tbuckley/cabot-search huggingface dataset:
Conventional B cells, not B-1 cells, are responsible for producing autoantibodies in lpr mice.
Authors: E A Reap, E S Sobel, P L Cohen, R A Eisenberg
Journal: The Journal of Experimental Medicine (1993)

Mice homozygous for the lpr gene develop autoantibodies and polyclonal B cell activation similar to what is seen in human systemic lupus erythematosus patients. We have previously shown that an lpr-specific intrinsic B cell defect was necessary for autoantibody production in this model. In the current study, we have further defined these autoantibody-producing B cells. Two major subsets of B cells have been described. B-1 cells (CD5+ B cells) can be distinguished from conventional B cells on the basis of phenotype, cytokine secretion, gene expression, anatomical location, and function. In addition, B-1 cells have been implicated in autoimmunity in several murine and human studies. To address the question of which B cell subset produces autoantibodies in lpr mice, we used immunoglobulin heavy chain (Igh) allotype-marked peritoneal (B-1 cell source) and bone marrow (conventional B cell source) cells from lpr mice to establish B cell chimeras. We used two general approaches. In one, we reconstituted sublethally irradiated mice with B-1 cells of one allotype and bone marrow cells of another allotype. In the second method, we suppressed endogenous B cells in neonatal mice with allotype-specific anti-IgM antibody, and injected peritoneal cells of another allotype. After antibody treatment was stopped, the mouse's conventional B cells recovered, but the B-1 subset was only reconstituted by the donor. In both types of chimeras, antichromatin, rheumatoid factor, and anti-single stranded DNA (ssDNA) autoantibodies were produced by the conventional B cell bone marrow source. In addition, an age-related decrease in peritoneal B-1 cells was seen, even in unmanipulated lpr mice. These data show that lpr B-1 cells are not important producers of autoantibodies. Conventional B cells are the source of autoantibodies directed at chromatin, ssDNA, and IgG.
Metabolic Consequence of Two-Week Fructose Feeding in Diabetic Subjects
Authors: Phyllis A Crapo, Orville G Kolterman, Robert R Henry
Journal: Diabetes Care (1986)

We studied the metabolic effects of 2-wk fructose feeding as the sweetener in the diet of seven noninsulin- dependent diabetic individuals. The data demonstrated reduced postprandial hyperglycemia to an oral glucose challenge after 14 days without a significant difference in insulin response. There was no change in the markedly blunted glucose response to a fructose challenge but a significantly lower insulin response (area under the 3-h curve) was observed after 14 days of fructose feeding. There was reduced postprandial hyperglycemia after 14 days of fructose feeding with test meals as compared with baseline, without significant differences in insulin response. We also found no significant difference in free fatty acids, cholesterol, high-density lipoprotein (HDL) cholesterol, pyruvate, lactate, or uric acid after fructose feedings. There was a 13% increase in triglyceride levels after 14 days in 5 subjects with initial fasting hypertriglyceridemia (&amp;gt;150 mg/dl). Insulin receptor binding to isolated adipocytes did not change after 14 days of fructose feeding.
Altered synaptic structure in the hippocampus in a mouse model of Alzheimer’s disease with soluble amyloid-β oligomers and no plaque pathology
Authors: Katherine A Price, Merina Varghese, Allison Sowa, Frank Yuk, Hannah Brautigam, Michelle E Ehrlich, Dara L Dickstein
Journal: Molecular Neurodegeneration (2014)

Mounting evidence suggests that soluble oligomers of amyloid-β (oAβ) represent the pertinent synaptotoxic form of Aβ in sporadic Alzheimer's disease (AD); however, the mechanistic links between oAβ and synaptic degeneration remain elusive. Most in vivo experiments to date have been limited to examining the toxicity of oAβ in mouse models that also possess insoluble fibrillar Aβ (fAβ), and data generated from these models can lead to ambiguous interpretations. Our goal in the present study was to examine the effects of soluble oAβ on neuronal and synaptic structure in the amyloid precursor protein (APP) E693Q ("Dutch") mouse model of AD, which develops intraneuronal accumulation of soluble oAβ with no detectable plaques in AD-relevant brain regions. We performed quantitative analyses of neuronal pathology, including dendrite morphology, spine density, and synapse ultrastructure in individual hippocampal CA1 neurons. When assessing neuronal morphology and complexity we observed significant alterations in apical but not in basal dendritic arbor length in Dutch mice compared to wild type. Moreover, Dutch mice exhibited a significant decrease in dendritic arborization with a decrease in dendritic length and number of intersections at 120 μm and 150 μm from the soma, respectively. We next examined synaptic parameters and found that while there were no differences in overall synaptic structure, Dutch mice displayed a significant reduction in the post-synaptic density (PSD) length of synapses on mushroom spines, in comparison to wild type littermates. The structural alterations to individual neurons in Dutch mice along with the changes in larger dendritic spines support the Aβ oligomer hypothesis, which postulates that the early cognitive impairments that occur in AD are attributed to the accumulation of soluble oAβ first affecting at the synaptic level with subsequent structural disturbances and cellular degeneration.
Polymerase chain reaction detection of Mycobacterium paratuberculosis and Mycobacterium avium subsp silvaticum in long term cultures from Crohn's disease and control tissues.
Authors: M T Moss, J D Sanderson, M L Tizard, J Hermon-Taylor, F A el-Zaatari, D C Markesich, D Y Graham
Journal: Gut (1992)

Thirty one cultures were established in MG3 medium from the intestinal tissues of 29 patients, including 18 with Crohn9s disease, five with ulcerative colitis, and six non-inflammatory bowel disease controls. All cultures grew either acid fast bacilli or uncharacterized spheroplasts. Pellets from these cultures were coded and assayed blind for M paratuberculosis and M avium subsp silvaticum using IS900- and IS902-PCR (polymerase chain reaction) assays, respectively. IS900 and IS902 are multicopy DNA insertion elements specific for these two organisms. Six Crohn9s disease cultures and a single non-inflammatory bowel disease control were positive for M paratuberculosis. A further six cultures were positive for M avium subsp silvaticum, of which two each were from Crohn9s disease, ulcerative colitis, and non-inflammatory bowel disease controls. The intensity of the IS900-PCR signals indicated very low numbers of M paratuberculosis organisms and bore no relation to visible spheroplastic or bacillary mycobacterial growth. The results suggest that M paratuberculosis isolated from man exists in a form which hardly replicates if at all when cultured in MG3 medium in vitro, and are consistent with the involvement of this known animal enteric pathogen in a proportion of chronic enteritis in man.
Induced Sputum 8-Isoprostane Concentrations in Inflammatory Airway Diseases
Authors: Lisa G. Wood, Manohar L. Garg, Jodie L. Simpson, Trevor A. Mori, Kevin D. Croft, Peter A. B. Wark, Peter G. Gibson
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Induced sputum 8-iso-prostaglandin F2α (PGF2α) concentrations may be a useful marker of oxidative stress in airways disease. This study examines oxidative stress (measured by 8-iso-PGF2α) in airway disease according to disease type (asthma and bronchiectasis), disease activity (stable and acute asthma), and disease pattern (intermittent, mild, moderate, and severe persistent asthma). We compared subjects with stable asthma (n = 71) and bronchiectasis (n = 23) with healthy control subjects (n = 29). Another group of patients with asthma (n = 39) were assessed during and after acute exacerbation. Induced sputum 8-iso-PGF2α concentrations were validated and found to be elevated in subjects with stable asthma and bronchiectasis versus control subjects (median [interquartile range] 216 [103–389] and 698 [264–1,613] ng/L vs. 123 [41–290] ng/L, p < 0.001) and increased as clinical asthma pattern worsened (intermittent 115 [42–153], mild persistent 116 [89–229] ng/L, moderate persistent 183 [110–317] ng/L, severe persistent 387 [102–587] ng/L; p = 0.010). Sputum 8-iso-PGF2α concentrations were elevated during acute asthma and decreased with recovery (458 [227–950] ng/L vs. 214 [148–304] ng/L, p = 0.0002). We conclude that 8-iso-PGF2α is involved in the pathophysiology of inflammatory airway diseases, being related to disease type, pattern, and activity. Analysis of 8-iso-PGF2α concentrations in induced sputum provides a useful tool for monitoring oxidative stress and investigating strategies aimed at reducing oxidative stress in airways disease.
Acne in a kidney transplant patient treated with cyclosporin A
Authors: P.L. Bencini, G. Montagnino, C. Crosti, F. Sala, A. Vecchi
Journal: British Journal of Dermatology (1986)

Journal Article Acne in a kidney transplant patient treated with cyclosporin A Get access P.L. Bencini, P.L. Bencini Istituto di Clinica Dematologica, I e Dermatologia Pediatrica, Universitå di Milano, Italy Search for other works by this author on: Oxford Academic Google Scholar G. Montagnino, G. Montagnino Divisione di Nefrologia e Dialisi, Ospedale Policlinico di Milano, Italy Search for other works by this author on: Oxford Academic Google Scholar C. Crosti, C. Crosti Istituto di Clinica Dematologica, I e Dermatologia Pediatrica, Universitå di Milano, Italy Search for other works by this author on: Oxford Academic Google Scholar F. Sala, F. Sala Istituto di Clinica Dematologica, I e Dermatologia Pediatrica, Universitå di Milano, Italy Search for other works by this author on: Oxford Academic Google Scholar A. De Vecchi A. De Vecchi Divisione di Nefrologia e Dialisi, Ospedale Policlinico di Milano, Italy Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 114, Issue 3, 1 March 1986, Pages 396–397, https://doi.org/10.1111/j.1365-2133.1986.tb02839.x Published: 01 March 1986
Cholesterol depletion alters amplitude and pharmacology of vascular calcium-activated chloride channels
Authors: William R. Sones, Alison J. Davis, Normand Leblanc, Iain A. Greenwood
Journal: Cardiovascular Research (2010)

Calcium-activated chloride channels (CACCs) share common pharmacological properties with Kcnma1-encoded large conductance K+ channels (BKCa or KCa1.1) and it has been suggested that they may co-exist in a macromolecular complex. As KCa1.1 channels are known to localize to cholesterol and caveolin-rich lipid rafts (caveolae), the present study investigated whether Ca2+-sensitive Cl− currents in vascular myocytes were affected by the cholesterol depleting agent methyl-β-cyclodextrin (M-βCD). Calcium-activated chloride and potassium currents were recorded from single murine portal vein myocytes in whole cell voltage clamp. Western blot was undertaken following sucrose gradient ultracentrifugation using protein lysates from whole portal veins. Ca2+-activated Cl− currents were augmented by 3 mg mL−1 M-βCD with a rapid time course (t0.5 = 1.8 min). M-βCD had no effect on the bi-modal response to niflumic acid or anthracene-9-carboxylate but completely removed the inhibitory effects of the KCa1.1 blockers, paxilline and tamoxifen, as well as the stimulatory effect of the KCa1.1 activator NS1619. Discontinuous sucrose density gradients followed by western blot analysis revealed that the position of lipid raft markers caveolin and flotillin-2 was altered by 15 min application of 3 mg mL−1 M-βCD. The position of KCa1.1 and the newly identified candidate for CACCs, TMEM16A, was also affected by M-βCD. These data reveal that CACC properties are influenced by lipid raft integrity.
Abstract 2304: Stem features associated with EMT are driven by TGFβ1 in liver-metastatic cells
Authors: Idoia G. Zubeldia, Carmen Gil-Puig, Alfonso Calvo, Leyre Larzabal, Alice Agliano, Javier Dotor, Fernando Vidal-Vanaclocha, Jon Lecanda
Journal: Cancer Research (2010)

Abstract The liver is a major target organ for metastasis. Development of metastases requires an early release of tumour-initiating-cells from the primary tumour and adhesion of metastatic-cells into a permissive niche. We hypothesized that Epithelial-Mesenchymal Transition (EMT) underlies not only the early events, but also the promotion of the most advanced stages of a successful dissemination process to the liver. It is believed that TGFβ1 might allow tumour-initiating-cells to acquire cancer stem cell properties via EMT as a mechanism that modulates the microenvironment contributing to primary and also metastatic tumor progression. However, the mechanism of EMT induction by TGFβ1 and its involvement in liver metastases remain largely unknown. Aiming to recapitulate the hepatic metastases, we established a murine model of highly metastatic colon carcinoma cells in the context of TGFβ1-signaling. To this end, luciferase-expressing cells (MC-38luc) were pre-treated with TGFβ1 (100 pM, 48 h), before intrasplenic injection of 106 cells in C57BL/6J mice. Larger primary tumours were consistently observed and liver metastasis was achieved more rapidly after injection of MC-38luc+TGFβ1 cells, than after injection of untreated MC-38luc cells. Histological examination of liver micrometastasis also revealed slightly increased staining of Ki67, α-SMA and F4/80 markers in MC-38luc+TGFβ1 tumours. Splenic co-injection of these liver-metastatic-stem cells with non transformed hepatocytes (AML-12 cells) accelerated the incidence of liver metastasis, indicating the supportive role of the normal hepatic parenchyma. Intraperitoneal injection with a novel TGFβ1-inhibitory peptide P17 (obtained from a peptide library binding to TGFβ1) resulted in reduced liver metastasis and decrease of both CECs and CEPs. We isolated liver-metastatic cells that showed higher cellular proliferation as compared to the parental counterparts. These cells posses increased tumorogenicity in vivo, a complete lack of E-cadherin expression, and increased TGFβ1/EMT signalling properties that all relate to stem cell features. Our results provide an insight into the molecular events leading to TGFβ1-mediated malignant progression and indicate that targeting TGFβ1/EMT might represent an optimal therapeutic strategy by impairing tumor growth, stemness and further liver metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2304.
Dihydropyridine receptors are primarily functional L-type calcium channels in rabbit ventricular myocytes.
Authors: W Y Lew, L V Hryshko, D M Bers
Journal: Circulation Research (1991)

We measured [3H]PN200-110 binding and patch-clamp currents in rabbit ventricular myocytes to determine if there is a disparity between the density of dihydropyridine-specific receptors and functional L-type calcium channels, as has been reported for skeletal muscle. The dihydropyridine receptor density was 74.7 +/- 4.2 fmol/mg protein (mean +/- SEM, Kd = 1.73 +/- 0.29 nM, n = 6) in ventricular homogenates and 147 +/- 6 fmol/mg protein (Kd = 1.15 +/- 0.16 nM, n = 4) in myocytes. Ventricular homogenates contained 121 +/- 9 mg protein/g wet wt (n = 7). These values were used to calculate a dihydropyridine receptor density of 12.9 dihydropyridine sites/micron2 for ventricular homogenates and 14.8 dihydropyridine sites/micron2 for myocytes. The number of functional L-type calcium channels (N) was calculated from measurements of whole-cell current (I), single-channel current (i), and open probability (po), where N = I/(i x po). We measured sodium current through calcium channels (I(ns)) to avoid calcium-induced inactivation. Whole-cell (I(ns)) and single-channel (i(ns) and po) measurements were obtained under similar ionic conditions at a test potential of -20 mV. In six cells, the peak I(ns) was approximately 105 pA/pF. The single-channel conductance was 40.8 +/- 2.6 pS (n = 12), and i(ns) at -20 mV was 1.96 pA. The mean po at -20 mV was 0.030 +/- 0.002 in 16 patches in which only a single channel was evident. The calculated density of functional L-type calcium channels was approximately 18 channels/micron2.(ABSTRACT TRUNCATED AT 250 WORDS)
Smoking and tuberculosis among silicotic patients
Authors: C. C. Leung, W. W. Yew, W. S. Law, C. M. Tam, M. Leung, Y. W. Chung, K. W. Cheung, K. W. Chan, F. Fu
Journal: European Respiratory Journal (2006)

The aim of the present study was to investigate the relationship between smoking and tuberculosis (TB) among high-risk silicotic patients in Hong Kong. A cohort of 435 silicotic patients tuberculin tested from 1995-2002 was prospectively followed-up until the end of 2005. Baseline characteristics were analysed with respect to positive tuberculin reaction (> or =10 mm) at baseline and subsequent development of TB. Smoking, alcohol use and body mass index were independent predictors of positive tuberculin reaction at baseline in multiple logistic regression analysis. Total cigarette pack-yrs did not demonstrate any significant effect. The annual incidences of TB were 1,841, 2,294 and 4,181 per 100,000 for never-, ex- and current smokers, respectively. On Cox proportional hazard analysis, current smokers have a significantly higher risk of TB than other silicotic patients (adjusted hazard ratio (95% confidence interval (CI)): 1.96 (1.14-3.35)) after controlling for age, alcohol use, tuberculin status, treatment for latent TB infection and other relevant background/disease factors. A significant dose-response relationship was also observed with the daily number of cigarettes currently smoked. Smoking cessation may reduce 32.4% (95% CI: 6.5-54.0) of the risk. Smoking increases the risk of both tuberculosis infection and subsequent development of the disease among silicotic patients.
On the Paradox of Insulin-Induced Hyperandrogenism in Insulin-Resistant States
Authors: LEONID PORETSKY
Journal: Endocrine Reviews (1991)

FREQUENT coexistence of insulin resistance and ovarian hyperandrogenism is a well known phenomenon. Although the precise mechanisms underlying this phenomenon have not been clearly defined, the hypothesis that hyperandrogenism of insulin-resistant states is due to ovarian stimulation by high levels of circulating insulin has gained popularity. Clinical observations and experimental data obtained in humans and in animals, both in vitro and in vivo, support this hypothesis. However, the following question is often raised: how can the ovary remain sensitive to insulin, when "classical" target organs for insulin (such as liver, fat or muscle) are insulin resistant, and thus do not respond to insulin normally? Although the answer to this question has not yet been found, a substantial body of data that shed light on this issue has accumulated in the literature. One can now envision a variety of circumstances in which the ovary may overproduce androgens in response to stimulation by insulin, even though other organs are insulin resistant. In this article I will discuss possible mechanisms of preserved ovarian sensitivity to insulin in insulin-resistant states. I will also outline directions of future studies in this exciting new area of endocrine knowledge.
Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA
Authors: Alain R Thierry, Florent Mouliere, Safia El Messaoudi, Caroline Mollevi, Evelyne Lopez-Crapez, Fanny Rolet, Brigitte Gillet, Celine Gongora, Pierre Dechelotte, Bruno Robert, Maguy Del Rio, Pierre-Jean Lamy, Frederic Bibeau, Michelle Nouaille, Virginie Loriot, Anne-Sophie Jarrousse, Franck Molina, Muriel Mathonnet, Denis Pezet, Marc Ychou
Journal: Nature Medicine (2014)
Prognostic and Clinicopathologic Associations of Oncogenic <i>BRAF</i> in Metastatic Melanoma
Authors: Georgina V. Long, Alexander M. Menzies, Adnan M. Nagrial, Lauren E. Haydu, Anne L. Hamilton, Graham J. Mann, T. Michael Hughes, John F. Thompson, Richard A. Scolyer, Richard F. Kefford
Journal: Journal of Clinical Oncology (2011)

To assess the frequency and type of oncogenic BRAF mutations in metastatic melanoma and correlate BRAF status with clinicopathologic features and outcome.Consecutive BRAF-tested Australian patients with metastatic melanoma (n = 197) were observed prospectively. A comprehensive range of clinicopathologic variables were correlated with BRAF mutation status, and a survival analysis was conducted.Forty-eight percent of patients had a BRAF mutation; 70 patients (74%) had V600E, 19 (20%) had V600K, and six (6%) had other genotypes. Other than age at diagnosis of distant metastasis (median age, 56 v 63 years for BRAF-mutant v BRAF wild-type patients, respectively; P < .001), there was no significant difference in clinical features of patients with metastatic melanoma by mutation status. Features of the antecedent primary melanoma significantly associated with a BRAF mutation (P < .05) were histopathologic subtype, presence of mitoses, single or occult primary melanoma, truncal location, and age at diagnosis of primary tumor ≤ 50 years. The interval from diagnosis of first-ever melanoma to distant metastasis was not significantly different between BRAF-mutant and BRAF wild-type patients; however, the median survival of patients with newly diagnosed metastatic melanoma was 5.7 months for BRAF-mutant patients not treated with a BRAF inhibitor, 8.5 months for BRAF wild-type patients, and not reached for BRAF-mutant patients treated with a BRAF inhibitor.V600K mutations comprised 20% of BRAF mutations. Characteristics of the antecedent primary melanoma and age at diagnosis differed in BRAF-mutant and BRAF wild-type patients. The presence of mutant BRAF had no impact on the disease-free interval from diagnosis of first-ever melanoma to first distant metastasis; however, it may have impacted survival thereafter.
Ameliorated Glomerular Injury in Mice Overexpressing Brain Natriuretic Peptide with Renal Ablation
Authors: MASATO KASAHARA, MASASHI MUKOYAMA, AKIRA SUGAWARA, HISASHI MAKINO, TAKAYOSHI SUGANAMI, YOSHIHIRO OGAWA, MASAYO NAKAGAWA, KENSEI YAHATA, MASAHISA GOTO, RIEKO ISHIBASHI, NAOHISA TAMURA, ISSEI TANAKA, KAZUWA NAKAO
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Brain natriuretic peptide (BNP) is a cardiac hormone produced by the ventricle, and its secretion is markedly increased in heart failure, hypertension, and renal failure. Transgenic mice that overexpress BNP in the liver (BNP-Tg) were recently generated, resulting in low BP. To elucidate the role of BNP in renal pathophysiology, the effect of chronic excess of BNP in transgenic mice on glomerular injury after subtotal nephrectomy induced by resection of the renal poles was examined. After nephrectomy, glomerular cross-sectional areas in control nontransgenic mice markedly increased as compared with those in sham-operated mice (+81 ± 7%), whereas there was only a modest increase in BNP-Tg (+10 ± 6%). Expansion of the mesangial area and increase in the intraglomerular cell number were also inhibited in BNP-Tg. Glomerular expressions of transforming growth factor-β and fibronectin were increased with hypertrophy and were significantly suppressed in BNP-Tg. Furthermore, increases in the urinary albumin excretion and BP were significantly ameliorated in BNP-Tg. Chronic hydralazine treatment in nephrectomized nontransgenic mice failed to inhibit glomerular hypertrophy. These findings indicate that the chronic excess of BNP in mice ameliorates glomerular hypertrophy and mesangial expansion after renal ablation. The results also suggest that the observed effects of natriuretic peptides under reduced renal mass are not due merely to systemic BP reduction and may be therapeutically applicable in various renal diseases.