tbuckley/cabot-search huggingface dataset:
Abstract 3663: Non-invasive detection of fusion, splicing and mutation events from circulating cell-free RNA in cancers
Authors: Zhixin Zhao
Journal: Cancer Research (2018)

Abstract Circulating cell-free DNA (cfDNA) and cell-free RNA (cfRNA) in cancer patients are valuable resource of biomarkers for early detection, diagnosis, treatment and monitoring of disease progression. Compared to cfDNA, cfRNA is more labile to degrade and fluctuate, and thus more challenging to be detected in blood. In the present study, we reported PrediSeq, a validated NGS-based liquid biopsy assay to detect fusions, splicing and mutation events using cfRNA. By using Predicine proprietary ultra-sensitive DeepSeaTM (Deterministic, Efficient, Precise, Sensitive Algorithm) variant detection algorithm, pre-analytical study demonstrated RNA-based detection of fusion, RNA splicing, and mutations using reference materials. In a LOD study, PrediSeq NGS assay is more sensitive than the digital PCR based assay in terms of mutation detection. In clinical validation study, tissue and plasma samples from various types of cancer patients (lung, breast, prostate etc) were used, where concordant fusion events with tissue were observed and RNA mutations confirmed variants detected at DNA level. In conclusion, a highly sensitive and accurate RNA-based liquid biopsy test has been developed to complement the use of cfDNA for detection of fusion, splicing and mutations. Citation Format: Zhixin Zhao. Non-invasive detection of fusion, splicing and mutation events from circulating cell-free RNA in cancers [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 3663.
A hand hygiene intervention to decrease hand, foot and mouth disease and absence due to sickness among kindergarteners in China: A cluster-randomized controlled trial
Authors: Xiaona Liu, Wanli Hou, Zhiguang Zhao, Jinquan Cheng, Ed F. van Beeck, Xiaodong Peng, Kylah Jones, Xia Fu, Yan Zhou, Zhen Zhang, Jan Hendrik Richardus, Vicki Erasmus
Journal: Journal of Infection (2018)
The prognostic role of microsatellite status, tumor mutational burden, and protein expression in CRC.
Authors: Sarit Schwartz, Yuan Tian, Fabiola Cecchi, Andrew Nguyen, Yeoun Jin Kim, Brian Goh, Min Hoe Chew, Choon Leong Tang, Ee-Lin Toh, Anders Skanderup, Si-Lin Koo, Clarinda Wei Ling Chua, Wei Qiang Leow, Iain Beehuat Tan, Charles Joseph Vaske, Zack Sanborn, Stephen Charles Benz, Kiat Hon Tony Lim, Todd A. Hembrough
Journal: Journal of Clinical Oncology (2018)

572 Background: Comprehensive molecular profiling of CRC can inform treatment decisions by identifying patient subgroups at varying risks of death. Microsatellite instability (MSI) is prognostic in CRC and is used to select patients for immunotherapy. High tumor mutational burden (TMB) is associated with genomic instability and is prognostic in melanoma. Expression of p16 protein is prognostic in many tumor types. We used proteomic and genomic profiling to measure MSI, TMB and p16 in CRC tumors and to assess associations with patient survival. Methods: In archived clinical samples of CRC, 76 proteins were quantitated with mass spectrometry-based proteomics. MSI was measured by WGS and RNA-seq; unstable loci were quantified in tumor and normal samples. Cutoffs were derived via ROC analysis: high TMB was defined as &gt; 4.5 somatic mutations per megabase; p16 as &gt; 108 amol/ug. Patients were grouped by microsatellite status (MSI vs. microsatellite stable [MSS]), TMB (high vs. low), and p16 protein expression level. Survival curves were compared with the Mantel-Cox log-rank test. Results: Of 145 samples, 39 (27%) had high TMB and 29 (20%) had MSI. Patients with MSI tumors had longer OS than patients with MSS tumors (HR: 0.096; p = 0.003). Similarly, patients with high TMB had longer OS than those with low TMB (HR: 0.076; p &lt; 0.001). High p16 expression was prognostic of poor survival (HR: 2.874; p = 0.019). Among patients with MSS tumors or low TMB, those with low p16 levels had longer OS than patients with high p16 (HR: 0.257; p = 0.002 and HR: 0.249; p = 0.002, for MSS and low TMB, respectively). A combination of MSS, low TMB, and low p16 also differentiated between long and short survivors (HR: 0.249; p = 0.002). These associations remained after adjustment for tumor sidedness. Further analyses of clinical correlates will be presented. Conclusions: A combination of MSS, low TMB and low p16 expression characterized a subset of patients with longer survival. This is important because patients with MSS tumors have limited treatment options but may respond to CDK4/6 inhibitors due to low p16 expression. Molecular profiling of CRC may identify patient subgroups with a relatively poor prognosis who could benefit from personalized therapy.
TREM-1 Mediates Inflammatory Injury and Cardiac Remodeling Following Myocardial Infarction
Authors: AmirBoufenzer, JérémieLemarié, TabassomeSimon, MarcDerive, YoucefBouazza, NguyenTran, FatihaMaskali, FrédériqueGroubatch, PhilippeBonnin, ClaireBastien, PatrickBruneval, Pierre-YvesMarie, RaphaelCohen, NicolasDanchin, Jean-SébastienSilvestre, HafidAit-Oufella, SébastienGibot
Journal: Circulation Research (2015)

Rationale:Optimal outcome after myocardial infarction (MI) depends on a coordinated healing response in which both debris removal and repair of the myocardial extracellular matrix play a major role. However, adverse remodeling and excessive inflammation can promote heart failure, positioning leucocytes as central protagonists and potential therapeutic targets in tissue repair and wound healing after MI. Objective:In this study, we examined the role of triggering receptor expressed on myeloid cells-1(TREM-1) in orchestrating the inflammatory response that follows MI. TREM-1, expressed by neutrophils and mature monocytes, is an amplifier of the innate immune response. Methods and Results:After infarction, TREM-1 expression is upregulated in ischemic myocardium in mice and humans. Trem-1 genetic invalidation or pharmacological inhibition using a synthetic peptide (LR12) dampens myocardial inflammation, limits neutrophils recruitment and monocyte chemoattractant protein-1 production, thus reducing classical m...
Abstract 4514: ASR458, a small molecule, targets Notch1 signaling in advanced colorectal cancer
Authors: Balaji Chandrasekaran, Deeksha Pal, Ashish Tyagi, Srinivasa R Ramisetti, Arun K Sharma, Murali Ankem, chendil Damodaran
Journal: Cancer Research (2018)

Abstract Cancer-related mortality rates are amongst the highest in colorectal cancer (CRC). Previously we have reported that Withaferin A (WA), a natural compound, induces apoptosis and inhibits AKT mediated pro-survival signaling resulting in growth inhibition both in vitro and in vivo models of colon cancer. Owing to the encouraging results with WA, we have developed a series of acetylated pro-drug conjugates of WA and our initial structure-activity relationship (SAR) studies led to the identification of a novel small molecule ASR-458 as the lead compound. Interestingly, ASR-458 has demonstrated better efficacy by inhibiting colon cancer cell growth at nano-molar concentration, even in AKT overexpressing (AKT/HCT) HCT-116 cells (IC50: 750nm). Induction of apoptosis was seen in both control vector and AKT overexpressed colon cancer cell lines. Induction of caspase mediated signaling confirmed the pro-apoptotic function of ASR-458 in colon cancer cells. Inhibition of pAKT (ser473) resulted in downregulation of Notch1 downstream signaling pathways (Presenilin 1, NFkB activation and BCl-2 expression) in AKT/HCT colon cancer cells. Epithelial to mesenchymal transition (EMT) is a major hallmark of metastatic colon cancer. ASR-458 also downregulated the expression of EMT markers snail as well as β-Catenin and significantly impaired invasive as well as the migratory efficiency of AKT/HCT cells. Our ongoing xenograft studies will validate the in vivo efficacy of ASR-458 (1mg/kg/BW by IP weekly 2 times for six weeks) will confirm the chemotherapeutic effect of the compound against colon cancer cells. Overall these results emphasize ASR-458 to be a promising small molecule as compared to WA. ASR-458 targets both AKT and Notch1 signaling pathways which remains an important target for the development of effective treatment of metastatic stage of CRC. Citation Format: Balaji Chandrasekaran, Deeksha Pal, Ashish Tyagi, Srinivasa R Ramisetti, Arun K Sharma, Murali Ankem, chendil Damodaran. ASR458, a small molecule, targets Notch1 signaling in advanced colorectal 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 4514.
Preprocedural Level of Soluble CD40L Is Predictive of Enhanced Inflammatory Response and Restenosis After Coronary Angioplasty
Authors: FrancescoCipollone, ClaudioFerri, GiovambattistaDesideri, LeonardoPaloscia, GuidoMaterazzo, MarcoMascellanti, MariaFazia, AnnalisaIezzi, ChiaraCuccurullo, BarbaraPini, MarcoBucci, AnnaSantucci, FrancoCuccurullo, AndreaMezzetti
Journal: Circulation (2003)

Background— Inflammation plays a pathogenic role in the development of restenosis after percutaneous transluminal coronary angioplasty (PTCA). CD40–CD40L interaction is involved in the pathogenesis of atherosclerosis; however, its role in the pathophysiology of restenosis is still unclear. We tested the hypothesis that soluble CD40L (sCD40L) may be involved in the process of restenosis and that it exerts its effect by triggering a complex group of inflammatory reactions on endothelial and mononuclear cells. Methods and Results— We studied 70 patients who underwent PTCA and who had repeated angiograms at 6-month follow-up. Plasma sCD40L was measured before and 1, 5, 15, and 180 days after PTCA, whereas plasma soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, E-selectin, and monocyte chemoattractant protein (MCP)-1 were measured before and 24 hours after PTCA. Furthermore, the release of adhesion molecules and MCP-1 and the ability to repair an injury in endothelial cells...
Abstract 24: Extracellular HMGA1 promotes tumor invasion and metastasis in breast cancer
Authors: Olga Méndez, Vicente Peg, Candida Salvans, Mireia Pujals, Yolanda Fernández, Ibane Abasolo, Jose Perez, Ana Matres, Josep Tabernero, Javier Cortés, Joaquín Arribas, Josep Villanueva
Journal: Cancer Research (2018)

Abstract The recent in-depth study of the cancer secretome suggests that a fraction of the intracellular proteome might be playing alternative roles in the extracellular space during tumorigenesis through its unconventional secretion. A proteomic study aimed at evaluating the role of unconventional protein secretion in the context of tumor invasion led us to investigate the high mobility group A1 (HMGA1) chromatin-binding protein whose overexpression has been correlated with high-grade carcinomas and reduced patient-survival. Here we show that HMGA1 is not only oversecreted in invasive breast tumor cells, but its blockage with specific antibodies in the extracellular space impairs tumor cell migration and invasion. The invasive phenotype caused by extracellular HMGA1 (eHMGA1) is dependent on ERK1/2 signaling and a blocking-Ab against eHMGA1 decreases pERK and re-localizes HMGA1 to the nucleus concomitantly to the loss of invasion capacity. Remarkably, pre-treatment of invasive breast tumor cells with an HMGA1-blocking Ab reduces their metastatic ability in an orthotopic breast cancer xenograft model. HMGA1 also shows a cytoplasmic localization in primary human triple-negative breast cancer (TNBC) tumors that developed distant metastasis while displaying a nuclear localization in TNBC tumors that did not progress to metastatic disease. Thus, eHMGA1 could be a novel drug target in aggressive breast cancer and a biomarker predicting the onset of distant metastasis. Citation Format: Olga Méndez, Vicente Peg, Candida Salvans, Mireia Pujals, Yolanda Fernández, Ibane Abasolo, Jose Perez, Ana Matres, Josep Tabernero, Javier Cortés, Joaquín Arribas, Josep Villanueva. Extracellular HMGA1 promotes tumor invasion and metastasis in breast 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 24.
Abstract 826: Th1 cytokines and EGFR inhibition: A combinatorial therapeutic strategy in TNBC
Authors: Amrita Basu, Krithika Kodumudi, Doris Wiener, Brian Czerniecki
Journal: Cancer Research (2018)

Abstract Oncodrivers are a promising target in novel breast cancer therapy development, owing to oncogene addiction of breast cancer cells to sustain their malignancy. We have previously shown progressive loss of CD4+ T-helper type 1 response to oncodrivers in triple negative breast cancer (TNBC) patients. TNBC is marked by lack of cell surface ER, PR and Her2 receptors and is the most aggressive subtype of breast cancer. Lack of therapeutic targets, resistance to existing hormone therapy, metastasis and poor survival in TNBC patients underline the need for novel TNBC therapy development. In this study, we investigated the effect of EGFR inhibitors (cetuximab, erlotinib and lapatinib) alone or combination with Th1 cytokines (IFN-γ and TNF-α) on growth and proliferation of MDA-MB-231 and MDA-MB-468 TNBC cells. We observed decrease in EGFR expression in TNBC cells when treated with IFN-γ alone and in combination with EGFR inhibitors. In addition, IFN-γ alone, in combination with TNF-α and all three EGFR inhibitors, markedly increased STAT1 phosphorylation, indicating suppression of growth and proliferation in TNBC cells. Decreased STAT3 phosphorylation by combination treatment in TNBC cells may induce apoptosis and inhibit proliferation further. Combination of cetuximab and IFN-γ increased cleaved caspase-3 expression in MDA-MB-231, but not in MDA-MB-468 TNBC cells. EGFR inhibition and Th1 cytokine treatment showed combination treatment resulted in severe cell loss and morphological alteration, while Th1 cytokines alone did not induce significant senescence in MDA-MB-231 cells in senescence associated β-galactosidase assay. We are currently investigating activation status of other signaling pathways in TNBC cells, following Th1 cytokines treatment with EGFR inhibition. Our data suggests a combinatorial treatment approach, including DC1 vaccination to elicit Th1 immune response and inhibition of EGFR oncodriver, may lead to an effective and novel therapeutic strategy for triple negative breast cancer. Citation Format: Amrita Basu, Krithika Kodumudi, Doris Wiener, Brian Czerniecki. Th1 cytokines and EGFR inhibition: A combinatorial therapeutic strategy in TNBC [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 826.
Abstract LB-028: Deep genomic, immune-infiltrate and neoantigen-based stratification of cancer predicts response to immune checkpoint inhibition
Authors: Roy Ronen, Boguslaw Kluge, Janusz Dutkowski
Journal: Cancer Research (2018)

Abstract Background: Immunotherapies are revolutionizing cancer care but identifying patients which are most likely to achieve clinical benefit remains a key challenge. Available predictors such as PD-1/PD-L1 expression, tumor mutation burden or MSI-H/d-MMR status have shown promise in predicting response in specific cancer types, they fail to explain or predict response for many patients. A more comprehensive understating of biology underlying response to therapy is needed. Approach: We developed an integrated machine-learning system that uses a mathematical model of cancer subtypes and a neoantigen fitness model to stratify multimodal omics data along with associated profiles of immune infiltration and immune pathway activity. The system holistically determines the underlying pathway-level architecture of genomic and other molecular alterations in each cancer. It further uses a new immune pathway deconvolution approach to determine subtype-specific immune-infiltrates and activation of key immune and immune-modulating pathways that may be associated with response to therapy. Results: The system is applied to stratify and interrogate subtypes in over 40 cancer types. Here we discuss results for two of the histologies for which immunotherapies are being pursued clinically. Comprehensive systems-level interrogation of tumor genomic architecture and tumor microenvironment leads to new molecular sub-typings for colorectal adenocarcinoma and skin cutaneous melanoma, here referred to as COADREAD_MUT_CNV_MODEL_6 and SKCM_MUT_CNV_MODEL_3, respectively. The model-based subtypes uncover critical patterns of co-occurring and mutually-exclusive somatic alterations not apparent using previous approaches, and show strong correlation with immune infiltration. Further integration of the subtyping model with a new neoantigen fitness model significantly improves performance in predicting response to checkpoint inhibition compared to existing methods. Citation Format: Roy Ronen, Boguslaw Kluge, Janusz Dutkowski. Deep genomic, immune-infiltrate and neoantigen-based stratification of cancer predicts response to immune checkpoint inhibition [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-028.
Alcohol Consumption and Risk of Heart Failure in the Physicians’ Health Study I
Authors: LucDjoussé, J. MichaelGaziano
Journal: Circulation (2007)

Background— Heart failure (HF) is the leading cause of hospitalization among the elderly, and 1 in 5 adults aged 40 years will develop HF in their lifetime. Data on the effects of moderate alcohol consumption on the risk of HF have been sparse and inconsistent. This study sought to evaluate the association between moderate alcohol consumption and incident HF. Methods and Results— A total of 21 601 participants of the Physicians’ Health Study I who were free of HF and provided data on alcohol intake at baseline were prospectively followed up from 1982 to 2005. Incident HF cases were ascertained through annual follow-up questionnaires and validated with the use of Framingham criteria. During an average follow-up of 18.4 years, 904 incident cases of HF occurred. The crude incidence rates of HF were 25.0, 20.0, 24.3, and 20.6 cases per 10 000 person-years for alcohol categories of  7 drinks per week, respectively. Corresponding hazard ratios (95% CI) were 1.0 (reference), 0.90 (0.76 to...
Coupling of Hemodynamic Measurements With Oxygen Consumption During Exercise Does Not Improve Risk Stratification in Patients With Heart Failure
Authors: DonnaMancini, StuartKatz, LisaDonchez, KeithAaronson
Journal: Circulation (1996)

Background Measurement of peak Vo2 has become an accepted method to select patients for cardiac transplantation. Some investigators have suggested that the addition of exercise hemodynamic measurements can further enhance risk stratification because these measurements may identify patients with a noncardiac limitation to exercise. Methods and Results Accordingly, we performed maximal bicycle exercise with respiratory gas analysis and hemodynamic measurements in 65 patients (47 men, 18 women) 53±10 years old (mean±SD) who underwent a transplant evaluation at Columbia Presbyterian Medical Center. Skeletal muscle oxygenation of the vastus lateralis during exercise was assessed with near-infrared spectroscopy. Exercise hemodynamic, ventilatory, and muscle oxygenation measurements were obtained in all patients. For each subject, a linear correlation was derived between Vo2 and pulmonary artery saturation (PA Sao2). The slope of this relationship and a theoretical Vo2max at a PA Sao2 of 0% (Vo2 intercept) w...
Relieving Severe Emphysema Symptoms
Authors: Rebecca Voelker
Journal: JAMA (2018)

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Prostaglandin E2 Protects the Heart From Ischemia-Reperfusion Injury via Its Receptor Subtype EP4
Authors: Chun-YangXiao, Koh-ichiYuhki, AkiyoshiHara, TakayukiFujino, ShuhkoKuriyama, TakehiroYamada, KojiTakayama, OsamuTakahata, HidejiKaribe, TakanobuTaniguchi, ShuhNarumiya, FumitakaUshikubi
Journal: Circulation (2004)

Background— In the heart with acute myocardial infarction, production of prostaglandin (PG) E2 increases significantly. In addition, several subtypes of PGE2 receptors (EPs) have been reported to be expressed in the heart. The role of PGE2 in cardiac ischemia-reperfusion (I/R) injury, however, remains unknown. We intended to clarify the role of PGE2 via EP4, an EP subtype, in I/R injury using mice lacking EP4 (EP4−/− mice). Methods and Results— In murine cardiac ventricle, competitive reverse transcription–polymerase chain reaction revealed the highest expression level of EP4 mRNA among EP mRNAs. EP4−/− mice had larger infarct size than wild-type mice in a model of I/R; the left anterior descending coronary artery was occluded for 1 hour, followed by 24 hours of reperfusion. In addition, isolated EP4−/− hearts perfused according to the Langendorff technique had greater functional and biochemical derangements in response to I/R than wild-type hearts. In vitro, AE1-329, an EP4 agonist, raised cAMP concentra...
Ventricular Septal Defect Associated with Aortic Insufficiency
Authors: Yasunarukawashima, Michiakidanno, Yukihikoshimizu, Ikarumatsuda, Takeshimiyamoto, Tsuyoshifujita, Takahirokozuka, Hisaomanabe
Journal: Circulation (1973)

Thirty-five consecutive patients with ventricular septal defect (VSD) associated with aortic insufficiency (AI) who underwent corrective surgery are presented. There were seven operative and three late deaths among the patients operated upon before 1968. No death, however, was encountered among the most recent 18 consecutive patients. The VSD was closed directly in 14 patients and with a Teflon patch in 21. The aortic valve was repaired in 16 patients, replaced in eight, and no interference was indicated in 11. They were classified from the surgical viewpoint according to the location of the VSD, the anatomic type of the right ventricular outflow tract, and the severity of the aortic herniation as follows: type Ia, supracristal VSD and AI without aortic cusp herniation; type lb, supracristal VSD and AI with aortic cusp herniation and conal muscular rim beneath the pulmonic valve; type Ic, supracristal VSD and AI with aortic cusp herniation without conal muscular rim beneath the pulmonic valve; type IIa, i...