tbuckley/cabot-search huggingface dataset:
Targeted Therapy for Metastatic Renal Cell Carcinoma
Authors: Robert J. Motzer, Ronald M. Bukowski
Journal: Journal of Clinical Oncology (2006)

The discovery of a relationship for the VHL tumor suppressor gene, hypoxia inducible factor-1 alpha, and vascular endothelial growth factor in the growth of clear-cell renal cell carcinoma (RCC) has identified a pathway for novel targeted therapy. This study evaluated the impact of these agents on metastatic RCC (mRCC), and highlights recent phase II and III trials. A systematic review examined the clinical data for novel targeted agents in mRCC, with a focus on randomized phase II and III trials of the novel targeted agents sunitinib, temsirolimus, sorafenib, and bevacizumab. Several agents, including the small-molecule targeted inhibitors sunitinib, temsirolimus, sorafenib, and the monoclonal antibody bevacizumab, have demonstrated antitumor activity in randomized trials. Superior activity was found with sunitinib and temsirolimus versus cytokines in first-line therapy. Improved progression-free survival was reported with sorafenib and bevacizumab given second-line compared with placebo. Targeted therapies show promising activity in this disease, and they have been changing patient management. Sunitinib and sorafenib were recently approved by the US Food and Drug Administration for treatment of mRCC, These drugs are currently included in clinical practice.
California will be only state to meet government target on smoking
Authors: DC Bob Roehr
Journal: BMJ (2006)

California is likely to be the only US state that will meet government targets on smoking cessation published in 2000, a conference heard last week.

In its document Healthy People 2010 the US Department of Health and Human Services said it wanted to see the percentage of smokers in the population reduced to 12% or less among adults and to 16% or less among young people. The current estimates are 21% and 22% respectively.

California was going to meet the target because of its ban on smoking in public and aggressive education and intervention campaigns, said Frederic Blow, a mental illness researcher at the Ann Arbor Veterans Administration Medical Center, Michigan, …
Hypermethylation of CpG Islands and Shores around Specific MicroRNAs and Mirtrons Is Associated with the Phenotype and Presence of Bladder Cancer
Authors: Ewa Dudziec, Saiful Miah, Hani M.Z Choudhry, Helen C. Owen, Sheila Blizard, Maggie Glover, Freddie C. Hamdy, James W.F. Catto
Journal: Clinical Cancer Research (2010)

Abstract Purpose: To analyze the role and translational potential for hypermethylation of CpG islands and shores in the regulation of small RNAs within urothelial cell carcinoma (UCC). To examine microRNAs (miR) and mirtrons, a new class of RNA located within gene introns and processed in a Drosha-independent manner. Experimental design: The methylation status of 865 small RNAs was evaluated in normal and malignant cell lines by using 5-azacytidine and microarrays. Bisulfite sequencing was used for CpG regions around selected RNAs. Prognostic and diagnostic associations for epigenetically regulated RNAs were examined by using material from 359 patients, including 216 tumors and 121 urinary samples (68 cases and 53 controls). Functional analyses examined the effect of silencing susceptible RNAs in normal urothelial cells. Results: Exonic/UTR-located miRs and mirtons are most susceptible to epigenetic regulation. We identified 4 mirtrons and 16 miRs with CpG hypermethylation across 35 regions in normal and malignant urothelium. For several miRs, hypermethylation was more frequent and dense in CpG shores than islands (e.g., miRs-9/149/210/212/328/503/1224/1227/1229), and was associated with tumor grade, stage, and prognosis (e.g., miR-1224 multivariate analysis OR = 2.5; 95% CI, 1.3–5.0; P = 0.006). The urinary expression of epigenetically silenced RNAs (miRs-152/328/1224) was associated with the presence of UCC (concordance index, 0.86; 95% CI, 0.80–0.93; ANOVA P &amp;lt; 0.016). Conclusions: Hypermethylation of mirtrons and miRs is common in UCC. Mirtrons appear particularly susceptible to epigenetic regulation. Aberrant hypermethylation of small RNAs is associated with the presence and behavior of UCC, suggesting potential roles as diagnostic and prognostic biomarkers. Clin Cancer Res; 17(6); 1287–96. ©2010 AACR.
Long-Term Outcomes in a Prospective Cohort of Apprentices Exposed to High-Molecular-Weight Agents
Authors: Denyse Gautrin, Heberto Ghezzo, Claire Infante-Rivard, Michèle Magnan, Jocelyne L'Archevêque, Eva Suarthana, Jean-Luc Malo
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Rationale: We conducted a long-term (8-yr) follow-up of 408 apprentices entering programs involving exposure to high-molecular-weight allergens.Objectives: The objectives were to assess the frequency of new and persisting sensitization, symptoms, and bronchial hyperresponsiveness in relation with job history after ending apprenticeship and to examine characteristics significantly associated with the incidence and remission of these occupational outcomes.Methods: A respiratory symptom questionnaire, skin prick tests with work-related allergens (laboratory animals, flour, and latex), spirometry, and methacholine challenge were administered. The association between incidence or remission of these outcomes and individual characteristics at baseline and end of apprenticeship was examined.Measurements and Main Results: In subjects who at any time during follow-up held a job related to their training (78%), the incidence of sensitization, rhinoconjunctival and chest symptoms, and bronchial hyperresponsiveness at follow-up was 1.3, 1.7, 0.7, and 2.0 per 100 person-years, respectively. The remission of these outcomes acquired during apprenticeship was 18.5, 9.6, 9.6, and 12.4 per 100 person-years, respectively, in subjects no longer in a job related to training. Several clinical, immunological, and functional characteristics at baseline and acquired during apprenticeship were found to be significantly associated with the incidence and remission of the outcomes.Conclusions: The incidence of sensitization, symptoms, and bronchial hyperresponsiveness was lower while at work than during the apprenticeship period. A high proportion of subjects in a job not related to training experienced remission of symptoms acquired during apprenticeship.
The management of chronic breathlessness in patients with advanced and terminal illness
Authors: M. P. Ekstrom, A. P. Abernethy, D. C. Currow
Journal: BMJ (2015)

<i>Abstract.</i> The decorin gene encodes a proteoglycan with putative structural and regulatory functions whose expression is markedly increased in human mesangial cells (HMC) exposed to high concentrations of glucose (15 to 30 mM). The gene has two promoters (P1 and P2) upstream of two alternative first exons. Transcripts driven by both promoters are present in HMC maintained in 4 mM D-glucose medium. After exposure to 30 mM D-glucose for 7 to 21 d, transcripts driven by P1 are markedly increased, whereas those driven by P2 decrease. Culture in 4 mM D-glucose medium containing transforming growth factor-β1 (TGF-β1) (1.25 ng/ml) has the same effect. However, addition of an excess of TGF-β neutralizing antibody to the 30 mM D-glucose cultures only partly suppressed increased decorin transcription from P1. In transformed HMC transfected with a reporter (p-SAEP) driven by P1 or P2, P1 activity increased twofold on treatment with either 30 mM D-glucose or TGF-β1 in 4 mM medium. P2 had little activity under any conditions. 5′ deletion of P1 showed that basal transcriptional activity lies within the proximal 378 bp, while the major high glucose and TGF-β response element is located in the -683 to -583-bp region. A putative cAMP response-like sequence (TGACGTTT) lies within this region. Electrophoretic mobility shift assays revealed the same pattern of multiple complexes between oligonucleotides containing this sequence and nuclear proteins extracted from HMC maintained in either 4 or 30 mM D-glucose conditions, but the latter were more prominent. cAMP response element binding protein (CREB) was identified as one transcription factor forming these complexes but other factors remain unidentified. Increased levels of phospho-(Ser 133) CREB were found in HMC exposed to 30 mM D-glucose. High glucose also activated and led to nuclear translocation of p42/44 mitogen-activated protein kinase and p38 mitogen-activated protein kinase, both of which can activate CREB by phosphorylation of serine 133.
Evaluation of an Improved Branch-Site Likelihood Method for Detecting Positive Selection at the Molecular Level
Authors: Jianzhi Zhang, Rasmus Nielsen, Ziheng Yang
Journal: Molecular Biology and Evolution (2005)

Detecting positive Darwinian selection at the DNA sequence level has been a subject of considerable interest. However, positive selection is difficult to detect because it often operates episodically on a few amino acid sites, and the signal may be masked by negative selection. Several methods have been developed to test positive selection that acts on given branches (branch methods) or on a subset of sites (site methods). Recently, Yang, Z., and R. Nielsen (2002. Codon-substitution models for detecting molecular adaptation at individual sites along specific lineages. Mol. Biol. Evol. 19:908-917) developed likelihood ratio tests (LRTs) based on branch-site models to detect positive selection that affects a small number of sites along prespecified lineages. However, computer simulations suggested that the tests were sensitive to the model assumptions and were unable to distinguish between relaxation of selective constraint and positive selection (Zhang, J. 2004. Frequent false detection of positive selection by the likelihood method with branch-site models. Mol. Biol. Evol. 21:1332-1339). Here, we describe a modified branch-site model and use it to construct two LRTs, called branch-site tests 1 and 2. We applied the new tests to reanalyze several real data sets and used computer simulation to examine the performance of the two tests by examining their false-positive rate, power, and robustness. We found that test 1 was unable to distinguish relaxed constraint from positive selection affecting the lineages of interest, while test 2 had acceptable false-positive rates and appeared robust against violations of model assumptions. As test 2 is a direct test of positive selection on the lineages of interest, it is referred to as the branch-site test of positive selection and is recommended for use in real data analysis. The test appeared conservative overall, but exhibited better power in detecting positive selection than the branch-based test. Bayes empirical Bayes identification of amino acid sites under positive selection along the foreground branches was found to be reliable, but lacked power.
Population-Based Validation of the Prognostic Model ADJUVANT! for Early Breast Cancer
Authors: Ivo A. Olivotto, Chris D. Bajdik, Peter M. Ravdin, Caroline H. Speers, Andrew J. Coldman, Brian D. Norris, Greg J. Davis, Stephen K. Chia, Karen A. Gelmon
Journal: Journal of Clinical Oncology (2005)

Purpose Adjuvant! ( www.adjuvantonline.com ) is a web-based tool that predicts 10-year breast cancer outcomes with and without adjuvant systemic therapy, but it has not been independently validated. Methods Using the British Columbia Breast Cancer Outcomes Unit (BCOU) database, demographic, pathologic, staging, and treatment data on 4,083 women diagnosed between 1989 and 1993 in British Columbia with T1-2, N0-1, M0 breast cancer were abstracted and entered into Adjuvant! to calculate predicted 10-year overall survival (OS), breast cancer–specific survival (BCSS), and event-free survival (EFS) for each patient. Individual BCOU observed outcomes at 10 years were independently determined. Predicted and observed outcomes were compared. Results Across all 4,083 patients, 10-year predicted and observed outcomes were within 1% for OS, BCSS, and EFS (all P &gt; .05). Predicted and observed outcomes were within 2% for most demographic, pathologic, and treatment-defined subgroups. Adjuvant! overestimated OS, BCSS, and EFS in women younger than age 35 years (predicted − observed = 8.6%, 9.6%, and 13.6%, respectively; all P &lt; .001) or with lymphatic or vascular invasion (LVI; predicted − observed = 3.6%, 3.8%, and 4.2%, respectively; all P &lt; .05); these two prognostic factors were not automatically incorporated within the Adjuvant! algorithm. After adjusting for the distribution of LVI, using the prognostic factor impact calculator in Adjuvant!, 10-year predicted and observed outcomes were no longer significantly different. Conclusion Adjuvant! performed reliably. Patients younger than age 35 or with known additional adverse prognostic factors such as LVI require adjustment of risks to derive reliable predictions of prognosis without adjuvant systemic therapy and the absolute benefits of adjuvant systemic therapy.
Expression and localisation of the new metalloproteinase inhibitor RECK (reversion inducing cysteine-rich protein with Kazal motifs) in inflamed synovial membranes of patients with rheumatoid arthritis
Authors: P L E M van Lent
Journal: Annals of the Rheumatic Diseases (2004)

To assess the expression and localisation of the new metalloproteinase inhibitor RECK, an inhibitor of matrix metalloproteinase-14 (MMP-14) secretion and activity, in the synovial membrane of patients with rheumatoid arthritis (RA).RECK expression in synovium samples from patients with RA, osteoarthritis (OA), and "trauma" were studied by quantitative real time reverse transcription-polymerase chain reaction (Q-PCR). RECK mRNA levels were compared with those of the enzyme MMP-14. RECK expression on cryostat sections of synovium was disclosed by goat-antihuman RECK monoclonal antibody. RECK protein was detected on synovial cryostat sections and measured by western blotting. RECK expression on macrophages was investigated by double staining of CD68 and RECK on cryostat sections and characterised by confocal microscopy. RECK expression on RA monocytes or normal monocytes was further investigated by FACS analysis.RECK expression in the synovial membrane of patients with RA was significantly lower than in OA and controls. MMP-14 mRNA levels were not significantly different between the three groups. In RA synovium, RECK protein was expressed mainly in the lining layer but also by macrophages around blood vessels. Fibroblasts and about 50% of the CD68 positive macrophages expressed RECK. In CD68 positive macrophages, RECK was only expressed in secretory granules and not on the membrane. The same pattern was found in M-CSF cultured macrophages of patients with RA and controls. In contrast, synovial fibroblasts showed a diffuse membrane expression within the synovium similar to cultured RA fibroblasts. RECK expression was low on the membrane of monocytes according to FACS analysis.The new MMP inhibitor RECK is expressed in synovial membranes of RA, OA, and controls. RECK mRNA is lowest in RA synovial membranes. In contrast with fibroblasts, macrophages in the synovium express RECK only cytoplasmically and not on their membrane.
Action of chloroquine phosphate in rheumatoid arthritis. 1. Immunosuppressive effect.
Authors: G S Panayi, W A Neill, J J Duthie, J N McCormick
Journal: Annals of the Rheumatic Diseases (1973)

<h3>Aim</h3> To identify the workload related to provision of a neonatal surgical service in a UK neonatal network in order to inform local and national service commissioning. <h3>Method</h3> Data relating to neonatal surgical admissions to a level 3 perinatal centre serving a network with 36 000 births per year collected prospectively over a 5-year period were analysed to identify annual activity. Daily dependency was assessed prospectively over a 6-month period and service costs calculated using existing local tariffs. Admissions from outside the network were excluded from analysis, and allowance was made for refused network admissions. <h3>Results</h3> On average 140 admissions required 2137 cot-days per year. At 80% occupancy, the service requires seven neonatal cots suggesting that there is a national requirement for one neonatal surgical cot per 5000 births. Intensive care, high care (HC) and special care accounted for 37%, 46% and 17% of cot-days, respectively. This equates to an annual service cost of £2m, about £250 000 per 5000 births. <h3>Conclusions</h3> This assessment of the facilities and costs required to provide a neonatal surgical service in a level 3 perinatal centre in the UK may be used to inform network and national commissioning.
Impact of Ramadan on physical performance in professional soccer players
Authors: Yacine Zerguini, Donald Kirkendall, Astrid Junge, Jiri Dvorak
Journal: British Journal of Sports Medicine (2007)

Ramadan is a period of daylight abstention from liquid or solid nutrients. As sports continue to be scheduled, an understanding of the effects of Ramadan on Muslim athletes is warranted.Two Algerian professional soccer teams (55 men) were studied. Field tests of physical and soccer performance were collected before, at the end and 2 weeks after Ramadan in 2004. Players were queried on sleeping habits and personal perception of training and match performance.Field setting at club training ground.Performance on fitness and skill tests.Performance declined significantly (p<0.05) for speed, agility, dribbling speed and endurance, and most stayed low after the conclusion of Ramadan. Nearly 70% of the players thought that their training and performance were adversely affected during the fast.The phase shift of food intake and disruption of sleep patterns affect actual and perceived physical performance. Islamic athletes need to explore strategies that will maximise performance during Ramadan.
Physical Activity and Coronary Heart Disease in Men
Authors: Howard D. Sesso, Ralph S. Paffenbarger, I-Min Lee
Journal: Circulation (2000)

Background —The quantity and intensity of physical activity required for the primary prevention of coronary heart disease (CHD) remain unclear. Therefore, we examined the association of the quantity and intensity of physical activity with CHD risk and the impact of other coronary risk factors. Methods and Results —We followed 12 516 middle-aged and older men (mean age 57.7 years, range 39 to 88 years) from 1977 through 1993. Physical activity was assessed at baseline in kilojoules per week (4.2 kJ=1 kcal) from blocks walked, flights climbed, and participation in sports or recreational activities. During follow-up, 2135 cases of incident CHD, including myocardial infarction, angina pectoris, revascularization, and coronary death, occurred. Compared with men expending &lt;2100 kJ/wk, men expending 2100 to 4199, 4200 to 8399, 8400 to 12 599, and ≥12 600 kJ/wk had multivariate relative risks of 0.90, 0.81, 0.80, and 0.81, respectively ( P for trend=0.003). When we considered the independent effects of specific physical activity components, only total sports or recreational activities ( P for trend=0.042) and vigorous activities ( P for trend=0.02) were inversely associated with the risk of CHD. These associations did not differ within subgroups of men defined by coronary risk factors. Finally, among men with multiple coronary risk factors, those expending ≥4200 kJ/wk had reduced CHD risk compared with men expending &lt;4200 kJ/wk. Conclusions —Total physical activity and vigorous activities showed the strongest reductions in CHD risk. Moderate and light activities, which may be less precisely measured, showed nonsignificant inverse associations. The association between physical activity and a reduced risk of CHD also extends to men with multiple coronary risk factors.
Effect of Cholesterol Feeding during Pregnancy on Blood Cholesterol Levels and Placental Vascular Lesions
Authors: CAMPBELL MOSES, GRACE L. RHODES, EVELYN LEATHAM, ROBERT S. GEORGE
Journal: Circulation (1952)

After establishing the normal variations in blood cholesterol levels on a recorded dietary regimen during pregnancy, 2 Gm. of cholesterol in chocolate candy were fed daily without significant alteration in blood cholesterol levels or placental vascular lesions.
Neutralization of the infectivity of sporozoites of Plasmodium knowlesi by antibodies to a synthetic peptide.
Authors: J Gysin, J Barnwell, D H Schlesinger, V Nussenzweig, R S Nussenzweig
Journal: The Journal of Experimental Medicine (1984)

Antibodies against a synthetic peptide representing the repetitive epitope of the circumsporozoite protein (CS) of Plasmodium knowlesi have properties similar to those of antibodies against the native protein. Either antibody reacts with the synthetic peptide, cross-links the CS protein on the membrane of the parasite giving the CSP reaction, and neutralizes the infectivity of sporozoites. The synthetic peptide and sporozoite extracts were equally effective when used in an immunoradiometric assay as antigens to detect antibodies to CS proteins. It is likely that the corresponding synthetic repeats from the human malaria parasites could be used to measure levels of anti-sporozoite antibodies in endemic areas, or to evaluate the humoral response to anti-sporozoite vaccines. The authors are grateful to Dr. Robert Gwadz, NIH, for supplying Anopheles mosquitoes and P. knowlesi sporozoites used in this study.
A Clinical Lecture ON HERNIA THROUGH THE SEMILUNAR LINE AND DIRECT INGUINAL HERNIA: Delivered at St. Thomas's Hospital, London
Authors: H. B. Robinson
Journal: BMJ (1908)

MANY cases of hernia come under your notice in your hospital work, but in the majority there is little difficulty in making a correct diagnosis.It is -ry object now to -draw your attention to some of the more rare forms which have been under my care, and of which the exact nature was not certain until it was settled by operation.HERNIA THROUGH THE SEMILUNAR LINE.The first case I bring before you is a herniatl4rough the semilunar line above the level'of the inguinal canal.Ventral herniae occurring along the' sdmilunar'line may be divided into two groups-those of cicatricial and those -of spontaneous origin-as is the case with those occurring el §ewhere throucrh the belly waUl; my cage belongs to the second group.birect inguinal herniae are of this same class, but they are, placed below the deep epigastric artery in ' the inguinal ca'nal, and to them I' shall refer'later.Along the 'rest of the semilunar line herniae are very rare above the level of the unibiicus; most of them are placed in the neighbourhood of the semilunar fold of Douglas, and .thefollowing case is an illustration:A widow, aged 70, was admitted under my care on March 29th, 1907.She .hadbeen healthy all her life.On the 24th she was unable to retain her food, vomiting a short time after -meals, and on the 26th there was acute pain in the right iliac fossaiat a point just above Poupart's ligament; there had been constipati n for fQur.days.Exsmination showed a little general distension of the belly without anyobyious peristalsis: there was no apparent hernial swelling.A small round lump about the size of a walnut was to be felt at the border of the rectus just above the inguinal canal; it seemed fixed behind the abdominal wall and not in it, and;apparently fluctuated; it was tender on pressure.There was no inlinmmation of the belly wall.An incision was 'made over the lump parallel to Poupart's ligament, and the external oblique was split in'the line of its fibres.The sac df a small hernia was then exposed which had