tbuckley/cabot-search huggingface dataset:
Cellular penetration and localization of polyethylene glycol
Authors: Deshan Yu, Yan Zhao, Yun H. Choe, Qiuxia Zhao, Ming-Ching Hsieh, Ping Peng
Journal: Cancer Research (2004)

644  Polyethylene glycol (PEG) has drawn extensive attention in recent years due to the marketing of several drugs using PEG as delivery system such as PEG-Intron, Neulasta and Pegasys. The advantages of PEGylated drugs are attributed to their extended blood circulating time, improved solubility, and reduced immunogenecity and toxicity over the unmodified counterparts. In target tissues and cells, the drugs function either in their released or pegylated form. However, little is known about the interaction of PEG itself and cells which may be implicated in the drug effectiveness. This study was designed to examine the cellular binding, uptake and trafficking of PEG. FACS analysis revealed that PEG (40 kDa) does not bind to J774A.1 mouse macrophages, indicating no specific receptors for PEG on these cells. To study cellular uptake, the macrophages were incubated with 40 kDa PEG at various doses and for different durations at 37°C, followed by extensive washing with medium, acid solution and PBS to remove the residual PEG. The cells were lysed and analyzed by SDS-PAGE and subsequent gel staining with iodine solution to reveal the PEG specifically. The results showed that the PEG accumulated in the macrophages in a time-and dose-dependent fashion. The accumulated PEG reached 60-80 μg/mg cell protein or 15-20 μg/106 cells at 30 h exposure. Confocal microscopic analysis demonstrated that FITC-labeled PEG was localized in the cytoplasm predominantly, and more interestingly, significant amount of PEG-FITC was also observed in the nucleus, suggesting that PEG is capable of penetrating cell membrane as well as nuclear membrane. The uptake was diminished completely at 4°C and reduced significantly by the treatment with metabolic inhibitors NaF and azide plus 2-deoxy-D-glucose. In contrast, the uptake was not sensitive to EGTA or excessive Ca+2. These observations suggest that the PEG uptake is energy-dependent but not a receptor-mediated endocytosis process. Taken together, our data suggest that PEG can be taken up appreciably by macrophages presumably via pinocytosis.
Prevalence and risk factors for HIV, hepatitis B, and hepatitis C in people with severe mental illness: a total population study of Sweden
Authors: Clarissa Bauer-Staeb, Lena Jörgensen, Glyn Lewis, Christina Dalman, David P J Osborn, Joseph F Hayes
Journal: The Lancet Psychiatry (2017)

Severe mental illness is associated with increased morbidity and mortality. The elevated risk of blood-borne viruses (BBVs) in people with severe mental illness is of concern, but the full extent of this problem is unclear. We aimed to determine the prevalence of and risk factors for BBVs in people with severe mental illness.In this nationwide, population-based, cross-sectional study, we estimated the point prevalence of HIV, hepatitis B (HBV), and hepatitis C (HCV) in people with severe mental illness, including the total adult (≥18 years) Swedish population. We defined severe mental illness as a clinical diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder, or other psychotic illness according to the Swedish version of the International Statistical Classification of Diseases version 8, 9, or 10. We used multivariable logistic regression to determine the odds of BBVs in individuals with severe mental illness, relative to the general population, and to identify independent risk factors (age, sex, immigration status, socioeconomic status, education, and substance misuse) for BBV infection. We also did a sensitivity analysis excluding BBV diagnoses made before the introduction of the Register for Infection Disease Control (1997).Of 6 815 931 adults in Sweden, 97 797 (1·43%) individuals had a diagnosis of severe mental illness. Prevalence of BBVs was elevated in people with severe mental illness, of which 230 (0·24%) had HIV, 518 (0·53%) had HBV, and 4476 (4·58%) had HCV. After accounting for sociodemographic characteristics, the odds of HIV were 2·57 (95% CI 2·25-2·94, p<0·0001) times higher in people with severe mental illness than in the general population, whereas the odds of HBV were 2·29 (2·09-2·51, p<0·0001) times higher and the odds of HCV were 6·18 (5·98-6·39, p<0·0001) times higher. Substance misuse contributed most to the increased risk of BBV: after adjustment, odds ratios were 1·61 (1·40-1·85, p<0·0001) for HIV, 1·28 (1·16-1·41, p<0·0001) for HBV, and 1·72 (1·67-1·78, p<0·0001) for HCV.Our results highlight the need to address the issue of higher prevalence of BBVs in people with severe mental illness and identify interventions preventing infection. Targeting of comorbid substance misuse would have particular effect on reduction of BBV prevalence in this population.Medical Research Council and Swedish Research Council.
AXL-Driven EMT State as a Targetable Conduit in Cancer
Authors: Jane Antony, Ruby Yun-Ju Huang
Journal: Cancer Research (2017)

Abstract The receptor tyrosine kinase (RTK) AXL has been intrinsically linked to epithelial–mesenchymal transition (EMT) and promoting cell survival, anoikis resistance, invasion, and metastasis in several cancers. AXL signaling has been shown to directly affect the mesenchymal state and confer it with aggressive phenotype and drug resistance. Recently, the EMT gradient has also been shown to rewire the kinase signaling nodes that facilitate AXL–RTK cross-talk, protracted signaling, converging on ERK, and PI3K axes. The molecular mechanisms underplaying the regulation between the kinome and EMT require further elucidation to define targetable conduits. Therapeutically, as AXL inhibition has shown EMT reversal and resensitization to other tyrosine kinase inhibitors, mitotic inhibitors, and platinum-based therapy, there is a need to stratify patients based on AXL dependence. This review elucidates the role of AXL in EMT-mediated oncogenesis and highlights the reciprocal control between AXL signaling and the EMT state. In addition, we review the potential in inhibiting AXL for the development of different therapeutic strategies and inhibitors. Cancer Res; 77(14); 3725–32. ©2017 AACR.
The DNA (cytosine-5-)-methyltransferase inhibitor 5-fluoro-2’-deoxycytidine induces RASSF1A expression in EJ6 human bladder carcinoma cells
Authors: Chun Li, Doris Villacorte, Edward M. Newman
Journal: Cancer Research (2005)

4114    RASSF1A  (Ras association domain family 1A) gene, a tumor suppressor gene, is located at chromosome 3p21.3 and is epigenetically inactivated in many human cancers. The re-expression of RASSF1A can arrest tumor cells in G1/S, inhibiting their proliferation. Recent studies have identified  RASSF1A  promoter methylation as a major mechanism of its silencing. We report here that 5-fluoro-2’-deoxycytidine (FdCyd) treatment of EJ6 human bladder carcinoma cells, in which RASSF1A is not expressed, decreases the  RASSF1A  promoter methylation and increases the  RASSF1A  mRNA expression. Primers specific for methylated and unmethylated sequences in the region of the  RASSF1A  promoter CpG Island were used for methylation-specific PCR (MSP) analysis of bisulfite-modified DNA. An unmethylated signal was observed in EJ6 cells treated with 1, 10 or 100 μM FdCyd for 3 days and was stronger after 3 weeks of treatment with 10 or 100 μM FdCyd and 9 weeks of treatment with 1 μM FdCyd. A methylated signal was observed in both FdCyd-treated and untreated EJ6 cells, indicating both successful bisulfate conversion and a lack of complete demethylation in all cells. The bisulfite modified DNA samples from EJ6 cells that were treated with 100 μM FdCyd from 3 days to 12 weeks were used for quantitative DNA CpG methylation analysis of  RASSF1A  by methylation-sensitive single-nucleotide primer extension (Ms-SNuPE). The average methylation of the four CpG sites examined was 0.96 in untreated EJ6 cells, 0.85 after treatment with 1 μM 5-azadeoxycytidine for 3 days. After the EJ6 cells were treated by FdCyd for 14 or 15 weeks at 1, 10 or 100 μM concentration, the average methylation was 0.80, 0.67 or 0.57 respectively. The expression of  RASSF1A  mRNA was examined by RT-PCR. A 245-bp amplification fragment of the  RASSF1A  message was undetected in untreated EJ6 cells and was detected after treatment of the cells with 100 μM FdCyd for 3 weeks. The signal was greater after longer exposures, up to 9 weeks. We compared the expression of  RASSF1A  mRNA (normalized to  HPRT ) in untreated and FdCyd-treated EJ6 cells to the expression in normal human fibroblasts (HF). In EJ6 cells treated with 100 μM FdCyd for 3 and 9 weeks, the relative  RASSF1A  mRNA expression was 2.0% and 39.9%, respectively, of the expression in HF. Thus, FdCyd, not only inhibits  RASSF1A  DNA methylation, but also increases  RASSF1A  mRNA expression. (Supported by CA81055 and CA33572.)
Global Initiative for Chronic Obstructive Lung Disease (GOLD) 20th Anniversary: a brief history of time
Authors: Roberto Rodriguez-Roisin, Klaus F. Rabe, Jørgen Vestbo, Claus Vogelmeier, Alvar Agustí
Journal: European Respiratory Journal (2017)

The publication of the 2017 report of the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease [2] marks the 20th anniversary of its birth back in 1997. The first Global Initiative for Chronic Obstructive Lung Disease (GOLD) Executive Summary was published in 2001 [3] and since then, GOLD updates the document annually and publishes a major report (revision) every five years. Thus, major reports have been published in 2006 [4], 2011 [5] and 2017 [6]. A brief history of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) on its 20th anniversary <http://ow.ly/rcFE30bZVZ0> Authors thank Rebecca Dekker, current Program Director of GOLD and Global Initiative for Asthma, for her current daily work in support of GOLD activities.
Open‐Loop Analysis of the Renin‐Angiotensin System in the Dog
Authors: A. W. COWLEY, J. P. MILLER, A. C. GUYTON
Journal: Circulation Research (1971)

The loop gain and time response of the renin-angiotensin system was determined in dogs in which the cardiovascular control loops of the central nervous system were eliminated by spinal cord destruction and decapitation.Step decreases in renal artery perfusion pressure were introduced for a 30minute period, and changes were measured in systemic arterial blood pressure, cardiac output, and renin activity.The calculated loop gain of both kidneys was -1.59 ±0.11 (SE) and for a single kidney was -0.92 ± 0.02 between renal perfusion pressures of 65 to 100 mm Hg.This indicates nearly a 65% and 50% compensation in pressure, respectively.Below renal perfusion pressures of 65 mm Hg, the gain decreased.The system exhibits a relatively rapid time course with maximum steady-state systemic pressure elevations occurring in an average of 20 minutes, and returning to control levels in an average of 17.8 minutes for bilateral constrictions and 31.9 minutes for single artery constrictions with contralateral nephrectomy.Cardiac outputs were not significantly changed during the constriction period.The arterial renin activity and renal renin secretion rates were consistently elevated during the constrictions.Systemic pressure changes were inhibited by infusion of angiotensin II before constriction and by the injection of angiotensin II antiserum.These results demonstrate that the systemic pressure changes were the result of the renin-angiotensin vasoconstrictor system.The results indicate that the renin-angiotensin system possesses sufficient time response and gain characteristics to participate significantly in the normal regulation of arterial pressure. KEY WORDSantiangiotensin II radioimmunoassay of angiotensin I renin secretion rate blood pressure regulation renal artery constriction time response of renin-angiotensin system • The renin-angiotensin system may play a role in the normal control of arterial pressure.Renin activity increases when man assumes the upright posture (1-3), and it has been shown to increase in hemorrhage (4, 5) and in hypotension without hemorrhage (6).Worcel et al. ( 7) reported a transitory hypotension following injection of a specific antibody against angiotensin II in normal rats and concluded that angiotensin plays a role in
Benzodiazepines and risk of all cause mortality in adults: cohort study
Authors: Elisabetta Patorno, Robert J Glynn, Raisa Levin, Moa P Lee, Krista F Huybrechts
Journal: BMJ (2017)

Objectives To evaluate the risk of all cause mortality associated with initiating compared with not initiating benzodiazepines in adults, and to address potential treatment barriers and confounding related to the use of a non-active comparator group.Design Retrospective cohort study.Setting Large de-identified US commercial healthcare database (Optum Clinformatics Datamart).Participants 1:1 high dimensional propensity score matched cohort of benzodiazepine initiators, and randomly selected benzodiazepine non-initiators with a medical visit within 14 days of the start of benzodiazepine treatment (n=1 252 988), between July 2004 and December 2013. To address treatment barriers and confounding, patients were required to have filled one or more prescriptions for any medication in the 90 days and 91-180 days before the index date (ie, the date of starting benzodiazepine treatment for initiators and the date of the selected medical visit for benzodiazepine non-initiators) and the high dimensional propensity score was estimated on the basis of more than 300 covariates.Main outcome measure All cause mortality, determined by linkage with the Social Security Administration Death Master File.Results Over a six month follow-up period, 5061 and 4691 deaths occurred among high dimensional propensity score matched benzodiazepine initiators versus non-initiators (9.3 v 9.4 events per 1000 person years; hazard ratio 1.00, 95% confidence interval 0.96 to 1.04). A 4% (95% confidence interval 1% to 8%) to 9% (2% to 7%) increase in mortality risk was observed associated with the start of benzodiazepine treatment for follow-ups of 12 and 48 months and in subgroups of younger patients and patients initiating short acting agents. In secondary analyses comparing 1:1 high dimensional propensity score matched patients initiating benzodiazepines with an active comparator, ie, patients starting treatment with selective serotonin reuptake inhibitor antidepressants, benzodiazepine use was associated with a 9% (95% confidence interval 3% to 16%) increased risk.Conclusions This large population based cohort study suggests either no increase or at most a minor increase in risk of all cause mortality associated with benzodiazepine initiation. If a detrimental effect exists, it is likely to be much smaller than previously stated and to have uncertain clinical relevance. Residual confounding likely explains at least part of the small increase in mortality risk observed in selected analyses.
Other UK nations should adopt Scotland’s “less combative approach” to industrial relations
Authors: Bryan Christie
Journal: BMJ (2017)

Governments in other UK nations should adopt Scotland’s “less combative approach” to industrial relations to help breed happier staff who engage more in quality improvement, a report has concluded.1

The report, from the Nuffield Trust, said that the NHS in Scotland had benefited from a cooperative spirit and consistency in policy direction that had led to positive staff relations. This approach “may be one factor in creating the trust that supports the use of intrinsic motivation for quality improvement,” it concluded.

But the report also warned that an impending …
Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: Analysis of two phase III studies
Authors: Jordi Bruix, Ann-Lii Cheng, Gerold Meinhardt, Keiko Nakajima, Yoriko De Sanctis, Josep Llovet
Journal: Journal of Hepatology (2017)

Sorafenib, an oral multikinase inhibitor, significantly prolonged overall survival (OS) vs. placebo in patients with unresectable hepatocellular carcinoma (HCC) in two phase III studies, SHARP (Sorafenib HCC Assessment Randomized Protocol) and Asia Pacific (AP). To assess prognostic factors for HCC and predictive factors of sorafenib benefit, we conducted a pooled exploratory analysis from these placebo-controlled phase III studies.To identify potential prognostic factors for OS, univariate and multivariate (MV) analyses were performed for baseline variables by Cox proportional hazards model. Hazard ratios (HRs) and median OS were evaluated across pooled subgroups. To assess factors predictive of sorafenib benefit, the interaction term between treatment for each subgroup was evaluated by Cox proportional hazard model.In 827 patients (448 sorafenib; 379 placebo) analyzed, strong prognostic factors for poorer OS identified from MV analysis in both treatment arms were presence of macroscopic vascular invasion (MVI), high alpha-fetoprotein (AFP), and high neutrophil-to-lymphocyte ratio (NLR; ⩽ vs. >median [3.1]). Sorafenib OS benefit was consistently observed across all subgroups. Significantly greater OS sorafenib benefit vs. placebo was observed in patients without extrahepatic spread (EHS; HR, 0.55 vs. 0.84), with hepatitis C virus (HCV) (HR, 0.47 vs. 0.81), and a low NLR (HR, 0.59 vs. 0.84).In this exploratory analysis, presence of MVI, high AFP, and high NLR were prognostic factors of poorer OS. Sorafenib benefit was consistently observed irrespective of prognostic factors. Lack of EHS, HCV, and lower NLR were predictive of a greater OS benefit with sorafenib.This exploratory pooled analysis showed that treatment with sorafenib provides a survival benefit in all subgroups of patients with HCC; however, the magnitude of benefit is greater in patients with disease confined to the liver (without extrahepatic spread), or in those with hepatitis C virus, or a lower neutrophil-to-lymphocyte ratio, an indicator of inflammation status. These results help inform the prognosis of patients receiving sorafenib therapy and provide further refinements for the design of trials testing new agents vs. sorafenib. Clinical Trial Numbers: NCT00105443 and NCT00492752.
Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with gastrointestinal cancers receiving moderately emetogenic chemotherapy regimens
Authors: Cindy Weinstein, Karin Jordan, Stuart Green, Saleem Khanani, Elizabeth Beckford-Brathwaite, Waldimir Vallejos, Annpey Pong, Stephen Noga, Bernardo Rapoport
Journal: Annals of Oncology (2017)
Genomic profiling of squamous malignancies across anatomic sites.
Authors: Christine H. Chung, Garrett Michael Frampton, Zachary Rockow Chalmers, Jon Chung, Saad A. Khan, Alexa Betzig Schrock, Laurie M. Gay, Neelesh Sharma, Julia Andrea Elvin, David Fabrizio, Caitlin F. Connelly, Hyunseok Kang, Philip J. Stephens, Vincent A. Miller, Jennifer Maria Johnson, Jeffrey S. Ross, Siraj Mahamed Ali, Shridar Ganesan
Journal: Journal of Clinical Oncology (2017)

11512 Background: Primary squamous cell carcinomas (SCCs) have diverse etiologies, but can share genomic features. We reviewed the genomic profiles of a series of SCC cases of differing anatomic origin. Methods: Hybrid-capture based genomic profiling of 182 or 236 or 315 genes was performed on 4783 squamous malignancies in the course of clinical care, with baits for HPV6, 11, 16, and 18, and assessment of tumor mutation burden (TMB; mutations/Mb) and microsatellite instability. Results: Sites of origin were head and neck (HNSCC, n = 1300), cervical (cSCC; n = 318), anal (aSCC, n = 248), esophageal (n = 242), lung (lSCC, n = 2386), and cutaneous (sSCC, n = 289) SCC cases. For HNSCC, cSCC, and aSCC (collectively termed HCA SCC), 395 (30%), 215 (68%), and 211 (83%) were HPV positive, respectively. For HCA SCC, the most common GA were in TP53 (45%), CDKN2A (29%), PIK3CA (24%), TERT (21%), and FAT1 (14%). The most frequent GA differentially associated with HPV status were in PIK3CA (34.9% versus 16.0%), CYLD (11.4% versus 1.4%) and PTEN (14.8% versus 6.1%) for HPV+ cases, and TP53 (3.8% versus 76.5%), CDKN2A ()1.4% versus 49.8%), and TERT (4.3% versus 33.0%) for HPV- cases. Mean TMB for HPV+ and HPV- cases were 6.6 (STDEV 7.3) and 13.7 (STDEV 29.7), respectively. TMB of all SCC cases was significantly different (p &lt; 10 -12 ) when stratified by HPV status. For lSCC and eSCC, the most common GA were found in TP53 (86%) CDKN2A (40%), and PIK3CA (26%) and mean TMB was 11.6 with HPV found in 3.1% of cases. In sSCC, the most common GA were in TP53 (85.5%), CDKN2A (54.3%), and TERT(44.0%), and mean TMB was 59.5 with HPV in 3.1% of cases. Subsets of SCC cases had defining and targetable GA including bi-allelic deletion of SMARCB1 ( &lt; 0.3%), amplification of PD-L1 (~2% ), and various kinase fusions. Cases demonstrating radiologic response to immunotherapy and matched targeted therapies, as well as subsequent development of multiple mechanisms of acquired resistance, will be presented. Conclusions: HPV driven SCC have similar genomic profiles regardless of of site origin, and have a significantly lower median TMB than HPV negative SCC. Early consistency of responses of SCC to matched therapies may strengthen the case for site independent genomic predictors of therapy response.
Children’s Urinary Environmental Carbon Load. A Novel Marker Reflecting Residential Ambient Air Pollution Exposure?
Authors: Nelly D. Saenen, Hannelore Bové, Christian Steuwe, Maarten B. J. Roeffaers, Eline B. Provost, Wouter Lefebvre, Charlotte Vanpoucke, Marcel Ameloot, Tim S. Nawrot
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: Ambient air pollution, including black carbon, entails a serious public health risk because of its carcinogenic potential and as climate pollutant. To date, an internal exposure marker for black carbon particles that have cleared from the systemic circulation into the urine does not exist.Objectives: To develop and validate a novel method to measure black carbon particles in a label-free way in urine.Methods: We detected urinary carbon load in 289 children (aged 9–12 yr) using white-light generation under femtosecond pulsed laser illumination. Children’s residential black carbon concentrations were estimated based on a high-resolution spatial temporal interpolation method.Measurements and Main Results: We were able to detect urinary black carbon in all children, with an overall average (SD) of 98.2 × 105 (29.8 × 105) particles/ml. The urinary black carbon load was positively associated with medium-term to chronic (1 mo or more) residential black carbon exposure: +5.33 × 105 particles/ml higher carbon load (95% confidence interval, 1.56 × 105 to 9.10 × 105 particles/ml) for an interquartile range increment in annual residential black carbon exposure. Consistently, children who lived closer to a major road (≤160 m) had higher urinary black carbon load (6.93 × 105 particles/ml; 95% confidence interval, 0.77 × 105 to 13.1 × 105).Conclusions: Urinary black carbon mirrors the accumulation of medium-term to chronic exposure to combustion-related air pollution. This specific biomarker reflects internal systemic black carbon particles cleared from the circulation into the urine, allowing investigators to unravel the complexity of particulate-related health effects.