tbuckley/cabot-search huggingface dataset:
Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males
Authors: Tao Sun, Nicole M. Warrington, Jingqin Luo, Michael D. Brooks, Sonika Dahiya, Steven C. Snyder, Rajarshi Sengupta, Joshua B. Rubin
Journal: Journal of Clinical Investigation (2014)

The prevalence of brain tumors in males is common but unexplained. While sex differences in disease are typically mediated through acute sex hormone actions, sex-specific differences in brain tumor rates are comparable at all ages, suggesting that factors other than sex hormones underlie this discrepancy. We found that mesenchymal glioblastoma (Mes-GBM) affects more males as the result of cell-intrinsic sexual dimorphism in astrocyte transformation. We used astrocytes from neurofibromin-deficient (Nf1(-/-)) mice expressing a dominant-negative form of the tumor suppressor p53 (DNp53) and treated them with EGF as a Mes-GBM model. Male Mes-GBM astrocytes exhibited greater growth and colony formation compared with female Mes-GBM astrocytes. Moreover, male Mes-GBM astrocytes underwent greater tumorigenesis in vivo, regardless of recipient mouse sex. Male Mes-GBM astrocytes exhibited greater inactivation of the tumor suppressor RB, higher proliferation rates, and greater induction of a clonogenic, stem-like cell population compared with female Mes-GBM astrocytes. Furthermore, complete inactivation of RB and p53 in Mes-GBM astrocytes resulted in equivalent male and female tumorigenic transformation, indicating that intrinsic differences in RB activation are responsible for the predominance of tumorigenic transformation in male astrocytes. Together, these results indicate that cell-intrinsic sex differences in RB regulation and stem-like cell function may underlie the predominance of GBM in males.
GAD65 and GAD67 Isoforms of the Glutamic Acid Decarboxylase Gene Originated Before the Divergence of Cartilaginous Fishes
Authors: K. Lariviere, L. MacEachern, V. Greco, G. Majchrzak, S. Chiu, G. Drouin, V. L. Trudeau
Journal: Molecular Biology and Evolution (2002)
Simultaneous occurrence of acute myeloid leukaemia with mutated nucleophosmin (NPM1) in the same family
Authors: G Cazzaniga, L Lo Nigro, I Cifola, G Milone, S Schnittger, T Haferlach, E Mirabile, F Costantino, M P Martelli, E Mastrodicasa, F Di Raimondo, F Aversa, A Biondi, B Falini
Journal: Leukemia (2008)
Systematic Implementation of an Advance Directive Program in Nursing Homes
Authors: D W Molloy, G H Guyatt, R Russo, R Goeree, B J O'Brien, M Bédard, A Willan, J Watson, C Patterson, C Harrison, T Standish, D Strang, P J Darzins, S Smith, S Dubois
Journal: JAMA (2000)

Although advance directives are commonly used in the community, little is known about the effects of their systematic implementation.To examine the effect of systematically implementing an advance directive in nursing homes on patient and family satisfaction with involvement in decision making and on health care costs.Randomized controlled trial conducted June 1, 1994, to August 31, 1998.A total of 1292 residents in 6 Ontario nursing homes with more than 100 residents each.The Let Me Decide advance directive program included educating staff in local hospitals and nursing homes, residents, and families about advance directives and offering competent residents or next-of-kin of mentally incompetent residents an advance directive that provided a range of health care choices for life-threatening illness, cardiac arrest, and nutrition. The 6 nursing homes were pair-matched on key characteristics, and 1 home per pair was randomized to take part in the program. Control nursing homes continued with prior policies concerning advance directives.Residents' and families' satisfaction with health care and health care services utilization over 18 months, compared between intervention and control nursing homes.Of 527 participating residents in intervention nursing homes, 49% of competent residents and 78% of families of incompetent residents completed advance directives. Satisfaction was not significantly different in intervention and control nursing homes. The mean difference (scale, 1-7) between intervention and control homes was -0.16 (95 % confidence interval [CI], -0.41 to 0.10) for competent residents and 0.07 (95% CI, -0.08 to 0.23) for families of incompetent residents. Intervention nursing homes reported fewer hospitalizations per resident (mean, 0.27 vs 0.48; P = .001) and less resource use (average total cost per patient, Can $3490 vs Can $5239; P = .01) than control nursing homes. Proportion of deaths in intervention (24%) and control (28%) nursing homes were similar (P = .20).Our data suggest that systematic implementation of a program to increase use of advance directives reduces health care services utilization without affecting satisfaction or mortality.
Intraperitoneal Administration of Anti–c-<i>fms</i>Monoclonal Antibody Prevents Initial Events of Atherogenesis but Does Not Reduce the Size of Advanced Lesions in Apolipoprotein E–Deficient Mice
Authors: Toshinori Murayama, Masayuki Yokode, Hiroshi Kataoka, Takeshi Imabayashi, Hiroyuki Yoshida, Hideto Sano, Satomi Nishikawa, Shin-Ichi Nishikawa, Toru Kita
Journal: Circulation (1999)

Background —Atherosclerosis results from complex inflammatory-fibroproliferative responses. To elucidate the central role of macrophage and macrophage-colony stimulating factor (M-CSF) during atherogenesis, we used a new strategy to administer to adult apolipoprotein E (apoE)-deficient mice a monoclonal antibody (AFS98) raised against c- fms , the receptor of M-CSF. Methods and Results —When 6-week-old apoE-deficient mice were fed a high-fat diet and injected with 2 mg of AFS98 intraperitoneally on alternate days for 6 weeks, accumulation of macrophage-derived foam cells in the aortic root was suppressed by 70% compared with that in controls. This preventive effect was associated with neither remarkable decrease of the number of circulating monocytes nor systemic growth retardation. In contrast, when apoE-deficient mice that had been fed a high-fat diet from 6 weeks of age were given AFS98 from 12 to 18 weeks of age, a minimal protective effect on lesion size was observed. Conclusions —These results suggest that (1) macrophage and M-CSF/c- fms play an essential role in the arterial wall during development of the fatty streak lesion and (2) blockade of the M-CSF/c- fms pathway could act as protection from at least early atherogenesis but could have a less preventive effect on maintenance of the advanced lesions.
Mutation signatures implicate aristolochic acid in bladder cancer development
Authors: Song Ling Poon, Mi Ni Huang, Yang Choo, John R McPherson, Willie Yu, Hong Lee Heng, Anna Gan, Swe Swe Myint, Ee Yan Siew, Lian Dee Ler, Lay Guat Ng, Wen-Hui Weng, Cheng-Keng Chuang, John Sp Yuen, See-Tong Pang, Patrick Tan, Bin Tean Teh, Steven G Rozen
Journal: Genome Medicine (2015)
Mobster: accurate detection of mobile element insertions in next generation sequencing data
Authors: Djie Tjwan Thung, Joep de Ligt, Lisenka EM Vissers, Marloes Steehouwer, Mark Kroon, Petra de Vries, Eline P Slagboom, Kai Ye, Joris A Veltman, Jayne Y Hehir-Kwa
Journal: Genome biology (2014)

Abstract Mobile elements are major drivers in changing genomic architecture and can cause disease. The detection of mobile elements is hindered due to the low mappability of their highly repetitive sequences. We have developed an algorithm, called Mobster, to detect non-reference mobile element insertions in next generation sequencing data from both whole genome and whole exome studies. Mobster uses discordant read pairs and clipped reads in combination with consensus sequences of known active mobile elements. Mobster has a low false discovery rate and high recall rate for both L1 and Alu elements. Mobster is available at http://sourceforge.net/projects/mobster .
Infective Hepatitis in a Mixed School, with High Attack Rate in Females
Authors: J. H. M. Tilley
Journal: BMJ (1960)

A small epidemic of infective hepatitis in an urban district of the County of Lancashire consisted almost entirely of girls at one mixed school, although there was no great excess of girls in any one class at the school.Pickles (1939), in his classical description of infective hepatitis in rural Yorkshire, does not give any figures showing that females are specially susceptible to this disease.
Estimating cardiac transmembrane activation and recovery times from unipolar and bipolar extracellular electrograms: a simulation study.
Authors: B M Steinhaus
Journal: Circulation Research (1989)

A model of one-dimensional action potential propagation was used to compare activation times and recovery times measured from simulated unipolar and bipolar electrograms with the activation and recovery times measured from simulated transmembrane action potentials. Theory predicts that the intrinsic deflection--the time of the maximum negative slope of the unipolar electrogram QRS complex--corresponds to the time of maximum positive slope of action potential depolarization. Similarly, the time of the maximum positive slope of the unipolar electrogram T wave corresponds to the time of maximum negative slope of action potential repolarization. This study showed that the difference between the unipolar electrogram activation time and the action potential activation time and the difference between the unipolar electrogram recovery time and the action potential recovery time were small during ideal conditions of uniform propagation in a long cable. Nonideal conditions, however, were associated with activation time differences in excess of 1.8 msec and recovery time differences in excess of 30 msec (243 msec in certain conditions). Nonideal conditions that had a major influence were changes in activation sequence, propagation in a short cable, and propagation through regions of nonuniform coupling resistance and/or nonuniform membrane properties. Nonideal conditions that had a smaller influence were variations in distance from the measurement site to the simulated tissue surface, nonzero reference potentials, and the addition of distant events. Recovery time differences were more sensitive to the nonideal conditions than were activation time differences, and both depended on the action potential shape. When distant events significantly contributed to the unipolar electrogram waveform, the time differences when bipolar electrograms were used were less than those when unipolar electrograms were used; however, under other conditions, the time differences were comparable. Results showed that activation times and especially recovery times measured from electrograms can be greatly affected by conditions independent of changes in the underlying action potential waveforms.
Antiestrogens Induce Transforming Growth Factor β–Mediated Immunosuppression in Breast Cancer
Authors: Christian M. Joffroy, Miriam B. Buck, Matthias B. Stope, Simone L. Popp, Klaus Pfizenmaier, Cornelius Knabbe
Journal: Cancer Research (2010)

Antiestrogens are universally used to treat estrogen receptor--positive breast cancer, but relapses occur commonly due to the development of drug resistance. The ability of antiestrogen to induce transforming growth factor beta (TGFbeta) in breast cancer cells may be relevant to the emergence of resistance, not only at the level of cell autonomous effects of TGFbeta on cancer progression but also at the level of its effects on the host immune system. To evaluate the potential role of tumor-derived, antiestrogen-induced TGFbeta as an immune suppressor, we established in vitro mixed lymphocyte tumor reactions (MLTR) using MCF-7 cells and peripheral blood mononuclear cells (PBMC), as well as tumor tissue and autologous tumor infiltrating lymphocytes (TIL) obtained from primary breast cancer biopsies. In allogeneic MLTR, antiestrogen-treated MCF-7 cells caused downregulation of the effector molecules granzyme B, perforin, and Fas ligand in CD8(+) T cells, and suppressed the generation of cytotoxic effector cells in a TGFbeta-dependent manner. Furthermore, we documented induction of regulatory T cells in CD4(+) T cells, based on Foxp3 expression and T-cell activation in cocultures. In autologous MLTR, antiestrogen treatment gave rise to enhanced Foxp3 expression of TIL/PBMC and decreased the number of apoptotic tumor cells. These effects were reversed by addition of a TGFbeta neutralizing antibody. Our findings offer evidence that antiestrogen induces immunosuppression in the tumor microenvironment, through a TGFbeta-dependent mechanism that may contribute to the development of antiestrogen resistance in breast cancer.
Impact of Statin Use on Outcomes After Coronary Artery Bypass Graft Surgery
Authors: Alexander Kulik, M. Alan Brookhart, Raisa Levin, Marc Ruel, Daniel H. Solomon, Niteesh K. Choudhry
Journal: Circulation (2008)

The benefits of statins have been demonstrated for patients with a remote history of coronary artery bypass grafting (CABG); however, no investigation to date has evaluated whether initiation of statin therapy in the early months after surgery improves clinical outcomes.A retrospective cohort of 7503 Medicare patients >/=65 years of age who underwent CABG (1995-2003) was assembled by use of linked hospital and pharmacy claims data. Rates of all-cause mortality and major adverse cardiovascular events were compared between patients who were (n=1745) and were not (n=5788) prescribed statins within 1 month of CABG discharge. Additional analyses evaluated the impact of statin initiation between 1 and 6 months after surgery. Multivariable and propensity score analysis demonstrated that statin use within 1 month of CABG discharge independently reduced the risk of all-cause mortality (adjusted hazard ratio 0.82, 95% confidence interval 0.72 to 0.94) compared with no statin use. Similarly, statin use within 1 month of CABG discharge independently reduced the risk of major adverse cardiovascular events (adjusted hazard ratio 0.89, 95% confidence interval 0.81 to 0.98). Initiation of statin therapy between 1 and 6 months after CABG discharge was also associated with reductions in major adverse cardiovascular events and mortality; however, outcome rates between early (</=1 month after CABG) and delayed (1 to 6 months after CABG) statin initiation were not significantly different.Statin therapy initiated in the early months after hospital discharge independently reduces all-cause mortality and major adverse cardiovascular events after CABG. These findings validate the widespread practice of prescribing long-term statin therapy after CABG.
Infection With <i>Helicobacter pylori</i> Is Not a Major Independent Risk Factor for Stable Coronary Heart Disease
Authors: Wolfgang Koenig, Dietrich Rothenbacher, Albrecht Hoffmeister, Markus Miller, Guenther Bode, Guido Adler, Vinzenz Hombach, Winfried März, Mark B. Pepys, Hermann Brenner
Journal: Circulation (1999)

Background —There is controversy about the association between Helicobacter pylori infection and manifestations of coronary heart disease (CHD), the potential role of the more virulent H pylori strains, and whether or not a positive serostatus is related to increased levels of markers of systemic inflammation. Methods and Results —We assessed the prevalence of an infection with H pylori and in particular the anti–cytotoxin-associated protein A (CagA) antibody response of the more virulent strains expressing CagA in 312 patients with stable CHD and in 479 control subjects. Serological prevalence of H pylori infection (IgG titer) was significantly higher in patients than in control subjects after adjustment for age and sex (44.2% versus 31.3%, P &lt;0.001). After adjustment for various covariates in multiple logistic regression, the odds ratio (OR) for CHD was 1.3 (95% CI, 0.9 to 1.9) given a positive IgG serostatus. The prevalence of CagA-positive strains was 27.9% in patients and 21.7% in control subjects ( P =0.076 adjusted for age and sex). The OR for CHD in the fully adjusted model was 1.1 (95% CI, 0.7 to 1.7). None of the inflammatory markers (C-reactive protein, fibrinogen, plasma viscosity, or leukocytes) was significantly different according to serostatus. Conclusions —In this large case-control study, the association of H pylori infection with stable CHD was strongly reduced and was no longer statistically significant after controlling for potential confounders. We also found no independent association between the more virulent strains and CHD. In addition, a positive serostatus was not associated with a systemic inflammatory response. Thus, these data do not support the hypothesis that infection with H pylori might be a major risk factor for stable CHD.
Deficit of osteoprotegerin release by osteoblasts from a patient with cystic fibrosis
Authors: A. Gimenez-Maitre, C. Le Henaff, C. Norez, C. Guillaume, B. Ravoninjatovo, D. Laurent-Maquin, F. Becq, J. Jacquot
Journal: European Respiratory Journal (2012)

To the Editors:

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations of the CF transmembrane conductance regulator (CFTR), a cyclic adenosine monophosphate (cAMP)-dependent anion channel expressed mostly in epithelia. Bone deficiency is commonly seen in patients with CF and begins at a young age. Low bone mass affects children and young adults with CF and is associated with significant morbidity due to fractures and decreased lung function. Brittle bones in CF disease have been confirmed by densitometric data, the presence of fractures, and impaired quality of life of young and adult patients [1]. Whether or not this is caused by bone disease around puberty due to a poor acquisition of peak bone mass and worsens with age, lower bone mineral density (BMD) gains are already being observed in CF children with mild disease and normal nutritional status, suggesting that CF-related low BMD may, in part, be due to a primary defect in bone metabolism [2]. In human bone cells, the expression of CFTR protein has been identified by immunohistological observations [3]; we further reported the expression of CFTR mRNA and protein in primary …
Medicine and South Africa
Authors: J. Gluckman
Journal: BMJ (1986)

SIR,-The president of the Hospital Consultants and Specialists Association states (18 January, p 206) that his association "was very surprised to read the evidenqe of the Short select, committee given by the spokesmen for the medical profession, including the consultant representative on, the BMA delegation, and felt obliged to conduct a survey to.find out if there had been a change of attitude to the hospital staffing structure."As'the "consultant representative" referred to above, I should like to put the-record straight.In 1982 the Central Committee for Hospital Medical Services supported the concept of a controlled.expansion of consultants in general surgery, general medicine, and obstetrics and gynaecology; a reduction in the number of UK graduate registrars in these specilties; and the introduction of an overseas doctors training scheme.These proposals were put to the con- sultant body t large, and 85% of the m,any respondents supported these proposals.This information was included in the select conputtee's *minutes of evidence for Wednesday 27 March 1985, to which the president of the HCSA referred in his letter.Indeed, it states quite clearly i'n those minutes (p 6, paragraph 16) that " HC:MS did not support the Social Servies Committee's geieral notion of a consultant provided service."-In oral evidence used the-phrase "consultant based," and from the subsequent paragraphs itis clear that I was using the phrase.todescribe the proposals tharhad been accepted by the profession in 1982.This includes an adequate numnber of
Harderoporphyria: a variant hereditary coproporphyria.
Authors: Y Nordmann, B Grandchamp, H de Verneuil, L Phung, B Cartigny, G Fontaine
Journal: Journal of Clinical Investigation (1983)

Three siblings with intense jaundice and hemolytic anemia at birth were found to excrete a high level of coproporphyrin in their urine and feces; the pattern of fecal porphyrin excretion was atypical for hereditary coproporphyria because the major porphyrin was harderoporphyrin (greater than 60%; normal value is less than 20%). The lymphocyte coproporphyrinogen III oxidase activity of each patient was 10% of control values, which suggests a homozygous state. Both parents showed only mild abnormalities in porphyrin excretion and lymphocyte coproporphyrinogen III oxidase activity decreased to 50% of normal values, as is expected in heterozygous cases of hereditary coproporphyria. Kinetic parameters of coproporphyrinogen III oxidase from these patients were clearly modified, with a Michaelis constant 15-20-fold higher than normal values when using coproporphyrinogen or harderoporphyrinogen as substrates. Maximal velocity was half the normal value, and we also observed a marked sensitivity to thermal denaturation. The possibility that a mutation affecting the enzyme on the active center which is specifically involved in the second decarboxylation (from harderoporphyrinogen to protoporphyrinogen) was eliminated by experiments on rat liver that showed that coproporphyrinogen and harderoporphyrinogen were metabolized at the same active center. The pattern of porphyrin excretion and the coproporphyrinogen oxidase from the three patients exhibited abnormalities that were different from the abnormalities found in another recently described homozygous case of hereditary coproporphyria. We suggest naming this variant of coproporphyrinogen oxidase defect "harderoporphyria."
Hypoxia-inducible factor-1α regulates β cell function in mouse and human islets
Authors: Kim Cheng, Kenneth Ho, Rebecca Stokes, Christopher Scott, Sue Mei Lau, Wayne J. Hawthorne, Philip J. O’Connell, Thomas Loudovaris, Thomas W. Kay, Rohit N. Kulkarni, Terumasa Okada, Xiaohui L. Wang, Sun Hee Yim, Yatrik Shah, Shane T. Grey, Andrew V. Biankin, James G. Kench, D. Ross Laybutt, Frank J. Gonzalez, C. Ronald Kahn, Jenny E. Gunton
Journal: Journal of Clinical Investigation (2010)

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that regulates cellular stress responses. While the levels of HIF-1alpha protein are tightly regulated, recent studies suggest that it can be active under normoxic conditions. We hypothesized that HIF-1alpha is required for normal beta cell function and reserve and that dysregulation may contribute to the pathogenesis of type 2 diabetes (T2D). Here we show that HIF-1alpha protein is present at low levels in mouse and human normoxic beta cells and islets. Decreased levels of HIF-1alpha impaired glucose-stimulated ATP generation and beta cell function. C57BL/6 mice with beta cell-specific Hif1a disruption (referred to herein as beta-Hif1a-null mice) exhibited glucose intolerance, beta cell dysfunction, and developed severe glucose intolerance on a high-fat diet. Increasing HIF-1alpha levels by inhibiting its degradation through iron chelation markedly improved insulin secretion and glucose tolerance in control mice fed a high-fat diet but not in beta-Hif1a-null mice. Increasing HIF-1alpha levels markedly increased expression of ARNT and other genes in human T2D islets and improved their function. Further analysis indicated that HIF-1alpha was bound to the Arnt promoter in a mouse beta cell line, suggesting direct regulation. Taken together, these findings suggest an important role for HIF-1alpha in beta cell reserve and regulation of ARNT expression and demonstrate that HIF-1alpha is a potential therapeutic target for the beta cell dysfunction of T2D.