tbuckley/cabot-search huggingface dataset:
Effects of Random Allocation to Vitamin E Supplementation on the Occurrence of Venous Thromboembolism
Authors: Robert J. Glynn, Paul M Ridker, Samuel Z. Goldhaber, Robert Y.L. Zee, Julie E. Buring
Journal: Circulation (2007)

Supplementation with vitamin E may antagonize vitamin K in healthy adults, but it is unclear whether intake of vitamin E decreases the risk of venous thromboembolism (VTE).The Women's Health Study randomized 39,876 women > or = 45 years of age to receive 600 IU of natural source vitamin E or placebo on alternate days. Before randomization, 26,779 participants gave blood samples, which were used to determine factor V Leiden, G20210A prothrombin, and 677C>T MTHFR polymorphisms. Documented VTE (including deep vein thrombosis or pulmonary embolism) and unprovoked VTE (no recent surgery, trauma, or cancer diagnosis) were prospectively evaluated, secondary end points of the trial. During a median follow-up period of 10.2 years, VTE occurred in 482 women: 213 in the vitamin E group and 269 in the placebo group, a significant 21% hazard reduction (relative hazard, 0.79; 95% CI, 0.66 to 0.94; P=0.010). For unprovoked VTE, the hazard reduction was 27% (relative hazard, 0.73; 95% CI, 0.57 to 0.94; P=0.016). In subgroup analyses, the 3% of participants who reported VTE before randomization had a 44% hazard reduction (relative hazard, 0.56; 95% CI, 0.31 to 1.00; P=0.048), whereas women without prior VTE had an 18% hazard reduction (relative hazard 0.82; 95% CI, 0.68 to 0.99; P=0.040). Women with either factor V Leiden or the prothrombin mutation had a 49% hazard reduction associated with vitamin E treatment (relative hazard, 0.51; 95% CI, 0.30 to 0.87; P=0.014).These data suggest that supplementation with vitamin E may reduce the risk of VTE in women, and those with a prior history or genetic predisposition may particularly benefit.
Characterization of a New Humanized Anti-CD20 Monoclonal Antibody, IMMU-106, and Its Use in Combination with the Humanized Anti-CD22 Antibody, Epratuzumab, for the Therapy of Non-Hodgkin’s Lymphoma
Authors: Rhona Stein, Zhengxing Qu, Susan Chen, Adriane Rosario, Victoria Shi, Marianne Hayes, Ivan D. Horak, Hans J. Hansen, David M. Goldenberg
Journal: Clinical Cancer Research (2004)

Abstract Purpose: A new humanized anti-CD20 monoclonal antibody (MAb), IMMU-106, was evaluated to elucidate its action as an antilymphoma therapeutic, as a single agent, and in combination with the anti-CD22 MAb, epratuzumab. Experimental Design: Antiproliferative effects, apoptotic effects, and the ability of IMMU-106 to mediate complement-mediated cytotoxicity and antibody-dependent cellular cytotoxicity on a panel of non-Hodgkin’s lymphoma (NHL) cell lines were compared with the chimeric anti-CD20 MAb, rituximab, and evaluated in light of the various levels of antigen expression by the cell lines. In vivo therapy studies were performed in SCID mice bearing disseminated Raji lymphoma. Results: The mechanisms of cytotoxicity of IMMU-106 were found to be similar to rituximab, and include direct apoptosis, antibody-dependent cellular cytotoxicity, and complement-mediated cytotoxicity. IMMU-106 was also found to be very similar to rituximab in terms of antigen-binding specificity, binding avidity, and dissociation constant. Treatment of Raji-bearing SCID mice with IMMU-106 yielded median survival increases of up to 4.2-fold compared with control mice. Survival in mice treated with IMMU-106 plus epratuzumab was compared with IMMU-106 treatment alone. Although the combined treatment did not improve median survival, an increased proportion of long-term survivors was observed. An enhanced antiproliferative effect was also observed in vitro in SU-DHL-6 cells when IMMU-106 was combined with epratuzumab. These findings are consistent with the up-regulation of CD22 expression observed after pretreatment of NHL cells in vitro with CD20 MAb (IMMU-106). Conclusions: It is expected that in humans IMMU-106 should be at least as effective as rituximab and, due to its human framework construction, it may exhibit different pharmacokinetic, toxicity, and therapy profiles. In addition, it may be possible to enhance efficacy by combination therapy comprised of anti-CD20 and other B-cell lineage targeting MAbs, such as epratuzumab. The current results emphasize that in vitro as well as in vivo studies with many of the NHL cell lines were generally predictive of the known activity of anti-CD20 MAbs in NHL patients, as well as the enhanced efficacy of epratuzumab combined with rituximab observed in early clinical trials.
Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas
Authors: Guro E Lind, Stine A Danielsen, Terje Ahlquist, Marianne A Merok, Kim Andresen, Rolf I Skotheim, Merete Hektoen, Torleiv O Rognum, Gunn I Meling, Geir Hoff, Michael Bretthauer, Espen Thiis-Evensen, Arild Nesbakken, Ragnhild A Lothe
Journal: Molecular Cancer (2011)

Abstract Background The presence of cancer-specific DNA methylation patterns in epithelial colorectal cells in human feces provides the prospect of a simple, non-invasive screening test for colorectal cancer and its precursor, the adenoma. This study investigates a panel of epigenetic markers for the detection of colorectal cancer and adenomas. Methods Candidate biomarkers were subjected to quantitative methylation analysis in test sets of tissue samples from colorectal cancers, adenomas, and normal colonic mucosa. All findings were verified in independent clinical validation series. A total of 523 human samples were included in the study. Receiver operating characteristic (ROC) curve analysis was used to evaluate the performance of the biomarker panel. Results Promoter hypermethylation of the genes CNRIP1, FBN1, INA, MAL, SNCA , and SPG20 was frequent in both colorectal cancers (65-94%) and adenomas (35-91%), whereas normal mucosa samples were rarely (0-5%) methylated. The combined sensitivity of at least two positives among the six markers was 94% for colorectal cancers and 93% for adenoma samples, with a specificity of 98%. The resulting areas under the ROC curve were 0.984 for cancers and 0.968 for adenomas versus normal mucosa. Conclusions The novel epigenetic marker panel shows very high sensitivity and specificity for both colorectal cancers and adenomas. Our findings suggest this biomarker panel to be highly suitable for early tumor detection.
Long-term Follow-up of Patients with Malignant Pleural Mesothelioma Receiving High-Dose Adenovirus Herpes Simplex Thymidine Kinase/Ganciclovir Suicide Gene Therapy
Authors: Daniel H. Sterman, Adriana Recio, Anil Vachani, Jing Sun, Lumei Cheung, Peter DeLong, Kunjlata M. Amin, Leslie A. Litzky, James M. Wilson, Larry R. Kaiser, Steven M. Albelda
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Delineation of the long-term follow-up data on a series of patients with malignant mesothelioma, who received a single intrapleural dose of a nonreplicative adenoviral (Ad) vector encoding the herpes simplex virus thymidine kinase “suicide gene” (Ad.HSVtk) in combination with systemic ganciclovir. Experimental Design: This report focuses on the 21 patients receiving “high-dose” therapy, defined by an intrapleural dose of vector (≥1.6 × 1013 viral particles), where transgene-encoded tk protein was reliably identified on immunohistochemical staining. In 13 patients, the vector was deleted in the E1 and E3 regions of the Ad; in the other eight patients, the vector had deletions in the Ad genes E1 and E4. Safety, immunologic responses, transgene expression, and clinical responses were evaluated. Results: Both the E1/E3-deleted vector and the E1/E4-deleted vector were well tolerated and safe, although production of the E1/E4 vector was more difficult. Posttreatment antibody responses against the tumors were consistently seen. Interestingly, we observed a number of clinical responses in our patients, including two long-term (&amp;gt;6.5 year) survivors, both of whom were treated with the E1/E4-deleted vector. Conclusions: Intrapleural Ad.HSVtk/ganciclovir is safe and well tolerated in mesothelioma patients and resulted in long-term durable responses in two patients. Given the limited amount of gene transfer observed, we postulate that Ad.HSVtk may have been effective due to induction of antitumor immune responses. We hypothesize that approaches aiming to augment the immune effects of Ad gene transfer (i.e., with the use of cytokines) may lead to increased numbers of therapeutic responses in otherwise untreatable pleural malignancies.
First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors
Authors: Alexander N. Starodub, Allyson J. Ocean, Manish A. Shah, Michael J. Guarino, Vincent J. Picozzi, Linda T. Vahdat, Sajeve S. Thomas, Serengulam V. Govindan, Pius P. Maliakal, William A. Wegener, Steven A. Hamburger, Robert M. Sharkey, David M. Goldenberg
Journal: Clinical Cancer Research (2015)

Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate (ADC) targeting Trop-2, a surface glycoprotein expressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. This phase I trial evaluated this ADC as a potential therapeutic for pretreated patients with a variety of metastatic solid cancers.Sacituzumab govitecan was administered on days 1 and 8 of 21-day cycles, with cycles repeated until dose-limiting toxicity or progression. Dose escalation followed a standard 3 + 3 scheme with 4 planned dose levels and dose delay or reduction allowed.Twenty-five patients (52-60 years old, 3 median prior chemotherapy regimens) were treated at dose levels of 8 (n = 7), 10 (n = 6), 12 (n = 9), and 18 (n = 3) mg/kg. Neutropenia was dose limiting, with 12 mg/kg the maximum tolerated dose for cycle 1, but too toxic with repeated cycles. Lower doses were acceptable for extended treatment with no treatment-related grade 4 toxicities and grade 3 toxicities limited to fatigue (n = 3), neutropenia (n = 2), diarrhea (n = 1), and leukopenia (n = 1). Using CT-based RECIST 1.1, two patients achieved partial responses (triple-negative breast cancer, colon cancer) and 16 others had stable disease as best response. Twelve patients maintained disease control with continued treatment for 16 to 36 weeks; 6 survived 15 to 20+ months. No preselection of patients based on tumor Trop-2 expression was done.Sacituzumab govitecan had acceptable toxicity and encouraging therapeutic activity in patients with difficult-to-treat cancers. The 8 and 10 mg/kg doses were selected for phase II studies.
Targeting the Wnt Pathway in Synovial Sarcoma Models
Authors: Whitney Barham, Andrea L. Frump, Taylor P. Sherrill, Christina B. Garcia, Kenyi Saito-Diaz, Michael N. VanSaun, Barbara Fingleton, Linda Gleaves, Darren Orton, Mario R. Capecchi, Timothy S. Blackwell, Ethan Lee, Fiona Yull, Josiane E. Eid
Journal: Cancer Discovery (2013)

Synovial sarcoma is an aggressive soft-tissue malignancy of children and young adults, with no effective systemic therapies. Its specific oncogene, SYT-SSX (SS18-SSX), drives sarcoma initiation and development. The exact mechanism of SYT-SSX oncogenic function remains unknown. In an SYT-SSX2 transgenic model, we show that a constitutive Wnt/β-catenin signal is aberrantly activated by SYT-SSX2, and inhibition of Wnt signaling through the genetic loss of β-catenin blocks synovial sarcoma tumor formation. In a combination of cell-based and synovial sarcoma tumor xenograft models, we show that inhibition of the Wnt cascade through coreceptor blockade and the use of small-molecule CK1α activators arrests synovial sarcoma tumor growth. We find that upregulation of the Wnt/β-catenin cascade by SYT-SSX2 correlates with its nuclear reprogramming function. These studies reveal the central role of Wnt/β-catenin signaling in SYT-SSX2-induced sarcoma genesis, and open new venues for the development of effective synovial sarcoma curative agents.Synovial sarcoma is an aggressive soft-tissue cancer that afflicts children and young adults, and for which there is no effective treatment. The current studies provide critical insight into our understanding of the pathogenesis of SYT–SSX-dependent synovial sarcoma and pave the way for the development of effective therapeutic agents for the treatment of the disease in humans.
First pass uptake of 14C-propranolol by the lung.
Authors: D M Geddes, K Nesbitt, T Traill, J P Blackburn
Journal: Thorax (1979)

Uptake of 14C-propranolol by the lungs during a single passage through the pulmonary circulation was measured in ten patients at cardiac catheterisation. Mean lung uptake of propranolol was 75% in seven patients who were not previously taking the drug and 33% in three patients who were taking it as regular oral treatment. Lung uptake of propranolol in man is therefore considerable and is partly saturable by normal oral doses. This may alter the dose response relation for propranolol and a wide range of other drugs when given intravenously. The method used to study lung uptake is simple and might be suitable for studies of endothelial cell function in disease.
Flow in branching vessels
Authors: R. BRECH, B. J. BELLHOUSE
Journal: Cardiovascular Research (1973)

Journal Article Flow in branching vessels Get access R. BRECH, R. BRECH From the Department of Engineering Science, Oxford University Search for other works by this author on: Oxford Academic PubMed Google Scholar B. J. BELLHOUSE B. J. BELLHOUSE From the Department of Engineering Science, Oxford University Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 7, Issue 5, September 1973, Pages 593–600, https://doi.org/10.1093/cvr/7.5.593 Published: 01 September 1973
Effects of six weeks of detraining on retention of functional fitness of old people after nine weeks of multicomponent training
Authors: N F Toraman, N Ayceman
Journal: British Journal of Sports Medicine (2005)

Objectives: To examine the effects of age on functional fitness after six weeks of detraining. Methods: Elderly subjects, aged 60–86 years, completed a nine week multicomponent exercise training programme. They performed the senior fitness test every two weeks during the six week detraining period, and the responses of 12 young-old subjects (YO, aged 60–73 years) and nine older subjects (O, aged 74–86 years) were compared. Results: Functional fitness improved during the exercise training period. Performances in the chair stand and six minute walk for the O group had significantly declined compared with post-training values after two weeks of detraining (p&lt;0.01), whereas there were no significant changes in the YO group. Scores on the functional fitness tests declined further between two and four weeks of detraining in both of the groups (p&lt;0.01). In the YO group, there were significant losses in performance on the chair stand, chair sit and reach, and six minute walk tests, and in the O group on the chair stand and up and go tests after six weeks of detraining compared with after four weeks of detraining (p&lt;0.01). The components of functional fitness most affected by detraining were lower extremity flexibility after two and four weeks of detraining, and agility/dynamic balance after six weeks of detraining. Conclusion: Changes in lower extremity flexibility, up and go, and six minute walk performances in response to six weeks of detraining are affected by age in elderly adults.
Stimulation of mono-ADP ribosylation in rat liver plasma membranes after long-term alcohol intake
Authors: Fumio Nomura, Masatoshi Noda
Journal: Hepatology (1993)

ADP ribosylation is considered one of the important covalent modifications of cellular proteins catalyzed by ADP ribosyltransferase, which transfers ADP ribose moiety of NAD to an acceptor protein. Because a growing body of evidence has suggested significant biological roles for mono-ADP ribosylations in transmembrane signal transduction and other cell metabolism, how alcohol intake alters them is of interest. Cholera toxin and pertussis toxin have been widely used as probes to investigate the roles of GTP-binding proteins (G-proteins) in the transduction of hormonal and sensory signals. We first tested effects of long-term alcohol intake on these toxin-catalyzed ADP ribosylations of G-proteins in rat liver plasma membranes. Treatment of rat liver plasma membrane with [32P]NAD and thiol-preactivated cholera toxin resulted in the labeling of a 44-kD band, most likely an alpha-subunit of the stimulatory GTP-binding protein, the extent of which was much greater in alcohol-fed rats than in pair-fed controls. Analogous experiments with pertussis toxin also demonstrated enhancement of toxin-catalyzed ADP ribosylation of the inhibitory GTP-binding protein after long-term alcohol intake. More interesting was that long-term alcohol intake remarkably stimulated endogenous mono-ADP ribosylation of a 58-kD protein in a GTP-dependent manner. In vitro, ethanol (50 mmol/L) or a single load of ethanol (3 gm/kg) did not stimulate the reaction. Thus long-term alcohol intake stimulated both toxin-catalyzed and endogenous mono-ADP ribosylations of proteins in rat liver plasma membranes. Pursuit of alcohol interaction with mono-ADP ribosylation may provide an interesting approach to the study of alcohol's effects on the liver.
Improvement in Survival and Cardiac Metabolism After Gene Transfer of Sarcoplasmic Reticulum Ca <sup>2+</sup> -ATPase in a Rat Model of Heart Failure
Authors: Federica del Monte, Eric Williams, Djemal Lebeche, Ulrich Schmidt, Anthony Rosenzweig, Judith K. Gwathmey, E. Douglas Lewandowski, Roger J. Hajjar
Journal: Circulation (2001)

Background — In heart failure, sarcoplasmic reticulum (SR) Ca 2+ -ATPase (SERCA2a) activity is decreased, resulting in abnormal calcium handling and contractile dysfunction. We have previously shown that increasing SERCA2a expression by gene transfer improves ventricular function in a rat model of heart failure created by ascending aortic constriction. Methods and Results — In this study, we tested the effects of gene transfer of SERCA2a on survival, left ventricular (LV) volumes, and metabolism. By 26 to 27 weeks after aortic banding, all animals developed heart failure (as documented by &gt;25% decrease in fractional shortening) and were randomized to receive either an adenovirus carrying the SERCA2a gene (Ad.SERCA2a) or control virus (Ad.βgal-GFP) by use of a catheter-based technique. Sham-operated rats, uninfected or infected with either Ad.βgal-GFP or Ad.SERCA2a, served as controls. Four weeks after gene transfer, survival in rats with heart failure treated with Ad.βgal-GFP was 9%, compared with 63% in rats receiving Ad.SERCA2a. LV volumes were significantly increased in heart failure (0.64±0.05 versus 0.35±0.03 mL, P &lt;0.02). Overexpression of SERCA2a normalized LV volumes (0.46±0.07 mL) in the failing hearts. 31 P NMR analysis showed a reduced ratio of phosphocreatine to ATP content in failing+Ad.βgal-GFP compared with sham+Ad.βgal-GFP (0.82±0.13 versus 1.38±0.14, P &lt;0.01). Overexpression of SERCA2a in failing hearts improved the phosphocreatine/ATP ratio (1.23±0.28). Conclusions — In this study, we show that unlike inotropic agents that improve contractile function at the expense of increased mortality and worsening metabolism, gene transfer of SERCA2a improves survival and the energy potential in failing hearts.
Psoriasis, psoriatic arthritis and increased risk of incident Crohn's disease in US women
Authors: Wen-Qing Li, Jia-Li Han, Andrew T Chan, Abrar A Qureshi
Journal: Annals of the Rheumatic Diseases (2012)

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), shares clinical and immunological features with psoriasis. Genome-wide association studies have found common susceptibility genes. However, epidemiologic data evaluating the association between psoriasis, psoriatic arthritis and risk of IBD are sparse. We aimed to evaluate the association between psoriasis, psoriatic arthritis and incident CD and UC among women in the USA.174 476 women were enrolled in the Nurses' Health Study (NHS) (1996-2008) and NHS II (1991-2007). Lifetime history of physician-diagnosed psoriasis and psoriatic arthritis was confirmed by supplementary questionnaires. Information on CD and UC was obtained by self-reported questionnaires and confirmed by medical record review.We documented 188 incident cases of CD and 240 incident cases of UC during follow-up. Psoriasis was associated with a significantly increased risk of subsequent CD with a multivariate-adjusted relative risk (RR) of 4.00 (95% CI 1.72 to 9.27) for NHS and 3.76 (1.82 to 7.74) for NHS II. By contrast, we did not observe a significant increase in risk of UC associated with psoriasis. In a pooled analysis of both cohorts, women with psoriasis experienced a significantly increased risk of CD (RR, 3.86, 95% CI 2.23 to 6.67), but not UC (RR, 1.17, 95% CI 0.41 to 3.36). The risk of CD was especially pronounced among psoriatics with concomitant psoriatic arthritis (RR, 6.43, 95% CI 2.04 to 20.32).Psoriasis with concomitant psoriatic arthritis is associated with an increased risk of incident CD.
Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement
Authors: Agustín Albillos, Antonio de la Hera, Mónica González, Jose-Luis Moya, Jose-Luis Calleja, Jorge Monserrat, Luis Ruiz-del-Arbol, Melchor Alvarez-Mon
Journal: Hepatology (2003)

Intestinal bacterial overgrowth and translocation, both common in cirrhosis with ascites, may lead to the activation of monocytes and lymphocytes, increased levels of proinflammatory cytokines, and enhanced synthesis of nitric oxide present in cirrhosis. Bacterial endotoxin promotes the synthesis of lipopolysaccharide (LPS)-binding protein (LBP), and forms a LPS-LBP complex that binds to CD14. This study was designed to evaluate LBP levels and their correlation to the immune response and the hemodynamic status in cirrhotic patients. Plasma LBP, endotoxin, soluble CD14 (sCD14), cytokines, renin, nitrites, and systemic vascular resistance were determined before and 4 weeks after norfloxacin or placebo in 102 cirrhotic patients and 30 controls. LBP was elevated in 42% of ascitic cirrhotic patients (15.7 +/- 0.7 versus 6.06 +/- 0.5 microg/mL, P <.01). In 60% of high LBP patients, endotoxin was within normal range. Among ascitic patients, those with high LBP showed greater (P <.05) levels of sCD14, tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), nitrites + nitrates (NOx)/creatinine, and renin, and lower vascular resistance. In the cirrhotic patients with high LBP, norfloxacin normalized (P <.01) LBP (from 16.6 +/- 0.5 to 5.82 +/- 0.8 microg/mL) and sCD14; reduced the level of cytokines, NOx/creatinine, and renin; and increased vascular resistance; but lacked effect in patients with normal LBP. Portal pressure was unchanged after norfloxacin in another group of 18 cirrhotic patients with high and 19 with normal LBP. In conclusion, the subset of ascitic cirrhotic patients with marked immune and hemodynamic derangement is identified by increased LBP levels. Amelioration of these abnormalities by norfloxacin suggests the involvement of enteric bacteria or their products in the triggering of the process.