tbuckley/cabot-search huggingface dataset:
Hypereosinophilic obliterative bronchiolitis: a distinct, unrecognised syndrome
Authors: Jean-François Cordier, Vincent Cottin, Chahéra Khouatra, Didier Revel, Clément Proust, Nathalie Freymond, Françoise Thivolet-Béjui, Jean-Charles Glérant
Journal: European Respiratory Journal (2012)

Biopsy-proven cases of eosinophilic bronchiolitis have only been reported in isolation, and all come from Japan. We present six patients with hypereosinophilic obliterative bronchiolitis (HOB), defined by the following criteria: 1) blood eosinophil cell count &gt;1 G·L −1 and/or bronchoalveolar lavage eosinophil count &gt;25%; 2) persistent airflow obstruction despite high-dose inhaled bronchodilators and corticosteroids; and 3) eosinophilic bronchiolitis at lung biopsy (n=1) and/or direct signs of bronchiolitis (centrilobular nodules and branching opacities) on computed tomography (n=6). Chronic dyspnoea and cough which was often severe, without the characteristic features of asthma, were the main clinical manifestations. Atopy and asthma were present in the history of three and two patients, respectively. One patient met biological criteria of the lymphoid variant of idiopathic hypereosinophilic syndrome. Mean blood eosinophil cell count was 2.7 G·L −1 and mean eosinophil differential percentage at bronchoalveolar lavage was 63%. Mean initial forced expiratory volume in 1 s/forced vital capacity ratio was 50%, normalising with oral corticosteroid therapy in all patients. HOB manifestations recurred when oral prednisone was decreased to 10–20 mg·day −1 , but higher doses controlled the disease. HOB is a characteristic entity deserving to be individualised among the eosinophilic respiratory disorders. Thorough analysis is needed to determine whether unrecognised and/or smouldering HOB may further be a cause of irreversible airflow obstruction in chronic eosinophilic respiratory diseases.
Effects of Age, Time Period, and Birth Cohort on the Prevalence of Diabetes and Obesity in Korean Men
Authors: Jin-Won Kwon, Yun-mi Song, Hye soon Park, Joohon Sung, Ho Kim, Sung-il Cho
Journal: Diabetes Care (2008)

We examined changes in the prevalence of diabetes, obesity, and overweight in 412,881 Korean men in birth cohorts from 1933 to 1972 over 8 years from 1992 to 2000 and separately analyzed the effects of age, time period, and birth cohort.The study included male employees of Korean government organizations and schools who were between 20 and 59 years of age in 1992. Diabetes was diagnosed on the basis of self-reports in 1992 or fasting blood glucose levels (>or=126 mg/ml, 7.0 mmol/l). The age-period-cohort model was used to estimate the effects of age, time period, and birth cohort.In Korean male birth cohorts from 1933 to 1972, the age-specific prevalence of diabetes, obesity, and overweight in men aged 28-59 years increased annually by 0.41% (3.03 to 6.29%), 0.18% (0.70 to 2.16%), and 1.49% (23.48 to 35.41%), respectively, from 1992 to 2000. The relative change in diabetes was largest among the younger cohorts (>400% increase over 8 years) and corresponded to the change in obesity. Apart from the contribution of age, clear cohort and period effects were evident for diabetes, although the magnitude of the effect was slightly less than that for obesity.Prevention of diabetes through the control of obesity, particularly in young men, clearly needs to be emphasized.
Pathogen DNA also contributes to interferon regulatory factor 3 activation in hepatic cells: Implications for alcoholic liver diseases
Authors: Yue Wang, Yingjun Guo, Fang Wang, Shuhan Sun
Journal: Hepatology (2010)

We read with great interest the recent article by Petrasek and colleagues,1 who reported that interferon regulatory factor 3 (IRF3) activation and type I interferon (IFN) production in parenchymal cells have protective effects in patients with alcoholic liver disease (ALD). The authors also suggested that IRF3 activation is a result of hepatic exposure to bacterial lipopolysaccharide (LPS). However, the authors failed to discuss gut bacterial and hepatic virus DNA, which is another immune-stimulating agent in addition to LPS that may also contribute to IRF3 activation in liver parenchymal cells and should be involved in the process of ALD. Besides LPS, excessive drinking of alcohol also results in an elevation of bacterial DNA in the portal blood.2 Recent studies have indicated that intracellular bacterial DNA can strongly activate IRF3 in liver parenchymal cells3 and thus induce the production of type I IFNs. In this respect, we suggest that gut-derived bacterial DNA also contributes to IRF3 activation and may play a key role in the prevention of alcoholic liver injury. We also believe that DNA-mediated hepatic IRF3 activation has great significance in China because of the high rate of hepatitis B virus (HBV) infection. Intracellular virus DNA4 has been proved to strongly activate IRF3 and induce type I IFN production. However, recent studies have found that components of HBV3 inhibit IRF3 activation via cleavage of the mitochondrial antiviral signaling protein, which is an essential component that activates IRF3 and thus induces the production of type I IFNs.5 Considering the current findings by Petrasek et al.,1 we hypothesize that HBV may also hinder the prevention functions of IRF3 and type I IFNs via the inhibition of the mitochondrial antiviral signaling protein and that HBV infection may increase the risk of ALD. This requires further investigation. Yue Wang M.D.*, Yingjun Guo M.D.*, Fang Wang M.D.*, Shuhan Sun M.D.*, * Department of Medical Genetics, Second Military Medical University, Shanghai, People's Republic of China.
Recent Advances in the Genetics of Autoimmune Disease
Authors: Peter K. Gregersen, Lina M. Olsson
Journal: Annual Review of Immunology (2008)

Extraordinary technical advances in the field of human genetics over the past few years have catalyzed an explosion of new information about the genetics of human autoimmunity. In particular, the ability to scan the entire genome for common polymorphisms that associate with disease has led to the identification of numerous new risk genes involved in autoimmune phenotypes. Several themes are emerging. Autoimmune disorders have a complex genetic basis; multiple genes contribute to disease risk, each with generally modest effects independently. In addition, it is now clear that common genes underlie multiple autoimmune disorders. There is also heterogeneity among subphenotypes within a disease and across major racial groups. The current crop of genetic associations are only the start of a complete catalog of genetic factors for autoimmunity, and it remains unclear to what extent common variation versus multiple rare variants contribute to disease susceptibility. The current review focuses on recent discoveries within functionally related groups of genes that provide clues to novel pathways of pathogenesis for human autoimmunity.
Structural and Functional Basis for Therapeutic Modulation of p53 Signaling
Authors: Emily A. Bassett, Wenge Wang, Farzan Rastinejad, Wafik S. El-Deiry
Journal: Clinical Cancer Research (2008)

Abstract Effective modulation of structural features and/or functional properties of the major tumor suppressor p53 as a wild-type or cancer-associated mutant protein represents a major challenge in drug development for cancer. p53 is an attractive target for therapeutic design because of its involvement as a mediator of growth arrest and apoptosis after exposure to chemoradiotherapy and/or radiotherapy. Although most clinically used cytotoxic agents target stabilization of wild-type p53, there are a number of approaches that hold promise for reactivation of mutant p53. On the other hand, brief blockade of p53 may reduce toxicity from systemic cytotoxic therapy. Screens for restoration of p53 transcriptional responses in p53-deficient cells may provide a functional means to develop anticancer therapeutics. Structure-based modulation continues to hold promise for development of peptides or small molecules capable of modulation of either wild-type or mutant p53 proteins.
Testing the druggable endothelial differentiation gene 2 knee osteoarthritis genetic factor for replication in a wide range of sample collections
Authors: R Dieguez-Gonzalez, M Calaza, D Shi, I Meulenbelt, J Loughlin, A Tsezou, J Dai, K N Malizos, E P Slagboom, M Kloppenburg, K Chapman, Q Jiang, D Kremer, J J Gomez-Reino, N Nakajima, S Ikegawa, A Gonzalez
Journal: Annals of the Rheumatic Diseases (2008)

To replicate a previously reported association with osteoarthritis (OA) of the promoter single nucleotide polymorphism (SNP) rs10980705 in the endothelial differentiation gene 2 (EDG2).Five collections of samples, four from Europe and one from China, were studied. They included patients with 3 OA phenotypes: 1501 with knee OA, 1497 with hip OA and 376 with generalised OA. A total of 2521 controls were also studied. Allele and genotype frequencies of the rs10980705 SNP were analysed in each individual sample collection and in pooled data. In addition, a meta-analysis to incorporate results from the original Japanese report was performed.The association of the rs10980705 SNP with knee OA was not replicated in any of the five sample collections studied or in their combined analysis (odds ratio (OR) 1.10, 95% CI 0.98 to 1.22; p = 0.10). Meta-analysis of all data, including the original Japanese study, did show association with knee OA (OR 1.15, 95% CI 1.06 to 1.26; p = 0.002) but the effect was accounted for by the Japanese data and was less significant than the original report. No association was found with hip OA or with generalised OA.The original report of a promising genetic association between a druggable G-protein coupled receptor, EDG2, and knee OA has not been replicated. This lack of replication could be due to a modest effect of the promoter polymorphism that will require even larger studies (the winners curse) although a more pronounced effect in the Asian population vs Europeans cannot be excluded.
Genetic variations in the epidermodysplasia verruciformis (EVER/TMC) genes, cutaneous human papillomavirus infection and squamous cell carcinoma of the skin
Authors: S.S. Hampras, D.E. Rollison, M. Tommasino, T. Gheit, M.B. Schabath, J.L. Messina, N.A. Fenske, B.S. Cherpelis, V.K. Sondak, M.R. Iannacone, M. Schmitt, M. Pawlita
Journal: British Journal of Dermatology (2015)
Genome-wide DNA methylation profiles in progression to in situand invasive carcinoma of the breast with impact on gene transcription and prognosis
Authors: Thomas Fleischer, Arnoldo Frigessi, Kevin C. Johnson, Hege Edvardsen, Nizar Touleimat, Jovana Klajic, Margit L.h. Riis, Vilde D. Haakensen, Fredrik Wärnberg, Bjørn Naume, Aslaug Helland, Anne Lise Børresen-Dale, Jörg Tost, Brock C. Christensen, Vessela N. Kristensen
Journal: Genome biology (2014)

Abstract Background Ductal carcinoma in situ (DCIS) of the breast is a precursor of invasive breast carcinoma. DNA methylation alterations are thought to be an early event in progression of cancer, and may prove valuable as a tool in clinical decision making and for understanding neoplastic development. Results We generate genome-wide DNA methylation profiles of 285 breast tissue samples representing progression of cancer, and validate methylation changes between normal and DCIS in an independent dataset of 15 normal and 40 DCIS samples. We also validate a prognostic signature on 583 breast cancer samples from The Cancer Genome Atlas. Our analysis reveals that DNA methylation profiles of DCIS are radically altered compared to normal breast tissue, involving more than 5,000 genes. Changes between DCIS and invasive breast carcinoma involve around 1,000 genes. In tumors, DNA methylation is associated with gene expression of almost 3,000 genes, including both negative and positive correlations. A prognostic signature based on methylation level of 18 CpGs is associated with survival of breast cancer patients with invasive tumors, as well as with survival of patients with DCIS and mixed lesions of DCIS and invasive breast carcinoma. Conclusions This work demonstrates that changes in the epigenome occur early in the neoplastic progression, provides evidence for the possible utilization of DNA methylation-based markers of progression in the clinic, and highlights the importance of epigenetic changes in carcinogenesis.
Evolution of the Sry genes
Authors: P. Pamilo, R. J. O'Neill
Journal: Molecular Biology and Evolution (1997)

Existing DNA sequence data on the Sry gene, the mammalian sex-determining locus in the Y chromosome, were analyzed for primates, rodents, and bovids. In all three taxonomic groups, the terminal sequences evolved faster than the HMG (high mobility group) boxes, and this applies both to synonymous (Ks) and nonsynonymous (Ka) nucleotide substitutions. Similar intragenic correlation between synonymous and nonsynonymous substitution rates was not found either in other mammalian genes that contain a conservative box (Sox, Msx) or in the MADS-box genes of plants. The rate of nonsynonymous substitutions exceeds significantly that of synonymous substitutions in the terminal Sry sequences of apes. We did not find good support for the hypothesis that the high evolutionary rate of Sry would be associated with a promiscuous mating system.
Effects of eicosapentaenoic acid on the early stage of type 2 diabetic nephropathy in KKAy/Ta mice: involvement of anti-inflammation and antioxidative stress
Authors: Minfang Zhang, Shinji Hagiwara, Masukazu Matsumoto, Leyi Gu, Mitsuo Tanimoto, Shinji Nakamura, Shigeru Kaneko, Tomohito Gohda, Jiaqi Qian, Satoshi Horikoshi, Yasuhiko Tomino
Journal: Metabolism (2006)
<i>In vivo</i> Inhibition of Lung Cancer by GRN163L: A Novel Human Telomerase Inhibitor
Authors: Z. Gunnur Dikmen, Ginelle C. Gellert, Shalmica Jackson, Sergei Gryaznov, Robert Tressler, Pakize Dogan, Woodring E. Wright, Jerry W. Shay
Journal: Cancer Research (2005)

Differential regulation of telomerase activity in normal and tumor cells provides a rationale for the design of new classes of telomerase inhibitors. The telomerase enzyme complex presents multiple potential sites for the development of inhibitors. GRN163L, a telomerase enzyme antagonist, is a lipid-modified 13-mer oligonucleotide N3' --> P5'-thio-phosphoramidate, complementary to the template region of telomerase RNA (hTR). We evaluated both the in vitro and in vivo effects of GRN163L using A549-luciferase (A549-Luc) human lung cancer cells expressing a luciferase reporter. GRN163L (1 micromol/L) effectively inhibits telomerase activity of A549-Luc cells, resulting in progressive telomere shortening. GRN163L treatment also reduces colony formation in soft agar assays. Surprisingly, after only 1 week of treatment with GRN163L, A549-Luc cells were unable to form robust colonies in the clonal efficiency assay, whereas the mismatch control compound had no effect. Finally, we show that in vivo treatment with GRN163L is effective in preventing lung metastases in xenograft animal models. These in vitro and in vivo data support the development of GRN163L as a therapeutic for the treatment of cancer.
A Novel Mechanism of Late Gene Silencing Drives SV40 Transformation of Human Mesothelial Cells
Authors: Michele Carbone, Antonio Pannuti, Lei Zhang, Joseph R. Testa, Maurizio Bocchetta
Journal: Cancer Research (2008)

Abstract Suppression of the late gene expression, usually by integration of the viral DNA into the host genome, is a critical step in DNA tumor virus carcinogenesis. SV40 induces high rates of transformation in infected primary human mesothelial cells in tissue culture, leading to the formation of immortal cell lines (SV40-transformed human mesothelial cell lines, S-HML). The studies described here were designed to elucidate the unusual susceptibility of primary human mesothelial cells to SV40 carcinogenesis. We found that S-HML contained wild-type, mostly episomal SV40 DNA. In these cells, the early genes that code for the viral oncogenes are expressed; at the same time, the synthesis of the late genes, capsid proteins, is suppressed and S-HML are not lysed. Late gene suppression is achieved through the production of antisense RNA molecules. These antisense RNA molecules originate in the early region of the SV40 circular chromosome and proceed in antisense orientation into the late gene region, leading to the formation of highly unstable double-strand RNA, which is rapidly degraded. Our results reveal a novel biological mechanism responsible for the suppression of late viral gene products, an important step in viral carcinogenesis in humans. [Cancer Res 2008;68(22):9488–96]
The nature and consequence of Karl Marx’s skin disease
Authors: S. Shuster
Journal: British Journal of Dermatology (2007)

From an analysis of the original correspondence, it has been possible to establish that Karl Marx’s incapacitating skin disease was hidradenitis suppurativa, not ‘boils’ as was universally assumed at the time and since; the psychological effect of this illness on the man and his work appears to have been considerable.
Determinants of survival in pediatric continuous hemofiltration.
Authors: W E Smoyer, C McAdams, B S Kaplan, J R Sherbotie
Journal: Journal of the American Society of Nephrology (1995)

Continuous hemofiltration (CH) is being used in increasing numbers of pediatric intensive care unit patients. Experience with 114 CH treatments in 98 critically ill children from March 1988 to March 1993 is presented in this study. Ages ranged from 1 day to 23 yr (mean +/- SE = 7.1 +/- 0.7 yr), and 54% of patients were male. Seventeen percent of all treatments were performed in neonates under 1 month of age. The most common primary diagnoses were sepsis and adult respiratory distress syndrome (11 patients each), liver transplantation and hypoplastic left heart syndrome (10 patients each), and hemolytic uremic syndrome (9 patients). The most frequent indications for CH were fluid overload and acute renal failure (42% each). Choices for CH included: continuous arteriovenous hemofiltration (CAVH, 50%), continuous arteriovenous hemodiafiltration (CAVH, 23%), continuous venovenous hemofiltration (CVVH, 18%), and continuous venovenous hemodiafiltration (CVVH-D, 9%). Choices for anticoagulation included: none (47%), regional (49%), and systemic (4%). Treatment duration ranged from 1 to 25 days (mean = 5.3 +/- 0.4 days). Mean filter life span for 363 filters was 0.94 +/- 0.1 filters/patient per day. Despite an overall survival rate of 43%, survival to discharge varied greatly (0 to 100%) among the 24 diagnostic groups: tumor lysis syndrome and systemic lupus erythematosus (3/3 patients each, 100%), hemolytic uremic syndrome (8/9 patients, 89%). This compares with: bone marrow transplantation (0/6 patients, 0%), hypoplastic left heart syndrome (2/10 patients, 20%), and leukemia (1/4 patients, 25%). Survival to hospital discharge was better in patients who did not receive pressors (P < 0.005) and in patients treated with combined ultrafiltration and dialysis (CAVH-D, CVVH-D) compared with ultrafiltration alone (CAVH, CVVH) (P < 0.005), but was not notably affected by patient age, sex, use of anticoagulation, filter life span, blood pump-assisted versus spontaneous CH, or duration of therapy. Filter life span was not affected by use of anticoagulation, but was remarkably longer in patients with arteriovenous versus venovenous CH (P < 0.004). It was concluded that: (1) empirical anticoagulation of patients treated with CH is not necessary; (2) children with a minority of underlying diseases and those requiring pressor support at initiation of CH appear to have relatively poor survival rates despite the technically effective use of CH; and (3) the addition of countercurrent dialysis to routine CH may enhance patient survival to hospital discharge.
Phase II trial of the novel taxane BMS-184476 as second-line in non-small-cell lung cancer
Authors: C. Camps, E. Felip, J.M. Sanchez, B. Massuti, A. Artal, L. Paz-Ares, A. Carrato, V. Alberola, A. Blasco, J. Baselga, L. Astier, M. Voi, R. Rosell
Journal: Annals of Oncology (2005)
Distribution of Abdominal Visceral and Subcutaneous Adipose Tissue and Metabolic Syndrome in a Korean Population
Authors: Soyeun Kim, Belong Cho, Hyejin Lee, Kyojoo Choi, Seung Sik Hwang, Donghee Kim, Kyoungwoo Kim, Hyuktae Kwon
Journal: Diabetes Care (2011)

This study aimed to assess the correlation between abdominal subcutaneous adipose tissue (SAT) and metabolic syndrome (MetS) in Korean adults after adjusting for the effects of visceral adipose tissue (VAT).The SAT/VAT ratio (SVR) was calculated using abdominal computed tomography in 2,655 subjects. We used regression analyses to assess whether the SVR predicted MetS.For both sexes, the prevalence of elevated triglycerides, reduced HDL, and elevated fasting glucose significantly decreased with increasing quintiles of SVR (P for trend < 0.05). The prevalence and odds ratios of MetS significantly decreased as the SVR increased (men: odds ratio 0.5 [95% CI 0.3-0.7]; women: 0.2 [0.1-0.5] for comparisons of lowest vs. highest quintile; P for trend < 0.05).After adjustment for VAT, abdominal SAT was inversely correlated with the occurrence of MetS.
Clinical Symptom Responses to Atypical Antipsychotic Medications in Alzheimer’s Disease: Phase 1 Outcomes From the CATIE-AD Effectiveness Trial
Authors: David L. Sultzer, Sonia M. Davis, Pierre N. Tariot, Karen S. Dagerman, Barry D. Lebowitz, Constantine G. Lyketsos, Robert A. Rosenheck, John K. Hsiao, Jeffrey A. Lieberman, Lon S. Schneider
Journal: American Journal of Psychiatry (2008)

Objective: The study measured the effects of atypical antipsychotics on psychiatric and behavioral symptoms in patients with Alzheimer’s disease and psychosis or agitated behavior. Method: The Clinical Antipsychotic Trials of Intervention Effectiveness—Alzheimer’s Disease (CATIE-AD) Alzheimer’s disease effectiveness study included 421 outpatients with Alzheimer’s disease and psychosis or agitated/aggressive behavior. Patients were assigned randomly to masked, flexible-dose treatment with olanzapine, quetiapine, risperidone, or placebo for up to 36 weeks. Patients could be randomly reassigned to a different medication at the clinician’s discretion, which ended phase 1. Psychiatric and behavioral symptoms, functioning, cognition, care needs, and quality of life were measured at regular intervals. Results: In relation to placebo, the last observation in phase 1 showed greater improvement with olanzapine or risperidone on the Neuropsychiatric Inventory total score, risperidone on the Clinical Global Impression of Changes, olanzapine and risperidone on the Brief Psychiatric Rating Scale (BPRS) hostile suspiciousness factor, and risperidone on the BPRS psychosis factor. There was worsening with olanzapine on the BPRS withdrawn depression factor. Among patients continuing phase 1 treatment at 12 weeks, there were no significant differences between antipsychotics and placebo on cognition, functioning, care needs, or quality of life, except for worsened functioning with olanzapine compared to placebo. Conclusion: In this descriptive analysis of outpatients with Alzheimer’s disease in usual care settings, some clinical symptoms improved with atypical antipsychotics. Antipsychotics may be more effective for particular symptoms, such as anger, aggression, and paranoid ideas. They do not appear to improve functioning, care needs, or quality of life.