tbuckley/cabot-search huggingface dataset:
Aldose Reductase Is an Obligatory Mediator of the Late Phase of Ischemic Preconditioning
Authors: KenShinmura, RobertoBolli, Si-QiLiu, Xian-LiangTang, EitaroKodani, Yu-tingXuan, SanjaySrivastava, AruniBhatnagar
Journal: Circulation Research (2002)

Aldose reductase (AR), a member of the aldo-keto reductase superfamily, has been shown to metabolize toxic aldehydes generated by lipid peroxidation, suggesting that it may serve as an antioxidant defense. To investigate its role in the late phase of ischemic preconditioning (PC), conscious rabbits underwent 6 cycles of 4-minute coronary occlusion/4-minute reperfusion. Twenty-four hours later, there was a marked increase in AR protein and activity and in the myocardial content of sorbitol, a unique product of AR catalysis. Pretreatment with Nω-nitro-l-arginine, a nitric oxide synthase inhibitor, or chelerythrine, a protein kinase C inhibitor (both given at doses that block late PC in this model), prevented the increase in AR protein 24 hours later, demonstrating that ischemic PC upregulates AR via nitric oxide- and protein kinase C-dependent signaling pathways. The AR-selective inhibitors tolrestat and sorbinil prevented AR-mediated accumulation of sorbitol and abrogated the infarct-sparing effect of late...
Intragland Shh gene delivery mitigated irradiation-induced hyposalivation in a miniature pig model
Authors: Liang Hu, Zhao Zhu, Bo Hai, Shimin Chang, Linsha Ma, Yipu Xu, Xiangchun Li, Xiaoyu Feng, Xiaoshan Wu, Qingguo Zhao, Lizheng Qin, Jingsong Wang, Chunmei Zhang, Fei Liu, Songlin Wang
Journal: Theranostics (2018)

Irreversible hypofunction of salivary glands is common in head and neck cancer survivors treated with radiotherapy and can only be temporarily relieved with current treatments. We found recently in mouse models that transient activation of Hedgehog pathway following irradiation rescued salivary gland function by preserving salivary stem/progenitor cells, parasympathetic innervation and microvessels. Due to huge differences between salivary glands of rodents and humans, to examine the translational potential of this approach, we evaluated effects of Shh gene transfer in a miniature pig model of irradiation-induced hyposalivation. Methods: The right parotid of each pig was irradiated with a single dose of 20 Gray. Shh and control GFP genes were delivered into irradiated parotid glands by noninvasive retrograde ductal instillation of corresponding adenoviral vectors 4 or 16 weeks after irradiation. Parotid saliva was collected every two weeks. Parotid glands were collected 5 or 20 weeks after irradiation for histology, Western blot and qRT-PCR assays. Results: Shh gene delivery 4 weeks after irradiation significantly improved stimulated saliva secretion and local blood supply up to 20 weeks, preserved saliva-producing acinar cells, parasympathetic innervation and microvessels as found in mouse models, and also activated autophagy and inhibited fibrogenesis in irradiated glands. Conclusion: These data indicate the translational potential of transient activation of Hedgehog pathway to preserve salivary function following irradiation.
Identification of Tissue-Specific DNA Methylation Signatures for Thyroid Nodule Diagnostics
Authors: John H. Yim, Audrey H. Choi, Arthur X. Li, Hanjun Qin, Sue Chang, Sun-Wing T. Tong, Peiguo Chu, Byung-Wook Kim, Daniel Schmolze, Ryan Lew, Yasmine Ibrahim, Valeriy A. Poroyko, Sylvana Salvatierra, Alysha Baker, Jinhui Wang, Xiwei Wu, Gerd P. Pfeifer, Yuman Fong, Maria A. Hahn
Journal: Clinical Cancer Research (2018)

Thyroid cancer is frequently difficult to diagnose due to an overlap of cytologic features between malignant and benign nodules. This overlap leads to unnecessary removal of the thyroid in patients without cancer. While providing some improvement over cytopathologic diagnostics, molecular methods frequently fail to provide a correct diagnosis for thyroid nodules. These approaches are based on the difference between cancer and adjacent thyroid tissue and assume that adjacent tissues are the same as benign nodules. However, in contrast to adjacent tissues, benign thyroid nodules can contain genetic alterations that can be found in cancer.Experimental Design: For the development of a new molecular diagnostic test for thyroid cancer, we evaluated DNA methylation in 109 thyroid tissues by using genome-wide single-base resolution DNA methylation analysis. The test was validated in a retrospective cohort containing 65 thyroid nodules.By conducting reduced representation bisulfite sequencing in 109 thyroid specimens, we found significant differences between adjacent tissue, benign nodules, and cancer. These tissue-specific signatures are strongly linked to active enhancers and cancer-associated genes. Based on these signatures, we developed a new epigenetic approach for thyroid diagnostics. According to the validation cohort, our test has an estimated specificity of 97% [95% confidence interval (CI), 81-100], sensitivity of 100% (95% CI, 87-100), positive predictive value of 97% (95% CI, 83-100), and negative predictive value of 100% (95% CI, 86-100).These data show that epigenetic testing can provide outstanding diagnostic accuracy for thyroid nodules.See related commentary by Mitmaker et al., p. 457.
The Adequacy of Subendocardial Oxygen Delivery
Authors: Johnbrazier, Normancooper, Geraldbuckberg
Journal: Circulation (1974)

The interactions of determinants of subendocardial oxygen delivery (flow and oxygen content) and oxygen demand were studied. In open chest dogs, oxygen requirements were increased with aortic stenosis and oxygen delivery reduced with normovolemic anemia. We estimated potential subendocardial flow from a Diastolic Pressure Time Index (DPTI) and oxygen demands from the Tension Time Index (TTI), and detected ischemia with endocardial (Endo) and epicardial (Epi) electrocardiograms (ECG). Subendocardial oxygen delivery per unit of TTI was significantly lowered and Endo ECGs showed ischemia (ST elevation) when Endo/Epi flow ratios (microsphere method) fell below 1.0 (P   10 g %) in severe aortic stenosis; with mild anemia (Hgb 5-10 g %) and mild aortic stenosis; and with severe anemia (Hgb < 5 g %) without aortic stenosis. Ischemic Endo ECGs occurred with mild supravalvar aortic stenosis and mild anemia despite a 63% (92 to 150 cc/100g/min) average increase in sub...
Abstract 361: Identification of a novel dependence on the SWI/SNF chromatin remodeling complex in uveal melanoma
Authors: Florencia Rago, Xiaoqin Xiang, Aurore Desplat, Emilie Niemezyk, David Ruddy, Grainne Kerr, Eusebio Manchado Robles, Deborah Castelletti, Zainab Jagani
Journal: Cancer Research (2018)

Abstract Uveal melanoma is a rare and aggressive cancer that originates in the pigmented tissues of the eye, which include the iris, the choroid and the ciliary body. To date, no targeted therapies have been approved for this cancer, and much remains to be described about the underlying biology of the disease. The most common driver mutation is an activating mutation in either the GNAQ or GNA11 GTPase, which in turns leads to hyperactivation of the MAPK pathway, but the precise downstream effectors driving tumorigenesis are poorly understood. Using pooled shRNA screening, we discovered that the SWI/SNF complex represents a novel genetic vulnerability in uveal melanoma, and further interrogated this dependency by a more targeted analysis across various uveal melanoma cell lines. While we observed the dropout of multiple SWI/SNF complex subunits in the screens, we defined the ATPase activity of SWI/SNF as central to the observed phenotype, implicating the chromatin remodeling function of the SWI/SNF complex in this phenotype. The regulation of gene expression by transcription factors can involve coordinated activity of SWI/SNF directed chromatin remodeling activity, so we began to investigate mechanistic links between SWI/SNF and other transcription factors such as MITF, which is known to play important roles in the differentiation of melanocytes. We observed that depletion of SWI/SNF affected transcription of certain MITF target genes, and are further investigating the precise pathways that are altered with SWI/SNF modulation. Taken together, these data suggest that the SWI/SNF complex plays an important role in maintaining tumor cell survival in uveal melanoma, and may represent a novel therapeutic target. Citation Format: Florencia Rago, Xiaoqin Xiang, Aurore Desplat, Emilie Niemezyk, David Ruddy, Grainne Kerr, Eusebio Manchado Robles, Deborah Castelletti, Zainab Jagani. Identification of a novel dependence on the SWI/SNF chromatin remodeling complex in uveal melanoma [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 361.
Abstract 4630: Characterizing oncogene addiction in alveolar rhabdomyosarcoma reveals novel strategies for combination therapy
Authors: Johannes Ommer, Marco Wachtel, Beat W. Schaefer
Journal: Cancer Research (2018)

Abstract Rhabdomyosarcoma is the most common soft tissue sarcoma in children. The aggressive alveolar subtype (aRMS) is characterized by chromosomal translocations, most often a t(2;13) resulting in the expression of the oncogenic fusion protein PAX3-FOXO1 which is critical for tumorigenesis and cell survival. Our aim here was to identify a pharmacological combination therapy approach interfering with PAX3-FOXO1 biology at different levels. Since loss of the fusion protein results in cell death, we first aimed to pharmacologically enhance this effect. To this end, we screened aRMS tumor cells with a library of 208 drugs while simultaneously silencing PAX3-FOXO1 by shRNA. This identified the BH3-mimetic ABT-263 to sensitize aRMS cells to cell death after PAX3-FOXO1 depletion. To further characterize the cell death mechanisms we used combined shRNA and CRISPR approaches to perform a BH3 protein profiling. In accordance with identification of ABT-263 we demonstrate that aRMS cells undergo intrinsic apoptosis in a NOXA-dependent manner upon depletion of PAX3-FOXO1. In a parallel approach, and to identify drugs altering PAX3-FOXO1 protein stability, we screened the same drug library directly measuring fusion protein levels as read-out. This revealed that inhibition of Aurora kinase A negatively affects PAX3-FOXO1 protein levels. Finally, using both aRMS cell lines and patient-derived xenografts we demonstrate that combination treatment of Aurora kinase A inhibitors together with ABT-263 synergistically induces cell death and greatly slows tumor growth in vitro and in vivo. Taken together, these data show a novel functional interaction of Aurora kinase A and PAX3-FOXO1 and suggest new opportunities for targeted combination treatment of aRMS. Citation Format: Johannes Ommer, Marco Wachtel, Beat W. Schaefer. Characterizing oncogene addiction in alveolar rhabdomyosarcoma reveals novel strategies for combination therapy [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 4630.
Abstract 17837: Patients With Familial Hypercholesterolemia Who Initiated Statin Treatment In Childhood Are At Lower Risk For Chd Then Their Affected Parents
Authors: Marjet J Braamskamp, D. M Kusters, Hans J Avis, Frits A Wijburg, John J Kastelein, Albert Wiegman, Barbara A Hutten
Journal: Circulation (2013)

Background: Statins are currently the preferred pharmacological therapy in children with familial hypercholesterolemia (FH) with the aim to prevent premature atherosclerosis and subsequent coronary...
Abstract 18257: Cardiovascular Response to Energy Drink Consumption in Healthy Adults
Authors: AnnaSvatikova, NaimaCovassin, KrishenSomers, FilipSoucek, TomasKara, LukasRuzek, JanBukartyk
Journal: Circulation (2014)

Introduction: An increasing number of healthy adults consume energy drinks to enhance their physical and mental performance. Energy drinks contain caffeine and multiple other “natural” stimulants and their combined effects on cardiac hemodynamics in healthy individuals are unclear. Hypothesis: We hypothesized that drinking a commercially available energy drink, Rockstar, compared to a placebo drink, increases resting blood pressure and heart rate in healthy adults, and these increases would be further accentuated by stress conditions. Methods: We enrolled 25 healthy, normotensive subjects (14 males), aged 29±1 years, with body mass index 24.5±1 kg/m2, in a randomized, double-blind, placebo-controlled, crossover study. Each subject consumed a placebo drink and a commercially available Rockstar energy drink (473 ml), in random order on two separate study days. Blood pressure and heart rate responses were recorded and compared before and 30 minutes after drink consumption, both at rest and then in response t...
Abstract 4527: Major pathologic response and biomarker predict survival in lung cancer patients receiving neoadjuvant chemotherapy
Authors: Apar Pataer, Ruping Shao, Arlene M. Correa, Ignacio I. Wistuba, Stephen G. Swisher
Journal: Cancer Research (2018)

Abstract In a previous study, we determined that major pathologic response (MPR) as indicated by the percentage of residual viable tumor cells predicted overall survival (OS) in patients with non-small cell lung cancer (NSCLC) who received neoadjuvant chemotherapy. In this study, we assessed whether 2 gene and 5 protein biomarkers could predict MPR and OS in 98 NSCLC patients receiving neoadjuvant chemotherapy. We assessed whether gene mutation status or protein expression was associated with MPR or OS. We observed that KRAS mutation tended to be associated with OS (p = 0.06), but EGFR mutation was not associated with OS. We found that patients with high RAD51 expression levels had a poorer prognosis than did those with low RAD51 expression. We also observed that RAD51 expression was associated with MPR. MPR and RAD51 expression were associated with OS in univariate and multivariate analyses (p = 0.04 and p = 0.02, respectively). Combination of MPR with RAD51 is a significant predictor of prognosis in NSCLC patients who received neoadjuvant chemotherapy. No association of MPR or VEGFR2, EZH2, ERCC1, RAD51, or PKR expression with KRAS or EGFR mutation was found. We demonstrated that MPR or RAD51 expression was associated with OS in NSCLC patients receiving neoadjuvant chemotherapy. Prediction of a patient's prognosis could be improved by combined assessment of MPR and RAD51 expression. Citation Format: Apar Pataer, Ruping Shao, Arlene M. Correa, Ignacio I. Wistuba, Stephen G. Swisher. Major pathologic response and biomarker predict survival in lung cancer patients receiving neoadjuvant chemotherapy [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 4527.
Accelerated Mitochondrial Adenosine Diphosphate/Adenosine Triphosphate Transport Improves Hypertension-Induced Heart Disease
Authors: ThomasWalther, CarstenTschöpe, AnjaSterner-Kock, DirkWestermann, SilviaHeringer-Walther, AlexanderRiad, AlenNikolic, YongWang, LindaEbermann, Wolf-EberhardSiems, MichaelBader, MehdiShakibaei, Heinz-PeterSchultheiss, AndreaDörner
Journal: Circulation (2007)

Background— Strong evidence suggests that mitochondrial malfunction, which leads to disturbed energy metabolism and stimulated apoptosis, is a linchpin in the induction and manifestation of cardiac failure. An adequate exchange of ATP and ADP over the inner mitochondrial membrane by the adenine nucleotide translocase (ANT) is thereby essential to guarantee the cellular energy supply. Methods and Results— To explore the effect of an ameliorated mitochondrial ATP/ADP transportation on cardiac dysfunction, we generated transgenic rats overexpressing ANT1 in the heart (ANT rats) and crossed them with renin-overexpressing rats (REN rats) suffering from hypertension-induced cardiac insufficiency. Cardiac-specific ANT1 overexpression resulted in a higher ATP/ADP transportation and elevated activities of respiratory chain complexes. Increased ANT activity in double-transgenic (ANT/REN) animals did not influence excessive hypertension seen in REN rats. Hypertension-induced cardiac hypertrophy in the REN rats was p...
Abstract 1148: Promising preclinical platform for evaluation of immuno-oncology drugs using Hu-PBL-NSG lung cancer models
Authors: Sun Min Lim, Kyoung-Ho Pyo, Jae Hwan Kim, Ji Min Lee, Seong Keun Kim, Sung Eun Kim, Ha Ni Jo, Jae Soek Cho, Hye Ryun Kim, Byoung Chul Cho
Journal: Cancer Research (2018)

Abstract Introduction: With the advance of immunotherapy, treatment of non-small-cell lung cancer (NSCLC) has revolutionized by having anti-PD-1 therapy in front-line setting. In this era of cancer immunotherapy, humanized mouse models which recapitulate human immune system, are needed for predicting immunotherapy response in patients. We established a Hu-PBL-NSG mouse model which can be used as a preclinical testing platform for assessing efficacy of different immunotherapeutic agents. Methods: Hu-PBL-NSG mouse model was established by engrafting human peripheral blood lymphocytes (PBLs) into NOD-scid (NSG) mice. The 6-7 week-old NSG mouse was transfused with 1 x 107 cells of PBL via tail vein, and human immune cells were characterized after 24 hours, and weekly thereafter. Cytokine array was performed to assess serological similarity between patient and the Hu-PBL-NSG mouse, and microscopic immune cell infiltration was observed in various organs mouse model. Human anti-PD-1 therapy was treated for assessing drug efficacy in patient-derived tumor. Results: hCD3+hCD45+ T-cells and antigen presenting cells (dendritic cells, macrophages, and MDSC) increased in the serum of Hu-PBL-NSG mouse 24 hour after the transfusion of human PBLs, and CD3+ T cells were observed in lung, liver, kidney, spleen sections. Cytokine arrays of human and Hu-PBL-NSG mouse revealed high similarity of Th1, Th2, Th17-related cytokines. A tumor xenograft was engrafted from an EML4-ALK patient, and Hu-PBL-NSG mouse was sacrificed for histological analyses. hCD3+ T cells were infiltrated within the tumor, and CD11c+ cells, which represent antigen-presenting capability, were seen in spleen, lung, liver and kidney. When anti-PD-1 Ab was treated intraperitoneally, xenograft tumor showed significant reduction in volume after day 6, and increased expression of immune response-related genes on microarray analysis in the tumor. Mostly IFN-gamma and its related gene sets were significantly changed (FDR &amp;lt; 0.25, GSEA). Conclusion: Hu-PBL-NSG mouse model which highly resembles human immune system was successfully established. This model could be a strong preclinical model for testing efficacy of immunotherapeutic agents, and also for pursuing novel immunotherapy treatment strategies in advanced NSCLC. Citation Format: Sun Min Lim, Kyoung-Ho Pyo, Jae Hwan Kim, Ji Min Lee, Seong Keun Kim, Sung Eun Kim, Ha Ni Jo, Jae Soek Cho, Hye Ryun Kim, Byoung Chul Cho. Promising preclinical platform for evaluation of immuno-oncology drugs using Hu-PBL-NSG lung cancer models [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 1148.
Endoscopically guided percutaneous suturing to facilitate closure of a large gastrocutaneous fistula with an over-the-scope clip
Authors: Robert A. Moran, Olaya Brewer Gutierrez, Juliana Yang, Tossapol Kerdsirichairat, Omid Sanaei, Vivek Kumbhari, Mouen A. Khashab
Journal: Endoscopy (2018)

Persistent gastrocutaneous fistula (GCF) after percutaneous endoscopic gastrostomy (PEG) tube removal is an uncommon complication [1]. Advances in endoscopy have enabled endoscopic closure of these defects with a multitude of modalities, including argon plasma coagulation (APC), endoscopic suturing, and over-the-scope clips (OTSCs) [2] [3] [4]. Percutaneous endoscopic suturing has recently been described for closure of GCF ([Fig. 1], [Video 1]) [5].
<i>BRCA1 </i>and<i> BRCA2</i> Testing in Medically Underserved Medicare Beneficiaries With Breast or Ovarian Cancer
Authors: Amy L. Gross, William J. Blot, Kala Visvanathan
Journal: JAMA (2018)

With Breast or Ovarian CancerIdentifying pathogenic germline mutations in BRCA1 and BRCA2 genes can affect therapeutic and preventive recommendations for individuals with cancer.It is unclear whether medically underserved individuals are afforded the option to test for such mutations.We assessed BRCA1 and BRCA2 test uptake in a cohort of medically underserved Medicare beneficiaries with breast cancer, ovarian cancer, or both.
Abstract 277: Midterm Outcome of Aortic Valvuloplasty Utilizing an Autologous Pericardial Patch in Patients with Severe Aortic Regurgitation
Authors: Takenori Otsuka, Makoto Suzuki, Hisao Yoshikawa, Go Hashimoto, Youko Ishikawa, Takako Ishida, Tsukasa Osaki, Masayoshi Matsuyama, Hiromasa Yamashita, Shin Uchida, Masao Moroi, Masato Nakamura, Shigeyuki Ozaki, Kaoru Sugi
Journal: Circulation (2011)

Background: We previously reported our experience with an aortic valve plasty (AVP) technique for repairing a stenotic aortic valve. We investigated the feasibility of AVP in patients with aortic regurgitation (AR). Method: Ninety patients underwent aortic valve plasty using a pericardial patch. Patients characteristics of the patients were as follows: mean age; 68 ± 12 years; the left ventricular ejection fraction, 56 ± 12%; and the left ventricular end-diastolic dimension, 58.1 ± 5.8 mm. Transesophageal and transthoracic echocardiography were performed up to three year after the operation. Results: There was no postoperative AR in 81 patients and trivial postoperative AR in 9 patients. The peak systolic pressure gradient across the aortic valve was 14.5 ± 5.6 mm Hg after valve plasty. No patient underwent reoperation for any reason. Peak systolic gradient was significantly lower in aortic valve plasty group compared with aortic valve replacement group using biosprosthetic valve with or without stent (14.5±5.6 vs 28.6±10.2, respectively, p&lt; 0.001).The peak systolic gradient was 13.0 ± 7.1 mm Hg after two year. Up to three years later, there was no significant increase in the peak systolic gradient or significant worseningin AR (Figure). Conclusion: Aortic valve plasty using an autologous pericardial patch to treat aortic regurgitation is safe and feasible
Abstract 31: Regulation of Acetylation Restores Proteolytic Function in Diseased Myocardium
Authors: DingWang, CaiyunFang, NobelZong, Tae-YoungKim, DavidLiem, MarioDeng, PeipeiPing
Journal: Circulation Research (2012)

RATIONALE: Proteasome complexes play essential roles in maintaining cardiac protein homeostasis in normal and stressed conditions. However, proteasomal function is often compromised in diseased myocardium; and the regulation of proteasomal dynamics remains poorly understood. METHODS AND RESULTS: We studied cardiac proteolytic function and its regulation by acetylation in murine and human models of heart disease. Proteasomes, from both normal and diseased myocardium, were treated with histone de-acetylases (HDACs) inhibitors and they exhibited enhanced proteolytic capacity in vitro and in vivo. This unique regulatory paradigm was first examined in a murine model of ischemic injury (n=5); where diminished proteolytic function in the ischemic hearts was restored by HDACs inhibition (either by SAHA or by Sodium Valproate) in a dose-dependent fashion. Importantly, this phenomenon was validated in human samples, where inhibition of HDACs augmented proteolytic functions in the diseased myocardium (n=5). Using hi...