tbuckley/cabot-search huggingface dataset:
The N <sup>6</sup> -Methyladenosine mRNA Methylase METTL3 Controls Cardiac Homeostasis and Hypertrophy
Authors: Lisa E. Dorn, Lior Lasman, Jing Chen, Xianyao Xu, Thomas J. Hund, Mario Medvedovic, Jacob H. Hanna, Jop H. van Berlo, Federica Accornero
Journal: Circulation (2019)

N6-Methyladenosine (m6A) methylation is the most prevalent internal posttranscriptional modification on mammalian mRNA. The role of m6A mRNA methylation in the heart is not known.To determine the role of m6A methylation in the heart, we isolated primary cardiomyocytes and performed m6A immunoprecipitation followed by RNA sequencing. We then generated genetic tools to modulate m6A levels in cardiomyocytes by manipulating the levels of the m6A RNA methylase methyltransferase-like 3 (METTL3) both in culture and in vivo. We generated cardiac-restricted gain- and loss-of-function mouse models to allow assessment of the METTL3-m6A pathway in cardiac homeostasis and function.We measured the level of m6A methylation on cardiomyocyte mRNA, and found a significant increase in response to hypertrophic stimulation, suggesting a potential role for m6A methylation in the development of cardiomyocyte hypertrophy. Analysis of m6A methylation showed significant enrichment in genes that regulate kinases and intracellular signaling pathways. Inhibition of METTL3 completely abrogated the ability of cardiomyocytes to undergo hypertrophy when stimulated to grow, whereas increased expression of the m6A RNA methylase METTL3 was sufficient to promote cardiomyocyte hypertrophy both in vitro and in vivo. Finally, cardiac-specific METTL3 knockout mice exhibit morphological and functional signs of heart failure with aging and stress, showing the necessity of RNA methylation for the maintenance of cardiac homeostasis.Our study identified METTL3-mediated methylation of mRNA on N6-adenosines as a dynamic modification that is enhanced in response to hypertrophic stimuli and is necessary for a normal hypertrophic response in cardiomyocytes. Enhanced m6A RNA methylation results in compensated cardiac hypertrophy, whereas diminished m6A drives eccentric cardiomyocyte remodeling and dysfunction, highlighting the critical importance of this novel stress-response mechanism in the heart for maintaining normal cardiac function.
The rapid molecular test Xpert MTB/RIF ultra: towards improved tuberculosis diagnosis and rifampicin resistance detection
Authors: O. Opota, J. Mazza-Stalder, G. Greub, K. Jaton
Journal: Clinical Microbiology and Infection (2019)

Tuberculosis diagnosis has dramatically improved since the introduction of the rapid molecular test Xpert MTB/RIF (Xpert) detecting M. tuberculosis and rifampicin resistance directly from clinical specimens, therefore shortening the turnaround time, reducing patient's isolation period and decreasing the time to start anti-TB drugs. The new version, Xpert MTB/RIF Ultra (Ultra), displays a higher sensitivity and an improved rifampicin resistance detection. Both tests have been endorsed by the World Health Organisation.Xpert and Ultra rapidly became widespread and paved the way for new approaches and new paradigms as well as for the development of molecular point-of-care tests (POCTs). In this narrative review, we aimed to address their performance in the diagnosis of tuberculosis and to discuss the expectations of these tests as well as their limits and the unmet needs.Peer-reviewed publications addressing the diagnostic performance of Ultra and Xpert.We focused on publications that evaluated the performance of Ultra and Xpert on the same group of patients or the same set of specimens in different tuberculosis-burden settings.The studies published so far reported an increased sensitivity of Ultra when compared to Xpert, which represents a benefit for tuberculosis diagnosis. The fact that such a sensitive assay cannot distinguish between alive and dead bacilli emphasizes that caution should be exercised regarding indications and interpretation of results. Additional studies are needed to determine the true performance for the diagnosis of extrapulmonary tuberculosis because of the great diversity of the specimens.
Cleaved Cochlin Sequesters Pseudomonas aeruginosa and Activates Innate Immunity in the Inner Ear
Authors: Jinsei Jung, Jee Eun Yoo, Young Ho Choe, Sang Chul Park, Hyun Jae Lee, Hack June Lee, Byunghwa Noh, Sung Huhn Kim, Gyeong-Yi Kang, Kang-Mu Lee, Sang Sun Yoon, Dong Su Jang, Joo-Heon Yoon, Young-Min Hyun, Jae Young Choi
Journal: Cell Host & Microbe (2019)
Atopic dermatitis in the elderly: a review of clinical and pathophysiological hallmarks
Authors: S. Williamson, J. Merritt, A. De Benedetto
Journal: British Journal of Dermatology (2019)

Atopic dermatitis (AD) is a multifactorial and complex disease, characterized by an impaired skin barrier function and abnormal immune response. Many elderly patients present with pruritus and xerosis to dermatology, allergy and primary care clinics, and there is a lack of information available to clinicians regarding the proper diagnosis and management of these patients. Although the elderly are described as having a distinct presentation of AD and important comorbidities, most investigations and clinical care guidelines pertaining to AD do not include patients aged 60 years and older as a separate group from younger adults. To summarize current information on pathophysiology, diagnosis and management of AD in the elderly population and identify areas of insufficient information to be explored in future investigations. We carried out a systematic review of published literature, which assessed changes in the skin barrier and immune function with ageing and current information available for physicians to use in the diagnosis and treatment of AD in elderly patients. Many age‐related changes overlap with key hallmarks observed in AD, most notably a decline in skin barrier function, dysregulation of the innate immune system, and skewing of adaptive immunity to a type‐2 T helper cell response, in addition to increased Staphylococcus aureus infection. While general physiological alterations with ageing overlap with key features of AD, a research gap exists regarding specific ageing‐related changes in AD disease development. More knowledge about AD in the elderly is needed to establish firm diagnostic and treatment methodologies. What's already known about this topic? Atopic dermatitis (AD) is a common inflammatory skin disease that causes significant burden worldwide. Recently, elderly patients have been considered a subgroup of patients with distinct AD manifestation. Limited studies have characterized the clinical presentation and role of IgE‐mediated allergy in elderly patients with AD. What does this study add? This review offers a summary of age‐related skin and immune alterations that correspond to pathogenic changes noted in patients with AD. The role of itch, environmental factors and skin microbiota in AD disease presentation in ageing patients is explored.
BPI19-013: Use of Clinical Decision Support and Peer Review to Increase NCCN Guidelines Adherence
Authors: Eric Gratias, David Spangler, Margaret Rausa
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: eviCore healthcare uses the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) to support its proprietary program for medical oncology drug management. All treatment regimens assigned NCCN Category of Evidence 1, 2A, or 2B are considered NCCN-adherent treatment selections in the eviCore program. The purpose of this study was to evaluate the pattern of NCCN adherence during the first year following program launch in regional payer markets. Methods: All cancer drug treatment authorization requests submitted in month 1 and month 12 following program launch for 4 regional third-party payers representing 13 different states were included, each of whom had management of high cost oncology drugs in place prior to eviCore program launch. Month 1 data were used as a surrogate for pre-program NCCN adherence, which is an overestimate as there is significant eviCore program impact on patients initiating therapy during that time. Requests with incomplete clinical data were excluded from analysis. Included requests were stratified by month 1 or month 12 from initial program launch date for each health plan. NCCN adherence was assigned based on the results of the clinical decision support and peer consultation processes utilized by eviCore to adjudicate the treatment request. NCCN adherence rate was calculated for each subgroup and a cumulative NCCN adherence rate for all included cases was calculated using weighted average accounting for volume differences by market. Results: There were 2,028 treatment regimen requests that were fully evaluable, with 1,285 occurring in month 1 and 743 occurring in month 12 following program launch. The rate of NCCN adherence increased for each health plan during the first program year, ranging from 69%–84% in month 1 and rising to 79%–91% in month 12. The weighted cumulative NCCN adherence during month 1 for all included plans was 75% and rose to 88% at month 12 following program launch. Conclusions: Use of clinical decision support supplemented by peer consultation is an effective means of increasing oncologists’ adherence to NCCN-recommended therapies across a broad range of regional provider markets. Additional study is warranted to determine whether this methodology can be applied to NCCN Categories of Preference to direct more patients toward preferred regimens with superior efficacy, safety, and affordability to further improve quality of care and lower total medical costs.
QIM119-120: Utilizing Technology to Identify Oncology Patients to Impact Patient Care
Authors: Brook Blackmore, Nicole Centers, Troy Gifford
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Sarah Cannon has established a standardized nurse navigation program for breast, lung, and Gi cancer patients. Navigators play a significant role in addressing barriers that may adversely impact patient outcomes. Historically, nurse navigators were spending up to 65% of their time data mining to identify new patients for navigation. This lost time compromises a navigator’s ability to effectively support patients. Sarah Cannon implemented a technology solution to address this manual process. Methods: A patient identification software application (patient ID), utilizing natural language processing technology, was developed to identify positive pathology reports across the enterprise in real time. Patient ID instantly routes those reports to a tumor site-specific oncology nurse navigator. The impact of this technology was assessed in 3 Hospital Corporation of America (HCA) markets from December 2016–March 2017. Total patient recall, total volume of reports reviewed, navigated patient volumes, navigator time allocation, and time from diagnosis to first treatment were studied. Results : Patient ID reviewed 47,544 pathology reports during the 4-month pilot, identifying 7,224 potential cancer reports. 2,782 of those represented breast, lung, or Gi cancer patients and were routed to a nurse navigator. Patient ID performed with an overall total patient recall of 98%, respectively. Decreased time spent data mining was observed, and navigator caseload increased by 71%. Time from diagnosis to first treatment decreased by an average of 6 days. Time allocated to direct patient contact and physician interaction increased by 35%. Conclusions: Implementation of a technology solution to rapidly identify new cancer patients for navigation in a community health system is feasible and associated with multiple benefits. Increased navigator patient volumes and navigator productivity were observed. Navigator time spent with patients and physicians increased with a concurrent reduction in data mining time. Timeliness of care metrics improved, suggesting a favorable impact on quality. This technology is now being deployed across the HCA enterprise.
Hemoglobin β93 Cysteine Is Not Required for Export of Nitric Oxide Bioactivity From the Red Blood Cell
Authors: Chiao-Wang Sun, Jiangning Yang, Andrei L. Kleschyov, Zhengbing Zhuge, Mattias Carlström, John Pernow, Nadeem Wajih, T. Scott Isbell, Joo-Yeun Oh, Pedro Cabrales, Amy G. Tsai, Tim Townes, Daniel B. Kim-Shapiro, Rakesh P. Patel, Jon O. Lundberg
Journal: Circulation (2019)

Nitrosation of a conserved cysteine residue at position 93 in the hemoglobin β chain (β93C) to form S-nitroso (SNO) hemoglobin (Hb) is claimed to be essential for export of nitric oxide (NO) bioactivity by the red blood cell (RBC) to mediate hypoxic vasodilation and cardioprotection.To test this hypothesis, we used RBCs from mice in which the β93 cysteine had been replaced with alanine (β93A) in a number of ex vivo and in vivo models suitable for studying export of NO bioactivity.In an ex vivo model of cardiac ischemia/reperfusion injury, perfusion of a mouse heart with control RBCs (β93C) pretreated with an arginase inhibitor to facilitate export of RBC NO bioactivity improved cardiac recovery after ischemia/reperfusion injury, and the response was similar with β93A RBCs. Next, when human platelets were coincubated with RBCs and then deoxygenated in the presence of nitrite, export of NO bioactivity was detected as inhibition of ADP-induced platelet activation. This effect was the same in β93C and β93A RBCs. Moreover, vascular reactivity was tested in rodent aortas in the presence of RBCs pretreated with S-nitrosocysteine or with hemolysates or purified Hb treated with authentic NO to form nitrosyl(FeII)-Hb, the proposed precursor of SNO-Hb. SNO-RBCs or NO-treated Hb induced vasorelaxation, with no differences between β93C and β93A RBCs. Finally, hypoxic microvascular vasodilation was studied in vivo with a murine dorsal skin-fold window model. Exposure to acute systemic hypoxia caused vasodilatation, and the response was similar in β93C and β93A mice.RBCs clearly have the fascinating ability to export NO bioactivity, but this occurs independently of SNO formation at the β93 cysteine of Hb.
AB0107 Multiple fibrosis: two cases of successful treatment
Authors: NG Guseva, MN Starovoitova, TA Nevskaya
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> Multiple fibrosis (MF) is a slowly progressive disease of unknown cause characterised by localised connective tissue accumulation with the formation of multiple dense sclerotic foci leading to the internal organ dysfunction. It?s a rare and often fatal disease resulting in the visceral organ insufficiency. The most common localizations of the fibrotic lesions are retroperitoneal, mediastinal and lung fibrosis, pseudotumor of pancreas, sclerosing cholangitis. A disease process is usually difficult to stem and often impossible to reverse. There is no specific treatment for MF. <h3>Methods</h3> <h3>Results</h3> We report two cases of successful MF treatment with the combination of D-penicillamine (DPA) and steroids (S). A. 36 yr old male presented with 4 yr history of ?cancer like? symptoms: progressive fatigue, weight loss, subfebrile fiver, accelerating ESR (40 mm/h), pulmonary (dry cough, dyspnoea, atelectasis of the left lower lobe of the lung by X ray and dense ?tumour? 60 mm. in diameter in the core part of the left lung with a massive ?infiltration? spreading along the lower pulmonary vein by thoracotomy) and eye (loss of sight and right eye pain, unilateral scleral congestion) manifestations. With suspicion on the lung and eye cancers the total left pulmonectomy and right eye enucleation were carried out without any state improvement. Two yr later fasciitis, hepatosplenomegaly and new round foci in the right lung (15 mm) and pancreas (27 × 35 mm) were found. MF was confirmed by histopathological finding and the combined therapy with DPA 1000 mg/d and oral steroids 30 mg/d (decreasing to 15 mg daily after 0.5 year and remaining the same for 1.5 year) was prescribed. Over the subsequent 4 months the general condition of the patient improved, the temperature subsided, fasciitis and abdomenalgia disappeared completely, the pt gained 7 kg of weight, ESR diminished to normal levels. In a year we revealed obvious decreasing of the liver and spleen sizes and complete disappearance of the foci in the right lung and pancreas. During a 9 yr follow up we did not find any fibrotic foci in tissues, all laboratory tests are within normal limits. The pt receives daily maintenance dose of 125 mg DPA and 7.5 mg S. No side effects of the drugs have been noticed. The second patient, a 39 yr old female with Ormond?s disease (retroperitoneal fibrosis which led to squeeze the ureters and bilateral hydronephrosis) had also been operated on – left nephrectomy – before a correct diagnosis was made. The administration of DPA 500 mg/d and S 20 mg/d check the progression of the disease during two years. <h3>Conclusion</h3> Our results support data on successful use of the combined therapy with DPA and S in MF. Such drug treatment allowes to get a reverse development of the fibrotic lesions and to maintain a long stable remission of the disease.
Active and passive case-finding in tuberculosis-affected households in Peru: a 10-year prospective cohort study
Authors: Matthew J Saunders, Marco A Tovar, Dami Collier, Matthew R Baldwin, Rosario Montoya, Teresa R Valencia, Robert H Gilman, Carlton A Evans
Journal: The Lancet Infectious Diseases (2019)

BackgroundActive case-finding among contacts of patients with tuberculosis is a global health priority, but the effects of active versus passive case-finding are poorly characterised. We assessed the contribution of active versus passive case-finding to tuberculosis detection among contacts and compared sex and disease characteristics between contacts diagnosed through these strategies.MethodsIn shanty towns in Callao, Peru, we identified index patients with tuberculosis and followed up contacts aged 15 years or older for tuberculosis. All patients and contacts were offered free programmatic active case-finding entailing sputum smear microscopy and clinical assessment. Additionally, all contacts were offered intensified active case-finding with sputum smear and culture testing monthly for 6 months and then once every 4 years. Passive case-finding at local health facilities was ongoing throughout follow-up.FindingsBetween Oct 23, 2002, and May 26, 2006, we identified 2666 contacts, who were followed up until March 1, 2016. Median follow-up was 10·0 years (IQR 7·5–11·0). 232 (9%) of 2666 contacts were diagnosed with tuberculosis. The 2-year cumulative risk of tuberculosis was 4·6% (95% CI 3·5–5·5), and overall incidence was 0·98 cases (95% CI 0·86–1·10) per 100 person-years. 53 (23%) of 232 contacts with tuberculosis were diagnosed through active case-finding and 179 (77%) were identified through passive case-finding. During the first 6 months of the study, 23 (45%) of 51 contacts were diagnosed through active case-finding and 28 (55%) were identified through passive case-finding. Contacts diagnosed through active versus passive case-finding were more frequently female (36 [68%] of 53 vs 85 [47%] of 179; p=0·009), had a symptom duration of less than 15 days (nine [25%] of 36 vs ten [8%] of 127; p=0·03), and were more likely to be sputum smear-negative (33 [62%] of 53 vs 62 [35%] of 179; p=0·0003).InterpretationAlthough active case-finding made an important contribution to tuberculosis detection among contacts, passive case-finding detected most of the tuberculosis burden. Compared with passive case-finding, active case-finding was equitable, helped to diagnose tuberculosis earlier and usually before a positive result on sputum smear microscopy, and showed a high burden of undetected tuberculosis among women.FundingWellcome Trust, Department for International Development Civil Society Challenge Fund, Joint Global Health Trials consortium, Bill & Melinda Gates Foundation, Imperial College National Institutes of Health Research Biomedical Research Centre, Foundation for Innovative New Diagnostics, Sir Halley Stewart Trust, WHO, TB REACH, and IFHAD: Innovation for Health and Development.
Robot-assisted Radical Prostatectomy After Focal Therapy: Oncological, Functional Outcomes and Predictors of Recurrence
Authors: Lorenzo Marconi, Thomas Stonier, Rafael Tourinho-Barbosa, Caroline Moore, Hashim U. Ahmed, Xavier Cathelineau, Mark Emberton, Rafael Sanchez-Salas, Paul Cathcart
Journal: European Urology (2019)
Negative Regulation of p53-Induced Senescence by N-WASP Is Crucial for DMBA/TPA-Induced Skin Tumor Formation
Authors: Hui Li, Simon Petersen, Alberto Garcia Mariscal, Cord Brakebusch
Journal: Cancer Research (2019)

Abstract Mice with a keratinocyte-restricted deletion of the actin polymerization–promoting molecule, N-WASP, display cyclic hair loss and skin inflammation. Here, we showed that these mice were also resistant to 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)–induced skin tumor formation. This resistance correlated with decreased expression of the senescence regulator, DNMT1, and increased expression of the senescence marker, p16Ink4a, in N-WASP–deficient epidermis. Moreover, primary N-WASP–null keratinocytes displayed a premature senescence phenotype in vitro. Expression and activation of p53, a major inducer of senescence, was not significantly altered in N-WASP–null keratinocytes. However, impairment of p53 function effectively rescued the senescence phenotype, indicating that N-WASP was an inhibitor of p53-induced senescence. Mechanistically, N-WASP regulated senescence by preventing p53-dependent degradation of the H3K9 methyltransferases, G9a/GLP, and the DNA methyltransferase, DNMT1, which both control keratinocyte senescence. This pathway collaborated with other N-WASP–independent, senescence-promoting signaling downstream of p53 and allowed the fine tuning of p53-induced senescence by N-WASP. Collectively, these data reveal N-WASP as an inhibitor of p53-induced senescence, which might be of importance for skin tumor formation and cellular aging of keratinocytes. Significance: These findings demonstrate that N-WASP regulates p53-dependent senescence in keratinocytes in vitro and in vivo.
JNK signaling in cancer cell survival
Authors: Qinghua Wu, Wenda Wu, Bishi Fu, Lei Shi, Xu Wang, Kamil Kuca
Journal: Medicinal Research Reviews (2019)

c-Jun N-terminal kinase (JNK) is involved in cancer cell apoptosis; however, emerging evidence indicates that this Janus signaling promotes cancer cell survival. JNK acts synergistically with NF-κB, JAK/STAT, and other signaling molecules to exert a survival function. JNK positively regulates autophagy to counteract apoptosis, and its effect on autophagy is related to the development of chemotherapeutic resistance. The prosurvival effect of JNK may involve an immune evasion mechanism mediated by transforming growth factor-β, toll-like receptors, interferon-γ, and autophagy, as well as compensatory JNK-dependent cell proliferation. The present review focuses on recent advances in understanding the prosurvival function of JNK and its role in tumor development and chemoresistance, including a comprehensive analysis of the molecular mechanisms underlying JNK-mediated cancer cell survival. There is a focus on the specific "Yin and Yang" functions of JNK1 and JNK2 in the regulation of cancer cell survival. We highlight recent advances in our knowledge of the roles of JNK in cancer cell survival, which may provide insight into the distinct functions of JNK in cancer and its potential for cancer therapy.