tbuckley/cabot-search huggingface dataset:
Concurrent Chemotherapy and Intensity-Modulated Radiation Therapy for Anal Canal Cancer Patients: A Multicenter Experience
Authors: Joseph K. Salama, Loren K. Mell, David A. Schomas, Robert C. Miller, Kiran Devisetty, Ashesh B. Jani, Arno J. Mundt, John C. Roeske, Stanley L. Liauw, Steven J. Chmura
Journal: Journal of Clinical Oncology (2007)

To report a multicenter experience treating anal canal cancer patients with concurrent chemotherapy and intensity-modulated radiation therapy (IMRT).From October 2000 to June 2006, 53 patients were treated with concurrent chemotherapy and IMRT for anal squamous cell carcinoma at three tertiary-care academic medical centers. Sixty-two percent were T1-2, and 67% were N0; eight patients were HIV positive. Forty-eight patients received fluorouracil (FU)/mitomycin, one received FU/cisplatin, and four received FU alone. All patients underwent computed tomography-based treatment planning with pelvic regions and inguinal nodes receiving a median of 45 Gy. Primary sites and involved nodes were boosted to a median dose of 51.5 Gy. All acute toxicity was scored according to the Common Terminology Criteria for Adverse Events, version 3.0. All late toxicity was scored using Radiation Therapy Oncology Group criteria.Median follow-up was 14.5 months (range, 5.2 to 102.8 months). Acute grade 3+ toxicity included 15.1% GI and 37.7% dermatologic toxicity; all acute grade 4 toxicities were hematologic; and acute grade 4 leukopenia and neutropenia occurred in 30.2% and 34.0% of patients, respectively. Treatment breaks occurred in 41.5% of patients, lasting a median of 4 days. Forty-nine patients (92.5%) had a complete response, one patient had a partial response, and three had stable disease. All HIV-positive patients achieved a complete response. Eighteen-month colostomy-free survival, overall survival, freedom from local failure, and freedom from distant failure were 83.7%, 93.4%, 83.9%, and 92.9%, respectively.Preliminary outcomes suggest that concurrent chemotherapy and IMRT for anal canal cancers is effective and tolerated favorably compared with historical standards.
Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes.
Authors: P S Linsley, J L Greene, P Tan, J Bradshaw, J A Ledbetter, C Anasetti, N K Damle
Journal: The Journal of Experimental Medicine (1992)

T cell costimulation by molecules on the antigen presenting cell (APC) is required for optimal T cell proliferation. The B7 molecule on APC binds the T lymphocyte receptor CD28, triggering increased interleukin 2 (IL-2) production and subsequent T cell proliferation. CTLA-4 is a predicted T cell membrane receptor homologous to CD28, which also binds the B7 counter receptor, but whose distribution and function are unknown. Here we have developed monoclonal antibodies (mAbs) specific for CTLA-4 and have investigated these questions. mAbs were produced that bound CTLA-4 but not CD28, and that blocked binding of CTLA-4 to B7. CTLA-4 expression as measured by these mAbs was virtually undetectable on resting T cells, but was increased several hundred-fold during T cell activation. On activated lymphocytes, CTLA-4 was expressed equally on CD4+ and CD8+ T cell subsets and was coexpressed with CD25, CD28, and CD45RO. CTLA-4 expression was lower than that of CD28, reaching a maximum of approximately 1/30-50 the level of CD28. Despite its lower expression, CTLA-4 was responsible for much of the B7 binding by large activated T cells. Anti-CTLA-4 mAb 11D4 and anti-CD28 mAb 9.3 acted cooperatively to inhibit T cell adhesion to B7, and to block T cell proliferation in primary mixed lymphocyte culture. When coimmobilized with anti T cell receptor (TCR) mAb, anti-CTLA-4 mAbs were less effective than anti-CD28 mAb 9.3 at costimulating proliferation of resting or activated T cells. However, coimmobilized combinations of anti-CD28 and anti-CTLA-4 were synergistic in their ability to augment anti-TCR-induced proliferation of preactivated CD4+ T cells. These results indicate that CTLA-4 is coexpressed with CD28 on activated T lymphocytes and cooperatively regulates T cell adhesion and activation by B7.
Role of RET and ko=PHOX2B gene polymorphisms in risk of Hirschsprung's disease in Chinese population
Authors: X. Miao, M.-M. Garcia-Barcelo, M.-t. So, T. Y.-Y. Leon, D. K.-c. Lau, T.-T. Liu, E. K.-W. Chan, L. C.-L. Lan, K. K.-y. Wong, V. C.-h. Lui, P. K.-h. Tam
Journal: Gut (2007)

Hirschsprung’s disease (OMIM 142623) is a complex congenital disorder characterised by the absence of ganglion cells of the plexus myentericus and plexus submucosus in the variable lengths of the digestive tract.1,2 Aganglionosis is attributed to a defect of the enteric nervous system, in which ganglion cells fail to innervate the lower gastrointestinal tract during embryonic development, resulting in failure to pass meconium, chronic severe constipation and colonic distention in the neonatal period.3 The receptor tyrosine kinase gene RET , which is expressed in neural crest cells during enteric neurogenesis and is required for normal development of the enteric nervous system, is the major susceptibility gene for Hirschsprung’s disease.4 There is growing evidence indicating that functional single nucleotide polymorphisms (SNPs) of RET could act as low susceptibility factors for Hirschsprung’s disease.5,6 In addition, PHOX2B encodes a transcription …
Use of Intravascular Stents in Systemic Venous and Systemic Venous Baffle Obstructions
Authors: Cameron J.B. Ward, Charles E. Mullins, Michael R. Nihill, Ronald G. Grifka, G. Wesley Vick
Journal: Circulation (1995)

Background Balloon-expandable intravascular stents are well accepted in the management of arterial obstructions. This study was undertaken to detail the immediate and short-term results of intravascular stent implantation in systemic venous and systemic venous baffle obstructions in children. Methods and Results Between September 1991 and June 1994, 12 patients had 21 stents implanted in 13 systemic venous obstructions, 1 patient having stents placed in 2 separate obstructions. In the baffle group, 4 of 13 obstructions were at the superior vena cava/right atrial junction after atrial baffling for transposition of the great arteries. One of 4 patients had complete obstruction requiring transseptal needle perforation before stent implantation. There was an immediate gradient reduction from 12±8.4 mm Hg (range, 4 to 20 mm Hg) to 1.3±1.9 mm Hg (range, 0 to 4 mm Hg, P =.05). The obstructed segment diameter increased from 3.5±3.9 mm (range, 0 to 8.5 mm) to 16±2.7 mm (range, 14 to 20 mm, P =.002). In the central vein group, 9 of 13 obstructions were in large central veins. Three of 9 patients had complete obstruction requiring transseptal needle perforation before stent implantation. There was an immediate gradient reduction from 10.3±8.5 mm Hg (range, 0 to 20 mm Hg) to 0.8±1.1 mm Hg (range, 0 to 3 mm Hg, P =.005). The obstructed segment diameter increased from 1.3±1.1 mm (range, 0 to 2.8 mm) to 9.4±1.7 mm (range, 7.6 to 12 mm, P &lt;.001). There were no acute complications in either group. In the follow-up group, patients were scheduled for clinical follow-up at 3, 6, and 12 months with echocardiography or magnetic resonance imaging (MRI) at 3 or 6 months and for repeat cardiac catheterization at 12 months. All stents were patent by echocardiography or MRI when studied at follow-up. Cardiac catheterization in 6 of 12 patients, 2 to 13 months after stent, demonstrated that all stents remained patent without compression or fracture. Follow-up and immediate poststent gradients were not significantly different (1±1.6 versus 0.7±1.2 mm Hg, P =NS). Neointimal hyperplasia (5 of 6 patients) reduced the stent lumen only from 12.5±4.7 mm (range, 8 to 20 mm) to 10.6±4.7 mm (range, 4.5 to 17.7 mm, P =NS). No stents required redilation. One of 18 stents placed in series had “unlocked” and rotated in the venous lumen but remained fully patent to flow. Conclusions Balloon-expandable intravascular stents can be safely and effectively used to relieve systemic venous and systemic venous baffle obstructions, even when obstruction is complete. Short-term follow-up suggests excellent continued patency, but further follow-up is required to observe for progression of neointimal hyperplasia. We postulate that balloon-expandable intravascular stents will become the treatment of choice for the relief of selected systemic venous and venous baffle obstructions in the pediatric population.
Generic, Simple Risk Stratification Model for Heart Valve Surgery
Authors: Gareth Ambler, Rumana Z. Omar, Patrick Royston, Robin Kinsman, Bruce E. Keogh, Kenneth M. Taylor
Journal: Circulation (2005)

Background— Heart valve surgery has an associated in-hospital mortality rate of 4% to 8%. This study aims to develop a simple risk model to predict the risk of in-hospital mortality for patients undergoing heart valve surgery to provide information to patients and clinicians and to facilitate institutional comparisons. Methods and Results— Data on 32 839 patients were obtained from the Society of Cardiothoracic Surgeons of Great Britain and Ireland on patients who underwent heart valve surgery between April 1995 and March 2003. Data from the first 5 years (n=16 679) were used to develop the model; its performance was evaluated on the remaining data (n=16 160). The risk model presented here is based on the combined data. The overall in-hospital mortality was 6.4%. The risk model included, in order of importance (all P &lt;0.01), operative priority, age, renal failure, operation sequence, ejection fraction, concomitant tricuspid valve surgery, type of valve operation, concomitant CABG surgery, body mass index, preoperative arrhythmias, diabetes, gender, and hypertension. The risk model exhibited good predictive ability (Hosmer-Lemeshow test, P =0.78) and discriminated between high- and low-risk patients reasonably well (receiver-operating characteristics curve area, 0.77). Conclusions— This is the first risk model that predicts in-hospital mortality for aortic and/or mitral heart valve patients with or without concomitant CABG. Based on a large national database of heart valve patients, this model has been evaluated successfully on patients who had valve surgery during a subsequent time period. It is simple to use, includes routinely collected variables, and provides a useful tool for patient advice and institutional comparisons.
Protection from anti-TCR/CD3-induced apoptosis in immature thymocytes by a signal through thymic shared antigen-1/stem cell antigen-2.
Authors: S Noda, A Kosugi, S Saitoh, S Narumiya, T Hamaoka
Journal: The Journal of Experimental Medicine (1996)

During T cell development in the thymus, the expression of thymic shared antigen-1 (TSA-1)/stem cell antigen-2 (Sca-2), a glycosylphosphatidylinositol (GPI)-anchored differentiation antigen, is developmentally regulated. The expression level of TSA-1 is the highest in most immature CD4- CD8- thymocytes, high in CD4+ CD8+ thymocytes, but barely detectable in mature CD4+ CD8- or CD4- CD8- thymocytes and peripheral T cells. We have previously shown that surface TSA-1 expression in peripheral T cells is induced upon activation and that anti-TSA-1 mAb inhibits the T cell receptor (TCR) signaling pathway in activated T cells. In the present study, we have analyzed a role of TSA-1 in thymic selection events, especially in TCR-mediated apoptosis. In in vitro experiments, anti-TSA-1 blocked anti-CD3-induced cell death of T cell hybridomas. When anti-TSA-1 was injected into newborn mice in vivo together with anti-CD3 epsilon or anti-TCR-beta, TCR/CD3-mediated apoptosis of thymocytes was almost completely blocked. The blockade of apoptosis was defined by the inhibition of, first, the decrease in total number of thymocytes; second, the decrease in percentages of CD4+ CD8+ thymocytes; and third, the induction of DNA fragmentation. However, anti-TSA-1 did not block either steroid- or radiation-induced apoptosis, indicating that a signal via TSA-1 does not inhibit a common pathway of thymocyte apoptosis. Since TCR-mediated apoptosis is pivotal in thymic ontogeny, these results suggest that TSA-1/Sca-2 is an important cell surface molecule regulating the fate of a developing T cell.
THE IMMUNOGENETICS OF HUMAN INFECTIOUS DISEASES
Authors: Adrian V. S. Hill
Journal: Annual Review of Immunology (1998)

▪ Abstract Twin and adoptee studies have indicated that host genetic factors are major determinants of susceptibility to infectious diseases in humans. Twin studies have also found high heritabilities for many humoral and cellular immune responses to pathogen antigens, with most of the genetic component mapping outside of the major histocompatibility complex. Candidate gene studies have implicated several immunogenetic polymorphisms in human infectious diseases. HLA variation has been associated with susceptibility or resistance to malaria, tuberculosis, leprosy, AIDS, and hepatitis virus persistence. Variation in the tumor necrosis factor gene promoter has also been associated with several infectious diseases. Chemokine receptor polymorphism affects both susceptibility to HIV-1 infection and the rate of progression to AIDS. Inactivating mutations of the γ-interferon receptor lead to increased susceptibility to atypical mycobacteria and disseminated BCG infection in homozygous children. The active form of vitamin D has immunomodulatory effects, and allelic variants of the vitamin D receptor appear to be associated with differential susceptibility to several infectious diseases. NRAMP1, a macrophage gene identified by positional cloning of its murine homologue, has been implicated in susceptibility to tuberculosis in Africans. Whole genome linkage analysis of multi-case families is now being used to map and identify new loci affecting susceptibility to infectious diseases. It is likely that susceptibility to most microorganisms is determined by a large number of polymorphic genes, and identification of these should provide insights into protective and pathogenic mechanisms in infectious diseases.
Genetic dissection of a behavioral quantitative trait locus shows that Rgs2 modulates anxiety in mice
Authors: Binnaz Yalcin, Saffron A G Willis-Owen, Jan Fullerton, Anjela Meesaq, Robert M Deacon, J Nicholas P Rawlins, Richard R Copley, Andrew P Morris, Jonathan Flint, Richard Mott
Journal: Nature Genetics (2004)
Repaglinide Versus Nateglinide Monotherapy
Authors: Julio Rosenstock, David R. Hassman, Robert D. Madder, Shari A. Brazinsky, James Farrell, Naum Khutoryansky, Paula M. Hale
Journal: Diabetes Care (2004)

OBJECTIVE—A randomized, parallel-group, open-label, multicenter 16-week clinical trial compared efficacy and safety of repaglinide monotherapy and nateglinide monotherapy in type 2 diabetic patients previously treated with diet and exercise. RESEARCH DESIGN AND METHODS—Enrolled patients (n = 150) had received treatment with diet and exercise in the previous 3 months with HbA1c &amp;gt;7 and ≤12%. Patients were randomized to receive monotherapy with repaglinide (n = 76) (0.5 mg/meal, maximum dose 4 mg/meal) or nateglinide (n = 74) (60 mg/meal, maximum dose 120 mg/meal) for 16 weeks. Primary and secondary efficacy end points were changes in HbA1c and fasting plasma glucose (FPG) values from baseline, respectively. Postprandial glucose, insulin, and glucagon were assessed after a liquid test meal (baseline, week 16). Safety was assessed by incidence of adverse events or hypoglycemia. RESULTS—Mean baseline HbA1c values were similar in both groups (8.9%). Final HbA1c values were lower for repaglinide monotherapy than nateglinide monotherapy (7.3 vs. 7.9%). Mean final reductions of HbA1c were significantly greater for repaglinide monotherapy than nateglinide monotherapy (−1.57 vs. −1.04%; P = 0.002). Mean changes in FPG also demonstrated significantly greater efficacy for repaglinide than nateglinide (−57 vs. −18 mg/dl; P &amp;lt; 0.001). HbA1c values &amp;lt;7% were achieved by 54% of repaglinide-treated patients versus 42% for nateglinide. Median final doses were 6.0 mg/day for repaglinide and 360 mg/day for nateglinide. There were 7% of subjects treated with repaglinide (five subjects with one episode each) who had minor hypoglycemic episodes (blood glucose &amp;lt;50 mg/dl) versus 0 patients for nateglinide. Mean weight gain at the end of the study was 1.8 kg in the repaglinide group as compared with 0.7 kg for the nateglinide group. CONCLUSIONS—In patients previously treated with diet and exercise, repaglinide and nateglinide had similar postprandial glycemic effects, but repaglinide monotherapy was significantly more effective than nateglinide monotherapy in reducing HbA1c and FPG values after 16 weeks of therapy.
Effect of stent implantation and glycoprotein IIb/IIIa receptor blockade on target vessel revascularization in diabetics after primary PCI in acute myocardial infarction: the CADILLAC trial
Authors: Thomas D. Stuckey, Cindy L. Grines, Bruce R. Brodie, David A. Cox, John J. Griffin, John Carroll, Giulio Guagliumi, Eulogio Garcia, Barry Rutherford, Mark Turco, James E. Tcheng, Gregg W. Stone
Journal: Journal of the American College of Cardiology (2002)
A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study)
Authors: Gerd R Burmester, Andrea Rubbert-Roth, Alain Cantagrel, Stephen Hall, Piotr Leszczynski, Daniel Feldman, Madura J Rangaraj, Georgia Roane, Charles Ludivico, Peng Lu, Lucy Rowell, Min Bao, Eduardo F Mysler
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> This study compared the efficacy and safety of subcutaneous (SC) versus intravenous (IV) formulations of tocilizumab in patients with rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs (DMARD). <h3>Methods</h3> Patients (n=1262) were randomly assigned to receive tocilizumab-SC 162 mg weekly+placebo-IV every 4 weeks or tocilizumab-IV 8 mg/kg every 4 weeks+placebo-SC weekly in combination with traditional DMARD. The primary outcome was to demonstrate the non-inferiority of tocilizumab-SC to tocilizumab-IV with regard to the proportion of patients in each group achieving an American College of Rheumatology (ACR) 20 response at week 24 using a 12% non-inferiority margin (NIM). Secondary outcomes were disease activity score using 28 joints (DAS28), ACR responses, health assessment questionnaire scores and safety assessments. <h3>Results</h3> At week 24, 69.4% (95% CI 65.5 to 73.2) of tocilizumab-SC-treated patients versus 73.4% (95% CI 69.6 to 77.1) of tocilizumab-IV-treated patients achieved an ACR20 response (weighted difference between groups −4.0%, 95% CI −9.2 to 1.2); the 12% NIM was met. ACR50/70 responses, DAS28 and physical function improvements were comparable between the tocilizumab-SC and tocilizumab-IV groups. The safety profiles of tocilizumab-SC and tocilizumab-IV were similar, and the most common adverse event was infection. Injection-site reactions (ISR) occurred more frequently in the tocilizumab-SC group than in the tocilizumab-IV (placebo-SC) group. No anaphylaxis was reported over the 24 weeks. <h3>Conclusions</h3> Tocilizumab-SC 162 mg weekly demonstrated comparable efficacy to tocilizumab-IV 8 mg/kg. The safety profile of tocilizumab-SC is consistent with the known and well-established safety profile of tocilizumab-IV, with the exception of a higher incidence of ISR, which were more common with tocilizumab-SC administration.
High incidence of Plasmodium vivax malaria in newly arrived Eritrean refugees in Sweden since May 2014
Authors: K Sondén, E Castro, L Trönnberg, C Stenström, A Tegnell, A Färnert
Journal: Eurosurveillance (2014)

Since May 2014, an increase in Plasmodium vivax malaria has been observed in Sweden. As of 31 August 2014, 105 malaria cases have been reported in newly arrived Eritrean refugees, 84 of them P. vivax. The patients were mainly young men and reported migration through Ethiopia and/or Sudan. Severe anaemia and long symptom duration reflect inadequate healthcare during migration. Countries currently hosting Eritrean refugees need to consider P. vivax malaria in this group of migrants.
NICE guideline: management of venous thromboembolic diseases and role of thrombophilia testing
Authors: Luke S Howard, Rodney J Hughes
Journal: Thorax (2012)

The National Institute for Health and Clinical Excellence recently published a clinical guideline on the management of venous thromboembolic disease and thrombophilia testing. Several stand-out recommendations are made which may be practice changing for many physicians, such as catheter-directed thrombolysis for ilio-femoral deep venous thrombosis, routine cancer screening and extended duration of anticoagulation for unprovoked events. In this article, we summarise the key points of the guideline and discuss remaining areas of controversy.
BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms
Authors: Katerina Hatzi, J. Philip Nance, Mark A. Kroenke, Marcella Bothwell, Elias K. Haddad, Ari Melnick, Shane Crotty
Journal: The Journal of Experimental Medicine (2015)

Follicular helper T cells (Tfh cells) are required for T cell help to B cells, and BCL6 is the defining transcription factor of Tfh cells. However, the functions of BCL6 in Tfh cells have largely remained unclear. Here we defined the BCL6 cistrome in primary human germinal center Tfh cells to assess mechanisms of BCL6 regulation of CD4 T cells, comparing and contrasting BCL6 function in T and B cells. BCL6 primarily acts as a repressor in Tfh cells, and BCL6 binding was associated with control of Tfh cell migration and repression of alternative cell fates. Interestingly, although some BCL6-bound genes possessed BCL6 DNA-binding motifs, many BCL6-bound loci were instead characterized by the presence of DNA motifs for AP1 or STAT. AP1 complexes are key positive downstream mediators of TCR signaling and external stimuli. We show that BCL6 can directly bind AP1, and BCL6 depends on AP1 for recruitment to BCL6-binding sites with AP1 motifs, suggesting that BCL6 subverts AP1 activity. These findings reveal that BCL6 has broad and multifaceted effects on Tfh biology and provide insight into how this master regulator mediates distinct cell context-dependent phenotypes.