tbuckley/cabot-search huggingface dataset:
Pharmacologic Inhibition of Cyclin-Dependent Kinases 4 and 6 Arrests the Growth of Glioblastoma Multiforme Intracranial Xenografts
Authors: Karine Michaud, David A. Solomon, Eric Oermann, Jung-Sik Kim, Wei-Zhu Zhong, Michael D. Prados, Tomoko Ozawa, C. David James, Todd Waldman
Journal: Cancer Research (2010)

Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in the majority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for the development of small molecule inhibitors. In the current study, we investigated the molecular determinants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, a cdk4/6-specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G(1) cell cycle arrest and induction of senescence in each of 16 retinoblastoma protein (Rb)-proficient cell lines regardless of other genetic lesions, whereas 5 cell lines with homozygous inactivation of Rb were completely resistant to treatment. Short hairpin RNA depletion of Rb expression conferred resistance of GBM cells to PD-0332991, further demonstrating a requirement of Rb for sensitivity to cdk4/6 inhibition. PD-0332991 was found to efficiently cross the blood-brain barrier and proved highly effective in suppressing the growth of intracranial GBM xenograft tumors, including those that had recurred after initial therapy with temozolomide. Remarkably, no mice receiving PD-0332991 died as a result of disease progression while on therapy. Additionally, the combination of PD-0332991 and radiation therapy resulted in significantly increased survival benefit compared with either therapy alone. In total, our results support clinical trial evaluation of PD-0332991 against newly diagnosed as well as recurrent GBM, and indicate that Rb status is the primary determinant of potential benefit from this therapy.
Transfusion in Myocardial Infarction: Bloodcurdling?
Authors: Pieter R. Tuinman, Marcella C. Muller, Nicole P. Juffermans
Journal: JAMA Internal Medicine (2013)

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Epithelial-to-Mesenchymal Transition and Autophagy Induction in Breast Carcinoma Promote Escape from T-cell–Mediated Lysis
Authors: Intissar Akalay, Bassam Janji, Meriem Hasmim, Muhammad Zaeem Noman, Fabrice André, Patricia De Cremoux, Philippe Bertheau, Cécile Badoual, Philippe Vielh, Annette K. Larsen, Michèle Sabbah, Tuan Zea Tan, Joan Herr Keira, Nicole Tsang Ying Hung, Jean Paul Thiery, Fathia Mami-Chouaib, Salem Chouaib
Journal: Cancer Research (2013)

Epithelial-to-mesenchymal transition (EMT) mediates cancer cell invasion, metastasis, and drug resistance, but its impact on immune surveillance has not been explored. In this study, we investigated the functional consequences of this mode of epithelial cell plasticity on targeted cell lysis by cytotoxic T lymphocytes (CTL). Acquisition of the EMT phenotype in various derivatives of MCF-7 human breast cancer cells was associated with dramatic morphologic changes and actin cytoskeleton remodeling, with CD24(-)/CD44(+)/ALDH(+) stem cell populations present exhibiting a higher degree of EMT relative to parental cells. Strikingly, acquisition of this phenotype also associated with an inhibition of CTL-mediated tumor cell lysis. Resistant cells exhibited attenuation in the formation of an immunologic synapse with CTLs along with the induction of autophagy in the target cells. This response was critical for susceptibility to CTL-mediated lysis because siRNA-mediated silencing of beclin1 to inhibit autophagy in target cells restored their susceptibility to CTL-induced lysis. Our results argue that in addition to promoting invasion and metastasis EMT also profoundly alters the susceptibility of cancer cells to T-cell-mediated immune surveillance. Furthermore, they reveal EMT and autophagy as conceptual realms for immunotherapeutic strategies to block immune escape.
Short-term smoking reduction is associated with reduction in measures of lower respiratory tract inflammation in heavy smokers
Authors: SI Rennard, D Daughton, J Fujita, MB Oehlerking, None Dobson, MG Stahl, RA Robbins, AB Thompson
Journal: European Respiratory Journal (1990)

The beneficial effect of short-term smoking reduction in reducing lower respiratory tract inflammation was assessed in 15 healthy heavy smokers. All underwent fibreoptic bronchoscopy and bronchoalveolar lavage and were then treated with at least 20 mg of nicotine gum daily. Self-reported cigarette consumption decreased from 50.7 +/- 2.3 to 18.8 +/- 1.5 (p less than 0.001) cigarettes daily, and expired CO decreased from 48.5 +/- 2.5 to 27.3 +/- 2.5 ppm (p less than 0.001). After two months, repeat bronchoscopy and bronchoalveolar lavage revealed that bronchial inflammation, as assessed by direct inspection, neutrophilia of bronchial lavage fluid, and the number of alveolar macrophages, the number of alveolar neutrophils and the concentration of neutrophil elastase alpha 1-antiprotease complex in alveolar lavage fluid, had improved significantly. The present study suggests that smoking reduction may be associated with an improvement in lower respiratory tract inflammation in heavy smokers and may, if persistent, be an alternative for smokers who cannot, or do not wish, to quit.
A Meta-Analysis of Head-to-Head Comparisons of Second-Generation Antipsychotics in the Treatment of Schizophrenia
Authors: Stefan Leucht, Katja Komossa, Christine Rummel-Kluge, Caroline Corves, Heike Hunger, Franziska Schmid, Claudia Asenjo Lobos, Sandra Schwarz, John M Davis
Journal: American Journal of Psychiatry (2008)

Whether there are differences in efficacy among second-generation antipsychotics in the treatment of schizophrenia is a matter of heated debate. The authors conducted a systematic review and meta-analysis of blinded studies comparing second-generation antipsychotics head-to-head.Searches of the Cochrane Schizophrenia Group's register (May 2007) and MEDLINE (September 2007) were conducted for randomized, blinded studies comparing two or more of nine second-generation antipsychotics in the treatment of schizophrenia. All data were extracted by at least three reviewers independently. The primary outcome measure was change in total score on the Positive and Negative Syndrome Scale; secondary outcome measures were positive and negative symptom subscores and rate of dropout due to inefficacy. The results were combined in a meta-analysis. Various sensitivity analyses and metaregressions were used to examine bias.The analysis included 78 studies with 167 relevant arms and 13,558 participants. Olanzapine proved superior to aripiprazole, quetiapine, risperidone, and ziprasidone. Risperidone was more efficacious than quetiapine and ziprasidone. Clozapine proved superior to zotepine and, in doses >400 mg/day, to risperidone. These differences were due to improvement in positive symptoms rather than negative symptoms. The results were rather robust with regard to the effects of industry sponsorship, study quality, dosages, and trial duration.The findings suggest that some second-generation antipsychotics may be somewhat more efficacious than others, but the limitations of meta-analysis must be considered. In tailoring drug treatment to the individual patient, small efficacy superiorities must be weighed against large differences in side effects and cost.
Prevalence of infection with<i> Cryptosporidium parvum</i>and<i> Cyclospora cayetanensis</i> among international travellers
Authors: T Jelinek, M Lotze, S Eichenlaub, T Löscher, H D Nothdurft
Journal: Gut (1997)

Background — Cryptosporidium parvum and Cyclospora cayetanensis are recognised as possible pathogens of traveller’s diarrhoea. Aims —To identify the prevalence of C parvum and Cyc cayetanensis in travellers returning from developing countries. Patients —Nine hundred and seventy eight stool samples were taken from 795 patients returning from developing countries. Methods —Microscopy (iron-haematoxylin stain, SAF concentration, modified acid fast stain) and a commercially available enzyme linked immunosorbent assay (ELISA) kit for the detection of Cryptosporidium antigen in stool. Results —Of the 795 patients in the study, 469 suffered from diarrhoea. Infection with Cyc cayetanensis could be detected in five subjects (1.1%) by acid fast stain, and 13 patients (2.8%) were infected with C parvum . On evaluation, the antigen capture ELISA turned out to be clearly less sensitive for detection of C parvum than microscopy. All patients with either C parvum or Cyc cayetanensis infection suffered from watery diarrhoea. Conclusions — C parvum and Cyc cayetanensis are not major causes of diarrhoea in international travellers. In cases of persistent watery diarrhoea, however, these pathogens should be taken into account in the differential diagnosis.
Altered O-glycan synthesis in lymphocytes from patients with Wiskott-Aldrich syndrome.
Authors: F Piller, F Le Deist, K I Weinberg, R Parkman, M Fukuda
Journal: The Journal of Experimental Medicine (1991)

The only molecular defect reported for the X-linked immunodeficiency Wiskott-Aldrich syndrome (WAS) is the abnormal electrophoretic behavior of the major T lymphocyte sialoglycoprotein CD43. Since the 70 to 80 O-linked carbohydrate chains of CD43 are known to influence markedly its electrophoretic mobility, we analyzed the structure and the biosynthesis of O-glycans of CD43 in lymphocytes from patients with WAS. Immunofluorescence analysis with the carbohydrate dependent anti-CD43 antibody T305 revealed that in 10 out of the 12 WAS patients tested increased numbers of T lymphocytes carry on CD43 an epitope which on normal lymphocytes is expressed only after activation. Other activation antigens were absent from WAS lymphocytes. Western blots of WAS cell lysates displayed a high molecular mass form of CD43 which reacted with the T305 antibody and which could be found on in vivo activated lymphocytes but was absent from normal unstimulated lymphocytes. To examine the O-glycan structures, carbohydrate labeled CD43 was immunoprecipitated and the released oligosaccharides identified. WAS lymphocyte CD43 was found to carry predominantly the branched structure NeuNAc alpha 2----3Gal beta 1----3 (NeuNAc alpha 2----3Gal beta 1----4G1cNAc beta 1----6) GalNAcOH whereas normal lymphocytes carry the structure NeuNAc alpha 2----3Gal beta 1----3 (NeuNAc alpha 2----6) GalNAcOH. Only after activation NeuNAc alpha 2----3Gal beta 1----3 (NeuNAc alpha 2----3Gal beta 1----4GlcNAc beta 1----6) GalNAcOH becomes the principal oligosaccharide on CD43 from normal lymphocytes. Analyzing the six glycosyltransferases involved in the biosynthesis of these O-glycan structures it was found that in WAS lymphocytes high levels of beta 1----6 N-acetyl-glucosaminyl transferase are responsible for the expression of NeuNAc alpha 2----3Gal beta 1----3 (NeuNAc alpha 2----3Gal beta 1----4GlcNAc beta 1----6) GalNAcOH on CD43. The gene responsible for WAS has not yet been identified but the results presented in this study suggest that the primary defect in WAS may affect a gene which is involved in the regulation of O-glycosylation.
Mother to child transmission of HIV in China
Authors: Katherine T Chen, Han-Zhu Qian
Journal: BMJ (2005)

without turning into the agents of destruction of creation itself." 3 Indeed, in his first homily as pope he stated that he would continue to underline unequivocally "the inviolability of human beings, the inviolability of human life from conception to natural death." 4 In response to the papal election the former Anglican archbishop of Cape Town, Desmond Tutu, said, "We would have hoped for someone more open to the recent developments in the world, the ministry of women, and a more reasonable position with regards to condoms and HIV/AIDS." 5 Yet Cardinal George Cottier, one of the Vatican's most influential theologists, supports the use of condoms as defence against HIV in special cases. 6 Furthermore, Cardinal Lozano Barragan, effectively the Vatican's minister of health, has said that a spouse has the right to use a condom or oblige their marriage partner to do so in self defence against HIV infection. 7Will Benedict XVI accept and even develop this revolutionary idea for Catholics?The defence of life is an essential Catholic philosophy, enshrined in the most influential and controversial encyclicals signed by past leaders of the Roman Catholic church: Humanae Vitae of Paul VI (1968) 2 and Evangelium Vitae of John Paul II (1995). 8 The Catholic church is traditionally against abortion, which it sees as a contravention of moral law, with the legal status of the unborn child starting at conception. 9 The church is also against euthanasia, which it considers to be a form of murder. 10Might the Vatican allow the condom's ability to defend life, albeit only within marriage, to take priority over its ability to prevent conception?The Catholic church opposes the use of stem cells derived from the human embryo. 11It is not, however, against scientific progress and supports some controversial recent advances such as adult stem cell research and xenotransplantation, despite their ethical problems.The Vatican supports organ transplantation, 12 and it sets ethical limits only around any related loss of human dignity, the use of the body as "a container" of organs, and any failure to use objective criteria to confirm the death of the donor.Ratzinger wrote three years ago: "It is legitimate to accept the culture of transplanted tissue and donation of organs spontaneously and in all conscience" and also declared: "I enrolled in the organisation (for organ donors) years ago and carry the paper saying that my organs will be made available to whoever may need them.It's a sign of love." 13
COMPARISON OF PLATELET REACTIVITY AND CLINICAL OUTCOMES IN PATIENTS TREATED WITH CLOPIDOGREL AND CORONARY INTERVENTION
Authors: Min Kim, Sang Yeub Lee, Ju-Hee Lee, Sang Min Kim, Jang-Whan Bae, Kyung-Kuk Hwang, Dong-Woon Kim, Myeong-Chan Cho
Journal: Journal of the American College of Cardiology (2014)
Markov model into the cost-utility over five years of etanercept and infliximab compared with usual care in patients with active ankylosing spondylitis
Authors: A Boonen
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To estimate the incremental cost-utility of etanercept and infliximab compared with usual care in active ankylosing spondylitis. <b>Methods:</b> A Markov model over five years with cycle times of three months was computed. Patients included all had active disease, defined as Bath ankylosing spondylitis disease activity index (BASDAI) ⩾4 and could reach low disease activity, defined as BASDAI &lt;4. Non-response to tumour necrosis factor α (TNFα) inhibitors was always followed by cessation of treatment. Response to TNFα inhibitors could be followed at any time by either relapse to BASDAI ⩾4, leading to cessation of treatment, or toxicity, leading to cessation of treatment if major. Probabilities for efficacy, relapse, and toxicity were derived from two European randomised controlled trials. Utilities and costs assigned to the BASDAI disease states were derived from a two year observational Dutch cohort. In sensitivity analyses probabilities of effectiveness, toxicity, costs, and utilities were varied. <b>Results:</b> Over five years the total quality adjusted life years varied from 2.57 to 2.89 for usual care, compared with 3.13 to 3.42 and 3.07 to 3.35 for etanercept or infliximab. Cumulative costs were between €49 555 to 69 982 for usual care compared with €59 574 to 91 183 or €28 3330 to 106 775 for etanercept and infliximab. This resulted in incremental cost-utility ratios varying between €42 914 and 123 761 per QALY for etanercept compared with usual care and €67 207 to 237 010 for infliximab. The model was sensitive to drug prices. <b>Conclusion:</b> Etanercept and infliximab have large clinical effects in ankylosing spondylitis. The present model suggests the high drug costs restricts efficient use in all patients who have a BASDAI &gt;4. The validity of the model is limited by insufficient insight in the natural course of the disease and long term effectiveness and toxicity of TNFα inhibitors.
The Effect of a Disease Management Intervention on Quality and Outcomes of Dementia Care
Authors: Barbara G. Vickrey, Brian S. Mittman, Karen I. Connor, Marjorie L. Pearson, Richard D. Della Penna, Theodore G. Ganiats, Robert W. DeMonte, Joshua Chodosh, Xinping Cui, Stefanie Vassar, Naihua Duan, Martin Lee
Journal: Annals of Internal Medicine (2006)

Background: Adherence to dementia guidelines is poor despite evidence that some guideline recommendations can improve symptoms and delay institutionalization of patients. Objective: To test the effectiveness of a dementia guideline–based disease management program on quality of care and outcomes for patients with dementia. Design: Clinic-level, cluster randomized, controlled trial. Setting: 3 health care organizations collaborating with 3 community agencies in southern California. Participants: 18 primary care clinics and 408 patients with dementia age 65 years or older paired with 408 informal caregivers. Intervention: Disease management program led by care managers and provided to 238 patient–caregiver pairs at 9 intervention clinics for more than 12 months. Measurements: Adherence to 23 guideline recommendations (primary outcome) and receipt of community resources and patient and caregiver health and quality-of-care measures (secondary outcomes). Results: The mean percentage of per-patient guideline recommendations to which care was adherent was significantly higher in the intervention group than in the usual care group (63.9% vs. 32.9%, respectively; adjusted difference, 30.1% [95% CI, 25.2% to 34.9%]; P < 0.001). Participants who received the intervention had higher care quality on 21 of 23 guidelines (P ≤ 0.013 for all), and higher proportions received community agency assistance (P ≤ 0.03) than those who received usual care. Patient health-related quality of life, overall quality of patient care, caregiving quality, social support, and level of unmet caregiving assistance needs were better for participants in the intervention group than for those in the usual care group (P < 0.05 for all). Caregiver health-related quality of life did not differ between the 2 groups. Limitations: Participants were well-educated, were predominantly white, had a usual source of care, and were not institutionalized. Generalizability to other patients and geographic regions is unknown. Also, costs of a care management program under fee-for-service reimbursement may impede adoption. Conclusions: A dementia guideline–based disease management program led to substantial improvements in quality of care for patients with dementia. Current Controlled Trials identifier: ISRCTN72577751.
Phylogenetic Patterns of GC-Biased Gene Conversion in Placental Mammals and the Evolutionary Dynamics of Recombination Landscapes
Authors: Nicolas Lartillot
Journal: Molecular Biology and Evolution (2012)

GC-biased gene conversion (gBGC) is a major evolutionary force shaping genomic nucleotide landscapes, distorting the estimation of the strength of selection, and having potentially deleterious effects on genome-wide fitness. Yet, a global quantitative picture, at large evolutionary scale, of the relative strength of gBGC compared with selection and random drift is still lacking. Furthermore, owing to its dependence on the local recombination rate, gBGC results in modulations of the substitution patterns along genomes and across time which, if correctly interpreted, may yield quantitative insights into the long-term evolutionary dynamics of recombination landscapes. Deriving a model of the substitution process at putatively neutral nucleotide positions from population-genetics arguments, and accounting for among-lineage and among-gene effects, we propose a reconstruction of the variation in gBGC intensity at the scale of placental mammals, and of its scaling with body-size and karyotypic traits. Our results are compatible with a simple population genetics model relating gBGC to effective population size and recombination rate. In addition, among-gene variation and phylogenetic patterns of exon-specific levels of gBGC reveal the presence of rugged recombination landscapes, and suggest that short-lived recombination hot-spots are a general feature of placentals. Across placental mammals, variation in gBGC strength spans two orders of magnitude, at its lowest in apes, strongest in lagomorphs, microbats or tenrecs, and near or above the nearly neutral threshold in most other lineages. Combined with among-gene variation, such high levels of biased gene conversion are likely to significantly impact midly selected positions, and to represent a substantial mutation load. Altogether, our analysis suggests a more important role of gBGC in placental genome evolution, compared with what could have been anticipated from studies conducted in anthropoid primates.
Expression and Growth Dependency of the Insulin-Like Growth Factor I Receptor in Craniopharyngioma Cells: A Novel Therapeutic Approach
Authors: Elfar Ulfarsson, Alexandra Karström, Shucheng Yin, Ada Girnita, Daiana Vasilcanu, Marja Thoren, Gunnar Kratz, Jan Hillman, Magnus Axelson, Olle Larsson, Leonard Girnita
Journal: Clinical Cancer Research (2005)

Craniopharyngioma is a rare benign intracranial epithelial tumor that, however, often recurs and sometimes kills the affected patients, one-third of which are children. In many cases, the patients acquire growth hormone deficiency and postoperatively need substitution. Generally, growth hormone promotes local release of insulin-like growth factor I (IGF-I), which in turn activates the IGF-I receptor (IGF-IR) if present. Together, these circumstances raise the question whether IGF-IR may be involved in craniopharyngioma growth. To address this issue, we analyzed phenotypically well-characterized primary low-passage craniopharyngioma cell lines from nine different patients for IGF-IR expression and IGF-I dependency. Two of the cell lines showed no/very low expression of the receptor and was independent on IGF-I, whereas five cell lines exhibited a strong expression and was clearly contingent on IGF-I. The two remaining cell lines had low receptor expression and IGF-I dependency. Upon treatment with an IGF-IR inhibitor, cells with high IGF-IR expression responded promptly with decreased Akt phosphorylation followed by growth arrest. These responses were not seen in cells with no/very low receptor expression. Growth of cell lines with low IGF-IR expression was only slightly affected by IGF-IR inhibition. Taken together, our data suggest that IGF-IR may be involved in the growth of a subset of craniopharyngiomas and points to the possibility of the involvement of IGF-IR inhibitors as a treatment modality to obtain complete tumor-free conditions before growth hormone substitution.