tbuckley/cabot-search huggingface dataset:
Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association
Authors: Ann C. Skulas-Ray, Peter W.F. Wilson, William S. Harris, Eliot A. Brinton, Penny M. Kris-Etherton, Chesney K. Richter, Terry A. Jacobson, Mary B. Engler, Michael Miller, Jennifer G. Robinson, Conrad B. Blum, Delfin Rodriguez-Leyva, Sarah D. de Ferranti, Francine K. Welty
Journal: Circulation (2019)

Hypertriglyceridemia (triglycerides 200-499 mg/dL) is relatively common in the United States, whereas more severe triglyceride elevations (very high triglycerides, ≥500 mg/dL) are far less frequently observed. Both are becoming increasingly prevalent in the United States and elsewhere, likely driven in large part by growing rates of obesity and diabetes mellitus. In a 2002 American Heart Association scientific statement, the omega-3 fatty acids (n-3 FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were recommended (at a dose of 2-4 g/d) for reducing triglycerides in patients with elevated triglycerides. Since 2002, prescription agents containing EPA+DHA or EPA alone have been approved by the US Food and Drug Administration for treating very high triglycerides; these agents are also widely used for hypertriglyceridemia. The purpose of this advisory is to summarize the lipid and lipoprotein effects resulting from pharmacological doses of n-3 FAs (>3 g/d total EPA+DHA) on the basis of new scientific data and availability of n-3 FA agents. In treatment of very high triglycerides with 4 g/d, EPA+DHA agents reduce triglycerides by ≥30% with concurrent increases in low-density lipoprotein cholesterol, whereas EPA-only did not raise low-density lipoprotein cholesterol in very high triglycerides. When used to treat hypertriglyceridemia, n-3 FAs with EPA+DHA or with EPA-only appear roughly comparable for triglyceride lowering and do not increase low-density lipoprotein cholesterol when used as monotherapy or in combination with a statin. In the largest trials of 4 g/d prescription n-3 FA, non-high-density lipoprotein cholesterol and apolipoprotein B were modestly decreased, indicating reductions in total atherogenic lipoproteins. The use of n-3 FA (4 g/d) for improving atherosclerotic cardiovascular disease risk in patients with hypertriglyceridemia is supported by a 25% reduction in major adverse cardiovascular events in REDUCE-IT (Reduction of Cardiovascular Events With EPA Intervention Trial), a randomized placebo-controlled trial of EPA-only in high-risk patients treated with a statin. The results of a trial of 4 g/d prescription EPA+DHA in hypertriglyceridemia are anticipated in 2020. We conclude that prescription n-3 FAs (EPA+DHA or EPA-only) at a dose of 4 g/d (>3 g/d total EPA+DHA) are an effective and safe option for reducing triglycerides as monotherapy or as an adjunct to other lipid-lowering agents.
Variant Interpretation for Cancer (VIC): a computational tool for assessing clinical impacts of somatic variants
Authors: Max M. He, Quan Li, Muqing Yan, Hui Cao, Yue Hu, Karen Y. He, Kajia Cao, Marilyn M. Li, Kai Wang
Journal: Genome Medicine (2019)

Clinical laboratories implement a variety of measures to classify somatic sequence variants and identify clinically significant variants to facilitate the implementation of precision medicine. To standardize the interpretation process, the Association for Molecular Pathology (AMP), American Society of Clinical Oncology (ASCO), and College of American Pathologists (CAP) published guidelines for the interpretation and reporting of sequence variants in cancer in 2017. These guidelines classify somatic variants using a four-tiered system with ten criteria. Even with the standardized guidelines, assessing clinical impacts of somatic variants remains to be tedious. Additionally, manual implementation of the guidelines may vary among professionals and may lack reproducibility when the supporting evidence is not documented in a consistent manner. We developed a semi-automated tool called "Variant Interpretation for Cancer" (VIC) to accelerate the interpretation process and minimize individual biases. VIC takes pre-annotated files and automatically classifies sequence variants based on several criteria, with the ability for users to integrate additional evidence to optimize the interpretation on clinical impacts. We evaluated VIC using several publicly available databases and compared with several predictive software programs. We found that VIC is time-efficient and conservative in classifying somatic variants under default settings, especially for variants with strong and/or potential clinical significance. Additionally, we also tested VIC on two cancer-panel sequencing datasets to show its effectiveness in facilitating manual interpretation of somatic variants. Although VIC cannot replace human reviewers, it will accelerate the interpretation process on somatic variants. VIC can also be customized by clinical laboratories to fit into their analytical pipelines to facilitate the laborious process of somatic variant interpretation. VIC is freely available at https://github.com/HGLab/VIC/ .
Novel NLRP12 variant presenting with familial cold autoimmunity syndrome phenotype
Authors: Latika Gupta, Sakir Ahmed, Bharati Singh, Satya Prakash, Shubha Phadke, Amita Aggarwal
Journal: Annals of the Rheumatic Diseases (2019)

There are still some caveats, such as homozygous variants are not known in this disorder nor have a mutation in LRR region been described.In view of these facts, the variant was classified as VOUS.These variants need to be tested in vitro to know their pathogenic significance.Widespread availability of whole exome sequencing is likely to identify many more such variants and in patients with atypical autoinflammatory syndrome, they may have significance.
Medulloblastomas associated with an APC germline pathogenic variant share the good prognosis of CTNNB1-mutated medulloblastomas
Authors: Aurore Surun, Pascale Varlet, Laurence Brugières, Brigitte Lacour, Cécile Faure-Conter, Pierre Leblond, Anne-Isabelle Bertozzi-Salomon, Claire Berger, Nicolas André, Eric Sariban, Sandra Raimbault, Fabienne Prieur, Françoise Desseigne, Hélène Zattara, Rosine Guimbaud, Marc Polivka, Marie-Bernadette Delisle, Alexandre Vasiljevic, Claude-Alain Maurage, Dominique Figarella-Branger, Florence Coulet, Léa Guerrini-Rousseau, Claire Alapetite, Christelle Dufour, Chrystelle Colas, François Doz, Franck Bourdeaut
Journal: Neuro-Oncology (2019)

Abstract Background Medulloblastomas may occur in a predisposition context, including familial adenomatosis polyposis. Medulloblastomas related to a germline pathogenic variant of adenomatous polyposis coli (APC) remain rare and poorly described. Their similarities with sporadic WNT medulloblastomas still require description. Methods We performed a multicentric retrospective review of 12 patients treated between 1988 and 2018 for medulloblastoma with an identified or highly suspected (personal or familial history) APC germline pathogenic variant. We report personal and familial history APC gene pathogenic variants whenever available: clinical and histologic characteristics of the medulloblastoma, treatments, and long-term outcome, including second tumor and late sequelae. Results Medulloblastomas associated with APC pathogenic variants are mainly classic (11/11 patients, 1 not available), nonmetastatic (10/12 patients) medulloblastomas, with nuclear immunoreactivity for ß-catenin (9/9 tested cases). Ten of 11 assessable patients are disease free with a median follow-up of 10.7 years (range, 1–28 y). Secondary tumors included desmoid tumors in 7 patients (9 tumors), 1 thyroid carcinoma, 2 pilomatricomas, 1 osteoma, 1 vertebral hemangioma, and 1 malignant triton in the radiation field, which caused the only cancer-related death in our series. Conclusions Medulloblastomas associated with an APC pathogenic variant have an overall favorable outcome, even for metastatic tumors. Yet, long-term survival is clouded by second tumor occurrence; treatment may play some role in some of these second malignancies. Our findings raise the question of applying a de-escalation therapeutic protocol to treat patients with APC germline pathogenic variants given the excellent outcome, and reduced intensity of craniospinal irradiation may be further evaluated.
Prediagnostic Plasma Bile Acid Levels and Colon Cancer Risk: A Prospective Study
Authors: Tilman Kühn, Magdalena Stepien, Marina López-Nogueroles, Antje Damms-Machado, Disorn Sookthai, Theron Johnson, Marta Roca, Anika Hüsing, Sandra González Maldonado, Amanda J Cross, Neil Murphy, Heinz Freisling, Sabina Rinaldi, Augustin Scalbert, Veronika Fedirko, Gianluca Severi, Marie-Christine Boutron-Ruault, Francesca Romana Mancini, Solomon A Sowah, Heiner Boeing, Paula Jakszyn, Maria J Sánchez, Susana Merino, Sandra Colorado-Yohar, Aurelio Barricarte, Kay Tee Khaw, Julie A Schmidt, Aurora Perez-Cornago, Antonia Trichopoulou, Anna Karakatsani, Paschalis Thriskos, Domenico Palli, Claudia Agnoli, Rosario Tumino, Carlotta Sacerdote, Salvatore Panico, Bas Bueno-de-Mesquita, Carla H van Gils, Alicia K Heath, Marc J Gunter, Elio Riboli, Agustín Lahoz, Mazda Jenab, Rudolf Kaaks
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract Background Bile acids have been proposed to promote colon carcinogenesis. However, there are limited prospective data on circulating bile acid levels and colon cancer risk in humans. Methods Associations between prediagnostic plasma levels of 17 primary, secondary, and tertiary bile acid metabolites (conjugated and unconjugated) and colon cancer risk were evaluated in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Bile acid levels were quantified by tandem mass spectrometry in samples from 569 incident colon cancer cases and 569 matched controls. Multivariable logistic regression analyses were used to estimate odds ratios (ORs) for colon cancer risk across quartiles of bile acid concentrations. Results Positive associations were observed between colon cancer risk and plasma levels of seven conjugated bile acid metabolites: the primary bile acids glycocholic acid (ORquartile 4 vs quartile 1= 2.22, 95% confidence interval [CI] = 1.52 to 3.26), taurocholic acid (OR = 1.78, 95% CI = 1.23 to 2.58), glycochenodeoxycholic acid (OR = 1.68, 95% CI = 1.13 to 2.48), taurochenodeoxycholic acid (OR = 1.62, 95% CI = 1.11 to 2.36), and glycohyocholic acid (OR = 1.65, 95% CI = 1.13 to 2.40), and the secondary bile acids glycodeoxycholic acid (OR = 1.68, 95% CI = 1.12 to 2.54) and taurodeoxycholic acid (OR = 1.54, 95% CI = 1.02 to 2.31). By contrast, unconjugated bile acids and tertiary bile acids were not associated with risk. Conclusions This prospective study showed that prediagnostic levels of certain conjugated primary and secondary bile acids were positively associated with risk of colon cancer. Our findings support experimental data to suggest that a high bile acid load is colon cancer promotive.
Non-inferiority versus superiority trial design for new antibiotics in an era of high antimicrobial resistance: the case for post-marketing, adaptive randomised controlled trials
Authors: Simone Lanini, John P A Ioannidis, Francesco Vairo, Michel Pletschette, Gina Portella, Virginia Di Bari, Alessia Mammone, Raffaella Pisapia, Stefano Merler, Boniface Nguhuni, Martin Langer, Antonino Di Caro, Sarah J L Edwards, Nicola Petrosillo, Alimuddin Zumla, Giuseppe Ippolito
Journal: The Lancet Infectious Diseases (2019)
Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study
Authors: Bernadet T Santema, Wouter Ouwerkerk, Jasper Tromp, Iziah E Sama, Alice Ravera, Vera Regitz-Zagrosek, Hans Hillege, Nilesh J Samani, Faiez Zannad, Kenneth Dickstein, Chim C Lang, John G Cleland, Jozine M Ter Maaten, Marco Metra, Stefan D Anker, Pim van der Harst, Leong L Ng, Peter van der Meer, Dirk J van Veldhuisen, Sven Meyer, Carolyn S P Lam, Adriaan A Voors, Arthur Mark Richards, Carolyn S.P. Lam, Inder Anand, Chung-Lieh Hung, Lieng Hsi Ling, Houng Bang Liew, Calambur Narasimhan, Tachapong Ngarmukos, Sang Weon Park, Eugenio Reyes, Bambang Budi Siswanto, Wataru Shimizu, Shu Zhang
Journal: The Lancet (2019)
A Multicenter, Randomized, Placebo‐Controlled Trial of Atorvastatin for the Primary Prevention of Cardiovascular Events in Patients With Rheumatoid Arthritis
Authors: George D. Kitas, Peter Nightingale, Jane Armitage, Naveed Sattar, Jill J. F. Belch, Deborah P. M. Symmons
Journal: Arthritis & Rheumatology (2019)

Objective Rheumatoid arthritis ( RA ) is associated with increased cardiovascular event ( CVE ) risk. The impact of statins in RA is not established. We assessed whether atorvastatin is superior to placebo for the primary prevention of CVE s in RA patients. Methods A randomized, double‐blind, placebo‐controlled trial was designed to detect a 32% CVE risk reduction based on an estimated 1.6% per annum event rate with 80% power at P &lt; 0.05. RA patients age &gt;50 years or with a disease duration of &gt;10 years who did not have clinical atherosclerosis, diabetes, or myopathy received atorvastatin 40 mg daily or matching placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, or any arterial revascularization. Secondary and tertiary end points included plasma lipids and safety. Results A total of 3,002 patients (mean age 61 years; 74% female) were followed up for a median of 2.51 years (interquartile range [ IQR ] 1.90, 3.49 years) (7,827 patient‐years). The study was terminated early due to a lower than expected event rate (0.70% per annum). Of the 1,504 patients receiving atorvastatin, 24 (1.6%) experienced a primary end point, compared with 36 (2.4%) of the 1,498 receiving placebo (hazard ratio [ HR ] 0.66 [95% confidence interval (95% CI ) 0.39, 1.11]; P = 0.115 and adjusted HR 0.60 [95% CI 0.32, 1.15]; P = 0.127). At trial end, patients receiving atorvastatin had a mean ± SD low‐density lipoprotein ( LDL ) cholesterol level 0.77 ± 0.04 mmoles/liter lower than those receiving placebo ( P &lt; 0.0001). C‐reactive protein level was also significantly lower in the atorvastatin group than the placebo group (median 2.59 mg/liter [ IQR 0.94, 6.08] versus 3.60 mg/liter [ IQR 1.47, 7.49]; P &lt; 0.0001). CVE risk reduction per mmole/liter reduction in LDL cholesterol was 42% (95% CI −14%, 70%). The rates of adverse events in the atorvastatin group (n = 298 [19.8%]) and placebo group (n = 292 [19.5%]) were similar. Conclusion Atorvastatin 40 mg daily is safe and results in a significantly greater reduction of LDL cholesterol level than placebo in patients with RA . The 34% CVE risk reduction is consistent with the Cholesterol Treatment Trialists’ Collaboration meta‐analysis of statin effects in other populations.
A Tumor Agnostic Therapeutic Strategy for Hexokinase 1–Null/Hexokinase 2–Positive Cancers
Authors: Shili Xu, Harvey R. Herschman
Journal: Cancer Research (2019)

Since Warburg's observation that most cancers exhibit elevated glycolysis, decades of research have attempted to reduce tumor glucose utilization as a therapeutic approach. Hexokinase (HK) activity is the first glycolytic enzymatic step; despite many attempts to inhibit HK activity, none has reached clinical application. Identification of HK isoforms, and recognition that most tissues express only HK1 while most tumors express HK1 and HK2, stimulated reducing HK2 activity as a therapeutic option. However, studies using HK2 shRNA and isogenic HK1+HK2- and HK1+HK2+ tumor cell pairs demonstrated that tumors expressing only HK1, while exhibiting reduced glucose consumption, progressed in vivo as well as tumors expressing both HK1 and HK2. However, HK1-HK2+ tumor subpopulations exist among many cancers. shRNA HK2 suppression in HK1-HK2+ liver cancer cells reduced xenograft tumor progression, in contrast to HK1+HK2+ cells. HK2 inhibition, and partial inhibition of both oxidative phosphorylation and fatty acid oxidation using HK2 shRNA and small-molecule drugs, prevented human liver HK1-HK2+ cancer xenograft progression. Using human multiple myeloma xenografts and mouse allogeneic models to identify potential clinical translational agents, triple therapies that include antisense HK2 oligonucleotides, metformin, and perhexiline prevent progression. These results suggest an agnostic approach for HK1-HK2+ cancers, regardless of tissue origin.
THU0056 Evidence of b cell activation in kawasaki disease
Authors: D Kim
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Kawasaki disease (KD) is an acute systemic vasculitis that primarily affects infants and young children below 5 years old. The cause of KD is still unknown, but the acute phase of KD is often accompanied by the alteration of circulating immune cells. The polyclonal activation of B cells during the course of disease is well documented. <h3>Objectives</h3> In this study, the evidence of B cell activation and the possible involvement of superantigen in KD were sought. <h3>Methods</h3> <h3>Results</h3> In 13 out of 15 KD patients, an increase in B cells expressing the VH3 family was seen during the acute phase of disease. Analysis of B cell clonal expansion showed the VH6 family clone of 9 amino acids to be the most common, observed in 5 out of 15 KD patients. Analysis of CDR3 size profile showed that various prominent bands appeared during the acute phase of disease, and some disappearing during the subacute phase, while other newly developed bands appeared during the subacute phase of disease. The DNA sequences of CDR3s showed no dominant clone. <h3>Conclusion</h3> These data suggest that KD may be caused by conventional antigen (s).
Resuming Anticoagulation After Cerebral Intraparenchymal Hemorrhage—Reply
Authors: Bradley A. Gross, Brian T. Jankowitz, Robert M. Friedlander
Journal: JAMA (2019)

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NICE rejects cannabidiol for two types of treatment resistant epilepsy in children
Authors: Stijntje Dijk, Pat Lok
Journal: BMJ (2019)

The National Institute for Health and Care Excellence (NICE) has rejected cannabidiol for treating two types of severe treatment resistant epilepsy in draft guidelines.12

The independent appraisal committee highlighted its concern that the evidence showing that cannabidiol reduces the main types of seizures associated with these conditions was based on clinical trials that lasted just 14 weeks, leaving doubts about its long term effectiveness. It said that it would work with GW Pharma, which makes the cannabidiol Epidiolex, to deal with the issues raised by the committee.

Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are types of epilepsy that begin in early childhood and are difficult to control.34 Current treatment often includes two or more antiepileptic drugs.

A 14 week double …
A neural circuit for comorbid depressive symptoms in chronic pain
Authors: Wenjie Zhou, Yan Jin, Qian Meng, Xia Zhu, Tongjian Bai, Yanghua Tian, Yu Mao, Likui Wang, Wen Xie, Hui Zhong, Na Zhang, Min-Hua Luo, Wenjuan Tao, Haitao Wang, Jie Li, Juan Li, Ben-Sheng Qiu, Jiang-Ning Zhou, Xiangyao Li, Han Xu, Kai Wang, Xiaochu Zhang, Yong Liu, Gal Richter-Levin, Lin Xu, Zhi Zhang
Journal: Nature Neuroscience (2019)
The ever-expanding phenotypical spectrum of human TBX4 mutations: from toe to lung
Authors: Meindina G. Haarman, Wilhelmina S. Kerstjens-Frederikse, Rolf M.F. Berger
Journal: European Respiratory Journal (2019)

<b>Since the discovery of the TBX4 gene, the phenotypical spectrum of human TBX4 mutations is rapidly expanding from syndromes with skeletal dysplasia, to pulmonary hypertension to developmental lung diseases, all associated with disrupted organ development</b>http://bit.ly/2MvYful
Targeting Autophagy in Cancer: Recent Advances and Future Directions
Authors: Ravi K. Amaravadi, Alec C. Kimmelman, Jayanta Debnath
Journal: Cancer Discovery (2019)

Abstract Autophagy, a multistep lysosomal degradation pathway that supports nutrient recycling and metabolic adaptation, has been implicated as a process that regulates cancer. Although autophagy induction may limit the development of tumors, evidence in mouse models demonstrates that autophagy inhibition can limit the growth of established tumors and improve response to cancer therapeutics. Certain cancer genotypes may be especially prone to autophagy inhibition. Different strategies for autophagy modulation may be needed depending on the cancer context. Here, we review new advances in the molecular control of autophagy, the role of selective autophagy in cancer, and the role of autophagy within the tumor microenvironment and tumor immunity. We also highlight clinical efforts to repurpose lysosomal inhibitors, such as hydroxychloroquine, as anticancer agents that block autophagy, as well as the development of more potent and specific autophagy inhibitors for cancer treatment, and review future directions for autophagy research. Significance: Autophagy plays a complex role in cancer, but autophagy inhibition may be an effective therapeutic strategy in advanced cancer. A deeper understanding of autophagy within the tumor microenvironment has enabled the development of novel inhibitors and clinical trial strategies. Challenges and opportunities remain to identify patients most likely to benefit from this approach.