tbuckley/cabot-search huggingface dataset:
Enhancement of the ATP-Sensitive K+ Current by Extracellular ATP in Rat Ventricular Myocytes
Authors: AndreyBabenko, GuyVassort
Journal: Circulation Research (1997)

Abstract ATP-sensitive K+ (KATP) channels are present at high density in membranes of cardiac cells, where they regulate cardiac function during metabolic impairment. The present study analyzes the effects of extracellular ATP (ATPe), a P2-purinergic agonist that can be released under various conditions in the myocardial cell bed, on KATP current (IK-ATP) in rat ventricular myocytes. Under the whole-cell patch-clamp configuration at a physiological level of intracellular ATP, applying ATPe in the micromolar range did not activate IK-ATP. However, dialyzing the cell with a low-ATP (100 μmol/L) pipette solution elicited a slowly, quasilinearly increasing IK-ATP that was markedly enhanced by applying ATPe in the presence of a P1-purinergic antagonist. The effect was reversible on washing out the agonist. The IK-ATP enhancement was inhibited by cholera toxin treatment of the myocytes, suggesting that a Gs protein was involved to mediate the effect. Experiments on excised patches allowed us to exclude a membra...
Transcutaneous Oxygen Pressure Measurements on the Buttocks During Exercise to Detect Proximal Arterial Ischemia
Authors: PierreAbraham, JeanPicquet, BrunoVielle, DominiqueSigaudo-Roussel, FrancinePaisant-Thouveny, BernardEnon, Jean-LouisSaumet
Journal: Circulation (2003)

Background— We sought to identify whether transcutaneous oxygen tension (tcPo2) measurements could be used to noninvasively detect lesions in the arterial network supplying blood flow to the hypogastric circulation. Methods and Results— A study was undertaken in vascular patients with suspected (PC, n=43) and not with suspected (NPC, n=34) proximal ischemia. TcPo2 was measured on both buttocks and with a chest reference electrode. Arteriography on the right or left side was positive for stenoses (≥75%) or occlusion of one or more of the following arteries: the aorta, the common iliac arteries, or the internal iliac arteries. The arteriography was compared with the resting tcPo2 values (REST) and with the minimal value (MIN) and maximal change from rest normalized to eventual chest changes (DROP) recorded during or after a treadmill test. REST, MIN, and DROP were, respectively, as follows in positive versus negative arteriograms (mean±SD; in mm Hg): 80.2±10.9 versus 78.6±11.5 (P>0.05), 55.2±20.0 versus 69....
Abstract 5044: Molecular analysis of HBV in histologically confirmed hepatocellular carcinoma in a tertiary hospital in Ghana
Authors: Babatunde M. Duduyemi, Du-bois Asante, Nicholas Titiloye, Mary Afihene
Journal: Cancer Research (2018)

Abstract Background: Hepatocellular carcinoma (HCC) is a leading cause of death in Africa. Viral hepatitis B is a leading cause of hepatocellular cancer in Ghana and most African countries except Egypt where hepatitis C virus is more prevalent. This study aims at reviewing the histopathological patterns of HCC and its association with hepatitis B virus in our environment. Method: Demographics and histological diagnosis were retrieved from the surgical daybook and archival FFPE tissue samples with histopathologically confirmed HCC were used for this study. Sections (10µm) were taken from the tissues and digested to obtain DNA lysates. The DNA lysates were used in polymerase chain reaction (PCR) to determine the prevalence of HBV in the biopsies. Result: Of the 24 confirmed cases of HCC seen in the 5 year period, there were 17 males and 7 females with M:F ratio of 2.4:1. The mean age of our patients was 39.92 ± 1.98 years with age range 13-85 years. 50% of the cases were moderately differentiated while 25% each were well and poorly differentiated. Out of the 24 archival HCC biopsies screened, HBV DNA PCR amplification was achieved in 11 after the restriction fragment length polymorphism PCR reaction. Out of the 24 archival HCC biopsies screened, HBV DNA PCR amplification was achieved in 11 (45.83%) after the restriction fragment length polymorphism PCR reaction. Eight of the 11 cases were found in the male and 3 in females. Of the 11 (45.83%) samples that were positive for HBV DNA, 3 were above 40 years and 8 were 40 years and below. Conclusion: The overall prevalence of HBV DNA in our study was 45.83% and a greater proportion seen in less than 40 years. This suggests that most of our patients are infected with HBV early in life in our environment. Citation Format: Babatunde M. Duduyemi, Du-bois Asante, Nicholas Titiloye, Mary Afihene. Molecular analysis of HBV in histologically confirmed hepatocellular carcinoma in a tertiary hospital in Ghana [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 5044.
Abstract 1218: An eQTL and mQTL study of 147 genetic variants associated with prostate cancer susceptibility
Authors: Xiaoyu Wang, Anqi Cheng, Janet L. Stanford, James Y. Dai
Journal: Cancer Research (2018)

Abstract Genome-wide association studies by the PRACTICAL consortium have identified and validated 147 single nucleotide polymorphisms (SNPs) associated with prostate cancer (PCa) risk (Schumacher et al., Nat Genet 2017). However, most of these genetic variants are in noncoding regions, which poses a challenge for understanding the molecular mechanisms underlying these risk loci. Herein we study both expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL) among these PCa risk loci to identify molecular alterations associated with these genetic variants. Data were available for a Fred Hutchinson (FH)-based cohort of patients diagnosed with localized stage PCa, including SNP genotypes (Infinium iCOGS and OncoArray-500K BeadChips) from the PRACTICAL consortium and genome-wide DNA methylation (Infinium Human Methylation450 BeadChip) and gene expression (HumanHT-12 v4 BeadChip) profiling of primary tumor tissues obtained at radical prostatectomy. Missing genotypes were imputed using the October 2014 (Phase 3) release of the 1KGP data as the reference panel. These data were used to identify eQTL (N=355) and mQTL (N=377) in cis-acting associations where the transcripts or CpG sites are located within 2Mb (±1Mb) of the genetic variants. The Matrix eQTL software was used to conduct eQTL and mQTL analyses. In total, 4,300 SNP-transcript pairs and 104,600 SNP-CpG pairs were tested for eQTL and mQTL, respectively, among which we identified 64 eQTL-transcript pairs (37 PCa risk loci and transcripts in 54 genes) and 1,405 mQTL-CpG pairs (116 PCa risk loci and CpGs in 321 genes), after correction for multiple testing (FDR&amp;lt;0.05). The remaining 29 (20%) PCa risk loci were neither eQTLs nor mQTLs. Interestingly, 35 (95%) eQTLs were also mQTLs, while the majority of mQTLs were not eQTLs (Fisher's exact test of independence, p=0.005), suggesting that DNA methylation may have alternative biologic regulatory functions other than directly affecting gene expression. Several of these genes associated with eQTLs such as INCENP, NUDT11, RGS17, ASCL2, C10orf32, MSMB, BHLHA15, and IRX4 were previously found in PCa. Furthermore, we discovered a number of novel genes such as HLA-DRB3 and HLA-DRB4 associated with eQTLs in our data. Further validation using the TCGA-PRAD data is under way. In summary, we identified eQTLs and mQTLs among newly established genetic risk loci for PCa. These results provide new insight into both the genetic and epigenetic mechanisms through which these SNPs may alter susceptibility to PCa. Citation Format: Xiaoyu Wang, Anqi Cheng, the PRACTICAL Consortium, Janet L. Stanford, James Y. Dai. An eQTL and mQTL study of 147 genetic variants associated with prostate cancer susceptibility [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 1218.
Photodynamic Therapy of Normal and Balloon-Injured Rat Carotid Arteries Using 5-Amino-Levulinic Acid
Authors: IsaacNyamekye, SandraAnglin, JeanMcEwan, AlexanderMacRobert, StephenBown, ChristopherBishop
Journal: Circulation (1995)

Background Although the management of atherosclerotic disease by the use of balloon angioplasty is widespread, the treatment is limited by restenosis in 30% to 50% of cases. Fibrocellular intimal hyperplasia, the main cause of restenosis, arises from proliferation and migration of medial smooth muscle cells (SMC) into the intimal layer. Factors leading to intimal hyperplasia are incompletely understood, and drugs have universally failed to influence clinical restenosis. Photodynamic therapy (PDT), the light activation of photosensitizing drugs to generate cytotoxic mediators, may have potential as prophylaxis for intimal hyperplasia. 5-Amino-levulinic acid–induced protoporphyrin IX (ALA-PPIX), a naturally occurring porphyrin precursor, and its product, -PPIX, offers a novel method of sensitization for PDT. We have investigated the pharmacokinetics of ALA in arteries and the effects of ALA-PPIX–sensitized PDT on normal and balloon-injured arteries. Methods and Results ALA (20 to 200 mg/kg) was injected int...
Abstract 5041: Repair of azoxymethane-induced nuclear and mitochondrial DNA lesions in mouse liver
Authors: Carlos A. Torres-Ramos, Adlin Rodriguez-Munoz, Joan Ballista-Hernandez, Ceidy Torres-Ortiz, Sylvette Ayala-Pena
Journal: Cancer Research (2018)

Abstract Background &amp; Objectives: Azoxymethane (AOM) is a carcinogen that induces DNA lesions mainly repaired by the base excision repair (BER) pathway. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central component of BER. Mice with homozygous deletion of the Apex1 gene (which encodes APE1) cannot survive development but heterozygous animals (Apex1+/-) have a normal lifespan. Our aim was to study the role of APE1 in the repair of DNA lesions and changes in mitochondrial DNA (mtDNA) abundance induced by AOM in the liver. Methods: We isolated DNA from 6-month-old C57BL/6 WT and Apex1+/- mice that were treated with a single AOM dose (10 mg/kg) and sacrificed 24, 48 and 72 hours after treatment. To quantify nuclear DNA (nDNA) lesions, mtDNA lesions and changes in mtDNA abundance in liver tissue we applied a PCR based assay (QPCR). Results: Our data show that 24h after AOM treatment both WT and Apex1+/- mice exhibit significant levels of nDNA and mtDNA damage. The lesion number decreases 48 and 72h after treatment but remains statistically elevated as compared to their respective controls. A two tailed ANOVA analysis shows no significant differences in DNA lesions between genotypes. However, Apex1+/- mice show a statistically significant 13% decrease in mtDNA abundance 72 hours after treatment. Conclusions: These results indicate that the liver is a major target of AOM and that APE1 plays a role in preventing AOM-induced loss of mtDNA abundance. Acknowledgments: Supported by R25GM061838, 2G12RR003051 and U54CA096297. Citation Format: Carlos A. Torres-Ramos, Adlin Rodriguez-Munoz, Joan Ballista-Hernandez, Ceidy Torres-Ortiz, Sylvette Ayala-Pena. Repair of azoxymethane-induced nuclear and mitochondrial DNA lesions in mouse liver [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 5041.
Abstract 5110: Runx knockout in breast luminal stem/progenitor cells induced precancerous lesion via robust expression of ERα
Authors: Junichi Matsuo, Naing Naing Mon, Akihiro Yamamura, Dede L. Heng, Linda SH Chuang, Motomi Osato, Yoshiaki Ito
Journal: Cancer Research (2018)

Abstract In breast cancer, 83% of patients were diagnosed as hormone receptor positive, luminal-type, breast cancer (Anderson et al., 2014). Although primary luminal-type breast cancer can be controlled by endocrine therapy, more than 20% of patients have recurrence in 20 years (Pan et al., 2017). Understanding of luminal-type breast cancer would provide benefits to a large number of patients. However, cell of origin and genes responsible for luminal-type breast cancer have not been fully understood. Luminal epithelial cells are considered as origin of breast cancer (Anderson et al., 2014), although not fully proven yet. In addition, extensive genomic analysis of breast cancer patients in TCGA study showed that RUNX genes were downregulated in luminal-type breast cancer: RUNX1 mutation was found in multiple patients, and RUNX3 gene was highly methylated. We previously reported that 270 bp Runx1 enhancer element (eR1) marks hematopoietic stem cell and stomach stem cell (Ng et al., 2010; Matsuo et al., 2017). We also found that this eR1 marks a subset of luminal epithelial cells in mouse mammary gland. Lineage-tracing experiment showed that the eR1+ cells mainly differentiated into luminal cells, but not to basal cells in vivo. These eR1+ cells also contribute to differentiation of alveolar cells in pregnant mice. Interestingly, in vitro lineage tracing by using organoid culture showed that eR1+ cells differentiated into both liminal and basal cells. Runx1 and Runx3 knockout in luminal stem cells showed increase of cell growth, and histology was similar to precancerous lesion such as hyperplasia and ductal carcinoma in situ (DCIS). These lesions showed robust expression of ERα compared with control mice. These results suggested that depletion of Runx in luminal stem cells induces precancerous lesion via robust expression of ERα. References: Anderson WF, Rosenberg PS, Prat A, et al. How many etiological subtypes of breast cancer: Two, three, four, or more? J Natl Cancer Inst 2014;106. Pan H, Gray R, Braybrooke J, et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med 2017:1836-46. Ng CE, Yokomizo T, Yamashita N, et al. A Runx1 intronic enhancer marks hemogenic endothelial cells and hematopoietic stem cells. Stem Cells 2010:1869-81. Matsuo J, Kimura S, Yamamura A, et al. Identification of stem cells in the epithelium of the stomach corpus and antrum of mice. Gastroenterology 2017:218-31. Citation Format: Junichi Matsuo, Naing Naing Mon, Akihiro Yamamura, Dede L. Heng, Linda SH Chuang, Motomi Osato, Yoshiaki Ito. Runx knockout in breast luminal stem/progenitor cells induced precancerous lesion via robust expression of ERα [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 5110.
Assessment of urinary 3-indoxyl sulfate as a marker for gut microbiota diversity and abundance of <i>Clostridiales</i>
Authors: Fedja Farowski, Gregor Els, Anastasia Tsakmaklis, Paul G. Higgins, Christian R. Kahlert, Christoph K. Stein-Thoeringer, Johanna S. Bobardt, Katja Dettmer-Wilde, Peter J. Oefner, Jörg Janne Vehreschild, Maria J.G.T. Vehreschild
Journal: Gut Microbes (2018)

Objectives: After allogeneic hematopoietic stem cell transplantation (allo-HCT), urinary levels of 3-indoxyl sulfate (3-IS) correlate with the relative abundance of bacteria from the class Clostridia (RAC), and antibiotic treatment is considered the major determinant of this outcome. A high RAC has been associated with favorable outcome after allo-HCT and protection from Clostridium difficile infection (CDI). We assessed correlations between alpha diversity, RAC and urinary 3-IS levels in a non-allo-HCT clinical cohort of antibiotic treated patients to further explore 3-IS as a biomarker of reduced diversity and predisposition to CDI.Methods: Fecal and urinary specimens were analyzed from 40 non-allo-HCT hospitalized patients before and 9 ± 2 days after initiation of intravenous antibiotic treatment. Fecal microbiota were analyzed by 16s RNA sequencing and urinary 3-IS was analyzed by liquid chromatography-tandem mass spectrometry. Receiver operating characteristic (ROC) analysis was performed to assess the predictive value of 3-IS.Results: At a RAC cutoff of <30%, the binary logarithm of 3-IS (medium 3-IS: ≤2.5; high 3-IS: >2.5) was predictive with an accuracy of 82% (negative predictive value: 87%, positive predictive value 67%). Accuracy was improved by combing antibiotic history with 3-IS levels (accuracy 89%, npv 88%, ppv 92%).Conclusion: In conjunction with patient antibiotic history, 3-IS is a candidate marker to predict RAC.
Beneficial Cardiovascular Pleiotropic Effects of Statins
Authors: JeanDavignon
Journal: Circulation (2004)

Pleiotropic effects of a drug are actions other than those for which the agent was specifically developed. These effects may be related or unrelated to the primary mechanism of action of the drug, and they are usually unanticipated. Pleiotropic effects may be undesirable (such as side effects or toxicity), neutral, or, as is especially the case with HMG-CoA reductase inhibitors (statins), beneficial. Pleiotropic effects of statins include improvement of endothelial dysfunction, increased nitric oxide bioavailability, antioxidant properties, inhibition of inflammatory responses, and stabilization of atherosclerotic plaques. These and several other emergent properties could act in concert with the potent low-density lipoprotein cholesterol-lowering effects of statins to exert early as well as lasting cardiovascular protective effects. Understanding the pleiotropic effects of statins is important to optimize their use in treatment and prevention of cardiovascular disease.
Abstract 1824: Mechanisms of resistance to anti-EGFR/HER2 therapy in breast cancer
Authors: Luis Daniel Borrero-García, Brian Vidal, Suranganie Dharmawardhane
Journal: Cancer Research (2018)

Abstract Therapy resistance to epidermal growth factor receptor family (EGFR and HER2) targeted therapies has been an obstacle for treatment success in breast cancer. Therefore, our goal is to investigate the mechanisms of resistance to these therapeutics and look for alternative ways to overcome such resistance. We previously created and characterized syngeneic gefitinib and lapatinib (EGFR and HER2 therapeutics) therapy resistant variants of the therapy sensitive SKBR3 human breast cancer cell line. We found that key mechanisms of resistance involved downregulation of miR-200a and upregulation of miR-221/222 families, which are known to regulate epithelial to mesenchymal transition (EMT). To validate the role of miR-221/222 in therapy resistance, western blots were performed for the miR-221/222 target Trichorhinophalangeal syndrome type I (TRPS1) protein. Downregulation of TRPS1 is known to promote EMT and metastasis. As expected, our results showed a downregulation of TRPS1 in the therapy resistant cells compare to the therapy sensitive cells. Since miR-200a was significantly downregulated in the therapy resistant cells, we ectopically expressed miR-200a in the EGFR therapy resistant SKBR3 cells using a lentiviral vector. MiR-200a expressing cells were selected by puromycin resistance. Preliminary data showed a decrease in the fold resistance of cells resistant to lapatinib transfected with lentiviral vector overexpressing miR-200a. These results suggest that overexpression of miR-200a in lapatinib resistant cells can be used to overcome therapy resistance in breast cancer. Citation Format: Luis Daniel Borrero-García, Brian Vidal, Suranganie Dharmawardhane. Mechanisms of resistance to anti-EGFR/HER2 therapy 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 1824.
Nudging Physicians to Reduce Quetiapine Prescribing Using Medicare Letters
Authors: Joshua M. Liao, Amol S. Navathe
Journal: JAMA Psychiatry (2018)

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A simple but profound mutation in mouse DNA polymerase ε drives tumorigenesis
Authors: Thomas A. Kunkel
Journal: Journal of Clinical Investigation (2018)

Over 40 years ago, Loeb and colleagues proposed that errors in DNA replication produce a mutator phenotype that is involved in generating the multiple mutations required for tumor development. In this issue of the JCI, Li, Castrillon, and colleagues describe a mouse model containing a single base change in the gene encoding replicative DNA polymerase ε (POLE) that mimics the "ultramutator" phenotype recently reported in many human tumors. Their seminal accomplishment validates Loeb's hypothesis and the use of mutational signatures to understand the origins and potentially the treatment of human tumors, and it offers an exciting opportunity to further explore the mechanisms responsible for normal DNA replication fidelity and their perturbations.