tbuckley/cabot-search huggingface dataset:
Intracellular calcium current disorder and disease phenotype in <i>OBSCN</i> mutant iPSC-based cardiomyocytes in arrhythmogenic right ventricular cardiomyopathy
Authors: Peipei Chen, Ying Xiao, Yuanpin Wang, Zhifa Zheng, Lianfeng Chen, Xufei Yang, Jingyi Li, Wei Wu, Shuyang Zhang
Journal: Theranostics (2020)

Obscurin participates in the development of striated muscles and maintenance of the functional sarcoplasmic reticulum. However, the role of obscurin in arrhythmogenic right ventricular cardiomyopathy (ARVC) is not well understood. We aimed to study the novel obscurin mutations in the pathogenesis of ARVC and the underlying mechanisms. Methods: We generated induced pluripotent stem cells (iPSC) through retroviral reprogramming of peripheral blood mononuclear cells isolated from a 46-year-old female diagnosed with ARVC, carrying a mutation in OBSCN. The cells differentiated into functional iPSC-based cardiomyocytes (iPSC-CMs), whose phenotype was determined by transmission electron microscopy, electrophysiological description, immunofluorescence staining, and Oil Red O staining. Molecular characterization was performed by bioinformatic analyses, and identification by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Results: ARVC-iPSC-CMs mutation in OBSCN showed significant accumulation of lipids, increased pleomorphism, irregular Z-bands, and increased L type calcium currents. Functional enrichment analysis identified pathways involved in focal adhesion and structure formation; the adipocytokines and PPAR signaling pathways were also activated in the ARVC group. Moreover, our results from ultra-high-resolution microscopy, qRT-PCR and Western blotting confirmed that the mutant OBSCN protein and its anchor protein, Ank1.5, showed structural disorder and decreased expression, but there was increased expression of junctional protein N-Cadherin. Further analysis revealed the gene expression of other desmosomal proteins in ARVC-iPSC-CMs was also decreased but some adipogenesis pathway-related proteins (PPARγ, C/EBPα, and FABP4) were increased. Conclusion: A novel frameshift mutation in OBSCN caused phenotypic alteration accompanied by disrupted localization and decreased expression of its anchoring protein Ank1.5. Furthermore, there was an accumulation of lipids with an increase in fatty fibrosis area and myocardial structural disorder, possibly leading to dysrhythmia in calcium channel-related myocardial contraction. These observations suggested the possibility of attenuating ARVC progression by therapeutic modulation of OBSCN expression.
LBA59 First-line nivolumab (NIVO) + ipilimumab (IPI) combined with 2 cycles of platinum-based chemotherapy (chemo) vs 4 cycles of chemo in advanced non-small cell lung cancer (NSCLC): Patient-reported outcomes (PROs) from CheckMate 9LA
Authors: M. Reck, T-E. Ciuleanu, M. Cobo, M. Schenker, B. Zurawski, J. Menezes, E. Richardet, J. Bennouna, Y. Cheng, L. Paz-Ares, S. Lu, T. John, B. Padilla, X. Sun, A. Moisei, J. Yan, Y. Yuan, S.I. Blum, D.P. Carbone
Journal: Annals of Oncology (2020)
716P Optimizing ipilimumab in metastatic renal cell carcinoma: SAKK 07/17 study
Authors: F. Stenner-Liewen, R. Cathomas, C.A. Rothermundt, J. Schardt, A. Patrikidou, D. Zihler, A.A. Erdmann, M. Küng, D. Dietrich, C. Berset, G. Godar, D. Berthold, H. Läubli
Journal: Annals of Oncology (2020)
1242P Characteristics of the first 615 patients enrolled in Pacific R: A study of the first real-world data on unresectable stage III NSCLC patients treated with durvalumab after chemoradiotherapy
Authors: N. Girard, R. Fietkau, M. Garassino, P. Garrido, J.K. Field, S. Peters, H.J.M. Smit, M. Pérol, P. Merle, A. Sibille, B. Markman, H. Bouchaab, M. Moskovitz, C. Schumann, V. Gregorc, A.B. Klein, I. Diaz Perez, W. Sawyer, M. Licour, D. Christoph
Journal: Annals of Oncology (2020)
LBA15 Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC)
Authors: D.W. Miles, J. Gligorov, F. André, D. Cameron, A. Schneeweiss, C.H. Barrios, B. Xu, A.M. Wardley, D. Kaen, L. Andrade, V. Semiglazov, M. Reinisch, M. Patre, L. Morales, K. Russell, M. Donica, J. O'Shaughnessy
Journal: Annals of Oncology (2020)
529MO Activity, safety and circulating tumour DNA (ctDNA) dynamics of paradox breaker BRAF inhibitor PLX8394 in patients with advanced cancer
Authors: M.A. Gouda, E.J. Sherman, G.W. Gilcrease, U.N. Vaishampayan, A. Parikh, L. Feun, S. Kummar, H. Huang, C. Zhang, P. Severson, K. Inokuchi, M. Silverman, G. Bollag, F. Janku
Journal: Annals of Oncology (2020)
253P Preliminary report on survival outcomes of BRCA mutation carriers with triple-negative breast cancer
Authors: A. Aranda-Gutierrez, A.S. Ferrigno, J.N. Weitzel, M. Moncada-Madrazo, A. Gomez-Picos, A. Castillo-Orozco, G.I. Magallanes-Garza, R. Ortiz-Lopez, C. Villarreal-Garza, D. Aguilar
Journal: Annals of Oncology (2020)
796TiP TROPHY-U-01 Cohort 3: Sacituzumab govitecan (SG) and pembrolizumab (pembro) in patients (pts) with progression or recurrence of metastatic urothelial cancer (mUC) after platinum (PLT)-based therapy
Authors: P. Grivas, C.N. Sternberg, N. Agarwal, D.P. Petrylak, S.T. Tagawa, Q. Hong, A. Gladden, C. Kanwal, T. Goswami, Y. Loriot
Journal: Annals of Oncology (2020)
458P Phase (Ph) I/Ib trial of fruquintinib (fru) in patients (pts) with advanced solid tumors: Preliminary results of the dose expansion (exp) cohort in refractory metastatic colorectal cancer (mCRC)
Authors: N.A. Dasari, A. Wang-Gillam, J.M. Hubbard, A. Fernandez, S. Nanda, M. Kania, W.R. Schelman, T.S. Bekaii-Saab
Journal: Annals of Oncology (2020)
1176P Expression and clinical significance of PD-L1 in small cell carcinoma of the esophagus
Authors: C. Zhang, G. Zhang, L. Xue, Q. Zeng, Z. Zhang, Y. Luo, F. Wang, Y. Che, B. Zheng, Z. Yang, Q. Xue, N. Sun, J. He
Journal: Annals of Oncology (2020)
Correspondence to ‘Prevalence of hospital PCR-confirmed COVID-19 cases in patients with chronic inflammatory and autoimmune rheumatic diseases’
Authors: Bo-Yao Wu, Chi-Ho Chan, James Cheng-Chung Wei
Journal: Annals of the Rheumatic Diseases (2020)

We read with great interest the article by Pablos et al .1 However, we consider some methods and findings in the study that need to be further clarified.

First, detection bias may exist in this study because patients with AI/IMD visit hospitals for medical examinations regularly. Therefore, patients under follow-up in rheumatology department exactly showed higher prevalence of hospital PCR+COVID-19 than the reference population.

Second, to the best of our knowledge, Sjogren’s syndrome is a slow-developing syndrome.2 However, we can find out that in …
516P Outcomes of patients with metastatic anal cancer according to HIV infection: A multicenter study
Authors: B.R.S. Mattos, M.P.G. Camandaroba, E. Ruiz, M.R. Luca, G. Mendez, I.K.F. Lustosa, S.F. Silva, J.M. O'Connor, R.S.P. Riechelmann
Journal: Annals of Oncology (2020)
Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study
Authors: Arnon P. Kater, Jenny Qun Wu, Thomas Kipps, Barbara Eichhorst, Peter Hillmen, James D’Rozario, Sarit Assouline, Carolyn Owen, Tadeusz Robak, Javier de la Serna, Ulrich Jaeger, Guillaume Cartron, Marco Montillo, Julie Dubois, Eric Eldering, Clemens Mellink, Anne-Marie Van Der Kevie-Kersemaekers, Su Young Kim, Brenda Chyla, Elizabeth Punnoose, Christopher R. Bolen, Zoe June Assaf, Yanwen Jiang, Jue Wang, Marcus Lefebure, Michelle Boyer, Kathryn Humphrey, John F. Seymour
Journal: Journal of Clinical Oncology (2020)

In previous analyses of the MURANO study, fixed-duration venetoclax plus rituximab (VenR) resulted in improved progression-free survival (PFS) compared with bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics.Patients with CLL were randomly assigned to 2 years of venetoclax (VenR for the first six cycles) or six cycles of BR. PFS, overall survival (OS), peripheral-blood minimal residual disease (MRD) status, genomic complexity (GC), and gene mutations were assessed.Of 389 patients, 194 were assigned to VenR and 195 to BR. Four-year PFS and OS rates were higher with VenR than BR, at 57.3% and 4.6% (hazard ratio [HR], 0.19; 95% CI, 0.14 to 0.25), and 85.3% and 66.8% (HR, 0.41; 95% CI, 0.26 to 0.65), respectively. Undetectable MRD (uMRD) at end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15). Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with GC than in those without GC (P = .042); higher GC was associated with shorter PFS. Higher MRD positivity rates were seen with BIRC3 and BRAF mutations at EOCT and with TP53, NOTCH1, XPO1, and BRAF mutations at EOT.Efficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS.
Advances in the assessment of minimal residual disease in mantle cell lymphoma
Authors: Dayoung Jung, Preetesh Jain, Yixin Yao, Michael Wang
Journal: Journal of Hematology & Oncology (2020)

Abstract The clinical impact of minimal residual disease detection at early time points or during follow-ups has been shown to accurately predict relapses among patients with lymphomas, mainly in follicular and diffuse large B cell lymphoma. The field of minimal residual disease testing in mantle cell lymphoma is still evolving but has great impact in determining the prognosis. Flow cytometry and polymerase chain reaction-based testing are most commonly used methods in practice; however, these methods are not sensitive enough to detect the dynamic changes that underline lymphoma progression. Newer methods using next-generation sequencing, such as ClonoSeq, are being incorporated in clinical trials. Other techniques under evolution include CAPP-seq and anchored multiplex polymerase chain reaction-based methods. This review article aims to provide a comprehensive update on the status of minimal residual disease detection and its prognostic effect in mantle cell patients. The role of circulating tumor DNA-based minimal residual disease detection in lymphomas is also discussed.
1016TiP LEAP-012 trial in progress: Pembrolizumab plus lenvatinib and transarterial chemoembolization (TACE) in patients with intermediate-stage hepatocellular carcinoma (HCC) not amenable to curative treatment
Authors: J.M. Llovet, A.B. El-Khoueiry, A. Vogel, D.C. Madoff, R.S. Finn, S. Ogasawara, Z. Ren, K. Mody, J. Jing Li, A.B. Siegel, L. Dubrovsky, M. Kudo
Journal: Annals of Oncology (2020)
161O Randomized preoperative window of opportunity (WOO) study with the CDK4/6 inhibitor abemaciclib in early breast cancer (EBC) patients and differential gene expression pathway analyses with palbociclib
Authors: M. Arnedos, D. Chaltiel, B. Cheaib, D. Drubay, D. Gentien, A. Vieillefon, V. Scott, I. Bouakka, J. Adam, I.J. Garberis, F. Rimareix, N. Leymarie, A.A. Viansone, M. Lacroix-Triki, S. Michiels, F. André
Journal: Annals of Oncology (2020)
952P Neutrophil-to-lymphocyte ratio (NLR) and survival in recurrent or metastatic head and neck cancer patients treated with immunotherapy
Authors: A. Franco, E. Tresch, I. Sakji, S. Makhloufi, C. Abdeddaim, M. Julieron, E. Dansin, D. Chevalier, F. Mouawad, G. Lefebvre
Journal: Annals of Oncology (2020)
1186P Impact of temozolomide (TEM) and capecitabine (CAP) dose reductions in toxicity and efficacy in patients (pts) with neuroendocrine neoplasms (NENs) treated with CAPTEM chemotherapy
Authors: J. Hernando, A. Garcia-Alvarez, D.H. Marmolejo Castaneda, D.A. Acosta Eyzaguirre, M. Diez Garcia, N. Saoudi Gonzalez, A. Casteras, M. Simo, A. Garcia Burillo, X. Merino, L. Blanco, J.L. Sanchez, M. Roca, J. Capdevila
Journal: Annals of Oncology (2020)
Central fatness and risk of all cause mortality: systematic review and dose-response meta-analysis of 72 prospective cohort studies
Authors: Ahmad Jayedi, Sepideh Soltani, Mahdieh Sadat Zargar, Tauseef Ahmad Khan, Sakineh Shab-Bidar
Journal: BMJ (2020)

Abstract Objective To quantify the association of indices of central obesity, including waist circumference, hip circumference, thigh circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index, with the risk of all cause mortality in the general population, and to clarify the shape of the dose-response relations. Design Systematic review and meta-analysis. Data sources PubMed and Scopus from inception to July 2019, and the reference lists of all related articles and reviews. Eligibility criteria for selecting studies Prospective cohort studies reporting the risk estimates of all cause mortality across at least three categories of indices of central fatness. Studies that reported continuous estimation of the associations were also included. Data synthesis A random effects dose-response meta-analysis was conducted to assess linear trend estimations. A one stage linear mixed effects meta-analysis was used for estimating dose-response curves. Results Of 98 745 studies screened, 1950 full texts were fully reviewed for eligibility. The final analyses consisted of 72 prospective cohort studies with 2 528 297 participants. The summary hazard ratios were as follows: waist circumference (10 cm, 3.94 inch increase): 1.11 (95% confidence interval 1.08 to 1.13, I 2 =88%, n=50); hip circumference (10 cm, 3.94 inch increase): 0.90 (0.81 to 0.99, I 2 =95%, n=9); thigh circumference (5 cm, 1.97 inch increase): 0.82 (0.75 to 0.89, I 2 =54%, n=3); waist-to-hip ratio (0.1 unit increase): 1.20 (1.15 to 1.25, I 2 =90%, n=31); waist-to-height ratio (0.1 unit increase): 1.24 (1.12 to 1.36, I 2 =94%, n=11); waist-to-thigh ratio (0.1 unit increase): 1.21 (1.03 to 1.39, I 2 =97%, n=2); body adiposity index (10% increase): 1.17 (1.00 to 1.33, I 2 =75%, n=4); and A body shape index (0.005 unit increase): 1.15 (1.10 to 1.20, I 2 =87%, n=9). Positive associations persisted after accounting for body mass index. A nearly J shaped association was found between waist circumference and waist-to-height ratio and the risk of all cause mortality in men and women. A positive monotonic association was observed for waist-to-hip ratio and A body shape index. The association was U shaped for body adiposity index. Conclusions Indices of central fatness including waist circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index, independent of overall adiposity, were positively and significantly associated with a higher all cause mortality risk. Larger hip circumference and thigh circumference were associated with a lower risk. The results suggest that measures of central adiposity could be used with body mass index as a supplementary approach to determine the risk of premature death.
169MO Development and validation of a magnetic resonance imaging radiomics-based signature to predict axillary lymph node metastasis and disease-free survival in patients with breast cancer: A multicenter cohort study
Authors: Y. Yu, Y. Tan, Q. Hu, J. Ouyang, Y. Chen, G. Yang, A. Li, N. Lu, Z. He, Y. Yang, K. Chen, Q. Ou, Y. Zhang, Z. Wu, F. Su, C. Xie, E. Song, H. Yao
Journal: Annals of Oncology (2020)
353TiP HER2CLIMB-02: A randomized, double-blind, phase III study of tucatinib or placebo with T-DM1 for unresectable locally advanced or metastatic HER2+ breast cancer
Authors: S.A. Hurvitz, L.T. Vahdat, N. Harbeck, A.C. Wolff, S.M. Tolaney, S. Loi, N. Masuda, J. O'Shaughnessy, C. Dong, L. Walker, E. Rustia, V. Borges
Journal: Annals of Oncology (2020)
Assessing the Safety of Glucose-Lowering Drugs — A New Focus for the FDA
Authors: William H. Chong, Lisa B. Yanoff, Eugenio Andraca-Carrera, Mary Thanh Hai
Journal: New England Journal of Medicine (2020)

The FDA is moving away from a narrow focus on evaluating the cardiovascular safety of drugs for glycemic control and recommending that such drugs be studied in broad, representative populations of patients to permit a meaningful assessment of various potential risks.
1385P Analysis of drug-induced RNA expression changes in NSCLC patient-derived explants as a potential tool for personalized therapy choice
Authors: E. Imyanitov, D. Kuznetsova, A.O. Ivantsov, S. Aleksakhina, S. Baskina, A. Kosmin, M. Maydin, A. Togo
Journal: Annals of Oncology (2020)
339P Impact of blood glucose levels on the efficacy of everolimus-exemestane in patients with advanced HR-positive/HER2 negative breast cancer: The EVERMET study
Authors: C. Vernieri, F. Nichetti, V. Guarneri, E. Cortesi, L. Moscetti, L. Del Mastro, A. Fabbri, G. Curigliano, F. Montemurro, A. Losurdo, D.G. Generali, A. Fabi, R. Pedersini, M. Ciccarese, A. Rocca, G. Arpino, N.M. La Verde, F. Puglisi, L. Mariani, F. de Braud
Journal: Annals of Oncology (2020)
BET inhibitor suppresses melanoma progression <i>via</i> the noncanonical NF-κB/SPP1 pathway
Authors: Guangtong Deng, Furong Zeng, Juan Su, Shuang Zhao, Rui Hu, Wu Zhu, Shuo Hu, Xiang Chen, Mingzhu Yin
Journal: Theranostics (2020)

Background: Bromodomain and extra-terminal domain (BET) inhibitors have shown profound efficacy against hematologic malignancies and solid tumors in preclinical studies. However, the underlying molecular mechanism in melanoma is not well understood. Here we identified secreted phosphoprotein 1 (SPP1) as a melanoma driver and a crucial target of BET inhibitors in melanoma. Methods: Bioinformatics analysis and meta-analysis were used to evaluate the SPP1 expression in normal tissues, primary melanoma, and metastatic melanoma. Real-time PCR (RT-PCR) and Western blotting were employed to quantify SPP1 expression in melanoma cells and tissues. Cell proliferation, wound healing, and Transwell assays were carried out to evaluate the effects of SPP1 and BET inhibitors in melanoma cells in vitro. A xenograft mouse model was used to investigate the effect of SPP1 and BET inhibitors on melanoma in vivo. Chromatin immunoprecipitation (ChIP) assay was performed to evaluate the regulatory mechanism of BET inhibitors on SPP1. Results: SPP1 was identified as a melanoma driver by bioinformatics analysis, and meta-analysis determined it to be a diagnostic and prognostic biomarker for melanoma. SPP1 overexpression was associated with poor melanoma prognosis, and silencing SPP1 suppressed melanoma cell proliferation, migration, and invasion. Through a pilot drug screen, we identified BET inhibitors as ideal therapeutic agents that suppressed SPP1 expression. Also, SPP1 overexpression could partially reverse the suppressive effect of BET inhibitors on melanoma. We further demonstrated that bromodomain-containing 4 (BRD4) regulated SPP1 expression. Notably, BRD4 did not bind directly to the SPP1 promoter but regulated SPP1 expression through NFKB2. Silencing of NFKB2 resembled the phenotype of BET inhibitors treatment and SPP1 silencing in melanoma. Conclusion: Our findings highlight SPP1 as an essential target of BET inhibitors and provide a novel mechanism by which BET inhibitors suppress melanoma progression via the noncanonical NF-κB/SPP1 pathway.
Pharmacogenomics of Antiretroviral Drug Metabolism and Transport
Authors: Zaikuan J. Yu, Eric P. Mosher, Namandjé N. Bumpus
Journal: The Annual Review of Pharmacology and Toxicology (2020)

Antiretroviral therapy has markedly reduced morbidity and mortality for persons living with human immunodeficiency virus (HIV). Individual tailoring of antiretroviral regimens has the potential to further improve the long-term management of HIV through the mitigation of treatment failure and drug-induced toxicities. While the mechanisms underlying anti-HIV drug adverse outcomes are multifactorial, the application of drug-specific pharmacogenomic knowledge is required in order to move toward the personalization of HIV therapy. Thus, detailed understanding of the metabolism and transport of antiretrovirals and the influence of genetics on these pathways is important. To this end, this review provides an up-to-date overview of the metabolism of anti-HIV therapeutics and the impact of genetic variation in drug metabolism and transport on the treatment of HIV. Future perspectives on and current challenges in pursuing personalized HIV treatment are also discussed.
A Basis to Be Here: Stories from International Graduate Students in the United States
Authors: Mackenzie Lemieux, Juan Manuel Colazo, Tamina Kienka, Ademi Zhakyp
Journal: Cell Reports Medicine (2020)

Recent guidance from the US Immigration and Customs Enforcement drastically altered the lives of international students in America, especially those who are matriculating. This commentary describes how international students still face uncertainty concerning their visa statuses and their place in American society.
844P KRAS mutant epithelial ovarian carcinomas (EOC) represent distinct genomic genotypes
Authors: K.A. Kilowski, M. Dietrich, J. Xiu, N. Jones, M. Powell, V.B. Galvan Turner, B. Erickson, D. Mutch, P. Thaker, A. ElNaggar, D. Dizon, S. Ahmad, T. Herzog, W.M. Korn, R.W. Holloway
Journal: Annals of Oncology (2020)
Critical thresholds: key to unlocking the door to the prevention and specific treatments for acute pancreatitis
Authors: Savio George Barreto, Aida Habtezion, Anna Gukovskaya, Aurelia Lugea, Christie Jeon, Dhiraj Yadav, Peter Hegyi, Viktória Venglovecz, Robert Sutton, Stephen J Pandol
Journal: Gut (2020)

Acute pancreatitis (AP), an acute inflammatory disorder of the exocrine pancreas, is one of the most common gastrointestinal diseases encountered in emergency departments with no specific treatments. Laboratory-based research has formed the cornerstone of endeavours to decipher the pathophysiology of AP, because of the limitations of such study in human beings. While this has provided us with substantial understanding, we cannot answer several pressing questions. These are: (a) Why is it that only a minority of individuals with gallstones, or who drink alcohol excessively, or are exposed to other causative factors develop AP? (b) Why do only some develop more severe manifestations of AP with necrosis and/or organ failure? (c) Why have we been unable to find an effective therapeutic for AP? This manuscript provides a state-of-the-art review of our current understanding of the pathophysiology of AP providing insights into the unanswered clinical questions. We describe multiple protective factors operating in most people, and multiple stressors that in a minority induce AP, independently or together, via amplification loops. We present testable hypotheses aimed at halting progression of severity for the development of effective treatments for this common unpredictable disease.