tbuckley/cabot-search huggingface dataset:
Clinical impact of gemcitabine mono-maintenance versus best supportive care after first-line gemcitabine with platinum in patients with metastatic urothelial carcinoma.
Authors: Seung-Hwan Lee, U-Syn Ha, Sung-Hoo Hong, Ji Youl Lee, In-Ho Kim
Journal: Journal of Clinical Oncology (2019)

404 Background: To evaluate the clinical impact of gemcitabine (GEM) monotherapy after 1st line GEM with platinum in patients with metastatic urothelial carcinoma. Methods: We retrospectively reviewed the medical records of 113 patients who showed with radiological response or stabilization after 4-6 cycles of GEM with platinum.61 patients received maintenance of GEM-mono (GEM group) as 1000 mg/m2 on day 1 and 8 every three weeks until progression or development of unacceptable toxicity. And 52 patients received best supportive care (BSC) with regular radiologic evaluation (BSC group). Progression free survival (PFS) and overall survival (OS) from start date of GEM-mono or BSC was examined. Results: After a median follow-up of all population of 8.21 months, 43 (70%) patients had progressed and 32 (52%) died in the GEM-mono arm, compared to 45 (86%) and 39 (76%) in the BSC arm, respectively. Maintenance of GEM-mono was for a median 6 cycles (2-19). Median PFS was 7–12 months (range 1.5-13.0) in the GEM-mono arm and 4–8 months (range 1.4-8.6) in the BSC arm (Hazard Ratio 0.580, 95%CI 0.38-0.95, p=0.032). Most common grade 3/4 adverse events in the GEM arm were neutropenia (n=11; 18%) and fatigue (n=13; 21%). After progression, 42 (68%) patients received treatment at the GEM and 30 (58%) at the BSC arm. Conclusions: Our data suggest that maintenance of GEM-mono therapy in patients who responded to 1st line GEM with platinum provides a significant prolongation of PFS, and with a manageable toxicity profile.
Multiparametric Cardiac Magnetic Resonance Imaging Can Detect Acute Cardiac Allograft Rejection After Heart Transplantation
Authors: Ryan S. Dolan, Amir A. Rahsepar, Julie Blaisdell, Kenichiro Suwa, Kambiz Ghafourian, Jane E. Wilcox, Sadiya S. Khan, Esther E. Vorovich, Jonathan D. Rich, Allen S. Anderson, Clyde W. Yancy, Jeremy D. Collins, James C. Carr, Michael Markl
Journal: JACC. Cardiovascular imaging (2019)
True 99th centile of high sensitivity cardiac troponin for hospital patients: prospective, observational cohort study
Authors: Mark Mariathas, Rick Allan, Sanjay Ramamoorthy, Bartosz Olechowski, Jonathan Hinton, Martin Azor, Zoe Nicholas, Alison Calver, Simon Corbett, Michael Mahmoudi, John Rawlins, Iain Simpson, James Wilkinson, Chun Shing Kwok, Paul Cook, Mamas A Mamas, Nick Curzen
Journal: BMJ (2019)

Abstract Objective To determine the distribution, and specifically the true 99th centile, of high sensitivity cardiac troponin I (hs-cTnI) for a whole hospital population by applying the hs-cTnI assay currently used routinely at a large teaching hospital. Design Prospective, observational cohort study. Setting University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom, between 29 June 2017 and 24 August 2017. Participants 20 000 consecutive inpatients and outpatients undergoing blood tests for any clinical reason. Hs-cTnI concentrations were measured in all study participants and nested for analysis except when the supervising doctor had requested hs-cTnI for clinical reasons. Main outcome measures Distribution of hs-cTnI concentrations of all study participants and specifically the 99th centile. Results The 99th centile of hs-cTnI for the whole population was 296 ng/L compared with the manufacturer’s quoted level of 40 ng/L (currently used clinically as the upper limit of normal; ULN). Hs-cTnI concentrations were greater than 40 ng/L in one in 20 (5.4%, n=1080) of the total population. After excluding participants diagnosed as having acute myocardial infarction (n=122) and those in whom hs-cTnI was requested for clinical reasons (n=1707), the 99th centile was 189 ng/L for the remainder (n=18 171). The 99th centile was 563 ng/L for inpatients (n=4759) and 65 ng/L for outpatients (n=9280). Patients from the emergency department (n=3706) had a 99th centile of 215 ng/L, with 6.07% (n=225) greater than the recommended ULN. 39.02% (n=48) of all patients from the critical care units (n=123) and 14.16% (n=67) of all medical inpatients had an hs-cTnI concentration greater than the recommended ULN. Conclusions Of 20 000 consecutive patients undergoing a blood test for any clinical reason at our hospital, one in 20 had an hs-cTnI greater than the recommended ULN. These data highlight the need for clinical staff to interpret hs-cTnI concentrations carefully, particularly when applying the recommended ULN to diagnose acute myocardial infarction, in order to avoid misdiagnosis in the absence of an appropriate clinical presentation. Trial registration Clinicaltrials.gov NCT03047785 .
The mass-action law-based new computer software, CompuSyn, for automated simulation of synergism and antagonism in drug combination studies
Authors: Ting-Chao Chou, Nick Martin
Journal: Cancer Research (2007)

637  Drug combination is the leading choice for treating most dreadful diseases, such as cancer and AIDS. The phrase “synergistic effect” has been cited 14,296; 7,186 and 903,000 times by PubMed, ISI and Google, respectively. Based on the unified theory of the median-effect equation of the mass-action law and the combination index theorem (Pharmacol. Rev. 58: 621-681, 2006), algorithms have been used to develop a new computer software “CompuSyn” for automated quantitative simulation of synergism or antagonism in drug combination studies, including anticancer agents, in vitro and in vivo. In this paper, we will demonstrate step-by-step, from experimental design (e.g., constant ratio and non-constant ratio combinations; simultaneous and sequential and reverse sequential combinations), to data entry, to automated simulation of synergism/antagonism, and to report generation, using specific examples of experimental data sets. This method determines the followings: 1) Whether there is a synergism? 2) If so, how much synergism? 3) Synergism at what dose levels? 4) Synergism at what effect levels? 5) How many folds of dose-reduction allowed for each drug as a result of synergism? 6) What is the optimal combination ratio for maximal synergy? and 7) What is the preferred combination schedule for better synergism? The computer generated color graphics include: 1) The dose-effect curves (including the mass-action law parametes for potency, shape and conformity statistics); 2) The median-effect plot; 3) The combination index (CI) plot for effect-oriented determination of synergism or antagonism at different effect levels; 4) The dose-reduction index (DRI) plot at different effect levels, 5) The isobologram for dose-oriented determination of synergism or antagonism, and 6) The polygonogram (for three or more drugs). The theoretical basis and utility of the above features in biomedical sciences will be demonstrated and illustrated with real examples. This theoretical development, experimental design, and computerized data analysis have facilitated dose-effect analysis for single drug evaluation and drug discovery as well as for drug or other entity combinations with different units (e.g., µM, µg/ml, international unit), different modalities (e.g., drug, radiation, hyperthermia), and different mechanisms (e.g., against different stages of cell life-cycle, enzymes, receptors, targets, pathways, etc.). This software is published by Combosyn, Inc. (www.combosyn.com).
Making sense of madness: What is really driving the disparities in lung cancer in Kentucky?
Authors: Jorge Arturo Rios-Perez, Malgorzata Oechsli, Kamila Izabela Cisak, Maiying Kong, Christina M Pinkston, Goetz H. Kloecker
Journal: Journal of Clinical Oncology (2015)

e17588 Background: Lung cancer is the leading cause of cancer death in the U.S. Kentucky (KY) has the highest lung cancer mortality rate in the U.S. Several factors are believed to contribute to these worse outcomes (poverty, smoking, inadequate insurance, reduced access to healthcare).Little data is available regarding which factors have the main impact. At a national level, 24.7% of patients with advanced non-small cell lung cancer (NSCLC) are never treated. We sought to determine the proportion of untreated patients in KY and to explore variations in non-treatment within the state. Methods: We queried the KY Cancer Registry to identify all patients diagnosed with advanced (Stage IV) NSCLC in KY who didn’t receive any cancer therapy (systemic therapy or radiation therapy). To investigate in-state variations, we identified those patients diagnosed within one of the largest health care networks in the state. Chi-square tests were used to identify significant differences between the eastern and western sides of the state, as well as between community facilities and an academic institution in KY. A logistic regression model was fit to estimate the proportion and 95% confidence limits of untreated patients by region and by institution type. Results: Between 2000 and 2008, 14904 people were diagnosed with advanced lung cancer in KY, 4913 of whom (32.96%, 95% CI, 31.65%-34.27%) never received any cancer treatment. This was significantly higher (p < 0.001) than the national level (24.7%; 95% CI, 24.6%-24.9%). There was a significant difference (p < 0.0001) of the proportion of untreated patients in a single academic center (18.7%; 95% CI, 15.1%-22.4%), compared to the community facilities within the network (49.37%; 95% CI, 47.13%-51.61%). There was a significant difference (p < 0.001) in the proportion of untreated patients between Western KY (45.5%; 95% CI, 42.8%-48.3%) and Eastern KY (54.8%; 95% CI, 51.5%-58.1%). Conclusions: A significantly higher proportion of advanced NSCLC patients remain untreated in KY compared to the rest of the U.S. There are also important differences within the state. Explaining these differences is a critical step to developing any effort aimed at improving the poorest lung cancer outcomes in the country.
Prevention of experimental human breast cancer bone metastasis in nude mice by tumor-targeting <i>Salmonella typhimurium </i>A1-R.
Authors: Shinji Miwa, Shuya Yano, Yong Zhang, Michael Bouvet, Hiroyuki Tsuchiya, Robert M. Hoffman, Ming Zhao
Journal: Journal of Clinical Oncology (2015)

e13513 Background: Bone metastasis is a lethal and morbid late stage of breast cancer that is currently treatment resistant. More effective treatments are necessary. Methods: High bone-metastatic variants of human breast cancer cells were selected in nude mice. After cardiac injection of a high bone-metastatic variant of breast cancer, all untreated mice had bone metastases. Results: Treatment of mice with tumor-targeting Salmonella typhimurium A1-R completely prevented experimental bone metastasis of the high-metastatic breast cancer variant in nude mice (P < 0.001). After injection of the highly bone-metastatic breast cancer variant to the tibia of nude mice, S. typhimurium A1-R treatment significantly reduced tumor growth in the bone (P < 0.001). Conclusions: S. typhimurium A1-R can prevent breast cancer bone metastasis and should be of future clinical use for breast cancer in the adjuvant setting.
Cell and Material‐Specific Phage Display Peptides Increase iPS‐MSC Mediated Bone and Vasculature Formation In Vivo
Authors: Harsha Ramaraju, David H. Kohn
Journal: Advanced Healthcare Materials (2019)

Abstract Biomimetically designed materials matching the chemical and mechanical properties of tissue support higher mesenchymal stem cell (MSC) adhesion. However, directing cell‐specific attachment and ensuring uniform cell distribution within the interior of 3D biomaterials remain key challenges in healing critical sized defects. Previously, a phage display derived MSC‐specific peptide (DPIYALSWSGMA, DPI) was combined with a mineral binding sequence (VTKHLNQISQSY, VTK) to increase the magnitude and specificity of MSC attachment to calcium‐phosphate biomaterials in 2D. This study investigates how DPI‐VTK influences quantity and uniformity of iPS‐MSC mediated bone and vasculature formation in vivo. There is greater bone formation in vivo when iPS‐MSCs are transplanted on bone‐like mineral (BLM) constructs coated with DPI‐VTK compared to VTK ( p &lt; 0.002), uncoated BLM ( p &lt; 0.037), acellular BLM/DPI‐VTK ( p &lt; 0.003), and acellular BLM controls ( p &lt; 0.01). This study demonstrates, for the first time, the ability of non‐native phage‐display designed peptides to spatially control uniform cell distribution on 3D scaffolds and increase the magnitude and uniformity of bone and vasculature formation in vivo. Taken together, the study validates phage display as a novel technology platform to engineer non‐native peptides with the ability to drive cell specific attachment on biomaterials, direct bone regeneration, and engineer uniform vasculature in vivo.
California jury awards $29m to woman who said Johnson &amp; Johnson talc caused mesothelioma
Authors: Owen Dyer
Journal: BMJ (2019)

Johnson & Johnson must pay $29m (£22m; €26m) to a California woman who was given a diagnosis of mesothelioma after using the company’s talcum based products for years, a further blow to a company that still faces nearly 13 000 similar lawsuits across the United States.

Terry Leavitt told the court that she used Johnson’s Baby Powder and another company product called Shower to Shower through the 1960s and 1970s. Her mesothelioma was diagnosed in 2017.

The jury in Oakland’s superior court found that the products were defective and that consumers had not been warned of the risks, awarding Leavitt $29.4m in damages.

“We respect the legal process …
Bcl-2 Is a Therapeutic Target for Hypodiploid B-Lineage Acute Lymphoblastic Leukemia
Authors: Ernesto Diaz-Flores, Evan Q. Comeaux, Kailyn L. Kim, Ella Melnik, Kyle Beckman, Kara L. Davis, Kevin Wu, Jon Akutagawa, Olga Bridges, Roberta Marino, Margo Wohlfeil, Benjamin S. Braun, Charles G. Mullighan, Mignon L. Loh
Journal: Cancer Research (2019)

Abstract Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The highest rates of treatment failure occur in specific genetic subsets of ALL, including hypodiploid B-cell ALL (B-ALL), for which effective alternative therapies to current intensive chemotherapy treatments have yet to be developed. Here, we integrated biochemical and genomic profiling with functional drug assays to select effective agents with therapeutic potential against hypodiploid B-ALL. ABT-199, a selective Bcl-2 inhibitor, was effective in reducing leukemic burden in vitro and in vivo in patient-derived xenograft models of hypodiploid B-ALL. Daily oral treatment with ABT-199 significantly increased survival in xenografted mice. The unexpected efficacy of ABT-199 observed in hypodiploid leukemias lacking BIM expression (the major reported mediator of ABT-199–induced apoptosis) led us to investigate the mechanism of action of ABT-199 in the absence of BIM. Treatment with ABT-199 elicited responses in a dose-dependent manner, from cell-cycle arrest at low nanomolar concentrations to cell death at concentrations above 100 nmol/L. Collectively, these results demonstrate the efficacy of Bcl-2 inhibition and potential therapeutic strategy in hypodiploid B-ALL. Significance: These results demonstrate the efficacy of ABT-199 in vivo and provide encouraging preclinical data of Bcl-2 as a potential target for the treatment of hypodiploid B-ALL.
Prognostic role of neutrophil-to-lymphocyte ratio in castration-resistant prostate cancer patients treated with docetaxel.
Authors: Atike Pinar, Ahmet Ozveren, Zeki Gokhan Surmeli, Ulus Ali Sanli, Ruchan Uslu, Burcak Karaca
Journal: Journal of Clinical Oncology (2015)

e16050 Background: Neutrophil-to-lymphocyte ratio (NLR) is a marker of inflammation and growing evidence supports its prognostic role in various cancers. We evaluated the prognostic impact of pretreatment NLR in castration-resistant prostate cancer receiving docetaxel. Methods: We retrospectively analyzed data of patients with metastatic castration-resistant prostate cancer who were to be treated with first-line docetaxel. Results: A total of 73 patients were included in analysis. Median age was 67 years, median Gleason score at diagnosis was 8, and median PSA level was 100 ng/mL. Thirty-two patients (43.8%) had a pretreatment NLR value of > 3.0. Median PSA reductions with docetaxel treatment were 86% and 54% in low and high NLR groups, respectively (p: 0.056). Patients in the high-NLR group had an inferior progression-free (median 7.1 vs 11.1 months, p:0.007) and inferior overall survival (17.5 vs 24.7 months, p:0.012). Multivariable analysis showed that elevated pretreatment NLR ( > 3.0) was an independent negative prognostic factor for overall survival (HR: 2.02, p:0.026). Conclusions: In CRPC patients receiving docetaxel, high pretreatment NLR is associated with inferior progression-free and overall survival. Our results demonstrate the negative prognostic role of NLR in this patient group.
Can treating vitamin D deficiency reduce exacerbations of chronic obstructive pulmonary disease?
Authors: Rob Cook, Vaughan Thomas, Rosie Martin
Journal: BMJ (2019)

The studyJolliffe D, Greenberg L, Hooper R, Mathyssen C, Rafiq R, de Jongh R, Camargo C, Griffiths C, Janssens W, Martineau A. Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials. Thorax 2019. doi:10.1136/thoraxjnl-2018-212092This project was funded by the National Institute for Health Research Health Technology Appraisal programme (project number 13/03/25).To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000737/treating-vitamin-d-deficiency-may-reduce-exacerbations-of-copd.
Legitimizing Values in Regulatory Science
Authors: Manuela Fernández Pinto, Daniel J. Hicks
Journal: Environmental Health Perspectives (2019)

Over the last several decades, scientists and social groups have frequently raised concerns about politicization or political interference in regulatory science. Public actors (environmentalists and industry advocates, politically aligned public figures, scientists and political commentators, in the United States as well as in other countries) across major political-regulatory controversies have expressed concerns about the inappropriate politicization of science. Although we share concerns about the politicization of science, they are frequently framed in terms of an ideal of value-free science, according to which political and economic values have no legitimate role to play in science. For several decades, work in philosophy of science has identified serious conceptual and practical problems with the value-free ideal.Our objectives are to discuss the literature regarding the conceptual and practical problems with the value-free ideal and offer a constructive alternative to the value-free ideal.We first discuss the prevalence of the value-free ideal in regulatory science, then argue that this ideal is self-undermining and has been exploited to delay protective regulation. To offer a constructive alternative, we analyze the relationship between the goals of regulatory science and the standards of good scientific activity. This analysis raises questions about the relationship between methodological and practical standards for good science, tensions among various important social goods, and tensions among various social interests. We argue that the aims of regulatory science help to legitimize value-laden choices regarding research methods and study designs. Finally, we discuss how public deliberation, adaptive management, and community-based participatory research can be used to improve the legitimacy of scientists as representatives of the general public on issues of environmental knowledge.Reflecting on the aims of regulatory science-such as protecting human health and the environment, informing democratic deliberation, and promoting the capacities of environmental justice and Indigenous communities-can clarify when values have legitimate roles in regulatory science. https://doi.org/10.1289/EHP3317.
Phase Ib (COSMIC-021) trial of cabozantinib (C) in urothelial carcinoma (UC) or C in combination with atezolizumab (A) in patients (pts) with UC, castrate resistant prostate cancer (CRPC) or renal cell carcinoma (RCC).
Authors: Sumanta K. Pal, Ulka N. Vaishampayan, Daniel E. Castellano, Andrea Necchi, Carla M.L.- Van Herpen, Giridharan Ramsingh, Yohann Loriot, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2019)

TPS683 Background: C is an inhibitor of tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER). Preclinical and clinical studies suggest that C promotes an immune-permissive tumor environment which may enhance response to immune checkpoint inhibitors (ICI) such as the anti-PD-L1 mAb, A. C is approved for pts with advanced RCC and has shown encouraging clinical activity in combination with a PD-1 targeting mAb in RCC, UC, and CRPC (Nadal et al 2017). A is approved for pts with advanced UC after prior platinum-containing chemo and for chemo-naïve pts with platinum ineligible UC or PD-L1+ cisplatin ineligible UC. Combination of C with A may enhance treatment efficacy in pts with genitourinary (GU) cancers. Here, we present the study design of an ongoing phase 1b trial of C + A which includes cohorts with advanced RCC, UC, and CRPC. Methods: This global multicenter, phase 1b, open-label trial will assess the safety, tolerability, activity, and pharmacokinetics of C or C + A (NCT03170960). The study comprises a dose-escalation stage and an expansion stage. The dose-escalation stage (3+3 design) is completed. C 40 mg qd + 1200 mg A q3w is the recommended dose for the expansion stage. In the expansion stage, 18 cohorts (each 30 pts) will be enrolled including 7 cohorts with GU cancers: (1) treatment naïve clear cell RCC; (2) non-clear cell RCC, treatment naïve or following systemic anticancer therapy; (3) UC after prior platinum-based therapy; (4) treatment naïve cisplatin-ineligible UC; (5) treatment naïve cisplatin-eligible UC; (6) UC after prior ICI therapy and (7) CRPC after prior enzalutamide and/or abiraterone. In addition, an exploratory cohort (30 pts) will evaluate single agent 60 mg C in pts with UC after prior ICI therapy. Pts will continue treatment as long as they experience clinical benefit per investigator or until unacceptable toxicity. The primary objective of the expansion stage is the objective response rate per RECIST 1.1 per investigator for each cohort. Secondary objectives will assess safety including immune related AEs. Clinical trial information: NCT03170960.