tbuckley/cabot-search huggingface dataset:
A Probabilistic Approach to Evaluate the Risk of Decreased Total Triiodothyronine Hormone Levels following Chronic Exposure to PFOS and PFHxS via Contaminated Drinking Water
Authors: Antero Vieira Silva, Joakim Ringblom, Christian Lindh, Kristin Scott, Kristina Jakobsson, Mattias Öberg
Journal: Environmental Health Perspectives (2020)

BACKGROUND: Extensive exposure to per-and polyfluoroalkyl substances (PFAS) have been observed in many countries.Current deterministic frameworks for risk assessment lack the ability to predict the likelihood of effects and to assess uncertainty.When exposure exceeds tolerable intake levels, these shortcomings hamper risk management and communication.OBJECTIVE: The integrated probabilistic risk assessment (IPRA) combines dose-response and exposure data to estimate the likelihood of adverse effects.We evaluated the usefulness of the IPRA for risk characterization related to decreased levels of total triiodothyronine (T 3 ) in humans following a real case of high exposure to PFAS via drinking water.METHODS: PFAS exposure was defined as serum levels from residents of a contaminated area in Ronneby, Sweden.Median levels were 270 ng=mL [perfluorooctane sulfonic acid (PFOS)] and 229 ng=mL [perfluorohexane sulfonic acid (PFHxS)] for individuals who resided in Ronneby 1 y before the exposure termination.This data was integrated with data from a subchronic toxicity study in monkeys exposed daily to PFOS.Benchmark dose modeling was employed to describe separate dose-effect relationship for males and females, and extrapolation factor distributions were used to estimate the corresponding human benchmark dose.The critical effect level was defined as a 10% decrease in total T 3 .RESULTS: The median probability of critical exposure, following a combined exposure to PFOS and PFHxS, was estimated to be [2.1% (90% CI: 0:4%-13:1%)].Gender-based analysis showed that this risk was almost entirely distributed among women, namely [3.9% (90% CI: 0:8%-21:6%)].DISCUSSION: The IPRA was compared with the traditional deterministic Margin of Exposure (MoE) approach.We conclude that probabilistic risk characterization represents an important step forward in the ability to adequately analyze group-specific health risks.Moreover, quantifying the sources of uncertainty is desirable, as it improves the awareness among stakeholders and will guide future efforts to improve accuracy.
Perspectives on neuroinflammation contributing to chronic cough
Authors: Alexandria K. Driessen, Anna-Claire Devlin, Fionnuala T. Lundy, S. Lorraine Martin, Gerard P. Sergeant, Stuart B. Mazzone, Lorcan P. McGarvey
Journal: European Respiratory Journal (2020)

Chronic cough can be a troublesome clinical problem. Current thinking is that increased activity and/or enhanced sensitivity of the peripheral and central neural pathways mediates chronic cough via processes similar to those associated with the development of chronic pain. While inflammation is widely thought to be involved in the development of chronic cough, the true mechanisms causing altered neural activity and sensitisation remain largely unknown. In this back-to-basics perspective article we explore evidence that inflammation in chronic cough may, at least in part, involve neuroinflammation orchestrated by glial cells of the nervous system. We summarise the extensive evidence for the role of both peripheral and central glial cells in chronic pain, and hypothesise that the commonalities between pain and cough pathogenesis and clinical presentation warrant investigations into the neuroinflammatory mechanisms that contribute to chronic cough. We open the debate that glial cells may represent an underappreciated therapeutic target for controlling troublesome cough in disease.
SO-20 Consensus molecular subtypes and CRCAssigner classifications in metastatic colorectal cancer (mCRC): Prognostic and predictive impact in the TRIBE2 study
Authors: B. Borelli, E. Fontana, M. Giordano, C. Antoniotti, F. Bergamo, S. Murgioni, F. Pietrantonio, F. Morano, E. Tamburini, A. Boccaccino, D. Santini, V. Conca, N. Pella, E. Maiello, C. Ugolini, G. Fontanini, A. Falcone, G. Nyamundanda, A. Sadanandam, C. Cremolini
Journal: Annals of Oncology (2020)
An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T Cells
Authors: Shogo Kumagai, Yosuke Togashi, Chika Sakai, Akihito Kawazoe, Masahito Kawazu, Toshihide Ueno, Eiichi Sato, Takeshi Kuwata, Takahiro Kinoshita, Masami Yamamoto, Sachiyo Nomura, Tetsuya Tsukamoto, Hiroyuki Mano, Kohei Shitara, Hiroyoshi Nishikawa
Journal: Immunity (2020)
Synergistic antitumor activity observed for a fixed ratio liposome formulation of Cytarabine (Cyt):Daunorubicin (Daun) against preclinical leukemia models
Authors: Sharon Johnstone, Pierrot Harvie, Clifford Shew, Salam Kadhim, Troy Harasym, Paul Tardi, Natashia Harasym, Marcel Bally, Lawrence D. Mayer
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

1405 

We have previously demonstrated that the in vitro and in vivo activity of anticancer drug combinations is dependent on the drug:drug ratio, where some ratios act synergistically while others can interact additively or antagonistically. We examined here the influence of drug ratio on the in vitro and in vivo anti-tumor effects of Cyt:Daun, a drug combination used for the treatment of acute myeloid leukemia. The median-effect analysis method (Chou and Talalay, Adv Enzyme Regul, 22: 27-55, 1984) provided a quantitative measure of synergy for MTT cytotoxicity assays with Cyt:Daun molar ratios ranging from 10:1 to 1:10. This combination exhibited drug ratio and concentration dependent synergy when tested against P388 and L1210 leukemia cells in vitro. Subsequently, Cyt:Daun was encapsulation inside liposomes engineered to maintain the 5:1 molar ratio in the plasma compartment over 24h post i.v. injection. When administered i.v. to mice bearing ascitic P388 tumors, this fixed ratio liposome formulation (hereafter referred to as CPX-351) provided 90% long-term survivors (60 day), whereas the free drug cocktail at its MTD achieved only a modest increase in life span (22 day median survival time). CPX-351 was also therapeutically superior to individual free drugs and individual liposomal drugs administered at their respective MTDs. Similar results were obtained in the L1210 leukemia model. Quantitative comparisons of in vivo tumor cell kill for CPX-351 vs. individual liposomal drugs were performed based on tumor doubling time values and treatment-induced increases in survival. This analysis demonstrated that CPX-351 therapeutic activity was approximately 500-fold greater than predicted based on additive efficacy contributions of the individual liposomal drugs in the P388 tumor model, indicating strong in vivo synergy. These results demonstrate that fixing synergistic drug:drug ratios in carriers such as liposomes can lead to dramatic improvements of in vivo therapeutic activity. Furthermore, this approach provides an avenue whereby in vitro information on drug:drug interactions can be directly translated in vivo , thus facilitating the optimization of drug combinations based on efficacy in preclinical development.
P-166 Baseline radiomics features in metastatic colorectal cancer: Correlation with metastatic site and clinical-pathological characteristics
Authors: A. Anghelone, R. Vivolo, L. Boldrini, J. Lenkowicz, G. Caliolo, F. Camarda, B. Di Stefano, M. Calegari, C. Pozzo, M. Basso, C. Liguori, A. De Gaetano, N. Dinapoli, R. Manfredi, V. Valentini, G. Tortora, L. Salvatore
Journal: Annals of Oncology (2020)
Genetic analysis in desmoid tumors from patients with familial adenomatous polyposis
Authors: Karin Alvarez, Marjorie De la Fuente, Ana Maria Wielandt, Paulina Orellana, Montserrat Hevia, Mauricio Oyarzo, David Munroe, Francisco Lopez-Kostner, Pilar Carvallo
Journal: Cancer Research (2008)

1735  Familial adenomatous polyposis (FAP) is characterized by the development of hundreds of adenomatous polyps in the colon and rectum. This disease is caused by germline mutations in the APC gene. Some FAP patients develop extracolonic tumors such as desmoid tumors. These tumors are the second cause of death in FAP patients. Genetic analysis of colonic tumors has shown specific gene alterations during the progression from normal mucosa to colorectal cancer. Nevertheless, there is scarce genetic knowledge about desmoid tumors. Our aims were 1) to determine the participation of specific genes in the development of desmoid tumors, and, 2) to determine chromosomal alterations in desmoid tumors allowing the identification of new genes. In this study, 6 biopsies of desmoid tumors were analyzed, looking for loss of heterozygosity (LOH) of APC, DCC and P53 genes through single strand conformation polymorphism technique (SSCP), DNA sequencing and amplification of STR markers. Furthermore, mutations in the oncogene k-ras were screened by DNA sequencing, and we analyzed the samples for chromosomal alterations by microarrays-comparative genomic hybridization (array-CGH). In this study, no LOH in the APC, DCC and P53 genes was found, nor mutations in the oncogene k-ras, in contrast of the presence of these alterations in colorectal cancer. On the other hand, the analysis by array-CGH has allowed us to identify common chromosomal gains 1q12-1q23, 6p22-6p21, 8q21-8q24, 11p15, 11q12-11q13 and one main deletion 2q21-2q34 in the 6 desmoid tumors. These regions may contain tumor suppressor genes and oncogenes that could contribute to the development of these tumors. Supported by National Grant FONDECYT 1040827
School Superintendents Confront COVID-19—“There Are No Good Options for Next Year”
Authors: Rita Rubin
Journal: JAMA (2020)

Katherine A. Auger, MD, MSc; Samir S. Shah, MD, MSCE; Troy Richardson, PhD; David Hartley, PhD, MPH; Matthew Hall, PhD; Amanda Warniment, MD; Kristen Timmons, MS; Dianna Bosse, BA; Sarah A. Ferris, BA; Patrick W. Brady, MD, MSc; Amanda C. Schondelmeyer, MD, MSc; Joanna E. Thomson, MD, MPH
Abstract 13787: Increased or Stable Chronotropic Index over 7 years Predict Reduced Risks of All-cause and Cardiovascular Mortality among Healthy Middle-aged Men
Authors: Christian Hodnesdal, Kristian Engeseth, Per Torger Skretteberg, Irene Grundvold, Knut Liestol, Sverre E Kjeldsen, Johan Bodegard, Jan Erikssen, Knut Gjesdal
Journal: Circulation (2013)

Background: The chronotropic index (CI), a measure of the ability to increase heart rate (HR) during exercise, is previously reported to predict morbidity and mortality. CI reflects the combined ef...
Adding an important piece to the pulmonary vascular resistance puzzle in pulmonary arterial hypertension
Authors: Bradley A. Maron, Marc Humbert
Journal: European Respiratory Journal (2020)

Clinical outcomes in pulmonary arterial hypertension (PAH) have improved substantially in the modern era, owing to greater clinician awareness, availability of numerous pulmonary vasodilator therapies and, now, more than two decades of sound clinical trial data informing optimal strategies for treating patients [1]. This arc of progress began with therapeutic interventions that aimed to simply delay mortality in patients with end-stage disease, at a time in which PAH was regarded as by-and-large uniformly fatal. The evolution of PAH into a contemporary and treatable disease has been marked by specific sentinel transition points, including proven efficacy of prescription exercise, sequential add-on treatment with different drug classes, and up-front combination therapy in newly diagnosed patients [2]. This has resulted in a collective shift toward greatly enhanced goals for defining treatment success in clinical practice, such as minimal symptom burden, preserved exercise tolerance, and favourable haemodynamic parameters [3]. Rethinking pulmonary vascular resistance in pulmonary arterial hypertension <https://bit.ly/2RmnTDw>
Good or bad: Application of RAAS inhibitors in COVID-19 patients with cardiovascular comorbidities
Authors: James Jiqi Wang, Matthew L. Edin, Darryl C. Zeldin, Chenze Li, Dao Wen Wang, Chen Chen
Journal: Pharmacology & Therapeutics (2020)

The coronavirus disease 2019 (COVID-19) pandemic is caused by a newly emerged coronavirus (CoV) called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). COVID-19 patients with cardiovascular disease (CVD) comorbidities have significantly increased morbidity and mortality. The use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor type 1 blockers (ARBs) improve CVD outcomes; however, there is concern that they may worsen the prognosis of CVD patients that become infected with SARS-CoV-2 because the virus uses the ACE2 receptor to bind to and subsequently infect host cells. Thus, some health care providers and media sources have questioned the continued use of ACE inhibitors and ARBs. In this brief review, we discuss the effect of ACE inhibitor-induced bradykinin on the cardiovascular system, on the renin-angiotensin-aldosterone system (RAAS) regulation in COVID-19 patients, and analyze recent clinical studies regarding patients treated with RAAS inhibitors. We propose that the application of RAAS inhibitors for COVID-19 patients with CVDs may be beneficial rather than harmful.
P-385 A phase 1/2 study of combination therapy of ivaltinostat, gemcitabine, and erlotinib in patients with unresectable, locally advanced and metastatic pancreatic adenocarcinoma
Authors: J. Jo, H. Lee, S. Park, D. Chung, S. Cho, H. Cha, J. Cho, S. Song
Journal: Annals of Oncology (2020)
Current challenges for assessing the long-term clinical benefit of cancer immunotherapy: a multi-stakeholder perspective
Authors: Casey Quinn, Louis P Garrison, Anja K Pownell, Michael B Atkins, Gérard de Pouvourville, Kevin Harrington, Paolo Antonio Ascierto, Phil McEwan, Samuel Wagner, John Borrill, Elise Wu
Journal: Journal for ImmunoTherapy of Cancer (2020)

Immuno-oncologics (IOs) differ from chemotherapies as they prime the patient's immune system to attack the tumor, rather than directly destroying cancer cells. The IO mechanism of action leads to durable responses and prolonged survival in some patients. However, providing robust evidence of the long-term benefits of IOs at health technology assessment (HTA) submission presents several challenges for manufacturers. The aim of this article was to identify, analyze, categorize, and further explore the key challenges that regulators, HTA agencies, and payers commonly encounter when assessing the long-term benefits of IO therapies. Insights were obtained from an international, multi-stakeholder steering committee (SC) and expert panels comprising of payers, economists, and clinicians. The selected individuals were tasked with developing a summary of challenges specific to IOs in demonstrating their long-term benefits at HTA submission. The SC and expert panels agreed that standard methods used to assess the long-term benefit of anticancer drugs may have limitations for IO therapies. Three key areas of challenges were identified: (1) lack of a disease model that fully captures the mechanism of action and subsequent patient responses; (2) estimation of longer-term outcomes, including a lack of agreement on ideal methods of survival analyses and extrapolation of survival curves; and (3) data limitations at the time of HTA submission, for which surrogate survival end points and real-world evidence could prove useful. A summary of the key challenges facing manufacturers when submitting evidence at HTA submission was developed, along with further recommendations for manufacturers in what evidence to produce. Despite almost a decade of use, there remain significant challenges around how best to demonstrate the long-term benefit of checkpoint inhibitor-based IOs to HTA agencies, clinicians, and payers. Manufacturers can potentially meet or mitigate these challenges with a focus on strengthening survival analysis methodology. Approaches to doing this include identifying reliable biomarkers, intermediate and surrogate end points, and the use of real-world data to inform and validate long-term survival projections. Wider education across all stakeholders-manufacturers, payers, and clinicians-in considering the long-term survival benefit with IOs is also important.
Graft IL-33 regulates infiltrating macrophages to protect against chronic rejection
Authors: Tengfang Li, Zhongqiang Zhang, Joe G. Bartolacci, Gaelen K. Dwyer, Quan Liu, Lisa R. Mathews, Murugesan Velayutham, Anna S. Roessing, Yoojin C. Lee, Helong Dai, Sruti Shiva, Martin H. Oberbarnscheidt, Jenna L. Dziki, Steven J. Mullet, Stacy G. Wendell, James D. Wilkinson, Steven A. Webber, Michelle Wood-Trageser, Simon C. Watkins, Anthony J. Demetris, George S. Hussey, Stephen F. Badylak, Hēth R. Turnquist
Journal: Journal of Clinical Investigation (2020)

Alarmins, sequestered self-molecules containing damage-associated molecular patterns, are released during tissue injury to drive innate immune cell proinflammatory responses. Whether endogenous negative regulators controlling early immune responses are also released at the site of injury is poorly understood. Herein, we establish that the stromal cell–derived alarmin interleukin 33 (IL-33) is a local factor that directly restricts the proinflammatory capacity of graft-infiltrating macrophages early after transplantation. By assessing heart transplant recipient samples and using a mouse heart transplant model, we establish that IL-33 is upregulated in allografts to limit chronic rejection. Mouse cardiac transplants lacking IL-33 displayed dramatically accelerated vascular occlusion and subsequent fibrosis, which was not due to altered systemic immune responses. Instead, a lack of graft IL-33 caused local augmentation of proinflammatory iNOS+ macrophages that accelerated graft loss. IL-33 facilitated a metabolic program in macrophages associated with reparative and regulatory functions, and local delivery of IL-33 prevented the chronic rejection of IL-33–deficient cardiac transplants. Therefore, IL-33 represents what we believe is a novel regulatory alarmin in transplantation that limits chronic rejection by restraining the local activation of proinflammatory macrophages. The local delivery of IL-33 in extracellular matrix–based materials may be a promising biologic for chronic rejection prophylaxis.
Epigenetic CRISPR Screens Identify <i>Npm1</i> as a Therapeutic Vulnerability in Non–Small Cell Lung Cancer
Authors: Fei Li, Wai-Lung Ng, Troy A. Luster, Hai Hu, Vladislav O. Sviderskiy, Catríona M. Dowling, Kate E.R. Hollinshead, Paula Zouitine, Hua Zhang, Qingyuan Huang, Michela Ranieri, Wei Wang, Zhaoyuan Fang, Ting Chen, Jiehui Deng, Kai Zhao, Hon-Cheong So, Alireza Khodadadi-Jamayran, Mousheng Xu, Angeliki Karatza, Val Pyon, Shuai Li, Yuanwang Pan, Kristen Labbe, Christina Almonte, John T. Poirier, George Miller, Richard Possemato, Jun Qi, Kwok-Kin Wong
Journal: Cancer Research (2020)

Despite advancements in treatment options, the overall cure and survival rates for non-small cell lung cancers (NSCLC) remain low. While small-molecule inhibitors of epigenetic regulators have recently emerged as promising cancer therapeutics, their application in patients with NSCLC is limited. To exploit epigenetic regulators as novel therapeutic targets in NSCLC, we performed pooled epigenome-wide CRISPR knockout screens in vitro and in vivo and identified the histone chaperone nucleophosmin 1 (Npm1) as a potential therapeutic target. Genetic ablation of Npm1 significantly attenuated tumor progression in vitro and in vivo. Furthermore, KRAS-mutant cancer cells were more addicted to NPM1 expression. Genetic ablation of Npm1 rewired the balance of metabolism in cancer cells from predominant aerobic glycolysis to oxidative phosphorylation and reduced the population of tumor-propagating cells. Overall, our results support NPM1 as a therapeutic vulnerability in NSCLC. SIGNIFICANCE: Epigenome-wide CRISPR knockout screens identify NPM1 as a novel metabolic vulnerability and demonstrate that targeting NPM1 is a new therapeutic opportunity for patients with NSCLC.
Systemic lupus erythematosus
Authors: Lucy H Mackillop, Sarah J Germain, Catherine Nelson-Piercy
Journal: BMJ (2007)

Systemic lupus erythematosus in pregnancy brings risks for the mother, and possible harm to the fetus if the disease is treated.This article discusses the challenges of management Systemic lupus erythematosus (SLE) is a multisystem relapsing and remitting autoimmune disease.The management of this condition in pregnancy provides the obstetrician, physician, and general practitioner with particular challenges and concerns related to the mother and her baby (see scenario box). How common is SLe?The condition is much more common in women than men (9:1), with peak onset during childbearing years. 1 A recent extensive review of published epidemiology studies showed that the prevalence ranges from 0.07 per 1000 in white Americans to 1.59 per 1000 in British Afro-Caribbeans.w1 How does pregnancy affect SLe?Several case studies suggest that pregnancy exacerbates SLE and increases the likelihood of a flare antenatally or in the puerperium. 2 w2 In one prospective case-control study 65% of patients with SLE who were pregnant had a flare compared with 42% of those who
Response to: ‘COVID-19 in patients with rheumatic diseases: what is the real mortality risk?’ by Marques<i>et al</i>
Authors: Kristin M D’Silva, Naomi Serling-Boyd, Rachel Wallwork, Tiffany Y-T Hsu, Jeffrey A Sparks, Zachary Scott Wallace
Journal: Annals of the Rheumatic Diseases (2020)

<h3>Objective</h3> Little is known about tumor necrosis factor-α (TNF-α) blockers, disease activity, and liver steatosis (hepatic steatosis; HS) in subjects with psoriatic arthritis (PsA). We prospectively evaluated changes in HS during treatment with TNF-α blockers. <h3>Methods</h3> In 48 patients with PsA who had evidence of HS before the beginning of TNF-α blocker treatment, an ultrasound followup examination was performed after a 12-month treatment period with TNF-α blockers. All subjects were stratified according to minimal disease activity (MDA) or not (n-MDA), during treatment with TNF-α blockers. Changes in grade of HS were evaluated in parallel in 42 controls with HS and without PsA. <h3>Results</h3> At baseline, no significant difference in HS score was found between PsA subjects and controls (HS scores 1.46 ± 0.65 vs 1.62 ± 0.66, respectively; p = 0.249). At 12-month followup, a worsening HS score was found in 20 (41.7%) patients with PsA and in 6 (14.3%) controls (p = 0.005). Overall, the grade of HS worsening was higher in patients with PsA (0.37 ± 0.70) than in controls (0.09 ± 0.43; p = 0.028). A significantly lower prevalence of worsening HS was found among patients with PsA with MDA, compared with n-MDA subjects (16.7% vs 66.7%, respectively; p = 0.001). Laboratory measures of liver function behaved similarly. The risk of worsening HS in patients with PsA who had MDA was similar to that in controls (HR 1.20, 95% CI 0.34–4.33, p = 0.77), and higher in patients who did not have MDA (HR 4.46, 95% CI 1.73–11.47, p = 0.001, regression analysis). <h3>Conclusion</h3> Compared with patients with MDA, those with active disease after 12-month treatment with TNF-α blockers exhibited significantly higher incidence of worsening liver steatosis.
P-274 RELEVANT study: Patient and physician perspectives on clinically-meaningful outcomes in advanced pancreatic ductal adenocarcinoma
Authors: R. Pihlak, M. Frizziero, S. Mak, C. Nuttall, A. Lamarca, R. Hubner, J. Yorke, J. Valle, M. McNamara
Journal: Annals of Oncology (2020)
P-215 phase 2 HEPANOVA study of tumor treating fields (TTFields, 150 kHz) concomitant with sorafenib in advanced hepatocellular carcinoma (HCC): Interim safety analysis
Authors: A. Grosu, Y. Touchefeu, T. Brunner, E. Gkika, R. Thimme, A. Cubillo
Journal: Annals of Oncology (2020)