tbuckley/cabot-search huggingface dataset:
Defining potentially conserved RNA regulons of homologous zinc-finger RNA-binding proteins
Authors: Tanja Scherrer, Christian Femmer, Ralph Schiess, Ruedi Aebersold, André P Gerber
Journal: Genome biology (2011)

Glucose inhibition of gluconeogenic growth suppressor 2 protein (Gis2p) and zinc-finger protein 9 (ZNF9) are conserved yeast and human zinc-finger proteins. The function of yeast Gis2p is unknown, but human ZNF9 has been reported to bind nucleic acids, and mutations in the ZNF9 gene cause the neuromuscular disease myotonic dystrophy type 2. To explore the impact of these proteins on RNA regulation, we undertook a systematic analysis of the RNA targets and of the global implications for gene expression. Hundreds of mRNAs were associated with Gis2p, mainly coding for RNA processing factors, chromatin modifiers and GTPases. Target mRNAs contained stretches of G(A/U)(A/U) trinucleotide repeats located in coding sequences, which are sufficient for binding to both Gis2p and ZNF9, thus implying strong structural conservation. Predicted ZNF9 targets belong to the same functional categories as seen in yeast, indicating functional conservation, which is further supported by complementation of the large cell-size phenotype of gis2 mutants with ZNF9. We further applied a matched-sample proteome-transcriptome analysis suggesting that Gis2p differentially coordinates expression of RNA regulons, primarily by reducing mRNA and protein levels of genes required for ribosome assembly and by selectively up-regulating protein levels of myosins. This integrated systematic exploration of RNA targets for homologous RNA-binding proteins indicates an unexpectedly high conservation of the RNA-binding properties and of potential targets, thus predicting conserved RNA regulons. We also predict regulation of muscle-specific genes by ZNF9, adding a potential link to the myotonic dystrophy related phenotypes seen in ZNF9 mouse models.
Comparison of macrorestriction analysis of genomic DNA by pulsed-field gel electrophoresis and ribotyping with conventional methods for differentiation of Escherichia coli 0124 isolates
Authors: Teresa Llovet, Pere Coll, Francesca March, Isaí Montserrat, Isabel Atela, Beatriz Mirelis, Guillermo Prats
Journal: Clinical Microbiology and Infection (1995)
Pharmacokinetic Interactions Augment Toxicities of Sirolimus/Cyclosporine Combinations
Authors: HEMANGSHU PODDER, STANISLAW M. STEPKOWSKI, KIMBERLY L. NAPOLI, JAMES CLARK, REGINA R. VERANI, TING-CHAO CHOU, BARRY D. KAHAN
Journal: Journal of the American Society of Nephrology (2001)

Abstract. This study correlated the dynamic effects of sirolimus (rapamycin; RAPA) and cyclosporine (CsA) alone versus in combination to produce renal dysfunction, myelosuppression, or hyperlipidemia, with their corresponding blood and tissue concentrations. After salt-depleted rats were treated with RAPA (0.4 to 6.4 mg/kg per d) and/or CsA (2.5 to 20.0 mg/kg per d) for 14 d, the GFR, lipid levels, bone marrow cellularity, and CsA/RAPA concentrations in whole blood versus liver or renal tissues were measured, and the median effect model was used to discern the type of drug interactions. Compared with vehicle controls (1.98 ± 0.34 ml/min), GFR values were reduced only by large doses of drug monotherapy, namely RAPA (3.2 mg/kg per d = 1.2 ± 0.02 ml/min or 6.4 mg/kg per d = 1.3 ± 0.2 ml/min; both P &lt; 0.01) or CsA (10.0 mg/kg per d = 1.2 ± 0.1 ml/min or 20.0 mg/kg per d = 0.8 ± 0.4 ml/min; both P &lt; 0.01). In contrast, hosts that were treated with smaller doses of CsA/RAPA combinations showed more pronounced effects in reduction of GFR values: 2.5/0.4 mg/kg per d, modestly (1.5 ± 0.5 ml/min; P &lt; 0.01); 5.0/0.8 mg/kg per d, moderately (0.23 ± 0.01 ml/min; P &lt; 0.001); and higher-dose groups, markedly. The exacerbation of renal dysfunction seemed to be due to a pharmacokinetic interaction of RAPA to greatly increase CsA concentrations in whole blood and, particularly, in kidney tissue. In contrast, the pharmacodynamic effects of CsA to potentiate two RAPA-mediated toxicities—myelosuppression and increased serum cholesterol/low-density lipoprotein cholesterol—occurred independently of pharmacokinetic interactions. RAPA aggravates CsA-induced renal dysfunction owing to a pharmacokinetic interaction, whereas CsA produces a pharmacodynamic effect that augments RAPA-induced myelosuppression and hyperlipidemia.
A Randomized Controlled Study of Propranolol for Prevention of Recurrent Gastrointestinal Bleeding in Patients with Cirrhosis: A Final Report
Authors: Didier Lebrec, Thierry Poynard, Jacques Bernuau, Eric Bercoff, Olivier Nouel, Jean-Pierre Capron, Raoul Poupon, Michel Bouvry, Bernard Rueff, Jean-Pierre Benhamou
Journal: Hepatology (1984)

We have previously reported the results of a controlled trial showing that continuous oral administration of propranolol reduced the risk of recurrent gastrointestinal bleeding in patients with cirrhosis; only part of our patients had been followed for 1 year. This controlled trial was continued for an additional year; accordingly, all of our patients have now been followed for at least 2 years. The purpose of the present study is to determine whether prolonged administration enhances the efficacy of this therapy. Seventy-four patients with cirrhosis, admitted for an episode of gastrointestinal bleeding, were included in this study; ascites, jaundice and encephalopathy were absent or mild and transient. The patients were randomly assigned to two groups; one group of 38 patients received propranolol twice daily at doses that reduced the resting heart rate by 25%, the other group of 36 patients received a placebo twice daily. The cumulative percentages of patients free of recurrent gastrointestinal bleeding 1 and 2 years after inclusion were 87 and 79% in the propranolol group, and 42 and 32% in the placebo group; both differences were highly significant (p < 0.0001). Furthermore, the cumulative percentages of surviving patients 1 and 2 years after inclusion were 94 and 90% in the propranolol group, and 84 and 57% in the placebo group; the difference between the two groups was not significant at 1 year, but was statistically significant at 2 years (p < 0.02). We conclude that, in patients with cirrhosis in good condition, propranolol reduced the risk of recurrent gastrointestinal bleeding and the mortality rate during the 2-year period of continuous oral administration of the drug.
NUTRITIONAL ENCEPHALOMALACIA IN CHICKS
Authors: Alwin M. Pappenheimer, Marianne Goettsch
Journal: The Journal of Experimental Medicine (1933)

1. Nutritional encephalomalacia may be induced in chicks up to the age of approximately 2 months. As the preliminary feeding period on a natural foods diet is increased, the percentage incidence of the disease becomes progressively less. The average time between institution of diet and appearance of the disease tends to diminish. 2. There is no correlation between growth and incidence of the disease. 3. White Leghorns, Barred Plymouth Rocks, Rhode Island Reds, and White Wyandottes are equally susceptible.
Aldosterone specific membrane receptors, rapid activation of the sodium-hydrogen exchanger, and cardiovascular implications
Authors: M. Wehling
Journal: Cardiovascular Research (1995)

Functional studies in extrarenal non-epithelial cells such as smooth muscle cells and easily accessible human lymphocytes have demonstrated that aldosterone not only produces classical genomic effects, but also rapid non-genomic effects on transmembrane electrolyte movements. These involve the activation of the Na+/H+ exchanger of the cell membrane at very low, physiological concentrations of aldosterone with an acute onset within one to two minutes. They cannot therefore be explained by genomic mechanisms which appear to succeed the membrane related rapid responses as late effects. The mechanisms underlying these fast aldosterone electrolyte effects have been studied extensively in human lymphocytes and rat vascular smooth muscle cells representing attractively valuable tools in the delineation of the receptor-effector mechanisms involved. This includes the demonstration of membrane binding sites in lymphocytes which are highly specific for aldosterone and transmit the rapid non-genomic responses to aldosterone, as suggested by the intriguing similarities of binding kinetics and pharmacology in the receptor and effector assays. The unique characteristics of this new pathway for steroid action includes its rapid time course, 10,000-fold selectivity for aldosterone over cortisol, and the ineffectiveness of spironolactones, the classical mineralocorticoid antagonists. The two step model for the membrane action of mineralocorticoids developed here shares many features with that developed for other steroid hormones, for example on their neural activity. Since not only lymphocytes but also vascular smooth muscle cells are equipped with the rapid aldosterone effector mechanism, this new model may become the basis for the developing concept of steroids as regulators of cardiovascular functions.
Asthma nervosa: old concept, new insights
Authors: J. Douwes, C. Brooks, N. Pearce
Journal: European Respiratory Journal (2011)

Stress has long been recognised to be associated with asthma. Hippocrates stated that to prevent an asthma attack “the asthmatic should guard himself against his own anger” 1. Maimonides in his treatise of asthma suggested that “mental anguish, fear, mourning or distress” may cause asthma whereas “gaiety and joy” which “gladden the heart and stimulate the blood and mental activity” may have the opposite effect 2. In his treatise, H.H. Salter wrote that “asthma is essentially, and with perhaps the exception of a single class of cases, exclusively a nervous disease; the nervous system is the seat of the essential pathological condition” 3, and W. Osler referred to asthma as “a neurotic affection” 4. Thus, until the second half of the 20th century, asthma was predominantly viewed as a psychosomatic disorder in which emotional stress and imbalances in the nervous system were key factors in its aetiology. As a result, relief of anxiety was considered the main therapeutic intervention for “asthma nervosa”; as it has been referred to historically.

Although the increased awareness in the second half of the 20th century of other triggers of asthma (allergens and air pollution) has shifted the focus away from psychosocial factors, these old concepts are going through a renaissance, with an increasing number of publications reporting consistent positive associations between psychosocial stress and asthma. Associations with asthma have been shown for a wide range of stressors including: post-traumatic stress disorder (PTSD) 5, 6; psychiatric disorders 7, 8; community violence 9; stressful life events 10; partner violence and housing quality 11; war-related stress 12; neuroticism and relational problems 13; perceived safety 14; social depravity and high crime rates 15; anxiety and attention disorders 16; psychological distress 17; …
The Relations of Subdiaphragmatic Abscess to the Thoracic Viscera; with Three Illustrative Cases
Authors: J. W. White
Journal: BMJ (1890)

tory of syphilis excludes this as a cause of the condition; and the changes present do not resemble those found in the red atrophy of liver of British authors.In classifying the case, however, one must take into consideration the clinical symptoms as well as the anatomical changes.These symptoms afford a marked contrast to those of hobnailed cirrhosis; there was no alcoholic taint, no ascites, no enlargement of spleen, nor dilatation of abdominal veins.On the other hand, jaundice wa3 present to a degree most unusual in ordinary cirrhosis, and death took place with sym- ptoms of malignant jaundice.The hbemorrhages which occurred late in the case may reasonably be attributed to the profound blood changes then present, and not as in hobnailed cirrhosis, to obstruction to the blood flow through the portal system.Both on clinical and anatomical grounds, then, the case corresponds to hypertrophic or biliary cirrhosis, "cirrkose hypertrophkque avec ictere" of the French, except that there was no hypertrophy, but 1Q05 May 3, 1890.
Phase II Study of Oral Capecitabine in Patients With Advanced or Metastatic Pancreatic Cancer
Authors: Thomas H. Cartwright, Allen Cohn, Jerry A. Varkey, Yin-Miao Chen, Ted P. Szatrowski, John V. Cox, Joseph J. Schulz
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To determine the safety and efficacy of capecitabine (Xeloda; Roche Laboratories, Nutley, NJ) in patients with metastatic or unresectable, locally advanced pancreatic cancer. PATIENTS AND METHODS: Forty-two patients were treated with oral capecitabine 1,250 mg/m2 administered twice daily (2,500 mg/m2/d) as intermittent therapy in 3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment. Tumor lesions were assessed by computed tomography scan or physical examination at 6-week intervals (after every two cycles). Adverse events were monitored continuously during treatment and for 28 days after the last dose of study drug. RESULTS: Ten (24%) of 42 patients experienced a clinical benefit response (95% confidence interval [CI], 12.1% to 39.5%) as evidenced by improvement in pain intensity, analgesic consumption, and/or Karnofsky performance status. Three (7.3%) of the 41 patients with measurable disease had an objective response (partial). The median time to objective response was 85 days (range, 47 to 91 days) and duration of response was 208, 260, and 566 days for the three responding patients. One patient with nonmeasurable but assessable disease had improved residual disease with a positive clinical benefit response, for a total of four responses among the 42 assessable patients, for an overall response rate of 9.5% (90% CI, 3.3% to 20.5%). Capecitabine was generally well tolerated. CONCLUSION: Treatment with capecitabine resulted in clinically significant beneficial effects on tumor-related symptoms and yielded objective response activity in patients with metastatic or locally advanced pancreatic cancer. These results together with its generally tolerable safety profile and the added advantage of oral administration provide the basis for further evaluating capecitabine as a single agent or in combination with other treatment modalities in this patient population.
T-bet and mucosal Th1 responses in the gastrointestinal tract
Authors: B Weigmann
Journal: Gut (2002)

T cells play an essential role in regulating mucosal immune responses in the gastrointestinal tract. Recent observations on T helper cell differentiation and activation by regulatory transcription factors-especially T-bet-in chronic inflammatory diseases have provided new perspectives for understanding mucosal immunity. Here we summarise recent advances in the field of transcription factors and discuss the implications of these findings for future therapeutic approaches in inflammatory bowel diseases. In particular, we have focused on the role of T-bet in controlling mucosal Th1 responses in the gastrointestinal tract.
Synthesis of 1,25-Dihydroxyvitamin D3 by Human Endothelial Cells Is Regulated by Inflammatory Cytokines
Authors: Daniel Zehnder, Rosemary Bland, Ravinder S. Chana, David C. Wheeler, Alexander J. Howie, Mary C. Williams, Paul M. Stewart, Martin Hewison
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. In addition to its calciotropic function, the secosteroid 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) has potent nonclassical effects. In particular, local production of 1,25D 3 catalyzed by the enzyme 1α-hydroxylase (1α-OHase) may act as an autocrine/paracrine immunomodulatory mechanism. To investigate the significance of this in vascular tissue the expression and function of 1α-OHase in human endothelial cells was characterized. Immunohistochemical and in situ hybridization analyses show, for the first time, the presence of 1α-OHase mRNA and protein in endothelial cells from human renal arteries as well as postcapillary venules from lymphoid tissue. Reverse transcription–PCR and Western blot analyses confirmed the presence of 1α-OHase in primary cultures of human umbilical vein endothelial cells (HUVEC). Enzyme activity in HUVEC (318 ± 56 fmoles 1,25(OH) 2 D 3 /hr/mg protein) increased after treatment with tumor necrosis factor–α (1054 ± 166, P &lt; 0.01), lipopolysaccharide (1381 ± 88, P &lt; 0.01), or forskolin (554 ± 56, P &lt; 0.05). Functional studies showed that exogenously added 1,25(OH) 2 D 3 or its precursor, 25-hydroxyvitamin D 3 (25(OH)D 3 ), significantly decreased HUVEC proliferation after 72 h of treatment (33% and 11%, respectively). In addition, after 24 h treatment, both 1,25(OH) 2 D 3 and 25(OH)D 3 increased the adhesion of monocytic U937 cells to HUVEC (159% and 153%, respectively). These data indicate that human endothelia are able to produce active vitamin D. The rapid induction of endothelial 1α-OHase activity by inflammatory cytokines suggests a novel autocrine/paracrine role for the enzyme, possibly as a modulator of endothelial cell adhesion.
Update in clinical allergy and immunology
Authors: S. von Gunten, B. J. Marsland, C. von Garnier, D. Simon
Journal: Allergy (2012)

Abstract In the recent years, a tremendous body of studies has addressed a broad variety of distinct topics in clinical allergy and immunology. In this update, we discuss selected recent data that provide clinically and pathogenetically relevant insights or identify potential novel targets and strategies for therapy. The role of the microbiome in shaping allergic immune responses and molecular, as well as cellular mechanisms of disease, is discussed separately and in the context of atopic dermatitis, as an allergic model disease. Besides summarizing novel evidence, this update highlights current areas of uncertainties and debates that, as we hope, shall stimulate scientific discussions and research activities in the field.
Maintenance of adrenergic vascular tone by MMP transactivation of the EGFR requires PI3K and mitochondrial ATP synthesis
Authors: Prabhakara Reddy Nagareddy, Fung Lan Chow, Li Hao, Xiang Wang, Tamiko Nishimura, Kathleen M. MacLeod, John H. McNeill, Carlos Fernandez-Patron
Journal: Cardiovascular Research (2009)

G-protein-coupled receptors (GPCRs) modulate vascular tone, at least in part, via matrix metalloproteinase (MMP) transactivation of the epidermal growth factor receptor (EGFR). We previously have identified novel signalling pathways downstream of the EGFR suggestive of mitogen-activated protein kinase and mitochondrial redox control of vascular tone. In the present study, we examined whether MMP modulation of vascular tone involves phosphoinositide 3-kinase (PI3K) and mitochondrial ATP synthesis. To determine whether PI3K is required for the maintenance of adrenergic vascular tone, we first constricted rat small mesenteric arteries with phenylephrine (PE) and then perfused with PI3K inhibitors, LY294002 and wortmannin, both of which produced a dose-dependent vasodilatation. Next, to investigate whether MMPs modulate PI3K activity, we cultured rat aortic vascular smooth muscle cells (VSMCs) and stimulated them with GPCR agonists such as PE and angiotensin II. Inhibition of MMPs (by GM6001) or EGFR (by AG1478) or suppressing the expression of MMP-2 or MMP-7 or the EGFR by small interfering RNA blunted the PI3K phosphorylation of Akt induced by PE. Further, in VSMCs, PI3K inhibitors reduced the PE-induced increase in ATP synthesis and glucose transporter-4 translocation, an effect that was also observed with MMP and the EGFR inhibitors. Further, the PE-induced increase in ATP synthesis activated MMP-7 by mechanisms involving purinergic (P2X) receptors and calcium. These data suggest that the maintenance of adrenergic vascular tone by the MMP–EGFR pathway requires PI3K activation and ATP synthesis. Further, our data support the view that elevated levels of GPCR agonists exaggerate the MMP transactivation of EGFR response and contribute to enhanced vascular tone and development of cardiovascular disease such as hypertension.
Radiosensitization by BRAF inhibitor therapy—mechanism and frequency of toxicity in melanoma patients
Authors: M. Hecht, L. Zimmer, C. Loquai, C. Weishaupt, R. Gutzmer, B. Schuster, S. Gleisner, B. Schulze, S.M. Goldinger, C. Berking, A. Forschner, P. Clemens, G. Grabenbauer, T. Müller-Brenne, J. Bauch, H.T. Eich, S. Grabbe, D. Schadendorf, G. Schuler, P. Keikavoussi, S. Semrau, R. Fietkau, L.V. Distel, L. Heinzerling
Journal: Annals of Oncology (2015)
Phase II/III Trial of Etoposide and High-Dose Ifosfamide in Newly Diagnosed Metastatic Osteosarcoma: A Pediatric Oncology Group Trial
Authors: A. M. Goorin
Journal: Journal of Clinical Oncology (2002)

PURPOSE: The objectives of this trial were to estimate the response rate, progression-free survival, and overall survival of patients who received therapy with etoposide and high-dose ifosfamide, and to define the toxicity of this combination when provided with standard chemotherapy in patients with newly diagnosed metastatic osteosarcoma. PATIENTS AND METHODS: Eligible patients received infusions of 100 mg/m2 per day of etoposide and 3.5 g/m2 per day of ifosfamide for 5 days. Therapy with granulocyte colony-stimulating factor was begun on day 6. This was repeated 3 weeks after therapy was begun. Response was determined at week 6 by both standard World Health Organization response criteria and by pathologic determination of tumor necrosis of the primary tumor. RESULTS: Forty-three patients were registered; 39 were assessable for response and 41 for toxicity and survival. Twenty-eight (68%) of 41 had metastatic sites only in the lung; 12 (29%) had metastatic sites in other bones with or without lung involvement. Four patients (10%) experienced complete response, and 19 patients (49%) experienced partial response, for an overall response rate of 59% ± 8%. The projected 2-year progression-free survival (PFS) for the 28 patients with metastases to lungs was 39% ± 11%. The projected 2-year PFS for the 12 patients with metastases to other bones (with or without pulmonary metastases) was 58% ± 17%. Two patients died as a result of therapy toxicity. Eighty-three percent of patients had grade 4 neutropenia, and 29% had grade 4 thrombocytopenia. Ten patients (24%) had sepsis. Fanconi’s syndrome was observed in five patients. CONCLUSION: The combination of etoposide and high-dose ifosfamide is effective induction chemotherapy for patients with metastatic osteosarcoma, despite significant associated myelosuppression sometimes complicated by infection and renal toxicity.
Diffusion Imaging, White Matter, and Psychopathology
Authors: Moriah E. Thomason, Paul M. Thompson
Journal: Annual Review of Clinical Psychology (2011)

The functional significance of the brain's white matter was not fully appreciated until new imaging methods were developed to visualize fiber pathways and connections in the living brain. Rapid advances in diffusion tensor imaging (DTI) have led to substantial insights into human brain development and disease processes and have thrust white matter into the focus of researchers and clinicians alike. The full clinical potential of this relatively new technique remains to be determined, but early indicators suggest that DTI will be a significant new technology in mapping mechanisms of human health and disease. Here we review brain changes that have been studied with DTI over the human lifespan and findings in a variety of neuropsychiatric disorders. We also suggest future areas where DTI is likely to have significant impact.