tbuckley/cabot-search huggingface dataset:
Abstract 468: Down-regulation of TNFSF15 (VEGI) in tumor vasculature under inflammatory conditions is a pre-requisite of tumor neovascularization
Authors: Weimin Deng, Yi Lu, Xin Gu, Paulina Huang Liang, Zhi Yao, Luyuan Li
Journal: Cancer Research (2011)

Abstract Tumor necrosis factor superfamily-15 (TNFSF15; VEGI) is an endogenous inhibitor of neovascularization. TNFSF15 is largely produced by quiescent vascular endothelial cells in an established vasculature but is markedly down-regulated in endothelial cells undergoing proliferation such as those in tumors or at a wound site. Recombinant TNFSF15 is a potent inhibitor of endothelial cell proliferation and tumor growth. We hypothesize that TNFSF15 as a negative regulator of angiogenesis must be down-regulated prior to the initiation of angiogenesis, and that the inflammatory conditions created by cancer cells and infiltrating lymphocytes lead to TNFSF15 down-modulation in the microenvironment, permitting new blood vessel growth. We analyzed normal ovary tissues (n=12) and clinical specimens of ovarian cancer (n=86; including stages I, II, III and IV) for the expression of TNFSF15, the endothelial cell marker PECAM (CD31), and tumor-infiltrating T-cell markers CD4 and CD25. We found that the degree of T-cell infiltration increases markedly while TNFSF15 expression diminishes as the disease progresses. We then determined the influence of human ovarian cancer cell line OVCAR-3 cell conditioned media on cytokine production by human CD4+ T-cells and CD4+CD25+ Treg cells, as well as the influence of the conditioned media of the latter two cells on TNFSF15 expression in human umbilical vein endothelial cells (HUVEC). We found that the conditioned media of Th1 or Treg cells can inhibit HUVEC TNFSF15 expression only after the lymphocytes being treated with OVCAR-3 conditioned media. Interestingly, we further found that mouse ovarian cancer ID8 cells implanted subcutaneously on mice treated with TNFSF15 shRNA at the injection sites exhibit significantly greater tumor growth rates compared with control shRNA treated ones. Our findings indicate that TNFSF15 plays a critical role in the maintenance of vascular stability as its down-modulation is a pre-requisite for the initiation of tumor neovascularization, and that TNFSF15 down-regulation is carried out by tumor-infiltrating T-cells under the influence of the cancer cells in the microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 468. doi:10.1158/1538-7445.AM2011-468
T2 Single nucleotide polymorphisms in the ficolin-2 gene predispose to Pseudomonas aeruginosa infection and disease severity in non-cystic fibrosis bronchiectasis
Authors: J. D. Chalmers, D. C. Kilpatrick, B. J. McHugh, M. P. Smith, J. R. W. Govan, C. Doherty, M. Matsushita, S. P. Hart, T. Sethi, A. T. Hill
Journal: Thorax (2011)

<h3>Introduction</h3> Bronchiectasis is associated with a destructive cycle of bacterial infection, airway inflammation and airway structural damage. Ficolins are a family of recently described serum pattern recognition molecules capable of binding to micro-organisms and activating complement through MBL associated serine protease-2 (MASP-2). Their role in chronic lung disease has not previously been investigated. <h3>Methods</h3> Serum levels of Ficolin-2 and MASP-2 were determined in 470 patients with idiopathic non-cystic fibrosis bronchiectasis and 400 matched control subjects by ELISA. Single nucleotide polymorphisms were determined using TaqMan PCR based genotyping. Bacterial binding was determined using ELISA and flow cytometry. Neutrophils from healthy donors were isolated by percoll gradient centrifugation and used in phagocytosis assays with FITC-labelled <i>Pseudomonas aeruginosa</i> strain PA01. <h3>Results</h3> Genotyping success was &gt;95% and all SNP9s were in Hardy–Weinburg equilibrium (p&gt;0.05). Bronchiectasis was associated with a homozygous mutation in the promoter of ficolin-2 (rs3124952) (28.5% vs 19.5%, p=0.002) and a homozygous mutation in exon-8 of the ficolin-2 gene causing impaired binding (rs17549193) (12% vs 8.4%, p=0.04). Low serum levels (&lt;1.6 μg/ml, 2 SD. below the mean for controls) were strongly associated with the promoter polymorphisms (p&lt;0.0001) and with bronchiectasis (18.7% vs 7.8%, p&lt;0.0001). In-vitro, ficolin-2 bound to over 60 strains of <i>P aeruginosa</i>, including clinical isolates and mucoid strains, activating the lectin pathway of complement and promoting C3 and C4 deposition. Ficolin-2 also bound to <i>Streptococcus pneumoniae, Haemophilus influenzae</i> and <i>Staphylococcus aureus</i>. Opsonisation with ficolin-2 promoted phagocytosis of <i>P aeruginosa</i> (PA01) by human neutrophils in a MASP-2 but not c1q dependent manner (p&lt;0.0001) (Abstract T2 figure 1). On multivariable analysis chronic bacterial colonisation (OR=3.5; p&lt;0.0001) and particularly <i>P aeruginosa</i> colonisation (OR=2.8, p=0.0001) were independently associated with ficolin-2 insufficiency. These patients also had more frequent outpatient exacerbations (mean 3.2/yr vs 2.4/yr, p=0.01) and unscheduled hospital admissions for exacerbations (OR=2.3; p&lt;0.0001). <h3>Conclusion</h3> Single nucleotide polymorphisms in the ficolin-2 gene affecting serum levels and carbohydrate binding are associated with non-CF bronchiectasis and increase susceptibility to colonisation with <i>P aeruginosa.</i>
The Thymus in Myasthenia Gravis
Authors: Nabih I. Abdou, Robert P. Lisak, Burton Zweiman, Ises Abrahamsohn, Audrey S. Penn
Journal: New England Journal of Medicine (1974)

Abstract Comparisons of several types of immunologic reactivity were made in thymic cells from six patients with myasthenia gravis and thymic hyperplasia, four patients with myasthenia gravis and thymoma and six age-matched control cardiac-surgery patients. In mixed leukocyte reactions, thymic cells from the subjects with hyperplasia were capable of stimulating autologous peripheral blood lymphocytes. Such reactivity was not seen in thymocyte-blood lymphocyte mixtures from the other two groups. There was an increased number of B cells in the thymic-cell populations from the myasthenic patients as compared to that in the control group, carrying predominantly IgM receptors. The thymic cells from myasthenic patients also responded more vigorously to pokeweed mitogen. These findings suggest altered populations of lymphoid cells in the thymus of myasthenic patients that react with autologous lymphocytes from other cell compartments. The pathogenic implications of these findings remain to be determined. (N Engl...
Abstract 1969: The potential tumor-suppressive role of Krüppel-like factor 9 in colorectal cancer.
Authors: Adam R. Brown, Trang T. Van, Rosalia C.M. Simmen, Frank A. Simmen
Journal: Cancer Research (2013)

Abstract Colorectal cancer (CRC) remains the third leading cause of cancer-related deaths in the United States. Recent attention has focused on several members of the Krüppel-like family (KLF) of transcription factors in pathogenesis of CRC. Published studies in mouse models have demonstrated that Krüppel-like Factors (KLF) 4 and 6 are important suppressors, while KLF5 is a promoter of CRC development and growth. Our and other laboratories have implicated KLF9 as another KLF with putative tumor-suppressive roles in colon and rectum. However, a causal role for KLF9 as a tumor suppressor has not been evaluated in vivo. In the present study, we generated C57BL/6J mice with two (wild-type, WT) and one (heterozygous, HET) Klf9 alleles within the ApcMin/+ model of intestinal cancer. At 16 weeks of age, male (by 2.5-fold, P=.0015) and female (by 1.5 fold, P=.002) Klf9 HET mice exhibited more colon tumors than WT (n=13-20 mice per gender/genotype). Further, HET females, but not males, showed increased (P=.011) colon tumor incidence compared to WT. Moreover, male HET exhibited greater numbers (P=.03) of large (&amp;gt;3mm diameter) colon tumors while corresponding female HET only showed a trend (P=.099), compared to WT. No significant difference was observed in the number of small intestine tumors in either males or females. Mean colon tumor size between genotypes of either sex was also comparable. Mice of both genotypes did not differ in body weights within specific female and male groups. Excised colon tumors and matched mucosa from male mice were embedded and subjected to immunohistochemistry. No significant differences in immunostaining intensity for β-Catenin were found in tumors nor in matched mucosa between the genotypes. A similar lack of differences in immunostaining for Lgr5, a surface marker for intestinal stem cells was noted in tumors or mucosa between the two genotypes. Since the ApcMin/+ model of intestinal cancer normally displays greater numbers of tumors in the small intestine than in the colon, results suggest a colon-specific contribution of KLF9 loss-of-expression to tumor development. Further, given that KLF9 is a unique thyroid hormone-inducible KLF family member, our results implicate the possible use of thyroid hormone or thyroid hormone receptor agonists in the prevention and/or treatment of CRC. Our collective findings provide early evidence for a tumor-suppressive role of KLF9 in the colon and rectum, the mechanism of which warrants further investigation. Supported by 1F31CA165665-01 and NIH RO1 CA136493. Citation Format: Adam R. Brown, Trang T. Van, Rosalia C.M. Simmen, Frank A. Simmen. The potential tumor-suppressive role of Krüppel-like factor 9 in colorectal cancer. [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 1969. doi:10.1158/1538-7445.AM2013-1969
P2Y12 RECEPTOR INHIBITION ACCORDING TO PREHOSPITAL ADMINISTRATION OF TICAGRELOR IN PRIMARY PCI FOR ST ELEVATION MYOCARDIAL INFARCTION: THE PRIVATE-ATLANTIC STUDY
Authors: Johanne Silvain, Robert Storey, Guillaume Cayla, Jean-Baptiste Esteve, Jean-Guillaume Dillinger, Eric Vicat, Jean-Philippe Collet, Anne Tsatsaris, Caroline Baradat, Néjoua Salhi, Frederic Lapostolle, Jens Lassen, Christian Hamm, Arnoud Van't Hof, Gilles Montalescot
Journal: Journal of the American College of Cardiology (2015)
PWE-122 Parallel Tipss for the Management of Shunt Insufficiency in Patients with Complications of Portal Hypertension: A Tertiary Liver Unit 19 Year Experience
Authors: N Rajoriya, H Merzhat, K Mangat, S Oliff, D Tripathi
Journal: Gut (2013)

<h3>Introduction</h3> Transjugular Intrahepatic Porto-Systemic Shunts (TIPSS) insufficiency can be addressed with a side placement of another TIPSS beside the original (“parallel” technique) thus improving portosystemic pressure gradient (PPG). There is a paucity of data assessing the efficacy of this technique. The Aim of this study was to assess the efficacy of parallel TIPSS in a large UK tertiary referral centre. <h3>Methods</h3> A retrospective study was performed from patient electronic databases. Parallel TIPSS were performed over a 19 year period. <h3>Results</h3> 11 patients (8M:3F) were identified (2% of all TIPSS procedures). Mean age at time of parallel TIPSS was 48.6(+/-13.7). Background aetiology of portal hypertension included: 5 ALD, 2 PSC, 2 PBC, 1 liver graft failure, 1 NCPH. Indications for index TIPSS (5 covered stents) were: 4 Oesophageal variceal (OV) haemorrhage, 3 gastric variceal (GV) haemorrhage, 1 stromal variceal haemorrhage and 3 for refractory ascites. At time of 1st TIPSS, documented mean PPG was 16.6(+/-7.71) and post TIPSS 10.8(+/-7.35) mmHg. Median time between index TIPSS and parallel TIPSS insertion was 72 days (IQR 4–1122 days). Prior to parallel stent placement, 7 patients had dilatation of the index TIPSS. At parallel TIPSS, the mean initial PPG was 16.0 (+/-7.40)/post procedure 6 (+/-2.28) mmHg. 63% had covered stent as the parallel TIPSS. One patient had transient encephalopathy, but no other complications were encountered. Nine patients had a resolution in symptoms. One patient had ongoing GV bleeding requiring Thrombin injection and 1 patient had ascites with no flow in parallel TIPSS 4 days post-procedure. Secondary patency was 82% with a median number of interventions of 1.5 (IQR 1–3). Median follow-up was 30 months (range 0.5–120). 92% patients were alive at 1 month with 86% 1 year survival. Two patients were transplanted during follow-up. <h3>Conclusion</h3> Parallel TIPSS is a safe and effective method to treat TIPSS insufficiency. The majority of patients not only had a good haemodynamic result, but also resolution of symptoms. <h3>Disclosure of Interest</h3> None Declared.
RT-36 * ONCOLOGIC OUTCOME OF HISPANIC PATIENTS WITH GLIOBLASTOMA TREATED WITH RADIOTHERAPY
Authors: T. Wang, A. Jani, S. Saad, Y. Qureshi, J. Estrada, M. Sisti, G. McKhann, S. Cheng, K. S. C. Chao, A. Lassman
Journal: Neuro-Oncology (2014)

BACKGROUND: Underutilization of radiotherapy in minorities with glioblastoma (GBM) has been reported. We sought to investigate whether patients of Hispanic descent with GBM had different presentation, treatment, oncologic outcomes compared to Caucasian patients. METHODS: We reviewed all patients with GBM treated with radiotherapy at Columbia University Medical Center from 1998 to 2013. Variables analyzed included age, gender, race, Karnofsky performance status, molecular markers, extent of resection, and radiotherapy scheme. RESULTS: From 1998 to 2013, 444 Caucasian and Hispanic patients with GBM were treated with radiotherapy at our institution. Baseline characteristics (age, gender, KPS) were similar among the two groups (Hispanic vs. Caucasian), as was extent of resection. For example, there were 85 patients of Hispanic descent with a median age of 58 (range 4-91) years, 51 (60%) were men, and median KPS was 80 (range 50-100). In Caucasians cohort (N = 361), the median age was 61 (range 7-87), 208 (58%) were men, and median KPS was 80 (range 30-100). Among the Hispanic patients, 85.5% had gross total or subtotal resection and 14.5% biopsy whereas in Caucasians, 83.2% had gross total or subtotal resection and 16.8% biopsy only. Hispanic and Caucasian patients had similar rates of MGMT methylation (38.5% vs. 42.9%), IDH-1 mutation (5.9% vs. 7.9%), and positive EGFR immunohistochemical staining (78.9% vs. 74.4%). Similar rates of Hispanic and Caucasian patients received intensity-modulated radiotherapy (50.0% vs. 52.4%) and three-dimensional conformal radiotherapy (35.4% vs. 45.4%); whereas more Hispanic patients received two-dimensional radiotherapy (14.5% vs. 2.2%). However, median survival was not statistically different among Hispanics than Caucasians: 287 vs. 388 days (HR: 1.147; 95%CI: 0.863-1.524; p = 0.346). CONCLUSIONS: We found that Hispanic patients with GBM had a trend toward worse but not statistically different overall survival than Caucasian patients having similar baseline characteristics, types of surgery, radiotherapy, and molecular markers.
Abstract LB-108: Exosome profiling of mRNAs and miRNAs in serum samples from GBM patients .
Authors: Johan Skog, Stefan Bentink, Lori LoGuidice, Charlotte Romain, Susan Belzer, Mikkel Noerholm
Journal: Cancer Research (2013)

Abstract Background: Biomarker discovery and development in oncology has traditionally required the use of tissue, either FFPE or frozen. In recent years, the use of Circulating Tumor Cells (CTCs), cell free DNA (cfDNA), and most recently, exosomes, has allowed biomarker research in biofluids to evolve. Exosomes contain mRNA, microRNA, DNA and protein in a protected, highly stable vesicle. Recently, we have shown that large panels of mRNA genes can be run on small samples of frozen, archived serum. The ability to assess the expressions patterns in blood represents a potentially important development for biomarker research and the development of non-invasive diagnostics. Methods: Frozen, archived serum (2ml) was obtained from a glioblastoma clinical trial cohort, containing serum from both responders and non-responders to a novel therapy. We isolated the microvesicle fraction from the serum, extracted the RNA, and qualified the RNA using an Agilent 2100 Bioanalyzer on an Agilent 6000 RNA Picochip. A standard in-house control extraction was processed in parallel and subjected to quality control on the Bioanalyzer as well as RT-qPCR. The first cohort of samples (n = 60) were reverse transcribed to cDNA, and the cDNA was assayed on a human cancer mRNA panel Array by qPCR (Life Technologies).The cancer panel includes a total of 648 cancer related genes including endogenous controls. The second cohort of samples (n = 40) was reverse transcribed and analyzed by a miRNA panel of 758 different miRNA assays and controls. Results: Our data clearly demonstrate the ability to detect relevant gene expression patterns in microvesicle RNA isolated from patient serum. High quality RNA was extracted from the samples received, and an average of 80% of the 648 cancer associated mRNA genes and 36% of the miRNAs were detected in the samples with the volumes used in this study. Data was demonstrated to be reproducible between and among samples and suggests a biological pattern of RNAs in serum exosomes that could be used to monitor response to treatment. Conclusions: RNA isolated from the microvesicle fraction of serum contains abundant, high-quality RNA, including mRNA. The analysis of a large panel of genes from a small sample of serum is possible, demonstrating that RNA isolated from microvesicles from peripheral blood has the potential to be used as a source of genetic material for non-invasive diagnostic tests. Citation Format: Johan Skog, Stefan Bentink, Lori LoGuidice, Charlotte Romain, Susan Belzer, Mikkel Noerholm. Exosome profiling of mRNAs and miRNAs in serum samples from GBM patients . [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 LB-108. doi:10.1158/1538-7445.AM2013-LB-108
Abstract P2-12-02: How Common Is Sexual Dysfunction among Women with Early Stage Breast Cancer?
Authors: SF Dent, DAM Frechette, S Verma, MJ Clemons, PF Wheatley-Price, SZ Gertler, X Song, TR Asmis, NA Graham, L. Paquet
Journal: Cancer Research (2010)

Abstract Background: Despite the high prevalence of sexual problems (50—90%) among women with early stage breast cancer (EBC), relatively little is known about the prevalence of clinically significant post-systemic treatment sexual dysfunction (SD) and its impact on quality of life (QOL). According to the American Psychiatric Association (APA), SD consists of sexual problems causing marked personal distress. While 40% of healthy US women report sexual problems, only 12% experience SD. No study has applied the APA criterion to document the prevalence of SD in women with EBC who have completed systemic therapy. The goal of this study is to address this gap and to examine some correlates (anxious predispositions and menopausal symptoms) of SD and the impact of SD on QOL. Methods: Post-menopausal women receiving cancer therapy for EBC or early colon cancer were approached for this study. Sexual problems were evaluated with the Female Sexual Function Index while sexual distress was assessed with the Female Sexual Distress Scale. QOL was measured with FACT-B, using its endocrine symptoms subscale (ES) to assess menopausal symptoms. Spielberger State-Trait Anxiety Inventory measured anxious predispositions. Participants completed questionnaires upon completion of adjuvant chemotherapy but prior to initiation of hormonal therapy (estrogen sensitive EBC). SD was assessed using the APA classification. Results: Between January 2009 and May 1 2010, 70 EBC patients entered this study. The proportion of women (mean age 61) reporting 1 or more sexual problems was high (93%) and included problems with 1) frequency (66%) and level (65%) of sexual desire, 2) frequency (66%), level (52%) and satisfaction (43%) of arousal, 3) frequency (21%) of vaginal dryness and difficulty becoming lubricated (47%) during sexual activity, 4) satisfaction with their sexual life (30%) and 5) pain during intercourse (18%). However, the APA criterion identified only 30% of patients as having SD. Multiple logistic regression showed that anxiety predispositions and menopausal symptoms predicted SD (p&amp;lt; .01). Women classified as having SD had higher anxiety scores (No SD=34 SD=41, p&amp;lt;.05) as well as higher levels of menopausal symptoms (i.e, lower ES scores; No SD= 62 SD=54, p&amp;lt;.01). QOL was negatively impacted by SD (r=-0.42, p&amp;lt;.01). Discussion: Despite the fact that an overwhelming majority of patients had sexual difficulties, the APA distress criterion identified far fewer patients (30 %) with SD. Nevertheless, we found a high prevalence rate of SD, which was 2.5 times higher (%2 &amp;lt; .01) than that reported in women without a cancer diagnosis. Women with anxious predispositions and high menopausal symptoms may be at risk for SD and may benefit from early interventions to prevent SD. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-12-02.
Choosing a house job
Authors: J. Westall
Journal: BMJ (1999)

For most students, choosing a house job seems like a big step on to a largely unplanned career ladder. Consultants see things differently: I was unequivocally reassured that house jobs were the least important career move I would ever make in terms of defining my future specialty. However, the post you end up in does affect your wellbeing, which is more than a short term consideration. How you feel about your first job as a doctor influences the way you feel about future career plans and will directly affect your reference and curriculum vitae. The year also acts as a foundation for the rest of your career in terms of skills and practical experience. In this article I outline a scheme for assessing the options.

#### Job assessment

To find out from the current house officer

To find out from the consultant

The key to finding a house job you are going to enjoy is to be informed before you apply. Firstly, you need to know what your personal priorities are as they will influence your choice of job. Whether it is more important to you to work with a consultant who shares your personal philosophy or …