tbuckley/cabot-search huggingface dataset:
Correlates and assessment of excess cardiovascular risk in bronchiectasis
Authors: Aarash D. Saleh, Bessie Kwok, Jeremy S. Brown, John R. Hurst
Journal: European Respiratory Journal (2017)

Patients with bronchiectasis are at increased risk of cardiovascular disease. We aimed to identify factors associated with elevated cardiovascular risk in bronchiectasis, measured using aortic stiffness and cardiac biomarkers. In addition, we sought to compare these direct measures against calculated QRISK2 scores. Aortic stiffness, cardiac biomarkers and systemic inflammation were measured in 101 adults with stable bronchiectasis. In addition, clinical and demographic data were collected to allow calculation of QRISK2 score and the bronchiectasis severity index (BSI) for each patient. The BSI score correlated with measured cardiovascular risk assessments, partly due to greater exacerbation frequency and lower forced expiratory volume in 1 s. Pulse-wave velocity was significantly higher in frequent exacerbators (≥3 events·year -1 ) than infrequent exacerbators (&lt;3 events·year -1 ; 10.5 versus 9.2 m·s −1 , p=0.01). In addition, frequent exacerbators had elevated serum C-reactive protein concentration, suggesting increased systemic inflammation (4.8 versus 2.2 mg·L −1 , p=0.005). QRISK2 systematically underestimated cardiovascular risk in this population (median change in relative risk 1.29). Underestimation was associated with frequent exacerbations and male sex. Patients with bronchiectasis have greater cardiovascular risk than published reference populations. Excess cardiovascular risk is associated with exacerbation frequency and impaired lung function. Cardiovascular risk assessment in bronchiectasis should be individualised, as calculation tools are likely to underestimate the risk in this population.
Abstract 15820: Early and Pre-clinical Transcriptome Analysis by RNA Sequencing Identifies Mitochondrial Dysfunction and Inflammation as Early Phenotypic Consequences of Lamin A/C Deficiency
Authors: Gaelle Auguste, Priyatansh Gurha, Cristian Coarfa, Raffaella Lombardi, Brett H Graham, Ali J Marian
Journal: Circulation (2016)

Introduction:  Mutations in the  LMNA  gene, encoding Lamin A/C, cause several distinct phenotypes collectively referred to as laminopathies. Cardiac involvement is the primary cause of death and manifests as dilated cardiomyopathy (DCM), conduction defects, arrhythmias, and sudden cardiac death. The pathogenesis of cardiac phenotype in laminopathies remains largely unknown.   Hypothesis:  We posit that early pre-clinical RNA-Sequencing could identify the primary events in the heart in laminopathies.   Methods:  Lmna-/- and control wild type (WT) mice were characterized for cardiac function (echocardiography) and cardiac histology at 2 and 4 weeks. Transcriptome was analyzed by RNA-Seq at 2 weeks, prior to expression of cardiac dysfunction, apoptosis, and fibrosis.   Results:  Hierarchal clustering of 908 differentially expressed transcripts in the heart (q Lmna -/- mice.   Conclusions:  Whole transcriptome analysis identifies mitochondrial dysfunction and myocardial inflammation, in part regulated by FOXO4 and E2F1 pathways, as early phenotypes preceding cardiac dysfunction and premature death. The findings implicate inflammation as a therapeutic target in cardiac involvement in laminopathies.
A novel Ruminococcus gnavus clade enriched in inflammatory bowel disease patients
Authors: Andrew Brantley Hall, Moran Yassour, Jenny Sauk, Ashley Garner, Xiaofang Jiang, Timothy Arthur, Georgia K. Lagoudas, Tommi Vatanen, Nadine Fornelos, Robin Wilson, Madeline Bertha, Melissa Cohen, John Garber, Hamed Khalili, Dirk Gevers, Ashwin N. Ananthakrishnan, Subra Kugathasan, Eric S. Lander, Paul Blainey, Hera Vlamakis, Ramnik J. Xavier, Curtis Huttenhower
Journal: Genome Medicine (2017)

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract that is associated with changes in the gut microbiome. Here, we sought to identify strain-specific functional correlates with IBD outcomes.We performed metagenomic sequencing of monthly stool samples from 20 IBD patients and 12 controls (266 total samples). These were taxonomically profiled with MetaPhlAn2 and functionally profiled using HUMAnN2. Differentially abundant species were identified using MaAsLin and strain-specific pangenome haplotypes were analyzed using PanPhlAn.We found a significantly higher abundance in patients of facultative anaerobes that can tolerate the increased oxidative stress of the IBD gut. We also detected dramatic, yet transient, blooms of Ruminococcus gnavus in IBD patients, often co-occurring with increased disease activity. We identified two distinct clades of R. gnavus strains, one of which is enriched in IBD patients. To study functional differences between these two clades, we augmented the R. gnavus pangenome by sequencing nine isolates from IBD patients. We identified 199 IBD-specific, strain-specific genes involved in oxidative stress responses, adhesion, iron-acquisition, and mucus utilization, potentially conferring an adaptive advantage for this R. gnavus clade in the IBD gut.This study adds further evidence to the hypothesis that increased oxidative stress may be a major factor shaping the dysbiosis of the microbiome observed in IBD and suggests that R. gnavus may be an important member of the altered gut community in IBD.
The associations of thiopurines with male fertility and paternally exposed offspring: a systematic review and meta-analysis
Authors: Melek Simsek, Cornelis B Lambalk, Janneke A Wilschut, Chris J J Mulder, Nanne K H de Boer
Journal: Human Reproduction Update (2017)

Thiopurines are widely used immunosuppressive agents. In high dosages, they inhibit the purine synthesis and are considered to be possibly harmful to spermatogenesis, and subsequently to men's fertility and their offspring. However, the clear association between thiopurine exposure and male fertility and reproduction safety, if any, is still poorly understood.The aim of this review was to systematically summarize and meta-analyse the available data, derived from animal and human studies, regarding the influence of thiopurine exposure on fertility and conception safety in men and their offspring.A systematic literature search of the MEDLINE and EMBASE databases was performed using a combination of relevant terms related to 'thiopurines', 'fertility', 'conception', 'reproduction', 'semen quality' and 'birth outcome', combined with 'male', 'men', 'father' and 'paternal'. The search was not restricted exclusively to human subjects, neither to a type of disease or condition, to gather all available studies with regards to this topic. All published articles on thiopurines and male fertility, written in English and published until May 2017, were screened for eligibility. The GRADE guidelines were used to assess the quality of evidence of the included articles.A total of 28 studies (including 14 observational studies in humans) were included in this review and six of these were included in the meta-analysis. In various rodents, thiopurines adversely affected the germ cells (in administered doses of 2 to 20 times the human equivalent dose). In human studies, thiopurine therapy was not evidently associated with impaired testicular function or semen quality in 83 men with a variety of underlying diseases. In total, 53 out of 975 offspring with congenital anomalies (5.4%, the background prevalence is 3%), possibly as a result of paternal thiopurine exposure, were described in all studies together. The risk of congenital anomalies was not significantly increased when compared with offspring without paternal thiopurine exposure (4.7%) (pooled odds ratio 1.32, 95% confidence interval 0.75, 2.34).Thiopurines have spermatotoxic effects in rodents. In humans, overall data are limited and derived from underpowered studies, and therefore not conclusive with regards to the possible effects of thiopurines on spermatogenesis or paternally exposed offspring. Larger, epidemiological trials evaluating the safety of thiopurines to men's fertility and their offspring are mandatory to adequately counsel thiopurine treated men who wish to conceive.
Outcomes of a specialized interdisciplinary approach for cancer patients with aberrant opioid-related behavior: A preliminary report.
Authors: Tonya Edwards, Joseph Anthony Arthur, Suresh Reddy, Kristy Nguyen, David Hui, Sriram Yennu, Minjeong Park, Diane D Liu, Eduardo Bruera
Journal: Journal of Clinical Oncology (2017)

212 Background: Data on the development and outcomes of effective interventions to address aberrant opioid-related behavior (AB) in cancer patients is lacking. Our outpatient supportive care clinic developed and implemented a specialized interdisciplinary team approach to manage patients with AB. The purpose of this study was to report clinical outcomes of this novel intervention. Methods: The medical records of 30 consecutive patients with evidence of AB who received the intervention and a random control group of 70 patients without evidence of AB between January 1, 2015 and August 31, 2016 were reviewed. Results: At baseline, pain intensity (p=0.002) and opioid dose (p=0.001) were significantly higher among patients with AB. During the course of the study, the median number of ABs per month significantly decreased from 3 pre-intervention to 0.4 post-intervention (p&lt;0.0001). The median morphine equivalent daily dose decreased from 165mg/day at the first intervention visit to 112mg/day at the last follow up (p=0.018) although pain intensity did not significantly change (p= 0.984). ‘Request for opioid medication refills in the clinic earlier than the expected time’ was the AB with the highest frequency prior to the intervention and the greatest improvement during the study period. Younger age (p&lt;0.0001) and higher ESAS anxiety score (p=0.005) were independent predictors of the presence of AB. Conclusions: The intervention was associated with a reduction in the frequency of AB and opioid utilization among cancer patients receiving chronic opioid therapy. More research is needed to further characterize the clinical effectiveness of this intervention. [Table: see text]
Implementing the Bereaved Family Survey for an advanced cancer population.
Authors: Jessica Kaltman, Anne Margaret Walling, Neil Wenger
Journal: Journal of Clinical Oncology (2017)

76 Background: Despite being endorsed as a National Quality Forum measure, the Bereaved Family Survey (BFS), a tool to assess a patient’s end-of-life (EOL) experience, has not been broadly used outside the Veteran’s Affairs Health System or in the outpatient setting. We adapted the BFS for an advanced cancer population and implemented it at an academic health system to identify areas for quality improvement in EOL care. Methods: Between August 2016 and May 2017, we surveyed caregivers of advanced cancer decedents. We included English-speaking decedents &gt; 18 years of age who were continuity patients of a health system oncologist and had documentation of metastatic disease in either problem list, oncology notes, or advanced imaging. Death was verified in the chart or by obituary found via internet search. Caregivers surveyed were the appointed healthcare agent in an advance directive or the first listed contact. Scoring was done via the top-box approach. Surveys were mailed 3 months after death with a follow-up post-card reminder and phone-call at 2 and 4 weeks, respectively. Results: Of 285 eligible decedents, 242 caregivers were mailed surveys with 83 completed (34% response rate) of whom 28% died in the hospital. Mean overall BFS score was 75 out of 100. Ratings were high for overall care quality (78% Always/Usually) and staff caring (74% Always) with lower ratings for communication (58% Always), emotional/spiritual support (37% Always with 30% not wanting support) and pain control (56% Always/Usually uncomfortable). Nearly 84% of respondents felt their loved one died in the right place and 67% felt staff caring for the patient provided a dignified death. 74% of patients were referred to hospice with 64% of caregivers stating the hospice referral was timely. Write-in responses mentioned concerns about caregiver support, the quality and timeliness of hospice care and communication between physician and patient/caregiver. Over half of statements were positive remarks about a physician or ancillary staff member. Conclusions: A post-mortem survey implemented for an advanced cancer population received a modest response rate but collected valuable information regarding gaps in care quality to drive quality improvement.
Standardizing Clinically Meaningful Outcome Measures Beyond HbA1c for Type 1 Diabetes: A Consensus Report of the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange
Authors: Gina Agiostratidou, Henry Anhalt, Dana Ball, Lawrence Blonde, Evgenia Gourgari, Karen N. Harriman, Aaron J. Kowalski, Paul Madden, Alicia H. McAuliffe-Fogarty, Molly McElwee-Malloy, Anne Peters, Sripriya Raman, Kent Reifschneider, Karen Rubin, Stuart A. Weinzimer
Journal: Diabetes Care (2017)

OBJECTIVE To identify and define clinically meaningful type 1 diabetes outcomes beyond hemoglobin A1c (HbA1c) based upon a review of the evidence, consensus from clinical experts, and input from researchers, people with type 1 diabetes, and industry. Priority outcomes include hypoglycemia, hyperglycemia, time in range, diabetic ketoacidosis (DKA), and patient-reported outcomes (PROs). While priority outcomes for type 1 and type 2 diabetes may overlap, type 1 diabetes was the focus of this work. RESEARCH AND METHODS A Steering Committee—comprising representatives from the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange—was the decision-making body for the Type 1 Diabetes Outcomes Program. Their work was informed by input from researchers, industry, and people with diabetes through Advisory Committees representing each stakeholder group. Stakeholder surveys were used to identify priority outcomes. The outcomes prioritized in the surveys were hypoglycemia, hyperglycemia, time in range, DKA, and PROs. To develop consensus on the definitions of these outcomes, the Steering Committee relied on published evidence, their clinical expertise, and feedback from the Advisory Committees. RESULTS The Steering Committee developed definitions for hypoglycemia, hyperglycemia, time in range, and DKA in type 1 diabetes. The definitions reflect their assessment of the outcome’s short- and long-term clinical impact on people with type 1 diabetes. Knowledge gaps to be addressed by future research were identified. The Steering Committee discussed PROs and concluded that further type 1 diabetes–specific development is needed. CONCLUSIONS The Steering Committee recommends use of the defined clinically meaningful outcomes beyond HbA1c in the research, development, and evaluation of type 1 diabetes therapies.
A systematic review and meta-analysis of randomized controlled trials to evaluate the risk of gastrointestinal and hepatic toxicities in patients with hormone receptor-positive HER2-negative metastatic breast cancer treated with CDK 4/6 inhibitors.
Authors: Myo Zaw, Kyaw Zin Thein, Aung Tun, Myat M. Han, Yu Yu Thar, Asha Nayak, Elizabeth Guevara
Journal: Journal of Clinical Oncology (2017)

209 Background: Hormonal therapies function through CDK4/CDK6/E2F axis which is essential in luminal estrogen receptor positive breast cancer. Reactivation of these CDK4 and CDK6 kinases has been implicated in endocrine resistance. Many CDK 4/6 inhibitors were employed in studies with noteworthy safety concerns. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the risk of gastrointestinal (GI) and hepatic toxicities. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through June 2017 were queried. RCTs that mention GI symptoms and elevation of liver enzymes as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio with 95% confidence interval (CI). Results: We included five RCTs with a total of 2671 patients treated with CDK 4/6 inhibitors. The study arm used palbociclib-letrozole, palbociclib-fulvestrant, ribociclib-letrozole and abemaciclib-fulvestrant while the control arm used placebo in combination with letrozole or fulvestrant. The relative risks (RR) of all-grade side effects were as follows: diarrhea, 1.72 (95% CI: 1.08 – 2.74, p = 0.02); stomatitis, 2.62 (95% CI: 1.43 – 4.79, p = 0.002); nausea, 1.59 (95% CI: 1.30–1.94; p &lt; 0.0001); vomiting, 1.65 (95% CI: 1.06–2.56; p = 0.02); elevated AST, 2.30 (95% CI: 1.34–3.93; p = 0.002); and elevated ALT, 2.78 (95% CI: 1.90–4.08; p &lt; 0.0001). The RR of high-grade side effects were as follows: diarrhea, 2.26 (95% CI: 0.39 – 13.09, p = 0.36); stomatitis, 2.14 (95% CI: 0.36 – 12.72, p = 0.40); nausea, 1.13 (95% CI: 0.28 –4.47; p = 0.86); vomiting, 0.79 (95% CI: 0.24 – 2.54; p = 0.69); elevated AST, 1.85 (95% CI: 0.74 – 4.64; p = 0.18); and elevated ALT, 4.33 (95% CI: 2.15 – 8.71; p &lt; 0.0001). Conclusions: The risk of developing any-grade diarrhea, stomatitis, nausea, vomiting and elevated AST and ALT, was high in CDK 4/6 inhibitors based regimen. Moreover, it increased the risk of high-grade elevated ALT.
t-Darpp Activates IGF-1R Signaling to Regulate Glucose Metabolism in Trastuzumab-Resistant Breast Cancer Cells
Authors: Gal Lenz, Angelica Hamilton, Shuhui Geng, Teresa Hong, Markus Kalkum, Jamil Momand, Susan E. Kane, Janice M. Huss
Journal: Clinical Cancer Research (2017)

Purpose: Increased glycolysis and glucose dependence is a hallmark of malignancy that enables tumors to maximize cell proliferation. In HER2+ cancers, an increase in glycolytic capacity is associated with trastuzumab resistance. IGF-1R activation and t-Darpp overexpression both confer trastuzumab resistance in breast cancer. We therefore investigated a role for IGF-1R and t-Darpp in regulating glycolytic capacity in HER2+ breast cancers.Experimental Design: We examined the relationship between t-Darpp and IGF-1R expression in breast tumors and their respective relationships with patient survival. To assess t-Darpp's metabolic effects, we used the Seahorse flux analyzer to measure glucose metabolism in trastuzumab-resistant SK-BR-3 cells (SK.HerR) that have high endogenous t-Darpp levels and SK.tDrp cells that stably overexpress exogenous t-Darpp. To investigate t-Darpp's mechanism of action, we evaluated t-Darpp:IGF-1R complexes by coimmunoprecipitation and proximity ligation assays. We used pathway-specific inhibitors to study the dependence of t-Darpp effects on IGF-1R signaling. We used siRNA knockdown to determine whether glucose reliance in SK.HerR cells was mediated by t-Darpp.Results: In breast tumors, PPP1R1B mRNA levels were inversely correlated with IGF-1R mRNA levels and directly associated with shorter overall survival. t-Darpp overexpression was sufficient to increase glucose metabolism in SK.tDrp cells and essential for the glycolytic phenotype of SK.HerR cells. Recombinant t-Darpp stimulated glucose uptake, glycolysis, and IGF-1R-Akt signaling in SK-BR-3 cells. Finally, t-Darpp stimulated IGF-1R heterodimerization with ErbB receptors and required IGF-1R signaling to confer its metabolic effects.Conclusions: t-Darpp activates IGF-1R signaling through heterodimerization with EGFR and HER2 to stimulate glycolysis and confer trastuzumab resistance. Clin Cancer Res; 24(5); 1216-26. ©2017 AACR.
Deprived, but not depraved: Prosocial behavior is an adaptive response to lower socioeconomic status
Authors: Angela R. Robinson, Paul K. Piff
Journal: Behavioral and Brain Sciences (2017)

Individuals of lower socioeconomic status (SES) display increased attentiveness to others and greater prosocial behavior compared to individuals of higher SES. We situate these effects within Pepper & Nettle's contextually appropriate response framework of SES. We argue that increased prosocial behavior is a contextually adaptive response for lower-SES individuals that serves to increase control over their more threatening social environments.
Irradiation Enhances Abscopal Anti-tumor Effects of Antigen-Specific Immunotherapy through Regulating Tumor Microenvironment
Authors: Ming-Cheng Chang, Yu-Li Chen, Han-Wei Lin, Ying-Cheng Chiang, Chi-Fang Chang, Shu-Feng Hsieh, Chi-An Chen, Wei-Zen Sun, Wen-Fang Cheng
Journal: Molecular Therapy (2017)

Ionizing radiation therapy is a well-established method of eradicating locally advanced tumors. Here, we examined whether local RT enhanced the potency of an antigen-specific DNA vaccine, and we investigated the possible underlying mechanism. Using the HPV16 E6/E7+ syngeneic TC-1 tumor, we evaluated the combination of CTGF/E7 vaccination with local irradiation with regard to synergistic antigen-specific immunity and anti-tumor effects. Tumor-bearing mice treated with local RT (6 Gy twice weekly) and CTGF/E7 DNA vaccination exhibited dramatically increased numbers of E7-specific CD8+ cytotoxic T cell precursors, higher titers of anti-E7 Abs, and significantly reduced tumor size. The combination of local RT and CTGF/E7 vaccination also elicited abscopal effects on non-irradiated local subcutaneous and distant pulmonary metastatic tumors. Local irradiation induced the expression of high-mobility group box 1 protein (HMGB-1) in apoptotic tumor cells and stimulated dendritic cell (DC) maturation, consequently inducing antigen-specific immune responses. Additionally, local irradiation eventually increased the effector-to-suppressor cell ratio in the tumor microenvironment. Overall, local irradiation enhanced the antigen-specific immunity and anti-tumor effects on local and distant metastatic tumors generated by an antigen-specific DNA vaccine. These findings suggest that the combination of irradiation with antigen-specific immunotherapy is a promising new clinical strategy for cancer therapy.
P2.07-030 Real Life Second-Line Nivolumab in Advanced Non-Small-Cell-Lung Cancer: A French Observational Multicenter Study of 259 Patients
Authors: M. Geier, R. Descourt, G. Quéré, R. Corre, G. Leveiller, R. Lamy, E. Goarant, J. Bizec, C. Bernier, F. Couturaud, G. Robinet
Journal: Journal of Thoracic Oncology (2017)
Response to: ‘Use of urate-lowering therapies is not associated with an increase in the risk of incident dementia in older adults’ by Lee and Song
Authors: Jasvinder A Singh, John Cleveland
Journal: Annals of the Rheumatic Diseases (2017)

We thank Lee and Song1 for their interest in our paper2 that found that compared with non-use, urate-lowering therapy (ULT) use was not associated with increased risk of dementia in adults aged 65 years or older.

We agree with Lee and Song that all observational studies have potential residual confounding related to study design, including our study and the observational studies they listed. Similar to our study, the two studies that Lee and Song have mentioned also did not adjust for serum urate3 4 putting them at the same risk for …
A Novel Anti-Lymphoma Immune Evasion Mediated By the Interaction Between PD-1 Enriched NK-Cells and CD163+PD-L1+PD-L2+ Tumor Associated Macrophages, That Is More Prominent in Hodgkin Lymphoma Than Diffuse Large B-Cell Lymphoma
Authors: Maher K Gandhi, David Arpon, Colm Keane, Erica Han, Josh Tobin, Robert Bird, Mark S Hertzberg, Marlene Self, Donna Cross, Annette Hernandez, Frank Vari
Journal: Blood (2016)
A Predictive Model for Response in Myelofibrosis Patients Treated with JAK2 Inhibitors: A Study from Three US Academic Centers and a Large Industry-Based Cohort
Authors: Kamal Menghrajani, Philip S. Boonstra, Cecelia Perkins, Krisstina L. Gowin, Ruben A. Mesa, Jason R. Gotlib, Moshe Talpaz
Journal: Blood (2016)