tbuckley/cabot-search huggingface dataset:
P161 The relation between the inflammatory status of human end stage oa synovium and levels of low density lipoprotein
Authors: N Kruisbergen, M van den Bosch, A Blom, P van Lent
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Student for a master or a PhD. <h3>Introduction</h3> High systemic levels of low density lipoprotein (LDL) is a shared metabolic risk factor for osteoarthritis (OA) and atherosclerosis, which may point to common biochemical pathways. One of the key events in atherosclerosis is formation and uptake of oxidized LDL (oxLDL) as a consequence of macrophage-mediated inflammation. In mice, high LDL levels enhanced synovial activation during development of collagenase-induced OA, and injection of oxidized LDL in naïve macrophage depleted joints led to infiltration of myeloid progenitor cells. However, a role for (ox)LDL in human OA has not yet been shown. <h3>Objectives</h3> In the present study, we investigated whether the inflammatory status of OA synovium is associated to systemic and local levels of (ox)LDL. <h3>Methods</h3> Blood was collected from patients planned to undergo total knee replacement and LDL serum levels were determined (n=16). After surgery, synovial explants from the same patients (2–8 per patient) were collected and incubated at 37 °C for 24 hours in presence of LDL (50 µg ApoB/mL), oxLDL (50 µg ApoB/mL) or control medium. Levels of IL-1β, TNF-α, IL-10 and MCP-1 secreted in the conditioned medium were measured using Luminex, and S100A8/A9 using ELISA. Immunohistochemical staining of ApoB was performed to assess presence and uptake of (ox)LDL in the synovium. Hematoxylin and eosin-stained sections were used to score cell infiltration and synovial hyperplasia. <h3>Results</h3> Around 50% of the patients in our cohort showed synovial activation exemplified by high secretion levels of IL-1β, TNF-α and IL-10. Cellular infiltration and synovial hyperplasia was observed in the majority of synovial tissue samples, their grades did however not correlate with cytokine secretion. Secretion levels of IL-1β positively correlated with serum levels of LDL and total cholesterol and did not correlate with BMI, suggesting a link that runs via systemic metabolic processes rather than increased weight-mediated joint loading. Staining of LDL associated protein ApoB in the synovia showed distinct speck-like staining within macrophages and endothelial cells especially, suggesting oxLDL accumulation in these cells. Unexpectedly, presence of high concentrations of LDL or oxLDL during incubation of synovial explants did not significantly affect secretion of IL-1β, TNF-α, IL-10 and MCP-1. <h3>Conclusions</h3> IL-1β secretion by end stage OA synovium is associated to systemic levels of LDL. Intervention with high concentrations of LDL or oxLDL for 24 hours after synovium extraction did however not alter cytokine secretion, suggesting that LDL and synovitis are linked through more long-term local interactions, or alternatively via systemic inflammatory factors. <h3>Disclosure of Interest</h3> None declared.
DNA damage responses in relation to late effects following radiotherapy for early breast cancer.
Authors: Melvin Chua
Journal: Journal of Clinical Oncology (2012)

10626 Background: In this study, we assessed if induction of apoptosis in G 0 blood lymphocytes following ex vivo irradiation correlated with clinical radiosensitivity and DNA double-strand (DSB) repair in breast radiotherapy (RT) patients. Using small molecule inhibitors, we examined the relationship between DSB repair and radiation-induced apoptosis. Methods: Breast cancer patients with minimal (controls) or marked late RT changes (cases) were selected. DSB were quantified by γH2AX/53BP1 immunostaining 0.5 and 24 h after exposure of lymphocytes to 0.5 and 4 Gy, respectively. Induction of apoptosis was assessed 48 h after 8 Gy using a fluorochrome inhibitor of caspases (FLICA) assay. Apoptotic cells were defined by small cell size and positive FLICA signal, measured using flow cytometry. Small molecule DNA-PK (Nu7441) and ATM (Ku55933) inhibitors were used at concentrations of 1 µM and 10 µM, respectively. Results: Despite similar foci induction at 0.5 h, residual foci levels 24 h after 4 Gy differed significantly between cases and controls (Foci per cell = 12.7 in cases, n = 8 vs 10.3 in controls, n = 8, p = 0.002). In contrast to residual foci levels, comparable levels of apoptosis were observed between cases and controls 48 h after 8 Gy. Mean proportion of apoptotic cells was 37.2% in cases and 34.7% in controls (p = 0.413). Residual foci levels were not correlated with levels of apoptosis in lymphocytes of the same patients (R = -0.059, p = 0.785). To determine if apoptosis is modulated by DSB repair, apoptosis measurements were repeated in lymphocytes treated with Nu7441 to inhibit non-homologous end-joining. We observed that Nu7441-treated cells had higher levels of residual foci and apoptosis compared to mock-treated cells, 48 h after 1 Gy. This effect was wholly dependent on an active ATM function as cells treated simultaneously with Nu7441 and Ku55933 had extremely low levels of apoptosis, comparable to levels observed in cells treated with Ku55933 alone. Conclusions: Higher levels of residual DSB observed among radiosensitive patients suggest a role for DSB repair in the pathogenesis of late radiation-induced effects. Induction of apoptosis appears to be dependent on DSB end-joining following exposure to ionising radiation.
The effect of BMI on systemic toxicity in AML patients receiving chemotherapy.
Authors: Manish J. Dave, Mansoor Burhani, Parameswaran Venugopal, Melissa L. Larson
Journal: Journal of Clinical Oncology (2013)

7108 Background: There are about 15,000 new cases of acute myeloid leukemia (AML) every year in the US, and about 9,000 will die annually from this disease. Because approximately 69.2% of adults in the US are overweight or obese, it is important to examine whether body mass index (BMI) can affect treatment outcomes. While there has been a study of survival based on BMI, there have been no studies to examine the effect of BMI on systemic toxicity with induction chemotherapy. Methods: 91 patients with AML were treated with a high-dose cytarabine and mitoxantrone regimen from 2008-2012. Prior to receiving induction chemotherapy, each patient’s BMI was recorded. All patients in this study were treated with doses based on actual weight. Two doses of cytarabine 3 gm/m 2 were given 12 hours apart followed by one dose of mitoxantrone 30 mg/m 2 on days 1 and 5. The lowest platelet and hemoglobin after each induction treatment was recorded, along with the number of red blood cell (RBC) and platelet transfusions. Systemic toxicity was further examined by presence of infection and/or bleeding. Results: The BMI groups are based on the World Health Organization classifications. Of the 91 AML patients in this study, 2 were underweight, 35 were normal weight, 29 were overweight, 16 were obese, and 9 were morbidly obese. The mean number of platelet transfusions for the underweight group was 8.5, 10.6 for normal weight, 13.8 for overweight, 12.1 for obese, and 5.0 for the morbidly obese group. The mean number of RBC transfusions for the underweight group was 6.0, 9.1 for normal weight, 11.2 for overweight, 9.1 for obese, and 9.2 for the morbidly obese group. The rates of infection by positive cultures were the following: 51% of normal, 58% of overweight, and 68% of obese patients. Rates of infection by imaging were 37% of normal, 31% of overweight, and 26% of morbidly obese patients. The percentage of patients bleeding after induction was 20% in the normal weight group, 31% for overweight, 12.5% of obese, and 33% of morbidly obese patients. Conclusions: The results of this study show that there is no difference in toxicity amongst the different BMI groups. The data demonstrates the importance of dosing chemotherapy on actual, rather than ideal, body weight.
Midlife Smaller and Larger Infarctions, White Matter Hyperintensities, and 20-Year Cognitive Decline
Authors: B. Gwen Windham, Michael E. Griswold, Steven R. Wilkening, Dan Su, Jonathan Tingle, Laura H. Coker, David Knopman, Rebecca F. Gottesman, Dean Shibata, Thomas H. Mosley
Journal: Annals of Internal Medicine (2019)

Background: Smaller (<3-mm) infarctions are associated with stroke and stroke mortality, but relationships with cognitive decline are unknown. Objective: To characterize the relationships of smaller, larger, and both smaller and larger infarctions in middle age with 20-year cognitive decline. Design: Longitudinal cohort study. Setting: Two ARIC (Atherosclerosis Risk in Communities) study sites with magnetic resonance imaging data (1993 to 1995) and up to 5 cognitive assessments over 20 years. Participants: Stroke-free participants aged 50 years or older. Measurements: Infarctions were categorized as none, smaller only, larger only (3 to 20 mm), or both smaller and larger. Global cognitive Z scores were derived from 3 cognitive tests administered up to 5 times. Mixed-effects models estimated adjusted associations between infarctions and cognitive decline. Results are the average difference in standardized cognitive decline associated with infarctions versus no infarctions. Results: Among 1884 participants (mean age, 62 years; 60% women; 50% black), 1611 (86%) had no infarctions, 50 (3%) had smaller infarctions only, 185 (10%) had larger infarctions only, and 35 (2%) had both. Participants with both smaller and larger infarctions had steeper cognitive decline by more than half an SD (difference, −0.57 SD [95% CI, −0.89 to −0.26 SD]) compared with those who had no infarctions. Amounts of cognitive decline associated with only smaller infarctions and only larger infarctions were similar and were not statistically different from that associated with no infarctions. Limitation: Few participants had only smaller infarctions or both smaller and larger infarctions, and the data lacked counts of smaller infarctions and volumes of white matter hyperintensities. Conclusion: The substantial cognitive decline from middle age associated with having both smaller and larger infarctions, but not larger infarctions alone, suggests that the combination of smaller and larger infarctions may escalate risk for cognitive decline later in life in stroke-free persons. Primary Funding Source: National Institutes of Health.
Defining Barriers and Facilitators to Advancement for Women in Academic Surgery
Authors: Julie A. Thompson-Burdine, Dana A. Telem, Jennifer F. Waljee, Erika A. Newman, Dawn M. Coleman, Hadley I. Stoll, Gurjit Sandhu
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Sex equity is elusive in academic surgery departments across the United States. Persistent inequities remain a considerable problem and inhibit professional advancement for female surgeons. Identifying the factors that promulgate sex discrepancies may provide a framework for institutional growth and personal progress for women. <h3>Objective</h3> To identify barriers and facilitators to success at the individual and organizational level to develop evidence-based interventions designed to close the sex gap in surgery. <h3>Design, Setting, and Participants</h3> This qualitative study included 26 female participants who were current and former surgical faculty employed by Michigan Medicine, the health system of the University of Michigan, between 2000 and 2017. Semistructured personal interviews were conducted from June 28 to September 29, 2017, via telephone. Each interview lasted 45 minutes to 1 hour. Interviews were recorded and then transcribed for analysis. <h3>Main Outcomes and Measures</h3> The interview included 7 questions referring to the surgeon's experience with the Michigan Medicine Department of Surgery and 7 questions referring to nonspecific areas of interest. <h3>Results</h3> The 26 participants in this study ranged in age from 32 to 64 years, with faculty experience ranging from 3 to 22 years. Thematic analysis was used to locate, analyze, and report patterns within the data related to barriers and facilitators for women in academic medicine. Three major themes were identified by researchers. Participants reported that (1) organizational culture and institutional policies affect opportunities for advancement; (2) relational interactions with leadership, mentors, colleagues, and staff affect promotion and attrition; and (3) individual characteristics mediate the perception of professional and personal success. <h3>Conclusions and Relevance</h3> In this qualitative study of 26 female academic surgeons, a complex matrix of organizational and individual factors were found to contribute to sex inequities in academic surgery. This research may provide insight into the sex biases that inhibit advancement, may inform strategies that facilitate progress, and may inspire interventions that could help eliminate institutional and individual barriers to the academic success of women.
A prospective evaluation of quality of life (QOL) in a phase II trial of pemetrexed (P) plus carboplatin (Cb) ± enzastaurin (E) versus docetaxel (D) plus Cb as first-line treatment of patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: R. N. Raju, M. Socinski, T. Stinchcombe, L. S. Couch, D. M. Kocs, R. Jotte, Y. Wang, J. Bromund, M. Marciniak, C. Obasaju
Journal: Journal of Clinical Oncology (2009)

e19050 Background: E is a selective, oral serine/threonine kinase inhibitor. PCb has shown promising clinical activity in two phase 2 trials of advanced NSCLC. This open-label, three-arm trial was designed to assess PCb ± E versus a control arm of DCb. QOL may be an important consideration with the introduction of targeted agents such as E that have a different toxicity profile than traditional chemotherapeutic agents. Methods: Pts with Stage IIIB (with pleural effusion) or IV NSCLC, ECOG PS of 0 or 1, and no prior systemic therapy were enrolled. Pts were equally randomized to one of three arms: (A) P 500 mg/m 2 and Cb AUC 6 every 3 wks X 6 cycles with E given orally as a loading dose of 1200 mg or 1125 mg followed by 500 mg daily until disease progression; (B) The same regimen of PCb without E; or (C) D 75 mg/m 2 and Cb AUC 6 every 3 wks X 6 cycles. Pts receiving P were also administered folic acid, vitamin B12 and steroid prophylaxis. Pts on D also received steroid prophylaxis. The Functional Assessment of Cancer Therapy-Lung (FACT-L) Questionnaire and FACT-Taxane toxicity subscale were used to evaluate QOL at baseline and every 3 weeks up to 18 weeks during treatment. A best overall response of improved or worsened was defined as an increase or decrease from baseline to last patient visit of ≥ 0.5 standard deviations of baseline scores. Results: The intent-to-treat population of this study consisted of 218 randomized pts (PCE: 72, PC: 74, DC: 72). Baseline and ≥ 1 post-baseline score was obtained from 54 pts receiving PCE (75%), 62 pts receiving PC (84%), and 54 pts receiving DC (75%). QOL data are summarized in the table below. Conclusions: Across treatment groups, differences in mean scores were not statistically significant. In addition, differences in classification of improved, stable, or worsened were not statistically significant across treatment groups. [Table: see text] [Table: see text]
Palliative chemotherapy in head and neck cancers: A tertiary care center experience with weekly paclitaxel and cetuximab.
Authors: Kumar Prabhash, Vanita Noronha, Amit Joshi, Vijay Patil, S Juvekar, Vamshi Muddu
Journal: Journal of Clinical Oncology (2012)

e16028 Background: The concept of combination of paclitaxel and cetuximab is an intersesting prospect as both these agents have single agent acitivity, minimal toxicity and hold a biological rationale for combination. The aim of our study was to see the safety,efficacy and feasibility of administration of this combination in a outpatient setting. Methods: This was a retrospective analysis of the prospectively collected data, of patients offered weekly paclitaxel and cetuximab from May 2010-May 2011. The standard schedule of cetuximab along with 80 mg/m 2 of weekly paclitaxel was administered till either disease progression or withdrawl of patient's consent. The toxicity profile was noted in accordance with CTCAE version 4.02 and response in accordance with RECIST criteria. SPSS version 16 has been utilized for analysis. Descriptive statistics are been presented and analyis of estimation of overall and progression free survival has been done with Kaplan-Meier survival method. Results: 42 patients with a median age of 52 years (35-81 years) were included. The KPS score was 60 in 1 (2.4%),70 in 11 (26.2%) and 80 in 30 patients(71.4%). Nearly half of our patients 22 (52.4%) had a primary in oral cavity. Except 3 (7.1%) patients rest all had received some form of previous treatment. The median event free period(EFP) from previous first line treatment was 231 days, it was below 180 days in 38.5% of patients. Best response observed was CR in 1 patient (2.4%), PR in 11 (26.2%), SD in 17 (40.5%) and PD in 13 (30.9%). Grade 3-4 skin changes were seen in 3 patients, grade 3-4 neuropathy was seen in 3 patients and there were no episodes of grade 3-4 gastrointestinal or haematological toxicity. The overall estimated median PFS and OS were 128 and 256 days. The median estimated PFS for patients with EFP less than 6 months versus more than 6 months was 115 and 165 days respectively (p = 0.132). Conclusions: The combination of paclitaxel and cetuximab was found to be safe, feasible and appears to be clinically beneficial.
A Neural Circuit Arbitrates between Persistence and Withdrawal in Hungry Drosophila
Authors: Sercan Sayin, Jean-Francois De Backer, K.P. Siju, Marina E. Wosniack, Laurence P. Lewis, Lisa-Marie Frisch, Benedikt Gansen, Philipp Schlegel, Amelia Edmondson-Stait, Nadiya Sharifi, Corey B. Fisher, Steven A. Calle-Schuler, J. Scott Lauritzen, Davi D. Bock, Marta Costa, Gregory S.X.E. Jefferis, Julijana Gjorgjieva, Ilona C. Grunwald Kadow
Journal: Neuron (2019)

In pursuit of food, hungry animals mobilize significant energy resources and overcome exhaustion and fear. How need and motivation control the decision to continue or change behavior is not understood. Using a single fly treadmill, we show that hungry flies persistently track a food odor and increase their effort over repeated trials in the absence of reward suggesting that need dominates negative experience. We further show that odor tracking is regulated by two mushroom body output neurons (MBONs) connecting the MB to the lateral horn. These MBONs, together with dopaminergic neurons and Dop1R2 signaling, control behavioral persistence. Conversely, an octopaminergic neuron, VPM4, which directly innervates one of the MBONs, acts as a brake on odor tracking by connecting feeding and olfaction. Together, our data suggest a function for the MB in internal state-dependent expression of behavior that can be suppressed by external inputs conveying a competing behavioral drive.
Elevated Fatty Liver Index as a Risk Factor for All‐Cause Mortality in Human Immunodeficiency Virus–Hepatitis C Virus–Coinfected Patients (ANRS CO13 HEPAVIH Cohort Study)
Authors: Tangui Barré, Camelia Protopopescu, Firouzé Bani‐Sadr, Lionel Piroth, Teresa Rojas Rojas, Dominique Salmon‐Ceron, Linda Wittkop, Laure Esterle, Philippe Sogni, Karine Lacombe, Julie Chas, Olivia Zaegel, Marie‐Laure Chaix, Patrick Miailhes, Lawrence Serfaty, Fabienne Marcellin, Maria Patrizia Carrieri
Journal: Hepatology (2019)

Background and Aims Human immunodeficiency virus (HIV)–hepatitis C virus (HCV)–coinfected patients are at high risk of metabolic complications and liver‐related events, which are both associated with hepatic steatosis and its progressive form, nonalcoholic steatohepatitis, a known risk factor for mortality. The fatty liver index (FLI), a noninvasive steatosis biomarker, has recently drawn attention for its clinical prognostic value, although its capacity to predict mortality risk in HIV–HCV‐coinfected patients has never been investigated. Using a Cox proportional hazards model for mortality from all causes, with data from the French National Agency for Research on Aids and Viral Hepatitis CO13 HEPAVIH cohort (983 patients, 4,432 visits), we tested whether elevated FLI (≥60) was associated with all‐cause mortality. Approach and Results After multiple adjustment, individuals with FLI ≥ 60 had almost double the risk of all‐cause mortality (adjusted hazard ratio [95% confidence interval], 1.91 [1.17‐3.12], P = 0.009), independently of the following factors: HCV cure (0.21 [0.07‐0.61], P = 0.004), advanced fibrosis (1.77 [1.00‐3.14], P = 0.05), history of hepatocellular carcinoma and/or liver transplantation (7.74 [3.82‐15.69], P &lt; 10 −3 ), history of indirect clinical signs of cirrhosis (2.80 [1.22‐6.41], P = 0.015), and HIV Centers for Disease Control and Prevention clinical stage C (2.88 [1.74‐4.79], P &lt; 10 −3 ). Conclusions An elevated FLI (≥60) is a risk factor for all‐cause mortality in HIV–HCV‐coinfected patients independently of liver fibrosis and HCV cure. In the present era of nearly 100% HCV cure rates thanks to direct‐acting antivirals, these findings encourage the more systematic use of noninvasive steatosis biomarkers to help identify coinfected patients with higher mortality risk.
Richard John Alexander Kell
Authors: Annette Abbott
Journal: BMJ (2019)

Richard John Alexander Kell was born into a farming family near Wisbech. He attended Framlingham College, then trained in medicine at the London Hospital. After qualifying in 1979, he worked in London, Manchester, and Dubai before settling in Halesworth, Suffolk, as a GP, where he was a partner and trainer for 29 years. He also worked as a police …
Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities
Authors: Chen Lu, Dawei Rong, Betty Zhang, Wubin Zheng, Xuehao Wang, Ziyi Chen, Weiwei Tang
Journal: Molecular Cancer (2019)

Incidence of hepatocellular carcinoma (HCC) is on the rise due to the prevalence of chronic hepatitis and cirrhosis. Although there are surgical and chemotherapy treatment avenues the mortality rate of HCC remains high. Immunotherapy is currently the new frontier of cancer treatment and the immunobiology of HCC is emerging as an area for further exploration. The tumor microenvironment coexists and interacts with various immune cells to sustain the growth of HCC. Thus, immunosuppressive cells play an important role in the anti-tumor immune response. This review will discuss the current concepts of immunosuppressive cells, including tumor-associated macrophages, marrow-derived suppressor cells, tumor-associated neutrophils, cancer-associated fibroblasts, and regulatory T cell interactions to actively promote tumorigenesis. It further elaborates on current treatment modalities and future areas of exploration.