tbuckley/cabot-search huggingface dataset:
Prognostic Factors in Patients with Advanced Cancer: A Comparison of Clinicopathological Factors and the Development of an Inflammation-Based Prognostic System
Authors: Barry J. Laird, Stein Kaasa, Donald C. McMillan, Marie T. Fallon, Marianne J. Hjermstad, Peter Fayers, Pal Klepstad
Journal: Clinical Cancer Research (2013)

In advanced cancer, oncological treatment is influenced by performance status (PS); however, this has limitations. Biomarkers of systemic inflammation may have prognostic value in advanced cancer. The study compares key factors in prognosis (performance status, patient-reported outcomes; PRO) with an inflammation-based score (Glasgow Prognostic Score, mGPS). A new method of prognosis in advanced cancer (combining performance status and mGPS) is tested and then validated.Two international biobanks of patients with advanced cancer were analyzed. Key prognostic factors [performance status, PROs (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C-30), and mGPS (using C-reactive protein and albumin concentrations)] were examined. The relationship between these and survival was examined using Kaplan-Meier and Cox regression methods, in a test sample before independent validation.Data were available on 1,825 patients (test) and 631 patients (validation). Median survival ranged from 3.2 months (test) to 7.03 months (validation). On multivariate analysis, performance status (HR 1.62-2.77) and mGPS (HR 1.51-2.27) were independently associated with, and were the strongest predictors of survival (P < 0.01). Survival at 3 months varied from 82% (mGPS 0) to 39% (mGPS 2) and from 75% (performance status 0-1) to 14% (performance status 4). When used together, survival ranged from 88% (mGPS 0, PS 0-1) to 10% (mGPS 2, performance status 4), P < 0.001.A systemic inflammation-based score, mGPS, and performance status predict survival in advanced cancer. The mGPS is similar to performance status in terms of prognostic power. Used together, performance status and mGPS act synergistically improving prognostic accuracy. This new method may be of considerable value in the management of patients with advanced cancer.
Genetic Risk Score and Risk of Myocardial Infarction in Hispanics
Authors: Lu Qi, Jiantao Ma, Qibin Qi, Jaana Hartiala, Hooman Allayee, Hannia Campos
Journal: Circulation (2011)

Genome-wide association studies have identified loci associated with coronary heart disease in whites of European ancestry. This study evaluated whether genetic markers previously identified in whites are associated with nonfatal acute myocardial infarction (MI) in Hispanics.Cases (n=1989) with a first nonfatal acute MI and population-based controls (n=2096) living in Costa Rica were studied. Fourteen single-nucleotide polymorphisms were genotyped. Seven single-nucleotide polymorphisms at 3 independent loci showed significant associations with MI. The odds ratios for the loci with the strongest associations were 1.16 (95 confidence interval [CI], 1.05 to 1.27) for rs4977574 (CDKN2A/2B), 1.15 (95 CI, 1.03 to 1.29) for rs646776 (CELSR2-PSRC1-SORT1), and 1.22 (95 CI, 1.08 to 1.38) for rs501120 (CXCL12); the corresponding PARs were 6.8, 10.5, and 15.2; respectively. We developed a genetic risk score by summing the number of the top 3 associated risk alleles. The OR for MI per genetic risk score unit was 1.18 (95 CI, 1.11 to 1.25; P=4.83 × 10(-8)). Discrimination of MI was significantly improved (P=0.02) when the genetic risk score was added to a model including clinical predictors. However, the increase in the area under the receiver-operating characteristic curve after the genetic risk score was added was moderate, from 0.67 (95 CI, 0.65 to 0.69) to 0.68 (95 CI, 0.66 to 0.70).These results indicate both the consistency and disparity of genetic effects on risk of MI between Hispanic and white populations. The improvement in the identified genetic markers on discrimination of MI in Hispanics was modest.
Angiographic Findings of the Multicenter Randomized Study With the Sirolimus-Eluting Bx Velocity Balloon-Expandable Stent (RAVEL)
Authors: E. Regar, P.W. Serruys, C. Bode, C. Holubarsch, J.L. Guermonprez, W. Wijns, A. Bartorelli, C. Constantini, M. Degertekin, K. Tanabe, C. Disco, E. Wuelfert, M.C. Morice
Journal: Circulation (2002)

Restenosis remains the major limitation of coronary catheter-based intervention. In small vessels, the amount of neointimal tissue is disproportionately greater than the vessel caliber, resulting in higher restenosis rates. In the Randomized Study With the Sirolimus-Eluting Bx Velocity Balloon-Expandable Stent (RAVEL) trial, approximately 40% of the vessels were small (<2.5 mm). The present study evaluates the relationship between angiographic outcome and vessel diameter for sirolimus-eluting stents.Patients were randomized to receive either an 18-mm bare metal Bx VELOCITY (BS group, n=118), or a sirolimus-eluting Bx VELOCITY stent (SES group, n=120). Subgroups were stratified into tertiles according to their reference diameter (RD; stratum I, RD <2.36 mm; stratum II, RD 2.36 mm to 2.84 mm; stratum III, RD >2.84 mm). At 6-month follow-up, the restenosis rate in the SES group was 0% in all strata (versus 35%, 26%, and 20%, respectively, in the BS group). In-stent late loss was 0.01+/-0.25 versus 0.80+/-0.43 mm in stratum I, 0.01+/-0.38 versus 0.88+/-0.57 mm in stratum II, and -0.06+/-0.35 versus 0.74+/-0.57 mm in stratum III (SES versus BS). In SES, the minimal lumen diameter (MLD) remained unchanged (Delta -0.72 to 0.72 mm) in 97% of the lesions and increased (=late gain, DeltaMLD <-0.72 mm) in 3% of the lesions. Multivariate predictors for late loss were treatment allocation (P<0.001) and postprocedural MLD (P= 0.008).Sirolimus-eluting stents prevent neointimal proliferation and late lumen loss irrespective of the vessel diameter. The classic inverse relationship between vessel diameter and restenosis rate was seen in the bare stent group but not in the sirolimus-eluting stent group.
S100B Promotes Glioma Growth through Chemoattraction of Myeloid-Derived Macrophages
Authors: Huaqing Wang, Leying Zhang, Ian Y. Zhang, Xuebo Chen, Anna Da Fonseca, Shihua Wu, Hui Ren, Sam Badie, Sam Sadeghi, Mao Ouyang, Charles D. Warden, Behnam Badie
Journal: Clinical Cancer Research (2013)

Abstract Purpose: S100B is member of a multigenic family of Ca2+-binding proteins, which is overexpressed by gliomas. Recently, we showed that low concentrations of S100B attenuated microglia activation through the induction of Stat3. We hypothesized that overexpression of S100B in gliomas could promote tumor growth by modulating the activity of tumor-associated macrophages (TAM). Experimental Design: We stably transfected GL261 glioma cell lines with constructs that overexpressed (S100Bhigh) or underexpressed (S100Blow) S100B and compared their growth characteristics to intracranial wild-type (S100Bwt) tumors. Results: Downregulation of S100B in gliomas had no impact on cell division in vitro but abrogated tumor growth in vivo. Interestingly, compared to S100Blow tumors, S100Bwt and S100Bhigh intracranial gliomas exhibited higher infiltration of TAMs, stronger inflammatory cytokine expression, and increased vascularity. To identify the potential mechanisms involved, the expression of the S100B receptor, receptor for advanced glycation end products (RAGE), was evaluated in gliomas. Although S100B expression induced RAGE in vivo, RAGE ablation in mice did not significantly inhibit TAM infiltration into gliomas, suggesting that other pathways were involved in this process. To evaluate other mechanisms responsible for TAM chemoattraction, we then examined chemokine pathways and found that C-C motif ligand 2 (CCL2) was upregulated in S100Bhigh tumors. Furthermore, analysis of The Cancer Genome Atlas's glioma data bank showed a positive correlation between S100B and CCL2 expression in human proneural and neural glioma subtypes, supporting our finding. Conclusions: These observations suggest that S100B promotes glioma growth by TAM chemoattraction through upregulation of CCL2 and introduces the potential utility of S100B inhibitors for glioma therapy. Clin Cancer Res; 19(14); 3764–75. ©2013 AACR.
Gene Editing of Human Embryonic Stem Cells via an Engineered Baculoviral Vector Carrying Zinc-finger Nucleases
Authors: Yuning Lei, Chi-Lin Lee, Kye-Il Joo, Jonathan Zarzar, Yarong Liu, Bingbing Dai, Victoria Fox, Pin Wang
Journal: Molecular Therapy (2011)

Human embryonic stem (hES) cells are renewable cell sources that have potential applications in regenerative medicine. The development of technologies to produce permanent and site-specific genome modifications is in demand to achieve future medical implementation of hES cells. We report herein that a baculoviral vector (BV) system carrying zinc-finger nucleases (ZFNs) can successfully modify the hES cell genome. BV-mediated transient expression of ZFNs specifically disrupted the CCR5 locus in transduced cells and the modified cells exhibited resistance to HIV-1 transduction. To convert the BV to a gene targeting vector, a DNA donor template and ZFNs were incorporated into the vector. These hybrid vectors yielded permanent site-specific gene addition in both immortalized human cell lines (10%) and hES cells (5%). Modified hES cells were both karyotypically normal and pluripotent. These results suggest that this baculoviral delivery system can be engineered for site-specific genetic manipulation in hES cells. Human embryonic stem (hES) cells are renewable cell sources that have potential applications in regenerative medicine. The development of technologies to produce permanent and site-specific genome modifications is in demand to achieve future medical implementation of hES cells. We report herein that a baculoviral vector (BV) system carrying zinc-finger nucleases (ZFNs) can successfully modify the hES cell genome. BV-mediated transient expression of ZFNs specifically disrupted the CCR5 locus in transduced cells and the modified cells exhibited resistance to HIV-1 transduction. To convert the BV to a gene targeting vector, a DNA donor template and ZFNs were incorporated into the vector. These hybrid vectors yielded permanent site-specific gene addition in both immortalized human cell lines (10%) and hES cells (5%). Modified hES cells were both karyotypically normal and pluripotent. These results suggest that this baculoviral delivery system can be engineered for site-specific genetic manipulation in hES cells.
Oxygen therapy or not: That is the question
Authors: Sabrina Della Patrona, Andrea Zanini, Maria Elena Altieri, Silvia Casale, Veronica Leoni, Marco Moscheni, Francesca Cherubino, Antonio Spanevello
Journal: European Respiratory Journal (2013)

Rationale: The utility of oxygen therapy has been demonstrated in patients with COPD with respiratory failure. Two historic studies conducted at the end of the 70s (Nocturnal Oxygen Therapy Trial (NOTT) and British Medical Research Council/MRC)) have demonstrated that LTOT (>15 hours/day) improves the survival of patients with severe COPD associated to hypoxemia at rest, but what happens to patients that desaturate during exercise and during night in the absence of hypoxemia at rest and without oxygen therapy?  Material and methods: 31 COPD patients with moderate-severe airflow obstruction and hospitalized in our division between 2009 and 2012 for pulmonary rehabilitation, were retrospectively analyzed. They were divided in two groups: hypoxemic at rest with prescription of continuous oxygen (group 1) and hypoxemic only during exercise and during night not treated with oxygen supplementation (group 2).  Results: Baseline characteristics of patients are reported in table 1 (Mean±DS). During three years of observation no significant difference between the two groups was identified on mortality, cardiovascular events, hospitalizations, exacerbations, decrease in gas exchange and in the respiratory function.  Conclusions: In conclusion, the presence of desaturation during exercise and during night doesn’t seem to justify the oxygen prescription in these COPD patients. The desaturation correction did not modify the described outcomes.
Role of the <i>CDKN2A</i> Locus in Patients With Multiple Primary Melanomas
Authors: Susana Puig, Josep Malvehy, Cèlia Badenas, Anna Ruiz, Dolores Jimenez, Francisco Cuellar, Antoni Azon, Urbá Gonzàlez, Teresa Castel, Antoni Campoy, Josep Herrero, Rosa Martí, Joan Brunet-Vidal, Montserrat Milà
Journal: Journal of Clinical Oncology (2005)

We have studied a consecutive case series of patients with multiple primary melanoma (MPM) for the involvement of the melanoma susceptibility loci CDKN2A and CDK4.One hundred four MPM patients (81 patients with two primary melanomas, 14 with three, five with four, one with five, two with six, and one with seven) were included.Seven different CDKN2A germline mutations were identified in 17 patients (16.3%). In total, we identified 15 CDKN2A exon 2, one exon 1alpha missense mutation, and one exon 1beta frameshift mutation. The age of onset was significantly lower and the number of primary melanomas higher in patients with mutations. CDKN2A mutations were more frequent in patients with familial history of melanoma (35.5%) compared with patients without (8.2%), with a relative risk (RR) of 4.32 (95% CI, 1.76 to 10.64; P = .001), and in patients with more than two melanomas (39.1%) compared with patients with only two melanomas (10%) with an RR of 3.29 (95% CI, 1.7 to 6.3; P = .002). The A148T polymorphism was more frequent in patients with MPMs than in the control population (P = .05). A variant of uncertain significance, A127S, was also detected in one patient. No CDK4 mutations were identified, suggesting that it has a low impact in susceptibility to MPM.MPM patients are good candidates for CDKN2A mutational screening. These patients and some of their siblings should be included in a program of specific follow-up with total body photography and digital dermoscopy, which will result in the early detection of melanoma in this subset of high-risk patients and improve phenotypic characterization.
The Ontogeny and Evolution of Sex-Biased Gene Expression in Drosophila melanogaster
Authors: Jennifer C. Perry, Peter W. Harrison, Judith E. Mank
Journal: Molecular Biology and Evolution (2014)

Sexually dimorphic phenotypes are thought to largely result from sex differences in gene expression, and genes with sex-biased expression have been well characterized in adults of many species. Although most sexual dimorphisms manifest in adults, many result from sex-specific developmental trajectories, implying that juveniles may exhibit significant levels of sex-biased expression. However, it is unclear how much sex-biased expression occurs before reproductive maturity and whether preadult sex-biased genes should exhibit the same evolutionary dynamics observed for adult sex-biased genes. In order to understand the continuity, or lack thereof, and evolutionary dynamics of sex-biased expression throughout the life cycle, we examined sex-biased genes in pre-gonad tissue of two preadult stages and compared them with the adult gonad of Drosophila melanogaster. We found that the majority of the genome is sex-biased at some point in the life cycle, with some genes exhibiting conserved sex-biased expression and others displaying stage-specific sex bias. Our results also reveal a far more complex pattern of evolution for sex-biased genes throughout development. The most rapid evolutionary divergence occurred in genes expressed only in larvae within each sex, compared with continuously expressed genes. In females-but not males-this pattern appeared to be due to relaxed purifying selection in larva-limited genes. Furthermore, genes that retained male bias throughout life evolved more rapidly than stage-specific male-biased genes, due to stronger purifying selection in stage-specific genes. However, female-biased genes that were specific to larvae evolved most rapidly, a pattern that could not be definitively attributed to differences in adaptive evolution or purifying selection, suggesting that pleiotropic constraints on protein-coding sequences can arise when genes are broadly expressed across developmental stages. These results indicate that the signature of sex-specific selection can be detected well before reproductive maturity and is strongest during development.
Gut Dysbiosis and Detection of “Live Gut Bacteria” in Blood of Japanese Patients With Type 2 Diabetes
Authors: Junko Sato, Akio Kanazawa, Fuki Ikeda, Tomoaki Yoshihara, Hiromasa Goto, Hiroko Abe, Koji Komiya, Minako Kawaguchi, Tomoaki Shimizu, Takeshi Ogihara, Yoshifumi Tamura, Yuko Sakurai, Risako Yamamoto, Tomoya Mita, Yoshio Fujitani, Hiroshi Fukuda, Koji Nomoto, Takuya Takahashi, Takashi Asahara, Takahisa Hirose, Satoru Nagata, Yuichiro Yamashiro, Hirotaka Watada
Journal: Diabetes Care (2014)

Mounting evidence indicates that the gut microbiota are an important modifier of obesity and diabetes. However, so far there is no information on gut microbiota and "live gut bacteria" in the systemic circulation of Japanese patients with type 2 diabetes.Using a sensitive reverse transcription-quantitative PCR (RT-qPCR) method, we determined the composition of fecal gut microbiota in 50 Japanese patients with type 2 diabetes and 50 control subjects, and its association with various clinical parameters, including inflammatory markers. We also analyzed the presence of gut bacteria in blood samples.The counts of the Clostridium coccoides group, Atopobium cluster, and Prevotella (obligate anaerobes) were significantly lower (P < 0.05), while the counts of total Lactobacillus (facultative anaerobes) were significantly higher (P < 0.05) in fecal samples of diabetic patients than in those of control subjects. Especially, the counts of Lactobacillus reuteri and Lactobacillus plantarum subgroups were significantly higher (P < 0.05). Gut bacteria were detected in blood at a significantly higher rate in diabetic patients than in control subjects (28% vs. 4%, P < 0.01), and most of these bacteria were Gram-positive.This is the first report of gut dysbiosis in Japanese patients with type 2 diabetes as assessed by RT-qPCR. The high rate of gut bacteria in the circulation suggests translocation of bacteria from the gut to the bloodstream.
Significant reduction in restenosis after the use of sirolimus-eluting stents in the treatment of chronic total occlusions
Authors: Angela Hoye, Kengo Tanabe, Pedro A Lemos, Jiro Aoki, Francesco Saia, Chourmouzios Arampatzis, Muzaffer Degertekin, Sjoerd H Hofma, Georgios Sianos, Eugene McFadden, Willem J van der Giessen, Pieter C Smits, Pim J de Feyter, Ron T van Domburg, Patrick W Serruys
Journal: Journal of the American College of Cardiology (2004)
Two-Photon Microscopy Reveals Stationary Podocytes in Living Zebrafish Larvae
Authors: Nicole Endlich, Ole Simon, Achim Göpferich, Henny Wegner, Marcus J. Moeller, Elisabeth Rumpel, Ahmed M. Kotb, Karlhans Endlich
Journal: Journal of the American Society of Nephrology (2013)

Podocytes are an essential component of the glomerular filtration barrier and cover the outer aspect of glomerular capillaries. They form a complex actin-based cytoskeleton in vivo and show prominent motility in vitro, but whether podocytes are stationary or mobile in vivo is debated. To address this question, the pronephros of translucent zebrafish larvae (casper) expressing enhanced green fluorescent protein (eGFP) specifically in podocytes (wt1a:eGFP larvae) was observed by intravital two-photon microscopy over extended periods of time. Podocyte cell bodies and the interdigitating branching pattern of major processes could be resolved with a resolution of approximately 1 µm in the xy-plane. Time-lapse imaging of zebrafish larvae at 5-7 days after fertilization demonstrated that podocytes neither migrated nor changed the branching pattern of their major processes over a time period of up to 23 hours. In summary, we show by extended intravital two-photon microscopy that podocytes are stationary cells in the intact glomerulus of a translucent zebrafish with fluorescently-labeled podocytes.
Ophthalmic manifestations of dermatomyositis
Authors: O. Backhouse, B. Griffiths, T. Henderson, P. Emery
Journal: Annals of the Rheumatic Diseases (1998)

Since their introduction in 2002, bond ETFs have grown dramatically, with more than $243 billion in assets by the end of 2012. Using data on gross flows from N-SAR filings, we provide the first comprehensive examination of bond ETF characteristics and cash flows. We find evidence of return chasing in the net flows of some fund styles; in particular, investment grade corporate, international, and TIPS funds. In addition to past returns, other factors related to fund flows are fund size, expense ratio, and premium/discounts. We also examine the relationship between short interest and fund flows, and find that lightly shorted funds have both lower inflows and net flows. Finally, we test if bond ETF investors optimally time their purchases and sales. We find evidence of smartness in the timing of ETF sales, with investors earning 30 basis points in alpha per month. <b>TOPICS:</b>Fixed income and structured finance, exchange-traded funds and applications, factor-based models
Oxidative stress and cardiovascular complications in diabetes: isoprostanes as new markers on an old paradigm
Authors: A Mezzetti
Journal: Cardiovascular Research (2000)

Long-term vascular complications still represent the main cause of morbidity and mortality in diabetic patients. Although randomized long-term clinical studies comparing the effects of conventional and intensive therapy have demonstrated a clear link between hyperglycemia and the development of complications of diabetes, they have not defined the mechanism through which excess glucose results in tissue damage. Evidence has accumulated indicating that oxidative stress may play a key role in the etiology of diabetic complications. Isoprostanes are emerging as a new class of biologically active products of arachidonic acid metabolism of potential relevance to human vascular disease. Their formation in vivo seems to reflect primarily, if not exclusively, a nonenzymatic process of lipid peroxidation. Enhanced urinary excretion of 8-iso-PGF2α has been described in association with both type 1 and type 2 diabetes mellitus, and correlates with impaired glycemic control. Besides providing a likely noninvasive index of lipid peroxidation in this setting, measurements of specific F2 isoprostanes in urine may provide a sensitive biochemical end point for dose-finding studies of natural and synthetic inhibitors of lipid peroxidation. Although the biological effects of 8-iso-PGF2α in vitro suggest that it and other isoeicosanoids may modulate the functional consequences of lipid peroxidation in diabetes, evidence that this is likely in vivo remains inadequate at this time.
Impact of FLT3-ITD location on sensitivity to TKI-therapy in vitro and in vivo
Authors: P Arreba-Tutusaus, T S Mack, L Bullinger, T M Schnöder, A Polanetzki, S Weinert, A Ballaschk, Z Wang, A J Deshpande, S A Armstrong, K Döhner, T Fischer, F H Heidel
Journal: Leukemia (2015)
BMA negotiator calls for more male medical students
Authors: W. Moore
Journal: BMJ (2002)

A member of the BMA's general practitioners' negotiating committee has said that medical schools should discriminate in favour of male applicants in response to growing concerns about doctor shortages.

Dr Peter Holden, a negotiator on the committee, said there was a “sound case” for considering biasing entry towards young men applying to medical schools. Currently 58% of applicants and 59% of successful entrants to medical school are women, according to figures for 2001 …