tbuckley/cabot-search huggingface dataset:
Prevalence of TTV DNA and GBV-C RNA in patients with systemic sclerosis, rheumatoid arthritis, and osteoarthritis does not differ from that in healthy blood donors
Authors: C A Seemayer
Journal: Annals of the Rheumatic Diseases (2001)

<h3>OBJECTIVE</h3> To determine the prevalence of GB virus-C (GBV-C) RNA and TT virus (TTV) DNA in patients with systemic sclerosis (SSc), rheumatoid arthritis (RA), and osteoarthritis (OA) as well as to compare the autoantibody pattern in patients with SSc with and without evidence of viral infection. <h3>PATIENTS AND METHODS</h3> The study included 168 patients (84 SSc, 41 RA, and 43 OA) diagnosed according to the American College of Rheumatology criteria and 122 volunteer blood donors. The presence of GBV-C RNA and TTV DNA in serum was assessed by nested reverse transcriptase-polymerase chain reaction (RT-PCR) and semi-nested PCR, respectively. Autoantibodies in patients with SSc were determined by enzyme linked immunosorbent assay (ELISA) and Hep-2 immunofluorescence. <h3>RESULTS</h3> TTV-DNA was detected in 10/84 (12%) patients with SSc, 9/41 (22%) patients with RA, 3/43 (7%) patients with OA, and 16/122 (13%) blood donors. GBV-C RNA was present in 4/84 (5%) patients with SSc, 2/43 (5%) patients with OA, and 5/122 (4%) blood donors. No patient with RA was positive for GBV-C RNA. One patient with SSc and one patient with OA showed a double infection with GBV-C and TTV. 74/84 (88%) patients with SSc were positive for at least one autoantibody species tested: 18/84 (21%) showed anticentromeric autoantibodies, 55/84 (66%) a speckled (36/84 (43%) fine, 19/84 (23%) coarse), and 20/84 (24%) a homogeneous nuclear Hep-2 pattern, and 21/84 (25%) had antinucleolar autoantibodies. Anti-Scl-70 antibodies were found in 31/84 (37%) and anti-RNP antibodies in 5/84 (6%) patients with SSc. No differences in the autoantibody pattern in patients with SSc with or without viral infection could be detected. <h3>CONCLUSION</h3> The prevalence of GBV-C RNA and TTV DNA in serum samples from patients with SSc, RA, and OA was low and comparable with that in blood donors. A continuing infection with TTV and or GBV-C was not associated with a significant change in the autoantibody pattern in patients with SSc. These data provide no evidence for an association between GBV-C and/or TTV infections and SSc and/or arthritis (RA and OA).
C-Peptide Levels Are Associated With Mortality and Cardiovascular Mortality in Patients Undergoing Angiography
Authors: Nikolaus Marx, Guenther Silbernagel, Vincent Brandenburg, Mathias Burgmaier, Marcus E. Kleber, Tanja B. Grammer, Bernhard R. Winkelmann, Bernhard O. Boehm, Winfried März
Journal: Diabetes Care (2012)

C-peptide is a proinsulin cleavage product released from the pancreas in amounts equimolar to insulin, and elevated levels of C-peptide have been found in patients with insulin resistance and early type 2 diabetes mellitus. Recent data suggest that C-peptide could play a causal role in the pathophysiology of vascular disease, but nothing is known about the prognostic value of C-peptide concentrations in the circulation.We examined whether C-peptide is associated with cardiovascular and total mortality in 2,306 patients from the Ludwigshafen Risk and Cardiovascular Health Study who underwent coronary angiography at baseline (1997-2000).During a mean follow-up of 7.6 years, 440 deaths (19.1%) occurred, 252 (10.9%) of which were due to cardiovascular causes. Age- and sex-adjusted hazard ratios (HRs) in the third compared with the first tertile of C-peptide were 1.46 (95% CI 1.15-1.85; P = 0.002) for all cause and 1.58 (1.15-2.18; P = 0.005) for cardiovascular mortality. After further adjustment for common risk factors as well as markers of glucose metabolism, these HRs remained significant at 1.46 (1.10-1.93; P = 0.008) and 1.55 (1.07-2.24; P = 0.022), respectively. Moreover, patients in higher tertiles of C-peptide exhibited higher levels of markers of endothelial dysfunction and atherosclerosis as well as a more severe extent of coronary lesions.In patients undergoing coronary angiography, C-peptide levels are independently associated with all cause and cardiovascular mortality as well as presence and severity of coronary artery disease. Further studies are needed to examine a potential causal role of C-peptide in atherogenesis in humans.
Incident Pneumonia and Mortality in Patients with Chronic Obstructive Pulmonary Disease. A Double Effect of Inhaled Corticosteroids?
Authors: Emir Festic, Paul D. Scanlon
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Inhaled corticosteroids are commonly prescribed for patients with severe chronic obstructive pulmonary disease. Although their use improves quality of life and reduces exacerbations, it is associated with increased risk of pneumonia. Curiously, their use has not been associated with increased risk of pneumonia-related or overall mortality. We review pertinent literature to further explore the effects of inhaled corticosteroids on incident pneumonia and mortality in patients with chronic obstructive pulmonary disease. The association of use of inhaled corticosteroids and incident pneumonia is substantial and has been present in the majority of the studies on the topic. This includes both randomized controlled trials and observational studies. However, all of the studies have substantial risk of bias. Most randomized trials are limited by lack of systematic ascertainment of pneumonia; they depended on adverse event reporting. Many observational studies included proper radiographic assessment of pneumonia, but they are limited by their retrospective, observational design. The unadjusted higher risk of pneumonia is associated with longer duration of use, more potent ICS compounds, and higher doses. That implies a dose-effect relationship. Unlike pneumonia, mortality is a precise outcome. Despite the robust association of inhaled corticosteroid use with increased risk of pneumonia, all studies find either no difference or a reduction in pulmonary-related and overall mortality associated with the use of inhaled corticosteroids. These observations suggest a double effect of inhaled corticosteroids (i.e., an adverse effect plus an unexplained mitigating effect).
Multiple Recombining Loci Encode MaSp1, the Primary Constituent of Dragline Silk, in Widow Spiders (Latrodectus: Theridiidae)
Authors: N. A. Ayoub, C. Y. Hayashi
Journal: Molecular Biology and Evolution (2007)

Spiders spin a functionally diverse array of silk fibers, each composed of one or more unique proteins. Most of these proteins, in turn, are encoded by members of a single gene family thought to have arisen through duplication and divergence of an ancestral silk gene. Because of its remarkable mechanical properties, orb weaver dragline silk, a composite of 2 proteins (MaSp1 and MaSp2), is the best studied. Here, we demonstrate that multiple loci encode MaSp1 in widow spiders (Latrodectus). Because these copies may be the result of more recent duplication events than those leading to the currently recognized silk gene paralogs, they offer insight into the early evolutionary fate of silk gene duplicates. In addition to 3 presumed functional MaSp1 loci in Latrodectus hesperus (Western black widow) and Latrodectus geometricus (brown widow) genomes, we find a MaSp1 pseudogene in L. hesperus, demonstrating the potential for unrecognized extinction of silk gene paralogs. We also document recombination events among L. hesperus MaSp1 loci and between Latrodectus MaSp1 loci and MaSp2. This result supports the hypothesis that concerted evolution occurs not only within an individual silk gene but also among silk gene paralogs. One of the L. geometricus MaSp1 copies encodes a protein that has diverged in amino acid composition and potentially converged on the secondary structure of MaSp2. Based on the presence of multiple MaSp1 loci and the phylogenetic distribution of MaSp1 versus MaSp2, we propose that MaSp2 is derived from an ancestral MaSp1 duplicate. Finally, divergence has occurred in the upstream flanking sequences of the L. hesperus MaSp1 loci, the region most likely to contain regulatory motifs, providing ample opportunity for differential expression. However, the benefits associated with increased protein production may be the primary mechanism maintaining multiple functional MaSp1 copies in widow genomes.
Smoking and Progression of Diabetic Nephropathy in Type 1 Diabetes
Authors: Peter Hovind, Peter Rossing, Lise Tarnow, Hans-Henrik Parving
Journal: Diabetes Care (2003)

OBJECTIVE—Cigarette smoking contributes to development of diabetic nephropathy. However, long-term studies on the effect of smoking on decline in kidney function in diabetic nephropathy are lacking. We assessed the impact of smoking on progression of diabetic nephropathy in type 1 diabetic patients enrolled in a prospective observational cohort study started in 1983. RESEARCH DESIGN AND METHODS—We identified all albuminuric type 1 diabetic patients (n = 301) followed for at least 3 years, median (range) 7 years (3–14), who underwent at least yearly measurement of glomerular filtration rate (GFR) by the 51Cr-EDTA plasma clearance technique (n = 8, range 3–24). In total, 192 men and 109 women were included (age [mean ± SD] 36 ± 11 years, duration of diabetes 22 ± 8 years); 271 patients were treated with antihypertensive drugs, predominantly ACE inhibitors in 179 patients. Patients were classified as smokers if they smoked more than one cigarette per day during a portion of or the entire observation period. Blood pressure, albuminuria, HbA1c, and serum cholesterol were measured every 3–4 months during the study. RESULTS—In all 301 patients, the mean (SE) rate of decline in GFR (ΔGFR) was 4.0 (0.2) ml · min−1 · year−1 during the investigation period. No difference in Δ GFR was demonstrated between nonsmokers (n = 94), ΔGFR 4.5 (0.4), ex-smokers (n = 31), ΔGFR 3.1 (0.7), and smokers (n = 176), ΔGFR 3.9 (0.3) ml · min−1 · year−1, respectively (NS). Adjustment for other risk factors for progression of diabetic nephropathy did not alter the results: smoking was not associated with ΔGFR, whereas blood pressure, albuminuria, HbA1c, and serum cholesterol were demonstrated to be independent progression promoters. CONCLUSIONS—In our study, smoking was not associated with decline in kidney function in type 1 diabetic patients with diabetic nephropathy.
Comparative uptake of rat and human serum low-density and high-density lipoproteins by rat aortic smooth muscle cells in culture.
Authors: O Stein, Y Stein
Journal: Circulation Research (1975)

Rat aortic smooth muscle cells in culture were exposed to rat and human serum (LDL) and high-density (HDL) lipoproteins labeled with 125-I. 125-I-lipid was taken up preferentially from all of the lipoproteins used. 125-I-protein uptake of both rat LDL and HDL was significantly higher than that of the corresponding human lipoproteins, and human LDL was preferred to human HDL. The uptake of delipidated high-density apolipoproteins of either rat or human origin was very low. About 3-4% of the interiorized rat LDL and HDL was catabolized during 48 hours of incubation. On electron microscopic autoradiography of cells incubated with rat 125-I-LDL, the concentration of label, representing mainly 125-I-protein, was associated with secondary lysosomes. These results suggest that, if the protein uptake represents particle uptake, the preferential uptake of human LDL compared with human HDL could account in part for the finding that LDL acts as a more potent feedback suppressor of 3-hydroxy-3-methylglutaryl CoA reductase than does HDL.
Quantitative <i>In vivo</i> Imaging of the Effects of Inhibiting Integrin Signaling via Src and FAK on Cancer Cell Movement: Effects on E-cadherin Dynamics
Authors: Marta Canel, Alan Serrels, Derek Miller, Paul Timpson, Bryan Serrels, Margaret C. Frame, Valerie G. Brunton
Journal: Cancer Research (2010)

Abstract Most cancer-related deaths are due to the development of metastatic disease, and several new molecularly targeted agents in clinical development have the potential to prevent disease progression. However, it remains difficult to assess the efficacy of antimetastatic agents in the clinical setting, and an increased understanding of how such agents work at different stages of the metastatic cascade is important in guiding their clinical use. We used optical window chambers combined with photobleaching, photoactivation, and photoswitching to quantitatively measure (a) tumor cell movement and proliferation by tracking small groups of cells in the context of the whole tumor, and (b) E-cadherin molecular dynamics in vivo following perturbation of integrin signaling by inhibiting focal adhesion kinase (FAK) and Src. We show that inhibition of Src and FAK suppresses E-cadherin–dependent collective cell movement in a complex three-dimensional tumor environment, and modulates cell-cell adhesion strength and endocytosis in vitro. This shows a novel role for integrin signaling in the regulation of E-cadherin internalization, which is linked to regulation of collective cancer cell movement. This work highlights the power of fluorescent, direct, in vivo imaging approaches in the preclinical evaluation of chemotherapeutic agents, and shows that inhibition of the Src/FAK signaling axis may provide a strategy to prevent tumor cell spread by deregulating E-cadherin–mediated cell-cell adhesions. Cancer Res; 70(22); 9413–22. ©2010 AACR.
Sports cardiology: current updates and new directions
Authors: Mathew G Wilson, Jonathan A Drezner
Journal: British Journal of Sports Medicine (2012)

In 1901, Dr W Collier1 submitted a paper to the British Medical Journal entitled, ‘The effects of severe muscular exertion, sudden and prolonged, in young adolescents’. This early article demonstrated the predicament faced by physicians when dealing with athletes suspected of, or diagnosed with, a cardiovascular disease. Collier describes the case of an Oxford University mile runner who was performing poorly and presented for medical consultation. Physical examination at rest was normal, but upon mild exercise, the athlete demonstrated a very distinct systolic murmur. Rightly or wrongly, Collier stated that he ‘had no doubt that it was over-dilation of the right ventricle’ and disqualified the athlete from competition. He even sent the athlete on a sea voyage, where the temptation to exercise was effectively removed. Despite much medical, academic and technological advancement in the 100 years after Collier's initial insights, many sports medicine physicians who undertake cardiovascular preparticipation screening may argue that following the diagnosis of an inherited cardiac disease, the limited ability to adequately risk stratify and provide evidence-based disqualification criteria for athletes indicates our management remains just as inadequate and imprecise.

Athletes are perceived as the epitome of health, owing to their unique lifestyle and physical achievements. However, a small proportion of athletes die suddenly from a pathological heart condition; so-called sudden cardiac death (SCD). Most of the deaths in athletes under 35 years, are attributed to inherited or congenital disorders of the heart that predispose to malignant ventricular arrhythmias. Due to the steady trickle of SCD's in young athletes, several major sport governing bodies, including the International Olympic Committee and Federation Internationale de Football Association have ‘recommended’ the implementation of systematic cardiac screening programmes—a trend increasingly being adopted by national and international sport governing bodies worldwide. Despite differences in screening methodology, both the American College of Cardiology/American Heart …
Blood Pressure Control in Chronic Kidney Disease
Authors: Julia B. Lewis
Journal: Journal of the American Society of Nephrology (2010)

BP control is critical in the treatment of patients with chronic kidney disease. Recent guidelines now recommend a BP goal of <130/80 mmHg. Clinical trials using a randomized, intention-to-treat design have not established the benefits of this goal; rather, observational data and secondary or subgroup analyses drove the development of the new guidelines. A variety of observations suggest potential adverse events associate with achieving too low a BP in patients with chronic kidney disease, and ongoing randomized trials will have to establish the benefits or risks of meeting this goal.
Differential Repair of the Two Major UV-Induced Photolesions in Trichothiodystrophy Fibroblasts
Authors: Lydia Riou, Eric Eveno, Anneke van Hoffen, Albert A. van Zeeland, Alain Sarasin, Leon H. F. Mullenders
Journal: Cancer Research (2004)

Abstract Defects in nucleotide excision repair have been shown to be associated with the photosensitive form of the disorder trichothiodystrophy (TTD). Most repair-deficient TTD patients are mutated in the XPD gene, a subunit of the transcription factor TFIIH. Knowledge of the kinetics and efficiency of repair of the two major UV-induced photolesions in TTD is critical to understand the role of unrepaired lesions in the process of carcinogenesis and explain the absence of enhanced skin cancer incidence in TTD patients contrarily to the xeroderma pigmentosum D patients. In this study, we used different approaches to quantify repair of UV-induced cyclobutane pyrimidine dimers (CPD) and pyrimidine (6–4) pyrimidone photoproducts (6–4PP) at the gene and the genome overall level. In cells of two TTD patients, repair of CPD and 6–4PP was reduced compared with normal human cells, but the reduction was more severe in confluent cells than in exponentially growing cells. Moreover, the impairment of repair was more drastic for CPD than 6–4PP. Most notably, exponentially growing TTD cells displayed complete repair 6–4PP over a broad dose range, albeit at a reduced rate compared with normal cells. Strand-specific analysis of CPD repair in a transcriptional active gene revealed that TTD cells were capable to perform transcription-coupled repair. Taken together, the data suggest that efficient repair of 6–4PP in dividing TTD cells in concert with transcription-coupled repair might account for the absence of increased skin carcinogenesis in TTD patients.
Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene
Authors: H E Wasmuth, A Glantz, H Keppeler, E Simon, C Bartz, W Rath, L-A Mattsson, H-U Marschall, F Lammert
Journal: Gut (2006)

Intrahepatic cholestasis of pregnancy (ICP) is characterised by troublesome maternal pruritus, raised serum bile acid levels and increased fetal risk. Mutations of the ABCB4 gene encoding the hepatobiliary phospholipid transporter have been identified in a small proportion of patients with cholestasis of pregnancy. In a recent prospective study on 693 patients with cholestasis of pregnancy, a cut-off level for serum bile acid (> or =40 micromol/l) was determined for increased risk of fetal complications.To investigate whether common combinations of polymorphic alleles (haplotypes) of the genes encoding the hepatobiliary ATP-binding cassette (ABC) transporters for phospholipids (ABCB4) and bile acids (ABCB11) were associated with this severe form of cholestasis of pregnancy.For genetic analysis, 52 women with bile acid levels > or =40 micromol/l (called cases) and 52 unaffected women (called controls) matched for age, parity and geographical residence were studied. Gene variants tagging common ABCB4 and ABCB11 haplotypes were genotyped and haplotype distributions were compared between cases and controls by permutation testing.In contrast with ABCB11 haplotypes, ABCB4 haplotypes differed between the two groups (p = 0.019), showing that the severe form of cholestasis of pregnancy is associated with the ABCB4 gene variants. Specifically, haplotype ABCB4_5 occurred more often in cases, whereas haplotypes ABCB4_3 and ABCB4_7 were more common in controls. These associations were reflected by different frequencies of at-risk alleles of the two tagging polymorphisms (c.711A: odds ratio (OR) 2.27, p = 0.04; deletion intron 5: OR 14.68, p = 0.012).Variants of ABCB4 represent genetic risk factors for the severe form of ICP in Sweden.
High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling
Authors: Hind Medyouf, Samuel Gusscott, Hongfang Wang, Jen-Chieh Tseng, Carol Wai, Oksana Nemirovsky, Andreas Trumpp, Francoise Pflumio, Joan Carboni, Marco Gottardis, Michael Pollak, Andrew L. Kung, Jon C. Aster, Martin Holzenberger, Andrew P. Weng
Journal: The Journal of Experimental Medicine (2011)

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of immature T cells that often shows aberrant activation of Notch1 and PI3K–Akt pathways. Although mutations that activate PI3K–Akt signaling have previously been identified, the relative contribution of growth factor-dependent activation is unclear. We show here that pharmacologic inhibition or genetic deletion of insulin-like growth factor 1 receptor (IGF1R) blocks the growth and viability of T-ALL cells, whereas moderate diminution of IGF1R signaling compromises leukemia-initiating cell (LIC) activity as defined by transplantability in syngeneic/congenic secondary recipients. Furthermore, IGF1R is a Notch1 target, and Notch1 signaling is required to maintain IGF1R expression at high levels in T-ALL cells. These findings suggest effects of Notch on LIC activity may be mediated in part by enhancing the responsiveness of T-ALL cells to ambient growth factors, and provide strong rationale for use of IGF1R inhibitors to improve initial response to therapy and to achieve long-term cure of patients with T-ALL.
Tildrakizumab (MK-3222), an anti-interleukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo-controlled trial
Authors: K. Papp, D. Thaçi, K. Reich, E. Riedl, R.G. Langley, J.G. Krueger, A.B. Gottlieb, H. Nakagawa, E.P. Bowman, A. Mehta, Q. Li, Y. Zhou, R. Shames
Journal: British Journal of Dermatology (2015)

Tildrakizumab is a high‐affinity, humanized, IgG1/κ, anti‐interleukin (IL)‐23p19 monoclonal antibody that does not bind human IL‐12 or p40 is being developed for the treatment of chronic plaque psoriasis. To evaluate the safety and efficacy of subcutaneous tildrakizumab in patients with moderate‐to‐severe chronic plaque psoriasis. A three‐part, randomized, double‐blind, phase IIb trial was conducted in 355 adults with chronic plaque psoriasis. Participants were randomized to receive subcutaneous tildrakizumab (5, 25, 100, 200 mg) or placebo at weeks 0 and 4 (part I) and every 12 weeks thereafter until week 52 (part II). Study drug was discontinued at week 52 and participants were followed through week 72 (part III). Primary efficacy end point was Psoriasis Area and Severity Index (PASI) 75 response at week 16. Adverse events (AEs) and vital signs were monitored throughout the study. At week 16, PASI 75 responses were 33·3% (n =14), 64·4% (n =58), 66·3% (n =59), 74·4% (n =64) and 4·4% (n =2) in the 5‐, 25‐, 100‐ and 200‐mg tildrakizumab and placebo groups, respectively (P ≤0·001 for each tildrakizumab dose vs. placebo). PASI 75 response was generally maintained through week 52; only eight of 222 participants who achieved PASI 75 response at week 52 and continued to part III relapsed following discontinuation up to week 72. Possible drug‐related serious AEs included bacterial arthritis and lymphoedema (part I), and melanoma, stroke, epiglottitis and knee infection (part II). Tildrakizumab had treatment effects that were superior to placebo, maintained for 52 weeks of treatment, and persisted for 20 weeks after cessation. Tildrakizumab was generally safe and well tolerated. These results suggest that IL‐23p19 is a key target for suppressing psoriasis.
Randomized phase II study of single-agent epirubicin +/— verapamil in patients with advanced metastatic breast cancer
Authors: K. Mross, C. Bohn, L. Edler, W. Jonat, W. Queisser, E. Heidemann, M. Goebel, D.K. Hossfeld
Journal: Annals of Oncology (1993)