tbuckley/cabot-search huggingface dataset:
Population-Based Study of Contralateral Prophylactic Mastectomy and Survival Outcomes of Breast Cancer Patients
Authors: I. Bedrosian, C.-Y. Hu, G. J. Chang
Journal: JNCI Journal of the National Cancer Institute (2010)

Despite increased demand for contralateral prophylactic mastectomy (CPM), the survival benefit of this procedure remains uncertain.We used the Surveillance, Epidemiology, and End Results database to identify 107 106 women with breast cancer who had undergone mastectomy for treatment between 1998 and 2003 and a subset of 8902 women who also underwent CPM during the same period. Associations between predictor variables and the likelihood of undergoing CPM were evaluated by use of chi(2) analyses. Risk-stratified (estrogen receptor [ER] status, stage, and age) adjusted survival analyses were performed by using Cox regression. Statistical tests were two-sided.In a univariate analysis, CPM was associated with improved disease-specific survival (hazard ratio [HR] of death = 0.63, 95% confidence interval [CI] = 0.57 to 0.69; P < .001). Risk-stratified analysis showed that this association was because of a reduction in breast cancer-specific mortality in women aged 18-49 years with stages I-II ER-negative cancer (HR of death = 0.68, 95% CI = 0.53 to 0.88; P = .004). Five year-adjusted breast cancer survival for this group was improved with CPM vs without (88.5% vs 83.7%, difference = 4.8%). Although rates of contralateral breast cancer among young women with stages I-II disease undergoing CPM were independent of ER status, women with ER-positive tumors in the absence of prophylactic mastectomy also had a lower overall risk for contralateral breast cancer than women with ER-negative tumors (0.46% vs 0.90%, difference = 0.44%; P < .001).CPM is associated with a small improvement in 5-year breast cancer-specific survival mainly in young women with early-stage ER-negative breast cancer. This effect is related to a higher baseline risk of contralateral breast cancer.
Adipose-derived Stem Cells as Therapeutic Delivery Vehicles of an Oncolytic Virus for Glioblastoma
Authors: Darnell T Josiah, Dongqin Zhu, Fernanda Dreher, John Olson, Grant McFadden, Hannah Caldas
Journal: Molecular Therapy (2009)

Glioblastoma multiforme (GBM) accounts for the majority of primary malignant brain tumors and remains virtually incurable despite extensive surgical resection, radiotherapy, and chemotherapy. Treatment difficulty is due to its exceptional infiltrative nature and proclivity to integrate into normal brain tissue. Long-term survivors are rare, and median survival for patients is about 1 year. Use of adult stem cells as cellular delivery vehicles for anticancer agents is a novel attractive therapeutic strategy. We hypothesized that adipose-derived stem cells (ADSCs) possess the ability to home and deliver myxoma virus to glioma cells and experimental gliomas. We infected ADSCs with vMyxgfp and found them to be permissive for myxoma virus replication. ADSCs supported single and multiple rounds of replication leading to productive infection. Further, we observed no significant impact on ADSC viability. We cocultured fluorescently labeled GBM cells with myxoma virus-infected ADSCs in three-dimensional assay and observed successful cross infection and concomitant cell death almost exclusively in GBM cells. In vivo orthotopic studies injected with vMyxgfp-ADSCs intracranially away from the tumor demonstrated that myxoma virus was delivered by ADSCs resulting in significant survival increase. Our data suggest that ADSCs are promising new carriers of oncolytic viruses, specifically myxoma virus, to brain tumors.
A healthcare curriculum for the 21st century: time for flexibility?
Authors: Olwyn MR Westwood, Samuel J Leinster, Julius R Weinberg
Journal: Journal of the Royal Society of Medicine (2008)

The purpose of healthcare education is to provide appropriately skilled individuals to deliver the care needed by the population. However, curricula are shaped by the regulation of professional groups, professional accountability and demarcation issues. Current changes in the delivery of healthcare, in educational theory that advocates increased integration of theory and practice1-3 and in the international agreements on mobility of qualifications have challenged our traditional educational pathways.

This paper argues that delivery of an effective healthcare workforce for the future is dependent upon a radical rethink of our education system. Although we largely draw upon experiences within the UK, these issues could apply to most healthcare systems.
Biochemistry, Molecular Biology, and Physiology of the Glucocorticoid Receptor*
Authors: JAN-ÅKE GUSTAFSSON, JAN CARLSTEDT-DUKE, LORENZ POELLINGER, SAM OKRET, ANN-CHARLOTTE WIKSTRÖM, MIKAEL BRÖNNEGÅRD, MIKAEL GILLNER, YU DONG, KJELL FUXE, ANTONIO CINTRA, ANDERS HÄRFSTRAND, LUIGI AGNATI
Journal: Endocrine Reviews (1987)

THE INTRACELLULAR receptor proteins for steroid hormones are a group of transcriptional regulatory proteins with several common features, acting by direct interaction with DNA. The protein must first be activated by the binding of the appropriate class of steroid. The steroid hormone receptor proteins, in particular the glucocorticoid receptor, and their role in gene regulation represent the best characterized eukaryotic gene regulating systems today, with major recent advances in knowledge of structure and function of both the protein and DNA components involved. During the 20 yr of research in this field, there are several major landmarks that have contributed to our understanding of gene regulation by steroid hormones, particularly by glucocorticoids, namely: 1) the synthesis of tritium-labeled steroids with high specific activity (1); 2) the demonstration of a high affinity, low capacity binding species, the putative receptor protein, for glucocorticoids (for review, see Refs. 2–5); 3) the interaction of the receptor with the nucleus or DNA (2–5); 4) the demonstration that glucocorticoids can regulate specific genes, their messenger RNAs (mRNAs) and their transcription (2–5); 5) the purification of the glucocorticoid-receptor complex (GR) (6–8); 6) the demonstration of specific GRbinding sequences within the genome (9); 7) the demonstration by gene transfer of glucocorticoid-responsive sequences (10); 8) the cloning of complementary DNA (cDNA) for the glucocorticoid (11–13), estrogen receptor (ER) (14–16), and progesterone (17–19) receptors (PR).
Endothelins, peptides with potent vasoactive properties, are produced by human macrophages.
Authors: H Ehrenreich, R W Anderson, C H Fox, P Rieckmann, G S Hoffman, W D Travis, J E Coligan, J H Kehrl, A S Fauci
Journal: The Journal of Experimental Medicine (1990)

Endothelins are peptides, originally isolated from endothelial cells, with potent vasoactive and mitogenic properties. In this study, we demonstrate that human macrophages synthesize and secrete endothelins. Cultured human macrophages were found by immunocytochemistry to stain positively for endothelin 1 and endothelin 3. Their capability to produce and release these peptides was confirmed by a combination of reverse-phase high-performance liquid chromatography and radioimmunoassays, specific for endothelin 1 and 3, respectively. Immunoreactive peptides were identified both in cellular extracts and in macrophage-conditioned medium. The secretion of endothelin 1, but not of endothelin 3, from macrophages could be stimulated 6-10-fold by lipopolysaccharide or phorbol myristate acetate (PMA). Northern blot analysis of total macrophage RNA using an endothelin 1 cDNA probe revealed induction of endothelin mRNA in PMA-treated macrophages. Furthermore, immunoreactive endothelin 1 and 3 were found in U937 cells, a human promonocytic line, and in freshly isolated human monocytes. In contrast, no immunoreactive endothelin was detected in cell extracts from human neutrophils and lymphocytes. The expression of endothelins in tissue macrophages was demonstrated in paraffin sections of human lung using immunohistochemistry. In conclusion, the finding that human macrophages produce endothelins suggests an important role for these peptides in the microenvironment of tissue macrophages. Macrophage-derived endothelins may have an essential function in blood vessel physiology, and aberrant production may contribute to vessel pathology.
Developmental Genes and Cancer: Role of Patched in Basal Cell Carcinoma of the Skin
Authors: M. R. Gailani, A. E. Bale
Journal: JNCI Journal of the National Cancer Institute (1997)

Many genes originally identified because of their role in embryonic development are also important in postnatal control of cell growth and differentiation. Mutations in some of these genes have been shown to cause cancer. Basal cell carcinoma (BCC) of the skin is the most common cancer in humans. More than 750 000 new cases are diagnosed annually, and the incidence is rising. BCCs are slow-growing, locally invasive tumors that rarely metastasize but can result in extensive morbidity through local recurrence and tissue destruction. Epidemiologic studies suggest that sunlight (particularly UVB radiation) is a strong risk factor for BCC formation, although other factors are also involved. The nevoid basal cell carcinoma syndrome (NBCCS), a rare genetic disorder, is characterized by predisposition to BCCs and other tumors as well as to a wide range of developmental defects. NBCCS maps to chromosome 9q22.3, and loss of heterozygosity at this site in both sporadic and hereditary BCCs suggests that it functions as a tumor suppressor. The gene for NBCCS was recently cloned and is the human homologue of the Drosophila gene "patched." Genetic studies in Drosophila show that patched is part of the hedgehog signaling pathway, which is important in determining embryonic patterning and cell fate in multiple structures of the developing embryo. Human patched is mutated in both hereditary and sporadic BCCs, and inactivation of this gene is probably a necessary, if not sufficient, step for BCC formation. Delineation of the biochemical pathway in which patched functions may lead to rational medical therapy for BCCs and possibly for other tumors associated with NBCCS.
Risk factors of readmission to hospital for a COPD exacerbation: a prospective study
Authors: J Garcia-Aymerich
Journal: Thorax (2003)

Exacerbations of chronic obstructive pulmonary disease (COPD) are a leading cause of admission to hospital among men in many countries, although the factors causing exacerbations are largely unknown. The association between readmission for a COPD exacerbation and a wide range of modifiable potential risk factors, after adjusting for sociodemographic and clinical factors, has been assessed.Three hundred and forty patients with COPD recruited during an admission for an exacerbation in four tertiary hospitals in the Barcelona area of Spain were followed for a mean period of 1.1 years. Information on potential risk factors, including clinical and functional status, medical care and prescriptions, medication adherence, lifestyle, health status, and social support, was collected at the recruitment admission. A Cox's proportional hazards model was used to obtain independent relative risks of readmission for COPD.During the follow up period 63% of patients were readmitted at least once, and 29% died. The final multivariate model showed the following risk (or protective) factors: > or =3 admissions for COPD in the year before recruitment (hazard ratio (HR)=1.66, 95% CI 1.16 to 2.39), forced expiratory volume in 1 second (FEV(1)) percentage predicted (0.97, 95% CI 0.96 to 0.99), oxygen tension (0.88, 95% CI 0.79 to 0.98), higher levels of usual physical activity (0.54, 95% CI 0.34 to 0.86), and taking anticholinergic drugs (1.81, 95% 1.11 to 2.94). Exposure to passive smoking was also related to an increased risk of readmission with COPD after adjustment for clinical factors (1.63, 95% CI 1.04 to 2.57) but did not remain in the final model.This is the first study to show a strong association between usual physical activity and reduced risk of readmission to hospital with COPD, which is potentially relevant for rehabilitation and other therapeutic strategies.
Respiratory tract disease and obstructive azoospermia.
Authors: E Neville, R Brewis, W K Yeates, A Burridge
Journal: Thorax (1983)

Male infertility may be linked to respiratory tract disease in conditions such as cystic fibrosis and Kartagener's syndrome. Young's syndrome constitutes another such link, in which bronchiectasis is found in association with obstructive azoospermia and normal testicular function. We have studied 34 infertile men with mechanical azoospermia and appropriate control subjects to assess the number of patients with respiratory tract disease and the type and frequency of such disorders. Nineteen patients (59%) had grossly abnormal sinus radiographs compared with six controls (18%) (p less than 0.01) and 19 (56%--NS) gave a history of sinusitis; of these, six (18%) had had sinus operations (p less than 0.01). Eleven patients (32%) had histories of repeated otitis media, of whom two had had mastoid operations. Twelve (35%) had chronic bronchitis, of whom three were non-smokers. Ten other patients had bronchiectasis (p less than 0.001) and three of these had had a lobectomy. The chest radiograph was abnormal in 18 patients (p less than 0.001), including all 10 with bronchiectasis. Two patients had severe airflow obstruction and 13 others had a mildly obstructive pattern. This controlled study confirms that a significant excess of sinorespiratory disease can be identified in young men with obstructive azoospermia. We have found no features in the history or in the results of examination or investigations to explain why some of these patients have respiratory tract disease while others do not.
Challenges and threats to implementing the fight against doping in sport
Authors: Jiri Dvorak, Martial Saugy, Yannis P Pitsiladis
Journal: British Journal of Sports Medicine (2014)

Prominent doping cases in certain sports have recently raised public awareness of doping and reinforced the perception that doping is widespread. Efforts to deal with doping in sport have intensified in recent years, yet the general public believes that the 'cheaters' are ahead of the testers. Therefore, there is an urgent need to change the antidoping strategy. For example, the increase in the number of individual drug tests conducted between 2005 and 2012 was approximately 90 000 and equivalent to an increase of about 50%, yet the number of adverse analytical findings remained broadly the same. There is also a strikingly different prevalence of doping substances and methods in sports such as a 0.03% prevalence of anabolic steroids in football compared to 0.4% in the overall WADA statistics. Future efforts in the fight against doping should therefore be more heavily based on preventative strategies such as education and on the analysis of data and forensic intelligence and also on the experiences of relevant stakeholders such as the national antidoping organisations, the laboratories, athletes or team physicians and related biomedical support staff. This strategy is essential to instigate the change needed to more effectively fight doping in sport.
HIV and viral hepatitis coinfections: advances and challenges
Authors: Karine Lacombe, Juergen Rockstroh
Journal: Gut (2012)

With a prevalence affecting over 30% of HIV infected patients, coinfection with hepatitis B (HBV) or C (HCV) virus remains one of the most frequent comorbidities in this population, with a significant impact in terms of morbidity and mortality associated with liver disease. Recent findings in the physiopathology of HIV in the liver have confirmed that it may contribute, along with hepatotoxicity of antiretrovirals and the burden of metabolic diseases, to a more rapid progression of liver fibrosis, especially when there is underlying chronic hepatitis coinfection. Both fields of research and clinical appraisal of HBV and HCV coinfection are rapidly evolving and prompt a change in the former paradigms of clinical care and management of chronic hepatic coinfection in the context of HIV. The advent of anti-HCV direct antiviral agents has indeed completely shaken up the treatment guidelines for HCV, and the tricky management of these new agents with antiretrovirals means referring patients to specialised centres. In HBV coinfection, therapeutic options have not changed recently but new challenges have emerged regarding the management of low replicating HBV-DNA in optimally treated patients and long term exposure to antivirals. Finally, the global increase in life expectancy in HIV infected patients has been accompanied in coinfected patients by a higher risk of emergence of end stage liver diseases for which access to orthotopic liver transplantation and innovative procedures such as targeted hepatocellular carcinoma therapies should be facilitated.
Preoperative Serum Tissue Factor Levels Are an Independent Prognostic Factor in Patients With Ovarian Carcinoma
Authors: Liz Y. Han, Charles N. Landen, Aparna A. Kamat, Adriana Lopez, David P. Bender, Peter Mueller, Rosemarie Schmandt, David M. Gershenson, Anil K. Sood
Journal: Journal of Clinical Oncology (2005)

Tissue factor (TF) is a procoagulant that plays an important part in tumor angiogenesis. We sought to determine the role of preoperative serum TF levels in predicting clinical outcome in patients with ovarian cancer.TF expression was determined by reverse transcriptase polymerase chain reaction in ovarian cell lines. Using enzyme-linked immunosorbent assay, we assessed preoperative serum TF levels in 98 women with invasive epithelial ovarian carcinoma, 30 with low malignant potential (LMP) tumors, 16 with benign tumors, and a separate validation group of 39 women with adnexal masses. Clinical information was gathered from chart review.TF was expressed in four of the five ovarian cancer cell lines, but absent in the nontransformed cells. Ovarian cancer patients had a median preoperative serum TF level of 85.2 pg/mL, which was significantly higher than in those with LMP tumors (12.8 pg/mL; P < .01) and benign adnexal disease (30.7 pg/mL; P < .01). TF >or= 190 pg/mL was significantly associated with decreased patient survival (P < .01). After adjusting for other clinical variables in a multivariate Cox regression model, TF >or= 190 pg/mL was an independent prognostic factor (P < .01). Analysis of serum TF levels from the validation set confirmed that high TF (>or=190 pg/mL) was associated with a 3.4-fold increase in risk of death from disease (P = .02) and shorter survival (P = .01).Preoperative serum TF levels are significantly elevated in patients with ovarian carcinoma. Elevated preoperative TF level is an independent prognostic factor for death from disease.
Deposition of calcium pyrophosphate dihydrate crystals in a soft tissue chondroma.
Authors: N A Athanasou, M Caughey, P Burge, C G Woods
Journal: Annals of the Rheumatic Diseases (1991)

Calcium pyrophosphate dihydrate (CPPD) crystal deposits were found in an extraarticular chondroma of the soft parts overlying the distal phalanx of the right middle finger. The lesion appeared to arise from the flexor tenosynovium. The pathogenesis of soft tissue chondroma and the relation of cartilage metaplasia to the process of CPPD crystal deposition were investigated.
mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice
Authors: Stefan Thiem, Thomas P. Pierce, Michelle Palmieri, Tracy L. Putoczki, Michael Buchert, Adele Preaudet, Ryan O. Farid, Chris Love, Bruno Catimel, Zhengdeng Lei, Steve Rozen, Veena Gopalakrishnan, Fred Schaper, Michael Hallek, Alex Boussioutas, Patrick Tan, Andrew Jarnicki, Matthias Ernst
Journal: Journal of Clinical Investigation (2013)

Gastrointestinal cancers are frequently associated with chronic inflammation and excessive secretion of IL-6 family cytokines, which promote tumorigenesis through persistent activation of the GP130/JAK/STAT3 pathway. Although tumor progression can be prevented by genetic ablation of Stat3 in mice, this transcription factor remains a challenging therapeutic target with a paucity of clinically approved inhibitors. Here, we uncovered parallel and excessive activation of mTOR complex 1 (mTORC1) alongside STAT3 in human intestinal-type gastric cancers (IGCs). Furthermore, in a preclinical mouse model of IGC, GP130 ligand administration simultaneously activated mTORC1/S6 kinase and STAT3 signaling. We therefore investigated whether mTORC1 activation was required for inflammation-associated gastrointestinal tumorigenesis. Strikingly, the mTORC1-specific inhibitor RAD001 potently suppressed initiation and progression of both murine IGC and colitis-associated colon cancer. The therapeutic effect of RAD001 was associated with reduced tumor vascularization and cell proliferation but occurred independently of STAT3 activity. We analyzed the mechanism of GP130-mediated mTORC1 activation in cells and mice and revealed a requirement for JAK and PI3K activity but not for GP130 tyrosine phosphorylation or STAT3. Our results suggest that GP130-dependent activation of the druggable PI3K/mTORC1 pathway is required for inflammation-associated gastrointestinal tumorigenesis. These findings advocate clinical application of PI3K/mTORC1 inhibitors for the treatment of corresponding human malignancies.
BMPR2 gene delivery shifts intracellular Smad activation profile
Authors: R. Harper, Paul Reynolds, Ann Reynolds
Journal: European Respiratory Journal (2012)

PAH is a fatal disease associated with decreased BMPR2 and increased TGF-β mediated cellular signalling. We have shown that BMPR2 upregulation in pulmonary endothelium reduces PAH in vivo, but the downstream signalling effects are unknown. BMPR2 is thought to signal primarily via Smad 1/5/8 and TGF-β via Smad 2/3, thus we hypothesised that BMPR2 upregulation may alter the relative activity of these pathways.  Aims and Objectives: To assess the effect of BMPR2 upregulation on downstream Smad signalling in endothelial cells, and the response to BMP ligands.  Methods: Human Microvascular Endothelial Cells (HMVEC) were transduced with an Adenoviral vector carrying the BMPR2 gene, and then stimulated with BMP7 or 9.  Results: Efficient upregulation of BMPR2 was confirmed by western blot and persisted beyond 48 hours. Incubation with BMP7 and 9 showed similar increases in p-Smad1/5/8 and Smad 5 at 24 hours following transduction, but by 48 hours after transduction, BMP7 effects were significantly greater than BMP9. Interestingly, BMP9 stimulated cells had increased Endoglin compared to BMP7 stimulated cells at 48hrs. Both ligands lead to reduced p-Smad 3 with a similar profile.  Conclusion: BMPR2 upregulation shifts the intracellular signalling profile toward Smad 1/5/8, and away from Smad 3 consistent with an alteration in downstream TGF-β/BMPR2 pathways, which may in part explain the effects on PAH seen in vivo. There may be differential effects depending on the BMP ligand involved, which requires further analysis.  Supported by NHMRC & NHF.