tbuckley/cabot-search huggingface dataset:
TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial
Authors: Charles F Burant, Prabhakar Viswanathan, John Marcinak, Charlie Cao, Majid Vakilynejad, Benhuai Xie, Eckhard Leifke
Journal: The Lancet (2012)
L166P mutant DJ-1 promotes cell death by dissociating Bax from mitochondrial Bcl-XL
Authors: Haigang Ren, Kai Fu, Chenchen Mu, Xuechu Zhen, Guanghui Wang
Journal: Molecular Neurodegeneration (2012)

Abstract Background Mutations or deletions in DJ-1/PARK7 gene are causative for recessive forms of early onset Parkinson’s disease (PD). Wild-type DJ-1 has cytoprotective roles against cell death through multiple pathways. The most commonly studied mutant DJ-1(L166P) shifts its subcellular distribution to mitochondria and renders cells more susceptible to cell death under stress stimuli. We previously reported that wild-type DJ-1 binds to Bcl-X L and stabilizes it against ultraviolet B (UVB) irradiation-induced rapid degradation. However, the mechanisms by which mitochondrial DJ-1(L166P) promotes cell death under death stimuli are largely unknown. Results We show that DJ-1(L166P) is more prone to localize in mitochondria and it binds to Bcl-X L more strongly than wild-type DJ-1. In addition, UVB irradiation significantly promotes DJ-1(L166P) translocation to mitochondria and binding to Bcl-X L . DJ-1(L166P) but not wild-type DJ-1 dissociates Bax from Bcl-X L , thereby leading to Bax enrichment at outer mitochondrial membrane and promoting mitochondrial apoptosis pathway in response to UVB irradiation. Conclusion Our findings suggest that wild-type DJ-1 protects cells and DJ-1(L166P) impairs cells by differentially regulating mitochondrial Bax/Bcl-X L functions.
Production of chemotactic factor, interleukin-8, from hepatocytes exposed to ethanol
Authors: Yasushi Shiratori, Hiroshi Takada, Yohko Hikiba, Ryo Nakata, Ken’Ichi Okano, Yutaka Komatsu, Yasuro Niwa, Masayuki Matsumura, Shuichiro Shiina, Masao Omata, Kazuo Kamii
Journal: Hepatology (1993)

In a previous paper, we demonstrated proteinous chemotactic factors released from hepatocytes exposed to ethanol. In this study, we further characterized the chemotactic factors released from ethanol-treated hepatocytes. After fractionating the conditioned medium with gel chromatography, we demonstrated chemotactic activity at molecular weights of around 20 and 40 kD. When the conditioned medium was mixed with antiserum against interleukin-8, chemotactic activity was almost completely abolished. In addition, antiserum against interleukin-8 completely reduced chemotactic activity of the 20-kD chemotactic factor but did not influence the chemotactic activity of the 40-kD chemotactic factor. After gel electrophoresis of the conditioned medium, the protein reacted with antibody against interleukin-8 was demonstrated at a molecular weight of 20 kD but was not found at a molecular weight of 40 kD. These results suggest that a major part of the proteinous chemotactic factors released from hepatocytes exposed to ethanol could be a dimer form of interleukin-8, one of the proinflammatory cytokines, possibly contributing to the pathogenesis of alcoholic hepatitis.
Systemic inflammation in chronic obstructive pulmonary disease
Authors: E­J.D. Oudijk, J­W.J. Lammers, L. Koenderman
Journal: European Respiratory Journal (2003)

Chronic obstructive pulmonary disease (COPD) is characterised by a chronic inflammation in the pulmonary tissue. The disease is associated with a switch from a self­limiting inflammatory response, mainly initiated by smoke inhalation, to a chronic persistent inflammatory response after prolonged interaction with cigarette smoke. The extent of the inflammatory reaction is correlated with the severity of the disease. Chronic inflammation in the pulmonary tissue is also associated with systemic effects. These effects range from cytokine­induced priming of peripheral leukocytes, to muscle wasting induced by cytokines such as tumour necrosis factor‐α. Despite a general consensus that chronic inflammation is a characteristic phenomenon of the disease, surprisingly little is known regarding the underlying pathogenetic mechanisms. A clear communication is present between the disease mechanisms in the pulmonary compartment and peripheral tissues, leading to the concept of COPD as a systemic inflammatory disease. This communication can be mediated by: 1) leakage of reactive oxygen species and stress­induced cytokines directly into the peripheral blood, 2) (pre)activation of peripheral blood leukocytes that can result in aberrant homing and activation of inflammatory cells in distant tissues, and 3) the liberation of pro­inflammatory mediators by leukocytes and/or stromal cells present in the pulmonary tissues during progression of the disease. The current authors hypothesise that the occurrence of a chronic inflammatory response after prolonged interaction of the pulmonary tissue with cigarette smoke causes aberrant homing of leukocytes to the tissue and delayed apoptosis. This leads to the autonomous characteristic of the inflammatory response in patients with chronic obstructive pulmonary disease.
Randomized Phase II Trial Comparing Obinutuzumab (GA101) With Rituximab in Patients With Relapsed CD20<sup>+</sup> Indolent B-Cell Non-Hodgkin Lymphoma: Final Analysis of the GAUSS Study
Authors: Laurie H. Sehn, Andre Goy, Fritz C. Offner, Giovanni Martinelli, M. Dolores Caballero, Ole Gadeberg, Tara Baetz, Andrew D. Zelenetz, Gianluca Gaidano, Luis E. Fayad, Rena Buckstein, Jonathan W. Friedberg, Michael Crump, Branimir Jaksic, Pier Luigi Zinzani, Swaminathan Padmanabhan Iyer, Deniz Sahin, Akiko Chai, Günter Fingerle-Rowson, Oliver W. Press
Journal: Journal of Clinical Oncology (2015)

Obinutuzumab (GA101), a novel glycoengineered type II anti-CD20 monoclonal antibody, demonstrated responses in single-arm studies of patients with relapsed/refractory non-Hodgkin lymphoma. This is the first prospective, randomized study comparing safety and efficacy of obinutuzumab with rituximab in relapsed indolent lymphoma. The primary end point of this study was the overall response rate (ORR) in patients with follicular lymphoma after induction and safety in patients with indolent lymphoma.A total of 175 patients with relapsed CD20(+) indolent lymphoma requiring therapy and with previous response to a rituximab-containing regimen were randomly assigned (1:1) to four once-per-week infusions of either obinutuzumab (1,000 mg) or rituximab (375 mg/m(2)). Patients without evidence of disease progression after induction therapy received obinutuzumab or rituximab maintenance therapy every 2 months for up to 2 years.Among patients with follicular lymphoma (n = 149), ORR seemed higher for obinutuzumab than rituximab (44.6% v 33.3%; P = .08). This observation was also demonstrated by a blinded independent review panel that measured a higher ORR for obinutuzumab (44.6% v 26.7%; P = .01). However, this difference did not translate into an improvement in progression-free survival. No new safety signals were observed for obinutuzumab, and the incidence of adverse events was balanced between arms, with the exception of infusion-related reactions and cough, which were higher in the obinutuzumab arm.Obinutuzumab demonstrated a higher ORR without appreciable differences in safety compared with rituximab. However, the clinical benefit of obinutuzumab in this setting remains unclear and should be evaluated within phase III trials.
Abstract IA1: microRNAs and lung cancer
Authors: Frank J. Slack
Journal: Clinical Cancer Research (2012)

Abstract microRNAs are small noncoding RNAs that regulate gene expression to control important aspects of development and metabolism such as cell differentiation, apoptosis and lifespan. let-7 encodes a microRNA implicated in human cancer. Specifically, human let-7 is poorly expressed or deleted in lung cancer, and over-expression of let-7 in lung cancer cells inhibits their growth, demonstrating a role for let-7 as a tumor suppressor in lung tissue. let-7 is expressed in the developing mammalian lung and regulates the expression of important oncogenes implicated in lung cancer, suggesting a mechanism for let-7's involvement in cancer. We are focused on the role of let-7 and other oncomiRs in regulating proto-oncogene expression during development and cancer, and on using miRNAs to suppress tumorigenesis.
Genital lichen sclerosus associated with morphoea or systemic sclerosis: clinical and HLA characteristics
Authors: A.M. Farrell, P.M. Marren, F. Wojnarowska
Journal: British Journal of Dermatology (2000)

Although patients with both morphoea and lichen sclerosus have been reported previously, in the majority of these reports the lichen sclerosus has been extragenital. We report nine patients in whom genital lichen sclerosus coexisted with scleroderma spectrum disorders including seven with morphoea, one with morphoea and lichen planus, and one with systemic sclerosis. The clinical features, associated autoimmune disease, autoantibodies and HLA type are reported. Antibodies to Borrelia burgdorferi were not detected in any of the patients. The coexistence of these diseases raises a number of intriguing questions about the relationship between them.
B cell origin of non-T cell acute lymphoblastic leukemia. A model for discrete stages of neoplastic and normal pre-B cell differentiation.
Authors: L M Nadler, S J Korsmeyer, K C Anderson, A W Boyd, B Slaughenhoupt, E Park, J Jensen, F Coral, R J Mayer, S E Sallan
Journal: Journal of Clinical Investigation (1984)

The expression of B cell associated and restricted antigens on tumor cells isolated from 138 patients with non-T cell acute lymphoblastic leukemia (non-T cell ALL) was investigated by flow cytometric analysis by means of a panel of monoclonal antibodies. Tumor cells from these patients could be assigned to one of four subgroups: human leukocyte antigen-DR-related Ia-like antigens (Ia) alone (4%, stage I); IaB4 (14%, stage II); IaB4CALLA (33%, stage III); and IaB4CALLAB1 (49%, stage IV). The expression of B cell-restricted antigens (B4 and B1) and rearrangements of Ig heavy chain genes provided strong evidence for the B cell lineage of stages II, III, and IV tumors. The lineage of the Ia alone group is still unknown. The B4 antigen was expressed on approximately 95% of all non-T cell ALLs tested, and given its absence on T cell and myeloid tumors, it appears to be an exceptional marker to define cells of B lineage. The demonstration that Ia alone, IaB4, IaB4CALLA, and IaB4CALLAB1 positive cells can be readily identified by dual fluorescence analysis in normal fetal and adult bone marrow provided critical support for the view that these leukemic pre-B cell phenotypes were representative of the stages of normal pre-B cell differentiation. It was interesting that the IaB4+ cell was more frequently identified in fetal bone marrow than in adult marrow, whereas the predominant cell found in adult marrow expressed the IaB4CALLAB1 phenotype. These data suggest that the leukemogenic event may be random, since the predominant pre-B cell leukemic phenotype appears to correspond to the normal pre-B cell phenotype present in these hematopoietic organs. Our observations provide an additional distinction between adult and childhood ALL, since these studies show that most non-T cell ALLs seen in children less than 2 yr old are of stage II phenotype, whereas the majority of non-T ALLs in adults are of stage IV phenotype. Finally, it should be noted that the present study suggests that the analysis of leukemic B cell phenotypes and their normal counterparts can provide a mechanism for the investigation and orderly definition of stages of pre-B cell differentiation in man.
Respiratory health and endotoxin: associations and modification by CD14/-260 genotype
Authors: I. Bakolis, G. Doekes, J. Heinrich, J.P. Zock, D. Heederik, M. Kogevinas, S. Guerra, D. Norbäck, A. Ramasamy, A. Nevalainen, C. Svanes, C.M. Chen, G. Verlato, M. Olivieri, F. Castro-Giner, D. Jarvis
Journal: European Respiratory Journal (2011)

Exposure to endotoxin has been associated with increased respiratory symptoms and decrements in lung function in occupational settings but little is known about the health effects of domestic exposure in adults. Here, we describe the association of respiratory disease, immunoglobulin (Ig)E sensitisation, bronchial reactivity and lung function with mattress endotoxin levels in adults, and determine whether these associations are modified by polymorphisms in CD14. Endotoxin levels in mattress dust from a population-based sample of 972 adults were measured. Associations were examined using generalised linear mixed models, adjusting for individual and household confounders. Effect modification of these associations by CD14/-260 (rs2569190) was assessed. Mattress endotoxin levels varied from 0.1 to 402.6 EU · mg(-1). Although there was no overall association of lung function with endotoxin exposure, there was evidence that the association of forced expiratory volume in 1 s and forced vital capacity with endotoxin was modified by CD14/-260 genotype (p-value for interaction 0.005 and 0.013, respectively). There was no evidence that symptoms, IgE sensitisation or bronchial reactivity were associated with mattress endotoxin levels. In this large epidemiological study of adults, there was no evidence that mattress endotoxin level was associated with respiratory symptoms or IgE sensitisation but the association of lung function with endotoxin levels may be modified by CD14 genotype.
... a joy forever
Authors: L. Farrell
Journal: BMJ (1999)

Andrew Lloyd Webber musicals, drugs reps personally demonstrating thixotropic nasal sprays; the world is full of unattractive things, and vomiting is reckoned among the worst of them.

Vomiting and the presence of a vomiting centre in the brain seems like yet more arguments against the existence of a benevolent God. There are other physical activities with better public relations which perhaps seem more deserving of a centre of their own, and in Thomas More's Utopia , all …
Implications of the Oropharyngeal Cancer Epidemic
Authors: Edmund A. Mroz, Arlene A. Forastiere, James W. Rocco
Journal: Journal of Clinical Oncology (2011)

Chaturvedi et al,1 analyzing specimens back to 1984, validate the long-held hypothesis that infection with human papillomavirus (HPV) has increased oropharyngeal squamous cell carcinoma (OPSCC) incidence in the US. They find the incidence of OPSCC in men—who have higher risks of both HPV-positive and HPV-negative OPSCC than women—similar to that of cervical cancer in women. From 1988 to 2004, incidence of HPV-negative OPSCC decreased in parallel with smoking whereas incidence of HPV-positive OPSCC increased at about 7.5% per year, so the percentage of OPSCC that was HPV-positive went from less than 20% to more than 70%.
Dynamics of Glomerular Ultrafiltration in the Rat. IV. DETERMINATION OF THE ULTRAFILTRATION COEFFICIENT
Authors: William M. Deen, Julia L. Troy, Channing R. Robertson, Barry M. Brenner
Journal: Journal of Clinical Investigation (1973)

Pressures and flow rates were measured in accessible surface glomeruli of mutant Wistar rats under conditions deliberately designed to prevent achievement of filtration pressure equilibrium, that is, the equalization of transcapillary hydrostatic and oncotic pressures by the efferent end of the glomerulus as typically observed in the normal hydropenic rat. Disequilibrium was obtained at elevated levels of glomerular plasma flow (GPF) brought about by acute expansion of plasma volume with a volume of rat plasma equal to 5% of body weight. Glomerular hydrostatic and oncotic pressures measured at high GPF were used to calculate the ultrafiltration coefficient, K(f), the product of effective hydraulic permeability and surface area. GPF was then either lowered (by aortic constriction) or raised (by carotid occlusion) in order to examine the dependence of K(f) on GPF. The value of K(f) per glomerulus, 0.08 nl/(s.mm Hg), was found not to vary over an approximately twofold range of GPF. This finding, taken together with data from previous studies from this laboratory, leads us to conclude that plasma-flow dependence of glomerular filtration rate (GFR) results primarily from flow-induced changes in mean ultrafiltration pressure, rather than large changes in K(f).
Understanding Changing Risk Factor Associations With Increasing Age in Adults
Authors: G. A. Kaplan, Mary N. Haan, Robert B. Wallace
Journal: Annual Review of Public Health (1999)

▪ Abstract With an increasingly older population, there is considerable interest in understanding the potential for risk factor interventions in order to prevent, postpone, or slow down the common diseases seen in older persons. However, it is often reported that the strength of association between risk factors and common disease outcomes decreases with increasing age. Actually, many different age-related patterns are observed. Understanding these patterns requires knowledge of issues related to the pathophysiology of aging, including age-related physiologic and metabolic alterations, detection and diagnosis of disease in the elderly, measurement of risk factors, sample selection, comorbidity, competing risks, selective survival, ceiling effects, and methods of analysis in aging populations.
Effect of childhood eczema and asthma on parental sleep and well-being: a prospective comparative study
Authors: K Moore, T J David, C S Murray, F Child, P D Arkwright
Journal: British Journal of Dermatology (2006)

The psychological impact of childhood atopic eczema on parents and carers is poorly quantified. Objectives To compare the impact of caring for a child with atopic eczema vs. asthma on parents' sleep and well-being.Ninety-two parents of 55 children who had moderate to severe atopic eczema or asthma took part in this prospective, questionnaire-based study. It was conducted at regional eczema and asthma outpatient clinics within a U.K. tertiary paediatric hospital. The main outcome measures were the number and duration of parents' sleep disturbances, as well as their anxiety and depression scores.Mothers caring for children with atopic eczema lost a median of 39 min of sleep per night and fathers lost 45 min sleep per night. This compared with a median of 0 min sleep lost by parents who had children with asthma (P < 0.001). These differences were independent of the age of the children, and whether the child came from a single-parent or two-parent family. There was a direct correlation between the severity of sleep disturbance and the level of maternal anxiety (rho = 0.58; P = 0.002) and depression (rho = 0.73; P < 0.001), as well as the level of paternal anxiety (rho = 0.59; P = 0.01).Compared with looking after a child with chronic asthma, caring for a child with chronic atopic eczema was associated with greater parental sleep disturbances. Disruption to parental sleep correlated with anxiety levels and, in the case of mothers, depression scores.
Giant cells in arthritic synovium.
Authors: L.S Wilkinson, A.A Pitsillides, J.C Edwards
Journal: Annals of the Rheumatic Diseases (1993)

Giant cells are commonly present in inflamed synovium, often in close association with the intimal layer. The nature of these multinucleate cells has been reassessed using new cytochemical and immunochemical techniques. Cryostat sections of non-inflamed, rheumatoid arthritic and osteoarthritic synovia were analysed for the presence of CD68 and non-specific esterase, markers associated with macrophages; activity of uridine diphosphoglucose dehydrogenase, associated with fibroblast-like synoviocytes; and tartrate resistant acid phosphatase and the vitronectin receptor subunit CD51, associated with osteoclasts. Giant cells were not seen in non-inflamed tissue. In diseased tissue giant cells in the intimal layer fell into two major groups: CD68 negative or dull cells with high uridine diphosphoglucose dehydrogenase (UDPGD) activity suggestive of true synoviocyte polykaryons; and CD68 positive cells with low UDPGD activity suggestive of macrophage polykaryons. The two groups were seen in samples from patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA), but the former were more prominent in OA and the latter in RA. Most CD68 positive giant cells also showed tartrate resistant acid phosphatase activity and prominent expression of CD51. As such they were histochemically indistinguishable from osteoclasts, but their bone resorbing capacity remains unknown. Giant cells in arthritic synovium appear to be of two types, one related to true synoviocytes and one to macrophages.
Accuracy of Clinical Assessment in the Diagnosis of Pulmonary Embolism
Authors: MASSIMO MINIATI, RENATO PREDILETTO, BRUNO FORMICHI, CARLO MARINI, GIORGIO Di RICCO, LUCIA TONELLI, GERMANA ALLESCIA, MASSIMO PISTOLESI
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

To provide clinical diagnostic criteria for pulmonary embolism (PE), we evaluated 750 consecutive patients with suspected PE who were enrolled in the Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis (PISA-PED). Prior to perfusion lung scanning, patients were examined independently by six pulmonologists according to a standardized diagnostic protocol. Study design required pulmonary angiography in all patients with abnormal scans. Patients are reported as two distinct groups: a first group of 500, whose data were analyzed to derive a clinical diagnostic algorithm for PE, and a second group of 250 in whom the diagnostic algorithm was validated. PE was diagnosed by angiography in 202 (40%) of the 500 patients in the first group. A diagnostic algorithm was developed that includes the identification of three symptoms (sudden onset dyspnea, chest pain, and fainting) and their association with one or more of the following abnormalities: electrocardiographic signs of right ventricular overload, radiographic signs of oligemia, amputation of hilar artery, and pulmonary consolidations compatible with infarction. The above three symptoms (singly or in some combination) were associated with at least one of the above electrocardiographic and radiographic abnormalities in 164 (81%) of 202 patients with confirmed PE and in only 22 (7%) of 298 patients without PE. The rate of correct clinical classification was 88% (440/500). In the validation group of 250 patients the prevalence of PE was 42% (104/250). In this group, the sensitivity and specificity of the clinical diagnostic algorithm for PE were 84% (95% CI: 77 to 91%) and 95% (95% CI: 91 to 99%), respectively. The rate of correct clinical classification was 90% (225/250). Combining clinical estimates of PE, derived from the diagnostic algorithm, with independent interpretation of perfusion lung scans helps restrict the need for angiography to a minority of patients with suspected PE.