tbuckley/cabot-search huggingface dataset:
Clinical trial screening of CDKN2A genomic alterations in patients with pancreatic cancer and hepatobiliary cancers requires greater precision than somatic sequencing alone.
Authors: Charles Joseph Vaske, Chad Garner, Tara Elisabeth Seery, Christopher Szeto, Sandeep K. Reddy
Journal: Journal of Clinical Oncology (2019)

287 Background: The TAPUR Study is a phase II multi‐basket study that evaluates the anti‐tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations known to be drug targets. Results in two cohorts of PC and GBC pts each with CDKN2A loss or mutation were reported at ASCO 2018. The conclusion was that monotherapy with palbocicilib is not associated with clinical activity in these patients. This may be a false conclusion if the genomic targets were absent in these patients. Methods: A total of 158 GI pts (P = 123, GB = 20, Bile Duct = 15) with deep whole exome sequencing (WES) of tumor and blood samples, and whole transcriptomic sequencing (RNA-Seq) (∼200x106 reads per tumor) were available for this analysis from a commercial database. Variant calling was performed through joint probabilistic analysis of tumor and normal DNA reads, with germline status of variants being determined by heterozygous or homozygous alternate allele fraction in the germline sample. Results: 26 somatic variants and 12 germline variants were detected, with one sample overlapping with a germline and a somatic variant (p.A148T and p.A76Rfs∗44). Counting all 11 discrete germline variants as false positives, a total 37 of 158 samples would be positive for CDKN2A mutant status, a rate of 23% (17%-31% CI). However, if the 8 common germline variants are excluded, the call rate is 29/158 = 18% (12%-25% CI). The false positive rate is 4/158 = 14% (4%-31% CI). By RNAseq, true somatic CDKN2A variants had significantly higher TPM counts than germline variants (T-test p = 0.0002). RB expression was not significantly different between the two groups. Conclusions: The failure of palbociclib to show benefit in CDKN2A mutated PC and GBC patients in the 20 patient cohort of the TAPUR study could possibly be explained by patient selection rather than solely drug failure. It is unlikely related to RB loss.
Blocking Histone Deacetylase Activity As A Novel Target For Epithelial Barrier Defects In Allergic Rhinitis
Authors: Brecht Steelant, Paulina Wawrzyniak, Katleen Martens, Anne-Charlotte Jonckheere, Krzysztof Krawczyk, Dominique Bullens, Rik Schrijvers, Cezmi A. Akdis, Peter W. Hellings
Journal: Journal of Allergy and Clinical Immunology (2019)
Timing of first surveillance colonoscopy in stage I colon cancer patients and the association with colon cancer-specific survival.
Authors: Robert Brooks Hines, Md Jibanul Haque Jiban, Adrian V. Specogna, Priya Vishnubhotla, Eunkyung Lee, Steven Troy, Shunpu Zhang
Journal: Journal of Clinical Oncology (2019)

618 Background: Surveillance colonoscopy following curative surgery in stage I colon cancer patients is controversial. This study was conducted to assess the relationship between timing of first surveillance colonoscopy and 5-year colon cancer-specific survival. Methods: This was a retrospective cohort study of the Surveillance, Epidemiology, and End Results database combined with Medicare claims. Stage I colon cancer patients (66-84 years of age) were categorized according to receipt of first colonoscopy following cancer-directed surgery as: Year 1, Year 2, Year 3, and No Colonoscopy within 3 years of surgery. Propensity score weighting was used to balance covariates. Cox regression was used to obtain hazard ratios for the relative risk of 5-year colon cancer-specific death, adjusted survival estimates, and the number needed to treat (NNT) with colonoscopy in Year 1 to prevent a colon cancer-specific death in the other groups. Results: There were 8,494 stage I colon cancer patients available for analysis. Regarding 5-year colon cancer-specific mortality, compared to Year 1 patients, the No Colonoscopy group experienced 2.2 times the risk of colon cancer-specific death (HR, 2.23; 95% CI, 1.38 to 3.61). Those who received ≥ 1 additional colonoscopies in the two years following their initial assessment experienced a significant 73% decreased risk of death (HR, 0.27; 95% CI, 0.16 to 0.45). Delaying colonoscopy (Years 2 &amp; 3) did not result in a statistically significant increased risk of death. Although the absolute difference in 5-year adjusted survival was small, if all patients in the No Colonoscopy group received a colonoscopy in Year 1, 46.2% (n = 49.9) of the 108 colon cancer deaths that occurred in this group could have been prevented. Conclusions: Although stage I colon cancer patients have a good prognosis, patients who received colonoscopy within one year of cancer-directed surgery experienced significantly better survival than patients who did not receive colonoscopy within 3 years of surgery. The results of this study justify efforts to ensure that stage I colon cancer patients receive colonoscopic surveillance testing approximately 1 year following cancer-directed surgery.
Comparative effectiveness of rituximab, abatacept, and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors: prospective cohort study
Authors: Jacques-Eric Gottenberg, Jacques Morel, Elodie Perrodeau, Thomas Bardin, Bernard Combe, Maxime Dougados, Rene-Marc Flipo, Alain Saraux, Thierry Schaeverbeke, Jean Sibilia, Martin Soubrier, Olivier Vittecoq, Gabriel Baron, Arnaud Constantin, Philippe Ravaud, Xavier Mariette
Journal: BMJ (2019)

Abstract Objective To compare the effectiveness and safety of three non-tumour necrosis factor (TNF) α inhibitors (rituximab, abatacept, and tocilizumab) in the treatment of rheumatoid arthritis. Design Population based prospective study. Setting 53 university and 54 non-university clinical centres in France. Participants 3162 adults (&gt;18 years) with rheumatoid arthritis according to 1987 American College of Rheumatology criteria, enrolled in one of the three French Society of Rheumatology registries; who had no severe cardiovascular disease, active or severe infections, or severe immunodeficiency, with follow-up of at least 24 months. Intervention Initiation of intravenous rituximab, abatacept, or tocilizumab for rheumatoid arthritis. Main outcome measure The primary outcome was drug retention without failure at 24 months. Failure was defined as all cause death; discontinuation of rituximab, abatacept, or tocilizumab; initiation of a new biologic or a combination of conventional disease modifying antirheumatic drugs; or increase in corticosteroid dose &gt;10 mg/d compared with baseline at two successive visits. Because of non-proportional hazards, treatment effects are presented as life expectancy difference without failure (LED wf ), which measures the difference between average duration of survival without failure. Results Average durations of survival without failure were 19.8 months for rituximab, 15.6 months for abatacept, and 19.1 months for tocilizumab. Average durations were greater with rituximab (LED wf 4.1, 95% confidence interval 3.1 to 5.2) and tocilizumab (3.5, 2.1 to 5.0) than with abatacept, and uncertainty about tocilizumab compared with rituximab was substantial (−0.7, −1.9 to 0.5). No evidence was found of difference between treatments for mean duration of survival without death, presence of cancer or serious infections, or major adverse cardiovascular events. Conclusion Among adults with refractory rheumatoid arthritis followed-up in routine practice, rituximab and tocilizumab were associated with greater improvements in outcomes at two years compared with abatacept.
A Synthetic Receptor as a Specific Antidote for Paraquat Poisoning
Authors: Xiangjun Zhang, Xiaoqiu Xu, Shengke Li, Lanlan Li, Jianxiang Zhang, Ruibing Wang
Journal: Theranostics (2019)

Accidental or suicidal ingestion of the world's most widely used herbicide, paraquat (PQ), may result in rapid multi-organ failure with a 60% fatality rate due to the absence of an effective detoxification solution. Effective, specific antidotes to PQ poisoning have been highly desired.
Anti-Glycoprotein V Autoantibodies in Patients with Immune Thrombocytopenia: Regularly Detectable and Functionally Relevant
Authors: Richard Vollenberg, Rabie Jouni, Peter A. A. Norris, Monika Burg-Roderfeld, Nina Cooper, Mathias J Rummel, Gregor Bein, Irene Marini, Alan H Lazarus, Tamam Bakchoul, Ulrich J Sachs
Journal: Blood (2018)
Early Life Sensitization Patterns and Risk for Allergic Rhinitis in the WHEALS Birth Cohort
Authors: Zeinab Saleh, Abigail Chatfield, Suzanne Havstad, Alexandra R. Sitarik, Haejin Kim, Christine L.M. Joseph, Edward M. Zoratti, Ganesa R. Wegienka, Dennis R. Ownby, Christine Cole Johnson
Journal: Journal of Allergy and Clinical Immunology (2019)
Polymers with distinctive anticancer mechanism that kills MDR cancer cells and inhibits tumor metastasis
Authors: Guansheng Zhong, Chuan Yang, Shaoqiong Liu, Yiran Zheng, Weiyang Lou, Jye Yng Teo, Chang Bao, Wei Cheng, Jeremy P.K. Tan, Shujun Gao, Nathaniel Park, Shrinivas Venkataraman, Yuan Huang, Min Han Tan, Xiaojia Wang, James L. Hedrick, Weimin Fan, Yi Yan Yang
Journal: Biomaterials (2019)
68Ga-DOTANOC PET/CT Detects Multifocal Hepatocellular Carcinoma
Authors: Elena Tabacchi, Davide Campana, Nicole Brighi, Stefano Fanti, Valentina Ambrosini
Journal: Clinical Nuclear Medicine (2019)

Abstract 68 Ga-DOTANOC PET/CT confirmed somatostatin receptor (SR) expression in hypervascularized liver lesions suggestive of neuroendocrine tumor that was later diagnosed as hepatocellular carcinoma (HCC). Being highly vascularized on CT, HCC lesions may mimic neuroendocrine tumors. Although HCC is not included among current indications for SR-PET/CT imaging, it may represent a pitfall in image interpretation when studying neuroendocrine tumor patients. Further studies are needed to better ascertain the potential diagnostic role of SR-imaging in HCC.
Acute Shortness of Breath in a Woman in Her 50s
Authors: Nureddin K. Almaddah, Aranyak Rawal, Neeraja Yedlapati
Journal: JAMA Cardiology (2019)

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Four courses versus eight courses of adjuvant S-1 for patients with stage II gastric cancer (JCOG1104 [OPAS-1]): an open-label, phase 3, non-inferiority, randomised trial
Authors: Takaki Yoshikawa, Masanori Terashima, Junki Mizusawa, Souya Nunobe, Yasunori Nishida, Takanobu Yamada, Masahide Kaji, Norimasa Fukushima, Shinji Hato, Yasuhiro Choda, Hiroshi Yabusaki, Kazuhiro Yoshida, Seiji Ito, Atsushi Takeno, Takashi Yasuda, Yasuyuki Kawachi, Hiroshi Katayama, Haruhiko Fukuda, Narikazu Boku, Takeshi Sano, Mitsuru Sasako
Journal: The Lancet. Gastroenterology & hepatology (2019)
Pharmacodynamics, Pharmacokinetics and Safety of Bay 1093884, an Antibody Directed Against Human TFPI, in Patients with Factor VIII or IX Deficiency (With and Without Inhibitors): A Phase 1 Study
Authors: Pratima Chowdary, Toshko Jelev Lissitchkov, Stefan Willmann, Stephan Schwers, Lisa A. Michaels, Anita Shah
Journal: Blood (2018)
Efficacy of PD-1 blockade in cervical cancer is related to a CD8+FoxP3+CD25+ T-cell subset with operational effector functions despite high immune checkpoint levels
Authors: A. M. Heeren, J. Rotman, A. G. M. Stam, N. Pocorni, A. A. Gassama, S. Samuels, M. C. G. Bleeker, C. H. Mom, H. J. M. A. A. Zijlmans, G. G. Kenter, E. S. Jordanova, T. D. de Gruijl
Journal: Journal for ImmunoTherapy of Cancer (2019)

Cervical cancer (CxCa) is mainly a locally invading disease that metastasizes to loco-regional lymph node basins before involving distant organs in more advanced stages. Local immune potentiation of tumor-draining lymph nodes (TDLN) may thus protect against tumor progression.To identify therapeutic targets for local immune modulation, multi-parameter flow cytometric T-cell profiling of primary cervical tumors (PT) and TDLN (n = 37) was performed. The in-vitro effect of PD-1 blockade on T-cell reactivity to HPV16 E6 oncoproteins was determined in cultures of TDLN and PT single cell suspensions (n = 19). Also, intracellular cytokine staining (ICS) upon anti-CD3 stimulation was performed in metastatic TDLN (LN+) and PT (n = 7), as well as multiplexed immunofluorescence histochemistry staining (n = 8).Our data revealed elevated rates of activated regulatory T cells (aTregs) and of central or effector memory CD8+ T cells in metastatic TDLN (LN+) as compared to tumor-free TDLN (LN-), and equally high or even higher rates of these subsets in PT. Both memory subsets co-expressed multiple immune checkpoints. PD-1 blockade significantly enhanced detectable E6-specific T-cell responses in 4/5 HPV16+ LN+ and in 1/5 HPV16+ PT. Whereas aTreg rates were higher in anti-PD-1 non-responders, in responders elevated levels of CD8+FoxP3+CD25+ T cells were observed, which correlated with the efficacy of PD-1 blockade (P = 0.018). This subset was characterized by an early effector memory phenotype with particularly high levels of co-expressed PD-1, CTLA-4, TIM-3 and LAG-3 checkpoints, but, rather than exhausted, was shown upon polyclonal activation to produce higher levels of Granzyme-B and effector cytokines as compared to its CD8+FoxP3- counterparts.These observations support local PD-(L)1 blockade to interrupt loco-regional immune suppression in CxCa and control metastatic spread to TDLN. Furthermore, our data identify CD8+FoxP3+CD25+ T cells as therapeutic targets, which may also serve as predictive biomarker for PD-(L)1 checkpoint blockade.
Effect of breakfast on weight and energy intake: systematic review and meta-analysis of randomised controlled trials
Authors: Katherine Sievert, Sultana Monira Hussain, Matthew J Page, Yuanyuan Wang, Harrison J Hughes, Mary Malek, Flavia M Cicuttini
Journal: BMJ (2019)

Abstract Objective To examine the effect of regular breakfast consumption on weight change and energy intake in people living in high income countries. Design Systematic review and meta-analysis. Data sources PubMed, Ovid Medline, and CINAHL were searched for randomised controlled trials published between January 1990 and January 2018 investigating the effect of breakfast on weight or energy intake. ClinicalTrials.gov and the World Health Organization’s International Clinical Trials Registry Platform search portal were also searched in October 2018 to identify any registered yet unpublished or ongoing trials. Eligibility criteria for selecting studies Randomised controlled trials from high income countries in adults comparing breakfast consumption with no breakfast consumption that included a measure of body weight or energy intake. Two independent reviewers extracted the data and assessed the risk of bias of included studies. Random effects meta-analyses of the effect of breakfast consumption on weight and daily energy intake were performed. Results Of 13 included trials, seven examined the effect of eating breakfast on weight change, and 10 examined the effect on energy intake. Meta-analysis of the results found a small difference in weight favouring participants who skipped breakfast (mean difference 0.44 kg, 95% confidence interval 0.07 to 0.82), but there was some inconsistency across trial results (I 2 =43%). Participants assigned to breakfast had a higher total daily energy intake than those assigned to skip breakfast (mean difference 259.79 kcal/day, 78.87 to 440.71; 1 kcal=4.18 kJ), despite substantial inconsistency across trial results (I 2 =80%). All of the included trials were at high or unclear risk of bias in at least one domain and had only short term follow-ups (mean period seven weeks for weight, two weeks for energy intake). As the quality of the included studies was mostly low, the findings should be interpreted with caution. Conclusion This study suggests that the addition of breakfast might not be a good strategy for weight loss, regardless of established breakfast habit. Caution is needed when recommending breakfast for weight loss in adults, as it could have the opposite effect. Further randomised controlled trials of high quality are needed to examine the role of breakfast eating in the approach to weight management. Study registration PROSPERO registration number CRD42017057687.
Abstract 13422: Mitochondrial Reductive Stress Induced by Over-Expression of SOD2 Enhances Cardiac Function
Authors: Patrick T Kang, Chwen-Lih Chen, Daniel J Luther, Vahagn Ohanyan, J. G Meszaros, William M Chilian, Yeong-Renn Chen
Journal: Circulation (2013)

Previously, it was reported that over-expression of a mutant human alphaB-Crystallin induces reductive stress and a cardiomyopathic phenotype in mice. However, the stress imposed by altered protein...
EGFR/Notch Antagonists Enhance the Response to Inhibitors of the PI3K-Akt Pathway by Decreasing Tumor-Initiating Cell Frequency
Authors: Wenyan Fu, Changhai Lei, Yue Yu, Shuowu Liu, Tian Li, Fangxing Lin, Xiaoyan Fan, Yafeng Shen, Min Ding, Ying Tang, Xuting Ye, Yongji Yang, Shi Hu
Journal: Clinical Cancer Research (2019)

Both EGFR and PI3K-Akt signaling pathways have been used as therapeutically actionable targets, but resistance is frequently reported. In this report, we show that enrichment of the cancer stem cell (CSC) subsets and dysregulation of Notch signaling underlie the challenges to therapy and describe the development of bispecific antibodies targeting both HER and Notch signaling.We utilized cell-based models to study Notch signaling in drug-induced CSC expansion. Both cancer cell line models and patient-derived xenograft tumors were used to evaluate the antitumor effects of bispecific antibodies. Cell assays, flow cytometry, qPCR, and in vivo serial transplantation assays were employed to investigate the mechanisms of action and pharmacodynamic readouts.We found that EGFR/Notch targeting bispecific antibodies exhibited a notable antistem cell effect in both in vitro and in vivo assays. Bispecific antibodies delayed the occurrence of acquired resistance to EGFR inhibitors in triple-negative breast cancer cell line-based models and showed efficacy in patient-derived xenografts. Moreover, the EGFR/Notch bispecific antibody PTG12 in combination with GDC-0941 exerted a stronger antitumor effect than the combined therapy of PI3K inhibitor with EGFR inhibitors or tarextumab in a broad spectrum of epithelial tumors. Mechanistically, bispecific antibody treatment inhibits the stem cell-like subpopulation, reduces tumor-initiating cell frequency, and downregulates the mesenchymal gene expression.These findings suggest that the coblockade of EGFR and Notch signaling has the potential to increase the response to PI3K inhibition, and PTG12 may gain clinical efficacy when combined with PI3K blockage in cancer treatment.
Ataxia-Telangiectasia: Epidemiological Survey in Latin America
Authors: Ellen Oliveira Dantas, Jessica Loekmanwidjaja, Juliana Themudo Lessa Mazzucchelli, Carolina S. Aranda, Maria Edith González Serrano, Liliana Bezrodnik, Ileana Moreira, Janaira Fernandes Severo Ferreira, Vera M. Dantas, Valéria Soraya de Farias Sales, Carmen C. Fernandez, Maria Marluce dos Santos Vilela, Isabella Prado Mota, Jose Franco, Julio C. Orellana, Cristina M. Kokron, Lorena Regairaz, Diana Cabanillas, Myrthes T. Barros, Carmen L. Navarrete Suarez, Nelson Augusto Rosario, Herberto J. Chong Neto, Olga Akiko Takano, Maria Isabel Santos Valdomir Nadaf, Lillian SL. Moraes, Fabiola Scancetti Tavares, Flaviane Rabello, Jessica Pino, Wilmer Cordova Calderon, Daniel Enrique Mendonza Quispe, Ekaterine S. Goudouris, Virginia Patiño, Cecilia Montenegro, Monica Souza, Aniela Castelo Branco, Antonio Condino-Neto, Wilma Carvalho Neves Forte, Flavia Amendola Anisio Carvalho, Gesmar Segundo, Marina Fernandes Almeida Cheik, Persio R. Junior, Maryanna Peres, Annie Mafra Oliveira, Arnaldo Carlos Porto Neto, Maria Claudia Ortega López, Alejandro Alozano, Natalia Alozano, Leticia Hernandez, Anete S. Grumach, Daniele Comin Costa, Nelma Maria Neves Antunes, Victor Nudelman, Camila Teles Machado Pereira, Maria Dolores Mogica Martinez, Francisco Javier Rodriguez Quiroz, Aristoteles Alvarez Cardona, Maria Enriqueta Nunez, Jairo Antonio Rodriguez, Célia Martínez Cuellar, Gustavo Vijoditz, Daniélli Christinni Bichuetti-Silva, Carolina CM. Prando, Beatriz Tavares Costa-Carvalho
Journal: Journal of Allergy and Clinical Immunology (2019)
An Insect Counteradaptation against Host Plant Defenses Evolved through Concerted Neofunctionalization
Authors: Hanna M Heidel-Fischer, Roy Kirsch, Michael Reichelt, Seung-Joon Ahn, Natalie Wielsch, Simon W Baxter, David G Heckel, Heiko Vogel, Juergen Kroymann
Journal: Molecular Biology and Evolution (2019)

Antagonistic chemical interactions between herbivorous insects and their host plants are often thought to coevolve in a stepwise process, with an evolutionary innovation on one side being countered by a corresponding advance on the other. Glucosinolate sulfatase (GSS) enzyme activity is essential for the Diamondback moth, Plutella xylostella, to overcome a highly diversified secondary metabolite-based host defense system in the Brassicales. GSS genes are located in an ancient cluster of arylsulfataselike genes, but the exact roles of gene copies and their evolutionary trajectories are unknown. Here, we combine a functional investigation of duplicated insect arylsulfatases with an analysis of associated nucleotide substitution patterns. We show that the Diamondback moth genome encodes three GSSs with distinct substrate spectra and distinct expression patterns in response to glucosinolates. Contrary to our expectations, early functional diversification of gene copies was not indicative of a coevolutionary arms race between host and herbivore. Instead, both copies of a duplicated arylsulfatase gene evolved concertedly in the context of an insect host shift to acquire novel detoxifying functions under positive selection, a pattern of duplicate gene retention that we call "concerted neofunctionalization."