tbuckley/cabot-search huggingface dataset:
Biological background of the genomic variations of cf-DNA in healthy individuals
Authors: J. Liu, X. Chen, J. Wang, S. Zhou, C.L. Wang, M.Z. Ye, X.Y. Wang, Y. Song, Y.Q. Wang, L.T. Zhang, R.H. Wu, H.M. Yang, S.D. Zhu, M.Z. Zhou, X.C. Zhang, H.M. Zhu, Z.Y. Qian
Journal: Annals of Oncology (2018)

BackgroundCell-free DNA (cf-DNA)-based liquid biopsy is emerging as a revolutionary new method in individualized cancer treatment and prognosis monitoring, although detecting early-stage cancers using cf-DNA remains challenging, partially because of the undefined biological background of cf-DNA.Materials and methodsWe investigated somatic mutations in the cf-DNA of 259 cancer-free individuals with a median age of 47 years using an endogenous barcoding duplex method with an ultralow base error rate (2 × 10−7) and compared the variant allele frequencies (VAFs) of these mutations between the cf-DNA and the corresponding blood cell DNA.ResultsSixty percent (155/259) of the samples showed at least one nonsynonymous mutation on either of two similar target panels covering 508 and 559 cancer-related genes. For individuals older than 50 years of age, the positive rate increased to 76%. Most cf-DNA mutations were also present at similar VAFs in the paired blood cell DNA. The most frequently mutated genes were driver genes of hematologic malignancies, including DNMT3A, TET2, AXSL1, and JAK2. However, the other 58.4% (192/329) of the mutations were likely 'passenger mutations' of clonal hematopoiesis, including mutations in NOTCH2, FAT3, EXT2, ERBB4, and ARID2, which are driver genes of solid tumors.ConclusionHematopoietic clone-derived mutations, including 'driver mutations' and 'passenger mutations', are prevalent in the cf-DNA of both healthy individuals and cancer patients and may be a potential source of false positives in the liquid biopsy. Our results also suggest the ineffectiveness for distinguishing clonal hematopoietic mutations of low VAF (≤0.1%) from tumor-derived mutations using conventional next-generation sequencing of blood cell DNA. However, an error correction model with an ultralow error rate and high coverage depth is required for blood cell DNA sequencing, which is difficult and costly to achieve with current technologies.
Neuropilin-2 is involved in tumor growth and angiogenesis of pancreatic adenocarcinoma
Authors: Nikolaos Dallas, Michael Gray, Ling Xia, Fan Fan, Sherry Lim, Puja Gaur, Shaija Samuel, Lee Ellis
Journal: Cancer Research (2008)

2518    Introduction.  Neuropilin-2 (NRP-2) is a co-receptor for vascular endothelial growth factor (VEGF) on endothelial cells and increases the binding affinity and activity of the VEGF tyrosine kinase receptors. NRP-2 is overexpressed in pancreatic adenocarcinoma cells relative to normal ductal epithelium; however, the role of NRP-2 on pancreatic cancer tumor cells remains to be elucidated.   Methods.  NRP-2 expression was reduced with stable short-hairpin RNA (shRNA) transfection. Western blot analyses were done for signaling intermediates. Semi-qiantitative RT-PCR was used to determine VEGF levels. Cellular proliferation was assessed by MTT assay. Migration and invasion studies were carried out in Boyden chambers. Anchorage-independent growth was determined by soft-agar colony formation.  In vivo  growth was evaluated in a murine subcutaneous xenograft model. Immunohistochemistry was used to quantitate  in vivo  proliferation and tumor vessel count and morphology.   Results.  Activation of Akt signaling was reduced in shRNA-NRP-2 clones relative to control clones. ShRNA-NRP-2 cells demonstrated decreased migration, invasion, and anchorage independent growth compared to control cells.  In vitro  proliferation rates were similar in control- and shRNA-transfected cells. Constitutive expression of the angiogenic mediator Jagged-1 was reduced in shRNA-NRP-2 cells by 57%, whereas VEGF levels were unchanged. Subcutaneous tumors in mice inoculated with shRNA-NRP-2 cells were significantly smaller than control transfected cells by 72-90% (p Conclusion.  Reduction of NRP-2 expression in pancreatic cancer cells decreased survival signaling, migration, invasion and ability to grow under anchorage-independent conditions.  In vivo , reduction of NRP-2 led to decreased growth of subcutaneous xenograft tumors with increased necrosis and decreased angiogenesis and patent vessels. This study provides evidence for NRP-2 as a potential target on pancreatic adenocarcinoma cells.
Abstract 14626: Circulating Secretoneurin Levels Provide Additional Prognostic Information in Patients With Acute Coronary Syndrome
Authors: Peder L Myhre, Sjur H Tveit, Nils Jakob Hoff, Geir Christensen, Stridsberg Mats, Torbjorn Omland, Helge Rosjo
Journal: Circulation (2017)

Introduction: Secretoneurin (SN) is associated with both myocardial ischemia and cardiomyocyte Ca2+ handling, and circulating SN levels provide incremental prognostic information to established risk indices in patients with acute heart failure, acute respiratory failure, and after cardiac arrest. Hypothesis: We hypothesize that SN would provide prognostic information in unselected patients with acute coronary syndrome (ACS). Methods: We included 411 patients hospitalized with chest pain at a teaching hospital and adjudicated all hospitalizations as ACS or non-ACS by two physicians working independently. Blood samples were drawn within 24 h from maximum chest pain symptoms and the average follow-up time was 6 y and 3 m. Results: In total, 168 patients (40%) were classified as hospitalized with ACS, including 80 patients with acute myocardial infarction. Circulating SN levels were higher in patients with ACS compared to patients with non-cardiac chest pain: (134 [Q1-3 115-155] vs. 123 [106-143] pmol/L, p=0....
PPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer
Authors: Vito W. Rebecca, Michael C. Nicastri, Colin Fennelly, Cynthia I. Chude, Julie S. Barber-Rotenberg, Amruta Ronghe, Quentin McAfee, Noel P. McLaughlin, Gao Zhang, Aaron R. Goldman, Rani Ojha, Shengfu Piao, Estela Noguera-Ortega, Alessandra Martorella, Gretchen M. Alicea, Jennifer J. Lee, Lynn M. Schuchter, Xiaowei Xu, Meenhard Herlyn, Ronen Marmorstein, Phyllis A. Gimotty, David W. Speicher, Jeffrey D. Winkler, Ravi K. Amaravadi
Journal: Cancer Discovery (2018)

Abstract Clinical trials repurposing lysosomotropic chloroquine (CQ) derivatives as autophagy inhibitors in cancer demonstrate encouraging results, but the underlying mechanism of action remains unknown. Here, we report a novel dimeric CQ (DC661) capable of deacidifying the lysosome and inhibiting autophagy significantly better than hydroxychloroquine (HCQ). Using an in situ photoaffinity pulldown strategy, we identified palmitoyl-protein thioesterase 1 (PPT1) as a molecular target shared across monomeric and dimeric CQ derivatives. HCQ and Lys05 also bound to and inhibited PPT1 activity, but only DC661 maintained activity in acidic media. Knockout of PPT1 in cancer cells using CRISPR/Cas9 editing abrogates autophagy modulation and cytotoxicity of CQ derivatives, and results in significant impairment of tumor growth similar to that observed with DC661. Elevated expression of PPT1 in tumors correlates with poor survival in patients in a variety of cancers. Thus, PPT1 represents a new target in cancer that can be inhibited with CQ derivatives. Significance: This study identifies PPT1 as the previously unknown lysosomal molecular target of monomeric and dimeric CQ derivatives. Genetic suppression of PPT1 impairs tumor growth, and PPT1 levels are elevated in cancer and associated with poor survival. These findings provide a strong rationale for targeting PPT1 in cancer. This article is highlighted in the In This Issue feature, p. 151
Immune/microbial interface perturbation in human IgA deficiency
Authors: Delphine Sterlin, Claire Fieschi, Marion Malphettes, Martin Larsen, Guy Gorochov, Jehane Fadlallah
Journal: Gut Microbes (2018)

In a recently published article we report the metagenomic analysis of human gut microbiomes evolved in the absence of immunoglobulin A (IgA). We show that human IgA deficiency is not associated with massive quantitative perturbations of gut microbial ecology. While our study underlines a rather expected pathobiont expansion, we at the same time highlight a less expected depletion in some typically beneficial symbionts. We also show that IgM partially supply IgA deficiency, explaining the relatively mild clinical phenotype associated with the early steps of this condition. Microbiome studies in patients should consider potential issues such as cohort size, human genetic polymorphism and treatments. In this commentary, we discuss how such issues were taken into account in our own study.
Immunoscore feasibility study in routine postsurgical pathologic review for early-stage colon cancer (CC) cases risk-assessment
Authors: K. Belaloui, E. Malifarge, J. Bohm, C. Bossard, R. Dienstmann, S. Garcia, C. Geppert, I. Gogenur, A. Hartmann, D. Hatzibougias, S. Landolfi, M. Mishaeli, D. Paez, P. Patel, M. Rodriguez-Justo, J. Szafranska, M. van den Eynde, E. Zavadova, S. Turcan, F. Hermitte
Journal: Annals of Oncology (2018)
Abstract 20596: Novel Navigation Software to Identify Leaks in Cryoballoon Ablation of Atrial Fibrillation
Authors: Christopher A Kowalewski, Tina Baykaner, Fernando Cruz, Javed Nasir, Chad Brodt, Sanjiv M Narayan, Paul J Wang
Journal: Circulation (2017)

Introduction: Cryoballoon ablation is increasingly used for pulmonary vein isolation (PVI) for atrial fibrillation (AF). In order to achieve good lesion quality, good cryoballoon apposition is cruc...
Abstract 15307: Dairy Intake and Risk of Cardiovascular Mortality in Singapore Chinese Adults
Authors: Mohammad Talaei Pashiri, Woon-Puay Koh, An Pan
Journal: Circulation (2015)

Introduction: Studies have suggested that dairy foods may be associated with lower risk of metabolic syndrome, HTN, and T2D. However, the relation of dairy products with CVD risk has been less clear, with mixed findings from various epidemiological studies. So far, few reports are from Chinese populations where the consumption levels are generally low. Methods: The Singapore Chinese Health Study is a population-based cohort that recruited 63,257 Chinese adults aged 45-74 years from 1993 to 1998 in Singapore. A validated 165-item semi-quantitative food-frequency questionnaire was used to assess usual diet at recruitment, and mortality information was identified via registry linkage up to December 31, 2013. Cox proportional hazard models were used to calculate HRs (95% CI) with adjustment for potential confounders. Results: The median total dairy intake was 20.1 g/d (ranged 0-1084 g/d). During 981,480 person-years of follow-up, we identified 5,484 CVD deaths. After controlling for socio-demographic, lifestyle and other dietary factors, marginally inverse association was observed, and the HRs (95% CI) for CVD mortality were 1.00, 0.95 (0.88-1.02), 0.96 (0.89-1.04), and 0.91 (0.84-0.99) for increasing quartiles of total dairy intake (P-trend=0.08). No significant association was observed for CHD deaths (n=3,033), and the HR comparing extreme quartiles was 0.93 (95% CI: 0.84-1.04; P-trend=0.27). Although the trend was not significant (P-trend=0.15) for stroke mortality (n=1544), the HRs were 1.00, 0.88 (0.77-1.02), 0.88 (0.76-1.01), and 0.84 (0.72-0.98) for increasing quartiles of total dairy intake. In men, higher total dairy intake was inversely associated with risk of CVD mortality [HR comparing extreme quartiles 0.89 (0.80-0.99); P-trend=0.02] and stroke mortality [0.72 (0.58-0.89); P-trend=0.005], but no significant association was observed in women [CVD mortality 0.99 (0.88-1.12); P-trend=0.41; and stroke mortality 0.93 (0.75-1.15); P-trend=0.97]. Conclusions: In this large cohort study of Chinese adults with generally low dairy consumption, high intake of total dairy products was associated with a modestly decreased risk of total CVD mortality, and this association was mainly observed for stroke mortality and only evident in men.
Preventing Late-Life Depression Through Task Sharing
Authors: Jagadisha Thirthalli, Palanimuthu T. Sivakumar, Bangalore N. Gangadhar
Journal: JAMA Psychiatry (2018)

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Multicenter Trial of a Combination Probiotic for Children with Gastroenteritis
Authors: Stephen B. Freedman, Sarah Williamson-Urquhart, Ken J. Farion, Serge Gouin, Andrew R. Willan, Naveen Poonai, Katrina Hurley, Philip M. Sherman, Yaron Finkelstein, Bonita E. Lee, Xiao-Li Pang, Linda Chui, David Schnadower, Jianling Xie, Marc Gorelick, Suzanne Schuh
Journal: New England Journal of Medicine (2018)

Gastroenteritis accounts for approximately 1.7 million visits to the emergency department (ED) by children in the United States every year. Data to determine whether the use of probiotics improves outcomes in these children are lacking. We conducted a randomized, double-blind trial involving 886 children 3 to 48 months of age with gastroenteritis who presented to six pediatric EDs in Canada. Participants received a 5-day course of a combination probiotic product containing Lactobacillus rhamnosus R0011 and L. helveticus R0052, at a dose of 4.0×109 colony-forming units twice daily or placebo. The primary outcome was moderate-to-severe gastroenteritis, which was defined according to a post-enrollment modified Vesikari scale symptom score of 9 or higher (scores range from 0 to 20, with higher scores indicating more severe disease). Secondary outcomes included the duration of diarrhea and vomiting, the percentage of children who had unscheduled physician visits, and the presence or absence of adverse events. Moderate-to-severe gastroenteritis within 14 days after enrollment occurred in 108 of 414 participants (26.1%) who were assigned to probiotics and 102 of 413 participants (24.7%) who were assigned to placebo (odds ratio, 1.06; 95% confidence interval [CI], 0.77 to 1.46; P=0.72). After adjustment for trial site, age, detection of rotavirus in stool, and frequency of diarrhea and vomiting before enrollment, trial-group assignment did not predict moderate-to-severe gastroenteritis (odds ratio, 1.06; 95% CI, 0.76 to 1.49; P=0.74). There were no significant differences between the probiotic group and the placebo group in the median duration of diarrhea (52.5 hours [interquartile range, 18.3 to 95.8] and 55.5 hours [interquartile range, 20.2 to 102.3], respectively; P=0.31) or vomiting (17.7 hours [interquartile range, 0 to 58.6] and 18.7 hours [interquartile range, 0 to 51.6], P=0.18), the percentages of participants with unscheduled visits to a health care provider (30.2% and 26.6%; odds ratio, 1.19; 95% CI, 0.87 to 1.62; P=0.27), and the percentage of participants who reported an adverse event (34.8% and 38.7%; odds ratio, 0.83; 95% CI, 0.62 to 1.11; P=0.21). In children who presented to the emergency department with gastroenteritis, twice-daily administration of a combined L. rhamnosus-L. helveticus probiotic did not prevent the development of moderate-to-severe gastroenteritis within 14 days after enrollment. (Funded by the Canadian Institutes of Health Research and others; PROGUT ClinicalTrials.gov number, NCT01853124 .).
Abstract 18426: Impact of Body Mass Index on Heart Failure With Preserved or Reduced Ejection Fraction: Outcomes According to Race and Ethnicity From Get With The Guidelines-Heart Failure (GWTG-HF) Registry
Authors: Selomie Kebede, Tiffany Powell-Wiley, Julius Ngwa, Di Lu, Phillip J Schulte, Deepak L Bhatt, Clyde Yancy, Gregg C Fonarow, Michelle A Albert
Journal: Circulation (2015)

Introduction: Research supports a J-shaped association between body mass index (BMI) and mortality in patients with coronary artery disease (CAD) regardless of race/ethnicity. However, whether a similar pattern is noted among heart failure (HF) patients is unclear, particularly since black patients are at highest risk for both obesity and heart failure. Methods: Patients ≥65 years old from the GWTG-HF registry linked to Medicare claims data from 2005-2011, were stratified by preserved (HFpEF) and reduced (HFrEF) ejection fraction HF and categorized by 5 racial/ethnic populations (white, black, Hispanic, Asian, and other). Adjusted-Cox regression assessed the association between BMI and 30-day mortality from live discharge. Restricted cubic splines illustrate the relationship. We used interaction terms to test whether the relationship between BMI and outcomes differed by race/ethnicity. Results: A total 39647 HF patients were included [white=32434 (81.8%); black=3809 (9.6%); Hispanic=1928 (4.9%); Asian=544 (1.4%);other=932 (2.3%)]. Blacks and Hispanics with HF were more likely class I obese or higher (BMI≥30) than whites or Asians (P &lt; 0.0001). Among HFpEF, higher BMI was associated with lower 30 day mortality, up to 30 kg/m 2 with little change in risk above 30 (Figure; BMI=30 vs BMI=15 hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.38 - 0.61). A smaller relationship was observed in HFrEF (BMI=30 vs BMI=15 HR 0.64, 95%CI 0.47 - 0.87). There were no significant BMI by race interactions related to mortality (P all &gt;0.05). Conclusions: Although black and Hispanic HF patients were more likely to be obese than whites or Asians, higher BMI was associated with lower 30 day mortality in each racial/ethnic group in a manner not consistent with a J-shaped relationship as noted for CAD. Additionally, the differential slope of the association of obesity and mortality among HFpEF and HFrEF patients suggests differing mechanistic factors requiring further exploration.
Phase I extension study of ETC-159 an oral PORCN inhibitor administered with bone protective treatment, in patients with advanced solid tumours
Authors: D. Tan, M. Ng, V. Subbiah, W. Messersmith, V. Teneggi, V. Diermayr, K. Ethirajulu, P. Yeo, B.H. Gan, L.H. Lee, S. Blanchard, R. Nellore, M. Yasin, D. Umrani, M.A. Lee, J. Hill, B. Madan, D. Virshup, A. Matter
Journal: Annals of Oncology (2018)
CLIC4/Arf6 Pathway
Authors: Vahitha B. Abdul-Salam, Giusy Russomanno, Chen Chien-Nien, Abdul S. Mahomed, Luke A. Yates, Martin R. Wilkins, Lan Zhao, Magdalena Gierula, Oliver Dubois, Ute Schaeper, Jens Endruschat, Beata Wojciak-Stothard
Journal: Circulation Research (2019)

Increased expression of CLIC4 (chloride intracellular channel 4) is a feature of endothelial dysfunction in pulmonary arterial hypertension, but its role in disease pathology is not fully understood.To identify CLIC4 effectors and evaluate strategies targeting CLIC4 signaling in pulmonary hypertension.Proteomic analysis of CLIC4-interacting proteins in human pulmonary artery endothelial cells identified regulators of endosomal trafficking, including Arf6 (ADP ribosylation factor 6) GTPase activating proteins and clathrin, while CLIC4 overexpression affected protein regulators of vesicular trafficking, lysosomal function, and inflammation. CLIC4 reduced BMPRII (bone morphogenetic protein receptor II) expression and signaling as a result of Arf6-mediated reduction in gyrating clathrin and increased lysosomal targeting of the receptor. BMPRII expression was restored by Arf6 siRNA, Arf inhibitor Sec7 inhibitor H3 (SecinH3), and inhibitors of clathrin-mediated endocytosis but was unaffected by chloride channel inhibitor, indanyloxyacetic acid 94 or Arf1 siRNA. The effects of CLIC4 on NF-κB (nuclear factor-kappa B), HIF (hypoxia-inducible factor), and angiogenic response were prevented by Arf6 siRNA and SecinH3. Sugen/hypoxia mice and monocrotaline rats showed elevated expression of CLIC4, activation of Arf6 and NF-κB, and reduced expression of BMPRII in the lung. These changes were established early during disease development. Lung endothelium-targeted delivery of CLIC4 siRNA or treatment with SecinH3 attenuated the disease, reduced CLIC4/Arf activation, and restored BMPRII expression in the lung. Endothelial colony-forming cells from idiopathic pulmonary hypertensive patients showed upregulation of CLIC4 expression and Arf6 activity, suggesting potential importance of this pathway in the human condition.Arf6 is a novel effector of CLIC4 and a new therapeutic target in pulmonary hypertension.
Abstract 15031: Defining a Coupling Ratio: Tissue Doppler Velocities in Systole and Diastole Predict Greater Diastolic Than Systolic Impairment in Hypertrophic Cardiomyopathy
Authors: Rohit Malhotra, Ara Tachjian, Gerard P Aurigemma
Journal: Circulation (2015)

Introduction: Mitral annular velocities, E’ and S’, (cm/s) measured by Tissue Doppler Imaging, are used in clinical cardiology and in research as important descriptors of systolic and diastolic function. We hypothesized that the relationship between these velocities in normal individuals would be linear, and would define a ventricular systolic/diastolic coupling ratio. We further hypothesized that departure from this normal coupling ratio might provide insight into certain disease states. Methods: We reviewed consecutive ECHOs performed at our institution to define the coupling ratio in normal individuals (n=57) and in 2 disease states dilated cardiomyopathy (DCM) (n=20), and hypertrophic cardiomyopathy (HCM) (n=19). The average of peak septal and lateral velocities, obtained in systole and diastole were compared (ANOVA). Results: Baseline characters as depicted in the table. In normals, there is a linear relationship between S’ and E’. While the S’ and E’ velocities are lower in absolute terms in DCM, the coupling ratio is similar to that seen in Normals. HCM, by contrast shows a relatively lower coupling ratio than Normals or DCM (Figure attached). Conclusion: We have defined a simple coupling ratio of systolic and diastolic velocities in normal and cardiomyopathy. The greater relative impairment on diastolic velocities in HCM appears to reflect a greater relative impairment in diastolic filling than in systolic shortening. In other words, for a given degree of systolic fiber shortening, fiber lengthening/stretch and perhaps utilization of the Frank Starling mechanism would be disproportionately impaired.