tbuckley/cabot-search huggingface dataset:
The CCND1 c.870G&gt;A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma
Authors: Niels Weinhold, David C Johnson, Daniel Chubb, Bowang Chen, Asta Försti, Fay J Hosking, Peter Broderick, Yussanne P Ma, Sara E Dobbins, Dirk Hose, Brian A Walker, Faith E Davies, Martin F Kaiser, Ni L Li, Walter A Gregory, Graham H Jackson, Mathias Witzens-Harig, Kai Neben, Per Hoffmann, Markus M Nöthen, Thomas W Mühleisen, Lewin Eisele, Fiona M Ross, Anna Jauch, Hartmut Goldschmidt, Richard S Houlston, Gareth J Morgan, Kari Hemminki
Journal: Nature Genetics (2013)
Effect of testosterone and endurance training on glycogen metabolism in skeletal muscle of chronic hyperglycaemic female rats
Authors: E van Breda, H Keizer, H Kuipers, G Kranenburg
Journal: British Journal of Sports Medicine (2003)

To investigate in glycolytic and oxidative muscles of trained (nine weeks) and untrained hyperglycaemic female rats the effect of hyperandrogenicity and/or endurance training on energy metabolic properties.Glycogen content and activity of muscle enzymes with regulatory functions in glycogen synthesis were examined.Testosterone treatment increased glycogen content of extensor digitorum longus (EDL) and soleus muscles of hyperglycaemic sedentary (18% and 84% respectively) and hyperglycaemic trained (7% and 16% respectively) rats. In both types of muscle of the hyperglycaemic testosterone treated exercised subgroup, less depletion of glycogen was found than in the untreated group (38% and 87% for EDL and soleus respectively).The mechanisms by which training and/or hyperandrogenism alone or in combination elicits their specific effects are complex. Differences in sex, surgery, levels of hormones administered, and exercise model used may be the main reasons for the observed discrepancies. Conclusions from the results: (a) hyperandrogenism is not a primary cause of the development of insulin resistance; (b) glycogen content of slow and fast twitch muscle is increased by training through increased glycogen synthase activity. The most plausible explanation for differences between different muscle fibre types is the different levels of expression of androgen receptors in these fibres. Hyperandrogenicity therefore acts on energy metabolic variables of hyperglycaemic animals by different mechanisms in glycolytic and oxidative muscle fibres.
INFLUENCE OF THE PHYSIOLOGICAL BLOOD CLOTTING PROCESS ON THE COAGULATION OF BLOOD BY STAPHYLOCOAGULASE
Authors: Morris Tager, Anne L. Lodge
Journal: The Journal of Experimental Medicine (1951)

The conversion of plasma to serum results in a variable loss of the coagulase-reacting factor (C.R.F.) of the plasma. The C.R.F. loss is incurred during the process of prothrombin conversion: conditions which favor the most effective prothrombin conversion result in maximal C.R.F. loss, while factors which interfere with prothrombin conversion spare the C.R.F. In a system containing an adequate concentration of calcium, thrombo-plastin, and prothrombin, the C.R.F. loss reflects the amount of prothrombin conversion-accelerating substances (factor V or AC globulin). If fibrin clots are produced directly by thrombin, and prothrombin conversion is excluded, there is no significant C.R.F. loss.
Acute blockade of nitric oxide synthase inhibits renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats.
Authors: L A Danielson, K P Conrad
Journal: Journal of Clinical Investigation (1995)

Because the kidneys are vasodilated and the endogenous production of nitric oxide is increased in gravid rats, we tested whether nitric oxide mediates the renal vasodilatory response to pregnancy.Chronically instrumented, conscious rats of gestational days 12-14 were studied concurrently with age-matched virgin control animals.GFR and effective renal plasma flow (ERPF) were determined by the renal clearances of inulin and para-aminohippurate before and during acute infusion of NW-nitro-L-arginine methyl ester (NAME; 2, 20, and 50 jag/min) or NG-monomethyl-L-argi- nine (100 jag/min).Baseline GFR and ERPF were signifi- cantly increased, and effective renal vascular resistance was decreased by 30-40% in gravid rats compared with virgin controls.During infusion of all three dosages of NAME and NG-monomethyl-L-arginine, effective renal vascular resis- tance, GFR, and ERPF were equalized in the pregnant and virgin rats (the only exception being GFR during the 20 jag/min NAME infusion).When compared with virgin rats, the gravid animals were more responsive to nitric oxide synthase inhibition, showing a significantly greater decline in GFR and ERPF and rise in effective renal vascular resis- tance at each timepoint during the infusion of inhibitor.To exclude the possibility that nonspecific renal vasoconstric- tion per se led to equalization of renal function in the two groups of rats, we investigated angiotensin II.In contrast to the results observed with nitric oxide synthase inhibitors, pregnant rats were less responsive to the renal vasoconstric- tory effects of angiotensin II, such that the baseline differ- ences in renal parameters measured before infusion of the hormone were increased during the infusion.To determine whether nitric oxide synthase was inhibited to a similar extent in gravid and virgin rats, aortic and renal cortical cGMP content was assayed ex vivo at the end of inhibitor infusion.The lower 2-pag/min dose of NAME consistently reduced cGMP content of these tissues to comparable levels in the two groups of rats.In conclusion, we suggest that
Expression and localisation of insulin receptor substrate 2 in normal intestine and colorectal tumours. Regulation by intestine-specific transcription factor CDX2
Authors: S Modica, A Morgano, L Salvatore, M Petruzzelli, M-T Vanier, R Valanzano, D L Esposito, G Palasciano, I Duluc, J-N Freund, R Mariani-Costantini, A Moschetta
Journal: Gut (2009)

<h3>Background and aims:</h3> Self-renewal and differentiation of intestinal epithelium is a tightly regulated process, whose perturbations are implicated in human colorectal tumourigenesis. The insulin/insulin-like growth factor (IGF) signalling pathway may play an important role in intestinal epithelium homeostasis. Insulin receptor substrate 2 (IRS2) is a poorly characterised component in this pathway. <h3>Methods:</h3> Using complementary in vitro and in vivo human and murine models, expression (mRNA and protein levels), localisation (immunohistochemistry) and regulation of IRS2 were investigated in the normal intestine and colorectal tumours. In silico analysis of the human <i>IRS2</i> promoter was performed together with reporter and chromatin immunoprecipitation assays. <h3>Results:</h3> Significant <i>IRS2</i> expression was detected in the intestine, with specific protein localisation in the villus region of the ileum and in the surface epithelium of the colon. In human HT29 and Caco2 cells, <i>IRS2</i> mRNA levels increased with spontaneous and induced differentiation, together with <i>CDX2</i> (caudal-related homeobox protein 2), <i>P21</i> and <i>KLF4</i> (Krüppel-like factor 4). Adenoviral infection with human CDX2 induced <i>IRS2</i> expression in APC- (adenomatous polyposis coli) and β-catenin-mutated cells. On the other hand, <i>IRS2</i> downregulation was observed in differentiated enterocytes after adenoviral infection with short hairpin CDX2 (shCDX2), in the intestine of CDX2 heterozygous mice and in colorectal tumours of Apc<sup>Min/+</sup> and patients with familial adenomatous polyposis (FAP). The human <i>IRS2</i> promoter region presents several CDX2-binding sites where CDX2 immunoprecipitated in vivo. IRS2 reporters were functionally activated via CDX2 and blocked via a dominant-negative CDX2 protein. <h3>Conclusions:</h3> Combining gain- and loss-of-function approaches, an intriguing scenario is presented whereby IRS2 is significantly expressed in the apical intestinal compartment and is directly controlled by CDX2 in normal intestine and tumours.
Mesangial cell proteoglycans
Authors: M Davies, G J Thomas, L D Shewring, R M Mason
Journal: Journal of the American Society of Nephrology (1992)

In cultures of human adult glomerular mesangial cells, large chondroitin sulfate proteoglycans (CSPG) and small dermatan sulfate proteoglycans (DSPG) are synthesized. The large CSPG has a core protein, M(r) of 400,000 (major) and M(r) of 500,000 (minor), and binds to hyaluronic acid to form large aggregates. The two small DSPGs (Mr of approximately 350,000 and M(r) of approximately 200,000) were related to biglycan and decorin, respectively. The majority of these proteoglycans were located in the culture medium, but a hydrophobic form of the CSPG was extracted from the cell layer. Mesangial cells in the growing phase synthesized and secreted all three types of proteoglycans, but in cells arrested in G0 by serum deprivation the incorporation of (35S)sulfate in CSPG was drastically reduced. In the same cells stimulated to proliferate by replacing the medium with one containing serum, the synthesis of CSPG dramatically enhanced. The synthesis of CSPG and DSPG was also elevated in cells cocultured with cytokines but in contrast was significantly reduced when cultured in medium containing hyperglycemic levels of glucose. Finally, preliminary experiments are reported that indicate that CSPG and DSPG bind to low-density lipoproteins in vitro. These observations suggest a possible specialized function for proteoglycans in cellular processes characteristic of glomerular disease.
Expression of a Dominant Negative Mutant of Interleukin-1β Converting Enzyme in Transgenic Mice Prevents Neuronal Cell Death Induced by Trophic Factor Withdrawal and Ischemic Brain Injury
Authors: Robert M. Friedlander, Valeria Gagliardini, Hideaki Hara, Klaus B. Fink, Weiwei Li, Glen MacDonald, Mark C. Fishman, Arnold H. Greenberg, Michael A. Moskowitz, Junying Yuan
Journal: The Journal of Experimental Medicine (1997)

To explore the role of the interleukin (IL)-1β converting enzyme (ICE) in neuronal apoptosis, we designed a mutant ICE gene (C285G) that acts as a dominant negative ICE inhibitor. Microinjection of the mutant ICE gene into embryonal chicken dorsal root ganglial neurons inhibits trophic factor withdrawal–induced apoptosis. Transgenic mice expressing the fused mutant ICE-lacZ gene under the control of the neuron specific enolase promoter appeared neurologically normal. These mice are deficient in processing pro–IL-1β, indicating that mutant ICEC285G blocks ICE function. Dorsal root ganglial neurons isolated from transgenic mice were resistant to trophic factor withdrawal–induced apoptosis. In addition, the neurons isolated from newborn ICE knockout mice are similarly resistant to trophic factor withdrawal–induced apoptosis. After permanent focal ischemia by middle cerebral artery occlusion, the mutant ICEC285G transgenic mice show significantly reduced brain injury as well as less behavioral deficits when compared to the wild-type controls. Since ICE is the only enzyme with IL-1β convertase activity in mice, our data indicates that the mutant ICEC285G inhibits ICE, and hence mature IL-1β production, and through this mechanism, at least in part, inhibits apoptosis. Our data suggest that genetic manipulation using ICE family dominant negative inhibitors can ameliorate the extent of ischemia-induced brain injury and preserve neurological function.
Cimetidine improves the therapeutic/toxic ratio of dapsone in patients on chronic dapsone therapy
Authors: L.E. Rhodes, M.D. Tingle, B.K. Park, P. Chu, J.L. Verbov, P.S. Friedmann
Journal: British Journal of Dermatology (2006)

We have previously shown that cimetidine, given concurrently for 2 weeks to patients on chronic dapsone therapy, reduced methaemoglobinaemia by inhibiting the formation of the toxic hydroxylamine metabolite of dapsone. The aim of the present study was to examine the effect of this combination on the benefit/toxic ratio of dapsone over a longer period. Eight patients (six dermatitis herpetiformis, one linear IgA disease, one folliculitis decalvans) on long-term dapsone 50-100 mg daily, took cimetidine 1.6 g daily concurrently for 3 months. At 3-weekly intervals, a clinical assessment was made, plasma dapsone and methaemoglobin were measured, and parameters of oxidative haemolysis were monitored. The dapsone level rose from 2298 +/- 849 ng/ml (mean +/- SD) at baseline to 3006 +/- 1131 ng/ml at week 3 of cimetidine (P < 0.01). This rise in plasma dapsone was sustained during cimetidine administration, falling to 2446 +/- 954 ng/ml when cimetidine was stopped (P < 0.02). The methaemoglobin fell from 5.5 +/- 2.2% (mean +/- SD) at baseline to 3.9 +/- 1.1% at week 3 (P < 0.01), and remained low until week 12, when there was a return to baseline values (P < 0.01). The haemoglobin did not change from the baseline of 12.7 +/- 0.3 g/dl (mean +/- SD), and other parameters of haemolysis were unaltered. There was a fall in the visual analogue score for headache (P < 0.05), but this was not associated with any deterioration in control of the skin disorders. Hence, long-term concurrent cimetidine results in increased plasma dapsone levels without increased haemolysis, and is accompanied by reduced methaemoglobinaemia for more than 2 months.(ABSTRACT TRUNCATED AT 250 WORDS)
The Editor 'The British Journal of Dermatology'. Dracontiasis in Greenock
Authors: M. Ganpule, W. Susskind
Journal: British Journal of Dermatology (1967)

Journal Article The Editor ‘The British Journal of Dermatology’. Dracontiasis in Greenock Get access M. Ganpule, M. Ganpule Victoria Infirmary's Glasgow, S.2 Search for other works by this author on: Oxford Academic Google Scholar W. Susskind W. Susskind Victoria Infirmary's Glasgow, S.2 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 79, Issue 10, 1 October 1967, Pages 566–568, https://doi.org/10.1111/j.1365-2133.1967.tb11414.x Published: 01 October 1967
Temporal Lobe Dysfunction in Childhood Autism: A PET Study
Authors: Mônica Zilbovicius, Nathalie Boddaert, Pascal Belin, Jean-Baptiste Poline, Philippe Remy, Jean-François Mangin, Lionel Thivard, Catherine Barthélémy, Yves Samson
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: The nature of the underlying brain dysfunction of childhood autism, a life-long severe developmental disorder, is not well understood. Although researchers using functional brain imaging have attempted to contribute to this debate, previous studies have failed to report consistent localized neocortical brain dysfunction. The authors reasoned that early methods may have been insensitive to such dysfunction, which may now be detectable with improved technology. METHOD: To test this hypothesis, regional cerebral blood flow was measured with positron emission tomography (PET) in 21 children with primary autism and in 10 nonautistic children with idiopathic mental retardation. Autistic and comparison groups were similar in average age and developmental quotients. The authors first searched for focal brain dysfunction in the autistic group by using a voxel-based whole brain analysis and then assessed the sensitivity of the method to detect the abnormality in individual children. An extension study was then performed in an additional group of 12 autistic children. RESULTS: The first autistic group had a highly significant hypoperfusion in both temporal lobes centered in associative auditory and adjacent multimodal cortex, which was detected in 76% of autistic children. Virtually identical results were found in the second autistic group in the extension study. CONCLUSIONS: PET and voxel-based image analysis revealed a localized dysfunction of the temporal lobes in school-aged children with idiopathic autism. Further studies will clarify the relationships between these temporal abnormalities and the perceptive, cognitive, and emotional developmental abnormalities characteristic of this disorder.
Specificity of HercepTest in Determining <i>HER-2</i>/<i>neu</i> Status of Breast Cancers Using the United States Food and Drug Administration–Approved Scoring System
Authors: Timothy W. Jacobs, Allen M. Gown, Hadi Yaziji, Melissa J. Barnes, Stuart J. Schnitt
Journal: Journal of Clinical Oncology (1999)

To evaluate the specificity of the HercepTest for Immunoenzymatic Staining (Dako Corp, Carpinteria, CA) for determining HER-2/neu protein expression in breast cancer.Forty-eight invasive breast cancers previously found to be HER-2/neu-negative by two different immunohistochemical (IHC) assays and not amplified for the HER-2/neu gene by fluorescence in situ hybridization were studied using the HercepTest kit. HercepTest was performed according to the manufacturer's guidelines, and the results were scored on a 0 to 3+ scale using the United States Food and Drug Administration (FDA)-approved grading system. In this system, cases scored as 2+ or 3+ are considered HER-2/neu-positive.Among these 48 cases, the IHC score using the FDA-approved scoring system was 0 in four cases (8.3%), 1+ in 16 (33.3%), 2+ in 21 (43.8%), and 3+ in seven (14.6%). Therefore, 58.4% of these cases were categorized as HER-2/neu-positive, and the specificity of the HercepTest kit for HER-2/neu expression was 41.6%. However, with the use of a modified scoring system that took into account the level of staining of nonneoplastic epithelium, the specificity increased to 93.2%.Our results indicate that the HercepTest kit, when used in accordance with the manufacturer's guidelines and the FDA-approved scoring system, results in a large proportion of breast cancers being categorized as positive for HER-2/neu protein expression and that many of these seem to be false-positives. Consideration of the level of staining of nonneoplastic epithelium resulted in improved specificity. The current FDA-approved scoring system for HercepTest results should be reevaluated before its widespread use in clinical practice.
HNF1B Mutations Associate with Hypomagnesemia and Renal Magnesium Wasting
Authors: Shazia Adalat, Adrian S. Woolf, Karen A. Johnstone, Andrea Wirsing, Lorna W. Harries, David A. Long, Raoul C. Hennekam, Sarah E. Ledermann, Lesley Rees, William van't Hoff, Stephen D. Marks, Richard S. Trompeter, Kjell Tullus, Paul J. Winyard, Janette Cansick, Imran Mushtaq, Harjeeta K. Dhillon, Coralie Bingham, Emma L. Edghill, Rukshana Shroff, Horia Stanescu, Gerhart U. Ryffel, Sian Ellard, Detlef Bockenhauer
Journal: Journal of the American Society of Nephrology (2009)

Mutations in hepatocyte nuclear factor 1B (HNF1B), which is a transcription factor expressed in tissues including renal epithelia, associate with abnormal renal development. While studying renal phenotypes of children with HNF1B mutations, we identified a teenager who presented with tetany and hypomagnesemia. We retrospectively reviewed radiographic and laboratory data for all patients from a single center who had been screened for an HNF1B mutation. We found heterozygous mutations in 21 (23%) of 91 cases of renal malformation. All mutation carriers had abnormal fetal renal ultrasonography. Plasma magnesium levels were available for 66 patients with chronic kidney disease (stages 1 to 3). Striking, 44% (eight of 18) of mutation carriers had hypomagnesemia (<1.58 mg/dl) compared with 2% (one of 48) of those without mutations (P < 0.0001). The median plasma magnesium was significantly lower among mutation carriers than those without mutations (1.68 versus 2.02 mg/dl; P < 0.0001). Because hypermagnesuria and hypocalciuria accompanied the hypomagnesemia, we analyzed genes associated with hypermagnesuria and detected highly conserved HNF1 recognition sites in FXYD2, a gene that can cause autosomal dominant hypomagnesemia and hypocalciuria when mutated. Using a luciferase reporter assay, we demonstrated HNF1B-mediated transactivation of FXYD2. These results extend the phenotype of HNF1B mutations to include hypomagnesemia. HNF1B regulates transcription of FXYD2, which participates in the tubular handling of Mg2+, thus describing a role for HNF1B not only in nephrogenesis but also in the maintenance of tubular function.
BCR/ABL1 and BCR are under the transcriptional control of the MYC oncogene
Authors: Nitesh Sharma, Vera Magistroni, Rocco Piazza, Stefania Citterio, Caterina Mezzatesta, Praveen Khandelwal, Alessandra Pirola, Carlo Gambacorti-Passerini
Journal: Molecular Cancer (2015)

Chronic Myeloid Leukaemia (CML) is caused by the BCR/ABL1 fusion gene. Both the presence and the levels of BCR/ABL1 expression seem to be critical for CML progression from chronic phase (CP) to blast crisis (BC). After the oncogenic translocation, the BCR/ABL1 gene is under the transcriptional control of BCR promoter but the molecular mechanisms involved in the regulation of oncogene expression are mostly unknown. A region of 1443bp of the functional BCR promoter was studied for transcription factor binding sites through in-silico analysis and Chromatin Immunoprecipitation experiments. BCR and BCR/ABL1 expression levels were analysed in CML cell lines after over-expression or silencing of MYC transcription factor. A luciferase reporter assay was used to confirm its activity on BCR promoter. In the present study we demonstrate that MYC and its partner MAX bind to the BCR promoter, leading to up-regulation of BCR and BCR/ABL1 at both transcriptional and protein levels. Accordingly, silencing of MYC expression in various BCR/ABL1 positive cell lines causes significant downregulation of BCR and BCR/ABL1, which consequently leads to decreased proliferation and induction of cell death. Here we describe a regulatory pathway modulating BCR and BCR/ABL1 expression, showing that the BCR promoter is under the transcriptional control of the MYC/MAX heterodimer. Since MYC is frequently over-expressed in BC, this phenomenon could play a critical role in BCR/ABL1 up-regulation and blast aggressiveness acquired during CML evolution.
Rethinking EAE pathogenesis
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Th1 cells have long been thought to mediate the pathogenesis of experimental autoimmune encephalitis (EAE), a mouse model for multiple sclerosis. But Langrish et al. now identify a new subset of T cells as the driving force behind brain inflammation in EAE (page 233).






Figure 

CD4+ T cells cultured in vitro with IL-23 (▪), but not IL-12 (▴) induce EAE pathogenesis.




Previous thinking on EAE culprits has focused on Th1 CD4+ T cells and their distinctive product IFN-γ, both of which are found at EAE inflammation sites. But the details were confused by the biology of p40—a subunit shared by both IL-12 (an inducer of Th1 cells) and IL-23. This group showed recently that EAE is suppressed after p40 inactivation because of the loss of IL-23 not IL-12.

The authors now explain the pathogenic effect of IL-23 by showing that this cytokine induces a newly recognized subset of CD4+ T cells, which produces large amounts of IL-17 and IL-6 but very little IFN-γ. These T cells and IFN-γ–producing Th1 cells both invaded the CNS during EAE in wild-type mice, but only IFN-γ–producing Th1 cells were found in the CNS in mice lacking IL-23. Furthermore, T cells cultured in vitro with IL-23, but not those cultured with IL-12, could transfer the disease to naive mice.

How these cells induce disease is not completely understood. IL-17 appears to be a key player, as blocking IL-17 in wild-type mice partially reversed disease. IL-17 is known to drive the production of inflammatory cytokines from memory T cells, and IL-23 induces proliferation of these cells—both of which may amplify inflammation. Whatever the mechanism, this study appears to exonerate traditional Th1 cells as the main players in the pathogenesis of EAE.