tbuckley/cabot-search huggingface dataset:
Efficacy of epothilone B in non-small cell lung cancer cells: Role of beta-tubulin isotypes
Authors: Pei Pei Gan, Maria Kavallaris
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

LB-196 

Objective: Lung cancer is the most common malignancy in the world and non-small cell lung carcinoma (NSCLC) accounts for the majority of cases. Advanced NSCLC treatment often includes combination therapy with a tubulin-binding agent (TBA) and a DNA damaging agent. Prognosis for patients with advanced NSCLC remains dismal due to resistance to therapy. Epothilones are a new class of agent that, like paclitaxel, disrupt microtubule dynamics by binding to the β-tubulin subunit of α/β-tubulin, stabilizing microtubules and inducing mitotic arrest and apoptosis. Epothilones have shown promising clinical activity in a Phase II trial in patients with NSCLC and have recently been approved for use in metastatic breast cancer. Altered expression of specific β-tubulin isotypes have been described in a number of taxane and vinca alkaloid resistant cell lines and clinically in paclitaxel-resistant lung, ovarian and breast tumors. Modulating expression of βIII-tubulin sensitizes NSCLC cells to taxanes and vinca alkaloids . We hypothesized that expression of specific β-tubulin isotypes could influence response to epothilones and provide markers capable of distinguishing patients with differential sensitivity to this promising new agent.    Methods: Small interfering RNA (siRNA) was used to specifically knockdown βII-, βIII- or βIVb- tubulin expression in two NSCLC cell lines, NCI-H460 (H460) and Calu-6. Gene and protein expression was determined using RT-PCR and Western blotting, respectively. Immunofluorescent staining of tubulin and digital imaging was used to assess microtubule morphology. Drug response was determined using clonogenic assays.    Results: βII-, βIII- and βIVb-tubulin siRNA potently inhibited the gene and protein expression of each of these targets respectively, while the expression of other major β-tubulin isotypes was not affected. Drug-treated clonogenic assays demonstrated that βII siRNA knockdown did not affect sensitivity to epothilone B in H460 or Calu-6 cells. In contrast, there was a small, but significant increase in sensitivity to epothilone B in both H460 and Calu-6 cells. Surprisingly, βIVb siRNA knockdown significantly reduced sensitivity to epothilone B in both NSCLC cell lines, compared to mock- and control siRNA-transfected cells. Despite the fact that paclitaxel and epothilone B share overlapping binding sites on β-tubulin, sensitivity to paclitaxel was not altered following βIVb siRNA knockdown.    Conclusions: This is the first demonstration that differential expression of β-tubulin isotypes plays a functional role in epothilone sensitivity in NSCLC cells. Tubulin isotype status may serve as valuable molecular markers to personalize patient therapy based on differential sensitivity to epothilones. These findings may have important implications for improving the targeting and treatment of drug-refractory NSCLC.
Reference values for vastus lateralis fiber size and type in healthy subjects over 40 years old. A systematic review and meta-analysis
Authors: Fares Gouzi, Jonathan Maury, Nicolas Molinari, Pascal Pomiès, Jacques Mercier, Préfaut Christian, Hayot Maurice
Journal: European Respiratory Journal (2013)

Skeletal muscle atrophy is a major systemic impairment in chronic diseases. Yet its determinants have been hard to identify because a clear research definition has not been agreed upon. The reduction in muscle fiber cross-sectional area (CSA) is a marker of muscle atrophy, but no reference values for the muscle fiber CSA at the age of the onset of chronic diseases have ever been published. Thus, we aimed to systematically review the studies providing data on the fiber CSA and fiber type proportion in the  vastus lateralis  of the quadriceps of healthy subjects (age >40 yrs) and then to pool and analyze the data from the selected studies in order to provide reference values for fiber CSA.  Following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), we identified 19 studies, including 423 subjects, that matched the inclusion criteria.  Based on fiber type and gender, the mean fiber CSA and the lower limits of normal (LLNs) were (%type I*60)+1743µm² and (%type I*60)-718µm², respectively, for males; and (%type I*70)+139µm² and (%type I*70)-1485µm², respectively, for females. The pooled type I fiber proportion was 50.3% (LLN=32.9%). In multivariate analysis, fiber CSA was significantly correlated with peakVO 2  (r=190.92; p=0.03), and type I fiber proportion was correlated with age (r=-0.024; p=0.005), BMI (r=0.096; p=0.005), and peakVO 2  (r=-0.053; p=0.005). Our meta-analysis of a homogeneous set of studies is the first to provide valuable LLNs for fiber CSA according to fiber type and gender. This analysis will be improved by prospective assessment in well-characterized healthy subjects.
Brief Report: Tumor Necrosis Factor and Interleukin‐6 Differentially Regulate Dkk‐1 in the Inflamed Arthritic Joint
Authors: Nataliya Yeremenko, Karin Zwerina, Gemma Rigter, Desiree Pots, Joao E. Fonseca, Jochen Zwerina, Georg Schett, Dominique Baeten
Journal: Arthritis & Rheumatology (2015)

Objective Tumor necrosis factor (TNF) drives bone destruction, but it also inhibits new bone formation by inducing Dkk‐1, an inhibitor of the Wnt pathway. Accordingly, blocking of Dkk‐1 reverses the phenotype in experimental arthritis from a pattern of bone destruction to a pattern of bone formation. To delineate the potential role of Dkk‐1 in the structural phenotype of human arthritis, we analyzed the expression of Dkk‐1 and its regulation by proinflammatory cytokines in the inflamed peripheral joints of patients with spondyloarthritis (SpA) and rheumatoid arthritis (RA). Methods Expression of Dkk‐1 and proinflammatory cytokines was determined by enzyme‐linked immunosorbent assay and microarray analysis in synovial fluid (SF) and synovial tissue, respectively. Regulation of Dkk‐1 production by proinflammatory cytokines was assessed in fibroblast‐like synoviocyte (FLS) cultures. Results TNF and interleukin‐1β (IL‐1β) levels, were higher in RA SF than in SpA SF ( P &lt; 0.001 for both), whereas levels of IL‐6 were not. Levels of Dkk‐1 were similar in SpA SF and RA SF and were not correlated with TNF and IL‐1β levels. However, Dkk‐1 levels showed an inverse correlation with IL‐6 levels in both SpA SF (r = −0.31, P = 0.04) and RA SF (r = −0.39, P = 0.01); this result was reproduced at the messenger RNA level in synovial tissue. In vitro experiments with FLS confirmed that Dkk‐1 production was strongly induced by TNF but clearly suppressed by IL‐6. Moreover, IL‐6 was able to suppress the TNF‐induced up‐regulation of Dkk‐1 production by FLS. Conclusion The inverse correlation of Dkk‐1 levels with IL‐6 levels observed in vivo in the inflamed joints was mirrored by the differential regulation of Dkk‐1 production by TNF and IL‐6 in vitro. The relative balance between these and other factors in the arthritic joints may determine functional Wnt signaling and tissue remodeling.
Assessing cumulative organophosphate pesticide exposure and risk among pregnant women living in an agricultural community
Authors: Rosemary Castorina, Asa Bradman, Thomas E. McKone, Dana B. Barr, Martha E. Harnly, Brenda Eskenazi
Journal: Environmental Health Perspectives (2002)

Author(s): Castorina, Rosemary; Bradman, Asa; McKone, Thomas E.; Barr, Dana B.; Harnly, Martha E.; Eskenazi, Brenda
Efficacy and Safety of Dabigatran Compared to Warfarin in Patients With Paroxysmal, Persistent, and Permanent Atrial Fibrillation
Authors: Greg Flaker, Michael Ezekowitz, Salim Yusuf, Lars Wallentin, Herbert Noack, Martina Brueckmann, Paul Reilly, Stefan H. Hohnloser, Stuart Connolly
Journal: Journal of the American College of Cardiology (2012)
Malignant hemangiopericytoma: A study of long-term outcomes
Authors: S. K. Yadav, L. Dwernychuk, A. S. Yadav, R. Alvi, I. Ahmad, S. Ahmed, K. Haider, A. Sami
Journal: Journal of Clinical Oncology (2006)

9560 Background: Malignant hemangiopericytoma (MH) is a rare disease with limited data on long term clinical outcomes. We presented a poster at ASCO 2005 annual meeting, outlining the long term follow up of 14 patients. We reviewed the data from 10 additional patients from our affiliated center and present here a combined analysis. Methods: Clinical characteristics, pathologic and treatment data of 24 patients diagnosed with MH between 1972 and 1995 was reviewed. All cases were histologically proven. Survival was determined by using Kaplan-Meier curve. Results: The median age was 52 yrs. (range 28 - 74). Male: female ratio was 1: 2.4. Patients presented with involvement of following primary sites: cranial/meningeal 8 (33.34%), extremities 4 (16.7%), uterus 3 (12.5%), metastatic 2 (8.3%), retroperitoneal 2 (8.3%), pelvis 2 (8.3%), sinonasal, middle ear and thyroid 1 each (4.2% each). 20 patients had definitive surgical resection at initial presentation. 4 patients received post operative radiation therapy (RT). No patient received adjuvant chemotherapy. 7 out of 8 patients who recurred died of disease. One patient who was alive 5 years after recurrence got stereotactic RT to localized recurrence. At disease recurrence, 2 patients received chemotherapy and RT, while 5 were treated with surgery and/or RT. 4 out of 8 patients with cranial/meningeal disease at diagnosis recurred. Two of them recurred after 6 years. Only one of the 4 recurred patients had post operative adjuvant RT. Median recurrence free survival was 5.25 years. Median survival after recurrence was 3.28 years. Fourteen year cause specific survival was 55%. Conclusions: Combined analysis of 24 patients shows that complete surgical resection is the main treatment with 55% of patients living at 14 years (median is not reached). Compared to our prior report, female preponderance was less marked. Radiation may play some part in adjuvant setting, but its role is not clearly defined. Role of systemic treatment is not clear. In our series 40% recurred after definitive treatment. Recurrences can occur several years after the initial diagnosis and definitive treatment. There is a need to develop effective adjuvant systemic treatments. No significant financial relationships to disclose.
Obesity and vascular disease
Authors: Debbie A Lawlor, Mike Lean, Naveed Sattar
Journal: BMJ (2006)

Previous articles in this series have discussed the relation of overweight and obesity with coronary heart disease (CHD) and individual cardiovascular disease risk factors-such as diabetes, raised blood pressure, and dyslipidaemia.This article examines the wider impact of obesity on vascular disease: the effect on cardiovascular disease of obesity as primary cause of the metabolic syndrome and of obesity as a risk factor for heart failure, stroke, other vascular conditions, and cognitive decline.
Abstract 11973: Proton Pump Inhibitors (PPIs) Increase Risk of MACE: Role of DDAH
Authors: Yohannes T Ghebremariam, Jerry C Lee, Paea LePendu, Daniel A Erlanson, Nigam H Shah, John P Cooke
Journal: Circulation (2012)

Background: Proton pump inhibitors (PPIs) are commonly used for gastric acid suppression. Emerging evidence in patients with acute coronary syndromes suggests that PPIs may be associated with incre...
Twenty-one days of isolation: A prospective observational cohort study of an Ebola-exposed hot zone community in Liberia
Authors: George Sie Williams, Jeremias Naiene, Joseph Gayflor, Theophil Malibiche, Bentoe Zoogley, Wimot G. Frank, Fariba Nayeri
Journal: Journal of Infection (2015)

BackgroundAs West Africa continues to suffer from a deadly Ebola epidemic, the national health sectors struggle to minimize the damages and stop the spread of disease.MethodsA cohort of inhabitants of a small village and an Ebola hot zone in Sinoe County of Liberia was followed on a day-by-day basis to search for new cases and to minimize the spread of Ebola to the other community members or to other regions. Technical, clinical, and humanistic aspects of the response are discussed in this report.ResultsOf the 22 confirmed Ebola cases in Sinoe County since the beginning of outbreak (June 16, 2014), 7 cases were inhabitants of Polay Town, a small village 5.5 miles east of Greenville, the Sinoe County capital. After the last wave of outbreak at the beginning of December, enhanced response activity provided essential coordination and mobilized the resources to stop the epidemic. Despite unprotected contacts in crowded houses, no new cases were detected among the contact families, or in the surrounding houses or communities.ConclusionsStrong national mobilization in a decentralized but harmonized system at the community level has been of great value in controlling the epidemic in Liberia. The major interventions include epidemiological surveillance, public information dissemination, effective communication, case management, and infection control.
HIV Programs for Sex Workers: Lessons and Challenges for Developing and Delivering Programs
Authors: David Wilson
Journal: PLoS Medicine (2015)

There is evidence that HIV prevention programs for sex workers, especially female sex workers, are cost-effective in several contexts, including many western countries, Thailand, India, the Democratic Republic of Congo, Kenya, and Zimbabwe. The evidence that sex worker HIV prevention programs work must not inspire complacency but rather a renewed effort to expand, intensify, and maximize their impact. The PLOS Collection "Focus on Delivery and Scale: Achieving HIV Impact with Sex Workers" highlights major challenges to scaling-up sex worker HIV prevention programs, noting the following: sex worker HIV prevention programs are insufficiently guided by understanding of epidemic transmission dynamics, situation analyses, and programmatic mapping; sex worker HIV and sexually transmitted infection services receive limited domestic financing in many countries; many sex worker HIV prevention programs are inadequately codified to ensure consistency and quality; and many sex worker HIV prevention programs have not evolved adequately to address informal sex workers, male and transgender sex workers, and mobile- and internet-based sex workers. Based on the wider collection of papers, this article presents three major clusters of recommendations: (i) HIV programs focused on sex workers should be prioritized, developed, and implemented based on robust evidence; (ii) national political will and increased funding are needed to increase coverage of effective sex worker HIV prevention programs in low and middle income countries; and (iii) comprehensive, integrated, and rapidly evolving HIV programs are needed to ensure equitable access to health services for individuals involved in all forms of sex work.
Epithelial mesenchymal transition in fibroblastic foci of different fibrosing lung diseases: Repair or remodeling?
Authors: Alexandre Todorovic Fabro, Iris Halbwedl, Edwin Roger Parras Cuentas, Vera Luiza Capelozzi, Helmut Popper
Journal: European Respiratory Journal (2013)

Fibroblastic foci (FF), a feature of usual interstitial pneumonia (UIP), are also found in smoking related interstitial fibrosis (SRIF). Recently studies suggested epithelial-mesenchymal transition (EMT) during formation of FF. To investigate the EMT in idiopathic pulmonary fibrosis (IPF-UIP), non-IPF-UIP and SRIF on immunohistochemistry, electron microscopy and confocal microscopy using quantitative methods, 19 patients with IPF, 17 with non-IPF, and 16 with SRIF who underwent lung biopsy and lobectomy were included. Epithelial marker was detected in 0.65% of the cells within FF in IPF, contrasting with 3.65% of cells in SRIF and 10.93% cells in non-IPF (p
Alcoholism in manic-depressive (bipolar) illness: familial illness, course of illness, and the primary-secondary distinction [published erratum appears in Am J Psychiatry 1995 Jul;152(7):1106]
Authors: G Winokur, W Coryell, H S Akiskal, J D Maser, M B Keller, J Endicott, T Mueller
Journal: American Journal of Psychiatry (1995)

This 5-year follow-up study was designed to explore the factors that might lead to alcoholism in patients with bipolar disorder.The authors studied patients with bipolar illness (70 with alcoholism and 161 without), their relatives, and a comparison group composed of relatives' acquaintances. All were evaluated with versions of the Schedule for Affective Disorders and Schizophrenia, and diagnoses were made according to the Research Diagnostic Criteria. Thirty of the bipolar alcoholic patients whose affective disorder was primary were also compared with 34 whose alcoholism was primary.Alcoholism was more frequent in the bipolar patients than in the comparison subjects. There no significant differences between the alcoholic and nonalcoholic bipolar patients in family history of alcoholism or affective disorders, suggesting that bipolar illness with alcoholism is not explicable by a family history of alcoholism and that the alcoholism seen in bipolar illness is dissimilar to alcoholism as a primary disorder. Alcoholism associated with bipolar illness was more likely to remit than primary alcoholism. There was no significant difference in family history between the patients with primary alcoholism and those with primary bipolar disorder. The patients with primary alcoholism had significantly fewer episodes of affective disorder during followup, suggesting that their type of bipolar illness was less severe and may have needed the added insult of alcoholism to make it manifest.The study supports the idea that not all alcoholism is primary with a corresponding familial diathesis. Rather, alcoholism associated with bipolar disorder is often a secondary complication.
A role for squamous metaplasia in COPD airway obstruction
Authors: Magnus Dillon
Journal: Thorax (2008)

Airway wall thickening has been established as an important factor in airway obstruction in patients with COPD, and squamous metaplasia of columnar epithelium correlates with the severity of airway obstruction. Here, through a number of experiments, the authors provide evidence for a mechanistic link between these two processes.

An …
Does short-term androgen depletion add to high-dose radiotherapy (80 Gy) in localized intermediate-risk prostate cancer? Intermediary analysis of GETUG 14 randomized trial (EU-20503/NCT00104741).
Authors: B. M. Dubray, V. Beckendorf, S. Guerif, E. Le Prise, A. Reynaud-Bougnoux, J. M. Hannoun Levi, T. D. Nguyen, C. Hennequin, J. Cretin, M. Fayolle-Campana, J. Lagrange, J. Bachaud, D. Azria, A. Grangirard, P. Pommier, J. Simon, V. Harter, M. Habibian
Journal: Journal of Clinical Oncology (2011)

4521 Background: randomized trial to evaluate the addition of 4-month androgen deprivation to high dose radiotherapy in localized intermediate risk prostate adenocarcinoma patients. Methods: eligible patients were randomly assigned to high dose radiotherapy (prostate 80 Gy; seminal vesicles 46 Gy) either alone (group RT) or in combination with 4-month androgen deprivation (flutamide + triptoreline starting 2 months before radiotherapy, group AD-RT). Lymphadenectomy was mandatory when the risk of node involvement was > 10% (Partin). The primary endpoint was biochemical (Phoenix definition) or clinical control. Secondary endpoints included survival, toxicity (CTCAE v3) and quality of life. The a-priori sample size was 450 patients (0.90 power to detect an increase from 75 to 85%, bilateral α = 0.05). An intermediate analysis was planned 6 months after the last patient inclusion (bilateral α = 0.005). Results: 377 patients were entered between October 2003 and July 2010. The trial was prematurely closed, due to slow accrual. Intention-to-treat analysis included 366 patients (188 RT, 178 AD-RT). Prognostic factors were well balanced between groups. The median follow-up duration was 37 months (range: 0 to 63). At 3 years, biochemical or clinical control probabilities were 86% [95% CI: 80%–92%] and 92% [87%–97%] in RT and AD-RT groups respectively (p = 0.09). Biochemical control probabilities were 91% [86%–96%] and 97% [94%–99.6%] in RT and AD-RT groups respectively (p = 0.04). The cumulative hazards of grade 3-4 toxicities were 6.4% and 2.8% (p=0.41) for digestive tract, 2.6% and 6.1% (p=0.14) for urinary tract, in RT and AD-RT groups respectively. Conclusions: The observed difference in favour of AD-RT did not reach statistical significance as defined for the present intermediary analysis. The final analysis is scheduled in 2013.
Early implementation of Enhanced Recovery After Surgery (ERAS®) protocol – Compliance improves outcomes: A prospective cohort study
Authors: Michał Pędziwiatr, Mikhail Kisialeuski, Mateusz Wierdak, Maciej Stanek, Michał Natkaniec, Maciej Matłok, Piotr Major, Piotr Małczak, Andrzej Budzyński
Journal: International Journal of Surgery (2015)

Enhanced Recovery After Surgery protocol in colorectal surgery allows shortening length of hospital stay and reducing complication rate. Despite the clear guidelines and conclusive evidence their full implementation and putting them into daily practice meets certain difficulties, especially in the early stage. The aim of the study was to analyse the course of implementation of the ERAS protocol into daily practice on the basis of adherence to the protocol. Group included 92 patients (43F/49M) with colorectal cancer submitted to laparoscopic resection during the years 2013-2014. Perioperative care in all of them based on ERAS protocol consisting of 16 items. Its principles and discharge criteria were based on the guidelines of the ERAS Society guidelines. The entire analysed group of patients was divided into 3 subgroups (30 patients) depending on the time from ERAS protocol implementation. We analysed the compliance with the protocol and its influence on length of hospital stay, postoperative complications and readmission rate in different subgroups. The average compliance with the protocol differed significantly between groups and was 65% in group 1, 83.9% in group 2 and 89.6% in group 3. The compliance with subsequent protocol elements was different. The length of stay and complication rate was statistically different in analysed subgroups. The whole group demonstrated an inverse correlation between compliance and length of stay. This analysis leads to the conclusion that the introduction of the ERAS protocol is a gradual process, and its compliance at the level of 80% or more requires at least 30 patients and the period of about 6 months. The initial derogation from the assumed proceedings is inevitable and should not discourage further action. Particular emphasis in the initial stage should be put on continuous training of personnel of all specialties and continuous evaluation of the results.
THE GENERAL PHARMACOLOGY OF THE HEAVY METALS
Authors: H. Passow, A. Rothstein, T.W. Clarkson
Journal: Pharmacological Reviews (1961)

A discussion of predominantly theoretical aspects of metal poisoning is presented. Heavy metals are capable of combining with a wide variety of organic molecules. The heavy metal binding was found to occur simultaneously at sensitive and insensitive sites. This diversion of the metals to insensitive sites protects the cell to some extent against the toxic action of metals, but at the same time tends to obscure the relation between metal binding and pharmacological response. The interactions of heavy metals with simple molecules, proteins, enzymes, cells, organs, and animals are reviewed. The responses of biological systems to heavy metals were considered in terms of inferences that could be made concerning the site of the original chemical insult. A listing and discussion of the most commonly seen responses are given. (M.C.G.)