tbuckley/cabot-search huggingface dataset:
Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants
Authors: Sanne Brun Jensen, Ulrik Fahnøe, Long V. Pham, Stéphanie Brigitte Nelly Serre, Qi Tang, Lubna Ghanem, Martin Schou Pedersen, Santseharay Ramirez, Daryl Humes, Anne Finne Pihl, Jonathan Filskov, Christina Søhoel Sølund, Julia Dietz, Slim Fourati, Jean‐Michel Pawlotsky, Christoph Sarrazin, Nina Weis, Kristian Schønning, Henrik Krarup, Jens Bukh, Judith Margarete Gottwein
Journal: Hepatology (2019)

Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistance–associated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as a RAS hotspot for genotype 1‐4, but not 5 and 6, escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156‐RASs were not maintained. For genotypes 1 and 2, persistence of 156‐RASs depended on genome‐wide substitution networks, co‐selected under continued PI treatment and identified by next‐generation sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156‐RASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir, and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and pre‐existing A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir/elbasvir and glecaprevir/pibrentasvir. In genotype 1 infected patients with treatment failure and 156‐RASs, we observed genome‐wide selection of substitutions under treatment. Conclusion : Comprehensive PI resistance profiling for HCV genotypes 1‐6 revealed 156‐RASs as key determinants of high‐level resistance across clinically relevant PIs. We obtained in vitro proof of concept for persistence of highly fit genotype 1‐3 156‐variants, which might pose a threat to clinically relevant combination treatments.
Cost-Effectiveness of Colonoscopy-Based Colorectal Cancer Screening in Childhood Cancer Survivors
Authors: Andrea Gini, Reinier G S Meester, Homa Keshavarz, Kevin C Oeffinger, Sameera Ahmed, David C Hodgson, Iris Lansdorp-Vogelaar
Journal: JNCI Journal of the National Cancer Institute (2019)

Childhood cancer survivors (CCS) are at increased risk of developing colorectal cancer (CRC) compared to the general population, especially those previously exposed to abdominal or pelvic radiation therapy (APRT). However, the benefits and costs of CRC screening in CCS are unclear. In this study, we evaluated the cost-effectiveness of early-initiated colonoscopy screening in CCS.We adjusted a previously validated model of CRC screening in the US population (MISCAN-Colon) to reflect CRC and other-cause mortality risk in CCS. We evaluated 91 colonoscopy screening strategies varying in screening interval, age to start, and age to stop screening for all CCS combined and for those treated with or without APRT. Primary outcomes were CRC deaths averted (compared to no screening) and incremental cost-effectiveness ratios (ICERs). A willingness-to-pay threshold of $100 000 per life-years gained (LYG) was used to determine the optimal screening strategy.Compared to no screening, the US Preventive Services Task Force's average risk screening schedule prevented up to 73.2% of CRC deaths in CCS. The optimal strategy of screening every 10 years from age 40 to 60 years averted 79.2% of deaths, with ICER of $67 000/LYG. Among CCS treated with APRT, colonoscopy every 10 years from age 35 to 65 years was optimal (CRC deaths averted: 82.3%; ICER: $92 000/LYG), whereas among those not previously treated with APRT, screening from age 45 to 55 years every 10 years was optimal (CRC deaths averted: 72.7%; ICER: $57 000/LYG).Early initiation of colonoscopy screening for CCS is cost-effective, especially among those treated with APRT.
Clinical implications of repeat tumor biopsy (RTB) in patients (pts) with advanced lung cancer (LC): The Cleveland Clinic (CC) experience.
Authors: Eberechi Sandra Agwa, Francisco Almeida, Abdo Haddad, Bruno R. Bastos, Roy Lee, Xuefei Jia, Patrick Ma
Journal: Journal of Clinical Oncology (2015)

8077 Background: RTB at disease progression (PD) is increasingly used to profile tumor biomarkers and identify drug resistance mechanisms. However, information on safety and clinical consensus on the use of RTB remain lacking. Methods: The aim of this study is to review RTB patterns and safety in LC pts at CC and impact on treatment (Rx) decisions. Pts who were diagnosed and underwent RTB for suspected LC PD between 2007 and 2013 were studied. Statistical analysis is primarily descriptive. Results: The study involved 184 (56% male) pts. Median age at diagnosis was 65Y (21-87). 100 (54%) were treated initially with single modality (Surgery = 41; Chemo = 33; Radiation = 17; targeted therapy = 9) and 83 (45%) with multimodality Rx (2-modality = 57, 3-modality = 26), 1 (1%) unknown. # Of RTB per patient: 1 in 66.3% (n = 122), 2 in 20.1% (n = 37), 3 in 11.4% (n = 21), and 4 in 2.2% (n = 4). The most common procedure at 1st RTB was bronchoscopy (44.6%, n = 82), followed by CT guided biopsy (bx) (20.7 %, n = 38), surgery (10.3%, n = 19), excision bx (8.2%, n = 15), fine needle aspiration of skin & lymph node (LN) (7.6%, n = 14), ultrasound guided bx (5.9%, n = 11) & others (2.7%, n = 5). Lung was the most commonly re-biopsied site (46%) followed by LN (15%). Complications occurred in 13 of 181 (7.2%) pts at 1st RTB (data missing in 3 pts), 3 of 61 (4.9%) at 2nd RTB, 1 of 25(4%) at 3rd RTB, and 0 of 4 (0%) at 4th RTB. The 17 (6.2%) complications are shown in the table below. Histologic change was seen in 13 cases, including adeno-to-squamous carcinoma (at erlotinib resistance) and vice-versa, and non-small cell to small cell histology. The T790M-EGFR mutation was noted in 6 cases, the PIK3CA mutation in 1, and a change in ALK status in 3. Medical decision making was impacted in 16% of cases. Conclusions: RTB can be safely performed using minimally invasive techniques and can benefit LC Rx decision making. Complication n Bleeding without hemodynamic compromise 6 Bleeding requiring transfusion 1 Pneumothorax 5 Hemodynamic instability after premedication 1 Cerebral salt wasting 1 Tracheoesophageal fistula 1 Severe cough 1 Incomplete procedure 1 Deaths 0
Circular RNAs and their roles in head and neck cancers
Authors: Yang Guo, Jiechao Yang, Qiang Huang, Chiyao Hsueh, Juan Zheng, Chunping Wu, Hui Chen, Liang Zhou
Journal: Molecular Cancer (2019)

Circular RNAs are abundant endogenous non-coding RNA with no 5′ cap and 3′ polyadenylation tail that modify liner mRNAs and have no terminal structures. Our knowledge of the biogenesis of circular RNAs has been expanded, and circular RNAs were shown to be key regulators of various diseases, especially cancers. Head and neck cancers are the sixth most popular cancers worldwide, and the overall survival rates remain unsatisfactory. Recent studies have indicated that circular RNAs are involved in the tumorigenesis, progression, invasion and chemosensitivity of head and neck cancers and that some circular RNAs could serve as diagnostic and prognostic biomarkers. In this study, we summarize research advances in the regulation of circular RNA biogenesis, their characteristics and functions, the involvement of circular RNAs in the pathophysiology of head and neck cancers and their potential clinical utilization, as well as the likely directions of future studies.
A retrospective analysis of patients with soft tissue sarcoma treated long-term with trabectedin.
Authors: Elizabeth J. Davis, Rashmi Chugh, Shreyaskumar Patel, Scott Schuetze
Journal: Journal of Clinical Oncology (2015)

10551 Background: Treating STS with systemic therapy beyond six months is challenging due to cumulative toxicity. Trabectedin (T) has demonstrated efficacy and tolerability in STS and became available in 2005 through an expanded access program (EAP). Results of the EAP noted better overall survival and response rates in patients (pts) with leiomyosarcoma (LMS) and liposarcoma (LPS) compared to other histologies. Multiple cycles of T were tolerable with 30% of pts receiving ≥ 6 cycles and 7% of pts receiving ≥ 1 year of therapy, but descriptions of pts receiving T beyond one year are limited. Methods: We performed a retrospective analysis of pts with STS at the University of Michigan and M.D. Anderson Cancer Center who received long-term (≥ 10 cycles) T. We further subdivided pts into those treated for more than one year (≥ 18 cycles) and two years (≥ 35 cycles). Variables evaluated included age, gender, histology, site of primary tumor, number of prior treatments, number of dose reductions, and reason for discontinuation of T. Results: Four hundred and twenty-two pts treated with T were identified. Sixty-two pts (15%) received ≥ 10 cycles; 95% of these pts were treated on the EAP. Twenty-two pts (5%) were treated for ≥ 1 year and seven pts (2%) for ≥ 2 years. All pts treated for ≥ 1 year had LMS or LPS. Five pts (23%) treated for ≥ 1 year did not require a dose reduction. The primary reason for discontinuation of T was sarcoma progression. Conclusions: Trabectedin is a tolerable long-term therapy for a subset of pts with STS. Pts with LMS and LPS may derive the most benefit from long-term treatment, but further study is needed in a larger number of pts. Clinically relevant toxicities leading to T discontinuation beyond 1 year were fatigue and myelosuppression. ≥ 10 cycles ≥ 18 cycles ≥ 35 cycles Number of patients 62 22 7 Gender Male 24 9 4 Female 38 13 3 Median age in years (range) 50.5 (22-74) 50 (37-74) 45 (37-68) Histology Liposarcoma 22 9 4 Myxoid/round cell 18 6 2 Leiomyosarcoma 33 13 3 Other 7 0 0 Site Extremity 22 7 3 Abdominal/pelvic (non-uterine) 20 8 3 Uterus 16 7 1 Chest 3 0 0 Head 1 0 0 Reason for discontinuation Progressive disease 47 15 5 Fatigue 4 3 0 Myelosuppression 3 2 1 Hepatotoxicity 2 0 0 Surgery/Radiation 4 1 0
SAT-393-Melatonin attenuates dysregulation of the circadian clock pathway in liver fibrosis and progression to hepatocarcinoma
Authors: Diana Isabel Sánchez, Bárbara González Fernández, Irene Crespo, Beatriz San Miguel de Vega, Francisco Jorquera, Javier González-Gállego, María Jesús Tuñón González
Journal: Journal of Hepatology (2019)
Multifaceted Program to Reduce Job Strain in ICU Nurses—Reply
Authors: Sabine Valera, Karine Baumstarck, Laurent Papazian
Journal: JAMA (2019)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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) 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
The micro-environmental cross talk between mast cells and lung cancer cells through cell-to-cell contact
Authors: R. Shemesh, Y. Gorzalczany, R. Sagi-Eisenberg, S. Geva, L.R.C. Roisman, N. Peled
Journal: Annals of Oncology (2019)

Background: Mast cells (MCs) are key effectors in allergic reactions, but are also involved in tissue remodeling, wound healing and protection against pathogens. MCs infiltrate tumors and their number within the tumor microenvironment in certain cancer types, such as lung cancer, have been correlated with poor prognosis. The nature of crosstalk between lung cancer and MCs remain poorly resolved. In this study, we investigated the activation patterns within the MCs following cell-to-cell contact with lung cancer cells showing CD73 involvement. Methods: Human MCs (HMC-1 and LAD-2) were exposed to Human lung cancer cells (H1299), derived membranes to recapitulate cell contact-mediated activation. Lysates of MCs were tested for protein expression and phosphorylation by targeted western blotting. We unraveled the intracellular signaling molecules that are necessary for this signaling pathway by a pharmacological approach using several inhibitors. Each condition was repeated at least three times. Results: H1299 membrane exposure activated the ERK 1/2 MAP kinases in HMC-1 and in LAD-2 cells. AKT signaling was also activated in LAD-2 cells as a result of this contact. CD73 dephosphorylates AMP to adenosine within the MCs. Interestingly enough, this ERK 1/2 activation was inhibited by CD73 inhibitor and A3 receptor antagonists in HMC-1 cells. ERK 1/2 activation was inhibited by A3 receptor antagonists and PI3K in LAD-2 cells. Furthermore, we discovered that protein kinase C (PKC) inhibitor augments the activation of ERK 1/2 in LAD-2 cells. In contrast, PKC inhibitor inhibits the activation of ERK 1/2 in HMC-1 cells. Conclusions: Our results suggest that H1299 membranes activate ERK 1/2 in HMC-1 cells by a mechanism that involves autocrine formation of adenosine and is mediated by CD 73 and A3 receptor. In addition, we discovered that there is an important difference between the ERK 1/2 MAP kinase signal transduction in HMC-1 and LAD-2 cells, PKC is an inhibitor of the H1299 activation of ERK 1/2 in LAD-2 cells. In contrast, the H1299 membrane activation of ERK 1/2 kinase in HMC-1 cells is mediated by PKC. This could be explained by the fact that LAD-2 MCs express wild type c-kit receptor, and HMC-1 MCs express an oncogenic constitutively active c-kit mutant. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Mortality in IgA Nephropathy: A Nationwide Population-Based Cohort Study
Authors: Simon Jarrick, Sigrid Lundberg, Adina Welander, Juan-Jesus Carrero, Jonas Höijer, Matteo Bottai, Jonas F. Ludvigsson
Journal: Journal of the American Society of Nephrology (2019)

The clinical course of IgA nephropathy (IgAN) varies from asymptomatic nonprogressive to aggressive disease, with up to one in four patients manifesting ESRD within 20 years of diagnosis. Although some studies have suggested that mortality appears to be increased in IgAN, such studies lacked matched controls and did not report absolute risk.We conducted a population-based cohort study in Sweden, involving patients with biopsy-verified IgAN diagnosed in 1974-2011; main outcome measures were death and ESRD. Using data from three national registers, we linked 3622 patients with IgAN with 18,041 matched controls; we also conducted a sibling analysis using 2773 patients with IgAN with 6210 siblings and a spousal analysis that included 2234 pairs.During a median follow-up of 13.6 years, 577 (1.1%) patients with IgAN died (10.67 per 1000 person-years) compared with 2066 deaths (0.7%) in the reference population during a median follow-up of 14.1 years (7.45 per 1000 person-years). This corresponded to a 1.53-fold increased risk and an absolute excess mortality of 3.23 per 1000 person-years (equaling one extra death per 310 person-years) and a 6-year reduction in median life expectancy. Similar increases in risk were seen in comparisons with siblings and spouses. IgAN was associated with one extra case of ESRD per 54 person-years. Mortality preceding ESRD was not significantly increased compared with controls, spouses, or siblings. Overall mortality did not differ significantly between patients with IgAN-associated ESRD and patients with ESRD from other causes.Patients with IgAN have an increased mortality compared with matched controls, with one extra death per 310 person-years and a 6-year reduction in life expectancy.
FRI-331-Do N1-methylnicotinamide and nicotinamaide administration defferentially alleviated hepatic steatosis?
Authors: Makoto Nakamuta, Kenji Ohe, Yusuke Murata, Masayoshi Mori, Shinichi Kiso, Yasushi Matsuzaki, Naoki Tanaka, Kazuhiro Tanabe, Nobuhiro Ookubo, Naoyuki Togawa, Akira Honda, Tadashi Ikegami, Kazufumi Dohmen, Munechika Enjoji
Journal: Journal of Hepatology (2019)
THU-233-Whole exome sequencing analysis of the role of rare human variation in chronic hepatitis B infection
Authors: Patrick R. Shea, Sarah Kleinstein, Nicholas Stong, Edward Gane, Kosh Agarwal, Zhaoshi Jiang, John F. Flaherty, Vithika Suri, Anuj Gaggar, Mani Subramanian, Maria Buti, Wan-Long Chuang, Scott Fung, David Goldstein
Journal: Journal of Hepatology (2019)
Dual‐Specificity Phosphatase 26 Protects Against Nonalcoholic Fatty Liver Disease in Mice Through Transforming Growth Factor Beta–Activated Kinase 1 Suppression
Authors: Ping Ye, Jijun Liu, Wuping Xu, Denghai Liu, Xiangchao Ding, Sheng Le, Hao Zhang, Shanshan Chen, Manhua Chen, Jiahong Xia
Journal: Hepatology (2018)

Nonalcoholic fatty liver disease (NAFLD), which has a wide global distribution, includes different stages ranging from simple steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and liver cirrhosis according to the degree of severity. Chronic low‐grade inflammation, insulin resistance, and lipid accumulation are the leading causes of NAFLD. To date, no effective medicine for NAFLD has been approved by governmental agencies. Our study demonstrated that the expression of dual‐specificity phosphatase 26 (Dusp26), a member of the Dusp protein family, was decreased in the liver tissue of mice with hepatic steatosis and genetically obese (ob/ob) mice. In our study, hepatic steatosis, inflammatory responses, and insulin resistance were exacerbated in liver‐specific Dusp26‐knockout (KO) mice but ameliorated in liver‐specific Dusp26‐transgenic mice induced by a high‐fat diet. In addition, the degree of liver fibrosis was aggravated in high‐fat high‐cholesterol diet–induced Dusp26‐KO mice. We further found that the binding of Dusp26 to transforming growth factor beta–activated kinase 1 (TAK1) to block the phosphorylation of TAK1 regulated the TAK1–p38/c‐Jun NH2‐terminal kinase signaling axis to alleviate hepatic steatosis and metabolic disturbance. Conclusion: These findings suggest that Dusp26 is a good TAK1‐dependent therapeutic target for NAFLD.
Making nutrition guidelines fit for purpose
Authors: Lisa A Bero, Susan L Norris, Mark A Lawrence
Journal: BMJ (2019)

Dietary risk factors are the leading contributors to the global burden of disease. 1 But what we choose to eat also affects the health of the planet. 2Nutrition guidance therefore serves multiple purposes, including promoting health and wellbeing, maintaining adequate nutrition, combating dietary excesses and imbalances associated with non-communicable diseases, and protecting sustainable food systems.However, existing nutritional guidelines often do not consider the right questions or fail to take full account of available evidence because they rely on methods borrowed from other fields.We need different types of evidence informed nutrition guidelines to tackle these unprecedented challenges to population health.
CC-122, a Novel Cereblon Modulating Agent, in Combination with Obinutuzumab (GA101) in Patients with Relapsed and Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (NHL)
Authors: Jean-Marie Michot, Reda Bouabdallah, Jeanette K. Doorduijn, Umberto Vitolo, Marie José Kersten, Annalisa Chiappella, Pier Luigi Zinzani, Rafael Sarmiento, Silvia Mosulen, Cristina Mendez, Michael Petrarca, Michael Pourdehnad, Kristen Hege, Li Li, Zariana Nikolova, Vincent Ribrag
Journal: Blood (2017)
THU-044-Cystatin C as a predictive biomarker of ACLF development and mortality on the liver transplant waiting list
Authors: Ezequiel Mauro, Gonzalo Crespo, Agustina Martinez Garmendia, Maria Nelly Gutierrez Acevedo, Juan Manuel Diaz, Carla Bermudez, Jorge Ortiz Patron, Lucrecia Garcia Olveira, Fernanda Zalazar, Adrian Narvaez, Juan Carlos Spina, Salvatore Piano, Sebastián Marciano, Adrian Gadano
Journal: Journal of Hepatology (2019)
Effect of iron nanoparticles on tumor cells and immunocytes.
Authors: Elena Yurievna Zlatnik, Galina I. Zakora, Larisa V. Peredreeva
Journal: Journal of Clinical Oncology (2015)

e22094 Background: The aim of the study was to analyze the effectof iron nanoparticles on functional state of tumor and mononuclear blood cells of patients with malignant tumors in vitro. Methods: Iron nanoparticles (NP Fe) were represented by ultradispered Fe pulver with 40-100 nm size. The concentrations of NP Fe 1 and 0.01 µg/ml in isotonic NaCl solution were used. NP Fe were added to cell cultures HeLa, K562, X653 and mononuclear blood cells of patients with malignant tumors and incubated in vitro during 30 min at 37oC. After the exposition cells` viability and functional activity were assessed by cytologic and immunologic methods. Results: The increase of percentage of injured tumor cells was noted after exposure to NP Fe, both apoptosis and necrosis were enhanced. NP Fe induced lysis of 29.7±4.14%K562 cells while in control samples it was 5.0±1.68%. Incubation with NP Fe caused 2.5-fold increase of Х653 cells` death and severe vacuolization in HeLa cells` cytoplasm. Incubation of NP Fe with blood immunocytes stimulated HLA-DR expression on monocytes. Regulatory effect of NP Fe on cytokines` production by monocytes was found: high production of TNF-α and IL-1α was decreased after exposure to NP Fe while the low one remained unchanged. Enhancement of oxygen-dependent reactions in neutrophils as a result of NP Fe` effect was registered. No effect on the expression of T-, B-, NK-lymphocytic receptors was observed after incubation with NP Fe. Conclusions: In vitro incubation with iron nanoparticles causes the enhancement of tumor cells culture death; induces no injure of Т-, В-, NК-lymphocytes and stimulates functional activity of neutrophils and monocytes of patients with malignant tumors also suppressing high level production of proinflammatory cytokines. The study was supported by RScF research project 14-35-00051.
An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity
Authors: Oded Kopper, Chris J. de Witte, Kadi Lõhmussaar, Jose Espejo Valle-Inclan, Nizar Hami, Lennart Kester, Anjali Vanita Balgobind, Jeroen Korving, Natalie Proost, Harry Begthel, Lise M. van Wijk, Sonia Aristín Revilla, Rebecca Theeuwsen, Marieke van de Ven, Markus J. van Roosmalen, Bas Ponsioen, Victor W. H. Ho, Benjamin G. Neel, Tjalling Bosse, Katja N. Gaarenstroom, Harry Vrieling, Maaike P. G. Vreeswijk, Paul J. van Diest, Petronella O. Witteveen, Trudy Jonges, Johannes L. Bos, Alexander van Oudenaarden, Ronald P. Zweemer, Hugo J. G. Snippert, Wigard P. Kloosterman, Hans Clevers
Journal: Nature Medicine (2019)