tbuckley/cabot-search huggingface dataset:
Abstract LB-381: Effects of sequencing parameters and panel size on mutational burden calculations
Authors: Scott Yourstone, Natalie Mola, Victor J. Weigman
Journal: Cancer Research (2018)

Abstract Immunotherapies are an emerging approach for cancer treatment that leverage the power of the immune system to attack cancer cells. By targeting immune check-point pathways such as PD-1, these treatments have been highly effective for some patients diagnosed with skin, bladder, lung, or kidney cancer. However, response rates for these treatments vary, making it beneficial to identify patients who are likely to respond to the treatment. Qualitative methods for predicting immunotherapy response are available but are technically challenging and subjective. An emerging quantitative predictor of immunotherapy response, tumor mutational burden (TMB), measures the number of somatic mutations per Mb of the genome. TMB calculations using whole exome data have been shown to correlate with patient response to immunotherapies. However, derivation of this score is not well characterized, nor is the score universally performed across laboratories. Here we describe the results from calculating TMB scores varying cancer panel size and amount of sequencing generated. First, variants are called in matched tumor and normal samples within Exomes. Then low coverage variants are removed along with variants outside the targeted, high-confidence regions in each panel. The remaining variants in the normal samples constitute the germline variants and are subtracted from the number of variants identified in tumor samples to yield the TMB score. We then repeated this across multiple indications across TCGA to review robustness of score in indications across the spectra of burden. TMB scores from the our comprehensive cancer closely resembles scores calculated using whole exome data across indications. We propose rules for gene content and sequencing depth for providing a range of burden scores that could be used for determining thresholds needed for determining therapeutic implications. We suggest that only a small subset of genes are required for accurate TMB estimation, thus reducing costs associated with predicting patient response to immunotherapy. Citation Format: Scott Yourstone, Natalie Mola, Victor J. Weigman. Effects of sequencing parameters and panel size on mutational burden calculations [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-381.
Sustained Inward Current During Pacemaker Depolarization in Mammalian Sinoatrial Node Cells
Authors: TamotsuMitsuiye, YasukoShinagawa, AkinoriNoma
Journal: Circulation Research (2000)

Abstract—Several time- and voltage-dependent ionic currents have been identified in cardiac pacemaker cells, including Na+ current, L- and T-type Ca2+ currents, hyperpolarization-activated cation current, and various types of delayed rectifier K+ currents. Mathematical models have demonstrated that spontaneous action potentials can be reconstructed by incorporating these currents, but relative contributions of individual currents vary widely between different models. In 1995, the presence of a novel inward current that was activated by depolarization to the potential range of the slow diastolic depolarization in rabbit sinoatrial (SA) node cells was reported. Because the current showed little inactivation during depolarizing pulses, it was called the sustained inward current (Ist). A similar current is also found in SA node cells of the guinea pig and rat and in subsidiary pacemaker atrioventricular node cells. Recently, single-channel analysis has revealed a nicardipine-sensitive, 13-pS Na+ current, whic...
Prospective Validation of the 0/1-h Algorithm for Early Diagnosis of Myocardial Infarction
Authors: Raphael Twerenbold, Johannes Tobias Neumann, Nils Arne Sörensen, Francisco Ojeda, Mahir Karakas, Jasper Boeddinghaus, Thomas Nestelberger, Patrick Badertscher, Maria Rubini Giménez, Christian Puelacher, Karin Wildi, Nikola Kozhuharov, Dominik Breitenbuecher, Ewelina Biskup, Jeanne du Fay de Lavallaz, Dayana Flores, Desiree Wussler, Òscar Miró, F. Javier Martín Sánchez, Beata Morawiec, Jiri Parenica, Nicolas Geigy, Dagmar I. Keller, Tanja Zeller, Tobias Reichlin, Stefan Blankenberg, Dirk Westermann, Christian Mueller
Journal: Journal of the American College of Cardiology (2018)
Abstract 2442: Detection of tissue hypoxia with EF5
Authors: Kevin Su, Amy Noble, Nick Asbrock, Cameron Koch, Vi Chu
Journal: Cancer Research (2018)

Abstract Hypoxia, a condition of oxygen deprivation, is a salient feature of the tumor microenvironment. Hypoxia tumors are frequently resistant to conventional cancer therapies and are correlated with increased migratory and metastatic behavior. A number of detection modalities exist for the detection of hypoxia; however, only EF5 (2-[2-nitro-1H-imidazol-1-yl]-N-(2,2,3,3,3-pentafluoropropyl) acetamide) provides detailed information on the distribution of hypoxia in tissues at both the physiologic and pathologic levels. EF5 is a compound that, when injected into animal tissues, selectively binds to hypoxic cells and forms adducts. These adducts are detected by a mouse monoclonal antibody, clone ELK3-51, conjugated to fluorescent dyes including Cyanine 3, Alexa Fluor 488 and Cyanine 5. The use of EF5 and its specific fluorescent monoclonal antibody to selectively detect regions of hypoxia in mouse tissues is described. BALB/c mice between 7 to 10 weeks old and weighing between 18 to 30 g were used in the study. Mouse #1 was not treated with EF5 and its spleen was harvested as a negative control. Mouse #2 was injected with 10 mM EF5 (typically 1% of animal weight in mL) and allowed to run aerobically for 4 hours before euthanization. Mouse #3 was injected with EF5, euthanized after 10 minutes and kept warm at 37°C for 40 minutes to mimic the anaerobic hypoxic condition before the spleen was harvested (hypoxic control). Examination of spleen samples indicated highly specific binding of the EF5 adducts only in the anaerobic hypoxic mouse spleen. The use of EF5 with fluorescent conjugated antibodies provides a sensitive and quantitative method for the detection and measurement of tissue hypoxia in animal and human tumor tissues and cells. Citation Format: Kevin Su, Amy Noble, Nick Asbrock, Cameron Koch, Vi Chu. Detection of tissue hypoxia with EF5 [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 2442.
Abstract 11579: Physical Activity versus Body Mass Index and Prevalence of Peripheral Arterial Disease
Authors: Aeshita Dwivedi, Caron Rockman, Yu Guo, Rich Stein, Mark Adelman, Jeffrey S Berger
Journal: Circulation (2016)

Introduction: Physical activity and body mass index (BMI) are independently associated with peripheral arterial disease (PAD). However, their relative significance and combined association with PAD remain unclear. Hypothesis: We hypothesize that physical activity is associated with a lower odds of PAD across the BMI spectrum and that physical activity attenuates the prevalence of PAD in obese patients. Methods: We studied 3,250,350 U.S. adults who self-referred for PAD screening from 2003-2008 (Life Line Screening Inc., Independence, Ohio). Subjects completed a medical/lifestyle questionnaire. They were categorized into physically active or physically inactive based on their response in the questionnaire to whether they engaged in any type of vigorous leisure time exercise on a regular basis. All subjects were evaluated for PAD by ankle brachial index, with &lt;0.9 considered abnormal. We divided participants into standardized BMI categories: underweight (&lt; 18.5), normal weight (18.5-24.9), overweight (25-29.9), obese class I (30-34.9), class II (35-39.9), and class III (&gt; 40). Multivariable logistic regression was used to estimate the odds of PAD among the BMI categories, based on physical activity. Results: Overall, mean age was 63.1 ± 10.5 years, 65.5% were female, and mean BMI was 27.7 ± 5.8 kg/m 2 . 41.5% were physically inactive. Average BMI was higher in the physically inactive versus physically active group (28.9 ± 6.3 vs. 27.0 ± 5.3, P&lt;0.0001). Prevalence of PAD initially decreased and then increased with BMI and was attenuated with physical activity. Following multivariable adjustment, physical activity was independently associated with lower odds of PAD across the BMI spectrum (Table). Conclusion: Physical activity is associated with lower odds of PAD in underweight, normal weight, overweight and obese individuals. The higher prevalence of PAD with increasing BMI is attenuated with physical activity.
三官能性抗体Catumaxomab(抗EpCAM×Anti-CD3)による治療を受けた悪性腹水患者の第2/3相試験に関する免疫モニタリング結果
Authors: Jaeger Michael, Schoberth Alexandra, Ruf Peter, Hess Juergen, Hennig Michael, Schmalfeldt Barbara, Wimberger Pauline, Stroehlein Michael, Theissen Bettina, M Heiss Markus, Lindhofer Horst
Journal: Cancer Research (2012)
Abstract 3605: Next generation sequencing from cerebral spine fluid yields actionable targets in leptomeningeal carcinomatosis
Authors: Louisa von Baumgarten, Anna Reischer, Jörg Kumbrink, Andreas Jung, Sibylle Liebmann, Steffen Ormanns, Klaus Metzeler, Julian Holch, Volker Heinemann, Thomas Kirchner, Benedikt Westphalen
Journal: Cancer Research (2018)

Abstract Background and Rationale: Leptomeningeal carcinomatosis is a cause of major morbidity and mortality in many solid malignancies. Therapeutic options are limited and include radiation therapy as well as intrathecal administration of cytotoxic agents. Accordingly, novel diagnostic and therapeutic modalities are needed in order to improve the prognosis of patients diagnosed with leptomeningeal carcinomatosis. Liquid biopsies are safe and offer great potential to define actionable targets in a variety of cancers. However, a role for liquid biopsies from cerebral spine fluid (CSF) has not been defined to date. Patients and Methods: CSF samples from ten consecutive patients diagnosed with leptomeningeal carcinomatosis were collected as part of clinical routine and evaluated by next generation sequencing. All cases were discussed in the Molecular Tumorboard (MTB) as part of the “Molecular Diagnostics and Therapy” unit at the Comprehensive Cancer Center Munich. Results: Samples from patients diagnosed with cholangiocarcinoma (1), ewing's sarcoma (1), breast (5), lung (2) and gastric cancer (1) were submitted for panel sequencing. Sequencing was technically successful in nine out of ten patients and circulating tumor DNA (ctDNA) was found in all of these nine patients. Of note, ctDNA was also detectable in cases in which microscopy did not reveal malignant cells in the CSF sample (4/10 cases). Tumorigenic alterations were found in seven out of these nine patients. Importantly, NGS of cerebral spine fluid detected previously unknown and therapeutically relevant alterations in this cohort. Case discussion in the Molecular Tumorboard led to therapeutic recommendations in three cases and targeted therapy was ultimately initiated in one case. Conclusions: Next generation sequencing from cerebral spine fluid is feasible in clinical practice and yields tumorigenic alterations in a large fraction of patients. Importantly, our approach demonstrated the therapeutic relevance of this approach in patients with leptomeningeal carcinomatosis. Citation Format: Louisa von Baumgarten, Anna Reischer, Jörg Kumbrink, Andreas Jung, Sibylle Liebmann, Steffen Ormanns, Klaus Metzeler, Julian Holch, Volker Heinemann, Thomas Kirchner, Benedikt Westphalen. Next generation sequencing from cerebral spine fluid yields actionable targets in leptomeningeal carcinomatosis [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 3605.
Abstract 180: OPNa variant expression is associated with matrix mineralization in thyroid cancer cell lines
Authors: Luciana B. Ferreira, Raquel T. Lima, Ana Clara Santos da Fonseca Bastos, Andreia Machado Silva, Catarina Tavares, Ana Pestana, Elisabete Rios, Catarina Eloy, Manuel Sobrinho-Simões, Etel Rodrigues Pereira Gimba, Paula Soares
Journal: Cancer Research (2018)

Abstract Osteopontin (OPN) and its three spliced variants (OPN-SV: OPNa, OPNb and OPNc) are overexpressed in several tumors and frequently associated with cancer progression. This holds true for papillary thyroid carcinoma (PTC), which is the most common variety of thyroid cancer (TC), being the histologic type which often presents desmoplasia (collagen deposition) and dystrophic calcification, including a fairly typical feature, the psammoma bodies (PB). This study aims to investigate the OPN-SV expression in classical variant of PTC (cPTC) and the role of OPN in calcification and collagen deposition into the extracellular matrix of thyroid cancer cell lines. Total OPN and OPN-SV expression was analyzed by immunohistochemistry and real time PCR in a series of 48 cPTC cases and three diffuse sclerosing PTCs. The association of OPN expression and the presence of PB as well as between PB in cPTC and the clinicopathological features of the tumors were evaluated. TPC-1 and c643 TC cell lines overexpressing OPN-SV were tested for the ability to promote calcification and to synthesize collagen in vitro. We also evaluated the expression of calcification markers, including osteocalcin and collagen I. Overexpression of OPNa transcripts was significantly associated with the presence of PB in cPTC samples. The presence of PB in cPTC was associated with younger patients and lymph node metastasis. Moreover, OPNa overexpression displayed a strong capacity to promote calcification and substantial collagen deposition in thyroid cancer cell lines. Upon OPN knockdown, the mRNA expression levels of calcification markers (osteocalcin and collagen I) were downregulated, further evidencing the involvement of OPN on activating these processes. Our data suggest that OPNa plays a role in the extracellular matrix calcification associated with cPTC. Basic research on the interactions between OPNa overexpression by tumor cells and the surrounding microenvironment can give clues for a better understanding of cPTC biology and phenotype. Citation Format: Luciana B. Ferreira, Raquel T. Lima, Ana Clara Santos da Fonseca Bastos, Andreia Machado Silva, Catarina Tavares, Ana Pestana, Elisabete Rios, Catarina Eloy, Manuel Sobrinho-Simões, Etel Rodrigues Pereira Gimba, Paula Soares. OPNa variant expression is associated with matrix mineralization in thyroid cancer cell lines [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 180.
Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status: a community-based cohort study
Authors: Hyun-Sik Yang, Lei Yu, Charles C White, Lori B Chibnik, Jasmeer P Chhatwal, Reisa A Sperling, David A Bennett, Julie A Schneider, Philip L De Jager
Journal: The Lancet Neurology (2018)
Reduction in Myocardial Ischemia/Reperfusion Injury in Group X Secretory Phospholipase A2–Deficient Mice
Authors: DaisukeFujioka, YukioSaito, TsuyoshiKobayashi, ToshiakiYano, HideoTezuka, YoshikazuIshimoto, NorikoSuzuki, YasunoriYokota, TakamitsuNakamura, Jyun-eiObata, MasakiKanazawa, Ken-ichiKawabata, KohjiHanasaki, KiyotakaKugiyama
Journal: Circulation (2008)

Background— Group X secretory phospholipase A2 (sPLA2-X) has the most potent hydrolyzing activity toward phosphatidylcholine and elicits a marked release of arachidonic acid among several types of sPLA2. sPLA2-X is expressed in neutrophils, but its pathogenic role remains unclear. Methods and Results— We generated mice that lack sPLA2-X and studied their response to myocardial ischemia/reperfusion. The sPLA2-X−/− mice had a significant reduction in myocardial infarct size and a decrease in myocardial myeloperoxidase activity compared with sPLA2-X+/+ mice. Myocardial infarct size was also significantly reduced in lethally irradiated sPLA2-X+/+ mice reconstituted with sPLA2-X−/− bone marrow compared with sPLA2-X+/+ bone marrow. The extent of myocardial ischemia/reperfusion injury was comparable between sPLA2-X−/− and sPLA2-X+/+ mice in Langendorff experiments using isolated hearts and blood-free perfusion buffer, supporting a potential role of sPLA2-X in blood in myocardial ischemia/reperfusion injury. In t...
Abstract SY14-02: Personalized therapies: Neoantigen discovery and vaccination
Authors: Nina Bhardwaj
Journal: Cancer Research (2018)

Abstract Tumor antigens derived from somatic mutations, or indels, are referred to as mutation-derived tumor antigens (MTAs) but are also known as neoantigens,or tumor-specific antigens. Evidence suggests that MTAs play a significant role in the endogenous adaptive immune response to tumors, and in the induced response following treatment with checkpoint inhibitors such as anti-CTLA-4 or anti-PD-1. This session will cover the concept of shared neoantigens in cancer and vaccine approaches to elicit adaptive antitumor immunity. Citation Format: Nina Bhardwaj. Personalized therapies: Neoantigen discovery and vaccination [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 SY14-02.
Abstract 4221: Association between SOX9 expression in Mexican patients with early colon cancer stage
Authors: Erika Ruiz-Garcia, Tatiana Galicia, Edith Fernandez Figueroa, Saul Lino-Silva, Cesar Lopez-Camarillo, Laurence Marchat, German Calderillo, Juan Zinser, Abelardo Meneses-Garcia, Horacio Astudillo-de la Vega
Journal: Cancer Research (2018)

Abstract Introduction. Colon cancer is the fourth leading cause of mortality worldwide. Between 30-40% of patients are diagnosed at early stage (I or II), sadly 20% will relapse. It is necessary to have a biomarker that identifies patients at high risk. SOX 9 is a transcription factor required for differentiation of different cells and is important for cell proliferation, senescence and lineage commitment. The exact role of SOX9 in carcinogenesis and cancer progression is controversial because could have oncogenic and tumor-suppressing functions. Reports show that strong levels of SOX 9 in colon cancer stage II are linked to low risk of relapse. Objective. The aim of this study was to investigate if the protein expression of SOX9 was associated with the stage, clinical characteristics and relapse of Mexican colon cancer patients. Methods. We obtained 97 samples embedded in paraffin. A pathologist blinded to the clinical information determined the immunoreactivity of SOX9 into 2 groups: low and high expression (by evaluating the percentage of positive nucleus and the tissue staining intensity). All statistical analyses were conducted with SPSS v.22 Statistics. Results. We include stage I (N= 34) and stage II (N=63) patients. The median follow-up period was 42 months. We found statistical difference between SOX9 expression and age (p=0.003), tumor localization (p=0.048) and stage (p&amp;lt0.001) for whole patients group. Twelve patients (12.3%) relapsed, 7 (at locally level) and 5 with distant metastasis: liver (N=3) and retroperitoneal nodes (N=2), all had low SOX9 expression; one patient with local relapse had died (because of surgical complications). In the relapse group, we found a significant correlation between SOX9 expression and stage (p=0.038) but not with relapse free survival (RFS). Conclusion. We found interesting data even though this is a retrospective study with limitations. This study could not associated SOX9 and RFS, because there are few events. Nevertheless, we observe that 41% patients had a systemic relapse. In the other hand, the youngest patients (&amp;lt40 y) and the right colon had the highest SOX9 expression. With this result, we have decided to increase the sample size before any assumption, and perform NGS to the five systemic relapses. Citation Format: Erika Ruiz-Garcia, Tatiana Galicia, Edith Fernandez Figueroa, Saul Lino-Silva, Cesar Lopez-Camarillo, Laurence Marchat, German Calderillo, Juan Zinser, Abelardo Meneses-Garcia, Horacio Astudillo-de la Vega. Association between SOX9 expression in Mexican patients with early colon cancer stage [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 4221.
Combination of the Immune Modulator Fingolimod With Alteplase in Acute Ischemic Stroke
Authors: ZilongZhu, YingFu, DecaiTian, NaSun, WeiHan, GuoqiangChang, YinhuaDong, XiaolinXu, QiangLiu, DeRenHuang, Fu-DongShi
Journal: Circulation (2015)

Background—Inflammatory and immune responses triggered by brain ischemia worsen clinical outcomes of stroke and contribute to hemorrhagic transformation, massive edema, and reperfusion injury associated with intravenous alteplase. We assessed whether a combination of the immune-modulator fingolimod and alteplase is safe and effective in attenuating reperfusion injury in patients with acute ischemic stroke treated within the first 4.5 hours of symptom onset. Methods and Results—In this multicenter trial, we randomly assigned 25 eligible patients with hemispheric ischemic stroke stemming from anterior or middle cerebral arterial occlusion to receive alteplase alone and 22 patients to receive alteplase plus oral fingolimod 0.5 mg daily for 3 consecutive days within 4.5 hours of the onset of ischemic stroke. Compared with patients who received alteplase alone, patients who received the combination of fingolimod with alteplase exhibited lower circulating lymphocytes, smaller lesion volumes (10.1 versus 34.3 mL...
Organ donation: opt-out system should be in place by 2020 in England
Authors: Jacqui Wise
Journal: BMJ (2018)

All adults in England will be presumed to be organ and tissue donors unless they have explicitly recorded a decision not to be, under a new system of consent announced by the government to tackle a shortage of donors.1

The plans follow a public consultation launched last December.2 The proposed new system, which needs to be ratified in parliament in the autumn, is expected to come into effect in England in spring 2020. This will give a 12 month transition period to allow people time for discussion with friends and family about organ donation preferences.

Groups excluded from the presumed consent include under 18s, people who lack the mental capacity to understand the changes, and people who have not …
Long-term Angiotensin-Converting Enzyme Inhibition With High-Dose Enalapril Retards Nitrate Tolerance in Large Epicardial Arteries and Prevents Rebound Coronary Vasoconstriction In Vivo
Authors: ThomasMünzel, EberhardBassenge
Journal: Circulation (1996)

Background Rebound myocardial ischemia develops in patients with unstable or stable angina pectoris after sudden cessation of nitroglycerin therapy. Long-term nitroglycerin infusion is associated with increases in plasma renin activity and catecholamine release rates, both of which may lead to excess angiotensin II and α-adrenergic–mediated vasoconstriction, particularly on withdrawal of nitroglycerin. Methods and Results Chronically instrumented dogs were treated for 5 days with nitroglycerin (1.5 μg·kg−1·min−1 IV) alone or in combination with the angiotensin-converting enzyme (ACE) inhibitor enalapril (0.1 mg/kg two times daily or 1 mg/kg). With long-term nitroglycerin therapy, the left anterior circumflex artery was maximally dilated 4 hours after the start of nitroglycerin infusion (9.5±0.6%) and returned to baseline levels within the third day of treatment (baseline, 2.52±0.07 mm; day 3, 2.55±0.07 mm; P=NS), indicating a complete loss of nitroglycerin-induced coronary vasodilatation. Nitroglycerin in...