tbuckley/cabot-search huggingface dataset:
Immuno–Fluorescence In Situ Hybridization Index Predicts Survival in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP: A GELA Study
Authors: Christiane Copie-Bergman, Philippe Gaulard, Karen Leroy, Josette Briere, Maryse Baia, Jean-Philippe Jais, Gilles A. Salles, Françoise Berger, Corinne Haioun, Herve Tilly, Jean-François Emile, Alison H. Banham, Nicolas Mounier, Christian Gisselbrecht, Pierre Feugier, Bertrand Coiffier, Thierry J. Molina
Journal: Journal of Clinical Oncology (2009)

Purpose To evaluate the prognostic value of cell of origin immunohistochemical markers and BCL2, BCL6, and c-MYC translocations in a homogeneous cohort of patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients and Methods Patients with CD20+ DLBCL were enrolled in the randomized LNH98-5 and 01-5B Groupe d'Etude des Lymphomes de l'Adulte trials. Paraffin-embedded tumor samples of 119 patients treated with R-CHOP were analyzed by immunohistochemistry for CD10, BCL6, MUM1/IRF4, LMO2, and forkhead box protein P1 (FOXP1) expression and for BCL2, BCL6, and c-MYC breakpoints by fluorescence in situ hybridization (FISH) on tissue microarray. Results LMO2 expression and BCL2 breakpoint were associated with the germinal center (GC) subtype defined by Hans' algorithm, respectively (P &lt; .0001; P = .0002) whereas FOXP1 expression and BCL6 breakpoint were associated with the non-germinal center (non-GC) subtype (P = .008 and P = .0001, respectively). The immunohistochemical markers analyzed independently, GC/non-GC phenotype and BCL2 breakpoint did not predict overall survival (OS). BCL6 breakpoint was significantly associated with an unfavorable impact on OS (P = .04). Interestingly, an immunoFISH index, defined by positivity for at least two of three non-GC markers (FOXP1, MUM1/IRF4, BCL6 breakpoint) was significantly associated with a shorter 5-year OS rate (44%; 95% CI, 28 to 60 v 78%; 95% CI, 59 to 89; P = .01) which was independent (P = .04) of the age-adjusted International Prognostic Index (P = .04) in multivariate analysis. Conclusion Our study demonstrates that combining immunohistochemistry with FISH allows construction of an immunoFISH index that significantly predicts survival in elderly DLBCL patients treated with R-CHOP.
Ulcerative colitis in the United States Army in 1944: Follow-up with particular reference to mortality in cases and controls
Authors: M. D. Nefzger, E. D. Acheson
Journal: Gut (1963)

This paper compares the mortality of 525 men admitted to U.S. Army hospitals in 1944 with ulcerative colitis compared with 518 controls matched for age, race, and rank. The excess mortality in the ulcerative colitis group as compared with the control group was due to approximately equal proportions of deaths from ulcerative colitis (2.9%) and cancer of the caecum, colon, and rectum (3.2%). The mortality from ulcerative colitis occurred mainly in the first and immediately subsequent years after diagnosis while most of the deaths from cancer occurred in later years. A striking correlation is shown between bad prognosis and the extent of radiological involvement of the colon in 1944.
Lung cancer gene associated with COPD: triple whammy or possible confounding effect?
Authors: R. P. Young, R. J. Hopkins, B. A. Hay, M. J. Epton, P. N. Black, G. D. Gamble
Journal: European Respiratory Journal (2008)

Recently, several large genome-wide association studies have identified a putative “lung cancer” locus in the nicotinic acetylcholine receptor subunit genes (nAChR) on 15q25. However, these findings may be confounded by the presence of chronic obstructive pulmonary disease (COPD), which is also strongly associated with smoking exposure and lung cancer. This is likely as the prevalence of COPD in lung cancer cohorts is as much as two-fold greater than that reported in smoking control populations (50 versu s 20%). The present authors compared the genotype frequencies of the most strongly associated single nucleotide polymorphism (rs16969968) in the α5 subunit of the nAChR gene cluster between three matched smoking cohorts. The AA genotype was found to be more frequent and was seen in 437 (16%) lung cancer cases and 445 (14%) COPD cases compared with 475 (9%) healthy smoking controls. More importantly, when 429 lung cancer cases were divided according to spirometry results (performed within 3 months of diagnosis, prior to surgery and in the absence of effusions or collapse), the AA genotype was present in 19 and 11% of cases with and without COPD, respectively. These findings suggest that the association between the α5 subunit nicotinic acetylcholine receptor single nucleotide polymorphism and lung cancer may, in part, be confounded by chronic obstructive pulmonary disease.
Overseas doctors work longer hours, Australian study shows
Authors: Stephen Pincock
Journal: BMJ (2007)

A study examining the practice patterns of overseas doctors working in Australia has shown that they work longer hours, prescribe more drugs, and order more tests than their counterparts who trained in Australia.

Australia relies heavily on medical graduates from overseas, said the study's lead author, Clare Bayram, from Sydney University's Family Medicine Research Centre. They make up 25% of the total workforce of doctors, but information on how they practise in the Australian setting is virtually non-existent, she said.

She and her colleagues compared 89 overseas trained doctors who were …
Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex
Authors: Hui-Hua Li, Vishram Kedar, Chunlian Zhang, Holly McDonough, Ranjana Arya, Da-Zhi Wang, Cam Patterson
Journal: Journal of Clinical Investigation (2004)

Calcineurin, which binds to the Z-disc in cardiomyocytes via α-actinin, promotes cardiac hypertrophy in response to numerous pathologic stimuli. However, the endogenous mechanisms regulating calcineurin activity in cardiac muscle are not well understood. We demonstrate that a muscle-specific F-box protein called atrogin-1, or muscle atrophy F-box, directly interacts with calcineurin A and α-actinin-2 at the Z-disc of cardiomyocytes. Atrogin-1 associates with Skp1, Cul1, and Roc1 to assemble an SCFatrogin-1 complex with ubiquitin ligase activity. Expression of atrogin-1 decreases levels of calcineurin A and promotes its ubiquitination. Moreover, atrogin-1 attenuates agonist-induced calcineurin activity and represses calcineurin-dependent transactivation and NFATc4 translocation. Conversely, downregulation of atrogin-1 using adenoviral small interfering RNA (siRNA) expression enhances agonist-induced calcineurin activity and cardiomyocyte hypertrophy. Consistent with these cellular observations, overexpression of atrogin-1 in hearts of transgenic mice reduces calcineurin protein levels and blunts cardiac hypertrophy after banding of the thoracic aorta. These studies indicate that the SCFatrogin-1 ubiquitin ligase complex interacts with and represses calcineurin by targeting calcineurin for ubiquitin-mediated proteolysis, leading to inhibition of cardiac hypertrophy in response to pathologic stimuli.
Molecular Regulation of Platelet-Dependent Thrombosis
Authors: Jane E. Freedman
Journal: Circulation (2005)

Hemostasis is a normal process preventing the sequelae of uncontrolled hemorrhage. In certain settings, these same processes cause adverse clinical events due to thrombotic occlusion of a vessel. The majority of unstable coronary syndromes result from disruption of an atherosclerotic plaque, leading to the exposure of subintimal contents, which triggers coagulation and the formation of a platelet-rich thrombus. The central role of platelet activation in the events that lead to vessel occlusion is well known. However, this process is complex and influenced by a myriad of cellular and plasma-derived mediators that regulate the balance between occlusive and nonocclusive thrombosis.
Lessons from Functional Analysis of Genome-Wide Association Studies
Authors: Inderpreet Sur, Sari Tuupanen, Thomas Whitington, Lauri A. Aaltonen, Jussi Taipale
Journal: Cancer Research (2013)

Most cancer-associated single-nucleotide polymorphisms (SNP) identified using genome-wide association studies are located outside of protein-coding regions, and their significance and mode of action have been a source of continuing debate. One proposed mechanism of action of the SNPs is that they would affect the activity of enhancer elements regulating critical target genes. In this review, we summarize recent results that substantiate this model. These studies have identified a cancer-specific enhancer element at the 8q24 gene desert that controls the expression of the MYC oncogene. We further discuss implications of the observed difference between normal growth control and cancer for drug development, and the inherent features of genome-wide association studies that may specifically lead to identification of disease-specific regulatory elements.
Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: a meta-analysis
Authors: E R Sutherland
Journal: Thorax (2003)

Chronic obstructive pulmonary disease (COPD) is a syndrome of chronic progressive airflow limitation which occurs as a result of chronic inflammation of the airways and lung parenchyma. However, the role of inhaled corticosteroids in the treatment of COPD is controversial. We hypothesised that inhaled corticosteroids reduce the progression of airflow limitation in COPD.A comprehensive literature search was conducted and data were analysed using random effects methodology. The effect of inhaled steroids on annual change in forced expiratory volume in 1 second (FEV1) was determined for all trials, for trials with high dose treatment regimens, and for trials in subjects with moderate to severe airflow limitation.Data from eight controlled clinical trials of > or =2 years were included (n=3715 subjects). Meta-analysis of all study data revealed that inhaled corticosteroids reduce the rate of FEV1 decline by 7.7 ml/year (95% confidence interval (CI) 1.3 to 14.2, p=0.02). Meta-analysis of studies with high dose regimens revealed a greater effect of 9.9 ml/year (95% CI 2.3 to 17.5, p=0.01) compared with the meta-analysis of all studies.Inhaled corticosteroid treatment for > or =2 years slows the rate of lung function decline in COPD. The effect observed with high dose regimens is greater than that with all regimens combined. These data suggest a potential role for inhaled corticosteroids in modifying the long term natural history of COPD.
Accuracy of Reported Family History of Diabetes Mellitus: Results From San Luis Valley Diabetes Study
Authors: Louise B Kahn, Julie A Marshall, Judith Baxter, Susan M Shetterly, Richard F Hamman
Journal: Diabetes Care (1990)

There are two possible sources of bias in the assessment of family history of diabetes: 1) a person with diabetes may be more likely to report a diabetic relative than a nondiabetic person would be, and 2) relatives of individuals with diabetes may be more likely to be tested for diabetes than relatives of nondiabetic individuals. We conducted a study on a subsample of families of subjects in the San Luis Valley Diabetes Study to examine these issues. A sample of 5 White and 5 Hispanic subjects (probands) with diabetic glucose tolerance tests and the same number with normal glucose tolerance were selected. The 20 probands all provided contact information on their 227 primary family members. Ninety-two percent of the family members had interviews completed by themselves or, if deceased, by surrogates other than the proband. Family members were asked by telephone if they had ever been tested for diabetes, when they had been most recently tested, why they had been tested, and if they had ever been told they had diabetes. The results showed that study subjects accurately reported family history of diabetes, because there were no discrepancies between proband and family reports. A positive family history of diabetes was associated with increased reported screening in Hispanics, but a similar effect in White families was not seen. Women were also more likely to report being screened than men regardless of whether there was a positive family history of diabetes. These data indicate that, although diabetic and control subjects accurately report their family history of known diabetes, indications of differential screening exist that may alter the amount of known and subsequently reported diabetes in families.
Effect of Discontinuation of Antihypertensive Treatment in Elderly People on Cognitive Functioning—the DANTE Study Leiden
Authors: Justine E. F. Moonen, Jessica C. Foster-Dingley, Wouter de Ruijter, Jeroen van der Grond, Anne Suzanne Bertens, Mark A. van Buchem, Jacobijn Gussekloo, Huub A. Middelkoop, Marieke J. H. Wermer, Rudi G. J. Westendorp, Anton J. M. de Craen, Roos C. van der Mast
Journal: JAMA Internal Medicine (2015)

Observational studies indicate that lower blood pressure (BP) increases risk for cognitive decline in elderly individuals. Older persons are at risk for impaired cerebral autoregulation; lowering their BP may compromise cerebral blood flow and cognitive function.To assess whether discontinuation of antihypertensive treatment in older persons with mild cognitive deficits improves cognitive, psychological, and general daily functioning.A community-based randomized clinical trial with a blinded outcome assessment at the 16-week follow-up was performed at 128 general practices in the Netherlands. A total of 385 participants 75 years or older with mild cognitive deficits (Mini-Mental State Examination score, 21-27) without serious cardiovascular disease who received antihypertensive treatment were enrolled in the Discontinuation of Antihypertensive Treatment in Elderly People (DANTE) Study Leiden from June 26, 2011, through August 23, 2013 (follow-up, December 16, 2013). Intention-to-treat analyses were performed from January 20 through April 11, 2014.Discontinuation (n=199) vs continuation (n=186) of antihypertensive treatment (allocation ratio, 1:1).Change in the overall cognition compound score. Secondary outcomes included changes in scores on cognitive domains, the Geriatric Depression Scale-15, Apathy Scale, Groningen Activity Restriction Scale (functional status), and Cantril Ladder (quality of life).Compared with 176 participants undergoing analysis in the control (continuation) group, 180 in the intervention (discontinuation) group had a greater increase (95% CI) in systolic BP (difference, 7.36 [3.02 to 11.69] mm Hg; P=.001) and diastolic BP (difference, 2.63 [0.34 to 4.93] mm Hg; P=.03). The intervention group did not differ from the control group in change (95% CI) in overall cognition compound score (0.01 [-0.14 to 0.16] vs -0.01 [-0.16 to 0.14]; difference, 0.02 [-0.19 to 0.23]; P=.84). The intervention and control groups did not differ significantly in secondary outcomes, including differences (95% CIs) in change in compound scores of the 3 cognitive domains (executive function, -0.07 [-0.29 to 0.15; P=.52], memory, 0.08 [-0.12 to 0.29; P=.43], and psychomotor speed, -0.85 [-1.72 to 0.02; P=.06]), symptoms of apathy (0.17 [-0.65 to 0.99; P=.68]) and depression (0.14 [-0.20 to 0.48; P=.41]), functional status (-0.72 [-1.52 to 0.09; P=.08]), and quality-of-life score (-0.09 [-0.34 to 0.16; P=.46]). Adverse events were equally distributed.In older persons with mild cognitive deficits, discontinuation of antihypertensive treatment did not improve cognitive, psychological, or general daily functioning at the 16-week follow-up.trialregister.nl Identifier: NTR2829.
Alopecia areata profiling shows TH1, TH2, and IL-23 cytokine activation without parallel TH17/TH22 skewing
Authors: Mayte Suárez-Fariñas, Benjamin Ungar, Shinji Noda, Anjali Shroff, Yasaman Mansouri, Judilyn Fuentes-Duculan, Annette Czernik, Xiuzhong Zheng, Yeriel D. Estrada, Hui Xu, Xiangyu Peng, Avner Shemer, James G. Krueger, Mark G. Lebwohl, Emma Guttman-Yassky
Journal: Journal of Allergy and Clinical Immunology (2015)
Role of FEF25-75 and Bronchodilator Response in Childhood Asthma Control and Morbidity Among Inner-City Children with Asthma
Authors: Watcharoot Kanchongkittiphon, Elizabeth C. Matsui, Jonathan M. Gaffin, Carter Petty, Rachel Miller, Matthew S. Perzanowski, Mary E. Bollinger, Wanda Phipatanakul
Journal: Journal of Allergy and Clinical Immunology (2015)
Phase I and Pharmacokinetic Study of PKC412, an Inhibitor of Protein Kinase C
Authors: D. J. Propper, A. C. McDonald, A. Man, P. Thavasu, F. Balkwill, J. P. Braybrooke, F. Caponigro, P. Graf, C. Dutreix, R. Blackie, S. B. Kaye, T. S. Ganesan, D. C. Talbot, A. L. Harris, C. Twelves
Journal: Journal of Clinical Oncology (2001)

PURPOSE: N-Benzoyl staurosporine (PKC412) is a protein kinase C inhibitor with antitumor activity in laboratory models. We determined the toxicity of oral PKC412 administered daily for repeat cycles of 28 days. PATIENTS AND METHODS: Thirty-two patients with advanced solid cancers were treated at seven dose levels (12.5 to 300 mg daily) for a total of 68 cycles. RESULTS: The most frequent treatment-related toxicities were nausea, vomiting, fatigue, and diarrhea. At the two top dose levels (225 and 300 mg/d), 15 of 16 patients experienced nausea/vomiting (common toxicity criteria [CTC], version 1), grade 2 in nine of 16 and grade 3 in three of 16 patients; and six of 16 patients developed CTC grade 2 diarrhea. After 1 month of treatment, there were significant reductions in circulating lymphocyte (P &lt; .02) and monocyte (P &lt; .01) counts in patients receiving doses ≥ 100 mg/d. Nevertheless, only two patients developed myelosuppression (both grade 2). Of two patients with progressive cholangiocarcinoma, one attained stable disease lasting 4.5 months and one a partial response lasting 4 months. There was a linear relationship between PKC412 dose and area under the curve 0-24 hours and maximum plasma concentration with marked interpatient variability. The estimated median elimination half-life was 1.6 days (range, 0.9 to 4.0 days), and a metabolite with a median half-life of 36 days was detected. Steady-state PKC412 plasma levels at the top three dose cohorts (150 to 300 mg) were five to 10 times the cellular 50% inhibitory concentration for PKC412 of 0.2 to 0.7 μmol/L. CONCLUSION: PKC412 can be safely administered by chronic oral therapy, and 150 mg/d is suitable for phase II studies. The pharmacokinetics and lack of conventional toxicity indicate that pharmacodynamic measures may be additionally needed to optimize the drug dose and schedule.
Anthrax as a Biological Weapon
Authors: Thomas V. Inglesby, Donald A. Henderson, John G. Bartlett, Michael S. Ascher, Edward Eitzen, Arthur M. Friedlander, Jerome Hauer, Joseph McDade, Michael T. Osterholm, Tara O'Toole, Gerald Parker, Trish M. Perl, Philip K. Russell, Kevin Tonat, None for the Working Group on Civilian Biodefense
Journal: JAMA (1999)

ObjectiveTo develop consensus-based recommendations for measures to be taken by medical and public health professionals following the use of anthrax as a biological weapon against a civilian population.ParticipantsThe working group included 21 representatives from staff of major academic medical centers and research, government, military, public health, and emergency management institutions and agencies.EvidenceMEDLINE databases were searched from January 1966 to April 1998, using the Medical Subject Headings anthrax, Bacillus anthracis, biological weapon, biological terrorism, biological warfare, and biowarfare. Review of references identified by this search led to identification of relevant references published prior to 1966. In addition, participants identified other unpublished references and sources.Consensus ProcessThe first draft of the consensus statement was a synthesis of information obtained in the formal evidence-gathering process. Members of the working group provided formal written comments which were incorporated into the second draft of the statement. The working group reviewed the second draft on June 12, 1998. No significant disagreements existed and comments were incorporated into a third draft. The fourth and final statement incorporates all relevant evidence obtained by the literature search in conjunction with final consensus recommendations supported by all working group members.ConclusionsSpecific consensus recommendations are made regarding the diagnosis of anthrax, indications for vaccination, therapy for those exposed, postexposure prophylaxis, decontamination of the environment, and additional research needs.
Inadequate antiasthma drug use in the north of Italy
Authors: I Cerveri, MC Zoia, M Bugiani, A Corsico, A Carosso, P Piccioni, L Casali, R De Marco
Journal: European Respiratory Journal (1997)

A multicentre survey of prevalence, determinants and management of asthma (the European Community Respiratory Health Survey (ECRHS)) has shown that the ratio of subjects declaring current use of antiasthmatic drugs to those reporting asthma attacks in the previous 12 months was particularly low (0.54) in the north of Italy. In this study, we used a standardized clinical interview to gather a more detailed insight into the issue of asthma undertreatment in the north of Italy. A total of 1,104 subjects were interviewed, 116 of whom had been defined as asthmatic by the family doctor. Fifty subjects had current asthma and 66 had a history of previous asthma. A considerable percentage (26%) of subjects with current asthma were not being treated with antiasthmatic therapy. Even when only patients with severe asthma were considered, the percentage of untreated patients was still high (21%). Forty two per cent of subjects used inhaled beta2-agonists alone, 28% inhaled steroids plus beta2-agonists, 2% inhaled steroids alone and 2% other drugs. Only 19% of the asthmatics on treatment, 85% of whom had more severe asthma, received daily treatment. Only 65% of the subjects who had received antiasthmatic drug prescriptions declared they had taken all the drugs prescribed; this percentage was 74% when respiratory symptoms were worsening. Of the patients with past asthma, 18% had taken antiasthmatic drugs. Most of these patients were those who had had more severe asthma. In conclusion, antiasthmatic drugs are underused in the north of Italy, at least in part due to low compliance.