tbuckley/cabot-search huggingface dataset:
Abstract 18947: Clonal C-kit-Positive Bone Marrow Cells and Cardiomyogenesis
Authors: Fumihiro Sanada, Junghyun Kim, Anna Czarna, Sergio Signore, Andrea Sorrentino, Chiara Mangiaracina, Ramaswamy Kannappan, Polina Goihberg, Marcello Rota, Toru Hosoda, Jan Kajstura, Piero Anversa, Annarosa Leri
Journal: Circulation (2013)

Conflicting results have been reported concerning the ability of c-kit-positive bone marrow cells (c-kit-BMCs) to transdifferentiate into cardiomyocytes. We have raised the possibility that c-kit-BMCs may constitute a functionally heterogeneous pool, containing cells with different cardiomyogenic potential. To test this hypothesis, multicellular clones derived from individual c-kit-BMCs were obtained and transplanted in acutely infarcted mice. Only a limited fraction of clonal c-kit-BMCs was found to be able to form cardiomyocytes and promote myocardial regeneration. On this basis, c-kit-BMC-derived clones were classified as myogenic or non-myogenic. The gene profile of these two categories of cells was studied by RNA-sequencing. Genes that showed a significant (p&lt;0.05) expression difference among cell groups were included in the analysis; 35 genes were uniquely upregulated in myogenic c-kit-BMCs. These results were subjected to functional annotation using gene ontology for the identification of molecular pathways showing different state of activation or repression in myogenic c-kit-BMCs. The 35 upregulated transcripts in myogenic c-kit-BMCs involved signal transduction and cell differentiation pathways. Similarly, a set of genes implicated in the response to stress were more represented in myogenic c-kit-BMCs, possibly reflecting the proficiency of this cell class to engraft in the microenvironment of the infarcted heart. A subset of these genes was found to be highly expressed in adult c-kit-positive resident cardiac stem cells. They included sequestosome1 and phosphodiesterase1C, which are highly expressed during cardiac development. Moreover, cathepsin D, which favors angiotensin II formation, sarcomeric accumulation, and myocyte hypertrophy, was more represented in myogenic c-kit-BMCs. With respect to the whole pool of freshly isolated c-kit-BMCs, 105 genes were downregulated in myogenic c-kit-BMCs, indicating that transdifferentation into cardiomyocytes requires the suppression of hematopoietic factors. In conclusion, c-kit-BMCs are functionally heterogeneous, containing cells with different cardiomyogenic potential.
Endothelin-1 Has a Unique Oxygen-Saving Effect by Increasing Contractile Efficiency in the Isolated Rat Heart
Authors: YuzoTakeuchi, YasukiKihara, KoichiInagaki, TakeshiYoneda, ShigetakeSasayama
Journal: Circulation (2001)

Background—The effect of endothelin (ET)-1 on cardiac energetics is not fully understood. Methods and Results—In isolated, coronary-perfused rat hearts, we measured left ventricular contractility index (Emax), pressure-volume area (PVA), and myocardial oxygen consumption (MVo2) before and after administration of ET-1 (1×10−9 mol/L). ET-1 increased Emax by 48±16% (P 0.99). ET-1 shifted MVo2-PVA upward, increasing the MVo2 intercept by 24±13%. At the same time, ET-1 decreased the slope (S), with 1/S (contractile efficiency) being 46±5% before and 56±5% after ET-1 (P<0.01). ET-1–induced increases in Emax and in contractile efficiency were abolished by an ETA receptor blocker (S-0139) but not by an ETB blocker (BQ-788). Although high [Ca2+] perfusion increased Emax and the intercept to the same extent as ET-1, it did not change S. NG-Nitro-l-arginine (an inhibitor of nitric oxide synthase) increa...
Abstract 19227: Weight History Influences the Likelihood of Subclinical Myocardial Injury
Authors: Chiadi Ndumele, Laura Cobb, Mariana Lazo, Natalie Bello, Amil Shah, Vijay Nambi, Roger S Blumenthal, Gary Gerstenblith, Scott D Solomon, Christie M Ballantyne, Elizabeth Selvin, Josef Coresh
Journal: Circulation (2015)

Introduction: Obesity is associated with myocardial injury as reflected by levels of high-sensitivity cardiac troponin T (hs-cTnT), and the combination of obesity and elevated hs-cTnT is linked to markedly increased heart failure risk. The association of weight history with myocardial injury is unknown. Hypothesis: We hypothesized that prior obesity increases the likelihood of myocardial injury among individuals without clinical cardiovascular disease (CVD). Methods: We evaluated 9,472 participants (mean age 63 years) at ARIC Visit 4 (1996-99) with BMI ≥ 18.5 kg/m2 and without prior CVD. BMI (kg/m2) at Visit 4 and BMI calculated from self-reported weight at age 25 were categorized as normal weight (18.5-24.9), overweight (25-29.9) and obese (≥30). We then cross-tabulated BMI categories at Visit 4 and at age 25. A cumulative weight measure of “BMI years” was also calculated by taking the average of the BMI values at ARIC visits 1-4 and at age 25 (with BMI centered at 25 kg/m2) and multiplying the average by the number of years from age 25 to visit 4. The primary outcome was elevated hs-cTnT (≥14 ng/L) at Visit 4. Logistic regression was used to estimate the associations of cross-categories of BMI at the two time points and of BMI years with elevated hs-cTnT. Results: Within each Visit 4 BMI category, a higher BMI category at age 25 was associated with increased odds of elevated hs-cTnT, with the highest odds seen among those with obesity at both time points (OR 4.97 [95% CI: 3.39-7.29]) compared to those with normal weight at both time points. BMI years ranged from -307 to 1,205 ((kg/m2) x years). A graded positive association was seen between BMI years and myocardial injury (Figure), with each 100 higher BMI years linked to a 27% higher likelihood of elevated hs-cTnT. Conclusions: Prior obesity and greater cumulative weight from young adulthood increase the likelihood of subclinical myocardial injury, underscoring the importance of long-term weight control for reducing CVD risk.
High Blood Pressure Trends in Children and Adolescents in National Surveys, 1963 to 2002
Authors: RebeccaDin-Dzietham, YongLiu, Marie-VeroBielo, FalahShamsa
Journal: Circulation (2007)

Background— Secular trend data on hypertension in children and adolescents are scarce and inconsistent. In the face of growing obesity, we sought to assess high blood pressure (HBP) secular trends in children and adolescents enrolled in national surveys and to determine whether the HBP trend reversed its course with the rise in obesity. Methods and Results— National survey data obtained from multistage probability sampling of the US noninstitutionalized population from 1963 to 2002 were examined; 8- to 17-year-old non-Hispanic blacks and whites and Mexican Americans were included. HBP ascertainment was based on age-, gender-, and height percentile–specific systolic and diastolic BPs. Weighted analyses were performed to account for the complex design. The BP, pre-HBP, and HBP trends were downward from 1963 to 1988 and upward thereafter. Pre-HBP and HBP increased 2.3% (P=0.0003) and 1% (P=0.17), respectively, between 1988 and 1999. Obesity increase, more so abdominal than general obesity, partially explaine...
Abstract 1543: Upregulation of mannose 6-phosphate receptor (MPR) has a potential to increase the efficacy of combined therapy for melanoma patients
Authors: Cigdem Atay, Sergio Lavilla-Alonso, Dmitry Gabrilovich
Journal: Cancer Research (2018)

Abstract BRAF -targeting therapy demonstrates impressive clinical response in patients with metastatic melanoma. However, patients quickly develop resistance associated with rapid tumor progression. Therefore, additional therapeutic approaches are necessary. Our group has previously shown that transient induction of cation-independent mannose 6-phosphate receptor (MPR) is important for the antitumor effect of chemo-immunotherapy. In this study, we aimed to decipher the role of MPR during possible combination therapy of BRAF inhibitor with adoptive T-cell therapy of BRAF inhibitor-resistant melanoma. For this aim, we have used PLX4720 as a BRAFV600E inhibitor and observed that in vitro PLX4720 treatment of human V600E-positive melanoma cells, including WM-35, SK-Mel-624 and WM983B, resulted in a dose-dependent upregulation of MPR on the cell surface. Importantly, increased levels of MPR on the cell surface induced the uptake of recombinant Granzyme B, which is a major mechanism of cell killing by cytotoxic T cells (CTL). We found that PLX4720 treatment rendered WM35 cells more prone to lysis by HLA-matching tumor-infiltrating lymphocytes (TILs) and increased cell killing is not due to PLX4720 treatment itself but increased levels of MPR on the cell surface. In order to prove this, we generated MPR-overexpressing WM35 cell line and showed that upregulation of MPR, independently of PLX4720 treatment, sensitizes melanoma cells for T cell killing in vitro. We further showed that PLX4720 treatment leads to upregulation of MPR in vivo by a mouse model bearing xenograft WM35-derived subcutaneous tumors as well. According to our data, 3 days of PLX4720 treatment is enough to induce MPR in tumors and this effect continues up to 6 days after 5 days treatment ends. Unexpectedly, we found that PLX4720 caused upregulation of MPR in resistant cell lines and that those cell lines became more sensitive to cytotoxic effect of TILs. Thus, our data suggest that adoptive T-cell therapy can be potentially effective in melanoma resistant to BRAF inhibitor. (This study is supported by NIH grant P50 CA168536.) Citation Format: Cigdem Atay, Sergio Lavilla-Alonso, Dmitry Gabrilovich. Upregulation of mannose 6-phosphate receptor (MPR) has a potential to increase the efficacy of combined therapy for melanoma patients [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 1543.
Pharmacological Activation of Soluble Guanylate Cyclase Protects the Heart Against Ischemic Injury
Authors: SevilKorkmaz, TamásRadovits, EnikőBarnucz, KristófHirschberg, PhilippNeugebauer, SivakkananLoganathan, GáborVeres, SzabolcsPáli, BeatriceSeidel, StefanZöllner, MatthiasKarck, GáborSzabó
Journal: Circulation (2009)

Background— The role of the nitric oxide/cGMP/cGMP–dependent protein kinase G pathway in myocardial protection and preconditioning has been the object of intensive investigations. The novel soluble guanylate cyclase activator cinaciguat has been reported to elevate intracellular [cGMP] and activate the nitric oxide/cGMP/cGMP–dependent protein kinase G pathway in vivo. We investigated the effects of cinaciguat on myocardial infarction induced by isoproterenol in rats. Methods and Results— Rats were treated orally twice a day for 4 days with vehicle or cinaciguat (10 mg/kg). Isoproterenol (85 mg/kg) was injected subcutaneously 2 days after the first treatment at an interval of 24 hours for 2 days to produce myocardial infarction. After 17 hours, histopathological observations and left ventricular pressure-volume analysis to assess cardiac function with a Millar microtip pressure-volume conductance catheter were performed, and levels of biochemicals of the heart tissues were measured. Gene expression analysi...
Abstract 3548: EPAC-RAP1, the alternative cyclic AMP signaling pathway, regulates cell cycle progression in primary melanoma cells
Authors: Aishwarya Krishnan, Kirthana Prabhakar, Mary Ndiaye, Nihal Ahmad, Carlos Ivan Rodriguez, Vijayasaradhi Setaluri
Journal: Cancer Research (2018)

Abstract Cyclic AMP (cAMP) is an important second messenger that acts as a key mediator in a wide range of cellular pathways. In melanocytes, the G-Protein Coupled Receptor (GPCR) Melanocortin-1-Receptor (MC1R), an important regulator of melanocyte proliferation and melanogenesis, activates cAMP signaling. Polymorphisms in MC1R lead to cAMP signaling impairments which are accompanied by higher risk for melanoma development. Despite the importance of cAMP signaling in melanocytes, very little is known about its role in melanoma. Exchange Protein directly Activated by cAMP (EPAC) constitutes an alternative pathway to cAMP signaling and is known to mediate the crosstalk between the cAMP and MAPK pathways. In this study, we show that pharmacological inhibition of EPAC, delays cell cycle progression and inhibits the growth of human primary melanoma cells. Flow cytometry and western blot analysis of cell cycle proteins showed that inhibition of EPAC arrests cells in G1-S and delays their mitotic progression. Paradoxically, inhibition of EPAC also caused an increase in AKT phosphorylation, suggesting a cell survival response elicited upon the cell cycle arrest caused by inhibition of EPAC allows continued survival of primary melanoma cells. Inhibition of EPAC in metastatic melanoma cells, on the other hand, stimulated their growth. These data show differential role of EPAC in primary and metastatic melanoma cells and provide a basis for targeting EPAC for prevention of cutaneous melanoma progression. Citation Format: Aishwarya Krishnan, Kirthana Prabhakar, Mary Ndiaye, Nihal Ahmad, Carlos Ivan Rodriguez, Vijayasaradhi Setaluri. EPAC-RAP1, the alternative cyclic AMP signaling pathway, regulates cell cycle progression in primary melanoma cells [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 3548.
Abstract 4424: Micro-RNA mediated deregulation of hHB-EGF in ovarian cancer
Authors: Md. Mustafizur Rahman, Razia Sultana, Ryo Iwamoto, Eisuke Mekada
Journal: Cancer Research (2018)

Abstract Background: Aberrant expression of microRNAs (miRNAs) has been implicated in human carcinogenesis where they function as oncogenes or tumor suppressor genes. Overexpression of HB-EGF, member of the epidermal growth factor (EGF) family, plays pivotal role in ovarian carcinogenesis. However the molecular mechanisms underlying miRNA(s) mediated aberrant function of HB-EGF in ovarian carcinoma remain unresolved. Here, we investigated the miRNA(s) mediated deregulation of HB-EGF in human ovarian carcinogenesis. Methods: Web-based bioinformatics algorithms were used to identify candidate miRNAs with putative binding sites on target hHB-EGF mRNA. Expression of miRNAs and mRNA were checked by real-time PCR whereas protein expression was investigated by western blotting assay. Luciferase reporter assay was carried out to examine miR-27a target on 3´UTR of hHB-EGF mRNA. Changes in the oncogenic effects of HB-EGF were studied after gain/loss -of-function of the miR-27a using soft agar colony formation assay and 3D collagen culture. In vivo tumor growth potential of miR-27a was measured in BALB/c nude mice. Results: By using web-based bioinformatics algorithms 11 miRNAs ((miR-27a/b, -29a/b/c, -96, -128, -132, -182,-194, -212) having putative binding sites on the 3′UTR of hHB-EGF mRNA have been selected for further analysis. Among the putative candidates miR-27a showed maximum reciprocal expression with hHB-EGF and thus we selected miR-27a as promising candidate for hHB-EGF regulation. Overexpression of miR-27a significantly inhibited the hHB-EGF expression in SKOV3 cells by almost 50% and miR-27a inhibitors (anti-miR-27a) upregulated the expression of endogenous hHB-EGF mRNA whereas miR-27a overexpression decreased hHB-EGF protein level in MCAS cells suggesting that miR-27a modulate endogenous hHB-EGF expression both at mRNA and protein level. Luciferase reporter assay revealed that miR-27a directly targets 3´UTR of hHB-EGF mRNA at the predicted site. Ectopic expression of miR-27a suppresses in-vitro growth of SKOV3 ovarian cancer cells. In addition, in-vivo tumorigenecity of SKOV3 cells was also inhibited by miR-27a treatment. Conclusion: The current study has identified novel miR-27a that negatively regulates hHB-EGF expression by directly targeting 3`UTR of its mRNA. This miR-27a might act as oncosupressor in human epithelial ovarian cancer. Citation Format: Md. Mustafizur Rahman, Razia Sultana, Ryo Iwamoto, Eisuke Mekada. Micro-RNA mediated deregulation of hHB-EGF in ovarian 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 4424.
TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading
Authors: Heidi Martini-Stoica, Allysa L. Cole, Daniel B. Swartzlander, Fading Chen, Ying-Wooi Wan, Lakshya Bajaj, David A. Bader, Virginia M.Y. Lee, John Q. Trojanowski, Zhandong Liu, Marco Sardiello, Hui Zheng
Journal: The Journal of Experimental Medicine (2018)

The progression of tau pathology in Alzheimer’s disease follows a stereotyped pattern, and recent evidence suggests a role of synaptic connections in this process. Astrocytes are well positioned at the neuronal synapse to capture and degrade extracellular tau as it transits the synapse and hence could potentially have the ability to inhibit tau spreading and delay disease progression. Our study shows increased expression and activity of Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, in response to tau pathology in both human brains with dementia and transgenic mouse models. Exogenous TFEB expression in primary astrocytes enhances tau fibril uptake and lysosomal activity, while TFEB knockout has the reverse effect. In vivo, induced TFEB expression in astrocytes reduces pathology in the hippocampus of PS19 tauopathy mice, as well as prominently attenuates tau spreading from the ipsilateral to the contralateral hippocampus in a mouse model of tau spreading. Our study suggests that astrocytic TFEB plays a functional role in modulating extracellular tau and the propagation of neuronal tau pathology in tauopathies such as Alzheimer’s disease.
Abstract 20393: Full-Dose Betrixaban Reduces Venous Thromboembolism-Related Mortality: An APEX Trial Substudy
Authors: C. Michael Gibson, Tarek Nafee, Samuel Z Goldhaber, Adrian F Hernandez, Russell D Hull, Alex Gold, Serge Korjian, Yazan Daaboul, Alexander T Cohen, Robert A Harrington, Gerald Chi
Journal: Circulation (2017)

Background: Extended thromboprophylaxis with full-dose betrixaban is effective in preventing venous thromboembolism (VTE). However, its effect on the hard endpoint of VTE-related mortality has not ...
Abstract 1195: Incidence rates of head and neck cancer across Thailand and the USA
Authors: Ilona Argirion, Katie Rentschler, Patravoot Vatanasapt, Hutcha Sriplung, Laura S. Rozek
Journal: Cancer Research (2018)

Abstract Background: Head and neck cancer is the sixth most common cancer in the world, with the largest burden occurring in developing countries. Although the primary risk factors have been well characterized, little is known about the temporal trends in head and neck cancer across Thailand. Using population based registries from three Thai provinces (Songkhla, Lampang and Khon Kaen), we have characterized the age-standardized incidence rates of head and neck cancer by sex and age and compared them to those observed in the United States. Methods: Cancer cases diagnosed between 1990 and 2014 were selected by ICD-10 code directly from the Songkhla, Lampang and Khon Kaen Cancer Registries as well as the Surveillance, Epidemiology, and End Results Program (SEER) for the following sites: oral cavity (00, 03-06), tongue (01-02), pharynx (09-10, 12-14), and larynx (32). The data were analyzed using R software (3.1.1) and Joinpoint Regression Software (4.4.0) to determine age-standardized incidence rates and trends of annual percent change. Incidence rates were standardized using the Segi (1960). Additional exploratory analyses using stratified linear regression models were conducted to assess temporal trends in head and neck cancer across 10-year age groupings. Results: Overall head and neck cancer rates are decreasing across all registries except Khon Kaen, where there is an observed, albeit not statistically significant, increase among males (APC: 0.53, p=0.3). Subsite analyses demonstrate consistent decreases in both larynx and oral cavity cancers, but suggested increases in pharynx and tongue cancers among both genders in the US (APC: 1.9 and 1.6, p&amp;lt;0.05 respectively) as well as pharynx cancer in Khon Kaen males (APC: 2.1, p&amp;lt;0.05). Furthermore, age-stratified APC analyses showed increased incidence in tongue cancer among Khon Kaen females age 30-39, Khon Kaen males age 30-59, Lampang males age 50-59, Songkhla females age 30-49, US females age 30-49 and 70-85+, as well as US males age 40-79. Pharynx cancers were seen to increase in Khon Kaen males age 40-59 and US males age 50-59. Conclusions: Although overall trends in head and neck cancer do seem to be decreasing across both Thailand and the United States, there is reason to believe that the etiological shift affecting both pharynx and tongue cancers in the US may be similarly presenting in Thailand. While disparities across gender and region do still exist, further investigation into the increased rates of early onset cancer is needed. Citation Format: Ilona Argirion, Katie Rentschler, Patravoot Vatanasapt, Hutcha Sriplung, Laura S. Rozek. Incidence rates of head and neck cancer across Thailand and the USA [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 1195.
Effect of Cell-Free DNA Screening vs Direct Invasive Diagnosis on Miscarriage Rates in Women With Pregnancies at High Risk of Trisomy 21
Authors: Valérie Malan, Laurence Bussières, Norbert Winer, Jean-Philippe Jais, Amandine Baptiste, Marc Le Lorc’h, Caroline Elie, Neil O’Gorman, Nicolas Fries, Véronique Houfflin-Debarge, Loic Sentilhes, Michel Vekemans, Yves Ville, Laurent J. Salomon
Journal: JAMA (2018)

Cell-free DNA (cfDNA) tests are increasingly being offered to women in the first trimester of pregnancies at a high risk of trisomy 21 to decrease the number of required invasive fetal karyotyping procedures and their associated miscarriages. The effect of this strategy has not been evaluated.To compare the rates of miscarriage following invasive procedures only in the case of positive cfDNA test results vs immediate invasive testing procedures (amniocentesis or chorionic villus sampling) in women with pregnancies at high risk of trisomy 21 as identified by first-trimester combined screening.Randomized clinical trial conducted from April 8, 2014, to April 7, 2016, in 57 centers in France among 2111 women with pregnancies with a risk of trisomy 21 between 1 in 5 and 1 in 250 following combined first-trimester screening.Patients were randomized to receive either cfDNA testing followed by invasive testing procedures only when cfDNA tests results were positive (n = 1034) or to receive immediate invasive testing procedures (n = 1017). The cfDNA testing was performed using an in-house validated method based on next-generation sequencing.The primary outcome was number of miscarriages before 24 weeks' gestation. Secondary outcomes included cfDNA testing detection rate for trisomy 21. The primary outcome underwent 1-sided testing; secondary outcomes underwent 2-sided testing.Among 2051 women who were randomized and analyzed (mean age, 36.3 [SD, 5.0] years), 1997 (97.4%) completed the trial. The miscarriage rate was not significantly different between groups at 8 (0.8%) vs 8 (0.8%), for a risk difference of -0.03% (1-sided 95% CI, -0.68% to ∞; P = .47). The cfDNA detection rate for trisomy 21 was 100% (95% CI, 87.2%-100%).Among women with pregnancies at high risk of trisomy 21, offering cfDNA screening, followed by invasive testing if cfDNA test results were positive, compared with invasive testing procedures alone, did not result in a significant reduction in miscarriage before 24 weeks. The study may have been underpowered to detect clinically important differences in miscarriage rates.ClinicalTrials.gov Identifier: NCT02127515.