tbuckley/cabot-search huggingface dataset:
A Randomized, Controlled Study of a Mandibular Advancement Splint for Obstructive Sleep Apnea
Authors: ATUL MEHTA, JIN QIAN, PETER PETOCZ, M. ALI DARENDELILER, PETER A. CISTULLI
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Although there is increasing interest in the use of oral appliances to treat obstructive sleep apnea (OSA), the evidence base for this is weak. Furthermore, the precise mechanisms of action are uncertain. We aimed to systematically investigate the efficacy of a novel mandibular advancement splint (MAS) in patients with OSA. The sample consisted of 28 patients with proven OSA. A randomized, controlled three-period (ABB/BAA) crossover study design was used. After an acclimatization period, patients underwent three polysomnographs with either a control oral plate, which did not advance the mandible (A), or MAS (B), 1 wk apart, in either the ABB or BAA sequence. Complete response (CR) was defined as a resolution of symptoms and a reduction in Apnea/Hypopnea Index (AHI) to < 5/h, and partial response (PR) as a ⩾ 50% reduction in AHI, but remaining ⩾ 5/h. Twenty-four patients (19 men, 5 women) completed the protocol. Subjective improvements with the MAS were reported by the majority of patients (96%). There were significant improvements in AHI (30 ± 2/h versus 14 ± 2/h, p < 0.0001), MinSaO2 (87 ± 1% versus 91 ± 1%, p < 0.0001), and arousal index (41 ± 2/h versus 27 ± 2/h, p < 0.0001) with MAS, compared with the control. The control plate had no significant effect on AHI and MinSaO2 . CR (n = 9) or PR (n = 6) was achieved in 62.5% of patients. The MAS is an effective treatment in some patients with OSA, including those patients with moderate or severe OSA.
Recombination and the Molecular Clock
Authors: Mikkel H. Schierup, Jotun Hein
Journal: Molecular Biology and Evolution (2000)

Much recent work focuses on the study of sequence evolution of fast-evolving RNA-based viruses such as HIV, influenza, and foot-and-mouth disease.From both an evolutionary and an epidemiological point of view, it is of interest to know whether sequences evolve according to a molecular clock or whether evolutionary rates vary among evolutionary lineages or over time.Present phylogenetic analyses based on the likelihood ratio test (Felsenstein 1981;Huelsenbeck and Rannala 1997) often reject a molecular clock (Elena, Gonzalezcandelas, and Moya 1992;Holmes, Pybus, and Harvey 1999, Kelsey, Crandall, andVoevodin 1999), which, in turn, is often taken as evidence for rate variation caused by varying selection pressures (Holmes, Pybus, and Harvey 1999).However, many viruses readily recombine (Robertson et al. 1995;Holmes, Worobey, and Rambaut 1999;Santti et al. 1999), which implies that no single phylogenetic tree describes the genealogy of the sampled sequences.We have found that very small levels of recombination invalidate the likelihood ratio test of the molecular clock.Data sets were simulated under the coalescent model with recombination (Hudson 1983) with the scaled recombination rate ϭ 4Nr, where N is the effective population size and r is the recombination rate per gene per generation.For each value of , 1,600-2,000 replicates were used.The simulation program was written in C and can be accessed through http://www.daimi.au.dk/ ϳcompbio/.To mimic an average viral data set, we simulated 1,000-bp sequences evolving according to a Jukes-Cantor model of substitution with constant rate (i.e., a molecular clock) and an average distance between sequences of 20% divergence.From the simulated data sets, the maximum-likelihood values of the most likely phylogenies with and without the assumption of a molecular clock were compared using the DNAml and DNAmlk programs of PHYLIP (Felsenstein 1995), assuming the Jukes-Cantor model under which the sequences were simulated.We restricted analysis to cases in which the two methods returned the same tree topology.This was done because use of the 2 distribution for likelihood ratio tests assumes that hypotheses are nested (Huelsenbeck and Rannala 1997;Whelan and Goldman 1999).In this case, ␦ ϭ Ϫ2⌬ln(likelihood) is approximately 2 distributed with n Ϫ 2 degrees of free-
Breast Cancer Subtypes and Response to Docetaxel in Node-Positive Breast Cancer: Use of an Immunohistochemical Definition in the BCIRG 001 Trial
Authors: Judith Hugh, John Hanson, Maggie Chon U. Cheang, Torsten O. Nielsen, Charles M. Perou, Charles Dumontet, John Reed, Maryla Krajewska, Isabelle Treilleux, Matthieu Rupin, Emmanuelle Magherini, John Mackey, Miguel Martin, Charles Vogel
Journal: Journal of Clinical Oncology (2009)

Purpose To investigate the prognostic and predictive significance of subtyping node-positive early breast cancer by immunohistochemistry in a clinical trial of a docetaxel-containing regimen. Methods Pathologic data from a central laboratory were available for 1,350 patients (91%) from the BCIRG 001 trial of docetaxel, doxorubicin, and cyclophosphamide (TAC) versus fluorouracil, doxorubicin, and cyclophosphamide (FAC) for operable node-positive breast cancer. Patients were classified by tumor characteristics as (1) triple negative (estrogen receptor [ER]–negative, progesterone receptor [PR]–negative, HER2/neu [HER2]–negative), (2) HER2 (HER2-positive, ER-negative, PR-negative), (3) luminal B (ER-positive and/or PR-positive and either HER2-positive and/or Ki67 high ), and (4) luminal A (ER-positive and/or PR-positive and not HER2-positive or Ki67 high ), and assessed for prognostic significance and response to adjuvant chemotherapy. Results Patients were subdivided into triple negative (14.5%), HER2 (8.5%), luminal B (61.1%), and luminal A (15.9%). Three-year disease-free survival (DFS) rates (P values with luminal B as referent) were 67% (P &lt; .0001), 68% (P = .0008), 82% (referent luminal B), and 91% (P = .0027), respectively, with hazard ratios of 2.22, 2.12, and 0.46. Improved 3-year DFS with TAC was found in the luminal B group (P = .025) and a combined ER-positive/HER2-negative group treated with tamoxifen (P = .041), with a marginal trend in the triple negatives (P = .051) and HER2 (P = .068) subtypes. No DFS advantage was seen in the luminal A population. Conclusion A simple immunopanel can divide breast cancers into biologic subtypes with strong prognostic effects. TAC significantly complements endocrine therapy in patients with luminal B subtype and, in the absence of targeted therapy, is effective in the triple-negative population.
TSC1/mTOR pathway promotes hypoxia-induced pulmonary hypertension in mice
Authors: Wang Wang, Jie Liu, Huan Guo, Ai-ping Ma, Kai-feng Xu, Jun Wang
Journal: European Respiratory Journal (2012)

Background:   Chronic hypoxia is a key trigger of pulmonary vascular remodeling in pulmonary hypertension (PH). The mammalian target of rapamycin (mTOR) is involved in cell proliferation, which is negatively regulated by Tuberous sclerosis complex 1( TSC1) . However, whether TSC1/mTOR pathway is involved in hypoxia-induced PH is still unknown.    Objective:   To find whether TSC1/mTOR pathway is involved in PH and provide a target for its therapy.    Methods:   Endothelial cell-specific mutation of  TSC1 in mice ( Tek-cre(+)/TSC1 fx/+  and Tek-cre(-)/TSC1 fx/+ ) (provided by prof. Kai-feng Xu) were used. The mice were exposed to either hypoxia(10% O 2 ) or normoxia (21% O 2 ), then the right ventricular systolic pressure(RVSP), and index of right ventricular hypertrophy(RVHI) were measured. Histological measurement was used to estimate the distal vascular remodeling. Western blot was used to detect the change of protein expression in mice lungs.    Results:   Those two genotypic mice under normoxia showed no differences. After hypoxia, RVSP and RVHI of those two genotypic mice was gradually increased, but Tek-cre(+)/TSC1 fx/+  mice were higher after 3 weeks (RVSP: 22.79±0.31 vs. 19.95±0.97mmHg, p fx/+  and Tek-cre(-)/TSC1 fx/+  showed progressive medial thicken under hypoxia, but the former was more obvious. The expression of phosphorylation of S6 (biomarker of mTOR) gradually increased in lungs of these two genotypic mice exposed to hypoxia in the first 2 weeks, then decreased. And Tek-cre(+)/TSC1 fx/+  mice showed higher amounts.    Conclusion:   TSC1/mTOR pathway can promote hypoxia-induced PH in mice, which provides a novel target for PH therapy.
Psychiatrists Disciplined by a State Medical Board
Authors: James Morrison, Theodore Morrison
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: This study determined the risk of discipline by a medical board for psychiatrists relative to other physicians and assessed the contributions to such risk. METHOD: Physicians disciplined by the California Medical Board in a 30-month period were compared with matched groups of nondisciplined physicians. RESULTS: Among 584 disciplined physicians, there were 75 (12.8%) psychiatrists, nearly twice the number of psychiatrists among nondisciplined physicians. Female psychiatrists were underrepresented in the disciplined group. Psychiatrists were significantly more likely than nonpsychiatrist physicians to be disciplined for sexual relationships with patients and about as likely to be charged with negligence or incompetence. The disciplined and nondisciplined psychiatrists did not differ significantly from a group of 75 nondisciplined psychiatrists on years since medical school graduation, international medical graduate status, or board certification. The disciplined group included significantly more psychiatrists who claimed child psychiatry as their first or second specialty and significantly fewer psychoanalysts. CONCLUSIONS: Organized psychiatry has an obligation to address sexual contact with patients and other causes for medical board discipline. This obligation may be addressable through enhanced residency training, recertification exams, and other means of education.
eIF4E Threshold Levels Differ in Governing Normal and Neoplastic Expansion of Mammary Stem and Luminal Progenitor Cells
Authors: Svetlana Avdulov, Jeremy Herrera, Karen Smith, Mark Peterson, Jose R. Gomez-Garcia, Thomas C. Beadnell, Kathryn L. Schwertfeger, Alexey O. Benyumov, J. Carlos Manivel, Shunan Li, Anja-Katrin Bielinsky, Douglas Yee, Peter B. Bitterman, Vitaly A. Polunovsky
Journal: Cancer Research (2014)

Translation initiation factor eIF4E mediates normal cell proliferation, yet induces tumorigenesis when overexpressed. The mechanisms by which eIF4E directs such distinct biologic outputs remain unknown. We found that mouse mammary morphogenesis during pregnancy and lactation is accompanied by increased cap-binding capability of eIF4E and activation of the eIF4E-dependent translational apparatus, but only subtle oscillations in eIF4E abundance. Using a transgenic mouse model engineered so that lactogenic hormones stimulate a sustained increase in eIF4E abundance in stem/progenitor cells of lactogenic mammary epithelium during successive pregnancy/lactation cycles, eIF4E overexpression increased self-renewal, triggered DNA replication stress, and induced formation of premalignant and malignant lesions. Using complementary in vivo and ex vivo approaches, we found that increasing eIF4E levels rescued cells harboring oncogenic c-Myc or H-RasV12 from DNA replication stress and oncogene-induced replication catastrophe. Our findings indicate that distinct threshold levels of eIF4E govern its biologic output in lactating mammary glands and that eIF4E overexpression in the context of stem/progenitor cell population expansion can initiate malignant transformation by enabling cells to evade DNA damage checkpoints activated by oncogenic stimuli. Maintaining eIF4E levels below its proneoplastic threshold is an important anticancer defense in normal cells, with important implications for understanding pregnancy-associated breast cancer.
A specific exercise strategy reduced the need for surgery in subacromial pain patients
Authors: Hanna C Björnsson Hallgren, Theresa Holmgren, Birgitta Öberg, Kajsa Johansson, Lars E Adolfsson
Journal: British Journal of Sports Medicine (2014)

Background and purpose A programme based on eccentric exercises for treating subacromial pain was in a previous study found effective at 3-month follow-up. The purposes of the present study were to investigate whether the results were maintained after 1 year and whether the baseline Constant-Murley score, rotator cuff status and radiological findings influenced the outcome. Patients and methods 97 patients on the waiting list for arthroscopic subacromial decompression had been randomised to a specific exercise programme or unspecific exercises (controls). After 3 months of exercises, the patients were asked whether they still wanted surgery and this option was available until a 1-year follow-up. 1 year after inclusion or 1 year after surgery, the number of patients who decided to have surgery in each group was compared. The choice of surgery was related to the baseline Constant-Murley score, ultrasound and radiographs taken at inclusion. Results All patients had improved significantly (p&lt;0.0001) in the Constant-Murley score at the 1-year follow-up. Significantly more patients in the control group decided to have surgery (63%) than those in the specific exercise group (24%; p&lt;0.0001). Patients who decided to have surgery had a significantly lower baseline Constant-Murley score and more often a full-thickness tear. Patients with partial tears did not differ from those with intact tendons. Interpretation The positive short-term results of specific exercises were maintained after 1 year, and this exercise strategy reduces the need for surgery. Full-thickness tear and a low baseline Constant-Murley score appear to be a predictive marker for a less good outcome. Trial registration number Clinical trials NCT01037673 .
BRAF Is a Therapeutic Target in Aggressive Thyroid Carcinoma
Authors: Giuliana Salvatore, Valentina De Falco, Paolo Salerno, Tito Claudio Nappi, Stefano Pepe, Giancarlo Troncone, Francesca Carlomagno, Rosa Marina Melillo, Scott M. Wilhelm, Massimo Santoro
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Oncogenic conversion of BRAF occurs in ∼44% of papillary thyroid carcinomas and 24% of anaplastic thyroid carcinomas. In papillary thyroid carcinomas, this mutation is associated with an unfavorable clinicopathologic outcome. Our aim was to exploit BRAF as a potential therapeutic target for thyroid carcinoma. Experimental Design: We used RNA interference to evaluate the effect of BRAF knockdown in the human anaplastic thyroid carcinoma cell lines FRO and ARO carrying the BRAF V600E (V600EBRAF) mutation. We also exploited the effect of BAY 43-9006 [N-(3-trifluoromethyl-4-chlorophenyl)-N'-(4-(2-methylcarbamoyl pyridin-4-yl)oxyphenyl)urea], a multikinase inhibitor able to inhibit RAF family kinases in a panel of six V600EBRAF-positive thyroid carcinoma cell lines and in nude mice bearing ARO cell xenografts. Statistical tests were two sided. Results: Knockdown of BRAF by small inhibitory duplex RNA, but not control small inhibitory duplex RNA, inhibited the mitogen-activated protein kinase signaling cascade and the growth of ARO and FRO cells (P &amp;lt; 0.0001). These effects were mimicked by thyroid carcinoma cell treatment with BAY 43-9006 (IC50 = 0.5-1 μmol/L; P &amp;lt; 0.0001), whereas the compound had negligible effects in normal thyrocytes. ARO cell tumor xenografts were significantly (P &amp;lt; 0.0001) smaller in nude mice treated with BAY 43-9006 than in control mice. This inhibition was associated with suppression of phospho–mitogen-activated protein kinase levels. Conclusions: BRAF provides signals crucial for proliferation of thyroid carcinoma cells spontaneously harboring the V600EBRAF mutation and, therefore, BRAF suppression might have therapeutic potential in V600EBRAF-positive thyroid cancer.
Nedd5, a novel autoantigen in systemic sclerosis: is it a marker of more severe disease?
Authors: V Riccieri, C Alessandri, V Germano, S Guiducci, V Rogai, T Colasanti, F Delunardo, P Margutti, E Ortona, M Matucci Cerinic, G Valesini
Journal: Annals of the Rheumatic Diseases (2009)

Nedd5 is an intracytoplasmic protein of the septin family, expressed on the endothelial cell surface after apoptotic stimuli, thus behaving as an autoantigen in different autoimmune diseases.1 2 Several cellular signalling pathways, acting either in cell cycle regulation or in apoptosis, may be altered by the upregulation of Nedd5 expression.3 4

Anti-Nedd5 autoantibodies are significantly higher in patients with psychiatric lupus erythematosus and in those affected by systemic sclerosis (SSc).5 Considering that the vascular endothelium has a pivotal position in the pathophysiology of SSc, although the great part of factors provoking the endothelial damage remains unknown,6 the aim of this study was to evaluate anti-Nedd5 serum immunoreactivity responses in patients with SSc and to find out whether it can be associated to the different aspects of this …
Direct Visualization of Heterogeneous Extravascular Distribution of Trastuzumab in Human Epidermal Growth Factor Receptor Type 2 Overexpressing Xenografts
Authors: Jennifer H.E. Baker, Kirstin E. Lindquist, Lynsey A. Huxham, Alastair H. Kyle, Jonathan T. Sy, Andrew I. Minchinton
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The high molecular weight and binding affinity of trastuzumab, a monoclonal antibody in use for treatment of breast cancers overexpressing human epidermal growth factor receptor type 2 (HER2), in combination with microenvironmental factors, may limit its distribution and efficacy. We assessed and mapped the distribution of systemically given, unlabeled trastuzumab at micrometer resolution in tumor xenografts using immunohistochemistry. Experimental Design: Mice bearing MDA-435/LCC6HER2 xenografts were given single doses of 4 or 20 mg/kg unlabeled trastuzumab with tumor harvest at various time points thereafter; bound trastuzumab was imaged directly in tumor cryosections using fluorescently tagged antihuman secondary antibodies. Combinations of additional markers, including HER2, 5-bromo-2-deoxyuridine, CD31, DioC7(3), desmin, and collagen IV were also mapped on the same tumor sections. Results: Distribution of trastuzumab in MDA-435/LCC6HER2 tumors is found to be heterogeneous, with tumor margins saturating more thoroughly in doses and times analyzed. Considerable intervessel heterogeneity is also seen. For example, in unsaturated tissues, there remain perfused vessels without any trastuzumab in addition to vessels with a few layers of positively stained perivascular cells, in addition to vessels with bound drug up to 150 μm away. This heterogeneity is independent of HER2 expression, microvessel density, and perfusion. A slightly greater proportion of vessels were associated with pericytes in sections with greater trastuzumab saturation, but this would not adequately account for observed heterogeneous trastuzumab distribution. Conclusions: Complete penetration of trastuzumab in tumor tissue was not seen in our study, leaving the possibility that inadequate distribution may represent a mechanism for resistance to trastuzumab.
Anxiety and depression in end-stage COPD
Authors: K. Hill, R. Geist, R. S. Goldstein, Y. Lacasse
Journal: European Respiratory Journal (2008)

Although feelings of anxiety and depression are common in patients with chronic obstructive pulmonary disease (COPD), estimates of their prevalence vary considerably. This probably reflects the variety of scales and methods used to measure such symptoms. Regardless of whether anxiety and depression are considered separately or as a single construct, their impact on COPD patients is important. A heightened experience of dyspnoea is likely to be a contributing factor to anxiety. Feelings of depression may be precipitated by the loss and grief associated with the disability of COPD. Smoking has been associated with nicotine addiction, and the factors that contribute to smoking may also predispose to anxiety and depressive disorders. Randomised controlled trials indicate that exercise training and carefully selected pharmacological therapy are often effective in ameliorating anxiety and depression. Most medical illnesses are influenced by the psychological responses and coping mechanisms that patients use. However, anxiety and depression are associated with dyspnoea, fatigue and altered sleep, all of which also occur in COPD. An understanding of the psychological history and coping mechanisms of patients and the role of anxiety and depressive reactions to illness may enable clinicians to reduce these symptoms and improve quality of life among patients with chronic obstructive pulmonary disease.
Best practice in symptom assessment: a review
Authors: E McColl
Journal: Gut (2004)

Assessment of symptoms is important both in the diagnosis of gastro-oesophageal reflux disease (GORD), and in monitoring response to therapeutic interventions. Key quality aims in assessing symptoms are to gather data that are valid, reliable, unbiased, discriminating, and responsive to change. Important considerations include who should assess symptoms, method of data collection, timing of assessment, and methods of assessing multiple symptoms.
Clinical significance of cytogenetic aberrations in bone marrow of patients with diffuse large B-cell lymphoma: prognostic significance and relevance to histologic involvement
Authors: Seon Young Kim, Hyo Jung Kim, Hye Jin Kang, Jin Seok Kim, Hyeon Seok Eom, Tae Min Kim, Sung-Soo Yoon, Cheolwon Suh, Dong Soon Lee
Journal: Journal of Hematology & Oncology (2013)

Although knowledge of the genetics of diffuse large B-cell lymphoma (DLBCL) has been increasing, little is known about the characteristics and prognostic significance of cytogenetic abnormalities and the clinical utility of cytogenetic studies performed on bone marrow (BM) specimens. To investigate the significance of isolated cytogenetic aberrations in the absence of histologic BM involvement, we assessed the implication of cytogenetic staging and prognostic stratification by a retrospective multicenter analysis of newly diagnosed DLBCL patients.We analyzed cytogenetic and clinical data from 1585 DLBCL patients whose BM aspirates had been subjected to conventional karyotyping for staging. If available, interphase fluorescence in situ hybridization (FISH) data were also collected from patients.Histologic BM involvement were found in 259/1585 (16.3%) patients and chromosomal abnormalities were detected in 192 (12.1%) patients (54 patients with single abnormalities and 138 patients with 2 or more abnormalities). Isolated cytogenetic aberrations (2 or more abnormalities) without histologic involvement were found in 21 patients (1.3%). Two or more cytogenetic abnormalities were associated with inferior overall survival (OS) compared with a normal karyotype or single abnormality in both patients with histologic BM involvement (5-year OS, 16.5% vs. 52.7%; P < 0.001) and those without BM involvement (31.8% vs. 66.5%; P < 0.001). This result demonstrated that BM cytogenetic results have a significant prognostic impact that is independent of BM histology. The following abnormalities were most frequently observed: rearrangements involving 14q32, 19q13, 19p13, 1p, 3q27, and 8q24; del(6q); dup(1q); and trisomy 18. In univariate analysis, several specific abnormalities including abnormalities at 16q22-q24, 6p21-p25, 12q22-q24, and -17 were associated with poor prognosis. Multivariate analyses performed for patients who had either chromosomal abnormalities or histologic BM involvement, revealed IPI high risk, = 2 cytogenetic abnormalities, and several specific chromosomal abnormalities, including abnormalities at 19p13, 12q22-q24, 8q24, and 19q13 were significantly associated with a worse prognosis.We suggest that isolated cytogenetic aberrations can be regarded as BM involvement and cytogenetic evaluation of BM improves staging accuracy along with prognostic information for DLBCL patients.