tbuckley/cabot-search huggingface dataset:
Abstract 3731: Directing combinatorial therapy of breast cancer using signaling pathway predictors
Authors: Jing-Ru Jhan, Eran Andrechek
Journal: Cancer Research (2012)

Abstract Heterogeneity in human breast cancers reflects the complexity of cancer, and has been characterized in both histology and gene expression patterns. In addition, heterogeneity is observed in the differential response to therapy. Indeed, the response of molecular-based target therapies, such as Herceptin, in specific populations of patients points out the importance of characterizing heterogeneity prior to therapy. However, only 35-50% of HER2+ patients are responsive to Herceptin and among those, some also developed drug resistance. Taken together, this indicates that combination targeted therapy in conjunction with an accurate diagnosis of they type of breast cancer is critical for development of effective breast cancer treatment. Here we develop a new strategy to develop combination therapies for subtypes of breast cancer. Using bioinformatic methods to analyze gene expression profiles of heterogeneous mammary tumors in MMTV-myc mice, we have developed combinatorial therapeutic treatment plans specific to the cell signaling pathways that have been activated. The activity of the cell signaling pathways was determined through a gene expression analysis coupled with training data for key signaling pathways. Our initial data shows that the individualized therapeutic combinations for certain histological subtypes of Myc tumors are safe for mice. The therapeutic efficacy will be evaluated first in immune-competent wild-type mice bearing with tumors from the heterogeneous MMTV-myc mice. The results will demonstrate a proof of principle in an effective, approach to rationalize breast cancer therapy using a limited number of available drugs after predicting the response to therapy. These results will also be expected to facilitate our understanding in roles of heterogeneity in breast cancer in response to therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3731. doi:1538-7445.AM2012-3731
MS-18 * PREDICTORS OF RESPONSE AND ADVERSE EVENTS FOR MENINGIOMAS MANAGED WITH GAMMA KNIFE RADIOSURGERY
Authors: A. Mansouri, S. Larjani, G. Klironomos, G. Zadeh
Journal: Neuro-Oncology (2014)

OBJECTIVE: To identify clinical, radiological, and dosimetric predictors of meningioma response to stereotactic radiosurgery (SRS), and post-SRS adverse radiation events (ARE). METHODS: A retrospective review of the database of meningioma patients treated with SRS between December 2005 and June 2013 at the University Health Network was performed. Seventy-five patients had at least 24 months of clinical and radiological follow-up, and were therefore included in this study. Tumor growth rates were calculated using the Specific Growth Rate (SGR). Tumor control was defined as any volumetric/diametric change less than +10%. Volumetric measurements were made using T1-Gadolinium enhanced 3T MRI scans with ITK-SNAP2.2 software. Univariate statistics were used to identify predictors of post SRS AREs. All statistical analyses were performed using IBM SPSS v20.0. RESULTS: The majority of patients (69.3%) were females and mean age at treatment was 58.6 years. Patients were followed up for a median time of 36.2 months. Twenty-one patients had undergone prior surgical resection. One patient required salvage surgical intervention following SRS. Volumetric tumor control (52%) was inferior to diametric control (92%). Twenty-six patients (34.6%) experienced some form of new-onset complication after SRS: Headache (17.3%), cranial neuropathy (10.6%), speech impairment (2.7%), tremor (2.7%), and ataxia (1.3%). Patients with meningiomas that had a growth rates of more than 10%/year were more likely to have long-term headache after SRS (p = 0.022). Fourteen patients (18.7%) experienced new onset T2 signal change signifying of edema; eight of these patients were symptomatic. Lower Conformity index (1.24 vs. 1.4), and higher treatment-volume ratio (TVR) (0.80 vs. 0.72) were significantly associated with development of edema after SRS (p<0.05, power > 0.8). CONCLUSION: Volume-based reporting of SRS outcomes for meningiomas is more accurate for reporting tumor control. Conformity index and TVR were identified as predictors of edema following radiosurgery.
AB0301 Characteristics of rheumatoid arthritis patients with adverse effects after the initiation of tocilizumab therapy
Authors: C. Diaz-Torne, M. A. Ortiz, M. V. Hernandez, D. Reina, I. Castellví, D. De la Fuente, B. Magallares, J. M. Ruiz-Martin, H. Corominas, C. Geli, R. Sanmartí, J. M. Llobet, S. Vidal
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Tocilizumab is a humanized monoclonal antibody that blocks IL-6 mediated pro-inflammatory signalling in rheumatoid arthritis patients. The safety profile of tocilizumab has been extensively evaluated in clinical trials. However, there is little data on markers at the initiation of tocilizumab therapy that may predict the development of adverse effects requiring drug withdrawal. <h3>Objectives</h3> To identify markers that predict the development of secondary effects that required drug withdrawal the 6 first months after initiating tocilizumab therapy. <h3>Methods</h3> Forty-six rheumatoid arthritis patients treated with tocilizumab in routine clinical practice were retrospectively evaluated 24 weeks after initiating therapy. Demographic and clinical data, complete blood cell counts, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), titers of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies, serum cytokines (IL-6, IL-15 and IL-17) and the frequency of activated CD4+, CD8+ and Treg cells were collected before tocilizumab administration (baseline). Characteristics of patients with and without adverse effects were compared. <h3>Results</h3> Twelve (26.1%) patients developed adverse effects that required drug withdrawal during the first six months of tocilizumab therapy. Seven patients suffered an allergic or infusional reaction and two patients had neutropenia. All recovered after drug withdrawal. Two further patients suffered an infection requiring hospitalization (salpingitis and periappendiceal abscess) and one patient had a myocardial infarction. Patients with and without adverse effects had comparable ages and disease evolution. Patients with adverse effects had lower neutrophil counts (4.1±2.6 vs 5.6±1.8, p&lt;0.05) and lower DAS28-CRP (5.1±1.2 vs 4.3±1.2, p&lt;0.05) at baseline than those without. No significant differences in IgG, IgM and IgA were observed between the two groups. However, fewer patients with higher CRP, titers of anti-CCP antibodies, or serum concentrations of IL-6 and IL-15 were observed in the group with adverse effects (Table 1). There were no differences in the frequency of T cell subsets and Tregs between patients with and without adverse effects before the treatment. <h3>Conclusions</h3> Patients with adverse effects presented fewer prognostic markers of severe disease. Higher levels of some markers (CRP, anti-CCP antibodies, IL-6, IL-15 and neutrophil counts) may identify patients less likely to suffer adverse effects due to tocilizumab therapy. <h3>Disclosure of Interest</h3> None Declared
ASSOCIATION OF MYOCARDIAL FIBROSIS ON CARDIAC MRI AND RISK FACTORS OF SUDDEN CARDIAC DEATH IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY
Authors: Sang-Chol Lee, Eun Kyung Kim, Sung A Chang, Shin Yi Chang, Eun Jeong Cho, Ji Won Hwang, Sung Mok Kim, Sung Ji Park, Jin Oh Choi, Seung Woo Park, Yeon Hyeon Choe, Jae Oh
Journal: Journal of the American College of Cardiology (2015)
P771Molecular model confirms experimental differences on polarization second harmonic signal from cardiac myosin isoforms
Authors: I Amat-Roldan, I Torre, P K Luther
Journal: Cardiovascular Research (2014)

Contraction in muscle occurs by the relative sliding of thick and thin filaments. The thick filaments are composed by myosin molecules, of which two main isoforms have been found in ventricles, the alpha- and beta-myosin heavy chain (MHC) homodimers. The expression of the two MHCs is developmentally regulated and controlled by numerous stimuli. Polarization Second Harmonic Generation (PSHG) enables the computation of the average helical pitch angle of peptides (AHPAP) of a number of proteins arranged in a fiber structure, like collagen or myosin. AHPAP of these proteins has been used to discriminate them in tissue. We also reported that AHPAP of cardiac tissue correlates consistently with aging of cardiac LV in rabbits and beta-MHC distribution. This study reports a molecular model based on public DNA sequences that directly explains the experimental differences of AHPAP of unlabeled histological sections of cardiac tissue expressing different MHC isoforms. We computed all second-order tensor elements from the 3D molecular distribution of peptides and its associated hyperpolarizability of the S2 subfragment of the rod domain of MHC for different isoforms, species and mutations: for human, MYH6 (alpha), MYH7 (beta) and E924K mutation; for mouse, MYH6 and MYH7; for rabbit, MYH7. Based on a reported biophysical model we computed the expected AHPAP for each isoform and species. We finally acquired PSHG images of transversal histological sections in three animal models: healthy mouse, which naturally expresses MYH6; a mouse fed a iodine-deficient diet containing 0.15% 6-propyl-2-thiouracil for 4 weeks which induces hyperthyroidism and subsequent shift to MYH7, and 1 year old rabbit which naturally expresses 95% of MYH7 of the heart myosin. We also computed the average AHPAP for the experimental data. We found agreement between experimental PSHG calculations and molecular model of 3D protein structure: for mouse, MYH6: 67,8° and 67,4°, MYH7: 71,3° and 71,2°; for rabbit MYH7: 73,3° and 72,5°. We then extended our results to 3D protein models of human isoforms and mutations: MYH6: 73,3°, MYH7: 63,7°, and E924K mutation: 66,0°. This study supports the hypothesis that PSHG can measure subtle differences in molecular structure of myosin that are available only through much more complex techniques (i.e. crystallography). We report a direct explanation for the experimental differences in PSHG signal. This suggests that PSHG can provide in-situ and in-vivo tissue information that might help to quantify the expression and spatial distribution of myosin isoforms and mutations in tissue.
NATIONAL TRENDS AND OUTCOMES IN DIALYSIS REQUIRING ACUTE KIDNEY INJURY AFTER PERCUTANEOUS CORONARY INTERVENTION AFTER ACUTE MYOCARDIAL INFARCTION
Authors: Bhavi Pandya, Achint Patel, Neil Joshi, Armaghan Soomro, Jonathan Spagnola, Pranav Garimella, Girish Nadkarni, Suzanne El-Sayegh, James Lafferty
Journal: Journal of the American College of Cardiology (2016)
Abstract P4-12-03: Towards a risk prediction model for breast cancer that utilizes breast tissue risk features
Authors: VS Pankratz, AC Degnim, DW Visscher, RD Frank, RA Vierkant, K Ghosh, N Aziza, CM Vachon, M Frost, DC Radisky, LC Hartmann
Journal: Cancer Research (2012)

Abstract Background: Optimal early detection and prevention strategies for breast cancer are predicated on our ability to accurately identify women at increased risk for disease. Current breast cancer risk prediction models rely on clinical and epidemiologic features. As demonstrated with other cancers, such as those of the cervix and colon, cancer risk assessment is enhanced when the tissue at risk is examined for evidence of premalignant abnormalities. Here, we present a multivariate model for individualized breast cancer risk prediction that incorporates tissue features identified from biopsies from women with benign breast disease (BBD). Methods: We used our cohort of more than 9000 women diagnosed with BBD at the Mayo Clinic from 1967–1991, and identified a nested case:control series of 377 women who developed cancer (cases) matched with 734 women who did not (controls). We identified a set of variables that either alone or in two-way interactions contributed to a multivariable risk prediction model. We combined this relative risk model with the baseline incidence of breast cancer and the baseline hazard of death from our full BBD cohort to develop a risk prediction tool that computes absolute risk estimates for breast cancer. We calculated 5-year risk predictions for these cases and controls using our model and using the Gail model and compared c-statistics from these risk predictions. We validated our model using an independent set of 378 breast cancer cases and 728 matched controls drawn from our BBD cohort. Results: Cases and controls in the model development data set differed significantly on a number of features when examined individually. Those included in a multivariable relative risk model for breast cancer among women with BBD are shown below. After including interactions between lobular involution, and histologic impression, with age at first live birth/number of children, and degree of involution with sclerosing adenosis, we devised a model that predicts the absolute risk of breast cancer. Predicted five-year risks in the model development series, we observed a c-statistic of 0.66, higher than the c-statistic of 0.61 for the Gail model. With risk prediction estimates from our validation series of cases and matched controls, the c-statistic of our model decreased to 0.59 and the c-statistic for the Gail model was 0.55. Conclusion: We have identified an initial risk prediction model for breast cancer in women with BBD. The identified model includes basic demographic information as well as a number of histologic features of the tissue samples. Its initial performance is promising, providing improved discrimination over the Gail model in our replication data set. Further work is needed to identify features which might provide additional predictive information for breast cancer risk. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-12-03.
P92 Miliary tuberculosis: data from a modern case-series in the United Kingdom
Authors: N Venkatraman, T King, G Woltmann, MJ Wiselka, D Bell, M Pareek
Journal: Thorax (2013)

<h3>Background</h3> Miliary tuberculosis (mTB), a severe manifestation of TB is classically associated with a high mortality. Modern data on the management and outcomes of mTB in developed world settings are lacking. We reviewed clinico-bacteriological features of mTB cases presenting to a teaching hospital in Leicester, UK serving an ethnically diverse population. <h3>Methods</h3> Retrospective descriptive case-series of all notified mTB cases admitted between 2007 and 2012. <h3>Results</h3> 41 cases were identified; median age 47 years (IQR:29–65 years), 61% were male and 80.5% patients were of Indian-Subcontinent origin. 92.5% of patients were foreign-born and median time between UK arrival and diagnosis was 4 years (IQR:1–10 years). 37(90.2%) patients had an HIV test; 4 were positive (median CD4 count 60;IQR 30–140). Weight loss (87.2%) and fevers (82.9%) were the most common presenting symptoms. 30 patients (73.2%) had abnormal examination findings; predominantly respiratory (63.3%). Initial bloods were diagnostically nonspecific apart from lymphopaenia and depressed lymphocyte:monocyte ratio. All patients had radiological evidence of pulmonary miliary nodules. 28/41(68.3%) patients had neuroimaging: 14/28(50%) had neuroradiological involvement–predominantly tuberculomas (12/28–42.9%). Lumbar punctures were undertaken in 73.2% of patients but only abnormal in 5 patients (17.2%) (and only 1 with normal imaging). Overall, 16(39%) patients had evidence of CNS involvement. 32/41(78.1%) patients were culture positive (all fully-sensitive) with sputum and BAL providing the highest yield. Antituberculous therapy was commenced within a median of 1 day following hospital admission. To date, 30 patients have successfully completed treatment, 3 are still on treatment, 5 have moved away and 3(7.3%) have died. In those subjects who successfully completed therapy, the lymphocyte:monocyte ratio increased significantly (p = 0.0201). Patients who died had a longer duration between admission and commencing antituberculous treatment (median 8 days; IQR 1–16 days), than those who successfully completed treatment (median 1 day; IQR 0–3 days). <h3>Conclusions</h3> In this developed world setting, mTB is not an uncommon presentation. Although there was a high prevalence of co-existing neurological involvement, overall mortality was low. Undertaking diagnostic procedures for culture is important and has a high yield. Early treatment may have resulted in improved outcomes and the lymphocyte:monocyte ratio may help to monitor response to treatment in miliary TB.
STEM- AND PROGENITOR-LIKE CELL CONTRIBUTION TO MALIGNANT ASTROCYTOMA HETEROGENEITY
Authors: C. Petritsch, R. Lerner, K. Lewis, N. Andor, T. Ozawa, Y. Yoshida, M. McMahon, T. Nicolaides, C. David James
Journal: Neuro-Oncology (2014)

BACKGROUND: Stem-like tumor propagating cells (TPCs) isolated from malignant astrocytoma (MA) are reportedly therapy-resistant. In contrast, progenitor-like TPCs with loss of asymmetric cell division (Cancer Cell. 20:328-40; 2011) are sensitive to temozolomide (Cancer Cell. 18:669-82; 2010). In a pediatric MA subset, an activating BRAFT1799A mutation leads to expression of hyperactivated BRafV600E kinase, and occurs with deletion of the cell cycle inhibitor CDKN2A (Cancer Res. 70:512-9; 2010). BRAFV600E-targeted therapies, including PLX4720, retard the growth of intracranial BRAFV600E MA xenografts (Clin. Cancer Res. 17:7595-604; 2011). Studies suggest that TPCs defined by current methods are not a homogeneous population and may contain subpopulations that respond differently to treatment. The divergent effects of targeted therapies on heterogeneous TPCs have yet to be explored. METHODS: Stem-like (CD133+) and progenitor-like (NG2+) cells were isolated from human MA cell lines and murine neurosphere cells with BRafV600E expression and Ink4a/Arf (CDKN2A) deletion. CD133+ and NG2+ cells labeled with proliferation markers were investigated for heterogeneity in cell cycle dynamics and division modes. Viability assays were used to determine PLX4720 IC50s, and RT-PCR was used to analyze cell cycle and polarity regulator gene expression. Pharmacological modulators of genes altered in NG2+ and CD133+ cells were tested alongside PLX4720 for anti-tumor efficacy in intracranial BRAFV600E MA xenografts. RESULTS: In murine CD133+ cells with BRafV600E expression and CDKN2A deletion, a low proliferation frequency and high rate of asymmetric division associate with reduced sensitivity to PLX4720-induced G1 arrest. Human CD133+ but not isogenic NG2+ cells have differential mRNA expression of G2-specific cell cycle regulators. Concurrently, CD133+ cells exhibit enhanced sensitivity to blockade of polo-like-kinase1 (PLK1), a cell cycle and polarity regulator. Results from ongoing analyses of the distinct proliferative capacities, cell cycle dynamics, cell division mode and responses to targeted BRafV600E and PLK1 inhibition of CD133+ and NG2+ MA cells will be presented. CONCLUSIONS: Our studies revealed that murine malignant astrocytoma TPCs are phenotypically and functionally heterogeneous. We further discovered a TPC-subpopulation specific therapy response, where CD133+ cells from malignant astrocytoma cell lines are more resistant to BRafV600E targeted inhibition but more sensitive to G2/M checkpoint kinase inhibition than NG2+ cells. This provides a potential mechanistic basis for the differential responses of stem and progenitor-like TPCs to treatment. Understanding why current treatment strategies preferentially target only certain cell-types will allow intelligent design of chemotherapeutic strategies with greater anti-tumor effects. SECONDARY CATEGORY: n/a.
PTU-092 Patient And Professionals Perceptions Of Travel Behaviour In Inflammatory Bowel Disease
Authors: J-P Mulligan, K Greveson, T Shepherd, M Hamilton, CD Murray
Journal: Gut (2014)

<h3>Introduction</h3> Travellers with inflammatory bowel disease (IBD) are at greater risk of travel-related morbidity.<sup>1</sup> ECCO recommend patients seek expert advice prior to travel, including information on vaccination and obtaining antibiotics for self-treatment of travellers diarrhoea.<sup>2</sup> Wasan <i>et al.</i> report only 3.5% of patients on immunosuppression therapy were counselled on avoiding particular live vaccines<sup>3</sup> and 30% of gastroenterologists would erroneously recommend live vaccines.<sup>4</sup> <h3>Methods</h3> We explored both patient and gastroenterology health care professionals (HCP) perceptions of IBD and travel: whether disease affected travel, interventions people took to travel, and whether ECCO guidelines were being followed. IBD patients attending our IBD clinic during November 2013 were asked to complete a questionnaire collecting demographic, disease specific and travel related information. Using N-ECCO and RCN IBD nurse network databases, HCP were asked to complete online questionnaire collecting information on perceptions of IBD and travel, confidence at providing travel advice, and the content of that advice. <h3>Results</h3> 136 IBD patients (67[49%] Crohn’s disease, 60[44%] male, median age 38 years[range 18–85]) and 105 HCP (98/105[93%] nurse specialists, 6/105[6%] consultant, 1/105[1%] registrar) responded. 85%[106/136] patients report feeling adequately prepared for travel, although only 24%[32/136] seek travel medical advice of any kind and only 11%[15/136] from the IBD team; all despite 60%[82/136] reporting their IBD affected travel. Despite recommendations, only 4%[5/136] had been prescribed antibiotics for self-medication of travellers diarrhoea. 52%[36/69] of immunosuppressed patients are unaware they should avoid live vaccines. 39%[53/136] patients buy travel insurance covering IBD, 70%[37/53] of which pay a premium. 70%[74/105] HCP felt IBD might limit travel in patients. 70%[74/105] HCP are confident giving travel advice, but 51%[38/74] refer them to a travel clinic. 90%[94/105] are confident giving advice on travellers diarrhoea, but only 54%[57/105] on vaccinations and 40%[42/105] on insurance. <h3>Conclusion</h3> Patients travel is affected by IBD, however, few seek expert medical advice prior to travel. HCP agree IBD affects travel and a majority are confident giving limited advice. It is concerning 52% of immunosuppressed patients are unaware they should avoid live vaccines, and only 54% of HCP are confident giving advice on vaccinations. Results support the need for further travel specific research and better education in both groups. <h3>References</h3> Soonwala <i>et al</i>. <i>Inflamm Bowel Dis</i> 2012;18(11):2079–85 Rahier <i>et al</i>. <i>Journal of Crohn’s and Colitis</i> 2009;3(2):47–91 Wasan <i>et al</i>. <i>Inflamm Bowel Dis</i> 2014;20(2):246–50 Wasan <i>et al</i>. <i>Inflamm Bowel Dis </i>2011;17(12):2536–60 <h3>Disclosure of Interest</h3> None Declared.
Britain launches pilot screening programme for chlamydia
Authors: H. Bower
Journal: BMJ (1998)

Two pilots schemes are to test whether a national screening programme for the sexually transmitted disease caused by Chlamydia trachomatis should be introduced in Britain.

The launch of the projects, which involve opportunistic screening by GPs and family planning clinics, follows a report by Department of Health experts who believe the infection is spreading exponentially, particularly among young sexually active people. Largely asymptomatic, C trachomatis infects men and women equally but has more severe long term consequences for women. It is thought to be the principal preventable cause of pelvic inflammatory disease, which is strongly linked to infertility, ectopic pregnancy, and chronic pelvic pain. Some studies have shown pelvic inflammatory disease to be a causal factor in 50% of female infertility.

Launching the £0.5m …