tbuckley/cabot-search huggingface dataset:
Abstract 4683: Distinct subsets of dysfunctional CD8+ T cells underlie response to checkpoint blockade
Authors: Brian C. Miller, Debattama R. Sen, Rose Al-Abosy, Kevin Bi, Kathleen B. Yates, Evisa Gjini, Kristen Felt, Robert T. Manguso, Scott J. Rodig, Arlene H. Sharpe, Nicholas Haining
Journal: Cancer Research (2018)

Abstract T-cell exhaustion is a heterogeneous state, with recent work in chronic viral infections revealing at least two subtypes with different functional properties: "stem-like" and "terminal" exhausted cells. Whether these two populations exist in tumors and have different roles to control tumor growth remains unknown. We performed single-cell RNA-seq on exhausted CD8+ T cells from chronic virally infected mice, generating unique transcriptional signatures of both exhausted populations. By transcriptional enrichment and flow cytometry, we discovered both the stem-like and terminal exhausted populations in the B16 mouse melanoma model and confirmed their presence in human melanoma samples with multiplex immunofluorescence. ATAC-seq revealed that these two subpopulations are defined by state-specific changes in chromatin accessibility. These states are shared between exhausted CD8+ T cells from both viral and tumor models, demonstrating a common epigenetic program of T-cell dysfunction. The two populations have different functional properties, with the stem-like cells having a more polyfunctional cytokine response whereas terminal cells are more cytotoxic. When transferred into new tumor-bearing mice, stem-like cells were better able to control tumor growth, suggesting superior long-term functionality. Checkpoint blockade with anti-PD-1 is known to increase CD8+ T cell numbers in the tumor microenvironment, but it is not known which subpopulation responds to therapy. Treatment with anti-PD-1 antibody resulted in proliferation of the stem-like population, which differentiate into the more cytotoxic terminal exhausted cells. We have shown that two subpopulations of exhausted CD8+ T cells exist in mouse and human tumors, and anti-PD-1 therapy activates the stem-like CD8+ T cells to promote tumor control. Citation Format: Brian C. Miller, Debattama R. Sen, Rose Al-Abosy, Kevin Bi, Kathleen B. Yates, Evisa Gjini, Kristen Felt, Robert T. Manguso, Scott J. Rodig, Arlene H. Sharpe, Nicholas Haining. Distinct subsets of dysfunctional CD8+ T cells underlie response to checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4683.
Glycometabolic State at Admission: Important Risk Marker of Mortality in Conventionally Treated Patients With Diabetes Mellitus and Acute Myocardial Infarction
Authors: KlasMalmberg, AnnaNorhammar, HansWedel, LarsRydén
Journal: Circulation (1999)

Background—The Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study addressed prognostic factors and the effects of concomitant treatment and glycometabolic control in diabetic patients with myocardial infarction (AMI). Methods and Results—Of 620 diabetic patients with AMI, 306 were randomly assigned to a ≥24-hour insulin-glucose infusion followed by multidose subcutaneous insulin. Three hundred fourteen patients were randomized as controls, receiving routine antidiabetic therapy. Thrombolysis and β-blockers were administered when possible. Univariate and multivariate statistical analyses were applied to study predictors of long-term mortality. During an average follow-up of 3.4 years (range, 1.6 to 5.6 years), 102 patients (33%) in the intensive insulin group and 138 (44%) in the control group died (P=0.011). Old age, previous heart failure, diabetes duration, admission blood glucose, and admission Hb AIc were independent predictors of mortality in the total cohort, whereas...
A Method Using Induced Waves to Study Pressure Propagation in Human Arteries
Authors: Miltonlandowne
Journal: Circulation Research (1957)

This report describes a method for utilizing externally induced impacts as a means of studying the propagation of pressure waves in intact human arteries. Because it is a new method its description is prefaced by a brief presentation of several factors relevant to wave propagation in living vessels; the description is followed by a critical evaluation.
Abstract 4482: MTAP regulates cell malignancy and is novel prognostic factor for kidney cancer
Authors: Carissa Huang, Jihao Xu, Yichin Wu, Robert H. Weiss, Ching-Hsien Chen
Journal: Cancer Research (2018)

Abstract Renal cell carcinoma (RCC), the 6th most common cancer in the US, is now considered a metabolic disease, which is increasing in incidence and demonstrates resistance usually within 2 years to all available therapies. Given that patients with metastatic RCC have unusually poor prognosis, it is urgent to discover potential molecules for predicting malignant changes that will lead to RCC. Herein, we have identified S-methyl- 5'-thioadenosine phosphorylase (MTAP) and its substrate methylthioadenosine (MTA) as a possible biomarker for early detection of RCC. In a screen of patients with RCC, we found that low MTAP expression is accompanied by high MTA level in RCC specimens, whereas concomitant high level of MTAP and low MTA abundance are detected in adjacent normal kidney tissues. Datasets for RCC (n=538) from The Cancer Genome Atlas (TCGA) showed that the patients with low MTAP levels have a significantly shorter overall survival as compared to the high MTAP group. Immunohistochemistry staining of normal kidney tissues confirmed an increase of MTAP protein expression compared to RCC tissues, and MTAP gene expression is inversely proportional to tumor grade. Accumulation of the metabolite MTA, a major substrate of MTAP, was observed in high-grade tumors showing high malignant potential. MTAP-knockout RCC cells displayed an elongated, spindle-like morphology with extended pseudopodial branches. Genetic manipulation of MTAP studies demonstrated that MTAP expression inhibits epithelial-mesenchymal transition, invasion and migration of RCC cells. Loss of MTAP resulted in an activation of IGF1R signaling in RCC cells. Taken together, our findings indicate a major contribution of MTAP loss to kidney cancer cell malignancy and provide a viable biomarker for tumor detections. Citation Format: Carissa Huang, Jihao Xu, Yichin Wu, Robert H. Weiss, Ching-Hsien Chen. MTAP regulates cell malignancy and is novel prognostic factor for kidney cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4482.
Regulation of 6-Pyruvoyltetrahydropterin Synthase Activity and Messenger RNA Abundance in Human Vascular Endothelial Cells
Authors: PhilippeLinscheid, AndreasSchaffner, NenadBlau, GabrieleSchoedon
Journal: Circulation (1998)

Background—The nitric oxide synthase cofactor tetrahydrobiopterin (BH4) is involved in the regulation of endothelium-dependent vascular functions mediated by nitric oxide. Vascular endothelial cells synthesize and secrete large amounts of BH4 on cytokine activation. There is scant knowledge about molecular mechanisms of cytokine-triggered BH4 production in endothelial cells. Methods and Results—Pteridine production, mRNA expression of GTP cyclohydrolase (GTPCH) and 6-pyruvoyltetrahydropterin synthase (PTPS) (both key enzymes of BH4 biosynthesis), and PTPS activity were studied in human umbilical vein endothelial cells (HUVECs) exposed to inflammatory cytokines. BH4 levels were ≤140-fold enhanced on treatment of HUVECs with combined interferon-γ/tumor necrosis factor-α/interleukin-1 (IFN/TNF/IL-1). Specific PTPS activity was ≈3-fold higher in cytokine-treated HUVECs than in untreated cells. Reverse-transcription/limiting-dilution polymerase chain reaction analysis showed that in response to IFN/TNF/IL-1, m...
Abstract 5788: Preclinical evaluation of HZB0071, a small molecule inhibitor of AKT
Authors: Gang Li, Lihong Hu, Weifeng Mao, Dongfang Li, Charles Z. Ding, Shuhui Chen
Journal: Cancer Research (2018)

Abstract Objective: AKT is a component of the PI3K/AKT/mTOR (PAM) pathway, which plays an important part in cell proliferation, growth and survival, activated in many cancers and has been validated as a therapeutic target in the clinic. Inhibition of AKT activity can block the PAM pathway and proliferation of various types of tumor cells with loss of tumor suppressor PTEN, mutational activation of p110a catalytic subunit of PI3K and amplification of the gene encoding either AKT or PI3K. The purpose of this study is to investigate the in vitro and in vivo antitumor activity of HZB0071, a small molecule AKT kinase inhibitor, in preclinical models of solid cancer with AKT overexpression. Method: Kinase inhibiting activity of HZB0071 was determined with AKT1, 2, 3 kinase assays. Cellular anti-proliferative activity was evaluated with AKT overexpressed LNcap cell line and DU145 cell line without AKT overexpression. The antitumor activity of HZB0071 was evaluate in vivo and the synergistic effect combined with Paclitaxel in AKT highly expressed patient-derived mouse xenograft (PDX) models of Gastric Cancer ST-02-0013 and cell-derived mouse xenograft (CDX) models of Breast Cancer BT474. Result: HZB0071 displayed potent kinase inhibiting activity for AKT1, 2, 3 with IC50 1.3±0.41 nM, 50.3±13.4 nM and 90.4±5.84 nM, respectively. HZB0071 inhibited cell proliferation in AKT overexpressed LNcap cells with IC50 67±7 nM. In contrast, HZB0071 showed much weaker anti-proliferative activity in DU145 cells with IC50 &amp;gt;10,000 nM. HZB0071 showed antitumor efficacy in AKT highly expressed gastric cancer PDX model ST-02-0013 (TGI = 62% @30 mpk, QD as single agent; TGI = 61% @15 mpk + Paclitaxel @10 mpk, QD, in combination with Paclitaxel), as well as in the breast cancer BT474 CDX model (TGI = 88% @30 mpk + Paclitaxel @15 mpk, QD). Conclusion: We have identified a novel potent AKT inhibitor HZB0071. Preclinical studies shows antitumor efficacy of HZB0071 in AKT overexpressed solid cancer models. HZB0071 represents a promising clinical candidate for treating solid cancers with high AKT expression. Citation Format: Gang Li, Lihong Hu, Weifeng Mao, Dongfang Li, Charles Z. Ding, Shuhui Chen. Preclinical evaluation of HZB0071, a small molecule inhibitor of AKT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5788.
Abstract 201: Multiregion joint somatic genotyping in ovarian cancer proves optimal tumor sampling for clinical sequencing
Authors: Lorinc Pongor, Gyongyi Munkacsy, Ildiko Vereczkey, Imre Pete, Balazs Gyorffy
Journal: Cancer Research (2018)

Abstract Introduction. Genetic heterogeneity of ovarian tumors is caused by the accumulation of novel mutations through time. A result of this process is a spatially heterogeneous tumor with a fractal-like architecture, comprising of a mixture of spatially separated clones, sub-clones, and single cells. Spatial heterogeneity renders clinical sequencing a challenging task because clinically relevant mutations can go undetected. Here, we compare the genetic composition of single tumors with multiple DNA samples extracted from different regions of the tumor in diverse combinations to examine the effects of spatial separation on tumor heterogeneity. Methods. We derived tumor samples from five patients with ovarian cancer. Three tumor tissue samples were collected from each patient, in each of these, DNA was extracted from a total of eight segments of different sizes (5x3x8 total segments). Exome sequencing was performed and we examined DNA mutations identified from a biopsy sample, from three merged tissue segments with immediate vicinity to the biopsy, and from segments from spatially distant tissue samples merged into one. We compared identified mutations and copy-number variations called from the exome-seq data. Results. Three patients had heterozygous germline alterations affecting the BRCA pathway, paired with somatic TP53 mutations, one patient had multiple somatic mutations affecting the PI3K pathway, the last patient had the most common activating mutations in the PIK3CA and KRAS genes. When comparing the different sequencing runs, increasing the size of the tumor sample did not affect the overall quantity of mutations identified. Clonal mutations were identifiable in all samples, while sub-clonal mutations shifted. In case of a hypermutating phenotype, increasing the sequenced sample size strongly decreased the number of identified somatic mutations, most probably due to dilution of sub-clones. These observations are confirmed by an in silico model, in which we shuffled regions from publicly available multi-region sequencing data into known compositions. Conclusion. In hypermutating tumors the number of detected mutations increases as the size of the sequenced sample decreases. Generally, increasing the tumor sample size did not affect the number of identifiable mutations. Our findings suggest that clinical sequencing using small biopsy samples can generate adequate mutation calling results. Citation Format: Lorinc Pongor, Gyongyi Munkacsy, Ildiko Vereczkey, Imre Pete, Balazs Gyorffy. Multiregion joint somatic genotyping in ovarian cancer proves optimal tumor sampling for clinical sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 201.
Abstract 17563: Upregulation of Anti-Oxidant Signal Pathway and Cytokine Release by Inhibition of p16INK4a in Aging Human Cardiac Progenitor Cells
Authors: Roshni V Khatiwala, Shuning Zhang, Xiuchun Li, Neil Devejian, Edward Bennett, Chuanxi Cai
Journal: Circulation (2017)

Introduction: Autologous human cardiac stem/progenitor cell (hCPC) therapy is a novel treatment for patients with cardiomyopathy. However, the CPCs of elderly patients, who are most susceptible to ...
Combination of a Brief Irrigation With Tissue Factor Pathway Inhibitor (TFPI) and Adenovirus-Mediated Local TFPI Gene Transfer Additively Reduces Neointima Formation in Balloon-Injured Rabbit Carotid Arteries
Authors: NobuhikoAtsuchi, TakahiroNishida, KousukeMarutsuka, YujiroAsada, YuichiKamikubo, AkiraTakeshita, HikaruUeno
Journal: Circulation (2001)

Background—Tissue factor pathway inhibitor (TFPI) is a physiological antagonist of TF. We tested whether a brief irrigation with TFPI protein (rTFPI) or TFPI gene transfer into injured arteries would suppress TF activity and reduce fibroproliferative changes and investigated whether a combination of these methods would show an additive effect. Methods and Results—We prepared adenoviruses expressing either TFPI (AdTFPI) or bacterial β-galactosidase (AdLacZ). Rabbit carotid arteries were balloon-injured and either infected with AdTFPI (or AdLacZ) or irrigated briefly with rTFPI (or saline). After injury, TF activity in arteries increased and was sustained; however, it was suppressed during the initial 24 hours by rTFPI irrigation (but not by gene transfer) and for a substantial period of time by TFPI gene transfer (but not by rTFPI irrigation). Four weeks later, the ratio of the intimal to medial areas was 34.3±8.7% (mean±SD, n=14) in saline-treated arteries and 33.3±4.2% in AdLacZ-infected arteries (P=NS v...
Abstract LB-318: Automated monitoring and analysis of kinetic live cell 3D spheroid-based tumor invasion within a hydrogel matrix
Authors: Brad Larson
Journal: Cancer Research (2018)

Abstract Metastasis is the main cause of death in cancer patients and one of the most complex biological processes in human diseases. The development of therapies designed to forestall the metastatic activity of tumors has been met with multiple challenges. The first is the initial focus on single target remedies. As many types of cancers develop multiple mutations during tumor progression, individual cancers are often little affected by this type of drug. The advancement of novel methods that allow for the discernment of the effect a potential therapy has on the invasive phenotype of a particular type of cancer has proven invaluable to circumventing these early failures. A second hurdle is the choice of an appropriate cell model. Tumors in vivo exist as a three-dimensional (3D) mass of multiple cell types, including cancer and stromal cells. Therefore, incorporating a 3D spheroid-type cellular structure that includes co-cultured cell types forming a tumoroid, provides a more predictive model than the use of individual cancer cells cultured on the bottom of a well in traditional two-dimensional (2D) format. A third impediment is the inclusion of proper incubation time. Traditionally in vitro assessments of anti-cancer drugs have included short-term incubations, sometimes limited to 48 hours. In vivo treatments, however, can consist of a multi-week regimen. Pre-clinical tests must also, then, extend a similar length of time. A final hindrance which is necessary to overcome is the proper capture and analysis of microscopic images. The ability to monitor the entire tumoroid with a degree of sensitivity across multiple z-planes as cells invade into the matrix, as well as quantify changes over time, is critical. The information presented here will demonstrate a combined procedure for the generation of 3D spheroidal tumoroid structures, creation of a suitable invasion matrix, automated kinetic image-based monitoring of tumor invasion, and cellular analysis of captured z-stacked images. Citation Format: Brad Larson. Automated monitoring and analysis of kinetic live cell 3D spheroid-based tumor invasion within a hydrogel matrix [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-318.
Digital Subtraction High-Frame-Rate Echocardiography in Detecting Delayed Onset of Regional Left Ventricular Relaxation in Ischemic Heart Disease
Authors: HiroyaKondo, TohruMasuyama, KenIshihara, ToshiakiMano, KazuhiroYamamoto, JohjiNaito, ReikoNagano, ShinjiKishimoto, JunTanouchi, MasatsuguHori, HiroshiTakeda, MichitoshiInoue, TakenobuKamada
Journal: Circulation (1995)

Background Because left ventricular (LV) diastolic function is impaired before systolic function in patients with ischemic heart disease and because ischemic heart disease is constituted of regional rather than global abnormalities of the left ventricle, measures of LV regional diastolic dysfunction, if possible, should provide the most sensitive assessment of the coronary involved region. The objectives of this study are to clarify whether high-frame-rate two-dimensional echocardiography, combined with digital subtraction image processing, may be used to visualize regional LV relaxation abnormalities in patients with ischemic heart disease and to clarify whether this technique provides a measure for the noninvasive assessment of the coronary involved region. Method and Results In 30 normal subjects and 59 patients with ischemic heart disease, two-dimensional echocardiograms obtained at a rate of 60 frames per second were provided on line for digital subtraction analysis, with which digitized images were ...
Acute Myocarditis with Bundle Branch Block due to Sulfonamide Sensitivity
Authors: Alfredlilienfeld, Elliothochstein, Williamweiss
Journal: Circulation (1950)

This is a case report of a patient who developed generalized manifestations of sulfonamide sensitivity, with evidence of involvement of the skin, mucous membrane, central nervous system, liver, and myocardium. Special attention is directed to the myocardial involvement, and particularly to the development of bundle branch block. The changes were reversible and complete recovery ensued.
Abstract 1551: Determination of the origin of oral squamous cell carcinoma by microarray analysis
Authors: Makoto Kinouchi, Sayaka Izumi, Daisuke Uchida, Nobuyuki Kuribayashi, Yuske Komiyama, Shuji Tsuchida, Atsushi Fujita, Hitoshi Kawamata
Journal: Cancer Research (2018)

Abstract More than 90% of oral cancer is histopathologically squamous cell carcinoma (SCC). According to its clinical behavior and histopathological features, we hypothesize that oral SCC can originate from either oral squamous epithelium or the minor salivary glands. In this study, we attempted to clarify the possibility of some oral SCC originating from the minor salivary glands, and to investigate whether these tumors showed particularly aggressive biological behavior. The mRNA expression profile of samples obtained from 6 patients with SCC of the oral floor (5 men, 1 woman; mean age 62.7 years) was analyzed by microarray containing 32,878 genes. Clustering analysis of the expression level of the 845 genes that were differentially expressed in normal oral squamous epithelium and normal salivary glands revealed that the 6 samples can be divided into 2 groups. The expression profile in four cases was similar to that of normal oral squamous epithelium, and in two cases was similar to that of normal salivary glands. Furthermore, we identified nine genes that reveal the origin of the oral SCC. Subsequently, we examined the expression levels of these 9 marker genes by reverse transcriptase-polymerase chain reaction to determine the origin of 66 oral SCCs. Twelve of the 66 oral SCCs were considered to originate from minor salivary glands, and these tumors showed high metastatic potential (p&amp;lt;0.05) and poor event free survival rate (p&amp;lt;0.05). In conclusion, determination of the origin of the oral SCC is helpful when making a treatment plan for patients with oral SCC. Citation Format: Makoto Kinouchi, Sayaka Izumi, Daisuke Uchida, Nobuyuki Kuribayashi, Yuske Komiyama, Shuji Tsuchida, Atsushi Fujita, Hitoshi Kawamata. Determination of the origin of oral squamous cell carcinoma by microarray analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1551.
End locum pay cap to ease rota gap crisis, says BMA
Authors: Abi Rimmer
Journal: BMJ (2018)

The government must lift the cap on locum doctors’ pay to help tackle rota gaps, the BMA has said. Government policies that undermine medical locums, such as the pay cap, harm the “organisational resilience of the NHS,” it said in a report on medical rota gaps in England.1

If the cap was lifted, said the report, doctors would be more willing to take on additional shifts to alleviate rota gaps. The cap on the hourly rate that NHS trusts can pay locum doctors was introduced in November 2015, although …