LDRL(-/-) and C57Bl6 mice, the effects of Aramchol on atherogenesis were non-atherogenic. CONCLUSIONS: Aramchol reduces SCD activity and is non-atherogenic. It may offer a means to obtain the desirable hepatic metabolic effects of SCD inhibition without the deleterious atherogenic effect. BACKGROUND & AIMS: Aramchol is a fatty acid-bile acid conjugate that reduces liver fat content and is being evaluated in a phase III clinical trial for non-alcoholic steatohepatitis (NASH). Aramchol attenuates NASH in mouse models and decreases steatosis by downregulating the fatty acid synthetic enzyme stearoyl CoA desaturase 1 (SCD1) in hepatocytes. Although hepatic stellate cells (HSCs) also store lipids as retinyl esters, the impact of Aramchol in this cell type is unknown. METHODS: We investigated the effects of Aramchol on a human HSC line (LX-2), primary human HSCs (phHSCs), and primary human hepatocytes (phHeps). RESULTS: In LX-2 and phHSCs, 10 μM Aramchol significantly reduced SCD1 mRNA while inducing PPARG (PPARγ) mRNA, with parallel changes in the 2 proteins; ACTA2, COL1A1, β-PDGFR (bPDGFR) mRNAs were also significantly reduced in LX-2. Secretion of collagen 1 (Col1α1) was inhibited by 10 μM Aramchol. SCD1 knockdown in LX-2 cells phenocopied the effect of Aramchol by reducing fibrogenesis, and addition of Aramchol to these cells did not rescue fibrogenic gene expression. Conversely, in LX-2 overexpressing SCD1, Aramchol no longer suppressed fibrogenic gene expression. The drug also induced genes in LX-2 that promote cholesterol efflux and inhibited ACAT2, which catalyses cholesterol synthesis. In phHeps, Aramchol also reduced SCD1 and increased PPARG mRNA expression. CONCLUSIONS: Aramchol downregulates SCD1 and elevates PPARG in HSCs, reducing COL1A1 and ACTA2 mRNAs and COL1A1 secretion. These data suggest a direct inhibitory effect of Aramchol in HSCs through SCD1 inhibition, as part of a broader impact on both fibrogenic genes as well as mediators of cholesterol homeostasis. These findings illustrate novel mechanisms of Aramchol activity, including potential antifibrotic activity in patients with NASH and fibrosis. LAY SUMMARY: In this study, we have explored the potential activity of Aramchol, a drug currently in clinical trials for fatty liver disease, in blocking fibrosis, or scarring, by hepatic stellate cells, the principal collagen-producing (i.e. fibrogenic) cell type in liver injury. In both isolated human hepatic stellate cells and in a human hepatic stellate cell line, the drug suppresses the key fat-producing enzyme, stearoyl CoA desaturase 1 (SCD1), which leads to reduced expression of genes and proteins associated with hepatic fibrosis, while inducing the protective gene, PPARγ. The drug loses activity when SCD1 is already reduced by gene knockdown, reinforcing the idea that inhibition of SCD1 is a main mode of activity for Aramchol. These findings strengthen the rationale for testing Aramchol in patients with NASH. Aramchol, an oral stearoyl-coenzyme-A-desaturase-1 inhibitor, has been shown to reduce hepatic fat content in patients with primary nonalcoholic fatty liver disease (NAFLD); however, its effect in patients with human immunodeficiency virus (HIV)-associated NAFLD is unknown. The aramchol for HIV-associated NAFLD and lipodystrophy (ARRIVE) trial was a double-blind, randomized, investigator-initiated, placebo-controlled trial to test the efficacy of 12 weeks of treatment with aramchol versus placebo in HIV-associated NAFLD. Fifty patients with HIV-associated NAFLD, defined by magnetic resonance imaging (MRI)-proton density fat fraction (PDFF) ≥5%, were randomized to receive either aramchol 600 mg daily (n = 25) or placebo (n = 25) for 12 weeks. The primary endpoint was a change in hepatic fat as measured by MRI-PDFF in colocalized regions of interest. Secondary endpoints included changes in liver stiffness using magnetic resonance elastography (MRE) and vibration-controlled transient elastography (VCTE), and exploratory endpoints included changes in total-body fat and muscle depots on dual-energy X-ray absorptiometry (DXA), whole-body MRI, and cardiac MRI. The mean (± standard deviation) of age and body mass index were 48.2 ± 10.3 years and 30.7 ± 4.6 kg/m2 , respectively. There was no difference in the reduction in mean MRI-PDFF between the aramchol group at -1.3% (baseline MRI-PDFF 15.6% versus end-of-treatment MRI-PDFF 14.4%, P = 0.24) and the placebo group at -1.4% (baseline MRI-PDFF 13.3% versus end-of-treatment MRI-PDFF 11.9%, P = 0.26). There was no difference in the relative decline in mean MRI-PDFF between the aramchol and placebo groups (6.8% versus 1.1%, P = 0.68). There were no differences in MRE-derived and VCTE-derived liver stiffness and whole-body (fat and muscle) composition analysis by MRI or DXA. Compared to baseline, end-of-treatment aminotransferases were lower in the aramchol group but not in the placebo arm. There were no significant adverse events. Conclusion: Aramchol, over a 12-week period, did not reduce hepatic fat or change body fat and muscle composition by using MRI-based assessment in patients with HIV-associated NAFLD (clinicaltrials.gov ID:NCT02684591). Publisher: Die nichtalkoholische Fettleber (NAFLD) ist die am stärksten zunehmende Lebererkrankung weltweit. Vielen Patienten gelingt es nicht, durch eine Änderung des Lebensstils einen positiven Einfluss auf die Erkrankung zu erzielen, und der Bedarf an einer pharmakologischen Therapie in dieser Gruppe ist hoch. In Analogie zu anderen metabolischen Erkrankungen wie z. B. dem Diabetes mellitus Typ 2 oder Fettstoffwechselstörungen wird vermutlich ein großer Teil von Patienten eine dauerhafte medikamentöse Therapie benötigten. Derzeit sind mehrere Substanzen mit verschiedenen pathophysiologischen Ansätzen in klinischer Testung. Dabei können metabolische, antiinflammatorische und antifibrotische Wirkmechanismen unterschieden werden. Mehrere Substanzen befinden sich bereits in Phase-3-Studien. Dazu zählen Elafibranor (PPAR-α/δ-Agonist), Cenicriviroc (CCR2/CCR5-Inhibitor), Obeticholsäure (FXR-Agonist), Aramchol (SCD1-Modulator) und Resmetrion (Thyroid-Hormon-Rezeptor-beta-Agonist). Weitere Studien mit pathophysiologisch vielversprechenden Wirkmechanismen, z. B. dem ASK-1-Inhibitor Selonsertib oder dem Caspase-Inhibitor Emricasan, haben bislang negative Ergebnisse gezeigt, werden jedoch z. T. in Kombinationstherapien weiter evaluiert. Die komplexe Pathophysiologie der Erkrankung, die Entzündung, Stoffwechsel und Fibrose verknüpft, hat dazu geführt, dass auch Kombinationen mehrerer Substanzen mit verschiedenen Wirkansätzen untersucht werden. Die vorliegende Übersicht fasst die Ende 2019 in klinischen Studien der Phase 3 befindlichen Substanzen für Patienten mit NASH ohne Leberzirrhose zusammen. Nonalcoholic steatohepatitis (NASH), a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular carcinoma. Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, double-blind, placebo-controlled, phase 2b trial randomized 247 patients with NASH (n = 101, n = 98 and n = 48 in the Aramchol 400 mg, 600 mg and placebo arms, respectively; NCT02279524 ). The primary end point was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600 mg of Aramchol. Key secondary end points included liver histology and alanine aminotransferase (ALT). Aramchol 600 mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (-3.1, 95% confidence interval (CI) -6.4 to 0.2, P = 0.066), precluding further formal statistical analysis. NASH resolution without worsening fibrosis was achieved in 16.7% (13 out of 78) of Aramchol 600 mg versus 5% (2 out of 40) of the placebo arm (odds ratio (OR) = 4.74, 95% CI = 0.99 to 22.7) and fibrosis improvement by ≥1 stage without worsening NASH in 29.5% versus 17.5% (OR = 1.88, 95% CI = 0.7 to 5.0), respectively. The placebo-corrected decrease in ALT for 600 mg was -29.1 IU l-1 (95% CI = -41.6 to -16.5). Early termination due to adverse events (AEs) was <5%, and Aramchol 600 and 400 mg were safe, well tolerated and without imbalance in serious or severe AEs between arms. Although the primary end point of a reduction in liver fat did not meet the prespecified significance level with Aramchol 600 mg, the observed safety and changes in liver histology and enzymes provide a rationale for SCD1 modulation as a promising therapy for NASH and fibrosis and are being evaluated in an ongoing phase 3 program. Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD) which sets the stage for further liver damage. The mechanism for the progression of NASH involves multiple parallel hits including oxidative stress, mitochondrial dysfunction, inflammation and others. Manipulation of any of these pathways may be an approach to prevent NASH development and progression. Aramchol (arachidyl-amido cholanoic acid) is presently in a phase IIb NASH study. The aim of this study was to investigate Aramchol's mechanism of action and its effect on fibrosis using the methionine- and choline-deficient (MCD) diet model of NASH. We collected liver and serum from mice fed a MCD diet containing 0.1% methionine (0.1MCD) for four weeks, which developed steatohepatitis and fibrosis, as well as mice receiving a control diet; the metabolomes and proteomes were determined. 0.1MCD fed mice were given Aramchol (5mg/kg/day for the last 2 weeks); liver samples were analyzed histologically. Aramchol administration reduced features of steatohepatitis and fibrosis in 0.1MCD fed mice. Aramchol downregulated stearoyl-CoA desaturase 1 (SCD1), a key enzyme involved in triglyceride biosynthesis whose loss enhances fatty acid β-oxidation. Aramchol increased the flux through the transsulfuration pathway, leading to a rise in glutathione (GSH) and GSH/GSSG ratio, the main cellular antioxidant that maintains intracellular redox status. Comparison of serum metabolomic pattern between 0.1MCD fed mice and NAFLD patients showed a substantial overlap. CONCLUSIONS: Aramchol treatment improved steatohepatitis and fibrosis by 1) decreasing SCD1, and 2) increasing the flux through the transsulfuration pathway maintaining cellular redox homeostasis. We also demonstrated that the 0.1MCD model resembles the metabolic phenotype observed in about 50% of NAFLD patients, which supports the potential use of Aramchol in NASH treatment.

What is the cause of the Diamond Blackfan Anemia?

Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome associated with ribosomal gene mutations that lead to ribosomal insufficiency.

[32630050, 32643123, 32620751]

Diamond-Blackfan anemia is an autosomal dominant syndrome, characterized by anemia and a predisposition for malignancies. Ribosomal proteins are responsible for this syndrome, and the incidence of colorectal cancer in patients with this syndrome is higher than the general population. This patient's Diamond-Blackfan anemia was caused by a novel ribosomal protein S19 gene mutation, and he received chemotherapy for colorectal cancer caused by it. In his cancer, ribosomal proteins S19 and TP53 were overexpressed. He received 5FU and cetuximab; however, his anemia made chemotherapy difficult, and he did not survive long. Patients with Diamond-Blackfan anemia should be screened earlier and more often for colorectal cancer than usual.

What are the functions of DNA and RNA G-quadruplexes?

G-Quadruplex, a unique secondary structure in nucleic acids found throughout human genome, elicited widespread interest in the field of therapeutic research. Being present in key regulatory regions of oncogenes, RNAs and telomere, G-Quadruplex structure regulates transcription, translation, splicing, etc

[19330720, 26350216, 33021960, 29517770, 34162892, 22376111, 23012368, 23458775, 32545267, 34166611, 22488917, 32056246, 22388183, 25207541, 21416921, 33733306, 34148284, 34285374]

Guanine-rich sequences of DNA and RNA may fold in vitro and in vivo into G-quadruplexes, four-stranded helical structures held together by a guanine core. G-quadruplexes have various biological functions, including inhibition of telomerase and the regulation of gene transcription and translation, and have become an active target for drug development, particularly for novel anticancer therapies. The physiological functions of G-quadruplexes are discussed in this review and the current knowledge of G-quadruplex ligand and drug development is outlined. 'If G-quadruplexes form so readily in vitro, Nature will have found a way of using them in vivo' (Statement by Aaron Klug over 30 years ago).During the last decade, four-stranded helical structures called G-quadruplex (or G4) have emerged from being a structural curiosity observed in vitro, to being recognized as a possible nucleic acid based mechanism for regulating multiple biological processes in vivo. The sequencing of many genomes has revealed that they are rich in sequence motifs that have the potential to form G-quadruplexes and that their location is non-random, correlating with functionally important genomic regions. In this short review, we summarize recent evidence for the in vivo presence and function of DNA and RNA G-quadruplexes in various cellular pathways including DNA replication, gene expression and telomere maintenance. We also highlight remaining open questions that will have to be addressed in the future. Growing evidence indicates that RNA G-quadruplexes have important roles in various processes such as transcription, translation, regulation of telomere length, and formation of telomeric heterochromatin. Investigation of RNA G-quadruplex structures associated with biological events is therefore essential to understanding the functions of these RNA molecules. We recently demonstrated that the sensitivity and simplicity of 19F NMR can be used to directly observe higher-order telomeric G-quadruplexes of labeled RNA molecules in vitro and in living cells, as well as their interactions with ligands and proteins. This protocol describes detailed procedures for preparing 19F-labeled RNA, the evaluation of 19F-labeled RNA G-quadruplexes in vitro and in living Xenopus laevis oocytes by 19F NMR spectroscopy, the quantitative characterization of thermodynamic properties of the G-quadruplexes, and monitoring of RNA G-quadruplex interactions with ligand molecules and proteins. This approach has several advantages over existing techniques. First, it is relatively easy to prepare 19F-labeled RNA molecules by introducing a 3,5-bis(trifluoromethyl) benzene moiety into its 5' terminus. Second, the absence of any natural fluorine background signal in RNA and cells results in a simple and clear 19F NMR spectrum and does not suffer from high background signals as does 1H NMR. Finally, the simplicity and sensitivity of 19F NMR can be used to easily distinguish different RNA G-quadruplex conformations under various conditions, even in living cells, and to obtain the precise thermodynamic parameters of higher-order G-quadruplexes. This protocol can be completed in 2 weeks. Cell identity is maintained by activation of cell-specific gene programs, regulated by epigenetic marks, transcription factors and chromatin organization. DNA G-quadruplex (G4)-folded regions in cells were reported to be associated with either increased or decreased transcriptional activity. By G4-ChIP-seq/RNA-seq analysis on liposarcoma cells we confirmed that G4s in promoters are invariably associated with high transcription levels in open chromatin. Comparing G4 presence, location and transcript levels in liposarcoma cells to available data on keratinocytes, we showed that the same promoter sequences of the same genes in the two cell lines had different G4-folding state: high transcript levels consistently associated with G4-folding. Transcription factors AP-1 and SP1, whose binding sites were the most significantly represented in G4-folded sequences, coimmunoprecipitated with their G4-folded promoters. Thus, G4s and their associated transcription factors cooperate to determine cell-specific transcriptional programs, making G4s to strongly emerge as new epigenetic regulators of the transcription machinery. Telomeric repeat-containing RNA, a non-coding RNA molecule, has recently been found in mammalian cells. The detailed structural features and functions of the telomeric RNA at human chromosome ends remain unclear, although this RNA molecule may be a key component of the telomere machinery. In this study, using model human telomeric DNA and RNA sequences, we demonstrated that human telomeric RNA and DNA oligonucleotides form a DNA-RNA G-quadruplex. We next employed chemistry-based oligonucleotide probes to mimic the naturally formed telomeric DNA-RNA G-quadruplexes in living cells, suggesting that the process of DNA-RNA G-quadruplex formation with oligonucleotide models of telomeric DNA and RNA could occur in cells. Furthermore, we investigated the possible roles of this DNA-RNA G-quadruplex. The formation of the DNA-RNA G-quadruplex causes a significant increase in the clonogenic capacity of cells and has an effect on inhibition of cellular senescence. Here, we have used a model system to provide evidence about the formation of G-quadruplex structures involving telomeric DNA and RNA sequences that have the potential to provide a protective capping structure for telomere ends. G-quadruplexes are four-stranded helical nucleic acid structures formed by guanine-rich sequences. A considerable number of studies have revealed that these noncanonical structural motifs are widespread throughout the genome and transcriptome of numerous organisms, including humans. In particular, G-quadruplexes occupy strategic locations in genomic DNA and both coding and noncoding RNA molecules, being involved in many essential cellular and organismal functions. In this review, we first outline the fundamental structural features of G-quadruplexes and then focus on the concept that these DNA and RNA structures convey a distinctive layer of epigenetic information that is critical for the complex regulation, either positive or negative, of biological activities in different contexts. In this framework, we summarize and discuss the proposed mechanisms underlying the functions of G-quadruplexes and their interacting factors. Furthermore, we give special emphasis to the interplay between G-quadruplex formation/disruption and other epigenetic marks, including biochemical modifications of DNA bases and histones, nucleosome positioning, and three-dimensional organization of chromatin. Finally, epigenetic roles of RNA G-quadruplexes in post-transcriptional regulation of gene expression are also discussed. Undoubtedly, the issues addressed in this review take on particular importance in the field of comparative epigenetics, as well as in translational research. Author information: (1)GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Microbiology Unit, Biosanitary Research Institute IBS.Granada, University Hospital Virgen de las Nieves, Granada 18014, Spain; Department of Biochemistry, Molecular Biology III and Immunology, University of Granada, Granada 18016, Spain. (2)Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA. (3)GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Centre for Intensive Mediterranean Agrosystems and Agri-food Biotechnology (CIAIMBITAL), University of Almeria, Almeria 04001, Spain. (4)GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Department of Physiology, University of Granada, Granada 18011, Spain. (5)GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Microbiology Unit, Biosanitary Research Institute IBS.Granada, University Hospital Virgen de las Nieves, Granada 18014, Spain. (6)Microbiology Unit, Biosanitary Research Institute IBS.Granada, University Hospital Virgen de las Nieves, Granada 18014, Spain; Department of Microbiology, University of Granada, Granada 18011, Spain. (7)GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Department of Biochemistry, Molecular Biology III and Immunology, University of Granada, Granada 18016, Spain. (8)Instituto de Química Física "Rocasolano", CSIC, Madrid 28006, Spain. (9)GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Microbiology Unit, Biosanitary Research Institute IBS.Granada, University Hospital Virgen de las Nieves, Granada 18014, Spain. Electronic address: jags@genyo.es. G-quadruplexes are noncanonical structures formed by G-rich DNA and RNA sequences that fold into a four-stranded conformation. Experimental studies and computational predictions show that RNA G-quadruplexes are present in transcripts associated with telomeres, in noncoding sequences of primary transcripts and within mature transcripts. RNA G-quadruplexes at these specific locations play important roles in key cellular functions, including telomere homeostasis and gene expression. Indeed, RNA G-quadruplexes appear as important regulators of pre-mRNA processing (splicing and polyadenylation), RNA turnover, mRNA targeting and translation. The regulatory mechanisms controlled by RNA G-quadruplexes involve the binding of protein factors that modulate G-quadruplex conformation and/or serve as a bridge to recruit additional protein regulators. In this review, we summarize the current knowledge on the role of G-quadruplexes in RNA biology with particular emphasis on the molecular mechanisms underlying their specific function in RNA metabolism occurring in physiological or pathological conditions. G-quadruplexes form folded structures because of tandem repeats of guanine sequences in DNA or RNA. They adopt a variety of conformations, depending on many factors, including the type of loops and cations, the nucleotide strand number, and the main strand polarity of the G-quadruplex. Meanwhile, the different conformations of G-quadruplexes have certain influences on their biological functions, such as the inhibition of transcription, translation, and DNA replication. In addition, G-quadruplex binding proteins also affect the structure and function of G-quadruplexes. Some chemically synthesized G-quadruplex sequences have been shown to have biological activities. For example, bimolecular G-quadruplexes of AS1411 act as targets of exogenous drugs that inhibit the proliferation of malignant tumours. G-quadruplexes are also used as vehicles to deliver nanoparticles. Thus, it is important to identify the factors that influence G-quadruplex structures and maintain the stability of G-quadruplexes. Herein, we mainly discuss the factors influencing G-quadruplexes and the synthetic G-quadruplex, AS1411. SIGNIFICANCE OF THE STUDY: This review summarizes the factors that influence G-quadruplexes and the functions of the synthetic G-quadruplex, AS1411. It also discusses the use of G-quadruplexes for drug delivery in tumour therapy. The expansion of a (G(4)C(2))n repeat within the human C9orf72 gene has been causally linked to a number of neurodegenerative diseases, most notably familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies have shown that the repeat expansion alters gene function in four ways, disrupting the gene's normal cellular roles and introducing toxic gain of function at the level of both DNA and RNA. (G(4)C(2))n DNA, as well as the RNA transcribed from it, are found to fold into four-stranded G-quadruplex structures. It has been shown that the toxicity of the RNA G-quadruplexes, often localized in intracellular RNA foci, lies in their ability to sequester many important RNA binding proteins. Herein we propose that a distinct toxic property of such RNA and DNA G-quadruplexes from the C9orf72 gene may arise from their ability to bind and oxidatively activate cellular heme. We show that G-quadruplexes formed by both (G(4)C(2))(4) RNA and DNA not only complex tightly with heme but also enhance its intrinsic peroxidase and oxidase propensities. By contrast, the antisense (C(4)G(2))(4) RNA and DNA neither bind heme nor influence its oxidative activity. Curiously, the ability of C9orf72 DNA and transcripts to bind and activate heme mirror similar properties that have been reported for the Aβ peptide and its oligomers in Alzheimer's disease neurons. It is therefore conceivable that C9orf72 RNA G-quadruplex tangles play roles in sequestering intracellular heme and promoting oxidative damage in ALS and FTD analogous to those proposed for Aβ peptide and its tangles in Alzheimer's Disease. Given that neurodegenerative diseases in general are characterized by mitochondrial and respiratory malfunctions, the role of C9orf72 DNA and RNA in heme sequestration as well as its inappropriate activation in ALS and FTD neurons may warrant examination. G-quadruplex is a kind of special secondary structure of nuclei acids, which exists in genome DNA and RNA and preferentially located in functional regions such as telomeres, promoters, 5' untranslated region (5' UTR) of mRNA and so on. G-quadruplex has been implicated by a lot of studies as an important structure in many biological processes including gene stability, telomere synthesis, transcriptional or translational regulation of gene expression and recombination. We here review the recent studies of G-quadruplex in genome DNA, RNA and G-quadruplex oligonucleotides, focusing on their biological function. Guanine (G)-rich single-stranded nucleic acids can adopt G-quadruplex structures. Accumulating evidence indicates that G-quadruplexes serve important regulatory roles in fundamental biological processes such as DNA replication, transcription, and translation, while aberrant G-quadruplex formation is linked to genome instability and cancer. Understanding the biological functions played by G-quadruplexes requires detailed knowledge of their protein interactome. Here, we report that both RNA and DNA G-quadruplexes are bound by human Dicer in vitro. Using in vitro binding assays, mutation studies, and computational modeling we demonstrate that G-quadruplexes can interact with the Platform-PAZ-Connector helix cassette of Dicer, the region responsible for anchoring microRNA precursors (pre-miRNAs). Consequently, we show that G-quadruplexes efficiently and stably inhibit the cleavage of pre-miRNA by Dicer. Our data highlight the potential of human Dicer for binding of G-quadruplexes and allow us to propose a G-quadruplex-driven sequestration mechanism of Dicer regulation. G-Quadruplex, a unique secondary structure in nucleic acids found throughout human genome, elicited widespread interest in the field of therapeutic research. Being present in key regulatory regions of oncogenes, RNAs and telomere, G-Quadruplex structure regulates transcription, translation, splicing, etc. Changes in its structure and stability leads to differential expression of oncogenes causing cancer. Thus, targeting G-Quadruplex structures with small molecules/other biologics has shown elevated research interest. Covering previous reports, in this review, we try to enlighten the facts on the structural diversity in G-Quadruplex ligands aiming to provide newer insights to design first-in-class drugs for the next-generation cancer treatment. G-quadruplexes (G4s) are higher-order structures formed by guanine-rich sequences of nucleic acids, such as the telomeric 5'-TTAGGG-3'/5'-UUAGGG-3' repeats and those in gene regulatory regions. G4s regulate various biological events, including replication, transcription, and translation. Imbalanced G4 dynamics is associated with diseases, such as cancer and neurodegenerative diseases. Telomestatin is a natural macrocyclic compound derived from Streptomyces anulatus 3533-SV4. It interacts with the guanine quartet via π-π stacking and potently stabilizes G4. Because G4 stabilization at the telomeric repeat inhibits the telomere-synthesizing enzyme telomerase, telomestatin was originally identified as a telomerase inhibitor. Whereas non-toxic doses of telomestatin induce gradual shortening of telomeres and eventual crisis in human cancer cells, higher doses trigger prompt replication stress and DNA damage responses, resulting in acute cell death. Suppression of the transcription and translation of G4-containing genes is also implicated in the anticancer effects of telomestatin. Because telomestatin is rare, labile, and insoluble, synthetic oxazole telomestatin derivatives have been developed and verified for their therapeutic efficacies in preclinical cancer models. Furthermore, a variety of G4-stabilizing compounds have been reported as promising seeds for molecular cancer therapeutics. To improve the design of future clinical studies, it will be important to identify predictive biomarkers of drug efficacy.

What is the effect of epiregulin expression in tumors?

Epiregulin has elevated expression in a variety of human cancers. Epiregulin expression promotes tumor progression and metastasis and reduces patient survival.

[30738695]

Author information: (1)Department of Oncology, The Affiliated Aoyang Hospital of Jiangsu University, Zhangjiagang 215617, China. (2)Department of Oncology, The Affiliated Aoyang Hospital of Jiangsu University, Zhangjiagang 215617, China; Jiangsu University Aoyang Institute of Oncology, Zhangjiagang 215617, China. (3)Department of Oncology, Huai'an Hospital Affiliated of Xuzhou Medical College and Huai'an Second People's Hospital, Huai'an 223200, China. (4)Clinical Biobank, Affiliated Hospital of Nantong University, Nantong 226001, China. (5)Department of Pathology, Nanjing Medical University, Nanjing 210029, China. (6)Huadong Medical Institute of Biotechniques, Nanjing 210029, China. (7)The Center for Pathology & Laboratory Medicine, The Affiliated Aoyang Hospital of Jiangsu University, Zhangjiagang 215617, China; School of Medicine, Jiangsu University, Zhenjiang 212013, China; The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. (8)Department of Oncology, The Affiliated Aoyang Hospital of Jiangsu University, Zhangjiagang 215617, China; Key Laboratory of Antibody Technique of Ministry of Health, Nanjing Medical University, Nanjing 210029, China; Collaborative Innovation Center for Cancer Personalized Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing 210029, China. Electronic address: fengzhenqing@njmu.edu.cn. (9)Department of Oncology, The Affiliated Aoyang Hospital of Jiangsu University, Zhangjiagang 215617, China; Department of Oncology, Shanghai Ruijin Hospital Luwan Branch, Shanghai Jiaotong University, Shanghai 200020, China. Electronic address: xia_shangzhou@163.com.

Name scRNA-seq workflows which harness graph attention networks

SCDRHA and CellVGAE

[34864884, 34512734]

Dimensionality reduction of high-dimensional data is crucial for single-cell RNA sequencing (scRNA-seq) visualization and clustering. One prominent challenge in scRNA-seq studies comes from the dropout events, which lead to zero-inflated data. To address this issue, in this paper, we propose a scRNA-seq data dimensionality reduction algorithm based on a hierarchical autoencoder, termed SCDRHA. The proposed SCDRHA consists of two core modules, where the first module is a deep count autoencoder (DCA) that is used to denoise data, and the second module is a graph autoencoder that projects the data into a low-dimensional space. Experimental results demonstrate that SCDRHA has better performance than existing state-of-the-art algorithms on dimension reduction and noise reduction in five real scRNA-seq datasets. Besides, SCDRHA can also dramatically improve the performance of data visualization and cell clustering.

Which molecule is targeted by Fenebrutinib?

Fenebrutinib is a noncovalent, oral, and highly selective inhibitor of Bruton's tyrosine kinase (BTK).

[34750553, 33806595, 31371481, 33689480, 34042314, 32270926, 33777941, 31907670, 31446134, 31494233, 32832028]

Conflict of interest statement: M. Metz reports receiving honoraria as a speaker and/or consultant for Amgen, Aralez, argenx, Moxie, Novartis, Roche, Sanofi, Shire and Uriach. G.S. reports serving as a principal investigator for Genentech, Novartis, CSL Behring, Shire, Sanofi, AstraZeneca, DBV Technologies, Aimmune Therapeutics, Greencross, Kedrion, ALK-Abelló, Stallergenes, LEO Pharma, Amgen, BioCryst, Regeneron and Cliantha; serving on advisory boards for Novartis, CSL Behring, Shire, Sanofi, Aralez, Pediapharm and AstraZeneca; serving as a speaker for Novartis, Sanofi, Aralez, Pediapharm, Genentech and AstraZeneca; receiving personal fees from Novartis, CSL Behring, Shire, Sanofi, Aralez, Pediapharm and AstraZeneca. T.T. reports receiving funding from Genentech to his institution for the conduct of this study. W.H.Y. reports receiving speakers’ fees from Novartis, Merck, CSL Behring, Takeda (Shire) and AstraZeneca; serving on advisory boards for Novartis, Takeda (Shire), CSL Behring, Sanofi, BioCryst and Merck; and receiving research grants from Novartis, Takeda (Shire), CSL Behring, BioCryst, AstraZeneca, Regeneron, Sanofi, Genentech, Glenmark, AnaptysBio, Dermira, Galderma, ALK, DBV Technologies, Aimmune Therapeutics, Colgene and Pharming. J.J.L., H.J.C., J.G., L.W.C., T.C., T.B., D.J.H. and T.T.L. are current or former employees of Genentech, a member of the Roche group, at the time this work was performed and own/owned Roche stock and/or options. L.W.C. is currently an employee of Principia Biopharma and owns Principia Biopharma stock and/or options. D.J.H. owns Principia Biopharma stock. T.T.L. is currently an employee of DiCE Molecules. M. Maurer is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Amgen, Aralez, AstraZeneca, Celldex, Centogene, CSL Behring, FAES, Genentech, GI Innovation, Innate Pharma, Kyowa Kirin, LEO Pharma, Lilly, Menarini, Moxie, Merck Sharp & Dohme, Novartis, Roche, Sanofi/Regeneron, Third Harmonic Bio, UCB and Uriach. R.G. and P.S. declare no competing interests. Fenebrutinib (GDC-0853) is an orally administered small molecule inhibitor of Bruton's tyrosine kinase being investigated for treatment of rheumatoid arthritis in patients with inadequate responses to methotrexate (MTX). This study interrogated the potential for pharmacokinetic drug interactions between fenebrutinib and MTX. Eighteen healthy male subjects were enrolled in the study. They received a single oral dose of MTX (7.5 mg) on day 1 followed by a 13-day washout period. Subsequently, on days 15-20 the participants received 200 mg of fenebrutinib twice daily. On day 21, they received a 7.5 mg dose of MTX and a 200 mg dose of fenebrutinib under fasting conditions. The geometric mean ratios of MTX area under the plasma concentration-time curve (AUC) and C max on day 21 relative to day 1 (90% confidence interval [CI]) were 0.96 (0.88-1.04) and 1.05 (0.94-1.18), respectively. The geometric mean ratios of fenebrutinib AUC and C max for day 21 relative to day 20 (90% CI) were 1.03 (0.95-1.11) and 1.02 (0.90-1.15), respectively. The combination treatment was well tolerated, with an adverse event profile similar to that reported in other MTX trials. These results indicate that there is no clinically significant pharmacokinetic interaction between fenebrutinib and MTX. Spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (BTK) play critical roles in platelet physiology, facilitating intracellular immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling downstream of platelet glycoprotein VI (GPVI) and GPIIb/IIIa receptors. Small molecule tyrosine kinase inhibitors (TKIs) targeting Syk and BTK have been developed as antineoplastic and anti-inflammatory therapeutics and have also gained interest as antiplatelet agents. Here, we investigate the effects of 12 different Syk and BTK inhibitors on GPVI-mediated platelet signaling and function. These inhibitors include four Syk inhibitors, Bay 61-3606, R406 (fostamatinib), entospletinib, TAK-659; four irreversible BTK inhibitors, ibrutinib, acalabrutinib, ONO-4059 (tirabrutinib), AVL-292 (spebrutinib); and four reversible BTK inhibitors, CG-806, BMS-935177, BMS-986195, and fenebrutinib. In vitro, TKIs targeting Syk or BTK reduced platelet adhesion to collagen, dense granule secretion, and alpha granule secretion in response to the GPVI agonist cross-linked collagen-related peptide (CRP-XL). Similarly, these TKIs reduced the percentage of activated integrin αIIbβ3 on the platelet surface in response to CRP-XL, as determined by PAC-1 binding. Although all TKIs tested inhibited phospholipase C γ2 (PLCγ2) phosphorylation following GPVI-mediated activation, other downstream signaling events proximal to phosphoinositide 3-kinase (PI3K) and PKC were differentially affected. In addition, reversible BTK inhibitors had less pronounced effects on GPIIb/IIIa-mediated platelet spreading on fibrinogen and differentially altered the organization of PI3K around microtubules during platelets spreading on fibrinogen. Select TKIs also inhibited platelet aggregate formation on collagen under physiological flow conditions. Together, our results suggest that TKIs targeting Syk or BTK inhibit central platelet functional responses but may differentially affect protein activities and organization in critical systems downstream of Syk and BTK in platelets. OBJECTIVE: To evaluate fenebrutinib, an oral and highly selective non-covalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA). METHODS: Patients with RA and inadequate response to methotrexate (cohort 1, n=480) were randomized to fenebrutinib (50 mg once daily, 150 mg once daily, 200 mg twice daily), 40 mg adalimumab every other week, or placebo. Patients with RA and inadequate response to tumor necrosis factor inhibitors (cohort 2, n=98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued methotrexate therapy. RESULTS: In cohort 1, American College of Rheumatology scores (ACR50) at week 12 were similar for fenebrutinib 50 mg once daily and placebo, and higher for fenebrutinib 150 mg once daily (28%) and 200 mg twice daily (35%) than placebo (15%) (p=0.017; p=0.0003). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (p=0.81). In cohort 2, more patients achieved ACR50 with fenebrutinib 200 mg twice daily (25%) than placebo (12%) (p=0.072). The most common adverse events for fenebrutinib included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers. CONCLUSION: Fenebrutinib demonstrated efficacy comparable to adalimumab in patients with an inadequate response to methotrexate, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA. PURPOSE: Fenebrutinib (GDC-0853), a Bruton's tyrosine kinase (BTK) inhibitor was investigated in a Phase 2 clinical trial in patients with rheumatoid arthritis (RA). Our aim was to apply a model-informed drug development (MIDD) approach to examine the totality of available clinical efficacy data. METHODS: Population pharmacokinetics (popPK) modeling, exposure-response (E-R) analysis, and model-based meta-analysis (MBMA) of fenebrutinib were performed based on the Phase 2 data. RESULTS: PopPK of fenebrutinib after oral administration was described using a 3-compartment model with linear elimination and a flexible absorption transit compartment model. Healthy subjects had a 52% higher apparent clearance than patients. E-R analyses based on longitudinal ACR20, ACR50, and ACR70 and DAS28 (CRP) data modeled fenebrutinib effect with an Emax function, and an efficacy plateau was achieved within the exposure range obtained in the Phase 2 clinical trial. Based on literature data, a summary-level clinical efficacy database was constructed, and MBMA determined ACR20, ACR50, and ACR70 responder rates in the placebo and adalimumab arms of the Phase 2 clinical trial were found to be consistent with historical data for these treatments. CONCLUSIONS: Our multi-pronged approach applied MIDD to maximize knowledge extraction of efficacy data and enabled robust interpretation from a Phase 2 clinical trial. OBJECTIVE: To review the published literature on current and new treatments for chronic spontaneous urticaria (CSU) and to provide guidance on the potential use of these therapeutics. DATA SOURCES: A PubMed search was performed to include English-language articles with the keywords chronic spontaneous urticaria, pathophysiology, quality of life, and treatments, with a preference to those articles written in the last 5 years. ClinicalTrials.gov was reviewed for recent relevant clinical trials related to potential CSU therapeutics. STUDY SELECTIONS: Literature was included if it provided information related to the current understanding of the pathophysiology and management of CSU as well as potential novel therapeutics currently in development. RESULTS: CSU has a significant effect on patients' quality of life. Current therapies include antihistamines, leukotriene receptor antagonists, omalizumab, and immunosuppressants; however, additional treatments are needed. New therapeutics under investigation include IgG1 anti-IgE monoclonal antibodies (ligelizumab), chemoattractant rector-homologous molecule expressed on TH2 cells antagonists (AZD1981), Bruton tyrosine kinase inhibitors (fenebrutinib), anti-siglec-8 monoclonal antibody (AK002), and topical spleen tyrosine kinase inhibitors (GSK2646264). We review the mechanisms of action as well as recently published data from clinical trials regarding the efficacy and safety of these treatments. CONCLUSION: The development of new treatments for CSU will lead to improved options for patients and may assist with improving our understanding of disease pathophysiology. Bruton's tyrosine kinase (Btk) is thought to play a pathogenic role in chronic immune diseases such as rheumatoid arthritis and lupus. While covalent, irreversible Btk inhibitors are approved for treatment of hematologic malignancies, they are not approved for autoimmune indications. In efforts to develop additional series of reversible Btk inhibitors for chronic immune diseases, we sought to differentiate from our clinical stage inhibitor fenebrutinib using cyclopropyl amide isosteres of the 2-aminopyridyl group to occupy the flat, lipophilic H2 pocket. While drug-like properties were retained-and in some cases improved-a safety liability in the form of hERG inhibition was observed. When a fluorocyclopropyl amide was incorporated, Btk and off-target activity was found to be stereodependent and a lead compound was identified in the form of the (R,R)- stereoisomer.

What is Cereblon?

Cereblon (CRBN) is a substrate recognition protein in the E3-ligase ubiquitin complex. The binding target of CRBN varies according to tissues and cells, and the protein regulates various biological functions by regulating tissue-specific targets.

[34489457, 34553266, 34588172, 34572892]

Author information: (1)Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA. (2)The Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, FL, USA. (3)Department of Medicine, University of Maryland, Baltimore, MD, USA. (4)Department of Molecular and Systems Biology and the Norris Cotton Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA. (5)Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA. (6)Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. (7)Center for Therapeutic Innovation, Department of Neurological Surgery, Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA. (8)Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA. (9)Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA. dr956@georgetown.edu. (10)Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. dr956@georgetown.edu. (11)Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA. dr956@georgetown.edu. (#)Contributed equally Cereblon (CRBN) is a substrate recognition protein in the E3-ligase ubiquitin complex. The binding target of CRBN varies according to tissues and cells, and the protein regulates various biological functions by regulating tissue-specific targets. As new endogenous targets of CRBN have been identified over the past decade, the physiological and pathological functions of CRBN and its potential as a therapeutic target in various diseases have greatly expanded. For this purpose, in this review article, we introduce the basic principle of the ubiquitin-proteasome system, the regulation of physiological/pathological functions related to the endogenous substrate of CRBN, and the discovery of immunomodulatory imide drug-mediated neo-substrates of CRBN. In addition, the development of CRBN-based proteolysis-targeting chimeras, which has been actively researched recently, and strategies for developing therapeutic agents using them are introduced. These recent updates on CRBN will be useful in the establishment of strategies for disease treatment and utilization of CRBNs in biomedical engineering and clinical medicine.

What is Abbreviated Injury Scale (AIS) used to determine?

The Abbreviated Injury Scale (AIS) is an objective anatomically-based injury severity scoring system that classifies each injury by body region on a 6 point scale. AIS is the system used to determine the Injury Severity Score (ISS) of the multiply injured trauma patient. AIS CLASSIFICATIONS The AIS classifies individual injuries by body region as follows: AIS 1 – Minor AIS 2 – Moderate AIS 3 – Serious AIS 4 – Severe AIS 5 – Critical AIS 6 – Maximal (currently untreatable)

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BACKGROUND: Injury severity measures are based either on the Abbreviated Injury Scale (AIS) or the International Classification of diseases (ICD). The latter is more convenient because routinely collected by clinicians for administrative reasons. To exploit this advantage, a proprietary program that maps ICD-9-CM into AIS codes has been used for many years. Recently, a program called ICDPIC trauma and developed in the USA has become available free of charge for registered STATA users. We compared the ICDPIC calculated Injury Severity Score (ISS) with the one from direct, prospective AIS coding by expert trauma registrars (dAIS). METHODS: The administrative records of the 289 major trauma cases admitted to the hospital of Udine-Italy from 1 July 2004 to 30 June 2005 and enrolled in the Italian Trauma Registry were retrieved and ICDPIC-ISS was calculated. The agreement between ICDPIC-ISS and dAIS-ISS was assessed by Cohen's Kappa and Bland-Altman charts. We then plotted the differences between the 2 scores against the ratio between the number of traumatic ICD-9-CM codes and the number of dAIS codes for each patient (DIARATIO). We also compared the absolute differences in ISS among 3 groups identified by DIARATIO. The discriminative power for survival of both scores was finally calculated by ROC curves. RESULTS: The scores matched in 33/272 patients (12.1%, k 0.07) and, when categorized, in 80/272 (22.4%, k 0.09). The Bland-Altman average difference was 6.36 (limits: minus 22.0 to plus 34.7). ICDPIC-ISS of 75 was particularly unreliable. The differences increased (p < 0.01) as DIARATIO increased indicating incomplete administrative coding as a cause of the differences. The area under the curve of ICDPIC-ISS was lower (0.63 vs. 0.76, p = 0.02). CONCLUSIONS: Despite its great potential convenience, ICPIC-ISS agreed poorly with its conventionally calculated counterpart. Its discriminative power for survival was also significantly lower. Incomplete ICD-9-CM coding was a main cause of these findings. Because this quality of coding is standard in Italy and probably in other European countries, its effects on the performances of other trauma scores based on ICD administrative data deserve further research. Mapping ICD-9-CM code 862.8 to AIS of 6 is an overestimation. Injuries from piercing or cutting instruments or objects are commonly seen in the pediatric emergency department. In this study, we present the epidemiology of piercing injuries resulting in hospitalization. Medical records for a one-year period with E-codes 920.0-920.9 were reviewed for victim-related demographic data, anatomic injury location, vehicle of injury, treatment, and hospital charges. The Abbreviated Injury Scale (AIS) was used to ascertain injury severity. The most common vehicles of injury were glass (n = 24, 34%), nails (n = 11, 16%), and needles (n = 10, 14%). The median AIS score was significantly higher for hand injuries compared to the sample median AIS. Piercing injuries from consumer-related products were associated with the highest AIS scores (median = 2.5). Although the mean AIS for all injuries was only 1.5, these injuries resulted in significant costs, with a mean hospitalization charge of $3884 +/- 3528. Surgical procedures under general anesthesia were required in 81% of the patients. Trauma, which accounts for a substantial part of the morbidity and mortality in industrial nations, is a natural area of interest for orthopaedic surgeons. Trauma, and trauma prevention, can be conveniently studied in emergency rooms and casualty units which are often run by hospital orthopaedic departments. In order to identify the most serious types of accidents and assign priorities as regards preventive measures it is necessary to be able to determine in an objective way the severity of different types of trauma. The Abbreviated Injury Scale is a system developed in the United States for ranking the severity of specific trauma lesions. This paper discusses general issues relating to injury scaling and accident epidemiology research. Chest injuries in children are part of polytrauma resulting from high-energy violence, most often caused by traffic accidents. Blunt chest injuries (95%) are significantly more frequent than penetrating injuries (5%). Lung contusion, rib fracture, pneumothorax or haemothorax, are the more common injuries, but tracheobronchial rupture, cardiac or diaphragmatic injuries may also occur. The anterior X-ray image remains the basic examination method for isolated chest injuries. CT trauma scan with a contrast medium is done in polytraumatized children. Blunt injuries of intra-thoracic organs in haemodynamically stable children are treated mostly conservatively (85%) under full monitoring at the ICU. Surgical treatment is necessary in a minority of patients. Mortality and morbidity of patients with chest injury depend on the actual combination of multiple body systems injury. The severity of total injury can be predicted using objective scoring systems (Abbreviated Injury Scale=AIS; Injury Severity Score=ISS). Overall mortality ranges from 6 to 20%. Mortality is high but this is mainly due to associated head injuries.Key words: multiple trauma thoracic trauma - paediatric lung contusion Injury Severity Score=ISS. Refinements in injury scaling of blunt trauma and expansion to include penetrating injuries have resulted in the publication of the 1985 revision of the Abbreviated Injury Scale (AIS). To simplify use of this scale for Injury Severity Scoring in clinical practice, two 8 1/2" x 11" charts, which can be included in the patient record, have been developed from the AIS dictionary. Separate charts apply to blunt and penetrating trauma. Previous experience with a condensed AIS chart (CAIS) using the 1980 revision of the dictionary suggests that such edited revisions can result in accurate injury scaling in more than 95% of patients presenting to a Level I Trauma Center. The availability of such charts assists in calculation of the ISS soon after admission, which may prove to be a valuable teaching tool and useful in resource allocation, audit, and assessment for prospective payment. To determine and to quantify outcome from injury demands that multiple factors be universally applied so that there is uniform understanding that the same outcome is understood for the same injury. It is thus important to define the variables used in any outcome assessment. Critical to defining outcomes is the need for a universal language that defines individual injuries. The abbreviated injury scale (AIS) is the only dictionary specifically designed as a system to define the severity of injuries throughout the body. In addition to a universal injury language, it provides measures of injury severity that can be used to stratify and classify injury severity in all body regions. Its revision, AIS 2005 will be discussed here. In the advanced nations trauma represents the third cause of death after cardiovascular diseases and tumours. Recently, great importance has been given to the need to treat traumas as quickly as possible in order to reduce mortality and morbidity. Prompt management of is the gold standard in the emergency setting and the phrase "golden hour" is now commonly used. The authors report on their experience with the management of multiple trauma, through the study of 617 clinical cases. Patients were evaluated with the Revised Trauma Score (RTS), Injury Severity Score (ISS) and Abbreviated Injury Scale (AIS). Of 420 (68%) cases of major trauma only one patient had ISS > 60. Patients were admitted on average after 47 +/- 18 min. Only two deaths occurred in the emergency unit. The task of the emergency unit is to stabilise the patients, anticipate the complications, including mainly shock and multiple organ failure, optimizing time, interventions and resources to reduce morbidity and mortality. INTRODUCTION: Various trauma scoring systems were developed in order to assess injury severity and aid in decision making regarding further therapy and probable outcome. ANATOMIC INJURY SEVERITY SCALES: AIS--Abbreviated Injury Scale is a summary of all the values (from 1-9) for each organ or body part that is injured. ISS--Injury Severity Scale scores three dominant injuries from AIS scale. The maximum score for ISS is 75. MISS--Modified Injury Severity Score is a square of the AIS value for the three body parts with most severe injuries. PHYSIOLOGIC INJURY SEVERITY SCALES: GCS--Glasgow Coma Score is a numerical scale that assesses the severity of CNS injuries, that is the most appropriate system for numerical assessment of consciousness disturbance. Trauma score is a sum of GCS decreased for 1/3, plus the assessment of cardiopulmonary function. COMBINED ANATOMIC-PHYSIOLOGIC SCORING SYSTEMS: TRISS score (TS-ISS--trauma and injury severity score) TRISS combines ISS, TS, age of the patient and mechanism of injury, in order to determine survival probability. PTS--Pediatric Trauma Score takes into consideration all of the peculiarities of pediatric patients in response to trauma. Score values are from -6 to +12. APACHE--Acute Physiology And Chronic Health Evaluation Although it is complicated for general use, it still represents the most commonly used scoring system in Intensive Care Units. NEW SCORING SYSTEMS: MPM--Mortality Probability Models. MODS--Multiple Organ Dysfunction Syndrome. LODS--Logistic Organ Dysfunction Syndrome. SAPS--Simplified Acute Physiologic Score. The new AIS (Abbreviated Injury Scale) was released with an update by the AAAM (Association for the Advancement of Automotive Medicine) in 2008. It is a universal scoring system in the field of trauma applicable in clinic and research. In engineering it is used as a classification system for vehicle safety. The AIS can therefore be considered as an international, interdisciplinary and universal code of injury severity. This review focuses on a historical overview, potential applications and new coding options in the current version and also outlines the associated problems. Background: The most widely used methods of describing traumatic brain injury (TBI) are the Glasgow Coma Scale (GCS) and the Abbreviated Injury Scale (AIS). Recent evidence suggests that presenting GCS in older patients may be higher than that in younger patients for an equivalent anatomical severity of TBI. This study aimed to assess these observations with a propensity-score matching approach using the data from Trauma Registry System in a Level I trauma center. Methods: We included all adult patients (aged ≥20 years old) with moderate to severe TBI from 1 January 2009 to 31 December 2016. Patients were categorized into elderly (aged ≥65 years) and young adults (aged 20-64 years). The severity of TBI was defined by an AIS score in the head (AIS 3‒4 and 5 indicate moderate and severe TBI, respectively). We examined the differences in the GCS scores by age at each head AIS score. Unpaired Student's t- and Mann-Whitney U-tests were used to analyze normally and non-normally distributed continuous data, respectively. Categorical data were compared using either the Pearson chi-square or two-sided Fisher's exact tests. Matched patient populations were allocated in a 1:1 ratio according to the propensity scores calculated using NCSS software with the following covariates: sex, pre-existing chronic obstructive pulmonary disease, systolic blood pressure, hemoglobin, sodium, glucose, and alcohol level. Logistic regression was used to evaluate the effects of age on the GCS score in each head AIS stratum. Results: The study population included 2081 adult patients with moderate to severe TBI. These patients were categorized into elderly (n = 847) and young adults (n = 1234): each was exclusively further divided into three groups of patients with head AIS of 3, 4, or 5. In the 162 well-balanced pairs of TBI patients with head AIS of 3, the elderly demonstrated a significantly higher GCS score than the young adults (14.1 ± 2.2 vs. 13.1 ± 3.3, respectively; p = 0.002). In the 362 well-balanced pairs of TBI patients with head AIS of 4, the elderly showed a significantly higher GCS score than the young adults (13.1 ± 3.3 vs. 12.2 ± 3.8, respectively; p = 0.002). In the 89 well-balance pairs of TBI patients with head AIS of 5, no significant differences were observed for the GCS scores. Conclusions: This study demonstrated that elderly patients with moderate TBI present higher GCS score than younger patients. This study underscores the importance of determining of TBI severity in this group of elderly patients based on the GCS score alone. A lower threshold of GCS cutoff should be adopted in the management of the elderly patients with TBI. BACKGROUND: The Abbreviated Injury Scale (AIS) is an anatomical-based coding system created by the Association for the Advancement of Automotive Medicine, utilized to classify and code injuries resulting from trauma, in order of severity. According to the latest version, all Thoraco-Lumbar Compression Fractures (TLCF), even without injury to other spine components and with >20% loss of height, were branded AIS 3 injuries, reflecting a serious threat to life or permanent disability. Advances in spine imaging, recent biomechanical studies, and long-term outcomes research offer the opportunity to consider these injuries differently. OBJECTIVE: To re-evaluate the percent compression threshold of TLCF of the spine from motor vehicle crashes (MVC) for serious risk to life identified as surgical treatment, delineating a reliable cut-off for fracture severity and morbidity. Little national data considers degree of compression and provides adequate followup imaging to determine degree of compression, justifying this effort. METHODS: Charts and radiographs of patients admitted to our institution due to vehicle crashes with isolated (vertebral body only) TLCF between 2008 and 2015 were reviewed. Data were collected on degree of compression, treatment, and long-term outcomes to determine the threshold of permanent injury. Vertebral bodies at the level of fracture were measured both anteriorly and posteriorly, and compared to adjacent segments; percentage compression was calculated. RESULTS: 1470 patient records with diagnoses of spine trauma were reviewed; 695 isolated compression fractures were identified, of which 194 were in vehicle crashes and had adequate imaging and follow-up. Ages ranged from 19 to 82, with a male: female ratio of 60:40. No patient with vertebral body compression of less than 30% underwent surgery unless presenting with a neurological deficit. All 22 surgical patients demonstrated significant retropulsion of bone into the spinal canal. Five surgical patients suffered eight complications; there were no adverse outcomes in the nonsurgical group. CONCLUSIONS: These results are consistent with evolving clinical thinking, resulting in decreasing surgical incidence and orthosis use. Our data strongly suggests that isolated compression fractures in the absence of neurologic deficit or severe cord compression due to retropulsed bone are self-limiting. Therefore, the AIS scores for these common injuries could be reconsidered and reflect their relatively benign outlook. BACKGROUND: The International Statistical Classification of Diseases and Related Health Problems (ICD) is currently undergoing a revision process to develop the Eleventh Revision (ICD-11), but substantial modification of chapter 19 has not been proposed despite its known problems in describing injury severity and multiple injuries. Many facilities treating trauma patients perform duplicate coding for trauma diagnoses using two different classification systems, the ICD for administrative purposes and the Abbreviated Injury Scale (AIS) for trauma registry, because unambiguous conversion of codes between the ICD and AIS is not always possible due to structural differences. AIM: We developed a new bridging classification system which can be unambiguously converted to both ICD and AIS. METHODS AND RESULTS: The bridging classification adopted multidimensional coding and addressed differences in granularity and classification boundaries by adopting the more detailed categorizations whenever the granularity and classification boundaries differed between the ICD and AIS. Then we showed that the bridging classification codes could unambiguously converted to both ICD and AIS. CONCLUSION: Once injuries are coded using the bridging classification, the ICD and AIS codes are readily available. Integrating the new bridging classification into the ICD-11, possibly as a clinical modification, would eliminate the necessity of complicated procedures for code conversion and duplicate coding, and benefit users by building on the strengths of both the ICD and AIS. OBJECTIVE: The purpose of this study is to investigate the injury patterns of noncatastrophic accidents by individual age groups. METHODS: Data were collected from the Korean In-Depth Accident Study database based on actual accident investigation. The noncatastrophic criteria were classified according to U.S. experts from the Centers for Disease Control and Prevention's recommendations for field triage guidelines of high-risk automobile crash criteria by vehicle intrusions more than 12 in. on occupant sites (including the roof) and more than 18 in. on any site. The Abbreviated Injury Scale (AIS) was used to determine injury patterns for each body region. Severely injured patients were classified as Maximum Abbreviated Injury Scale (MAIS) 3 or higher. RESULTS: In this study, the most significant injury regions were the head and neck, extremities, and thorax. In addition, the incidence of severe injury among elderly patients was nearly 1.6 times higher than that of non-elderly patients. According to age group, injured body regions among the elderly were the thorax, head and neck, and extremities, in that order. For the non-elderly groups, these were head and neck, extremities, and thorax. Severe injury rates were slightly different for the elderly group (head and neck, abdomen) and non-elderly group (thorax, head and neck). CONCLUSIONS: In both age groups, the rate of severe injury is proportional to an increase in crush extent zone. Front airbag deployment may have a relatively significant relationship to severe injuries. INTRODUCTION: There is no specific injury among fatally injured frontal car-occupants in frontal car collisions, used in forensic expertise. We tried to point out the usefulness of the Abbreviated Injury Scale (AIS) and Injury Severity Score (ISS) for the expertise in such cases. OBJECTIVE: Analyzing the severity of body region injuries and total injury severity of deceased car occupants, to point out their importance in forensic expertise. METHOD: Retrospective autopsy study was performed. Autopsy records of all deceased car-occupants in frontal car collisions were analyzed in order to establish the severity of injuries in body regions (AIS) and total severity of injuries (ISS). Statistical analysis was performed using the chi-square test, t-test, and logistic regression, with significance set at p < 0.05. RESULTS: A total of 500 cases were analyzed: 282 car-drivers and 218 front car-passengers, average age of 41.48 +/- 15.31 and 39.78 +/- 16.93. There were 401 males and 99 females. The most injured body region was head with neck: AIS = 3.50 +/- 2.48, for car-drivers, and AIS = 3.54 +/- 2.50, for front car-passengers, as well as thorax: AIS = 3.63 +/- 2.16 car-drivers, and AIS = 3.37 +/- 2.14, for front car-passengers. More severe injuries of head (AIS > or =4) suggested that deceased was a front car-passenger (Wald = 13.27; p = 0.04). More severe injuries of thorax and abdomen (AIS > or =5) indicated that deceased was a car-driver (Wald = 5.72; p = 0.02, and Wald = 8.23; p = 0.01, respectively). The injury severity of the face and limbs were useless in such expertise (Wald = 1.72; p = 0.19, and Wald =0.89; p = 0.34, respectively). An average ISS was 57.31 +/- 20.16 for car-drivers, and 54.54 +/- 21.01 for front car-passengers. The ISS value was useless in expertise (t=1.50; p = 0.13, and Wald = 2.24; p = 0.13). CONCLUSION: As the injury of the head is more severe, the deceased is more likely to be the front car-passenger. Severe thoracic and abdominal injuries are more characteristic for car-drivers. A total injury severity is useless for forensic expertise in cases of fatally injured in car collisions. One of the more often used measures of multiple injuries is the injury severity score (ISS). Determination of the ISS is based on the abbreviated injury scale (AIS). This paper suggests a new algorithm to sort the AISs for each case and calculate ISS. The program uses unsorted abbreviated injury scale (AIS) levels for each case and rearranges them in descending order. The first three sorted AISs representing the three most severe injuries of a person are then used to calculate injury severity score (ISS). This algorithm should be useful for analyses of clusters of injuries especially when more patients have multiple injuries. In-hospital complications in trauma patients are frequent and associated with increased morbidity and mortality. The aim of this study was to analyze the association between posttraumatic complications and the injured body region, injury and trauma severity, length of stay, and mortality in hospitalized trauma patients. This observational and retrospective study included 147 trauma patients with posttraumatic complications hospitalized in a university hospital located in São Paulo, Brazil. The injury and trauma severity was measured using the Abbreviated Injury Scale (AIS) and the Injury Severity Score (ISS), respectively. The association between variables was verified applying χ test, Fisher exact text, likelihood ratio, and Mann-Whitney U test, considering significance level of 5%. The most frequent in-hospital complications were infectious, cardiovascular, metabolic, and renal. Patients with head injury AIS score of 3 or more had higher percentage of neurological complications and those with lower extremity injury AIS score of less than 3 had higher percentage of metabolic and renal complications. There was no association between thoracic injury and cardiovascular complications, nor between types of complications and trauma severity (ISS). Patients without cardiovascular complication and those with infections had longer hospital length of stay, and mortality was higher in those with cardiovascular complications. Complication's studies in trauma patients may contribute to identify events related with poor outcome and to implement specific measures for improving quality of trauma care and patient security.

Which protein family is epiregulin a member of?

EREG (epiregulin), a member of the epidermal growth factor (EGF) family.

[32700456]

OBJECTIVES: EREG (epiregulin), a member of the epidermal growth factor (EGF) family, plays a role in inflammation, wound healing, normal physiology and malignancies. However, little is known about its function on hair growth. MATERIALS AND METHODS: Cell growth assay, QPCR and immunostaining were carried out. Telogen-to-anagen transition and organ culture were conducted. ROS level was monitored by staining DCFDA. RESULTS: We investigated the hair inductive effect of EREG and the mechanism of stimulation on DPCs and ORS cells during hair cycling. Whereas EREG promoted hair growth, EREG knockdown inhibited hair growth as evidenced by telogen-to-anagen transition and organ culture models. EREG was expressed in epidermal cells including ORS cells in vivo. EREG activated phospho-ErbB4 in DPCs during hair cycling and stimulated DPCs via ErbB4 activation in vitro. In terms of the underlying mechanism, reactive oxygen species (ROS) played a key role in DPC stimulation. EREG also activated phospho-EGF receptor (EGFR) in epidermal cells including matrix and ORS cells in vivo and stimulated ORS cells via EGFR activation in vitro. CONCLUSIONS: EREG, which is released from ORS cells, activated EGFR and ErbB4 on epidermal cells and DPCs during hair cycling, respectively. As a result, EREG stimulated epidermal cells a positive feedback and DPCs via regulating ROS generation for hair growth. Therefore, EREG therapy may be a novel solution for hair loss treatment.

Describe Cap Trap RNA-seq

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Cap Trap RNA-seq is a technology which combines cap trapping and long read MinION sequencing.

[34078885]

Collaborators: Abugessaisa I, Aitken S, Aken BL, Alam I, Alam T, Alasiri R, Alhendi AMN, Alinejad-Rokny H, Alvarez MJ, Andersson R, Arakawa T, Araki M, Arbel T, Archer J, Archibald AL, Arner E, Arner P, Asai K, Ashoor H, Astrom G, Babina M, Baillie JK, Bajic VB, Bajpai A, Baker S, Baldarelli RM, Balic A, Bansal M, Batagov AO, Batzoglou S, Beckhouse AG, Beltrami AP, Beltrami CA, Bertin N, Bhattacharya S, Bickel PJ, Blake JA, Blanchette M, Bodega B, Bonetti A, Bono H, Bornholdt J, Bttcher M, Bougouffa S, Boyd M, Breda J, Brombacher F, Brown JB, Bult CJ, Burroughs AM, Burt DW, Busch A, Caglio G, Califano A, Cameron CJ, Cannistraci CV, Carbone A, Carlisle AJ, Carninci P, Carter KW, Cesselli D, Chang JC, Chen JC, Chen Y, Chierici M, Christodoulou J, Ciani Y, Clark EL, Coskun M, Dalby M, Dalla E, Daub CO, Davis CA, de Hoon MJL, de Rie D, Denisenko E, Deplancke B, Detmar M, Deviatiiarov R, Di Bernardo D, Diehl AD, Dieterich LC, Dimont E, Djebali S, Dohi T, Dostie J, Drablos F, Edge ASB, Edinger M, Ehrlund A, Ekwall K, Elofsson A, Endoh M, Enomoto H, Enomoto S, Faghihi M, Fagiolini M, Farach-Carson MC, Faulkner GJ, Favorov A, Fernandes AM, Ferrai C, Forrest ARR, Forrester LM, Forsberg M, Fort A, Francescatto M, Freeman TC, Frith M, Fukuda S, Funayama M, Furlanello C, Furuno M, Furusawa C, Gao H, Gazova I, Gebhard C, Geier F, Geijtenbeek TBH, Ghosh S, Ghosheh Y, Gingeras TR, Gojobori T, Goldberg T, Goldowitz D, Gough J, Greco D, Gruber AJ, Guhl S, Guigo R, Guler R, Gusev O, Gustincich S, Ha TJ, Haberle V, Hale P, Hallstrom BM, Hamada M, Handoko L, Hara M, Harbers M, Harrow J, Harshbarger J, Hase T, Hasegawa A, Hashimoto K, Hatano T, Hattori N, Hayashi R, Hayashizaki Y, Herlyn M, Heutink P, Hide W, Hitchens KJ, Sui SH, 't Hoen PAC, Hon CC, Hori F, Horie M, Horimoto K, Horton P, Hou R, Huang E, Huang Y, Hugues R, Hume D, Ienasescu H, Iida K, Ikawa T, Ikemura T, Ikeo K, Inoue N, Ishizu Y, Ito Y, Itoh M, Ivshina AV, Jankovic BR, Jenjaroenpun P, Johnson R, Jorgensen M, Jorjani H, Joshi A, Jurman G, Kaczkowski B, Kai C, Kaida K, Kajiyama K, Kaliyaperumal R, Kaminuma E, Kanaya T, Kaneda H, Kapranov P, Kasianov AS, Kasukawa T, Katayama T, Kato S, Kawaguchi S, Kawai J, Kawaji H, Kawamoto H, Kawamura YI, Kawasaki S, Kawashima T, Kempfle JS, Kenna TJ, Kere J, Khachigian L, Kiryu H, Kishima M, Kitajima H, Kitamura T, Kitano H, Klaric E, Klepper K, Klinken SP, Kloppmann E, Knox AJ, Kodama Y, Kogo Y, Kojima M, Kojima S, Komatsu N, Komiyama H, Kono T, Koseki H, Koyasu S, Kratz A, Kukalev A, Kulakovskiy I, Kundaje A, Kunikata H, Kuo R, Kuo T, Kuraku S, Kuznetsov VA, Kwon TJ, Larouche M, Lassmann T, Law A, Le-Cao KA, Lecellier CH, Lee W, Lenhard B, Lennartsson A, Li K, Li R, Lilje B, Lipovich L, Lizio M, Lopez G, Magi S, Mak GK, Makeev V, Manabe R, Mandai M, Mar J, Maruyama K, Maruyama T, Mason E, Mathelier A, Matsuda H, Medvedeva YA, Meehan TF, Mejhert N, Meynert A, Mikami N, Minoda A, Miura H, Miyagi Y, Miyawaki A, Mizuno Y, Morikawa H, Morimoto M, Morioka M, Morishita S, Moro K, Motakis E, Motohashi H, Mukarram AK, Mummery CL, Mungall CJ, Murakawa Y, Muramatsu M, Murata M, Nagasaka K, Nagase T, Nakachi Y, Nakahara F, Nakai K, Nakamura K, Nakamura Y, Nakamura Y, Nakazawa T, Nason GP, Nepal C, Nguyen QH, Nielsen LK, Nishida K, Nishiguchi KM, Nishiyori H, Nitta K, Noguchi S, Noma S, Notredame C, Ogishima S, Ohkura N, Ohno H, Ohshima M, Ohtsu T, Okada Y, Okada-Hatakeyama M, Okazaki Y, Oksvold P, Orlando V, Ow GS, Ozturk M, Pachkov M, Paparountas T, Parihar SP, Park SJ, Pascarella G, Passier R, Persson H, Philippens IH, Piazza S, Plessy C, Pombo A, Ponten F, Poulain S, Poulsen TM, Pradhan S, Prezioso C, Pridans C, Qin XY, Quackenbush J, Rackham O, Ramilowski J, Ravasi T, Rehli M, Rennie S, Rito T, Rizzu P, Robert C, Roos M, Rost B, Roudnicky F, Roy R, Rye MB, Sachenkova O, Saetrom P, Sai H, Saiki S, Saito M, Saito A, Sakaguchi S, Sakai M, Sakaue S, Sakaue-Sawano A, Sandelin A, Sano H, Sasamoto Y, Sato H, Saxena A, Saya H, Schafferhans A, Schmeier S, Schmidl C, Schmocker D, Schneider C, Schueler M, Schultes EA, Schulze-Tanzil G, Semple CA, Seno S, Seo W, Sese J, Severin J, Sheng G, Shi J, Shimoni Y, Shin JW, SimonSanchez J, Sivertsson A, Sjostedt E, Soderhall C, Laurent GS 3rd, Stoiber MH, Sugiyama D, Summers KM, Suzuki AM, Suzuki H, Suzuki K, Suzuki M, Suzuki N, Suzuki T, Swanson DJ, Swoboda RK, Tagami M, Taguchi A, Takahashi H, Takahashi M, Takamochi K, Takeda S, Takenaka Y, Tam KT, Tanaka H, Tanaka R, Tanaka Y, Tang D, Taniuchi I, Tanzer A, Tarui H, Taylor MS, Terada A, Terao Y, Testa AC, Thomas M, Thongjuea S, Tomii K, Torlai Triglia E, Toyoda H, Tsang HG, Tsujikawa M, Uhlén M, Valen E, van de Wetering M, van Nimwegen E, Velmeshev D, Verardo R, Vitezic M, Vitting-Seerup K, von Feilitzen K, Voolstra CR, Vorontsov IE, Wahlestedt C, Wasserman WW, Watanabe K, Watanabe S, Wells CA, Winteringham LN, Wolvetang E, Yabukami H, Yagi K, Yamada T, Yamaguchi Y, Yamamoto M, Yamamoto Y, Yamamoto Y, Yamanaka Y, Yano K, Yasuzawa K, Yatsuka Y, Yo M, Yokokura S, Yoneda M, Yoshida E, Yoshida Y, Yoshihara M, Young R, Young RS, Yu NY, Yumoto N, Zabierowski SE, Zhang PG, Zucchelli S, Zwahlen M.

What is the use of the Canadian C-Spine Rule?

The Canadian C-spine rule clinically clears cervical spine fracture without imaging.

[32965634, 34108196, 17288613, 28844294, 32373348, 32805098, 32348267, 16730989, 33987067, 34548412, 19394111]

Author information: (1)Department of Intensive Care Nursing, School of Nursing and Midwifery, Tehran University of Medical Sciences, Tehran, Iran. (2)Road Traffic Injury Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. (3)Department of Clinical Pharmacy (Pharmacotherapy), Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. (4)Tuberculosis and Lung Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. (5)Pre-Hospital and Hospital Research Center, Tehran University of Medical Sciences, Tehran, Iran. (6)Department of Emergency Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran. (7)Community Medicine, College of Medicine, University of Sulaimani, Sulaimani, Iraq. (8)Department of Emergency Medicine, Maragheh University of Medical Sciences, Maragheh, Iran. (9)Community Health Department, Technical College of Health, Sulaimani Polytechnic University, Sulaimani, Iraq. (10)Emergency Department, 9-Day Hospital, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran. (11)Department of Epidemiology and Biostatistics School of Public Health, Tehran University of Medical Sciences, Poursina Ave, Tehran, Iran. (12)Department of Emergency Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. (13)Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK. (14)Physiology Research Center, School of Medicine, Iran University of Medical Sciences, Hemmat Highway, Tehran, Iran. (15)Physiology Research Center, School of Medicine, Iran University of Medical Sciences, Hemmat Highway, Tehran, Iran. yousefifard.m@iums.ac.ir. (16)Department of Epidemiology and Biostatistics School of Public Health, Tehran University of Medical Sciences, Poursina Ave, Tehran, Iran. mhossein110@yahoo.com. (17)Pediatric Chronic Kidney Disease Research Center, University of Medical Sciences, Tehran, Iran. mhossein110@yahoo.com. BACKGROUND: A consistent approach to cervical spine injury (CSI) clearance for patients 65 and older remains a challenge. Clinical clearance algorithms like the National Emergency X-Radiography Utilisation Study (NEXUS) criteria have variable accuracy and the Canadian C-spine rule excludes older patients. Routine CT of the cervical spine is performed to rule out CSI but at an increased cost and low yield. Herein, we aimed to identify predictive clinical variables to selectively screen older patients for CSI. METHODS: The University of Iowa's trauma registry was interrogated to retrospectively identify all patients 65 years and older who presented with trauma from a ground-level fall from January 2012 to July 2017. The relationship between predictive variables (demographics, NEXUS criteria and distracting injuries) and presence of CSI was examined using the generalised linear modelling (GLM) framework. A training set was used to build the statistical models to identify clinical variables that can be used to predict CSI and a validation set was used to assess the reliability and consistency of the model coefficients estimated from the training set. RESULTS: Overall, 2312 patients ≥65 admitted for ground-level falls were identified; 253 (10.9%) patients had a CSI. Using the GLM framework, the best predictive model for CSI included midline tenderness, focal neurological deficit and signs of trauma to the head/face, with midline tenderness highly predictive of CSI (OR=22.961 (15.178-34.737); p<0.001). The negative predictive value (NPV) for this model was 95.1% (93.9%-96.3%). In the absence of midline tenderness, the best model included focal neurological deficit (OR=2.601 (1.340-5.049); p=0.005) and signs of trauma to the head/face (OR=3.024 (1.898-4.815); p<0.001). The NPV was 94.3% (93.1%-95.5%). CONCLUSION: Midline tenderness, focal neurological deficit and signs of trauma to the head/face were significant in this older population. The absence of all three variables indicates lower likelihood of CSI for patients≥65. Future observational studies are warranted to prospectively validate this model. INTRODUCTION: The Canadian C-Spine Rule (CCR) is a clinical decision aid to facilitate the safe removal of cervical collars in the alert, orientated, low-risk adult trauma patient. Few health care settings have assessed initiatives to train charge nurses to use the CCR. This practice improvement project conducted in a secondary trauma center in Canada aimed to (1) train charge nurses of the emergency room to use the CCR, (2) monitor its use throughout the project period, and (3) compare the assessments of the charge nurses with those of emergency physicians. METHODS: The project began with the creation of an interdisciplinary team. Clinical guidelines were established by the interdisciplinary project team. Nine charge nurses of the emergency room were then trained to use the CCR (3 on each 8-hour shift). The use of the CCR was monitored throughout the project period, from June 1 to October 5, 2016. RESULTS: The 3 aims of this practice improvement project were attained successfully. Over a 5-month period, 114 patients were assessed with the CCR. Charge nurses removed the cervical collars for 54 of 114 patients (47%). A perfect agreement rate (114 of 114 patients, 100%) was attained between the assessments of the nurses and those of physicians. DISCUSSION: This project shows that the charge nurses of a secondary trauma center can use the CCR safely on alert, orientated, and low-risk adult trauma patients as demonstrated by the agreement in the assessments of emergency room nurses and physicians. Author information: (1)Department of Emergency Medicine, University of Iowa, Iowa City, IA. The Canadian c-spine rule (CCR) allows safe, reproducible use of radiography in alert, stable patients with potential c-spine injury in the emergency setting [Stiell, I., Clement, C., McKnight, R., Brison, R., Schull, M., Lowe, B., Worthington, J., Eisenhauer, M., Cass, D., Greenberg, G., MacPhail, I., Dreyer, J., Lee, J., Bandiera, G., Reardon, M., Holroyd, B., Lesiuk, H., G. Wells, 2003. The Canadian c-spine rule versus the nexus low-risk criteria in patients with trauma. The New England journal of medicine 349 (26), 2510-2518; Stiell, I., Wells, G., Vandemheen, K., Clement, C., 2001. The Canadian c-spine rule for radiography in alert and stable trauma patients. JAMA 286 (15), 1841]. This paper reports on a study of emergency nurses' ability to identify patients requiring immobilisation using the CCR. Emergency department triage nurses (N = 112) were trained in the use of the CCR and then asked to use the tool over the following 14 months in the assessment of 460 patients who presented with potential c-spine injury. Trained medical staff repeated 55% of the clinical assessments independently using the rule. The level of agreement between nurse and medical judgement was calculated. The inter-rater reliability using the kappa statistic was 0.6 (95% CI 0.50-0.62 N = 254) indicating a 'good' level of agreement. The majority of nurses indicated they were comfortable using the rule. The results suggest that UK emergency department nurses were able to use the Canadian c-spine rule to successfully guide selective immobilisation. A 25% reduction in immobilisation rates would have been achieved if the rule had been followed. Further studies are needed to test the reduction in levels of immobilisation that could be achieved in clinical practice. The unique anatomy and flexibility of the cervical spine predispose it to a risk of injury. Trauma to the cervical spine encompasses a wide range of injuries from minor muscular strains to life-threatening fracture-dislocations associated with spinal cord lesions. Initial assessment and management should follow the Advanced Trauma Life Support (ATLS) protocols with adequate protection of the cervical spine through triple immobilisation to prevent any unnecessary movement, which can make the patient susceptible to further neurological injuries. Although the presence of cervical spine injury is very often overt, reliance on clinical examination alone is sometimes not sufficient and potentially requires further imaging. Clinical decision rules such as the Canadian C-Spine Rule are frequently used to risk-stratify patients needing radiography. The level of cervical spine instability and knowledge of their unique classification systems is of paramount importance and assists in the decision-making process to guide definitive management. In this review, we also propose an algorithm to aid the initial management of a patient with suspected cervical spine injury in the emergency department. OBJECTIVE: The Canadian C-Spine Rule (CCR) and the National Emergency X-Radiography Utilization Study (NEXUS) criteria are two commonly used clinical decision rules which use midline cervical spine (c-spine) tenderness on palpation as an indication for c-spine imaging post-trauma. This study was undertaken to determine the prevalence and location of midline c-spine tenderness in the non-trauma population. METHODS: We prospectively evaluated consenting adult patients presenting to an urban ED or university sport medicine clinic in Montreal, Canada between 2018 and 2020 for atraumatic non-head and neck-related reports over a 20-month period. The presence and location of pain during midline c-spine palpation as assessed by two examiners during separate evaluations was recorded. Patient information such as age, neck length and circumference, gender, body mass index (BMI) and scaphoid tenderness was also collected. RESULTS: Of 478 patients enrolled, 286 (59.8%) had midline c-spine tenderness on palpation with both examiners. The majority of those with tenderness were female (70.6%). When examining all patients, tenderness was present in the upper third of the c-spine in 128 (26.8%) patients, middle third in 270 (56.5%) patients and lower third in 6 (1.3%) patients. Factors associated with having increased odds of midline c-spine tenderness on palpation included a lower BMI and the presence of scaphoid tenderness on palpation. CONCLUSIONS: There is a high prevalence of c-spine tenderness on palpation in patients who have not undergone head or neck trauma. This finding may help explain the low specificity in some of the validation studies examining the CCR and the NEXUS criteria.

What is the Daughterless gene?

The daughterless (da) gene in Drosophila encodes a broadly expressed transcriptional regulator whose specific functions in the control of sex determination and neurogenesis have been extensively examined.

[8217842, 11731451, 8149916]

The daughterless (da) gene in Drosophila functions in the regulation of at least three significant developmental pathways: sex determination, neurogenesis and oogenesis. As a member of the helix-loop-helix (HLH) family of DNA binding proteins, the da gene product appears to act as a transcription factor. Based on the genetic and molecular characterization of da, it has been proposed that the da protein (Da) functions as a generic member of this family, serving throughout development as a necessary binding partner for an assortment of other HLH proteins. As a result of temporally and/or spatially restricted expression, these binding partners would provide some regulatory specificity to the functional transcription complex. In order to participate in this way in the regulation of multiple genes, Da must be expressed in numerous times and places during development. Using anti-Da antibodies, we validate two predictions of this scenario of Da function: (1) Da protein is not only nuclear localized, but also associated with chromosomes in vivo; and (2) Da protein is widely distributed, both spatially and temporally, throughout development. With regard to the essential role of maternal da+ in progeny sex determination, little, if any, Da protein is synthesized in the maternal germline. This suggests that the female-specific germline function of da+ is provided to the zygote as maternally synthesized RNA that becomes translated early in embryogenesis. As the only class I helix-loop-helix transcription factor in Drosophila, Daughterless (Da) has generally been regarded as a ubiquitously expressed binding partner for other developmentally regulated bHLH transcription factors. From analysis of a novel tissue-specific allele, da(lyh), we show that da expression is not constitutive, but is dynamically regulated. This transcriptional regulation includes somatic ovary-specific activation, autoregulation and negative regulation. Unexpectedly, the diverse functions of da may require that expression levels be tightly controlled in a cell and/or tissue-specific manner. Our analysis of da(lyh) identifies it as the first springer insertion that functions as an insulating element, with its disruptive activity mediated by the product of a fourth chromosome gene, Suppressor of lyh [Su(lyh)]. The daughterless (da) gene in Drosophila encodes a broadly expressed transcriptional regulator whose specific functions in the control of sex determination and neurogenesis have been extensively examined. We describe here a third major developmental role for this regulatory gene: follicle formation during oogenesis. A survey of da RNA and protein distribution during oogenesis reveals a multiphasic expression pattern that includes both germline and soma. Whereas the germline expression reflects da's role in progeny sex determination, the somatic ovary expression of da correlates with the gene's role during egg chamber morphogenesis. Severe, but viable, hypomorphic da mutant genotypes exhibit dramatic defects during oogenesis, including aberrantly defined follicles and loss of interfollicular stalks. The follicular defects observed in da mutant ovaries are qualitatively very similar to those described in Notch (N) or Delta (Dl) mutant ovaries. Moreover, in the ovary da- alleles exhibit dominant synergistic interactions with N or Dl mutations. We propose that all three of these genes function in the same regulatory pathway to control follicle formation.

Is telomestatin, a novel statin drug used to treat high cholesterol?

Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4 and has been shown to be a very potent telomerase inhibitor and is used to treat cancer.

[11878947, 12917635, 15283144, 23909929, 28611443, 16652154]

Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4 and has been shown to be a very potent telomerase inhibitor. The structural similarity between telomestatin and a G-tetrad suggested to us that the telomerase inhibition might be due to its ability either to facilitate the formation of or trap out preformed G-quadruplex structures, and thereby sequester single-stranded d[T(2)AG(3)](n) primer molecules required for telomerase activity. Significantly, telomestatin appears to be a more potent inhibitor of telomerase (5 nM) than any of the previously described G-quadruplex-interactive molecules. In this communication we provide the first experimental evidence that telomestatin selectively facilitates the formation of or stabilizes intramolecular G-quadruplexes, in particular, that produced from the human telomeric sequence d[T(2)AG(3)](4). A simulated annealing (SA) docking approach was used to study the binding interactions of telomestatin with the intramolecular antiparallel G-quadruplex structure. Each intramolecular G-quadruplex molecule was found to bind two telomestatin molecules (unpublished results). A 2:1 model for the telomestatin bound in the external stacking mode in an energy minimized complex with the human telomeric basket-type G-quadruplex was constructed. Our observation that a G-quadruplex-interactive molecule without significant groove interactions is able to reorient in a G-quadruplex structure proints to the importance of core interaction with an asymmetric G-quadruplex structure in producing selective binding. Furthermore, the G-quadruplex interactions of telomestatin are more selective for the intramolecular structure in contrast to other G-quadruplex-interactive agents, such as TMPyP4. The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. In order to determine whether G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), might have effects on telomere dynamics and to evaluate the clinical utility, we assessed the effects of telomestatin on BCR-ABL-positive human leukemia cells. We found that treatment with telomestatin reproducibly inhibited telomerase activity in the BCR-ABL-positive leukemic cell lines OM9;22 and K562, resulting in telomere shortening. Inhibition of telomerase activity by telomestatin disrupts telomere maintenance and ultimately results in telomere dysfunction. Telomestatin completely suppressed the plating efficiency of K562 cells at 1 microM; however, telomestatin had less effects on BFU-Es and CFU-GMs colony formation from normal bone marrow CD34-positive cells. Enhanced chemosensitivity toward imatinib and chemotherapeutic agents was also observed in telomestatin-treated K562 cells. Further, the combination of telomestatin plus imatinib more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. Last, telomestatin induced the activation of ATM and Chk2, and subsequently increased the expression of p21(CIP1) and p27(KIP1). These results demonstrate that telomere dysfunction induced by telomestatin activates the ATM-dependent DNA damage response. We conclude that telomerase inhibitors combined with the use of imatinib and other chemotherapeutic agents may be very useful for the treatment of human leukemia. A novel telomerase inhibitor, telomestatin, isolated from Streptomyces anulatus is the most potent telomerase inhibitor so far. Telomestatin specifically inhibited telomerase without affecting reverse transcriptases and polymerases. In addition, telomestatin induced telomere shortening, but its ratio was extremely faster than that observed in physiological telomere shortening. These results suggested the existence of other mechanisms to inhibit telomerase. Telomeres consist of guanine rich sequences which compose a characteristic three-dimensional structure designated as G-quadruplex. Stabilization of G-quadruplex structure inhibited the catalysis of not only telomerase but also other DNA interacting molecules. Telomestatin potently stabilized G-quadruplex structure in a specific manner. G-quadruplex structure is also involved in a lot of oncogene promoters. Thus, telomestatin provide the novel therapeutic molecular target for cancer chemotherapy. Guanine-rich human telomeric DNA can adopt secondary structures known as G-quadruplexes, which can be targeted by small molecules to achieve anticancer effects. So far, the structural information on complexes between human telomeric DNA and ligands is limited to the parallel G-quadruplex conformation, despite the high structural polymorphism of human telomeric G-quadruplexes. No structure has been yet resolved for the complex with telomestatin, one of the most promising G-quadruplex-targeting anticancer drug candidates. Here we present the first high-resolution structure of the complex between an intramolecular (3 + 1) human telomeric G-quadruplex and a telomestatin derivative, the macrocyclic hexaoxazole L2H2-6M(2)OTD. This compound is observed to interact with the G-quadruplex through π-stacking and electrostatic interactions. This structural information provides a platform for the design of topology-specific G-quadruplex-targeting compounds and is valuable for the development of new potent anticancer drugs. Author information: (1)Technology Research Association for Next Generation Natural Products Chemistry, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan. (2)RIKEN Center for Sustainable Resource Science, Natural Product Biosynthesis Research Unit, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. (3)Kitasato Institute for Life Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan. (4)Japan Biological Informatics Consortium, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan. (5)Department of Chemistry, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo, 152-8551, Japan. (6)RIKEN Center for Sustainable Resource Science, Molecular Structure Characterization Unit, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. (7)RIKEN Center for Sustainable Resource Science, Chemical Biology Research Group, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. (8)RIKEN Center for Sustainable Resource Science, Natural Product Biosynthesis Research Unit, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. shunjitaka@riken.jp. (9)National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan. k-shinya@aist.go.jp. The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. Recently, we have demonstrated that treatment with a G-quadruplex-interactive agent, telomestatin reproducibly inhibited telomerase activity in the BCR-ABL-positive leukemic cell lines. In the present study, we investigated the mechanisms of apoptosis induced by telomerase inhibition in acute leukemia. We have found the activation of caspase-3 and poly-(ADP-ribose) polymerase in telomestatin-treated U937 cells (PD20) and dominant-negative DN-hTERT-expressing U937 cells (PD25). Activation of p38 mitogen-activated protein (MAP) kinase and MKK3/6 was also found in telomestatin-treated U937 cells (PD20) and dominant-negative DN-hTERT-expressing U937 cells (PD25); however, activation of JNK and ASK1 was not detected in these cells. To examine the effect of p38 MAP kinase inhibition on growth properties and apoptosis in telomerase-inhibited cells, we cultured DN-hTERT-expressing U937 cells with or without SB203580. Dominant-negative-hTERT-expressing U937 cells stopped proliferation on PD25; however, a significant increase in growth rate was observed in the presence of SB203580. Treatment of SB203580 also reduced the induction of apoptosis in DN-hTERT-expressing U937 cells (PD25). These results suggest that p38 MAP kinase has a critical role for the induction of apoptosis in telomerase-inhibited leukemia cells. Further, we evaluated the effect of telomestatin on the growth of U937 cells in xenograft mouse model. Systemic intraperitoneal administration of telomestatin in U937 xenografts decreased tumor telomerase levels and reduced tumor volumes. Tumor tissue from telomestatin-treated animals exhibited marked apoptosis. None of the mice treated with telomestatin displayed any signs of toxicity. Taken together, these results lay the foundations for a program of drug development to achieve the dual aims of efficacy and selectivity in vivo.

What is amphiregulin a ligand of?

Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand.

[34893673]

Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand. The aim of this study was to investigate the effects of baseline plasma AREG levels in KRAS, NRAS, and BRAF wild-type metastatic colorectal cancer (CRC) on treatment outcome with palliative first-line cetuximab + FOLFIRI chemotherapy. Chemotherapy outcomes were analyzed based on baseline plasma AREG levels. The clinical findings were further validated using an in vitro model of CRC. Among 35 patients, the progression-free survival (PFS) was significantly inferior in patients with high AREG than in those with low AREG levels: 10.9 vs. 24.2 months, respectively (p = 0.008). However, after failure of first-line chemotherapy, AREG levels were associated with neither PFS (4.8 vs. 11.6 months; p = 0.215) nor overall survival (8.4 vs. 13.3 months; p = 0.975). In SNU-C4 and Caco-2 cells which were relatively sensitive to cetuximab among the seven CRC cell lines tested, AREG significantly decreased the anti-proliferative effect of cetuximab (p < 0.05) via AKT and ERK activation. However, after acquiring cetuximab resistance with gradual exposure for more than 6 months, AREG neither increased colony formation nor activated AKT and ERK after cetuximab treatment. Our results suggest that plasma AREG is a potential biomarker to predict clinical outcomes after cetuximab-based chemotherapy.

Which genetic susceptibility loci are implicated in irritable bowel syndrome (IBS)?

There have been six genetic susceptibility loci identified and confirmed for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6.

[34741163]

Author information: (1)Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK. (2)Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. (3)Center for Molecular Medicine & Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. (4)School of Biological Sciences, Monash University, Clayton, Victoria, Australia. (5)IBD Pharmacogenetics, College of Medicine and Health, University of Exeter, Exeter, UK. (6)Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK. (7)William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, UK. (8)Nuffield Department of Population Health, University of Oxford, Oxford, UK. (9)23andMe, Inc., Sunnyvale, CA, USA. (10)Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. (11)Saint Edmund Hall, University of Oxford, Oxford, UK. (12)Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA. (13)Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany. (14)Department of Dermatology, Quincke Research Center, University Hospital Schleswig-Holstein, Kiel, Germany. (15)Department of Biostatistics, University of Michigan, School of Public Health, Ann Arbor, MI, USA. (16)Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway. (17)Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway. (18)Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway. (19)Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. (20)Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia. (21)Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands. (22)Clinical Enteric Neuroscience Translational and Epidemiological Research and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA. (23)David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. (24)Neurogastroenterology Unit, Wythenshawe Hospital, Centre for Gastrointestinal Sciences, University of Manchester, Manchester, UK. (25)Nottingham Digestive Diseases Centre, National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK. (26)Center for Molecular Medicine & Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. mdamato@cicbiogune.es. (27)School of Biological Sciences, Monash University, Clayton, Victoria, Australia. mdamato@cicbiogune.es. (28)Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany. mdamato@cicbiogune.es. (29)Biodonostia Health Research Institute, San Sebastian, Spain. mdamato@cicbiogune.es. (30)Gastrointestinal Genetics Lab, CIC bioGUNE - Basque Research and Technology Alliance, Derio, Spain. mdamato@cicbiogune.es. (31)IKERBASQUE, The Basque Science Foundation, Bilbao, Spain. mdamato@cicbiogune.es. (32)Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK. luke.jostins@kennedy.ox.ac.uk. (33)Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. luke.jostins@kennedy.ox.ac.uk. (34)Christ Church, University of Oxford, Oxford, UK. luke.jostins@kennedy.ox.ac.uk. (35)Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK. miles.parkes@addenbrookes.nhs.uk. (36)Department of Gastroenterology, Cambridge University Hospital, Cambridge, UK. miles.parkes@addenbrookes.nhs.uk. (#)Contributed equally

Is there an association between Guillain–Barré syndrome and covid vaccine?

Yes. There series reporting Guillain–Barré syndrome after COVID-19 vaccination.

[34649856, 33968610, 34648420, 34330729, 32896460, 34560365, 34306190, 34617967, 34484780, 34418708, 34538679, 34548920, 34187803]

In March 2020, the WHO declared COVID-19 to be a global pandemic and since December 2020, millions of vaccines have been administered. To date, cases of Guillain-Barré syndrome (GBS) following a COVID vaccine (Pfizer, Johnson & Johnson, Janssen, AstraZeneca) have been reported. A 61-year-old woman developed bilateral asymmetrical lower motor neuron (LMN) facial weakness followed by limb symptoms, 10 days after receiving the first dose of AstraZeneca COVID vaccine. The second patient was a 56-year-old man who, 9 days after receiving first dose of AstraZeneca COVID vaccine, developed bilateral asymmetrical LMN facial weakness with limb symptoms. Intravenous immunoglobulin was administered with rapid recovery. These cases of GBS following the AstraZeneca COVID vaccine add to cohort of patients reported. We flag up to raise awareness of this condition post-COVID-19 vaccine and highlight the prominent bifacial involvement. Early diagnosis and prompt treatment with intravenous immunoglobulin led to rapid recovery. Safety monitoring is of paramount importance for vaccines authorized for emergent use (EUA) by the US Food and Drug Administration (FDA) against SARS-CoV-2. Mass immunization is an essential tool to end the current pandemic, but vaccine surveillance is necessary to identify any potentially associated harms. At the same time, probability of temporal bias should be borne in mind before making conclusions about causality between the vaccine and an attributable undesired effect. We report a case of Guillain-Barré syndrome after the first dose of SARS-CoV-2 vaccine and believe this is a temporal, rather than causal association. We conducted a multi-institutional study in Taiwan and a systematic review of the literature for reports of Guillain-​Barré syndrome after coronavirus disease vaccination. This condition, mostly the classic form and the acute inflammatory demyelinating polyneuropathy subtype, has been reported in 39 cases and has occurred within 2 weeks of vaccine administration. The emergence of the coronavirus 2019 (COVID-19) pandemic has presented an unprecedented global challenge. Vaccines against COVID have been developed to date. Covid-19 has been linked with the development of Guillain-Barre Syndrome (GBS), a rare immune-mediated demyelinating neuropathy. We report three cases of Guillain-Barre Syndrome and one case of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), presenting to a Tasmanian hospital, and review 15 other reported cases and discuss likely immunopathology. Nearly all reported cases of post-COVID-19 vacciation inflammatory demyelinating polyneuropathy are linked to AstraZeneca vaccination and a variant with bifacial weakness is the most reported form of GBS globally. IMPORTANCE: As part of postauthorization safety surveillance, the US Food and Drug Administration (FDA) has identified a potential safety concern for Guillain-Barré syndrome (GBS) following receipt of the Ad26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccine. OBJECTIVE: To assess reports of GBS received in the Vaccine Adverse Event Reporting System (VAERS) following Ad26.COV2.S vaccination. DESIGN, SETTING, AND PARTICIPANTS: Reports of presumptive GBS were identified in a US passive reporting system (VAERS) February-July 2021 and characterized, including demographics, clinical characteristics, and relevant medical history. EXPOSURES: Receipt of the Ad26.COV2.S vaccine; the comparator was the background rate of GBS in the general (unvaccinated) population that had been estimated and published based on a standardized case definition. MAIN OUTCOMES AND MEASURES: Presumptive GBS; the reporting rate was analyzed, including calculation of the observed to expected ratio based on background rates and vaccine administration data. Because of limited availability of medical records, cases were not assessed according to the Brighton Collaboration criteria for GBS. RESULTS: As of July 24, 2021, 130 reports of presumptive GBS were identified in VAERS following Ad26.COV2.S vaccination (median age, 56 years; IQR, 45-62 years; 111 individuals [86.0%] were < 65 years; 77 men [59.7%]). The median time to onset of GBS following vaccination was 13 days (IQR, 10-18 days), with 105 cases (81.4%) beginning within 21 days and 123 (95.3%) within 42 days. One hundred twenty-one reports (93.1%) were serious, including 1 death. With approximately 13 209 858 doses of vaccine administered to adults in the US, the estimated crude reporting rate was 1 case of GBS per 100 000 doses administered. The overall estimated observed to expected rate ratio was 4.18 (95% CI, 3.47-4.98) for the 42-day window, and in the worst-case scenario analysis for adults 18 years or older, corresponded to an estimated absolute rate increase of 6.36 per 100 000 person-years (based on a rate of approximately 8.36 cases per 100 000 person-years [123 cases per 1 472 162 person-years] compared with a background rate of approximately 2 cases per 100 000 person-years). For both risk windows, the observed to expected rate ratio was elevated in all age groups except individuals aged 18 through 29 years. CONCLUSIONS AND RELEVANCE: These findings suggest a potential small but statistically significant safety concern for Guillain-Barré syndrome following receipt of the Ad26.COV2.S vaccine. However, the findings are subject to the limitations of passive reporting systems and presumptive case definition, and they must be considered preliminary pending analysis of medical records to establish a definitive diagnosis. Patients with neurological symptoms should be enquired about recent vaccination history. It is important after the COVID-19 mRNA vaccine, which is newly introduced as it might link to the development of a wider variety of neurological diseases. We report a case of Guillain-Barré syndrome (GBS) following the first dose of Oxford/AstraZeneca COVID-19 vaccine with papilledema as atypical onset. As the COVID-19 vaccination campaign progresses worldwide, GBSs vaccine-related have been increasingly reported. After reviewing the available literature, considering the annual incidence of GBS, in this historical moment, the public health systems cannot afford an unjustified distrust in vaccines, caused by misinterpretation of epidemiological data. Nonetheless, it is important for clinicians to promptly recognize neurological complications potentially associated with COVID-19 vaccinations and report them to pharmacovigilance agencies. BACKGROUND: Guillain-Barré Syndrome (GBS) is a rapidly progressive immune-mediated polyneuropathy often associated with an antecedent infectious illness or vaccination. The classic presentation of GBS is characterized by ascending limb weakness and numbness with loss of reflexes. However, atypical variants involving the face and arms or with purely sensory symptoms also exist. In up to 30% of cases, GBS progresses to respiratory failure, with patients requiring mechanical ventilation. CASE REPORT: We report a case of atypical GBS occurring after Coronavirus disease 2019 (COVID-19) vaccination in an otherwise healthy 38-year-old man. The patient's clinical presentation was characterized by bilateral hand and foot paresthesias, dysarthria, bilateral facial weakness, and an absence of classic ascending limb weakness. Albuminocytological dissociation within the cerebrospinal fluid was suggestive of GBS. The patient received intravenous immunoglobulin therapy, with modest improvement in his symptoms at the time of his discharge from the hospital. Why Should an Emergency PhysicianBe Aware of This? Patients with GBS are at risk for life-threatening complications, including respiratory failure requiring mechanical ventilation. It is critical for emergency physicians to be aware of the manifold presentations of GBS for early recognition and treatment. This may be of particular importance in the context of a worldwide vaccination campaign in response to the COVID-19 pandemic. ChAdOx1 nCoV-19 is an effective and well-tolerated coronavirus disease 2019 (COVID-19) vaccine. Rare cases of serious adverse events have been reported with this vaccine. We report three patients who developed Guillain-Barré syndrome following ChAdOx1 nCoV-19 vaccination, who did not have active or prior COVID-19 infection. The neurological illness in all patients had an onset of 11-13 days after the first dose of vaccine. All were characterized by sensorimotor weakness of the upper and lower limbs, with facial diplegia in one and dysautonomia in the other. Nerve conduction studies were consistent with demyelination in two and axonopathy in one. Cerebrospinal fluid analysis showed albuminocytological dissociation in two patients. All patients had moderate-to-severe disability. They were treated with intravenous immunoglobulin, with stabilization of the disease. Proper monitoring and prompt reporting of such cases is required to ensure safety of the vaccine.

What is the function of the protein calreticulin?

Calreticulin (CALR) is an endoplasmic reticulum (ER)-resident protein involved in a spectrum of cellular processes. In healthy cells, CALR operates as a chaperone and Ca2+ buffer to assist correct protein folding within the ER.

[34495528, 34472223, 32733014, 33360823]

N-glycosylation is a highly conserved glycan modification, and more than 7000 proteins are N-glycosylated in humans. N-glycosylation has many biological functions such as protein folding, trafficking, and signal transduction. Thus, glycan modification to proteins is profoundly involved in numerous physiological and pathological processes. The N-glycan precursor is biosynthesized in the endoplasmic reticulum (ER) from dolichol phosphate by sequential enzymatic reactions to generate the dolichol-linked oligosaccharide composed of 14 sugar residues, Glc3Man9GlcNAc2. The oligosaccharide is then en bloc transferred to the consensus sequence N-X-S/T (X represents any amino acid except proline) of nascent proteins. Subsequently, the N-glycosylated nascent proteins enter the folding step, in which N-glycans contribute largely to attaining the correct protein fold by recruiting the lectin-like chaperones, calnexin, and calreticulin. Despite the N-glycan-dependent folding process, some glycoproteins do not fold correctly, and these misfolded glycoproteins are destined to degradation by proteasomes in the cytosol. Properly folded proteins are transported to the Golgi, and N-glycans undergo maturation by the sequential reactions of glycosidases and glycosyltransferases, generating complex-type N-glycans. N-Acetylglucosaminyltransferases (GnT-III, GnT-IV, and GnT-V) produce branched N-glycan structures, affording a higher complexity to N-glycans. In this chapter, we provide an overview of the biosynthetic pathway of N-glycans in the ER and Golgi. BACKGROUND: Calreticulin (CRT), an endoplasmic reticulum-resident protein generally overexpressed in cancer cells, is associated with radiation resistance. CRT shows higher transacetylase activity, as shown by us earlier, in the presence of the polyphenolic acetates (like 7, 8-diacetoxy-4-methylcoumarin, DAMC) and modifies the activity of a number of proteins, thereby influencing cell signaling. AIM: To investigate the relationship between CRT expression and radiation response in a human glioma cell line and to evaluate the radiomodifying effects of DAMC. METHODS AND RESULTS: Studies were carried out in an established human glioma cell line (BMG-1) and its isogenic clone overexpressing CRT (CROE, CRT-overexpressing cells) by analyzing clonogenic survival, cell proliferation, micronuclei analysis, and protein levels by Western blotting as parameters of responses. CRT overexpression conferred resistance against radiation-induced cell death in CROE cells (D37 = 7.35 Gy, D10 = 12.6 Gy and D0 = 7.25 Gy) as compared to BMG-1 cells (D37 = 5.70 Gy, D10 = 9.2 Gy and D0 = 5.6 Gy). A lower level of radiation-induced micronuclei formation observed in CROE cells suggested that reduced induction and/or enhanced DNA repair partly contributed to the enhanced radioresistance. Consistent with this suggestion, we noted that CRT-mediated radioresistance was coupled with enhanced grp78 level and reduced P53 activation-mediated prodeath signaling, while no changes were noted in acetylation of histone H4. DAMC-enhanced radiation-induced delayed (secondary) apoptosis, which was higher in CROE cells. CONCLUSION: CRT overexpression confers resistance against radiation-induced death of human glioma cells, which can be overcome by the polyphenolic acetate DAMC. The lectin chaperones calnexin (CNX) and calreticulin (CRT) localized in the endoplasmic reticulum play important roles in glycoprotein quality control. Although the interaction between these lectin chaperones and ERp57 is well known, it has been recently reported that endoplasmic reticulum protein 29 (ERp29), a member of PDI family, interacts with CNX and CRT. The biochemical function of ERp29 is unclear because it exhibits no ERp57-like redox activity. In this study, we addressed the possibility that ER chaperones CNX and CRT are connected via ERp29, based on our observation that ERp29 exists as a dimer. As a result, we showed that CNX dimerizes through ERp29. These results endorse the hypothesis that ERp29 serves as a bridge that links two molecules of CNX. Also, we showed that similar complexes such as CNX-CRT were formed via ERp29.

Atlanto-axial rotary instability (Fielding type 1) is common to what diseases?

Atlanto-axial instability (AAI) is common in the connective tissue disorders, such as rheumatoid arthritis, and increasingly recognized in the heritable disorders of Stickler, Loeys-Dietz, Marfan, Morquio, and Ehlers-Danlos (EDS) syndromes as well as infectious disease.

[15776322, 6523080, 33763273, 16272271, 32623537, 2645074, 22665557, 11301365, 33850389, 16525818, 2492542]

Atlanto-axial rotatory fixation (AARF) is a rare cause of childhood torticollis that may occur spontaneously or in association with trauma and upper respiratory infections. We describe the clinical findings, as well as the effectiveness of imaging in the diagnosis and the treatment of 4 children with AARF, in whom acute fixed non-dystonic torticollis was the presenting symptom. Onset of torticollis was spontaneous in Case 1, after general anesthesia for cholesteatoma surgery in Case 2, after a trauma in Case 3, and during hypersomnia in Case 4. Duration of torticollis prior to diagnosis was 3 months in the first two patients and 20 days in the other two. All the patients underwent cervical X-rays examinations, which were not contributory to the diagnosis, followed by CT, which demonstrated C1-C2 rotatory fixation. One patient had a spontaneous resolution; treatment with Gardner's tongs and soft collar permitted restoration of the normal alignment in the other 3 patients. AARF must be considered in all the patients with persistent painful torticollis. Atlantoaxial rotatory fixation (AARF) resulting from drug-induced cervical dystonia (DICD) represents an extremely rare complication of antipsychotic treatment, requiring a comprehensive assessment of pharmacologic therapy and timely radiologic workup. We report a chronic case of Fielding type I, Pang type I AARF secondary to schizophrenia treatment in a 16-year-old girl, along with a review of the literature on the management challenges posed in this condition. In this scenario, torticollis may just represent the tip of the iceberg, and only an effective multidisciplinary approach increases the chances of satisfactory correction with closed reduction, hence avoiding the burden of more invasive treatment options. The cervical spine often becomes involved early in the course of rheumatoid arthritis, leading to three different patterns of instability: atlantoaxial subluxation, atlantoaxial impaction, and subaxial subluxation. Although radiographic changes are common, the prevalence of neurologic injury is relatively low. The primary goal of treatment is to prevent permanent neurologic injury while avoiding potentially dangerous and unnecessary surgery. Strategies include patient education, lifestyle modification, regular radiographic follow-up, and early surgical intervention, when indicated. Magnetic resonance imaging is indicated when neurologic deficit (myelopathy) occurs or when plain radiographs show atlantoaxial subluxation with a posterior atlantodental interval < or =14 mm, any degree of atlantoaxial impaction, or subaxial stenosis with a canal diameter < or =14 mm. Surgery should be considered promptly for any of the following: progressive neurologic deficit, chronic neck pain in the setting of radiographic instability that does not respond to nonnarcotic pain medication, any degree of atlantoaxial impaction or cord stenosis, a posterior atlantodental interval < or =14 mm, atlantoaxial impaction represented by odontoid migration > or =5 mm rostral to McGregor's line, sagittal canal diameter <14 mm, or a cervicomedullary angle <135 degrees. Grisel's syndrome is a unilateral or bilateral subluxation of C1 on C2, associated with an infectious condition in the head or neck. Anatomic studies have demonstrated the existence of a periodontoidal vascular plexus that drains the posterior superior pharyngeal region. No lymph nodes are present in this plexus, so septic exudates may be freely transferred from the pharynx to the C1-C2 articulation. The resulting synovial and vascular engorgements may cause mechanical and chemical damage to the transverse and facet capsular ligaments leading to subluxation. The primary treatment of Grisel's syndrome is medical: the underlying infectious organism must be isolated and appropriate antibiotics prescribed. The subluxation is reduced in halter or skeletal traction. The authors use the classification scheme of rotary subluxation proposed by Fielding, so that treatment appropriate to the specific type of subluxation is used. Based on biomechanical data predicting articular instability and canal compromise proportional to the extent of ligamentous injury, the following specific forms of immobilization are recommended to ensure ligamentous healing: Fielding Type I (transverse ligament intact and bilateral facet capsular injury) soft collar; Type II (transverse ligament and unilateral facet capsular injury) Philadelphia collar or SOMI brace; and Type III (transverse ligament and bilateral facet capsular ligament injury) halo. Following six to eight weeks of immobilization, stability is assessed by the study of flexion-extension roentgenograms. Should residual instability be demonstrated, arthrodesis is indicated. Spondyloepiphyseal dysplasia congenita (SED) is a rare form of skeletal systemic disease, characterized by congenital dwarfism with a short trunk and epiphysial dysplasia in the long bones and vertebral bodies. Patients also frequently suffer from atlanto-axial instability due to os odontoideum. Compression of the spinal cord caused by atlanto-axial instability is a common, serious complication in SED patients, and causes severe spinal cord symptoms or occasionally sudden death. We present an SED patient who underwent a posterior fusion of the occiput to the cervical spine for severe spinal cord symptoms due to atlanto-axial instability. A relatively rare report of an 8-year-old girl with Maroteaux-Lamy syndrome that is Type VI mucopolysaccharidosis who presented with symptoms of spastic quadriparesis related to atlantoaxial instability is presented. Atlantoaxial stabilization resulted in rapid and sustained neurological recovery. L’instabilité de la charnière occipito atloïdienne affecte 10 à 20% des sujets présentant un Down syndrome (trisomie 21). Cette instabilité est souvent asymptomatique et seulement diagnostiquée sur les radiographies qui montrent un élargissement de la distance antérieure atloïdo-odontoide. L’asymptologie de l’instabilité occipito atloïdienne affecte 1 à 2% des sujets présentant un Down syndrome avec des signes manifestes de compression médullaire. La spondylose cervicale qui est habituelle dans le Down syndrome peut potentialiser des lésions de la moelle. 44 sujets Koweitis présentant un Down syndrome dont l’âge était supérieur à 15 ans ont été évalués cliniquement et radiographiquement. Des radiographies de la colonne cervicale de profil ont été effectuées en position neutre et en position de flexion. Une instabilité occipito atloïdienne a été diagnostiquée chez 8 sujets (18%) avec des anomalies congénitales de C1 C2, chez 5 sujets (12%). 5 patients présentaient une instabilité uniquement en flexion et 3 patients présentaient une telle instabilité sur tous les clichés. 3 patients avec une instabilité occipito atloïdienne présentaient des anomalies de l’odontoide aggravant encore les conditions locales. Lorsqu’il existe une instabilité occipito atloïdienne, la distance C1 odontoide doit être évaluée car elle indique l’espace possible pour la moelle. Une spondylolyse cervicale a été relevée chez 16 patients (36% des sujets). Avec l’âge, les lésions dégénératives peuvent évoluer, survenant plus tôt que dans la population normale et peuvent léser les différents niveaux de la colonne cervicale. La moitié des patients avec une instabilité occipito atloïdienne ont une spondylolyse cervicale, avec une co-morbidité entraînant une moelle à risque. We report a 15-year-old boy with mucopolysaccharidosis (MPS) Type VII (Sly disease) who was found to have atlantoaxial instability with quadriparesis. Subluxation of C1 on C2 has also been documented in patients with Type I and Type IV MPS. Routine screening of the cervical spine is recommended in patients with "MPS Type VII" so that delayed diagnosis of instability, which may lead to neurologic compromise, is avoided.

Is Erythropoietin effective for neuroprotection of Preterm Infants.

No. High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age.

[34030616, 32961562, 31940698]

Preterm infants are at high risk of brain injury. With more understanding of the preterm brain injury's pathogenesis, neuroscientists are looking for more effective methods to prevent and treat it, among which erythropoietin (Epo) is considered as a prime candidate. This review tries to clarify the possible mechanisms of Epo in preterm neuroprotection and summarize updated evidence considering Epo as a pharmacological neuroprotective strategy in animal models and clinical trials. To date, various animal models have validated that Epo is an anti-apoptotic, antiinflammatory, anti-oxidant, anti-excitotoxic, neurogenetic, erythropoietic, angiogenetic, and neurotrophic agent, thus preventing preterm brain injury. However, although the scientific rationale and preclinical data for Epo's neuroprotective effect are promising, when translated to bedside, the results vary in different studies, especially in its long-term efficacy. Based on existing evidence, it is still too early to recommend Epo as the standard treatment for preterm brain injury. Despite improvements in viability, the long-term neurodevelopmental outcomes of preterm babies remain serious concern as a significant percentage of these infants develop neurological and/or intellectual impairment, and they are also at increased risk of psychiatric illnesses later in life. The current challenge is to develop neuroprotective approaches to improve adverse outcomes in preterm survivors. The purpose of this review was to provide an overview of the current evidence on pharmacological agents targeting the neuroprotection of the preterm brain. Among them, magnesium sulfate, given antenatally to pregnant women with imminent preterm birth before 30 to 34 weeks of gestation, as well as caffeine administered to preterm infants after birth, exhibited neuroprotective effects for human preterm brain. Erythropoietin treatment of preterm infants did not result in neuroprotection at 2 years of age in two out of three published large randomized controlled trials; however, long-term follow-up of these infants is needed to come to definite conclusions. Further studies are also required to assess whether melatonin, neurosteroids, inhaled nitric oxide, allopurinol, or dietary supplements (omega-3 fatty acids, choline, curcumin, etc.) could be implemented as neuroprotectants in clinical practice. Furthermore, other pharmacological agents showing promising signs of neuroprotective efficacy in preclinical studies (growth factors, hyaluronidase inhibitors or treatment, antidiabetic drugs, cannabidiol, histamine-H3 receptor antagonists, etc.), as well as stem cell- or exosomal-based therapies and nanomedicine, may prove useful in the future as potential neuroprotective approaches for human preterm brain. KEY POINTS: · Magnesium and caffeine have neuroprotective effects for the preterm brain.. · Follow-up of infants treated with erythropoietin is needed.. · Neuroprotective efficacy of several drugs in animals needs to be shown in humans.. BACKGROUND: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established. METHODS: In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events. CONCLUSIONS: High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.).

What is the SPRTN protein function?

The protease SPRTN emerged as the essential enzyme for DNA-protein crosslink proteolysis repair.

[34551432, 33348378, 34189469, 33183910]

The antitumor activity of poly(ADP-ribose) polymerase inhibitors (PARPis) has been ascribed to PARP trapping, which consists in tight DNA-protein complexes. Here we demonstrate that the cytotoxicity of talazoparib and olaparib results from DNA replication. To elucidate the repair of PARP1-DNA complexes associated with replication in human TK6 and chicken DT40 lymphoblastoid cells, we explored the role of Spartan (SPRTN), a metalloprotease associated with DNA replication, which removes proteins forming DPCs. We find that SPRTN-deficient cells are hypersensitive to talazoparib and olaparib, but not to veliparib, a weak PARP trapper. SPRTN-deficient cells exhibit delayed clearance of trapped PARP1 and increased replication fork stalling upon talazoparib and olaparib treatment. We also show that SPRTN interacts with PARP1 and forms nuclear foci that colocalize with the replicative cell division cycle 45 protein (CDC45) in response to talazoparib. Additionally, SPRTN is deubiquitinated and epistatic with translesion synthesis (TLS) in response to talazoparib. Our results demonstrate that SPRTN is recruited to trapped PARP1 in S-phase to assist in the excision and replication bypass of PARP1-DNA complexes. Repair of covalent DNA-protein crosslinks (DPCs) by the metalloprotease SPRTN prevents genome instability, premature aging and carcinogenesis. SPRTN is specifically activated by DNA structures containing single- and double-stranded features, but degrades the protein components of DPCs promiscuously and independent of amino acid sequence. This lack of specificity is useful to target diverse protein adducts, however, it requires tight control in return, in order to prohibit uncontrolled proteolysis of chromatin proteins. Here, we discover the components and principles of a ubiquitin switch, which negatively regulates SPRTN. We demonstrate that monoubiquitylation is induced in an E3 ligase-independent manner and, in contrast to previous assumptions, does not control chromatin access of the enzyme. Data obtained in cells and in vitro reveal that monoubiquitylation induces inactivation of the enzyme by triggering autocatalytic cleavage in trans while also priming SPRTN for proteasomal degradation in cis. Finally, we show that the deubiquitylating enzyme USP7 antagonizes this negative control of SPRTN in the presence of DPCs. Author information: (1)Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, OX3 7DQ, Oxford, UK. (2)Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, OX3 7DQ, Oxford, UK. Electronic address: kristijan.ramadan@oncology.ox.ac.uk.

What part of the body is associated with Cauda equina

The cauda equina is the sack of nerve roots (nerves that leave the spinal cord between spaces in the bones of the spine to connect to other parts of the body) at the lower end of the spinal cord.

[33261250, 27753733, 32541159, 3356808, 11311464, 22764663, 34321945, 18664636, 22254963, 10797973, 22996855, 26442520, 25495513, 23101243, 3806684]

Malignant spinal cord compression(MSCC)is defined as a compression of the spinal cord or cauda equina with neuropathy caused by tumor spreading to the vertebral body. The common symptoms of MSCC are back pain, neck pain, muscle weakness, sensory reduction, bladder and rectal disturbance. The risk of MSCC is relatively high in patients with lung cancer, breast cancer, and prostate cancer. MSCC is one of the oncologic emergencies that requires prompt diagnosis and treatment to preserve and improve neurological function. Evaluation by magnetic resonance imaging(MRI)and computed tomography( CT)are useful for the diagnosis. The prognosis of these patients is often poor at the time of diagnosis of MSCC, thus it is important for deciding the treatment strategy to consider the prognosis and background of the patient in addition to the objective findings including the degree of MSCC and spinal instability. Treatment options consist of medical, surgical, and radiation therapy. We need a multidisciplinary approach because the pathology of MSCC involves multiple departments, such as medical oncology, orthopedics, and radiology. Supportive care including rehabilitation and preventing skeletal related events are also important. The cancer board, in which each physician and multidisciplinary health care professionals regularly have a discussion and review the cases, is required. Using a variety of neuroanatomical and histological techniques, we compare the spinal cord and peripheral nerve distribution in the tails of larvae from Xenopus laevis and three species of Rana. The relatively large, postsacral spinal cord of Xenopus contains abundant motoneurons and their axons. Spinal nerves exit from the spinal cord in a regular array, one nerve per myotome, from the cervical region to near the end of the tail. Somata of motoneurons innervating caudal myotomes are found along the entire length of the tail. In contrast, the caudal cord of Rana is reduced to a filum terminale consisting of little more than an ependymal tube; spinal nerves to all caudal myotomes leave the cord in the sacral region and reach their motor targets via a cauda equina and caudal plexus. Motoneuron cell bodies innervating caudal myotomes are found only in the sacral region. The Rana larval pattern is similar to that of adult frogs and mammals, whereas the Xenopus larval pattern is more like that of salamanders and reptiles. These gross neuroanatomical differences are not due to differences in the size or developmental stage of the tadpoles, but instead are associated with differences in the swimming behavior of the larvae. The presence of motoneurons in the caudal spinal cord of Xenopus may provide local intermyotomal control within the tail; the elongated topography of the cord appears to permit finer, rostral-to-caudal regulation of neuromuscular activity. The Rana spinal cord, on the other hand--with motoneurons clustered anteriorly--may produce concurrent firing of adjacent ipsilateral myotomes, but at the expense of fine intermyotomal regulation. The fact that nerves in the tail of Xenopus enter and exit from the spinal cord locally, as opposed to far anteriorly as in Rana, means that for tadpoles of the same size, reflex arc lengths are many times shorter in Xenopus. Single or double-level compression of the lumbosacral nerve roots located in the dural sac results in a polyradicular symptomatology clinically diagnosed as cauda equina syndrome. The cauda equina nerve roots provide the sensory and motor innervation of most of the lower extremities, the pelvic floor and the sphincters. Therefore, in a fully developed cauda equina syndrome, multiple signs of sensory disorders may appear. These disorders include low-back pain, saddle anesthesia, bilateral sciatica, then motor weakness of the lower extremities or chronic paraplegia and, bladder dysfunction. Multiple etiologies can cause the cauda equina syndrome. Among them, non-neoplastic compressive etiologies such as herniated lumbosacral discs and spinal stenosis and spinal neoplasms play a significant role in the development of the cauda equina syndrome. Non-compressive etiologies of the cauda equina syndrome include ischemic insults, inflammatory conditions, spinal arachnoiditis and other infectious etiologies. The use of canine, porcine and rat models mimicking the cauda equina syndrome enabled discovery of the effects of the compression on nerve root neural and vascular anatomy, the impairment of impulse propagation and the changes of the neurotransmitters in the spinal cord after compression of cauda equina. The involvement of intrinsic spinal cord neurons in the compression-induced cauda equina syndrome includes anterograde, retrograde and transneuronal degeneration in the lumbosacral segments. Prominent changes of NADPH diaphorase exhibiting, Fos-like immunoreactive and heat shock protein HSP72 were detected in the lumbosacral segments in a short-and long-lasting compression of the cauda equina in the dog. Developments in the diagnosis and treatment of patients with back pain, sciatica and with a herniated lumbar disc are mentioned, including many treatment options available. Intradural extramedullary type of spinal hydatid disease is a rare variety of hydatid disease, and is even rarer in paediatric age group. Spinal hydatid disease should be considered in the differential diagnosis of spinal cord compression syndrome in endemic countries and should be evaluated with imaging and serological investigations. Our case was a 9- year-old boy who presented with lower back pain lasting for 8 months and progressive bilateral lower extremities weakness lasting for 2 month. Neurological examination was suggestive of lower motor neuron type of paraperesis. Magnetic resonance images of the lumbar spine showed an intradural cystic lesion displacing and compressing the lower cord and cauda equina. The cystic mass was explored with L1-L4 laminectomy and after durotomy; it was separated from cord and dura mater by hydrodissection. It contained a clear fluid. The pathological diagnosis was hydatid disease. Cauda equina syndrome is a relatively uncommon condition typically associated with a large, space-occupying lesion within the canal of the lumbosacral spine. The syndrome is characterized by varying patterns of low back pain, sciatica, lower extremity sensorimotor loss, and bowel and bladder dysfunction. The pathophysiology remains unclear but may be related to damage to the nerve roots composing the cauda equina from direct mechanical compression and venous congestion or ischemia. Early diagnosis is often challenging because the initial signs and symptoms frequently are subtle. Classically, the full-blown syndrome includes urinary retention, saddle anesthesia of the perineum, bilateral lower extremity pain, numbness, and weakness. Decreased rectal tone may be a relatively late finding. Early signs and symptoms of a developing postoperative cauda equina syndrome are often attributed to common postoperative findings. Therefore, a high index of suspicion is necessary in the postoperative spine patient with back and/or leg pain refractory to analgesia, especially in the setting of urinary retention. Regardless of the setting, when cauda equina syndrome is diagnosed, the treatment is urgent surgical decompression of the spinal canal. Penetrating spinal cord injuries (P.S.C.I.) are rarely described in Sub Saharian countries in spite of an increasing number of wars. To study epidemiology management and prognosis of P.S.C.I. in Senegal, population of 16 patients collected from Fann Hospital in Dakar has been studied. 9 cases were related on gunshot or shrapnel injuries and 6 were stab-wounded. 8 came from war practice and 7 from civilian practice. The point of entry was at the posterior or lateral part of the body and continuous leaking of cerebral spinal fluid from this point was founded only in one patient. Patients showed a clinical picture of a complete spinal cord section syndrome, 3 spinal cord hemisection Brown Sequard syndromes, 3 cauda equina syndromes and 1 monoradicular syndrome. Spinal X-rays or myelography may lead to an accurate evaluation of the extent of bone tissue destruction. Anatomical evaluation of roots and spinal cord lesions were more difficult when C.T. scan or R.M.I. is not available. Penetrating spinal cord injury with foreign body included or myelography stop or showing cauda equina syndrome should be operated on. 9 of our patients has benefited of spine surgical posterior approach (laminectomy). Immediate vital prognosis is good regarding the fact that visceral associated lesions were rare (2 cases). Functional recovery is fair only 46.6% of patients expressed partial or complete recovery. Prognosis factors such as injuring agent and initial neurological status has been discussed. Prognosis of penetrating spinal cord injuries could be improved by immediate and multidisciplinary management. Cauda equina syndrome is a well described state of neurologic compromise due to lumbosacral root compression. In most cases, it is due to a herniated disc, tumor, infection, or hematoma. We report a case of rapid lumbar synovial cyst expansion leading to acute cauda equina syndrome and compare it to similar cases in the literature. The patient is a 49-year-old woman with a history of chronic low back pain who developed cauda equina syndrome. Serial lumbar magnetic resonance imaging studies demonstrated a significant increase in the size of a lumbar synovial cyst over a 2 week interval. After an unsuccessful attempt to relieve her acute symptoms with computed tomography-guided cyst aspiration, an L4-5 posterior spinal decompression with excision of the synovial cyst was performed. Postoperatively the patient's perineal numbness, bladder incontinence, and associated pain complaints resolved. The only residual symptom at one month follow-up was continued numbness in the right lower limb in an L5 distribution. This report adds to 6 other well described similar cases found in the literature by illustrating several important points. First, a lumbar synovial cyst is a rare but possible cause of acute cauda equina syndrome. Second, magnetic resonance imaging is the test of choice to diagnose and characterize lumbar synovial cysts; serial imaging can detect fluctuations in cyst size. Third, percutaneous treatment of lumbar synovial cysts is variable in efficacy and proved to be unsuccessful in our patient. Finally, surgical management has shown high success rates for symptomatic cysts. Specifically, in the setting of acute cauda equina syndrome secondary to a lumbar synovial cyst, urgent surgical decompression has led to resolution of neurologic symptoms in most reported cases. A lumbar synovial cyst is an uncommon cause of acute cauda equina syndrome. Prompt diagnosis and treatment may lead to reduced morbidity associated with this condition. INTRODUCTION: Schwannoma is a relatively common benign spinal cord and/or cauda equina tumor; however, giant cauda equina schwannoma with extensive scalloping of the lumbar vertebral body is a rare pathology, and the treatment strategy, including the use of surgical procedures, is controversial. In this report, we present a rare case of a giant lumbar schwannoma of the cauda equina with extremely large scalloping of the vertebral body, and we discuss the surgical strategy we used to treat this pathology. CASE PRESENTATION: A 42-year-old Japanese man presented to our department with complaints of a gait disturbance and muscle weakness in the left lower limb. His muscle strength in the proximal part of the left lower limb was grade 2 or 3/5, and he exhibited a mild urinary disturbance on the first visit. X-ray and computed tomography myelography of the lumbar spine showed an extremely large erosive lesion at the L3 vertebral body. Magnetic resonance imaging of the lumbar spine showed a large soft-tissue mass in the spinal canal at L2-L3 and the vertebral body at L3. A one-stage complete tumor resection and instrumented circumferential fusion were performed via a posterior approach, and a good outcome was achieved after the surgery. CONCLUSIONS: We performed one-stage posterior surgery in a patient with a giant cauda equina schwannoma with extensive scalloping of the vertebral body, and a good post-operative outcome was achieved. Thermoesthesia-and-algesthesia disorders have been registered in the dermatomes of cauda equina roots of patients with lumbar spine osteochondrosis in all the cases. Negative changes in the sensitivity of this type are manifested themselves as follows: 1) 2-8-degree increases of thresholds; 2) 3-6-degree decreases of thresholds; 3) absence of thermal sense. In the presence of reflex syndromes (lumbalgia and lumbar ischialgia) the disorders in L4, L5, S1 dermatomes have been determined to the greatest degree. Thermoesthesia-and-algesthesia disorders are more pronounced in patients with the radicular syndrome than in those with the reflex syndromes. The most improvement ofthermoesthesia-and-algesthesia values is observed in L5 dermatome of patients with lumbalgia and lumbar ischialgia after complex conservative therapy. The treatment performed does not result in significant thermoesthesia-and-algesthesia improvement for the limb with radiculopathy events and in the dermatome of the root compressed in patients with the radicular syndrome. Positive changes in contralateral limb are more pronounced. The spinal cord of two tetraodontiform fishes, the Japanese file fish (Navodon modestus) and the panther puffer (Takifugu pardalis), are unusual among vertebrates in having a markedly abbreviated spinal cord with a long and flattened filum terminale. Only the rostral short part of the cord of both species is cylindrical; the greater part of the cord is markedly flat. The majority of the spinal nerve roots leave the short cylindrical part. The flattened part of the cord contains the central canal, myelinated nerve fibers, and a few motoneurons surrounding the cauda equina, and it is histologically similar to the filum terminale of amphibians and mammals. The spinal cords of other teleosts, the sun-fish and angler, also are abbreviated and possess a filum terminale and cauda equina. These orders possess an enormous head and short trunk. However, the correlation between this body form and an abbreviated cord is not causal, since the tetraodontiform species described here show ordinary body proportions. The spinal cord may be abbreviated in tetraodontiform fishes in general.

What is the use of Brain Metastasis Velocity (BMV) Model?

Brain metastasis velocity (BMV) is a metric that describes the rate of development of new brain metastases (BM) after initial stereotactic radiosurgery.

[34775780, 29740743, 28586952, 33817641, 30524969, 29464141, 31526671]

OBJECTIVE: To provide a review of the current status of predictive nomograms and brain metastasis velocity (BMV) in the prognostication of brain metastasis outcomes. BACKGROUND: Statistical analyses have been used for many years in an attempt to predict clinical outcomes of brain metastasis patients. Such models have attempted to predict such endpoints as survival and which patients would most benefit from stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT). METHODS: This narrative review includes documents the history of statistical models and nomograms through the stage migration of the brain metastasis population from a population with large symptomatic brain metastases to the modern population with small asymptomatic metastases found on surveillance imaging. It also tells the history of the derivation and validation of BMV, a recently identified biomarker for survival and neurologic death in the brain metastasis population treated with SRS. CONCLUSIONS: Statistical models predicting brain metastasis behavior continue to evolve with the changing landscape of systemic therapy and the more aggressive use of SRS. Previous models with ultimately need to integrate biologic data and will continue to be updated. PURPOSE: Prior statistical models attempted to identify risk factors for time to distant brain failure (DBF) or time to salvage whole-brain radiation therapy (WBRT) to predict the benefit of early WBRT versus stereotactic radiosurgery (SRS) alone. We introduce a novel clinical metric, brain metastasis velocity (BMV), for predicting clinical outcomes after initial DBF following upfront SRS alone. METHODS AND MATERIALS: BMV was defined as the cumulative number of new brain metastases that developed over time since first SRS in years. Patients were classified by BMV into low-, intermediate-, and high-risk groups, consisting of <4, 4 to 13, and >13 new metastases per year, respectively. Histology, number of metastases at the time of first SRS, and systemic disease status were assessed for effect on BMV. RESULTS: Of 737 patients treated at our institution with upfront SRS without WBRT, 286 had ≥1 DBF event. A lower BMV predicted for improved overall survival (OS) following initial DBF (log-rank P<.0001). Median OS for the low, intermediate, and high BMV groups was 12.4 months (95% confidence interval [CI], 10.4-16.9 months), 8.2 months (95% CI, 5.0-9.7 months), and 4.3 months (95% CI, 2.6-6.7 months), respectively. Multivariate analysis showed that BMV remained the dominant predictor of OS, with a hazard ratio of 2.75 for the high BMV group (95% CI, 1.94-3.89; P<.0001) and a hazard ratio of 1.65 for the intermediate BMV group (95% CI, 1.18-2.30; P<.004). A lower BMV was associated with decreased rates of salvage WBRT (P=.02) and neurologic death (P=.008). Factors predictive for a higher BMV included ≥2 initial brain metastases (P=.004) and melanoma histology (P=.008). CONCLUSIONS: BMV is a novel metric associated with OS, neurologic death, and need for salvage WBRT after initial DBF following upfront SRS alone. BACKGROUND: Brain metastasis velocity (BMV) predicts outcomes after initial distant brain failure (DBF) following upfront stereotactic radiosurgery (SRS). We developed an integrated model of clinical predictors and pre-SRS MRI-derived radiomic scores (R-scores) to identify high-BMV (BMV-H) patients upon initial identification of brain metastases (BMs). METHODS: In total, 256 patients with BMs treated with upfront SRS alone were retrospectively included. R-scores were built from 1246 radiomic features in 2 target volumes by using the Extreme Gradient Boosting algorithm to predict BMV-H groups, as defined by BMV at least 4 or leptomeningeal disease at first DBF. Two R-scores and 3 clinical predictors were integrated into a predictive clinico-radiomic (CR) model. RESULTS: The related R-scores showed significant differences between BMV-H and low BMV (BMV-L), as defined by BMV less than 4 or no DBF (P < .001). Regression analysis identified BMs number, perilesional edema, and extracranial progression as significant predictors. The CR model using these 5 predictors achieved a bootstrapping corrected C-index of 0.842 and 0.832 in the discovery and test sets, respectively. Overall survival (OS) after first DBF was significantly different between the CR-predicted BMV-L and BMV-H groups (median OS: 26.7 vs 13.0 months, P = .016). Among patients with a diagnosis-specific graded prognostic assessment of 1.5-2 or 2.5-4, the median OS after initial SRS was 33.8 and 67.8 months for CR-predicted BMV-L, compared to 13.5 and 31.0 months for CR-predicted BMV-H (P < .001 and <.001), respectively. CONCLUSION: Our CR model provides a novel approach showing good performance to predict BMV and clinical outcomes. INTRODUCTION: Brain metastasis velocity (BMV) is a prognostic metric that describes the recurrence rate of new brain metastases after initial treatment with radiosurgery (SRS). We have previously risk stratified patients into high, intermediate, and low-risk BMV groups, which correlates with overall survival (OS). We sought to externally validate BMV in a multi-institutional setting. METHODS: Patients from nine academic centers were treated with upfront SRS; the validation cohort consisted of data from eight institutions not previously used to define BMV. Patients were classified by BMV into low (<4 BMV), intermediate (4-13 BMV), and high-risk groups (>13 BMV). Time-to-event outcomes were estimated using the Kaplan-Meier method. Cox proportional hazards methods were used to estimate the effect of BMV and salvage modality on OS. RESULTS: Of 2829 patients, 2092 patients were included in the validation dataset. Of these, 921 (44.0%) experienced distant brain failure (DBF). Median OS from initial SRS was 11.2 mo. Median OS for BMV < 4, BMV 4-13, and BMV > 13 were 12.5 mo, 7.0 mo, and 4.6 mo (p < 0.0001). After multivariate regression modeling, melanoma histology (β: 10.10, SE: 1.89, p < 0.0001) and number of initial brain metastases (β: 1.52, SE: 0.34, p < 0.0001) remained predictive of BMV (adjusted R2 = 0.06). CONCLUSIONS: This multi-institutional dataset validates BMV as a predictor of OS following initial SRS. BMV is being utilized in upcoming multi-institutional randomized controlled trials as a stratification variable for salvage whole brain radiation versus salvage SRS after DBF.

What is "cell competition"?

Cell competition is a social cellular phenomenon in which unfit cells are selectively eliminated to maintain tissue homeostasis. At the initial stage of carcinogenesis, cell competition often occurs between newly emerging transformed cells and the neighboring normal cells, leading to the elimination of transformed cells from the epithelial layer.

[34500336, 33357449, 34485872, 33508854]

Complex multicellular organisms require quantitative and qualitative assessments on each of their constitutive cell types to ensure coordinated and cooperative behavior towards overall functional proficiency. Cell competition represents one of the operating arms of such quality control mechanisms and relies on fitness comparison among individual cells. However, what is exactly included in the fitness equation for each cell type is still uncertain. Evidence will be discussed to suggest that the ability of the cell to integrate and collaborate within the organismal community represents an integral part of the best fitness phenotype. Thus, under normal conditions, cell competition will select against the emergence of altered cells with disruptive behavior towards tissue integrity and/or tissue pattern formation. On the other hand, the winner phenotype prevailing as a result of cell competition does not entail, by itself, any degree of growth autonomy. While cell competition per se should not be considered as a biological driving force towards the emergence of the neoplastic phenotype, it is possible that the molecular machinery involved in the winner/loser interaction could be hijacked by evolving cancer cell populations. Cell competition is a social cellular phenomenon in which unfit cells are selectively eliminated to maintain tissue homeostasis.1-3 Recent studies have revealed that mechanical forces induce competitive cell-cell interactions in Drosophila.4-6 This mechanical cell competition has also been reported to play an important role in mammalian cells, using Madin-Darby canine kidney (MDCK) cells depleted of a polarity regulator Scribble in a tetracycline-inducible manner (scribKD cells).7scribKD cells are hypersensitive to crowding due to the lower homeostatic density than wild-type (WT) cells,7,8 and in the context of cell competition, scribKD cells are compacted and eliminated by WT cells.7-10 Although p38 and p53 are involved in this process,7,10 the molecular mechanism by which WT cells recognize and mechanically eliminate scribKD cells remains unclear. Here, we report that scribKD cells secrete fibroblast growth factor 21 (FGF21) to drive cell competition. Knockdown of FGF21 in scribKD cells or loss of FGFR1 in WT cells suppresses cell competition, suggesting that WT cells recognize scribKD cells through FGF21. FGF21-containing culture medium of scribKD cells activates cell motility. Moreover, FGF21 promotes the compression and elimination of scribKD cells by attracting surrounding WT cells. We also demonstrate that activation of the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway in scribKD cells induces FGF21 to drive cell competition. Our findings reveal a mechanism whereby WT cells mechanically eliminate scribKD cells and propose a new function for FGF21 in cell-cell communication. At the initial stage of carcinogenesis, cell competition often occurs between newly emerging transformed cells and the neighboring normal cells, leading to the elimination of transformed cells from the epithelial layer. For instance, when RasV12-transformed cells are surrounded by normal cells, RasV12 cells are apically extruded from the epithelium. However, the underlying mechanisms of this tumor-suppressive process still remain enigmatic. We first show by electron microscopic analysis that characteristic finger-like membrane protrusions are projected from both normal and RasV12 cells at their interface. In addition, FBP17, a member of the F-BAR proteins, accumulates in RasV12 cells, as well as surrounding normal cells, which plays a positive role in the formation of finger-like protrusions and apical elimination of RasV12 cells. Furthermore, cdc42 acts upstream of these processes. These results suggest that the cdc42/FBP17 pathway is a crucial trigger of cell competition, inducing "protrusion to protrusion response" between normal and RasV12-transformed cells. Cell competition involves a conserved fitness-sensing process during which fitter cells eliminate neighbouring less-fit but viable cells1. Cell competition has been proposed as a surveillance mechanism to ensure normal development and tissue homeostasis, and has also been suggested to act as a barrier to interspecies chimerism2. However, cell competition has not been studied in an interspecies context during early development owing to the lack of an in vitro model. Here we developed an interspecies pluripotent stem cell (PSC) co-culture strategy and uncovered a previously unknown mode of cell competition between species. Interspecies competition between PSCs occurred in primed but not naive pluripotent cells, and between evolutionarily distant species. By comparative transcriptome analysis, we found that genes related to the NF-κB signalling pathway, among others, were upregulated in less-fit 'loser' human cells. Genetic inactivation of a core component (P65, also known as RELA) and an upstream regulator (MYD88) of the NF-κB complex in human cells could overcome the competition between human and mouse PSCs, thereby improving the survival and chimerism of human cells in early mouse embryos. These insights into cell competition pave the way for the study of evolutionarily conserved mechanisms that underlie competitive cell interactions during early mammalian development. Suppression of interspecies PSC competition may facilitate the generation of human tissues in animals.

Is METTL3 an m6A writer, reader or eraser?

The methyltransferase METTL3 is an m6A writer.

[34535671]

Author information: (1)Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China. (2)Institute of Immunology, University of Science and Technology of China, Hefei, Anhui, 230027, China. (3)Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China. (4)State Key Laboratory of Genetic Engineering, Human Phenome Institute, Institutes of Biomedical Sciences, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. (5)Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06520, USA. (6)Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA. (7)Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. (8)Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China. huipeng@ustc.edu.cn. (9)Institute of Immunology, University of Science and Technology of China, Hefei, Anhui, 230027, China. huipeng@ustc.edu.cn. (10)Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China. tzg@ustc.edu.cn. (11)Institute of Immunology, University of Science and Technology of China, Hefei, Anhui, 230027, China. tzg@ustc.edu.cn. (12)Research Unit of NK Cell Study, Chinese Academy of Medical Sciences, Hefei, Anhui, 230027, China. tzg@ustc.edu.cn.

Which drugs were included in the polypill that was tested in TIPS-3 trial?

Polypill tested in the TIPS-3 trial was comprised of atenolol, ramipril, hydrochlorothiazide, and a statin.

[30342297]

BACKGROUND: It is hypothesized that in individuals without clinical cardiovascular disease (CVD), but at increased CVD risk, a 50% to 60% reduction in CVD risk could be achieved using fixed dose combination (FDC) therapy (usually comprised of multiple blood-pressure agents and a statin [with or without aspirin]) in a single "polypill". However, the impact of a polypill in preventing clinical CV events has not been evaluated in a large randomized controlled trial. METHODS: TIPS-3 is a 2x2x2 factorial randomized controlled trial that will examine the effect of a FDC polypill on major CV outcomes in a primary prevention population. This study aims to determine whether the Polycap (comprised of atenolol, ramipril, hydrochlorothiazide, and a statin) reduces CV events in persons without a history of CVD, but who are at least at intermediate CVD risk. Additional interventions in the factorial design of the study will compare the effect of (1) aspirin versus placebo on CV events (and cancer), (2) vitamin D versus placebo on the risk of fractures, and (3) the combined effect of aspirin and the Polycap on CV events. RESULTS: The study has randomized 5713 participants across 9 countries. Mean age of the study population is 63.9 years, and 53% are female. Mean INTERHEART risk score is 16.8, which is consistent with a study population at intermediate CVD risk. CONCLUSION: Results of the TIP-3 study will be key to determining the appropriateness of FDC therapy as a strategy in the global prevention of CVD.

What is the drug gantenerumab targeting?

Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain.

[33336218, 34155411, 34198582]

Previous findings from the positron emission tomography (PET) substudy of the SCarlet RoAD and Marguerite RoAD open-label extension (OLE) showed gantenerumab doses up to 1200 mg every 4 weeks administered subcutaneously resulted in robust beta-amyloid (Aβ) plaque removal over 24 months in people with prodromal-to-moderate Alzheimer's disease (AD). In this 36-month update, we demonstrate continued reduction, with mean (standard error) centiloid values at 36 months of -4.3 (7.5), 0.8 (6.7), and 4.7 (8.0) in the SCarlet RoAD (double-blind pooled placebo and active groups), Marguerite RoAD double-blind placebo, and Marguerite RoAD double-blind active groups respectively, representing a change of -57.0 (10.3), -90.3 (9.0), and -74.9 (10.5) centiloids respectively. These results demonstrate that prolonged gantenerumab treatment, at doses up to 1200 mg, reduces amyloid plaque levels below the amyloid positivity threshold. The ongoing GRADUATE Phase III trials will evaluate potential clinical benefits associated with gantenerumab-induced amyloid-lowering in people with early (prodromal-to-mild) AD. Author information: (1)Warren Alpert Medical School of Brown University, Providence, RI, USA. (2)Indiana University School of Medicine, Indianapolis, IN, USA. (3)Washington University School of Medicine, St. Louis, MO, USA. (4)Hitchcock Regulatory Consulting, Inc, Fishers, IN, USA. (5)Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6)University College London, London, UK. (7)Centre Hospitalier Universitaire de Rouen, Rouen, France. (8)University of Pittsburgh Medical Center, Pittsburgh, PA, USA. (9)Emory University Medical Center, Atlanta, GA, USA. (10)University of Puerto Rico School of Medicine, San Juan, Puerto Rico. (11)University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA. (12)Yale University School of Medicine, New Haven, CT, USA. (13)Columbia University Medical Center, New York, NY, USA. (14)Hospital Clínic i Provincial de Barcelona, August Pi i Sunyer Biomedical Research Institute-Universitat de Barcelona, Barcelona, Spain. (15)Neuroscience Research Australia, University of New South Wales Medicine, Randwick, New South Wales, Australia. (16)McGill Center for Studies in Aging, McGill University, Montreal, Quebec, Canada. (17)University of California San Diego, San Diego, CA, USA. (18)University of Melbourne, Melbourne, Victoria, Australia. (19)University of British Columbia, Vancouver, British Columbia, Canada. (20)University of Washington School of Medicine, Seattle, WA, USA. (21)Hospices Civils de Lyon, Lyons, France. (22)Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. (23)Australian Alzheimer's Research Foundation, University of Western Australia, Perth, Western Australia, Australia. (24)Centre Hospitalier Universitaire de Toulouse, Toulouse, France. (25)Neurological Institute, Salpetriere University Hospital, Paris, France. (26)Centre Hospitalier Régional Universitaire de Lille, Lille, France. (27)Mayo Clinic, Rochester, MN, USA. (28)University of Michigan, Ann Arbor, MI, USA. (29)University of Rhode Island, Kingston, RI, USA. (30)Keck School of Medicine, University of Southern California, San Diego, CA, USA. (31)Berry Consultants, LLC, Austin, TX, USA. (32)Eli Lilly and Company, Indianapolis, IN, USA. (33)F. Hoffmann-La Roche Ltd, Basel, Switzerland. (34)Washington University School of Medicine, St. Louis, MO, USA. batemanr@wustl.edu. (#)Contributed equally

Is Ameloblastoma (AB) a common benign tumor occurring in the brain?

Ameloblastoma (AM) is a slow growing and aggressive benign tumor with an odontogenic epithelial origin arising from the mandible or maxilla.

[20051072, 34508164, 27721617, 17170964, 28212886, 32698263, 14970780, 25298718, 29274152, 19995435, 28187692, 27099699, 10895162, 32484411, 26261564, 21717310, 28191811, 30420932, 33394372, 21968082, 30126803, 32659412, 25567699, 26925653, 26015700, 1569364, 34599642, 23986011, 31674718, 34510060, 29747056, 21371124, 31990904, 34594553, 30196986, 34511355, 25206141, 27435007]

Ameloblastoma (AB) is the most common benign epithelial odontogenic tumor occurring in the jawbone. AB is a slowly growing tumor but sometimes shows a locally invasive and an aggressive growth pattern with a marked bone resorption. In addition, the local recurrence and distant metastasis of AB also sometimes occurs, which resembles one of the typical malignant potentials. From these points of view, to understand better the mechanisms of AB cell migration or invasion is necessary for the better clinical therapy and improvements of the patients' quality of life. Microtubules in eukaryotic cells reveal the shape of hollow cylinders made up of polymerized alpha (α)- and beta (β)-tubulin dimers and form the cytoskeleton together with microfilaments and intermediate filaments. Microtubules play important roles in cell migration by undergoing assembly and disassembly with post-translational modifications. Stability of microtubules caused by their acetylation is involved in cell migration. In this study, we investigated the expression and distribution of acetylated α-tubulin and alpha-tubulin N-acetyltransferase 1 (αTAT1), an enzyme which acetylates Lys-40 in α-tubulin, in AB specimens, and analyzed how tubulin was acetylated by αTAT1 activation in a human AB cell line, AM-1. Finally, we clarified that TGF-β-activated kinase1 (TAK1) was phosphorylated by TGF-β stimulation, then, induced tubulin acetylation via αTAT1 activation, which subsequently activated the migration and invasion of AB cells. Ameloblastoma is the second most common benign epithelial odontogenic tumor and though it is of a benign nature, it is locally invasive, has a high recurrence rate and could potentially become malignant. Many theories have been proposed to explain the pathogenesis of ameloblastoma. Proper understanding of the pathogenic mechanism involved in ameloblastoma and its proliferation aids in constituting proper treatment of choice at an early stage, preventing morbidity associated with extensive therapy. An attempt has been made to discuss the current concepts related to molecular and genetic changes that occur in ameloblastoma as these could affect treatment plan and prognosis. Ameloblastomas are histologically benign tumors derived from the odontogenic apparatus. Although these tumors are locally invasive, they rarely invade the paranasal sinuses, orbits, or intracranial cavity, and, thus, they rarely produce ophthalmologic signs and symptoms. In this report, we describe the neuro-ophthalmologic features of three patients with chronically aggressive ameloblastoma. Two of the patients developed a progressive and recurrent orbital apex and cavernous sinus syndromes. One of these patients is, to our knowledge, the first patient described with orbital and cavernous simus involvement by an ameloblastoma initially arising in the mandible. The other is only the second case described with bilateral orbital involvement. The third patient in this series developed a trigeminal sensory neuropathy as the only sign of the tumor. Although ameloblastomas are benign, slowly growing tumors, they may, often over a long period of time, cause significant neuro-ophthalmologic and orbital manifestutions that can only be partially ameliorated by surgery. Ameloblastoma is a locally aggressive tumor derived from odontogenic epithelium. Although benign, its clinical behavior can often exhibit malignant characteristics. It is marked by slow and persistent growth with infiltration of adjacent tissues. Almost 70% occur in the mandible in patients older than 30 years. Recurrence of ameloblastoma from inadequate treatment is frequent. Because of its slow growth, recurrences can present decades after primary surgery. A primary ameloblastoma in an area outside the mandibular, maxillary, and infratemporal fossa regions has not been described in detail to date, with only 1 possible case mentioned in the literature. The authors present a case of primary temporal bone ameloblastoma in a 17-year-old boy. The tumor originated in the left mastoid, infiltrated the lateral semicircular canal, facial nerve, and cochlea, and adhered to the sigmoid sinus and posterior cranial fossa dura. Although invasion of multiple structures in the infratemporal fossa and temporal bone leads to variable disease presentation, this case is unique because the first symptom of disease was sudden and recurring unilateral sensorineural hearing loss. Surgery required transection of the facial nerve. Histopathology confirmed primary temporal bone ameloblastoma. The difficulties in achieving wide surgical margins, diagnostics, and further management are addressed. Ameloblastoma is a benign locally invasive odontogenic tumor. It is the most common odontogenic tumor [1]. Usually, in the middle-aged population, it is more common in the mandible with about 5-20% occurring in the maxilla. We report a case of maxillary unicystic ameloblastoma in a 3.5-year-old girl. Which presented clinically as a large facial swelling causing severe facial deformation and pressure symptoms on the left eye. CT scan showed that the swelling extended to involve the orbital floor. The lesion was diagnosed and confirmed by incisional biopsy then was successfully managed by maxillectomy and immediate reconstruction using the buccal pad of fat. One year follow up with no further complaints and no recurrence was observed. "Written informed consent was obtained from the patient guardians for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request". OBJECTIVE: Parathyroid hormone-related protein (PTHrP) production has been demonstrated in a variety of tumor subtypes. Local production of PTHrP by metastatic tumor cells in bone has been linked to bone destruction and tumor growth. Ameloblastoma (AB) is a relatively common odontogenic epithelial neoplasm that manifests local infiltrative intraosseous growth. AB recapitulates the developing enamel epithelium, in which PTHrP recently has been demonstrated. Yet PTHrP expression in a series of ABs has not been studied to date. The purpose of this investigation is to assess the expression of PTHrP in ameloblastoma. STUDY DESIGN: Formalin-fixed, paraffin-embedded tissue sections of ameloblastoma (n = 30; 24 conventional, 4 unicystic, and 2 arising in dentigerous cyst) were immunostained with anti-PTHrP antibody using a multistep streptavidin-peroxidase technique. Semiquantitative scoring of immunoreactivity was assessed as mild, moderate, and intense. RESULTS: All cases (100%) demonstrated positive immunoreactivity, with mild reaction in 3 conventional ABs, 1 unicystic and 1 AB arising in dentigerous cyst, and with moderate reaction in 12 conventional ABs, 3 unicystic and 1 AB arising in dentigerous cyst. Intense immunoreactivity was seen in 9 cases of conventional AB. This difference in immunostaining was not statistically significant (Sigma2 = 4.41, df = 4, P = .358). CONCLUSION: The results of this investigation suggest that PTHrP may play a significant role in local bone resorption, offering at least partial explanation for the tumor's infiltrative growth and destructive behavior. The uniformity of PTHrP expression by AB, as detailed in this study, may harbor significant therapeutic implications, particularly through PTHrP-blocking treatment modalities. Ameloblastoma or adamantinoma is the rarest of the three forms of tumor of the odontogenic type. They are benign, locally aggressive neoplasms arising from ameloblasts, which typically occur at the angle of the mandible, and are often associated with an un-erupted tooth and must, therefore, be differentiated from a dentigerous cyst which will be centered on the crown. When in the maxilla (less common), they are located in the premolar region, and can extend up in the maxillary sinus. Ameloblastoma is reported to constitute about 1-3% of tumors and cysts of the jaws. The tumor is by far more common in the mandible than in the maxilla and shows predilection for various parts of the mandible in different racial groups. The relative frequency of the mandible to maxilla is reported as varying from 80-20% to 99-1%. Here, we are representing a case of ameloblastoma of anterior mandible which was considered as a rare site of occurrence. BACKGROUND: Ameloblastoma is a neoplasm classified as a benign epithelial odontogenic tumor of the jaws, grow slowly and are locally invasive. The aim of the present study was to investigate the incidence, treatment, and complication of patients with ameloblastoma in East-Indonesia during six years retrospective study. MATERIAL AND METHODS: This retrospective study included 84 patients who were diagnosed with ameloblastoma from 2011 to 2016. There were 56 patients with treatment data available. Data from each patient, including gender, age, histologic type, the size of the tumor, radiologic form, tumor location, type of treatment, and complication were reviewed and analyzed retrospectively. RESULTS: Fourteen patients were diagnosed with unicystic ameloblastoma (25%), thirty two patients with multicystic follicular ameloblastoma (57%) and ten patients with an unspecified multicystic ameloblastoma (18%). A total of about 35 patients were treated conservatively (62.5%) and 21 patients were treated radically (37.5%). Swelling was present as a pre-operative complication in all 56 cases (100%). There were no complaints concerning speech. CONCLUSIONS: The majority findings of the histologic type were multicystic ameloblastoma and their location were in the mandible. Most ameloblastoma were treated conservatively and reconstructions were made with only titanium plates and not bone graft. BACKGROUND: Ameloblastoma is a frequent odontogenic benign tumor characterized by local invasiveness, high risk of recurrence and occasional metastasis and malignant transformation. Matrix metalloproteinase-2 (MMP-2) promotes tumor invasion and progression by destroying the extracellular matrix (ECM) and basement membrane. For this proteolytic activity, the endogenous inhibitor is reversion-inducing cysteine rich protein with Kazal motifs (RECK). The aim of this study was to characterize the relationship between RECK and MMP-2 expression and the clinical manifestation of ameloblastoma. METHODS: Immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) were employed to detect the protein and mRNA expression of RECK and MMP-2 in keratocystic odontogenic tumor (KCOT), ameloblastoma and ameloblastic carcinoma. RESULTS: RECK protein expression was significantly reduced in KCOT (87.5%), ameloblastoma (56.5%) and ameloblastic carcinoma (0%) (P < 0.01), and was significantly lower in recurrent ameloblastoma compared with primary ameloblastoma (P < 0.01), but did not differ by histological type of ameloblastoma. MMP-2 protein expression was significantly higher in ameloblastoma and ameloblastic carcinoma compared with KCOT (P < 0.01). RECK mRNA expression was significantly lower in ameloblastoma than in KCOT (P < 0.01), lower in recurrent ameloblastoma than in primary ameloblastoma, and was negative in ameloblastic carcinoma. MMP-2 mRNA expression was significantly higher in ameloblastoma compared with KCOT (P < 0.01), but was no different in recurrent ameloblastoma versus primary ameloblastoma. RECK protein expression was negatively associated with MMP-2 protein expression in ameloblastoma (r = -0.431, P < 0.01). CONCLUSION: Low or no RECK expression and increased MMP-2 expression may be associated with negative clinical findings in ameloblastoma. RECK may participate in the invasion, recurrence and malignant transformation of ameloblastoma by regulating MMP-2 at the post-transcriptional level. OBJECTIVE AND IMPORTANCE: Ameloblastoma is a locally aggressive benign tumor, commonly occurring in the mandible. While giant ameloblastoma of multicystic or plexiform variant have been reported, the authors report a rare case of giant unicystic ameloblastoma of luminal variant, which was treated by compartmental resection and planned for delayed reconstruction. CLINICAL PRESENTATION: A 46 year old male patient reported to the oral surgery out-patient department with a swelling of the left side mandible region of 2 years duration. He had undergone ayurvedic treatment for the same with no improvement. The size of the lesion on presenting was approximately 9 × 12 cm. INTERVENTION: Compartmental resection with plan for secondary reconstruction, after adequate follow up period. CONCLUSION: While conservative management is being explored as a treatment option for unicystic ameloblastoma, resection is still the standard of care regardless of the histopathological subtype for giant lesions. Ameloblastoma is a histologically benign tumor derived from odontogenic apparatus. The tumor can infiltrate into surrounding tissues. Although it is benign, it presents symptoms of a malignant tumor, such as infiltration into the lungs, pleura, regional and distant metastases, orbit, base of skull, brain and has resulted in death. It also has a high incidence of recurrences, the existence of regional or distant metastasis, showing a microscopic pattern of ameloblastic carcinoma with cytologic features of an increasing nuclear/cytoplastic ratio, nuclear hyperchromatism, and the presence of mitosis. We report a study of 12 patients of ameloblastoma of the jaws between January 1992 and December 1996 consisting of 8 affected in the mandible and 4 in the maxilla. One patient with a tumor in the maxilla was excluded from this study, due to a different histological and clinical behaviour of the ameloblastoma. BACKGROUND: The ameloblastoma is the most common odontogenic epithelial tumor, which belong to benign neoplasms that present a painless course, and usually occur in the oromaxillo-facial region. Although the histopathological manifestation of ameloblastoma is benign, it has unique biological behavior, for example local invasion and recurrence repeatedly. A few case of ameloblastoma was locally aggressive growth, and rarely metastasis to other tissue, for example the lungs, lymph nodes, and spine. CASE REPORT: A 64-year-old Chinese man, diagnosed with metastatic ameloblastoma, was treated with palliative chemotherapy consisting of cyclophosphamide, doxorubicin, and cisplatin for six cycles, and radiotherapy for 50 Gy after the last cycle chemotherapy. During the surveillance CT scan after the therapy, the tissues of the tumor were nearly complete response. CONCLUSION: The purpose of this study was to report a case of a patient with a right mandible ameloblastoma that recurred repeatedly and metastasized into bilateral lung. After the chemotherapy and radiotherapy, the tissues of the tumor were nearly complete response. This case is interesting because it investigated the diagnosis and treatment of the malignancy ameloblastoma, as this may help diagnose and treatment for clinician to the metastatic ameloblastoma. Ameloblastoma (AB), which is the most common odontogenic tumor, may originate from the dental lamina remnants. The expression of CD56, which is a transmembrane molecule, is associated with neuroectodermal differentiation of the embryonal cells. The aim of this study was to evaluate the expression of CD56 in AB, in comparison with other odontogenic cysts. We used formalin-fixed, paraffi n-embedded specimens from 34 cases of AB, 10 cases of keratocystic odontogenic tumor (KCOT), and 7 cases of dentigerous cyst (DC). We immunohistochemically examined CD56, NeuroD1, and N-cadherin expression in these tumors as compared with the expression patterns of various epithelial markers. Seventy-four percent of AB showed immunopositivity for CD56, and both CD56 and N-cadherin were diffusely positive in the outer columnar cells of AB. The immunopositivities for NeuroD1 and N-cadherin were also observed in the outer cells of AB. None of the DC cases was positive for CD56, whereas half the cases of KCOT were positive. Because CD56 is expressed in the inner enamel epithelium of enamel organs, the outer columnar cells of AB are likely to be the differentiation phenotype of the inner enamel epithelium, which is associated with neuroectodermal differentiation. The aberrant NeuroD1 expression may induce CD56 expression in AB and KCOT. Ameloblastoma is a rare odontogenic tumor of the jaw. It is a benign neoplasm but local recurrence is common. Metastasis from this tumor is all the more rare. The commonest site for metastasis is lung. Brain is a very uncommon site of involvement. Overall prognosis is good. We hereby discuss ameloblastoma of lower jaw in a young adult which had metastasized to brain. Patient was operated for the metastatic lesion of brain and is doing well on follow-up. Author information: (1)Professor & Head, Department of Oral Pathology, Faculty of Dental Sciences, Sri Ramachandra Institute of Higher Education & Research (DU), Porur, Chennai, India. (2)Professor, Department of Oral & Maxillofacial Surgery, Faculty of Dental Sciences, Sri Ramachandra Institute of Higher Education & Research (DU), Porur, Chennai, India. (3)Assoc. Professor, Department of Oral &Maxillofacial Surgery, Faculty of Dental Sciences, Sri Ramachandra Institute of Higher Education & Research (DU), Porur, Chennai, India. (4)Senior Lecturer in Oral Pathology, Department of Oral &Maxillofacial Surgery, Faculty of Dental Sciences, Sri Ramachandra Institute of Higher Education & Research (DU), Porur, Chennai, India. (5)Professor, Department of Oral Pathology, Faculty of Dental Sciences, Sri Ramachandra Institute of Higher Education & Research (DU), Porur, Chennai, India. BACKGROUND: Ameloblastoma is a rare benign odontogenic tumor with locally aggressive behavior and a high recurrence rate. When metastases occur, which are uncommon, lungs constitute the most frequent site involved. Malignant ameloblastomas are different from ameloblastic carcinomas. Malignant ameloblastomas are tumors considered metastatic despite the appearance of well-differentiated or benign histology, while ameloblastic carcinomas are histologically malignant in both primary and metastatic sites. CASE PRESENTATION: A 24-year-old Moroccan man presented a malignant ameloblastoma of the mandible. The tumor was entirely resected. Five years later, a local recurrence occurred. Our patient was treated by exclusive radiotherapy with persistence of a residual disease. After two years he developed multiple lung metastases. Our patient received a combination chemotherapy using doxorubicin and cisplatin. CONCLUSION: Less than 50 cases of ameloblastoma with metastases have been reported. There is still no standard treatment for metastatic ameloblastoma. Only through continuous reporting of such cases will clinicians be able to draw an optimal strategy for management of this pathology. Ameloblastoma is a benign odontogenic tumor which undergoes malignant transformation to ameloblastic carcinoma. However, rarely it metastasizes without undergoing cytological malignant changes, an entity referred to as Metastasizing Ameloblastoma (MA). Through this study, we aimed to review cases of MA reported since 2000 to explore the impact of clinico-demographic variables on its prognosis. Based on PRISMA guidelines, a review of relevant literature from PubMed/Medline, Science Direct and Cochrane database was performed from January 2000 to March 2019. A total of 65 cases were considered for further evaluation as per predefined inclusion and exclusion criteria. Results showed that lungs followed by lymph nodes were the most common sites for benign metastatic deposits. Multiple recurrences and inadequate surgical removal increase the probability of distant metastatic spread. Despite having benign cytological features, tumor recurrence and metastasis were associated with an unfavorable clinical outcome in MA. Ameloblastoma is the most common aggressive benign odontogenic tumor of the jaws. Ameloblastoma is a benign epithelial odontogenic tumor that typically arises in the mandible or maxilla or, rarely, in the immediate adjacent soft tissues. A clinical, radiographic and histopathological report is presented of a case of acanthomatous ameloblastoma in relation to molar in the left mandible of a 30-year-old healthy male. The histopathological examination of the removed specimen revealed the histopathological pattern of an acanthomatous ameloblastoma. The radiographic appearance of the lesion showed the presence of multilocular radiolucencies, which were crossing the midline, which is rarely found in ameloblastoma. Due to its rarity and lack of data, we take this opportunity to present a world first case of acanthomatous ameloblastoma which was crossing the midline. Ameloblastoma is the most common epithelial odontogenic tumor. It may show locally invasive behavior resulting in recurrence and malignancy. Therefore, appropriate diagnosis of this tumor is necessary. The aim of this study was to evaluate clinicopathological characteristics of ameloblastomas in an Iranian population. We present a 40-year retrospective study of patients diagnosed from 1971 to 2010 in the Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Mashhad, Iran. Information gathered from patient records included age, gender, tumor location and histologic type. The frequency of odontogenic tumors among all lesions was 2.08% and ameloblastoma with 88 samples demonstrated the greatest prevalence (41.5%). Regarding gender, 60% of samples occurred in males. The mean age of studied patients was 33.02± 15.74 years with a peak of occurrence in the third decade of life. The most frequent location of tumor was the mandibles (93.2%). Eighty five (96.6%) tumors were recorded as benign and 3 (3.4%) as malignant. Of benign tumors, 62 (72.9%), 20 (23.5%) and 3 (3.6%) cases were of conventional, unicyctic and peripheral types, respectively. In contrast to most previous studies, the most common histologic subtype in the present study was plexiform. Knowledge of the incidence of ameloblastoma and its clinicopathologic features including most common location, gender and age distribution in different ethnogeographic backgrounds is necessary for accurate diagnosis and proper treatment. Ameloblastoma is a benign odontogenic tumor generally present in the jaw bone. The tumor originates from the residual epithelium of the tooth germ, epithelium of odontogenic cysts stratified squamous epithelium and epithelium of the enamel organ. It represents approximately 1% of oral tumors. About 80% of ameloblastomas occur in the mandible mainly the third molar region and the remaining 20% in the upper jaw. Ameloblastoma clinically appears as an aggressive odontogenic tumor, often asymptomatic and slow-growing, with no evidence of swelling. This article deals with a complete review on ameloblastoma. Ameloblastic carcinoma (AC) is defined as a rare primary epithelial odontogenic malignant neoplasm and the malignant counterpart of benign epithelial odontogenic tumor of ameloblastoma (AB) by the WHO classification. AC develops pulmonary metastasis in about one third of the patients and reveals a poor prognosis. However, the mechanisms of AC oncogenesis remain unclear. In this report, we aimed to clarify the mechanisms of malignant transformation of AB or AC carcinogenesis. The relatively important genes in the malignant transformation of AB were screened by DNA microarray analysis, and the expression and localization of related proteins were examined by immunohistochemistry using samples of AB and secondary AC. Two genes of hypoxia-inducible factor 1 alpha subunit (HIF1A) and zinc finger E-box-binding homeobox 1 (ZEB1) were significantly and relatively upregulated in AC than in AB. Both genes were closely related in hypoxia and epithelial-mesenchymal transition (EMT). In addition, expressions of HIF-1α and ZEB1 proteins were significantly stronger in AC than in AB. In the cell assays using ameloblastoma cell line, AM-1, hypoxia condition upregulated the expression of transforming growth factor-β (TGF-β) and induced EMT. Furthermore, the hypoxia-induced morphological change and cell migration ability were inhibited by an antiallergic medicine tranilast. Finally, we concluded that hypoxia-induced HIF-1α and ZEB1 were critical for the malignant transformation of AB via TGF-β-dependent EMT. Then, both HIF-1α and ZEB1 could be potential biomarkers to predict the malignant transformation of AB. Ameloblastomas are benign tumors that most commonly affecting the mandible. The current standard of treatment for ameloblastomas is resection followed by reconstruction that has historically been accomplished through the use of a microsurgical vascularized flaps taken from the iliac crest or fibula. Alloplastic reconstruction methods have gained popularity over recent years with success reported in the reconstruction of many pathologies, including ankylosis, condylar fracture, neoplasia involving extensive resection, severe inflammatory/degenerative temporomandibular joint (TMJ) disease, and congenital TMJ abnormalities. The authors present a patient who successfully underwent ameloblastoma resection and TMJ reconstruction with a custom TMJ Concepts alloplastic implant. The authors also present a review of the literature on alloplastic TMJ reconstruction following ameloblastoma resection. To our knowledge, this is the second report in the literature on the use of a TMJ Concepts implant after ameloblastoma resection. BACKGROUND: Ameloblastoma is a benign odontogenic tumor, exhibiting local invasiveness and high rate of recurrence. Metallothionein is a protein associated with tumorigenesis, serving as prognostic factor in different neoplasms. We are interested in mechanisms underlying ameloblastoma local invasiveness. Thus, we decided to analyze expression of metallothionein in this tumor. MATERIALS AND METHODS: An immunohistochemical evaluation of metallothionein in ameloblastoma was carried out. As control, we assessed expression of the same molecule in calcifying cystic odontogenic tumor (CCOT), a non-invasive odontogenic neoplasm with ameloblastomatous epithelium. RESULTS: We studied 12 cases of solid/multicystic ameloblastomas. Metallothionein was observed in all samples. This molecule was observed in columnar cells in the periphery and in central polyhedral cells. CCOT (four cases) also showed the presence of metallothionein. Morphometry of stained areas showed that expression of metallothionein in ameloblastoma was significantly higher compared to CCOT (P < 0.0001). CONCLUSIONS: This protein may have an impact on ameloblastoma behavior. Metallothionein would act as a zinc reservoir for important proteases related to ameloblastoma biology, such as MMPs. This protein could also display pro-mitotic and anti-apoptotic features in the tumor. BACKGROUND Ameloblastoma (AB) is a common odontogenic epithelial tumor, with locally invasive behavior and high recurrence. In this study, we hypothesized that miR-524-5p could be involved in the tumor microenvironment by targeting interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) in AB. MATERIAL AND METHODS The microRNA (miRNA) expression profile of AB tissues and normal oral mucosa tissues (NOM; 6 paired samples) was analyzed. The miRNAs with fold change ≥2 and P<0.05 were considered to be differentially expressed. Among them, downregulated miR-524-5p was verified by real-time qPCR. Potential targets of miR-524-5p were predicted by bioinformatics analysis. The expression levels of target genes were detected using real-time qPCR and Western blot, respectively. Immunohistochemistry analysis of target genes was performed, and we also assessed the correlation between miR-524-5p and its target. RESULTS Microarray analysis results first indicated miR-524-5p is a downregulated miRNA in AB tissues. Real-time qPCR results confirmed the expression pattern of miR-524-5p in AB tissues. Moreover, IL-33 and its receptor ST2 were significantly overexpressed. As shown in immunohistochemistry results, IL-33 was positively expressed in lymphocytes and plasma cells, suggesting that IL-33/ST2 participates in tumor immune responses in the tumor microenvironment. Correlation analysis suggested that miR-524-5p expression was negatively correlated with IL-33/ST2. CONCLUSIONS Our findings reveal that downregulated miR-524-5p can participate in the tumor microenvironment of AB by targeting the IL-33/ST2 axis. Ameloblastoma(AB) is an aggressive and slow-growing tumor with high recurrence rate, which arises from odontogenic epithelium. AB mostly shows osteolytic growth, but the specific pathogenesis is not yet clear. Periostin is a considered a prominent oncogene, which was mainly produced by osteoblasts and their precursors cells, it have been proved that Periostin play an important role in bone lysis. However, the precise role of Periostin in AB progression remains unknown. In this article, the surgical specimens from cases of AB were collected, and the Periostin expression was tested and the results were analyzed for possible correlations with clinical characteristics. In addition, the proliferation、cell cycle and migration of AM-1 cells were evaluated after transfection of siPeriostin. The results showed that Periostin levels were significantly higher in patients with AB than in controls. Moreover, Periostin levels in patients with AB were significantly associated with the number of disease. Furthermore, the results suggested that Periostin expression significantly promoted the proliferation and migration, in addition to cell cycle progression of AM-1 cells. The present study demonstrated that Periostin may be important in the pathogenesis and progression of AB and indicated its potential therapeutic value. Author information: (1)Department of Oral Biology and Oral Pathology, School of Dentistry, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa. (2)Department of Oral Biology and Oral Pathology, School of Dentistry, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa; Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. (3)Department of Oral Surgery and Diagnosis, Odilon Behrens Hospital, Belo Horizonte, Brazil. (4)Department of Oral Biology and Oral Pathology, School of Dentistry, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa. Electronic address: willie.vanheerden@up.ac.za. The ameloblastoma is a benign but aggressive neoplasm of odontogenic origin. However, no enamel or hard tissue is formed by the tumor cells. Ameloblastomas are infamous for their invasive growth and their tendency to recur. Robinson (1937) as a benign tumor that is 'usually unicentric, nonfunctional, intermittent in growth, anatomically benign and clinically persistent.' They may occur at any age, even though nearly half of the tumors do occur between the ages of 20 and 40 years. This is the most common neoplasm affecting the jaws, yet only accounts for 1% of all tumors of the maxilla and mandible and 11% of all odontogenic tumors. This report presents a case of ameloblastoma involving entire ramus and part of body of mandible with resorption of the mesial and distal root apices of second molar and distal root of mandibular first molar. The lesion extending till the base of mandible surrounding the crown of the unerupted third molar resembling the dentigerous cyst. This was surgically resected followed by harvesting the contralateral sixth costochondral rib graft. How to cite this article: Celur S, Babu KS. Plexiform Ameloblastoma. Int J Clin Pediatr Dent 2012;5(1):78-83. BACKGROUND AND OVERVIEW: Ameloblastoma is an odontogenic tumor predominantly occurring in patients who are in their 20s and 30s. Approximately 10% to 15% of ameloblastomas occur in patients younger than 18 years. Although it is a benign tumor, an ameloblastoma can have a devastating effect on children both physically and emotionally. The aim of this case report is to demonstrate how tissue engineering and surgical techniques can minimize morbidity and recovery time after extirpation and immediate reconstruction of a mandibular ameloblastoma. CASE DESCRIPTION: An 11-year-old girl was referred for surgical evaluation of a lesion found on a routine dental radiograph. Resection of a mandibular unicystic ameloblastoma resulted, including immediate reconstruction using a costochondral rib graft, allogeneic bone, bone marrow aspirate concentrate, and recombinant human morphogenetic protein-2. One year postoperatively, the patient had no evidence of recurrence as well as excellent mandibular bone height and width with good facial form. The patient has returned to her daily life without any disabilities or disfigurement. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Dentists are typically the first health care providers to discover oral pathology in patients. The coordination of care by the dental care providers and the oral and maxillofacial specialist was key to the successful outcome for this patient. With biotechnology and surgical techniques, the dental surgeon can extirpate an ameloblastoma and reconstruct the mandible defect to the ideal shape and size with minimal morbidity and recovery time.

In which aspects of the immune response is m6A methylation implicated?

m6A is a novel regulator of immune system homeostasis and activation. m6A modifications and m6A modifying proteins play a critical role in pathogen recognition, immune cell activation, immune cell fate decisions, and immune reactions. These modifications modulate the fate decisions of innate and adaptive immune cells and regulate immune responses in immune-associated diseases, including viral infections and cancer.

[34515345]

N6 -methyladenosine (m6 A) RNA methylation is a reversible posttranscriptional modification in eukaryotes involving three types of functional proteins: "writers", "erasers", and "readers". m6 A regulates the metabolism of messenger RNAs and noncoding RNAs through RNA structure, splicing, stability, export, and translation, thereby participating in various physiological and pathological processes. Here, we summarize the current state of m6 A methylation researches, focusing on how these modifications modulate the fate decisions of innate and adaptive immune cells and regulate immune responses in immune-associated diseases, including viral infections and cancer. These studies showed that m6 A modifications and m6 A modifying proteins play a critical role in pathogen recognition, immune cell activation, immune cell fate decisions, and immune reactions. m6 A is a novel regulator of immune system homeostasis and activation.

Describe nextNEOpi

NextNEOpi is a comprehensive and fully-automated bioinformatic pipeline to predict tumor neoantigens from raw DNA and RNA sequencing data. In addition, nextNEOpi quantifies neoepitope- and patient-specific features associated with tumor immunogenicity and response to immunotherapy.

[34788790]

SUMMARY: Somatic mutations and gene fusions can produce immunogenic neoantigens mediating anticancer immune responses. However, their computational prediction from sequencing data requires complex computational workflows to identify tumor-specific aberrations, derive the resulting peptides, infer patients' Human Leukocyte Antigen types and predict neoepitopes binding to them, together with a set of features underlying their immunogenicity. Here, we present nextNEOpi (nextflow NEOantigen prediction pipeline) a comprehensive and fully automated bioinformatic pipeline to predict tumor neoantigens from raw DNA and RNA sequencing data. In addition, nextNEOpi quantifies neoepitope- and patient-specific features associated with tumor immunogenicity and response to immunotherapy. AVAILABILITY AND IMPLEMENTATION: nextNEOpi source code and documentation are available at https://github.com/icbi-lab/nextNEOpi. CONTACT: dietmar.rieder@i-med.ac.at or francesca.finotello@uibk.ac.at. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

What is the use of the ATRIA score?

ATRIA score determines bleeding risk for patients on warfarin.

[29560065, 28363682, 29274754, 31800901, 29030869, 24991318, 33550837]

INTRODUCTION: Many patients with atrial fibrillation or atrial flutter (AF/FL) who are high risk for ischemic stroke are not receiving evidence-based thromboprophylaxis. We examined anticoagulant prescribing within 30 days of receiving dysrhythmia care for non-valvular AF/FL in the emergency department (ED). METHODS: This prospective study included non-anticoagulated adults at high risk for ischemic stroke (ATRIA score ≥7) who received emergency AF/FL care and were discharged home from seven community EDs between May 2011 and August 2012. We characterized oral anticoagulant prescribing patterns and identified predictors of receiving anticoagulants within 30 days of the index ED visit. We also describe documented reasons for withholding anticoagulation. RESULTS: Of 312 eligible patients, 128 (41.0%) were prescribed anticoagulation at ED discharge or within 30 days. Independent predictors of anticoagulation included age (adjusted odds ratio [aOR] 0.89 per year, 95% confidence interval [CI] 0.82-0.96); ED cardiology consultation (aOR 1.89, 95% CI [1.10-3.23]); and failure of sinus restoration by time of ED discharge (aOR 2.65, 95% CI [1.35-5.21]). Reasons for withholding anticoagulation at ED discharge were documented in 139 of 227 cases (61.2%), the most common of which were deferring the shared decision-making process to the patient's outpatient provider, perceived bleeding risk, patient refusal, and restoration of sinus rhythm. CONCLUSION: Approximately 40% of non-anticoagulated AF/FL patients at high risk for stroke who presented for emergency dysrhythmia care were prescribed anticoagulation within 30 days. Physicians were less likely to anticoagulate older patients and those with ED sinus restoration. Opportunities exist to improve rates of thromboprophylaxis in this high-risk population. PURPOSE: To evaluate the outcome of patients with an established indication for oral anticoagulation (OAC) undergoing coronary stent implantation (PCI-S) and stratified by the baseline risk of bleeding. MATERIAL AND METHODS: The database of the prospective, multicentre, observational WAR-STENT registry (ClinicalTrials.gov identifier NCT00722319) was analyzed and patients with atrial fibrillation and CHA2DS2-VASc score ≥2, mechanical heart valve, prior cardiac embolism, intra-cardiac thrombus and recent venous thromboembolism who were treated with either triple (warfarin, aspirin and clopidogrel) or dual (warfarin and clopidogrel) or dual antiplatelet (aspirin and clopidogrel) therapy, identified. Patients were then sorted into two groups at non-low and low risk of bleeding, as defined by an ATRIA score >3 and ≤3 respectively, and compared regarding major adverse cardiac and vascular events (MACVE) and bleeding. RESULTS: At 12-month follow up, MACVE were comparable in the two groups, whereas total, major and minor bleeding, as well as combined MACVE and total bleeding, were significantly more frequent in the non-low bleeding risk group. Upon Cox univariate and multivariable analysis, non-low bleeding risk category confirmed as an independent predictor of major bleeding. The choice of antithrombotic therapy however, appeared not to be influenced by the bleeding risk category at baseline. CONCLUSIONS: In patients with an established indication for OAC undergoing PCI-S, non-low bleeding risk category is the most potent independent predictor of major bleeding. Stratification of the bleeding risk at baseline should therefore be regarded as an indispensable process to be carried out before selection of the antithrombotic therapy. BACKGROUND: Various bleeding risk scores have been proposed to assess the risk of bleeding in patients with atrial fibrillation taking oral anticoagulants. Limited data are available with these scores, in users of non-vitamin K antagonist oral anticoagulants. METHODS: Using the Danish registries, we evaluated and compared the risk classification properties of the Hypertension, Age, Stroke, Bleeding tendency/predisposition, Labile international normalized ratios, Elderly age/frailty, Drugs such as concomitant aspirin/nonsteroidal anti-inflammatory drugs or alcohol excess (HAS-BLED), Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA), and Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT) scores for predicting major bleeding in 57,930 atrial fibrillation patients (44.6% female; mean age 73.5 years, standard deviation 11.4 years; mean CHA2DS2-VASc score 3.2, standard deviation 1.8). RESULTS: At 1-year follow-up, C-statistics for ATRIA, HAS-BLED, and ORBIT were approximately 0.59, with only minor differences between scores. Both ATRIA and ORBIT categorized more patients as "low risk" (both >83%, when compared with HAS-BLED, only 53%), and qualitatively, the receiver operating characteristic curves revealed higher sensitivity (62.8%) for HAS-BLED compared with ATRIA (29.7%) and ORBIT (37.1%). The clinical usefulness of scores was evaluated using decision curve analyses at a 1-year perspective. If the intervention threshold is low (<1.7%), the benefit is toward monitoring all patients. If preference is for a major bleeding risk threshold between 1.7% and 2.0%, most benefit was obtained by using HAS-BLED. The ORBIT and ATRIA scores provided better benefit for thresholds between 2.0% and 6.0%. CONCLUSION: This analysis of contemporary bleeding risk score stratification in a "real-world" non-vitamin K antagonist oral anticoagulant users population with atrial fibrillation showed modest predictive values using C-statistics. The scores represent different risk thresholds, with HAS-BLED classifying least patients at low risk and achieving the highest benefit if applying a major bleeding intervention threshold of approximately 2%, whereas benefit from using either ATRIA score or ORBIT score was only evident using higher intervention thresholds. BACKGROUND: The AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) risk score used to detect the thromboembolic and hemorrhagic risk in atrial fibrillation patients has been shown recently to predict poor clinical outcomes in patients with acute myocardial infarction (ACS), regardless of having atrial fibrillation (AF). We aimed to analyze the relationship between different risk scores and contrast-induced nephropathy (CIN) development in patients with ACS who underwent urgent percutaneous coronary intervention (PCI) and compare the predictive ability of the ATRIA risk score with the MEHRAN risk score. METHODS: We analyzed 429 patients having St-segment Elevation Myocardial Infarction (STEMI) who underwent urgent PCI between January 2016 and February 2017. Patients were divided into two groups: those with and those without CIN and both groups were compared according to clinical, laboratory, and demographic features, including the CHA2DS2-VASc and ATRIA risk score. Predictors of CIN were determined by multivariate regression analysis. Receiver operating characteristics (ROC) curve analysis was used to analyze the prognostic value of CHA2DS2-VASc and ATRIA risk score for CIN, following STEMI. RESULTS: Multivariate regression analysis showed that Athe TRIA risk score, Opaque/Creatinine Clearance ratio, and low left ventricular ejection fraction was an independent predictor of CIN. The C-statistics for the ATRIA risk score and CHA2DS2-VASC risk score were 0.66 and 0.64 (p<0.001, and p<0.001), respectively. A pair-wise comparison of ROC curves showed that both scores were not inferior to the MEHRAN score in predicting CIN. CONCLUSION: The ATRIA and CHA2DS2-VASC scoring systems were useful for detecting CIN following STEMI. WHAT IS KNOWN AND OBJECTIVE: Bleeding risk scores (BRSs) aid in the assessment of oral anticoagulant-related bleeding risk in patients with atrial fibrillation. Ideally, the applicability of a BRS needs to be assessed, prior to its routine use in a population other than the original derivation cohort. Therefore, we evaluated the performance of 6 established BRSs to predict major or clinically relevant bleeding (CRB) events associated with the use of oral anticoagulant (OAC) among Malaysian patients. METHODS: The pharmacy supply database and the medical records of patients with non-valvular atrial fibrillation (NVAF) receiving warfarin, dabigatran or rivaroxaban at two tertiary hospitals were reviewed. Patients who experienced an OAC-associated major or CRB event within 12 months of follow-up, or who have received OAC therapy for at least 1 year, were identified. The BRSs were fitted separately into patient data. The discrimination and the calibration of these BRSs as well as the factors associated with bleeding events were then assessed. RESULTS: A total of 1017 patients with at least 1-year follow-up period, or those who developed a bleeding event within 1 year of OAC use, were recruited. Of which, 23 patients experienced a first major bleeding event, whereas 76 patients, a first CRB event. Multivariate logistic regression results show that age of 75 or older, prior bleeding and male gender are associated with major bleeding events. On the other hand, prior gastrointestinal bleeding, a haematocrit value of less than 30% and renal impairment are independent predictors of CRB events. All the BRSs show a satisfactory calibration for major and CRB events. Among these BRSs, only HEMORR2 HAGES (C-statistic = 0.71, 95% CI 0.60-0.82, P < .001) and ATRIA score (C-statistic = 0.70, 95% CI 0.58-0.82, P < .001) show acceptable discrimination performance for major bleeding events. All the 6 BRSs, however, lack acceptable predictive performance for CRB events. WHAT IS NEW AND CONCLUSION: To the best of our knowledge, this is the first evaluation study of the predictive performance of these 6 BRSs on clinically relevant bleeding events applied to the same cohort consisting of mainly Asian novel oral anticoagulant users. These BRSs show poor to acceptable predictive performance on OAC-induced major or CRB events. An improvement in the existing BRSs for OAC users is warranted. BACKGROUND: Clinical guidelines recommend oral anticoagulation for stroke prevention in patients with atrial fibrillation (AF) at moderate or high risk for stroke but not at high risk for bleeding; however, studies consistently report suboptimal use of such therapy. This study used Medicare Part D claims data to assess the use of warfarin in the Medicare population. OBJECTIVES: To compare real-world warfarin utilization with current treatment guideline recommendations, and to assess the effect of warfarin exposure level on patient outcomes in Medicare beneficiaries with nonvalvular AF (NVAF). METHODS: Patients who were recently diagnosed with NVAF were identified using a random 5% sample of Research Identifiable Files of Medicare beneficiaries in 2006 or 2007. Individuals with moderate-to-high stroke risk per CHADS2 but not at high bleeding risk per ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) bleeding risk score were evaluated for warfarin use, as identified by the presence of ≥1 warfarin prescription claims within 12 months after the index diagnosis. Warfarin exposure level was assessed by the proportion of days covered during the 12-month follow-up period. The effect of warfarin exposure on ischemic stroke and major bleeding event rates during the 12-month follow-up period were assessed using multivariate logistic regression. RESULTS: Data from 14,149 newly diagnosed patients with NVAF (mean age, 79 years; 58.7% female) were analyzed, and of these, 7524 (53.2%) patients were identified as having moderate-to-high stroke risk and not being at high bleeding risk. Of these patients, 3110 (41.3%) did not receive warfarin within 12 months of the index diagnosis. The risk for ischemic stroke was significantly lower in those with warfarin exposure versus no warfarin exposure (adjusted odds ratio [OR], 0.51; confidence interval [CI], 0.43-0.61; P <.001) and in patients with warfarin proportion of days covered ≥80% versus those with proportion of days covered <80% (adjusted OR, 0.59; 95% CI, 0.48-0.72; P<.001). Warfarin exposure was associated with a significantly higher major bleeding rate (adjusted OR, 1.19; 95% CI, 1.04-1.36; P = .013), with this significant difference being driven by patients aged >65 years. CONCLUSIONS: Based on a risk-stratification scheme composed of previously published tools, such as CHADS2 and the ATRIA bleeding risk index, a significant proportion of Medicare beneficiaries with AF are not receiving guideline-recommended anticoagulation therapy, which leads to an excess rate of ischemic stroke in this patient population. These findings highlight quality-of-care issues for patients with AF and the need to improve compliance with anticoagulation guidelines in the Medicare population.

Which protein is targeted by Herceptin?

Her2 is targeted by Herceptin.

[33468562, 34532642]

BACKGROUND: On encountering a susceptible target, natural killer (NK) cells mediate cytotoxicity through highly regulated steps of directed degranulation. Cytotoxic granules converge at the microtubule organizing center and are polarized toward the immunological synapse (IS), followed by granule exocytosis. NK cell retargeting by chimeric antigen receptors (CARs) or mAbs represents a promising strategy for overcoming tumor cell resistance. However, little is known about the lytic granule dynamics of such retargeted NK cells toward NK-cell-resistant tumors. METHODS: Here, we used spinning disk confocal microscopy for live-cell imaging to analyze granule-mediated NK cell cytotoxicity in ErbB2-targeted CAR-expressing NK-92 cells (NK-92/5.28.z) and high-affinity FcR transgenic NK-92 cells plus Herceptin toward ErbB2-positive breast cancer cells (MDA-MB-453), which are resistant to parental NK-92. RESULTS: Unmodified NK-92 cells cocultured with resistant cancer cells showed stable conjugate formation and granule clustering, but failed to polarize granules to the IS. In contrast, retargeting by CAR or FcR+Herceptin toward the MDA-MB-453 cells enabled granule polarization to the IS, resulting in highly effective cytotoxicity. We found that in NK-92 the phosphoinositide 3-kinase pathway was activated after contact with resistant MDA-MB-453, while phospholipase C-γ (PLCγ) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) were not activated. In contrast, retargeting by CAR or antibody-dependent cell-mediated cytotoxicity (ADCC) provided the missing PLCγ and MEK/ERK signals. CONCLUSIONS: These observations suggest that NK cells can create conjugates with resistant cancer cells and respond by granule clustering, but the activation signals are insufficient to induce granule polarization and consequent release of lytic enzymes. Retargeting by CAR and/or the FcR/mAb (ADCC) axis provide the necessary signals, leading to granule polarization and thereby overcoming tumor cell resistance. BACKGROUND: ERBB2 is a proto-oncogene of multiple cancers including breast and gastric cancers with HER2 protein overexpression or gene amplification and has been proven clinically as a valid target for these cancers. HER2-targeting agents such as Herceptin®, Kadcyla® and ENHERTU® have been approved by the FDA for the treatment of breast cancer, but these drugs still face the challenge of acquired resistance and/or severe adverse reactions in clinical use. Therefore, there is significant unmet medical need for developing new agents that are more effective and safer for patients with advanced HER2-positive solid tumors including breast and gastric cancers. METHODS: We report here the making of MRG002, a novel HER2-targeted antibody drug conjugate (ADC), and preclinical characterization including pharmacology, pharmacodynamics and toxicology and discuss its potential as a novel agent for treating patients with HER2-positive solid tumors. RESULTS: MRG002 exhibited similar antigen binding affinity but much reduced antibody-dependent cellular cytotoxicity (ADCC) activity compared to trastuzumab. In addition to potent in vitro cytotoxicity, MRG002 showed tumor regression in both high- and medium-to-low HER2 expressing in vivo xenograft models. Furthermore, MRG002 showed enhanced antitumor activity when used in combination with an anti-PD-1 antibody. Main findings from toxicology studies are related to the payload and are consistent with literature report of other ADCs with monomethyl auristatinE. CONCLUSION: MRG002 has demonstrated a favorable toxicity profile and potent antitumor activities in the breast and gastric PDX models with varying levels of HER2 expression, and/or resistance to trastuzumab or T-DM1. A phase I clinical study of MRG002 in patients with HER2-positive solid tumors is ongoing (CTR20181778).

What are the main clinical components of the brain death exam?

The three essential findings in brain death are coma, absence of brain stem reflexes by neurologic exam including ancillary testing, and apnea. Studies can highlight the variability in practice in regard to the AT and supports the use of ancillary tests to determine BD in patients. Coma and brain stem reflexes can be determined by several ancillary tests Ancillary tests include electroencephalography, brainstem auditory evoked potentials, included somatosensory evoked potentials, transcranial Doppler ultrasonography, conventional cerebral angiography, and nuclear medicine flow study

[33273410, 18514082, 32648194, 20724258, 31456011, 21604079, 32667440, 32524528, 22522447, 32312535]

Forty years after the publication of a landmark paper by the Ad Hoc Committee of the Harvard Medical School, the general concept of brain death has achieved widespread acceptance. In the United States, irreversible dysfunction of the brain and brainstem are required for the diagnosis of brain death. Although primarily based on clinical evaluation, confirmatory examinations, including radionuclide blood flow studies, play an important role in augmenting the physical examination in special situations when some of its specific components cannot be performed or reliably evaluated. The 2 main radionuclidic techniques used in evaluation of brain death are radionuclide angiography with nonlipophilic radiopharmaceuticals and parenchymal imaging with lipophilic agents. Specific technical guidelines for determination of brain death have been promulgated by professional medical societies. In the vast majority of cases, blood flow examinations are useful in confirming brain death. Nonetheless, on occasion patients clinically diagnosed with brain death will exhibit persistent intracranial blood flow or electrical activity. Existence of these contradictory cases reveals underlying inconsistencies in the definitions of brain death. We hypothesize that the existence of these apparent contradictions is related to differences in sensitivity of the physical examination and the confirmatory examinations, differences in localization of the physical examination and confirmatory tests, and differences between blood flow and cerebral function as markers of brain death. OBJECTIVE: We sought to identify similarities and differences in the diagnostic requirements for ancillary testing for determination of brain death/death by neurologic criteria (BD/DNC) around the world. METHODS: We reviewed diagnostic requirements for ancillary testing for BD/DNC in 78 unique official national BD/DNC protocols obtained from contacts worldwide between January 2018 and April 2019. RESULTS: Details provided on the performance and interpretation of ancillary tests for determination of BD/DNC were variably provided and inconsistent. Approximately half of all protocols that included each ancillary test provided details about study performance: 63% of protocols that included conventional cerebral angiography, 55% of protocols that included electroencephalography, 50% of protocols that included somatosensory evoked potentials, 48% of protocols that included transcranial Doppler ultrasonography, 43% of protocols that included nuclear medicine flow study and 41% of protocols that included brainstem auditory evoked potentials. Similarly, about half of all protocols that included each ancillary test provided details about study interpretation: 66% of protocols that included electroencephalography, 59% of protocols that included brainstem auditory evoked potentials, 56% of protocols that included somatosensory evoked potentials, 55% of protocols that included transcranial Doppler ultrasonography, 52% of protocols that included conventional cerebral angiography and 49% of protocols that included nuclear medicine flow study. INTERPRETATION: Diagnostic requirements for ancillary testing in BD/DNC determination vary around the world. We hope that the World Brain Death Project will improve worldwide consensus on the diagnostic requirements for ancillary testing in BD/DNC, both for performance and interpretation. BACKGROUND: In Canada, ancillary tests, such as selective four vessels angiography (S4VA), are sometimes necessary for brain death (BD) diagnosis when the clinical exam cannot be completed or confounding factors are present. Recent Canadian guidelines assert that brain death is supported by the absence of arterial blood flow at the surface of the brain and that venous return should not be considered. However, neuropathologic and angiographic studies have suggested that arteries might still be patent in BD patients. Current clinical practices in BD diagnosis following S4VA need to be better understood. METHODS: We conducted a retrospective study of all S4VA performed for the determination of BD in a level 1 NeuroTrauma centre from 2003 to 2007. The objective of the study was to describe the prevalence of intracranial arterial, capillary (parenchymogram) and venous opacification in our study population. All tests were reviewed independently by two neuroradiologists. Disagreements were resolved by consensus. RESULTS: Thirty two patients were declared BD following S4VA during the study period. Nine of these patients (28%) presented some proximal opacification of intracranial arteries (95% CI 15-45%). As opposed, none had a cerebral capillary and deep venous drainage opacification (95% CI 0-10%). CONCLUSION: The absence of cerebral deep venous drainage or parenchymogram might represent a better objective marker of cerebral circulatory arrest for brain death diagnosis when the use of S4VA is required. These findings open the path for further research in enhancing our interpretation of angiographic studies for brain death diagnosis. The apnea test, which involves disconnection from the mechanical ventilator, presents risks during the determination of brain death, especially in hypoxemic patients. We describe the performance of the apnea test without disconnection from the mechanical ventilator in two patients. The first case involved an 8-year-old boy admitted with severe hypoxemia due to pneumonia. He presented with cardiorespiratory arrest, followed by unresponsive coma due to hypoxic-ischemic encephalopathy. Two clinical exams revealed the absence of brainstem reflexes, and transcranial Doppler ultrasound revealed brain circulatory arrest. Three attempts were made to perform the apnea test, which were interrupted by hypoxemia; therefore, the apnea test was performed without disconnection from the mechanical ventilator, adjusting the continuous airway pressure to 10cmH2O and the inspired fraction of oxygen to 100%. The oxygen saturation was maintained at 100% for 10 minutes. Posttest blood gas analysis results were as follows: pH, 6.90; partial pressure of oxygen, 284.0mmHg; partial pressure of carbon dioxide, 94.0mmHg; and oxygen saturation, 100%. The second case involved a 43-year-old woman admitted with subarachnoid hemorrhage (Hunt-Hess V and Fisher IV). Two clinical exams revealed unresponsive coma and absence of all brainstem reflexes. Brain scintigraphy showed no radioisotope uptake into the brain parenchyma. The first attempt at the apnea test was stopped after 5 minutes due to hypothermia (34.9°C). After rewarming, the apnea test was repeated without disconnection from the mechanical ventilator, showing maintenance of the functional residual volume with electrical bioimpedance. Posttest blood gas analysis results were as follows: pH, 7.01; partial pressure of oxygen, 232.0mmHg; partial pressure of carbon dioxide, 66.9mmHg; and oxygen saturation, 99.0%. The apnea test without disconnection from the mechanical ventilator allowed the preservation of oxygenation in both cases. The use of continuous airway pressure during the apnea test seems to be a safe alternative in order to maintain alveolar recruitment and oxygenation during brain death determination. Apnea is one of the three cardinal findings in brain death (BD). Apnea testing (AT) is physiologically and practically complex. We sought to review described modifications of AT, safety and complication rates, monitoring techniques, performance of AT on extracorporeal membrane oxygenation (ECMO), and other relevant considerations regarding AT. We conducted a systematic scoping review to answer these questions by searching the literature on AT in English language available in PubMed or EMBASE since 1980. Pediatric or animal studies were excluded. A total of 87 articles matched our inclusion criteria and were qualitatively synthesized in this review. A large body of the literature on AT since its inception addresses a variety of modifications, monitoring techniques, complication rates, ways to perform AT on ECMO, and other considerations such as variability in protocols, lack of uniform awareness, and legal considerations. Only some modifications are widely used, especially methods to maintain oxygenation, and most are not standardized or endorsed by brain death guidelines. Future updates to AT protocols and strive for unification of such protocols are desirable. OBJECTIVE: To review practices of brain death (BD) determination in patients on extracorporeal membrane oxygenation (ECMO). METHODS: A systematic search was applied to PubMed and 6 electronic databases from inception to May 22, 2019. Studies reporting methods of BD assessment in adult patients (>18 years old) while on ECMO were included, after which data regarding BD assessment were extracted. RESULTS: Twenty-two studies (n = 177 patients) met the inclusion criteria. Eighty-eight patients (50%) in 19 studies underwent the apnea test (AT); most commonly through decreasing the ECMO sweep flow in 14 studies (n = 42, 48%), followed by providing CO2 through the ventilator in 2 studies (n = 6, 7%), and providing CO2 through the ECMO oxygenator in 1 study (n = 1, 1%). The details of the AT were not reported in 2 studies (n = 39, 44%). In 19 patients (22%), the AT was nonconfirmatory due to hemodynamic instability, hypoxia, insufficient CO2 rise, or unreliability of the AT. A total of 157 ancillary tests were performed, including electroencephalogram (62%), computed tomography angiography (22%), transcranial Doppler ultrasound (6%), cerebral blood flow nuclear study (5%), cerebral angiography (4%), and other (1%). Forty-seven patients (53% of patients with AT) with confirmatory AT still underwent additional ancillary for BD confirmation. Only 21 patients (12% of all patients) were declared brain-dead using confirmatory ATs alone without ancillary testing. CONCLUSIONS: Performing AT for patients with ECMO was associated with high failure rate and hemodynamic complications. Our study highlights the variability in practice in regard to the AT and supports the use of ancillary tests to determine BD in patients on ECMO.

What variables are included in the MuLBSTA score?

MuLBSTA score includes Multilobular infiltration, hypo-Lymphocytosis, Bacterial coinfection, Smoking history, hyper-Tension and Age.

[33573696, 32923449, 33729130, 32860431]

OBJECTIVES: The primary objectives of the study are to determine the effectiveness of the Kaba Sura Kudineer (KSK) & Nilavembu Kudineer (NVK) along with standard Allopathy Treatment to compared with Placebo (Decaffeinated Tea) with standard Allopathy Treatment in the management of Symptomatic COVID 19 patients and also in reduction of Hospital Stay Time & Changes in Immunological (IL6) and Bio Chemical Markers (Ferritin, CRP, D-Dimer and LDH). The secondary objectives are to evaluate the safety of the trial medicines and their effects in the reduce the risks of the disease. In addition, to document the profile of Symptomatic COVID 19 patients as per Siddha Principles. TRIAL DESIGN: A Double Blinded, Three arm, Single Centre, Placebo Controlled, Exploratory and comparative Randomized Controlled Trial PARTICIPANTS: Patients who were admitted to the COVID Care Centre at Govt. Institute of Medical Sciences. Noida in India will be recruited. These will be patients with Mild and Moderate symptoms with laboratory confirmed COVID 19 (RT - PCR Tested Positive) aged 18-65, willing and consenting to participate. INTERVENTION AND COMPARATOR: Arm I: Decaffeinated Tea (Placebo - similar in taste and appearance to the other Two Decoctions), 60 Ml Morning and Night after Food, along with standard Allopathy Treatment for 10 days. Arm II: Nilavembu Kudineer (The Siddha Medicines which is used as a standard Anti-Viral drug for the past Pandemics by Siddha Physicians) 60 Ml Morning and Night after Food, along with standard Allopathy Treatment for 10 days. Arm III: Kaba Sura Kudineer (The Siddha Medicine which is proposed to be used as a Treatment for COVID 19 based on Siddha Literature) 60 Ml Morning and Night after Food, along with standard Allopathy Treatment for 10 days. The investigational drugs are registered products under the Govt.of India and bought from GMP Certified Manufacturing Units. MAIN OUTCOMES: Primary outcomes: 1. Reduction in Viral load of SARS-CoV-2 at the end of treatment (10 days). 2. Time taken to convert Patient from symptomatic to Asymptomatic based on Reduction in clinical symptoms (10 days). 3. Effect of drugs inflammatory markers (IL6,) at the end of treatment (10 days). 4. Reduction in hospital stay time (20 days follow up). (Based on RT PCR CT Value 3rd, 6th if needed 10th day). (Based on IL 6 Value needed 10th day or IL6 value on turning negative. (entry level/exit level). Secondary outcomes (10 days): 1. Reduction in use of Intensive Supportive Care. 2. Reduction in incidence of complications (Acute Respiratory Distress Syndrome, other systemic complications). 3. MuLBSTA score for viral pneumonia (multinodular infiltration, hypo-lymphocytosis, bacterial co infection, Total Leucocyte Count (TLC ≤ 0.8 x 109/L), smoking history, hyper-tension and age) score. 4. Laboratory markers (Haematological & Biochemical Markers). 5. Adverse events/effects Siddha-based measurements. 6. Siddha Udaliyal assessment by using Yakkai Ilakkanam (YI) Tool to diagnose body condition for covid-19 patients. RANDOMISATION: The assignment of the participants into 3 Groups will be allocated in 1:1:1 Ratio through randomization Blocks in Microsoft Excel by a Statistician who is not involved in the study. The allocation scheme will be made by another statistician by using a closed envelope after the assessment of eligibility and Informed consent procedures. The groups will be balanced for age and sex with 3:1 Ratio in each group for mild: severe COVID-19 symptoms. BLINDING: The Study is Double Blinded. Participants and Investigators were blinded. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Sample size could not be calculated, Since there are no prior trials on KSK and NVK as a comparative trial. In addition, there are no prior trials on KSK and NVK in this region. A total Number of 120 Patients, 40 each in 3 groups will be recruited in 1:1:1 Ratio. TRIAL STATUS: Protocol Number : SCRUND GIMS Noida Study 1,Version: 2.0 Protocol Date : 20.08.2020 The recruitment period is completed for the trial. The Trial started its recruitment on 22.8.2020. We anticipate study including data analysis will finish in January 2021. This is to state that it was a late submission from authors for publication of the protocol to the BMC, after enrolment in the study was over. TRIAL REGISTRATION: The trial protocol was registered with CTRI (Clinical Trial Registry of India) and number is CTRI/2020/08/027286 on 21.08.2020 FULL PROTOCOL: The full Protocol is attached as an additional file, Accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated. This letter serves as a summary of the key elements of the full protocol. The Study protocol has been reported in accordance with the SPIRIT guidelines. Background: Despite an increase in the familiarity of the medical community with the epidemiological and clinical characteristics of coronavirus disease 2019 (COVID-19), there is presently a lack of rapid and effective risk stratification indicators to predict the poor clinical outcomes of COVID-19 especially in severe patients. Methods: In this retrospective single-center study, we included 117 cases confirmed with COVID-19. The clinical, laboratory, and imaging features were collected and analyzed during admission. The Multi-lobular infiltration, hypo-Lymphocytosis, Bacterial coinfection, Smoking history, hyper-Tension and Age (MuLBSTA) Score and Confusion, Urea, Respiratory rate, Blood pressure, Age 65 (CURB65) score were used to assess the death and intensive care unit (ICU) risks in all patients. Results: Among of all 117 hospitalized patients, 21 (17.9%) patients were admitted to the ICU care, and 5 (4.3%) patients were died. The median hospital stay was 12 (10-15) days. There were 18 patients with MuLBSTA score ≥ 12 points and were all of severe type. In severe type, ICU care and death patients, the proportion with MuLBSTA ≥ 12 points were greater than that of CURB65 score ≥ 3 points (severe type patients, 50 vs. 27.8%; ICU care, 61.9 vs. 19.0%; death, 100 vs. 40%). For the MuLBSTA score, the ROC curve showed good efficiency of diagnosis death (area under the curve [AUC], 0.956; cutoff value, 12; specificity, 89.5%; sensitivity, 100%) and ICU care (AUC, 0.875; cutoff value, 11; specificity, 91.7%; sensitivity, 71.4%). The K-M survival analysis showed that patients with MuLBSTA score ≥ 12 had higher risk of ICU (log-rank, P = 0.001) and high risk of death (log-rank, P = 0.000). Conclusions: The MuLBSTA score is valuable for risk stratification and could effectively screen high-risk patients at admission. The higher score at admission have higher risk of ICU care and death in patients infected with COVID. OBJECTIVE: To explore the correlation between early inflammation indicators and the severity of coronavirus disease 2019 (COVID-19). METHODS: A retrospective study was conducted. Patients with COVID-19 admitted to Wenzhou Central Hospital from January 17 to February 14, 2020 were enrolled. The general information, chest CT before admission, the first laboratory parameters and chest CT within 24 hours after admission were collected. Patients were followed up for 30 days after the first onset of dyspnea or pulmonary imaging showed that the lesions progressed more than 50% within 24 to 48 hours (according to the criteria for severe cases) as the study endpoint. According to the endpoint, the patients were divided into two groups: mild type/common type group and severe/critical group, and the differences in general information and inflammation index of the two groups were compared. Logistic regression was used to analyze the inflammation index and the severity of COVID-19. Receiver operating characteristic (ROC) curve was draw to evaluate the predictive value of early inflammation indicators for severe/critical in patients with COVID-19. RESULTS: A total of 140 patients with COVID-19 were included, 74 males and 66 females; the average age was (45±14) years old; 6 cases (4.3%) of mild type, 107 cases (76.4%) of common type, and 22 cases (15.7%) of severe type, 5 cases (3.6%) were critical. There were significantly differences in ages (years old: 43±13 vs. 57±13), the proportion of patients with one chronic disease (17.7% vs. 55.6%), C-reactive protein [CRP (mg/L): 7.3 (2.3, 21.0) vs. 40.1 (18.8, 62.6)], lymphocyte count [LYM (×109/L): 1.3 (1.0, 1.8) vs. 0.8 (0.7, 1.1)], the neutrophil/lymphocyte ratio [NLR: 2.1 (1.6, 3.0) vs. 3.1 (2.2, 8.8)] and multilobularinltration, hypo-lymphocytosis, bacterial coinfection, smoking history, hyper-tension and age [MuLBSTA score: 5.0 (3.0, 5.0) vs. 5.0 (5.0, 7.0)] between mild/common group and severe/critical group (all P < 0.05). Univariate Logistic regression analysis showed that CRP, NLR, MuLBSTA score, age, and whether chronic diseases were associated with the severity of COVID-19 [odds ratio (OR) and 95% confidence interval (95%CI) were 1.037 (1.020-1.055), 1.374 (1.123-1.680), 1.574 (1.296-1.911), 1.082 (1.042-1.125), 6.393 (2.551-16.023), respectively, all P < 0.01]. Further multivariate Logistic regression analysis showed that CRP and MuLBSTA score were risk factors for the development of COVID-19 to severe/critical cases [OR and 95%CI were 1.024 (1.002-1.048) and 1.321 (1.027-1.699) respectively, both P < 0.05]. ROC curve analysis showed that the area under the curve for CRP and MuLBSTA score to predict severe/critical cases were both 0.818, and the best cut-off points were 27.4 mg/L and 6.0 points, respectively. CONCLUSIONS: CRP and MuLBSTA score are related to the severity of COVID-19, and may have good independent predictive ability for the development of severe/critical illness.

Which organisms are the focus of the Wormbase?

WormBase continues to advance its practices on data acquisition, curation and retrieval to most effectively deliver comprehensive knowledge about Caenorhabditis elegans, and genomic information about other nematodes and parasitic flatworms.

[29069413, 31642470, 32185395, 31552661, 29761466]

WormBase (https://wormbase.org/) is a mature Model Organism Information Resource supporting researchers using the nematode Caenorhabditis elegans as a model system for studies across a broad range of basic biological processes. Toward this mission, WormBase efforts are arranged in three primary facets: curation, user interface and architecture. In this update, we describe progress in each of these three areas. In particular, we discuss the status of literature curation and recently added data, detail new features of the web interface and options for users wishing to conduct data mining workflows, and discuss our efforts to build a robust and scalable architecture by leveraging commercial cloud offerings. We conclude with a description of WormBase's role as a founding member of the nascent Alliance of Genome Resources. Biological knowledgebases rely on expert biocuration of the research literature to maintain up-to-date collections of data organized in machine-readable form. To enter information into knowledgebases, curators need to follow three steps: (i) identify papers containing relevant data, a process called triaging; (ii) recognize named entities; and (iii) extract and curate data in accordance with the underlying data models. WormBase (WB), the authoritative repository for research data on Caenorhabditis elegans and other nematodes, uses text mining (TM) to semi-automate its curation pipeline. In addition, WB engages its community, via an Author First Pass (AFP) system, to help recognize entities and classify data types in their recently published papers. In this paper, we present a new WB AFP system that combines TM and AFP into a single application to enhance community curation. The system employs string-searching algorithms and statistical methods (e.g. support vector machines (SVMs)) to extract biological entities and classify data types, and it presents the results to authors in a web form where they validate the extracted information, rather than enter it de novo as the previous form required. With this new system, we lessen the burden for authors, while at the same time receive valuable feedback on the performance of our TM tools. The new user interface also links out to specific structured data submission forms, e.g. for phenotype or expression pattern data, giving the authors the opportunity to contribute a more detailed curation that can be incorporated into WB with minimal curator review. Our approach is generalizable and could be applied to additional knowledgebases that would like to engage their user community in assisting with the curation. In the five months succeeding the launch of the new system, the response rate has been comparable with that of the previous AFP version, but the quality and quantity of the data received has greatly improved. WormBase ( www.wormbase.org ) provides the nematode research community with a centralized database for information pertaining to nematode genes and genomes. As more nematode genome sequences are becoming available and as richer data sets are published, WormBase strives to maintain updated information, displays, and services to facilitate efficient access to and understanding of the knowledge generated by the published nematode genetics literature. This chapter aims to provide an explanation of how to use basic features of WormBase, new features, and some commonly used tools and data queries. Explanations of the curated data and step-by-step instructions of how to access the data via the WormBase website and available data mining tools are provided.

Is Ameloblastoma (AB) a benign tumor that never metastasizes?

Ameloblastomas are benign but locally invasive neoplasms which can be metastatic

[32712102, 18230377, 6575436, 23775022, 28944145, 21558899, 24374844, 31674718]

Ameloblastomas are benign but locally invasive neoplasms which may grow to massive proportions and cause significant morbidity. Although some types of ameloblastoma can be treated predictably with aggressive surgical treatment, recurrent ameloblastoma and metastasising ameloblastoma are still difficult to treat. Recent studies have identified recurrent somatic and activating mutations in the mitogen-activated protein kinase (MAPK) and sonic hedgehog (SHH) signalling pathways in ameloblastoma. This development provided a possibility that molecular targeted therapies can be used as neoadjuvant treatment. In this review, we provide a summary of the latest WHO classification of ameloblastoma, the current understanding of genetic mutations and novel molecular targeted therapies arising from the recent developments. Ameloblastoma is an odontogenic tumor, usually benign, which rarely metastasizes to distant organs. The case of a 27-year-old white woman is described, who presented a metastatic pulmonary ameloblastoma 7 years after the removal of a mandibular ameloblastoma. She presented no pulmonary symptoms, but a lung nodule was found in a chest x-ray during a routine check-up for job admission. Computed tomography (CT) revealed a 2-cm well-defined solitary round nodule without calcifications, leading to the hypothesis of a metastatic tumor. Clinical and CT investigation confirmed no ameloblastoma recurrence in the jaw and no other primary tumor. The diagnosis of metastatic ameloblastoma was confirmed by microscopic evaluation of the pulmonary nodule. Ameloblastoma is a locally invasive, histologically nonmalignant tumor that may on very rare occasions give rise to metastases. A patient with a mandibular ameloblastoma presenting typical histologic appearances developed a pulmonary metastasis confirmed by histology as arising from the primary tumor. Two groups of these extremely rare malignant ameloblastomas can be distinguished: those without histologic signs of degeneration that give rise to metastases identical to the primary lesion, and those with degenerative signs provoking metastases with the histologic appearance of undifferentiated carcinoma. No relation appears to exist between size of primary tumor, histologic type of ameloblastoma, or its course and tendency to produce metastases. Ameloblastoma is a locally aggressive, epithelial odontogenic tumor involving mandibles and maxillas. Distant metastasis is a very rare condition and is designated as metastasizing (malignant) ameloblastoma despite its benign histological appearance. Up to now, only 27 well-documented cases of metastasizing ameloblastomas are reported in the literature, and lung is the most commonly involved organ. In previous reports of pulmonary metastasizing ameloblastomas, there was little description of the histopathologic finding. Here, the authors report 2 cases of pulmonary metastasizing ameloblastomas with special emphasis on their interesting, interstitial spread along alveolar septa, resulting in a unique 2-cell pattern under microscopic examination. Pulmonary metastasizing ameloblastoma may pose difficulty in diagnosis if the pathologist is not aware of patient's clinical history of ameloblastoma. Ameloblastoma of the maxilla is a rare odontogenic tumor that rarely metastasizes. We report a patient who was diagnosed with ameloblastoma of the maxilla 6 years ago and had undertaken the operation. However, the recurrence occurred, and further pulmonary disease was discovered. He did not experience chest pain and other respiratory systematic symptoms. Whether this metastasizing ameloblastoma should be ranged among malignant or benign is discussed. The term benign metastasizing ameloblastoma is suggested to describe this kind of tumor. Ameloblastic carcinoma (AC) is defined as a rare primary epithelial odontogenic malignant neoplasm and the malignant counterpart of benign epithelial odontogenic tumor of ameloblastoma (AB) by the WHO classification. AC develops pulmonary metastasis in about one third of the patients and reveals a poor prognosis. However, the mechanisms of AC oncogenesis remain unclear. In this report, we aimed to clarify the mechanisms of malignant transformation of AB or AC carcinogenesis. The relatively important genes in the malignant transformation of AB were screened by DNA microarray analysis, and the expression and localization of related proteins were examined by immunohistochemistry using samples of AB and secondary AC. Two genes of hypoxia-inducible factor 1 alpha subunit (HIF1A) and zinc finger E-box-binding homeobox 1 (ZEB1) were significantly and relatively upregulated in AC than in AB. Both genes were closely related in hypoxia and epithelial-mesenchymal transition (EMT). In addition, expressions of HIF-1α and ZEB1 proteins were significantly stronger in AC than in AB. In the cell assays using ameloblastoma cell line, AM-1, hypoxia condition upregulated the expression of transforming growth factor-β (TGF-β) and induced EMT. Furthermore, the hypoxia-induced morphological change and cell migration ability were inhibited by an antiallergic medicine tranilast. Finally, we concluded that hypoxia-induced HIF-1α and ZEB1 were critical for the malignant transformation of AB via TGF-β-dependent EMT. Then, both HIF-1α and ZEB1 could be potential biomarkers to predict the malignant transformation of AB.

Is there any role of the 'Greek islands' in olfactory receptor choice?

Yes. 'Greek islands' first contribute to the formation of olfactory receptor compartments and then form a multi-chromosomal super-enhancer that associates with the single active olfactory receptor gene. The Greek-island-bound transcription factor LHX2 and adaptor protein LDB1 regulate the assembly and maintenance of olfactory receptor compartments, Greek island hubs and olfactory receptor transcription, providing mechanistic insights into and functional support for the role of trans interactions in gene expression.

[30626972]

The genome is partitioned into topologically associated domains and genomic compartments with shared chromatin valence. This architecture is constrained by the DNA polymer, which precludes interactions between genes on different chromosomes. Here we report a marked divergence from this pattern of nuclear organization that occurs in mouse olfactory sensory neurons. Chromatin conformation capture using in situ Hi-C on fluorescence-activated cell-sorted olfactory sensory neurons and their progenitors shows that olfactory receptor gene clusters from 18 chromosomes make specific and robust interchromosomal contacts that increase with differentiation of the cells. These contacts are orchestrated by intergenic olfactory receptor enhancers, the 'Greek islands', which first contribute to the formation of olfactory receptor compartments and then form a multi-chromosomal super-enhancer that associates with the single active olfactory receptor gene. The Greek-island-bound transcription factor LHX2 and adaptor protein LDB1 regulate the assembly and maintenance of olfactory receptor compartments, Greek island hubs and olfactory receptor transcription, providing mechanistic insights into and functional support for the role of trans interactions in gene expression.

What is ASTRAL Score?

ASTRAL Score is used to predict prognosis of stroke patients.

[23559264, 31706753, 22649218, 30077603, 23493731, 32208843, 29994736, 28236594, 34431455]

BACKGROUND: Acute ischemic stroke (AIS) has a higher morbidity and mortality rate. Many prediction tools have been developed to predict the risk of poor outcomes in patients after AIS, such as the THRIVE score, the iScore score, and the ASTRAL score. However, the predictive value of above 3 prediction tools in Chinese patients with AIS need to be further verified. So, this study aimed to determine the ability of the THRIVE score, the iScore score, and the ASTRAL score in predicting clinical poor outcomes in Chinese patients with AIS at 1 year. METHODS: A total of 772 patients with AIS were included in this study. The baseline data of all patients were collected. The THRIVE score, the iScore score, and the ASTRAL score were calculated. All patients were followed up at 1 year. The poor outcome was defined as death, moderate/severe disabilities (modified Rankin scale, mRS > 2), most severe disability (mRS ≥ 5). Model discrimination was quantified by calculating the area under the receiver operating characteristic curve (AUC). The calibration was assessed using Hosmer-Lemeshow goodness-of-fit test and Pearson correlation coefficient. RESULTS: We identified 576 (74.6%) patients with good prognosis and 196 (25.4%) patients with poor prognosis. AUC values of THRIVE score in predicting 1-year poor prognosis was lower than the iScore score and the ASTRAL scores (P < .05). The chi-square values of Hosmer-Lemeshow for the 3 prediction tools were 2.114, 4.877, 5.838 (all P < .05), respectively. There was a high correlation between the observed and the expected poor prognosis (Pearson correlation coefficient, .985, .693, and .620; all P < .05). AUC values of THRIVE score in predicting 1-year mortality and severe disability were lower than the iScore scores (all P < .05). CONCLUSIONS: The iScore score and the ASTRAL score reliably predict 1-year poor outcomes in Chinese patients with AIS, and the iScore score can accurately predict 1-year mortality and severe disability in Chinese AIS patients. BACKGROUND AND PURPOSE: The ASTRAL score was recently introduced as a prognostic tool for acute ischemic stroke. It predicts 3-month outcome reliably in both the derivation and the validation European cohorts. We aimed to validate the ASTRAL score in a Chinese stroke population and moreover to explore its prognostic value to predict 12-month outcome. METHODS: We applied the ASTRAL score to acute ischemic stroke patients admitted to 132 study sites of the China National Stroke Registry. Unfavorable outcome was assessed as a modified Rankin Scale score >2 at 3 and 12 months. Areas under the curve were calculated to quantify the prognostic value. Calibration was assessed by comparing predicted and observed probability of unfavorable outcome using Pearson correlation coefficient. RESULTS: Among 3755 patients, 1473 (39.7%) had 3-month unfavorable outcome. Areas under the curve for 3 and 12 months were 0.82 and 0.81, respectively. There was high correlation between observed and expected probability of unfavorable 3- and 12-month outcome (Pearson correlation coefficient: 0.964 and 0.963, respectively). CONCLUSIONS: ASTRAL score is a reliable tool to predict unfavorable outcome at 3 and 12 months after acute ischemic stroke in the Chinese population. It is a useful tool that can be readily applied in clinical practice to risk-stratify acute stroke patients. BACKGROUND: Disability and mortality represent the most relevant clinical outcomes after acute ischemic stroke. Recently, a number of prognostic models of acute ischemic stroke have been developed, but they have not been extensively validated. In this study, we evaluated the ability of 3 prognostic models including the iScore, the PLAN score, and the ASTRAL score in predicting clinical poor outcomes or mortality at 6 months in patients with acute ischemic stroke. METHODS: A total of 323 patients were divided into a good-prognosis group and a poor-prognosis group based on the modified Rankin Scale. Model discrimination was quantified by calculating the area under the receiver operating characteristic (ROC) curve, and calibration was assessed by Hosmer-Lemeshow goodness of fit test and Pearson correlation coefficient. RESULTS: We identified 96 (29.7%) patients with poor prognosis, including 21 who were dead. All 3 models showed good ability in predicting poor prognosis and mortality in patients with acute ischemic stroke (all ROC > .70). There was no difference between these 3 models in terms of sensitivity and accuracy (all P > .05). CONCLUSIONS: The results of this study suggest that the iScore, the PLAN score, and the ASTRAL score were equal in predicting 6-month poor prognosis and mortality in patients with acute ischemic stroke. Overall, there was a very high correlation between observed and expected outcomes at the risk score level. BACKGROUND: : Various tools are currently available to quantify the risks of adverse clinical outcomes after an ischemic stroke. This study aimed to validate and compare prognostic scales among Chinese patients with ischemic stroke. METHODS: : We compared three stroke prognostic scales (Stroke Prognostication using Age and the National Institutes of Health Stroke Scale-100 [SPAN-100], Totaled Health Risks in Vascular Events [THRIVE], and Acute Stroke Registry and Analysis of Lausanne [ASTRAL]) in 3870 Chinese patients with ischemic stroke from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The 2-year primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3). RESULTS: : Among all the scales, the ASTRAL score had the best accuracy for predicting 2-year prognosis in Chinese patients with ischemic stroke. The C-statistic of the ASTRAL score for the 2-year primary outcome was 0.79 (95% confidence interval [CI]: 0.78-0.80), and the Hosmer-Lemeshow goodness-of-fit test showed that the ASTRAL score fitted Chinese patients with ischemic stroke well (χ2 = 9.83, P = 0.277). The incidences of the primary outcome in the <5%, 5%-9.9%, 10%-19.9%, and ≥20% risk groups based on the ASTRAL scores were 3.93%, 7.55%, 14.29%, and 41.81%, respectively (odds ratio: 1.23; 95% CI: 1.21-1.26; P < 0.001). CONCLUSION: : The ASTRAL score had higher efficacy than the SPAN-100 and THRIVE scores in predicting 2-year adverse outcomes among Chinese patients with ischemic stroke, suggesting that it could be a valuable risk assessment tool for the 2-year prognosis of such patients.

Is paxillin affected by RANKL?

Yes, RANKL promotes paxillin serine and tyrosine phosphorylation.

[32193744, 30609675, 22807029]

As a crucial virulence factor of Porphyromonas gingivalis, gingipains play an important role in periodontal destruction. This study aimed to investigate the effect of gingipains on osteoclastogenesis. We used RAW264.7 cells as osteoclast precursors in our study. In experimental groups, cells were treated with gingipains and/or receptor activator of nuclear factor-κB ligand (RANKL). Tartrate-resistant acid phosphatase (TRAP) activity staining assay showed osteoclast precursors and RANKL-induced mature osteoclasts were increased in a gingipains dose-dependent manner. Real-time reverse transcription polymerase chain reaction analysis demonstrated that gingipains upregulated osteoclastic genes including the protease cathepsin K (Ctsk), matrix metalloprotein 9 (Mmp9), nuclear factor of activated T cells 1 (Nfatc1) and acid phosphatase 5, tartrate resistant (Acp5) in a time-dependent manner. Western blotting assays presented upregulated expressions of TNF receptor-activating factor 6 (TRAF6) and integrin β3 induced by gingipains and RANKL compared to RANKL alone. Enhanced integrin-related signaling was also demonstrated by elevated phosphorylations of FAK and paxillin compared to control. Moreover, the pit resorption assays showed that gingipains augmented bone resorptive function of osteoclasts induced by RANKL. When we used Cilengitide to block integrin αvβ3, gingipains reversed the reduction of formation and resorptive function in RANKL-induced osteoclasts, as they enhanced integrin αvβ3 levels more than RANKL treatment alone. In conclusion, our data suggest that gingipains augmented the differentiation and function of mature osteoclasts induced by RANKL through the increase in integrin αvβ3. Proinflammatory cytokine production, cell chemotaxis, and osteoclastogenesis can lead to inflammatory bone loss. Previously, we showed that sphingosine-1-phosphate receptor 2 (S1PR2), a G protein coupled receptor, regulates inflammatory cytokine production and osteoclastogenesis. However, the signaling pathways regulated by S1PR2 in modulating inflammatory bone loss have not been elucidated. Herein, we demonstrated that inhibition of S1PR2 by a specific S1PR2 antagonist (JTE013) suppressed phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinases (MAPKs), and nuclear factor kappa-B (NF-κB) induced by an oral bacterial pathogen, Aggregatibacter actinomycetemcomitans, and inhibited the release of IL-1β, IL-6, TNF-α, and S1P in murine bone marrow cells. In addition, shRNA knockdown of S1PR2 or treatment by JTE013 suppressed cell chemotaxis induced by bacteria-stimulated cell culture media. Furthermore, JTE013 suppressed osteoclastogenesis and bone resorption induced by RANKL in murine bone marrow cultures. ShRNA knockdown of S1PR2 or inhibition of S1PR2 by JTE013 suppressed podosome components, including PI3K, Src, Pyk2, integrin β3, filamentous actin (F-actin), and paxillin levels induced by RANKL in murine bone marrow cells. We conclude that S1PR2 plays an essential role in modulating proinflammatory cytokine production, cell chemotaxis, osteoclastogenesis, and bone resorption. Inhibition of S1PR2 signaling could be a novel therapeutic strategy for bone loss associated with skeletal diseases. Osteoclastic bone resorption depends upon the cell's ability to organize its cytoskeleton via the αvβ3 integrin and osteoclastogenic cytokines. Because paxillin associates with αvβ3, we asked if it participates in skeletal degradation. Unlike deletion of other αvβ3-associated cytoskeleton-regulating molecules, which impairs the cell's ability to spread, paxillin-deficient (Pax(-/-) ) osteoclasts, generated from embryonic stem cells, "superspread" in response to receptor activator of NF-κB ligand (RANKL) and form large, albeit dynamically atypical, actin bands. Despite their increased size, Pax(-/-) osteoclasts resorb bone poorly, excavating pits approximately one-third normal depth. Ligand-occupied αvβ3 or RANKL promotes paxillin serine and tyrosine phosphorylation, the latter via cellular sarcoma (c-Src). The abnormal Pax(-/-) phenotype is rescued by wild-type (WT) paxillin but not that lacking its LD4 domain. In keeping with the appearance of mutant osteoclasts, WT paxillin, overexpressed in WT cells, contracts the cytoskeleton. Most importantly, the abnormal phenotype of Pax(-/-) osteoclasts likely represents failed RANKL-mediated delivery of myosin IIA to the actin cytoskeleton via the paxillin LD4 domain but is independent of tyrosine phosphorylation. Thus, in response to RANKL, paxillin associates with myosin IIA to contract the osteoclast cytoskeleton, thereby promoting its bone-degrading capacity.

What organ is associated with a Gleason pattern or Gleason Score?

The Gleason score is an important parameter for clinical outcome in prostate cancer patients

[26439747, 17277764, 25189638, 12385930, 14562287, 10652560, 25228336, 15475927, 21862072, 32350585, 30363387, 32686748, 22367295]

Patients with Gleason score 7 prostate cancer on radical prostatectomy demonstrate a wide range in clinical outcome. Gleason grade 4 prostate cancer encompasses a heterogeneous group of tumor growth patterns including fused, ill-defined, cribriform, and glomeruloid glandular structures. Our objective was to determine the prognostic value of different Gleason grade 4 growth patterns. We performed a nested case-control study among 535 patients with Gleason score 7 prostate cancer at radical prostatectomy, treated between March 1985 and July 2013 at a university hospital in the Netherlands. We analyzed 52 cases (with metastasis, disease-specific mortality or both) and 109 controls, matched for age, PSA level, and pT stage. Presence of the following Gleason grade 4 patterns was recorded: fused, ill-defined, cribriform, and glomeruloid. Intraductal carcinoma of the prostate and tertiary Gleason grade 5 were additionally assessed. Outcomes were metastasis-free survival and disease-specific survival. We used Cox proportional hazards regression to determine the predictive value of Gleason grade 4 patterns for survival time. The overall prevalence of Gleason grade 4 patterns was as follows: fused 75% (n=121), ill-defined 64% (n=102), cribriform 48% (n=83), and glomeruloid 25% (n=40). Cribriform pattern was the only pattern with an unequal distribution between cases and controls. Forty-two out of 52 cases (81%) had cribriform growth pattern versus 41/109 controls (38%). In multivariate analysis, presence of cribriform growth was an adverse independent predictor for distant metastasis-free survival (HR 8.0, 95% CI 3.0-21; P<0.001) and disease-specific survival (HR 5.4, 95% CI 2.0-15, P=0.001). In conclusion, cribriform growth in Gleason grade 4 is a strong prognostic marker for distant metastasis and disease-specific death in patients with Gleason score 7 prostate cancer at radical prostatectomy. OBJECTIVES: Most adenocarcinomas of the prostate with a Gleason score greater than 8 at radical prostatectomy have extraprostatic extension and a high risk of progression. With prostate-specific antigen screening, we have seen some cases of earlier detected, organ-confined, high-grade adenocarcinoma. Few data are available as to the likelihood of cure in these cases. METHODS: We reviewed 27 cases of pathologically organ-confined adenocarcinoma with a prostatectomy Gleason score of 8 to 10. To exclude cases with a significant proportion of Gleason pattern 3, we excluded cases of Gleason score 3+5=8 and Gleason score 5+3=8. All cases of Gleason score 8 at radical prostatectomy were Gleason score 4+4. The prognostic value of the clinical parameters (clinical stage, serum prostate-specific antigen level, age) and pathologic factors (biopsy Gleason score, radical prostatectomy Gleason score, prostatectomy tumor volume) were tested to predict postoperative progression. RESULTS: The mean age at diagnosis was 59.7 years (range 46 to 69) with preoperative serum prostate-specific antigen levels ranging from 1.4 to 28 ng/mL (mean 7.8). All tumors were classified as pathologic Stage T2N0Mx. Fifteen patients (55.6%) had a Gleason score of 8, 11 patients (40.7%) had a Gleason score of 9, and 1 had a Gleason score of 10 (3.7%). Tumor volumes ranged from 0.02 to 1.44 cm(3) (mean 0.56). Follow-up information was available for all men. The mean follow-up for those without progression was 30.6 months (range 7 to 73) and for those with progression was 23.6 months (range 9 to 44). The 33-month actuarial risk of progression was 32%, with 10 men developing progression during the study. None of the preoperative or postoperative variables predicted progression. CONCLUSIONS: Even when high-grade tumor is organ confined, it is associated with a relatively unfavorable short-term outcome that is not predictable on the basis of either preoperative clinicopathologic data or postoperative pathologic information obtained from the radical prostatectomy specimen. If multiple biopsy cores contain prostate cancer with differing Gleason scores, should an overall Gleason score be assigned, or should each core be graded separately? We obtained data on 127 men with prostate cancer on needle biopsy who underwent subsequent radical prostatectomy at our institution. We compared the Gleason scores found on needle biopsy with the grade and stage (organ-confined, extra-prostatic extension, positive seminal vesicles or lymph nodes) at radical prostatectomy. On biopsy, 40 men had a pure Gleason score of 4 + 3 = 7, 25 men had a Gleason score of 4 + 3 = 7 with a Gleason score of 3 + 3 = 6 on a separate core of the biopsy specimen, 27 men had a pure Gleason score of 4 + 4 = 8, and 35 men had a Gleason score of 4 + 4 = 8 with separate cores containing Gleason pattern grade 3. A Gleason score of 4 + 4 = 8 with pattern grade 3 in other cores had a more advanced stage than a pure Gleason score of 4 + 3 = 7 (P = 0.008). There was no clear pattern analyzing pathological stage of men with a pure Gleason score of 4 + 3 = 7 in comparison with those with Gleason scores of 4 + 3 = 7 and 3 + 3 = 6 in other cores. The group with a Gleason score of 4 + 4 = 8 and Gleason pattern grade 3 on other cores had a higher overall grade on radical prostatectomy than the group with a pure Gleason score of 4 + 3 = 7 (P = 0.001). If one had assigned an overall Gleason score, then a biopsy with Gleason score 4 + 4 = 8 on 1 or more cores and some pattern grade 3 in other cores, would be designated as a Gleason score of 4 + 3 = 7. Based on our findings, patients with a Gleason score of 4 + 4 = 8 on one or more cores with pattern grade 3 in other cores should be given a final Gleason score of 4 + 4 = 8 instead of 4 + 3 = 7, because these patients are more likely to have higher stage and grade on radical prostatectomy, comparable to a pure Gleason score of 4 + 4 = 8. Each core should be assigned a separate Gleason score, especially in cases with high Gleason score cancer on at least 1 core. Cathepsin B (CB) is involved in degradation of extracellular matrix proteins during tumor progression in human solid organ tumors (such as colorectal, bladder, and breast cancers), including human prostate cancer. Its activities are regulated by endogenous inhibitors (such as stefins or cystatins). Increased expression of cathepsin B message, protein, and membrane association have been linked to malignancy, but there are very few studies of their mRNA expression in prostate cancer using in situ hybridization techniques. Our objective was to determine the relationship of CB and stefin A (cystatin A) mRNA localization to the Gleason grading system for histologic scores in the hope of distinguishing aggressive and less aggressive variants of prostate cancer. We used a 25-base biotinylated oligonucleotide CB cDNA antisense probe to localize CB message and a 27-base biotinylated oligonucleotide stefin A cDNA antisense probe to localize stefin A message. Prostate samples from 41 prostatectomy patients were collected along with their pre-surgery serum PSA levels and clinical stage of the disease. Sections prepared from frozen prostate tissue samples were hybridized with the CB and stefin A and control pBR 322 probes using techniques reported by Sinha et al. [1] and their distribution quantitated by an image analysis system. Prostate sections treated with RNAse before hybridization or incubated with the pBR 322 control probe showed little or no reaction products, confirming that localization of CB and stefin A probes was specific. In prostate cancer, the reaction products were found in neoplastic and invasive cells and occasionally in stromal cells. The ratios of CB to stefin A were similar in normal prostate and benign prostatic hyperplasia (BPH) whereas they varied consistently within and between Gleason histologic scores for prostate cancer. These variations showed three localization patterns; namely, prostate cancers with higher levels of CB than stefin A, lower levels of CB than stefin A, and similar levels of CB and stefin A. All three patterns and ratios for CB and stefin A were found in prostate samples (22/41) represented by the Gleason histologic score 6 tumors. In these tumors, serum PSA levels ranged from 1 to 78 ng/ml and prostate cancers showed B, C, and D clinical stages. There was no correlation of CB/stefin A ratio and serum PSA values or clinical stage in a limited number of prostate cancer cases. Our data showed that there were prostate cancer cases within Gleason histologic scores which expressed high, similar, and low levels of CB when compared to stefin A. We postulate that prostate cancer cases showing higher levels of CB compared to stefin A probably represent an aggressive variant of this cancer within any one Gleason histologic score. If this is the case, aggressive variants of prostate cancer would occur within Gleason scores 3 to 10 even though higher scores are usually considered more aggressive forms of prostate cancers. Since our study is based upon a very limited number of frozen prostate samples, we emphasize that a larger series of archival prostate cancer samples along with their survival data should be analyzed to establish any relationship of CB/stefin A ratio and aggressive variants of this cancer. Therefore, our conclusion is tentative. Our study provides a partial explanation for differences in the clinical course of prostate cancer in patients. This is the first study to show that determination of CB and stefin A mRNA ratios may lead to identification of aggressive and less aggressive variants of prostate cancer within a Gleason histologic score. Accurate recognition of Gleason pattern 5 (GP5) prostate adenocarcinoma (PCa) on core biopsy (NBX) is critical because it is associated with disease progression and the worst clinical outcome. We evaluated 1557 consecutive and prospectively collected NBXs to determine the frequency of diagnosis, morphologic subpatterns, and their relation to the amount and pattern distribution of GP5 PCa based on the 2005 modified Gleason grading system. Tertiary GP5 was upgraded to a secondary pattern to derive the final Gleason score. GP5 accounted for 6% of all NBXs and 14% of PCa cases. GP5 PCas were associated with high-risk preoperative clinical and biopsy characteristics, regardless of the amount of GP5. Most patients (85%) with % GP5 greater than 5% of PCa had the final Gleason score of 9 to 10, compared with % GP5 of 5% or less of PCa (P < .0001). The morphologic subpatterns of GP5 PCas were as follows: infiltrating cords (96%), single cells (76%), solid sheets (29%), and comedocarcinoma (2%). Infiltrating cords and single-cell patterns frequently coexisted (76%). The GP5 was distributed in a tertiary (66%), followed by secondary (32%) and primary (2%) components of PCa. Infiltrating cords and single cells were the 2 most frequently encountered patterns, specifically when GP5 involved 5% or less of PCa and represented secondary or tertiary component of PCa. GP5 PCa is a relatively frequent presentation in the contemporary NBX practice. Because of its important prognostic and therapeutic implications, pathologists must be aware of its varied morphologic presentations and to the fact that most cases with GP5 represent a tertiary component of PCa. The Gleason score of prostate adenocarcinomas is an important preoperative predictor of cancer behavior, and is used to help guide treatment. In the setting of more than two positive biopsy sites, pathologists usually grade the tumor at each site separately, and the Gleason score may differ from each positive site. This study seeks to determine if the highest Gleason score in all biopsy sites, or the Gleason score in the site with the highest tumor volume on the needle biopsy is the best predictor of final Gleason score in the radical prostatectomy specimens. Various preoperative biopsy findings were analyzed. All 151 patients had at least two positive biopsy sites and underwent radical prostatectomy. Primary and secondary Gleason pattern grades were assigned for each positive biopsy site. The tumor volume in the needle biopsy site was defined by the percentage of areas of biopsy cores involved by cancer. The radical prostatectomy specimens were completely embedded and processed in the whole-mount method. The Gleason score from both the biopsy site with the highest Gleason score and the biopsy site with the highest tumor volume on the needle biopsy correlated equally well with final Gleason score at radical prostatectomy (Spearman correlation coefficient =0.54 for both, P<0.001). The Gleason score from both the biopsy site with the highest Gleason score and the biopsy site with the highest tumor volume on the needle biopsy also correlated with primary Gleason pattern grade at radical prostatectomy (Spearman correlation coefficient =0.53 for both, P<0.001). Secondary Gleason pattern grade from the biopsy site with the highest tumor volume on the needle biopsy correlated with secondary Gleason pattern grade at radical prostatectomy slightly better than those from the biopsy site with the highest Gleason score (Spearman correlation coefficient, 0.32 vs 0.24; both P<0.001). Our data indicate that the highest Gleason score from all sites and the Gleason score from the site with the highest tumor volume on the needle biopsy are equally and significantly predictive of final Gleason score on radical prostatectomy. Both methods of prediction are significantly predictive of primary and secondary Gleason pattern grade on radical prostatectomy. We recommend that the highest Gleason score from all positive biopsy sites should be used when assigning an initial score using needle biopsies. The Gleason score remains the most reliable prognosticator in men with prostate cancer. One of the recent important modifications in the Gleason grading system recommended from the International Society of Urological Pathology consensus conference is recording the percentage of Gleason pattern 4 in the pathology reports of prostate needle biopsy and radical prostatectomy cases with Gleason score 7 prostatic adenocarcinoma. Limited data have indeed suggested that the percent Gleason pattern 4 contributes to stratifying the prognosis of patients who undergo radical prostatectomy. An additional obvious benefit of reporting percent pattern 4 includes providing critical information for treatment decisions. This review summarizes and discusses available studies assessing the utility of the percentage of Gleason pattern 4 in the management of prostate cancer patients. The Gleason score is an important parameter for clinical outcome in prostate cancer patients. Gleason score 8 is a heterogeneous disease including Gleason score 3 + 5, 4 + 4, and 5 + 3 tumors, and encompasses a broad range of tumor growth patterns. Our objective was to characterize individual growth patterns and identify prognostic parameters in Gleason score 8 prostate cancer patients. We reviewed 1064 radical prostatectomy specimens, recorded individual Gleason 4 and 5 growth patterns as well as presence of intraductal carcinoma, and evaluated biochemical recurrence- and metastasis-free survival. Gleason score 8 disease was identified in 140 (13%) patients, of whom 76 (54%) had Gleason score 3 + 5, 46 (33%) 4 + 4, and 18 (13%) 5 + 3 disease. Invasive cribriform and/or intraductal carcinoma (n = 87, 62%) was observed more frequently in Gleason score 4 + 4 (93%) than 3 + 5 (47%; P < 0.001) and 5 + 3 (44%; P < 0.001) patients. Gleason pattern 5 was present in 110 (79%) men: as single cells and/or cords in 99 (90%) and solid fields in 32 (29%) cases. Solid field pattern 5 coexisted with cribriform architecture (23/32, 72%) more frequently than nonsolid pattern 5 cases (36/78, 46%, P = 0.02). In multivariable analysis including age, prostate-specific antigen, pT-stage, surgical margin status, and lymph node metastases, presence of cribriform architecture was an independent parameter for biochemical recurrence-free (hazard ratio (HR) 2.0, 95% confidence interval (CI) 1.0-3.7; P = 0.04) and metastasis-free (HR 3.5, 95% CI 1.0-12.3; P = 0.05) survival. In conclusion, invasive cribriform and/or intraductal carcinoma occurs more frequently in Gleason score 4 + 4 prostate cancer patients than in Gleason score 3 + 5 and 5 + 3, and is an independent parameter for biochemical recurrence and metastasis. Therefore, cribriform architecture has added value in risk stratification of Gleason score 8 prostate cancer patients. High Gleason score 8 to 10 adenocarcinoma is the most aggressive and potentially lethal form of prostate cancer. The 2005 International Society of Urological Pathology (ISUP)-modified Gleason grading scheme defines several gland arrangements of high Gleason grade patterns 4 and 5. The aim of this investigation was to quantitate the frequency of the ISUP-defined high Gleason grade patterns in needle biopsy tissue, to determine the common admixtures and to characterize patterns not presented in the 2005 ISUP report. For patients who underwent radical prostatectomy, we analyzed for association of specific high-grade patterns in needle biopsy with extraprostatic extension in radical prostatectomy tissues. A total of 268 prostate needle biopsy cases with Gleason score of 8 to 10 were examined. A mean of 3.6 patterns (range, 1 to 8) were identified per case and only 12% of cases had a pure single pattern. Ill-defined glands with poorly formed lumina (at 57%) and fused microacinar glands (at 53%) comprised the predominant and most frequently admixed patterns. Single cells and single signet ring cells were present in 53% and 31% of cases, respectively. Additional patterns in order of frequency included cords (35%), cribriform glands (25%), sheets of cells (19%), chains (4%), glomeruloid (3%), comedonecrosis (2%), and hypernephromatoid (1 case=0.3%). Gleason score 8 to 10 carcinomas are typically extensive in needle core tissue, with a mean of 4.4 positive cores (range, 1 to 15 cores) per case. Only 14 cases (5%) had high-grade minimal carcinoma measuring <1 mm in needle core tissue. Gleason grade patterns not described in the 2005 ISUP report include single file growth, solid cylinders, and nested patterns. The single file pattern was present in 40% of cases, and the small solid nested pattern was detected in 24% of cases. One case displayed solid cylinders. Only the single file pattern was associated with extraprostatic extension at radical prostatectomy (P=0.005). These results show that the 2005 ISUP-defined patterns of high Gleason score 8 to 10 prostatic adenocarcinoma can be stratified on the basis of frequency of occurrence in needle biopsy tissue. Three patterns not defined in the 2005 ISUP scheme have been characterized, including single file, nested, and solid cylinder arrangements. As aggressive and potentially lethal prostate cancer is most often of Gleason score 8 to 10, it is important for diagnostic recognition purposes to be aware of the frequency of various patterns encountered in high Gleason score 8 to 10 adenocarcinomas, the types of pattern admixtures, and the histomorphologic presentation of unusual patterns. We propose that Gleason grade assignments should incorporate single file, solid nested, and solid cylinder arrangements as high-grade pattern 5 because of the absence of glandular luminal space formation.

What are the targets of Tirbanibulin?

Tirbanibulin is Src kinase signaling inhibitor and tubulin polymerisation inhibitor that is being developed for the topical treatment of actinic keratosis, and psoriasis.

[33713299, 34349652, 33196758, 33567191, 34783452]

Tirbanibulin (Klisyri®) is a first-in-class Src kinase signaling inhibitor and tubulin polymerisation inhibitor being developed by Athenex in conjunction with global partners for the topical treatment of actinic keratosis, and psoriasis. Based on the data from two pivotal phase III trials the drug was recently approved for marketing in the US as a topical treatment for actinic keratosis. This article summarizes the milestones in the development of tirbanibulin leading to this first approval. Tirbanibulin (KX-01) is the first clinical Src inhibitor of the novel peptidomimetic class that targets the peptide substrate site of Src providing more specificity toward the Src kinase. This study assessed the impact of KX-01 on cobalt chloride (CoCl2)-treated L929 cells and bleomycin (BLM)-induced pulmonary fibrosis in rats to evaluate the efficacy of this compound in vitro and in vivo, respectively. In CoCl2-treated L929 cells, KX-01 significantly reduced the expression of smooth muscle actin (α-SMA), collagen I, collagen III, hypoxia inducing factor (HIF-1α), signal transducers and transcriptional activators (p-STAT3), and p-Src. In BLM-induced pulmonary fibrosis rats, KX-01 reduced pathological scores, collagen deposition, α-SMA, collagen I, collagen III, p-Src, HIF-1α, and p-STAT3. Overall, these findings revealed that KX-01 can alleviate experimental pulmonary fibrosis via suppressing the p-SRC/p-STAT3 signaling pathways. BACKGROUND: Current field-directed treatments of actinic keratosis (AK), a pre-malignant condition, are often limited by severe local reactions and/or complex treatment. Tirbanibulin, a novel potent anti-proliferative synthetic agent that inhibits tubulin polymerization and Src kinase signalling, is being developed as a convenient, safe, and effective field treatment of actinic keratosis. HYPOTHESIS: A short course of tirbanibulin ointment 1% safely reduces AK lesions. METHODS: In the Phase 1 study, 4 treatment cohorts with forearm lesions received tirbanibulin ointment 1% over 25 or 100 cm2 once daily for 3 or 5 days and were evaluated through day 45. In the Phase 2 study, 2 treatment cohorts with face or scalp lesions received tirbanibulin ointment 1% once daily for 3 or 5 days over 25 cm2 and were evaluated through day 57. Lesion reductions, clearance rates, safety, and pharmacokinetics were assessed. RESULTS: Forearm AK lesions were reduced by day 45 in all Phase 1 cohorts (N=30). Complete AK clearance at day 57 for face/scalp AK lesions in Phase 2 cohorts (N=168) was demonstrated in 43% and 32% of participants of the 5-day and 3-day cohorts, respectively. Adverse reactions were mainly transient mild local erythema and flaking/scaling, pruritus, and pain. Tirbanibulin plasma concentrations were low or undetectable. CONCLUSION: Tirbanibulin ointment 1% was well tolerated and active in AK reduction. Based on activity, the 5-day regimen was selected for Phase 3 development. Clinicaltrials.gov: NCT02337205; NCT02838628 J Drugs Dermatol. 2020;19(11):1093-1100. doi:10.36849/JDD.2020.5576THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS. BACKGROUND: The tubulin polymerization and Src kinase signaling inhibitor tirbanibulin is being investigated as a topical treatment for actinic keratosis, a precursor of squamous-cell carcinoma. METHODS: In two identically designed double-blind trials, we randomly assigned, in a 1:1 ratio, adults with actinic keratoses on the face or scalp to receive either topical tirbanibulin or vehicle (placebo) ointment. The ointment was applied by the patients to a 25-cm2 contiguous area containing four to eight lesions once daily for 5 consecutive days. The primary outcome was the percentage of patients with a complete (100%) reduction in the number of lesions in the application area at day 57. The secondary outcome was the percentage of patients with a partial (≥75%) reduction in the number of lesions within the application area at day 57. The incidence of recurrence was evaluated at 1 year. Local reactions were scored with the use of 4-point scale (ranging from 0 [absent] to 3 [severe]). RESULTS: A total of 702 patients were enrolled in the two trials (351 patients per trial). Complete clearance in trial 1 occurred in 44% of the patients (77 of 175) in the tirbanibulin group and in 5% of those (8 of 176) in the vehicle group (difference, 40 percentage points; 95% confidence interval [CI], 32 to 47; P<0.001); in trial 2, the percentages were 54% (97 of 178 patients) and 13% (22 of 173), respectively (difference, 42 percentage points; 95% CI, 33 to 51; P<0.001). The percentages of patients with partial clearance were significantly higher in the tirbanibulin groups than in the vehicle groups. At 1 year, the estimated percentage of patients with recurrent lesions was 47% among patients who had had a complete response to tirbanibulin. The most common local reactions to tirbanibulin were erythema in 91% of the patients and flaking or scaling in 82%. Adverse events with tirbanibulin were application-site pain in 10% of the patients and pruritus in 9%, all of which resolved. CONCLUSIONS: In two identically designed trials, tirbanibulin 1% ointment applied once daily for 5 days was superior to vehicle for the treatment of actinic keratosis at 2 months but was associated with transient local reactions and recurrence of lesions at 1 year. Trials comparing tirbanibulin with conventional treatments and that have longer follow-up are needed to determine the effects of tirbanibulin therapy on actinic keratosis. (Funded by Athenex; ClinicalTrials.gov numbers, NCT03285477 and NCT03285490.). Tirbanibulin is a novel tubulin polymerization and Src kinase signaling inhibitor. This study was designed to fully characterize tirbanibulin pharmacokinetics (PK) when applied topically under maximal use conditions. This was an open-label, parallel-group PK safety study of tirbanibulin ointment 1% applied to 25 cm2 of the face or balding scalp in adults with actinic keratosis (AK). Eligible subjects self-applied tirbanibulin once-daily for 5 days. PK sampling occurred on days 1, 3 and 4 at 0 hour (before dosing), and on day 5 at prespecified time points up to 24 hours after application. Safety assessments included adverse events and local skin reactions were evaluated up to day 29. Eighteen subjects (face or scalp, n = 9 each) completed the study. Subjects were White (100%), of mean [range] age 66.4 [43-83] years, predominantly men (83.3%) with Fitzpatrick skin type I to III (94.4%); baseline AK lesion count, mean [range] 8.2 [6-14]. All subjects had quantifiable but low plasma concentrations of tirbanibulin. On day 5, overall mean (standard deviation) maximum concentration (Cmax ) was 0.26 (0.23) ng/mL (or 0.60 nM), median time to maximum concentration was 6.91 hours, and mean (standard deviation) area under the plasma concentration-time curve from time 0 to 24 hours was 4.09 (3.15) ng ∙ h/mL. Four subjects experienced a total of 5 treatment-emergent adverse events that resolved. Mild to moderate erythema, flaking, or scaling in the treatment area peaked around day 8 before resolving or returning to baseline by day 29. In conclusion, under maximal use conditions, tirbanibulin ointment 1% for 5 days in the treatment of AK on the face or scalp was well tolerated and resulted in low systemic exposure with subnanomolar plasma concentrations.

Is retinol binding protein 4 an adipokine?

Yes, Retinol-binding protein 4 (RBP4) is a prominent adipokine.

[33199363, 33484131, 34575030]

Pancreatic β-cell dysfunction plays a decisive role in the progression of type 2 diabetes. Retinol-binding protein 4 (RBP4) is a prominent adipokine in type 2 diabetes, although its effect on β-cell function remains elusive, and the underlying mechanisms are unknown. Here, we found that elevated circulating RBP4 levels were inversely correlated with pancreatic β-cell function in db/db mice across different glycemic stages. RBP4 directly suppressed glucose-stimulated insulin secretion (GSIS) in primary isolated islets and INS-1E cells in a dose- and time-dependent manner. RBP4 transgenic (RBP4-Tg) overexpressing mice showed a dynamic decrease of GSIS, which appeared as early as 8 weeks old, preceding the impairment of insulin sensitivity and glucose tolerance. Islets isolated from RBP4-Tg mice showed a significant decrease of GSIS. Mechanistically, we demonstrated that the stimulated by retinoic acid 6 (STRA6), RBP4's only known specific membrane receptor, is expressed in β-cells and mediates the inhibitory effect of RBP4 on insulin synthesis through the Janus kinase 2/STAT1/ISL-1 pathway. Moreover, decreasing circulating RBP4 level could effectively restore β-cell dysfunction and ameliorate hyperglycemia in db/db mice. These observations revealed a role of RBP4 in pancreatic β-cell dysfunction, which provides new insight into the diabetogenic effect of RBP4. CONTEXT: Data on the presence/quantification of the neurotrophic adipokines retinol-binding protein-4 (RBP4), clusterin, and pigment epithelium-derived factor (PEDF) in human cerebrospinal fluid (CSF) are scarce and migration of these adipokines across of the blood-brain barrier (BBB) is uncertain. OBJECTIVE: This work aimed to quantify RBP4, PEDF, and clusterin in paired serum and CSF samples of patients undergoing neurological evaluation. METHODS: A total of 268 patients (109 male, 159 female) were included. Adipokine serum and CSF concentrations were measured by enzyme-linked immunosorbent assay in duplicate. RESULTS: RBP4 was abundant in serum (mean, 31.9 ± 24.2 μg/mL). The serum concentrations were approximately 145 times higher than in CSF (CSF to serum RBP4 ratio, 8.2 ± 4.3 × 10-3). PEDF was detectable in serum (mean, 30.2 ± 11.7 μg/mL) and concentrations were approximately 25 times higher than in CSF (CSF to serum PEDF ratio, 42.3 ± 15.6 × 10-3). Clusterin serum concentrations were abundant with mean levels of 346.0 ± 114.6 μg/mL, which were approximately 40 times higher than CSF levels (CSF to serum clusterin ratio, 29.6 ± 23.4 × 10-3). RBP4 and PEDF serum levels correlated positively with CSF levels, which were increased in overweight/obese patients and in type 2 diabetic patients. The CSF concentrations of all 3 adipokines increased with BBB dysfunction. RBP4 in CSF correlated positively with inflammatory parameters. In detail, only RBP4 showed the kinetics and associations that are mandatory for a putative mediator of the fat-brain axis. CONCLUSION: RBP4, PEDF, and clusterin are permeable to the BBB and increase with the measure of BBB dysfunction. RBP4 represents an inflammatory neurotrophic adipokine and is a promising mediator of the fat-brain axis.

What is the function of BACH1

BACH1) is the first mammalian heme-binding transcription factor that belongs to the basic region leucine zipper (bZIP) family and a member of CNC (cap 'n' collar

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Cellular senescence prevents the aberrant proliferation of damaged cells. The transcription factor Bach1 binds to p53 to repress cellular senescence, but it is still unclear how the Bach1-p53 interaction is regulated. We found that the Bach1-p53 interaction was inhibited by oncogenic Ras, bleomycin, and hydrogen peroxide. Proteomics analysis of Bach1 complex revealed its interaction with p19(ARF), a tumor suppressor that competitively inhibited the Bach1-p53 interaction when overexpressed within cells. Reduction of MDM2 expression in wild-type murine embryonic fibroblasts (MEFs) did not result in slower proliferation, showing that Bach1 plays a role in keeping the proliferation of MEFs independent of MDM2. Consistent with this interpretation, expression of p21 was highly induced in MEFs when both Bach1 and MDM2 were abrogated. The level of Bach1 protein was reduced on knockdown of p53. These results suggest that p53 activation involves its dissociation from Bach1, achieved in part by the competitive binding of p19(ARF) to Bach1. The p19(ARF)-Bach1 interaction constitutes a regulatory pathway of p53 in parallel with the p19(ARF)-MDM2 pathway. BRCA1 interacts in vivo with a novel protein, BACH1, a member of the DEAH helicase family. BACH1 binds directly to the BRCT repeats of BRCA1. A BACH1 derivative, bearing a mutation in a residue that was essential for catalytic function in other helicases, interfered with normal double-strand break repair in a manner that was dependent on its BRCA1 binding function. Thus, BACH1/BRCA1 complex formation contributes to a key BRCA1 activity. In addition, germline BACH1 mutations affecting the helicase domain were detected in two early-onset breast cancer patients and not in 200 matched controls. Thus, it is conceivable that, like BRCA1, BACH1 is a target of germline cancer-inducing mutations. A central mechanism in cellular defence against oxidative or electrophilic stress is mediated by transcriptional induction of genes via the ARE (antioxidant-response element), a cis-acting sequence present in the regulatory regions of genes involved in the detoxification and elimination of reactive oxidants and electrophiles. The ARE binds different bZIP (basic-region leucine zipper) transcription factors, most notably Nrf2 (nuclear factor-erythroid 2-related factor 2) that functions as a transcriptional activator via heterodimerization with small Maf proteins. Although ARE activation by Nrf2 is relatively well understood, the mechanisms by which ARE-mediated signalling is down-regulated are poorly known. Transcription factor BACH1 [BTB (broad-complex, tramtrack and bric-a-brac) and CNC (cap'n'collar protein) homology 1] binds to ARE-like sequences, functioning as a transcriptional repressor in a subset of ARE-regulated genes, thus antagonizing the activator function of Nrf2. In the present study, we have demonstrated that BACH1 itself is regulated by Nrf2 as it is induced by Nrf2 overexpression and by Nrf2-activating agents in an Nrf2-dependent manner. Furthermore, a functional ARE site was identified at +1411 from the transcription start site of transcript variant 2 of BACH1. We conclude that BACH1 is a bona fide Nrf2 target gene and that induction of BACH1 by Nrf2 may serve as a feedback-inhibitory mechanism for ARE-mediated gene regulation. Bach1 is a member of the basic leucine zipper transcription factor family, and the Bach1/small Maf heterodimer specifically represses transcriptional activity directed by the Maf recognition element (MARE). Because Bach1 is a repressor of the oxidative stress response, we examined the function(s) of Bach1 in keratinocytes subjected to oxidative stress. Oxidative stress induced by H(2)O(2) led to an increase in MARE activity and expression of heme oxygenase-1 (HO-1), an inducible antioxidant defense enzyme. Bach1 depletion by small interfering RNAs or by deletion of Bach1 enhanced HO-1 expression in the absence of H(2)O(2), indicating that Bach1 is a critical repressor of HO-1 in keratinocytes. Although Bach1-deficient or -reduced keratinocytes expressed higher levels of HO-1 than control cells in response to H(2)O(2), Bach1 down-regulation did not attenuate the production of reactive oxygen species by H(2)O(2). In contrast, Bach1 overexpression abolished HO-1 induction by H(2)O(2), which led to increased reactive oxygen species accumulation. HO-1 was induced during keratinocyte differentiation, but MARE activity did not change during differentiation. Furthermore, Bach1 overexpression did not inhibit differentiation-associated induction of HO-1 expression, suggesting that HO-1 induction in differentiation is independent of Bach1. Thus, in response to oxidative stress, Bach1 regulates the oxidation state through the negative control of HO-1 expression prior to terminal keratinocyte differentiation. However, Bach1-mediated repression is negated during keratinocyte differentiation. A limited number of overexpressed transcription factors are associated with cancer progression in many types of cancer. BTB and CNC homology 1 (BACH1) is the first mammalian heme-binding transcription factor that belongs to the basic region leucine zipper (bZIP) family and a member of CNC (cap 'n' collar). It forms heterodimers with the small musculoaponeurotic fibrosarcoma (MAF) proteins and stimulates or suppresses the expression of target genes under a very low intracellular heme concentration. It possesses a significant regulatory role in heme homeostasis, oxidative stress, cell cycle, apoptosis, angiogenesis, and cancer metastasis progression. This review discusses the current knowledge about how BACH1 regulates cancer metastasis in various types of cancer and other carcinogenic associated factors such as oxidative stress, cell cycle regulation, apoptosis, and angiogenesis. Overall, from the reported studies and outcomes, it could be realized that BACH1 is a potential pharmacological target for discovering new therapeutic anticancer drugs. Maintenance of stem-cell identity requires proper regulation of enhancer activity. Both transcription factors OCT4/SOX2/NANOG and histone methyltransferase complexes MLL/SET1 were shown to regulate enhancer activity, but how they are regulated in embryonic stem cells (ESCs) remains further studies. Here, we report a transcription factor BACH1, which directly interacts with OCT4/SOX2/NANOG (OSN) and MLL/SET1 methyltransferase complexes and maintains pluripotency in mouse ESCs (mESCs). BTB domain and bZIP domain of BACH1 are required for these interactions and pluripotency maintenance. Loss of BACH1 reduced the interaction between NANOG and MLL1/SET1 complexes, and decreased their occupancy on chromatin, and further decreased H3 lysine 4 trimethylation (H3K4me3) level on gene promoters and (super-) enhancers, leading to decreased enhancer activity and transcription activity, especially on stemness-related genes. Moreover, BACH1 recruited NANOG through chromatin looping and regulated remote NANOG binding, fine-tuning enhancer-promoter activity and gene expression. Collectively, these observations suggest that BACH1 maintains pluripotency in ESCs by recruiting NANOG and MLL/SET1 complexes to chromatin and maintaining the trimethylated state of H3K4 and enhancer-promoter activity, especially on stemness-related genes. The mammalian transcription factor Bach1 functions as a repressor of the enhancers of heme oxygenase-1 (HO-1) gene (Hmox-1) by forming heterodimers with the small Maf proteins such as MafK. The transcription of Hmox-1 is regulated by the substrate of HO-1, heme. Heme induces expression of Hmox-1 in part by inhibiting the binding of Bach1 to the enhancers and inducing the nuclear export of Bach1. A dipeptide motif of cysteine and proline (CP motif) in Bach1 is essential for the heme-mediated regulation. In this study, we show that five molecules of heme bind to Bach1 by the heme-titration assay. The Bach1-heme complex exhibits an absorption spectrum with a major Soret peak at 371 nm and Raman band at 343 cm(-1) in high amounts of heme and a spectrum containing the major Soret peak at 423 nm at low heme concentrations. The spectroscopic characterization indicates that Bach1 has two kinds of heme-binding sites with different coordination structures. Mutagenesis studies have established that four molecules of heme bind to the cysteine residues of four CP motifs in the C terminus of Bach1. These results raise the possibility that two separated activities of Bach1, DNA-binding and nuclear export, are regulated by heme binding at the different CP motifs of Bach1 respectively, but not by cooperative heme-binding. Bach1 functions as a transcriptional repressor of heme oxygenase-1 (HO-1) and the beta-globin genes. The enhancer regions of these genes contain multiple Maf recognition elements (MAREs) to which Bach1 can bind. Previous studies have shown that increased levels of heme and cadmium induce the nuclear export of Bach1, resulting in cytoplasmic accumulation. By means of a yeast two hybrid screening using Bach1 as bait, we identified the intracellular hyaluronic acid binding protein (IHABP) as a potential regulator of Bach1. IHABP is a microtubule-associated protein that may regulate the organization of the cytoskeletal network. A series of domain analyses revealed that a region of Bach1 previously implicated in cytoplasmic accumulation was necessary for IHABP-binding. A C-terminal region of IHABP was necessary for Bach1-binding. Overexpressed Bach1 colocalized with IHABP in the cytoplasm, forming fiber-like structures on microtubules. Fluorescence recovery after photobleaching (FRAP) analysis revealed a dynamic nature of the Bach1-IHABP interaction in living cells. The repression of HO-1 reporter activity by Bach1 was attenuated by co-transfecting IHABP in a dose-dependent manner. Moreover, the overexpression of IHABP induced the endogenous HO-1 gene in NIH3T3 cells. The overall results suggest that IHABP regulates the subcelluar localization of Bach1 in order to fine-tune transactivation of Bach1 target genes such as HO-1. Bach1 is a known transcriptional repressor of the heme oxygenase-1 (HO-1) gene. The purpose of this study was to determine whether angiogenesis is accelerated by genetic ablation of Bach1 in a mouse ischemic hindlimb model. Hindlimb ischemia was surgically induced in wild-type (WT) mice, Bach1-deficient (Bach1-/-) mice, apolipoprotein E-deficient (ApoE-/-) mice, and Bach1/ApoE double-knockout (Bach1-/-/ApoE-/-) mice. Blood flow recovery after hindlimb ischemia showed significant improvement in Bach1-/- mice compared with that in WT mice. Bach1-/-/ApoE-/- mice showed significantly improved blood flow recovery compared with that in ApoE-/- mice to the level of that in WT mice. Migration of endothelial cells in ApoE-/- mice was significantly decreased compared with that in WT mice. Migration of endothelial cells significantly increased in Bach1-/-/ApoE-/- mice compared with that in ApoE-/- mice to the level of that in WT mice. The expression levels of HO-1, peroxisome proliferator-activated receptor γ co-activator-1α, angiopoietin 1, and fibroblast growth factor 2 in endothelial cells isolated from Bach1-/-/ApoE-/- mice were significantly higher than those in ApoE-/- mice. Oxidative stress assessed by anti-acrolein antibody staining in ischemic tissues and urinary 8-isoPGF2α excretion were significantly increased in ApoE-/- mice compared with those in WT and Bach1-/- mice. Oxidative stress was reduced in Bach1-/-/ApoE-/- mice compared with that in ApoE-/- mice. These findings suggest that genetic ablation of Bach1 plays an important role in ischemia-induced angiogenesis under the condition of increased oxidative stress. Bach1 could be a potential therapeutic target to reduce oxidative stress and potentially improve angiogenesis for patients with peripheral arterial disease. The link between defects in BRCA1 and breast cancer development may be best understood by deciphering the role of associated proteins. BRCA1 associated C-terminal helicase (BACH1) interacts directly with the BRCA1 C-terminal BRCT repeats, which are important for BRCA1 DNA repair and are mutated in the majority of BRCA1 familial cancers. Thus, BACH1 is a likely candidate for mediating BRCA1 DNA repair and tumor suppression functions. Although previous evidence using overexpression of a dominant negative BACH1 has suggested that BACH1 is involved in BRCA1-DNA repair function, our results using BACH1 deficient cells provide direct evidence for involvement of BACH1 in DNA repair as well as for localizing BRCA1. Following DNA damage BACH1 is modified by phosphorylation, displays a BRCA1-like nuclear foci pattern and colocalizes with gamma-H2AX. Given that the BACH1/BRCA1 complex is unaltered by DNA damage and the intensity of BRCA1 foci is diminished in BACH1 deficient cells, BACH1 may serve to not only facilitate DNA repair, but also maintain BRCA1 in DNA damage foci. Bach1 is a transcriptional repressor of the cytoprotective enzyme heme oxygenase-1 (HO-1). Although HO-1 protects against atherosclerosis, the function of Bach1 in this process is poorly understood. We isolated peritoneal macrophages and aortic smooth muscle cells (SMC) from wild-type and bach1-deficient mice. bach1-Deficient macrophages expressed increased levels of HO-1 and showed elevated phagocytic activity when incubated with 0.75 microm microspheres. In SMC, bach1-ablation resulted in increased expression of HO-1 and decreased proliferation in bromodeoxyuridine incorporation assay as compared with wild-type cells. The up-regulated phagocytic activity and reduced SMC proliferation of bach1-deficient cells were not restored by Zinc (II) protoporphyrin IX, an inhibitor of HO, suggesting that HO-independent mechanisms are also involved in the regulation of phagocytosis of macrophages and proliferation of SMC by Bach1. In wild-type mice, cuff placement around femoral artery caused pronounced intimal proliferation without affecting the media, thus resulting in intimal to medial (I/M) volume ratio of 65.6%. bach1-deficient mice had less degree of intimal growth (I/M ratio of 45.6%). These results indicate that Bach1 plays a critical role in the regulation of HO-1 expression, macrophage function, SMC proliferation and neointimal formation. Bach1 may regulate gene expression in these cells during inflammation and atherogenesis. Up-regulation of heme oxygenase 1 (HO-1) by ultraviolet A (UVA; 320-380 nm) irradiation of human skin cells protects them against oxidative stress. The role of Nrf2 in up-regulation of HO-1 and other phase II genes is well established. The mechanism underlying Bach1-mediated HO-1 repression is less well understood although cellular localization seems to be crucial. Because prolonged HO-1 overexpression is likely to be detrimental, it is crucial that activation of the gene is transient. We now show that UVA irradiation of cultured human skin fibroblasts enhances accumulation of Bach1 mRNA and protein severalfold. Endogenous Bach1 protein accumulates in the nucleus after 8h and may occupy MARE sites after HO-1 activation thus providing a compensatory mechanism to control HO-1 overexpression. Overexpression of Bach1, together with MafK, represses basal and UVA-mediated HO-1 protein expression, whereas silencing of the Bach1 gene by Bach1-specific siRNAs causes robust enhancement of constitutive HO-1 levels. UVA treatment of cells in which Bach1 has been silenced leads to higher levels of induction of the HO-1 protein. Although Bach1 protein is exported from the nucleus 12h after UVA irradiation, the release of free cellular heme from microsomal heme-containing proteins is immediate rather than delayed. Although heme does promote the export of Bach1 via the Crm1/exportin 1 pathway and is involved in the delayed UVA-mediated export of the protein, it is not clear how this occurs. OBJECTIVE: The diverse clinical phenotype of hemoglobin E (HbE)/β-thalassemia has not only confounded clinicians in matters of patient management but has also led scientists to investigate the complex mechanisms involved in maintaining the delicate red cell environment where, even with apparent similarities of α- and β-globin genotypes, the phenotype tells a different story. The BTB and CNC homology 1 (BACH1) protein is known to regulate α- and β-globin gene transcriptions during the terminal differentiation of erythroid cells. With the mutations involved in HbE/β-thalassemia disorder, we studied the role of BACH1 in compensating for the globin chain imbalance, albeit for fine-tuning purposes. MATERIALS AND METHODS: A total of 47 HbE/β-thalassemia samples were analyzed using real-time quantitative polymerase chain reaction and correlated with age, sex, red blood cell parameters, globin gene expressions, and some clinical data. RESULTS: The BACH1 expression among the β-thalassemia intermedia patients varied by up to 2-log differences and was positively correlated to age; α-, β-, and γ-globin gene expression level; and heme oxygenase 1 protein. BACH1 was also negatively correlated to reticulocyte level and had a significant correlation with splenectomy. CONCLUSION: This study indicates that the expression of BACH1 could be elevated as a compensatory mechanism to decrease the globin chain imbalance as well as to reduce the oxidative stress found in HbE/β-thalassemia. Heme oxygenase 1 (HO-1) catalyzes heme breakdown, eventually releasing iron, carbon monoxide, and bilirubin IXalpha. HO-1 is induced by its substrate heme and various environmental factors, which represents a protective response against oxidative stresses. Here we show that hypoxia represses HO-1 expression in three human cell types but induces it in rat, bovine, and monkey cells, indicating the inter-species difference in the hypoxic regulation of HO-1 expression. The hypoxia-mediated repression of HO-1 expression is consistently associated with the induction of Bach1, a heme-regulated transcriptional repressor, in human cells. Bach1 is a basic leucine zipper protein, forming a heterodimer with a small Maf protein. Expression of HO-1 was also reduced in human cells when exposed to interferon-gamma or an iron chelator desferrioxamine, each of which induced Bach1 expression. In contrast, induction of HO-1 expression by CoCl(2) is associated with reduced expression of Bach1 mRNA. Thus, expression of HO-1 and Bach1 is inversely regulated. We have identified a Maf recognition element in the human HO-1 gene that is required for repression of a reporter gene by hypoxia and targeted by Bach1. Therefore, Bach1 functions as a hypoxia-inducible repressor for the HO-1 gene, thereby contributing to fine-tuning of oxygen homeostasis in human cells. Oxidative stress has been implicated in tissue damage from traumatic brain injury. Heme oxygenase-1 (HO-1) is an inducible enzyme that degrades prooxidant heme to radical-scavenging biliverdin/bilirubin in order to protect cells from oxidative stress. Although HO-1 is induced after induction of brain damage, the regulatory mechanism of HO-1 in the brain is still unclear. Bach1 is a transcriptional repressor of the HO-1 gene, and plays a critical role in tissue protection from oxidative stress by reperfusion injury of the myocardium. In this study, we examined the role of Bach1 in HO-1 regulation of the various brain sites by investigating the expression of Bach1 and HO-1 in brain tissues of mice bearing Bach1-deficient (Bach1(-/-)) or wild-type (Bach1(+/+)) genes. While the expression levels of Bach1 mRNA in the olfactory bulb were significantly higher than other brain areas, those at the cortex showed the lowest activity. Bach1(-/-) mice showed significantly higher HO-1 mRNA expression levels than Bach1(+/+) mice in all brain sites studied. Moreover, higher induction of HO-1 was observed around damaged tissues after cold injury in Bach1(-/-) than Bach1(+/+) mice. Thus, Bach1 plays an important role in regulating the constitutive and inducible expression levels of HO-1 in the brain. Although a significantly higher level of HO-1 was observed in Bach1(-/-) than Bach1(+/+) mice, genetic ablation of the Bach1 gene failed to show any tissue protective effect after cold injury was inflicted on the cortex. Oxidative stress plays an essential role in inflammation and fibrosis. Bach1 is an important transcriptional repressor that acts by modulating oxidative stress and represents a potential target in the treatment of pulmonary fibrosis (PF). In this study, we knocked down Bach1 using adenovirus-mediated small interfering RNA (siRNA) to determine whether the use of Bach1 siRNA is an effective therapeutic strategy in mice with bleomycin (BLM)‑induced PF. Mouse lung fibroblasts (MLFs) were incubated with transforming growth factor (TGF)-β1 (5 ng/ml) and subsequently infected with recombined adenovirus-like Bach1 siRNA1 and Bach1 siRNA2, while an empty adenovirus vector was used as the negative control. The selected Bach1 siRNA with higher interference efficiency was used for the animal experiments. A mouse model of BLM-induced PF was established, and Bach1 siRNA (1x109 pfu) was administered to the mice via the tail vein. The results revealed that the Bach1 mRNA and protein levels were significantly downregulated by Bach1 siRNA. Furthermore, the MLFs infected with Bach1 siRNA exhibited increased mRNA and protein expression levels of heme oxygenase-1 and glutathione peroxidase 1, but decreased levels of TGF-β1 and interleukin-6 in the cell supernatants compared with the cells exposed to TGF-β1 alone. Bach1 knockdown by siRNA also enhanced the expression of antioxidant factors, but suppressed that of fibrosis‑related cytokines in mice compared with the BLM group. Finally, the inflammatory infiltration of alveolar and interstitial cells and the destruction of lung structure were significantly attenuated in the mide administered Bach1 siRNA compared with those in the BLM group. On the whole, our findings demonstrate that Bach1 siRNA exerts protective effects against BLM-induced PF in mice. Our data may provide the basis for the development of novel targeted therapeutic strategies for PF. The cystic fibrosis transmembrane conductance regulator (CFTR) gene lies within a topologically associated domain (TAD) in which multiple cis-regulatory elements (CREs) and transcription factors (TFs) regulate its cell-specific expression. The CREs are recruited to the gene promoter by a looping mechanism that depends upon both architectural proteins and specific TFs. An siRNA screen to identify TFs coordinating CFTR expression in airway epithelial cells suggested an activating role for BTB domain and CNC homolog 1 (BACH1). BACH1 is a ubiquitous master regulator of the cellular response to oxidative stress. Here, we show that BACH1 may have a dual effect on CFTR expression by direct occupancy of CREs at physiological oxygen (∼8%), while indirectly modulating expression under conditions of oxidative stress. Hence BACH1, can activate or repress the same gene, to fine tune expression in response to environmental cues such as cell stress. Furthermore, our 4C-seq data suggest that BACH1 can also directly regulate CFTR gene expression by modulating locus architecture through occupancy at known enhancers and structural elements, and depletion of BACH1 alters the higher order chromatin structure. AIMS: The purpose of this study was to investigate the potential correlation between metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and the transcription factor BTB and CNC homology 1 (BACH1) and their clinicopathological significance in triple-negative breast cancer (TNBC). SUBJECTS AND METHODS: MALAT1 and BACH1 were detected by immunohistochemistry using TNBC tissue microarrays of 240 patients. The association between MALAT1 and BACH1 expression levels was statistically analyzed. Moreover, the prognostic roles as well as clinical and pathological significance of MALAT1 and BACH1 expression in TNBC were determined. STATISTICAL ANALYSIS USED: Two-tailed Pearson correlation was used to examine the correlation of BACH1 and MALA1 expression. Comparisons of clinicopathological variables between different BACH1 and MALA1 expression groups were performed using χ2 tests. Overall survival (OS) and disease-free survival (DFS) curves were plotted with the Kaplan-Meier method and the differences in OS and DFS between three groups were compared by the log-rank test. Multiple comparisons were performed using χ2 tests for subsequent individual group comparisons. RESULTS: MALAT1 and BACH1 expression was significantly correlated with tumor-node-metastasis stage, distant metastasis, pathological stage, and survival outcomes of patients. Patients with high MALAT1 and BACH1 expression exhibited shorter overall survival and disease-free survival. CONCLUSIONS: These findings provide further insight into the expression pattern of MALAT1 and BACH1 in TNBC and suggest them as prognostic biomarkers for TNBC. Bach1 is a transcriptional repressor of the heme oxygenase (HO)-1 gene. Bach1-null (Bach1(-/-)) mice are reported to be protected from myocardial ischemia/reperfusion injury; however, the effect of Bach1 disruption on another oxidative stress model of hyperoxic lung injury has yet to be determined. To investigate the role of Bach1 in hyperoxic lung injury, Bach1(-/-) mice and wild-type (WT) mice were exposed to 90% O(2). During hyperoxic exposure, the survival of Bach1(-/-) mice was significantly longer than that of WT mice. However, the administration of zinc protoporphyrin, an inhibitor of HO-1 activity, did not change the mortality in either of the mice, thus suggesting that this protective effect was not mediated by an HO-1 overexpression in Bach1(-/-) mice. The indices of lung injury in the lungs of Bach1(-/-) mice were lower than those of WT mice; unexpectedly, however, the levels of IL-6 in bronchoalveolar lavage (BAL) fluid from Bach1(-/-) mice were significantly higher than those of WT mice. Interestingly, the intrapulmonary administration of small interfering RNA against IL-6 was shown to reduce the IL-6 levels in BAL fluids and shorten the survival in Bach1(-/-) mice during hyperoxic exposure. In addition, a chromatin immunoprecipitation analysis revealed the binding of Bach1 to the IL-6 promoter and its detachment after oxidative stress. Considering the previous observation that the transgenic mice overexpressing IL-6 are protected from hyperoxic lung injury, these results therefore indicate that IL-6 mediates an increased survival in Bach1(-/-) mice during hyperoxic exposure. Intracellular heme is a redox active molecule that can be detrimental to cells at high concentrations or under oxidizing conditions. To prevent accumulation, the inducible enzyme heme oxygenase-1 (HMOX1) catalyzes degradation of heme. In the absence of elevated intracellular heme or oxidative stress, the basic region leucine zipper transcriptional regulator BACH1 binds HMOX1 antioxidant response elements and represses transcription. Conversely, increased intracellular heme or sulfhydryl oxidation inactivate BACH1, permitting transcriptional induction of HMOX1. Here, we investigate the effect of BACH1 inactivation on the induction of HMOX1 and as a mechanism for broader gene induction. We show that BACH1 is inactivated at low micromolar arsenite concentrations and that BACH1 inactivation is necessary and sufficient for transcriptional induction of HMOX1. Because BACH1 is thought to interact with antioxidant response element motifs, we further examined the role of BACH1 as a regulator of inducible antioxidant gene expression by assessing the global profile of gene expression following BACH1 knockdown using small interfering RNA. The loss of BACH1 function in human keratinocytes results almost exclusively in HMOX1 induction, suggesting that BACH1 may function as a rheostat regulating levels of intracellular free heme.

What does the gene symbol EREG stand for?

The gene symbol EREG stands for the gene epiregulin.

[34667080]

Epidermal growth factor receptor (EGFR) plays a pivotal role in collective cell migration by mediating cell-to-cell propagation of extracellular signal-regulated kinase (ERK) activation. Here, we aimed to determine which EGFR ligands mediate the ERK activation waves. We found that epidermal growth factor (EGF)-deficient cells exhibited lower basal ERK activity than the cells deficient in heparin-binding EGF (HBEGF), transforming growth factor alpha (TGFα) or epiregulin (EREG), but all cell lines deficient in a single EGFR ligand retained the ERK activation waves. Surprisingly, ERK activation waves were markedly suppressed, albeit incompletely, only when all four EGFR ligands were knocked out. Re-expression of the EGFR ligands revealed that all but HBEGF could restore the ERK activation waves. Aiming at complete elimination of the ERK activation waves, we further attempted to knockout NRG1, a ligand for ErbB3 and ErbB4, and found that NRG1-deficiency induced growth arrest in the absence of all four EGFR ligand genes. Collectively, these results showed that EGFR ligands exhibit remarkable redundancy in the propagation of ERK activation waves during collective cell migration.

Which tool has been developed for proteome-wide detection of membrane lipid-binding proteins?

MBPpred is a profile Hidden Markov Model based method capable of detecting Membrane Binding Proteins (MBPs) from information encoded in their amino acid sequence.

[27048983]

A large number of modular domains that exhibit specific lipid binding properties are present in many membrane proteins involved in trafficking and signal transduction. These domains are present in either eukaryotic peripheral membrane or transmembrane proteins and are responsible for the non-covalent interactions of these proteins with membrane lipids. Here we report a profile Hidden Markov Model based method capable of detecting Membrane Binding Proteins (MBPs) from information encoded in their amino acid sequence, called MBPpred. The method identifies MBPs that contain one or more of the Membrane Binding Domains (MBDs) that have been described to date, and further classifies these proteins based on their position in respect to the membrane, either as peripheral or transmembrane. MBPpred is available online at http://bioinformatics.biol.uoa.gr/MBPpred. This method was applied in selected eukaryotic proteomes, in order to examine the characteristics they exhibit in various eukaryotic kingdoms and phyla.

What disease can be treated with Avacopan?

Avacopan is effective for ANCA-associated vasculitis.

[33164993, 33596356, 34484454, 34224265, 33625803, 34006155, 29718732, 34553355, 34473462, 32088663, 34826105, 33128347, 28400446]

PURPOSE OF REVIEW: Vasculitides can affect small, medium and/or large vessels, leading to end-organ damage, decreased quality of life and death. Glucocorticoids remain the backbone of treatment for systemic vasculitis but are associated with numerous toxicities. In recent years, the efficacy of glucocorticoid-sparing biologic and novel small molecule therapies has been demonstrated. RECENT FINDINGS: In giant cell arteritis, tocilizumab was superior to glucocorticoid monotherapy in maintenance remission and cumulative glucocorticoid exposure and is now approved for the treatment of giant cell arteritis. In addition to the previously demonstrated efficacy of rituximab for remission induction in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, recent trials have also demonstrated its superiority for remission maintenance compared to alternative approaches. Mepolizumab is superior to standard of care alone with regard to remission rates and glucocorticoid-sparing effect in refractory eosinophilic granulomatosis with polyangiitis. Avacopan has shown significant promise in ANCA-associated vasculitis as part of a glucocorticoid-free induction regimen in a recently completed phase 3 trial. Use of biologics in rarer vasculitides remains guided by reports from small case series. SUMMARY: Biologics and other novel therapies have an increasingly important role in the management of systemic vasculitis. Additional studies are needed to define their optimal use and to guide their use in more rare forms of vasculitis. Collaborators: Au Peh C, Chakera A, Cooper B, Kurtkoti J, Langguth D, Levidiotis V, Luxton G, Mount P, Mudge D, Noble E, Phoon R, Ranganathan D, Ritchie A, Ryan J, Suranyi M, Rosenkranz A, Lhotta K, Kronbichler A, Demoulin N, Bovy C, Hellemans R, Hougardy J, Sprangers B, Wissing K, Pagnoux C, Barbour S, Brachemi S, Cournoyer S, Girard L, Laurin L, Liang P, Philibert D, Walsh M, Tesar V, Becvar R, Horak P, Rychlik I, Szpirt W, Dieperink H, Gregersen J, Ivarsen P, Krarup E, Lyngsoe C, Rigothier C, Augusto J, Belot A, Chauveau D, Cornec D, Jourde-Chiche N, Ficheux M, Karras A, Klein A, Maurier F, Mesbah R, Moranne O, Neel A, Quemeneur T, Saadoun D, Terrier B, Zaoui P, Schaier M, Benck U, Bergner R, Busch M, Floege J, Grundmann F, Haller H, Haubitz M, Hellmich B, Henes J, Hohenstein B, Hugo C, Iking-Konert C, Arndt F, Kubacki T, Kotter I, Lamprecht P, Lindner T, Halbritter J, Mehling H, Schönermarck U, Venhoff N, Vielhauer V, Witzke O, Szombati I, Szucs G, Garibotto G, Alberici F, Brunetta E, Dagna L, De Vita S, Emmi G, Gabrielli A, Manenti L, Pieruzzi F, Roccatello D, Salvarani C, Dobashi H, Atsumi T, Fujimoto S, Hagino N, Ihata A, Kaname S, Kaneko Y, Katagiri A, Katayama M, Kirino Y, Kitagawa K, Komatsuda A, Kono H, Kurasawa T, Matsumura R, Mimura T, Morinobu A, Murakawa Y, Naniwa T, Nanki T, Ogawa N, Oshima H, Sada K, Sugiyama E, Takeuchi T, Taki H, Tamura N, Tsukamoto T, Yamagata K, Yamamura M, van Daele P, Rutgers A, Teng Y, Walker R, Chua I, Collins M, Rabindranath K, de Zoysa J, Svensson M, Grevbo B, Kalstad S, Little M, Clarkson M, Molloy E, Agraz Pamplona I, Anton J, Barrio Lucia V, Ciggaran S, Cinta Cid M, Diaz Encarnacion M, Fulladosa Oliveras X, Soler JM, Rusinol MH, Praga M, Quintana Porras L, Segarra A, Bruchfeld A, Segelmark M, Soveri I, Thomaidi E, Westman K, Neumann T, Burnier M, Daikeler T, Dudler J, Hauser T, Seeger H, Vogt B, Jayne D, Burton J, Al Jayyousi R, Amin T, Andrews J, Baines L, Brogan P, Dasgupta B, Doulton T, Flossmann O, Griffin S, Harper J, Harper L, Kidder D, Klocke R, Lanyon P, Luqmani R, McLaren J, Makanjuola D, McCann L, Nandagudi A, Selvan S, O'Riordan E, Patel M, Patel R, Pusey C, Rajakariar R, Robson J, Robson M, Salama A, Smyth L, Sznajd J, Taylor J, Merkel P, Sreih A, Belilos E, Bomback A, Carlin J, Chang Chen Lin Y, Derebail V, Dragoi S, Dua A, Forbess L, Geetha D, Gipson P, Gohh R, Greenwood GT, Hugenberg S, Jimenez R, Kaskas M, Kermani T, Kivitz A, Koening C, Langford C, Marder G, Mohamed A, Monach P, Neyra N, Niemer G, Niles J, Obi R, Owens C, Parks D, Podoll A, Rovin B, Sam R, Shergy W, Silva A, Specks U, Spiera R, Springer J, Striebich C, Swarup A, Thakar S, Tiliakos A, Tsai Y, Waguespack D, Chester Wasko M. Die Pathogenese von ANCA(antineutrophile zytoplasmatische Antikörper)-assoziierten Vaskulitiden (AAV) ist komplex, das bessere Verständnis der letzten Jahre hat jedoch neue therapeutische Ansätze ermöglicht. In den letzten Jahren stand die Minimierung toxischer Therapieeffekte im Vordergrund. In der Remissionsinduktion stehen für die schwere Granulomatose mit Polyangiitis (GPA) und die mikroskopische Polyangiitis (MPA) neben Glukokortikoiden Cyclophosphamid und Rituximab zur Verfügung. Die aktuellen Empfehlungen ermöglichen eine raschere Reduktion der Steroiddosis und sehen den Einsatz der Plasmapherese zurückhaltend. Zur Remissionserhaltung stehen Rituximab und Azathioprin zur Verfügung. Medikamentenwahl und Dauer der Remissionserhaltung richten sich insbesondere nach dem Rezidivrisiko. Der Stellenwert von niedrig dosierten Steroiden ist nicht endgültig geklärt. Neue Therapieansätze wie der C5a-Rezeptor-Inhibitor Avacopan könnten in Zukunft eine steroidminimierte Therapie ermöglichen. Die Therapie der eosinophilen Granulomatose mit Polyangiitis (EGPA) ist weniger evidenzbasiert und beinhaltet Glukokortikoide, Immunsuppressiva je nach Erkrankungsschwere und zunehmend Biologika (z. B. Interleukin[IL]-5-Blockade). Supportive Maßnahmen (Impfungen, Infektionsprophylaxe, kardiovaskuläres Risikomanagement) gewinnen an Bedeutung. Zukünftige Therapiestrategien müssen das individuelle Risiko (z. B. ANCA-Subtyp, Rezidivrisiko) für Auswahl und Dauer der Therapien besser berücksichtigen. Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med. 2021;384:599-609. 33596356. Publisher: L’étude du complément bénéficie depuis quelques années d’un regain d’intérêt dû en grande partie à la mise au point de nouveaux modulateurs du complément, notamment le bloqueur du C5, l’éculizumab. Ce dernier a significativement amélioré le pronostic de certaines pathologies rénales, comme le syndrome hémolytique et urémique atypique. Cette avancée est un exemple parfait d’une recherche translationnelle ayant débouché sur des applications cliniques pour les patients. Actuellement, de nouvelles molécules sont en cours de développement et certaines ont déjà démontré une efficacité clinique, comme l’avacopan (bloqueur du C5aR) dans les vasculites à anticorps anticytoplasme des polynucléaires neutrophiles. Du côté de la transplantation rénale, les inhibiteurs du complément pourraient faire évoluer le traitement de certaines complications comme le rejet humoral. Cependant, ces nouvelles thérapies ciblées ont des effets secondaires, notamment infectieux, et un coût important. Introduction: Anti-neutrophil cytoplasm autoantibodies (ANCA)-associated vasculitides (AAVs) are a group of rare heterogeneous diseases characterized by blood vessel inflammation resulting in organ destruction and death. Although various treatment strategies have resulted in marked improvement in vasculitis-specific outcomes, many patients with AAV continue to suffer from complications related to the prolonged use of glucocorticoids (GC) such as infections, metabolic abnormalities, and increased cardiovascular morbidity. Recently, activation of the alternative complement pathway has been implicated in the augmentation of the damage caused by AAV via the complement C5a receptor (C5aR1, CD88). Specifically targeting this pathway may lead to improved outcomes in patients with AAV.Areas covered: In this article, we have summarized the rationale for targeting the complement pathway in AAV. The relevant pre-clinical, phase I, II and III findings with emphasis on the efficacy, and safety of avacopan, a new oral competitive inhibitor that interferes with the binding of C5a to C5aR1 (CD88), are reviewed.Expert opinion: These results are encouraging, may led to major changes in the treatment approach for AAV, and give rise to future studies utilizing complement inhibitors in AAV patients, and potentially in other immune mediated diseases. Publisher: REMISSIONSINDUKTION BEI GRANULOMATOSE MIT POLYANGIITIS (GPA)/MIKROSKOPISCHER POLYANGIITIS (MPA): Das Komplementsystem spielt in der Pathogenese, anders als früher vermutet, eine bedeutsame Rolle. Durch diese Erkenntnis war es möglich, einen vollständig neuen Therapieansatz zu etablieren. Die Blockade des C5a-Rezeptors mit Avacopan erwies sich in klinischen Studien als effektiv und ermöglichte erstmals eine (fast) GC-freie Remissionsinduktion. Avacopan ist eine kleines, gezielt eingreifendes Molekül und wird absehbar in die Therapie der GPA/MPA Einzug halten. Die therapeutische Bedeutung der Plasmapherese tritt weiter in den Hintergrund. Diese Therapieform bleibt aktuell wenigen Ausnahmesituationen vorbehalten und kann nicht mehr generell bei Glomerulonephritis oder pulmorenalem Syndrom empfohlen werden. Therapieprotokolle mit vermindertem GC-Einsatz zeigen ähnlich gute Erfolge wie Hochdosisprotokolle. Der GC-Einsatz kann daher weiter limitiert werden. GPA/MPA-REMISSIONSERHALTUNG: Vor allem die MAINRITSAN-Studien zeigen, dass Rituximab dem Azathioprin in der Remissionserhaltung überlegen ist und dass eine längere Erhaltungstherapie, insbesondere bei Risikopatienten, mit klinisch relevant geringeren Rezidivraten einhergeht. GENETIK DER EOSINOPHILEN GRANULOMATOSE MIT POLYANGIITIS (EGPA): Trotz der Seltenheit der EGPA konnte ein internationales Konsortium eine genomweite Assoziationsstudie (GWAS) durchführen. Hierbei bestätigte sich auch auf der genetischen Ebene der klinische Eindruck zweier distinkter Subgruppen. Es kann ein mehr vaskulitisch geprägter Subtyp von einem durch die Eosinophilie dominierten unterschieden werden. Diese Ergebnisse werden für zukünftige Therapiekonzepte relevant sein. EGPA-THERAPIE: Die bisher größte RCT bei EGPA wies eine verminderte Rezidivrate sowie einen GC-einsparenden Effekt eines Anti-IL-5-Antikörpers (Mepolizumab) nach. Der klinische Nutzen bestätigte sich in einer weiteren Analyse der Daten und auch in der „Real Life“-Anwendung. The antineutrophil cytoplasmic antibody (ANCA) vasculitides include several closely related, often severe, multisystem autoimmune diseases characterized by antibodies against serine proteinase 3 (PR3) or myeloperoxidase. Loss of tolerance to these antigens triggers a cascade of events, beginning with the priming of neutrophils by proinflammatory cytokines and complement activation, translocation of ANCA-specific antigens to the plasma membrane, neutrophil hyperactivation, and further activation of the alternative complement pathway, leading to tissue damage and the clinical manifestations of ANCA vasculitis. Due to the heterogeneity in presentation of these diseases, diagnosis is often substantially delayed, leading to poor outcomes. The current treatment pathway for most patients involves induction with cyclophosphamide or rituximab in combination with glucocorticoids, followed by a maintenance phase with rituximab, azathioprine, or methotrexate, during which time glucocorticoids are tapered. Current therapies are often effective in inducing and maintaining remission but are associated with a range of toxicities. Several new therapies are in development for ANCA vasculitis. Avacopan, an orally administered inhibitor of the complement fragment 5a (C5a) receptor, has been assessed in a phase 3 clinical trial and may play a role in reducing the cumulative glucocorticoid dose. Preliminary data suggest that cluster of differentiation (CD) 80 and CD86 blockade with abatacept may also have a role in the management of ANCA vasculitis. There is an unmet need for additional therapeutic options for patients with these diseases. Alternative C activation is involved in the pathogenesis of ANCA-associated vasculitis. However, glucocorticoids used as treatment contribute to the morbidity and mortality of vasculitis. We determined whether avacopan (CCX168), an orally administered, selective C5a receptor inhibitor, could replace oral glucocorticoids without compromising efficacy. In this randomized, placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. The primary efficacy measure was the proportion of patients achieving a ≥50% reduction in Birmingham Vasculitis Activity Score by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in the control and 22 in each of the avacopan groups. Clinical response at week 12 was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1%; P=0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control 11.0%; two-sided 90% confidence limit, -11.0% to 32.9%; P=0.01 for noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19 of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21 of 22 (96%) patients in the avacopan without prednisone group. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis.

What disease is also known as Bechterew's Disease?

Ankylosing spondylitis (Bechterew's disease) is the most typical form of axial SpA whereby sacroiliitis can be found on X-rays of the SI joints.

[11803718, 25050151, 29101454, 22744304, 3923615, 32349490, 22085520, 18650743, 6461592, 2233790, 6983935]

Cervical spine changed by Bechterew's disease is severely endangered with any increased load. Even decent trauma is enough to produce a fracture with affection of spinal cord. Because of little knowledge in these special items, late diagnosis of overlooked injury is not rare, especially in two-level injuries. Neurolesions following secondary fracture dislocations may occur ("fatal pause"). From january 1990 to february 2000 12 patients underwent surgery (dorsoventral stabilisation, ventral stabilisation, laminectomy). Diagnostic procedures, levels of injury, pre- and postoperative neurostatus (following Frankel's score), operative technique, typical complications and follow-up (Ø 17.8 months) were analyzed and compared with the literature. 11 patients showed preoperative neurodeficits. They were better in five cases and disappeared at all in another five cases after surgery (83% positive neurological outcome). There was no increase of neurology failure. Two patients died (ARDS and cerebral ischemia with destruction of vertebral arteries). One patient had to be reoperated because of implant dislocation. MRI is obvious in diagnostic for these lesions. There is also an absolute need for total (both clinical and radiological) examination of the whole spinal column, because there is often injury of more than one level (three times in our study). Therapy should be operative (dorsoventral stabilisation, in certain cases only anterior procedure or laminectomy). Late diagnosis and therapy with secondary worsening after fracture dislocation is not rare because of "overlooked injury". There were four patients, that would not have suffered cervical spine fracture (minimal injury force) without Bechterew's changes. There is often pulmonary failure through limitation of thoracic movement and cerebral ischemia following rupture of vertebral arteries as typical complications. Mortality (2 cases; 16%) in our collective is less than literature's medium rates (35-57%). Ankylosing spondylitis (AS) or Bechterew disease is a chronic, usually progressive, systemic inflammatory joint disease, which predominantly affects the spine and sacroiliac joints. In these joints, early inflammatory changes are followed by lumbosacral pain and progressive restriction of spinal movement associated with radiologically visible intervertebral ossification. Peripheral joint involvement occurs in 10 to 30% of patients and shows a predilection for the shoulders, knees, ankles, feet, and wrists. Temporomandibular joint (TMJ) involvement has been described, and its reported frequency varies from 11 to 35%. However, ankylosis is uncommon with a single documented case utilizing an alloplastic prosthesis for total joint replacement. A case report of bilateral ankylosis of the jaw treated with alloplastic prostheses for total TMJ replacement using a Brazilian system in a patient with AS is presented. Ankylosing spondylitis is an inflammatory rheumatic disease that is often associated with back pain and restricted spinal movement. In the later stages of the disease, complete ossification of the entire spine and severe deformity can occur, often resulting in a marked reduction in quality of life and an increased risk of loss of independence due to diminished visual field. Patients with ankylosing spondylitis are at greater risk of spinal fractures. These are generally complex fractures associated with high morbidity and mortality; in addition, neurological deficits are not unusual. Conventional radiological diagnosis is often insufficient to establish a diagnosis. Conservative treatment of fractures of the spine in this patient group is unsatisfactory. Surgical procedures, if necessary combined with decompression, are often the preferred treatment of choice in the fractured or malaligned ankylosed spine. Rebalancing of the sagittal profile with normalization of the visual axis and an improvement of quality of life is achieved through corrective osteotomies. Despite the high rate of complications, long-term results following spinal surgery in patients with ankylosing spondylitis are good. Minimally invasive surgery is appropriate for a further reduction in the complication rate. Meticulous preoperative planning is essential in the treatment of patients with ankylosing spondylitis. The term axial spondyloarthritis covers patients with established structural changes visible on x-ray in sacroiliac joints and/or in the spine (classical ankylosing spondylitis) but also patients with non-radiographic axial spondyloarthritis in whom early inflammatory signs of the disease can only be visualized with magnetic resonance imaging (MRI). The MRI technique plays an important role in the diagnosis of this disease and an early diagnosis is normally based on a combination of clinical, laboratory and imaging parameters. Only non-steroidal anti-inflammatory drugs and TNF-α blockers are effective in the treatment of axial spondyloarthritis. Patients with short disease duration and elevated acute phase reactant levels demonstrate best therapy response and, therefore, should be closely followed-up and consistently treated. Spondyloarthritis (SpA) is an umbrella term for a group of rheumatic diseases characterised by inflammation of the sacroiliac (SI) joints and vertebral column; today, differentiation is made between axial SpA and peripheral SpA. Ankylosing spondylitis (Bechterew's disease) is the most typical form of axial SpA whereby sacroiliitis can be found on X-rays of the SI joints. Axial SpA can, however, also be present without radiographic evidence of sacroiliitis. A range of SpA-related symptoms can also manifest themselves outside the musculoskeletal system, for example, uveitis, psoriasis and inflammatory intestinal diseases. Tumour necrosis factor (TNF)-α inhibitors play an important role in the treatment of SpA. New classification criteria have recently been established in which MRI of the SI joints and the presence of the HLA-B27 tissue antigen are key. Axial and peripheral SpA should be recognized early in order to be able to successfully treat these conditions. Although involvement of the temporomandibular joint in patients with ankylosing spondylitis (AS, Bechterew disease) has been described previously, hyperplasia of the mandibular coronoid process in those patients has not been reported yet. Case notes were studied, and records were made of age, sex, clinical symptoms, radiography, and treatment in all patients with a confirmed diagnosis of coronoid hyperplasia presenting at the Department of Oral and Maxillofacial Surgery, University of Bonn, between 1995 and 2007. Sixteen cases of coronoid hyperplasia were recruited, of which 12 were bilateral and 4 were unilateral. Four patients had AS, 3 of them were HLA-B27-positive. Temporomandibular joint symptoms are frequently seen in patients with AS. Nevertheless, it must be considered that a limitation of jaw mobility in those patients might also be caused by an elongation of the mandibular coronoid process. Ankylosing spondylitis is a disease with clinically and radiologically very variable features. It is the intention to direct the attention from the old by orthopedists' influenced association of the stiff back to the polymorphism of the disease especially to the early stages which still frequently are recognized too late. The paper deals with the nosology, the various states of the clinical course with the numerous radiological criteria including therapeutical approaches. The authors have used the modified method of the direct gene cloning suggested by Nichols et al to isolate HLA-B27 gene from a patient suffering from ankylosing spondylitis. Five restriction enzymes (ClaI, HindIII, SnaBI, PvuI, SalGI) which had no recognition sites within the 6.0 kb EcoRI-BamHI-DNA fragment supposedly containing the HLA-B27 gene have been chosen by blotting-hybridization of the restriction fragments of the patients DNA with HLA-B27-specific probe. The 6.0 +/- 0.5 kb DNA fragments were isolated and cloned after the DNA treatment by 300 micrograms of all of these restriction enzymes. The obtained mini-library containing 280 recombinants has been screened with the use of HLA-B27 specific oligonucleotide probe. The clone PB27-2 has been isolated the restriction map of which is identical to HLA-B27k. The authors are planning to determine the sequence of the isolated gene in order to find a possible structural defect in it. One hundred and twenty-two consecutive patients hospitalized for ankylosing spondylitis (AS) were reexamined. The frequency of clinical signs and results of tests for associations are presented. Psoriasis was associated with a distal pattern of peripheral arthropathy. Spinal rigidity was predominantly seen in males. Males with phalangeal arthropathy exhibited preserved spinal mobility. This was the case also when HLA B27 positives and patients who did not have psoriasis were considered separately. HLA B27 positive patients in this group had frequently experienced acute anterior uveitis. It seems possible that the disease in such males is the result of combined predisposition to ankylosing spondylitis and psoriatic arthropathy. Hip arthropathy was frequently present in males with spinal rigidity. The associations observed confirm that AS is a heterogenous group of diseases. The term "syndrome" may be suitable for such a heterogenous group, and we prefer the term "Bechterew's syndrome" as the name of this group. When these new findings are added to the previous observations that acute anterior uveitis probably is a clinical, sex-influenced characteristic of HLA B27 positive Bechterew's syndrome, that HLA B27 negative patients with Bechterew's syndrome frequently had psoriasis and were HLA B13 and B17 negative, and that psoriasis was frequent in HLA B27 positive patients as well, we tentatively conclude that different and interacting genetic mechanisms may be involved in the etiology of Bechterew's syndrome.

Was ALVAC-HIV effective for HIV prevention in the HVTN 702 trial?

No. The ALVAC-gp120 regimen did not prevent HIV-1 infection among participants in South Africa despite previous evidence of immunogenicity

[32554928, 34029515, 33761206]

The RV144 HIV-1 vaccine trial results showed moderate reduction in viral infections among vaccinees as well as induction of antibody-dependent cellular cytotoxicity and vaccine-specific IgG and IgG3 responses directed at variable loop regions 1 and 2 of the HIV envelope protein. However, with the recent failure of the HVTN 702 clinical trial, comprehensive profiling of humoral immune responses may provide insight for these disappointing results. One of the changes included in the HVTN 702 study was the addition of a late boost, aimed at augmenting peak immunity and durability. The companion vaccine trial RV305 was designed to permit the evaluation of the immunologic impact of late boosting with either the boosting protein antigen alone, the canarypox viral vector ALVAC alone, or a combination of both. Although previous data showed elevated levels of IgG antibodies in both boosting arms, regardless of ALVAC-HIV vector incorporation, the effect on shaping antibody effector function remains unclear. Thus, here we analyzed the antibody and functional profile induced by RV305 boosting regimens and found that although IgG1 levels increased in both arms that included protein boosting, IgG3 levels were reduced compared with the original RV144 vaccine strategy. Most functional responses increased upon protein boosting, regardless of the viral vector-priming agent incorporation. These data suggest that the addition of a late protein boost alone is sufficient to increase functionally potent vaccine-specific antibodies previously associated with reduced risk of infection with HIV. The advanced-phase HIV prevention vaccine trials done in South Africa (HVTN 702) and in Thailand (RV144), which both investigated canarypox vectors and adjuvanted gp120 proteins, gave rise to different results. The South African trial did not find vaccine efficacy, whereas the Thai trial had modest, but statistically significant, success with the modified intention-to-treat analysis prespecified in the protocols of both studies. An understanding of the differences between the studies is required to avoid the possible, but erroneous, conclusion that the results from the South African trial negatively affect the results of the Thai trial. Author information: (1)From the Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center (G.E.G., Z.M., N. Grunenberg, Y.H., D.G., B.P., J.J.K., J.H., C.B., S.R., S.T., M.J., M. Sikhosana, M. Andrasik, J.G.K., M.J.M., P.B.G., H.J., L.C.), Seattle; the Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand (G.E.G., F.L., E.L., B.M., T.P., S.T.), the National Institute for Communicable Diseases, National Health Laboratory Service (A.P.), and Aurum Institute (C.I., M. Sebe, W.B., P.S., T.A., G. Kobane), Johannesburg, Desmond Tutu HIV Centre (L.-G.B., S.K., C.N.N., M. Atujuna), the Department of Medicine, Wellcome Centre for Infectious Diseases Research in Africa, and Institute of Infectious Disease and Molecular Medicine (G.M., A.M.W.), and the Division of Clinical Pharmacology, Department of Medicine (L.W.), University of Cape Town, Cape Town, Setshaba Research Centre, Soshanguve (M.M., K.S.M.), Mecru Clinical Research Unit, Sefako Mkgatho Health Sciences University, Ga-Rankuwa (M.N., M.P.M.), Nelson Mandela Academic Clinical Research Unit and Department of Internal Medicine and Pharmacology, Walter Sisulu University, Mthatha (T.D., P.M.), the School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, Pretoria (S.T.), the South African Medical Research Council (G.E.G., D.K., N.S., V.N., G. Kistnasami, Z.G.) and the Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal (N.N., N. Garrett), Durban, and Qhakaza Mbokodo Research Clinic, Ladysmith (P.K., P.B.M.) - all in South Africa; the Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda (M. Allen), and GlaxoSmithKline Vaccines, Rockville (N.K.-T.) - both in Maryland; the Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta (D.B.); GSK Vaccines, Cambridge, MA (S.W.B.); Sanofi Pasteur, Swiftwater, PA (S.P., C.D.G.); GlaxoSmithKline, Siena, Italy (S.P.); GlaxoSmithKline, Wavre (M.K.), and GlaxoSmithKline, Rixensart (O.V.D.M.) - both in Belgium; and the Graduate Group in Biostatistics and the Center for Computational Biology, University of California, Berkeley (N.S.H.).

Do Afamin bind Vitamin E?

Yes, Afamin is a plasma vitamin E-binding glycoprotein.

[29587878, 33409873, 30247793, 30220025, 28877915]

PURPOSE: Oxidative stress is involved in the pathogenesis of hypertensive disorders such as preeclampsia (PE) and associated with the human vitamin E-binding protein afamin. The aim of this study was, therefore, to analyse afamin in the first trimester of patients developing PE later in pregnancy and in control subjects without pregnancy complications. METHODS: In this retrospective study, 137 serum samples from the first trimester of pregnancy were analysed in a case-control study design. 39 patients developed PE (10 patients with early-onset and 29 patients with late onset disease) and 98 women had an uncomplicated pregnancy. Mann-Whitney U test, t test, logistic regression and ROC analyses were performed for statistical evaluation. RESULTS: Pregnant women developing PE presented with higher afamin concentrations in the first trimester [median 101.81 mg/L; interquartile range (IQR) 88.94-113.26] compared to subjects with uncomplicated pregnancy (median 86.40; IQR 75.26-96.92; p < 0.001). After adjusting for confounders, the odds ratio per afamin standard deviation was 1.60 (95% CI: 1.04-2.58; p = 0.04). An afamin threshold concentration of 87.8 mg/L exhibited the best sensitivity (79.5%) and specificity (57.1%) in predicting PE. Subgroup analysis of early- and late-onset disease resulted in substantially higher afamin concentrations in women with developing late-onset PE compared to controls (p < 0.001) with an odds ratio per afamin standard deviation of 1.62 (95% CI: 0.98-2.70; p = 0.06). CONCLUSIONS: Serum afamin concentrations are elevated in the first trimester among patients developing PE compared to controls. Substantial differences were observed mainly among patients with late-onset PE. Author information: (1)Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria. (2)Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. (3)German Center for Diabetes Research (DZD), München-Neuherberg, Germany. (4)Department of Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland. (5)Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. (6)Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland. (7)Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland. (8)Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, University College London, London, U.K. (9)Cardiovascular Genetics Division, University of Utah School of Medicine, Salt Lake City, UT. (10)Department of Genetic Medicine, Weill Cornell Medicine, Doha, Qatar. (11)Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. (12)First Department of Internal Medicine, Paracelsus Private Medical University, Salzburg, Austria. (13)Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. (14)Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. (15)German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany. (16)Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland. (17)Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, Finland. (18)Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland. (19)Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. (20)Vitateq Biotechnology GmbH, Innsbruck, Austria. (21)Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria florian.kronenberg@i-med.ac.at.

Is disruption of immune regulation mechanisms associated with adverse pregnancy outcomes, including preeclampsia (PE)?

Inflammation and oxidative stress at the maternal-fetal interface characterize the placental dysfunction that underlies the pregnancy disorder preeclampsia.

[32573856, 21498785, 32161574, 19683334, 34509865, 34191338, 30058156, 9272206, 34412079, 34599631, 31608721, 34847253, 29756666, 30079067, 34576285, 27108670, 24520479]

Inflammation and oxidative stress at the maternal-fetal interface characterize the placental dysfunction that underlies the pregnancy disorder preeclampsia. Specialized fetal trophoblasts directly interact with leukocytes at both sites of the maternal-fetal interface; the uterine wall decidua; and the placenta. TLR3 has been implicated in the harmful inflammation at the maternal-fetal interface in preeclampsia, but the cellular involvement in the decidua and placenta has not been determined. This study aimed to characterize and quantify cell-specific TLR3 expression and function at the maternal-fetal interface in normal and preeclamptic pregnancies. TLR3 expression was assessed by immunohistochemistry and quantified by a novel image-based and cell-specific quantitation method. TLR3 was expressed at the maternal-fetal interface by all decidual and placental trophoblast types and by maternal and fetal leukocytes. Placental, but not decidual, TLR3 expression was significantly higher in preeclampsia compared to normal pregnancies. This increase was attributed to placental intravillous tissue and associated with both moderate and severe placental dysfunction. TLR3 pathway functionality in the decidua and placenta was confirmed by TLR3 ligand-induced cytokine response, but the TLR3 expression levels did not correlate between the two sites. In conclusion, functional TLR3 was broadly expressed by maternal and fetal cells at both sites of the maternal-fetal interface and the placental intravillous expression was increased in preeclampsia. This suggests TLR3-mediated inflammatory involvement with local regulation at both sites of the maternal-fetal interface in normal and preeclamptic pregnancies. OBJECTIVE: Increased oxidative stress and immune dysfunction are implicated in preeclampsia (PE) and may contribute to the two- to fourfold increase in PE prevalence among women with type 1 diabetes. Prospective measures of fat-soluble vitamins in diabetic pregnancy are therefore of interest. RESEARCH DESIGN AND METHODS: Maternal serum carotenoids (α- and β-carotene, lycopene, and lutein) and vitamins A, D, and E (α- and γ-tocopherols) were measured at first (12.2 ± 1.9 weeks [mean ± SD], visit 1), second (21.6 ± 1.5 weeks, visit 2), and third (31.5 ± 1.7 weeks, visit 3) trimesters of pregnancy in 23 women with type 1 diabetes who subsequently developed PE (DM PE+) and 24 women with type 1 diabetes, matched for age, diabetes duration, HbA(1c), and parity, who did not develop PE (DM PE-). Data were analyzed without and with adjustment for baseline differences in BMI, HDL cholesterol, and prandial status. RESULTS: In unadjusted analysis, in DM PE+ versus DM PE-, α-carotene and β-carotene were 45 and 53% lower, respectively, at visit 3 (P < 0.05), before PE onset. In adjusted analyses, the difference in β-carotene at visit 3 remained significant. Most participants were vitamin D deficient (<20 ng/mL), and vitamin D levels were lower in DM PE+ versus DM PE- throughout the pregnancy, although this did not reach statistical significance. CONCLUSIONS: In pregnant women with type 1 diabetes, low serum α- and β-carotene were associated with subsequent development of PE, and vitamin D deficiency may also be implicated. Reproduction involves tightly regulated series of events and the immune system is involved in an array of reproductive processes. Disruption of well-controlled immune functions leads to infertility, placental inflammation, and numerous pregnancy complications, including preeclampsia (PE). Inflammasomes are involved in the process of pathogen clearance and sterile inflammation. They are large multi-protein complexes that are located in the cytosol and play key roles in the production of the pivotal inflammatory cytokines, interleukin (IL)-1β and IL-18, and pyroptosis. The nucleotide-binding oligomerization domain, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) inflammasome is a key mediator of sterile inflammation induced by various types of damage-associated molecular patterns (DAMPs). Recent evidence indicates that the NLRP3 inflammasome is involved in pregnancy dysfunction, including PE. Many DAMPs (uric acid, palmitic acid, high-mobility group box 1, advanced glycation end products, extracellular vesicles, cell-free DNA, and free fatty acids) are increased and associated with pregnancy complications, especially PE. This review focuses on the role of the NLRP3 inflammasome in the pathophysiology of PE. Maternal immunity undergoes subtle adjustment in order to tolerate the semi-allogeneic embryo and maintain the host defense against potential pathogens. Concomitantly, coagulation systems change from an anti-coagulant state to a pro-coagulant state to meet the hemostatic challenge of placentation and delivery. Innate immunity and blood coagulation systems are the first line of defense to protect a host against exogenous challenges, including alloantigens and mechanical insults, and preserve the integrity of an organism. The interactions between coagulation and immune systems have been extensively studied. Immune cells play a pivotal role in the initiation of the coagulation cascade, whereas coagulation proteases display substantial immuno-modulatory effects. Upon exogenous challenges, the immune and coagulation systems are capable of potentiating each other leading to a vicious cycle. Natural killer (NK) cells, macrophages (Mphis) and dendritic cells (DCs) are three major innate immune cells that have been demonstrated to play essential roles in early pregnancy. However, immune maladaptation and hemostatic imbalance have been suggested to be responsible for adverse pregnant outcomes, such as preeclampsia (PE), miscarriage, recurrent spontaneous abortion (RSA) and intrauterine growth restriction (IUGR). In this review, we will summarize the mutual regulation between blood coagulation and innate immune systems as well as their roles in the maintenance of normal pregnancy and in the pathogenesis of adverse pregnancy outcomes. INTRODUCTION: Maternal immune system tolerance to the semi-allogeneic fetus is critical to a successful pregnancy. We previously reported that myeloid-derived suppressor cells (MDSC) was associated with maternal immune imbalance. T cell immunoglobulin and mucin-containing protein 3 (Tim-3)/Galectin-9 (Gal-9) pathway modulates function of various immune cells in maternal-fetal interface. However, the regulatory effects of Tim-3/Gal-9 signaling on MDSCs and its role in preeclampsia (PE) remain unclear. METHODS: In the current study we investigated the expression of Tim-3 on MDSC in preeclampsia (PE) patients to further explore the pathogenesis of PE. RESULTS: The proportion of Tim-3+ M-MDSC (monocytic MDSC) cells was higher in PE patients than in healthy control. Meanwhile, the protein expression of Gal-9, as the ligand of Tim-3, was increased in placenta of PE patients. M-MDSC also expressed a higher level of interferon-γ (IFN-γ) and a lower level of transforming growth factor-β (TGF-β) in PE. Furthermore, our study suggested that blocking Tim-3 could attenuate the inhibitory function of MDSC. DISCUSSION: The abnormal expression of Tim-3 on MDSC might be involved in the pathogenesis of PE, and could be a marker to evaluate the immune function in PE. Fetomaternal immune tolerance is required to prevent fetal rejection during pregnancy; simultaneously, the maternal immune system must also protect the fetus from harmful endogenous and exogenous antigens, including those associated with viral and bacterial infections. Therefore, a delicate immune balance is critical for the maintenance of a successful pregnancy, while disruption of this balance can induce complications such as implantation failure, miscarriage, preterm birth/labor, preeclampsia and fetal growth restriction. While the adaptive immune system is critical for the development of tolerance, this review summarizes evidence that modulation of the innate immunity is also essential for achieving this delicate balance between tolerance and protection. Canonical cells of the innate immune system, including dendritic cells, macrophages, natural killer cells and invariant natural killer T cells, contribute to the modulation of the immune balance at the fetomaternal interface. The newly identified myeloid-derived suppressor cells and innate lymphoid cells also appear important for successful reproduction. Moreover, it is possible that sterile inflammation facilitates complications of pregnancy via the innate immune system. In this review, the characteristic features and functions of innate immune cells in fetomaternal immunity and their contributions to pregnancy complications related to sterile inflammation are discussed. These insights on innate immune system function in reproduction may provide new perspectives for understanding the mechanisms of fetomaternal tolerance and the etiology of pregnancy complications. OBJECTIVES: Maternal systemic and placental inflammatory responses participate in the pathogenesis of hypertensive disorders of pregnancy including preeclampsia, a pregnancy-specific syndrome, although the role of inflammation remains unclear. The NLRP3 inflammasome has been implicated in the control of sterile inflammation involved in preeclampsia. In the present study, we hypothesized that S100A9, as major alarmin, are associated with the pathogenesis of preeclampsia and induction of a preeclampsia-like phenotype in pregnant mice. METHODS: Plasma were taken from normal pregnant women and preeclampsia patients. Human placental tissues, trophoblast cell line Sw.71 cells, and human umbilical vein endothelial cells (HUVEC) were treated with S100A9 with or without inhibitors associated with NLRP3 inflammasome. Pregnant mice were administered S100A9. RESULTS: S100A9 was elevated in plasma and released from placentas of preeclampsia patients. S100A9 activated the NLRP3 inflammasome, resulting in IL-1β secretion, by human placental tissues and trophoblasts. In addition, secretion of soluble endoglin, a main contributor to the pathogenesis of preeclampsia, is regulated via S100A9-stimulated NLRP3 inflammasome activation in the human placenta and HUVECs. S100A9 administration significantly elevated maternal blood pressure and neutrophil accumulation within the placentas of pregnant mice, and both were significantly decreased in Nlrp3-knock out pregnant mice. CONCLUSION: The results of this study demonstrated that S100A9 acts as a danger signal to activate the NLRP3 inflammasome in the placenta, associating with hypertension during pregnancy. INTRODUCTION: Preeclampsia has the highest rate of obstetric morbidity and mortality. METHODS: We recruited 21 women with preeclampsia and 27 women with uncomplicated pregnancies. We used a quantitative protein macroarray that allowed for analysis of 40 proteins. RESULTS: We found a statistically significant increase in the concentration of DR3, LIF and a significant decrease of VEGF, PlGF, syndecan-4 and galectin-2, in the plasma of women with preeclampsia. CONCLUSIONS: There are no previous studies assessing syndecan 4, galectin 2, and DR3 concentrations in women with preeclampsia; Our results indicate these proteins are new factors that play important roles in the immunological pathomechanism of preeclampsia. PROBLEM: The lymphatic vasculature controls leukocytes trafficking and limits the adaptive immune response. In previous models of preeclampsia (PE), defective immune function caused by disruption of lymphangiogenesis was shown to be involved in the disease pathophysiology. Especially, the dysfunction of regulatory T cells (Treg) at the maternal-fetal interface may be one of the causes of severe PE. In particular, activation of Tregs to obtain immune tolerance requires adequate antigen presentation through the lymphatic system. We hypothesized that impaired lymphangiogenesis and imbalanced Tregs at the maternal-fetal interface are associated with the pathophysiology of severe PE. However, the current research addressing this hypothesis is limited. Therefore, to compare differences in lymphangiogenesis in severe PE and normal conditions, we aimed to examine the location of lymphatics at the maternal-fetal interface and to investigate the association between lymphangiogenesis and Tregs in severe PE. METHOD OF STUDY: We obtained entire uterus from normal pregnant mice. Placental and fetal membranes, including decidua, were obtained from 10 pregnant women with severe PE and 10 gestational age-matched controls. Immunohistochemistry for LYVE1 was used to localize the distribution of lymphatic vessels and CD4, CD25, and FOXP3 for Treg. RESULTS: LYVE1-positive vessels were present in the uterine wall of mice. LYVE1-positive lymphatic vessels were localized on the human decidua. Tubular lymphatics were abundant in the control decidua, but significantly reduced in severe PE. Furthermore, lymphatic vessel density correlated with the number of decidual Tregs. CONCLUSION: Abnormal decidual lymphangiogenesis is associated with reduced numbers of decidual Tregs in severe PE. Preeclampsia is a pregnancy-specific disorder, of which one of its major subtypes, the placental subtype is considered a response to an ischemic placental environment, impacting fetal growth and pregnancy outcome. Inflammatory immune responses have been linked to metabolic and inflammatory disorders as well as reproductive failures. In healthy pregnancy, immune regulatory mechanisms prevent excessive systemic inflammation. However, in preeclampsia, the regulation of immune responses is disrupted as a result of aberrant activation of innate immune cells and imbalanced differentiation of T-helper cell subsets creating a cytotoxic environment in utero. Recognition events that facilitate immune interaction between maternal decidual T cells, NK cells, and cytotrophoblasts are considered an indirect cause of the incomplete remodeling of spiral arteries in preeclampsia. The mechanisms involved include the activation of immune cells and the subsequent secretion of cytokines and placental growth factors affecting trophoblast invasion, angiogenesis, and eventually placentation. In this review, we focus on the role of excessive systemic inflammation as the result of a dysregulated immune system in the development of preeclampsia. These include insufficient control of inflammation, failure of tolerance toward paternal antigens at the fetal-maternal interface, and subsequent over- or insufficient activation of immune mediators. It is also possible that external stimuli, such as bacterial endotoxin, may contribute to the excessive systemic inflammation in preeclampsia by stimulating the release of pro-inflammatory cytokines. In conclusion, a disrupted immune system might be a predisposing factor or result of placental oxidative stress or excessive inflammation in preeclampsia. Preeclampsia can thus be considered a hyperinflammatory state associated with defective regulation of the immune system proposed as a key element in the pathological events of the placental subtype of this disorder. For many years, the innate immunity was of less interest than the adaptive immunity because it was perceived to have secondary importance in the functionality of the immune system. During the past decades, with the advancement of knowledge about innate immune system, interest in innate immunity has grown dramatically and thus its function has been extensively studied. Innate immunity plays fundamental roles in the initiation and induction of adaptive immune responses. It consists of several cells and receptors including natural killer (NK) cells, macrophages (MQs), dendritic cells (DCs) and pattern recognition receptors (PRRs). Two decades ago, Toll like receptors (TLRs) family was known as one of the important PRRs with unique functions especially in protection against invading pathogens. Since the female reproductive tract has access to the outside environment and has a unique interaction with different pathogens whether invading microorganisms or normal flora, allogenic sperm and semi allogenic fetus, it has an essential need for effective immune responses. It has therefore been suggested that TLRs may play important roles in the immune regulation of the female reproductive tract. In addition, it has been demonstrated that immune disturbance may be responsible for some adverse pregnancy outcomes such as preeclampsia (PE), recurrent spontaneous abortion (RSA) and intrauterine growth restriction (IUGR). Our focus in this review is to show the importance of TLRs in pregnancy with emphasis on the expression of these receptors in different tissues related to pregnancy.

Can autophagy related lncRNAs be used for colorectal cancer prognosis?

Yes, a prognostic prediction model of CRC was built based on nine ARlncRNAs (NKILA, LINC00174, AC008760.1, LINC02041, PCAT6, AC156455.1, LINC01503, LINC00957, and CD27-AS1). The 5-year overall survival rate was significantly lower in the high-risk group than in the low-risk group among train set, validation set, and all patients (all p < 0.001). The model had high sensitivity and accuracy in predicting the 1-year overall survival rate (area under the curve = 0.717). The prediction model risk score was an independent predictor of CRC.

[34692467]

INTRODUCTION: Colorectal cancer (CRC) is the most common gastrointestinal cancer and has a low overall survival rate. Tumor-node-metastasis staging alone is insufficient to predict patient prognosis. Autophagy and long noncoding RNAs play important roles in regulating the biological behavior of CRC. Therefore, establishing an autophagy-related lncRNA (ARlncRNA)-based bioinformatics model is important for predicting survival and facilitating clinical treatment. METHODS: CRC data were retrieved from The Cancer Genome Atlas. The database was randomly divided into train set and validation set; then, univariate and multivariate Cox regression analyses were performed to screen prognosis-related ARlncRNAs for prediction model construction. Interactive network and Sankey diagrams of ARlncRNAs and messenger RNAs were plotted. We analyzed the survival rate of high- and low-risk patients and plotted survival curves and determined whether the risk score was an independent predictor of CRC. Receiver operating characteristic curves were used to evaluate model sensitivity and specificity. Then, the expression level of lncRNA was detected by quantitative real-time polymerase chain reaction, and the location of lncRNA was observed by fluorescence in situ hybridization. Additionally, the protein expression was detected by Western blot. RESULTS: A prognostic prediction model of CRC was built based on nine ARlncRNAs (NKILA, LINC00174, AC008760.1, LINC02041, PCAT6, AC156455.1, LINC01503, LINC00957, and CD27-AS1). The 5-year overall survival rate was significantly lower in the high-risk group than in the low-risk group among train set, validation set, and all patients (all p < 0.001). The model had high sensitivity and accuracy in predicting the 1-year overall survival rate (area under the curve = 0.717). The prediction model risk score was an independent predictor of CRC. LINC00174 and NKILA were expressed in the nucleus and cytoplasm of normal colonic epithelial cell line NCM460 and colorectal cancer cell lines HT29. Additionally, LINC00174 and NKILA were overexpressed in HT29 compared with NCM460. After autophagy activation, LINCC00174 expression was significantly downregulated both in NCM460 and HT29, while NKILA expression was significantly increased. CONCLUSION: The new ARlncRNA-based model predicts CRC patient prognosis and provides new research ideas regarding potential mechanisms regulating the biological behavior of CRC. ARlncRNAs may play important roles in personalized cancer treatment.

What is the target of Sotorasib?

Sotorasib is a KRASG12C inhibitor.

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Evidence continues to grow that KRAS, once considered an "undruggable" target, can be targeted successfully in non-small cell lung cancer. In a phase I trial, the KRASG12C inhibitor sotorasib elicited responses in about a third of patients with the disease and was generally well tolerated. Publisher: IMMUNONKOLOGISCHE MONOTHERAPIE DES NICHTKLEINZELLIGEN LUNGENKARZINOMS: 5-Jahres-Überlebensdaten der KEYNOTE-024-Studie bestätigen die anhaltende Wirksamkeit einer immunonkologischen Monotherapie bei Patienten mit nichtkleinzelligem Lungenkarzinom (NSCLC) mit hoher PD-L1-Expression (≥ 50 %). DUALE IMMUNTHERAPIE IN KOMBINATION MIT CHEMOTHERAPIE ALS ERSTLINIENTHERAPIE DES NICHTKLEINZELLIGEN LUNGENKARZINOMS: Nivolumab plus Impilimumab in Kombination mit 2 Zyklen platinhaltiger Chemotherapie verbessern das Überleben von NSCLC-Patienten. NEUE TARGETS UND THERAPIEOPTIONEN: Entrectinib und Larotrectinib mit Wirksamkeit bei NTRK-Fusions-positivem NSCLC. Selpercatinib und Pralsetinib mit Wirksamkeit bei RET-Fusions-positivem NSCLC. Mobocertinib mit Wirksamkeit bei EGFRex20ins-Mutation des EGFR-Gens. Sotorasib mit Wirksamkeit bei kRAS-G12C-Mutation des NSCLC. NATIONALES NETZWERK GENOMISCHE MEDIZIN LUNGENKREBS: Das bundesweite Nationale Netzwerk Genomische Medizin Lungenkrebs (nNGM) ermöglicht NSCLC-Patienten den Zugang zu modernster molekularer Diagnostik und neuesten Therapieoptionen. The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers. These mutations render RAS GTP-bound and active, constitutively binding effector proteins to promote signaling conducive to tumorigenic growth. To further elucidate how RAS oncoproteins signal, we mined RAS interactomes for potential vulnerabilities. Here we identify EFR3A, an adapter protein for the phosphatidylinositol kinase PI4KA, to preferentially bind oncogenic KRAS. Disrupting EFR3A or PI4KA reduces phosphatidylinositol-4-phosphate, phosphatidylserine, and KRAS levels at the plasma membrane, as well as oncogenic signaling and tumorigenesis, phenotypes rescued by tethering PI4KA to the plasma membrane. Finally, we show that a selective PI4KA inhibitor augments the antineoplastic activity of the KRASG12C inhibitor sotorasib, suggesting a clinical path to exploit this pathway. In sum, we have discovered a distinct KRAS signaling axis with actionable therapeutic potential for the treatment of KRAS-mutant cancers. RAS is the most frequently mutated oncogene in human cancer. Scientists attempted for decades to target this protein or its pathways, however, all the attempts failed and RAS was labeled as "undruggable". With KRAS-G12C covalent inhibitors entering clinical trials, the myth of this "undruggable" RAS is fading away. In 2021, the Food and Drug Administration (FDA) approved the use of Sotorasib (Lumakras) for the treatment of adult patients with KRAS-G12C mutated locally advanced or metastatic NSCLC, following at least one prior systemic therapy. However, and as every other drug, KRAS-G12C inhibitors are facing intrinsic and acquired resistances. In order to overcome these resistances, researchers are now working on combination strategies. Furthermore, studies are currently ongoing to better elucidate the status of KRAS-G12C as a predictive and prognostic tool and to strengthen its role in the field of personalized medicine. Sotorasib is a first-in class KRASG12C covalent inhibitor in clinical development for the treatment of tumors with the KRAS p.G12C mutation. In the nonclinical toxicology studies of sotorasib, the kidney was identified as a target organ of toxicity in the rat but not the dog. Renal toxicity was characterized by degeneration and necrosis of the proximal tubular epithelium localized to the outer stripe of the outer medulla (OSOM), which suggested that renal metabolism was involved. Here, we describe an in vivo mechanistic rat study designed to investigate the time course of the renal toxicity and sotorasib metabolites. Renal toxicity was dose- and time-dependent, restricted to the OSOM, and the morphologic features progressed from vacuolation and necrosis to regeneration of tubular epithelium. The renal toxicity correlated with increases in renal biomarkers of tubular injury. Using mass spectrometry and matrix-assisted laser desorption/ionization, a strong temporal and spatial association between renal toxicity and mercapturate pathway metabolites was observed. The rat is reported to be particularly susceptible to the formation of nephrotoxic metabolites via this pathway. Taken together, the data presented here and the literature support the hypothesis that sotorasib-related renal toxicity is mediated by a toxic metabolite derived from the mercapturate and β-lyase pathway. Our understanding of the etiology of the rat specific renal toxicity informs the translational risk assessment for patients. Mutations in codon 12 of KRAS have been identified in 13% of non-small cell lung cancer patients. Developing targeted therapies against KRASG12C mutation has proven to be challenging due to the abundance of GTP in the cytoplasm, rapid hydrolysis of GTP, and difficulty designing small molecules to achieve sufficient concentration for KRAS inhibition. Based on promising results in both preclinical and clinical trials, sotorasib, a novel KRASG12C inhibitor, was given conditional approval by the FDA in May 2021. The Phase I portion of the clinical trial produced 32% confirmed response with 56% of patients with stable disease. About 91.2% of patients who received the highest dose of 960mg daily achieved disease control. The Phase II portion, which used 960mg daily dosing resulted in 37.1% of patients with confirmed response and 80.6% of patients with disease control. Both phase I and phase II had similar progression-free survival, in 6.3 months and 6.8 months, respectively. In both phases, grade 4 adverse events occurred in only one patient. The most common adverse events were elevations in LFTs, which down-trended upon dose reduction and steroid treatment. While the conditional approval of sotorasib was a major breakthrough for those patients harboring KRASG12C mutations, resistance mutations to sotorasib are increasingly common. Many proposals have been made to address this, such as the use of combination therapy for synthetic lethality, which are producing encouraging results. Here, we explore in further detail the development of sotorasib, its efficacy, mechanism of resistance, and strategies to overcome these resistances. Author information: (1)From the Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, University of Texas M.D. Anderson Cancer Center, Houston (D.S.H., F.M.-B.); the Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte (M.G.F.), the University of California, San Francisco, San Francisco (P.N.M.), and Amgen, Thousand Oaks (H.H., J.N., G.N., J.K., B.E.H., J.C., J.R.L., G.F.) - all in California; Duke University Medical Center, Durham, NC (J.H.S.); Royal Melbourne Hospital/Peter MacCallum Cancer Centre, Melbourne, VIC (J.D.), Queen Elizabeth Hospital and University of Adelaide, Woodville South, SA (T.J.P.), and Scientia Clinical Research, Randwick, NSW (J.C. Kuo) - all in Australia; the Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis (G.A.D.); Dana-Farber Cancer Institute, Harvard Medical School, Boston (G.I.S.); the Sarah Cannon Research Institute at HealthONE, Denver (G.S.F.); Princess Margaret Cancer Centre, University Health Network, Toronto (A.S.); Fox Chase Cancer Center, Philadelphia (C.S.D.); the University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh, Pittsburgh (T.F.B.); Seoul National University College of Medicine (Y.-J.B.), Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.), and the Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine (T.W.K.) - all in Seoul, South Korea; Roswell Park Cancer Institute, Buffalo (G.K.D.), and Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York (P.L., B.T.L.) - all in New York; the University of Michigan, Ann Arbor (J.C. Krauss); the Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan (Y.K.); the Department of Medicine, Division of Oncology, University of Washington, Seattle (A.L.C.); Aix Marseille University, Centre National de la Recherche Scientifique, INSERM, Centre de Recherche en Cancérologie de Marseille, Assistance Publique-Hôpitaux de Marseille, Marseille, France (F.B.); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, St. Louis (R.G.). KRAS genes belong to the most frequently mutated family of oncogenes in cancer. The G12C mutation, found in a third of lung, half of colorectal and pancreatic cancer cases, is believed to be responsible for a substantial number of cancer deaths. For 30 years, KRAS has been the subject of extensive drug-targeting efforts aimed at targeting KRAS protein itself, but also its post-translational modifications, membrane localization, protein-protein interactions and downstream signalling pathways. So far, most KRAS targeting strategies have failed, and there are no KRAS-specific drugs available. However, clinical candidates targeting the KRAS G12C protein have recently been developed. MRTX849 and recently approved Sotorasib are covalent binders targeting the mutated cysteine 12, occupying Switch II pocket.Herein, we describe two fragment screening drug discovery campaigns that led to the identification of binding pockets on the KRAS G12C surface that have not previously been described. One screen focused on non-covalent binders to KRAS G12C, the other on covalent binders. Cancer is the leading cause of death worldwide, and its treatment and outcomes have been dramatically revolutionised by targeted therapies. As the most frequently mutated oncogene, Kirsten rat sarcoma viral oncogene homologue (KRAS) has attracted substantial attention. The understanding of KRAS is constantly being updated by numerous studies on KRAS in the initiation and progression of cancer diseases. However, KRAS has been deemed a challenging therapeutic target, even "undruggable", after drug-targeting efforts over the past four decades. Recently, there have been surprising advances in directly targeted drugs for KRAS, especially in KRAS (G12C) inhibitors, such as AMG510 (sotorasib) and MRTX849 (adagrasib), which have obtained encouraging results in clinical trials. Excitingly, AMG510 was the first drug-targeting KRAS (G12C) to be approved for clinical use this year. This review summarises the most recent understanding of fundamental aspects of KRAS, the relationship between the KRAS mutations and tumour immune evasion, and new progress in targeting KRAS, particularly KRAS (G12C). Moreover, the possible mechanisms of resistance to KRAS (G12C) inhibitors and possible combination therapies are summarised, with a view to providing the best regimen for individualised treatment with KRAS (G12C) inhibitors and achieving truly precise treatment. Sotorasib is a first-in-class KRASG12C covalent inhibitor in clinical development for the treatment of tumors with the KRAS p.G12C mutation. A comprehensive nonclinical safety assessment package, including secondary/safety pharmacology and toxicology studies, was conducted to support the marketing application for sotorasib. Sotorasib was negative in a battery of genotoxicity assays and negative in an in vitro phototoxicity assay. Based on in vitro assays, sotorasib had no off-target effects against various receptors, enzymes (including numerous kinases), ion channels, or transporters. Consistent with the tumor-specific target distribution (ie, KRASG12C), there were no primary pharmacology-related on-target effects identified. The kidney was identified as a target organ in the rat but not the dog. Renal toxicity in the rat was characterized by tubular degeneration and necrosis restricted to a specific region suggesting that the toxicity was attributed to the local formation of a putative toxic reactive metabolite. In the 3-month dog study, adaptive changes of hepatocellular hypertrophy due to drug metabolizing enzyme induction were observed in the liver that was associated with secondary effects in the pituitary and thyroid gland. Sotorasib was not teratogenic and had no direct effect on embryo-fetal development in the rat or rabbit. Human, dog, and rat circulating metabolites, M24, M10, and M18, raised no clinically relevant safety concerns based on the general toxicology studies, primary/secondary pharmacology screening, an in vitro human ether-à-go-go-related gene assay, or mutagenicity assessment. Overall, the results of the nonclinical safety program support a high benefit/risk ratio of sotorasib for the treatment of patients with KRAS p.G12C-mutated tumors. The FDA has approved the first KRAS-targeted therapy, sotorasib, for patients with previously treated non-small cell lung cancer with KRASG12C mutations. In a phase II trial, the drug yielded a median progression-free survival of 6.8 months in patients whose disease had advanced despite treatment with standard therapies, namely platinum-based chemotherapy and PD-1-PD-L1 inhibitors. In phase I/II KRYSTAL-1 trial, the KRASG12C inhibitor adagrasib demonstrated encouraging clinical activity against metastatic colorectal cancer, both as a monotherapy and when combined with the EGFR inhibitor cetuximab. In patients who received adagrasib alone, the disease control rate was 87% and progression-free survival was 5.6 months. Among patients who received the drug combination, the disease control rate was 100%; data on progression-free survival were immature. The findings, along with data on the KRASG12C inhibitor sotorasib, were presented at the 2021 European Society for Medical Oncology Congress. Across a broad range of human cancers, gain-of-function mutations in RAS genes (HRAS, NRAS, and KRAS) lead to constitutive activity of oncoproteins responsible for tumorigenesis and cancer progression. The targeting of RAS with drugs is challenging because RAS lacks classic and tractable drug binding sites. Over the past 30 years, this perception has led to the pursuit of indirect routes for targeting RAS expression, processing, upstream regulators, or downstream effectors. After the discovery that the KRAS-G12C variant contains a druggable pocket below the switch-II loop region, it has become possible to design irreversible covalent inhibitors for the variant with improved potency, selectivity and bioavailability. Two such inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), were recently evaluated in phase I-III trials for the treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a new era of precision oncology. In this review, we outline the mutations and functions of KRAS in human tumors and then analyze indirect and direct approaches to shut down the oncogenic KRAS network. Specifically, we discuss the mechanistic principles, clinical features, and strategies for overcoming primary or secondary resistance to KRAS-G12C blockade. KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of "undruggable". Recent efforts to produce subtype specific inhibitors have been more successful, and several KRASG12C inhibitors have reached clinical trials, including adagrasib and sotorasib, which have shown early evidence of efficacy in patients. Lessons from other inhibitors of the RAS pathway suggest that the effect of these drugs will be limited in vivo by the development of drug resistance, and pre-clinical studies of G12C inhibitors have identified evidence of this. In this review we discuss the current evidence for G12C inhibitors, the mechanisms of resistance to G12C inhibitors and potential approaches to overcome them. We discuss possible targets of combination therapy, including SHP2, receptor tyrosine kinases, downstream effectors and PD1/PDL1, and review the ongoing clinical trials investigating these inhibitors. INTRODUCTION: KRAS mutations have been recognized as undruggable for many years. Recently, novel KRAS G12C inhibitors, such as sotorasib and adagrasib, are being developed in clinical trials and have revealed promising results in metastatic NSCLC. Nevertheless, it is strongly anticipated that acquired resistance will limit their clinical use. In this study, we developed in vitro models of the KRAS G12C cancer, derived from resistant clones against sotorasib and adagrasib, and searched for secondary KRAS mutations as on-target resistance mechanisms to develop possible strategies to overcome such resistance. METHODS: We chronically exposed Ba/F3 cells transduced with KRASG12C to sotorasib or adagrasib in the presence of N-ethyl-N-nitrosourea and searched for secondary KRAS mutations. Strategies to overcome resistance were also investigated. RESULTS: We generated 142 Ba/F3 clones resistant to either sotorasib or adagrasib, of which 124 (87%) harbored secondary KRAS mutations. There were 12 different secondary KRAS mutations. Y96D and Y96S were resistant to both inhibitors. A combination of novel SOS1 inhibitor, BI-3406, and trametinib had potent activity against this resistance. Although G13D, R68M, A59S and A59T, which were highly resistant to sotorasib, remained sensitive to adagrasib, Q99L was resistant to adagrasib but sensitive to sotorasib. CONCLUSIONS: We identified many secondary KRAS mutations causing resistance to sotorasib, adagrasib, or both, in vitro. The differential activities of these two inhibitors depending on the secondary mutations suggest sequential use in some cases. In addition, switching to BI-3406 plus trametinib might be a useful strategy to overcome acquired resistance owing to the secondary Y96D and Y96S mutations. Kirsten rat sarcoma virus oncogene (KRAS) mutation accounts for approximately 85% of RAS-driven cancers, and participates in multiple signaling pathways and mediates cell proliferation, differentiation and metabolism. KRAS has been considered as an "undruggable" target due to the lack of effective direct inhibitors, although high frequency of KRAS mutations have been identified in multiple carcinomas in the past decades. Encouragingly, the KRASG12C inhibitor AMG510 (sotorasib), which has been approved for treating NSCLC and CRC recently, makes directly targeting KRAS the most promising strategy for cancer therapy. To better understand the current state of KRAS inhibitors, this review summarizes the biological functions of KRAS, the structure-activity relationship studies of the small-molecule inhibitors that directly target KRAS, and highlights the therapeutic agents with improved selectivity, bioavailability and physicochemical properties. Furthermore, the combined medication that can enhance efficacy and overcome drug resistance of KRAS covalent inhibitors is also reviewed.

Is ASF1 phopshorylated by the Tousled-like kinases?

Yes, Asf1, a key histone H3-H4 chaperone required for this process, is phosphorylated by Tousled-like kinases (TLKs).

[24598821, 23869254, 20222959, 23946870, 32755577]

During DNA replication, nucleosomes are rapidly assembled on newly synthesized DNA to restore chromatin organization. Asf1, a key histone H3-H4 chaperone required for this process, is phosphorylated by Tousled-like kinases (TLKs). Here, we identify TLK phosphorylation sites by mass spectrometry and dissect how phosphorylation has an impact on human Asf1 function. The divergent C-terminal tail of Asf1a is phosphorylated at several sites, and this is required for timely progression through S phase. Consistent with this, biochemical analysis of wild-type and phospho-mimetic Asf1a shows that phosphorylation enhances binding to histones and the downstream chaperones CAF-1 and HIRA. Moreover, we find that TLK phosphorylation of Asf1a is induced in cells experiencing deficiency of new histones and that TLK interaction with Asf1a involves its histone-binding pocket. We thus propose that TLK signalling promotes histone supply in S phase by targeting histone-free Asf1 and stimulating its ability to shuttle histones to sites of chromatin assembly. The Tousled-like kinases (TLKs) function in processes of chromatin assembly, including replication, transcription, repair, and chromosome segregation. TLKs interact specifically (and phosphorylate) with the chromatin assembly factor Asf1, a histone H3-H4 chaperone, histone H3 itself at Ser10, and also Rad9, a key protein involved in DNA repair and cell cycle signaling following DNA damage. These interactions are believed to be responsible for the action of TLKs in double-stranded break repair and radioprotection and also in the propagation of the DNA damage response. Hence, I propose that TLKs play key roles in maintenance of genome integrity in many organisms of both kingdoms. In this paper, I highlight key issues of the known roles of these proteins, particularly in the context of DNA repair (IR and UV), their possible relevance to genome integrity and cancer development, and as possible targets for intervention in cancer management. BACKGROUND: The Tousled Like Kinases (TLKs) are involved in chromatin dynamics, including DNA replication and repair, transcription, and chromosome segregation. Indeed, the first two TLK1 substrates were identified as the histone H3 and Asf1 (a histone H3/H4 chaperone), which immediately suggested a function in chromatin remodeling. However, despite the straightforward assumption that TLK1 acts simply by phosphorylating its substrates and hence modifying their activity, TLK1 also acts as a chaperone. In fact, a kinase-dead (KD) mutant of TLK1B is functional in stimulating chromatin assembly in vitro. However, subtle effects of Asf1 phosphorylation are more difficult to probe in chromatin assembly assays. Not until very recently was the Asf1 site phosphorylated by TLK1 identified. This has allowed for probing directly the functionality of a site-directed mutant of Asf1 in chromatin assembly assays. FINDINGS: Addition of either wt or non-phosphorylatable mutant Asf1 to nuclear extract stimulates chromatin assembly on a plasmid. Similarly, TLK1B-KD stimulates chromatin assembly and it synergizes in reactions with supplemental Asf1 (wt or non-phosphorylatable mutant). CONCLUSIONS: Although the actual function of TLKs as mediators of Asf1 activity cannot be easily studied in vivo, particularly since in mammalian cells there are two TLK genes and two Asf1 genes, we were able to study specifically the stimulation of chromatin assembly in vitro. In such assays, clearly the TLK1 kinase activity was not critical, as neither a non-phosphorylatable Asf1 nor use of the TLK1B-KD impaired the stimulation of nucleosome formation.

What is Luteolin?

Luteolin has been reviewed as a flavonoid possessing potential cardioprotective, anti-inflammatory, anti-cancer activities.

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Luteolin is a common dietary flavonoid present in Chinese herbal medicines that has been reported to have important anti-inflammatory properties. Previous studies have shown that luteolin is an anti-inflammatory and anti-oxidative agent. In this study, the anti-virus inflammatory capacity of luteolin and its molecular mechanisms of action were analyzed. The cytotoxic effects of luteolin were assessed in the presence or absence of pseudorabies virus (PRV) via LDH and MTT assays. The results showed that luteolin (<10μM) had no toxic effects and there were tendencies toward higher cell survival. In PRV-infected RAW264.7 cells, luteolin potently inhibited the production of NO, iNOS, COX-2 and inflammatory cytokine production. Luteolin did not inhibit the phosphorylation of ERK 1/2, p38, and JNK 1/2 either. We found that PRV-induced NF-κB activation is regulated through inhibition of STAT1and STAT3 phosphorylation in response to luteolin. Additionally, luteolin caused the induction of HO-1 via upregulation of Nrf2, both of which are involved in the secretion of proinflammatory mediators. The blockade of HO-1 expression with SnPP, a HO-1 inhibitor, attenuated HO-1 induction by luteolin and thus mitigated its anti-inflammatory effects during PRV-infected RAW264.7 cells. Taken together, our data indicate that luteolin diminishes the proinflammatory mediators NO, inflammatory cytokines and the expression of their regulatory genes, iNOS and COX-2, in PRV-infected RAW264.7 cells by inhibiting STAT1/3 dependent NF-κB activation and inducing Nrf2mediated HO-1 expression. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is an important member of the TNF superfamily with great potential in cancer therapy. Luteolin is a dietary flavonoid commonly found in some medicinal plants. Here we found that pretreatment with a noncytotoxic concentration of luteolin significantly sensitized TRAIL-induced apoptosis in both TRAIL-sensitive (HeLa) and TRAIL-resistant cancer cells (CNE1, HT29, and HepG2). Such sensitization is achieved through enhanced caspase-8 activation and caspase-3 maturation. Further, the protein level of X-linked inhibitor of apoptosis protein (XIAP) was markedly reduced in cells treated with luteolin and TRAIL, and ectopic expression of XIAP protected against cell death induced by luteolin and TRAIL, showing that luteolin sensitizes TRAIL-induced apoptosis through down-regulation of XIAP. In search of the molecular mechanism responsible for XIAP down-regulation, we found that luteolin and TRAIL promoted XIAP ubiquitination and proteasomal degradation. Next, we showed that protein kinase C (PKC) activation prevented cell death induced by luteolin and TRAIL via suppression of XIAP down-regulation. Moreover, luteolin inhibited PKC activity, and bisindolylmaleimide I, a general PKC inhibitor, simulated luteolin in sensitizing TRAIL-induced apoptosis. Taken together, these results present a novel anticancer effect of luteolin and support its potential application in cancer therapy in combination with TRAIL. In addition, our data reveal a new function of PKC in cell death: PKC activation stabilizes XIAP and thus suppresses TRAIL-induced apoptosis. Transthyretin (TTR) is a homotetrameric plasma protein with amyloidogenic properties that has been linked to the development of familial amyloidotic polyneuropathy (FAP), familial amyloidotic cardiomyopathy, and senile systemic amyloidosis. The in vivo role of TTR is associated with transport of thyroxine hormone T4 and retinol-binding protein. Loss of the tetrameric integrity of TTR is a rate-limiting step in the process of TTR amyloid formation, and ligands with the ability to bind within the thyroxin binding site (TBS) can stabilize the tetramer, a feature that is currently used as a therapeutic approach for FAP. Several different flavonoids have recently been identified that impair amyloid formation. The flavonoid luteolin shows therapeutic potential with low incidence of unwanted side effects. In this work, we show that luteolin effectively attenuates the cytotoxic response to TTR in cultured neuronal cells and rescues the phenotype of a Drosophila melanogaster model of FAP. The plant-derived luteolin analogue cynaroside has a glucoside group in position 7 of the flavone A-ring and as opposed to luteolin is unable to stabilize TTR tetramers and thus prevents a cytotoxic effect. We generated high-resolution crystal-structures of both TTR wild type and the amyloidogenic mutant V30M in complex with luteolin. The results show that the A-ring of luteolin, in contrast to what was previously suggested, is buried within the TBS, consequently explaining the lack of activity from cynaroside. The flavonoids represent an interesting group of drug candidates for TTR amyloidosis. The present investigation shows the potential of luteolin as a stabilizer of TTR in vivo. We also show an alternative orientation of luteolin within the TBS which could represent a general mode of binding of flavonoids to TTR and is of importance concerning the future design of tetramer stabilizing drugs. Luteolin is a naturally occurring flavone that reportedly has anti-inflammatory effects. Because most luteolin is conjugated following intestinal absorption, free luteolin is likely present at low levels in the body. Therefore, luteolin metabolites are presumably responsible for luteolin bioactivity. Here we confirmed that luteolin glucuronides, especially luteolin-3'-O-glucuronide, are the major metabolites found in plasma after oral administration of luteolin (aglycone) or luteolin glucoside (luteolin-7-O-glucoside) to rats. Luteolin-4'-O-glucuronide and luteolin-7-O-glucuronide were also detectable together with luteolin-3'-O-glucuronide in the liver, kidney, and small intestine. Next, we prepared these luteolin glucuronides and compared the anti-inflammatory effects of luteolin and luteolin glucuronides on gene expression in lipopolysaccharide-treated RAW264.7 cells. Luteolin glucuronides, especially luteolin-7-O-glucuronide, reduced expression of inflammatory genes in the cells, although their effects were weaker than those of luteolin. These results indicate that the active compound responsible for the anti-inflammatory effect of luteolin in vivo would be luteolin glucuronide and/or residual luteolin. Luteolin is a natural flavonoid with strong anti-oxidative properties that is reported to have an anti-cancer effect in several malignancies other than bladder cancer. In this study, we describe the effect of luteolin on a human bladder cancer cell line, T24, in the context of the regulation of p21, thioredoxin-1 (TRX1) and the mechanistic target of rapamycin (mTOR) pathway. Luteolin inhibited cell survival and induced G2/M cell-cycle arrest, p21 upregulation and downregulation of phospho(p)-S6, which is downstream of mTOR signaling. Luteolin also upregulated TRX1 and reduced intracellular reactive oxygen species production. In a subcutaneous xenograft mouse model using the rat bladder cancer cell line, BC31, tumor volumes were significantly decreased in mice orally administered luteolin compared to control. Immunohistochemical analysis revealed that increased p21 and decreased p-S6 expression were induced in the luteolin treatment group. Moreover, in another in vivo N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced rat bladder cancer model, the oral administration of luteolin led to a trend of decreased bladder tumor dimension and significantly decreased the Ki67-labeling index and p-S6 expression. Furthermore, the major findings on the metabolism of luteolin suggest that both plasma and urine luteolin-3'-O-glucuronide concentrations are strongly associated with the inhibition of cell proliferation and mTOR signaling. Moreover, a significant decrease in the squamous differentiation of bladder cancer is attributed to plasma luteolin-3'-glucuronide concentration. In conclusion, luteolin, and in particular its metabolized product, may represent another natural product-derived therapeutic agent that acts against bladder cancer by upregulating p21 and inhibiting mTOR signaling. Glutamatergic excitotoxicity is crucial in the pathogenesis of numerous brain disorders. Luteolin, a flavonoid compound, inhibits glutamate release, however, its ability to affect glutamate-induced brain injury is unknown. Therefore, this study evaluated the protective effect of luteolin against brain damage induced by kainic acid (KA), a glutamate analog. Rats were treated with luteolin (10 or 50mg/kg, intraperitoneally) 30min before an intraperitoneal injection of KA (15mg/kg). Luteolin treatment reduced the KA-induced seizure score and elevations of glutamate levels in the hippocampus. A histopathological analysis showed that luteolin attenuated KA-induced neuronal death and microglial activation in the hippocampus. An immunoblotting analysis showed that luteolin restored the KA-induced reduction in Akt phosphorylation in the hippocampus. Furthermore, a Morris water maze test revealed that luteolin effectively prevented KA-induced learning and memory impairments. The results suggest that luteolin protected rat brains from KA-induced excitotoxic damage by reducing glutamate levels, mitigating inflammation, and enhancing Akt activation in the hippocampus. Therefore, luteolin may be beneficial for preventing or treating brain disorders associated with excitotoxic neuronal damage. Luteolin is a flavone which occurs in medicinal plants as well as in some vegetables and spices. It is a natural anti-oxidant with less pro-oxidant potential than the flavonol quercetin, the best studied flavonoid, but apparently with a better safety profile. It displays excellent radical scavenging and cytoprotective properties, especially when tested in complex biological systems where it can interact with other anti-oxidants like vitamins. Luteolin displays specific anti-inflammatory effects at micromolar concentrations which are only partly explained by its anti-oxidant capacities. The anti-inflammatory activity includes activation of anti-oxidative enzymes, suppression of the NFkappaB pathway and inhibition of pro-inflammatory substances. In vivo, luteolin reduced increased vascular permeability and was effective in animal models of inflammation after parenteral and oral application. Although luteolin is only a minor component in our nutrition (less than 1 mg/day) epidemiological studies indicate that it has the potential to protect from diseases associated with inflammatory processes such as cardiovascular disease. Luteolin often occurs in the form of glycosides in plants, but these are cleaved and the aglycones are conjugated and metabolized after nutritional uptake which has to be considered when evaluating in vitro studies. Some data for oral and topical bioavailability exist, but more quantitative research in this field is needed to evaluate the physiological and therapeutical potential of luteolin. Metastatic breast cancer is typically an extremely aggressive cancer with poor prognosis. Metastasis requires the orchestration of homeostatic factors and cellular programs, many of which are potential therapeutic targets. Luteolin (2-[3,4-dihydroxyphenyl]-5,7-dihydroxy-4-chromenone), is a naturally occurring flavonoid found in fruits and vegetables that exhibits many anticancer properties. Luteolin obstructs metastasis through both direct and indirect mechanisms. For instance, luteolin may suppress breast cancer invasion by acting as an antiangiogenic therapeutic inhibiting VEGF production and its receptor's activity. Furthermore, luteolin decreases epithelial-mesenchymal transition markers and metastatic proclivity. Luteolin also acts as an antiproliferative by suppressing receptor tyrosine-kinase activity and apoptosis, both of which could prevent incipient colonization of breast cancer. Many of these antimetastatic characteristics accredited to luteolin are likely functionally related. For instance, the PI3K/Akt pathway, which is impeded by luteolin, has several downstream programs involved in increased proliferation, survival, and metastatic potential in breast cancer. In this review, luteolin's ability to ameliorate breast cancer is summarized. The paper also offers insight into the molecular mechanisms by which luteolin may suppress breast cancer metastasis. BACKGROUND: Inflammation of adipocytes has been a therapeutic target for treatment of obesity and metabolic disorders which cause insulin resistance and hence lead to type II diabetes. Luteolin is a bioflavonoid with many beneficial properties such as antioxidant, antiproliferative, and anti-cancer. OBJECTIVES: To elucidate the potential anti-inflammatory response and the underlying mechanism of luteolin in 3T3-L1 adipocytes. MATERIALS AND METHODS: We stimulated 3T3-L1 adipocytes with the mixture of tumor necrosis factor-α, lipopolysaccharide, and interferon-γ (TLI) in the presence or absence of luteolin. We performed Griess' method for nitric oxide (NO) production and measure mRNA and protein expressions by real-time polymerase chain reaction and western blotting, respectively. RESULTS: Luteolin opposed the stimulation of inducible nitric oxide synthase and NO production by simultaneous treatment of adipocytes with TLI. Furthermore, it reduced the pro-inflammatory genes such as cyclooxygenase-2, interleukin-6, resistin, and monocyte chemoattractant protein-1. Furthermore, luteolin improved the insulin sensitivity by enhancing the expression of insulin receptor substrates (IRS1/2) and glucose transporter-4 via phosphatidylinositol-3K signaling pathway. This inhibition was associated with suppression of Iκ-B-α degradation and subsequent inhibition of nuclear factor-κB (NF-κB) p65 translocation to the nucleus. In addition, luteolin blocked the phosphorylation of ERK1/2, c-Jun N-terminal Kinases and also p38 mitogen-activated protein kinases (MAPKs). CONCLUSIONS: These results illustrate that luteolin attenuates inflammatory responses in the adipocytes through suppression of NF-κB and MAPKs activation, and also improves insulin sensitivity in 3T3-L1 cells, suggesting that luteolin may represent a therapeutic agent to prevent obesity-associated inflammation and insulin resistance. BACKGROUND: Luteolin (3',4',5,7-tetrahydroxyflavone) is a flavone with a yellow crystalline appearance present in numerous plants such as broccoli, green chili, and carrot. Luteolin is considered to be an endocrine disruptor with potent estrogen agonist activity and potent progesterone antagonist activity. Luteolin has effects on smooth muscle. Luteolin relaxed guinea pig trachea smooth muscle as it inhibited both phosphodiesterase and reduced intracellular Ca2+. Luteolin also caused vasorelaxation in rat thoracic aorta smooth muscle by inhibiting intracellular Ca2+ release, inhibition of sarcolemmal Ca2+ channels, and activation of K+ channels. Luteolin or its glycosides from artichoke extracts may have an ameliorating effect on irritable bowel syndrome. The purpose of this study was to determine if luteolin had an effect on gallbladder motility. METHODS: An in vitro pharmacologic technique was utilized. Either cholecystokinin octapeptide (CCK) or KCl were used to induce tension in male guinea pig gallbladder strips maintained in Sawyer-Bartlestone chambers. Luteolin relaxed either the CCK- or KCl-induced tension in a concentration dependent manner. Various blockers were added to the chambers to determine which second messenger system(s) mediated the observed relaxation. Paired t-tests were used for statistical analysis. Differences between mean values of P < 0.05 were considered significant. RESULTS: Treatment of the gallbladder strips with luteolin prior to either KCl or CCK significantly (P < 0.001) decreased the amount of either KCl- or cholecystokinin-induced tension. The 2-aminoethoxydiphenylborane was used to ascertain if the release of intracellular Ca2+ mediated the luteolin-induced relaxation. It significantly (P < 0.001) decreased the amount of luteolin-induced relaxation. To ascertain if PKA mediated the luteolin-induced relaxation, PKA inhibitor 14-22 amide myristolated was used. It significantly (P < 0.01) reduced the amount of luteolin-induced relaxation. Neither KT5823, NG-methyl-L-arginine acetate salt, genistein, tetraethylammonium, nor fulvestrant had a significant effect. To ascertain if PKC mediated the luteolin-induced relaxation, the PKC inhibitors bisindolymaleimide IV and chelerythrine Cl- were used together. They had no significant effect. CONCLUSIONS: Luteolin relaxed cholecystokinin- or KCl-induced tension by blocking extracellular Ca2+ entry as well as intracellular Ca2+ release. In addition, the actions of PKA are also involved in mediating the luteolin effect. Acute lung injury (ALI), instilled by lipopolysaccharide (LPS), is a severe illness with excessive mortality and has no specific treatment strategy. Luteolin is an anti-inflammatory flavonoid and widely distributed in the plants. Pretreatment with luteolin inhibited LPS-induced histological changes of ALI and lung tissue edema. In addition, LPS-induced inflammatory responses, including increased vascular permeability, tumor necrosis factor (TNF)-α and interleukin (IL)-6 production, and expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), were also reduced by luteolin in a concentration-dependent manner. Furthermore, luteolin suppressed activation of NFκB and its upstream molecular factor, Akt. These results suggest that the protection mechanism of luteolin is by inhibition of NFκB activation possibly via Akt. BACKGROUND: Luteolin, a plant derived flavonoid, exerts a variety of pharmacological activities and anti-oxidant properties associated with its capacity to scavenge oxygen and nitrogen species. Luteolin also shows potent anti-inflammatory activities by inhibiting nuclear factor kappa B (NFkB) signaling in immune cells. To better understand the immuno-modulatory effects of this important flavonoid, we performed a genome-wide expression analysis in pro-inflammatory challenged microglia treated with luteolin and conducted a phenotypic and functional characterization. METHODS: Resting and LPS-activated BV-2 microglia were treated with luteolin in various concentrations and mRNA levels of pro-inflammatory markers were determined. DNA microarray experiments and bioinformatic data mining were performed to capture global transcriptomic changes following luteolin stimulation of microglia. Extensive qRT-PCR analyses were carried out for an independent confirmation of newly identified luteolin-regulated transcripts. The activation state of luteolin-treated microglia was assessed by morphological characterization. Microglia-mediated neurotoxicity was assessed by quantifying secreted nitric oxide levels and apoptosis of 661W photoreceptors cultured in microglia-conditioned medium. RESULTS: Luteolin dose-dependently suppressed pro-inflammatory marker expression in LPS-activated microglia and triggered global changes in the microglial transcriptome with more than 50 differentially expressed transcripts. Pro-inflammatory and pro-apoptotic gene expression was effectively blocked by luteolin. In contrast, mRNA levels of genes related to anti-oxidant metabolism, phagocytic uptake, ramification, and chemotaxis were significantly induced. Luteolin treatment had a major effect on microglial morphology leading to ramification of formerly amoeboid cells associated with the formation of long filopodia. When co-incubated with luteolin, LPS-activated microglia showed strongly reduced NO secretion and significantly decreased neurotoxicity on 661W photoreceptor cultures. CONCLUSIONS: Our findings confirm the inhibitory effects of luteolin on pro-inflammatory cytokine expression in microglia. Moreover, our transcriptomic data suggest that this flavonoid is a potent modulator of microglial activation and affects several signaling pathways leading to a unique phenotype with anti-inflammatory, anti-oxidative, and neuroprotective characteristics. With the identification of several novel luteolin-regulated genes, our findings provide a molecular basis to understand the versatile effects of luteolin on microglial homeostasis. The data also suggest that luteolin could be a promising candidate to develop immuno-modulatory and neuroprotective therapies for the treatment of neurodegenerative disorders. Endoplasmic reticulum (ER) stress designates a cellular response to the accumulation of misfolded proteins, which is related to disease progression in the liver. Luteolin (3',4',5,7-tetrahydroxyflavone) is a phytochemical found frequently in medicinal herbs. Although luteolin has been reported to possess the therapeutic potential to prevent diverse stage of liver diseases, its role in hepatic ER stress has not been established. Thus, the present study aimed to determine the role of luteolin in tunicamycin (Tm)-induced ER stress, and to identify the relevant mechanisms involved in its hepatoprotective effects. In hepatocyte-derived cells and primary hepatocytes, luteolin significantly decreased Tm- or thapsigargin-mediated C/EBP homologous protein (CHOP) expression. In addition, luteolin reduced the activation of three canonical signaling pathways related to the unfolded protein response, and decreased mRNA levels of glucose-regulated protein 78, ER DNA J domain-containing protein 4, and asparagine synthetase. Luteolin also significantly upregulated sestrin 2 (SESN2), and luteolin-mediated CHOP inhibition was blocked in SESN2 (+/-) cells. Moreover, luteolin resulted in phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2), as well as increased nuclear Nrf2 expression. Deletion of the antioxidant response element in the human SESN2 promoter inhibited increased luciferase activation by luteolin, suggesting that Nrf2 is a critical transcription factor for luteolin-dependent SESN2 expression. In a Tm-mediated liver injury model, luteolin decreased serum alanine aminotransferase and aspartate aminotransferase activities, prevented degenerative changes and apoptosis of hepatocytes, and inhibited CHOP and glucose-regulated protein 78 expression in hepatic tissues. Therefore, luteolin may be an effective phytochemical to manage ER stress-related liver injury. Neonatal sepsis is a life-threatening inflammatory condition. Extracellular cold-inducible RNA-binding protein (CIRP), a proinflammatory mediator, plays a critical role in the pathogenesis of sepsis-induced lung injury in neonates. Luteolin, a polyphenolic flavonoid, has potent anti-inflammatory properties. However, the effects of luteolin on CIRP production and neonatal sepsis-induced lung injury remained unknown. We therefore hypothesize that treatment with luteolin suppresses CIRP production and attenuates lung injury in neonatal sepsis. To study this, sepsis was induced in C57BL/6J mouse pups (5-7 days) by intraperitoneal cecal slurry injection (CSI). One hour after CSI, luteolin (10 mg/kg body weight) or vehicle (normal saline) was administered through intraperitoneal injection. CIRP mRNA and protein were determined and lung injury was assessed at 10 h after CSI. Our results showed that administration of luteolin decreased CIRP mRNA and protein, improved lung architecture, reduced lung edema, and apoptosis after CSI. To examine the direct effect of luteolin on CIRP production, peritoneal macrophages were isolated from neonatal mice and stimulated with 100 ng/mL LPS with or without the presence of luteolin. The result indicates that luteolin directly inhibited LPS-induced CIRP production in neonatal macrophages. In addition, luteolin also downregulated hypoxia-inducible factor-1α (HIF-1α) and NOD-like receptor 3 (NLRP3) expression in septic neonates and in LPS-stimulated neonatal macrophages. In conclusion, administration of luteolin suppresses CIRP production and attenuates lung injury in neonatal sepsis. The beneficial effect of luteolin may be related to downregulation of HIF-1α and NLRP3 expression in neonatal macrophages. Luteolin may be developed as an adjunctive therapy for neonatal sepsis. Luteolin is a flavonoid with antioxidant properties already demonstrated in studies related to inflammation, tumor, and cardiovascular processes; however, there are no available information regarding its antioxidant effects at the venous endothelial site. We investigated the effects of luteolin (10, 20, and 50 μmol/L) in cultures of rat venous endothelial cells. Nitric oxide (NO) and reactive oxygen species (ROS) were analyzed by fluorimetry; 3-nitrotyrosine (3-NT) residues were evaluated by immunofluorescence, and prostacyclin (PGI2) release was investigated by colorimetry. Intracellular NO levels were significantly enhanced after 10 min of luteolin incubation, with a parallel decrease in ROS generation. These results were accompanied by a significant reduction in the expression of 3-NT residues and enhanced PGI2 rates. Therefore, luteolin is effective in reducing ROS thereby improving NO availability in venous endothelial cells. Besides, luteolin-induced decrease in 3-NT residues may correlate with the enhancement in endothelial PGI2 bioavailability. These findings suggest the future application of this flavonoid as a protective agent by improving endothelial function in several circulatory disorders related to venous insufficiency. Luteolin is a flavonoid present in plants in the form of aglycone or glucosides. In this study, luteolin glucosides (i.e., luteolin-7- O-β-d-glucoside, luteolin-7- O-[2-(β-d-apiosyl)-β-d-glucoside], and luteolin-7- O-[2-(β-d-apiosyl)-6-malonyl-β-d-glucoside]) prepared from green pepper leaves as well as luteolin aglycone were orally administered to rats. Regardless of the administered luteolin form, luteolin glucuronides were mainly detected from plasma and organs. Subsequently, luteolin aglycone, the most absorbed form of luteolin in rats, was orally administered to humans. As a result, luteolin-3'- O-sulfate was mainly identified from plasma, suggesting that not only luteolin form but also animal species affect the absorption and metabolism of luteolin. When LPS-treated RAW264.7 cells were treated with luteolin glucuronides and luteolin sulfate (the characteristic metabolites identified from rats and humans, respectively), the different luteolin conjugates were metabolized in different ways, suggesting that such difference in metabolism results in their difference in anti-inflammatory effects.

Does sphingosine-1 phosphoate suppress epiregulin?

Sphingosine-1 phosphate induces epiregulin (EREG) gene expression.

[33189864]

BACKGROUND AND AIMS: Sphingosine-1 phosphate (S1P) is a lysosphingolipid present in the ovarian follicular fluid. The role of the lysosphingolipid in gonads of the female is widely unclear. At nanomolar concentrations, S1P binds and activates five specific G protein-coupled receptors (GPCRs), known as S1P1-5, modulating different signaling pathways. S1P1 and S1P3 are highly expressed in human primary granulosa lutein cells (hGLC), as well as in the immortalized human primary granulosa cell line hGL5. In this study, we evaluated the signaling cascade activated by S1P and its synthetic analogues in hGLC and hGL5 cells, exploring the biological relevance of S1PR-stimulation in this context. METHODS AND RESULTS: hGLC and hGL5 cells were treated with a fixed dose (0.1 μM) of S1P, or by S1P1- and S1P3-specific agonists SEW2871 and CYM5541. In granulosa cells, S1P and, at a lesser extent, SEW2871 and CYM5541, potently induced CREB phosphorylation. No cAMP production was detected and pCREB activation occurred even in the presence of the PKA inhibitor H-89. Moreover, S1P-dependent CREB phosphorylation was dampened by the mitogen-activate protein kinase (MEK) inhibitor U0126 and by the L-type Ca2+ channel blocker verapamil. The complete inhibition of CREB phosphorylation occurred by blocking either S1P2 or S1P3 with the specific receptor antagonists JTE-013 and TY52156, or under PLC/PI3K depletion. S1P-dependent CREB phosphorylation induced FOXO1 and the EGF-like epiregulin-encoding gene (EREG), confirming the exclusive role of gonadotropins and interleukins in this process, but did not affect steroidogenesis. However, S1P or agonists did not modulate granulosa cell viability and proliferation in our conditions. CONCLUSIONS: This study demonstrates for the first time that S1P may induce a cAMP-independent activation of pCREB in granulosa cells, although this is not sufficient to induce intracellular steroidogenic signals and progesterone synthesis. S1P-induced FOXO1 and EREG gene expression suggests that the activation of S1P-S1PR axis may cooperate with gonadotropins in modulating follicle development.

Which is the literature-based database of phenotypes?

PheneBank is a Web-portal for retrieving human phenotype-disease associations that have been text-mined from the whole of Medline. This approach exploits state-of-the-art machine learning for concept identification by utilising an expert annotated rare disease corpus from the PMC Text Mining subset. Evaluation of the system for entities is conducted on a gold-standard corpus of rare disease sentences and for associations against the Monarch initiative data.

[34788791]

MOTIVATION: Significant effort has been spent by curators to create coding systems for phenotypes such as the Human Phenotype Ontology, as well as disease-phenotype annotations. We aim to support the discovery of literature-based phenotypes and integrate them into the knowledge discovery process. RESULTS: PheneBank is a Web-portal for retrieving human phenotype-disease associations that have been text-mined from the whole of Medline. Our approach exploits state-of-the-art machine learning for concept identification by utilizing an expert annotated rare disease corpus from the PMC Text Mining subset. Evaluation of the system for entities is conducted on a gold-standard corpus of rare disease sentences and for associations against the Monarch initiative data. AVAILABILITY AND IMPLEMENTATION: The PheneBank Web-portal freely available at http://www.phenebank.org. Annotated Medline data is available from Zenodo at DOI: 10.5281/zenodo.1408800. Semantic annotation software is freely available for non-commercial use at GitHub: https://github.com/pilehvar/phenebank. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Idecabtagene vicleucel can be used for treatment of which disease?

Idecabtagene vicleucel was shown to be effective for Relapsed and Refractory Multiple Myeloma.

[33598857, 34145225, 33626253, 34625232, 34854741, 34527606, 34461271, 33896344, 34104374, 34256668]

BACKGROUND AND OBJECTIVE: Registrational trials for ciltacabtagene autoleucel [cilta-cel]) and idecabtagene vicleucel [ide-cel] chimeric antigen receptor T-cell (CAR-T) therapies were single-arm studies conducted with relapse refractory multiple myeloma (MM) patients who were triple-class-exposed (TCE) or triple-class-refractory (TCR). It is critical for researchers conducting comparative effectiveness research (CER) to carefully consider the most appropriate data sources and comparable patient populations. The aim of this study was to identify potential data sources and populations for comparing to single-arm CAR-T trials CARTITUDE-1 (cilta-cel) and KarMMa (ide-cel). METHODS: A 2-part global systematic literature search produced a review of (1) clinical trials of National Comprehensive Cancer Network (NCCN) guideline preferred regimens in previously treated MM, and (2) real-world data cohorts of TCE or TCR populations, published between 1/1/2015 and 12/10/2020, with sample sizes of > 50 patients and reporting survival-related outcomes. Implications on CER and accepted best practices are discussed. RESULTS: Nine clinical trials of NCCN preferred regimens were identified along with five real-world data-based publications. No clinical trials evaluated patients with TCE or TCR MM. Among the real-world data-based publications, two evaluated patients exclusively with TCR MM, two analyzed a mixed population of patients with TCE or TCR MM, and one publication assessed patients exclusively with TCE MM. Real-world data treatment patterns were heterogeneous. CONCLUSION: Current NCCN preferred regimens were not specifically studied in TCE or TCR MM patients, although some studies do include a proportion of these types of patients. Therefore, appropriate matching of populations using either real-world data or patient level clinical trial data is critical to putting trials of novel CAR-Ts (i.e., CARTITUDE-1 or KarMMa) into appropriate comparative context. Conflict of interest statement: S.J. served as a consultant for Bristol Myers Squibb (BMS), Janssen, Legend Biotech, Sanofi, and Takeda. Y.L. served as a consultant for Kite/Gilead, Celgene (a BMS Company), Juno Therapeutics (a BMS Company), bluebird bio, Janssen, Legend Biotech, Gamida Cells, and Novartis; received research funding from Kite/Gilead, Celgene (a BMS Company), bluebird bio, Janssen, Merck, and Takeda; is a member of Sorrento Therapeutics Data and Safety Monitoring Board. H.G. received grants and/or provision of investigational medicinal product from Amgen, BMS, Celgene (a BMS Company), Chugai, Dietmar-Hopp-Foundation, Janssen, Johns Hopkins University, and Sanofi; received research funding from Amgen, BMS, Celgene (a BMS Company), Chugai, Janssen, Incyte, Molecular Partners, Merck, Sharp and Dohme, Sanofi, Mundipharma, Takeda, and Novartis; served as a member of advisory board for Adaptive Biotechnologies, Amgen, BMS, Janssen, Sanofi, and Takeda; participated in the speakers’ bureau for Amgen, BMS, Celgene (a BMS Company), Chugai, GlaxoSmithKline (GSK), Janssen, Novartis, and Sanofi. D.R. served as a consultant for Celgene (a BMS Company), Janssen, Takeda, Amgen, and Karyopharm; received honoraria from Celgene (a BMS Company), Janssen, Takeda, and Amgen; received research funding from Celgene (a BMS Company), Janssen, Takeda, Otsuka, Merck, and BMS; provided expert testimony for Celgene (a BMS Company) and Amgen. A.N. served as a consultant for Spectrum Pharmaceuticals, BMS, Adaptive Biotechnologies, Amgen, Celgene (a BMS Company), Takeda, Karyopharm, Oncopeptides, GSK, and Janssen; received research funding from BMS, Amgen, Celgene (a BMS Company), Takeda, Karyopharm, GSK, and Janssen. P.R.O. served as a consultant for Celgene (a BMS Company), Janssen, AbbVie, Kite Pharma, and Sanofi; participated in the speakers’ bureau for Celgene (a BMS Company), Janssen, and Amgen; received travel funding from Celgene (a BMS Company). K.M. received honoraria from Celgene (a BMS Company), Takeda, and Janssen. N.S. served as a consultant for Genentech, Seagen Inc., Oncopeptides, Karyopharm, Surface Oncology, Precision Biosciences, GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi, and BMS; received research funding from Celgene (a BMS Company), Janssen, bluebird bio, Sutro Biopharma, and Teneobio. L.D.A. served as a consultant for Amgen, BMS, GSK, Janssen, and Karyopharm; received research funding and honoraria from GSK, BMS, Janssen, Karyopharm, and Amgen. K.W., H.V.L., A.A. are employees and equity owners with BMS. A.S.S. was an employee of BMS at the time the work was completed. D.S.S. served as a consultant for Amgen, Celgene (a BMS Company), Takeda, Janssen, BMS, Karyopharm, and Merck; participated in the speakers’ bureau for Amgen, Celgene (a BMS Company), Takeda, Janssen, and BMS; received research funding from Celgene (a BMS Company); is an equity owner with Celularity. A.S., R.P., and M.S. declare no conflict of interest. BACKGROUND: Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma. METHODS: In this phase 2 study, we sought to confirm the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma. Patients with disease after at least three previous regimens including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody were enrolled. Patients received ide-cel target doses of 150 × 106 to 450 × 106 CAR-positive (CAR+) T cells. The primary end point was an overall response (partial response or better); a key secondary end point was a complete response or better (comprising complete and stringent complete responses). RESULTS: Of 140 patients enrolled, 128 received ide-cel. At a median follow-up of 13.3 months, 94 of 128 patients (73%) had a response, and 42 of 128 (33%) had a complete response or better. Minimal residual disease (MRD)-negative status (<10-5 nucleated cells) was confirmed in 33 patients, representing 26% of all 128 patients who were treated and 79% of the 42 patients who had a complete response or better. The median progression-free survival was 8.8 months (95% confidence interval, 5.6 to 11.6). Common toxic effects among the 128 treated patients included neutropenia in 117 patients (91%), anemia in 89 (70%), and thrombocytopenia in 81 (63%). Cytokine release syndrome was reported in 107 patients (84%), including 7 (5%) who had events of grade 3 or higher. Neurotoxic effects developed in 23 patients (18%) and were of grade 3 in 4 patients (3%); no neurotoxic effects higher than grade 3 occurred. Cellular kinetic analysis confirmed CAR+ T cells in 29 of 49 patients (59%) at 6 months and 4 of 11 patients (36%) at 12 months after infusion. CONCLUSIONS: Ide-cel induced responses in a majority of heavily pretreated patients with refractory and relapsed myeloma; MRD-negative status was achieved in 26% of treated patients. Almost all patients had grade 3 or 4 toxic effects, most commonly hematologic toxic effects and cytokine release syndrome. (Funded by bluebird bio and Celgene, a Bristol-Myers Squibb company; KarMMa ClinicalTrials.gov number, NCT03361748.). Important advances in the treatment landscape of multiple myeloma (MM) had been seen over the past two decades leading to improved overall survival but despite the progress multiple myeloma is still considered incurable and the prognosis of the pentarefractory patients have been poor. The development of immunotherapy and in particular adoptive cell therapy with chimeric antigen receptor (CAR) T cells have dramatically improved the outcomes of heavily pretreated relapsed/refractory MM patients. The bulk of CAR T-cell constructs currently in clinical development target the B-cell maturation antigen (BCMA) and to date only idecabtagene vicleucel (ide-cel) is approved by the Food and Drug Administration (FDA) for commercial use in adult patients with relapsed or refractory MM based on the promising clinical responses and positive safety record shown in the pivotal KarMMa study. This review focus on the development of CAR T-cell therapy for multiple myeloma as well as a brief review of the mechanisms of resistance, toxicity and new approaches under development. Whereas the treatment of MM was dependent solely on alkylating agents and corticosteroids during the prior three decades, the landscape of therapeutic measures to treat the disease began to expand enormously early in the current century. The introduction of new classes of small-molecule drugs, such as proteasome blockers (bortezomib and carfilzomib), immunomodulators (lenalidomide and pomalidomide), nuclear export inhibitors (selinexor), and histone deacetylase blockers (panobinostat), as well as the application of autologous stem cell transplantation (ASCT), resulted in a seismic shift in how the disease is treated. The picture changed dramatically once again starting with the 2015 FDA approval of two monoclonal antibodies (mAbs) - the anti-CD38 daratumumab and the anti-SLAMF7 elotuzumab. Daratumumab, in particular, has had a great impact on MM therapy and today is often included in various regimens to treat the disease, both in newly diagnosed cases and in the relapse/refractory setting. Recently, other immunotherapies have been added to the arsenal of drugs available to fight this malignancy. These include isatuximab (also anti-CD38) and, in the past year, the antibody-drug conjugate (ADC) belantamab mafodotin and the chimeric antigen receptor (CAR) T-cell product idecabtagene vicleucel (ide-cel). While the accumulated benefits of these newer agents have resulted in a doubling of the disease's five-year survival rate to more than 5 years and improved quality of life, the disease remains incurable. Almost without exception patients experience relapse and/or become refractory to the drugs used, making the search for innovative therapies all the more essential. This review covers the current scope of anti-myeloma immunotherapeutic agents, both those in clinical use and on the horizon, including naked mAbs, ADCs, bi- and multi-targeted mAbs, and CAR T-cells. Emphasis is placed on the benefits of each along with the challenges that need to be overcome if MM is to be considered curable in the future. Idecabtagene vicleucel (ide-cel, bb2121), a chimeric antigen receptor (CAR) T cell therapy, has been investigated in patients with relapsed and refractory multiple myeloma (RRMM) who have received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody in the single-arm phase 2 KarMMa clinical trial. Two therapies with distinct mechanisms of action - selinexor plus dexamethasone (Sd) and belantamab mafodotin (BM) - are currently approved in the United States for heavily pretreated patients, including those who are triple-class refractory. To compare ide-cel versus Sd and ide-cel versus BM, matching-adjusted indirect comparisons were performed. Ide-cel extended progression-free survival (PFS) and overall survival (OS) versus both Sd and BM (hazard ratio (HR); 95% confidence interval (CI)). PFS: ide-cel versus Sd, 0.46; 0.28-0.75; ide-cel versus BM, 0.45; 0.27-0.77. OS: ide-cel versus Sd, 0.23; 0.13-0.42; ide-cel versus BM, 0.35; 0.14-0.87. These results suggest ide-cel offers clinically meaningful improvements over currently approved regimens for patients with heavily pretreated RRMM. The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody-drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma. OBJECTIVE: This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus the approved idecabtagene vicleucel (ide-cel) dose range of 300-460 × 106 CAR-positive T-cells for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody (i.e. triple-class exposed) using matching-adjusted indirect treatment comparisons (MAICs). METHODS: MAICs were performed with individual patient data for cilta-cel (CARTITUDE-1; NCT03548207) and published summary-level data for ide-cel (KarMMa; NCT03361748). Treated patients from CARTITUDE-1 who satisfied the eligibility criteria for KarMMa were included in the analyses. The MAIC adjusted for unbalanced baseline covariates of prognostic significance identified in the literature and by clinical expertise. Comparative efficacy was estimated for overall response rate (ORR), complete response or better (≥CR) rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). RESULTS: Cilta-cel was associated with statistically significantly improved ORR (odds ratio [OR]: 94.93 [95% confidence interval [CI]: 21.86, 412.25; p < .0001]; relative risk [RR]: 1.34), ≥CR rate (OR: 5.49 [95% CI: 2.47, 12.21; p < .0001]; RR: 2.21), DoR (hazard ratio [HR]: 0.50 [95% CI: 0.29, 0.87; p = .0137]), and PFS (HR: 0.37 [95% CI: 0.22, 0.62; p = .0002]) when compared with ide-cel. For OS, the results were in favor of cilta-cel and clinically meaningful but with a CI overlapping one (HR: 0.55 [95% CI: 0.29, 1.05; p = .0702]). CONCLUSIONS: These analyses demonstrate improved efficacy with cilta-cel versus ide-cel for all outcomes, highlighting its therapeutic potential in patients with triple-class exposed RRMM.

LINC00339 is a diagnostic, prognostic and treatment efficacy biomarker for what disease?

LINC00339 as a cancer diagnostic, prognostic and treatment efficacy biomarker.

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BACKGROUND: Liver hepatocellular carcinoma (LIHC) is a lethal cancer. This study aimed to identify the N6 -methyladenosine (m6 A)-targeted long non-coding RNA (lncRNA) related to LIHC prognosis and to develop an m6 A-targeted lncRNA model for prognosis prediction in LIHC. METHODS: The expression matrix of mRNA and lncRNA was obtained, and differentially expressed (DE) mRNAs and lncRNAs between tumor and normal samples were identified. Univariate Cox and pathway enrichment analyses were performed on the m6 A-targeted lncRNAs and the LIHC prognosis-related m6 A-targeted lncRNAs. Prognostic analysis, immune infiltration, and gene DE analyses were performed on LIHC subgroups, which were obtained from unsupervised clustering analysis. Additionally, a multi-factor Cox analysis was used to construct a prognostic risk model based on the lncRNAs from the LASSO Cox model. Univariate and multivariate Cox analyses were used to assess prognostic independence. RESULTS: A total of 5031 significant DEmRNAs and 292 significant DElncRNAs were screened, and 72 LIHC-specific m6 A-targeted binding lncRNAs were screened. Moreover, a total of 29 LIHC prognosis-related m6 A-targeted lncRNAs were obtained and enriched in cytoskeletal, spliceosome, and cell cycle pathways. An 11-m6 A-lncRNA prognostic model was constructed and verified; the top 10 lncRNAs included LINC00152, RP6-65G23.3, RP11-620J15.3, RP11-290F5.1, RP11-147L13.13, RP11-923I11.6, AC092171.4, KB-1460A1.5, LINC00339, and RP11-119D9.1. Additionally, the two LIHC subgroups, Cluster 1 and Cluster 2, showed significant differences in the immune microenvironment, m6 A enzyme genes, and prognosis of LIHC. CONCLUSION: The m6 A-lncRNA prognostic model accurately and effectively predicted the prognostic survival of LIHC. Immune cells, immune checkpoints (ICs), and m6 A enzyme genes could act as novel therapeutic targets for LIHC. Background: Extensive research has shown that long noncoding RNA (lncRNA) is involved in tumorigenesis, including hepatocellular carcinoma (HCC). The lncRNA LINC00339 was reported to regulate the development of lung cancer or breast cancer. However, whether LINC00339 participates in HCC progression remains unclear. Here, our results showed that LINC00339 was upregulated in HCC. Methods: qRT-PCR and in situ hybridization (ISH) was used to analyze LINC00339 expression in tumor tissues and cell lines. CCK8 and colony formation assays were used to analyze cell proliferation. Transwell assay was used to analyze cell migration and invasion. Xenograft experiment was used to test tumor growth in vivo. Results: LINC00339 overexpression was correlated with an advanced stage, metastasis, and bad prognosis in HCC patients. Functional investigation showed that LINC00339 knockdown significantly suppressed HCC cell proliferation, migration, and invasion. Moreover, decreased LINC00339 expression inhibited HCC growth in vivo. Mechanistically, LINC00339 could interact with miR-1182 to promote SKA1 expression. We also demonstrated that SKA1 acted as an oncogene and SKA1 upregulation reversed the effect of LINC00339 silencing. Conclusion: Our results illustrated that the LINC00339/miR-1182/SKA1 axis plays an essential role in HCC progression. Recently, long noncoding RNAs (lncRNAs) have become the key gene regulators and prognostic biomarkers in various cancers. Through microarray data, Linc00339 was identified as a candidate oncogenic lncRNA. We compared the expression levels of Linc00339 in several breast cancer cell lines and normal mammary gland epithelial cell line. The effects of Linc00339 on tumor progression were examined both in vitro and in vivo. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays were applied to evaluate the functions of Linc00339, miR-377-3p, and HOXC6 on cell proliferation. Flow cytometry analysis was used to detect apoptosis and cell cycle distribution. Overall survival (OS) was analyzed using data from The Cancer Genome Atlas and molecular taxonomy of breast cancer international consortium (METABRIC). Dual luciferase assay and RNA immunoprecipitation were performed to confirm the interaction between Linc003339 and miR-377-3p. Linc00339 was increased in breast cancer cell lines compared with the normal epithelial cell. Through in vitro and in vivo experiments, Linc00339 overexpression promoted triple-negative breast cancer (TNBC) proliferation, inhibited cell cycle arrest, and suppressed apoptosis. Silencing of Linc00339 obtained the opposite effects. Mechanistic investigations demonstrated that Linc00339 could sponge miR-377-3p and regulate its expression. Higher expression of miR-377-3p indicated longer OS in breast cancer patients, especially in TNBC patients. Overexpression of miR-377-3p retarded TNBC cell growth through regulating cell cycle distribution and apoptosis. And miR-377-3p was involved in Linc00339-mediated TNBC proliferation through regulating HOXC6 expression. Knockdown of HOXC6 inhibited TNBC progression. In conclusion, our results illuminated that the novel Linc00339/miR-377-3p/HOXC6 axis played a critical role in TNBC progression and might be a promising therapeutic target for TNBC treatment. INTRODUCTION: Accumulating evidence has indicated that long noncoding RNAs (lncRNAs) are pivotal regulators involved in the pathogenesis of cancer; however, the molecular mechanism of LINC00339 in colorectal cancer (CRC) remains unclear. METHODS: The quantitative real-time polymerase chain reaction for the expression of LINC00339 and miR-378a-3p and Western blots for MED19 were performed. A dual-luciferase assay was used to investigate the interaction between LIN00339 and miR-378a-3p, as well as between miR-378a-3p and MED19. Cell proliferation was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and 5-ethynyl-2'-deoxyuridine (EdU) assay. The cell cycle was analyzed by propidium iodide staining followed by flow cytometry analysis. The wound-healing and transwell invasion assays were used to evaluate cell migration and invasion. RESULTS: The expression of LINC00339 was significantly upregulated in CRC cells and tissues, and high LINC00339 expression indicated an advanced tumor stage. Further experiments demonstrated that SP1 activated LINC00339 expression by binding to its promoter region. Luciferase activity and RNA pull-down assays demonstrated a direct interaction between LINC00339 and miR-378a-3p. miR-378a-3p expression was decreased in CRC samples and negatively correlated with LINC00339 expression in tumors. Gain- and loss-of-function assays indicated that LINC00339 contributed to cell proliferation, cell cycle progression, migration, and invasion, while miR-378a-3p reversed these effects. Furthermore, cotransfection of wild-type MED19 3'-UTR reporters and miR-378a-3p significantly reduced luciferase activity. MED19 mRNA and protein expression was inhibited and enhanced by miR-378a-3p and LINC00339, respectively. MED19 overexpression reversed the effect of miR-378a-3p on cellular processes. Moreover, LINC00339 promoted tumor growth in vivo and induced epithelial-mesenchymal transition (EMT) and activated the Wnt/β-catenin signaling pathway in cells. CONCLUSION: Our findings demonstrate the regulatory role of the SP1/LINC00339/miR-378a-3p/MED19 axis in CRC tumorigenesis and provide novel insight into the molecular mechanism underlying CRC. Laryngeal squamous cell carcinoma (LSCC) is a very common neoplasm of the head and neck in the world. Long noncoding RNAs play key roles in cell infiltration, fate, apoptosis, and invasion. However, the functional role and expression of LINC00339 remains unclear in LSCC. In this study, we showed that the expression level of LINC00339 was upregulated in LSCC tissues and cell lines. LINC00339 silencing suppressed the proliferation, invasion, and epithelial-mesenchymal transition (EMT) progression of LSCC cells. In addition, we showed that LINC00339 acted as a sponge of miR-145, and LINC00339 silencing promoted the expression of miR-145 in Hep2 cell. Furthermore, the expression of miR-145 was lower in LSCC tissues than in their paired normal samples and the miR-145 expression level was negatively correlated with LINC00339 expression in LSCC tissues. The knockdown of miR-145 promoted the proliferation, invasion, and EMT progression of LSCC cells. Finally, we indicated that LINC00339 silencing inhibited the proliferation, invasion, and EMT progression of LSCC cells by suppressing the miR-145 expression. These data suggested that LINC00339 acted as an oncogene in the development of LSCC, partly by regulating the miR-145 expression. Differential expression of LINC00339 is involved in the malignancy of multiple human cancer types. Nonetheless, the expression profile, functions, and potential mechanisms of action of LINC00339 in gastric cancer are yet to be fully elucidated. This study aimed at measuring LINC00339 expression in gastric cancer and examining the prognostic significance of LINC00339 in patients with gastric cancer. The detailed functions of LINC00339 with regard to the aggressive characteristics of gastric cancer cells and the underlying molecular mechanisms were investigated. Here, we found that LINC00339 expression was aberrantly high in gastric cancer and significantly associated with lymph node metastasis, invasive depth, and TNM stage. Patients with gastric cancer in a LINC00339 high-expression group showed shorter overall survival than patients in a LINC00339 low-expression group. A knockdown of LINC00339 suppressed gastric cancer cell proliferation, migration, and invasion and induced apoptosis in vitro and slowed tumor growth in vivo. In terms of the mechanism, LINC00339 was found to act as a molecular sponge on microRNA-539 (miR-539). SRY-box 9 (SOX9) was confirmed as a direct target gene of miR-539 in gastric cancer cells. An miR-539 knockdown attenuated the effects of the LINC00339 knockdown on the malignant characteristics of gastric cancer cells. Overall, LINC00339 plays a critical role in the malignancy of gastric cancer by regulating SOX9 via sponging of miR‑539. Our findings highlight the importance of the LINC00339-miR-539-SOX9 pathway in gastric cancer pathogenesis and may point to novel targets for the diagnosis, prognosis, and/or treatment of gastric cancer. Objective: To investigate the expression of long non-coding RNA LINC00339 in colorectal cancer patients and its effect and mechanism on proliferation and apoptosis of colorectal cancer cells. Methods: A retrospective analysis of 158 pathology-confirmed colorectal cancer patients, who were enrolled from August 2015 to January 2017, was performed. LINC00339 expression in colorectal cancer tissues and adjacent colorectal sampleswas detected by Real-time PCR. The correlation between LINC00339 expression and clinicopathological features as well as the relationship between LINC00339 and microRNA (miR)-218 expression was assayed. The interaction between LINC00339 and miR-218 was further confirmed by dual luciferase report system. Downregulation of LINC00339 was performed by siRNA interference technology in LoVo and HCT116 cells. Real-time PCR was used to detect miR-218 expression. 3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) analysis was carried out to examine cell viability. Flow cytometry was used to determine cell apoptosis. Additionally, LINC00339 siRNA and miR-218 antagomirs (anti-miR-218) were co-transfected into LoVo and HCT116 cells, and then cell viability and apoptosis were detected. Results: LINC00339 expression was significantly increased in colorectal cancer tissues compared with adjacent colorectal tissues (4.69±1.52 vs 1.02±0.38, P<0.05). LINC00339 expression was not related to the age and gender of patients (P>0.05), but was associated with TNM stage, lymphatic metastasis, tumor maximum diameters, and differentiation degree (all P<0.05). LINC00339 expression was negatively correlated with miR-218 expression in colorectal cancer tissues (P<0.05). miR-218 mimics remarkably suppressed the fluorescence intensity of wild-type LINC00339 plasmid (P=0.001), but did not affect the fluorescence intensity of the mutant ones(P=0.88). Knockdown of LINC00339 remarkably inhibited proliferation, but promoted apoptosis of LoVo and HCT116 cells (all P<0.05). Compared with cells transfected with LINC00339 siRNA only, downregulation of miR-218 elevated proliferation and decreased apoptosis of LoVoand HCT116 cells. Conclusions: LINC00339 expression is upregulated in colorectal cancer tissues and correlated with patients' clinicopathological features. LINC00339 promotes proliferation, and suppresses apoptosis of colorectal cancer cells via downregulating miR-218. BACKGROUND/AIMS: Emerging evidence have demonstrated that long noncoding RNAs are involved in the development and metastasis of various cancers including hepatocellular carcinoma (HCC). However, the role of LINC00339 in HCC progression is still unknown. METHODS: The LINC00339 expression in HCC cancer cells (HUH7, HepG2, HUH-6, and SK-Hep-1) and tissues was assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Functional experiments including cell counting Kit-8 wound-healing assay and transwell assay were used to explore the cell proliferation, migration, and invasion, respectively. The related molecular mechanisms were determined by Western blot. The RNA pull-down assay, luciferase reporters assay, qRT-PCR, and Western blot were performed to explore and confirm the interaction between LINC00339 and miR-152, between miR-152 and ROCK1. The role of LINC00339 in tumor formation and metastasis were explored through in vivo experiments. RESULTS: LINC00339 was highly expressed in HCC tissues and cell lines. LINC00339 promoted the cell proliferation, migration, and invasion of HCC cells, while knockout of LINC00339 showed the opposite trends. The proliferation and migration of HCC cells induced by LINC00339 overexpression were mostly reversed after transfected with miR-152 mimics. LINC00339 exerted oncogenesis effect on HCC progression by targeting miR-152/ROCK1, and the expression of LINC00339 was negatively correlated with miR-152 expression and positively correlated with ROCK1 expression in clinical HCC samples. Moreover, we also proved that LINC00339 overexpression exacerbated the tumor formation and metastases in nude mice and LINC00339 silence showed the opposite results. CONCLUSION: LINC00339 might act as a potential therapeutic target for HCC. Huaier, as known as Trametes robiniophila Murr, is a traditional Chinese medicine. Various studies have demonstrated that Huaier could inhibit cancer progression and improve the prognosis of patients. In the present study, we comprehensively screened the expression profiles of lncRNAs, miRNAs, and mRNAs in Huaier-treated breast cancer cells. Using bioinformatic analysis, hub genes were identified and functionally annotated. Weighted gene coexpression network analysis was applied to construct the molecular network influenced by Huaier. Linc00339 was then found to play a critical role in Huaier-mediated cancer suppression. To validate the effects of linc00339 and identify the downstream targets, we performed in vitro and in vivo experiments. Finally, we identified that Huaier could inhibit the proliferation of breast cancer cells through modulating linc00339/miR-4656/CSNK2B signaling pathway. Glioma is recognized as a highly angiogenic malignant brain tumor. Vasculogenic mimicry (VM) greatly restricts the therapeutic effect of anti-angiogenic tumor therapy for glioma patients. However, the molecular mechanisms of VM formation in glioma remain unclear. Here, we demonstrated that LINC00339 was upregulated in glioma tissue as well as in glioma cell lines. The expression of LINC00339 in glioma tissues was positively correlated with glioma VM formation. Knockdown of LINC00339 inhibited glioma cell proliferation, migration, invasion, and tube formation, meanwhile downregulating the expression of VM-related molecular MMP-2 and MMP-14. Furthermore, knockdown of LINC00339 significantly increased the expression of miR-539-5p. Both bioinformatics and luciferase reporter assay revealed that LINC00339 regulated the above effects via binding to miR-539-5p. Besides, overexpression of miR-539-5p resulted in decreased expression of TWIST1, a transcription factor known to play an oncogenic role in glioma and identified as a direct target of miR-539-5p. TWIST1 upregulated the promoter activities of MMP-2 and MMP-14. The in vivo study showed that nude mice carrying tumors with knockdown of LINC00339 and overexpression of miR-539-5p exhibited the smallest tumor volume through inhibiting VM formation. In conclusion, LINC00339 may be used as a novel therapeutic target for VM formation in glioma. Non-small cell lung cancer (NSCLC) is one of leading causes of cancer-related death worldwide. Long noncoding RNAs (lncRNAs) has been identified to modulate the tumorigenesis of NSCLC. However, the precise molecular mechanism of lncRNAs in the course is still unclear. Results showed that LINC00339 was significantly up-regulated in NSCLC tissue and cells, which indicated the poor prognosis of NSCLC patients. Loss-of-function experiments showed that LINC00339 silencing inhibited the proliferation and invasion, accelerated the apoptosis, and suppressed the tumor growth of NSCLC cells in vitro and in vivo. Luciferase reporter assay and RNA immunoprecipitation (RIP) revealed that LINC00339 promoted the NSCLC progression via FOXM1 via targeting miR-145. In conclusion, our results identify the important role of the LINC00339/miR-145/FOXM1 axis in the NSCLC tumorigenesis, providing neoteric mechanism for the NSCLC tumorigenesis. PURPOSE: To investigate the role and mechanism of long non-coding (lnc) RNA LINC00339 in pancreatic cancer (PANC), and provided a potential target for its biological diagnosis and treatment. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of LINC00339 in PANC tissue specimens and cell lines. The experimental cell lines differentially expressing LINC00339 were constructed by using small interfering RNA and lentivirus transfection. Cell proliferation was examined by cell counting kit-8 (CCK-8) and colony formation experiments and transwell experiments were used to assess cell invasion and migration abilities. The luciferase assay and RNA immunoprecipitation (RIP) were employed to study the target gene for LINC00339, and western blot analysis was utilized to measure protein expression of the downstream gene. RESULTS: The level of LINC00339 expression in PANC tissues or cells was significantly higher than that in their respective control groups. Interfering expression of LINC00339 could notably inhibit the proliferation, invasion and migration of SW1990 cells, while the over-expressing expression of LINC00339 obviously increased the growth and metastasis abilities of PANC-1 cells. LINC00339 could act as a miR-497-5p sponge, adsorbing miR-497-5p, thereby inhibiting its action by increasing the expression of its target gene IGF1R. The expression of miR-497-5p and its target gene IGF1R could be significantly altered by altering the expression of LINC00339. CONCLUSIONS: LINC00339 was markedly over-expressed in PANC tissues and cells and promoted cell proliferation, invasion, and migration via sponging miR-497-5p, thereby increasing IGF1R expression. Our study could provide a novel target for PANC diagnosis and biotherapy. In recent years, triple-negative breast cancer (TNBC) has emerged as the most aggressive subtype of breast cancer and is usually associated with increased mortality worldwide. The severity of TNBC is primarily observed in younger women, with cases ranging from approximately 12%-24% of all breast cancer cases. The existing hormonal therapies offer limited clinical solutions in completely circumventing the TNBC, with chemoresistance and tumor recurrences being the common hurdles in the path of TNBC treatment. Accumulating evidence has correlated the dysregulation of long noncoding RNAs (lncRNAs) with increased cell proliferation, invasion, migration, tumor growth, chemoresistance, and decreased apoptosis in TNBC. Various clinical studies have revealed that aberrant expression of lncRNAs in TNBC tissues is associated with poor prognosis, lower overall survival, and disease-free survival. Due to these specific characteristics, lncRNAs have emerged as novel diagnostic and prognostic biomarkers for TNBC treatment. However, the underlying mechanism through which lncRNAs perform their actions remains unclear, and extensive research is being carried out to reveal it. Therefore, understanding of mechanisms regulating the modulation of lncRNAs will be a substantial breakthrough in effective treatment therapies for TNBC. This review highlights the association of several lncRNAs in TNBC progression and treatment, along with their possible functions and mechanisms.

What is the role of PCAT6 in human cancers?

PCAT6, is a carcinogenic lncRNA. It is abnormally elevated in various human malignant tumors. PCAT6 has been found to sponge various miRNAs to activate the signaling pathways, which further affects tumor cell proliferation, migration, invasion, cycle, apoptosis, radioresistance, and chemoresistance. It is believed to have diagnostic and prognostic value and clinical applications in various human malignancies.

[34885209, 31676070]

LncRNAs are involved in the occurrence and progressions of multiple cancers. Emerging evidence has shown that PCAT6, a newly discovered carcinogenic lncRNA, is abnormally elevated in various human malignant tumors. Until now, PCAT6 has been found to sponge various miRNAs to activate the signaling pathways, which further affects tumor cell proliferation, migration, invasion, cycle, apoptosis, radioresistance, and chemoresistance. Moreover, PCAT6 has been shown to exert biological functions beyond ceRNAs. In this review, we summarize the biological characteristics of PCAT6 in a variety of human malignancies and describe the biological mechanisms by which PCAT6 can facilitate tumor progression. Finally, we discuss its diagnostic and prognostic values and clinical applications in various human malignancies. Long noncoding RNAs (lncRNAs) play crucial roles in tumor development of osteosarcoma (OS). LncRNA PCAT6 was involved in the progression of multiple human cancers. However, the biological function of PCAT6 in OS remains largely unknown. We found that PCAT6 was elevated in OS tissues relative to that in their adjacent normal tissues. The upregulation of PCAT6 was positively associated with metastasis status and advanced stages and predicted poor overall and progression-free survivals in patients with OS. Functionally, silencing PCAT6 inhibited the proliferation, migration and invasion abilities of OS cells. Mechanistically, PCAT6, acting as a competitive endogenous RNA, upregulated expression of TGFBR1 and TGFBR2 to activate TGF-β pathway via sponging miR-185-5p. This study uncovers a novel underlying molecular mechanism of PCAT6-miR-185-5p-TGFBR1/2-TGF-β signaling axis in promoting tumor progression in OS, which indicates that PCAT6 may serve as a promising prognostic factor and therapeutic target again OS.

What are the targets of avapritinib?

Avapritinib is a novel inhibitor of KIT/PDGFRA. It is approved in the U.S. for the treatment of adults with PDGFRA exon 18-mutant unresectable or metastatic gastrointestinal stromal tumors.

[33307872, 29233825, 33453089, 32972961, 32615108, 33465704, 30274985, 34552008, 33301227, 31117741, 32821296, 34580817, 33876372, 34023541, 34343033, 32100250, 33025950]

INTRODUCTION: 90% of gastrointestinal stromal tumors (GISTs) harbor an activating mutation in the KIT or PDGFRα oncogene, and these are known to confer imatinib sensitivity. AREAS COVERED: The author reviews the data regarding the current management of GIST, mechanisms of resistance to imatinib, and new drugs currently in clinical development and provides his unique perspectives on the subject matter. EXPERT OPINION: Several studies have shown that the response to imatinib in GIST patients mainly depends on the mutational status of KIT or PDGFRα. Moreover, most, if not all, patients treated with imatinib for advanced GIST will develop a secondary progressive disease under the treatment. In most cases, such progressions are the result of acquired resistance due to the occurrence of secondary c-KIT mutations, especially in GISTs with primary exon 11 mutations. Sunitinib and regorafenib are inhibitors of multiple tyrosine kinases, including KIT, PDGFRα, PDGFRβ, and VEGFRs, and are approved for the management of imatinib- and imatinib/sunitinib-refractory GIST patients, respectively. Clearly, better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors such as avapritinib and ripretinib will provide new individualized therapeutic strategies for GIST patients. In a phase I trial of avapritinib (formerly BLU-285), which targets D816V mutant KIT, for the treatment of advanced systemic mastocytosis, patients experienced rapid and durable disease control. The overall response rate was 72%, and 56% of patients experienced a complete or partial response. No patients discontinued treatment due to adverse events, most of which were mild to moderate in nature. BACKGROUND: Most gastrointestinal stromal tumors (GIST) driven by KIT or platelet-derived growth factor receptor A (PDGFRA) mutations develop resistance to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a two-part, single-arm, dose escalation and expansion study designed to evaluate safety and antineoplastic activity of avapritinib, a selective, potent inhibitor of KIT and PDGFRA, in patients with unresectable or metastatic GIST. MATERIALS AND METHODS: Eligible patients were 18 years or older with histologically or cytologically confirmed unresectable GIST and Eastern Cooperative Oncology Group performance status ≤2 and initiated avapritinib at 300 mg or 400 mg once daily. Primary endpoints were safety in patients who initiated avapritinib at 300 mg or 400 mg once daily and overall response rate (ORR) in patients in the safety population with three or more previous lines of TKI therapy. RESULTS: As of November 16, 2018, in the safety population (n = 204), the most common adverse events (AEs) were nausea (131 [64%]), fatigue (113 [55%]), anemia (102 [50%]), cognitive effects (84 [41%]), and periorbital edema (83 [41%]); 17 (8%) patients discontinued due to treatment-related AEs, most frequently confusion, encephalopathy, and fatigue. ORR in response-evaluable patients with GIST harboring KIT or non-D842V PDGFRA mutations and with at least three prior therapies (n = 103) was 17% (95% confidence interval [CI], 10-25). Median duration of response was 10.2 months (95% CI, 7.2-10.2), and median progression-free survival was 3.7 months (95% CI, 2.8-4.6). CONCLUSION: Avapritinib has manageable toxicity with meaningful clinical activity as fourth-line or later treatment in some patients with GIST with KIT or PDGFRA mutations. IMPLICATIONS FOR PRACTICE: In the NAVIGATOR trial, avapritinib, an inhibitor of KIT and platelet-derived growth factor receptor A tyrosine kinases, provided durable responses in a proportion of patients with advanced gastrointestinal stromal tumors (GIST) who had received three or more prior therapies. Avapritinib had a tolerable safety profile, with cognitive adverse events manageable with dose interruptions and modification in most cases. These findings indicate that avapritinib can elicit durable treatment responses in some patients with heavily pretreated GIST, for whom limited treatment options exist. Author information: (1)Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany. (2)DKTK partner site Essen, German Cancer Consortium (DKTK), Heidelberg, Germany. (3)Portland VA Health Care System, Portland, Oregon; Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon; and Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon. (4)Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany. (5)Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), Dortmund, Germany. (6)Gerhard-Domagk-Institute of Pathology, University of Münster Medical Center, Münster, Germany. (7)Institute of Pathology, University Medical Center Essen, Essen, Germany. (8)Department of Visceral Surgery, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany. (9)Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. (10)Blueprint Medicines, Cambridge, Massachusetts. (11)Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany. sebastian.bauer@uk-essen.de. (#)Contributed equally Conflict of interest statement: Conflict of interest statement Dr Jones reported receiving grants from MSD; and personal fees from Adaptimmune, Athenex, Blueprint Medicines Corporation, Clinigen, Eisai, Eli Lilly, Epizyme, Daichii Sankyo, Deciphera Pharmaceuticals, Helsinn, Immunedesign, Merck, PharmaMar, Tracon and UptoDate outside the submitted work. Dr Serrano reported receiving other support from Bayer, Blueprint Medicines Corporation, Deciphera Pharmaceuticals, Eli Lilly, Novartis, Pfizer and PharmaMar; and grants from Bayer, Deciphera Pharmaceuticals and Pfizer outside the submitted work. Dr von Mehren reported receiving other support from Blueprint Medicines Corporation during the conduct of the study; and other support from Arog Pharmaceuticals, Deciphera Pharmaceuticals, Exelixis and Novartis outside the submitted work. Dr George reported receiving research support to her institution from Ariad, Bayer, Blueprint Medicines Corporation, Daiichi Sankyo, Deciphera Pharmaceuticals, Novartis and Pfizer; and advisory board/consulting fees from AstraZeneca, Blueprint Medicines Corporation, Daiichi Sankyo, Deciphera Pharmaceuticals and Eli Lilly. Dr Heinrich reported receiving grants and personal fees from Blueprint Medicines Corporation; and personal fees and other support from Molecular MD during the conduct of the study; personal fees and other from Novartis; and grants and personal fees from Deciphera Pharmaceuticals outside the submitted work. Dr Heinrich also has a patent “Treatment of Gastrointestinal Stromal Tumors” licenced to Novartis, and a patent “Activating Mutations of PDGFRA” issued. Dr Kang reported receiving personal fees from ALX Oncology, Amgen, Bristol Myers Squibb, Daehwa Pharmaceutical, MacroGenics, Novartis, Surface Oncology and Zymeworks outside the submitted work. Dr Schöffski reported receiving personal fees from Deciphera Pharmaceuticals; other support from Adaptimmune, Blueprint Medicines Corporation, Deciphera Pharmaceuticals, Exelixis, Eisai, Eli Lilly, Ellipses Pharma, Genmab, Intellisphere, Loxo Oncology, Merck, Plexxikon, Servier and Transgene; and grants from Ipsen and MSD outside the submitted work. Dr Cassier reported receiving personal fees from Blueprint Medicines Corporation during the conduct of the study; other support from AbbVie, Bayer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck Serono, MSD, Novartis and Roche/Genentech; personal fees from Amgen, Bristol Myers Squibb, MSD, Novartis and Roche/Genentech; non-financial support from MSD and Novartis; and grants from Novartis outside the submitted work. Dr Mir reported receiving consulting fees from Eli Lilly, Janssen, Lundbeck, Pfizer, Roche, Servier and Vifor Pharma; and owns stock options from Amplitude Surgical, Transgene and Ipsen. Dr Chawla reported receiving funding from ADI, Amgen, GlaxoSmithKline, Ignyta, Immix Bopharma, Inhibrx, Janssen, Karyopharm Therapeutics, Roche, SARC and Tracon outside the submitted work. Dr Eskens has nothing to disclose. Dr Rutkowski reported receiving personal fees from Blueprint Medicines Corporation, Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Pfizer, Roche and Sanofi outside the submitted work. Dr Tap reported receiving other support from Blueprint Medicines Corporation during the conduct of the study; receiving personal fees from Agios Pharmaceuticals, Blueprint Medicines Corporation, Daiichi Sankyo, Deciphera Pharmaceuticals, Eli Lilly, EMD Serono, Eisai, GlaxoSmithKline, Janssen, Immune Design, Loxo Oncology and NanoCarrier outside the submitted work; having a patent Companion Diagnostic for CDK4 inhibitors – 14/854,329 pending to MSKCC/SKI; attending scientific advisory boards for Atropos Therapeutics and Certis Oncology Solutions; being a consultant for Daiichi Sankyo; having stock ownership in Atropos Therapeutics and Daiichi Sankyo; and having involvement in an FDA ODAC meeting for pexidartinib. Dr Zhou is a former employee of Blueprint Medicines Corporation. Dr Roche reported receiving other support from Epizyme outside the submitted work; and being a current employee and shareholder of Blueprint Medicines Corporation. Dr Bauer reported receiving grants from Blueprint Medicines Corporation, Incyte and Novartis; personal fees from Bayer, Blueprint Medicines Corporation, Deciphera Pharmaceuticals, Exelixis and Novartis during the conduct of the study; and personal fees from ADC Therapeutics, Daiichi Sankyo, Eli Lilly, Exelixis, Janssen-Cilag, Nanobiotix, PharmaMar and Plexxikon outside the submitted work. Author information: (1)Medical Oncology Department, University Hospital Fundación Jimenez Diaz, Madrid, Spain. jmartin@mustbesevilla.org. (2)University Hospital General de Villalba, Madrid, Spain. (3)Instituto de Investigacion Sanitaria Fundacion Jimenez Diaz (IIS/FJD), Madrid, Spain. (4)Institute of Biomedicine of Sevilla (IBIS, HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain. (5)Pathology Department, University Hospital Son Espases, Mallorca, Spain. (6)Soft Tissue and Bone Pathology, Histopathology and Pediatric Pathology Unit, Diagnostic Pathology and Laboratory Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Nazionale Tumori, Milan, Italy. (7)Pathology Department, University Hospital Vall D'Hebron, Barcelona, Spain. (8)Centro de Investigación Biomédica en RED (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain. (9)Pathology Department, Santa Creu I Sant Pau Hospital, Barcelona, Spain. (10)Anatomic Pathology Unit, Humanitas Clinical and Research Center - IRCCS -, Rozzano (MI), Italy. (11)Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy. (12)Pathology Department, Service d'Anatomie Pathologique, Institut Bergonié, Bordeaux, France. (13)Bergonie Institute, Department of Biopathology, Bordeaux, and Bordeaux University, Talence, France. (14)Clinical Bioinformatics Area. Fundación Progreso y Salud (FPS). CDCA, Hospital Virgen del Rocio, Sevilla, Spain. (15)Bioinformatics in Rare Diseases (BiER). Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Rocio, Sevilla, Spain. (16)INB-ELIXIR-es FPS, Hospital Virgen del Rocío, Sevilla, Spain. (17)Department of Anatomy and Pathological Histology, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy. (18)Research and Statistics Infrastructure, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy. (19)Chemotherapy Unit, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy. (20)Cancer Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy. (21)Department of Surgery, Istituto Clinico Humanitas, Rozzano, Italy. (22)Medical Oncology Department, Santa Creu I Sant Pau Hospital, Barcelona, Spain. (23)Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy. (24)Department of Medical Oncology, Centre Léon Bérard & Université Claude Bernard Lyon I, Lyon, France. (25)Department of Oncology, Medical Oncology 1 Unit, Istituto Oncologico Veneto IOV, IRCCS, Padova, Italy. (26)Hematology Department, Son Espases University Hospital, Mallorca, Spain. (27)Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain. (28)Medical Oncology Department, University Hospital Fundación Jimenez Diaz, Madrid, Spain. (29)Department of Pathology, Treviso General Hospital, Treviso, Italy. (30)University of Padua, Padova, Italy. (31)Laboratory of Oncologic Research, Istituto Ortopedico Rizzoli, Bologna, Italy. (32)Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. (#)Contributed equally BACKGROUND: Avapritinib, a novel inhibitor of KIT/PDGFRA, is approved in the U.S. for the treatment of adults with PDGFRA exon 18-mutant unresectable or metastatic gastrointestinal stromal tumors (U/M GISTs). We assessed the safety of avapritinib and provide evidence-based guidance on management of avapritinib-associated adverse events (AEs), including cognitive effects and intracranial bleeding. MATERIALS AND METHODS: We performed a post hoc analysis of data from a two-part, single-arm dose escalation/expansion phase I study (NAVIGATOR; NCT02508532) in patients with U/M GISTs treated with oral avapritinib 30-600 mg once daily. The primary endpoints were safety and tolerability; the impact of dose modification (interruption and/or reduction) on progression-free survival (PFS) was a secondary endpoint. Efficacy analyses were limited to patients who started avapritinib at 300 mg (approved dose). RESULTS: Of 250 patients enrolled in the study, 74.0% presented with KIT mutation and 24.8% presented with PDGFRA exon 18-mutation; 66.8% started avapritinib at 300 mg. The most common treatment-related AEs (any grade) were nausea (59.2%), fatigue (50.0%), periorbital edema (42.0%), anemia (39.2%), diarrhea (36.0%), vomiting (36.0%), and increased lacrimation (30.8%). No treatment-related deaths occurred. Among 167 patients starting on 300 mg avapritinib, all-cause cognitive effects rate (grade 1-2) was 37.0% in all patients and 52.0% in patients ≥65 years. Cognitive effects improved to a lower grade more quickly with dose modification (1.3-3.1 weeks) than without (4.9-7.6 weeks). Median PFS was 11.4 months with dose modification and 7.2 months without. CONCLUSION: Tolerability-guided dose modification of avapritinib is an effective strategy for managing AEs in patients with GISTs. IMPLICATIONS FOR PRACTICE: Early recognition of adverse events and tailored dose modification appear to be effective approaches for managing treatment-related adverse events and maintaining patients on avapritinib. Dose reduction does not appear to result in reduced efficacy. Patients' cognitive function should be assessed at baseline and monitored carefully throughout treatment with avapritinib for the onset of cognitive adverse events. Dose interruption is recommended at the first sign of any cognitive effect, including grade 1 events. The frequent occurrence of multidrug resistance (MDR) conferred by the overexpression of ATP-binding cassette (ABC) transporters ABCB1 and ABCG2 in cancer cells remains a therapeutic obstacle for scientists and clinicians. Consequently, developing or identifying modulators of ABCB1 and ABCG2 that are suitable for clinical practice is of great importance. Therefore, we have explored the drug repositioning approach to identify candidate modulators of ABCB1 and ABCG2 from tyrosine kinase inhibitors with known pharmacological properties and anticancer activities. In this study, we discovered that avapritinib (BLU-285), a potent, selective, and orally bioavailable tyrosine kinase inhibitor against mutant forms of KIT and platelet-derived growth factor receptor alpha (PDGFRA), attenuates the transport function of both ABCB1 and ABCG2. Moreover, avapritinib restores the chemosensitivity of ABCB1- and ABCG2-overexpressing MDR cancer cells at nontoxic concentrations. These findings were further supported by results of apoptosis induction assays, ATP hydrolysis assays, and docking of avapritinib in the drug-binding pockets of ABCB1 and ABCG2. Altogether, our study highlights an additional action of avapritinib on ABC drug transporters, and a combination of avapritinib with conventional chemotherapy should be further investigated in patients with MDR tumors. Metastatic vulvar melanoma is a rare and aggressive disease and survival is usually poor. Vulvar melanomas harbor BRAF V600 mutations only infrequently; consequently, target therapy is a rare therapeutic option and immunotherapy usually has only a weak effect. On the other hand, KIT mutations are rare in cutaneous melanomas, but relatively frequent in mucosal melanomas, particularly in vulvar-vaginal melanomas, and can be a therapeutic target. Herein, we report a clinical case of a patient with metastatic vulvar melanoma, harboring an exon 17 c-KIT mutation, treated with avapritinib (BLU-285) - a highly potent and selective oral kinase inhibitor designed to treat imatinib-resistant gastro-intestinal stromal tumors (GIST) by targeting KIT/PDGFRα activation loop mutants (exons 17/18). After failure of the combination of ipilimumab + nivolumab first and then nivolumab alone, the patient received avapritinib 300 mg/daily for central nervous system (CNS), lymph-nodal, right adrenal gland, lung, and subcutaneous metastases. Best response was partial remission, according to RECIST 1.1 criteria. Time to treatment progression was 11 months. Main toxicities were grade 2 cutaneous vasculitis that required avapritinib discontinuation, and grade 2 uveitis of unknown origin, treated by vitrectomy and empiric antibiotic and antiviral therapy due to negative cultural tests. Uveitis was detected at the time of progression and therapy was definitively discontinued. In conclusion, avapritinib proved to be effective even in the presence of a pretreated disease, a high tumor burden, and brain metastases. In our experience, treatment was feasible and toxicity manageable. Considering the lack of effective therapies and the poor outcome of the disease, determination of c-KIT mutations should be performed routinely in cases of metastatic mucosal melanoma. Gastrointestinal stromal tumors (GIST) are rare neoplasms arising from the interstitial cell of Cajal in the gastrointestinal tract. Two thirds of GIST in adult patients have c-Kit mutation and smaller fractions have platelet derived growth factor receptor alpha (PDGFRA) mutation. Surgery is the only curative treatment for localized disease. Imatinib improves survival when used adjuvantly and in advanced disease. Several targeted therapies have also improved survival in GIST patients after progression on imatinib including sunitinib and regorafenib. Recently, United States Federal and Drug Administration (FDA) approved two new tyrosine kinase inhibitors for the treatment of heavily pretreated advanced/unresectable GIST including avapritinib (a selective inhibitor for PDGFRA exon 18 mutation including D842V mutations) and ripretinib (a broad-spectrum kinase inhibitor of c-Kit and PDGFRA). In this article, we will provide a comprehensive review of GIST including the current standard of care treatment and exploring future paradigm shifts in therapy. Avapritinib is a protein kinase inhibitor designed to selectively inhibit oncogenic KIT and platelet-derived growth factor receptor alpha (PDGFRA) mutants by targeting the active conformation of the kinase. On 24 September 2020, a marketing authorisation valid through the European Union was issued for avapritinib as treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumours (GIST) harbouring the PDGFRA D842V mutation. The drug was evaluated in an open-label, phase I, first-in-human, dose-escalation, open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of avapritinib in adults with unresectable or metastatic GIST. The benefit of avapritinib was observed in patients with GIST harbouring the PDGFRA D842V mutation. The overall response rate was 95% (95% confidence interval 82.3%-99.4%), with a median duration of response of 22.1 months (95% confidence interval 14.1-not estimable months). The most common adverse events were nausea, fatigue, anaemia, periorbital and face oedema, hyperbilirubinaemia, diarrhoea, vomiting, increased lacrimation, and decreased appetite. Most of the reported cognitive effects were mild memory impairment. Rarer events were cases of severe encephalopathy and intracranial or gastrointestinal bleeding. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval in the European Union. Conflict of interest statement: Yoon-Koo KangConsulting or Advisory Role: DAEHWA Pharmaceutical, Bristol Myers Squibb, Zymeworks, ALX Oncology, Amgen, Novartis, Macrogenics, Surface Oncology, Blueprint Medicines Suzanne GeorgeStock and Other Ownership Interests: Abbott LaboratoriesConsulting or Advisory Role: Blueprint Medicines, Deciphera, Bayer, Lilly, UpToDate, Research to Practice, MORE Health, Daiichi, KayotheraResearch Funding: Blueprint Medicines, Deciphera, Daiichi Sankyo RD Novare, Merck, Eisai, SpringWorks TherapeuticsPatents, Royalties, Other Intellectual Property: UptoDateExpert Testimony: BayerOther Relationship: Research to Practice, WCG Robin L. JonesConsulting or Advisory Role: Lilly, Immune Design, Merck Serono, Adaptimmune, Daiichi Sankyo, Eisai, Morphotek, TRACON Pharma, Immodulon Therapeutics, Deciphera, PharmaMar, Blueprint Medicines, Clinigen Group, Epizyme, Boehringer Ingelheim, Bayer, Karma Oncology, UpToDateResearch Funding: GlaxoSmithKlineTravel, Accommodations, Expenses: PharmaMar Piotr RutkowskiHonoraria: Bristol Myers Squibb, MSD, Novartis, Roche, Lilly, Pfizer, Pierre Fabre, Sanofi, MerckConsulting or Advisory Role: Novartis, Blueprint Medicines, Bristol Myers Squibb, Pierre Fabre, MSD, AmgenSpeakers' Bureau: Pfizer, Novartis, LillyResearch Funding: Novartis, Roche, Bristol Myers SquibbTravel, Accommodations, Expenses: Orphan Europe, Pierre Fabre Olivier MirStock and Other Ownership Interests: Transgene, Amplitude Surgical, IpsenHonoraria: RocheConsulting or Advisory Role: Lilly, Pfizer, Roche, Lundbeck, JanssenSpeakers' Bureau: Lilly, Roche, PfizerResearch Funding: Ipsen, AstraZeneca, Blueprint MedicinesTravel, Accommodations, Expenses: Roche, Pfizer Shreyaskumar PatelConsulting or Advisory Role: Novartis, Immune Design, MaxiVax, Epizyme, Janssen, Lilly, Daiichi Sankyo, Bayer, Dova Pharmaceuticals, DecipheraResearch Funding: Blueprint Medicines, Hutchinson Med Pharma Margaret von MehrenConsulting or Advisory Role: Deciphera, ExelixisResearch Funding: ArQule, Novartis, Blueprint Medicines, Deciphera, Gradalis, Springworks Therapeutics, Lilly, Arog, Genmab, ASCOTravel, Accommodations, Expenses: Deciphera Pharmaceuticals, NCCNOther Relationship: NCCN Peter HohenbergerHonoraria: Roche, AstraZeneca, GlaxoSmithKline, BLUMedicine, NovartisConsulting or Advisory Role: Nanobiotix, PfizerResearch Funding: Novartis, Siemens Healthcare DiagnosticsTravel, Accommodations, Expenses: PharmaMar Victor VillalobosEmployment: Janssen OncologyConsulting or Advisory Role: Janssen, Lilly, Novartis, AbbVie, Ignyta, Agios, Epizyme, Blueprint Medicines, Springworks Therapeutics, NanoCarrier, Daiichi SankyoTravel, Accommodations, Expenses: Lilly, Janssen, Xencor, GenMab, Epizyme Mehdi BrahmiExpert Testimony: BayerTravel, Accommodations, Expenses: PharmaMar, Mundipharma William D. TapLeadership: Certis Oncology Solutions, Atropos, Innova TherapeuticsStock and Other Ownership Interests: Certis Oncology Solutions, AtroposConsulting or Advisory Role: EMD Serono, Lilly, Daiichi Sankyo, Blueprint Medicines, Agios, NanoCarrier, Deciphera, C4 Therapeutics, Mundipharma, Adcendo, Ayala Pharmaceuticals, Kowa Pharmaceutical, Servier, AbMaxBioResearch Funding: Novartis, Lilly, Plexxikon, Daiichi Sankyo, TRACON Pharma, Blueprint Medicines, Immune Design, BioAtla, DecipheraPatents, Royalties, Other Intellectual Property: Companion Diagnostic for CDK4 inhibitors—14/854,329, Enigma and CDH18 as companion Diagnostics for CDK4 inhibition—SKI2016-021-03 Jonathan TrentConsulting or Advisory Role: Novartis, Lilly, Janssen, Blueprint Medicines, Deciphera, Daiichi Sankyo, Epizyme, Agios, C4 Therapeutics, Bayer Patrick SchöffskiHonoraria: Deciphera, Blueprint Medicines, Boehringer IngelheimConsulting or Advisory Role: Blueprint Medicines, Ellipses Pharma, Adaptimmune, Intellisphere, Transgene, Deciphera, Exelixis, Boehringer Ingelheim, Medscape, Guided Clarity, Ysios Capital, Studiecentrum voor KernenergieResearch Funding: CoBioRes NV, Eisai, G1 Therapeutics, Novartis, PharmaMarTravel, Accommodations, Expenses: MSD, Ipsen, Boehringer Ingelheim Kevin HeEmployment: Blueprint Medicines, AgiosStock and Other Ownership Interests: Blueprint Medicines, Agios, Incyte Paggy HewEmployment: Blueprint MedicinesStock and Other Ownership Interests: Blueprint MedicinesTravel, Accommodations, Expenses: Blueprint Medicines Kate NewberryEmployment: Blueprint MedicinesStock and Other Ownership Interests: Blueprint Medicines Maria RocheEmployment: Blueprint Medicines, EpizymeStock and Other Ownership Interests: Blueprint Medicines, Epizyme Michael C. HeinrichStock and Other Ownership Interests: MolecularMDHonoraria: NovartisConsulting or Advisory Role: MolecularMD, Novartis, Blueprint Medicines, Deciphera, Theseus PharmaceuticalsPatents, Royalties, Other Intellectual Property: Patent on treatment of GIST-licensed to NovartisExpert Testimony: Novartis Sebastian BauerHonoraria: Novartis, Pfizer, Bayer, Pharmamar, GlaxoSmithKlineConsulting or Advisory Role: Blueprint Medicines, Bayer, Lilly, Deciphera, Nanobiotix, Daiichi Sankyo, Exelixis, Janssen-Cilag, ADC Therapeutics, Mundipharma, GlaxoSmithKlineResearch Funding: Blueprint Medicines, Novartis, IncyteTravel, Accommodations, Expenses: PharmamarNo other potential conflicts of interest were reported.

What is Jackhammer esophagus?

Jackhammer esophagus (JE) is a hypercontractile esophageal motor disorder defined by at least two swallows with a distal contractile integral (DCI) >8000 mm Hg.s.cm during high-resolution manometry (HRM).

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BACKGROUND/AIMS: Jackhammer esophagus is an uncommon heterogeneous motility disorder associated with a distal contractile integral > 8000 mmHg∙sec∙cm. The spectrum of abnormality ranges from a relatively normal looking contraction to chaotic repetitive contractions akin to a jackhammer. Although previous studies have shown an uncertain correlation between peristaltic vigor and symptoms, we hypothesize that symptoms may be more severe with repetitive contractions as opposed to an elevated contractile measure. Thus, this study aims to investigate whether symptom severity is related to the contraction pattern in the patients with hypercontractile esophagus. METHODS: Patients with hypercontractile esophagus were retrospectively identified, their demographic and high-resolution manometry characteristics were collected. Contraction pattern on high-resolution manometry was categorized into single-peak and multiple-peak. Comparison was performed between patients with single-peak and multiple-peak. RESULTS: Altogether 35 patients (age range, 45-70 years; female:male, 24:11) were included. Seven patients presented with single-peak hypercontractile swallows, while 28 patients presented with multiple-peak hypercontractile swallows. The patients with multiple-peak showed higher Brief Esophageal Dysphagia Questionnaire scores compared with patients with single-peak. The jackhammer swallows with multiple-peak were associated with higher distal contractile integral values, longer distal latency intervals, and a lower integrated relaxation pressure. CONCLUSIONS: Repetitive contractions akin to a jackhammer were common amongst patients with hypercontractile esophagus. Patients with the jackhammer pattern also presented with more severe symptoms. Further distinction of hypercontractile esophagus into a jackhammer dominant subtype may be warranted. Hypercontractile esophagus (nicknamed jackhammer esophagus) is a recently defined disease within the esophageal motility disorders classification. Responses to treatments for jackhammer esophagus have been inconsistent in previous trials, possibly due to its heterogeneous manifestation. Thus, we reviewed 10 patients diagnosed with jackhammer esophagus and compared their clinical and manometric features at baseline. Additionally, manometric and symptomatic responses after treatment with known smooth muscle relaxants, including anticholinergic drugs (cimetropium bromide and scopolamine butylbromide) and a phosphodiesterase-5 inhibitor (sildenafil) were compared. We observed two distinct subgroups in the findings: one with hypercontractility and normal distal latencies ("classic jackhammer esophagus," n=7) and the other with hypercontractility and short distal latencies ("spastic jackhammer esophagus," n=3). The two types also differed in their responses to medications in that symptoms improved upon treatment with an anticholinergic agent in classic jackhammer esophagus patients, while spastic jackhammer esophagus was unresponsive to both the anticholinergic drugs and the phosphodiesterase-5 inhibitor. In conclusion, hypercontractile esophagus may be a heterogeneous disease with different underlying pathophysiologies. We introduced two novel terms, "classic jackhammer esophagus" and "spastic jackhammer esophagus," to distinguish the two types. Hypercontractile esophagus (HE), also known as jackhammer esophagus, is an esophageal motility disorder. Nowadays, high-resolution manometry (HRM) is used to diagnose the disorder. According to the latest iteration of the Chicago classification, HE is present when at least 2 out 10 liquid swallow-induced peristaltic waves have an abnormally high Distal Contractile Integral. In the era of conventional manometry, a similar condition, referred to as nutcracker esophagus, was diagnosed when the peristaltic contractions had an abnormally high mean amplitude. Although the HRM diagnosis of HE is relatively straight-forward, effective management of the disorder is challenging as the correlation with symptoms is variable and treatment effects are dubious. In this mini-review, we discuss the most troublesome uncertainties that still surround HE, in the light of new data on etiology and epidemiology published in this issue of Neurogastroenterology and Motility. Jackhammer esophagus (JE) is a recently recognized esophageal motility disorder that is characterized by hypercontractile peristalsis. More than 500 cases have been reported in the literature. Among patients referred for esophageal motility disorders, the prevalence of JE ranges from 0.42% to 9%, with most series describing a prevalence of 2% to 4%. Most cases are women (60.5%). The mean reported age of patients with JE is 65.2 years, and patients commonly have dysphagia (62.8%). Reflux symptoms occur in ∼40% of patients, and chest pain affects more than one-third of patients (36.4%). JE is a heterogenous disorder that is associated with several conditions, including obesity, opioid use, lung transplantation, eosinophilic infiltration of the esophagus, neoplasia, and systemic diseases. The cause and pathogenesis remain unknown, but several observations suggest that it is the result of multiple conditions that likely precipitate increased excitation and abnormal inhibition of neuromuscular function. The natural course of JE also is unknown, but progression to achalasia has been observed in a few patients. Treatment is challenging, in part because of the insufficient understanding of the disorder's underlying mechanisms. Various therapeutic modalities have been used, ranging from observation only to pharmacologic and endoscopic interventions (eg, botulinum toxin injection) to peroral endoscopic myotomy. Treatment efficacy remains largely anecdotal and insufficiently studied. BACKGROUND: Jackhammer esophagus is a rare esophageal motility disorder that can result in dysphagia, chest pain, and gastro-esophageal reflux symptoms. High-resolution manometry is the gold standard for diagnosis, while corkscrew esophagus on upper gastrointestinal endoscopy is an uncommon manifestation. CASE PRESENTATION: 72-year-old man who presented with progressive dysphagia for three months without symptoms of chest pain or heartburn. Initial workup showed a corkscrew esophagus on upper gastrointestinal endoscopy; subsequently, high-resolution manometry revealed an esophago-gastric junction outflow obstruction with hypercontractile (jackhammer) esophagus. Treatment with calcium channel blockers and proton pump inhibitors was successful and relieved his symptoms near completion. CONCLUSIONS: Even though the corkscrew esophagus is typically for distal esophageal spasm, the hypercontractile (jackhammer) esophagus can appear. The high-resolution manometry can help to distinguish each specific motility disorder. Jackhammer esophagus (JE) is a hypercontractile disorder, the pathogenesis of which is incompletely understood. Multiple rapid swallows (MRS) and rapid drink challenge (RDC) are complementary tests used during high-resolution manometry (HRM) that evaluate inhibitory and excitatory neuromuscular function and latent obstruction, respectively. Our aim was to evaluate esophageal pathophysiology using MRS and RDC in 83 JE patients (28 men; median age: 63 yr; IQR: 54-70 yr). Twenty-one healthy subjects (11 men; median age: 28 yr; range: 26-30 yr) were used as a control group. All patients underwent solid-state HRM with ten 5-ml single swallows (SS) and one to three 10-ml MRS; 34 patients also underwent RDC. Data are shown as median (interquartile range). Abnormal motor inhibition was noted during at least one MRS test in 48% of JE patients compared with 29% of controls ( P = 0.29). Mean distal contractile integral (DCI) after MRS was significantly lower than after SS [6,028 (3,678-9,267) mmHg·cm·s vs. 7,514 (6,238-9,197) mmHg·cm·s, P = 0.02], as was highest DCI ( P < 0.0001). Consequently, 66% of JE patients had no contraction reserve. At least one variable of obstruction during RDC (performed in 34 patients) was outside the normal range in 25 (74%) of JE patients. Both highest DCI after SS and pressure gradient across the esophagogastric junction (EGJ) during RDC were higher in patients with dysphagia versus those without ( P = 0.04 and 0.01, respectively). Our data suggest altered neural control in JE patients with heterogeneity in inhibitory function. Furthermore, some patients had latent EGJ obstruction during RDC, which correlated with the presence of dysphagia. NEW & NOTEWORTHY Presence of abnormal inhibition was observed during multiple rapid swallows (MRS) in some but not all patients with jackhammer esophagus (JE). Unlike healthy subjects, JE patients were more strongly stimulated after single swallows than after MRS. An obstructive pattern was frequently observed during rapid drink challenge (RDC) and was related to presence of dysphagia. MRS and RDC during high-resolution manometry are useful to show individual pathophysiological patterns in JE and may guide optimal therapeutic strategies. BACKGROUND: Jackhammer Esophagus is defined as intact esophageal peristaltic contractions with extremely elevated amplitudes. We conducted a retrospective study to identify the frequency of esophageal hypercontractility and the clinical characteristics of Jackhammer Esophagus. METHODS: Charts for the patients referred for manometric study at a tertiary-care motility center were reviewed. Data were collected utilizing the new Chicago classification criteria for Jackhammer Esophagus. Concomitant clinical variables were also explored. RESULTS: Eight patients were identified with Jackhammer Esophagus from a total of 205 (127 female/77 male) patients referred for high-resolution esophageal manometry. Jackhammer patients had an average distal contractile integral (DCI) of 9061 mmHg/ sec/ cm and median maximal DCI of 16,433 mmHg/ sec/ cm. The greatest DCI from 15 swallows was 28,875 mmHg/ sec/ cm. Hypercontractility was associated with multipeaked contractions in every Jackhammer patient. The mean lower esophageal sphincter (LES) pressure was 41 mm Hg with 4 patients having a hypertensive pressure of >40 mm Hg. Three of the 8 (37.5%) Jackhammer group had incomplete LES relaxation by integrated relaxation pressure criteria (>15 mm Hg residual pressure). Dysphagia (8/8) was the dominant indication for the manometric study, whereas the clinical background setting was gastroesophageal reflux disease (4/8) and hiatal hernia (1/8). Treatments included smooth muscle relaxation, antireflux regimens, and pneumatic dilation of the LES. CONCLUSIONS: Jackhammer Esophagus, an extreme manometric phenotype, was identified in 4.0% of patients referred to a University Motility Center. The patients with these esophageal hypercontractility states present mainly with dysphagia. A subgroup of Jackhammer did have accompanying incomplete LES relaxation and responded to targeted therapy with pneumatic dilatation. BACKGROUND AND STUDY AIMS: With the success of peroral endoscopic myotomy (POEM) in treatment of achalasia, its successful application to other spastic esophageal motility disorders such as Jackhammer esophagus has been noted. The question of whether the lower esophageal sphincter (LES) should be included in the myotomy for Jackhammer esophagus is a topic of current debate. Here, we report our experience and results with four patients with Jackhammer esophagus treated with POEM. The clinical and manometric results are presented and their potential implications are discussed. PATIENTS AND METHODS: Between January 2014 and July 2015, four patients underwent POEM for treatment of Jackhammer esophagus at our center. Manometry was performed prior to and after POEM. All patients met the Chicago classification criteria for Jackhammer esophagus and received a barium esophagram and endoscopic examination before having POEM. RESULTS: All patients had uneventful procedures without any intraoperative or post-procedure complications. Patients in which the LES was included during POEM had resolution or significant improvement in symptoms. One patient in whom the LES was preserved had resolution of chest pain but developed significant dysphagia and regurgitation. Subsequently this individual received a repeat POEM which included the LES, resulting in symptom resolution. CONCLUSIONS: POEM is a suitable treatment for patients with Jackhammer esophagus. Until there are larger-scale randomized studies, we speculate that based on our clinical experience and physiologic and manometric observations, obligatory inclusion of the LES is justified to reduce the risk of symptom development from iatrogenic ineffective esophageal motility or subsequent progression to achalasia. BACKGROUND: Jackhammer esophagus is a hypercontractile esophageal disorder recently brought to light with the advent of high resolution manometry (HRM). As little is known about its clinical presentation, the aim of this study was to identify the clinical characteristics associated with this new gastrointestinal motility disorder. METHODS: A retrospective study was conducted on patients visiting the CHUM's Gastro-Intestinal Motility Center from January 2015 to December 2017. The HRM diagnoses were collated in a database along with age and sex of every individual. The latest Chicago classification (version 3.0) was used. Among all the patients subjected to HRM, those diagnosed with Jackhammer esophagus were included in the study. Patient charts were reviewed to collect relevant demographic and clinical data. KEY RESULTS: A total of 36 patients with Jackhammer esophagus were included (62 ± 13 years age, 89% females). Their main symptoms were dysphagia (72%), pyrosis (42%), retrosternal chest pain (36%), and epigastralgia (33%). Other manometric findings were hypertonia (22%) and/or inadequate relaxation (19%) of the lower esophageal sphincter. Among the 26 patients who had esogastroduodenoscopy, hiatal hernia was seen in 3 patients. Pathological gastroesophageal reflux was found in 4 of the 10 patients investigated by pH-monitoring. CONCLUSIONS AND INFERENCES: Jackhammer esophagus represents 3% of the HRM diagnoses in this study, with a significant female preponderance. In more than two-thirds of cases, the clinical presentation of Jackhammer esophagus is dysphagia. BACKGROUND: Jackhammer esophagus (JE) is a rare esophageal motility disorder defined in the Chicago Classification of Esophageal Motility by presence of excessively high distal contractile integral (DCI) on high-resolution manometry (HRM), with unknown natural manometric course. We examined the development of achalasia over time in patients with JE. METHODS: Through a retrospective longitudinal design, patients with Jackhammer contractions who had more than one HRM between 2005 and 2015 were identified. Any change in manometric finding was assessed for the presence of achalasia. Demographic and manometric risk factors for this progression were then sought in univariate analysis. KEY RESULTS: Of 3363 HRM studies, 229 subjects had multiple manometries, accounting for 528 studies. Twelve subjects met our inclusion criteria for JE on any of the multiple tests, represented by 27 studies for a total of 347 patient-months of manometric follow-up. Subjects with JE whose manometry included impedance demonstrated consistent esophageal bolus clearance. Of 12 subjects with Jackhammer contractions, three subjects progressed to type III achalasia, over a mean of 24 months (range: 19-31 months). At the time of diagnosis with JE, impaired esophago-gastric junction relaxation was seen in all three subjects and was the only risk factor that could predict progression to achalasia (P<.01). CONCLUSIONS & INFERENCES: In this unique study of the natural course of JE, we have shown that JE can progress to achalasia. Manometric findings at the time of JE diagnosis might predict this progression. The jackhammer esophagus is a rare hypercontractile disorder and diagnosis is based on high-resolution manometry. Peroral endoscopic myotomy (POEM) of the spastic esophagus segments has been described. We report a pediatric patient with jackhammer esophagus that was treated endoscopically. Nutcracker esophagus and jackhammer esophagus are largely unknown motility disorders, also sometimes called hypertensive and hypercontractile peristalsis, respectively. There is currently no standardized diagnostic or management plan for these diseases. Here, we report on three patients with jackhammer/nutcracker esophagus who were treated with either peroral endoscopic myotomy or a systemic steroid regimen, focusing particularly on two novel presentations of nutcracker and jackhammer esophagus involving eosinophilic infiltration into the muscularis propria, and their responses to both interventions. BACKGROUND/AIMS: Jackhammer esophagus (JE) is a hypercontractile esophageal motor disorder defined by at least two swallows with a distal contractile integral (DCI) >8000 mm Hg.s.cm during high-resolution manometry (HRM). The relationship between symptoms and hypercontractility and the response to therapies have been poorly evaluated. The aim of this study was to determine the clinical presentation, manometric diagnosis, and therapeutic results in a large cohort of JE patients. METHODS: Patients with JE diagnosed among the HRM tests performed in nine academic French centers from 01/01/2010 to 08/31/2016 were included. Patient charts were reviewed to collect clinical and therapeutic data. RESULTS: Among the 16 264 HRM tests performed during this period, 227 patients (60.8 ± 13.8 years, 151 male) had JE (1.7%). Dysphagia was the most frequent symptom (74.6%), followed by regurgitation (37.1%) and chest pain (36.6%); 4.7% of the patients were asymptomatic. The diagnostic workup was heterogeneous, and only a minority of patients had esophageal biopsies. None of the individual symptoms were significantly associated with any of the manometric parameters defined, except for dysphagia, which was significantly associated with the mean of all DCIs >8000 mm Hg.s.cm (P = .04). Additionally, the number of symptoms was not associated with any manometric parameter. Medical treatment and endoscopic treatments had poor efficacy and a high relapse rate. CONCLUSION: Jackhammer esophagus is a rare motility disorder. Diagnostic workup is heterogeneous and should be standardized. Symptoms are poorly associated with manometric parameters. The medical treatments and endoscopic therapies currently used are inefficient. This trial was designed to assess the prevalence and characteristics of Jackhammer esophagus (JE), a novel hypercontractile disorder associated with progression to achalasia and limited outcomes following anti-reflux surgery in patients with typical symptoms of GERD and responsiveness to proton pump inhibitor (PPI) therapy. Consecutive patients, who were referred for surgical therapy because of PPI responsive typical symptoms of GERD, were prospectively assessed between January 2014 and May 2017. Patients diagnosed with JE subsequently underwent rigorous clinical screening including esophagogastroduodenoscopy (EGD), ambulatory pH impedance monitoring off PPI and a PPI trial. Out of 2443 evaluated patients, 37 (1.5%) subjects with a median age of 56.3 (51.6; 65) years were diagnosed with JE and left for final analysis. Extensive testing resulted in 16 (43.2%) GERD positive patients and 5 (13.9%) participants were observed to have an acid hypersensitive esophagus. There were no clinical parameters that differentiated phenotypes of JE. The prevalence of JE in patients with typical symptoms of GERD and response to PPI therapy is low. True GERD was diagnosed in less than half of this selected cohort, indicating the need for objective testing to stratify phenotypes of JE. (NCT03347903). GOALS: The aim of our study was to characterize jackhammer esophagus symptoms and their relationship with the distal contractile integral (DCI) and bolus transit. BACKGROUND: Jackhammer esophagus is defined by the Chicago Classification version 3.0. This diagnosis is relatively new, with the most current definition being established in 2014. The forerunners of this diagnosis, nutcracker (or hypercontractile) esophagus, have been associated with noncardiac chest pain (NCCP). STUDY: A retrospective chart review was performed of motility studies from 2011 to 2016. Studies with a diagnosis of jackhammer esophagus, hypercontractile esophagus, nutcracker, esophagogastric junction outflow obstruction, or hypertensive lower esophageal sphincter were reread using Chicago Classification version 3.0, and were included if they met criteria for jackhammer esophagus. Unpaired t-tests were used for analysis (P≤0.05). RESULTS: In total, 142 studies were identified with the above diagnoses. After excluding 84 studies, 58 remained for analysis and 17 were found to have jackhammer esophagus (29%). The mean age was 54 (28 to 75), 5 (29%) were males and 12 (71%) were females. The primary indications were NCCP (5), dysphagia (8), and other causes (4) (cough, heartburn, or regurgitation). The mean DCIs were 17,245 mm Hg×s×cm (NCCP), 14,669 mm Hg×s×cm (dysphagia), and 11,264 mm Hg×s×cm (other causes). The mean DCIs were compared: NCCP versus dysphagia (P=0.41), and NCCP versus other causes (P=0.05). Fifteen (88%) had normal bolus transit for both liquid and viscous swallows. CONCLUSIONS: In our small sample size, dysphagia was frequently the presenting symptom followed by NCCP. Those with NCCP have a trend toward a higher DCI. Bolus transit appeared to be normal in this patient population. More data are needed to further elucidate the genesis of symptoms and how they relate to the degree of contractility.

Can METTL3 methylate long noncoding RNAs?

Yes, METTL3 can modulate methylation and expression of lncRNA.

[34505967]

OBJECTIVES: This study aimed to explore the regulatory mechanism of methyltransferase3 (METTL3) -mediated long non-coding RNA (lncRNA) N6-methyladenosine (m6A) modification in the osteogenic differentiation of human adipose-derived stem cells (hASCs) induced by NEL-like 1 protein (NELL-1). MATERIALS AND METHODS: Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and high- throughput sequencing for RNA (RNA-seq) were performed on hASCs. Osteogenic ability was detected by alkaline phosphatase (ALP) staining, Alizarin Red S(ARS) staining, ALP quantification and Quantitative real-time polymerase chain reaction analysis (qRT-PCR). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis predicted the osteogenesis-related pathways enriched for the lncRNAs and identified the target lncRNAs. After overexpression and knockdown of METTL3, methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) and qRT-PCR were used to detect the levels of m6A modification and the expression of the target lncRNA, and the binding of both was confirmed by RNA binding protein immunoprecipitation (RIP) assay. The effects of lncRNA and METTL3 on phosphorylation of the key proteins of the pathway were detected by western blot analysis. RESULTS: In vitro experiments showed that METTL3 can promote osteogenic differentiation and that its expression level is upregulated. KEGG pathway analysis predicted that lncRNAs with differentially upregulated methylated peaks were enriched mostly in the mitogen-activated protein kinase (MAPK) signaling pathway, in which Serine/threonine protein kinase 3 (STK3) was the predicted target gene of the lncRNA RP11-44 N12.5. The m6A modification and expression of RP11-44 N12.5 were both regulated by METTL3. Subsequently, lncRNA RP11-44 N12.5 and METTL3 were found to regulate the phosphorylation levels of three key proteins in the MAPK signaling pathway, ERK, JNK and p38. CONCLUSIONS: This study shows, for the first time, that METTL3 can activate the MAPK signaling pathway by regulating the m6A modification and expression of a lncRNA, thereby enhancing the osteogenic differentiation of hASCs.

Which disease is caused by repeat expansion in VWA1?

An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy.

[33559681]

Author information: (1)NIHR Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. (2)Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK. (3)Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, National Institutes of Health, Bethesda, MD, USA. (4)Department of Human Genetics, Sidra Medicine, Doha, Qatar. (5)Institute of Human Genetics, Center for Molecular Medicine Cologne (CMMC), Institute of Genetics, and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany. (6)William Harvey Research Institute, Queen Mary University of London, London, UK. (7)Genomics England, London, UK. (8)Centogene AG, Rostock, Germany. (9)Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran. (10)Department of Neurology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. (11)The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle, UK. (12)Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK. (13)Department of Paediatric Neurology - Neuromuscular Service, Evelina Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, UK. (14)Department of Neurology, Royal Devon and Exeter NHS Trust, Exeter, UK. (15)Randall Division of Cell and Molecular Biophysics Muscle Signalling Section, King's College London, London, UK. (16)Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. (17)Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands. (18)Department of Neurology, Salford Royal NHS Foundation Trust, Manchester, UK. (19)Department of Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands. (20)West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, UK. (21)Divisions of Neurology and Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. (22)Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Sweden. (23)The Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital Trust, London, UK. (24)GeneDx, Gaithersburg, 20877 MD, USA. (25)Mitochondrial Medicine Frontier Program, Division of Human Genetics, Children's Hospital of Philadelphia, PA, USA. (26)Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. (27)Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford, UK. (28)Department of Neurology, King's College Hospital, London, UK. (29)Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Trust, Exeter, UK. (30)Division of Pediatric Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (31)Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA, USA. (32)Department of Neurology, Center for Rare Diseases Cologne, University Hospital Cologne, Cologne, Germany. (33)College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar. (34)Department of Genetic Medicine, Weill Cornell Medical College, Doha, Qatar. (35)School of Health Science, Division Biomedicine and Translational Medicine, University of Skovde, Sweden.

What is the use of the Apfel Score?

The Apfel simplified risk score, developed in 1999, is the most widely used tool for risk stratification of postoperative nausea and vomiting.

[33832577, 27902493, 34041090, 34782501, 33250474, 33721198, 32415631, 31230771, 11861340, 17236637, 33683710, 34067551]

Postoperative nausea and vomiting (PONV) degrades patient experience and increases healthcare costs. Estimates of PONV range from 10% to 80%. The Apfel Simplified Score is an evidence-based instrument for determining individual risk of PONV. Scoring enables anesthesia providers to match antiemetic strategies with the calculated risk of PONV. Data were collected across 3 times. After the Apfel scoring system was automated into the electronic medical record, providers were more likely to increase PONV prophylaxis for patients at highest risk and reduce prophylaxis for patients at lowest risk. Rates of PONV remained similar at baseline (34.7%) and in the early postimplementation period (38.8%); a modest reduction was observed in the final period (26.5%). Intravenous ondansetron, the most common antiemetic at baseline, was not available in the early postimplementation period, which may partially explain the initial increase in PONV. While ondansetron was unavailable, providers began using 3 other antiemetics, a practice that persisted once intravenous ondansetron returned. The Apfel score is an evidence-based tool that providers can use to reduce the risk of PONV. This electronic tool and the reminder cards have been shared across the US Military Health System, fostering an organizational culture that values targeted prophylaxis for PONV. BACKGROUND: Simplified risk models, such as the Apfel score, have been developed to calculate the risk of postoperative nausea-vomiting (PONV) for adult patients. In the absence of any risk factors, PONV risk is assumed to be 10%. While the presence of one of the four risk factors determined as female gender, non-smoking, PONV/car sickness history, and postoperative opioid use is associated with 20% risk for PONV, the risk increases by 20% with the addition of each risk factor, and reaches to 80% if four factors are present. AIM: : Our aim in this study is to investigate the prevalence of PONV, and whether the scoring systems used for nausea-vomiting in the literature are still valid. PATIENTS AND METHODS: Five groups of patients were included in the study with an Apfel score of 0, 1, 2, 3, 4. Each case was taken to the recovery room at the end of the operation. They were observed whether had nausea-vomiting was recorded according to the Abramowitz emesis score. RESULTS: While the PONV risk for women is 24.637 times higher than men, the PONV risk of those who had gynecological surgery is 6.27 times higher than that of the other type of surgery. Those who had urological surgery are 0.345 times less than the other type of surgery. Those who had lower abdominal surgery had a risk of PONV of 4.56 times higher than the others. As the duration of the case increases, the risk of PONV increases 1.01 times (P values P < 0.001, P < 0.001, P < 0.001, P = 0.048, P < 0.001, respectively). CONCLUSION: As a result, our PONV prevalence is considerably lower than the frequency rates mentioned in the literature. PONV scoring systems need long-term studies with larger populations to be updated. BACKGROUND: The incidence and risk factors of postoperative nausea and vomiting (PONV) and early PONV (ePONV) were evaluated in patients who underwent breast surgery with volatile anesthesia. METHODS: In this retrospective study, multivariate logistic regression was used to determine incidence and identify risk factors for PONV. RESULTS: Among 928 patients, 166 (18%) and 220 (24%) had ePONV and PONV, respectively. In multivariate analysis, anesthesia duration and use of desflurane were independent risk factors for ePONV. For PONV, anesthesia duration and Apfel score were independent risk factors. CONCLUSIONS: Our results indicate that desflurane was the main cause of ePONV. However, during the delayed phase, a higher Apfel score was the strongest predictor. In the early and delayed phases, long anesthesia duration was associated with high risk of PONV. Thus, prolonged anesthesia and desflurane use should be avoided for patients at high risk of PONV, particularly those with high Apfel scores. Publisher: RéSUMé: OBJECTIF: Le score simplifié d’Apfel, mis au point en 1999, est l’outil le plus utilisé pour la stratification des risques de nausées et vomissements postopératoires (NVPO). Il comprend quatre facteurs de risque : le sexe féminin, un statut de non-fumeur, les antécédents de NVPO ou de mal des transports, et l’utilisation d’opioïdes postopératoires. Néanmoins, il existe une hétérogénéité considérable dans la définition et l’application de ces facteurs de risque dans la recherche sur les NVPO. Notre objectif était de déterminer comment ces facteurs de risque étaient appliqués dans les études utilisant le score Apfel. MéTHODE: Les citations comportant dans leur index une mention du score d’Apfel entre le 1er septembre 1999 et le 1er septembre 2019 ont été identifiées dans la base de données Scopus. Les comptes rendus originaux en texte intégral en anglais mesurant les quatre facteurs de risque ont été inclus dans notre analyse. Les données recueillies comprenaient la définition, le moment et la méthode de collecte des quatre facteurs de risque. RéSULTATS: Parmi les études identifiées, 255 sur 535 documentaient les quatre facteurs de risque, et les scores d’Apfel calculés ont été rapportés dans 116 des 255 (46 %) articles. Le tabagisme, les NVPO, le mal des transports et l’utilisation postopératoire d’opioïdes ont été définis dans quatre (2 %), zéro (0 %), un (0,4 %) et sept (3 %) articles, respectivement. La consommation postopératoire d’opioïdes a été définie comme « anticipée » dans 138 (54 %) études et « réelle » dans 72 (18 %) études, et n’était pas claire dans 45 (28 %) études. CONCLUSION: Il existe d’importantes variations dans la façon dont les facteurs de risque d’Apfel sont définis et appliqués dans la recherche sur les NVPO, particulièrement en ce qui concerne l’utilisation postopératoire d’opioïdes. Des recommandations plus claires pour l’application de cet outil pourraient optimiser l’estimation des risques et la prophylaxie pour les NVPO, et potentiellement améliorer la qualité de la recherche. Author information: (1)Associate Professor of Anesthesiology, University of Central Florida, Orlando, FL, USA. pziemann@yahoo.com. (2)Envision Healthcare, Saint Augustine, FL, USA. pziemann@yahoo.com. (3)Anesthesiology and Surgery, Tufts University School of Medicine, Boston, USA. (4)Anesthesia for Research and Development, Department of Anesthesiology and Critical Care, VA Boston Healthcare System, Boston, USA. (5)Surgery, Vanderbilt University Medical Center, Nashville, USA. (6)Bariatric and Minimally Invasive Surgery, Yale School of Medicine, New Haven, USA. (7)Associate Professor of Anesthesiology, University of California, San Diego, CA, USA. (8)Outcomes Research Consortium, Cleveland, USA. (9)International Society for the Perioperative Care of Obese Patients, Louisville, USA. A common predictive measure of postoperative nausea and vomiting (PONV) is the Apfel score. Although tested in many different operations, it has not been tested extensively in oral and maxillofacial surgery (OMFS). This study was designed to determine whether it applied to OMFS and whether there were other factors in this population that would improve its accuracy. A retrospective chart review was carried out on a randomly selected group of patients who had OMFS during a 10-month period. In addition to the Apfel score risk factors, PONV data were collected in relation to type of anesthetic induction and maintenance, type of surgery, use of maxillomandibular fixation (MMF), use of opioids, and anesthesia and surgery times. One-hundred and sixty-seven patients were included in the analysis; 24% had nausea and 11% had nausea and vomiting. Patients who had orthognathic or temporomandibular joint surgery had the highest rate of PONV. Young age, anesthesia and operation time, and use of MMF were also associated with increased PONV. Adding age, MMF or limited postoperative mouth opening, and surgery type to the Apfel score should make it more predictive in OMFS. PURPOSE: To compare two of the latest published scores for predicting postoperative nausea and vomiting (PONV) in potentially high-risk patients. METHODS: Adult in-patients scheduled for throat, thyroid, breast or gynecological surgery under general inhalational anesthesia were studied prospectively over 24 hr for PONV. The latest published score considers four risk factors: female gender, previous history of PONV or motion sickness, non-smoking status and postoperative use of opioids (Apfel-score). The previously published score includes, in addition to these factors, duration, type of anesthesia and surgery (Sinclair-score). The two scores were compared by calculating the area under a receiver operating characteristic (ROC)-curve and plotting calibration curves of the predicted and the observed incidence of PONV. RESULTS: Five hundred consecutive patients were studied and patients who received prophylactic antiemetics were excluded. Of the remaining 428 patients 49.5% suffered from PONV. Multivariable analysis revealed that age, gender, previous history of PONV or motion sickness and postoperative use of opioids had an impact on PONV. The area under the ROC-curve was significantly greater for the Apfel-score compared to the Sinclair-score (0.71 vs 0.64, P=0.008). The correlation between the predicted (x) and the observed (y) incidence for the Apfel-score and for the Sinclair-score was y=1.08x - 0.07 and y=0.93x + 0.27. CONCLUSION: In our hospital, the simplified Apfel-score presented with favourable discriminating and calibration properties for predicting the risk of PONV. Therefore, we have implemented this score in our daily clinical practice as well as in an ongoing antiemetic trial. OBJECTIVE: Postoperative nausea and vomiting (PONV) still represent an important problem in surgery. Treatment and prevention of PONV requires accurate risk stratification. The simplified Apfel-score includes the four factors female gender, no smoking, postoperative use of opioides and previous PONV or motion-sickness in patients' history. Each of these risk factors is supposed to elevate the PONV-incidence about 20%. The aim of the study was to validate this clinical risk assessment score in patients with high risk for PONV. METHODS: In a prospective study 93 patients with high risk preoperative score for PONV (Apfel Score III and IV) were analyzed. Patients and nurses were interviewed using a standardized questionnaire at the time of discharge from the post-anesthesia care unit (PACU) as well as 6 hours and 24 hours after admission to the PACU. General anaesthesia was applied as total intravenous anaesthesia (TIVA) with mivacurium, propofol and remifentanil (no nitrous oxide / FI 02 0.5) RESULTS: In the group with Apfel score III PONV occurred in 59.7% of patients and in the Apfel score group IV in 91.3% of all patients. The incidence of PONV corresponds to the predicted values of 60% for Apfel III and 80% for Apfel IV although the use of TIVA should have reduced the incidence of PONV about 26%. This apparent overestimation could be explained by the frequent questioning of patients and nurses for PONV leading to assessment of very minor symptoms. CONCLUSION: The Apfel-score is a useful and simple tool for stratification of patients with high risk for PONV.

Is PPROM a condition that occurs in males or females?

Preterm premature rupture of fetal membranes (PPROM) occurs in pregnant females.

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OBJECTIVES: Preterm premature rupture of membranes (PPROM) is defined as a rupture of the amniotic membranes occurring before 37 weeks of gestation and before the onset of labor. Extreme PPROM occurs prior to 26 weeks gestation and contributes to an increased risk of prematurity, leading to maternal and fetal complications. This study aims to estimate the risk factors associated with various maternal complications and to determine the worst outcomes in Omani females with extreme PPROM. METHODS: A retrospective cohort study was conducted on 44 women with extreme PPROM, who delivered at Sultan Qaboos University Hospital (SQUH) from January 2006 to December 2011. Women with incomplete information, multiple gestations, or a preterm delivery resulting from medical intervention, as well as women who delivered elsewhere were excluded from the study. RESULTS: Forty-four women with extreme PPROM were included in our study. The results revealed the most important risk factor to be history of infection, which was noted in 24 study participants. The mean maternal age was 30 years. The mean gestational age at PPROM and at delivery were 20.7±3.2 (range: 16-26 weeks) and 29.7±7.6 weeks (range: 17-40 weeks), respectively. The maternal complications observed in this study included; infection which was seen in 20 (45%) patients, antepartum hemorrhage in 11 (25%) patients, and cesarean section which was required in 12 (27%) patients. There was no significant association between risk factors such as gestational age at delivery, parity, maternal age at PPROM, or maternal Body Mass Index (BMI) and cesarean section rate. Infection played a major role, both as a risk factor and in causing extreme PPROM, which in turn increased in 12 patients (27%). In the multivariable model for predicting the need for cesarean section (gestational age at delivery, parity, maternal age at PPROM in years and maternal BMI), none of the factors were statistically significant. CONCLUSION: Overall, concurrent infection rate was high among patients presenting with extreme PPROM. None of the baseline maternal factors predicted the need for cesarean section. This is likely due to the small sample size; hence, larger prospective studies are needed to confirm these findings. Preterm premature rupture of membranes (PPROM) is defined as rupture of membrane that happens before the onset of labor and 37 weeks. Subclinical intrauterine infection is major etiological factor in the pathogenesis that increases mortality and morbidity associated with PPROM. This study was performed to evaluate the levels of maternal serum urokinase plasminogen activator receptor (uPAR), ST2 and interleukin (IL)-33 in PPROM and its relation with maternofetal infectious and morbidity. A total of 74 pregnant women, of which 49 with PPROM between 24 and 34 weeks gestation, and 25 normal pregnant women without PPROM were included in the study. Study group was seperated into 2 subgroups as PPROM and PPROM-histological chorioamnionitis (PPROM-HC). The blood samples were taken before the any medication. The mean serum IL-33, ST2, and uPAR values in the PPROM-HC group were significantly higher than PPROM and control group. The cut-off values of IL-33, ST2, and uPAR were determined as 5.2, 2 and 6.4 ng/mL, respectively. A cut-off value of IL-33 of 5.2 ng/mL, the cut-off of ST2 of 2 ng/mL and the cut-off of uPAR of 6.4 ng/mL showed similar sensitivity, specificity to IL-6 and the better sensitivity and specificity as compared to C-reactive protein and total leucocyte count in predicting infection in PPROM. We evaluated the predictive value of uPAR, ST2 and IL-33 in PPROM and we concluded that all of them can be used as reliable biomarkers to determine infection without any clinical signs but it is necessary to be studied in different cohort groups and infectious diseases. A 32-year-old Caucasian woman of body mass index (BMI) 46 presented with urinary symptoms to accident and emergency (A&E). Acute pyelonephritis was the diagnosis. Transabdominal scan revealed a live term fetus. Both the partners were unaware of the ongoing pregnancy until diagnosed. She underwent emergency cesarean under general anaesthesia (GA) for nonreassuring CTG, severe chorioamnionitis, and moderate preecclampsia. A live male baby weighing 4400 grams delivered in poor condition. Placental tissue on culture exhibited scanty growth of pseudomonas aeruginosa. Chorioamnionitis due to pseudomonas is rare, with high neonatal morbidity and mortality. It is mostly reported among preterm prelabor rupture of membranes (PPROM). Educating the community especially morbidly obese women if they put on excessive weight or with irregular periods should seek doctor's advice and exclude pregnancy. For the primary care provider, it is of great importance to exclude pregnancy in any reproductive woman presenting with abdominal complaints. This case also brings to clinicians notice that pseudomonas can be community-acquired and can affect term pregnancies with intact or prolonged rupture of membranes. Objective: To evaluate the efficacy and safety of amniopatch in pregnancies associated with spontaneous preterm premature rupture of fetal membranes (PPROM).Methods: A randomized controlled trial that involved 100 women diagnosed with PPROM between 24 and 34 weeks of gestational age. Participants were randomized equally into two groups. Group I in which amniopatch was done in addition to the routine management. Group II was treated with routine management including antibiotics and corticosteroids.Results: Amniopatch was successful in complete sealing of the membrane defect in 6/50 (12%) of women while none the control group have undergone similar sealing (p = .0144, RR = 0.88). Women in the amniopatch group showed a significant increase of AFI compared to controls (12 versus 0, p = .0001, RR = 0.56).Conclusion: The amniopatch procedure is a successful technique that safely enhances sealing of fetal membranes and restore the AFI.Clinical trial registration: NCT03473210SynopsisThe amniopatch procedure is a successful technique that could be done safely to enhance sealing the fetal membranes and restoring the AFI after PPROM. Preterm premature rupture of membranes (PPROM) is a condition leading to an increased risk of maternal and neonatal morbidity and mortality in pregnant women. To prevent this complication, some studies have proposed using prophylactic progesterone. However, due to lack of sufficient relevant data, there is still need for further studies in this regard. This study was performed to determine the effect of rectal progesterone on the latent phase and maternal and neonatal outcome variables in females with PPROM. During the present randomized clinical trial study (IRCT201512077676N4), a total of 120 patients with PPROM at pregnancy ages between 26 and 32 weeks were randomly assigned to 2 equal intervention and control groups. In the intervention group, progesterone suppositories (400 mg per night) were administered until delivery or completion of the 34th gestational week and was compared with placebo effect in control group. The latent phase and maternal and neonatal outcome variables were compared between the two groups. The mean age of patients was 29.56±5.66 (19-42) and 29.88±5.57 (17-40) years in the intervention and control group, respectively. The two groups were almost identical in the confounding factors. The median latent phase was 8.5 days in the intervention group vs. 5 days in the control group in the 28th-30th weeks of gestation, which was significantly higher in the intervention group (P=0.001). Among maternal and neonatal outcome variables, only the mean birth-weight was significantly higher in the intervention group than that in the controls (1609.92±417.28 gr vs. 1452.03±342.35 gr, P=0.03). Administration of progesterone suppository in patients with PPROM at gestational ages of 28 to 30 weeks is effective in elongating the latent phase and increasing birth-weight with no significant complications. The preterm premature rupture of membranes (PPROM) is a common condition in pregnant women and is associated with significant maternal and perinatal morbidity. Most of the time, the diagnosis is done during physical examination. However, in 10%-20% of equivocal cases, biological markers are needed to confirm the diagnosis, especially when leakage of fluid is low or intermittent. In these cases, a quick and reliable diagnosis is necessary for applying the appropriate measures to reduce perinatal complications. The prognosis in PPROM is linked to maternal inflammatory markers that might predict perinatal infection, and therefore be helpful to decide the timing of the delivery. Nevertheless, further research is needed to identify robust biological markers for the diagnosis of PPROM in equivocal cases and for the prognosis. OBJECTIVE: The primary aim of this study was to assess the rate and load of amniotic fluid Chlamydia trachomatis DNA and their associations with intra-amniotic infection and intra-uterine inflammatory complications in women with preterm prelabor rupture of membranes (PPROM). The secondary aim was to assess the short-term morbidity of newborns from PPROM pregnancies complicated by amniotic fluid C. trachomatis DNA. METHODS: A retrospective study of 788 women with singleton pregnancies complicated by PPROM between 24 + 0 and 36 + 6 weeks of gestation was performed. Transabdominal amniocenteses were performed at the time of admission. C. trachomatis DNA in the amniotic fluid was assessed by real-time polymerase chain reaction using a commercial AmpliSens® C. trachomatis/Ureaplasma/Mycoplasma hominis-FRT kit, and the level of Ct DNA was quantified. RESULTS: Amniotic fluid C. trachomatis DNA complicated 2% (16/788) of the PPROM pregnancies and was present in very low loads (median 57 copies DNA/mL). In addition to amniotic fluid C. trachomatis DNA, other bacteria were detected in 62% (10/16) of the C. trachomatis DNA-complicated PPROM pregnancies. Amniotic fluid C. trachomatis DNA was associated with intra-amniotic infection, histologic chorioamnionitis (HCA), and funisitis in 31%, 47%, and 33%, respectively. The presence of C. trachomatis DNA accompanied by Ureaplasma species in the amniotic fluid was associated with a higher rate of HCA than the presence of amniotic fluid C. trachomatis DNA alone. The composite neonatal morbidity in newborns from PPROM pregnancies with amniotic fluid C. trachomatis DNA was 31%. CONCLUSION: The presence of C. trachomatis DNA in the amniotic fluid is a relatively rare condition in PPROM. Amniotic fluid C. trachomatis DNA in PPROM is not related to intensive intra-amniotic and intr-auterine inflammatory responses or adverse short-term neonatal outcomes. Objective: To show that infants delivered prematurely because of preterm premature rupture of the membranes (PPROM) show a tendency for asymmetric intrauterine growth retardation (IUGR). At the same time, to demonstrate that these pregnancies exhibit nutritional deprivation by the presence of correspondingly smaller placentas, as demonstrated by the placental-fetal ratio.Study Design: A prospective study was performed over 2 years comparing the tendency for IUGR in infants born of pregnancies with PPROM (N = 86), as compared to normal term controls (N = 351). The tendency for growth restriction in the neonate was determined using the ponderal index at birth. Exclusion criteria included pregnancies complicated by diabetes, hypertension, preeclampsia, multiple gestations, genetic, and other recognized causes of IUGR. Four controls were selected for each study patient who delivered the same day. The mean ponderal index (PI(m)) was compared, as were the mean placental-fetal weight ratios (PWt/PI)(m), for both groups. A comparison of the PI(m) and (PWt/PI)(m) for infants delivered prematurely with and without rupture of membranes was also noted. Analysis was by the paired Student's t test and chi(2) test.Results: The newborn PI was found to be independent of maternal age, gravidy, and parity. The number of male and female infants were not significantly different in the control and study groups. The PI(m) for the PPROM group (PI(m) = 2.33, SD = 0.29) was significantly smaller than that for the controls (PI(m) = 2.52, SD = 0.23) (P <.0005). Similarly the (PWt/PI)(m) for the PPROM group (mean = 194.8, SD = 49.9) was significantly smaller than that for the control group (mean = 273.4, SD = 54.2) (P <.0005). Mean values of PI and PWt/PI for preterm deliveries with, as compared to without rupture of membranes, showed no significant differences.Conclusions: Using the ponderal index to detect IUGR, a significant association of IUGR is noted in infants delivered subsequent to PPROM. This growth impairment is accompanied by significantly smaller placentas. OBJECTIVES: The purpose of this study was to examine the potential impact of severe Ovarian hyper stimulation syndrome (OHSS) on the risk of preterm birth. Severe ovarian hyperstimulation syndrome is a serious complication in the methods of in vitro fertilization. The pathophysiology of this process is not clear enough and the treatment is symptomatic. Human chorionic gonadotropin (h-CG) is the most important known cause of this condition. Findings of other authors often do not match when it comes to complications that may occur in pregnancy. METHODS: In the Gynecology and Obstetrics Clinic "Narodni Front" a case control study was conducted on 50 female patients with severe forms of OHSS in the period from January 2008 to March 2015. A control group was created based on age and it involved 59 patients with pregnancy achieved with IVF/ICSI during the same period, but in which OHSS did not occur. RESULTS: Patients with the pregnancy complicated by OHSS, had a considerably higher rate of preterm labor, whether this was labor before gestation week 37 (56.0% vs. 30.5%) or before gestation week 34 (34.0% vs. 6.8%); significantly lower weight of newborns, as in the newborns with low body weight <2500g (45.6% vs. 25.0%) and specially in the newborn with very low body weight <1500 grams (19.1% vs. 3.8%), as well as preterm premature rupture of membranes (PPROM), (11.76% vs. 1.59%). CONCLUSIONS: Pregnancy achieved by the IVF/ICSI method in which severe form of OHSS has been developed could have an increased risk of preterm birth. AIM: To determine whether preterm premature rupture of membranes (PPROM) before 24 weeks is an independent risk factor for poor outcome in preterm neonates. METHODS: A retrospective comparative cohort study was conducted, including viable premature infants born between 25 and 34-weeks gestation. Each preterm case with early PPROM was matched with two preterm controls of the same gestational age at birth, sex and birth date and who were born spontaneously with intact membranes. Logistic regression was performed to identify independent risk factors associated with composite respiratory and perinatal adverse outcomes for the overall population of preterm infants. RESULTS: Thirty-five PPROM cases were matched with 70 controls. Extreme prematurity (26-28 weeks) was an independent risk factor for composite perinatal adverse outcomes [odds ratio (OR) 43.9; p = 0.001]. Extreme prematurity (OR 42.9; p = 0.001), PPROM (OR 7.1; p = 0.01), male infant (OR 5.2; p = 0.02) and intrauterine growth restriction (IUGR, OR 4.8; p = 0.04) were factors for composite respiratory adverse outcomes. CONCLUSION: Preterm premature rupture of membranes before viability represents an independent risk factor for composite respiratory adverse outcomes in preterm neonates. Extreme prematurity may represent the main risk factor for both composite respiratory and perinatal adverse outcomes. Background: Placental dysfunction, inflammation and degradation of fetal membranes has been hypothesized as a cause of preterm prelabor of rupture of membranes.Objective: To examine the effect of aspirin, an anti-inflammatory agent, on the prevalence of preterm prelabor rupture of membranes (PPRoMs).Methods: A retrospective analysis was conducted to examine the effect of aspirin on the prevalence of PPRoM. Aspirin (150 mg, nocte) was prescribed to women who were identified through a screening program at 11-13+6 weeks' gestation as being at high risk for developing early-onset preeclampsia. Women who were at low risk for developing preeclampsia did not receive aspirin. The prevalence of PPRoM was compared with an observational cohort.Results: In the observational cohort, there were 3027 women, including 32 (1.1%) cases of PPRoM. The prevalence of PPRoM in the high risk group was 3.1% (4/128) and was statistically significantly higher compared to the low risk group (1.0%) (28/2899). The relative risk was 3.02 (95% CI 1.2-7.7; p= .04). In the interventional cohort, there were 7280 women, with 114 (1.6%) cases of PPRoM. The prevalence of PPRoM in the high risk group who were treated with aspirin was 1.8% (14/766) compared to 1.5% (100/6516) in the low risk group (p= .54). The prevalence of PPRoM in high risk patients in the observational group (who did not receive aspirin) compared with the high risk patients in the interventional group (who were treated with aspirin) was not statistically significant (p= .31).Conclusions: PPRoM is significantly associated with a description of high risk for ePET; although, this algorithm is not a good screening tool for predicting PPRoM. Aspirin treatment of women deemed high risk for ePET is safe in the context of PPRoM and there may be some reduction in prevalence of PPRoM in treated high risk women; although, this study was not powered to demonstrate a small reduction in the prevalence of PPRoM. The findings merit further investigation through a larger prospective study with adequate sample size. Preterm premature rupture of membranes (PPROM) occurs in 1% to 2% of births. Impact of PPROM is greatest in low- and middle-income countries where prematurity-related deaths are most common. Recent investigations identify cytokine and matrix metalloproteinase activation, oxidative stress, and apoptosis as primary pathways to PPROM. These biological processes are initiated by heterogeneous etiologies including infection/inflammation, placental bleeding, uterine overdistention, and genetic polymorphisms. We hypothesize that pathways to PPROM overlap and act synergistically to weaken membranes. We focus our discussion on membrane composition and strength, pathways linking risk factors to membrane weakening, and future research directions to reduce the global burden of PPROM. BACKGROUND: Bronchopulmonary dysplasia (BPD), a major source of morbidity in premature neonates, has been associated with intrauterine infection and preterm birth. Both preterm premature rupture of membranes (PPROM) and spontaneous preterm labor (sPTL) are linked with intrauterine inflammation. Whether PPROM and sPTL, as two phenotypic categories of preterm birth, are associated with exposure to different degrees and durations of inflammation that might impact fetal lung development is unknown. PPROM may be associated with longer latency until delivery, which is beneficial for neonatal mortality, but may impart greater injury risk to the developing fetal lungs. It is unknown if PPROM is associated with a greater risk of adverse neonatal respiratory outcomes than sPTL. OBJECTIVE: The objective of this study was to determine if PPROM imparts a differentially greater risk for neonatal BPD than sPTL. A secondary objective was to determine if PPROM was associated with a greater risk of adverse neonatal respiratory outcomes other than BPD and whether gestational latency following PPROM or sPTL diagnosis constitutes a risk factor for fetal lung injury. STUDY DESIGN: We conducted a retrospective secondary analysis of a large cohort of women at risk for spontaneous preterm birth, who were originally enrolled in a randomized controlled trial of magnesium sulfate versus placebo examining neuroprotection. For our study, we included women with a singleton pregnancy complicated by PPROM or sPTL and delivery between 24 and 34 weeks gestational age. Cases with multiple gestation, congenital anomalies, maternal seropositivity for human immunodeficiency virus, or hypertensive diseases of pregnancy (including preeclampsia) were excluded. The primary outcome was BPD. Secondary outcomes were respiratory distress syndrome (RDS), transient tachypnea of the newborn (TTN), requirement for mechanical ventilation, pneumonia, neonatal sepsis, fetal or neonatal death, and a composite of adverse neonatal respiratory outcomes including (BPD, pneumonia, RDS, and TTN). Statistical analyses included chi-square, Student's t-test and logistic and multiple regression. RESULTS: A total of 1729 women were included in this analysis including 1554 with PPROM and 175 with sPTL. Women in the PPROM group were more likely to be older, not of Hispanic race, married, more educated, have smoked during pregnancy and have a greater body mass index. The BPD rate was not significantly different following PPROM versus sPTL. Neonates in the PPROM group experienced a lower rate of pneumonia (p = .001), neonatal sepsis (p = .009) and patent ductus arterious (PDA) requiring either medical or surgical therapy (p < .001) than neonates in the sPTL group. Chorioamnionitis was more common in the PPROM group (p = .008) than the sPTL group. After multivariable logistic regression with BPD or composite of adverse neonatal respiratory outcomes as the dependent outcomes, and controlling for gestational age at delivery, maternal smoking history, duration of mechanical ventilation and RDS, there was no significant difference between PPROM and sPTL. CONCLUSIONS: BPD rates were not significantly different in neonates born to women following PPROM versus sPTL. However, PPROM was associated with lower rates of pneumonia, neonatal sepsis, and PDA requiring therapy in the univariate analysis, but not the multivariate analysis. Neonatal respiratory outcomes may have a similar phenotypic overlap regardless of whether preterm birth follows PPROM or sPTL.

What is the target of Sutimlimab?

Sutimlimab is a novel humanized monoclonal antibody directed against classical pathway complement factor C1s.

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Deposition of autoantibodies (α-BP180 and BP230) and complement along the dermal-epidermal-junction is a hallmark of bullous pemphigoid and was shown to be important for pathogenesis. Given the adverse effects of standard treatment (glucocorticoids, immunosuppressants), there is an unmet need for safe and effective therapies. In this phase 1 trial, we evaluated the safety and activity of BIVV009 (sutimlimab, previously TNT009), a targeted C1s inhibitor, in 10 subjects with active or past bullous pemphigoid (NCT02502903). Four weekly 60 mg/kg infusions of BIVV009 proved sufficient for inhibition of the classical complement pathway in all patients, as measured by CH50. C3c deposition along the dermal-epidermal junction was partially or completely abrogated in 4 of 5 patients, where it was present at baseline. BIVV009 was found to be safe and tolerable in this elderly population, with only mild to moderate adverse events reported (e.g., headache, fatigue). One serious adverse event (i.e., fatal cardiac decompensation) occurred at the end of the post-treatment observation period in an 84-year-old patient with a history of diabetes and heart failure, but was deemed unlikely to be related to the study drug. This trial provides the first results with a complement-targeting therapy in bullous pemphigoid, to our knowledge, and supports further studies on BIVV009's efficacy and safety in this population. BACKGROUND: Cold agglutinin disease is a rare autoimmune hemolytic anemia characterized by hemolysis that is caused by activation of the classic complement pathway. Sutimlimab, a humanized monoclonal antibody, selectively targets the C1s protein, a C1 complex serine protease responsible for activating this pathway. METHODS: We conducted a 26-week multicenter, open-label, single-group study to assess the efficacy and safety of intravenous sutimlimab in patients with cold agglutinin disease and a recent history of transfusion. The composite primary end point was a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without red-cell transfusion or medications prohibited by the protocol. RESULTS: A total of 24 patients were enrolled and received at least one dose of sutimlimab; 13 patients (54%) met the criteria for the composite primary end point. The least-squares mean increase in hemoglobin level was 2.6 g per deciliter at the time of treatment assessment (weeks 23, 25, and 26). A mean hemoglobin level of more than 11 g per deciliter was maintained in patients from week 3 through the end of the study period. The mean bilirubin levels normalized by week 3. A total of 17 patients (71%) did not receive a transfusion from week 5 through week 26. Clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study. Activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay. Increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue coincided with inhibition of the classic complement pathway. At least one adverse event occurred during the treatment period in 22 patients (92%). Seven patients (29%) had at least one serious adverse event, none of which were determined by the investigators to be related to sutimlimab. No meningococcal infections occurred. CONCLUSIONS: In patients with cold agglutinin disease who received sutimlimab, selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue. (Funded by Sanofi; CARDINAL ClinicalTrials.gov number, NCT03347396.). Cold agglutinin disease (CAD) causes predominantly extravascular hemolysis and anemia via complement activation. Sutimlimab is a novel humanized monoclonal antibody directed against classical pathway complement factor C1s. We aimed to evaluate the safety and efficacy of long-term maintenance treatment with sutimlimab in patients with CAD. Seven CAD patients treated with sutimlimab as part of a phase 1B study were transitioned to a named patient program. After a loading dose, patients received biweekly (once every 2 weeks) infusions of sutimlimab at various doses. When a patient's laboratory data showed signs of breakthrough hemolysis, the dose of sutimlimab was increased. Three patients started with a dose of 45 mg/kg, another 3 with 60 mg/kg, and 1 with a fixed dose of 5.5 g every other week. All CAD patients responded to re-treatment, and sutimlimab increased hemoglobin from a median initial level of 7.7 g/dL to a median peak of 12.5 g/dL (P = .016). Patients maintained near normal hemoglobin levels except for a few breakthrough events that were related to underdosing and which resolved after the appropriate dose increase. Four of the patients included were eventually treated with a biweekly 5.5 g fixed-dose regimen of sutimlimab. None of them had any breakthrough hemolysis. All patients remained transfusion free while receiving sutimlimab. There were no treatment-related serious adverse events. Overlapping treatment with erythropoietin, rituximab, or ibrutinib in individual patients was safe and did not cause untoward drug interactions. Long-term maintenance treatment with sutimlimab was safe, effectively inhibited hemolysis, and significantly increased hemoglobin levels in re-exposed, previously transfusion-dependent CAD patients. Conflict of interest statement: S Berentsen has received research support from Mundipharma, travel support from Alexion and Apellis, lecture honoraria from Alexion, Bioverativ, and Janssen-Cilag, and has consulted for Apellis, Bioverativ, Momenta Pharmaceuticals, and True North Therapeutics, outside the submitted work. A Röth has received research support from Alexion and Roche, travel support from Alexion and AbbVie, lecture honoraria from Alexion, Roche, and Novartis, and has consulted for Alexion, Bioverativ, Novartis, and True North Therapeutics, outside the submitted work. U Randen reports no conflicts of interest. B Jilma has received reimbursement for travel for presentations and scientific advice from True North Therapeutics (a Bioverativ Company), outside the submitted work. GE Tjønnfjord has received research support from Mundipharma, Janssen-Cilag and Alexion Pharma, and lecture honoraria from Janssen-Cilag, Alexion Pharma, and Roche Pharma, outside the submitted work. Complement-mediated hemolytic anemias can either be caused by deficiencies in regulatory complement components or by autoimmune pathogenesis that triggers inappropriate complement activation. In paroxysmal nocturnal hemoglobinuria (PNH) hemolysis is entirely complement-driven. Hemolysis is also thought to be complement-dependent in cold agglutinin disease (CAD) and in paroxysmal cold hemoglobinuria (PCH), whereas warm antibody autoimmune hemolytic anemia (wAIHA) is a partially complement-mediated disorder, depending on the subtype of wAIHA and the extent of complement activation. The pathophysiology, clinical presentation, and current therapies for these diseases are reviewed in this article. Novel, complement-directed therapies are being rapidly developed. Therapeutic terminal complement inhibition using eculizumab has revolutionized the therapy and prognosis in PNH but has proved less efficacious in CAD. Upstream complement modulation is currently being investigated and appears to be a highly promising therapy, and two such agents have entered phase II and III trials. Of these, the anti-C1s monoclonal antibody sutimlimab has shown favorable activity in CAD, while the anti-C3 cyclic peptide pegcetacoplan appears to be promising in PNH as well as CAD, and may also have a therapeutic potential in wAIHA. The last decades have seen great progress in the treatment of cold agglutinin disease (CAD). Comparative trials are lacking, and recommendations must be based mainly on nonrandomized trials and will be influenced by personal experience. Herein, current treatment options are reviewed and linked to 3 cases, each addressing specific aspects of therapy. Two major steps in CAD pathogenesis are identified, clonal B-cell lymphoproliferation and complement-mediated hemolysis, each of which constitutes a target of therapy. Although drug treatment is not always indicated, patients with symptomatic anemia or other bothersome symptoms should be treated. The importance of avoiding ineffective therapies is underscored. Corticosteroids should not be used to treat CAD. Studies on safety and efficacy of relevant drugs and combinations are briefly described. The author recommends that B cell-directed approaches remain the first choice in most patients requiring treatment. The 4-cycle bendamustine plus rituximab combination is highly efficacious and sufficiently safe and induces durable responses in most patients, but the time to response can be many months. Rituximab monotherapy should be preferred in frail patients. The complement C1s inhibitor sutimlimab is an emerging option in the second line and may also find its place in the first line in specific situations. Cold agglutinin disease is a difficult-to-treat autoimmune hemolytic anemia in which immunoglobulin M antibodies bind to erythrocytes and fix complement, resulting in predominantly extravascular hemolysis. This trial tested the hypothesis that the anti-C1s antibody sutimlimab would ameliorate hemolytic anemia. Ten patients with cold agglutinin disease participated in the phase 1b component of a first-in-human trial. Patients received a test dose of 10-mg/kg sutimlimab followed by a full dose of 60 mg/kg 1 to 4 days later and 3 additional weekly doses of 60 mg/kg. All infusions were well tolerated without premedication. No drug-related serious adverse events were observed. Seven of 10 patients with cold agglutinin disease responded with a hemoglobin increase >2 g/dL. Sutimlimab rapidly increased hemoglobin levels by a median of 1.6 g/dL within the first week, and by a median of 3.9 g/dL (interquartile range, 1.3-4.5 g/dL; 95% confidence interval, 2.1-4.5) within 6 weeks (P = .005). Sutimlimab rapidly abrogated extravascular hemolysis, normalizing bilirubin levels within 24 hours in most patients and normalizing haptoglobin levels in 4 patients within 1 week. Hemolytic anemia recurred when drug levels were cleared from the circulation 3 to 4 weeks after the last dose of sutimlimab. Reexposure to sutimlimab in a named patient program recapitulated the control of hemolytic anemia. All 6 previously transfused patients became transfusion-free during treatment. Sutimlimab was safe, well tolerated, and rapidly stopped C1s complement-mediated hemolysis in patients with cold agglutinin disease, significantly increasing hemoglobin levels and precluding the need for transfusions. This trial was registered at www.clinicaltrials.gov as #NCT02502903. Complement is an elaborate system of innate immunity. Genetic variants and autoantibodies leading to excessive complement activation are implicated in a variety of human diseases. Among them, the hematologic disease paroxysmal nocturnal hemoglobinuria (PNH) remains the prototypic model of complement activation and inhibition. Eculizumab, the first-in-class complement inhibitor, was approved for PNH in 2007. Addressing some of the unmet needs, a long-acting C5 inhibitor, ravulizumab, and a C3 inhibitor, pegcetacoplan, have also now been approved for PNH. Novel agents, such as factor B and factor D inhibitors, are under study, with very promising results. In this era of several approved targeted complement therapeutics, selection of the proper drug must be based on a personalized approach. Beyond PNH, complement inhibition has also shown efficacy and safety in cold agglutinin disease, primarily with the C1s inhibitor of the classical complement pathway sutimlimab, as well as with pegcetacoplan. Furthermore, C5 inhibition with eculizumab and ravulizumab, as well as inhibition of the lectin pathway with narsoplimab, is being investigated in transplantation-associated thrombotic microangiopathy. With this revolution of next-generation complement therapeutics, additional hematologic entities, such as delayed hemolytic transfusion reaction or immune thrombocytopenia, might also benefit from complement inhibitors. Therefore, this review aims to describe state-of-the-art knowledge of targeting complement in hematologic diseases, focusing on (1) complement biology for the clinician, (2) complement activation and therapeutic inhibition in prototypic complement-mediated hematologic diseases, (3) hematologic entities under investigation for complement inhibition, and (4) other complement-related disorders of potential interest to hematologists.

Can parasite infections by Schistosoma japonicum prevent or improve asthma?

A peptide named as SJMHE1 from Schistosoma japonicum can suppress asthma in mice.

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The "hygiene hypothesis" is a theory try to explain the dramatic increases in the prevalence of autoimmune and allergic diseases over the past two to three decades in developed countries. According to this theory, reduced exposure to parasites and microorganisms in childhood is the main cause for the increased incidences of both T helper 1 (Th1)-mediated autoimmunity and Th2-mediated allergy. In this study, we investigated the impact of Schistosoma japonicum infection on the allergic airway inflammation induced by repeated intracheal inoculations of house dust mites (HDM), which is a Th17 and neutrophils dominant murine asthma model, mimicking severe asthma. We found that S. japonicum infection downregulated airway hyperresponsiveness. The infiltrating cells, Th17 and Th2 effector cytokines in the bronchoalveolar lavage (BAL) fluids and lungs were significantly reduced in the infected mice. Our findings indicated that S. japonicum infection was able to effectively inhibit host's allergic airway inflammation, which may be related to the upregulated Treg cells upon infection. To our knowledge, it is the first study to reveal the impact of S. japonicum infection on house dust mite induced severe asthma. More in depth investigation is need to elucidate the underlying mechanisms. Helminths and their products can shape immune responses by modulating immune cells, which are dysfunctional in inflammatory diseases such as asthma. We previously identified SJMHE1, a small molecule peptide from the HSP60 protein of Schistosoma japonicum. SJMHE1 can inhibit delayed-type hypersensitivity and collagen-induced arthritis in mice. In the present study, we evaluated this peptide's potential intervention effect and mechanism on ovalbumin-induced asthma in mice. SJMHE1 treatment suppressed airway inflammation in allergic mice, decreased the infiltrating inflammatory cells in the lungs and bronchoalveolar lavage fluid, modulated the production of pro-inflammatory and anti-inflammatory cytokines in the splenocytes and lungs of allergic mice, reduced the percentage of Th2 cells and increased the proportion of Th1 and regulatory T cells (Tregs). At the same time, Foxp3 and T-bet expression increased, and GATA3 and RORγt decreased in the lungs of allergic mice. We proved that SJMHE1 can interrupt the development of asthma by diminishing airway inflammation in mice. The down-regulation of Th2 response and the up-regulation of Th1 and Tregs response may contribute to the protection induced by SJMHE1 in allergic mice. SJMHE1 can serve as a novel therapy for asthma and other allergic or inflammatory diseases. Asthma, a chronic inflammatory disorder of the airways, is coordinated by Th2 cells in both human asthmatics and animal models of allergic asthma. It has been shown that helminth infections including Schistosoma mansoni may modulate atopic diseases including asthma. In the present study, BALB/c mice were infected with bisexual and unisexual (male) S. japonicum, respectively, prior to ovalbumin (OVA) sensitization and challenge. Compared to mice with OVA sensitization/challenge alone, S. japonicum infection led to a significant decrease of eosinophil accumulation in bronchoalveolar lavage fluid (BALF) collected 48 h postchallenge, as well as to a marked reduction in inflammatory cell infiltration around the airways and pulmonary blood vessels. Compared to OVA-immunized uninfected mice, the level of OVA-specific serum IgE as well as interleukin (IL)-4 and IL-5 in BALF were reduced, but IL-10 was strongly elevated in mice with preexisting S. japonicum infection prior to OVA immunization. These results suggest that both bisexual and male S. japonicum infections may modulate the development of allergic asthma. A number of epidemiological and clinical studies have suggested an inverse association between allergy and helminth infection, such as Schistosomiasis. Therefore, we hypothesize that Schistosoma japonicum egg antigens, a type of native antigen, can induce production of CD4(+) CD25(+) T cells with regulatory activity, modulating airway inflammation and inhibiting asthma development. The frequency of CD4(+) CD25(+) T cells was determined by flow cytometry for mice treated with ovalbumin (OVA), CD25(+) depletion/OVA, schistosome egg antigens, schistosome egg antigens/OVA and for control mice. The ability of CD25(+) T cells from these mice to suppress T-cell proliferation and cytokine production was investigated both in vivo and in vitro. Results showed that the CD4(+) CD25(+) T cells of OVA-treated mice exhibited impaired control of dysregulated mucosal T helper 2 responses compared to the controls (P < 0.05). Depletion of CD25(+) cells accelerated OVA-induced airway inflammation and increased the expression of interleukin (IL)-5 and IL-4. Treatment with schistosome egg antigens increased the number and suppressive activity of CD4(+) CD25(+) T cells, which made IL-10, but little IL-4. In a murine model of asthma, S. japonicum egg antigens decreased the expression of Th2 cytokines, relieved antigen-induced airway inflammation, and inhibited asthma development. Thus, we provided evidence that S. japonicum egg antigens induced the production of CD4(+) CD25(+) T cells, resulting in constitutive immunosuppressive activity and inhibition of asthma development. These results reveal a novel form of protection against asthma and suggest a mechanistic explanation for the protective effect of helminth infection on the development of allergy. Schistosoma japonicum infection showed protective effects against allergic airway inflammation (AAI). However, controversial findings exist especially regarding the timing of the helminth infection and the underlying mechanisms. Most previous studies focused on understanding the preventive effect of S. japonicum infection on asthma (infection before allergen sensitization), whereas the protective effects of S. japonicum infection (allergen sensitization before infection) on asthma were rarely investigated. In this study, we investigated the protective effects of S. japonicum infection on AAI using a mouse model of OVA-induced asthma. To explore how the timing of S. japonicum infection influences its protective effect, the mice were percutaneously infected with cercaria of S. japonicum at either 1 day (infection at lung-stage during AAI) or 14 days before ovalbumin (OVA) challenge (infection at post-lung-stage during AAI). We found that lung-stage S. japonicum infection significantly ameliorated OVA-induced AAI, whereas post-lung-stage infection did not. Mechanistically, lung-stage S. japonicum infection significantly upregulated the frequency of regulatory T cells (Treg cells), especially OVA-specific Treg cells, in lung tissue, which negatively correlated with the level of OVA-specific immunoglobulin E (IgE). Depletion of Treg cells in vivo partially counteracted the protective effect of lung-stage S. japonicum infection on asthma. Furthermore, transcriptomic analysis of lung tissue showed that lung-stage S. japonicum infection during AAI shaped the microenvironment to favor Treg induction. In conclusion, our data showed that lung-stage S. japonicum infection could relieve OVA-induced asthma in a mouse model. The protective effect was mediated by the upregulated OVA-specific Treg cells, which suppressed IgE production. Our results may facilitate the discovery of a novel therapy for AAI. In areas where schistosomiasis is endemic, a negative correlation is observed between atopy and helminth infection, associated with a low prevalence of asthma. We investigated whether Schistosoma mansoni infection or injection of parasite eggs can modulate airway allergic inflammation in mice, examining the mechanisms of such regulation. We infected BALB/c mice with 30 S. mansoni cercariae or intraperitoneally injected 2,500 schistosome eggs, and experimental asthma was induced by ovalbumin (OVA). The number of eosinophils in bronchoalveolar lavage fluid was higher in the asthmatic group than in asthmatic mice infected with S. mansoni or treated with parasite eggs. Reduced Th2 cytokine production, characterized by lower levels of interleukin-4 (IL-4), IL-5, and immunoglobulin E, was observed in both S. mansoni-treated groups compared to the asthmatic group. There was a reduction in the number of inflammatory cells in lungs of S. mansoni-infected and egg-treated mice, demonstrating that both S. mansoni infection and the egg treatment modulated the lung inflammatory response to OVA. Only allergic animals that were treated with parasite eggs had increased numbers of CD4(+) CD25(+) Foxp3(+) T cells and increased levels of IL-10 and decreased production of CCL2, CCL3, and CCL5 in the lungs compared to the asthmatic group. Neutralization of IL-10 receptor or depletion of CD25(+) T cells in vivo confirmed the critical role of CD4(+) CD25(+) Foxp3(+) regulatory T cells in experimental asthma modulation independent of IL-10. Diabetes and obesity have become the most popular metabolic diseases in the world. A large number of previous studies have shown that glucose and lipid metabolism disorder is an important risk factor and a main cause of diabetes and obesity. Schistosoma is a parasite transmitted by freshwater snails. It can induce a series of inflammatory and immune reactions after infecting the human body, causing schistosomiasis. However, in recent years, studies have found that Schistosoma infection or Schistosoma related products can improve or prevent some immune and inflammatory diseases, such as severe asthma, inflammatory bowel disease, diabetes and so on. Further experiments have also revealed that Schistosoma can promote the secretion of anti-inflammatory factors and regulate the glucose and lipid metabolism in the host body by polarizing immune cells such as T cells, B cells and dendritic cells (DCs). In this review, we summarize studies that investigated Schistosoma and Schistosoma-derived products and their relationship with glycolipid metabolism and related diseases, highlighting potential protective mechanisms.

Describe Multilocus Inherited Neoplasia Allele Syndrome (MINAS)

Genetic testing of hereditary cancer using comprehensive gene panels can identify patients with more than one pathogenic mutation in high and/or moderate-risk-associated cancer genes. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS), which has been potentially linked to more severe clinical manifestations.

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IMPORTANCE: Genetic testing of hereditary cancer using comprehensive gene panels can identify patients with more than one pathogenic mutation in high and/or moderate-risk-associated cancer genes. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS), which has been potentially linked to more severe clinical manifestations. OBJECTIVE: To determine the prevalence and clinical features of MINAS in a large cohort of adult patients with hereditary cancer homogeneously tested with the same gene panel. PATIENTS AND METHODS: A cohort of 1023 unrelated patients with suspicion of hereditary cancer was screened using a validated panel including up to 135 genes associated with hereditary cancer and phakomatoses. RESULTS: Thirteen (1.37%) patients harbouring two pathogenic mutations in dominant cancer-predisposing genes were identified, representing 5.7% (13/226) of patients with pathogenic mutations. Most (10/13) of these cases presented clinical manifestations associated with only one of the mutations identified. One case showed mutations in MEN1 and MLH1 and developed tumours associated with both cancer syndromes. Interestingly, three of the double mutants had a young age of onset or severe breast cancer phenotype and carried mutations in moderate to low-risk DNA damage repair-associated genes; two of them presented biallelic inactivation of CHEK2. We included these two patients for the sake of their clinical interest although we are aware that they do not exactly fulfil the definition of MINAS since both mutations are in the same gene. CONCLUSIONS AND RELEVANCE: Genetic analysis of a broad cancer gene panel identified the largest series of patients with MINAS described in a single study. Overall, our data do not support the existence of more severe manifestations in double mutants at the time of diagnosis although they do confirm previous evidence of severe phenotype in biallelic CHEK2 and other DNA repair cancer-predisposing genes.