tbuckley/cabot-search huggingface dataset:
Non-viral opportunistic infections in new users of tumour necrosis factor inhibitor therapy: results of the SAfety Assessment of Biologic ThERapy (SABER) Study
Authors: John W Baddley, Kevin L Winthrop, Lang Chen, Liyan Liu, Carlos G Grijalva, Elizabeth Delzell, Timothy Beukelman, Nivedita M Patkar, Fenglong Xie, Kenneth G Saag, Lisa J Herrinton, Daniel H Solomon, James D Lewis, Jeffrey R Curtis
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To determine among patients with autoimmune diseases in the USA whether the risk of non-viral opportunistic infections (OI) was increased among new users of tumour necrosis factor α inhibitors (TNFI), when compared to users of non-biological agents used for active disease. <h3>Methods</h3> We identified new users of TNFI among cohorts of rheumatoid arthritis (RA), inflammatory bowel disease and psoriasis-psoriatic arthritis-ankylosing spondylitis patients during 1998–2007 using combined data from Kaiser Permanente Northern California, two pharmaceutical assistance programmes for the elderly, Tennessee Medicaid and US Medicaid/Medicare programmes. We compared incidence of non-viral OI among new TNFI users and patients initiating non-biological disease-modifying antirheumatic drugs (DMARD) overall and within each disease cohort. Cox regression models were used to compare propensity-score and steroid- adjusted OI incidence between new TNFI and non-biological DMARD users. <h3>Results</h3> Within a cohort of 33 324 new TNFI users we identified 80 non-viral OI, the most common of which was pneumocystosis (n=16). In the combined cohort, crude rates of non-viral OI among new users of TNFI compared to those initiating non-biological DMARD was 2.7 versus 1.7 per 1000-person-years (aHR 1.6, 95% CI 1.0 to 2.6). Baseline corticosteroid use was associated with non-viral OI (aHR 2.5, 95% CI 1.5 to 4.0). In the RA cohort, rates of non-viral OI among new users of infliximab were higher when compared to patients newly starting non-biological DMARD (aHR 2.6, 95% CI 1.2 to 5.6) or new etanercept users (aHR 2.9, 95% CI 1.5 to 5.4). <h3>Conclusions</h3> In the USA, the rate of non-viral OI was higher among new users of TNFI with autoimmune diseases compared to non-biological DMARD users.
Exercise Induces Hippocampal BDNF through a PGC-1α/FNDC5 Pathway
Authors: Christiane D. Wrann, James P. White, John Salogiannnis, Dina Laznik-Bogoslavski, Jun Wu, Di Ma, Jiandie D. Lin, Michael E. Greenberg, Bruce M. Spiegelman
Journal: Cell Metabolism (2013)
Prediction of survival benefits from progression-free survival in patients with advanced non small cell lung cancer: Evidence from a pooled analysis of 2,838 patients randomized in 7 trials
Authors: M. E. Buyse, P. Squifflet, S. Laporte, F. V. Fossella, V. Georgoulias, J. Pujol, K. Kubota, A. Monnier, S. Kudoh, J. Douillard
Journal: Journal of Clinical Oncology (2008)

8019 Background: Survival benefits can be predicted from progression-free survival in advanced colorectal cancer (Buyse et al, JCO 2007; 25:5218), but not in advanced breast cancer (Burzykowski et al, JCO 2007; in press). We investigated whether progression-free survival (PFS) could be considered a valid surrogate for overall survival (OS) in patients with advanced non small cell lung cancer (NSCLC). Methods: Individual patient data were collected from all trials comparing docetaxel to vinca alkaloids for the first-line treatment of patients with NSCLC (Douillard et al, J Thoracic Oncol 2007;2:939). Surrogacy of PFS for OS was assessed through the association between these endpoints and between the treatment effects on these endpoints. Treatment effects were estimated through hazard ratios in the 322 participating centers. Centers with less than 3 patients per treatment arm were grouped. Squared correlation coefficients were estimated along with their 95% confidence interval (CI). The surrogate threshold effect was defined as the minimum treatment effect on PFS required to predict a non-zero treatment effect on OS in a future trial. Results: The median follow-up of patients still alive was 23.4 months, median OS 10.0 months, median PFS 5.5 months. PFS was correlated with OS (R² = 0.68, CI = 0.676 - 0.681), with PFS explaining two thirds of the variance in OS. The treatment effects on PFS and on OS were also correlated (R² = 0.83, CI = 0.62 - 1.05), with treatment effects on PFS explaining four fifths of the variance in treatment effects on OS. The surrogate threshold effect was a PFS hazard ratio of 0.70, indicating that a risk reduction of 30% in terms of PFS predicts a significant effect on OS. Conclusions: PFS may be an acceptable surrogate for OS in future trials in advanced NSCLC. Treatments that reduce the PFS hazard by at least 30% are expected to lead to significant benefits in terms of overall survival. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Alfacell Corporation Alfacell, Amgen, AstraZeneca, Boehringer Ingelheim, Hoffmann-La Roche, Lilly Alfacell, Alfacell Corporation Bayer Healthcare, Boehringer Ingelheim, Hoffmann-La Roche, Lilly, Pierre Fabre Merck
Severe mycoplasma pneumonia.
Authors: S Holt, W F Ryan, E J Epstein
Journal: Thorax (1977)

A patient who developed who developed a protracted illness following severe mycoplasma pneumonia is described. The acute phase of the infection was complicated by myocarditis and haemolytic anaemia. The respiratory symptoms abated and lung function tests improved with the administration of systemic and inhaled corticosteroids.
Angiotensin-converting-enzyme 2 inhibits liver fibrosis in mice
Authors: Christoph H. Österreicher, Kojiro Taura, Samuele De Minicis, Ekihiro Seki, Melitta Penz-Österreicher, Yuzo Kodama, Johannes Kluwe, Manfred Schuster, Gavin Y. Oudit, Josef M. Penninger, David A. Brenner
Journal: Hepatology (2009)

The renin-angiotensin system (RAS) plays a major role in liver fibrosis. Recently, a homolog of angiotensin-converting-enzyme 1 (ACE1), termed ACE2, has been identified that appears to be a negative regulator of the RAS by degrading Ang II to Ang(1-7). The aim of this study was to characterize the long-term effects of gene deletion of ACE2 in the liver, to define the role of ACE2 in acute and chronic liver disease, and to characterize the role of Ang(1-7) in hepatic stellate cell (HSC) activation. Ace2 knockout (KO) mice and wild-type (wt) littermates underwent different models of acute and chronic liver injury. Liver pathology was analyzed by histology, immunohistochemistry, alpha smooth muscle actin (alpha-SMA) immunoblotting, and quantitative polymerase chain reaction (qPCR). Murine HSCs were isolated by collagenase-pronase-perfusion, and density gradient centrifugation. One-year-old ace2 KO mice spontaneously developed an inflammatory cell infiltration and mild hepatic fibrosis that was prevented by treatment with irbesartan. Ace2 KO mice showed increased liver fibrosis following bile duct ligation for 21 days or chronic carbon tetrachloride (CCl(4)) treatment. In contrast, ace2 KO mice subjected to acute liver injury models did not differ from wt littermates. Treatment with recombinant ACE2 attenuated experimental fibrosis in the course of cholestatic and toxic liver injury. HSCs express the Ang(1-7) receptor Mas and Ang(1-7) inhibited Ang II-induced phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 in cultured HSCs.ACE2 is a key negative regulator of the RAS and functions to limit fibrosis through the degradation of Ang II and the formation of Ang(1-7). Whereas loss of ACE2 activity worsens liver fibrosis in chronic liver injury models, administration of recombinant ACE2 shows therapeutic potential.
Abrogation of Bronchial Eosinophilic Inflammation and Airway Hyperreactivity in Signal Transducers and Activators of Transcription (STAT)6-deficient Mice
Authors: Toshihiko Akimoto, Fumio Numata, Misato Tamura, Yoshimi Takata, Noriko Higashida, Tohru Takashi, Kiyoshi Takeda, Shizuo Akira
Journal: The Journal of Experimental Medicine (1998)

Signal transducers and activators of transcription 6 (STAT6) is essential for interleukin 4–mediated responses, including class switching to IgE and induction of type 2 T helper cells. To investigate the role of STAT6 in allergic asthma in vivo, we developed a murine model of allergen-induced airway inflammation. Repeated exposure of actively immunized C57BL/6 mice to ovalbumin (OVA) aerosol increased the level of serum IgE, the number of eosinophils in bronchoalveolar lavage (BAL) fluid, and airway reactivity. Histological analysis revealed peribronchial inflammation with pulmonary eosinophilia in OVA-treated mice. In STAT6-deficient (STAT6−/−) C57BL/6 mice treated in the same fashion, there were no eosinophilia in BAL and significantly less peribronchial inflammation than in wild-type mice. Moreover STAT6−/− mice had much less airway reactivity than wild-type mice. These findings suggest that STAT6 plays a crucial role in the pathogenesis of allergen-induced airway inflammation.
Krüppel-like Factor 4 Induces <i>p27Kip1</i> Expression in and Suppresses the Growth and Metastasis of Human Pancreatic Cancer Cells
Authors: Daoyan Wei, Masahsi Kanai, Zhiliang Jia, Xiangdong Le, Keping Xie
Journal: Cancer Research (2008)

Abstract The zinc finger transcription factor Krüppel-like factor 4 (KLF4) has been implicated in both tumor suppression and progression. However, its function in pancreatic cancer has not been well characterized. Here, we show that pancreatic cancer cell lines expressed various levels of KLF4 RNA and protein. Ectopic expression of KLF4 by FG and BxPC-3 pancreatic cancer cells resulted in cell cycle arrest and marked inhibition of cell growth in vitro and attenuation of tumor growth and metastasis in an orthotopic mouse model. Overexpression of KLF4 also led to significant induction of p27Kip1 expression, at both the RNA and protein levels, in a dose- and time-dependent manner, indicating that KLF4 transcriptionally regulates the expression of p27Kip1. Chromatin immunoprecipitation assays consistently showed that KLF4 protein physically interacts with the p27Kip1 promoter. Promoter deletion and point mutation analyses indicated that a region between nucleotides −435 and −60 of the p27Kip1 promoter and intact of the three KLF4-binding sites within that region were required for the full induction of p27Kip1 promoter activity by KLF4. Our findings suggest that KLF4 transactivates p27Kip1 expression and inhibits the growth and metastasis of human pancreatic cancer. [Cancer Res 2008;68(12):4631–9]
Transient Low Doses of DNA-Demethylating Agents Exert Durable Antitumor Effects on Hematological and Epithelial Tumor Cells
Authors: Hsing-Chen Tsai, Huili Li, Leander Van Neste, Yi Cai, Carine Robert, Feyruz V. Rassool, James J. Shin, Kirsten M. Harbom, Robert Beaty, Emmanouil Pappou, James Harris, Ray-Whay Chiu Yen, Nita Ahuja, Malcolm V. Brock, Vered Stearns, David Feller-Kopman, Lonny B. Yarmus, Yi-Chun Lin, Alana L. Welm, Jean-Pierre Issa, Il Minn, William Matsui, Yoon-Young Jang, Saul J. Sharkis, Stephen B. Baylin, Cynthia A. Zahnow
Journal: Cancer Cell (2012)
Severe Respiratory Syncytial Virus Bronchiolitis in Infancy and Asthma and Allergy at Age 13
Authors: Nele Sigurs, Per M. Gustafsson, Ragnar Bjarnason, Fredrik Lundberg, Susanne Schmidt, Fridrik Sigurbergsson, Bengt Kjellman
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

We have prospectively studied wheezing disorder and allergy in 47 children hospitalized with respiratory syncytial virus (RSV) bronchiolitis in infancy and 93 matched control subjects. Subjects with at least three episodes of wheezing were defined as recurrent wheezers and as having asthma if the episodes were doctor verified. Here we report the outcome at age 13 years in 46/47 children with RSV and 92/93 control subjects. Wheezing disorder and clinical allergy were estimated using a questionnaire. Skin prick tests were performed and serum IgE antibodies measured. Spirometry was undertaken at rest, after dry air challenge, and after beta2-agonist inhalation. The occurrence of symptoms over the previous 12 months was significantly higher in the RSV group than among the control subjects, 43% versus 8% for asthma/recurrent wheezing and 39% versus 15% for allergic rhinoconjunctivitis. Sensitization to common inhaled allergens was more frequent in the RSV group than in the control subjects, judged by skin prick tests (50% versus 28%; p = 0.022), or by serum IgE antibodies (45% versus 26%; p = 0.038). Compared with the control subjects, the RSV group showed mild airway obstruction both at rest and after bronchodilation, and had slightly more reactive airways. RSV bronchiolitis in infancy severe enough to cause hospitalization is a risk factor for allergic asthma in early adolescence.
Alexander Pope (1688-1744): his spinal deformity and his doctors
Authors: OP Sharma
Journal: European Respiratory Journal (1999)

Alexander Pope was the towering figure of 18th century England. A poet and a wit he commanded unswerving loyalty from his friends and penetrating hatred from his enemies. His spinal deformity, either due to tuberculosis, trauma or congenital weakness, shaped his career. This brief report highlights the illness and the medical men who were involved in treating Alexander Pope.
DNA Methylation Alterations in the Pancreatic Juice of Patients with Suspected Pancreatic Disease
Authors: Hiroyuki Matsubayashi, Marcia Canto, Norihiro Sato, Alison Klein, Tadayoshi Abe, Keishi Yamashita, Charles J. Yeo, Anthony Kalloo, Ralph Hruban, Michael Goggins
Journal: Cancer Research (2006)

Abstract Molecular markers of pancreatic neoplasia could aid in the evaluation of visible pancreatic lesions and indicate neoplasia invisible to imaging. We evaluated methylation-specific PCR (MSP) assays that detect aberrantly methylated DNA for their use as markers of pancreatic neoplasia. Methylation analysis was done on pancreatic juice collected endoscopically or surgically from 155 individuals with suspected pancreatic disease: 56 patients had pancreatic ductal adenocarcinoma, 17 had intraductal papillary mucinous neoplasms, 26 had symptomatic chronic pancreatitis, 12 controls lacked evidence of pancreatic disease, and 44 were asymptomatic individuals at increased risk of developing familial pancreatic cancer undergoing screening for pancreatic neoplasia. Pancreatic juice DNA was analyzed for promoter methylation using conventional MSP assays for 17 genes. For six genes, pancreatic juice methylation was quantified using real-time quantitative MSP (QMSP; Cyclin D2, FOXE1, NPTX2, ppENK, p16, and TFPI2). Quantifying pancreatic juice methylation using QMSP with a cutoff of &amp;gt;1% methylated DNA could better predict pancreatic cancer than detecting methylation using conventional MSP. In the endoscopic group, 9 of 11 patients with pancreatic cancer, but none of 64 individuals without neoplasia had ≥1% methylation for two or more of the best five QMSP assays (82% sensitivity and 100% specificity; P &amp;lt; 0.0001). The prevalence of pancreatic juice methylation in patients with chronic pancreatitis was less than in patients with pancreatic cancer but higher than in controls and similar to high-risk individuals. The detection and quantification of aberrantly methylated DNA in pancreatic juice is a promising approach to the diagnosis of pancreatic cancer. (Cancer Res 2006; 66(2): 1208-17)
Comparison between universal molecular screening for Lynch syndrome and revised Bethesda guidelines in a large population-based cohort of patients with colorectal cancer
Authors: Lucía Pérez-Carbonell, Clara Ruiz-Ponte, Carla Guarinos, Cristina Alenda, Artemio Payá, Alejandro Brea, Cecilia M Egoavil, Adela Castillejo, Victor M Barberá, Xavier Bessa, Rosa M Xicola, María Rodríguez-Soler, Cristina Sánchez-Fortún, Nuria Acame, Sergi Castellví-Bel, Virgínia Piñol, Francesc Balaguer, Luis Bujanda, María-Luisa De-Castro, Xavier Llor, Montserrat Andreu, Angel Carracedo, José-Luis Soto, Antoni Castells, Rodrigo Jover
Journal: Gut (2011)

<h3>Background</h3> The selection of patients for genetic testing to rule out Lynch syndrome is currently based on fulfilment of at least one of the revised Bethesda criteria followed by mismatch repair (MMR) status analysis. A study was undertaken to compare the present approach with universal MMR study-based strategies to detect Lynch syndrome in a large series of patients with colorectal cancer (CRC). <h3>Methods</h3> 2093 patients with CRC from the EPICOLON I and II cohorts were included. Immunohistochemistry for MMR proteins and/or microsatellite instability (MSI) analysis was performed in tumour tissue. Germline <i>MLH1</i> and <i>MSH2</i> mutation analysis was performed in patients whose tumours showed loss of MLH1 or MSH2 staining, respectively. <i>MSH6</i> genetic testing was done in patients whose tumours showed lack of MSH6 expression or a combined lack of MSH2 and MSH6 expression but did not have <i>MSH2</i> mutations. <i>PMS2</i> genetic testing was performed in patients showing isolated loss of PMS2 expression. In patients with MSI tumours and normal or not available MMR protein expression, all four MMR genes were studied. <h3>Results</h3> A total of 180 patients (8.6%) showed loss of expression of some of the MMR proteins and/or MSI. Four hundred and eighty-six patients (23.2%) met some of the revised Bethesda criteria. Of the 14 (0.7%) patients who had a MMR gene mutation, 12 fulfilled at least one of the revised Bethesda criteria and two (14.3%) did not. <h3>Conclusions</h3> Routine molecular screening of patients with CRC for Lynch syndrome using immunohistochemistry or MSI has better sensitivity for detecting mutation carriers than the Bethesda guidelines.
Genome-wide Hypomethylation in Human Glioblastomas Associated with Specific Copy Number Alteration, Methylenetetrahydrofolate Reductase Allele Status, and Increased Proliferation
Authors: Benoît Cadieux, Tsui-Ting Ching, Scott R. VandenBerg, Joseph F. Costello
Journal: Cancer Research (2006)

Abstract Genome-wide reduction in 5-methylcytosine is an epigenetic hallmark of human tumorigenesis. Experimentally induced hypomethylation in mice promotes genomic instability and is sufficient to initiate tumorigenesis. Here, we report that global hypomethylation is common in primary human glioblastomas [glioblastoma multiforme (GBM)] and can affect up to an estimated 10 million CpG dinucleotides per haploid tumor genome. Demethylation involves satellite 2 (Sat2) pericentromeric DNA at chromosomes 1 and 16, the subtelomeric repeat sequence D4Z4 at chromosomes 4q and 10q, and interspersed Alu elements. Severe hypomethylation of Sat2 sequences is associated with copy number alterations of the adjacent euchromatin, suggesting that hypomethylation may be one factor predisposing to specific genetic alterations commonly occurring in GBMs. An additional apparent consequence of global hypomethylation is reactivation of the cancer-testis antigen MAGEA1 via promoter demethylation, but only in GBMs and GBM cell lines exhibiting a 5-methylcytosine content below a threshold of ∼50%. Primary GBMs with significant hypomethylation tended to be heterozygous or homozygous for the low-functioning Val allele of the rate-limiting methyl group metabolism gene methylenetetrahydrofolate reductase (MTHFR), or had a deletion encompassing this gene at 1p36. Tumors with severe genomic hypomethylation also had an elevated proliferation index and deletion of the MTHFR gene. These data suggest a model whereby either excessive cell proliferation in the context of inadequate methyl donor production from MTHFR deficiency promotes genomic hypomethylation and further genomic instability, or that MTHFR deficiency–associated demethylation leads to increased proliferative activity in GBM. (Cancer Res 2006; 66(17): 8469-76)
Cloning of the structural genes of three H8 antigens and of protein III of Neisseria gonorrhoeae.
Authors: E C Gotschlich, M S Blake, J M Koomey, M Seiff, A Derman
Journal: The Journal of Experimental Medicine (1986)

A bank of gonococcal DNA was constructed in the lambda gt11 expression vector. immunological screening of the bank resulted in the isolation of a clone that contains the structural gene of protein III. In addition, several clones reactive with mAbs specific for the H8 antigen were isolated. DNA hybridization studies revealed that these H8-reactive clones were derived from three different gonococcal genes. When the products produced by these clones were used to absorb antibodies from a rabbit antiserum, and the eluted antibodies were used in immunological studies, it could be shown that the parent gonococcus expressed the product of two of these H8 genes, and in strain R10, these had Mr of approximately 19,700 21,200 respectively. The larger form has not been recognized hitherto because the epitope reactive with the H8 mAb may be masked in this product.
Thymidylate Synthase and Methylenetetrahydrofolate Reductase Gene Polymorphisms and Toxicity to Capecitabine in Advanced Colorectal Cancer Patients
Authors: Rohini Sharma, Janelle M. Hoskins, Laurent P. Rivory, Manuela Zucknick, Rosyln London, Christopher Liddle, Stephen J. Clarke
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To evaluate the effect of thymidylate synthase (TYMS) and methylenetetrahydrofolate reductase (MTHFR) genotypes on toxicity in patients treated with capecitabine for advanced colorectal cancer and to determine the effect of these polymorphisms on the pretreatment levels of serum folate and plasma homocysteine. Experimental Design: Fifty-four patients with a diagnosis of metastatic colorectal cancer were treated with fixed-dose capecitabine. Germ line DNA from patients was genotyped for TYMS TSER, TSER*3G&amp;gt;C, and 3′-untranslated 6 bp insertion/deletion (3′ untranslated region insertion/deletion), and MTHFR c.677C&amp;gt;T and c.1298A&amp;gt;C using PCRs and RFLP. Toxicity was graded by National Cancer Institute Common Toxicity Criteria version 2.0. Response was assessed by Response Evaluation Criteria in Solid Tumors. Results: MTHFR c.677C&amp;gt;T and c.1298A&amp;gt;C genotypes and diplotypes predicted for grade 2/3 toxicities, whereas the TYMS genotypes had no influence. MTHFR c.677 genotype tended to predict overall survival (P = 0.08). MTHFR c.677 influenced pretreatment homocysteine (P &amp;lt; 0.05) and serum folate levels (P &amp;lt; 0.05). Multivariate analysis suggests that MTHFR c.1298 is an independent predictor of toxicity. Conclusions: This study suggests that common genetic variation in MTHFR but not TYMS may be useful for predicting toxicity from capecitabine in patients with advanced colorectal cancer. In addition, MTHFR single nucleotide polymorphisms predicted serum folate and plasma homocysteine levels, and, combined, these factors may be important predictors of capecitabine-induced toxicity.