tbuckley/cabot-search huggingface dataset:
An activated aryl hydrocarbon receptor causes DNA damage and stress response in mouse liver
Authors: Stefanie Knerr, Saskia Both, Angela Mally, Wolfgang Dekant, Dieter Schrenk
Journal: Cancer Research (2006)

1065   2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), was classified as a group I carcinogen by the International Agency for Research on Cancer (IARC). It acts through an aryl hydrocarbon receptor (AhR) mediated mechanism, active in humans and exprimental animals. The activated AhR, a nuclear transcription factor, forms in the presence of TCDD an heterodimer with the aromatic hydrocarbon nuclear translocator (ARNT) protein and induces or suppresses the transcription of numerous genes, including cytochrome P450 1A1 (CYP1A1). It has been hypothesised that TCDD may be indirectly genotoxic via generation of reactive oxygen species (ROS). This may lead to DNA damage via direct interaction or via generation of reactive metabolites from endogenous compounds. We determined the amount of the oxidative damage marker 8-oxo-2′-deoxyguanosine (8-oxo-dG) using HPLC-MS/MS in mouse liver after treatment of the animals with TCDD. We also measured 8-oxo-dG in livers of a transgenic mouse model, which expresses a constitutively active AhR (CA-AhR). Transcription of the AhR gene battery in this mouse model is stimulated in the absence of any ligand. Microarrays, representing genes involved in stress and toxicity, were performed with hepatic RNA isolated from TCDD-treated, and from transgenic mice and compared to wild type and vehicle controls, respectively. 96 h after treatment of wild type mice with 1 μg/kg TCDD increased levels of 8-oxo-dG were observed in hepatic DNA. In the livers of CA-AhR mice basal 8-oxo-dG levels were even higher than in TCDD-treated wild type mice. Interestingly, the effect seems to be higher in male than in female mice. In contrast, the catalytic activity of hepatic CYP1A enzymes, measured as 7-ethoxyresorufin-O-deethylase (EROD), was much lower in CA-AhR than in TCDD-treated wild type mice. Apart from an explicit induction of CYP1A1, microarray data indicate, among others, differential expression of hepatic genes involved in apoptotic processes, e.g. Bcl-2 or Bax for both the TCDD-treated and the transgenic mice. In conclusion, a (permanent) activation of the AhR leads on the one hand to increased oxidative hepatic DNA damage. On the other hand apoptotic pathways seem to be modified, possibly in response to oxidative stress.
Wide Variation in Use and Interpretation of Gene Mutation Profiling Panels Among Health Care Providers of Patients with Myelodysplastic Syndromes (MDS): Results of a Large Web-Based Survey
Authors: Alexander B Pine, Nora B Chokr, Maximilian Stahl, David P. Steensma, Mikkael A. Sekeres, Mark R. Litzow, Selina Luger, Richard M. Stone, Peter L Greenberg, Rafael Bejar, Steven D. Gore, Amer M. Zeidan
Journal: Blood (2018)
Abstract P076: Regression of Prediabetes and Diabetes is Associated with Mild Weight and Waist Loss - ELSA-Brasil
Authors: Scheine Canhada, Bruce B Duncan, Vivian C Luft, Isabela M Bensenor, Sandhi M Barreto, Maria I Schmidt
Journal: Circulation (2019)

Introduction: The prevalence of diabetes has risen dramatically in the last decades. Prediabetes, or intermediate hyperglycemia, represents an early stage of diabetes development. Structured diabetes prevention programs can lead to regression of prediabetes, but observational studies may reflect better a real-world scenario for public health planning. Hypothesis: We assessed the hypothesis that regression of prediabetes to normoglycemia (and from newly diagnosed diabetes to prediabetes) is associated with weight loss and with decrease in waist circumference in a well-characterized, nonintervention contemporary cohort, ELSA-Brasil. Methods: We enrolled 15105 civil servants (34-75 years) in 6 capital cities in Brazil from 2008-10 and followed those without previously known diabetes for an average of 3.7 years. We performed a standardized oral glucose tolerance test and measured fasting and 2h plasma glucose as well as HbA1c in a central laboratory. Diabetes and prediabetes were defined using American Diabetes Association criteria at each visit. We measured weight and waist circumference with standardized protocols and obtained sample characteristics by questionnaire. Those with abnormal glycemia were instructed to seek medical attention. Results: Of the 6301 participants with prediabetes at baseline not receiving anti-diabetic medication at either visit, 1671 (27%) had regressed to normal values at follow-up. In Poisson regression analyses adjusting for age, sex, race, family history of diabetes and baseline BMI, glycemia and physical activity, in comparison with those with no change or weight gain, those with weight loss ≤2.05kg had a 30% greater probability of returning to normoglycemia (RR=1.30; 95%CI 1.17-1.43) and those with greater weight loss had a 59% greater probability (RR=1.59; 1.44-1.75). Findings were similar for a decreased waist circumference in comparison to no change or a gain (≤2.6cm loss: RR=1.18; 1.05-1.31; &gt;2.6cm loss: RR=1.52; 1.37-1.68). Of the 661 participants newly ascertained with diabetes at baseline and not receiving medication at either visit, 375 (57%) had non-diabetic values at follow-up. Regression among these newly ascertained cases was also greater among those with decreased weight or waist circumference, though only statistically significant for those with a greater decrease in weight (&gt;2.7kg loss: RR=1.39; 1.19-1.62) or waist circumference (&gt;2.6cm loss: RR=1.35; 1.14-1.61) Conclusion: Small decreases in weight or waist circumference in a free-living population not receiving structured interventions to prevent diabetes can lead to important improvement in glycemia, with impact on the prevalence of prediabetes and newly ascertained diabetes.
Significance of tertiary pattern 5 in patients with gleason score 7 after radical prostatectomy.
Authors: Jiakun Li, Yaochuan Guo, Shi Qiu, Mingjing He, Kun Jin, Xinyang Liao, Xiaonan Zheng, Xiang Tu, Lu Yang, Qiang Wei
Journal: Journal of Clinical Oncology (2019)

117 Background: To evaluate the association between tertiary Gleason pattern (TGP) 5 and the biochemical recurrence (BCR) in patients with prostate cancer (PCa) of Gleason score (GS) 7 after radical prostatectomy(RP). Methods: This retrospective study collected 387 patients received RP and diagnosed GS 7 (3+4 or 4+3) in the West China Hospital from January 2009 to December 2017.Regardlessly the first Gleason pattern, patients were divide into 2 groups: TGP5 absence and TGP5 presence. Furthermore, we added the primary Gleason pattern to divided patients into 4 groups: GS 3+4, GS 3+4/TGP 5, Gleason 4+3, Gleason 4+3/TGP 5. Cox proportional-hazards models was used to evaluate the association between the status of TGP5 and BCR after adjusting the confounding factors with follow-up time as the underlying time scale. All the analyses were conducted with the use of statistical software packages Rnand EmpowerStats and conducted as two sides and P values less than 0.05 were considered statistical significance. Results: In the results by using Cox proportional-hazards model, regardless the primary Gleason pattern, comparing TGP5 absence (89.7%) and presence (10.3%), the risk of BCR for patients with tertiary Gleason pattern 5 presence was statistically significantly higher than absence (P = 0.02, HR = 2.24, 95%Cl: 1.12-4.49). In terms of the patients with primary Gleason pattern 4, the risk of BCR for patients with Gleason 4+3/TGP5 was statistically significantly higher than Gleason 4+3.(P = 0.02, HR = 2.56, 95%Cl: 1.16-5.67). There was a marked trend that patients with Gleason 3+4/TGP 5 has a higher risk of BCR compared with patients with Gleason 3+4, although there was no statistical difference (P = 0.58, HR = 1.82, 95%Cl: 0.22-14.96). Conclusions: The TGP5 in patients with GS 7 had strong association with the risk of BCR and it was an independent predictor for BCR. This result was more obvious in patients with GS 7 (4+3) in our study. Further researches with larger data size were needed to confirm these funding.
Assessment of Machine Learning vs Standard Prediction Rules for Predicting Hospital Readmissions
Authors: Daniel J. Morgan, Bill Bame, Paul Zimand, Patrick Dooley, Kerri A. Thom, Anthony D. Harris, Soren Bentzen, Walt Ettinger, Stacy D. Garrett-Ray, J. Kathleen Tracy, Yuanyuan Liang
Journal: JAMA Network Open (2019)

Hospital readmissions are associated with patient harm and expense. Ways to prevent hospital readmissions have focused on identifying patients at greatest risk using prediction scores.To identify the type of score that best predicts hospital readmissions.This prognostic study included 14 062 consecutive adult hospital patients with 16 649 discharges from a tertiary care center, suburban community hospital, and urban critical access hospital in Maryland from September 1, 2016, through December 31, 2016. Patients not included as eligible discharges by the Centers for Medicare & Medicaid Services or the Chesapeake Regional Information System for Our Patients were excluded. A machine learning rank score, the Baltimore score (B score) developed using a machine learning technique, for each individual hospital using data from the 2 years before September 1, 2016, was compared with standard readmission risk assessment scores to predict 30-day unplanned readmissions.The 30-day readmission rate evaluated using various readmission scores: B score, HOSPITAL score, modified LACE score, and Maxim/RightCare score.Of the 10 732 patients (5605 [52.2%] male; mean [SD] age, 54.56 [22.42] years) deemed to be eligible for the study, 1422 were readmitted. The area under the receiver operating characteristic curve (AUROC) for individual rules was 0.63 (95% CI, 0.61-0.65) for the HOSPITAL score, which was significantly lower than the 0.66 for modified LACE score (95% CI, 0.64-0.68; P < .001). The B score machine learning score was significantly better than all other scores; 48 hours after admission, the AUROC of the B score was 0.72 (95% CI, 0.70-0.73), which increased to 0.78 (95% CI, 0.77-0.79) at discharge (all P < .001). At the hospital using Maxim/RightCare score, the AUROC was 0.63 (95% CI, 0.59-0.69) for HOSPITAL, 0.64 (95% CI, 0.61-0.68) for Maxim/RightCare, and 0.66 (95% CI, 0.62-0.69) for modified LACE score. The B score was 0.72 (95% CI, 0.69-0.75) 48 hours after admission and 0.81 (95% CI, 0.79-0.84) at discharge. In directly comparing the B score with the sensitivity at cutoff values for modified LACE, HOSPITAL, and Maxim/RightCare scores, the B score was able to identify the same number of readmitted patients while flagging 25.5% to 54.9% fewer patients.Among 3 hospitals in different settings, an automated machine learning score better predicted readmissions than commonly used readmission scores. More efficiently targeting patients at higher risk of readmission may be the first step toward potentially preventing readmissions.
Prostate cancer-derived anti-GRP78 autoantibodies compromise the blood-brain barrier and accelerate atherosclerosis progression <i>in vivo</i>.
Authors: Ali Al-Hashimi, Bobby Shayegan, Richard Austin, Kevin Doyoon Won
Journal: Journal of Clinical Oncology (2019)

205 Background: Pathological conditions of prostate cancer (PCa) drive the translocation of the endoplasmic reticulum-resident chaperone, GRP78, to the cell surface (cs) where it acts as an antigenic protein with signaling properties. In PCa, csGRP78 drives the production of anti-GRP78 autoantibodies (AutoAbs) that engage csGRP78 and promote PCa survival/progression. New studies now demonstrate csGRP78 expression on endothelial cells (EC) that line the arterial vasculature and the blood-brain barrier (BBB) suggesting that these AutoAbs can affect other systems in the body. Based on this, we investigated how the engagement of anti-GRP78 AutoAbs to csGRP78 on EC can contribute to EC-dysfunction that can promote atherosclerosis and compromise the integrity of the BBB. Methods: Anti-GRP78 AutoAbs were purified from PCa patients (St. Joseph’s Healthcare Hamilton); human aortic EC and the ApoE -/- mouse model were used for in vitro and in vivo investigations, respectively. EC or mice were treated with anti-GRP78 AutoAbs or IgG control (60µg/mL); EC-dysfunction was investigated by measuring attachment protein expression, in vitro. In vivo evaluation was carried out by studying atherosclerotic plaque progression (immunohistochemistry; aorta); the BBB integrity was examined using the Evans Blue dye. Results: Mice injected with anti-GRP78 AutoAbs, and not human IgG, demonstrated larger atherosclerotic plaque volume and hallmarks of a leaky BBB. In terms of a mechanism, in vitro studies demonstrated that treating EC with anti-GRP78 AutoAbs resulted in activation of the NFκB pathway that led to increased expression of attachment proteins. All these effects were reversed by using a recombinant molecule that interfere with the binding of the AutoAb to csGRP78. Conclusions: We have identified anti-GRP78 AutoAb as a driver of EC-dysfunction that promote atherosclerotic plaque progression and damage to the BBB. Our results indicate that interfering with anti-GRP78 AutoAb:csGRP78 complex can reverse the pathological effects of the AutoAbs. This novel data suggests that patient-derived anti-GRP78 autoantibodies systemically drive pathologies, other than cancer, in vivo.
Abstract P290: Dietary and Serum Omega-6 and Omega-3 Fatty Acids Are Associated With Physical and Metabolic Dysfunction in Chronic Stroke Survivors
Authors: Monica Serra, Charlene Hafer-Macko, Alice Ryan
Journal: Circulation (2019)

Background: Higher dietary intake of omega-6/omega-3 ratios is associated with reduced physical functioning in older adults, but is not well documented in chronic stroke survivors. Purpose: The purpose of this study was to quantify dietary intake of omega-6 and omega-3 fatty acids, their habitual dietary intake ratios and systemic omega-6/omega-3 profiles and to determine their relationship with physical and metabolic function in a cohort of chronic adult stroke survivors. Methods: Twenty-five older chronic stroke survivors (age: 63±8 yrs; BMI: 31±7 kg/m 2 ; mean±SD) were assessed for fitness (VO 2 peak) and six-minute walk distance (6MWD). Plasma lipid and glucose profiles were measured and HOMA-IR calculated. Dietary (5-day food records) and serum (mass spectrometry) omega-6/omega-3 profiles were assessed. Results: Participants were severely deconditioned (VO 2 peak: 19±4 ml/kg/min; 6MWD: 295±121 m) and at elevated metabolic risk (HOMA-IR: 6.3±4.5). The dietary intake ratio of omega-6/omega-3 fatty acids averaged 12.6±7.1 and the serum concentration ratio was 1.21±0.37, which were positively correlated (r=0.88, P&lt;0.01). Higher dietary intake and serum concentrations of omega-6/omega-3 fatty acids were associated with lower 6MWD (diet: r=-0.49; serum: r=-0.43) and higher HOMA-IR (diet: r=0.39; serum: r=0.34, while a higher serum omega-6/omega-3 concentration index was associated with lower VO 2 peak (r=-0.38) (all P&lt;0.05). Conclusion: These preliminary data suggest that both dietary omega 6 and omega 3 fatty acids (quantitated as their intake ratio) and the serum concentration ratio of omega-6/omega-3 may be important indices of physical dysfunction and insulin resistance in chronic stroke survivors.
Molecular events regulating clear cell renal cell cancer resistance to tyrosine kinase inhibitors.
Authors: Anna Malgorzata Czarnecka, Zofia F Bielecka, Katarzyna Kaminska, Damian Matak, Lukasz Szymanski, Mohammed Imran Khan, Wojciech Solarek, Anna Kornakiewicz, Kamila Maliszewska-Olejniczak, Cezary Szczylik
Journal: Journal of Clinical Oncology (2015)

e15600 Background: Cancer cell drug resistance is regulated by arising molecular and biochemical abnormalities in cancer cell on one hand and by tumor micro-environmental factors on the other. A complex network of different cell-cell and cell-matrix interactions and auto-, para- and endocrine signals influence ccRCC cells proliferation. These molecular factors are also responsible for tyrosine kinase inhibitors resistance and RCC disease progression. Aims of this study included analysis of hypoxia, IL-6, triiodothyronine, insulin and insulin-like growth factors impact on the proliferation and metastatic potential of ccRCC cells under TKI treatment. The second aim was to measure the effect of niche factors including 3D interactions on TKI activity on ccRCC cells including cancer stem cells. The goal of this research was to enable understanding of cellular events responsible for clinically relevant TKI resistance. Methods: ccRCC cells from primary and metastatic tumors (ATCC, MSKCC collection) along with ccRCC cancer progenitor cells (CD133+) were cultured in normoxic or hypoxic conditions; cells were cultured in defined media and induced by T3, IN or IGF; and/or inhibited by IL-6, TRβ antagonist, sunitinib, sorafenib and axitinib in 2D and 3D conditions. Cell proliferation and TKI toxicity were evaluated (Alamar Blue/MTT). FACS and ICC analysis was undertaken to verify mesenchymal stem cell markers expression. Colony formation potential was evaluated and TRβ/IL-6R/STAT3 gene expression was evaluated with RealTime-RT PCR , WB. Normal kidney proximal tube cells were used as negative control. Results: ccRCC cells including cancer stem cells proliferation may be promoted by hypoxia T3, IN, IL-6sR and IGF in primary tumor and metastatic sites. Conclusions: Multiple micro-environmental factors modify the ccRCC cells resistance to TKI. Understanding of the complex interactions between cancer cells and the 3D microenvironment may enable the identification of novel treatment targets. (Sponsored by: UMO-2012/05/D/NZ5/01844, 2011/01/B/NZ4/01602, Lider/031/625/L-4/NCBR/2013 and CRU/WIM/275/2012)
Cumulative Incidence of Blood Stream Infections during Acute Myeloid Leukemia Treatment in the Netherlands: A 15-Year Overview
Authors: Emily Risa Schwartz, Kim Klein, Valerie de Haas, Birgit Lissenberg-Witte, Lynn Ball, Natasja Dors, Marry M Van den Heuvel-Eibrink, Rutger Knops, Wim Tissing, Birgitta A. Versluys, Christian M. Zwaan, Raphaele R.L. van Litsenburg, Gertjan J.L. Kaspers
Journal: Blood (2018)
Utilization of capecitabine-oxaliplatin (CAPOX) versus infusional 5-fluorouracil and oxaliplatin (FFOX) in the adjuvant treatment (AT) of resected high-risk colon cancer.
Authors: Aaron Sha, Shirin Abadi, Sharlene Gill
Journal: Journal of Clinical Oncology (2015)

e14696 Background: Patients with high-risk Stage II or Stage III colon cancer are candidates for adjuvant chemotherapy with CAPOX or mFOLFOX6. Our primary outcome was to identify the utilization rates and review the patient characteristics, dose-delivery and toxicities associated with both protocols. Methods: All patients receiving adjuvant CAPOX or FFOX (given as mFOLFOX6) for Stage II or Stage III colon cancer from October 1st, 2011 to January 1st, 2014 were identified using the provincial pharmacy database of the BC Cancer Agency. Data was collected from electronic patient health records and pharmacy database. Patient demographics, treatment site, co-morbidities, stage, treatment, dose-limiting toxicities (DLTs) and the total number of completed cycles were collected. Results: 315 patients were eligible for inclusion, 87% with stage III disease. 218 patients (69%) received FFOX, while 97 patients (31%) received CAPOX. Patients assigned to CAPOX were significantly younger (age < = 50y: 29% vs 11%; p = 0.022), were more frequently working (48% vs 38%, p = 0.19), and were less likely to require a central line (10% vs 100%). More patients on CAPOX experienced DLTs (95% vs 81%, p = 0.004). The most common DLTs included peripheral neuropathy (38% CAPOX vs 42% FFOX, p = 0.66), diarrhea (32% CAPOX vs 11% FFOX, p = 0.0004), neutropenia (7% CAPOX vs 28% FFOX, p < 0.0001), fatigue (16% CAPOX vs 11% FFOX, p = 0.41), hand-foot syndrome (16% CAPOX vs 3% FFOX, p = 0.003), nausea/emesis (10% CAPOX vs 5% FFOX, p = 0.28), and mucositis (1% CAPOX vs 11% FFOX, p = 0.004). 77% of patients on FFOX completed the planned number of cycles versus 64% on CAPOX (p = 0.045). Conclusions: In this contemporary, population-based cohort of patients with resected colon cancer, CAPOX was less commonly prescribed, with only 31% of patients receiving CAPOX. Overall, DLTs were more common with CAPOX with significantly more diarrhea and hand-foot syndrome, but less neutropenia and mucositis. Despite the perceived convenience of CAPOX, FFOX is the preferred AT regimen in practice, and is associated with significantly higher rates of treatment completion.
PD-1 Blockade Following Isolated Limb Perfusion with Vaccinia Virus Prevents Local and Distant Relapse of Soft-tissue Sarcoma
Authors: Henry G. Smith, David Mansfield, Victoria Roulstone, Joan N. Kyula-Currie, Martin McLaughlin, Radhika R. Patel, Katharina F. Bergerhoff, James T. Paget, Magnus T. Dillon, Aadil Khan, Alan Melcher, Khin Thway, Kevin J. Harrington, Andrew J. Hayes
Journal: Clinical Cancer Research (2019)

Abstract Purpose: The prevention and treatment of metastatic sarcoma are areas of significant unmet need. Immune checkpoint inhibitor monotherapy has shown little activity in sarcoma and there is great interest in identifying novel treatment combinations that may augment responses. In vitro and in vivo, we investigated the potential for an oncolytic vaccinia virus (GLV-1h68) delivered using isolated limb perfusion (ILP) to promote antitumor immune responses and augment response to PD-1 blockade in sarcoma. Experimental Design: In an established animal model of extremity sarcoma, we evaluated the potential of locoregional delivery of a vaccinia virus (GLV-1h68) alongside biochemotherapy (melphalan/TNFα) in ILP. Complementary in vitro assays for markers of immunogenic cell death were performed in sarcoma cell lines. Results: PD-1 monotherapy had minimal efficacy in vivo, mimicking the clinical scenario. Pretreatment with GLV-1h68 delivered by ILP (viral ILP) significantly improved responses. Furthermore, when performed prior to surgery and radiotherapy, viral ILP and PD-1 blockade prevented both local and distant relapse, curing a previously treatment-refractory model. Enhanced therapy was associated with marked modulation of the tumor microenvironment, with an increase in the number and penetrance of intratumoral CD8+ T cells and expansion and activation of dendritic cells. GLV-1h68 was capable of inducing markers of immunogenic cell death in human sarcoma cell lines. Conclusions: Viral ILP augments the response to PD-1 blockade, transforming this locoregional therapy into a potentially effective systemic treatment for sarcoma and warrants translational evaluation.