tbuckley/cabot-search huggingface dataset:
Brain Graphs: Graphical Models of the Human Brain Connectome
Authors: Edward T. Bullmore, Danielle S. Bassett
Journal: Annual Review of Clinical Psychology (2011)

Brain graphs provide a relatively simple and increasingly popular way of modeling the human brain connectome, using graph theory to abstractly define a nervous system as a set of nodes (denoting anatomical regions or recording electrodes) and interconnecting edges (denoting structural or functional connections). Topological and geometrical properties of these graphs can be measured and compared to random graphs and to graphs derived from other neuroscience data or other (nonneural) complex systems. Both structural and functional human brain graphs have consistently demonstrated key topological properties such as small-worldness, modularity, and heterogeneous degree distributions. Brain graphs are also physically embedded so as to nearly minimize wiring cost, a key geometric property. Here we offer a conceptual review and methodological guide to graphical analysis of human neuroimaging data, with an emphasis on some of the key assumptions, issues, and trade-offs facing the investigator.
KRAS Mutations and Sensitivity to Epidermal Growth Factor Receptor Inhibitors in Colorectal Cancer: Practical Application of Patient Selection
Authors: Antonio Jimeno, Wells A. Messersmith, Fred R. Hirsch, Wilbur A. Franklin, S. Gail Eckhardt
Journal: Journal of Clinical Oncology (2009)

Recent retrospective evidence from several randomized studies has established that advanced colorectal cancer patients with tumors harboring a mutation in the KRAS gene do not derive benefit from the administration of epidermal growth factor receptor-directed monoclonal antibodies, such as cetuximab or panitumumab. This represents a paradigm-changing event and will have substantial impact on current and future anticancer drug development. These results add to the economic and ethical considerations involved in the development of novel targeted therapies and should increase our scrutiny of mechanisms of resistance and predictive biomarkers while in earlier developmental stages. In this article we will review the available clinical data, discuss the potential implications for future drug development in colorectal cancer, and provide a comprehensive overview of the technical aspects of KRAS mutation testing. In particular we aimed at enumerating the available procedures for mutation detection and their main characteristics, as well as comparing them from a clinical feasibility standpoint. While the true specificity and sensitivity of these methods have yet to be fully characterized, a better understanding of the differences between tests will be critical so that clinicians and pathologists can fully integrate this testing into the routine care of patients with colorectal cancer.
Arterial and renal consequences of partial genetic deficiency in tissue kallikrein activity in humans
Authors: Michel Azizi, Pierre Boutouyrie, Alvine Bissery, Mohsen Agharazii, Francis Verbeke, Nora Stern, Alessandra Bura-Rivière, Stéphane Laurent, François Alhenc-Gelas, Xavier Jeunemaitre
Journal: Journal of Clinical Investigation (2005)

Tissue kallikrein (TK), the major kinin-forming enzyme, is synthesized in several organs, including the kidney and arteries. A loss-of-function polymorphism of the human TK gene (R53H) induces a substantial decrease in enzyme activity. As inactivation of the TK gene in the mouse induces endothelial dysfunction, we investigated the vascular, hormonal, and renal phenotypes of carriers of the 53H allele. In a crossover study, 30 R53R-homozygous and 10 R53H-heterozygous young normotensive white males were randomly assigned to receive both a low sodium–high potassium diet to stimulate TK synthesis and a high sodium–low potassium diet to suppress TK synthesis, each for 1 week. Urinary kallikrein activity was 50–60% lower in R53H subjects than in R53R subjects. Acute flow-dependent vasodilatation and endothelium-independent vasodilatation of the brachial artery were both unaffected in R53H subjects. In contrast, R53H subjects consistently exhibited an increase in wall shear stress and a paradoxical reduction in artery diameter and lumen compared with R53R subjects. Renal and hormonal adaptation to diets was unaffected in R53H subjects. The partial genetic deficiency in TK activity is associated with an inward remodeling of the brachial artery, which is not adapted to a chronic increase in wall shear stress, indicating a new form of arterial dysfunction affecting 5–7% of white people.
Potassium chloride lowers blood pressure and causes natriuresis in older patients with hypertension.
Authors: S R Smith, P E Klotman, L P Svetkey
Journal: Journal of the American Society of Nephrology (1992)

Epidemiologic surveys, experimental studies in animals, and clinical trials in young and middle-aged patients with hypertension indicate that dietary potassium lowers blood pressure. The mechanism of the antihypertensive effect is not well defined. Variations in serum potassium within the physiologic range may directly affect vascular smooth muscle tone. Potassium may also influence the regulation of blood pressure through effects on sodium handling, aldosterone secretion, the renin/angiotensin system, renal kallikrein, eicosanoids, and atrial natriuretic peptide. This study was undertaken to confirm the blood pressure-lowering effect of potassium in older patients and to determine the mechanism of the antihypertensive effect. Twenty-two patients greater than or equal to 60 yr of age were admitted to a Clinical Research Unit for 8 days after a 2-wk period free of antihypertensive medication. Patients were placed on an isocaloric diet containing 200 mmol/day of Na+, 70 mmol/day of K+, and 500 mg/day of Ca2+ and were treated in a randomized, double-blinded manner with either potassium chloride (120 mmol/day) or placebo. After 4 days, patients were crossed over to the alternate treatment. Systolic blood pressure decreased 8.6 mm Hg (95% confidence interval -14.6, -2.6), and diastolic blood pressure decreased 4.0 mm Hg (-6.9, -1.0) during potassium chloride supplementation. There was no significant change in blood pressure during treatment with placebo. Serum K+ was 3.9 +/- 0.1 mmol/L after 3 days of placebo and 4.3 +/- 0.1 after 4 days of potassium chloride (P less than 0.002). Urinary sodium excretion averaged 192 +/- 11 mmol/day after placebo and 221 +/- 8 after potassium treatment (P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
A randomized phase II study of sequential docetaxel and doxorubicin/cyclophosphamide in patients with metastatic breast cancer
Authors: E.A. Perez, L. Geeraerts, V.J. Suman, A.A. Adjei, A.T. Baron, A.K. Hatfield, N. Maihle, J.C. Michalak, S.A. Kuross, J.W. Kugler, J.M. Lafky, J.N. Ingle
Journal: Annals of Oncology (2002)
Phase I study of BBR 2778, a new aza-anthracenedione, in advanced or refractory non-Hodgkin’s lymphoma
Authors: P Borchmann, R Schnell, R Knippertz, J O Staak, G M Camboni, A Bernareggi, K Hübel, P Staib, A Schulz, V Diehl, A Engert
Journal: Annals of Oncology (2001)
Supplemental oxygen during pulmonary rehabilitation in patients with COPD with exercise hypoxaemia
Authors: R Garrod
Journal: Thorax (2000)

<h3>BACKGROUND</h3> Supplemental oxygen in patients with chronic obstructive pulmonary disease (COPD) and exercise hypoxaemia improves exercise capacity and dyspnoea. However, the benefit of oxygen during pulmonary rehabilitation in these patients is still unknown. <h3>METHODS</h3> Twenty five patients with stable COPD (mean (SD) forced expiratory volume in one second (FEV<sub>1</sub>) 0.76 (0.29) l and 30.0 (9.89)% predicted, arterial oxygen tension (Pao<sub>2</sub>) 8.46 (1.22) kPa, arterial carbon dioxide tension (Paco<sub>2</sub>) 6.32 (1.01) kPa) and significant arterial desaturation on exercise (82.0 (10.4)%) were entered onto a pulmonary rehabilitation programme. Patients were randomised to train whilst breathing oxygen (OT) (n = 13) or air (AT) (n = 12), both at 4 l/min. Assessments included exercise tolerance and associated dyspnoea using the shuttle walk test (SWT) and Borg dyspnoea score, health status, mood state, and performance during daily activities. <h3>RESULTS</h3> The OT group showed a significant reduction in dyspnoea after rehabilitation compared with the AT group (Borg mean difference –1.46 (95% CI –2.72 to –0.19)) but there were no differences in other outcome measures: SWT difference –23.6 m (95% CI –70.7 to 23.5), Chronic Respiratory Disease Questionnaire 3.67 (95% CI –7.70 to 15.1), Hospital Anxiety and Depression Scale 1.73 (95% CI –2.32 to 5.78), and London Chest Activity of Daily Living Scale –2.18 (95% CI –7.15 to 2.79). At baseline oxygen significantly improved SWT (mean difference 27.3 m (95% CI 14.7 to 39.8) and dyspnoea (–0.68 (95% CI –1.05 to –0.31)) compared with placebo air. <h3>CONCLUSIONS</h3> This study suggests that supplemental oxygen during training does little to enhance exercise tolerance although there is a small benefit in terms of dyspnoea. Patients with severe disabling dyspnoea may find symptomatic relief with supplemental oxygen.
EULAR points to consider for conducting clinical trials in systemic lupus erythematosus: literature based evidence for the selection of endpoints: Table 1
Authors: G K Bertsias, J P A Ioannidis, J Boletis, S Bombardieri, R Cervera, C Dostal, J Font, I M Gilboe, F Houssiau, T Huizinga, D Isenberg, C G M Kallenberg, M Khamashta, J C Piette, M Schneider, J Smolen, G Sturfelt, A Tincani, R van Vollenhoven, D T Boumpas, C Gordon
Journal: Annals of the Rheumatic Diseases (2008)

To assess available evidence on the use of end-points (outcome measures) in clinical trials in systemic lupus erythematosus (SLE), as a part of the development of evidence-based recommendations for points to consider in clinical trials in SLE.The European League Against Rheumatism (EULAR) Task Force on SLE comprised 19 specialists, a clinical epidemiologist and a research fellow. Key questions addressing the evidence for clinical trial end-points in SLE were compiled using the Delphi technique. A systematic search of the PubMed and Cochrane Library databases was performed using McMaster/Hedges clinical query strategies and an array of relevant terms. Evidence was categorised based on sample size and type of design, and the categories of available evidence were identified for each recommendation. The strength of recommendation was assessed based on the category of available evidence and agreement on the statements was measured across the 19 specialists.Eight questions were generated regarding end-points for clinical trials. The evidence to support each proposition was evaluated. The literature review revealed that most outcome measures used in phase 2/3 trials in SLE have not been formally validated in clinical trials, although some indirect validation has been undertaken.This systematic literature review forms the evidence base considered in the development of the EULAR recommendations for end-points in clinical trials in SLE.
Paracetamol: not as safe as we thought? A systematic literature review of observational studies
Authors: Emmert Roberts, Vanessa Delgado Nunes, Sara Buckner, Susan Latchem, Margaret Constanti, Paul Miller, Michael Doherty, Weiya Zhang, Fraser Birrell, Mark Porcheret, Krysia Dziedzic, Ian Bernstein, Elspeth Wise, Philip G Conaghan
Journal: Annals of the Rheumatic Diseases (2015)

Objectives We conducted a systematic literature review to assess the adverse event (AE) profile of paracetamol. Methods We searched Medline and Embase from database inception to 1 May 2013. We screened for observational studies in English, which reported mortality, cardiovascular, gastrointestinal (GI) or renal AEs in the general adult population at standard analgesic doses of paracetamol. Study quality was assessed using Grading of Recommendations Assessment, Development and Evaluation. Pooled or adjusted summary statistics were presented for each outcome. Results Of 1888 studies retrieved, 8 met inclusion criteria, and all were cohort studies. Comparing paracetamol use versus no use, of two studies reporting mortality one showed a dose–response and reported an increased relative rate of mortality from 0.95 (0.92 to 0.98) to 1.63 (1.58 to 1.68). Of four studies reporting cardiovascular AEs, all showed a dose–response with one reporting an increased risk ratio of all cardiovascular AEs from 1.19 (0.81 to 1.75) to 1.68 (1.10 to 2.57). One study reporting GI AEs reported a dose–response with increased relative rate of GI AEs or bleeds from 1.11 (1.04 to 1.18) to 1.49 (1.34 to 1.66). Of four studies reporting renal AEs, three reported a dose–response with one reporting an increasing OR of ≥30% decrease in estimated glomerular filtration rate from 1.40 (0.79 to 2.48) to 2.19 (1.4 to 3.43). Discussion Given the observational nature of the data, channelling bias may have had an important impact. However, the dose–response seen for most endpoints suggests a considerable degree of paracetamol toxicity especially at the upper end of standard analgesic doses.
Matched Unrelated or Matched Sibling Donors Result in Comparable Survival After Allogeneic Stem-Cell Transplantation in Elderly Patients With Acute Myeloid Leukemia: A Report From the Cooperative German Transplant Study Group
Authors: Johannes Schetelig, Martin Bornhäuser, Christoph Schmid, Bernd Hertenstein, Rainer Schwerdtfeger, Hans Martin, Matthias Stelljes, Ute Hegenbart, Kerstin Schäfer-Eckart, Monika Füssel, Barbel Wiedemann, Christian Thiede, Joachim Kienast, Herrad Baurmann, Arnold Ganser, Hans Jochem Kolb, Gerhard Ehninger
Journal: Journal of Clinical Oncology (2008)

Purpose In patients with acute myeloid leukemia (AML), differential indications for matched sibling and unrelated hematopoietic stem-cell transplantation (HCT) are considered, and arbitrary age limits for HCT exist. We sought to determine whether donor type is a prognostic factor in elderly patients in the era of high-resolution DNA-based HLA typing. Patients and Methods We performed univariate and multivariate analyses of event-free survival (EFS) and overall survival (OS) in patients older than 50 years with standard- or high-risk AML who had received an allogeneic HCT between 1995 and 2005. Available DNA from donors and recipients of unrelated HCT was retyped so that the HLA-A, -B, -C, and -DRB1 alleles could be characterized in detail. Unrelated donors (UDs) were classified as matched (8/8), possibly matched (matched, but incomplete information), partially matched (one mismatch), or poorly matched (two or more mismatches) according to the final typing results. Results Data from 368 patients with a median age of 57 years (range, 50 to 73 years) were included. Multivariate Cox regression analysis revealed that patients’ disease status at HCT (P < .001) and the cytogenetic risk (P < .001) highly significantly predicted EFS and OS. Compared with patients with matched sibling donors, the adjusted relative risk of EFS was 0.7 (95% CI, 0.4 to 1.1) for patients with matched UDs and 1.0 (95% CI, 0.7 to 1.6) for patients with partially matched UDs. Conclusion Donor type is not a major prognostic factor for HCT in elderly patients with standard- or high-risk AML.
Vitamin D–Binding Protein and Vitamin D Status of Black Americans and White Americans
Authors: Camille E. Powe, Michele K. Evans, Julia Wenger, Alan B. Zonderman, Anders H. Berg, Michael Nalls, Hector Tamez, Dongsheng Zhang, Ishir Bhan, S. Ananth Karumanchi, Neil R. Powe, Ravi Thadhani
Journal: New England Journal of Medicine (2013)

Low levels of total 25-hydroxyvitamin D are common among black Americans. Vitamin D–binding protein has not been considered in the assessment of vitamin D deficiency.
Structured Conversion from Thrice Weekly to Weekly Erythropoietic Regimens Using a Computerized Decision-Support System
Authors: Cae Tolman, Donald Richardson, Cherry Bartlett, Eric Will
Journal: Journal of the American Society of Nephrology (2005)

In view of the recent interest in weekly erythropoietic regimens and the lack of studies directly comparing the available agents, the clinical effectiveness of darbepoetin-alpha (DA) and epoetin-beta (EB), when administered via the subcutaneous route on a weekly basis, after conversion from thrice-weekly subcutaneous EB, was studied. In this 9-mo, single-center, randomized study of an unselected hemodialysis population, anemia was managed with a computerized decision-support system. Per-protocol analysis of the 81 patients in each arm who completed the study showed similar hemoglobin outcomes between treatment arms, both at randomization and at the end of the study. After conversion from thrice-weekly EB to DA (at a ratio of 200 IU:1 microg, at which products are cost-neutral in the European Union), a significant fall in dose from a mean of 0.59 microg/kg per wk after randomization to 0.46 microg/kg per wk in the last month (P = 0.002) was observed; in the comparator arm, the reduction in frequency of administration of EB was associated with a significant dose increase from a mean of 107.5 to 133.2 IU/kg per wk (P = 0.002) during the same period. At hemoglobin stability, mean EB dose was found to be 44% higher than DA dose (when multiplied by 200). Similar significant dose differences were apparent in a modified intention-to-treat analysis. The study demonstrated that, under a decision-support system, both products were capable of adequately maintaining hemoglobin outcome when administered on a weekly basis but with significant dose differences at 9 mo.
Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females
Authors: E. D. Austin, J. D. Cogan, J. D. West, L. K. Hedges, R. Hamid, E. P. Dawson, L. A. Wheeler, F. F. Parl, J. E. Loyd, J. A. Phillips
Journal: European Respiratory Journal (2009)

Mutations in bone morphogenetic protein receptor type 2 ( BMPR2 ) cause familial pulmonary arterial hypertension (FPAH), but the penetrance is reduced and females are significantly overrepresented. In addition, gene expression data implicating the oestrogen-metabolising enzyme CYP1B1 suggests a detrimental role of oestrogens or oestrogen metabolites. We examined genetic and metabolic markers of altered oestrogen metabolism in subjects with a BMPR2 mutation. Genotypes for CYP1B1 Asn453Ser ( N453S ) were determined for 140 BMPR2 mutation carriers (86 females and 54 males). Nested from those subjects, a case–control study of urinary oestrogen metabolite levels (2-hydroxyoestrogen (2-OHE) and 16α-hydroxyoestrone (16α-OHE 1 )) was conducted in females (five affected mutation carriers versus six unaffected mutation carriers). Among females, there was four-fold higher penetrance among subjects homozygous for the wild-type genotype (N/N) than those with N/S or S/S genotypes (p = 0.005). Consistent with this finding, the 2-OHE/16α-OHE 1 ratio was 2.3-fold lower in affected mutation carriers compared to unaffected mutation carriers (p = 0.006). Our findings suggest that variations in oestrogens and oestrogen metabolism modify FPAH risk. Further investigation of the role of oestrogens in this disease with profound sex bias may yield new insights and, perhaps, therapeutic interventions.
Hyperlipaemia intensifies the course of acute oedematous and acute necrotising pancreatitis in the rat.
Authors: B Hofbauer, H Friess, A Weber, K Baczako, P Kisling, M Schilling, W Uhl, C Dervenis, M W Buchler
Journal: Gut (1996)

Serum triglyceride concentrations higher than 10 to 20 mmol/l are probably a risk factor for developing acute pancreatitis in humans.To therefore analyse the influence of hyperlipaemia on the course of acute oedematous and acute necrotising pancreatitis in rats.Male Wistar rats were used in all experiments.Six different groups of animals were used: two groups without pancreatitis (controls), two with acute oedematous pancreatitis, and two with acute necrotising pancreatitis. One group from each pair was treated with Triton WR 1339, which induces endogenous hyperlipaemia. Blood samples were taken from all subjects to measure triglyceride, cholesterol, amylase, and lipase. Pancreatic tissue samples were taken and the degree of pancreatic damage was judged microscopically.In the control groups no significant changes occurred, either in serum enzyme activities or in histology. The hyperlipaemic subgroup of animals with acute oedematous pancreatitis developed significantly higher (p < 0.001) serum amylase activities and a greater degree of histological damage (p < 0.01) than the animals of the non-hyperlipaemic acute oedematous pancreatitis group. In the animals with necrotising pancreatitis, serum lipase activity and the histological degree of pancreatic damage were significantly higher in the hyperlipaemic animals than in the non-hyperlipaemic animals.This study shows that hyperlipaemia intensifies the course of acute oedematous and acute necrotising pancreatitis in rats.
Efficacy of Systemically Administered Oncolytic Vaccinia Virotherapy for Malignant Gliomas Is Enhanced by Combination Therapy with Rapamycin or Cyclophosphamide
Authors: Xue Qing Lun, Ji-Hyun Jang, Nan Tang, Helen Deng, Renee Head, John C. Bell, David F. Stojdl, Catherine L. Nutt, Donna L. Senger, Peter A. Forsyth, J. Andrea McCart
Journal: Clinical Cancer Research (2009)

The oncolytic effects of a systemically delivered, replicating, double-deleted vaccinia virus has been previously shown for the treatment of many cancers, including colon, ovarian, and others. The purpose of this study was to investigate the oncolytic potential of double-deleted vaccinia virus alone or in combination with rapamycin or cyclophosphamide to treat malignant gliomas in vitro and in vivo.Rat (RG2, F98, C6) and human (A172, U87MG, U118) glioma cell lines were cultured in vitro and treated with live or UV-inactivated vaccinia virus. Viral gene [enhanced green fluorescent protein (EGFP)] expression by fluorescence-activated cell sorting, relative cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and assays for cytopathic effects were examined. S.c. murine tumor xenografts (U87MG, U118, C6) and i.c. (RG2, F98) tumor models in immunocompetent rats were treated with systemic administration of EGFP-expressing vaccinia virus (vvDD-EGFP), alone or in combination with rapamycin or cyclophosphamide, or controls. Tumor size, viral biodistribution, and animal survival were assessed. Lastly, the oncolytic effects of vvDD-EGFP on human malignant glioma explants were evaluated.vvDD-EGFP was able to infect and kill glioma cells in vitro. A single systemic dose of vvDD-EGFP significantly inhibited the growth of xenografts in athymic mice. Systemic delivery of vvDD-EGFP alone was able to target solitary and multifocal i.c. tumors and prolong survival of immunocompetent rats, whereas combination therapy with rapamycin or cyclophosphamide enhanced viral replication and further prolonged survival. Finally, vvDD-EGFP was able to infect and kill ex vivo primary human malignant gliomas.These results suggest that vvDD-EGFP is a promising novel agent for human malignant glioma therapy, and in combination with immunosuppressive agents, may lead to prolonged survival from this disease.