tbuckley/cabot-search huggingface dataset:
The Mutational Landscape of Relapse in High Risk Myeloma Is Significantly Impacted By the Depth of Response but Not Maintenance Lenalidomide
Authors: John R Jones, Niels Weinhold, Cody Cody Ashby, Charlotte Pawlyn, Brian A Walker, Christopher P. Wardell, Lorenzo Melchor, Leo Rasche, David C. Johnson, Sidra Ellis, Amy L Sherborne, Gordon Cook, Matthew W Jenner, Martin F Kaiser, Walter M Gregory, Mark T Drayson, Roger G Owen, Graham Jackson, Faith E. Davies, Melvyn F. Greaves, Gareth J. Morgan
Journal: Blood (2017)
Optimal biologic dose-finding based on toxicity and biomarker expression in phase I/II oncology trial settings
Authors: B. Nebiyou Bekele, Yu Shen
Journal: Cancer Research (2005)

4129  In this poster we propose a Bayesian approach to phase I/II dose-finding oncology trials by jointly modeling a binary toxicity outcome and a continuous biomarker expression outcome. We apply our method to a clinical trials drawn from various cancers. Within a given trial, biomarker expression indicates biological activity of a therapy. For ethical reasons, the trial is conducted sequentially, with the dose for each successive patient chosen using both toxicity and activity data from patients previously treated in the trial. The modeling framework that we use naturally incorporates correlation between the binary toxicity and continuous activity outcome via a latent Gaussian variable. The dose-escalation/de-escalation decision rules are based on the posterior distributions of both toxicity and activity. A flexible state-space model is used to relate the activity outcome and dose. Extensive simulation studies show that the design reliably choose the preferred dose using both toxicity and expression outcomes under various clinical scenarios. This poster is based on a paper that has been accepted for publication by Biometrics.
Insight into vitronectin structural evolution on material surface chemistries: The mediation for cell adhesion
Authors: Tianjie Li, Lijing Hao, Jiangyu Li, Chang Du, Yingjun Wang
Journal: Bioactive Materials (2020)

Biomaterial surface chemistry engenders profound consequences on cell adhesion and the ultimate tissue response by adsorbing proteins from extracellular matrix, where vitronectin (Vn) is involved as one of the crucial mediator proteins. Deciphering the adsorption behaviors of Vn in molecular scale provides a useful account of how to design biomaterial surfaces. But the details of structural dynamics and consequential biological effect remain elusive. Herein, both experimental and computational approaches were applied to delineate the conformational and orientational evolution of Vn during adsorption onto self-assembled monolayers (SAMs) terminating with -COOH, -NH2, -CH3 and -OH. To unravel the interplay between cell binding and the charge and wettability of material surface, somatomedin-B (SMB) domain of Vn holding the RGD cell-binding motif was employed in molecular dynamics (MD) simulations, with orientation initialized by Monte Carlo (MC) method. Experimental evidences including protein adsorption, cell adhesion and integrin gene expressions were thoroughly investigated. The adsorption of Vn on different surface chemistries showed very complex profiles. Cell adhesion was enabled on all Vn-adsorbed surfaces but with distinct mechanisms mostly determined by conformational change induced reorientation. Higher amount of Vn was observed on negatively charged surface (COOH) and hydrophobic surface (CH3). However, advantageous orientations defined by RGD loop conditions were only obtained on the charged surfaces (COOH and NH2). Specifically, COOH surface straightened up the Vn molecules and accumulated them into a higher density, whereas CH3 surface squashed Vn and stacked them into higher density multilayer by tracking adsorption but with the RGD loops restrained. These findings may have a broad implication on the understanding of Vn functionality and would help develop new strategies for designing advanced biomaterials.
P-283 Analysis of KRAS mutation allele in circulating cell-free DNA derived from urine in colorectal cancer patients
Authors: R. Ohta, T. Yamada, S. Shinji, A. Matsuda, G. Takahashi, T. Iwai, K. Takeda, K. Ueda, S. Kuriyama, H. Yoshida
Journal: Annals of Oncology (2020)
Germany’s digital health reforms in the COVID-19 era: lessons and opportunities for other countries
Authors: Sara Gerke, Ariel D. Stern, Timo Minssen
Journal: npj Digital Medicine (2020)

Abstract Reimbursement is a key challenge for many new digital health solutions, whose importance and value have been highlighted and expanded by the current COVID-19 pandemic. Germany’s new Digital Healthcare Act (Digitale–Versorgung–Gesetz or DVG) entitles all individuals covered by statutory health insurance to reimbursement for certain digital health applications (i.e., insurers will pay for their use). Since Germany, like the United States (US), is a multi-payer health care system, the new Act provides a particularly interesting case study for US policymakers. We first provide an overview of the new German DVG and outline the landscape for reimbursement of digital health solutions in the US, including recent changes to policies governing telehealth during the COVID-19 pandemic. We then discuss challenges and unanswered questions raised by the DVG, ranging from the limited scope of the Act to privacy issues. Lastly, we highlight early lessons and opportunities for other countries.
COVID-19 and liver transplantation
Authors: Tommaso Di Maira, Marina Berenguer
Journal: Nature Reviews Gastroenterology & Hepatology (2020)

The effect of coronavirus disease 2019 (COVID-19) on liver transplantation programmes and recipients is still not completely understood but overall involves the risk of donor-derived transmission, the reliability of diagnostic tests, health-care resource utilization and the effect of immunosuppression. This Comment reviews the effect of COVID-19 on liver transplantation and summarizes recommendations for donor and recipient management.
Lack of sensitivity of an IVD/CE-labelled kit targeting the S gene for detection of SARS-CoV-2
Authors: L.-M. Matzkies, E. Leitner, E. Stelzl, K. Assig, M. Bozic, D. Siebenhofer, M.E. Mustafa, I. Steinmetz, H.H. Kessler
Journal: Clinical Microbiology and Infection (2020)
Correction: Frequency of infections in 948 MPN patients: a prospective multicenter patient-reported pilot study
Authors: Carl C. Crodel, Kathleen Jentsch-Ullrich, Steffen Koschmieder, Dietrich Kämpfe, Martin Griesshammer, Konstanze Döhner, Philipp J. Jost, Denise Wolleschak, Susanne Isfort, Frank Stegelmann, Stefanie Jilg, Verena Hofmann, Guiseppe Auteri, Tobias Rachow, Philipp Ernst, Annamaria Brioli, Marie von Lilienfeld-Toal, Andreas Hochhaus, Francesca Palandri, Florian H. Heidel
Journal: Leukemia (2020)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
インドメタシンとポリイノシン酸:ポリシチジル酸によるin vivoにおける免疫反応の修飾と関連するしゅようの発育抑制 | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: Droller M J, Gomolka D
Journal: Cancer Research (1982)
Discovery and characterization of new small-molecule inhibitors of Mcl-1 by high-throughput screening
Authors: Zaneta Nikolovska-Coleska, Su Qiu, Jianting long, Chao-Yie Yang, Martha Larsen, York Tomita, Pat Gee, Han Yi, Krzysztof Krajewski, Jeanne Stuckey, Peter Roller, Shaomeng Wang
Journal: Cancer Research (2008)

4148  Apoptosis, or programmed cell death, plays a key role in normal tissue homeostasis ensuring a proper balance between cell production and cell loss. Anti-apoptotic Bcl-2-family proteins are key regulators of the apoptotic pathway and their increased expression in human malignancies is associated with disease progression, tumor resistance to chemotherapy, radiation and poor clinical outcome. Recently,a novel Bcl-2/Bcl-xL/Bcl-w inhibitor (ABT-737) has been developed, which is highly potent in killing tumor cells displayinghigh levels of Bcl-2 and dependent upon Bcl-2 forsurvival. However, ABT-737 exhibits a relatively low affinityfor Mcl-1 and is considerably less efficient in killing tumor cellsexpressing high Mcl-1 levels. Several groups provide strong evidence that Mcl-1 is the major factor that causes resistance to ABT-737 in cancer cells derived from diverse solid tumors, and one approach for overcoming this resistance could be the combination of ABT-737 with agentscapable of down-regulating/inhibiting Mcl-1.  Here, we describe a high throughput screening approach that led to the identification of several chemical classes, small molecule Mcl-1 inhibitors. The compounds were characterized in a number of assays including in vitro binding using fluorescence polarization based assay, SPR solution competitive assay, heteronuclear single quantum correlation (HSQC) NMR spectroscopy, pull-down assay, functional assay for cytochrome c and Smac release and a cell-based viability assay with human cancer cells.  The most potent of the inhibitors identified was compound 65, which binds to Mcl-1 protein with IC50 of 0.3 μM, showing >100-fold selectivity over Bcl-xL and 60-fold selectivity over Bcl-2 protein. 15N HSQC spectra conclusively showed that compound 65 interacts with the BH3 domain in Mcl-1 protein and many residues in the BH3 binding groove of Mcl-1 protein were affected by 65. Furthermore, pull-down assay demonstrates that the compound 65 is able in dose dependent manner to disrupt interactions between endogenous Mcl-1 protein and biotin labeled Noxa and Bid BH3 peptides, but not between Bid BH3 peptide and other members of Bcl-2 family (Bcl-xL and Bcl-2). Functional studies showed that compound 65 effectively antagonizes recombinant Mcl-1 protein and promotes release of cytochrome c and Smac from isolated mitochondria. Compound 65 displayed cytotoxicity with IC50 from 3 μM to 8 μM against a number of human cancer cell lines with high level of Mcl-1 protein. Collectively, these data indicate that 65 represents a novel and bone fide small-molecule inhibitor of Mcl-1 and a promising lead compound for further optimization toward developing a new class of anticancer drugs by targeting the Mcl-1 protein.
David Oliver: Covid-19 should increase our commitment to publicly funded and provided healthcare
Authors: David Oliver
Journal: BMJ (2020)

The BBC reports that the UK has been hit hardest by covid-19 among the G7 nations. 1 Over the 11 peak pandemic weeks it had the highest increases in deaths, deaths per 100 000 population, and excess deaths as a proportion of usual levels.This is not a set of league tables anyone should be proud to top.
Plasma Gelsolin Inhibits CD8+ T-cell Function and Regulates Glutathione Production to Confer Chemoresistance in Ovarian Cancer
Authors: Meshach Asare-Werehene, Laudine Communal, Euridice Carmona, Youngjin Han, Yong Sang Song, Dylan Burger, Anne-Marie Mes-Masson, Benjamin K. Tsang
Journal: Cancer Research (2020)

Although initial treatment of ovarian cancer is successful, tumors typically relapse and become resistant to treatment. Because of poor infiltration of effector T cells, patients are mostly unresponsive to immunotherapy. Plasma gelsolin (pGSN) is transported by exosomes (small extracellular vesicle, sEV) and plays a key role in ovarian cancer chemoresistance, yet little is known about its role in immunosurveillance. Here, we report the immunomodulatory roles of sEV-pGSN in ovarian cancer chemoresistance. In chemosensitive conditions, secretion of sEV-pGSN was low, allowing for optimal CD8+ T-cell function. This resulted in increased T-cell secretion of IFNγ, which reduced intracellular glutathione (GSH) production and sensitized chemosensitive cells to cis-diaminedichloroplatinum (CDDP)-induced apoptosis. In chemoresistant conditions, increased secretion of sEV-pGSN by ovarian cancer cells induced apoptosis in CD8+ T cells. IFNγ secretion was therefore reduced, resulting in high GSH production and resistance to CDDP-induced death in ovarian cancer cells. These findings support our hypothesis that sEV-pGSN attenuates immunosurveillance and regulates GSH biosynthesis, a phenomenon that contributes to chemoresistance in ovarian cancer. SIGNIFICANCE: These findings provide new insight into pGSN-mediated immune cell dysfunction in ovarian cancer chemoresistance and demonstrate how this dysfunction can be exploited to enhance immunotherapy.
P-291 Retrospective comparison efficacy and toxicity FOLFIRI plus aflibercept or bevacizumab in patients with metastatic colorectal cancer: Results of the multicenter observational study
Authors: M. Fedyanin, V. Chubenko, A. Belonogov, S. Beluhin, L. Vladimirova, A. Zhabina, A. Kudryavtseva, F. Moiseenko, A. Khasanova, H. Musaeva, O. Novikova, I. Stradaeva, G. Mukhametshina, R. Orlova, A. Micshenko, I. Popova, M. Lyadova, A. Popova, L. Bolotina, B. Kertiev, E. Kuzmina, S. Tjulandin
Journal: Annals of Oncology (2020)
Increased expression of tissue transglutaminase (TG2) is associated with chemo-resistance in ovarian cancer cell lines
Authors: Chel Hun Choi, Byoung-Gie Kim, Woo Young Kim, Jung-Joo Choi, Young Ae Park, Tae-Joong Kim, Jeong-Won Lee, Heeseok Kang, Je-Ho Lee, Duk-Soo Bae
Journal: Cancer Research (2008)

3222  Objective : To investigate whether regulation of TG2 can induce activation of cell survival and antiapoptotic signaling pathways and thereby bestowing chemoresistant to the tumor cells.  Materials and Methods: Human ovarian carcinoma cell line, 2774 and PA-1 (ATCC) was maintained at 37°C and 5% CO2 in complete media. For analysis of cell viability to the anti-cancer agents, Docetaxel and Paclitaxel, MTT assay was used according to the manufacturer’s instruction. Regulation of expression level of TG2 was induced by transfection of siRNA or plasmid DNA parenting full length of human TG2 using LipofectAMINE reagent. Expression level of each protein was analyzed by western blotting by PAGE-method with each protein’s antibody.  Results: The IC50 value of anti-cancer agents in each cell line (2774 vs PA-1) was 30nM vs 10nM for Docetaxel, 40nM vs 15nM for Paclitaxel, and 2.1uM vs 0.2uM for cisplatin. The TG2 expression level was higher in 2774 than PA-1 ovarian cancer cell lines. The sensitivity to anticancer agents ( paclitaxel or docetaxel) was elevated after 2774 cells were transfected with TG2 siRNA (down regulation of TG2) at the concentration or 50 and 100nM. The resistance to anticancer agent was elevated after PA-1 cells were transfected with 0.2ug of TG2 plasmid or its parental vector ( over expression of TG2 ). Western blotting assay showed that down-regulation of TG2 resulted in inhibition of phosphorylation of FAK (Focal Adhesion of Kinase) and that overexpression of TG2 resulted in activation of phosphorylation of FAK.  Conclusion : Increased expression of TG-2 was correlated with drug resistance in ovarian cancer cell lines (2774 and PA-1) Understanding of TG2-mediated cell-survival signaling pathways and their contribution in the development of drug resistance may help to define the new targets and in developing effective approaches for treating aggressive tumors. Further analysis of candidate genes associated with TG2 induced resistance of anticancer reagent will be necessary.
Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma: A Rare Case of Diffuse Ulcers in the Intestine
Authors: Changqin Liu, Lijin Feng, Xiaomin Sun
Journal: Clinical Gastroenterology and Hepatology (2020)

A 48-year-old female patient presented with abdominal pain, distention, vomiting followed by watery diarrhea, and weight loss within 1 month. Magnetic resonance enterography showed wall thickening of jejunum with mild dilatation and fluid collection (Figure A). A positron emission tomography scan was performed, showing irregular thickening of the small bowel and colon accompanied with fluorodeoxyglucose hypermetabolism of spleen, liver, abdominal lymph nodes, and bone marrow. Both magnetic resonance enterography and positron emission tomography/computed tomography imaging revealed intestinal lymphoma. Esophagogastroduodenoscopy revealed multiple semicircular ulcerations from the descending part of duodenum to the jejunum. The bottom of ulcerations was clean, and there were thick lip-like margins around the ulcerations (Figure B). Colonoscopy exhibited hyperemia and irregular-shaped ulcers with superficial exudates. But the feature of the margins was the same as those in duodenum (Figure C). Multiple biopsies were obtained and the histologic examination revealed infiltration of monotonous small to medium-sized atypical lymphoid cells with pale cytoplasm in the epithelium, crypts, and the lamina propria (Figure D). A diagnosis of monomorphic epitheliotropic intestinal T-cell lymphoma was confirmed. Monomorphic epitheliotropic intestinal T-cell lymphoma has a poor prognosis even with aggressive treatment. The patient received chemotherapy but her condition did not improve. A month later she died. The authors thank Dr Binghui Zhao and Dr Chao Ma for the help of interpreting magnetic resonance enterography and positron emission tomography/computed tomography imaging, respectively. The authors thank Dr Zhanju Liu for help with checking and correcting the article.
Organoid Models of Tumor Immunology
Authors: Kanako Yuki, Ning Cheng, Michitaka Nakano, Calvin J. Kuo
Journal: Trends in Immunology (2020)

Cellular interactions in the tumor microenvironment (TME) significantly govern cancer progression and drug response. The efficacy of clinical immunotherapies has fostered an exponential interest in the tumor immune microenvironment, which in turn has engendered a pressing need for robust experimental systems modeling patient-specific tumor-immune interactions. Traditional 2D in vitro tumor immunotherapy models have reconstituted immortalized cancer cell lines with immune components, often from peripheral blood. However, newly developed 3D in vitro organoid culture methods now allow the routine culture of primary human tumor biopsies and increasingly incorporate immune components. Here, we present a viewpoint on recent advances, and propose translational applications of tumor organoids for immuno-oncology research, immunotherapy modeling, and precision medicine.
Abstract 16007: Impact of Estimated Pulse Wave Velocity and Its Response to Treatment on Survival: A Secondary Analysis of the Systolic Blood Pressure Intervention Trial
Authors: Dimitrios Terentes-Printzios, Charalambos Vlachopoulos, Stephane Laurent, Peter Nilsson, Athanasios Protogerou, Konstantinos Aznaouridis, Panagiotis Xaplanteris, Iosif Koutagiar, Hirofumi Tomiyama, Akira Yamashina, Dimitrios Tousoulis
Journal: Circulation (2019)

Introduction: Aortic stiffness, as assessed by carotid-femoral pulse wave velocity (cfPWV) is an independent predictor of events in hypertension. Recent data suggest a predictive role of estimated ...
P-314 Supine VMAT versus prone 3D-EBRT in preoperative rectal cancer: Dosimetric comparison and pathological response with each radiotherapy technique
Authors: L. Diaz Gomez, A. Seguro Fernandez, I. Fajardo, J. Tisaire, F. Campos, J. Jaen Olasolo
Journal: Annals of Oncology (2020)
Proxy indicators to estimate appropriateness of antibiotic prescriptions by general practitioners: a proof-of-concept cross-sectional study based on reimbursement data, north-eastern France 2017
Authors: Nathalie Thilly, Ouarda Pereira, Jeroen Schouten, Marlies EJL Hulscher, Céline Pulcini
Journal: Eurosurveillance (2020)

BackgroundIn most countries, including France, data on clinical indications for outpatient antibiotic prescriptions are not available, making it impossible to assess appropriateness of antibiotic use at prescription level.AimOur objectives were to: (i) propose proxy indicators (PIs) to estimate appropriateness of antibiotic use at general practitioner (GP) level based on routine reimbursement data; and (ii) assess PIs' performance scores and their clinimetric properties using a large regional reimbursement database.MethodsA recent systematic literature review on quality indicators was the starting point for defining a set of PIs, taking French national guidelines into account. We performed a cross-sectional study analysing National Health Insurance data (available at prescriber and patient levels) on antibiotics prescribed by GPs in 2017 for individuals living in north-eastern France. We measured performance scores of the PIs and their case-mix stability, and tested their measurability, applicability, and room for improvement (clinimetric properties).ResultsThe 3,087 GPs included in this study prescribed a total of 2,077,249 antibiotic treatments. We defined 10 PIs with specific numerators, denominators and targets. Performance was low for almost all indicators ranging from 9% to 75%, with values < 30% for eight of 10 indicators. For all PIs, we found large variation between GPs and patient populations (case-mix stability). Regarding clinimetric properties, all PIs were measurable, applicable, and showed high improvement potential.ConclusionsThe set of 10 PIs showed satisfactory clinimetric properties and might be used to estimate appropriateness of antibiotic prescribing in primary care, in an automated way within antibiotic stewardship programmes.
Lipocalin-2 counteracts metabolic dysregulation in obesity and diabetes
Authors: Ioanna Mosialou, Steven Shikhel, Na Luo, Peristera Ioanna Petropoulou, Konstantinos Panitsas, Brygida Bisikirska, Nyanza J. Rothman, Roxane Tenta, Bertrand Cariou, Matthieu Wargny, Elisabeth Sornay-Rendu, Thomas Nickolas, Mishaela Rubin, Cyrille B. Confavreux, Stavroula Kousteni
Journal: The Journal of Experimental Medicine (2020)

Regulation of food intake is a recently identified endocrine function of bone that is mediated by Lipocalin-2 (LCN2). Osteoblast-secreted LCN2 suppresses appetite and decreases fat mass while improving glucose metabolism. We now show that serum LCN2 levels correlate with insulin levels and β-cell function, indices of healthy glucose metabolism, in obese mice and obese, prediabetic women. However, LCN2 serum levels also correlate with body mass index and insulin resistance in the same individuals and are increased in obese mice. To dissect this apparent discrepancy, we modulated LCN2 levels in mice. Silencing Lcn2 expression worsens metabolic dysfunction in genetic and diet-induced obese mice. Conversely, increasing circulating LCN2 levels improves metabolic parameters and promotes β-cell function in mouse models of β-cell failure acting as a growth factor necessary for β-cell adaptation to higher metabolic load. These results indicate that LCN2 up-regulation is a protective mechanism to counteract obesity-induced glucose intolerance by decreasing food intake and promoting adaptive β-cell proliferation.
Ensuring Choice for People with Kidney Failure — Dialysis, Supportive Care, and Hope
Authors: Kamyar Kalantar-Zadeh, Aaron Wightman, Solomon Liao
Journal: New England Journal of Medicine (2020)

For patients with advanced kidney disease, especially hospitalized patients, dialysis may be presented as the opposite end of the treatment spectrum from comfort care. Collaborative efforts and amended policies could allow patients to have a better range of options.
P-280 The comparison of mFOLFOX-6, mDCF, mFOLFIRINOX in the first-line treatment of advanced gastric cancer
Authors: E. Ignatova, M. Fedyanin, I. Pokataev, A. Tryakin, A. Popova, I. Bazin, D. Chekini, O. Sekhina, M. Lyadova, A. Rumyantsev, V. Nikulin, Y. Vakhabova, F. Moiseenko, V. Chubenko, S. Tjulandin
Journal: Annals of Oncology (2020)
SO-22 Atypical non-V600E BRAF (aBRAF) mutations as a prognostic and predictive factor in real-life metastatic colorectal cancer patients from the Nordic countries
Authors: E. Osterlund, H. Isoniemi, S. Kytölä, J. Kononen, P. Pfeiffer, L. Soveri, M. Keinänen, H. Sorbye, L. Nunes, T. Salminen, L. Nieminen, P. Halonen, A. Ålgars, J. Sundström, R. Kallio, R. Ristamäki, A. Lamminmäki, E. Heervä, T. Kuopio, B. Glimelius, A. Ristimäki, P. Osterlund
Journal: Annals of Oncology (2020)