tbuckley/cabot-search huggingface dataset:
New therapies for inflammatory bowel disease: from the bench to the bedside
Authors: Silvio Danese
Journal: Gut (2011)

The mechanisms underlying the chronic intestinal inflammation that is a hallmark of inflammatory bowel diseases (IBD) are complex. Components of the pathological response include the adaptive and innate immune systems, as well as the intestinal epithelium and endothelium. Advances in the understanding of the roles of each of these components have resulted in the development of multiple biological agents that all represent an alternative to the use of current therapies in patients with refractory Crohn's disease or ulcerative colitis. This study systematically reviews the mechanisms of action, efficacy and safety of new and emerging therapies that are currently in clinical trials and discusses future directions in the treatment of IBD.
Users' Guides to the Medical Literature
Authors: Mitchell Levine
Journal: JAMA (1994)

<h3>CLINICAL SCENARIO</h3> You are having lunch in the hospital cafeteria when one of your colleagues raises the issue of the safety of β-adrenergic agonists in the treatment of asthma. Your colleague feels uncertain about how to respond to patients asking him about media reports of an increased risk of death associated with these medications. Another colleague mentions a key article on this topic that generated much of the publicity, but she cannot recall the details. You all agree that this is an issue that arises frequently enough in your practices that you should become familiar with the evidence contained in the article that your patients have heard about. You volunteer to search the literature for the key article and report back to your colleagues in the next few days. <h3>THE SEARCH</h3> The next day you do a MEDLINE search using the following terms: asthma (MH) (MH stands for MeSH heading,
Urologist Density and County-Level Urologic Cancer Mortality
Authors: Anobel Y. Odisho, Matthew R. Cooperberg, Vincent Fradet, Ardalan E. Ahmad, Peter R. Carroll
Journal: Journal of Clinical Oncology (2010)

The surgical work force distribution at the county level varies widely across the United States, and the impact of differential access on cancer outcomes is unclear. We used urologists as a test case because they are the first care providers for urologic cancers, can easily be identified from available data sources, and are unevenly distributed throughout the country. The goal of this study was to determine the effect of increasing urologist density on local prostate, bladder, and kidney cancer mortality.Using county-level data from the Area Resource File, US Census, National Cancer Institute, and Centers for Disease Control, regression models were built for prostate, bladder, and kidney cancer mortality, controlling for categorized urologist density, county demographics, socioeconomic factors, and preexisting health care infrastructure.For each of the three cancers, there was a statistically significant cancer-specific mortality reduction associated with counties that had more than zero urologists (16% to 22% reduction for prostate cancer, 17% to 20% reduction for bladder cancer, and 8% to 14% reduction for kidney cancer with increasing urologist density) relative to zero urologists. However, increasing density greater than two urologists per 100,000 people had no statistically significant impact on mortality for any of the tumors studied.The presence of a urologist is associated with lower mortality for urologic cancers in that county, but increasing urologist density does not yield further improvements. Therefore, a nuanced and geographically aware policy toward the size and distribution of the future work force is most likely to provide the greatest population-level improvement in cancer mortality outcomes.
Exon creation and establishment in human genes
Authors: André Corvelo, Eduardo Eyras
Journal: Genome biology (2008)

Abstract Background A large proportion of species-specific exons are alternatively spliced. In primates, Alu elements play a crucial role in the process of exon creation but many new exons have appeared through other mechanisms. Despite many recent studies, it is still unclear which are the splicing regulatory requirements for de novo exonization and how splicing regulation changes throughout an exon's lifespan. Results Using comparative genomics, we have defined sets of exons with different evolutionary ages. Younger exons have weaker splice-sites and lower absolute values for the relative abundance of putative splicing regulators between exonic and adjacent intronic regions, indicating a less consolidated splicing regulation. This relative abundance is shown to increase with exon age, leading to higher exon inclusion. We show that this local difference in the density of regulators might be of biological significance, as it outperforms other measures in real exon versus pseudo-exon classification. We apply this new measure to the specific case of the exonization of anti-sense Alu elements and show that they are characterized by a general lack of exonic splicing silencers. Conclusions Our results suggest that specific sequence environments are required for exonization and that these can change with time. We propose a model of exon creation and establishment in human genes, in which splicing decisions depend on the relative local abundance of regulatory motifs. Using this model, we provide further explanation as to why Alu elements serve as a major substrate for exon creation in primates. Finally, we discuss the benefits of integrating such information in gene prediction.
Type I interferons produced by hematopoietic cells protect mice against lethal infection by mammalian reovirus
Authors: Cecilia Johansson, J. Denise Wetzel, JianPing He, Carmen Mikacenic, Terence S. Dermody, Brian L. Kelsall
Journal: The Journal of Experimental Medicine (2007)

We defined the function of type I interferons (IFNs) in defense against reovirus strain type 1 Lang (T1L), which is a double-stranded RNA virus that infects Peyer's patches (PPs) after peroral inoculation of mice. T1L induced expression of mRNA for IFN-α, IFN-β, and Mx-1 in PPs and caused localized intestinal infection that was cleared in 10 d. In contrast, T1L produced fatal systemic infection in IFNαR1 knockout (KO) mice with extensive cell loss in lymphoid tissues and necrosis of the intestinal mucosa. Studies of bone-marrow chimeric mice indicated an essential role for hematopoietic cells in IFN-dependent viral clearance. Dendritic cells (DCs), including conventional DCs (cDCs), were the major source of type I IFNs in PPs of reovirus-infected mice, whereas all cell types expressed the antiviral protein Mx-1. Neither NK cells nor signaling via Toll-like receptor 3 or MyD88 were essential for viral clearance. These data demonstrate a requirement for type I IFNs in the control of an intestinal viral infection and indicate that cDCs are a significant source of type I IFN production in vivo. Therefore, innate immunity in PPs is an essential component of host defense that limits systemic spread of pathogens that infect the intestinal mucosa.
Accelerated resolution of laser-induced bruising with topical 20% arnica: a rater-blinded randomized controlled trial
Authors: S. Leu, J. Havey, L.E. White, N. Martin, S.S. Yoo, A.W. Rademaker, M. Alam
Journal: British Journal of Dermatology (2010)

Background Dermatological procedures can result in disfiguring bruises that resolve slowly. Objectives To assess the comparative utility of topical formulations in hastening the resolution of skin bruising. Methods Healthy volunteers, age range 21–65 years, were enrolled for this double (patient and rater) blinded randomized controlled trial. For each subject, four standard bruises of 7 mm diameter each were created on the bilateral upper inner arms, 5 cm apart, two per arm, using a 595-nm pulsed-dye laser (Vbeam; Candela Corp., Wayland, MA, U.S.A.). Randomization was used to assign one topical agent (5% vitamin K, 1% vitamin K and 0·3% retinol, 20% arnica, or white petrolatum) to exactly one bruise per subject, which was then treated under occlusion twice a day for 2 weeks. A dermatologist not involved with subject assignment rated bruises [visual analogue scale, 0 (least)–10 (most)] in standardized photographs immediately after bruise creation and at week 2. Results There was significant difference in the change in the rater bruising score associated with the four treatments (anova, P = 0·016). Pairwise comparisons indicated that the mean improvement associated with 20% arnica was greater than with white petrolatum (P = 0·003), and the improvement with arnica was greater than with the mixture of 1% vitamin K and 0·3% retinol (P = 0·01). Improvement with arnica was not greater than with 5% vitamin K cream, however. Conclusions Topical 20% arnica ointment may be able to reduce bruising more effectively than placebo and more effectively than low-concentration vitamin K formulations, such as 1% vitamin K with 0·3% retinol.
Fully Human Monoclonal Antibodies to Hepatocyte Growth Factor with Therapeutic Potential against Hepatocyte Growth Factor/c-Met–Dependent Human Tumors
Authors: Teresa Burgess, Angela Coxon, Susanne Meyer, Jan Sun, Karen Rex, Trace Tsuruda, Qing Chen, Shu-Yin Ho, Luke Li, Stephen Kaufman, Kevin McDorman, Russell C. Cattley, Jilin Sun, Gary Elliott, Ke Zhang, Xiao Feng, Xiao-Chi Jia, Larry Green, Robert Radinsky, Richard Kendall
Journal: Cancer Research (2006)

Abstract c-Met is a well-characterized receptor tyrosine kinase for hepatocyte growth factor (HGF). Compelling evidence from studies in human tumors and both cellular and animal tumor models indicates that signaling through the HGF/c-Met pathway mediates a plethora of normal cellular activities, including proliferation, survival, migration, and invasion, that are at the root of cancer cell dysregulation, tumorigenesis, and tumor metastasis. Inhibiting HGF-mediated signaling may provide a novel therapeutic approach for treating patients with a broad spectrum of human tumors. Toward this goal, we generated and characterized five different fully human monoclonal antibodies that bound to and neutralized human HGF. Antibodies with subnanomolar affinities for HGF blocked binding of human HGF to c-Met and inhibited HGF-mediated c-Met phosphorylation, cell proliferation, survival, and invasion. Using a series of human-mouse chimeric HGF proteins, we showed that the neutralizing antibodies bind to a unique epitope in the β-chain of human HGF. Importantly, these antibodies inhibited HGF-dependent autocrine-driven tumor growth and caused significant regression of established U-87 MG tumor xenografts. Treatment with anti-HGF antibody rapidly inhibited tumor cell proliferation and significantly increased the proportion of apoptotic U-87 MG tumor cells in vivo. These results suggest that an antibody to an epitope in the β-chain of HGF has potential as a novel therapeutic agent for treating patients with HGF-dependent tumors. (Cancer Res 2006; 66(3): 1721-9)
Immunoglobulin switch transcript production in vivo related to the site and time of antigen-specific B cell activation.
Authors: K M Toellner, A Gulbranson-Judge, D R Taylor, D M Sze, I C MacLennan
Journal: The Journal of Experimental Medicine (1996)

Immunoglobulin (Ig) class switch recombination is associated with the production and splicing of germline IgCH messenger RNA transcripts. Levels of gamma 1 transcripts in mouse spleen sections were assessed by semiquantitative analysis of reverse transcriptase polymerase chain reaction (PCR) products during primary and secondary antibody responses to chicken gamma globulin (CGG). This was correlated with the appearance of CGG-specific B cells and their growth and differentiation to plasma cells. After primary immunization with CGG, gamma 1 switch transcripts appeared after 4 d, peaked at a median of six times starting levels between 10 and 18 d after immunization, and returned to background levels before secondary immunization at 5 wk. By contrast, after secondary challenge with CGG, a sevenfold increase in transcripts occurs during the first d. The level again doubles by day 3, when it is six times that which is seen at the peak of the primary response. After day 4, there was a gradual decline over the next 2-3 wk. Within 12 h of secondary immunization, antigen-specific memory B cells appeared in the outer I zone and by 24 h entered S phase, presumably as a result of cognate interaction with primed T cells. Over the next few hours, they migrated to the edge of the red pulp, where they grew exponentially until the fourth day, when they synchronously differentiated to become plasma cells. The same pattern was seen for the migration, growth, and differentiation of virgin hapten-specific B cells when CGG-primed mice were challenged with hapten protein. The continued production of transcripts after day 3 indicates that switching also occurs in germinal centers, but in a relatively small proportion of their B cells. The impressive early production of switch transcripts during T cell-dependent antibody responses occurs in cells that are about to undergo massive clonal expansion. It is argued that Ig class switching at this time, which is associated with cognate T cell-B cell interaction in the T zone, has a major impact on the class and subclasses of Ig produced during the response.
NEW CONCEPTS IN THE MANAGEMENT OF MYCOSIS FUNGOIDES
Authors: Zvi Fuks, Malcolm A. Bagshaw, Eugene M. Farber
Journal: British Journal of Dermatology (1974)

Journal Article NEW CONCEPTS IN THE MANAGEMENT OF MYCOSIS FUNGOIDES Get access Zvi Fuks, Zvi Fuks Stanford University School of Medicine, California, U.S.A Search for other works by this author on: Oxford Academic Google Scholar Malcolm A. Bagshaw, Malcolm A. Bagshaw Stanford University School of Medicine, California, U.S.A Search for other works by this author on: Oxford Academic Google Scholar Eugene M. Farber Eugene M. Farber Stanford University School of Medicine, California, U.S.A Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 90, Issue 3, 1 March 1974, Pages 355–356, https://doi.org/10.1111/j.1365-2133.1974.tb06415.x Published: 01 March 1974
Outcome Prediction for Estrogen Receptor-Positive Breast Cancer Based on Postneoadjuvant Endocrine Therapy Tumor Characteristics
Authors: M. J. Ellis, Y. Tao, J. Luo, R. A'Hern, D. B. Evans, A. S. Bhatnagar, H. A. Chaudri Ross, A. von Kameke, W. R. Miller, I. Smith, W. Eiermann, M. Dowsett
Journal: JNCI Journal of the National Cancer Institute (2008)

Understanding how tumor response is related to relapse risk would help clinicians make decisions about additional treatment options for patients who have received neoadjuvant endocrine treatment for estrogen receptor–positive (ER+) breast cancer. Tumors from 228 postmenopausal women with confirmed ER+ stage 2 and 3 breast cancers in the P024 neoadjuvant endocrine therapy trial, which compared letrozole and tamoxifen for 4 months before surgery, were analyzed for posttreatment ER status, Ki67 proliferation index, histological grade, pathological tumor size, node status, and treatment response. Cox proportional hazards were used to identify factors associated with relapse-free survival (RFS) and breast cancer–specific survival (BCSS) in 158 women. A preoperative endocrine prognostic index (PEPI) for RFS was developed from these data and validated in an independent study of 203 postmenopausal women in the IMPACT trial, which compared treatment with anastrozole, tamoxifen, or the combination 3 months before surgery. Statistical tests were two-sided. Median follow-up in P024 was 61.2 months. Patients with confirmed baseline ER+ clinical stage 2 and 3 tumors that were downstaged to stage 1 or 0 at surgery had 100% RFS (compared with higher stages, P < .001). Multivariable testing of posttreatment tumor characteristics revealed that pathological tumor size, node status, Ki67 level, and ER status were independently associated with both RFS and BCSS. The PEPI model based on these factors predicted RFS in the IMPACT trial ( P = .002). Breast cancer patients with pathological stage 1 or 0 disease after neoadjuvant endocrine therapy and a low-risk biomarker profile in the surgical specimen (PEPI score 0) have an extremely low risk of relapse and are therefore unlikely to benefit from adjuvant chemotherapy.
Screening for pulmonary arteriovenous malformations using transthoracic contrast echocardiography: a prospective study
Authors: M. W. F. van Gent, M. C. Post, J. G. L. M. Luermans, R. J. Snijder, C. J. J. Westermann, H. W. M. Plokker, T. T. Overtoom, J. J. Mager
Journal: European Respiratory Journal (2008)

Pulmonary arteriovenous malformations (PAVMs) are associated with severe neurological complications in patients with hereditary haemorrhagic telangiectasia (HHT). The objective of the present study was to prospectively establish the diagnostic value of transthoracic contrast echocardiography (TTCE) as a screening technique for PAVM using chest high-resolution computed tomography (HRCT) as the gold standard for PAVMs. All consecutive adult patients referred for HHT screening underwent a chest HRCT (n = 299), TTCE (n = 281), arterial blood gas analysis (n = 291), shunt fraction measurement (n = 111) and chest radiography (n = 296). TTCE was positive in 87 (58.8%), 12 (16.7%) and four (6.7%) patients, and chest HRCT was positive in 54 (36.5%), three (4.2%) and zero (0%) patients with a definite, possible and negative clinical diagnosis of HHT, respectively. Two patients with a negative TTCE were diagnosed with PAVMs after computed tomography; in both cases the PAVMs were too small to be treated by embolotherapy. The sensitivity of TTCE was 97% (95% confidence interval (CI) 93.6–98.3) and negative predictive value 99% (95% CI 96.9–99.8). The other diagnostic tests showed a considerable lower diagnostic value. The present prospective study shows that transthoracic contrast echocardiography has an excellent diagnostic value and can be used as an initial screening procedure for pulmonary arteriovenous malformations. The high false-positive rate of transthoracic contrast echocardiography possibly represents microscopic pulmonary arteriovenous malformations.
Tumor suppression after tumor cell-targeted tumor necrosis factor alpha gene transfer.
Authors: T Blankenstein, Z H Qin, K Uberla, W Müller, H Rosen, H D Volk, T Diamantstein
Journal: The Journal of Experimental Medicine (1991)

The tumor necrosis factor alpha (TNF-alpha) gene was introduced by retroviral gene transfer into the TNF-alpha-insensitive tumor cell line J558L. Production of 40 pg/ml TNF-alpha by clone J2T12 consistently did not change the growth rate in vitro, but drastically suppressed tumor growth when injected into syngeneic BALB/c mice. Within 2 wk, 90% of the mice inoculated with J558L cells developed a tumor, but none of the mice injected with J2T12 did so. Within the observation period (greater than 3 mo), 60% of the mice inoculated with J2T12 did not develop a tumor. In the other 40% of the mice, tumor manifestation was significantly delayed. Mice injected simultaneously with J2T12 cells and an anti-TNF-alpha monoclonal antibody developed tumors similar to parental J558L cells. Similarly, the tumor-suppressive effects of TNF-alpha were abolished, e.g., by injection of an anti-type 3 complement receptor (CR3) monoclonal antibody that is known to prevent migration of inflammatory cells. These results and the observation of tumor-infiltrating macrophages suggest that lack of tumorigenicity of J2T12 cells is due to the TNF-alpha secretion by the tumor cells and that TNF-alpha acts indirectly by a mechanism that involves chemotactic recruitment and activation of cells, predominantly of macrophages. In contrast, the tumor growth was not affected when, instead of TNF-alpha, interleukin 6 was expressed by J558L cells. Together, our results support the concept of tumor cell-targeted cytokine gene transfer as a tool for cancer treatment, and particularly demonstrate that extremely low doses of TNF-alpha produced by tumor cells are sufficient to inhibit tumor growth without detectable side effects.
A Double-Blind Placebo-Controlled Trial Evaluating the Safety and Efficacy of Acarbose for the Treatment of Patients With Insulin-Requiring Type II Diabetes
Authors: Robert F Coniff, Jo Ann Shapiro, Timothy B Seaton, Byron J Hoogwerf, John A Hunt
Journal: Diabetes Care (1995)

OBJECTIVE To determine whether a forced titration of acarbose (from 50 to 300 mg three times daily) administered over a 24-week period, in conjunction with diet and insulin therapy, improves glycemic control and reduces daily insulin requirements in insulin-requiring type II diabetes. RESEARCH DESIGN AND METHODS This multicenter, randomized, double-blind, placebo-controlled trial was 36 weeks in duration. The trial consisted of a 6-week pretreatment period, a 24-week double-blind treatment period, and a 6-week post-treatment follow-up period. The primary efficacy variables were the mean change from baseline in HbA1c levels and the mean percentage change from baseline in total daily insulin dose. RESULTS Treatment with acarbose was associated with significant reductions in HbA1c levels of 0.40% (P = 0.0001) and in total daily insulin dose of 8.3% (P = 0.0015). There were also significant reductions in all plasma glucose variables measured, including a 0.9 mmol/l reduction in fasting glucose (P = 0.0440), a 2.6 mmol/l reduction in glucose Cmax (P = 0.0001) and a 270 mmol·min−1·l−1 reduction in glucose area under the curve (P = 0.0002). Although acarbose treatment was associated with a greater incidence of adverse events than was placebo treatment, primarily flatulence and diarrhea, these events did not generally prevent patients from completing the study. CONCLUSIONS The results of this study suggest that acarbose is a safe and effective adjunct to diet and insulin therapy for the management of insulin-requiring type II diabetes.
Arteriogenesis Proceeds via ICAM-1/Mac-1- Mediated Mechanisms
Authors: Imo E. Hoefer, Niels van Royen, John E. Rectenwald, Elisabeth Deindl, Jing Hua, Marco Jost, Sebastian Grundmann, Michiel Voskuil, C. Keith Ozaki, Jan J. Piek, Ivo R. Buschmann
Journal: Circulation Research (2004)

Monocyte adhesion to shear stress-activated endothelium stands as an important initial step during arteriogenesis (collateral artery growth). Using multiple approaches, we tested the hypothesis that monocyte adhesion via intercellular adhesion molecule-1 (ICAM-1) and selectin interactions is essential for adaptive arteriogenesis. Forty-eight New Zealand White rabbits received either solvent, monocyte chemoattractant protein-1 (MCP-1) alone, MCP-1 plus ICAM-mab, or MCP-1 plus an IgG2a isotype control via osmotic minipumps. After 7 days, collateral conductance was evaluated: solvent 4.01 (mL/min per 100 mm Hg), MCP-1 plus ICAM-mab 8.04 (versus solvent P=NS), and MCP-1 alone 33.11 (versus solvent P<0.05). Furthermore, the right femoral arteries of ICAM-1-/-, Mac-1-/- and mice having defective selectin interactions (FT4/7-/-) as well as their corresponding controls were ligated. One week later, perfusion ratios were determined by the use of fluorescent microspheres. FT4/7-/- mice did not show any significant difference in perfusion restoration whereas ICAM-1-/- and Mac-1-/- mice had a significant reduction in arteriogenesis as compared with matching controls (FT4/7-WT 37+/-9%, FT4/7-/- 32+/-3%, P=0.31; C57BL/6J 59+/-9%, ICAM-1-/- 36+/-8%, P<0.05; Mac-1-/- 42+/-3%, P<0.05). ICAM-1/Mac-1-mediated monocyte adhesion to the endothelium of collateral arteries is an essential step for arteriogenesis, whereas this process can proceed via selectin interaction independent mechanisms. Furthermore, in vivo treatment with monoclonal antibodies against ICAM-1 totally abolishes the stimulatory effect of MCP-1 on collateral artery growth, suggesting that the mechanism of the MCP-1-induced arteriogenesis proceeds via the localization of monocytes rather than the action of the MCP-1 molecule itself.