tbuckley/cabot-search huggingface dataset:
Molecular Interactions Mediating T Cell Antigen Recognition
Authors: P. Anton van der Merwe, Simon J. Davis
Journal: Annual Review of Immunology (2003)

Over the past decade, key protein interactions contributing to T cell antigen recognition have been characterized in molecular detail. These have included interactions involving the T cell antigen receptor (TCR) itself, its coreceptors CD4 and CD8, the accessory molecule CD2, and the costimulatory receptors CD28 and CTLA-4. A clear view is emerging of how these molecules interact with their ligands at the cell-cell interface. Structural and binding studies have confirmed that the proteins span small but comparable distances and that, overall, they interact very weakly. However, there have been important surprises as well: that TCR interactions with peptide-MHC are topologically constrained and characterized by considerable conformational flexibility at the binding interface; that coreceptors engage peptide-MHC with extraordinarily fast kinetics and at angles apparently precluding direct interactions with the TCR bound to the same peptide-MHC; that the structural mechanisms allowing recognition by costimulatory and accessory molecules to be weak and yet specific are very heterogeneous; and that because of differences in both binding affinity and stoichiometry, there is enormous variation in the stability of the various costimulatory receptor/ligand complexes. These studies provide the necessary framework for exploring how these molecular interactions initiate T cell activation.
Bevacizumab Plus Irinotecan in Recurrent Glioblastoma Multiforme
Authors: James J. Vredenburgh, Annick Desjardins, James E. Herndon, Jennifer Marcello, David A. Reardon, Jennifer A. Quinn, Jeremy N. Rich, Sith Sathornsumetee, Sridharan Gururangan, John Sampson, Melissa Wagner, Leighann Bailey, Darell D. Bigner, Allan H. Friedman, Henry S. Friedman
Journal: Journal of Clinical Oncology (2007)

Purpose The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan. Patients and Methods This phase II trial included two cohorts of patients. The initial cohort, comprising 23 patients, received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan was based on the patient's anticonvulsant: Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) received 340 mg/m 2 , and patients not taking EIAEDs received 125 mg/m 2 . After this regimen was deemed safe and effective, the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus irinotecan and bevacizumab. The second cohort, comprising 12 patients, received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each cycle was 6 weeks long and concluded with patient evaluations, including magnetic resonance imaging. Results The 6-month progression-free survival among all 35 patients was 46% (95% CI, 32% to 66%). The 6-month overall survival was 77% (95% CI, 64% to 92%). Twenty of the 35 patients (57%; 95% CI, 39% to 74%) had at least a partial response. One patient developed a CNS hemorrhage, which occurred in his 10th cycle. Four patients developed thromboembolic complications (deep venous thrombosis and/or pulmonary emboli). Conclusion Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity.
An institutional commitment to pain management.
Authors: B R Ferrell, G E Dean, M Grant, P Coluzzi
Journal: Journal of Clinical Oncology (1995)

PURPOSE To share the development, implementation, and evaluation of a program called "An Institutional Commitment to Pain Management," which is based on the philosophy of organizational influence on pain management. METHODS A tested pain education model was disseminated to 32 physician/nurse teams in settings throughout California, after which the 64 professionals returned to their institutions to serve as role models and catalysts to change the practice of pain management. Each team member completed a 39-item survey about knowledge and attitudes related to pain, which was developed by B.R.F. and colleagues, and also identified three goals for the implementation of course information. Precourse data also included administration of the knowledge and attitudes survey to participating physicians' and nurses' colleagues (10 physicians and 20 nurses per institution). Each team completed five chart audits using the pain audit tool (PAT), which was developed by B.R.F. and colleagues at the City of Hope National Medical Center. The PAT identifies how pain is managed currently at the institutional level. Final course evaluation 8 months after course completion included a summary of activities implemented by the teams as well as the factors that served as barriers and benefits to improve the quality of pain management. RESULTS Two hundred seventy-two physicians and 629 nurses completed the survey about knowledge and attitudes related to pain, and 154 PATs were submitted. These results, as well as evaluation at the completion of the course, are discussed. CONCLUSION The Institutional Commitment to Pain Management program is an evolving model that was developed to overcome barriers to pain relief by obtaining the commitment from institutions to improve the management of pain for their patients.
Peroxisome proliferation-activated receptor-γ ligands ameliorate experimental autoimmune myocarditis
Authors: Z Yuan
Journal: Cardiovascular Research (2003)

Background: Peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands have been shown to ameliorate a variety of inflammatory conditions. The present study tested the hypothesis that PPAR-γ ligands reduce experimental autoimmune myocarditis (EAM) associated with inhibition of the expansion and activation of T cells, as well as suppression of the expression of proinflammatory cytokines. Methods and results: EAM was induced in Lewis rats by immunization with porcine cardiac myosin. PPAR-γ ligands, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) 200 μg/kg/day i.p. and pioglitazone (PIO) 10 mg/kg/day orally, were administered for 3 weeks to rats with EAM. The results showed that enhanced PPAR-γ expression was prominently stained in the nuclear and perinuclear regions of infiltrating inflammatory cells. Administration of PPAR-γ ligands markedly reduced the severity of myocarditis, as shown by comparing the heart weight/body weight ratio, pericardial effusion scores, macroscopic scores and microscopic scores. PPAR-γ ligands suppressed myocardial mRNA expression of inflammatory cytokines and the expression of interleukin (IL)-1β protein in rats with EAM. In addition, 15d-PGJ2 and PIO treatment suppressed the proliferative response and interferon-γ production of T cell-enriched splenocytes from rats with EAM. Furthermore, the cytotoxic activity and myocardiogenic potential of these T cells were inhibited by 15d-PGJ2 treatment. Conclusions: PPAR-γ may play a role in the pathophysiology of EAM. PPAR-γ ligands ameliorate the EAM associated with suppression of the expansion and activation of myocardiogenic T cells, as well as inhibition of the expression of proinflammatory cytokines. These results suggest that PPAR-γ ligands such as 15d-PGJ2 and PIO may have the potential to modulate human inflammatory heart diseases such as myocarditis.
American Indian and Alaska Native Mental Health: Diverse Perspectives on Enduring Disparities
Authors: Joseph P. Gone, Joseph E. Trimble
Journal: Annual Review of Clinical Psychology (2012)

As descendants of the indigenous peoples of the United States, American Indians and Alaska Natives (AI/ANs) have experienced a resurgence in population and prospects since the beginning of the twentieth century. Today, tribally affiliated individuals number over two million, distributed across 565 federally recognized tribal communities and countless metropolitan and nonreservation rural areas. Although relatively little evidence is available, the existing data suggest that AI/AN adults and youth suffer a disproportionate burden of mental health problems compared with other Americans. Specifically, clear disparities have emerged for AI/AN substance abuse, posttraumatic stress, violence, and suicide. The rapid expansion of mental health services to AI/AN communities has, however, frequently preceded careful consideration of a variety of questions about critical components of such care, such as the service delivery structure itself, clinical treatment processes, and preventive and rehabilitative program evaluation. As a consequence, the mental health needs of these communities have easily outpaced and overwhelmed the federally funded agency designed to serve these populations, with the Indian Health Service remaining chronically understaffed and underfunded such that elimination of AI/AN mental health disparities is only a distant dream. Although research published during the past decade has substantially improved knowledge about AI/AN mental health problems, far fewer investigations have explored treatment efficacy and outcomes among these culturally diverse peoples. In addition to routine calls for greater clinical and research resources, however, AI/AN community members themselves are increasingly advocating for culturally alternative approaches and opportunities to address their mental health needs on their own terms.
Daytime and night time motor activity of the small bowel after solid meals of different caloric value in humans.
Authors: J Schonfeld, D F Evans, D L Wingate
Journal: Gut (1997)

BACKGROUND: Meals disrupt the interdigestive pattern of small bowel motor activity and convert it into the postprandial pattern. Previous studies have shown that duration of postprandial motor activity depends on the caloric value of a meal, but results from two recent human studies suggested that there is a caloric ceiling, above which an additional increase in the caloric load fails to prolong the postprandial period further. AIM: To investigate the hypothesis of a caloric ceiling by studying daytime motor activity of the human small bowel in response to five solid meals, covering a wide range of calories. METHODS: Eight healthy male volunteers underwent five separate, ambulatory small bowel manometry studies and had a total of 80 meals. For lunch, volunteers ate between one and five portions of a solid meal (220, 440, 660, 880, or 1100 kcal). Ten hours later and 30 minutes before they went to bed, they ate either two or four portions of the same meal (440 kcal or 880 kcal). Recordings were analysed visually for phase III of the migrating motor complex and a validated computer program calculated incidence and amplitude of contractions. RESULTS: Apart from two versus three portions (440 kcal v 660 kcal), postprandial motor activity was significantly prolonged by each 220 kcal increase in the caloric load of the lunch (168 (SEM 14), 305 (22), 298 (23), 368 (36), and 398 (38) min). Mean incidence of contractions was significantly different only between the two extremes tested: 220 kcal and 1100 kcal (2.9 (0.3) v 4.5 (0.6) min-1). Amplitude of contractions did not depend on meal size. Daytime and night time postprandial activity were not significantly different. This was true for duration of fed activity, as well as mean incidence and amplitude of contractions during the postprandial period. CONCLUSION: Caloric value of a meal regulates duration of the fed activity in the human small bowel over a wide range of calories, and-for caloric loads up to 1100 kcal-there is no maximum duration of postprandial motor activity. Furthermore the postprandial small bowel motor activity is very similar between daytime and night time.
The relationship between the frequency of football practice during skeletal growth and the presence of a cam deformity in adult elite football players
Authors: Igor Tak, Adam Weir, Rob Langhout, Jan Hendrik Waarsing, Janine Stubbe, Gino Kerkhoffs, Rintje Agricola
Journal: British Journal of Sports Medicine (2015)

Cam deformity (CD) is likely a bony adaptation in response to high-impact sports practice during skeletal growth. We ascertained whether a dose-response relationship exists between the frequency of football practice during skeletal growth and the presence of a CD in adulthood, and if the age at which a football player starts playing football is associated with the presence of a CD in adulthood.Prevalence of a CD (α angle>60°) and a pathological CD (α angle>78°) was studied using standardised anteroposterior (AP) and frog-leg lateral (FLL) radiographs that were obtained during seasonal screening. The age of starting to play football with a low frequency (LF; ≤3 times/week) and high frequency (HF; ≥4 times/week) was retrospectively assessed. The differences in prevalence of a CD per hip, in either view, between groups were calculated by logistic regression with generalised estimating equations.63 players (mean(±SD) age 23.1(±4.2) years) participated, yielding 126 hips for analysis. The prevalence of a CD in the FLL was 40% (n=82) in players who started playing HF football from the age of 12 years or above, and 64% (n=44) in those playing HF football before the age of 12 years (p=0.042). This was also true for a pathological CD (12% vs 30%, p=0.038). The AP views revealed no difference.Our results indicate a probable dose-response relationship between the frequency of football practice during skeletal growth and the development of a CD, which should be confirmed in future prospective studies.
Magnetic resonance measurements of renal blood flow as a marker of disease severity in autosomal-dominant polycystic kidney disease11Thomas Andreoli, M.D., served as Guest Editor for this paper.
Authors: Bernard F. King, Vicente E. Torres, Marijn E. Brummer, Arlene B. Chapman, Kyongtae T. Bae, James F. Glockner, Kraisthith Arya, Joel P. Felmlee, Jared J. Grantham, Lisa M. Guay-Woodford, William M. Bennett, Saulo Klahr, Gladys H. Hirschman, Paul L. Kimmel, Paul A. Thompson, J. Phillip Miller
Journal: Kidney International (2003)
Mathematical Model of an Adult Human Atrial Cell
Authors: A. Nygren, C. Fiset, L. Firek, J. W. Clark, D. S. Lindblad, R. B. Clark, W. R. Giles
Journal: Circulation Research (1998)

Abstract —We have developed a mathematical model of the human atrial myocyte based on averaged voltage-clamp data recorded from isolated single myocytes. Our model consists of a Hodgkin-Huxley–type equivalent circuit for the sarcolemma, coupled with a fluid compartment model, which accounts for changes in ionic concentrations in the cytoplasm as well as in the sarcoplasmic reticulum. This formulation can reconstruct action potential data that are representative of recordings from a majority of human atrial cells in our laboratory and therefore provides a biophysically based account of the underlying ionic currents. This work is based in part on a previous model of the rabbit atrial myocyte published by our group and was motivated by differences in some of the repolarizing currents between human and rabbit atrium. We have therefore given particular attention to the sustained outward K + current ( I sus ), which putatively has a prominent role in determining the duration of the human atrial action potential. Our results demonstrate that the action potential shape during the peak and plateau phases is determined primarily by transient outward K + current, I sus , and L-type Ca 2+ current ( I Ca,L ) and that the role of I sus in the human atrial action potential can be modulated by the baseline sizes of I Ca,L , I sus , and the rapid delayed rectifier K + current. As a result, our simulations suggest that the functional role of I sus can depend on the physiological/disease state of the cell.
Primary Metastatic Osteosarcoma: Presentation and Outcome of Patients Treated on Neoadjuvant Cooperative Osteosarcoma Study Group Protocols
Authors: Leo Kager, Andreas Zoubek, Ulrike Pötschger, Ulrike Kastner, Silke Flege, Beate Kempf-Bielack, Detlev Branscheid, Rainer Kotz, Mechthild Salzer-Kuntschik, Winfried Winkelmann, Gernot Jundt, Hartmut Kabisch, Peter Reichardt, Heribert Jürgens, Helmut Gadner, Stefan S. Bielack
Journal: Journal of Clinical Oncology (2003)

To determine demographic data and define prognostic factors for long-term outcome in patients presenting with high-grade osteosarcoma of bone with clinically detectable metastases at initial presentation.Of 1,765 patients with newly diagnosed, previously untreated high-grade osteosarcomas of bone registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies before 1999, 202 patients (11.4%) had proven metastases at diagnosis and therefore were enrolled onto an analysis of demographic-, tumor-, and treatment-related variables, response, and survival. The intended therapeutic strategy included pre- and postoperative multiagent chemotherapy as well as aggressive surgery of all resectable lesions.With a median follow-up of 1.9 years (5.5 years for survivors), 60 patients were alive, 37 of whom were in continuously complete surgical remission. Actuarial overall survival rates at 5 and 10 (same value for 15) years were 29% (SE = 3%) and 24% (SE = 4%), respectively. In univariate analysis, survival was significantly correlated with patient age, site of the primary tumor, number and location of metastases, number of involved organ systems, histologic response of the primary tumor to preoperative chemotherapy, and completeness and time point of surgical resection of all tumor sites. However, after multivariate Cox regression analysis, only multiple metastases at diagnosis (relative hazard rate [RHR] = 2.3) and macroscopically incomplete surgical resection (RHR = 2.4) remained significantly associated with inferior outcomes.The number of metastases at diagnosis and the completeness of surgical resection of all clinically detected tumor sites are of independent prognostic value in patients with proven primary metastatic osteosarcoma.
A Novel Signal Transduction Cascade Involving Direct Physical Interaction of the Renin/Prorenin Receptor With the Transcription Factor Promyelocytic Zinc Finger Protein
Authors: Jan H. Schefe, Mario Menk, Jana Reinemund, Karin Effertz, Robin M. Hobbs, Pier Paolo Pandolfi, Patricia Ruiz, Thomas Unger, Heiko Funke-Kaiser
Journal: Circulation Research (2006)

A human renin/prorenin receptor (RER) has recently been cloned. To gain insight into the molecular function of the RER, we studied its signal transduction mechanisms. Initially, we found a ubiquitous and intracellular expression pattern of the human RER. Consistently, we observed several transcriptional start sites and a high promoter activity of the human RER. We could identify the transcription factor promyelocytic zinc finger (PLZF) protein as a direct protein interaction partner of the C-terminal domain of the RER by yeast 2-hybrid screening and coimmunoprecipitation. Coimmunoprecipitation experiments also indicated homodimerization of the RER. On activation of the RER by renin, PLZF is translocated into the nucleus and represses transcription of the RER itself, thereby creating a very short negative feedback loop, but activates transcription of the p85α subunit of the phosphatidylinositol-3 kinase (PI3K-p85α). Small interfering RNA against the RER abolished these effects. A PLZF cis -element in the RER promoter was identified by site-directed mutagenesis and electrophoretic mobility-shift assay. Renin stimulation caused a 6-fold recruitment of PLZF to this promoter region as shown by chromatin immunoprecipitation. Moreover, renin stimulation of rat H9c2 cardiomyoblasts induced an increase of cell number and a decrease of apoptosis. These effects were partly abolished by PI3K inhibition and completely abrogated by small interfering RNA against PLZF. Finally, experiments in PLZF knockout mice confirmed the role of PLZF as an upstream regulator of RER and PI3K-p85α. Our data demonstrate the existence of a novel signal transduction pathway involving the ligand renin, RER, and the transcription factor PLZF, which is of physiological and putative pathophysiological relevance.
Rituximab Maintenance Treatment of Relapsed/Resistant Follicular Non-Hodgkin's Lymphoma: Long-Term Outcome of the EORTC 20981 Phase III Randomized Intergroup Study
Authors: Marinus H.J. van Oers, Martine Van Glabbeke, Livia Giurgea, Richard Klasa, Robert E. Marcus, Max Wolf, Eva Kimby, Mars van t Veer, Andrej Vranovsky, Harald Holte, Anton Hagenbeek
Journal: Journal of Clinical Oncology (2010)

In 2006, we published the results of the European Organisation for Research and Treatment of Cancer phase III trial EORTC 20981 on the role of rituximab in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). At that time, the median follow-up for the maintenance phase was 33 months. Now, we report the long-term outcome of maintenance treatment, with a median follow-up of 6 years.Overall, 465 patients were randomly assigned to induction with either six cycles of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or rituximab plus CHOP (R-CHOP). Those in complete remission or partial remission after induction (n = 334) were randomly assigned to maintenance treatment with rituximab (375 mg/m(2) intravenously once every 3 months) or observation.Rituximab maintenance significantly improved progression-free survival (PFS) compared with observation (median, 3.7 years v 1.3 years; P < .001; hazard ratio [HR], 0.55), both after CHOP induction (P < .001; HR, 0.37) and R-CHOP (P = .003; HR, 0.69). The 5-year overall survival (OS) was 74% in the rituximab maintenance arm, and it was 64% in the observation arm (P = .07). After progression, a rituximab-containing salvage therapy was given to 59% of patients treated with CHOP followed by observation, compared with 26% after R-CHOP followed by rituximab maintenance. Rituximab maintenance was associated with a significant increase in grades 3 to 4 infections: 9.7% v 2.4% (P = .01).With long-term follow-up, we confirm the superior PFS with rituximab maintenance in relapsed/resistant FL. The improvement of OS did not reach statistical significance, possibly because of the unbalanced use of rituximab in post-protocol salvage treatment.
Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis
Authors: Hong Xia, Deanna Diebold, Richard Nho, David Perlman, Jill Kleidon, Judy Kahm, Svetlana Avdulov, Mark Peterson, John Nerva, Peter Bitterman, Craig Henke
Journal: The Journal of Experimental Medicine (2008)

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive lung disease in which fibroblasts accumulate in the alveolar wall within a type I collagen–rich matrix. Although lung fibroblasts derived from patients with IPF display durable pathological alterations in proliferative function, the molecular mechanisms differentiating IPF fibroblasts from their normal counterparts remain unknown. Polymerized type I collagen normally inhibits fibroblast proliferation, providing a physiological mechanism to limit fibroproliferation after tissue injury. We demonstrate that β1 integrin interaction with polymerized collagen inhibits normal fibroblast proliferation by suppression of the phosphoinositide 3-kinase (PI3K)–Akt–S6K1 signal pathway due to maintenance of high phosphatase activity of the tumor suppressor phosphatase and tensin homologue (PTEN). In contrast, IPF fibroblasts eluded this restraint, displaying a pathological pattern of β1 integrin signaling in response to polymerized collagen that leads to aberrant activation of the PI3K–Akt–S6K1 signal pathway caused by inappropriately low PTEN activity. Mice deficient in PTEN showed a prolonged fibroproliferative response after tissue injury, and immunohistochemical analysis of IPF lung tissue demonstrates activation of Akt in cells within fibrotic foci. These results provide direct evidence for defective negative regulation of the proliferative pathway in IPF fibroblasts and support the theory that the pathogenesis of IPF involves an intrinsic fibroblast defect.