tbuckley/cabot-search huggingface dataset:
Enteric infection induces Lark-mediated intron retention at the 5′ end of Drosophila genes
Authors: Maroun Bou Sleiman, Michael Vincent Frochaux, Tommaso Andreani, Dani Osman, Roderic Guigo, Bart Deplancke
Journal: Genome biology (2020)

Abstract Background RNA splicing is a key post-transcriptional mechanism that generates protein diversity and contributes to the fine-tuning of gene expression, which may facilitate adaptation to environmental challenges. Here, we employ a systems approach to study alternative splicing changes upon enteric infection in females from classical Drosophila melanogaster strains as well as 38 inbred lines. Results We find that infection leads to extensive differences in isoform ratios, which results in a more diverse transcriptome with longer 5′ untranslated regions (5′UTRs). We establish a role for genetic variation in mediating inter-individual splicing differences, with local splicing quantitative trait loci ( local -sQTLs) being preferentially located at the 5′ end of transcripts and directly upstream of splice donor sites. Moreover, local -sQTLs are more numerous in the infected state, indicating that acute stress unmasks a substantial number of silent genetic variants. We observe a general increase in intron retention concentrated at the 5′ end of transcripts across multiple strains, whose prevalence scales with the degree of pathogen virulence. The length, GC content, and RNA polymerase II occupancy of these introns with increased retention suggest that they have exon-like characteristics. We further uncover that retained intron sequences are enriched for the Lark/RBM4 RNA binding motif. Interestingly, we find that lark is induced by infection in wild-type flies, its overexpression and knockdown alter survival, and tissue-specific overexpression mimics infection-induced intron retention. Conclusion Our collective findings point to pervasive and consistent RNA splicing changes, partly mediated by Lark/RBM4, as being an important aspect of the gut response to infection.
Coronary microvascular dysfunction in stable ischaemic heart disease (non-obstructive coronary artery disease and obstructive coronary artery disease)
Authors: Udo Sechtem, David Brown, Shigeo Godo, Gaetano Antonio Lanza, Hiro Shimokawa, Novalia Sidik
Journal: Cardiovascular Research (2020)

Diffuse and focal epicardial coronary disease and coronary microvascular abnormalities may exist side-by-side. Identifying the contributions of each of these three players in the coronary circulation is a difficult task. Yet identifying coronary microvascular dysfunction (CMD) as an additional player in patients with coronary artery disease (CAD) may provide explanations of why symptoms may persist frequently following and why global coronary flow reserve may be more prognostically important than fractional flow reserve measured in a single vessel before percutaneous coronary intervention. This review focuses on the challenges of identifying the presence of CMD in the context of diffuse non-obstructive CAD and obstructive CAD. Furthermore, it is going to discuss the pathophysiology in this complex situation, examine the clinical context in which the interaction of the three components of disease takes place and finally look at non-invasive diagnostic methods relevant for addressing this question.
HHLA2 and PD-L1 co-expression predicts poor prognosis in patients with clear cell renal cell carcinoma
Authors: Qiang-Hua Zhou, Kai-Wen Li, Xu Chen, Hai-Xia He, Sheng-Meng Peng, Shi-Rong Peng, Qiong Wang, Ze-An Li, Yi-Ran Tao, Wen-Li Cai, Ran-Yi Liu, Hai Huang
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Although clear cell renal cell carcinoma (ccRCC) is well known as a highly immunogenic tumor, only a small subset of patients could benefit from current immunotherapy, which might be due to the heterogeneity of immune microenvironment in ccRCC. So, it is meaningful to explore novel immunotherapy or combination therapy for improving therapeutic efficacy. HHLA2, a newly discovered B7 family member, is prevalently expressed in numerous tumors, including ccRCC. This study aimed to investigate the prognostic impact of HHLA2/PD-L1 co-expression and its relationship with tumor-infiltrating lymphocytes (TILs). Methods The expression levels of HHLA2, PD-L1, CD8, and CD4 in cancer tissues from cases (206 in the training cohort and 197 in the validation cohort) with surgically resectable primary ccRCC were evaluated by immunohistochemistry. Results The positive rates of HHLA2 were much higher than those of PD-L1 in ccRCC tissues. HHLA2-positive expression was significantly associated with necrosis, microvascular invasion, advanced Fuhrman nuclear, and TNM stage and indicated a shorter progression-free survival (PFS) and overall survival (OS) in both cohorts. Moreover, patients with HHLA2/PD-L1 co-expression suffered the highest risk of disease progression and death by a significant margin. Besides, HHLA2/PD-L1 co-expression was significantly associated with a high density of CD8 + and CD4 + TILs. Notably, a new immune classification, based on HHLA2/PD-L1 co-expression and TILs, successfully stratified PFS and OS, especially in patients with TILs positivity. Conclusions The expression of HHLA2 is more frequent than PD-L1 in ccRCC. HHLA2/PD-L1 co-expression had an adverse impact on the prognoses of patients with ccRCC; this finding provides a rationale for combination immunotherapy with anti-HHLA2 and PD-L1 blockage for patients with ccRCC in the future.
Neoadyuvant Chemotherapy Followed by Chemorradiation in Locally-Advanced Squamous Cervical Cancer
Authors: M. Vieito Villar, N. Martinez Lago, J.F. Cueva, E. Gonzalez Patiño, M.T. Curiel, P. Palacios Ozores, S. Candamio Folgar, N. Salvador Garrido, B. Taboada, R. Lopez
Journal: Annals of Oncology (2012)
Abstract 4011: Notch 1/2/3 mutation as a potential biomarker for immunotherapy in smokers with non-small cell lung cancer via increasing tumor mutational burden
Authors: Xiaohua Hong, Aijun Shen, Yu Xu, Chengcheng Li, Guoqiang Wang, Li Liu, Chuang Qi
Journal: Cancer Research (2019)

Abstract Background: Smoking status have been discovered to be associated with the response of anti-PD-1/PD-L1 treatment in advanced non-small cell lung cancer (NSCLC), on account of the smoking-induced higher tumor mutational burden (TMB). However, merely partial smokers with NSCLC exhibit high TMB and respond to anti-PD-1/PD-L1 therapy. The underlying signalling pathway that involved in the accumulation of mutational burden and response to immunotherapy in smokers with NSCLC has not been clarified. Methods: Data from Rizvi study (n = 240, nivolumab, tissue-sample NGS) and OAK study (n = 642, atezolizumab vs. docetaxel, blood-sample NGS) was retrieved and analysed as training cohorts, followed with validation in our independent NSCLC cohort (n = 44, anti-PD-1/PD-L1, blood-sample NGS). In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. Results: In Rizvi cohort, mutation of Notch 1/2/3 was associated with higher TMB in smokers with NSCLC (P &amp;lt; 0.001) not in non-smokers with NSCLC (P = 0.908). Notch 1/2/3mut was associated with prolonged progression-free survival (PFS) compared with Notch 1/2/3wt in smokers with NSCLC (P = 0.015; HR, 0.51, 95% CI, 0.30-0.88), while not in non-smokers with NSCLC (P = 0.73; HR, 0.83, 95% CI, 0.30-2.35). Consistent results were observed in OAK study that Notch 1/2/3mut was associated with higher TMB (P &amp;lt; 0.001) and longer PFS exclusively in current smokers with NSCLC treated with immunotherapy (P = 0.018; HR, 0.28, 95% CI, 0.10-0.81). No association of Notch 1/2/3 status and PFS was observed in smokers with NSCLC treated with chemotherapy (P = 0.80; HR, 0.92, 95% CI, 0.47-1.78). We further validated these results in our independent cohort. Similar upregulation of TMB was observed in the Notch1/2/3-mutated smokers with NSCLC, and Notch1/2/3mut improved DCR (100% vs. 41.2%, P = 0.065) and significantly prolonged PFS (P = 0.046; adjusted HR, 0.12, 95% CI, 0.01-0.96). Conclusions: Notch1/2/3 mutation may serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in smokers with NSCLC via upregulating TMB. Citation Format: Xiaohua Hong, Aijun Shen, Yu Xu, Chengcheng Li, Guoqiang Wang, Li Liu, Chuang Qi. Notch 1/2/3 mutation as a potential biomarker for immunotherapy in smokers with non-small cell lung cancer via increasing tumor mutational burden [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4011.
A39 Reactive Cutaneous Capillary Endothelial Proliferation Caused by Camrelizumab (SHR-1210) Through Activation of HIF-1α/VEGF Signaling Pathway
Authors: X. Wu, X. Zhang, P. Shu, Q. Ma, Y. Chen, D. Li, Y. Wang
Journal: Journal of Thoracic Oncology (2020)
Discussion points for Bayesian inference
Authors: Balazs Aczel, Rink Hoekstra, Andrew Gelman, Eric-Jan Wagenmakers, Irene G. Klugkist, Jeffrey N. Rouder, Joachim Vandekerckhove, Michael D. Lee, Richard D. Morey, Wolf Vanpaemel, Zoltan Dienes, Don van Ravenzwaaij
Journal: Nature Human Behaviour (2020)
US Organ Donation Policy
Authors: Alex Chan
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Longitudinal metabolic and gut bacterial profiling of pregnant women with previous bariatric surgery
Authors: Kiana Ashley West, Chidimma Kanu, Tanya Maric, Julie Anne Kathryn McDonald, Jeremy K Nicholson, Jia V Li, Mark R Johnson, Elaine Holmes, Makrina D Savvidou
Journal: Gut (2020)

Objective Due to the global increase in obesity rates and success of bariatric surgery in weight reduction, an increasing number of women now present pregnant with a previous bariatric procedure. This study investigates the extent of bariatric-associated metabolic and gut microbial alterations during pregnancy and their impact on fetal development. Design A parallel metabonomic (molecular phenotyping based on proton nuclear magnetic resonance spectroscopy) and gut bacterial (16S ribosomal RNA gene amplicon sequencing) profiling approach was used to determine maternal longitudinal phenotypes associated with malabsorptive/mixed (n=25) or restrictive (n=16) procedures, compared with women with similar early pregnancy body mass index but without bariatric surgery (n=70). Metabolic profiles of offspring at birth were also analysed. Results Previous malabsorptive, but not restrictive, procedures induced significant changes in maternal metabolic pathways involving branched-chain and aromatic amino acids with decreased circulation of leucine, isoleucine and isobutyrate, increased excretion of microbial-associated metabolites of protein putrefaction (phenylacetlyglutamine, p- cresol sulfate, indoxyl sulfate and p- hydroxyphenylacetate), and a shift in the gut microbiota. The urinary concentration of phenylacetylglutamine was significantly elevated in malabsorptive patients relative to controls (p=0.001) and was also elevated in urine of neonates born from these mothers (p=0.021). Furthermore, the maternal metabolic changes induced by malabsorptive surgery were associated with reduced maternal insulin resistance and fetal/birth weight. Conclusion Metabolism is altered in pregnant women with a previous malabsorptive bariatric surgery. These alterations may be beneficial for maternal outcomes, but the effect of elevated levels of phenolic and indolic compounds on fetal and infant health should be investigated further.
Abstract 14979: Prenatal NSAID Therapy to Mitigate Circular Shunt Physiology in Fetuses With Severe Ebstein Anomaly
Authors: Lindsay R Freud, Louise E Wilkins-Haug, Rebecca S Beroukhim, Terra Lafranchi, Colin K Phoon, Carol J Buzzard, Julie S Glickstein, Kristopher M Cumbermack, Majd Makhoul, Shaine A Morris, Heather Y Sun, Queralt Ferrer, Simone Pedra, Wayne Tworetzky
Journal: Circulation (2018)

Background: Ebstein anomaly and tricuspid valve dysplasia (EA/TVD) are rare congenital malformations associated with nearly 50% mortality when diagnosed in utero. The diseases often produce severe ...
Phase II study of orally administered rigosertib (ON 01910.Na) in transfusion-dependent lower-risk myelodysplastic syndrome (MDS) patients.
Authors: Azra Raza, Siddhartha Mukherjee, Andrew Eisenberger, J. Gregory Mears, Francois Wilhelm
Journal: Journal of Clinical Oncology (2013)

7031 Background: Rigosertib, a novel small molecule inhibitor of PI3-Kinase and PLK pathways is currently evaluated (IV infusions) in a phase III trial in higher risk MDS patients who have failed hypomethylating agents. A previous phase I study found good bioavailability and activity of orally administered rigosertib in transfusion-dependent MDS patients (ASH 2011). Here we report preliminary results from an ongoing phase II study. Methods: This is a randomized, two-arm study of oral rigosertib (560 mg bid) administered either intermittently (2 out of 3 weeks) or continuously. Transfusion-dependent patients must have received at least 4 units RBC transfusions over 8 weeks before randomization, and can receive transfusions and erythrocyte stimulating agents (ESAs) while on study. Results: Twenty nine MDS patients (25 intermediate-1 and 4 low risk per IPSS classification) have been randomized as of December 17, 2012. Overall oral rigosertib was well tolerated except for a high incidence (5 of 9 patients) of grade 2+ urinary side effects (dysuria, hematuria, cystitis, and urinary urgency), in the continuous dosing arm. Accordingly, the protocol was amended to allow all patients to be treated with intermittent dosing, with option of dose interruption/reduction resulting in a much lower frequency of urinary side effects (4/20 patients with urinary grade 2+ toxicity). Fifteen patients (none of them with del5q cytogenetic) have been treated with intermittent dosing for at least 8 weeks. Seven (47%) patients achieved transfusion independence (no RBC transfusion for at least 8 consecutive weeks), which lasted 8 to 27 + weeks. Six of 7 responding patients were refractory to prior treatment with ESAs and 5 of these 7 patients received concomitant ESAs, suggesting an effect of rigosertib on ESA resistance. Conclusions: Preliminary results of this phase II study indicate that intermittent dosing of rigosertib administered orally is well tolerated and active in producing transfusion independence in approximately 50% transfusion dependent, lower risk MDS patients. The contributing role of rigosertib and ESAs in these transfusion responses is being investigated. Clinical trial information: NCT01584531.
Which Postmenopausal Women Should Use Testosterone for Low Sexual Desire?
Authors: Anita Slomski
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Chronic Kidney Disease, Diabetes, and Risk of Mortality After Acute Myocardial Infarction: Insight From the FAST-MI Program
Authors: Louis Potier, Ronan Roussel, Marianne Zeller, François Schiele, Etienne Puymirat, Tabassome Simon, Nicolas Danchin
Journal: Diabetes Care (2020)

Diabetes is associated with a substantially increased risk of all-cause death, mainly driven by cardiovascular (CV) mortality. Furthermore, diabetes is associated with poorer outcomes after acute myocardial infarction (AMI) (1). Impaired glomerular filtration rate (GFR) is also associated with an increased risk of CV mortality (2). However, whether diabetes still confers a higher risk of mortality in patients with impaired GFR remains unknown.

The aim of this study was to assess the long-term prognostic significance of both diabetes and renal impairment in two prospective nationwide cohorts of AMI patients: FAST-MI (French Registry of Acute ST-Elevation or non-ST-elevation Myocardial Infarction) 2005 ( n = 3,670 [reg. no. NCT00673036, ClinicalTrials.gov]) and FAST-MI 2010 ( n = 4,169 [NCT01237418]) (3). Both registries consecutively included patients with AMI admitted to cardiac intensive care units within 48 h of symptom onset during a specified 1-month period. AMI was defined by increased levels of cardiac biomarkers together with either compatible symptoms or electrocardiogram changes. Vital status at 5 years was available in >95%. We assessed all-cause mortality at 5 years according to estimated GFR (eGFR) (calculated with Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula and based on KDIGO [Kidney Disease: Improving Global Outcomes] GFR categories with eGFR <30 and <15 mL/min/1.73 m2 pooled) and diabetes status at inclusion. Multivariable proportional hazards models (assumptions checked) were used with covariates chosen based on their potential prognostic relevance: year of inclusion; sex; age; BMI categories; hypertension; current smoking; prior AMI; peripheral artery disease; history of heart failure, stroke, cancer, and chronic obstructive pulmonary disease; type of myocardial infarction (MI) (STEMI or NSTEMI); GRACE risk score; percutaneous coronary …
Mutual inhibition between Prkd2 and Bcl6 controls T follicular helper cell differentiation
Authors: Takuma Misawa, Jeffrey A. SoRelle, Jin Huk Choi, Tao Yue, Kuan-wen Wang, William McAlpine, Jianhui Wang, Aijie Liu, Koichi Tabeta, Emre E. Turer, Bret Evers, Evan Nair-Gill, Subhajit Poddar, Lijing Su, Feiya Ou, Liyang Yu, Jamie Russell, Sara Ludwig, Xiaoming Zhan, Sara Hildebrand, Xiaohong Li, Miao Tang, Anne R. Murray, Eva Marie Y. Moresco, Bruce Beutler
Journal: Science Immunology (2020)

Prkd2-dependent phosphorylation of Bcl6 inhibits T FH cell differentiation.
Elagolix for Heavy Menstrual Bleeding in Women with Uterine Fibroids
Authors: William D. Schlaff, Ronald T. Ackerman, Ayman Al-Hendy, David F. Archer, Kurt T. Barnhart, Linda D. Bradley, Bruce R. Carr, Eve C. Feinberg, Sandra M. Hurtado, JinHee Kim, Ran Liu, R. Garn Mabey, Charlotte D. Owens, Alfred Poindexter, Elizabeth E. Puscheck, Henry Rodriguez-Ginorio, James A. Simon, Ahmed M. Soliman, Elizabeth A. Stewart, Nelson B. Watts, Ozgul Muneyyirci-Delale
Journal: New England Journal of Medicine (2020)

Uterine fibroids are hormone-responsive neoplasms that are associated with heavy menstrual bleeding. Elagolix, an oral gonadotropin-releasing hormone antagonist resulting in rapid, reversible suppression of ovarian sex hormones, may reduce fibroid-associated bleeding.
Abstract 3229: Radiation and chemotherapies result in increasing neoantigen intratumor heterogeneity and resistance to nivolumab in a patient with pleomorphic lung cancer
Authors: Xiaohua Hong, Yuting Liu, Yiying Liu, Yue Hu, Qifan Yang, Di Wu, Kai Zhang, Yongchao Li, Jinsong Yang, Jiaqian Wang, Jun Liu, Li Liu
Journal: Cancer Research (2019)

Abstract BACKGROUND:Immune checkpoint inhibitors (ICIs) have significantly changed the landscape of cancer treatment, but the response rate of non-small-cell lung carcinoma (NSCLC) to ICIs is less than 30%. Tumor mutational burden (TMB) is the most promising predictive biomarker for NSCLC immunotherapies. However, some NSCLC patients with high-TMB have little response to ICIs. The neoantigen intratumor heterogeneity (ITH), which determined by the ratio of subclonal neoantigen in the tumor, has been verified to be a potential therapeutic biomarker for immunotherapies in some cancer types. Pulmonary pleomorphic carcinoma, a rare subtype of pulmonary sarcomatoid carcinoma, has been shown to respond remarkably to ICIs, but the biomarkers for ICIs in pulmonary pleomorphic carcinoma have not been fully proven. CASE PRESENTATION:A 57 years old female pulmonary pleomorphic carcinoma patient, who underwent surgery, chemotherapy, anti-angiogenic therapy, radiotherapy, and anti-PD1 therapy, with disease relapse at the last, was included in this study. Primary and relapse tumor samples were collected for gene sequencing by a target sequencing panel which covered 811 cancer genes, during ICIs treatment. Peripheral bloods were collected for ctDNA and T cell receptor sequencing every two months. The results showed that the TMB (&amp;gt;10 muts/Mb) was high, but the clonal neoantigen load (1.33 neos/Mb) was low. The neoantigen ITH was increased after chemotherapy and radiotherapy with a score at nearly 0% in the primary tumor but increased to 85.72% in relapse tissues. The clonal neoantigen ratio detected by ctDNA was increased ~0.8 fold, while the high-frequency clonotypes of TCR to neoantigens dropped during ICIs treatment. CONCLUSIONS:Our results indicated that cytotoxic chemotherapy and radiotherapy can induce the subclonal neoantigens production and increase the neoantigen ITH, thus might negatively regulating patients’ response to ICIs therapy. These results highlight that the neoantigen ITH might be an important auxiliary to TMB in predicting patient response to immune therapies. More studies and clinical trials are needed to further validate these results. Citation Format: Xiaohua Hong, Yuting Liu, Yiying Liu, Yue Hu, Qifan Yang, Di Wu, Kai Zhang, Yongchao Li, Jinsong Yang, Jiaqian Wang, Jun Liu, Li Liu. Radiation and chemotherapies result in increasing neoantigen intratumor heterogeneity and resistance to nivolumab in a patient with pleomorphic lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3229.
A02 Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma
Authors: M.A. Gillette, S. Satpathy, S. Cao, S. Dhanasekaran, S. Vasaikar, K. Krug, F. Petralia, Y. Li, W.-W. Liang, B. Reva, R. Hong, S. Savage, G. Getz, Q.K. Li, B. Zhang, H. Rodriguez, K. Ruggles, A.I. Robles, K.C. Clauser, R. Govindan, P. Wang, A. Nesvizhskii, L. Ding, D.R. Mani, S.A. Carr
Journal: Journal of Thoracic Oncology (2020)