tbuckley/cabot-search huggingface dataset:
Fenretinide inactivation of Mcl-1 enhanced activity of the Bcl-2 family inhibitor ABT-737 in acute lymphoblastic leukemia cell lines
Authors: Min Kang, Zesheng Wan, Yun Hee Kang, Robert Locke, C. Reynolds
Journal: Cancer Research (2007)

1800  We previously reported that ABT-737, a BH3-mimetic, synergistically increased cytotoxcity in combination with 4-HPR, a cytotoxic retinoid in acute lymphobastic leukemia (ALL) cell lines (Proc AACR, abstract #1336, 2006). We further investigated the mechanism of synergy and the differential cytotoxicity between leukemia cells and normal cells of ABT-737 + 4-HPR. Cytotoxicity was determined using a fluorescence-based digital imaging assay (DIMSCAN). Changes in Bcl-2 family proteins were detected by immunoblotting. Reactive oxygen species (ROS) generation (DCFDA fluorescence) and phospho-Jun kinase (p-JNK) were measured by flow cytometry. ABT-737 increased Mcl-1 protein only in ABT-737-resistant ALL cell lines, while 4-HPR inactivated Mcl-1 via reactive oxygen species (ROS) generation and JNK phosphorylation. In CEM cells the antioxidant ascorbic acid (AA), completely abrogated ROS generation (43.5 ± 2.67-fold increase by 10 μM 4-HPR alone versus 0.75 ± 0.07-fold increase by AA + 4-HPR relative to untreated control), JNK phosphorylation and Mcl-1 inactivation, and attenuated the cytotoxicity of 4-HPR (p
P-88 A multicenter analysis of the correlation between overall survival and progression-free survival and the number of chemotherapeutic key drugs used in patients with advanced/unresectable pancreatic cancer: Results from the NAPOLEON study
Authors: T. Shirakawa, Y. Ueda, M. Shimokawa, F. Koga, J. Nakazawa, A. Komori, S. Arima, M. Fukahori, A. Makiyama, H. Taguchi, T. Honda, S. Uneda, M. Yoshida, T. Shibuki, K. Nio, Y. Ide, N. Ureshino, K. Mitsugi, T. Otsuka
Journal: Annals of Oncology (2020)
P-208 Is there a role for adjuvant chemotherapy in ypN0 disease rectal cancer patients?
Authors: R. Félix Soares, A. Monteiro, F. Macedo, T. Cunha Pereira, J. Paulo, M. Marques, N. Bonito, P. Jacinto, J. Ribeiro, G. Sousa
Journal: Annals of Oncology (2020)
Airborne Transmission of SARS-CoV-2
Authors: Michael Klompas, Meghan A. Baker, Chanu Rhee
Journal: JAMA (2020)

Michael Klompas, MD, MPH; Michael C. Pandolfi, BS; Ansa B. Nisar, BS; Meghan A. Baker, MD, ScD; Chanu Rhee, MD, MPH
Cell type-specific genome scans of DNA methylation divergence indicate an important role for transposable elements
Authors: Önder Kartal, Marc W. Schmid, Ueli Grossniklaus
Journal: Genome biology (2020)

Abstract In population genomics, genetic diversity measures play an important role in genome scans for divergent sites. In population epigenomics, comparable tools are rare although the epigenome can vary at several levels of organization. We propose a model-free, information-theoretic approach, the Jensen-Shannon divergence (JSD), as a flexible diversity index for epigenomic diversity. Here, we demonstrate how JSD uncovers the relationship between genomic features and cell type-specific methylome diversity in Arabidopsis thaliana . However, JSD is applicable to any epigenetic mark and any collection of individuals, tissues, or cells, for example to assess the heterogeneity in healthy organs and tumors.
Functional characterization of human multidrug resistance protein 8 (MRP8, ABCC11).
Authors: Antonios Klokouzas, Xiang-Hong Peng, Zuben E. Sauna, Marianna Muller, Suresh V. Ambudkar
Journal: Cancer Research (2004)

2461  MRP8 (ABCC11), a newly identified member of the ATP-binding cassette (ABC) transporter superfamily, has recently been shown to be highly expressed at mRNA level in breast, testis and prostate. We have examined the functional properties of this protein using the baculovirus heterologous expression system. Using a specific affinity-purified polyclonal antibody against MRP8, we have detected and localized this protein (∼150 kDa) in the plasma membrane and in intracellular vesicles of the HighFive insect cells. The topological configuration of MRP8, similar to MRP4 and MRP5, is comprised of two membrane-spanning domains (each with six putative transmembrane helices) and two ATP sites ([MSD-NBD]2). MRP8 can be specifically photocrosslinked with an ATP analogue, 8-azido-α-[32P]ATP. In the presence of vanadate (Vi) or beryllium fluoride (BeFx) MRP8 trapped 8-azido-α-[32P]ADP in the post-hydrolysis transition state. Both Vi- and BeFx-induced nucleotide trapping by MRP8 was divalent cation-dependent (Mn2+>Mg2+) though Co2+ did not support trapping. MRP8 showed a basal Vi-sensitive ATPase activity of about 30 nmol of Pi min-1 (mg of protein)-1, and a Km value for ATP of approximately 500 μM. The basal ATPase activity of MRP8 was stimulated by the estrogen, 17β-estradiol (2-fold), and inhibited by the anti-estrogen drug, tamoxifen (IC50 of 40 μM) which is used in breast cancer treatment. By comparison, 17β-estradiol glucuronide did not stimulate the ATPase activity of MRP8 but had a mild inhibitory effect. Progesterone, a natural steroid, had an inhibitory effect while the steroid testosterone had no marked effect on the MRP8 ATPase activity. Other compounds, which showed a marked effect on the ATPase activity of MRP8, include methotrexate (stimulation followed by inhibition), the cyclic nucleotide cGMP (inhibition), and the pyrimidine nucleotide analog, AZT (inhibition). Using inside-out membrane vesicles prepared from HighFive insect cells expressing MRP8, we have shown that MRP8 mediates ATP-dependent transport of the cyclic nucleotide [3H]-cGMP although with a low affinity and that the classical MRP inhibitor MK-571 inhibited this transport. The data presented here provide an insight into the functional properties of MRP8 as a transporter with overlapping substrate specificity to that of MRP4 and/or MRP5. Uniquely, how\. ever, MRP8 seems to be involved in sterol transport. In aggregate, our results indicate that MRP8 is an active organic anion efflux pump whose overexpression might be associated with sterol transport as well as in the development of resistance to anticancer drugs in hormone-sensitive cancers of breast, testis and prostate.
Race/Ethnicity, Underlying Medical Conditions, Homelessness, and Hospitalization Status of Adult Patients with COVID-19 at an Urban Safety-Net Medical Center — Boston, Massachusetts, 2020
Authors: Heather E. Hsu, Erin M. Ashe, Michael Silverstein, Melissa Hofman, Samantha J. Lange, Hilda Razzaghi, Rebecca G. Mishuris, Ravin Davidoff, Erin M. Parker, Ana Penman-Aguilar, Kristie E.N. Clarke, Anna Goldman, Thea L. James, Karen Jacobson, Karen E. Lasser, Ziming Xuan, Georgina Peacock, Nicole F. Dowling, Alyson B. Goodman
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Abbreviation: COVID-19 = coronavirus disease 2019.* Inpatients include surviving patients whose highest level of care included non-intensive care unit hospitalization or intensive care unit hospitalization with or without invasive mechanical ventilation.
Revealing COVID-19 transmission in Australia by SARS-CoV-2 genome sequencing and agent-based modeling
Authors: Rebecca J. Rockett, Alicia Arnott, Connie Lam, Rosemarie Sadsad, Verlaine Timms, Karen-Ann Gray, John-Sebastian Eden, Sheryl Chang, Mailie Gall, Jenny Draper, Eby M. Sim, Nathan L. Bachmann, Ian Carter, Kerri Basile, Roy Byun, Matthew V. O’Sullivan, Sharon C-A Chen, Susan Maddocks, Tania C. Sorrell, Dominic E. Dwyer, Edward C. Holmes, Jen Kok, Mikhail Prokopenko, Vitali Sintchenko
Journal: Nature Medicine (2020)

In January 2020, a novel betacoronavirus (family Coronaviridae), named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the etiological agent of a cluster of pneumonia cases occurring in Wuhan City, Hubei Province, China1,2. The disease arising from SARS-CoV-2 infection, coronavirus disease 2019 (COVID-19), subsequently spread rapidly causing a worldwide pandemic. Here we examine the added value of near real-time genome sequencing of SARS-CoV-2 in a subpopulation of infected patients during the first 10 weeks of COVID-19 containment in Australia and compare findings from genomic surveillance with predictions of a computational agent-based model (ABM). Using the Australian census data, the ABM generates over 24 million software agents representing the population of Australia, each with demographic attributes of an anonymous individual. It then simulates transmission of the disease over time, spreading from specific infection sources, using contact rates of individuals within different social contexts. We report that the prospective sequencing of SARS-CoV-2 clarified the probable source of infection in cases where epidemiological links could not be determined, significantly decreased the proportion of COVID-19 cases with contentious links, documented genomically similar cases associated with concurrent transmission in several institutions and identified previously unsuspected links. Only a quarter of sequenced cases appeared to be locally acquired and were concordant with predictions from the ABM. These high-resolution genomic data are crucial to track cases with locally acquired COVID-19 and for timely recognition of independent importations once border restrictions are lifted and trade and travel resume. The combination of nearly real-time genome sequencing of SARS-CoV-2 in infected patients during the first 10 weeks of COVID-19 containment in Australia and epidemiological modeling is helping in understanding the dynamics of the COVID-19 pandemic and potentially guiding public health decisions.
P-73 Clinical prognostic factors for overall survival and time to progression in RAS-wild type metastatic colorectal cancer treated with anti-EGFR monoclonal antibodies as third or subsequent-line therapy
Authors: T. Lewandowski, P. Stelmasiak, M. Chmielowiec, R. Biernacka, M. Gryziak
Journal: Annals of Oncology (2020)
Human papillomavirus vaccination 2020 guideline update: American Cancer Society guideline adaptation
Authors: Debbie Saslow, Kimberly S. Andrews, Deana Manassaram‐Baptiste, Robert A. Smith, Elizabeth T. H. Fontham
Journal: CA A Cancer Journal for Clinicians (2020)

Abstract The American Cancer Society (ACS) presents an adaptation of the current Advisory Committee on Immunization Practices recommendations for human papillomavirus (HPV) vaccination. The ACS recommends routine HPV vaccination between ages 9 and 12 years to achieve higher on‐time vaccination rates, which will lead to increased numbers of cancers prevented. Health care providers are encouraged to start offering the HPV vaccine series at age 9 or 10 years. Catch‐up HPV vaccination is recommended for all persons through age 26 years who are not adequately vaccinated. Providers should inform individuals aged 22 to 26 years who have not been previously vaccinated or who have not completed the series that vaccination at older ages is less effective in lowering cancer risk. Catch‐up HPV vaccination is not recommended for adults aged older than 26 years. The ACS does not endorse the 2019 Advisory Committee on Immunization Practices recommendation for shared clinical decision making for some adults aged 27 through 45 years who are not adequately vaccinated because of the low effectiveness and low cancer prevention potential of vaccination in this age group, the burden of decision making on patients and clinicians, and the lack of sufficient guidance on the selection of individuals who might benefit.
Effects of Liraglutide on Cardiovascular Outcomes in Type 2 Diabetes Patients With and Without Baseline Metformin Use: Post Hoc Analyses of the LEADER Trial
Authors: Matthew J. Crowley, Darren K. McGuire, Anastasia-Stefania Alexopoulos, Thomas Jon Jensen, Søren Rasmussen, Hans A. Saevereid, Subodh Verma, John B. Buse
Journal: Diabetes Care (2020)

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) reduce cardiovascular (CV) events among patients with type 2 diabetes and high CV risk. Because consensus professional society recommendations endorse metformin as the first-line medication for type 2 diabetes, the CV efficacy of GLP-1RAs has primarily been studied with background metformin therapy (1). However, the European Society of Cardiology now recommends GLP-1RAs as a first-line type 2 diabetes treatment for patients at high CV risk (2). These discordant recommendations raise the question of how background metformin might influence the CV benefits of GLP-1RAs. Using data from the LEADER trial, we sought to answer this question by exploring possible heterogeneity in the CV efficacy of liraglutide related to baseline metformin treatment (3).

The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (NCT01179048, ClinicalTrials.gov) has been described elsewhere (3). Patients with type 2 diabetes and high CV risk underwent double-blind randomization to daily liraglutide versus placebo in addition to existing care.

Each patient contributed data from randomization until censoring. The primary outcome was time from randomization to first occurrence of a composite of CV death, myocardial infarction, or stroke. Prespecified secondary outcomes included an expanded composite (primary plus coronary revascularization or hospitalization for unstable angina or heart failure), the composite components, and all-cause death. All outcomes were centrally adjudicated.

Metformin treatment was identified at the baseline trial visit and each visit thereafter. Within each baseline metformin treatment subgroup, effect estimates for liraglutide versus placebo (hazard ratio [HR], 95% CI) were derived using Cox proportional hazards regression models; multivariable adjustment for baseline demographic and clinical factors was performed. Inverse probability for treatment weighting (IPTW) was used to account for imbalances in covariates between baseline metformin treatment subgroups (4). For multivariable analyses with IPTW, heterogeneity in the association between baseline metformin …
Abstract 336: A Machine Learning Algorithm for Detecting Pulse During Out-Of-Hospital Cardiac Arrest
Authors: Erik Alonso, Elisabete Aramendi, Unai Irusta, Mohamud R Daya
Journal: Circulation (2019)

Introduction: Pulse detection during out-of-hospital cardiac arrest (OHCA) is a challenge still not satisfactorily solved. An automated and accurate method for detecting pulse would reduce hands-off intervals and allow for more prompt post-cardiac arrest care. The aim of this study was to develop a method based on machine learning (ML) to detect pulse during OHCA. Materials and methods: Data were gathered from 187 OHCA patients treated by Tualatin Valley Fire &amp; Rescue (Tigard, OR, USA) using the Philips HeartStart MRx monitor/defibrillator between 2010 and 2014. The dataset used in the study contained 1140 5-s epochs presenting organized rhythms, 792 pulse-generating rhythms (PRs) and 348 pulseless electrical activity (PEA), annotated by consensus between two clinicians and a biomedical engineer using the available clinical information and the capnography signal. The dataset was split patient-wise into training (60%) and test (40%) sets. Each epoch contained the ECG and the thoracic impedance that were first preprocessed and then used to adaptively extract the impedance circulation component (ICC). The ICC shows a small fluctuation with each effective heartbeat. A total of 7 well-known waveform features were computed from the ECG and ICC and fed as observations to a discrete observation density hidden Markov model that classified each observation as PR (pulse) or PEA (no-pulse). The training set was used to develop and optimize the method, while the test set was used to measure the performance in terms of sensitivity (PR detection) and specificity (PEA detection). This procedure was repeated 50 times to estimate the distributions of the performance metrics. Results: The method showed a mean (SD) sensitivity and specificity of 95.4%(2.2) and 91.6% (3.4), respectively. Results were slightly above those previously reported by other authors using different ML techniques. Conclusions: A method based on a discrete observation density hidden Markov model can accurately detect pulse during OHCA. Further studies with larger datasets are needed to confirm these findings.
Association of Delirium With Long-term Cognitive Decline
Authors: Terry E. Goldberg, Chen Chen, Yuanjia Wang, Eunice Jung, Antoinette Swanson, Caleb Ing, Paul S. Garcia, Robert A. Whittington, Vivek Moitra
Journal: JAMA Neurology (2020)

Delirium is associated with increased hospital costs, health care complications, and increased mortality. Long-term consequences of delirium on cognition have not been synthesized and quantified via meta-analysis.To determine if an episode of delirium was an independent risk factor for long-term cognitive decline, and if it was, whether it was causative or an epiphenomenon in already compromised individuals.A systematic search in PubMed, Cochrane, and Embase was conducted from January 1, 1965, to December 31, 2018. A systematic review guided by Preferred Reporting Items for Systematic Reviews and Meta-analyses was conducted. Search terms included delirium AND postoperative cognitive dysfunction; delirium and cognitive decline; delirium AND dementia; and delirium AND memory.Inclusion criteria for studies included contrast between groups with delirium and without delirium; an objective continuous or binary measure of cognitive outcome; a final time point of 3 or more months after the delirium episode. The electronic search was conducted according to established methodologies and was executed on October 17, 2018.Three authors extracted data on individual characteristics, study design, and outcome, followed by a second independent check on outcome measures. Effect sizes were calculated as Hedges g. If necessary, binary outcomes were also converted to g. Only a single effect size was calculated for each study.The planned main outcome was magnitude of cognitive decline in Hedges g effect size in delirium groups when contrasted with groups that did not experience delirium.Of 1583 articles, data subjected from the 24 studies (including 3562 patients who experienced delirium and 6987 controls who did not) were included in a random-effects meta-analysis for pooled effect estimates and random-effects meta-regressions to identify sources of study variance. One study was excluded as an outlier. There was a significant association between delirium and long-term cognitive decline, as the estimated effect size (Hedges g) for 23 studies was 0.45 (95% CI, 0.34-0.57; P < .001). In all studies, the group that experienced delirium had worse cognition at the final time point. The I2 measure of between-study variability in g was 0.81. A multivariable meta-regression suggested that duration of follow-up (longer with larger gs), number of covariates controlled (greater numbers were associated with smaller gs), and baseline cognitive matching (matching was associated with larger gs) were significant sources of variance. More specialized subgroup and meta-regressions were consistent with predictions that suggested that delirium may be a causative factor in cognitive decline.In this meta-analysis, delirium was significantly associated with long-term cognitive decline in both surgical and nonsurgical patients.
Safety and efficacy of anti-il6-receptor tocilizumab use in severe and critical patients affected by coronavirus disease 2019: A comparative analysis
Authors: Roberto Rossotti, Giovanna Travi, Nicola Ughi, Matteo Corradin, Chiara Baiguera, Roberto Fumagalli, Maurizio Bottiroli, Michele Mondino, Marco Merli, Andrea Bellone, Andriano Basile, Ruggero Ruggeri, Fabrizio Colombo, Mauro Moreno, Stefano Pastori, Carlo Federico Perno, Paolo Tarsia, Oscar Massimiliano Epis, Massimo Puoti
Journal: Journal of Infection (2020)

As the novel SARS-CoV-2 pandemic occurred, no specific treatment was yet available. Inflammatory response secondary to viral infection might be the driver of severe diseases. We report the safety and efficacy (in terms of overall survival and hospital discharge) of the anti-IL6 tocilizumab (TCZ) in subjects with COVID-19.This retrospective, single-center analysis included all the patients consecutively admitted to our Hospital with severe or critical COVID-19 who started TCZ treatment from March 13th to April 03rd, 2020. A 1:2 matching to patients not treated with TCZ was performed according to age, sex, severity of disease, P/F, Charlson Comorbidity Index and length of time between symptoms onset and hospital admittance. Descriptive statistics and non-parametric tests to compare the groups were applied. Kaplan Meier probability curves and Cox regression models for survival, hospital discharge and orotracheal intubation were used.Seventy-four patients treated with TCZ were matched with 148 matched controls. They were mainly males (81.5%), Caucasian (82.0%) and with a median age of 59 years. The majority (69.8%) showed critical stage COVID-19 disease. TCZ use was associated with a better overall survival (HR 0.499 [95% CI 0.262-0.952], p = 0.035) compared to controls but with a longer hospital stay (HR 1.658 [95% CI 1.088-2.524], p = 0.019) mainly due to biochemical, respiratory and infectious adverse events.TCZ use resulted potentially effective on COVID-19 in terms of overall survival. Caution is warranted given the potential occurrence of adverse events.Some of the tocilizumab doses used in the subjects included in this analysis were provided by the "Multicenter study on the efficacy and tolerability of tocilizumab in the treatment of patients with COVID-19 pneumonia" (EudraCT Number: 2020-001110-38) supported by the Italian National Agency for Drugs (AIFA). No specific funding support was planned for study design, data collection and analysis and manuscript writing of this paper.
Withdrawal of inhaled corticosteroids in COPD
Authors: Alvar Agusti
Journal: European Respiratory Journal (2020)

<b>Withdrawal of inhaled steroid treatment in COPD patients is challenging. The history of the patient needs to be carefully assessed to exclude that they are not being effective and/or safe; and a stepwise approach with careful monitoring seems advisable.</b>https://bit.ly/2y3Tt2k