tbuckley/cabot-search huggingface dataset:
Relative effects of alpha 1-adrenoceptor blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog.
Authors: K M McDonald, M Garr, P F Carlyle, G S Francis, K Hauer, D W Hunter, T Parish, A Stillman, J N Cohn
Journal: Circulation (1994)

BACKGROUND Progressive ventricular remodeling after myocardial damage is associated with a poor prognosis. Optimal prevention of the histopathological processes involved in remodeling requires a more complete understanding of the mechanisms involved in initiating and maintaining these structural changes. Since the sympathetic nervous system and the renin-angiotensin system may be involved in the remodeling process, the structural effects of pharmacological inhibitors have been evaluated in a canine model of localized myocardial injury resulting from transmyocardial DC shock. METHODS AND RESULTS The study is comprised of two protocols run in series. In protocol 1, zofenopril (Z), a converting enzyme inhibitor (CEI), prevented the increase in left ventricular mass (LVM) and end-diastolic volume (LVV) observed in the control group (C) at 16 weeks (Z: LVM, 69.8 +/- 3.4 to 65.4 +/- 2.6 g, P = NS; LVV, 45.4 +/- 2.7 to 51.6 +/- 2.7 mL, P = NS; C: LVM, 68.4 +/- 3.2 to 91.4 +/- 2.9 g, P = .0001; LVV, 56.6 +/- 3.0 to 71.9 +/- 2.4 mL, P = .0003). Terazosin, an alpha 1-adrenoceptor antagonist, failed to prevent remodeling at 16 weeks despite continued receptor blockade. In protocol 2, the antiremodeling effect of full-dose CEI therapy with ramipril was confirmed. Low-dose ramipril that exerted no hemodynamic effect failed to prevent remodeling (LVM, 89.7 +/- 4.6 to 105.7 +/- 3.4 g, P = .01; LVV, 61.8 +/- 3.8 to 76.8 +/- 3.3 mL, P = .002). An angiotensin II subtype 1 receptor blocker also failed to prevent the increase in LVM or LVV (LVM, 89.0 +/- 4.6 to 109.7 +/- 5.3 g, P = .0001; LVV, 66.0 +/- 1.9 to 78.4 +/- 3.6 mL, P = .007). CONCLUSIONS High-dose CEI therapy can prevent progressive structural changes resulting from localized myocardial damage induced by DC shock. the failure of alpha 1-adrenoceptor blockade and angiotensin II subtype 1 blockade to attenuate remodeling argues against an important direct role for norepinephrine acting through alpha 1-receptors or angiotensin II acting through the type 1 receptor in the remodeling process in this model.
Unsupervised Analysis of Transcriptomic Profiles Reveals Six Glioma Subtypes
Authors: Aiguo Li, Jennifer Walling, Susie Ahn, Yuri Kotliarov, Qin Su, Martha Quezado, J. Carl Oberholtzer, John Park, Jean C. Zenklusen, Howard A. Fine
Journal: Cancer Research (2009)

Abstract Gliomas are the most common type of primary brain tumors in adults and a significant cause of cancer-related mortality. Defining glioma subtypes based on objective genetic and molecular signatures may allow for a more rational, patient-specific approach to therapy in the future. Classifications based on gene expression data have been attempted in the past with varying success and with only some concordance between studies, possibly due to inherent bias that can be introduced through the use of analytic methodologies that make a priori selection of genes before classification. To overcome this potential source of bias, we have applied two unsupervised machine learning methods to genome-wide gene expression profiles of 159 gliomas, thereby establishing a robust glioma classification model relying only on the molecular data. The model predicts for two major groups of gliomas (oligodendroglioma-rich and glioblastoma-rich groups) separable into six hierarchically nested subtypes. We then identified six sets of classifiers that can be used to assign any given glioma to the corresponding subtype and validated these classifiers using both internal (189 additional independent samples) and two external data sets (341 patients). Application of the classification system to the external glioma data sets allowed us to identify previously unrecognized prognostic groups within previously published data and within The Cancer Genome Atlas glioblastoma samples and the different biological pathways associated with the different glioma subtypes offering a potential clue to the pathogenesis and possibly therapeutic targets for tumors within each subtype. [Cancer Res 2009;69(5):2091–9]
Cross-reactive immunity between viral mimics and cytochrome P4502D6254–271, the immunodominant epitope of LKM-1 autoantibody is associated with a specific immunogenetic background
Authors: D.P. Bogdanos, M. Lenzi, M. Okamoto, Yun Ma, U.C. Sharma, E. Rigopoulou, L. Muratori, R. Williams, D. Tsantoulas, F.B. Bianchi, D. Vergani
Journal: Journal of Hepatology (2001)
SYNERGISM OF THYMUS AND BONE MARROW IN THE PRODUCTION OF GRAFT-VERSUS-HOST SPLENOMEGALY IN X-IRRADIATED HOSTS
Authors: Henry R. Hilgard
Journal: The Journal of Experimental Medicine (1970)

Graft-versus-host splenomegaly may be elicited from 500 R X-irradiated F(1) hybrid hosts if the hosts are injected with bone marrow cells and thymus cells from parental strain donors. Cells from thymus only or bone marrow only will not elicit graft-versus-host splenomegaly in these hosts. In this requirement for cells from both sources, the bone marrow cells play a nonimmunologic, proliferative role in the splenomegaly, and the thymus cells carry out the immunologic attack. Thus the mechanism of this synergism is quite different from that reported for the humoral immune response to sheep erythrocytes in which both thymus and marrow interact in the production of the specific immunologic response itself.
MicroRNAs Regulate Renal Tubule Maturation through Modulation of Pkd1
Authors: Vishal Patel, Sachin Hajarnis, Darren Williams, Ryan Hunter, Donovan Huynh, Peter Igarashi
Journal: Journal of the American Society of Nephrology (2012)

MicroRNAs (miRNAs) contribute to the regulation of early kidney development, but their role during later stages of renal tubule maturation is not well understood. Here, we found that ablation of the miRNA-processing enzyme Dicer from maturing renal tubules produces tubular and glomerular cysts in mice. Inactivation of Dicer is associated with downregulation of miR-200, a kidney-enriched miRNA family, and upregulation of the polycystic kidney disease gene Pkd1. Inhibition of miR-200 in cultured renal epithelial cells disrupted tubulogenesis and led to upregulation of Pkd1. Using bioinformatic and in vitro approaches, we found that miR-200b/c/429 induce post-transcriptional repression of Pkd1 through two conserved binding sites in the 3'-Untranslated regions of Pkd1. Overexpression of PKD1 in renal epithelial cells was sufficient to disrupt tubulogenesis and produce cyst-like structures. In conclusion, miRNAs are essential for the maturation of renal tubules, and Pkd1 is a target of miR-200. These results also suggest that miRNAs may modulate PKD1 gene dosage and play a role in the initiation of cystogenesis.
The age-of-onset of psoriasis and the relationship to parental psoriasis
Authors: M.C. HOLGATE
Journal: British Journal of Dermatology (1975)

In a series of 419 consecutive patients with psoriasis the peak age-of-onset was between 5 and 9 years of age in girls and between 15 and 20 years in boys. Subsequently, there was a gradual decline in relation to age. The incidence of psoriasis in a parent of a proband was shown to be significantly higher in those patients where a detailed examination of the family was undertaken, as compared with the information obtained only from case records.
Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women
Authors: A Yeo
Journal: Gut (2004)

Serotonin (5-hydroxtryptamine, 5-HT) is an important factor in gut function, playing key roles in intestinal peristalsis and secretion, and in sensory signalling in the brain-gut axis. Removal from its sites of action is mediated by a specific protein called the serotonin reuptake transporter (SERT or 5-HTT). Polymorphisms in the promoter region of the SERT gene have effects on transcriptional activity, resulting in altered 5-HT reuptake efficiency. It has been speculated that such functional polymorphisms may underlie disturbance in gut function in individuals suffering with disorders such as irritable bowel syndrome (IBS). The aim of this study was to assess the potential association between SERT polymorphisms and the diarrhoea predominant IBS (dIBS) phenotype.A total of 194 North American Caucasian female dIBS patients and 448 female Caucasian controls were subjected to genotyping.Leucocyte DNA of all subjects was analysed by polymerase chain reaction based technologies for nine SERT polymorphisms, including the insertion/deletion polymorphism in the promoter (SERT-P) and the variable tandem repeat in intron 2. Statistical analysis was performed to assess association of any SERT polymorphism allele with the dIBS phenotype.A strong genotypic association was observed between the SERT-P deletion/deletion genotype and the dIBS phenotype (p = 3.07x10(-5); n = 194). None of the other polymorphisms analysed was significantly associated with the presence of disease.Significant association was observed between dIBS and the SERT-P deletion/deletion genotype, suggesting that the serotonin transporter is a potential candidate gene for dIBS in women.
Evolution of Infant and Young Child Feeding: Implications for Contemporary Public Health
Authors: Daniel W. Sellen
Journal: Annual Review of Nutrition (2007)

Evolutionary anthropological and ethnographic studies are used to develop a general conceptual framework for understanding prehistoric, historic, and contemporary variation in human lactation and complementary feeding patterns. Comparison of similarities and differences in human and nonhuman primate lactation biology suggests humans have evolved an unusually flexible strategy for feeding young. Several lines of indirect evidence are consistent with a hypothesis that complementary feeding evolved as a facultative strategy that provided a unique adaptation for resolving tradeoffs between maternal costs of lactation and risk of poor infant outcomes. This evolved flexibility may have been adaptive in the environments in which humans evolved, but it creates potential for mismatch between optimal and actual feeding practices in many contemporary populations.
Regulated Membrane Trafficking of the Insulin-Responsive Glucose Transporter 4 in Adipocytes
Authors: Robert T. Watson, Makoto Kanzaki, Jeffrey E. Pessin
Journal: Endocrine Reviews (2004)

Since the discovery of insulin roughly 80 yr ago, much has been learned about how target cells receive, interpret, and respond to this peptide hormone. For example, we now know that insulin activates the tyrosine kinase activity of its cell surface receptor, thereby triggering intracellular signaling cascades that regulate many cellular processes. With respect to glucose homeostasis, these include the function of insulin to suppress hepatic glucose production and to increase glucose uptake in muscle and adipose tissues, the latter resulting from the translocation of the glucose transporter 4 (GLUT4) to the cell surface membrane. Although simple in broad outline, elucidating the molecular intricacies of these receptor-signaling pathways and membrane-trafficking processes continues to challenge the creative ingenuity of scientists, and many questions remain unresolved, or even perhaps unasked. The identification and functional characterization of specific molecules required for both insulin signaling and GLUT4 vesicle trafficking remain key issues in our pursuit of developing specific therapeutic agents to treat and/or prevent this debilitating disease process. To this end, the combined efforts of numerous research groups employing a range of experimental approaches has led to a clearer molecular picture of how insulin regulates the membrane trafficking of GLUT4.
Angiotensin II Stimulation In Vitro Induces Hypertrophy of Normal and Postinfarcted Ventricular Myocytes
Authors: Yu Liu, Annarosa Leri, Baosheng Li, Xiaowei Wang, Wei Cheng, Jan Kajstura, Piero Anversa
Journal: Circulation Research (1998)

Abstract —To determine whether angiotensin II (Ang II) stimulation of adult ventricular myocytes in vitro results in cellular hypertrophy, the changes in myocyte volume and protein content per cell were examined by confocal microscopy. Moreover, the possibility was considered that the upregulation of Ang II receptors on myocytes after infarction may potentiate and/or accelerate Ang II–mediated myocyte growth. Left ventricular myocytes isolated from control and failing hearts 3 days after infarction were cultured for 3 and 7 days in the presence of Ang II. Normal myocytes did not show an increase in volume and protein content at 3 days, but a 16% and 20% increase in these respective parameters was found at 7 days. Cell growth was faster and greater in myocytes from postinfarcted hearts. In these cells, myocyte volume increased 23% and protein content increased 28% at 3 days after Ang II administration. The higher hypertrophic reaction of myocytes from infarcted hearts occurred in spite of a 19% larger volume at isolation. In both groups of myocytes, the AT 1 receptor blocker losartan completely inhibited the consequences of Ang II. Conversely, the AT 2 receptor antagonist PD123319 had no effect on Ang II–induced hypertrophy. In conclusion, Ang II promotes myocyte growth through the activation of AT 1 receptors, which modulate the time and magnitude of this cellular response.
THE PATHOGENESIS OF ICTERUS
Authors: G. H. Whipple, J. H. King
Journal: The Journal of Experimental Medicine (1911)

These experiments indicate that, in obstructive jaundice, the bile which escapes from the liver is absorbed by the hepatic capillaries and carried by the blood to the kidneys. The presence of a thoracic duct fistula influences in no way the development of icterus after total obstruction of the common bile duct. Bile pigments, sufficient to give a Salkowski test, may or may not appear in the lymph of the thoracic duct in such experiments, their appearance possibly depending upon the rapidity of bile secretion and the amount of lymph flow. Chronic icterus developing in an animal with a thoracic duct fistula gives an interesting distribution of bile pigments in the body fluids. The lymph and pericardial fluid contain the same amount, which is much less than the content of bile pigment in the blood serum and urine. It seems clear that in both acute and chronic obstructive jaundice the lymphatic apparatus takes no essential or active part in the absorption of bile pigments from the liver. At best, the lymphatic system is a secondary factor in the mechanism of jaundice.
Noninvasive Characterization of Epicardial Activation in Humans With Diverse Atrial Fibrillation Patterns
Authors: Phillip S. Cuculich, Yong Wang, Bruce D. Lindsay, Mitchell N. Faddis, Richard B. Schuessler, Ralph J. Damiano, Li Li, Yoram Rudy
Journal: Circulation (2010)

Background— Various mechanisms of atrial fibrillation (AF) have been demonstrated experimentally. Invasive methods to study these mechanisms in humans have limitations, precluding continuous mapping of both atria with sufficient resolution. In this article, we present continuous biatrial epicardial activation sequences of AF in humans using noninvasive electrocardiographic imaging (ECGI). Methods and Results— In the testing phase, ECGI accuracy was evaluated by comparing ECGI with coregistered CARTO images during atrial pacing in 6 patients. Additionally, correlative observations from catheter mapping and ablation were compared with ECGI in 3 patients. In the study phase, ECGI maps during AF in 26 patients were analyzed for mechanisms and complexity. ECGI noninvasively imaged the low-amplitude signals of AF in a wide range of patients (97 procedural success). Spatial accuracy for determining initiation sites from pacing was 6 mm. Locations critical to maintenance of AF identified during catheter ablation were identified by ECGI; ablation near these sites restored sinus rhythm. In the study phase, the most common patterns of AF were multiple wavelets (92), with pulmonary vein (69) and non–pulmonary vein (62) focal sites. Rotor activity was seen rarely (15). AF complexity increased with longer clinical history of AF, although the degree of complexity of nonparoxysmal AF varied widely. Conclusions— ECGI offers a noninvasive way to map epicardial activation patterns of AF in a patient-specific manner. The results highlight the coexistence of a variety of mechanisms and variable complexity among patients. Overall, complexity generally increased with duration of AF.
Altered coronary vascular responsiveness to leukotrienes in alloxan-diabetic rats.
Authors: D M Roth, D K Reibel, A M Lefer
Journal: Circulation Research (1984)

Altered responsiveness to and metabolism of various eicosanoids in diabetic animals and patients has been reported by several investigators. The purpose of this investigation was to examine the coronary vascular responsiveness of alloxan-diabetic rats to the leukotrienes. Hearts from 12- to 16-week-old alloxan-diabetic rats and weight-matched controls were perfused at constant flow by the Langendorff method. Coronary vasoactivity to leukotrienes B4, C4, D4 and E4 was assessed by measuring the change in coronary perfusion pressure upon infusion of these eicosanoids. Hearts from diabetic rats showed increased responsiveness to leukotrienes C4 (4-40 nM) and D4 (10-100 nM). Both control and diabetic rat hearts were only slightly responsive to leukotriene E4, and no difference between the two groups existed in the reactivity to this leukotriene. Neither group was responsive to the chemotactic leukotriene, B4. Perfusion of the hearts with the cyclooxygenase inhibitor, ibuprofen, failed to alter the coronary vascular responses to the leukotrienes. The coronary constrictor effects of the leukotrienes are the primary effect of these agents on the rat heart, since heart rate does not change significantly, and changes in contractile force are secondary to the coronary vascular constriction. These alterations in responsiveness to leukotrienes may play a role in the cardiovascular complications associated with diabetes.
Randomized Phase II Trial of Docetaxel/Irinotecan and Gemcitabine/Irinotecan With or Without Celecoxib in the Second-Line Treatment of Non–Small-Cell Lung Cancer
Authors: Rogerio Lilenbaum, Mark A. Socinski, Nasser K. Altorki, Lowell L. Hart, Roger S. Keresztes, Subramanian Hariharan, Mark E. Morrison, Rana Fayyad, Phillip Bonomi
Journal: Journal of Clinical Oncology (2006)

Trials combining irinotecan/docetaxel and irinotecan/gemcitabine in second-line treatment of non-small-cell lung cancer (NSCLC) have yielded promising results. Preliminary data suggested that the selective cyclooxygenase -2 inhibitor celecoxib (CBX) might enhance efficacy of chemotherapeutic regimens. This multicenter, phase II, randomized trial investigated efficacy and safety of irinotecan and docetaxel and irinotecan and gemcitabine, with or without CBX, in second-line treatment of NSCLC.Patients 18 years or older were randomly assigned to receive irinotecan 60 mg/m2 and docetaxel 35 mg/m2, or irinotecan 100 mg/m2 and gemcitabine 1,000 mg/m2, with or without CBX 400 mg twice daily, for four cycles. Primary efficacy end points were median and 1-year survival probabilities. Patient-reported symptoms were assessed by the Lung Cancer Symptoms Scale (LCSS).A total of 133 patients were assessable for efficacy and safety. Median survival time was 6.31 months for patients treated with CBX and 8.99 months for those treated with chemotherapy alone. One-year survival rates were 24% and 36% respectively. The overall toxicity rates and LCSS scores were similar between patients treated or not treated with CBX. Four deaths were considered possibly treatment related.Survival results for the second-line regimens in this study were similar to results reported for single-agent therapy in this setting. CBX did not appear to enhance efficacy or improve patient-reported symptoms. The addition of high-dose CBX to second-line chemotherapy in NSCLC cannot be recommended.
Identification and characterization of Smyd2: a split SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex
Authors: Mark A Brown, Robert J Sims, Paul D Gottlieb, Philip W Tucker
Journal: Molecular Cancer (2006)

Abstract Background Disrupting the balance of histone lysine methylation alters the expression of genes involved in tumorigenesis including proto-oncogenes and cell cycle regulators. Methylation of lysine residues is commonly catalyzed by a family of proteins that contain the SET domain. Here, we report the identification and characterization of the SET domain-containing protein, Smyd2. Results Smyd2 mRNA is most highly expressed in heart and brain tissue, as demonstrated by northern analysis and in situ hybridization. Over-expressed Smyd2 localizes to the cytoplasm and the nucleus in 293T cells. Although accumulating evidence suggests that methylation of histone 3, lysine 36 (H3K36) is associated with actively transcribed genes, we show that the SET domain of Smyd2 mediates H3K36 dimethylation and that Smyd2 represses transcription from an SV40-luciferase reporter. Smyd2 associates specifically with the Sin3A histone deacetylase complex, which was recently linked to H3K36 methylation within the coding regions of active genes in yeast. Finally, we report that exogenous expression of Smyd2 suppresses cell proliferation. Conclusion We propose that Sin3A-mediated deacetylation within the coding regions of active genes is directly linked to the histone methyltransferase activity of Smyd2. Moreover, Smyd2 appears to restrain cell proliferation, likely through direct modulation of chromatin structure.
Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice
Authors: Ivana De Domenico, Tian Y. Zhang, Curry L. Koening, Ryan W. Branch, Nyall London, Eric Lo, Raymond A. Daynes, James P. Kushner, Dean Li, Diane M. Ward, Jerry Kaplan
Journal: Journal of Clinical Investigation (2010)

Hepcidin is a peptide hormone that regulates iron homeostasis and acts as an antimicrobial peptide. It is expressed and secreted by a variety of cell types in response to iron loading and inflammation. Hepcidin mediates iron homeostasis by binding to the iron exporter ferroportin, inducing its internalization and degradation via activation of the protein kinase Jak2 and the subsequent phosphorylation of ferroportin. Here we have shown that hepcidin-activated Jak2 also phosphorylates the transcription factor Stat3, resulting in a transcriptional response. Hepcidin treatment of ferroportin-expressing mouse macrophages showed changes in mRNA expression levels of a wide variety of genes. The changes in transcript levels for half of these genes were a direct effect of hepcidin, as shown by cycloheximide insensitivity, and dependent on the presence of Stat3. Hepcidin-mediated transcriptional changes modulated LPS-induced transcription in both cultured macrophages and in vivo mouse models, as demonstrated by suppression of IL-6 and TNF-alpha transcript and secreted protein. Hepcidin-mediated transcription in mice also suppressed toxicity and morbidity due to single doses of LPS, poly(I:C), and turpentine, which is used to model chronic inflammatory disease. Most notably, we demonstrated that hepcidin pretreatment protected mice from a lethal dose of LPS and that hepcidin-knockout mice could be rescued from LPS toxicity by injection of hepcidin. The results of our study suggest a new function for hepcidin in modulating acute inflammatory responses.