tbuckley/cabot-search huggingface dataset:
Kinetics of Metastatic Breast Cancer Cell Trafficking in Bone
Authors: Pushkar A. Phadke, Robyn R. Mercer, John F. Harms, Yujiang Jia, Andra R. Frost, Jennifer L. Jewell, Karen M. Bussard, Shakira Nelson, Cynthia Moore, John C. Kappes, Carol V. Gay, Andrea M. Mastro, Danny R. Welch
Journal: Clinical Cancer Research (2006)

In vivo studies have focused on the latter stages of the bone metastatic process (osteolysis), whereas little is known about earlier events, e.g., arrival, localization, and initial colonization. Defining these initial steps may potentially identify the critical points susceptible to therapeutic intervention.MDA-MB-435 human breast cancer cells engineered with green fluorescent protein were injected into the cardiac left ventricle of athymic mice. Femurs were analyzed by fluorescence microscopy, immunohistochemistry, real-time PCR, flow cytometry, and histomorphometry at times ranging from 1 hour to 6 weeks.Single cells were found in distal metaphyses at 1 hour postinjection and remained as single cells up to 72 hours. Diaphyseal arrest occurred rarely and few cells remained there after 24 hours. At 1 week, numerous foci (2-10 cells) were observed, mostly adjacent to osteoblast-like cells. By 2 weeks, fewer but larger foci (> or =50 cells) were seen. Most bones had a single large mass at 4 weeks (originating from a colony or coalescing foci) which extended into the diaphysis by 4 to 6 weeks. Little change (<20%) in osteoblast or osteoclast numbers was observed at 2 weeks, but at 4 to 6 weeks, osteoblasts were dramatically reduced (8% of control), whereas osteoclasts were reduced modestly (to approximately 60% of control).Early arrest in metaphysis and minimal retention in diaphysis highlight the importance of the local milieu in determining metastatic potential. These results extend the Seed and Soil hypothesis by demonstrating both intertissue and intratissue differences governing metastatic location. Ours is the first in vivo evidence that tumor cells influence not only osteoclasts, as widely believed, but also eliminate functional osteoblasts, thereby restructuring the bone microenvironment to favor osteolysis. The data may also explain why patients receiving bisphosphonates fail to heal bone despite inhibiting resorption, implying that concurrent strategies that restore osteoblast function are needed to effectively treat osteolytic bone metastases.
GC-Biased Gene Conversion in Yeast Is Specifically Associated with Crossovers: Molecular Mechanisms and Evolutionary Significance
Authors: Yann Lesecque, Dominique Mouchiroud, Laurent Duret
Journal: Molecular Biology and Evolution (2013)

GC-biased gene conversion (gBGC) is a process associated with recombination that favors the transmission of GC alleles over AT alleles during meiosis. gBGC plays a major role in genome evolution in many eukaryotes. However, the molecular mechanisms of gBGC are still unknown. Different steps of the recombination process could potentially cause gBGC: the formation of double-strand breaks (DSBs), the invasion of the homologous or sister chromatid, and the repair of mismatches in heteroduplexes. To investigate these models, we analyzed a genome-wide data set of crossovers (COs) and noncrossovers (NCOs) in Saccharomyces cerevisiae. We demonstrate that the overtransmission of GC alleles is specific to COs and that it occurs among conversion tracts in which all alleles are converted from the same donor haplotype. Thus, gBGC results from a process that leads to long-patch repair. We show that gBGC is associated with longer tracts and that it is driven by the nature (GC or AT) of the alleles located at the extremities of the tract. These observations invalidate the hypotheses that gBGC is due to the base excision repair machinery or to a bias in DSB formation and suggest that in S. cerevisiae, gBGC is caused by the mismatch repair (MMR) system. We propose that the presence of nicks on both DNA strands during CO resolution could be the cause of the bias in MMR activity. Our observations are consistent with the hypothesis that gBGC is a nonadaptive consequence of a selective pressure to limit the mutation rate in mitotic cells.
Nuclear pore rearrangements and nuclear trafficking in cardiomyocytes from rat and human failing hearts
Authors: Mirna N. Chahine, Maxime Mioulane, Markus B. Sikkel, Peter O'Gara, Cristobal G. Dos Remedios, Grant N. Pierce, Alexander R. Lyon, Gábor Földes, Sian E. Harding
Journal: Cardiovascular Research (2014)

During cardiac hypertrophy, cardiomyocytes (CMs) increase in the size and expression of cytoskeletal proteins while reactivating a foetal gene programme. The process is proposed to be dependent on increased nuclear export and, since nuclear pore trafficking has limited capacity, a linked decrease in import. Our objective was to investigate the role of nuclear import and export in control of hypertrophy in rat and human heart failure (HF). In myocardial tissue and isolated CMs from patients with dilated cardiomyopathy, nuclear size was increased; Nucleoporin p62, cytoplasmic RanBP1, and nuclear translocation of importins (α and β) were decreased while Exportin-1 was increased. CM from a rat HF model 16 weeks after myocardial infarction (MI) reproduced these nuclear changes. Nuclear import, determined by the rate of uptake of nuclear localization sequence (NLS)-tagged fluorescent substrate, was also decreased and this change was observed from 4 weeks after MI, before HF has developed. Treatment of isolated rat CMs with phenylephrine (PE) for 48 h produced similar cell and nuclear size increases, nuclear import and export protein rearrangement, and NLS substrate uptake decrease through p38 MAPK and HDAC-dependent pathways. The change in NLS substrate uptake occurred within 15 min of PE exposure. Inhibition of nuclear export with leptomycin B reversed established nuclear changes in PE-treated rat CMs and decreased NLS substrate uptake and cell/nuclear size in human CMs. Nuclear transport changes related to increased export and decreased import are an early event in hypertrophic development. Hypertrophy can be prevented, or even reversed, by targeting import/export, which may open new therapeutic opportunities.
Dimensional Representations of DSM-IV Personality Disorders: Relationships to Functional Impairment
Authors: Andrew E. Skodol, John M. Oldham, Donna S. Bender, Ingrid R. Dyck, Robert L. Stout, Leslie C. Morey, M. Tracie Shea, Mary C. Zanarini, Charles A. Sanislow, Carlos M. Grilo, Thomas H. McGlashan, John G. Gunderson
Journal: American Journal of Psychiatry (2005)

This study compared three-dimensional representations of DSM-IV personality disorders and standard categories with respect to their associations with psychosocial functioning.Six hundred sixty-eight patients with semistructured interview diagnoses of schizotypal, borderline, avoidant, or obsessive-compulsive personality disorders or with major depressive disorder and no personality disorder completed questionnaires assessing three-factor and five-factor dimensional models of personality. Personality disorder categories, dimensional representations of the categories based on criteria counts, and three- and five-factor personality dimensions were compared on their relationships to impairment in seven domains of functioning, as measured by the Longitudinal Interval Follow-up Evaluation-Baseline Version.Both the categorical and dimensional representations of DSM-IV personality disorders had stronger relationships to impairment in functioning in the domains of employment, social relationships with parents and friends, and global social adjustment and to DSM-IV axis V ratings than the three- and five-factor models. DSM-IV dimensions predicted functional impairment best of the four approaches. Although five-factor personality traits captured variance in functional impairment not predicted by DSM-IV personality disorder dimensions, the DSM-IV dimensions accounted for significantly more variance than the measures of personality.Scores on dimensions of general personality functioning do not appear to be as strongly associated with functional impairment as the psychopathology of DSM personality disorder. A compromise in the ongoing debate over categories versus dimensions of personality disorder might be the dimensional rating of the criteria that comprise traditional categories.
Continuing medical education at a university—evaluation of an MSc programme in general practice
Authors: L Ridsdale, M Walker
Journal: Journal of the Royal Society of Medicine (1990)

In 1986 London University launched a new MSc programme for GPs. This paper describes the problems met with, and the progress made by course members and tutors during the first part-time, 2-year course. We also describe some early measures of the outcome of this form of CME.
P2X7 Deficiency Attenuates Renal Injury in Experimental Glomerulonephritis
Authors: Simon R.J. Taylor, Clare M. Turner, James I. Elliott, John McDaid, Reiko Hewitt, Jennifer Smith, Matthew C. Pickering, Darren L. Whitehouse, H. Terence Cook, Geoffrey Burnstock, Charles D. Pusey, Robert J. Unwin, Frederick W.K. Tam
Journal: Journal of the American Society of Nephrology (2009)

The P2X7 receptor is a ligand-gated cation channel that is normally expressed by a variety of immune cells, including macrophages and lymphocytes. Because it leads to membrane blebbing, release of IL-1β, and cell death by apoptosis or necrosis, it is a potential therapeutic target for a variety of inflammatory diseases. Although the P2X7 receptor is usually not detectable in normal renal tissue, we previously reported increased expression of both mRNA and protein in mesangial cells and macrophages infiltrating the glomeruli in animal models of antibody-mediated glomerulonephritis. In this study, we used P2X7-knockout mice in the same experimental model of glomerulonephritis and found that P2X7 deficiency was significantly renoprotective compared with wild-type controls, evidenced by better renal function, a striking reduction in proteinuria, and decreased histologic glomerular injury. In addition, the selective P2X7 antagonist A-438079 prevented the development of antibody-mediated glomerulonephritis in rats. These results support a proinflammatory role for P2X7 in immune-mediated renal injury and suggest that the P2X7 receptor is a potential therapeutic target.
The Role of Physicians in Conflicts and Humanitarian Crises
Authors: H. Jack Geiger
Journal: JAMA (1993)

Violations of human rights in wars, civil conflicts, and brutal repression mounted by governments against their own citizens often have profound consequences to individual and public health and may, in turn, produce humanitarian crises. The skills of physicians, medical and forensic scientists, and other health workers are uniquely valuable in human rights investigations and documentation, producing evidence of abuse more credible and less vulnerable to challenge than traditional methods of case reporting. Only in recent decades, however, have physicians organized specifically to meet this responsibility. This article presents case studies from the field missions of Physicians for Human Rights to illustrate the investigation and documentation of violations of medical neutrality, refugee health crises, the use of indiscriminate weapons, torture, deliberate injury and rape, and mass executions. Participation of health workers in the defense of human rights now includes investigation and documentation of health effects in threatened populations as well as individual victims.
Long term effect of depression care management on mortality in older adults: follow-up of cluster randomized clinical trial in primary care
Authors: J. J. Gallo, K. H. Morales, H. R. Bogner, P. J. Raue, J. Zee, M. L. Bruce, C. F. Reynolds
Journal: BMJ (2013)

<b>Objective</b> To investigate whether an intervention to improve treatment of depression in older adults in primary care modified the increased risk of death associated with depression. <b>Design</b> Long term follow-up of multi-site practice randomized controlled trial (PROSPECT—Prevention of Suicide in Primary Care Elderly: Collaborative Trial). <b>Setting</b> 20 primary care practices in New York City, Philadelphia, and Pittsburgh, USA, randomized to intervention or usual care. <b>Participants</b> 1226 participants identified between May 1999 and August 2001 through a two stage, age stratified (60-74; ≥75 years) depression screening of randomly sampled patients; enrollment included patients who screened positive and a random sample of patients who screened negative. <b>Intervention</b> For two years, a depression care manager worked with primary care physicians in intervention practices to provide algorithm based care for depression, offering psychotherapy, increasing antidepressant dose if indicated, and monitoring symptoms, adverse effects of drugs, and adherence to treatment. This paper reports the long term follow-up. <b>Main outcome measure</b> Mortality risk based on a median follow-up of 98 (range 0.8-116.4) months through 2008. <b>Results</b> In baseline clinical interviews, 396 people were classified as having major depression, 203 had clinically significant minor depression, and 627 did not meet criteria for depression. At follow-up, 405 patients had died. Patients with major depression in usual care were more likely to die than were those without depression (hazard ratio 1.90, 95% confidence interval 1.57 to 2.31). In contrast, patients with major depression in intervention practices were at no greater risk than were people without depression (hazard ratio 1.09, 0.83 to 1.44). Patients with major depression in intervention practices, relative to usual care, were 24% less likely to have died (hazard ratio 0.76, 0.57 to 1.00; P=0.05). Preliminary data on cause of death are provided. No significant effect on mortality was found for minor depression. <b>Conclusions</b> Older adults with major depression in practices provided with additional resources to intensively manage depression had a mortality risk lower than that observed in usual care and similar to older adults without depression. <b>Trial registration</b> Clinical trials NCT00000367.
Central Serotonin Transporter Availability Measured With [<sup>123</sup>I]β-CIT SPECT in Relation to Serotonin Transporter Genotype
Authors: Christopher H. van Dyck, Robert T. Malison, Julie K. Staley, Leslie K. Jacobsen, John P. Seibyl, Marc Laruelle, Ronald M. Baldwin, Robert B. Innis, Joel Gelernter
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: A functional polymorphism has been described in the promoter region of the gene (SLC6A4) coding for the serotonin transporter protein (SERT). This polymorphism has two common alleles, designated as long and short. Each allele has been linked with a number of human clinical phenotypes, including neuropsychiatric diseases associated with dysregulation of serotonin transmission. In vitro studies of nonneural cells have suggested that the long allele may have higher transcriptional activity than the short allele. However, the relevance of these findings for SERT levels in the brain remains unclear. METHOD: The authors assessed genotypes at the SLC6A4 promoter polymorphism in 96 healthy European American subjects who underwent single photon emission computed tomography scanning with [123I]2β-carbomethoxy-3β-(4-iodophenyl) tropane ([123I]β-CIT) for measurement of central SERT availability. A ratio of specific to nondisplaceable brain uptake (i.e., V3′′=[brainstem-diencephalon – occipital]/occipital), a measure proportional to the binding potential (Bmax/KD), was derived. RESULTS: The results showed that the main effect of genotype was significant. Post hoc Tukey pairwise comparisons revealed that the short-short homozygotes had significantly greater SERT availability than the long-short heterozygotes. There was a nonsignificant tendency for the long-long homozygotes to have greater SERT availability than the heterozygotes, but no difference was observed between the long-long homozygotes and the short-short homozygotes. The effect of age was significant in the analysis of covariance model. CONCLUSIONS: These results do not suggest higher central SERT levels in association with the long allele in European American subjects but point to a more complex relationship between SLC6A4 genotype and protein availability.
Role of American Society of Clinical Oncology in Low- and Middle-Income Countries
Authors: Jyoti D. Patel, Matthew D. Galsky, Anees B. Chagpar, Doug Pyle, Patrick J. Loehrer
Journal: Journal of Clinical Oncology (2011)

The American Society of Clinical Oncology (ASCO) is a global community of health care professionals whose stated purpose is to "make a world of difference" by improving cancer care around the world. Unfortunately, cancer survival rates vary significantly among countries with differing financial and infrastructural resources. Because ASCO is a professional oncology society committed to conquering cancer through research, education, prevention, and delivery of high-quality patient care, it is ideally suited to address this issue. ASCO could bring together oncology professionals and other necessary stakeholders from around the world to improve cancer care and lessen suffering for patients worldwide. As part of the ongoing commitment of ASCO to the future of cancer care, the Leadership Development Program was created to foster the leadership skills of early and midcareer oncologists and provide these participants with a working knowledge of the depth and breadth of the organization. As participants in the inaugural class of the ASCO Leadership Development Program, we were charged with investigating how ASCO might favorably affect cancer prevention and treatment in resource-poor countries in a cost-effective, scalable, and sustainable fashion. ASCO can significantly influence cancer care in low- and middle-income countries through a comprehensive approach that promotes cancer awareness and education, improves clinical practice by identifying and removing barriers to delivery of quality cancer care, and fosters innovation to initiate novel solutions to complex problems.
Antibiotics in exacerbations of COPD: lessons from the past
Authors: M. Miravitlles, A. Torres
Journal: European Respiratory Journal (2004)

The controversy about the use of the adequate antibiotic therapy for exacerbations of chronic obstructive pulmonary disease (COPD) continues. The new antibiotics, particularly the fluoroquinolones, have been included in most guidelines based on their excellent in vitro activity against respiratory pathogens, optimal bronchial penetration and convenient regimens of administration. However, clinical trials have only demonstrated equivalence of fluoroquinolones to traditional antibiotics and no conclusive evidence exists of their superiority in clinical practice.

In this context, we must either accept that no differences exist between antibiotics in this indication or that the majority of studies performed so far are inadequate to demonstrate them. The authors firmly believe that the second statement is more likely to be true than the first 1. In fact, observational studies suggested that moxifloxacin produces a faster resolution of symptoms of exacerbation in COPD patients compared with amoxicillin-clavulanate, clarithromycin or cefuroxime 2. In addition, the direct costs of exacerbations treated with clarithromycin appeared to be higher than the costs associated with the use of moxifloxacin or amoxicillin-clavulanate, due to the higher rate of relapse with the macrolide 3. However, the definitive evidence of superiority derived from randomised, double-blind, clinical trials is scarce, and most guidelines recommend the new and supposedly more potent antibiotics for patients more at risk of relapse, based more on common sense rather than on scientific evidence, which is well recognised by the authors of the guidelines themselves 4.

In an attempt to demonstrate differences in outcomes between a fluoroquinolone, levofloxacin, and clarithromycin, Lode et al. 6 in this issue of the Journal present the results of a randomised, double-blind, clinical trial in patients with exacerbations of COPD. This trial presents two strengths, in comparison with most of the trials performed previously: the inclusion …
Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4
Authors: M Broggini, S V Marchini, E Galliera, P Borsotti, G Taraboletti, E Erba, M Sironi, J Jimeno, G T Faircloth, R Giavazzi, M d'Incalci
Journal: Leukemia (2003)
Phase II Study of Twice-Daily High-Dose Thoracic Radiotherapy Alternating With Cisplatin and Vindesine for Unresectable Stage III Non-Small-Cell Lung Cancer: Japan Clinical Oncology Group Study 9306
Authors: I. Sekine
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To evaluate the efficacy and toxicity of high-dose thoracic radiotherapy (TRT) alternating with chemotherapy (CH) for unresectable stage III non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-one patients received TRT with 1.5 Gy twice daily, 5 days a week, on weeks 1, 2, 5, 6, and 9, up to a total dose of 66 to 72 Gy, alternating with cisplatin 80 mg/m2 on day 1 and vindesine 3 mg/m2 on days 1 and 8, repeated every 4 weeks, for two or three courses beginning on week 3. RESULTS: The median (range) total dose of TRT and number of CH courses were 72 Gy (16.5 to 72 Gy) and three (zero to three), respectively. Delay in TRT ≥ 5 days was observed in 24 (75%) of 32 patients who completed the projected treatment, due to leukopenia in 12, esophagitis in seven, infection in two, and other causes in three patients. Partial responses were obtained in 36 patients (88%). The median survival time and 3- and 5-year survival rates were 18.4 months, 24%, and 10%, respectively. Grade 3 or 4 leukopenia ...
Ambulatory arrhythmias in resuscitated victims of cardiac arrest.
Authors: W D Weaver, L A Cobb, A P Hallstrom
Journal: Circulation (1982)

One hundred forty-four patients with coronary heart disease previously resuscitated from out-of-hospital ventricular fibrillation underwent 24-hour ambulatory ECG monitoring 5 months (median) after cardiac arrest. Patients were then followed for an average of 31.7 months. Fifty-one patients died, 32 from subsequent unexpected cardiac arrest. One hundred twenty-nine patients (90%) had uniform ventricular ectopy. Two-thirds had complex ventricular ectopy (Bigeminy/trigeminy, repetitive forms or frequent multiforms). Complex ectopy, present in 20% or more of the 30-minute recording intervals, occurred in 18 of the patients (56%) who developed subsequent cardiac arrest, compared with 26 of 92 (28%) who survived (P less than 0.005, specificity 72%, relative risk 2.3). Other forms of ventricular ectopy, e.g., uniform, multiform and repetitive beats, were more sensitive but less specific predictors of death or recurrent ventricular fibrillation. Complex ventricular ectopy was associated with certain clinical histories: it occurred in 95% of patients with a history of congestive heart failure and in 79% with remote myocardial infarction, compared with 59% and 56% without these histories (p less than 0.001 and p less than 0.01). As expected, mortality was also greater in patients who had these clinical characteristics. Complex ectopy was related to mortality regardless of the clinical history.