tbuckley/cabot-search huggingface dataset:
RIG-I, a novel DAMPs sensor for myoglobin, activates NF-κB/caspase-3 signaling in CS-AKI model
Authors: Peng-Tao Wang, Ning Li, Xin-Yue Wang, Jia-Le Chen, Chen-Hao Geng, Zi-Quan Liu, Hao-Jun Fan, Qi Lv, Shi-Ke Hou, Yan-Hua Gong
Journal: Military Medical Research (2021)

Abstract Background Acute kidney injury (AKI) is the main life-threatening complication of crush syndrome (CS), and myoglobin is accepted as the main pathogenic factor. The pattern recognition receptor retinoicacid-inducible gene I (RIG-I) has been reported to exert anti-viral effects function in the innate immune response. However, it is not clear whether RIG-I plays a role in CS-AKI. The present research was carried out to explore the role of RIG-I in CS-AKI. Methods Sprague-Dawley rats were randomly divided into two groups: the sham and CS groups ( n = 12). After administration of anesthesia, the double hind limbs of rats in the CS group were put under a pressure of 3 kg for 16 h to mimic crush conditions. The rats in both groups were denied access to food and water. Rats were sacrificed at 12 h or 36 h after pressure was relieved. The successful establishment of the CS-AKI model was confirmed by serum biochemical analysis and renal histological examination. In addition, RNA sequencing was performed on rat kidney tissue to identify molecular pathways involved in CS-AKI. Furthermore, NRK-52E cells were treated with 200 μmol/L ferrous myoglobin to mimic CS-AKI at the cellular level. The cells and cell supernatant samples were collected at 6 h or 24 h. Small interfering RNAs (siRNA) was used to knock down RIG-I expression. The relative expression levels of molecules involved in the RIG-I pathway in rat kidney or cells samples were measured by quantitative Real-time PCR (qPCR), Western blotting analysis, and immunohistochemistry (IHC) staining. Tumor necrosis factor-α (TNF-α) was detected by ELISA. Co-Immunoprecipitation (Co-IP) assays were used to detect the interaction between RIG-I and myoglobin. Results RNA sequencing of CS-AKI rat kidney tissue revealed that the different expression of RIG-I signaling pathway. qPCR, Western blotting, and IHC assays showed that RIG-I, nuclear factor kappa-B (NF-κB) P65, p-P65, and the apoptotic marker caspase-3 and cleaved caspase-3 were up-regulated in the CS group ( P &lt; 0.05). However, the levels of interferon regulatory factor 3 (IRF3), p-IRF3 and the antiviral factor interferon-beta (IFN-β) showed no significant changes between the sham and CS groups. Co-IP assays showed the interaction between RIG-I and myoglobin in the kidneys of the CS group. Depletion of RIG-I could alleviate the myoglobin induced expression of apoptosis-associated molecules via the NF-κB/caspase-3 axis. Conclusion RIG-I is a novel damage-associated molecular patterns (DAMPs) sensor for myoglobin and participates in the NF-κB/caspase-3 signaling pathway in CS-AKI. In the development of CS-AKI, specific intervention in the RIG-I pathway might be a potential therapeutic strategy for CS-AKI.
Mannose-binding lectin-associated serine protease-2 (masp-2) plasma concentration in children with asthma exacerbation
Authors: S. Tereshchenko, M. Smolnikova, M. Shubina, M. Malinchik
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Mannose-binding lectin (MBL)-associated serine protease-2 (MASP-2) is an indispensable enzyme for the activation of the lectin pathway (LP) of complement - one of the important pathways of the first line non-specific defence against infections. MASP-2 complexed with pattern recognition molecules such as MBL, other collectins, and ficolins and has been implicated in the activation of the LP of complement. Some studies describe the dual behaviour of the MASP: the low genetic expression, as well as non-functional MASP-proteins, which lead to a compromised immune response against the pathogen, facilitating infection and disease progression or, conversely, increased levels of MASP-2, which may be harmful due to the possibility of an unbalanced proinflammatory response and an additional host injury in serious diseases conditions, such as COVID-SARS (J. Dobo, 2016;M. I. Garcia-Laorden, 2020;A. Rambaldi 2020). The role of the MASP-2 according to severity, control and exacerbation of asthma poorly understood and we aimed to evaluate the MASP-2 plasma level according to asthma severity and exacerbation status in children. METHODS: Total 95 children aged 7-18 referred to a pediatric allergy centre (European population of East Siberia, Russia) were divided into three groups: mild, moderate and severe asthma. The diagnosis, severity of the disease were established according to GINA-2020. Control group was represented by 70 age- and sex-matched none-asthmatics (essentially healthy children without signs of infection or allergies). MASP-2 levels were measured using an ELISA kit (Hycult Biotech, The Netherlands). Quantitative data are shown as median (25-75% quartiles). RESULTS: We have found that in children with virusinduced asthma exacerbation (n=95) MASP-2 plasma concentration increased in severe asthma (Fig. 1). Additionally, plasma MASP-2 levels were increased in asthma exacerbation groups, regardless of virus-induced/allergen-induced exacerbation status: non-asthmatics (1) (n=70) - 241.5 (114-564) ng/ml, remission (2) (n=34) - 490 (241-925) ng/ml, virus-induced exacerbation (3) (n=5) - 604 (540-605) ng/ml, allergen-induced exacerbation (4) (n=54) - 529 (346-1040), p1,2 = 0.005, p1,4 = 0.0001. CONCLUSION: Our data suggest that increased levels of MASP-2 may be associated with asthma severity in children and may be used as a new marker of asthma exacerbation, especially in severe asthma. The reported study was funded by Krasnoyarsk Regional Fund of supporting scientific and technological activities according to the research project 2020090306591.
Phase II Trial of Pembrolizumab Plus Gemcitabine, Vinorelbine, and Liposomal Doxorubicin as Second-Line Therapy for Relapsed or Refractory Classical Hodgkin Lymphoma
Authors: Alison J. Moskowitz, Gunjan Shah, Heiko Schöder, Nivetha Ganesan, Esther Drill, Helen Hancock, Theresa Davey, Leslie Perez, Sunyoung Ryu, Samia Sohail, Alayna Santarosa, Natasha Galasso, Rachel Neuman, Brielle Liotta, William Blouin, Anita Kumar, Oscar Lahoud, Connie L. Batlevi, Paul Hamlin, David J. Straus, Ildefonso Rodriguez-Rivera, Colette Owens, Philip Caron, Andrew M. Intlekofer, Audrey Hamilton, Steven M. Horwitz, Lorenzo Falchi, Erel Joffe, William Johnson, Christina Lee, M. Lia Palomba, Ariela Noy, Matthew J. Matasar, Georgios Pongas, Gilles Salles, Santosha Vardhana, Beatriz Wills Sanin, Gottfried von Keudell, Joachim Yahalom, Ahmet Dogan, Andrew D. Zelenetz, Craig H. Moskowitz
Journal: Journal of Clinical Oncology (2021)

We conducted a phase II study evaluating pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembro-GVD) as second-line therapy for relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) (ClinicalTrials.gov identifier: NCT03618550).Transplant eligible patients with rel/ref cHL following first-line therapy were treated with two to four cycles of pembrolizumab (200 mg intravenous [IV], day 1), gemcitabine (1,000 mg/m2 IV, days 1 and 8), vinorelbine (20 mg/m2 IV, days 1 and 8), and liposomal doxorubicin (15 mg/m2, days 1 and 8), given on 21-day cycles. The primary end point was complete response (CR) following up to four cycles of pembro-GVD. Patients who achieved CR by labeled fluorodeoxyglucose-positron emission tomography (Deauville ≤ 3) after two or four cycles proceeded to high-dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). HDT/AHCT was carried out according to institutional standards, and brentuximab vedotin maintenance was allowed following HDT/AHCT.Of 39 patients enrolled, 41% had primary ref disease and 38% relapsed within 1 year of frontline treatment. 31 patients received two cycles of pembro-GVD, and eight received four cycles. Most adverse events were grade 1 or two, whereas few were grade 3 and included transaminitis (n = 4), neutropenia (n = 4), mucositis (n = 2), thyroiditis (n = 1), and rash (n = 1). Of 38 evaluable patients, overall and CR rates after pembro-GVD were 100% and 95%, respectively. Thirty-six (95%) patients proceeded to HDT/AHCT, two received pre-HDT/AHCT involved site radiation, and 13 (33%) received post-HDT/AHCT brentuximab vedotin maintenance. All 36 transplanted patients are in remission at a median post-transplant follow-up of 13.5 months (range: 2.66-27.06 months).Second-line therapy with pembro-GVD is a highly effective and well-tolerated regimen that can efficiently bridge patients with rel/ref cHL to HDT/AHCT.
Abstract 126: Triptonide is an Effective Inhibitor of Wnt Signaling
Authors: Jijun Hao, Jessica Chinison, Jose S Aguilar, Alan Avalos, Ying Huang, Moses Chow, Joshua Cameron
Journal: Circulation Research (2016)

Canonical Wnt/β-catenin signaling plays important roles during vertebrate heart development and inhibition of this pathway has been shown to improve injured heart repair by promoting cardiac progenitor cells’ differentiation. Despite extensive research, to date, no approved Wnt inhibitors are available in clinic. Triptonide is a key bioactive small molecule identified in a traditional Chinese medicine named Tripterygium wilfordii Hook F., and its cellular target has not been identified. Here we showed that triptonide effectively inhibited canonical Wnt/β-catenin signaling by targeting a very downstream nuclear component associated with c-termini-transaction domain of β-catenin. Tripterygium wilfordii Hook F., which contains triptonide, has been traditionally used in clinic in China, suggesting that triptonide may have ideal drug properties. Our discovery of triptonide as an effective Wnt inhibitor may represent an important step in identification of bioactive small molecule drugs to stimulate endogenous cardiac progenitor cells for cardiac repair.
Is it part of the locum's job to whistleblow?
Journal: BMJ (1999)

“Who would have thought the old man to have had so much blood in him,” said Lady Macbeth; we sense her unrelenting ambition beginning to ebb and I reckon that Shakespeare must have been painfully conversant with both the spiritual and practical import of spilt blood. It can be a cathartic sight, and it makes a spectacle totally disproportionate to the amount bled.

Just the smallest drop can masquerade as a life threatening haemorrhage. “Don’t be such a big baby, it’s only a wee scratch,” we say, coincidently both withering and reassuring, but even as we speak the mess on the floor, palpably sufficient to turn the multitudinous seas incarnadine, is making a barefaced liar out of us.

I was a casualty officer in the early 80s and in those days unless you were steeped in gore up to the armpits you weren’t cool. Blood held no atavistic terrors for us doctors, if somebody vomited blood over you it was a lot less revolting than somebody vomiting vomit. AIDS was as yet unknown, the first reports of GRIDs (Gay Related Immunity Disorders) were just coming though from the west coast of the United States, the rumble of distant thunder at a picnic.

The bogey then was hepatitis B, especially after the junior doctors in Colin Douglas’s novels started dying like Greek flies who have indulged in multiple sexual indiscretions with blood relatives in a play by Aristophanes. Even so, we wore gloves even less often than condoms, and would ridicule the lab technicians who, if they pricked themselves, would need months of sick leave, counselling, cuddling, cosseting, and ultimately compensation. In contrast, we were real men, we were immortal, invulnerable, too important and too vital to get sick, or so our dysfunctional culture told us.

The last time I shed blood myself, however involuntarily, I was almost proud. It was rich and crimson and sumptuous, a dark rose triumphant, a stark defiant shout of virility, a reaffirmation of the sheer indomitability and exuberance of life, the Red of Red Riding Hood, the biological equivalent of a Pepsi Cola advertisement. “Lo, see what a miracle I am,” it trumpeted, “I live, I breathe, I bleed.” It is, after all, the second most romantic body fluid.
Downregulation of the FTO m6A RNA demethylase promotes EMT-mediated progression of epithelial tumors and sensitivity to Wnt inhibitors
Authors: Jana Jeschke, Evelyne Collignon, Clémence Al Wardi, Mohammad Krayem, Martin Bizet, Yan Jia, Soizic Garaud, Zéna Wimana, Emilie Calonne, Bouchra Hassabi, Renato Morandini, Rachel Deplus, Pascale Putmans, Gaurav Dube, Nitesh Kumar Singh, Alexander Koch, Kateryna Shostak, Lara Rizzotto, Robert L. Ross, Christine Desmedt, Yacine Bareche, Françoise Rothé, Jacqueline Lehmann-Che, Martine Duterque-Coquillaud, Xavier Leroy, Gerben Menschaert, Luis Teixeira, Mingzhou Guo, Patrick A. Limbach, Pierre Close, Alain Chariot, Eleonora Leucci, Ghanem Ghanem, Bi-Feng Yuan, Karen Willard-Gallo, Christos Sotiriou, Jean-Christophe Marine, François Fuks
Journal: Nature Cancer (2021)
Cerebrovascular Anomalies: Perspectives From Immunology and Cerebrospinal Fluid Flow
Authors: Justin Rustenhoven, Catherine Tanumihardja, Jonathan Kipnis
Journal: Circulation Research (2021)

Appropriate vascular function is essential for the maintenance of central nervous system homeostasis and is achieved through virtue of the blood-brain barrier; a specialized structure consisting of endothelial, mural, and astrocytic interactions. While appropriate blood-brain barrier function is typically achieved, the central nervous system vasculature is not infallible and cerebrovascular anomalies, a collective terminology for diverse vascular lesions, are present in meningeal and cerebral vasculature supplying and draining the brain. These conditions, including aneurysmal formation and rupture, arteriovenous malformations, dural arteriovenous fistulas, and cerebral cavernous malformations, and their associated neurological sequelae, are typically managed with neurosurgical or pharmacological approaches. However, increasing evidence implicates interacting roles for inflammatory responses and disrupted central nervous system fluid flow with respect to vascular perturbations. Here, we discuss cerebrovascular anomalies from an immunologic angle and fluid flow perspective. We describe immune contributions, both common and distinct, to the formation and progression of diverse cerebrovascular anomalies. Next, we summarize how cerebrovascular anomalies precipitate diverse neurological sequelae, including seizures, hydrocephalus, and cognitive effects and possible contributions through the recently identified lymphatic and glymphatic systems. Finally, we speculate on and provide testable hypotheses for novel nonsurgical therapeutic approaches for alleviating neurological impairments arising from cerebrovascular anomalies, with a particular emphasis on the normalization of fluid flow and alleviation of inflammation through manipulations of the lymphatic and glymphatic central nervous system clearance pathways.
Abstract 421: Point of Care Ultrasound Sonography (POCUS) in Cardiac Arrest: Predicting Survivorship
Authors: Ada Wong, Hassan Patail, Sahar Ahmad
Journal: Circulation (2019)

Introduction: Survival after in hospital (IH) cardiac arrest (CA) is at 17% suggesting that CA represents an arena of medical practice which deserves more attention. Ultrasound (US) may have a role in both intra-arrest management and peri-arrest prognosis. Very little is known about the role of ultrasound for IH CA. Hypothesis: Intra- arrest POCUS can provide prognostic value. Methods: This was a single center, prospective observational study and we included all IH CA which occurred when a provider was available to perform a standardized POCUS protocol. US and echocardiography imaging was collected during the intra- arrest period and compared with outcome measures of return of spontaneous circulation (ROSC) and survival to 24 hours post-ROSC. Results: Echocardiographic features which may reflect survivorship include cardiac standstill, right ventricle (RV) blood flow stasis, and the appearance of thrombus formation at or around the tricuspid valve. 10 of 16 (62.50%) patients with cardiac standstill alone and 1 of 3 (33.33%) RV stasis alone did not achieve ROSC. Of those that did achieve ROSC in these two groups, none of the patients survived beyond 24 hours of the CA. 11 of 19 (57.89%) patients with RV stasis in combination with cardiac standstill did not achieve ROSC, and of the remaining 8 patients that achieved ROSC, only 1 patient survived past 24 hours. The combination of cardiac standstill, RV stasis, and tricuspid valve thrombus had 2 of 3 (66.67%) patients fail to achieve ROSC, with the remaining 1 patient surviving only to 24 hours. The presence of cardiac standstill alone confers an association with death, with an odds ratio (OR) of 1.212. RV stasis plus cardiac standstill on intra-arrest POCUS confer a markedly higher OR 0.8250 in association with death. Conclusions: Our preliminary work brings to light the role of POCUS for predicting short term survivorship based on echocardiographic patient features. This may have implications for resource utilization in such events.
Lumbar spinal stenosis
Authors: Rikke Krüger Jensen, Biswadjiet S Harhangi, Frank Huygen, Bart Koes
Journal: BMJ (2021)

Recent guidelines suggest that duration of antibiotic therapy for hospitalized patients with community-acquired pneumonia (CAP) can be reduced by individualising treatment based on patient9s clinical response. However, the degree of application of this principle in clinical practice is unknown. Duration of therapy was analysed in patients identified from the Community-Acquired Pneumonia Organization database and evaluated with respect to severity of the disease on admission and time to clinical stability (TCS). Among the 2,003 patients enrolled, mean duration of total antibiotic therapy was 11 days. Neither the pneumonia severity index (r<sup>2</sup> = 0.005) nor the CRB-65 (r<sup>2</sup> = 0.004) scores were related to total duration of therapy. Duration of intravenous antibiotic therapy was related to TCS (r<sup>2</sup> = 0.198). Conversely, TCS was not related to duration of either oral (r<sup>2</sup> = 0.014) or total (r<sup>2</sup> = 0.02) antibiotic therapy. Neither TCS nor other characteristics were found to be significantly associated with duration of total therapy by logistic regression analysis (r<sup>2</sup>&lt;0.09). The individualised approach suggested by recent guidelines has not been adopted in current clinical practice. Duration of therapy is not influenced by either the severity of disease at the time of hospitalisation or the clinical response to therapy.
Integrated mRNA and miRNA Profiling Revealed Deregulation of the Cellular Stress Response in Bone Marrow Mesenchymal Stem Cells Derived from Patients with Immune Thrombocytopenia
Authors: Jia-Min Zhang, Xiao-Lu Zhu, Jing Xue, Xiao Liu, Qi Chen, Ya-Nan Wang, Chen-Cong Wang, Yun He, Qian-Ming Wang, Yuan Kong, Hai-Xia Fu, Ying-Jun Chang, Kai-Yan Liu, Xiao-Jun Huang, Xiaohui Zhang
Journal: Blood (2017)
Cytokine Release Syndrome By T-cell–Redirecting Therapies: Can We Predict and Modulate Patient Risk?
Authors: Arthur J. Van De Vyver, Estelle Marrer-Berger, Ken Wang, Thorsten Lehr, Antje-Christine Walz
Journal: Clinical Cancer Research (2021)

Abstract T-cell–redirecting therapies are promising new therapeutic options in the field of cancer immunotherapy, but the development of these modalities is challenging. A commonly observed adverse event in patients treated with T-cell–redirecting therapies is cytokine release syndrome (CRS). Its clinical manifestation is a burden on patients, and continues to be a big hurdle in the clinical development of this class of therapeutics. We review different T-cell–redirecting therapies, discuss key factors related to cytokine release and potentially leading to CRS, and present clinical mitigation strategies applied for those modalities. We propose to dissect those risk factors into drug-target-disease–related factors and individual patient risk factors. Aiming to optimize the therapeutic intervention of these modalities, we illustrate how the knowledge on drug-target-disease–related factors, such as target expression, binding affinity, and target accessibility, can be leveraged in a model-based framework and highlight with case examples how modeling and simulation is applied to guide drug discovery and development. We draw attention to the current gaps in predicting the individual patient's risk towards a high-grade CRS, which requires further considerations of risk factors related, but not limited to, the patient's demographics, genetics, underlying pathologies, treatment history, and environmental exposures. The drug-target-disease–related factors together with the individual patient's risk factors can be regarded as the patient's propensity for developing CRS in response to therapy. As an outlook, we suggest implementing a risk scoring system combined with mechanistic modeling to enable the prediction of an individual patient's risk of CRS for a given therapeutic intervention.
The 2021 WHO Classification of Tumors of the Central Nervous System: a summary
Authors: David N Louis, Arie Perry, Pieter Wesseling, Daniel J Brat, Ian A Cree, Dominique Figarella-Branger, Cynthia Hawkins, H K Ng, Stefan M Pfister, Guido Reifenberger, Riccardo Soffietti, Andreas von Deimling, David W Ellison
Journal: Neuro-Oncology (2021)

Abstract The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.
Case 19-2021: A 54-Year-Old Man with Irritability, Confusion, and Odd Behaviors
Authors: Nicholas Kontos, Michael W. Parsons, Alessandro Biffi, R. Gilberto González
Journal: New England Journal of Medicine (2021)

A 54-year-old man was evaluated in the neuropsychology clinic because of irritability, confusion, and odd behaviors. Nine months earlier, he had been treated for cancer, after which chronic pain had developed. Six weeks before the current evaluation, he had been found unresponsive with medication bottles nearby. A diagnostic test was performed.