tbuckley/cabot-search huggingface dataset:
Inhibition of Interleukin 7 Receptor Signaling by Antigen Receptor Assembly
Authors: Fiona M. Smart, Ashok R. Venkitaraman
Journal: The Journal of Experimental Medicine (2000)

After the productive rearrangement of immunoglobulin (Ig) heavy chain genes, precursor (pre-)B lymphocytes undergo a limited number of cell divisions in response to interleukin (IL)-7. Here, we present evidence that this phase of IL-7–dependent expansion is constrained by an inhibitory signal initiated by antigen receptor assembly. A line of pre-B cells from normal murine bone marrow that expresses a μ heavy chain with a D-proximal VH7183.2 region divides continuously in IL-7. IL-7 responsiveness ceases upon differentiation to the μ1, κ1 stage, despite continuing expression of the IL-7 receptor (IL-7R), suggesting that antigen receptor assembly inhibits IL-7 responsiveness. This is confirmed by introduction of a rearranged λ light chain gene, which inhibits proliferative signaling through the IL-7R. Inhibition is specific to the IL-7R, because it is overcome by replacement of the IL-7R cytoplasmic domain with corresponding sequences from the closely related IL-2Rβ chain. Alteration of a single tyrosine residue, Tyr410, in the IL-7R cytoplasmic domain to phenylalanine also prevents the inhibition of proliferation after antigen receptor assembly. Thus, the loss of IL-7 responsiveness after antigen receptor assembly may be mediated through the recruitment of an inhibitory molecule to this residue. Our findings identify a novel mechanism that limits cytokine-dependent proliferation during B lymphopoiesis. This mechanism may be essential for the proper regulation of peripheral B lymphocyte numbers.
Effects of Comprehensive Lifestyle Modification on Diet, Weight, Physical Fitness, and Blood Pressure Control: 18-Month Results of a Randomized Trial
Authors: Patricia J. Elmer, Eva Obarzanek, William M. Vollmer, Denise Simons-Morton, Victor J. Stevens, Deborah Rohm Young, Pao-Hwa Lin, Catherine Champagne, David W. Harsha, Laura P. Svetkey, Jamy Ard, Phillip J. Brantley, Michael A. Proschan, Thomas P. Erlinger, Lawrence J. Appel
Journal: Annals of Internal Medicine (2006)

Background: The main 6-month results from the PREMIER trial showed that comprehensive behavioral intervention programs improve lifestyle behaviors and lower blood pressure. Objective: To compare the 18-month effects of 2 multicomponent behavioral interventions versus advice only on hypertension status, lifestyle changes, and blood pressure. Design: Multicenter, 3-arm, randomized trial conducted from January 2000 through November 2002. Setting: 4 clinical centers and a coordinating center. Patients: 810 adult volunteers with prehypertension or stage 1 hypertension (systolic blood pressure, 120 to 159 mm Hg; diastolic blood pressure, 80 to 95 mm Hg). Interventions: A multicomponent behavioral intervention that implemented long-established recommendations ("established"); a multicomponent behavioral intervention that implemented the established recommendations plus the Dietary Approaches to Stop Hypertension (DASH) diet ("established plus DASH"); and advice only. Measurements: Lifestyle variables and blood pressure status. Follow-up for blood pressure measurement at 18 months was 94%. Results: Compared with advice only, both behavioral interventions statistically significantly reduced weight, fat intake, and sodium intake. The established plus DASH intervention also statistically significantly increased fruit, vegetable, dairy, fiber, and mineral intakes. Relative to the advice only group, the odds ratios for hypertension at 18 months were 0.83 (95% CI, 0.67 to 1.04) for the established group and 0.77 (CI, 0.62 to 0.97) for the established plus DASH group. Although reductions in absolute blood pressure at 18 months were greater for participants in the established and the established plus DASH groups than for the advice only group, the differences were not statistically significant. Limitations: The exclusion criteria and the volunteer nature of this cohort may limit generalizability. Although blood pressure is a well-accepted risk factor for cardiovascular disease, the authors were not able to assess intervention effects on clinical cardiovascular events in this limited time and with this sample size. Conclusions: Over 18 months, persons with prehypertension and stage 1 hypertension can sustain multiple lifestyle modifications that improve control of blood pressure and could reduce the risk for chronic disease.
Early life origins of chronic obstructive pulmonary disease
Authors: C Svanes, J Sunyer, E Plana, S Dharmage, J Heinrich, D Jarvis, R de Marco, D Norback, C Raherison, S Villani, M Wjst, K Svanes, J M Anto
Journal: Thorax (2009)

<h3>Background and Objectives:</h3> There is uncertainty about the association between alcohol consumption and stroke, particularly for low-moderate intake. We explored these associations in a large international study. <h3>Methods:</h3> INTERSTROKE, a case-control study, is the largest international study of risk factors for acute stroke. Alcohol consumption was self-reported and categorised by drinks/week as low (1-7), moderate (7-14 for females, 7-21 for males) or high (&gt;14 for females, &gt;21 for males). Heavy episodic drinking (HED) was defined as &gt;5 drinks on ≥1 day per month. Multivariable conditional logistic regression was used to determine associations. <h3>Results:</h3> We included 12,913 cases and 12,935 controls; 25.0% (n=6,449) were current drinkers, 16.7% (n=4,318) former and 58.3% (n=15,076) never drinkers. Current drinkers were younger, male, smokers, active and with higher-paid occupations. Current drinking was associated with all stroke (OR 1.14; 95% CI 1.04-1.26) and intracerebral hemorrhage (ICH) (OR 1.50, 95% CI 1.21-1.84) but not ischaemic stroke (OR 1.06; 95% CI 0.95-1.19). HED pattern was associated with all stroke (OR 1.39; 95% CI 1.21-1.59), ischaemic stroke (OR 1.29; 95% CI 1.10-1.51) and ICH (OR 1.76; 95% CI 1.31-2.36). High level of alcohol intake was consistently associated with all stroke, ischaemic stroke and ICH. Moderate intake was associated with all stroke and ICH, but not ischaemic stroke. Low alcohol intake was not associated with stroke overall but there were regional differences; low intake was associated with reduced odds of stroke in Western Europe/North America (OR 0.66; 95%CI 0.45-0.96) and increased odds in India (OR 2.18; 95%CI 1.42-3.36)(p-interaction 0.037). Wine consumption was associated with reduced odds of all stroke and ischaemic stroke but not ICH. The magnitudes of association were greatest in those without hypertension and current smokers. <h3>Discussion:</h3> High and moderate intake were associated with increased odds of stroke, while low intake was not associated with stroke. However, there were important regional variations, which may relate to differences in population characteristics of alcohol consumers, types or patterns of consumption.
Association Between Human Fetuin-A and the Metabolic Syndrome
Authors: Joachim H. Ix, Michael G. Shlipak, Vincent M. Brandenburg, Sadia Ali, Markus Ketteler, Mary A. Whooley
Journal: Circulation (2006)

Fetuin-A is a multifunctional hepatic secretory protein that inhibits the action of insulin in experimental animals. We evaluated the association between human serum fetuin-A and the metabolic syndrome (MetS) in a cohort of persons with coronary artery disease.We defined MetS by the National Cholesterol Education Program criteria among 711 nondiabetic outpatients with coronary artery disease. The mean age was 67 years, and 82% were male. We divided participants into quartiles by serum fetuin-A concentrations. A total of 45% of participants (80 of 177) in the highest quartile of fetuin-A had MetS compared with 24% of participants (42 of 177) in the lowest quartile (odds ratio, 2.7; 95% confidence interval, 1.7 to 4.2; P<0.001). This association persisted after adjustment for potential confounding variables, including hypertension, body mass index, and inflammatory biomarkers (adjusted odds ratio, 2.0; 95% confidence interval, 1.1 to 3.5; P=0.02). Higher fetuin-A quartiles were also strongly and independently associated with higher low-density lipoprotein, non-high-density lipoprotein (HDL), and triglyceride concentrations and lower HDL concentrations (all P<0.01).Higher human fetuin-A concentrations are strongly associated with MetS and an atherogenic lipid profile. Future studies should evaluate whether fetuin-A predicts coronary artery disease risk.
Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-α
Authors: Simone Cenci, M. Neale Weitzmann, Cristiana Roggia, Noriyuki Namba, Deborah Novack, Jessica Woodring, Roberto Pacifici
Journal: Journal of Clinical Investigation (2000)

Estrogen deficiency induces bone loss by upregulating osteoclastogenesis by mechanisms not completely defined. We found that ovariectomy-enhanced T-cell production of TNF-α, which, acting through the TNF-α receptor p55, augments macrophage colony-stimulating factor–induced (M-CSF–induced) and RANKL-induced osteoclastogenesis. Ovariectomy failed to induce bone loss, stimulate bone resorption, or increase M-CSF– and RANKL-dependent osteoclastogenesis in T-cell deficient mice, establishing T cells as essential mediators of the bone-wasting effects of estrogen deficiency in vivo. These findings demonstrate that the ability of estrogen to target T cells, suppressing their production of TNF-α, is a key mechanism by which estrogen prevents osteoclastic bone resorption and bone loss.
SOLITARY NEUROFIBROMA OF SCALP
Authors: E. LIPMAN COHEN
Journal: British Journal of Dermatology (1945)

Journal Article SOLITARY NEUROFIBROMA OF SCALP Get access E. LIPMAN COHEN E. LIPMAN COHEN Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology and Syphilis, Volume 57, Issue 9-10, 1 September 1945, Pages 172–174, https://doi.org/10.1111/j.1365-2133.1945.tb11225.x Published: 01 September 1945
High Frequency of Multiple Melanomas and Breast and Pancreas Carcinomas in CDKN2A Mutation-Positive Melanoma Families
Authors: A. Borg, T. Sandberg, K. Nilsson, O. Johannsson, M. Klinker, A. Masback, J. Westerdahl, H. Olsson, C. Ingvar
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: Inherited mutations in the CDKN2A tumor suppressor gene, which encodes the p16INK4a protein, and in the cyclin-dependent kinase 4 (CDK4) gene confer susceptibility to cutaneous malignant melanoma. We analyzed families with two or more cases of melanoma for germline mutations in CDKN2A and CDK4 to elucidate the contribution of these gene defects to familial malignant melanoma and to the occurrence of other cancer types. Methods: The entire CDKN2A coding region and exon 2 of the CDK4 gene of an affected member of each of 52 families from southern Sweden with at least two cases of melanoma in first- or second-degree relatives were screened for mutations by use of polymerase chain reaction–single-strand conformation polymorphism analysis. Statistical tests were two-sided. Results: CDKN2A mutations were found in 10 (19%) of the 52 families. Nine families carried an identical alteration consisting of the insertion of arginine at position 113 of p16INK4a, and one carried a missense mutation, in which the valine at position 115 was replaced with a glycine. The 113insArg mutant p16INK4a was unable to bind cdk4 and cdk6 in an in vitro binding assay. Six of the 113insArg families had at least one member with multiple primary melanomas; the 113insArg families also had a high frequency of other malignancies—in particular, breast cancer (a total of eight cases compared with the expected 2.1; P = .0014) and pancreatic cancer (a total of six cases compared with the expected 0.16; P<.0001). Families with breast cancer also had a propensity for multiple melanomas in females, suggesting that a sex-dependent factor may modify the phenotypic expression of CDKN2A alterations. Conclusions: Our findings confirm that the majority of CDKN2A-associated melanoma families in Sweden are due to a single founder mutation. They also show that families with the CDKN2A 113insArg mutation have an increased risk not only of multiple melanomas and pancreatic carcinoma but also of breast cancer.
Prevalence, Genetics, and Clinical Features of Patients Carrying Podocin Mutations in Steroid-Resistant Nonfamilial Focal Segmental Glomerulosclerosis
Authors: Gianluca Caridi, Roberta Bertelli, Alba Carrea, Marco Di Duca, Paolo Catarsi, Mary Artero, Michele Carraro, Cristina Zennaro, Giovanni Candiano, Luca Musante, Marco Seri, Fabrizio Ginevri, Francesco Perfumo, Gian Marco Ghiggeri
Journal: Journal of the American Society of Nephrology (2001)

ABSTRACT. Podocin mutations (NPHS2 gene) are responsible for the autosomal recessive form of steroid-resistant nephrotic syndrome. As a result of a screening for these gene alterations in a cohort of Italian patients with nonfamilial nephrotic syndrome and histologic focal segmental glomerulosclerosis (FSGS), nine patients with NPHS2 gene homozygous or composite heterozygous mutations were found. In addition to the previously described defects, two novel mutations at exon 4 were identified (frameshift, L169P); four single nucleotide polymorphisms (SNPs) and one dinucleotide repeat were also identified. On the basis of haplotype analysis, a founder effect was suggested for the 419delG mutation, the most frequently observed in the patients studied. Patients carrying NPHS2 mutations and without a family history of nephrotic syndrome were indistinguishable from those with idiopathic FSGS on the basis of the clinical phenotype. Two of the nine patients had normal renal function at 3 and 10 yr of age, despite the presence of the nephrotic syndrome. The other seven had reached end-stage renal failure at a mean age of 9.6 yr (range, 4 to 17 yr) and had received renal allografts. In those presenting with end-stage renal failure, the clinical and laboratory features both before and after transplantation were similar, including the age at onset, the amount of proteinuria, and the absence of any response to steroids and other immunosuppressants. Finally, two children presented recurrence of mild proteinuria after transplantation, which promptly remitted after plasmapheresis combined with cyclophosphamide. These data demonstrate that podocin mutations in nonfamilial cases of steroid-resistant nephrotic syndrome are frequent and may be due in one case to a founder effect. The pretransplantation and posttransplantation outcomes in the group of patients with mutations of the podocin gene are similar to classical idiopathic FSGS, including the possibility of recurrence of proteinuria that is mild and responsive to plasmapheresis. These observations support a role of molecular screening of the podocin gene in patients with nephrotic syndrome before immunosuppressive treatment is started.
Intergenerational Health Responses to Adverse and Enriched Environments
Authors: Lars Olov Bygren
Journal: Annual Review of Public Health (2013)

Health consequences of relative or absolute poverty constitute a definitive area of study in social medicine. As demonstrated in the extreme example of the Dutch Hunger Winter from 1944 to 1945, prenatal hunger can lead to adult schizophrenia and depression. A Norwegian study showed how childhood poverty resulted in a heightened risk of myocardial infarction in adulthood. In England, a study of extended impaired prenatal nutrition indicated three different types of increased cardiovascular risk at older ages. Current animal and human studies link both adverse and enriched environmental exposures to intergenerational transmission. We do not fully understand the molecular mechanisms for it; however, studies that follow up epigenetic marks within a generation combined with exploration of gametic epigenetic inheritance may help explain the prevalence of certain conditions such as cardiovascular disease, schizophrenia, and alcoholism, which have complex etiologies. Insights from these studies will be of great public health importance.
Bronchioloalveolar Carcinoma
Authors: David R. Gandara, Howard West, Kari Chansky, Angela M. Davies, Derick H. M. Lau, John Crowley, Paul H. Gumerlock, Fred R. Hirsch, Wilbur A. Franklin
Journal: Clinical Cancer Research (2004)

Abstract Bronchioloalveolar carcinoma (BAC) is a previously uncommon subset of non-small cell lung cancer (NSCLC) with unique epidemiology, pathology, clinical features, radiographic presentation, and natural history compared with other NSCLC subtypes. Recent data suggest that the incidence of BAC is increasing, notably in younger nonsmoking women. Despite reports of prolonged survival after repeated surgical resection of multifocal lesions and slow growth kinetics, advanced bilateral or recurrent diffuse BAC remains incurable, with the vast majority of patients dying of respiratory failure or intercurrent pneumonia within 5 years. Limited data suggest that chemotherapy may yield poor results in BAC. However, anecdotal reports of prolonged complete response to tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR), a member of the human epidermal growth factor receptor (erbB) family, have raised considerable interest in studying this NSCLC subset. Here we present clinical data and preliminary results of correlative science studies analyzing human epidermal growth factor receptor pathways from the following two prospective Southwest Oncology Group clinical trials performed in advanced stage BAC: S9714 testing a 96-h continuous infusion of paclitaxel (Taxol) and S0126 evaluating the small molecule EGFR inhibitor gefitinib (ZD1839 or Iressa). These studies provide a biological rationale for investigating BAC as a model of predictive markers of EGFR inhibition.
Periodic leg movement, sleep fragmentation and central sleep apnoea in two cases: reduction with Clonazepam
Authors: C Guilleminault, C Crowe, MA Quera-Salva, L Miles, M Partinen
Journal: European Respiratory Journal (1988)

Two subjects presented with periodic leg movement (PLM) syndrome during sleep that was characterized by marked sleep fragmentation and repetitive short central apnoeas. Treatment of PLM using Clonazepam, a benzodiazepine with hypnotic properties, markedly reduced the sleep fragmentation due to PLM and, despite its depressant properties on the central nervous system, controlled the repetitive central apnoeas. These two observations, although rare, give insight into the role of non-ventilatory variables in the development of sleep apnoea. Significant sleep fragmentation should be considered when assessing factors leading to respiratory instability during sleep and/or the pathophysiology of sleep apnoea syndromes.
A First-in-Human Study of Conatumumab in Adult Patients with Advanced Solid Tumors
Authors: Roy S. Herbst, Razelle Kurzrock, David S. Hong, Manuel Valdivieso, Cheng-Pang Hsu, Lovely Goyal, Gloria Juan, Yuying C. Hwang, Susan Wong, John S. Hill, Greg Friberg, Patricia M. LoRusso
Journal: Clinical Cancer Research (2010)

Abstract Purpose: To determine the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of conatumumab, an investigational, fully human monoclonal agonist antibody against human death receptor 5, in patients with advanced solid tumors. Experimental Design: In the dose-escalation phase, patients received escalating intravenous doses of conatumumab (0.3, 1, 3, 10, or 20 mg/kg, 3–9 per cohort) every 2 weeks. In the dose-expansion phase, 10 patients with colorectal cancer (CRC) and 7 with non–small cell lung cancer (NSCLC) received 20 mg/kg of conatumumab every 2 weeks. Results: Thirty-seven patients received 1 or more doses of conatumumab. Conatumumab seemed to be well tolerated; there were no dose-limiting toxicities. Of adverse events possibly related to treatment, only 3 patients (8%) had a grade 3 event (fatigue and/or elevated lipase), and no anticonatumumab antibodies were detected. An MTD was not reached. Conatumumab exhibited dose linear kinetics from 3 to 20 mg/kg, with a mean terminal half-life of 13 to 19 days. One patient with NSCLC (0.3 mg/kg) had a confirmed partial response (PR) at week 32 (38% reduction in tumor size), with further reduction (48%) by week 96; this patient remains on conatumumab after 4.2 years with a sustained PR. Fourteen patients had a best response of stable disease, 2 for 32 weeks or more. One patient with CRC (0.3 mg/kg) and stable disease for 24 weeks had a 24% reduction in tumor size by RECIST (Response Evaluation Criteria in Solid Tumors) and a 35% reduction in the sum of standardized uptake values of all lesions measured by [18F]fluorodeoxyglucose positron emission tomographic scan. Changes in tumor levels of activated caspase-3 did not appear to be associated with tumor response. Conclusions: Conatumumab can be administered safely up to the target dose of 20 mg/kg every 2 weeks. Clin Cancer Res; 16(23); 5883–91. ©2010 AACR.
Abstract 74: The Inflammatory Phenotype Of Mesenchymal Fibroblasts And Its Role In Aging Dependent Cardiac Fibrosis- A Target For Statins?
Authors: Katarzyna A Cieslik, JoAnn Trial, Mark L Entman
Journal: Circulation Research (2014)

In the aging mouse (C57BL/6) myocardium fibrosis steadily increases after 14 months of age and is accompanied by elevated numbers of myeloid derived fibroblasts. Recently, we proposed a mechanism by which inflammatory mesenchymal fibroblasts (IMF) derived from mesenchymal stem cells secrete monocyte chemoattractant protein-1 (MCP-1) necessary for myeloid fibroblast induction in the aging heart. The current study extends the characterization of this inflammatory phenotype by describing elevated interleukin-6 (IL-6) secretion and increased expression of IL-6 receptor (IL-6R) in IMF. Since IL-6R lacks an intracellular domain it requires a co-receptor gp130 (generally expressed) to induce an intracellular signal. Thus, generation of an IL-6R soluble receptor allows IL-6 signaling on cells that do not express IL-6R (or expression is low), such as endothelial cells. We investigate the function of IL-6 and IL-6R in the promotion of transendothelial migration of monocytes through cardiac endothelium and their maturation into myeloid fibroblasts in in vitro assay. Treatments with IL-6 and more extensively IL-6+IL-6R resulted in a 3-5 fold increase (above the control level) in myeloid cell migration and maturation into myeloid fibroblasts. Thus IMF can contribute both IL-6 and IL-6R to endothelial cells and facilitate myeloid cell transendothelial migration. In agreement with these data, analysis of the aged mouse heart revealed the presence of fibroblasts expressing IL-6 (procollagen type I + IL-6 + cells), M1 macrophages (CD86 + cells) and M2 macrophages (CD301 + procollagen type I + cells) that were absent in hearts from young mice. The mechanisms by which expression of these factors is upregulated in IMF are being investigated; our data suggest that MCP-1 and IL-6 expression are controlled by the farnesyltransferase (FTase)-Ras-Erk1/2 pathway. Interestingly, since atorvastatin interferes with farnesyl synthesis it also reduced MCP-1 and IL-6 expression in IMF. These data may introduce a new use of this class of drugs in the prevention of the age-related fibrosis.