tbuckley/cabot-search huggingface dataset:
Serum type III procollagen peptide, dynamic liver function tests and hepatic fibrosis in psoriatic patients receiving methotrexate
Authors: DEBORAH MITCHELL, A. SMITH, BRENDA ROWAN, T.W. WARNES, N.Y. HABOUBI, S.B. LUCAS, R.J.G. CHALMERS
Journal: British Journal of Dermatology (1990)

The serum level of the aminoterminal peptide of type III procollagen (P3NP) was measured in 51 psoriatic patients on long-term, once weekly, low-dose methotrexate and in a control group of patients with extensive psoriasis who had never had systemic treatment. Serum P3NP levels were normal in all control patients, but were elevated in the majority of methotrexate-treated patients, even those with normal or non-specific liver histology. Although the highest P3NP values were found in the groups of patients with fibrosis and cirrhosis, isolated P3NP measurements did not discriminate between individuals with and without significant liver pathology. Neither standard nor dynamic liver function tests were able to identify patients with significant liver damage and in most cases results were in the normal range.
An analysis of mortality among patients with tuberculosis (TB) in Sri Lanka
Authors: Dushantha Madegedara, Prasanne Wijerathne, Lakshika Monaragala, Duminda Yasaratne, Neranjan Dissanayake
Journal: European Respiratory Journal (2011)

Introduction: Sri Lanka has a TB prevalence of 101 and a mortality of 9.2 per 100,000.

Objective: To define characteristics of patients who died during treatment for TB in a unit from Central Sri Lanka.

Method: We retrospectively analysed TB related deaths during 2006 to 2010.

Results: We observed a mean mortality rate of 5.4% (228/4199) for the 5-year period. The lowest rate of 3.2% was in 2010. Of the total deaths, 78.5% were males and 50.4% were above 60 years; 4.3% were below 20 years. Pulmonory TB (PTB) contributed to 75% of the deaths.

![Figure][1] 



Significant differences in mortality were noted between males and females (6.7% vs. 3.2%, X2=23.1, p < 0.001) and between new and re-treatment cases (5.1% vs. 9.8%, X2=9.622, p=0.002). No significant differences in mortality rates were seen between smear positive vs. negative PTB and induction vs. continuation phases of treatment.

Conclusion: Mortality in TB was high among males and retreatment patients.

 [1]: pending:yes
Carpopedal spasm in an elderly man: an unusual presentation of coeliac disease
Authors: K. Schmidt, T. Shirazi, M. Powari, B. Vaidya
Journal: Journal of the Royal Society of Medicine (2007)

Coeliac disease typically presents in a young person with diarrhoea, abdominal pain, weight loss, anaemia and malabsorption.Increasingly atypical presentations of this condition are recognized.
Frequent Inactivation of a Putative Tumor Suppressor, Angiopoietin-Like Protein 2, in Ovarian Cancer
Authors: Ryoko Kikuchi, Hitoshi Tsuda, Ken-ichi Kozaki, Yae Kanai, Takahiro Kasamatsu, Kazuo Sengoku, Setsuo Hirohashi, Johji Inazawa, Issei Imoto
Journal: Cancer Research (2008)

Angiopoietin-like protein 2 (ANGPTL2) is a secreted protein belonging to the angiopoietin family, the members of which are implicated in various biological processes, although its receptor remains unknown. We identified a homozygous loss of ANGPTL2 (9q33.3) in the course of screening a panel of ovarian cancer (OC) cell lines for genomic copy-number aberrations using in-house array-based comparative genomic hybridization. ANGPTL2 mRNA expression was observed in normal ovarian tissue and immortalized normal ovarian epithelial cells, but was reduced in some OC lines without its homozygous deletion (18 of 23 lines) and restored after treatment with 5-aza 2'-deoxycytidine. The methylation status of sequences around the ANGPTL2 CpG-island with clear promoter activity inversely correlated with expression. ANGPTL2 methylation was frequently observed in primary OC tissues as well. In an immunohistochemical analysis of primary OCs, ANGPTL2 expression was frequently reduced (51 of 100 cases), and inversely correlated with methylation status. Patients with OC showing reduced ANGPTL2 immunoreactivity had significantly worse survival in the earlier stages (stages I and II), but better survival in advanced stages (stages III and IV). The restoration of ANGPTL2 expression or treatment with conditioned medium containing ANGPTL2 inhibited the growth of OC cells originally lacking the expression of this gene, whereas the knockdown of endogenous ANGPTL2 accelerated the growth of OC cells with the expression of ANGPTL2. These results suggest that, at least partly, epigenetic silencing by hypermethylation of the ANGPTL2 promoter leads to a loss of ANGPTL2 function, which may be a factor in the carcinogenesis of OC in a stage-dependent manner.
Transient early wheeze is not associated with impaired lung function in 7‐yr-old children
Authors: S. Lau, S. Illi, C. Sommerfeld, B. Niggemann, K. Völkel, C. Madloch, C. Grüber, R. Nickel, J. Forster, U. Wahn
Journal: European Respiratory Journal (2003)

The aim of the present study was to analyse determinants of lung function in 7-yr-old children with different wheezing patterns (early, persistent and late onset) in a prospective cohort study. The German Multicentre Allergy Study (MAS) followed 1,314 children from birth onwards. Annual assessments included clinical check-ups, a structured interview and repeated measurement of specific immunoglobulins Ig(E) directed against food and inhalant allergens. At the age of 7 yrs, lung function was measured by body plethysmography in 800 children. Episodes of wheezing in the past 12 months ("current wheeze") were strongly associated with reduced lung function at age 7 yrs. Children with wheezing episodes only during the first 3 yrs of life showed a slight impairment in maximal expiratory flow when 50% of the forced vital capacity remains to be exhaled (98.9 +/- 24.2 versus 103.2 +/- 22.8% of the predicted value in children who never wheeze). Separate analysis of determinants of pulmonary function within these subgroups resulted in distinctly different patterns. Determinants of impaired lung function in the group of current wheezers were: time in years since first wheeze, a parental history of atopy, current sensitisation to indoor allergens, elevated cord blood IgE levels and a low ponderal index at birth. In the group of transient early wheezers, frequent lower respiratory tract infections early in life and maternal smoking during pregnancy were significant but weak determinants of impaired lung function. The present results indicate that determinants of pulmonary function in 7-yr-old children differ with respect to different wheezing phenotypes, demanding different therapeutic strategies. Although transient early wheezers were found to have normal-to-subnormal lung function, children with asthmatic symptoms (persistent and late-onset disease) at age 7 yrs already show significant impairment of expiratory flow volumes.
Lentivirus-mediated Reprogramming of Somatic Cells in the Absence of Transgenic Transcription Factors
Authors: Nicole M Kane, Ali Nowrouzi, Sayandip Mukherjee, Michael P Blundell, Jenny A Greig, Wai Kwong Lee, Miles D Houslay, Graeme Milligan, Joanne C Mountford, Christof von Kalle, Manfred Schmidt, Adrian J Thrasher, Andrew H Baker
Journal: Molecular Therapy (2010)

Retroviral vectors remain the most efficient and widely applied system for induction of pluripotency. However, mutagenic effects have been documented in both laboratory and clinical gene therapy studies, principally as a result of dysregulated host gene expression in the proximity of defined integration sites. Here, we report that cells with characteristics of pluripotent stem cells can be produced from normal human fibroblasts in the absence of reprogramming transcription factors (TFs) during lentiviral (LV) vector–mediated gene transfer. This occurred via induced alterations in host gene and microRNA (miRNA) expression and detrimental changes in karyotype. These findings demonstrate that vector-induced genotoxicity may alone play a role in somatic cell reprogramming derivation and urges caution when using integrating vectors in this setting. Clearer understanding of this process may additionally reveal novel insights into reprogramming pathways. Retroviral vectors remain the most efficient and widely applied system for induction of pluripotency. However, mutagenic effects have been documented in both laboratory and clinical gene therapy studies, principally as a result of dysregulated host gene expression in the proximity of defined integration sites. Here, we report that cells with characteristics of pluripotent stem cells can be produced from normal human fibroblasts in the absence of reprogramming transcription factors (TFs) during lentiviral (LV) vector–mediated gene transfer. This occurred via induced alterations in host gene and microRNA (miRNA) expression and detrimental changes in karyotype. These findings demonstrate that vector-induced genotoxicity may alone play a role in somatic cell reprogramming derivation and urges caution when using integrating vectors in this setting. Clearer understanding of this process may additionally reveal novel insights into reprogramming pathways.
Regulation of Ceramide Synthase–Mediated Crypt Epithelium Apoptosis by DNA Damage Repair Enzymes
Authors: Jimmy A. Rotolo, Judith Mesicek, Jerzy Maj, Jean-Philip Truman, Adriana Haimovitz-Friedman, Richard Kolesnick, Zvi Fuks
Journal: Cancer Research (2010)

Acute endothelial cell apoptosis and microvascular compromise couple gastrointestinal tract irradiation to reproductive death of intestinal crypt stem cell clonogens (SCCs) following high-dose radiation. Genetic or pharmacologic inhibition of endothelial apoptosis prevents intestinal damage, but as the radiation dose is escalated, SCCs become directly susceptible to an alternate cell death mechanism, mediated via ceramide synthase (CS)-stimulated de novo synthesis of the proapoptotic sphingolipid ceramide, and p53-independent apoptosis of crypt SCCs. We previously reported that ataxia-telangiectasia mutated deficiency resets the primary radiation lethal pathway, allowing CS-mediated apoptosis at the low-dose range of radiation. The mechanism for this event, termed target reordering, remains unknown. Here, we show that inactivation of DNA damage repair pathways signals CS-mediated apoptosis in crypt SCCs, presumably via persistent unrepaired DNA double-strand breaks (DSBs). Genetic loss of function of sensors and transducers of DNA DSB repair confers the CS-mediated lethal pathway in intestines of sv129/B6Mre11(ATLD1/ATLD1) and C57BL/6(Prkdc/SCID) (severe combined immunodeficient) mice exposed to low-dose radiation. In contrast, CS-mediated SCC lethality was mitigated in irradiated gain-of-function Rad50(s/s) mice, and epistasis studies order Rad50 upstream of Mre11. These studies suggest unrepaired DNA DSBs as causative in target reordering in intestinal SCCs. As such, we provide an in vivo model of DNA damage repair that is standardized, can be exploited to understand allele-specific regulation in intact tissue, and is pharmacologically tractable.
STX140 Is Efficacious <i>In vitro</i> and <i>In vivo</i> in Taxane-Resistant Breast Carcinoma Cells
Authors: Simon P. Newman, Paul A. Foster, Chloe Stengel, Joanna M. Day, Yaik T. Ho, Jean-Gabriel Judde, Myriam Lassalle, Gregoire Prevost, Mathew P. Leese, Barry V.L. Potter, Michael J. Reed, Atul Purohit
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The aim of these studies was to characterize the action of STX140 in a P-glycoprotein–overexpressing tumor cell line both in vitro and in vivo. In addition, its efficacy was determined against xenografts derived from patients who failed docetaxel therapy. Experimental Design: The effects of STX140, Taxol, and 2-methoxyestradiol (2-MeOE2) on cell proliferation, cell cycle, and apoptosis were assessed in vitro in drug-resistant cells (MCF-7DOX) and the parental cell line (MCF-7WT). Mice bearing an MCF-7DOX tumor on one flank and an MCF-7WT tumor on the other flank were used to assess the in vivo efficacy. Furthermore, the responses to STX140 of three xenografts, derived from drug-resistant patients, were assessed. Results: In this study, STX140 caused cell cycle arrest, cyclin B1 induction, and subsequent apoptosis of both MCF-7DOX and MCF-7WT cells. Taxol and 2-MeOE2 were only active in the MCF-7WT parental cell line. Although both STX140 and Taxol inhibited the growth of xenografts derived from MCF-7WT cells, only STX140 inhibited the growth of tumors derived from MCF-7DOX cells. 2-MeOE2 was ineffective at the dose tested against both tumor types. Two out of the three newly derived docetaxel-resistant xenografts, including a metastatic triple-negative tumor, responded to STX140 but not to docetaxel treatment. Conclusions: STX140 shows excellent efficacy in both MCF-7WT and MCF-7DOX breast cancer xenograft models, in contrast to Taxol and 2-MeOE2. The clinical potential of STX140 was further highlighted by the efficacy seen in xenografts recently derived from patients who had failed on taxane therapy.
Glutathione and HIV infection
Authors: Richard Horton, Marie-Anne Gougerot-Pocidalo, Maryse Levacher, Jean-Marie Dupuy, Jean-Pierre Revillard, EvanM Hersh, RaphaëlleEl Habib, Jean Caraux, RobertF Cathcart, Connie Jarstrand, Börje Åkerlund, Björn Lindeke, JohnA Henry
Journal: The Lancet (1990)
Antiphosphatidylserine Antibody Combined with Irradiation Damages Tumor Blood Vessels and Induces Tumor Immunity in a Rat Model of Glioblastoma
Authors: Jin He, Yi Yin, Troy A. Luster, Linda Watkins, Philip E. Thorpe
Journal: Clinical Cancer Research (2009)

The vascular targeting antibody bavituximab is being combined with chemotherapy in clinical trials in cancer patients. Bavituximab targets the membrane phospholipid, phosphatidylserine, complexed with beta2-glycoprotein I. Phosphatidylserine is normally intracellular but becomes exposed on the luminal surface of vascular endothelium in tumors. Phosphatidylserine exposure on tumor vessels is increased by chemotherapy and irradiation. Here, we determined whether treatment with the murine equivalent of bavituximab, 2aG4, combined with irradiation can suppress tumor growth in a rat model of glioblastoma.F98 glioma cells were injected into the brains of syngeneic rats where they grow initially as a solid tumor and then infiltrate throughout the brain. Rats with established tumors were treated with 10 Gy whole brain irradiation and 2aG4.Combination treatment doubled the median survival time of the rats, and 13% of animals were rendered disease free. Neither treatment given individually was as effective. We identified two mechanisms. First, irradiation induced phosphatidylserine exposure on tumor blood vessels and enhanced antibody-mediated destruction of tumor vasculature by monocytes/macrophages. Second, the antibody treatment induced immunity to F98 tumor cells, which are normally weakly immunogenic. Surviving rats were immune to rechallenge with F98 tumor cells. In vitro, 2aG4 enhanced the ability of dendritic cells (DCs) to generate F98-specific cytotoxic T cells. Phosphatidylserine exposure, which is induced on tumor cells by irradiation, likely suppresses tumor antigen presentation, and 2aG4 blocks this tolerogenic effect.Bavituximab combined with radiotherapy holds promise as a vascular targeting and immune enhancement strategy for the treatment of human glioblastoma.
The Intraductal Approach to Breast Cancer Biomarker Discovery
Authors: R. Sascha Dua, Clare M. Isacke, Gerald P.H. Gui
Journal: Journal of Clinical Oncology (2006)

Established methods of breast cancer detection have well-described limitations, and new diagnostic techniques are evolving continually to improve diagnostic accuracy. The intraductal approach encompasses the modalities of nipple aspiration, ductal lavage, and duct endoscopy, and is a means of directly accessing the microenvironment of the breast and either sampling or visualizing this intraductal milieu. The aim of sampling this mammary microenvironment is to obtain samples from the physical surroundings of cells that are undergoing malignant transformation, thereby providing a new method of detection before the development of a clinically or radiologically discernible mass. A literature review was conducted to investigate the evolution of the intraductal approach and its particular application in the field of biomarker discovery, primarily using the intraductal technique of nipple aspiration, in combination with emerging protein profiling techniques.
The integrated stress response prevents demyelination by protecting oligodendrocytes against immune-mediated damage
Authors: Wensheng Lin, Samantha L. Bailey, Hanson Ho, Heather P. Harding, David Ron, Stephen D. Miller, Brian Popko
Journal: Journal of Clinical Investigation (2007)

In response to ER stress, the pancreatic endoplasmic reticulum kinase (PERK) coordinates an adaptive program known as the integrated stress response (ISR) by phosphorylating the α subunit of eukaryotic translation initiation factor 2 (eIF2α). IFN-γ, which activates the ER stress response in oligodendrocytes, is believed to play a critical role in the immune-mediated CNS disorder multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). Here we report that CNS delivery of IFN-γ before EAE onset ameliorated the disease course and prevented demyelination, axonal damage, and oligodendrocyte loss. The beneficial effects of IFN-γ were accompanied by PERK activation in oligodendrocytes and were abrogated in PERK-deficient animals. Our results indicate that IFN-γ activation of PERK in mature oligodendrocytes attenuates EAE severity and suggest that therapeutic approaches to activate the ISR could prove beneficial in MS.
S-carboxymethylcysteine normalises airway responsiveness in sensitised and challenged mice
Authors: K. Takeda, N. Miyahara, T. Kodama, C. Taube, A. Balhorn, A. Dakhama, K. Kitamura, A. Hirano, M. Tanimoto, E. W. Gelfand
Journal: European Respiratory Journal (2005)

S -carboxymethylcysteine ( S -CMC) has been used as a mucoregulator in respiratory diseases. However, the mechanism of action of S -CMC on allergic airway inflammation has not yet been defined. In the present study, BALB/c mice were initially sensitised and challenged to ovalbumin (OVA) and, weeks later, re-challenged with OVA (secondary challenge). S -CMC (5–100 mg·kg −1 ) was administered from 2 days before the secondary challenge through to the day of assay. Mice developed airway hyperresponsiveness (AHR) 6 h after the secondary challenge and increased numbers of neutrophils were present in the bronchoalveolar lavage (BAL) fluid. At 72 h after secondary challenge, mice again developed AHR, but the BAL fluid contained large numbers of eosinophils. S -CMC treatment was found to reduce AHR and neutrophilia at 6 h, as well as eosinophilia and AHR at 72 h. These effects appeared to be dose dependent. Goblet cell hyperplasia, observed at 72 h, was reduced by S -CMC. In BAL fluid, increased levels of interferon-γ, interleukin (IL)-12 and IL-10 and decreased levels of IL-5 and IL-13 were detected. In conclusion, the data indicate that S -carboxymethylcysteine is effective in reducing airway hyperresponsiveness and airway inflammation at two distinct phases of the response to the secondary allergen challenge in sensitised mice.
Plasma MicroRNA Profiling Reveals Loss of Endothelial MiR-126 and Other MicroRNAs in Type 2 Diabetes
Authors: Anna Zampetaki, Stefan Kiechl, Ignat Drozdov, Peter Willeit, Ursula Mayr, Marianna Prokopi, Agnes Mayr, Siegfried Weger, Friedrich Oberhollenzer, Enzo Bonora, Ajay Shah, Johann Willeit, Manuel Mayr
Journal: Circulation Research (2010)

Rationale: MicroRNAs (miRNAs) have been implicated in the epigenetic regulation of key metabolic, inflammatory, and antiangiogenic pathways in type 2 diabetes (DM) and may contribute to common disease complications. Objective: In this study, we explore plasma miRNA profiles in patients with DM. Methods and Results: Total RNA was extracted from plasma samples of the prospective population-based Bruneck study. A total of 13 candidate miRNAs identified by microarray screening and miRNA network inference were quantified by quantitative PCR in all diabetic patients of the Bruneck study and age- and sex-matched controls (1995 evaluation, n=80 each). Quantitative PCR assessment revealed lower plasma levels of miR-20b, miR-21, miR-24, miR-15a, miR-126, miR-191, miR-197, miR-223, miR-320, and miR-486 in prevalent DM, but a modest increase of miR-28-3p. Findings emerged as robust in multivariable analysis and were independent of the standardization procedure applied. For endothelial miR-126, results were confirmed in the entire Bruneck cohort (n=822) in univariate (odds ratio [95% confidence interval], 0.38 [0.26 to 0.55]; P =2.72×10 −7 ) and multivariate analyses (0.57 [0.37 to 0.86]; P =0.0082). Importantly, reduced miR-15a, miR-29b, miR-126, miR-223, and elevated miR-28-3p levels antedated the manifestation of disease. Most differences in miRNA levels were replicated in plasma obtained from hyperglycemic Lep ob mice. High glucose concentrations reduced the miR-126 content of endothelial apoptotic bodies. Similarly in patients with DM, the reduction of miR-126 was confined to circulating vesicles in plasma. Conclusions: We reveal a plasma miRNA signature for DM that includes loss of endothelial miR-126. These findings might explain the impaired peripheral angiogenic signaling in patients with DM.
OSW-1: a Natural Compound With Potent Anticancer Activity and a Novel Mechanism of Action
Authors: Yan Zhou, Celia Garcia-Prieto, Dennis A. Carney, Rui-hua Xu, Helene Pelicano, Ying Kang, Wensheng Yu, Changgang Lou, Seiji Kondo, Jinsong Liu, David M. Harris, Zeev Estrov, Michael J. Keating, Zhendong Jin, Peng Huang
Journal: JNCI Journal of the National Cancer Institute (2005)

The naturally occurring compound 3β,16β,17α-trihydroxycholest-5-en-22-one 16- O -(2- O -4-methoxybenzoyl-β- D -xylopyranosyl)-(1→3)-(2- O -acetyl-α- L -arabinopyranoside) (OSW-1) is found in the bulbs of Ornithogalum saudersiae and is highly cytotoxic against tumor cell lines. Using various human cancer and nonmalignant cell lines, we investigated the anticancer activity and selectivity of OSW-1 and its underlying mechanisms of action. OSW-1 exhibited extremely potent cytotoxic activity against cancer cells in vitro. Nonmalignant cells were statistically significantly less sensitive to OSW-1 than cancer cells, with concentrations that cause a 50% loss of cell viability 40–150-fold greater than those observed in malignant cells. Electron microscopy and biochemical analyses revealed that OSW-1 damaged the mitochondrial membrane and cristae in both human leukemia and pancreatic cancer cells, leading to the loss of transmembrane potential, increase of cytosolic calcium, and activation of calcium-dependent apoptosis. Clones of leukemia cells with mitochondrial DNA defects and respiration deficiency that had adapted the ability to survive in culture without mitochondrial respiration also were resistant to OSW-1. In vitro analysis revealed that OSW-1 effectively killed primary leukemia cells from chronic lymphocytic leukemia patients with disease refractory to fludarabine. The promising anticancer activity of OSW-1 and its unique mechanism of action make this compound worthy of further investigation for its potential to overcome drug resistance.