tbuckley/cabot-search huggingface dataset:
Abstract 5088: Targeting the mTORC2/HIF-2alpha/p53 pathway in clear cell renal cell carcinoma.
Authors: Jogitha Selvarajah, Abdeladim Moumen, Veronica A. Carroll
Journal: Cancer Research (2013)

Abstract Inactivating mutations in the von Hippel Lindau (VHL) tumour suppressor gene leads to both hereditary and sporadic clear cell renal cell carcinoma (ccRCC). Loss of VHL function results in stabilisation of hypoxia inducible factors 1 and 2 (HIF-1α and HIF-2α) with HIF-2α critical for renal tumour progression, angiogenesis and resistance to radiotherapy and chemotherapy. Previous work in VHL defective RCC cell lines that express HIF-2α has shown that loss of HIF-2α, either with siRNA or by reintroduction of VHL, increases phosphorylation and stabilisation of p53 which restored sensitivity to radiation and chemotherapy. Furthermore, as recent evidence suggests that mTORC2 is required for HIF-2α protein synthesis in VHL defective cells, we investigated the effects of pharmacological inhibition of HIF-2α with the mTORC1/2 kinase inhibitor pp242 alone or in combination with DNA damaging agents. Phosphorylated p53 and total p53 levels were significantly elevated in VHL competent RCC cells lacking HIF-2α as compared with VHL defective cells, confirming a role for HIF-2α mediated inhibition of p53. We analysed the effects of the mTORC1/2 kinase inhibitor pp242 on HIF-2α protein levels by Western blot. pp242 inhibited phosphorylation of both mTOR and its substrate p70S6K and significantly reduced protein levels of HIF-2α as compared with the mTORC1 inhibitor rapamycin, which had no effect on HIF-2α. Since the DNA damaging agent camptothecin (CPT) is a potent inhibitor of HIF-1α we also determined its effects on HIF-2α expression. CPT reduced HIF-2α protein levels in VHL defective RCC cells and increased p53 stabilisation, which was significantly augmented in VHL competent cells following complete loss of HIF-2α. Consistent with its inhibition of the p53 pathway, HIF-2α prevented both spontaneous and CPT induced apoptosis of RCC cells as demonstrated by FACS analysis of cells in sub G1 and Western blot analysis of cleaved PARP. Taken together these results confirm that HIF-2α negatively regulates p53, confers resistance to DNA damage induced apoptosis in VHL defective RCC cell lines and that further studies investigating the pharmacological inhibition of HIF-2α mediated by mTORC1/2 kinase inhibitors alone or in combination with DNA damaging agents for the treatment of ccRCC are warranted. Citation Format: Jogitha Selvarajah, Abdeladim Moumen, Veronica A. Carroll. Targeting the mTORC2/HIF-2alpha/p53 pathway in clear cell renal cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5088. doi:10.1158/1538-7445.AM2013-5088
Abstract 1267: Identification of HPV-derived CD4+ T-helper epitopes for improving therapeutic anti-HPV vaccine potency.
Authors: Agnieszka K. Grabowska, Stephanie Hoppe, Renata Blatnik, Angelika B. Riemer
Journal: Cancer Research (2013)

Abstract Persistent infection with high-risk types of human papillomavirus (HPV) can lead to malignant transformation and the development of various human malignancies, such as cervical cancer, anal cancer or a subset of oropharyngeal carcinomas. Fortunately, most HPV infections are successfully eradicated by the immune system. Accumulating evidence suggests that both CD8+ and CD4+ T cell responses play a pivotal role in the clearance and control of HPV infection. Up to now, therapeutic anti-HPV vaccines have mostly been developed to elicit CD8+T cell responses. The exclusive targeting of HLA class I-restricted HPV epitopes might be insufficient, as HLA class I surface expression may be reduced as a result of HPV immune evasion strategies. In contrast, HLA class II molecules are expressed in high-grade cervical lesions and cervical cancer. Therefore in this study, we aim to identify novel E2-, E5-, E6- and E7-derived CD4+ T cell epitopes that bind to multiple HLA class II alleles, are naturally processed and presented, and immunogenic. We started with in silico epitope predictions using several web-based prediction algorithms. 15-mer candidate epitopes from the HPV16 E2, E5, E6 and E7 proteins were determined for seven HLA class II alleles - DRB1*0101 (DR1), DRB1*0301 (DR3), DRB1*0401 (DR4), DRB1*0701 (DR7), DRB1*1101 (DR11), DRB1*1501 (DR2b), and DRB1*0901 (DR9); together providing &amp;gt;90% population coverage. To identify promiscuous epitopes, the average binding score to multiple HLA-DR alleles was calculated and peptides ranked accordingly. To assess immunogenicity of HPV-derived candidate peptides, IFN-γ-ELISPOT assays were conducted with lymphocytes isolated from healthy donors. T cells isolated from the majority of healthy donors responded to at least one HPV-derived peptide. The most reactive HPV-derived peptides were further investigated in long-term T cell cultures. Significant production of IFN-γ as well as T cell proliferation was observed in nearly 100% of tested individuals against this panel of epitopes. As the above immunoreactivities most likely represent memory responses that led to viral clearance in healthy donors, we conclude that the identified CD4+ T-helper epitopes are candidates for the development of comprehensive epitope-specific HPV immunotherapy approaches. Citation Format: Agnieszka K. Grabowska, Stephanie Hoppe, Renata Blatnik, Angelika B. Riemer. Identification of HPV-derived CD4+ T-helper epitopes for improving therapeutic anti-HPV vaccine potency. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1267. doi:10.1158/1538-7445.AM2013-1267
The inevitability of normative analysis
Authors: Sahotra Sarkar
Journal: Behavioral and Brain Sciences (2014)

Abstract Wilson et al. make the case for taking control of our future using evolutionary analysis. However, they are entirely silent on the ethical questions that must be addressed. This piece emphasizes this problem and notes that the relevant answers will require nontrivial analysis. This is where the humanities become relevant – in particular, philosophy and cultural anthropology.
Abstract 601: Antioxidant inhibition of GSK-3β stabilizes anti-apoptotic factor Mcl-1 leading to decreased apoptosis and increased cell survival.
Authors: Suryakant K. Niture, Anil K. Jaiswal
Journal: Cancer Research (2013)

Abstract Antioxidant-mediated stabilization of Nrf2 is known to up-regulate anti-apoptotic factors Bcl-2 and Bcl-xL that leads to reduced apoptosis and increased cell survival. In this report we investigated and found that anti-apoptotic factor Mcl-1 is coordinately induced with Bcl-2 and Bcl-xL factors in response to antioxidants. However, unlike Bcl-2 and Bcl-xL, Nrf2 did not control antioxidant-mediated up-regulation of Mcl-1. Further studies revealed that ERK1/2 phosphorylation of Mcl-1T163 primes Mcl-1 for phosphorylation by GSK3β at position S159. This modification degrades Mcl-1 and contributes to the maintenance of physiological level of Mcl-1 and cellular apoptosis. Exposure of Hep-G2 cells to antioxidant tert-butyl hydroquinone (t-BHQ) for 4-16h led to time dependent Akt-mediated inactivation of GSK3β, decreased Mcl-1S159 phosphorylation resulting in stabilization of Mcl-1 protein. Antioxidant-mediated increased Mcl-1 heterodimerized with Bim and Bax and down regulated cellular apoptosis. The contribution of antioxidant increased Mcl-1 in reduced apoptosis was further confirmed by siRNA-mediated inhibition of Mcl-1 that increased susceptibility to etoposide-mediated cell death and reduced cell survival through the activation of caspases 3/7. These results provided evidence that antioxidant control of GSK-3β led to increase in Mcl-1 that contributed to decreased apoptosis and increased cell survival. The results collectively suggest that antioxidant stabilized Nrf2 and GSK3β both through distinct mechanisms lead to increased anti-apoptotic factors Bcl-2, Bcl-xL and Mcl-1 that reduces apoptosis and promotes cell survival. Citation Format: Suryakant K. Niture, Anil K. Jaiswal. Antioxidant inhibition of GSK-3β stabilizes anti-apoptotic factor Mcl-1 leading to decreased apoptosis and increased cell survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 601. doi:10.1158/1538-7445.AM2013-601
Abstract 4691: Evaluating the effectiveness of community based breast cancer and prostate cancer interventions among African Americans
Authors: Judithe Louis, Camille Brown, Crystal Cannon, Jeffrey Wilkins, Amura Cameron, Jasmine Patrice, Jonathan Livingston, Dorothy Singleton
Journal: Cancer Research (2010)

Abstract Health disparities among African Americans have been of key concern for the past decade. High rates of morbidity due to HIV/AIDS, heart disease, and cancer have led to the creation of new and more innovative efforts to educate African Americans about health disparities. The current paper is an assessment of the use of Community Theater to educate African Americans about breast and prostate cancers. To assess the effectiveness of theater, a team of health professionals, psychologists, and biomedical scientists were convened to develop two scripts written by a local playwright: “Stealing Clouds” which focused on breast cancer and “Fourth and a Mile” which focused on prostate cancer. A retrospective pre/post-test design with a 3-month delayed time series follow up was employed using surveys from participants upon viewing the plays. Results of both theatre presentations indicated that the plays were significant in increasing knowledge and awareness about both breast and prostate cancers. Furthermore, results indicated that participants, as a result of viewing the plays, reported increased likelihood of engaging in healthier behaviors (i.e., physician visits, testing). To assess the impact of Community Theatre as an effective medium, data was collected from a local health center indicating higher increases in mammography and prostate cancer exams as results of the plays. Given the high rates of cancer among African Americans, continued creation and evaluation of the effectiveness of such community-based efforts should be of key import in reducing and addressing cancer disparities. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4691.
Abstract 5231: Highly conserved ceRNA regulatory interactions cooperate with genomic variability to modulate drivers of tumorigenesis.
Authors: Hua-Sheng Chiu, Xuerui Yang, María Rodríguez Martínez, Archana Iyer, Pavel Sumazin, Andrea Califano
Journal: Cancer Research (2013)

Abstract MicroRNAs (miRs) have been repeatedly linked to tumorigenesis and tumor progression, suggesting their potential value as biomarkers and targets for therapeutic intervention. Recent evidence suggests that mRNAs compete for binding and regulation by a finite pool of miRs, thus regulating each other as competitive endogenous RNAs (ceRNAs). The extent of this new regulatory layer and its potential to alter the expression of cancer genes has been shown in several tumor types, but the actual impact of ceRNA interactions on disease remains unclear. In this study, using TCGA (The Cancer Genome Atlas) tumor datasets, we provide evidence that ceRNA play an important role in tumor etiology. Leveraging millions of shRNA-mediated perturbations from LINCS (Library of Integrated Network-based Cellular Signatures), we extensively validated ceRNA interactions in breast and prostate cancer. Moreover, we identified over 160,000 ceRNA interactions that are conserved across tumor types despite being implemented by miR programs with tumor type-specific expression. We present evidence that these ultraconserved interactions are mechanistically responsible for the dysregulation of the majority of oncogenes and tumor suppressors through TCGA-profiled genomic alteration of their cognate ceRNA regulators. Using targeted biochemical validation in cell lines, we verified the potential of ceRNA regulators to target ESR1, an established oncogene and drug target in breast cancer, and APC, an established tumor suppressor in colon adenocarcinoma. Our analysis suggests that ceRNA interactions are implemented through competition for multiple miRNAs, rendering them virtually independent of single miRNA kinetics and availability, and more likely to be conserved across contexts. Using TCGA samples, we demonstrated that conserved ceRNA interactions enable systematic identification of genomic alterations that contribute to aberrant expression of hundreds of cancer genes in each of eight distinct tumor contexts. We submit this network as a resource for analyzing ceRNA regulation in datasets where reverse engineering context-specific networks is infeasible due to low sample number or lack of miRNA expression profiles. Citation Format: Hua-Sheng Chiu, Xuerui Yang, María Rodríguez Martínez, Archana Iyer, Pavel Sumazin, Andrea Califano. Highly conserved ceRNA regulatory interactions cooperate with genomic variability to modulate drivers of tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5231. doi:10.1158/1538-7445.AM2013-5231
Abstract 351: Mutations of genes in the c-Kit receptor tyrosine kinase signaling pathway are inactive in adenoid cystic carcinoma of the salivary glands: Implications for c-Kit targeted therapy
Authors: Osamu Tetsu, Janyaporn Phuchareon, Annie Chou, Darren P. Cox, David W. Eisele, Richard CK Jordan
Journal: Cancer Research (2010)

Abstract Adenoid cystic carcinoma (ACC) is a malignant salivary gland tumor well-known for spreading in wide local area and invasion of vital structures of the head and neck. Unfortunately, conventional therapies have not improved longer-term survival, resulting in significant morbidity and a very low overall survival rate. Improved systemic therapies are clearly needed for this population. ACC tumors overexpress the receptor tyrosine kinase c-Kit, which is thought to be a therapeutic target. However, the role of c-Kit in the pathogenesis of ACC is not currently understood. We addressed this question through a functional genomic study with 17 sporadic ACC tumor specimens. We found heterogeneous missense mutations in three genes in the c-Kit signaling pathway, although mutations were identified at a low frequency. Two ACC tumors had distinct missense mutations in the gene KIT, resulting in G664R and R796G amino acid substitutions in the c-Kit kinase domain. Furthermore, two ACC tumors without KIT mutations had missense mutations in either KRAS or BRAF, causing S17N K-Ras and V590I B-Raf mutants. KRAS and BRAF are downstream effectors of c-Kit. We explored the functional consequences of these amino acid substitutions and found that all of c-Kit, K-Ras and B-Raf mutations in our ACC samples were inactive. These observations suggest that the c-Kit signaling pathway must be dispensable for maintaining established ACC. As a result, we believe that selective c-Kit inhibition is not a suitable treatment for the patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 351.
Case 29-2002
Authors: Bradley J. Bloom, R. Neal Smith
Journal: New England Journal of Medicine (2002)

Presentation of CaseA 17-year-old boy was admitted to the hospital because of acute mitral regurgitation and pulmonary edema.The patient had received a diagnosis of juvenile spondyloarthropathy two years earlier. He had intermittent acral arthralgia, which affected mainly the left wrist. He had used indomethacin, but it had been discontinued about 10 days before admission because of painless hematuria, and ibuprofen had been substituted. Six days before admission, vomiting developed in the evening, and the ibuprofen was discontinued. The vomiting recurred daily. On the third day of the illness, the vomitus was bile-stained and contained red mucus. No frank . . .
SAT0430 Association between Serum 25-Hydroxy (OH) Vitamin D Level and Muscle Strength in Patients with Knee Osteoarthritis: Results of the AMS-OA Cohort
Authors: M. Van Der Leeden, E. Koeckhoven, J. Dekker, L.D. Roorda, M. van der Esch, W.F. Lems
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Muscle weakness is frequent in patients with knee osteoarthritis (OA) and is an important contributor to pain and activity limitations<sup>1</sup>. Determinants of muscle weakness in knee OA include pain, disuse, aging and low-grade inflammation. In addition, vitamin D deficiency, which is common in older adults, has been linked to muscle weakness since low serum 25-hydroxy (OH) vitamin D level has been found to be related to impaired muscle cell function<sup>2</sup>. In knee OA, the association between serum 25(OH) vitamin D level and muscle strength has not been studied profoundly. <h3>Objectives</h3> To assess the association between serum 25(OH) vitamin D level and muscle strength in patients with knee OA. <h3>Methods</h3> Baseline data from 297 patients (105 men and 193 women with a mean age of 60.6±8.2 years) with knee OA from the Amsterdam Osteoarthritis (AMS-OA) cohort were used. Muscle strength (in N/kg) of the upper leg (flexion and extension) was measured with an isokinetic dynamometer. In blood serum, 25(OH) vitamin D level (in nmol/L) was measured. Uni- and multivariable linear regression analyses were used to analyze the association between 25(OH) vitamin D level and muscle strength. Confounders that were considered relevant included age, gender, body mass index (BMI), season of blood collection (summer/winter), erythrocyte sedimentation rate value, C-reactive protein value and WOMAC-physical functioning subscale. <h3>Results</h3> Lower level of 25(OH) vitamin D was associated with lower muscle strength (B=0.003, 95%CI 0.001 to 0.005, p&lt;0.001). The association was not significant when BMI was incorporated in the model (B=0.001, 95%CI -.001 to 0.003, p=0.254). <h3>Conclusions</h3> Low 25(OH) vitamin D level and muscle weakness are associated. BMI affects this association strongly. Further studies are needed explaining the associations between vitamin D, fat metabolism and muscle strength in knee osteoarthritis. <h3>References</h3> Holla JF, van der Leeden M, Peter WF, Roorda LD, van der Esch M, Lems WF, Gerritsen M, Voorneman RE, Steultjens MP, Dekker J. Proprioception, laxity, muscle strength and activity limitations in early symptomatic knee osteoarthritis: results from the CHECK cohort. J Rehabil Med. 2012 Oct;44(10):862-8. Wicherts IS, van Schoor NM, Boeke AJ, Visser M, Deeg DJ, Smit J, Knol DL, Lips P. Vitamin D status predicts physical performance and its decline in older persons. J Clin Endocrinol Metab 2007;92:2058-65. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4957
FRI0100 Sustained development of cardiovascular disease in rheumatoid arthritis despite cardioprotective treatment: The 7-year prospective carre-study
Authors: A.M. van Sijl, I.A. van den Oever, M.J. Peters, V.P. van Halm, Y.M. Smulders, A.E. Voskuyl, M.T. Nurmohamed
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid arthritis (RA) is a chronic inflammatory joint disease which is associated with an increased cardiovascular (CV) risk. Still unknown is whether CV risk factors or the underlying inflammatory process in RA renders these patients more at risk of CV disease (CVD). An increment in these factors over several years might explain this predisposition. <h3>Objectives</h3> The present study compared changes in these factors over time in RA-patients who did and did not develop CVD during follow-up. <h3>Methods</h3> 7-year incidence rate of CVD was determined in a prospective cohort of 353 RA-patients. CV risk factors, RA-related factors and medication use were assessed at baseline, at 3-years and at 7-years of follow-up. Associations between the changes in investigated factors and development of CVD were assessed using generalized estimating equation (GEE) analyses. <h3>Results</h3> After 7 years, there were 62 events over 2361 patientyears of follow-up, incidence rate (IR) of 26.3/1.000 patientyears. This was similar to the IR after 3-years of follow-up. GEE analyses showed that, during follow-up, changes in disease activity score of 28 joints (DAS28) and overall 10-year CV risk estimation (as calculated by SCORE) were associated with incident CVD. Use of biologics increased significantly in patients who did not develop incident CVD vs. those who did (26% vs. 6%), while use of statins increased significantly in patients who did develop incident CVD vs. those who did not (43% vs. 14%). <h3>Conclusions</h3> An increased risk of incident CVD persists in patients with RA. Changes in both DAS-28 as well as 10-year CV risk estimation (SCORE) were associated with the 7-year CVD incidence. Cardioprotective treatment did not seem to extenuate this association. A more aggressive cardioprotective and anti-inflammatory treatment of RA might mitigate the burden of CVD in RA. <h3>Disclosure of Interest</h3> None Declared
Soundings: Love's a funny thing
Authors: Liam Farrell
Journal: BMJ (2004)

This is a delicate and touchy subject, but I feel it must be addressed. I recently met a large, fat acquaintance whom I cordially dislike, for reasons that will soon become obvious, and who told me he'd had a hip replacement.

“And how have you been since?” I asked, out of politeness, not really caring, my emotional commitment stalled somewhere between apathy and pity.

“Very sore to start with, but much better now,” he leered, drooling beer over my shoes, “I started wanking again last night.” This man is a bit too comfortable with his own body, I thought, trying to erase the mental image and failing miserably.

But the more I considered it the more I began to see an important truth behind the nauseating image; perhaps I was being too squeamish. In medicine all we can usually measure is structure and process, yet here, right in front of our noses, even unpleasantly so, is surely the ultimate outcome. As an indicator of recovery from hip surgery masturbation provides a practical and objective evaluation of both physical dexterity and mental wellbeing. To masturbate frequently and effectively most of our joints and muscles need to be in good working order and you have to feel happy with yourself (I read this in a book, you understand).

And why limit such a rich vein of clinical information to post-op assessment? Part of the routine system review in any case history includes discreet inquiries about bowels and waterworks. We should also be asking about masturbation; how often, and was it good for you? A positive reply implies that things are looking up.

And as a bonus it is a fertile ground for opportunistic health promotion. A recent report suggested that men who ejaculated more than five times each week in their 20s, 30s, and 40s reduced their risk of developing prostate cancer by a third (British Journal of Urology 2003;92; 211 [PubMed]). Of course, further research is needed, you know how guys love to boast, and anyway these were Australians.

Encouraging patients to masturbate more often is the next logical step, again one that I will find difficult; it's not exactly the Capulets and the Montagues, is it? A public health approach would be preferable, perhaps with dedicated helplines and magazines; maybe a cable channel, or two.