tbuckley/cabot-search huggingface dataset:
Estimated clinical benefit of protecting neurogenesis in the developing brain during radiation therapy for pediatric medulloblastoma
Authors: M. Blomstrand, N. P. Brodin, P. Munck af Rosenschold, I. R. Vogelius, G. Sanchez Merino, A. Kiil-Berthlesen, K. Blomgren, B. Lannering, S. M. Bentzen, T. Bjork-Eriksson
Journal: Neuro-Oncology (2012)

We sought to assess the feasibility and estimate the benefit of sparing the neurogenic niches when irradiating the brain of pediatric patients with medulloblastoma (MB) based on clinical outcome data. Pediatric MB survivors experience a high risk of neurocognitive adverse effects, often attributed to the whole-brain irradiation that is part of standard management. Neurogenesis is very sensitive to radiation, and limiting the radiation dose to the hippocampus and the subventricular zone (SVZ) may preserve neurocognitive function. Radiotherapy plans were created using 4 techniques: standard opposing fields, intensity-modulated radiotherapy (IMRT), intensity-modulated arc therapy (IMAT), and intensity-modulated proton therapy (IMPT). Mean dose to the hippocampus and SVZ (mean for both sites) could be limited to 88.3% (range, 83.6%–91.0%), 77.1% (range, 71.5%–81.3%), and 42.3% (range, 26.6%–51.2%) with IMAT, IMRT, and IMPT, respectively, while maintaining at least 95% of the prescribed dose in 95% of the whole-brain target volume. Estimated risks for developing memory impairment after a prescribed dose of 23.4 Gy were 47% (95% confidence interval [CI], 21%–69%), 44% (95% CI, 21%–65%), 41% (95% CI, 22%–60%), and 33% (95% CI, 23%–44%) with opposing fields, IMAT, IMRT, and IMPT, respectively. Neurogenic niche sparing during cranial irradiation of pediatric patients with MB is feasible and is estimated to lower the risks of long-term neurocognitive sequelae. Greatest sparing is achieved with intensity-modulated proton therapy, thus making this an attractive option to be tested in a prospective clinical trial.
Role of Protein C in Renal Dysfunction after Polymicrobial Sepsis
Authors: Akanksha Gupta, David T. Berg, Bruce Gerlitz, Ganesh R. Sharma, Samreen Syed, Mark A. Richardson, George Sandusky, Josef G. Heuer, Elizabeth J. Galbreath, Brian W. Grinnell
Journal: Journal of the American Society of Nephrology (2007)

Protein C (PC) plays an important role in vascular function, and acquired deficiency during sepsis is associated with increased mortality in both animal models and in clinical studies. This study explored the consequences of PC suppression on the kidney in a cecal ligation and puncture model of polymicrobial sepsis. This study shows that a rapid drop in PC after sepsis is strongly associated with an increase in blood urea nitrogen, renal pathology, and expression of known markers of renal injury, including neutrophil gelatinase-associated lipocalin, CXCL1, and CXCL2. The endothelial PC receptor, which is required for the anti-inflammatory and antiapoptotic activity of activated PC (APC), was significantly increased after cecal ligation and puncture as well as in the microvasculature of human kidneys after injury. Treatment of septic animals with APC reduced blood urea nitrogen, renal pathology, and chemokine expression and dramatically reduced the induction of inducible nitric oxide synthase and caspase-3 activation in the kidney. The data demonstrate a clear link between acquired PC deficiency and renal dysfunction in sepsis and suggest a compensatory upregulation of the signaling receptor. Moreover, these data suggest that APC treatment may be effective in reducing inflammatory and apoptotic insult during sepsis-induced acute renal failure.
Inhibition of Tumor Growth and Metastasis Establishment by Adenovirus-mediated Gene Transfer Delivery of the Antiangiogenic Factor 16K hPRL
Authors: Ngoc-Quynh-Nhu Nguyen, Anne Cornet, Silvia Blacher, Sébastien P Tabruyn, Jean-Michel Foidart, Agnès Noël, Joseph A Martial, Ingrid Struman
Journal: Molecular Therapy (2007)

Tumor metastases, the most fearsome aspect of cancer, are generally resistant to conventional therapies. Angiogenesis is a crucial aspect of tumor growth and metastatic dissemination. Antiangiogenic therapy, therefore, holds potential as an attractive strategy for inhibiting metastasis development. Human 16K PRL (16K hPRL), a potent inhibitor of angiogenesis, has been demonstrated to prevent tumor growth in two xenograft mouse models, but whether it also affects tumor metastasis is unknown. In this study we will investigate the ability of 16K hPRL to prevent the establishment of metastasis. We demonstrate that 16K hPRL administered via adenovirus-mediated gene transfer, inhibits tumor growth by 86% in a subcutaneous (SC) B16-F10 mouse melanoma model. Computer-assisted image analysis shows that 16K hPRL treatment results in a reduction of tumor-vessel length and width, leading to a 57% reduction of average vessel size. In a pre-established tumor model, moreover, 16K hPRL can significantly delay tumor development. Finally, for the first time, we provide evidence that 16K hPRL considerably reduces the establishment of B16-F10 metastasis in an experimental lung metastasis model. Both the number and size of metastases are reduced by 50% in 16K hPRL-treated mice. These results highlight a potential role for 16K hPRL in anticancer therapy for both primary tumors and metastases.
Diagnostic Reliability of Telepsychiatry in American Indian Veterans
Authors: Jay H Shore, Daniel Savin, Heather Orton, Jan Beals, Spero M Manson
Journal: American Journal of Psychiatry (2007)

Objective: This study examined the reliability of the Structured Clinical Interview for DSM-III-R (SCID) in the administration of psychiatric assessments by real-time videoconferencing compared to face-to-face assessment within a rural American Indian community. Method: The SCID was administered to 53 male American Indian veterans who were randomly assigned over two separate occasions by different interviewers to face-to-face and real-time interactive videoconferencing within 2 weeks. Comparisons were made with prevalences, the McNemar test, and the kappa statistic. Results: With the exception of past-year substance dependence and abuse/dependence combined, there were no significant differences between face-to-face and videoconference administration. The majority of kappas calculated (76%) indicated a good or fair level of agreement. Externalizing disorders tended to elicit greater concordance than internalizing disorders. Conclusions: Overall, SCID assessment by live interactive videoconferencing did not differ significantly from face-to-face assessment in this population. Videoconferencing is a viable vehicle for clinical and research purposes.
Human Prostate Cancer Harbors the Stem Cell Properties of Bone Marrow Mesenchymal Stem Cells
Authors: Haiyen E. Zhau, Hui He, Christopher Y. Wang, Majd Zayzafoon, Colm Morrissey, Robert L. Vessella, Fray F. Marshall, Leland W. K. Chung, Ruoxiang Wang
Journal: Clinical Cancer Research (2011)

Prostate tumor cells frequently show the features of osteoblasts, which are differentiated from bone marrow mesenchymal stem cells. We examined human prostate cancer cell lines and clinical prostate cancer specimens for additional bone marrow mesenchymal stem cell properties.Prostate cancer cell lines were induced for osteoblastogenic and adipogenic differentiation, detected by standard staining methods and confirmed by lineage-specific marker expression. Abnormal expression of the markers was then assessed in clinical prostate cancer specimens.After osteoblastogenic induction, cells of the LNCaP lineage, PC-3 lineage, and DU145 displayed osteoblastic features. Upon adipogenic induction, PC-3 lineage and DU145 cells differentiated into adipocyte-like cells. The adipocyte-like cancer cells expressed brown adipocyte-specific markers, suggesting differentiation along the brown adipocyte lineage. The adipogenic differentiation was accompanied by growth inhibition, and most of the adipocyte-like cancer cells were committed to apoptotic death. During cyclic treatments with adipogenic differentiation medium and then with control medium, the cancer cells could commit to repeated adipogenic differentiation and retrodifferentiation. In clinical prostate cancer specimens, the expression of uncoupling protein 1 (UCP1), a brown fat-specific marker, was enhanced with the level of expression correlated to disease progression from primary to bone metastatic cancers.This study thus revealed that prostate cancer cells harbor the stem cell properties of bone marrow mesenchymal stem cells. The abnormally expressed adipogenic UCP1 protein may serve as a unique marker, while adipogenic induction can be explored as a differentiation therapy for prostate cancer progression and bone metastasis.
Epitope-Specific Regulation
Authors: Leonore A. Herzenberg, Takeshi Tokuhisa, Kyoko Hayakawa
Journal: Annual Review of Immunology (1983)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
Radial Artery Free and T Graft Patency as Coronary Artery Bypass Conduit Over a 15-Year Period
Authors: Hendrick B. Barner, Marci Bailey, Tracey J. Guthrie, Michael K. Pasque, Marc R. Moon, Ralph J. Damiano, Jennifer S. Lawton
Journal: Circulation (2012)

Background— The radial artery is often used as the second arterial graft for coronary artery bypass grafting. Little is known about the differences in long-term patency between radial free and T grafts. This study was performed to determine long-term radial artery patency over a 15-year period. Methods and Results— Radial arteries were used as free grafts or T grafts for coronary artery bypass grafting over a 15-year period. Patients were contacted to determine if postoperative cardiac catheterization was performed and examination of any reports and films was performed. Grafts were graded as patent, luminal irregularity, or occluded. Each sequential graft was counted separately. Between September 1993 and December 2008, 13 926 patients underwent isolated coronary artery bypass grafting and 3248 patients had at least one radial artery graft used as a conduit. Catheterizations were performed at a mean of 7.4±3.8 years (range, 3 days to 14.4 years) on 372 radial artery grafts (103 free and 269 T) in 215 patients. Kaplan-Meier freedom from occlusion for radial free and T grafts at 1 and 10 years was 97.1% and 75.4% and 99.6% and 62.9%, respectively ( P =0.146 free versus T). Kaplan-Meier survival to 15 years was not statistically different between free and T graft patients ( P =0.5). Conclusions— In 215 patients with postoperative catheterization after coronary artery bypass grafting with a radial artery graft, radial free and T grafts had similar and acceptable long-term patency to support their use as a coronary artery bypass graft conduit.
The genes that underlie fatty liver disease: The harvest has begun
Authors: Ralf Weiskirchen, Hermann E. Wasmuth, Kris Kowdley, Geoffrey McCaughan, Christian Trautwein
Journal: Hepatology (2009)

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ancestry groups. To identify genetic variants contributing to differences in hepatic fat content, we carried out a genome-wide association scan of nonsynonymous sequence variations (n = 9,229) in a population comprising Hispanic, African American and European American individuals. An allele in PNPLA3 (rs738409[G], encoding I148M) was strongly associated with increased hepatic fat levels (P = 5.9 × 10(-10)) and with hepatic inflammation (P = 3.7 × 10(-4)). The allele was most common in Hispanics, the group most susceptible to NAFLD; hepatic fat content was more than twofold higher in PNPLA3 rs738409[G] homozygotes than in noncarriers. Resequencing revealed another allele of PNPLA3 (rs6006460[T], encoding S453I) that was associated with lower hepatic fat content in African Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ancestry-related and inter-individual differences in hepatic fat content and susceptibility to NAFLD.
Carbon dioxide responsiveness in COPD patients with and without chronic hypercapnia
Authors: G Scano, A Spinelli, R Duranti, M Gorini, F Gigliotti, P Goti, J Milic-Emili
Journal: European Respiratory Journal (1995)

To ascertain whether and to what extent the reduced ventilatory response to a hypercapnic stimulus in chronic obstructive pulmonary disease (COPD) patients depends on a blunted chemoresponsiveness of central origin or to mechanical impairment, we studied two groups of COPD patients without (group A) and with (group B) chronic hypercapnia, but with similar degrees of airway obstruction and hyperinflation. The study was performed on 17 patients (9 normocapnic and 8 hypercapnic). Six age-matched normal subjects (group C) were also studied as a control. During a CO2 rebreathing test, ventilation (VE), mouth occlusion pressure (P0.1), and the electromyographic activity of diaphragm (Edi) were recorded and then plotted against end-tidal carbon dioxide tension (PCO2). Inspiratory muscle strength was significantly lower in the hypercapnic group (group B) compared to normocapnic group (A), and in these groups compared to the control group (C). Both patient groups exhibited significantly lower delta VE/delta PCO2 than the control group. In hypercapnics, delta P0.1/delta PCO2 was significantly lower than in normocapnics and control group, whilst mouth occlusion pressure as % of maximal inspiratory pressure delta P0.1 (% MIP)/delta PCO2 did not differ significantly among the three groups. delta Edi/delta PCO2 increased from C to A. At a PCO2 of 8.65 kPa, VE was similar in the normocapnic and control group, but lower in hypercapnics; Edi was similar in hypercapnic and control group; but greater in normocapnics. P0.1(% MIP) did not differ significantly among groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Delivering regional thrombolysis via a hub-and-spoke model
Authors: Barry Moynihan, Daniel Davis, Anthony Pereira, Geoffrey Cloud, Hugh S Markus
Journal: Journal of the Royal Society of Medicine (2010)

Summary Objectives Audits in the United Kingdom and other countries show that only a small proportion of eligible stroke patients receive thrombolysis. Providing 24-hour thrombolysis cover presents major challenges in both infrastructure and staffing. One model for improving access is to provide out-of-hours cover in a regional centre but this may present problems including greater delays to hospital admissions. Design Evaluation of the introduction of a ‘hub-and-spoke’ model of thrombolysis to increase access to thrombolysis for patients in south west London. One-year data are presented. Setting A network in south-west London comprised of a hub hospital and three district ‘spoke’ hospitals. Participants All suspected stroke admissions to a regional stroke centre. Main outcome measures Thrombolysis rates for acute stroke. Results Increased out-of-hours thrombolysis rates were achieved with only a small increase in stroke admissions (approximately 10%) in the hub hospital. Thrombolysis rates increased from 1.2 per 100 stroke admissions for the local daytime service to 6 per 100 admissions for the regional service. Most patients thrombolysed were not local to the hub hospital. Only 1 in 4 patients considered for thrombolysis was thrombolysed, in line with previous data. Ten percent of all thrombolysis calls were not stroke but represented stroke mimics. Median length of stay was 6 days (target was 3 days). Fifty percent of the thrombolysed patients from spoke hospitals were discharged directly home. Conclusions In an urban area, a hub-and-spoke thrombolysis model increased access to thrombolysis without resulting in a marked increase in overall stroke admission numbers for the hub hospital. Proactive plans to repatriate patients back to district hospitals are required, and repatriation protocols have to prioritize regional patients over other targets in spoke hospitals to facilitate capacity in the hub hospital.
Clopidogrel with or without Omeprazole in Coronary Artery Disease
Authors: Deepak L Bhatt, Byron L Cryer, Charles F Contant, Marc Cohen, Angel Lanas, Thomas J Schnitzer, Thomas L Shook, Pablo Lapuerta, Mark A Goldsmith, Loren Laine, Benjamin M Scirica, Sabina A Murphy, Christopher P Cannon
Journal: New England Journal of Medicine (2010)

Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel.We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing.We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole.Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.).
CD99 Triggering in Ewing Sarcoma Delivers a Lethal Signal through p53 Pathway Reactivation and Cooperates with Doxorubicin
Authors: Clara Guerzoni, Valentina Fiori, Mario Terracciano, Maria Cristina Manara, Diego Moricoli, Michela Pasello, Marika Sciandra, Giordano Nicoletti, Mara Gellini, Sabrina Dominici, Claudia Chiodoni, Pier Maria Fornasari, Pier-Luigi Lollini, Mario P. Colombo, Piero Picci, Maurizio Cianfriglia, Mauro Magnani, Katia Scotlandi
Journal: Clinical Cancer Research (2014)

The paucity of new drugs for the treatment of Ewing sarcoma (EWS) limits the cure of these patients. CD99 has a strong membranous expression in EWS cells and, being also necessary for tumor survival, is a suitable target to aim at. In this article, we described a novel human monospecific bivalent single-chain fragment variable diabody (dAbd C7) directed against CD99 of potential clinical application.In vitro and in vivo evaluation of cell death and of the molecular mechanisms triggered by anti-CD99 agents were performed alone or in combination with doxorubicin to demonstrate efficacy and selectivity of the new dAbd C7.The dAbd C7 induced rapid and massive EWS cell death through Mdm2 degradation and p53 reactivation. Mdm2 overexpression as well as silencing of p53 in p53wt EWS cells decreased CD99-induced EWS cell death, whereas treatment with nutlin-3 enhanced it. Furthermore, cell death was associated with induction of p21, bax, and mitochondrial depolarization together with substantial inhibition of tumor cell proliferation. Combined treatment of anti-CD99 dAbd C7 with doxorubicin was additive both in vitro and in vivo against EWS xenografts. Normal mesenchymal stem cells showed no p53 activation and were resistant to cell death, unless transformed by EWS-FLI, the oncogenic driver of EWS.These results indicate that dAbd C7 is a suitable candidate tool to target CD99 in patients with EWS able to spare normal stem cells from death as it needs an aberrant genetic context for the efficient delivery of CD99-triggered cell death.
Consultants call for extra money to be spent on discretionary salary points
Authors: A. Gulland
Journal: BMJ (2003)

Consultants have rejected incentive payments put forward by health secretary Alan Milburn last month as “divisive” and will be calling on their colleagues to push for a new allocation of discretionary points to improve salaries.

Under Mr Milburn's proposals, put together after consultants overwhelmingly rejected a new contract last year, trusts had three options for rewarding senior clinicians. The first was to implement the disputed contract, if staff agreed. The second was to introduce annual incentive payments, with doctors performing best getting the greatest rewards. And the final option was to allocate money in the form of discretionary points and clinical excellence awards, which would be given …
Cognitive Correlates of Job Tenure Among Patients With Severe Mental Illness
Authors: James M Gold, Richard W Goldberg, Scot W McNary, Lisa B Dixon, Anthony F Lehman
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: There is clear evidence that cognitive performance is a correlate of functional outcome among patients with schizophrenia. However, few studies have specifically examined the cognitive correlates of competitive employment performance or the longer-term outcomes of vocational rehabilitation. The objective of the present study was to examine the cognitive predictors of vocational functioning in the context of a controlled clinical trial by comparing two approaches to vocational rehabilitation. METHOD: A broad neuropsychological battery was administered to 150 patients upon entry into the vocational rehabilitation trial. Vocational performance was assessed over a 24-month follow-up interval. RESULTS: There were no differences in baseline cognitive performance between the 40 patients who obtained competitive employment and the 110 patients who remained unemployed over the follow-up interval. In contrast, multiple cognitive measures were significantly correlated with the total number of hours that patients were employed. The cognition-job tenure relationship appears to be fairly general, involving measures of IQ, attention, working memory, and problem solving. CONCLUSIONS: Cognitive performance was a significant predictor of job tenure but not job attainment in the context of a clinical trial of two vocational rehabilitation approaches. It appears that many persistently unemployed patients are capable of obtaining competitive employment with effective vocational services. Longer-term employment success, however, may be related to multiple aspects of baseline cognitive performance.