tbuckley/cabot-search huggingface dataset:
Membrane Ia expression and antigen-presenting accessory cell function of L cells transfected with class II major histocompatibility complex genes.
Authors: M A Norcross, D M Bentley, D H Margulies, R N Germain
Journal: The Journal of Experimental Medicine (1984)

To study the relationship between the structure and function of Ia antigens, as well as the physiologic requirements for antigen presentation to major histocompatibility complex-restricted T cells, class II A alpha and A beta genes from the k and d haplotypes were transfected into Ltk- fibroblasts using the calcium phosphate coprecipitation technique. Individually transfected genes were actively transcribed in the L cells without covalent linkage to, or cotransformation with, viral enhancer sequences. However, cell surface expression of detectable I-A required the presence of transfected A alpha dA beta d or A alpha kA beta k pairs in a single cell. The level of I-A expression under these conditions was 1/5-1/10 that of Ia+ B lymphoma cells, or B lymphoma cells expressing transfected class II genes. These I-A-expressing transfectants were tested for accessory cell function and shown to present polypeptide and complex protein antigens to T cell clones and hybridomas in the context of the transfected gene products. One T cell clone, restricted to I-Ak plus GAT (L-glutamic acid60-L-alanine30-L-tyrosine10), had a profound cytotoxic effect on I-Ak- but not I-Ad-expressing transfectants in the presence of specific antigen. Assays of unprimed T cells showed that both Ia+ and Ia- L cells could serve as accessory cells for concanavalin A-induced proliferative responses. These data indicate that L cells can transcribe, translate, and express transfected class II genes and that such I-A-bearing L cells possess the necessary metabolic mechanisms for presenting these antigens to T lymphocytes in the context of their I-A molecules.
EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2013 Guidelines
Authors: J. Alfred Witjes, Eva Compérat, Nigel C. Cowan, Maria De Santis, Georgios Gakis, Thierry Lebret, Maria J. Ribal, Antoine G. Van der Heijden, Amir Sherif
Journal: European Urology (2013)
Association Between Hypermethylated Tumor and Paired Surgical Margins in Head and Neck Squamous Cell Carcinomas
Authors: Tiziana Martone, Anna Gillio-Tos, Laura De Marco, Valentina Fiano, Milena Maule, Andrea Cavalot, Massimiliano Garzaro, Franco Merletti, Giorgio Cortesina
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Surgical margin status is reported to be a relevant prognostic factor in head and neck squamous cell carcinoma (HNSCC), associated with a high risk of local recurrence. This study examines whether gene-promoter hypermethylation could be detected in HNSCC surgical margins with no histologic evidence of malignancy, and if so, whether it reflects epigenetic events of primary tumors. Experimental Design: Promoter methylation status of MGMT, p16, and DAP-K genes was evaluated by methylation-specific PCR in 20 primary HNSCC tumors. Histopathologically negative surgical margins of hypermethylated tumors were collected, and their methylation status compared with the primary tumor status. Results: Promoter hypermethylation in at least one of the three tested genes was detected in 65% (13 of 20) of tumors. MGMT was hypermethylated in 50% (10 of 20), DAP-K in 45% (9 of 20), and p16 in 20% (4 of 20) of tumors. Methylation status was analyzed in 35 margins from 11 of 13 patients showing promoter hypermethylation in the tumor tissue. Identical methylation events were seen for at least one gene in primary tumor and surgical margins in 9 of 11 cases (82%). Association was found for gene-specific hypermethylation status in tumors and paired surgical margins, and gene-specific concordance was 63% for MGMT (κ = 0.24), 90% for DAP-K (κ = 0.74), and 90% for p16 (κ = 0.79). Conclusions: Our results support the hypothesis that detection of gene promoter hypermethylation in HNSCC tumor cells–free surgical margins may be a helpful biomarker to identify molecularly altered fields in areas adjacent to the tumor.
Therapeutic Lung Lavage in the Piglet Model of Meconium Aspiration Syndrome
Authors: Peter A. Dargaville, John F. Mills, Bevan M. Headley, Yuen Chan, Lee Coleman, Peter M. Loughnan, Colin J. Morley
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Therapeutic lung lavage is an emerging treatment for meconium aspiration syndrome. Our objective was to investigate the type of fluid and aliquot volume most appropriate for lung lavage in this condition. Meconium injury was induced in 2-week-old piglets, followed by a 30 ml/kg lavage in two aliquots 40 minutes later. Lavage with either dilute bovine surfactant (2.5 mg/ml) or a perfluorocarbon emulsion (20% wt/vol) improved oxygenation compared with a nonlavaged control group, but only with dilute surfactant was there a sustained improvement in oxygenation (alveolar-arterial oxygen difference at 5 hours: dilute surfactant 250 mm Hg; perfluorocarbon emulsion 460 mm Hg; controls 460 mm Hg; p = 0.0031). There was histologic and biochemical evidence of decreased lung injury in the dilute surfactant group. In a further study, 30 ml/kg dilute surfactant lavage was performed 40 minutes after meconium injury using either two aliquots of 15 ml/kg, or multiple 3-ml aliquots. Aliquot volume of 15 ml/kg was associated with increased meconium removal, better post-lavage lung function, and less lung injury. Dilute surfactant lavage using two 15-ml/kg aliquots is an effective therapy in the piglet model of meconium aspiration, and should be evaluated in human infants with this condition.
Cardiac anaplerosis in health and disease: food for thought
Authors: C. Des Rosiers, F. Labarthe, S. G. Lloyd, J. C. Chatham
Journal: Cardiovascular Research (2011)

There has been a resurgence of interest for the field of cardiac metabolism catalysed by the increased need for new therapeutic targets for patients with heart failure. The primary focus of research in this area to date has been on the impact of substrate selection for oxidative energy metabolism; however, anaplerotic metabolism also has significant interest for its potential cardioprotective role. Anaplerosis refers to metabolic pathways that replenish the citric acid cycle intermediates, which are essential to energy metabolism; however, our understanding of the role and regulation of this process in the heart, particularly under pathophysiological conditions, is very limited. Therefore, the goal of this article is to provide a foundation for future directions of research on cardiac anaplerosis and heart disease. We include an overview of anaplerotic metabolism, a critical evaluation of current methods available for its quantitation in the intact heart, and a discussion of its role and regulation both in health and disease as it is currently understood based mostly on animal studies. We also consider genetic diseases affecting anaplerotic pathways in humans and acute intervention studies with anaplerotic substrates in the clinics. Finally, as future perspectives, we will share our thoughts about potential benefits and practical considerations on modalities of interventions targeting anaplerosis in heart disease, including heart failure.
The Tyrosine Kinase Inhibitor Cediranib Blocks Ligand-Induced Vascular Endothelial Growth Factor Receptor-3 Activity and Lymphangiogenesis
Authors: Caroline A. Heckman, Tanja Holopainen, Maria Wirzenius, Salla Keskitalo, Michael Jeltsch, Seppo Ylä-Herttuala, Stephen R. Wedge, Juliane M. Jürgensmeier, Kari Alitalo
Journal: Cancer Research (2008)

Abstract Solid tumors express a range of factors required to sustain their growth and promote their dissemination. Among these are vascular endothelial growth factor-A (VEGF-A), the key angiogenic stimulant, and VEGF-C, a primary mediator of lymphangiogenesis. Small molecule tyrosine kinase inhibitors offer the potential to inhibit more than one kinase and impede tumor growth by multiple mechanisms. However, their potency toward individual targets can vary. Cediranib (RECENTIN; AZD2171) is an inhibitor of VEGF signaling that has been shown in experimental models to prevent VEGF-A–induced angiogenesis and primary tumor growth, yet the effects of cediranib on VEGF receptor (VEGFR)-3–mediated endothelial cell function and lymphangiogenesis are unknown. To better understand the activity of cediranib against VEGFR-3 and its associated signaling events compared with its activity against VEGFR-2, we used the receptor-specific ligands VEGF-E and VEGF-C156S. In human endothelial cells, cediranib inhibited VEGF-E–induced phosphorylation of VEGFR-2 and VEGF-C156S–induced phosphorylation of VEGFR-3 at concentrations of ≤1nmol/L and inhibited activation of downstream signaling molecules. Additionally, cediranib blocked VEGF-C156S–induced and VEGF-E–induced proliferation, survival, and migration of lymphatic and blood vascular endothelial cells. In vivo, cediranib (6 mg/kg/d) prevented angiogenesis and lymphangiogenesis induced by VEGF-E–expressing and VEGF-C156S–expressing adenoviruses, respectively. Cediranib (6 mg/kg/day) also blocked angiogenesis and lymphangiogenesis induced by adenoviruses expressing VEGF-A or VEGF-C and compromised the blood and lymphatic vasculatures of VEGF-C–expressing tumors. Cediranib may, therefore, be an effective means of preventing tumor progression, not only by inhibiting VEGFR-2 activity and angiogenesis, but also by concomitantly inhibiting VEGFR-3 activity and lymphangiogenesis. [Cancer Res 2008;68(12):4754–62]
The diagnosis and treatment of carpal tunnel syndrome
Authors: Brent Graham
Journal: BMJ (2006)

Surgery—whether open or closed—works, but only if the diagnosis is right 

The randomised controlled trial of Atroshi and colleagues (p 1473) in this week's BMJ shows that there are no substantive differences in the outcome of carpal tunnel syndrome treated with either a conventional open decompression of the median nerve or an endoscopic approach.1 Their findings confirm those of earlier studies which also found no fundamental difference in outcome that could be attributed to the technique of surgical release of the carpal tunnel.2–4

Given that the result of surgical treatment for carpal tunnel syndrome is not universally successful, however, what other factors might have an important impact on the outcome? One key determinant is probably the accuracy of the diagnosis.5 6 When …
Hypothermia Therapy for Brain Injury
Authors: Kenneth R. Diller, Liang Zhu
Journal: Annual Review of Biomedical Engineering (2009)

Induced hypothermia is an acknowledged useful therapy for treating conditions that lead to cell and tissue damage caused by ischemia, including traumatic brain injury, stroke, and cardiac arrest. An accumulating body of clinical evidence, together with several decades of research, has documented that the efficacy of hypothermia is dependent on achieving a reduced temperature in the target tissue before or soon following the ischemia-precipitating event. The temperature must be lowered to within a rather small range of values to effect therapeutic benefit without introducing collateral problems. Rewarming must be much slower than cooling. Many different methods and devices have been used for cooling, with mixed results. There are existing opportunities for bioengineers to improve our understanding of the mechanisms of hypothermia and to develop more effective methods of cooling the brain following trauma.
Association of <i>TP53</i> Mutational Status and Gender with Survival after Adjuvant Treatment for Stage III Colon Cancer: Results of CALGB 89803
Authors: Robert S. Warren, Chloe E. Atreya, Donna Niedzwiecki, Vivian K. Weinberg, David B. Donner, Robert J. Mayer, Richard M. Goldberg, Carolyn C. Compton, Marlene B. Zuraek, Cynthia Ye, Leonard B. Saltz, Monica M. Bertagnolli
Journal: Clinical Cancer Research (2013)

Abstract Purpose: The TP53 tumor suppressor is frequently mutated in colon cancer, but the influence of such mutations on survival remains controversial. We investigated whether mutations in the DNA-binding domain of TP53 are associated with survival in stage III colon cancer. Experimental Design: The impact of TP53 genotype was prospectively evaluated in Cancer and Leukemia Group B 89803, a trial that randomized stage III colon cancer patients to receive adjuvant 5-fluorouracil/leucovorin (5FU/LV) or 5FU/LV with irinotecan (IFL). Results: TP53 mutations were identified in 274 of 607 cases. The presence of any TP53 mutation did not predict disease-free survival (DFS) or overall survival with either adjuvant regimen when men and women were considered together or as separate groups. However, outcome differences among women became apparent when tumor TP53 genotype was stratified as wild-type versus zinc- or non-zinc-binding mutations in the TP53 DNA-binding domain. DFS at 5 years was 0.59, 0.52, and 0.78 for women with TP53 wild-type tumors, and tumors with zinc- or non-zinc-binding mutations, respectively. Survival at 5 years for these same women was 0.72, 0.59, and 0.90, respectively. No differences in survival by TP53 genotype were observed in men. Conclusions: The presence of any TP53 mutation within the DNA-binding domain did not predict survival in stage III colon cancer. However, TP53 genotype was predictive of survival in women following adjuvant therapy. Future colon cancer therapeutic trials, with inclusion of correlative molecular markers, should be designed to permit evaluation of survival and/or response to treatment in women separately from men. Clin Cancer Res; 19(20); 5777–87. ©2013 AACR.
Interleukin 1 enhances growth factor-dependent proliferation of the clonogenic cells in acute myeloblastic leukemia and of normal human primitive hemopoietic precursors.
Authors: T Hoang, A Haman, O Goncalves, F Letendre, M Mathieu, G G Wong, S C Clark
Journal: The Journal of Experimental Medicine (1988)

IL-1 is released by activated monocytes and is thought to be a key mediator of the host immune response. The availability of the purified and, more recently, recombinant IL-1 has allowed the characterization of other biological properties of this molecule. Thus, IL-1 is thought to have the same properties as hemopoietic 1, a growth factor that has been shown to act on primitive murine hemopoietic cells. Here we report that rIL-1 acts synergistically with granulocyte/macrophage CSF (GM-CSF) or granulocyte CSF in the stimulation of clonogenic cells from many patients with acute myeloblastic leukemia (AML). Although IL-1 by itself has no effect on AML blasts, it can support colony formation under conditions where there is detectable production of endogenous GM-CSF. IL-1 also promotes the growth of multipotential progenitors from normal human bone marrow cells in the presence of GM-CSF. These observations support the hypothesis that in the hemopoietic system, IL-1 has a selective effect on primitive precursors.
Selective effect of low protein diets in chronic renal diseases.
Authors: A M El Nahas, A Masters-Thomas, S A Brady, K Farrington, V Wilkinson, A J Hilson, Z Varghese, J F Moorhead
Journal: BMJ (1984)

It has recently been established that the rate of progression of chronic renal failure in man can be slowed by restricting dietary protein. Consequently, the short term and long term effects of a low protein diet on the course of different chronic nephropathies were studied in an attempt to delineate the factors that determine the response to such a diet. When a low protein diet was given for six months renal function improved significantly in nine patients with chronic tubulointerstitial nephritis (p less than 0.025); the diet had a marginally beneficial effect in 12 patients with chronic glomerulonephritis (p less than 0.05) and no effect in nine with hypertensive nephrosclerosis. The heterogeneous functional response in the patients with chronic glomerulonephritis correlated closely with the effect of the diet on these patients9 proteinuria (r = 0.76, p less than 0.01). In a short term study (four weeks) of 12 patients with chronic renal failure changes in renal plasma flow were proportional to dietary protein intake. Renal vascular resistance fell during a high protein diet and increased when dietary protein was restricted. The changes in renal plasma flow during the low protein diet correlated well with the patients9 long term functional response to the diet (r = 0.76, p less than 0.01). It is concluded that the response to a low protein diet in chronic renal failure is determined, firstly, by the nature of the underlying nephropathy, with maximal benefit being observed in non-glomerular disorders; secondly, by the effect of the diet on the proteinuria in chronic glomerulonephritis; and, thirdly, by the haemodynamic response to the diet, with patients with a reactive renal vascular bed improving with a low protein diet.
Retinal Vascular Fractal Dimension and Risk of Early Diabetic Retinopathy
Authors: Shueh Wen Lim, Ning Cheung, Jie J. Wang, Kim C. Donaghue, Gerald Liew, F.M. Amirul Islam, Alicia J. Jenkins, Tien Y. Wong
Journal: Diabetes Care (2009)

OBJECTIVE To examine the prospective association of retinal vascular fractal dimension with diabetic retinopathy risk in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS This was a hospital-based prospective study of 590 patients aged 12–20 years with type 1 diabetes free of retinopathy at baseline. All patients had seven-field retinal photographs taken of both eyes. Incident retinopathy was ascertained from retinal photographs taken at follow-up visits. Fractal dimension was measured from baseline photographs using a computer-based program following a standardized protocol. RESULTS Over a mean ± SD follow-up period of 2.9 ± 2.0 years, 262 participants developed mild nonproliferative diabetic retinopathy (15.0 per 100 person-years). After adjusting for age, sex, diabetes duration, A1C, and other risk factors, we found no association between retinal vascular fractal dimension and incident retinopathy. CONCLUSIONS Retinal vascular fractal dimension was not associated with incident early diabetic retinopathy in this sample of children and adolescents with type 1 diabetes.
Exogenous antigens gain access to the major histocompatibility complex class I processing pathway in B cells by receptor-mediated uptake.
Authors: Y Ke, J A Kapp
Journal: The Journal of Experimental Medicine (1996)

Professional antigen-presenting cells, such as macrophages, dendritic cells, or B cells, take up soluble, exogenous antigens (Ags) and process them through the class II pathway. Several reports have shown that phagocytic macrophages also process particulate or soluble forms of exogenous Ag via the class I pathway. By contrast, B cells normally do not process soluble, exogenous Ag by way of the class I pathway unless Ags are directly introduced into the cytoplasm. Here we report that B cells present exogenous Ag via the class I pathway when Ags are taken up by receptor-mediated endocytosis. Thus, specialized methods of Ag uptake such as phagocytosis or receptor-mediated endocytosis deliver exogenous Ag into the class I pathway of Ag processing and presentation.
The Association of Factor V Leiden and Prothrombin Gene Mutation and Placenta-Mediated Pregnancy Complications: A Systematic Review and Meta-analysis of Prospective Cohort Studies
Authors: Marc A. Rodger, Marisol T. Betancourt, Peter Clark, Pelle G. Lindqvist, Donna Dizon-Townson, Joanne Said, Uri Seligsohn, Marc Carrier, Ophira Salomon, Ian A. Greer
Journal: PLoS Medicine (2010)

Marc Rodger and colleagues report the results of their systematic review and meta-analysis of prospective cohort studies that estimated the association of maternal factor V Leiden and prothrombin gene mutation carrier status and placenta-mediated pregnancy complications.
Effect of peak expiratory flow data quantity on diagnostic sensitivity and specificity in occupational asthma
Authors: W. Anees, P.F. Gannon, V. Huggins, C.F.A. Pantin, P.S. Burge
Journal: European Respiratory Journal (2004)

Serial peak expiratory flow records are recommended in the first-line investigation of suspected occupational asthma. The effects of sequentially reducing the numbers of working weeks, consecutive days at work and readings taken per day on diagnostic sensitivity and specificity were investigated, using good quality peak expiratory flow records from 81 workers with independently confirmed occupational asthma and 60 asthmatics without occupational exposure. Sensitivity was 81.8% for records of 4 weeks' duration and 70% for those of 2 weeks' duration (specificity 93.8 and 82.4% respectively). The sensitivity fell to 56.7% if there were only 2 consecutive workdays in each work period. Although best at 8 readings·day −1 , sensitivity and specificity were acceptable with four daily readings (82.4 and 87%). The effect of defining a record as being of adequate quality if it was of ≥2.5 weeks' duration, with ≥4 readings·day −1 and ≥3 consecutive workdays in each work period, was tested in records not used in the initial data reduction process. The sensitivity and specificity respectively of adequate records were 78.1 and 91.8 versus 63.6 and 83.3% for inadequate records. Peak expiratory flow records for the diagnosis of occupational asthma should be interpreted with caution if they do not satisfy the suggested minimum data quantity criteria.
Clinical significance of high-dose cytarabine added to cyclophosphamide/total-body irradiation in bone marrow or peripheral blood stem cell transplantation for myeloid malignancy
Authors: Yasuyuki Arai, Kazunari Aoki, June Takeda, Tadakazu Kondo, Tetsuya Eto, Shuichi Ota, Hisako Hashimoto, Takahiro Fukuda, Yukiyasu Ozawa, Yoshinobu Kanda, Chiaki Kato, Mineo Kurokawa, Koji Iwato, Makoto Onizuka, Tatsuo Ichinohe, Yoshiko Atsuta, Akiyoshi Takami
Journal: Journal of Hematology & Oncology (2015)

Addition of high-dose cytarabine (HDCA) to the conventional cyclophosphamide/total-body irradiation (CY/TBI) regimen significantly improved prognosis after cord blood transplantation (CBT) for adult acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). The efficacy of HDCA in bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT), however, has not yet been elucidated. We conducted a cohort study to compare the prognosis of HDCA/CY/TBI (N = 435) and CY/TBI (N = 1667) in BMT/PBSCT for AML/MDS using a Japanese transplant registry database. The median age was 38 years, and 86.0 % of the patients had AML. Unrelated donors comprised 54.6 %, and 63.9 % of donors were human leukocyte antigen (HLA)-matched. Overall survival (OS) was not improved in the HDCA/CY/TBI group (adjusted hazard ratio (HR), 1.14; p = 0.13). Neutrophil engraftment was inferior (HR, 0.80; p < 0.01), and the incidence of hemorrhagic cystitis and thrombotic microangiopathy increased in HDCA/CY/TBI (HR, 1.47 and 1.60; p = 0.06 and 0.04, respectively), leading to significantly higher non-relapse mortality (NRM; HR, 1.48; p < 0.01). Post-transplant relapse and tumor-related mortality were not suppressed by the addition of HDCA. This study indicated the inefficacy of HDCA/CY/TBI in BMT/PBSCT for AML/MDS. Our results should be validated in large-scale prospective studies.