tbuckley/cabot-search huggingface dataset:
Wnt Signaling Stimulates Transcriptional Outcome of the Hedgehog Pathway by Stabilizing GLI1 mRNA
Authors: Felicite K. Noubissi, Srikanta Goswami, Nicholas A. Sanek, Kazuyuki Kawakami, Toshinari Minamoto, Amy Moser, Yevgenya Grinblat, Vladimir S. Spiegelman
Journal: Cancer Research (2009)

Wnt and Hedgehog signaling pathways play central roles in embryogenesis, stem cell maintenance, and tumorigenesis. However, the mechanisms by which these two pathways interact are not well understood. Here, we identified a novel mechanism by which Wnt signaling pathway stimulates the transcriptional output of Hedgehog signaling. Wnt/beta-catenin signaling induces expression of an RNA-binding protein, CRD-BP, which in turn binds and stabilizes GLI1 mRNA, causing an elevation of GLI1 expression and transcriptional activity. The newly described mode of regulation of GLI1 seems to be important to several functions of Wnt, including survival and proliferation of colorectal cancer cells.
Effects of insulin-like growth factor on nitrogen balance during hypoxic exposure
Authors: Y. Iioka, K. Tatsumi, K. Sugito, T. Moriya, T. Kuriyama
Journal: European Respiratory Journal (2002)

Acute exacerbations of chronic obstructive pulmonary disease (COPD) accompanied with hypoxaemia may induce net protein catabolism and hypoxaemia could be an important trigger of a systemic catabolic response. The aim of this study was to examine the anabolic effects of recombinant human insulin-like growth factor‐I (IGF‐I) in rats exposed to hypoxia. Although acute hypoxia is usually accompanied with a decrease in dietary intake, the usual nitrogen intake was maintained in this study. Sprague-Dawley rats were maintained by continuous infusion of solution for total parenteral nutrition for 6 days. The animals were then randomly assigned to a normoxic (N) or a hypoxic (H) group. During the last 3 days of the experiment N and H rats were randomised to receive either IGF‐I or vehicle. Exposure to hypoxia caused a decrease in body-weight gain accompanied by a negative nitrogen balance, which was mainly due to increased urinary nitrogen excretion. No effect of recombinant human IGF‐I treatment on body weight was observed during exposure to hypoxia, although nitrogen balance normalised. The co-infusion of recombinant human insulin-like growth factor‐1 and total parenteral nutrition has a significant net anabolic effect, as demonstrated by nitrogen retention and reduction in urine protein excretion observed in rats. Insulin-like growth factor‐1 may help to ameliorate the protein catabolism observed under hypoxic conditions.
Patients' readiness to start highly active antiretroviral treatment for HIV
Authors: Hirut T Gebrekristos, Koleka P Mlisana, Quarraisha Abdool Karim
Journal: BMJ (2005)

Assessing whether patients are ready to start antiretroviral treatment may improve HIV prevention and treatment outcomes 

Initiatives to increase access to antiretroviral treatment in resource constrained settings are growing, but the scale and magnitude of the HIV epidemic in these settings raises a number of operational and ethical challenges. Most people infected with HIV are unaware of their status, and people who are aware of their status fear stigmatisation and discrimination. Key themes about access to treatment include who gets treatment, when is the best time to start treatment, and how to ensure therapeutic success.

Numerous guidelines for treatment have been developed nationally and internationally. One concern is how initiation of antiretroviral treatment should relate to patients' readiness and commitment. Although patients' readiness is emphasised as a requirement for starting treatment in several guidelines,1–4 the guidelines are neither clear nor in consensus about what constitutes readiness and how this readiness should be assessed. Given this ambiguity, readiness may be used to ration resources, particularly in resource poor settings, in which access to antiretrovirals is currently gaining support. The potential of using readiness to improve HIV prevention and care outcomes, however, mandates that we closely examine the use of readiness for starting highly active antiretroviral treatment (HAART).

Studies about assessing patients' readiness for starting HAART or the impact of this on therapeutic success are few. One small study found that lack of readiness resulted in interrupted treatment and risky sexual behaviour; therefore, readiness for treatment may help care givers to make decisions about when to start treatment with antiretrovirals for each patient.5 The potential importance of treatment readiness for therapeutic success is why a more structured and systematic approach to evaluating readiness is needed. In addition, a systematic evaluation of the use of treatment readiness becomes particularly …
Transcription factor FOXO3a controls the persistence of memory CD4+ T cells during HIV infection
Authors: Julien van Grevenynghe, Francesco A Procopio, Zhong He, Nicolas Chomont, Catherine Riou, Yuwei Zhang, Sylvain Gimmig, Genevieve Boucher, Peter Wilkinson, Yu Shi, Bader Yassine-Diab, Elias A Said, Lydie Trautmann, Mohamed El Far, Robert S Balderas, Mohamed-Rachid Boulassel, Jean-Pierre Routy, Elias K Haddad, Rafick-Pierre Sekaly
Journal: Nature Medicine (2008)
A randomized, phase II trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer
Authors: A. Jimeno, K. Shirai, M. Choi, J. Laskin, M. Kochenderfer, A. Spira, V. Cline-Burkhardt, E. Winquist, D. Hausman, L. Walker, R.B. Cohen
Journal: Annals of Oncology (2014)
The thioredoxin system—From science to clinic
Authors: Stephan Gromer, Sabine Urig, Katja Becker
Journal: Medicinal Research Reviews (2003)

Abstract The thioredoxin system—formed by thioredoxin reductase and its characteristic substrate thioredoxin—is an important constituent of the intracellular redox milieu. Interactions with many different metabolic pathways such as DNA‐synthesis, selenium metabolism, and the antioxidative network as well as significant species differences render this system an attractive target for chemotherapeutic approaches in many fields of medicine—ranging from infectious diseases to cancer therapy. In this review we will present and evaluate the preclinical and clinical results available today. Current trends in drug development are emphasized. © 2003 Wiley Periodicals, Inc. Med Res Rev, 24, No. 1, 40–89, 2004
Acute allergic reaction and demonstration of specific IgE antibodies against alpha-1-protease inhibitor
Authors: FJ Meyer, M Wencker, H Teschler, H Steveling, J Sennekamp, U Costabel, N Konietzko
Journal: European Respiratory Journal (1998)

A 44 yr-old female with severe pulmonary emphysema and reduced alpha-1-protease inhibitor (alpha1-PI) serum levels developed an acute anaphylactic reaction following the third intravenous infusion of human alpha1-PI which was administered to prevent the progression of pulmonary emphysema. Specific immunoglobulin E-antibodies against human alpha1-PI could be demonstrated in the patient's serum using an enzyme allergosorbent test. Because of the risk of further severe anaphylactic reaction, the replacement therapy with alpha1-PI was discontinued. Physicians should be aware of this rare complication.
PMO-229 MicroRNA expression profiling in stricturing Crohn's disease identifies miR-34a as a functionally relevant influence on disease phenotype
Authors: A Nijhuis, P Biancheri, C Lai, A Ghosh, T Boitsova, C Chan, T MacDonald, J Lindsay, A Silver
Journal: Gut (2012)

<h3>Introduction</h3> Intestinal fibrosis is a frequent complication in Crohn9s disease (CD), with subsequent stricture development that may require surgical intervention. MicroRNAs (miRNAs) are a novel class of post-transcriptional gene regulators implicated in cardiac, hepatic and pulmonary fibrosis. MiRNAs play a key role as modulators of the potent pro-fibrotic cytokine transforming growth factor (TGF)-β, which is up-regulated in CD intestinal strictures. Here, we aimed to identify and investigate the functional characteristics of miRNAs with differential expression between strictured and non-strictured CD. <h3>Methods</h3> Intestinal surgical specimens were collected from 17 patients with fibrostenosing CD, and total RNA was extracted from uninflamed ileal mucosa. MiRNA expression profiling was performed using Illumina v2.0 microRNA array comparing matched strictured to non-strictured areas from the same patient within each experimental group. Subsequent validation of differentially expressed miRNAs was performed using qRT-PCR. Primary mucosal fibroblast cultures were derived from strictured CD and healthy control tissue. Overexpression of miRNAs was induced by transfection with Dharmafect agent under optimised conditions and changes in mRNA expression were detected by RT-qPCR and protein expression by IHC and Western Blotting. <h3>Results</h3> We detected 11 miRNAs significantly up-regulated and 10 miRNAs significantly down-regulated (all p&lt;0.02) between the strictured and non-strictured ileum. Validation experiments confirmed the changes of miR-34a in an independent set of 8 matched strictured vs non-strictured tissues. MiR-34a has been identified as a direct target of P53 which is involved in murine kidney fibrosis. When overexpressed in primary fibroblast cell lines, miR-34a increases expression of <i>COL1A2</i> and <i>COL3A1</i> mRNA in strictured CD cell line. However, upregulation of P53 mRNA or protein was not detected in 6 matched paired tissues, indicating a P53-independent mechanism by which miR-34a exerts its pro-fibrotic effects. <h3>Conclusion</h3> This study confirms that differences in miRNA expression profiles between CD strictured and non-strictured areas can be detected. Upregulation of collagen mRNA shows that miR-34a might play a functional role in modulating fibrosis in CD, however further studies to investigate the impact of increased collagen protein are required. Manipulation of miRNA profiles may be a novel therapeutic strategy against fibrosis in Crohn9s disease. <h3>Competing interests</h3> None declared.
Psychiatrists in Court: Some Perspectives on the Insanity Defense
Authors: ABRAHAM S. GOLDSTEIN
Journal: American Journal of Psychiatry (1969)

If the insanity defense is to be rescued from the stereotypes that have dominated it, lawyers and psychiatrists will have to learn more about the open texture of the legal process and the variety of evidence and issues that may be presented. The author foresees a revolution in legal services that will result in a fuller exploration not only of the insanity defense but also of other issues surrounding mental disorder and the criminal law.
Podocyte-Specific Deletion of Dicer Alters Cytoskeletal Dynamics and Causes Glomerular Disease
Authors: Scott J. Harvey, George Jarad, Jeanette Cunningham, Seth Goldberg, Bernhard Schermer, Brian D. Harfe, Michael T. McManus, Thomas Benzing, Jeffrey H. Miner
Journal: Journal of the American Society of Nephrology (2008)

MicroRNAs (miRNAs) regulate gene expression by binding the 3' untranslated region of mRNAs. To define their role in glomerular function, miRNA biogenesis was disrupted in mouse podocytes using a conditional Dicer allele. Mutant mice developed proteinuria by 3 wk after birth and progressed rapidly to end-stage kidney disease. Podocyte pathology included effacement, vacuolization, and hypertrophy with crescent formation. Despite normal expression of WT1, podocytes underwent dedifferentiation, exemplified by cytoskeletal disruption with early transcriptional downregulation of synaptopodin. These abnormalities differed from Cd2ap(-/-) mice, indicating they were not a general consequence of glomerular disease. Glomerular labeling of ezrin, moesin, and gelsolin was altered at 3 wk, but expression of nestin and alpha-actinin was unchanged. Abnormal cell proliferation or apoptosis was not responsible for the glomerular injury. Mutant podocytes were incapable of synthesizing mature miRNA, as revealed by their loss of miR-30a. In contrast, expression of glomerular endothelial and mesangial cell miRNAs (miR-126 and miR-145, respectively) was unchanged. These findings demonstrate a critical role for miRNA in glomerular function and suggest a pathway that may participate in the pathogenesis of kidney diseases of podocyte origin. The unique architecture of podocytes may make them especially susceptible to cytoskeletal alterations initiated by aberrant miRNA dynamics.
Bone marrow oedema predicts structural progression in a 1-year follow-up of 85 patients with RA in remission or with low disease activity with low-field MRI
Authors: F Gandjbakhch, V Foltz, A Mallet, P Bourgeois, B Fautrel
Journal: Annals of the Rheumatic Diseases (2011)

To identify the predictive factors of MRI-determined structural progression in patients with rheumatoid arthritis (RA) in remission or with low disease activity (LDA). In this 1-year longitudinal study, patients with RA in clinical remission (disease activity score (DAS) 44≤1.6) or with LDA (1.6<DAS 44≤2.4) underwent low-field MRI of the dominant hand at baseline and at 6 and 12 months. MRI images were scored by the rheumatoid arthritis MRI system (RAMRIS) by rheumatologists blind to clinical and biological data. Structural progression was defined as a change in the RAMRIS(erosion) score between baseline and 1 year greater than the smallest detectable difference. Predictive factors of structural disease progression were analysed by logistic and linear regression. 85 patients with RA in remission (n=47) or with LDA (n=38) were included. Their mean age was 50 ± 13 years, 81% were female, mean disease duration was 35 ± 20 months, rheumatoid factor (RF)/anti-CCP positivity was 63%/64% and 77% had radiographic erosion. At baseline most patients showed inflammatory activity on MRI: 87% had at least one synovitis and 23% at least one location of bone marrow oedema (BME). BME at baseline was predictive of change in RAMRIS(erosion) (OR 1.25, 95% CI 1.09 to 1.43, p=0.0013, area under the curve=0.78). BME is a predictive factor of MRI-determined structural progression in patients with RA in clinical remission or with LDA.
Hereditary Angioedema — Therapies Old and New
Authors: B. Paul Morgan
Journal: New England Journal of Medicine (2010)

Hereditary angioedema is a rare syndrome characterized by episodic, nonpruritic, localized subcutaneous and submucosal swelling. Laryngeal edema can precipitate fatal respiratory obstruction. Nearly 50 years ago, Donaldson and Evans linked hereditary angioedema with a deficiency of the plasma inhibitor of the first component of complement, C1 inhibitor — a serine protease inhibitor that inactivates target proteases by means of irreversible binding.1 Its primary targets are the complement proteases C1r and C1s (for which it is the sole plasma inhibitor), the coagulation-system proteases factors XIa and XIIa, and the contact-system protease kallikrein (Figure 1). C1 inhibitor deficiency causes dysregulation in these . . .
MRI-Guided Nanorobotic Systems for Therapeutic and Diagnostic Applications
Authors: Panagiotis Vartholomeos, Matthieu Fruchard, Antoine Ferreira, Constantinos Mavroidis
Journal: Annual Review of Biomedical Engineering (2011)

This review presents the state of the art of magnetic resonance imaging (MRI)-guided nanorobotic systems that can perform diagnostic, curative, and reconstructive treatments in the human body at the cellular and subcellular levels in a controllable manner. The concept of an MRI-guided nanorobotic system is based on the use of an MRI scanner to induce the required external driving forces to propel magnetic nanocapsules to a specific target. It is an active targeting mechanism that provides simultaneous propulsion and imaging capabilities, which allow the implementation of real-time feedback control of the targeting process. The architecture of the system comprises four main modules: (a) the nanocapsules, (b) the MRI propulsion module, (c) the MRI tracking module (for image processing), and (d) the controller module. A key concept is the nanocapsule technology, which is based on carriers such as liposomes, polymer micelles, gold nanoparticles, quantum dots, metallic nanoshells, and carbon nanotubes. Descriptions of the significant challenges faced by the MRI-guided nanorobotic system are presented, and promising solutions proposed by the involved research community are discussed. Emphasis is placed on reviewing the limitations imposed by the scaling effects that dominate within the blood vessels and also on reviewing the control algorithms and computational tools that have been developed for real-time propulsion and tracking of the nanocapsules.
Promoter Hypermethylation Profile of Kidney Cancer
Authors: Essel Dulaimi, Inmaculada Ibanez de Caceres, Robert G. Uzzo, Tahseen Al-Saleem, Richard E. Greenberg, Thomas J. Polascik, James S. Babb, William E. Grizzle, Paul Cairns
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Promoter hypermethylation is an important mechanism of inactivation of tumor suppressor genes in cancer cells. Kidney tumors are heterogeneous in their histology, genetics, and clinical behavior. To gain insight into the role of epigenetic silencing of tumor suppressor and cancer genes in kidney tumorigenesis, we determined a hypermethylation profile of kidney cancer. Experimental Design: We examined the promoter methylation status of 10 biologically significant tumor suppressor and cancer genes in 100 kidney tumors (50 clear cell, 20 papillary, 6 chromophobe, 5 collecting duct, 5 renal cell unclassified, 7 oncocytoma, 6 transitional cell carcinomas of the renal pelvis, and 1 Wilms’ tumor) by methylation-specific PCR. The hypermethylation profile was examined with regard to clinicopathological characteristics of the kidney cancer patients. Results: Hypermethylation of one or more genes was found in 93 (93%) of 100 tumors. A total of 33% of kidney tumors had one gene, 35% two genes, 14% three genes, and 11% four or more genes hypermethylated. The frequency of hypermethylation of the 10 genes in the 100 tumor DNAs was VHL 8% (all clear cell), p16INK4a 10%, p14ARF 17%, APC 14%, MGMT 7%, GSTP1 12%, RARβ2 12%, RASSF1A 45%, E-cadherin 11%, and Timp-3 58%. Hypermethylation was observed in all of the histological cell types and grades and stages examined. No hypermethylation was observed in specimens of normal kidney or ureteral tissue from 15 patients. Hypermethylation of VHL was specific to clear cell tumors. RASSF1A methylation was detected at a significantly higher frequency in papillary renal cell tumors and in high-grade tumors of all cell types. MGMT methylation was more frequent in nonsmokers. Simultaneous methylation of five or more genes was observed in 3 (3%) of 100 tumors and may indicate a methylator phenotype in kidney cancer. In addition, the CpG island in the promoter of the fumarate hydratase (FH) tumor suppressor gene was bisulfite sequenced and was found to be unmethylated in 15 papillary renal tumors. Conclusions: Promoter hypermethylation is common, can occur relatively early, may disrupt critical pathways, and, thus, likely plays an important role in kidney tumorigenesis. A hypermethylation profile may be useful in predicting a patient’s clinical outcome and provide molecular markers for diagnostic and prognostic approaches to kidney cancer.
Incidence, risk factors and clinical implications of venous thromboembolism in cancer patients treated within the context of phase I studies: the ‘SENDO experience’
Authors: M. Mandala`, M. Clerici, I. Corradino, C. Vitalini, S. Colombini, V. Torri, A. De Pascale, S. Marsoni
Journal: Annals of Oncology (2011)
Injuries to the throwing arm
Authors: M. B. Bottomley
Journal: British Journal of Sports Medicine (1986)

The relationship between changes in plasma free fatty acids (FFA), in glucose and in lactic acid and the rise in oxygen consumption produced by sympathomimetic amines was studied in intact, anesthetized dogs and rats. In the dog norepinephrine (NE) and isoproterenol (ISO) (1 µg/kg/min) produced similar rises in plasma FFA, but ISO produced a more marked calorigenesis than did NE. ISO increased plasma glucose and lactic acid, whereas NE did not. In the dog MJ 1999 completely inhibited NE-induced lipolysis and calorigenesis; whereas in the rat, with epinephrine (E) as the agonist, MJ 1999 prevented the rise in lactic acid and only reduced the rise in glucose and in oxygen consumption, but MJ 1999 did not inhibit the rise in FFA. Nicotinic acid suppressed the rise in FFA regularly produced by ISO in the dog and by E in the rat; but nicotinic acid had little effect on the rise in glucose, in lactic acid or in oxygen consumption. In the rat dihydroergotamine also completely inhibited the rise in FFA, reduced the rise in glucose but had no significant effect on the rise in oxygen consumption or in lactic acid in response to E. In the rat the combination of MJ 1999 plus nicotinic acid completely inhibited the rise in all three plasma substrates regularly produced by E, but this combination of agents only reduced the rise in oxygen consumption. A possible supportive, rather than causative, role of FFA, lactic acid and glucose in catecholamine-induced calorigenesis is discussed. Since selective antagonists of catecholamine effects differentially influence the increase in FFA and the calorigenic effect, the rise in FFA does not appear to be the cause of the increased oxygen consumption.
Identification of Aldo-Keto Reductase AKR1B10 as a Selective Target for Modification and Inhibition by Prostaglandin A1: Implications for Antitumoral Activity
Authors: Beatriz Díez-Dacal, Javier Gayarre, Severine Gharbi, John F. Timms, Claire Coderch, Federico Gago, Dolores Pérez-Sala
Journal: Cancer Research (2011)

Cyclopentenone prostaglandins (cyPG) are reactive eicosanoids that may display anti-inflammatory and antiproliferative actions, possibly offering therapeutic potential. Here we report the identification of members of the aldo-keto reductase (AKR) family as selective targets of the cyPG prostaglandin A(1) (PGA(1)). AKR enzymes metabolize aldehydes and drugs containing carbonyl groups and are involved in inflammation and tumorigenesis. Thus, these enzymes represent a class of targets to develop small molecule inhibitors with therapeutic activity. Molecular modeling studies pointed to the covalent binding of PGA(1) to Cys299, close to the active site of AKR, with His111 and Tyr49, which are highly conserved in the AKR family, playing a role in PGA(1) orientation. Among AKR enzymes, AKR1B10 is considered as a tumor marker and contributes to tumor development and chemoresistance. We validated the direct modification of AKR1B10 by biotinylated PGA(1) (PGA(1)-B) in cells, and confirmed that mutation of Cys299 abolishes PGA(1)-B incorporation, whereas substitution of His111 or Tyr49 reduced the interaction. Modification of AKR1B10 by PGA(1) correlated with loss of enzymatic activity and both effects were increased by depletion of cellular glutathione. Moreover, in lung cancer cells PGA(1) reduced tumorigenic potential and increased accumulation of the AKR substrate doxorubicin, potentiating cell-cycle arrest induced by this chemotherapeutic agent. Our findings define PGA(1) as a new AKR inhibitor and they offer a framework to develop compounds that could counteract cancer chemoresistance.