tbuckley/cabot-search huggingface dataset:
Endoplasmic Reticulum Stress Causes Liver Cancer Cells to Release Exosomal miR‐23a‐3p and Up‐regulate Programmed Death Ligand 1 Expression in Macrophages
Authors: Jiatao Liu, Lulu Fan, Hanqing Yu, Ju Zhang, Yong He, Dechun Feng, Fang Wang, Xiaoqiu Li, Qingqing Liu, Yuhuan Li, Zhenli Guo, Bin Gao, Wei Wei, Hua Wang, Guoping Sun
Journal: Hepatology (2019)

Endoplasmic reticulum (ER) stress promotes tumor cell escape from immunosurveillance. However, the underlying mechanisms remain unknown. We hypothesized that ER stress induces hepatocellular carcinoma (HCC) cells to release exosomes, which attenuate antitumor immunity by modulating the expression of programmed death ligand 1 (PD-L1) in macrophages. In this study, we demonstrated that expression of several ER stress markers (glucose-regulated protein 78, activating transcription factor 6, protein kinase R-like ER kinase, and inositol-requiring enzyme 1α) was up-regulated in HCC tissues and negatively correlated with the overall survival and clinicopathological scores in patients with HCC. Expression of ER stress-related proteins positively correlated with CD68+ macrophage recruitment and PD-L1 expression in HCC tissues. High-throughput sequencing analysis identified miR-23a-3p as one of the most abundant microRNAs in exosomes derived from tunicamycin (TM)-treated HCC cells (Exo-TMs). miR-23a-3p levels in HCC tissues negatively correlated with overall survival. Treatment with Exo-TMs up-regulated the expression of PD-L1 in macrophages in vitro and in vivo. Bioinformatics analysis suggests that miR-23a-3p regulates PD-L1 expression through the phosphatase and tensin homolog (PTEN)-phosphatidylinositol 3-kinase-protein kinase B (AKT) pathway. This notion was confirmed by in vitro transfection and coculture experiments, which revealed that miR-23a-3p inhibited PTEN expression and subsequently elevated phosphorylated AKT and PD-L1 expression in macrophages. Finally, coculture of T cells with Exo-TM-stimulated macrophages decreased CD8+ T-cell ratio and interleukin-2 production but increased T-cell apoptosis in vitro. Conclusion: ER-stressed HCC cells release exosomes to up-regulate PD-L1 expression in macrophages, which subsequently inhibits T-cell function through an exosome miR-23a-PTEN-AKT pathway. Our findings provide insight into the mechanism how tumor cells escape from antitumor immunity.
Maintenance immunotherapy in patients with advanced cancer (AC): Long term follow-up of a phase II study.
Authors: Francesco Recchia, Giampiero Candeloro, Stefano Necozione, Massimo Bratta, Michele Rosselli, Silvio Rea
Journal: Journal of Clinical Oncology (2015)

e14005 Background: Patients with AC may have prolonged clinical benefit (CB) from chemotherapy: However, nearly the majority of them will ultimately relapse. High expression of vascular endothelial growth factor (VEGF) promotes tumor progression through neoangiogenesis and natural killer cells (NK) mediate lytic activity against cancer cell lines. We have shown that low-dose interleukin-2 (IL-2) and 13-cis retinoic acid (RA) decreased VEGF and increased NK cells, in patients with AC with a CB from chemotherapy (Clin Cancer Res 2001). We speculated that IL-2 and RA might improve the clinical outcome through immune-mediated mechanisms, when administered in a minimal residual disease setting. Methods: Between 03/1998 and 09/2009, 500 patients (252 males), with a median age of 61y (range 21-80) who had received 4400 courses of chemotherapy, with a CB, were entered. Treatment consisted of self-administered subcutaneous IL-2, 1.8 X 106IU and oral RA, 0.5 mg/Kg for 5 days/week for 2 consecutive cycles of 3 weeks, with a 1-week rest, for 1 year, continued for a maximum of five years. Primary endpoints were VEGF and NK cells. Secondary endpoints were disease-free survival (DFS), overall survival (OS) and toxicity. Results: As of 9-30-2014, after a median follow-up of 112 months, 2634 courses of immunotherapy were administered. A statistically significant increase of NK cells (p < 0.001) and a decrease of VEGF (p < 0.001), with respect to baseline values, were observed. 16-year DFS and OS rates were 30% and 32.9%, respectively. Even with all the limitations of different patient populations, a significant improvement, with respect to NCI SEER data (http://seer.cancer.gov*), was observed in the 5-year OS rates for the most common AC: Breast 55.7% vs 25% *, lung 22.8% vs 4% *, colorectal 46.4% vs 12.9%*, No WHO grade 3 or 4 toxicity was observed, while grade 2 cutaneous toxicity and fever occurred in 20% and 13% of patients, respectively. Mild hypothyroidism was observed in 5% of patients. Conclusions: These data show that the administration of IL-2/RA, determines, with a modest toxicity profile, a sustained decrease of VEGF, an improvement of NK cells, and unpredicted 5-year survival rates. Phase III randomized studies are in progress.
Abstract P070: Hemoglobin A1c Trajectories and Two-year Mortality in Individuals With Diabetes After Cardiac Catheterization
Authors: Sridharan Raghavan, Wenhui G Liu, Anna E Baron, Mary E Plomondon, Michael Ho, Liron Caplan, Thomas M Maddox
Journal: Circulation (2019)

Background: Guidelines advise relaxing glycemic control goals in diabetes patients with coronary artery disease (CAD). However, the hemoglobin A1c (HbA1c) trajectories that occur in routine clinical care in diabetes patients with objectively assessed CAD have not been described, and their association with mortality is unknown. Methods: We studied 7780 individuals with diabetes using data from the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program, a registry of US Veterans who have undergone coronary angiography since 2005. We used HbA1c values from the measurement closest in time preceding catheterization and all values during two years of follow-up to fit longitudinal latent class models. We determined optimal trajectory model fit by Bayes Information Criteria, varying the functional form of time and the numbers of HbA1c trajectory classes. We then fit a joint latent class longitudinal mixed model to estimate associations between HbA1c trajectory class and two-year mortality, adjusting for clinical and demographic covariates, including an interaction term between HbA1c trajectory and CAD burden (no, non-obstructive, or obstructive), and with an autoregressive correlation structure for repeated HbA1c measurements. Results: Three trajectory classes best fit the data: individuals with stable glycemia after catheterization (class 1; 89%, 6934 of 7780), those with a decline in HbA1c after catheterization (class 2; 4.7%, 364 of 7780), and those with an increase in HbA1c after catheterization (class 3; 6.2%, 482 of 7780). Class 1 participants were older, more likely to be white, less likely to have congestive heart failure, and more likely to be adherent to cardioprotective medications. In multivariable joint mixed models, two-year mortality was 4.3% in class 1, 4.7% in class 2, and 5.0% in class 3 and differed significantly across HbA1c trajectory classes (p=0.047). In pairwise comparisons, two-year mortality differed significantly between individuals in classes 1 and 3 (p=0.03), but not between those in classes 1 and 2 (p=0.9) or between those in classes 2 and 3 (p=0.5). The interaction between trajectory class and CAD burden was non-significant (p=0.1), but limited by the number of participants with no or non-obstructive CAD. In individuals with obstructive CAD, we observed a significant association between HbA1c trajectory and mortality (p=0.04), driven by a difference between classes 1 and 3 (p=0.04) as in the full cohort. Conclusions: Distinct HbA1c trajectories were evident within 6 months after cardiac catheterization in patients with diabetes and were associated with two-year mortality. Serial HbA1c measurements in outpatient follow-up after cardiac catheterization could classify individuals with diabetes based on HbA1c trajectory; these trajectories may inform mortality risk stratification, especially in those with obstructive CAD.
Abstract 18556: Renal Sympathetic Denervation Modulates Cardiac Repolarization in a Post Myocardial Infarction Pig Model
Authors: Govind Krishna Kumar Nair, Sigfus Gizurarson, Nicholas Jackson, Benjamin King, Xudong Hu, Andrew Ramadeen, Nima Zamiri, Andreu Porta-Sanchez, Marjan Kusha, Stéphane Massé, Patrick F Lai, Abdul Al-Hesayen, John J Graham, Paul Dorian, Kumaraswamy Nanthakumar
Journal: Circulation (2015)

Introduction: Changes in cardiac repolarization parameters such as QT interval and QT dispersion have been implicated in cardiac arrhythmogenesis following acute myocardial infarction (AMI). These parameters are susceptible to sympathetic modulation. We therefore hypothesized that renal sympathetic denervation (RDN) may produce potential anti-arrhythmic actions through its effects on cardiac repolarization. Methods: Fifteen pigs randomized to AMI &amp; RDN (6 pigs), AMI &amp; sham RDN (6 pigs) and sham MI &amp; sham RDN (3 pigs) underwent percutaneous occlusion of the mid to distal LAD to achieve AMI. 2 weeks after infarction, the St. Jude EnligHTN® basket catheter was used to perform RDN bilaterally. Cardiac repolarization parameters were measured at 3 time points over the course of the 3 week study: baseline (immediately before MI), midpoint (2 weeks post MI; at time of RDN) and end (1 week post RDN). ECG data were acquired from limb leads. Results: In a ten beat span, the range in the durations of the QT interval was seen to increase from 18+/-7ms to 19+/-11ms in the real AMI &amp; sham RDN group while in the real AMI &amp; real RDN group it decreased from 17+/-5ms to 14+/-5ms (p=0.11). The mean QT interval which increased by 25% in the real AMI &amp; sham RDN group saw only an 11% increase in the real AMI &amp; real RDN group (p=0.048). The standard deviation of the average QT intervals post AMI, which quantifies the reduction in global dispersion of repolarization, saw a 41% decrease with RDN compared to an 8% decrease with sham RDN. The temporal dispersion of repolarization was also diminished by RDN. The dispersion of T wave peak to T wave end durations which increased in the real AMI &amp; sham RDN group (from 15+/-6ms to 22+/-10ms), was decreased in the real AMI &amp; real RDN group (from 19+/-7ms to 16+/-6ms) (p=0.05). T wave alternans values displayed no significant response to RDN (p=0.977). Conclusions: Adverse changes in cardiac repolarization parameters were attenuated via renal denervation in this post infarct pig model. These effects may mitigate post infarct arrhythmogenesis but require further study to evaluate the influence of local, reflex and circulating mediators.
Tobacco industry involvement in children’s sugary drinks market
Authors: Kim H Nguyen, Stanton A Glantz, Casey N Palmer, Laura A Schmidt
Journal: BMJ (2019)

<b>Kim H Nguyen and colleagues</b> examine how tobacco companies applied their knowledge of flavours, colours, and child focused marketing to&nbsp;develop leading children's sugar sweetened drink&nbsp;brands. These techniques continue to be used by drinks companies despite industry agreement not to promote unhealthy products in this way
Abstract P189: Blood Pressure Control Among Older Adults - Results From the Atherosclerosis Risk in Communities Study
Authors: Kathryn Foti, Lawrence J Appel, Kunihiro Matsushita, Silvia Koton, Keenan Walker, Josef Coresh, Elizabeth Selvin
Journal: Circulation (2019)

Introduction: Recent ACC/AHA guidelines recommend systolic blood pressure (SBP) treatment to &lt;130 mmHg among adults ≥65 with hypertension, though treatment goals for older adults are controversial. Examining SBP levels and associated characteristics among a community-based sample of older adults should increase our understanding of contemporary hypertension management. Hypothesis: Among adults ≥65 with hypertension (BP ≥140/90 mmHg or on treatment), those with higher socioeconomic status and physical and cognitive functioning are more likely to meet the ACC/AHA SBP goal (&lt;130 mmHg). It is uncertain whether comorbidities are associated with higher or lower SBP. Methods: We conducted a cross-sectional analysis at ARIC visit 5 which took place in 2011-2013; all participants were ≥65. We examined hypertension prevalence and the proportion of adults meeting different SBP goals overall and by demographic, lifestyle, and clinical factors. We used Poisson regression with robust variance to estimate prevalence ratios for SBP &lt;130 mmHg. Results: Overall, 74.2% of 5,537 participants had hypertension. Among those with hypertension, 44.2% had SBP &lt;130, 19.6% had SBP 130-&lt;140, 18.2% had SBP 140-&lt;150, and 18.1% had SBP ≥150 mmHg. The prevalence of SBP &lt;130 mmHg was inversely related to age ( Table, see adjusted prevalence ratio ). Men, whites in Washington County, MD, those with higher income, overweight or obesity, diabetes, kidney disease, or cardiovascular disease were more likely, while blacks in Jackson, MS and those with probable dementia were less likely to have SBP &lt;130 mmHg. Conclusions: Over 40% of participants met the ACC/AHA SBP goal. Only those in the highest income category were more likely to meet the goal. Those with comorbidities were more likely to meet the goal, which may reflect greater health care seeking, more intensive management, or BP-lowering comorbidities, such as heart failure. Our study highlights the burden of hypertension but shows SBP &lt;130 mmHg has been achieved in a substantial proportion of older adults.
A phase II study of <i>nab</i>-paclitaxel in refractory CIMP-high metastatic colorectal cancer.
Authors: Michael J. Overman, Bryan K. Kee, David R. Fogelman, Cathy Eng, Eduardo Vilar Sanchez, Rachna T. Shroff, Arvind Dasari, Robert A. Wolff, Jeffrey Morris, Scott Kopetz
Journal: Journal of Clinical Oncology (2015)

e14700 Background: Hypermethylation of promoter CpG islands (CIMP) represents a unique pathway for the development of colorectal cancer (CRC). CIMP-high CRC is characterized by the lack of chromosomal instability (CIN) and a low rate of APC mutations. Pre-clinical studies have correlated taxane resistance with both CIN and APC mutation status. This phase II was designed to evaluate taxane sensitivity in this unique subset of CRC. Methods: The primary objective was response rate by RECIST v1.1. Eligibility included: ECOG PS 0/1, refractory disease (prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, and anti-EGFR therapy if KRAS wt), and CIMP-high status ( ≥ 2/6 methylation-specific PCR markers: hMLH1, P16, P14, MINT1, MINT2, and MINT31). nab-paclitaxel was given as 260 mg/m2 every 3wks, but was subsequently reduced to 220 mg/m2every 3 weeks after 2 grade 4 adverse events (sepsis and neutropenic fever) in the first 6 patients. Results: 21 pts [M/F 14/7, median age: 57 yrs (range: 33-76), ECOG PS 0/1: 3/18, median number of prior therapies: 4.5] were enrolled from 11/2012 to 4/2014. 15 pts were considered efficacy evaluable [6 patients were withdrawn due to toxicity (2) and due to clinical progression (4)]. Rates of CIMP high methylated markers were 2/6 in 10 pts, 3/6 in 7 pts, and ≥ 4/6 in 4 pts. KRAS mutation was noted in 11/21 pts; BRAF V600E in 0/21 pts; and APC mutation in 8/15 pts (6 not tested). Microsatellite status was available in 15 pts: MSS/MSI-low in 14 and MSI-high in 1. Common grade 2 toxicities were alopecia (13, 62%), myalgia (7, 33%), and nausea (6, 29%). Common grade 3/4 toxicities were fatigue (4, 19%), febrile neutropenia (3, 14%), neutropenia (3, 14%), and thrombocytopenia (3, 14%). The response rate was 0 PR, 3 SD, 12 PD. Best response in the one MSI-high patient was PD. Median duration of stable disease was 3.9 months. Median PFS and median OS were 2.1m and 10.9m, respectively. No correlation between clinical benefit and the degree of tumor methylation was noted (2/6 vs. ≥ 3/6 markers, P = not significant). Conclusions: Though pre-clinical studies suggested taxane resistance was associated with CIN and APC mutation status. Single agent nab-paclitaxel was inactive in metastatic CIMP-high colorectal cancer. Clinical trial information: NCT01730586.
Robot-assisted Partial Nephrectomy for Complex (PADUA Score ≥10) Tumors: Techniques and Results from a Multicenter Experience at Four High-volume Centers
Authors: Nicolò Maria Buffi, Alberto Saita, Giovanni Lughezzani, James Porter, Paolo Dell’Oglio, Daniele Amparore, Cristian Fiori, Geert Denaeyer, Francesco Porpiglia, Alex Mottrie
Journal: European Urology (2019)
The adaptive self: Culture and social flexibility in feedback networks
Authors: Daina Crafa, Saskia K. Nagel
Journal: Behavioral and Brain Sciences (2019)

Abstract Culture contextualizes the contents and intentionality of many mental statuses. Cognitive mediation of cultural information shapes these contents and intentionalities, as well as many of the false beliefs of pathology. Flexibility of cognitive mediation processes and resulting beliefs and pathologies may vary by individual, be a key mechanism of the feedback loop, and help characterize network connections.
Utilization and outcomes of adjuvant radiation therapy after cystectomy for urothelial carcinoma.
Authors: Kenneth Verlage, Sudhir Isharwal
Journal: Journal of Clinical Oncology (2019)

487 Background: Positive surgical margins with radical cystectomy for invasive urothelial cancer are associated with adverse prognosis. In non-metastatic patients, adjuvant radiation therapy (ART) is sometimes employed for patients with positive margins or locally advanced stage. However, evidence for benefit of ART in these patients to improve survival is limited. In this study, using a national database we investigate the factors associated with use of ART and its impact of the overall survival. Methods: National Cancer Database was queried for patients who underwent radical cystectomy from 2004-2013 for invasive urothelial cancer. Inclusion criteria were urothelial histology, pT2 stage with positive surgical margins or ³pT3 , and no evidence metastasis. Patients with regional or distant metastasis or patient who underwent adjuvant chemotherapy were excluded. Univariate and multivariate analysis performed to assess the factors associated with the use of ART. Overall survival was compared using log rank test. Results: In total, 18,828 patients met the inclusion criteria, of which 359 (1.91%) underwent ART. Mean duration between radical cystectomy and ART was 4.4 months. On univariable analysis, Black or Hispanic race, Medicare/Medicaid insurance status, treatment at community health center, ileal conduit diversion, advanced pathological stage (pT3/T4) were associated with higher use of ART (all p&lt;0.005). On multivariate analysis community health facility and adequate lymph node dissection (&gt;10 lymph nodes excision) were associated with use of ART (all p&lt;0.05) (see table). The use of ART was not associated with improved overall survival. Conclusions: The utilization of ART after radical cystectomy for urothelial carcinoma is low. The benefit of ART on the overall survival is not clear and would need further investigation. [Table: see text]
Life expectancy in England and Wales has fallen by six months
Authors: Harriet Pike
Journal: BMJ (2019)

Life expectancy of adults in England and Wales has fallen by around six months, show new figures from the Institute and Faculty of Actuaries.1

The institute, which calculates life expectancy on behalf of the UK pensions and insurance industries, expects men who are now aged 65 to die at 86.9 years on average. This is down from last year’s estimate of 87.4 years. The average age of death of women who are now 65 is 89.2 years, down from 89.7 years.

Compared with 2015, projections of life expectancy are down by 13 months …
The Skin Commensal Yeast Malassezia Triggers a Type 17 Response that Coordinates Anti-fungal Immunity and Exacerbates Skin Inflammation
Authors: Florian Sparber, Corinne De Gregorio, Simone Steckholzer, Filipa M. Ferreira, Tamas Dolowschiak, Fiorella Ruchti, Florian R. Kirchner, Sarah Mertens, Immo Prinz, Nicole Joller, Thorsten Buch, Martin Glatz, Federica Sallusto, Salomé LeibundGut-Landmann
Journal: Cell Host & Microbe (2019)
Increased risk of chikungunya infection in travellers to Thailand during ongoing outbreak in tourist areas: cases imported to Europe and the Middle East, early 2019
Authors: Emilie Javelle, Simin-Aysel Florescu, Hilmir Asgeirsson, Shilan Jmor, Gilles Eperon, Eyal Leshem, Johannes Blum, Israel Molina, Vanessa Field, Nancy Pietroski, Carole Eldin, Victoria Johnston, Ioana Ani Cotar, Corneliu Popescu, Davidson H Hamer, Philippe Gautret
Journal: Eurosurveillance (2019)

We report nine travellers with confirmed chikungunya virus infection, returning from tourist areas of Thailand to Sweden, Switzerland, the United Kingdom, Romania, Israel and France, diagnosed in January and February 2019. These sentinel tourists support the intensification of chikungunya virus circulation in Thailand and highlight the potential for importation to areas at risk of local transmission.
Effects of free maternity service policy in Kenya: an interrupted time series analysis
Authors: Evaline Lang'at, L Mwanri, M Temmerman
Journal: The Lancet Global Health (2019)

BackgroundIn Kenya, more than 6 000 maternal deaths, and 35 000 stillbirths occur each year. In June, 2013, the Government of Kenya abolished user fees for maternity care in all public health facilities under the Free Maternity Service (FMS) policy, to make maternity services accessible and affordable, and to reduce maternal and perinatal deaths. This study aims to establish whether the FMS policy has influenced use of, access to, and quality of maternity care in Kenya.MethodsWe did an observational retrospective study in three counties in Kenya. We used daily maternity registers in 90 public health facilities to extract monthly observations for six maternal health indicators in the time period 2 years before and 2 years after the introduction of the FMS policy. We used interrupted time series analysis with a single group to assess the effects of the FMS policy. Standard linear regression using generalised least squares model was used to run the final results for each of the six variables. We calculated absolute and relative changes using model coefficients.FindingsA total of 82 962 women from Kilifi, Turkana, and Wajir counties were included in the study. Data were collected between June, 2011, and July, 2015. After policy implementation, there was an increase in antenatal care visits, health facility deliveries, and livebirths of 98% (p=0·0008), 97% (p<0·0001), and 89% (p<0·0001), respectively. The six maternal health output indicators were observed 24 months before implementation of the free maternity service policy (June, 2011, to May, 2013) and 25 months after implementation (June, 2013, to June, 2015), giving 49 observations. We noted an immediate and significant increase of 27% in women who received emergency obstetric care in the first month after policy implementation (p=0·0149). No significant change was observed in rates of stillbirth (p=0·4985) or caesarean section (p=0·4361).InterpretationThe 2013 introduction of free maternity services in Kenya saw an immediate, and then sustained, increase in the use of skilled care during pregnancy and childbirth. This sharp rise in the uptake of services suggest that the hospital cost is the main expense incurred by most women and their families when seeking maternity care services and that this cost is, therefore, a barrier to uptake of maternity care.FundingAfya Bora Consortium fellowship career development award.