tbuckley/cabot-search huggingface dataset:
Arsenic Exposure and Glucose Intolerance/Insulin Resistance in Estrogen-Deficient Female Mice
Authors: Chun-Fa Huang, Ching-Yao Yang, Ding-Cheng Chan, Ching-Chia Wang, Kuo-How Huang, Chin-Ching Wu, Keh-Sung Tsai, Rong-Sen Yang, Shing-Hwa Liu
Journal: Environmental Health Perspectives (2015)

Epidemiological studies have reported that the prevalence of diabetes in women > 40 years of age, especially those in the postmenopausal phase, was higher than in men in areas with high levels of arsenic in drinking water. The detailed effect of arsenic on glucose metabolism/homeostasis in the postmenopausal condition is still unclear.We investigated the effects of arsenic at doses relevant to human exposure from drinking water on blood glucose regulation in estrogen-deficient female mice.Adult female mice who underwent ovariectomy or sham surgery were exposed to drinking water contaminated with arsenic trioxide (0.05 or 0.5 ppm) in the presence or absence of 17β-estradiol supplementation for 2-6 weeks. Assays related to glucose metabolism were performed.Exposure of sham mice to arsenic significantly increased blood glucose, decreased plasma insulin, and impaired glucose tolerance, but did not induce insulin resistance. Blood glucose and insulin were higher, and glucose intolerance, insulin intolerance, and insulin resistance were increased in arsenic-treated ovariectomized mice compared with arsenic-treated sham mice. Furthermore, liver phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was increased and liver glycogen content was decreased in arsenic-treated ovariectomized mice compared with arsenic-treated sham mice. Glucose-stimulated insulin secretion in islets isolated from arsenic-treated ovariectomized mice was also significantly decreased. Arsenic treatment significantly decreased plasma adiponectin levels in sham and ovariectomized mice. Altered glucose metabolism/homeostasis in arsenic-treated ovariectomized mice was reversed by 17β-estradiol supplementation.Our findings suggest that estrogen deficiency plays an important role in arsenic-altered glucose metabolism/homeostasis in females.Huang CF, Yang CY, Chan DC, Wang CC, Huang KH, Wu CC, Tsai KS, Yang RS, Liu SH. 2015. Arsenic exposure and glucose intolerance/insulin resistance in estrogen-deficient female mice. Environ Health Perspect 123:1138-1144; http://dx.doi.org/10.1289/ehp.1408663.
IM-03 * SERIAL METABOLISM OF DIFFUSE INTRINSIC PONTINE GLIOMA TREATED WITH PEPTIDE BASED VACCINE THERAPY
Authors: A. Panigrahy, B. Kurland, R. Ceschin, S. Abberbock, H. Okada, R. Jakacki, I. Pollack, S. Bluml
Journal: Neuro-Oncology (2015)

PURPOSE: Diffuse intrinsic pontine glioma (DIPG) carries the worst prognosis in pediatric neurooncology, with no improvement in outcomes for decades. The goal of this study was to examine myo-inositol (mI)/choline and other metabolites (measured by serial MRS) as predictors of overall survival in (1) a DIPG cohort treated with standard radiochemotherapy and (2) a DIPG cohort treated with radio-therapy followed by peptide-based vaccine therapy. METHODS: 50 MRS studies were performed in 11 patients with DIPG enrolled in a phase 1 clinical trial of peptide based vaccine therapy. 56 MRS studies were performed in 14 patients receiving only radio-chemotherapy. Metabolic profiles were binned into comparable time points after radiation therapy. All spectra were acquired using a single-voxel PRESS sequence (TE = 35ms, TR = 1.5s, 128 averages). Spectra were processed with fully automated LCModel (version 6.3-1c) software. Concentrations of the main metabolites (NAA, Cr, Cho, mI) and metabolite ratios relative to Cho were evaluated. Generalized estimating equations were used to evaluate longitudinal associations between metabolites and/or therapy group and overall survival. RESULTS: The 25 patients survived 6-25 months after diagnosis. Study baseline (post radiotherapy/pre-vaccine, 78-116 days post-diagnosis) mI/choline measures did not predict overall survival, but at subsequent time points higher mI/choline was associated with longer overall survival (p <0.05). A statistical interaction in the model with scans 159-250 days post-diagnosis (p < 0.001) suggested that the association with survival was much greater in the vaccine group (47 days' greater expected survival for each unit higher mI/choline ratio, after ∼2 vaccine doses) than for the non-vaccine group (13 days). DISCUSSION: mI/choline ratio may be a predictive marker for early response to peptide-based vaccine therapy of pediatric DIPG. A larger sample study is needed to further validate that MRS could be used to optimize/adjust peptide based vaccine therapy of DIPG patients.
Clinical Course and Prognosis of Hypertrophic Cardiomyopathy in an Outpatient Population
Authors: Paolo Spirito, Francesco Chiarella, Lorenzo Carratino, Massimo Zoni Berisso, Paolo Bellotti, Carlo Vecchio
Journal: New England Journal of Medicine (1989)

Hypertrophic cardiomyopathy has been investigated mainly at referral institutions. Thus, the clinical history of the disease that emerges from published studies could be influenced by a bias in patient selection. In the present study, we compared the clinical features of an outpatient population of 25 patients who had hypertrophic cardiomyopathy with those reported in 78 studies published during the past five years. In the 25 study patients, age, sex, and the extent of left ventricular hypertrophy, as well as the prevalence of diastolic filling abnormalities, subaortic obstruction, and ventricular arrhythmias, were similar to those in patients described in the literature. Cardiac symptoms, however, were much less severe in the study patients. Eighteen patients (72 percent) were asymptomatic, six (24 percent) had mild symptoms, and only one (4 percent) had moderate-to-severe symptoms. Of 24 patients followed for a mean period of 4.4 years (range, 2.9 to 5.7), none died or had clinical deterioration. Of 3404 patients described in the 78 studies we reviewed, 2483 (73 percent) came from only two referral institutions. Of the 1721 patients in whom severity of symptoms was reported, 757 (44 percent) had moderate-to-severe symptoms. However, 727 (96 percent) of these patients were studied at one of the same two referral institutions. We conclude that the natural history of hypertrophic cardiomyopathy may be more benign than can be inferred from published reports. (N Engl J Med 1989; 320: 749–55.)
Transmission of an Encephalitogenic Agent from Brains of Patients with Subacute Sclerosing Panencephalitis to Ferrets
Authors: Michael Katz, Lucy Balian Rorke, William S. Masland, Hilary Koprowski, Samuel H. Tucker
Journal: New England Journal of Medicine (1968)

Ten per cent suspensions of brain tissue from three patients with subacute sclerosing panencephalitis were inoculated intracerebrally into ferrets. These animals manifested a neurologic disease, characterized by ataxia and loss of interest in the environment, approximately five months after the inoculation. Examination of brains and spinal cords revealed encephalomyelitis, whose histologic picture included gliosis, round-cell and plasma-cell infiltration with perivascular cuffing and neuronophagia. Inoculation of 10 per cent suspensions of brains from these ferrets into new ferrets reproduced the disease after a shorter (three months') incubation period. Injection of suspensions of three human brains obtained at autopsy of patients who did not have panencephalitis and of a suspension of a normal ferret brain did not produce this disease in ferrets. Electroencephalography revealed abnormal patterns before signs of clinical disease appeared.
Alveolar hypoxia increases lung fluid filtration in unanesthetized newborn lambs.
Authors: M A Bressack, R D Bland
Journal: Circulation Research (1980)

We studied the pulmonary vascular response to hypoxia and associated transvascular flux of fluid into the lungs of newborn lambs.After a 2-hour baseline period, 14 unanesthetized lambs, 1-3 weeks old, breathed 10-12% oxygen in nitrogen for 3-6 hours.We measured steady state lung lymph flow, pulmonary arterial and left atrial pressures, blood flow to the lungs, and the concentration of protein in lymph and plasma.As Pao 2 decreased from 81 ± 3 torr to 32 ± 1 torr, pressure in the pulmonary artery almost doubled, left atrial pressure was unchanged, and pulmonary blood flow increased by 14%.Calculated pulmonary vascular resistance increased by 69%.Contrary to results of previous experiments performed with mature sheep, lymph flow increased by 80%, and the concentration of protein in lymph decreased during hypoxia.These results suggest that hypoxia increased the pulmonary transvascular gradient of hydraulic pressure in the lambs, increasing filtration of fluid into the lungs.Possible explanations are that pulmonary vasconstriction during hypoxia (1) occurred distal to the sites of transvascular fluid flux or (2) redistributed the increased blood flow to fewer lung vessels, thereby increasing intravascular pressure at the sites of fluid exchange.Postmortem lung blood content was significantly less than that of control lambs, but there was no difference in extravascular lung water content or lung histology, suggesting that pulmonary lymph flow kept pace with transvascular filtration of fluid and prevented pulmonary edema.The concentration of protein in lymph relative to that in plasma decreased with hypoxia, and the ratio of [albumin] to [globulin] in lymph was unchanged, indicating that sustained alveolar hypoxia of this magnitude had no demonstrable effect on the sieving characteristics of the pulmonary endothelium of the lambs.
Signet-ring cell carcinoma of the nonampullary duodenum and proximal jejunum: a case report with an immunohistochemical study
Authors: T. Terada
Journal: Endoscopy (2014)

Fewer than 20 cases of signet-ring cell carcinoma (SRCC) of the ampulla of Vater have been reported [1] [2] [3] [4]. There have been no reports to date of SRCC of the nonampullary duodenum and ileum.
A Randomized Trial of Care in a Hospital Medical Unit Especially Designed to Improve the Functional Outcomes of Acutely Ill Older Patients
Authors: C. Seth Landefeld, Robert M. Palmer, Denise M. Kresevic, Richard H. Fortinsky, Jerome Kowal
Journal: New England Journal of Medicine (1995)

Older persons who are hospitalized for acute illnesses often lose their independence and are discharged to institutions for long-term care.
Abstract 5320: miR-211 expression inhibits MMP-9-induced phenotype and tumor growth in lung adenocarcinoma cancer stem cells <i>in vitro</i> and <i>in vivo</i>.
Authors: Chandramu Chetty, Subramanyam Chittivelu, Jasti S. Rao
Journal: Cancer Research (2013)

Abstract MicroRNAs are small non-coding RNAs that post-transcriptionally modulate gene expression by degrading or repressing the translation of target messenger RNAs (mRNA). MicroRNAs play fundamental roles in diverse biological and pathological processes, including cell proliferation, differentiation, apoptosis, and carcinogenesis. MicroRNAs have been revealed to be involved in various stages of cancer development, showing that abnormal miRNA expression plays a critical role in modulating expression of known oncogenes or tumor suppressor genes during cancer progression. In the present study, we observed that miR-211 expression was significantly lower in human non-small cell lung cancer (NSCLC) than their matched normal tissue samples, and we elucidated the tumor suppressor role of miR-211 using in vitro and in vivo models. We demonstrated that the expression of precursor of miR-211 (p-mir-211) inhibits radiation-induced invasive nature and tumor progression of NSCLC-initiating cells (NSCLC-ICs) in vitro and in vivo. Overexpression of miR-211 in NSCLC-ICs inhibited radiation-induced MMP-9 expression and invasive nature. Overexpression of miR-211 also inhibited epithelial to mesenchymal transition (EMT), which caused a decline in the mesenchymal markers vimentin, beta catenin and TGF-beta signaling molecules while increasing the epithelial marker, E-cadherin. Further, miR-211-treatment inhibited pre-established tumors in orthotopic mouse models. In addition, MMP-9 immunoreactivity decreased in tumor sections from mice that received miR-211 treatment as compared to tumor sections from mice that received control treatments. Finally, the apoptotic population was significantly increased in tumor sections from mice that received miR-211 treatment. Our data suggest miR-211 as a novel approach for the inhibition of radiation-induced invasion and tumor growth in NSCLC-ICs. Citation Format: Chandramu Chetty, Subramanyam Chittivelu, Jasti S. Rao. miR-211 expression inhibits MMP-9-induced phenotype and tumor growth in lung adenocarcinoma cancer stem cells in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5320. doi:10.1158/1538-7445.AM2013-5320
Abstract 4129: Effects of the metabolism of omega-3 fatty acid EPA by CYP1A1 in breast cancer proliferation and survival
Authors: Mariangellys Rodriguez, Ranjana Mitra, Zhijun Guo, Marc A. Becker, Douglas Yee, David A. Potter
Journal: Cancer Research (2010)

Abstract Omega-3 fatty acids are widely known for their importance in heart disease. However, the impact of omega-3 fatty acids in breast cancer is not fully understood. Through these studies we seek to understand the role of the metabolism of the omega-3 fatty acid known as eicosapentaenoic acid (EPA) in breast cancer and determine whether it may affect breast cancer progression. It is known that high levels (60uM) of EPA have anti-proliferative effects in various cancer lines. Consistent with these reports, we found that EPA treatment (60uM) of the estrogen receptor positive line MCF7 and the estrogen receptor negative line MDA-MB-231 decreases cell proliferation. Interestingly, lower dosing of EPA (15uM-40uM) significantly stimulated the proliferation of these lines. It has been shown that cytochrome P450 1A1 (CYP1A1) selectively epoxygenates EPA to 17(18)-epoxyeicosatetraenoic acid (17,18-EpETE). Measurement of cell growth by MTT assay shows that 17,18-EpETE promotes the proliferation of the MCF7 and MDA-MB-231 lines in a dose- (≥ 1uM) and time-dependent (max effect at 48-72hrs) manner. Together, these results led us to hypothesize that CYP1A1 metabolizes EPA into 17,18-EpETE, thereby promoting breast cancer proliferation and survival. To better understand this epoxygenase mechanism, we studied the impact of CYP1A1 and the 17,18-EpETE metabolite of EPA on cell proliferation by MTT assay, cell cycle progression by propidium iodine staining, and apoptosis by Annexin V flow cytometry. We found that CYP1A1 is expressed in MCF7 and MDA-MB-231 lines and siRNA-mediated knock down significantly inhibits the proliferation of these lines. CYP1A1 knock down also blocks the proliferative effect of treatment with 15uM EPA. Our preliminary data also indicate that 17,18-EpETE promotes growth of the MDA-MB-231 line, in part, by decreasing apoptosis and increasing the S- and G2/M cell populations. Consistently, knock down of CYP1A1 in MDA-MB-231 line increases the G0/1 cell population and decreases number of cells in the S and G2/M phases, consistent with a G1 block. The mechanism of action in MCF7 cells is yet to be determined. Better understanding of the mechanism by which EPA metabolism affects breast cancer may impact our understanding of breast cancer prevention and therapeutics. We propose that CYP1A1 may be of significant importance in breast cancer progression through novel mechanisms that depend on biosynthetic pathways promoting EPA epoxygenation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4129.
Abstract P2-10-29: Time dependent breast cancer metastasis prediction using novel biological imaging, clinico-pathological and genomic data combined with Bayesian modeling to reduce over-fitting and improve on inter-cohort reproducibility.
Authors: I Sheeba, M Kelleher, K Lawler, F Festy, P Barber, E Shamill, P Gargi, G Weitsman, J Barrett, G Fruhwirth, L Huang, I Tullis, N Woodman, S Pinder, E Ofo, L Fernandes, M Beutler, S Ameer-Beg, L Holmberg, A Purushotham, F Fraternali, J Condeelis, A Hanby, C Gillett, P Ellis, B Vojnovic, A Coolen, T Ng
Journal: Cancer Research (2012)

Abstract Background: Breast cancer heterogeneity demands that prognostic models must be biologically driven and recent clinical evidence indicates that future prognostic signatures need evaluation in the context of early versus late metastatic risk prediction. The aim of our work was to identify biologically validated quantitative imaging parameters with improved correlation to clinical outcome, and to address some of the remaining obstacles for a truly robust prognostic model in clinical use. Method: We identified 4 seed proteins (ezrin/radixin/moesin-cofilin), along with several kinases as biologically relevant subnetwork of proteins that control tumor cell motility and metastasis. Patient-derived breast cancer tumour samples were used to perform a combination of imaging methods such as Fluoresecence lifetime imaging microscopy, automated segmentation and co-localisation intensity analysis. A complexity optimized Bayesian proportional hazard regression model was performed on a total of 419 breast cancer patients to validate time dependent predictions using traditional clinicopathological, genomic and our novel optical imaging-derived parameters. An independent dataset of 300 patient samples from the Leeds Institute of Molecular Medicine is currently being evaluated, representing a large cross centre validation of our integrated model. Results: We demonstrate that the traditional gold standard clinico-pathological variables are poor predictors for patients that survive long periods, and that their predictive significance (in terms of hazard ratios) varies significantly between two temporal cohorts where the adjuvant treatments are vastly different. Moreover, we investigate the predictive accuracy of a combined imaging/clinicopathological model compared with genomic/clinicopathological models. We demonstrate how to reduce over-fitting to help improve the performance of prognostic models. Results of an integrated model combining genomic and imaging parameters are still awaited. Discussion: We have produced the first optical imaging-derived multivariate tumour metastatic signature, which measures underlying key biological variables involved in regulating cancer cell motility. Using Bayesian proportional hazards regression in a time-dependent manner, we highlight the inadequacies of existing prediction tools and present a model combining the clinicopathological parameters with our imaging-based metastatic signature, as an integrative reproducible prognostic tool across different temporal cohorts. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-29.
BM-02 * NEW DISEASE SPECIFIC GRADED PROGNOSTIC ASSESSMENT OF BRAIN METASTASIS FROM LUNG, BREAST, MELANOMA AND RENAL MALIGNANCIES
Authors: M. Ahluwalia, V. A. Venur, M. Chi, S. Chao, A. Lilyana, P. Elson, J. Suh, G. Barnett
Journal: Neuro-Oncology (2014)

BACKGROUND: Brain metastases (BM) are a serious complication of systemic malignancies. Common cancers causing BM include small cell and non-small cell lung cancer (SCLC, NSCLC), breast, melanoma, and renal cancer. The disease-specific Graded Prognostic Assessment (DS-GPA) is a useful tool for evaluating prognosis in these patients. We evaluated the DS-GPA within the context of other clinical factors to see if it could be improved. METHODS: The Cleveland Clinic's IRB approved database was used to identify BM patients treated between 2000 and 2013. The primary endpoint was overall survival (OS) from BM diagnosis. Cox proportional hazards models with stepwise variable selection were used for data analysis. RESULTS: 2247 BM patients were analyzed: NSCLC-50%, breast-20%, melanoma-10%, renal-10%, SCLC-9%. Median age at BM diagnosis was 60 (range, 24-93); 54% were female. Median number of BM was 2 (42% had 1, 25% had >5). Most patients had good performance status (70% had KPS > 80). 43% of patients were treated with whole brain radiotherapy (WBRT), 24% stereotactic-radiosurgery (SRS), 12% WBRT + SRS, 11% surgery + WBRT, 3% surgery + SRS. 84% of patients have died; median OS for the cohort was 8.8 months (95% C.I., 8.1-9.5). DS-GPA was prognostic for each cancer (all p < .0001); however separation between groups was variable. Considering clinical factors not used to determine the DS-GPA, revised indices were developed that improved prognostication. The factors, in addition to DS-GPA, included in the revisions are: breast - number of extra-cranial metastases (ECM), controlled primary (PC), BM location, and leptomeningeal disease; NSCLC - PC, number of ECM, histology, hemorrhagic metastases, and gender; melanoma - number of ECM and age; renal - PC and BM-free interval; SCLC - PC, and number of ECM. Median OS (in months) for the revised GPA groups ranged from 3.1-27.6 (breast), 2.5-26.4 (NSCLC), 2.3-15.4 (melanoma), 3.5-41.6 (renal), and 3.5-15.3 (SCLC). CONCLUSIONS: A revised DS-GPA is proposed.
Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis
Authors: Sabine Klein, Johanna Rick, Jennifer Lehmann, Robert Schierwagen, Irela Gretchen Schierwagen, Len Verbeke, Kanishka Hittatiya, Frank Erhard Uschner, Steffen Manekeller, Christian P Strassburg, Kay-Uwe Wagner, Peter P Sayeski, Dominik Wolf, Wim Laleman, Tilman Sauerbruch, Jonel Trebicka
Journal: Gut (2015)

<h3>Objective</h3> Angiotensin II (AngII) activates via angiotensin-II-type-I receptor (AT1R) Janus-kinase-2 (JAK2)/Arhgef1 pathway and subsequently RHOA/Rho-kinase (ROCK), which induces experimental and probably human liver fibrosis. This study investigated the relationship of JAK2 to experimental and human portal hypertension. <h3>Design</h3> The mRNA and protein levels of JAK2/ARHGEF1 signalling components were analysed in 49 human liver samples and correlated with clinical parameters of portal hypertension in these patients. Correspondingly, liver fibrosis (bile duct ligation (BDL), carbon tetrachloride (CCl<sub>4</sub>)) was induced in floxed-<i>Jak2</i> knock-out mice with SM22-promotor (SM22<sup>Cre+</sup>-<i>Jak2</i><sup>f/f</sup>). Transcription and contraction of primary myofibroblasts from healthy and fibrotic mice and rats were analysed. In two different cirrhosis models (BDL, CCl<sub>4</sub>) in rats, the acute haemodynamic effect of the JAK2 inhibitor AG490 was assessed using microsphere technique and isolated liver perfusion experiments. <h3>Results</h3> Hepatic transcription of JAK2/ARHGEF1 pathway components was upregulated in liver cirrhosis dependent on aetiology, severity and complications of human liver cirrhosis (Model for End-stage Liver disease (MELD) score, Child score as well as ascites, high-risk varices, spontaneous bacterial peritonitis). SM22<sup>Cre+</sup>- <i>Jak2</i><sup>f/f</sup> mice lacking <i>Jak2</i> developed less fibrosis and lower portal pressure (PP) than SM22<sup>Cre−</sup>-<i>Jak2</i><sup>f/f</sup> upon fibrosis induction. Myofibroblasts from SM22<sup>Cre+</sup>-<i>Jak2</i><sup>f/f</sup> mice expressed less collagen and profibrotic markers upon activation. AG490 relaxed activated hepatic stellate cells in vitro. In cirrhotic rats, AG490 decreased hepatic vascular resistance and consequently the PP in vivo and in situ. <h3>Conclusions</h3> Hepatic JAK2/ARHGEF1/ROCK expression is associated with portal hypertension and decompensation in human cirrhosis. The deletion of <i>Jak2</i> in myofibroblasts attenuated experimental fibrosis and acute inhibition of JAK2 decreased PP. Thus, JAK2 inhibitors, already in clinical use for other indications, might be a new approach to treat cirrhosis with portal hypertension.