Guadecitabine, in combination with Cyclophosphamide, promotes anti- cancer immunity in BALB/c mice bearing 4T1 mouse mammary carcinoma

Background: The extremely high mortality rate of patients diagnosed with triple negative breast cancer makes it one of the deadliest forms of cancer. Due to the heterogenous nature of tumors, complete clearance is not achieved and clonal selection occurs resulting in tumor cells evading the immune system. I aim to design a therapeutic intervention that is able to elicit an effective immune response against the tumor and instill immunological memory to eradicate primary and metastatic lesions. I hypothesize that the combination of Guad and Cyp will synergize and promote anticancer immunity via increased expression of neo-tumor antigens and depletion of MDSCs and T-regs. Methods: Guadecitabine (Guad), is a second-generation DNA methyltransferase inhibitor (DMNTi) that has been reported to increase antigenicity and deplete myeloid-derived suppressor cells (MDSC’s). Cyclophosphamide (Cyp) is a chemotherapy that has been shown to deplete regulatory T-cells (T-regs). Both MDSD’s and T-regs suppress antitumor immunity. BALB/c mice were challenged with 4T1 tumor cells subcutaneously in the mammary fat pad region. 4T1-bearing mice were administered low-dose Guad and Cyp for ten consecutive days. Tumor growth curves, tumor-infiltrating lymphocytes (TILs) were measured and MDSC’s and T- regs levels were assessed by flow cytometry. Results: Results from this experiment showed significant synergy between Guad and Cyp with both drugs reducing the tumor size over monotherapy. Conclusions: Further analysis of the data along with future experiments will elucidate if this synergy is driven by the depletion of MDSC’s and T-regs alone or the increase in tumor antigenicity inducing increased numbers of TILs.https://scholarscompass.vcu.edu/gradposters/1078/thumbnail.jp

Independent and combined effects of improved water, sanitation, and hygiene, and improved complementary feeding, on child stunting and anaemia in rural Zimbabwe: a cluster-randomised trial.

BACKGROUND: Child stunting reduces survival and impairs neurodevelopment. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF) on stunting and anaemia in in Zimbabwe. METHODS: We did a cluster-randomised, community-based, 2 × 2 factorial trial in two rural districts in Zimbabwe. Clusters were defined as the catchment area of between one and four village health workers employed by the Zimbabwe Ministry of Health and Child Care. Women were eligible for inclusion if they permanently lived in clusters and were confirmed pregnant. Clusters were randomly assigned (1:1:1:1) to standard of care (52 clusters), IYCF (20 g of a small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counselling; 53 clusters), WASH (construction of a ventilated improved pit latrine, provision of two handwashing stations, liquid soap, chlorine, and play space plus hygiene counselling; 53 clusters), or IYCF plus WASH (53 clusters). A constrained randomisation technique was used to achieve balance across the groups for 14 variables related to geography, demography, water access, and community-level sanitation coverage. Masking of participants and fieldworkers was not possible. The primary outcomes were infant length-for-age Z score and haemoglobin concentrations at 18 months of age among children born to mothers who were HIV negative during pregnancy. These outcomes were analysed in the intention-to-treat population. We estimated the effects of the interventions by comparing the two IYCF groups with the two non-IYCF groups and the two WASH groups with the two non-WASH groups, except for outcomes that had an important statistical interaction between the interventions. This trial is registered with ClinicalTrials.gov, number NCT01824940. FINDINGS: Between Nov 22, 2012, and March 27, 2015, 5280 pregnant women were enrolled from 211 clusters. 3686 children born to HIV-negative mothers were assessed at age 18 months (884 in the standard of care group from 52 clusters, 893 in the IYCF group from 53 clusters, 918 in the WASH group from 53 clusters, and 991 in the IYCF plus WASH group from 51 clusters). In the IYCF intervention groups, the mean length-for-age Z score was 0·16 (95% CI 0·08-0·23) higher and the mean haemoglobin concentration was 2·03 g/L (1·28-2·79) higher than those in the non-IYCF intervention groups. The IYCF intervention reduced the number of stunted children from 620 (35%) of 1792 to 514 (27%) of 1879, and the number of children with anaemia from 245 (13·9%) of 1759 to 193 (10·5%) of 1845. The WASH intervention had no effect on either primary outcome. Neither intervention reduced the prevalence of diarrhoea at 12 or 18 months. No trial-related serious adverse events, and only three trial-related adverse events, were reported. INTERPRETATION: Household-level elementary WASH interventions implemented in rural areas in low-income countries are unlikely to reduce stunting or anaemia and might not reduce diarrhoea. Implementation of these WASH interventions in combination with IYCF interventions is unlikely to reduce stunting or anaemia more than implementation of IYCF alone. FUNDING: Bill & Melinda Gates Foundation, UK Department for International Development, Wellcome Trust, Swiss Development Cooperation, UNICEF, and US National Institutes of Health.The SHINE trial is funded by the Bill & Melinda Gates Foundation (OPP1021542 and OPP113707); UK Department for International Development; Wellcome Trust, UK (093768/Z/10/Z, 108065/Z/15/Z and 203905/Z/16/Z); Swiss Agency for Development and Cooperation; US National Institutes of Health (2R01HD060338-06); and UNICEF (PCA-2017-0002)

Diastolic Dysfunction and Health Status Outcomes After Transcatheter Aortic Valve Replacement

Background: Baseline left ventricular diastolic dysfunction (LVDD) is associated with poor health status in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement (TAVR), but health status improvement after TAVR appears similar across all grades of LVDD. Here, we aim to examine the relationship between changes in LVDD severity and health status outcomes following TAVR. Methods: Patients who underwent TAVR and had evaluable LVDD at both baseline and 1 year in the PARTNER (Placement of Aortic Transcatheter Valves) 2 SAPIEN 3 registries and PARTNER 3 trial were analyzed. LVDD grade was evaluated using echocardiography core lab data and an adapted definition of American Society of Echocardiography guidelines. Health status was assessed using the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score. The association between ΔLVDD severity and ΔKCCQ-OS was examined using linear regression models adjusted for baseline KCCQ-OS. Results: Of 1100 patients, 724 (65.8%), 283 (25.7%), and 93 (8.5%) had grade 0/1, 2, and 3 LVDD at baseline, respectively. At 1 year, LVDD severity was unchanged in 790 (71.8%) patients, improved in 189 (17.2%), and worsened in 121 (11.0%). Among 376 patients with baseline grade 2 or 3 LVDD, 50.3% had improvement in LVDD. In the overall cohort, KCCQ-OS score improved by 21.9 points at 1 year. There was a statistically significant association between change in LVDD severity (improved, unchanged, and worsened) and ΔKCCQ-OS at 1 year (p = 0.007). Conclusions: Change in LVDD grade was associated with change in health status 1 year following TAVR

Identification of genes associated with ovarian cancer metastasis using microarray expression analysis.

Although the transition from early- to advanced-stage ovarian cancer is a critical determinant of survival, little is known about the molecular underpinnings of ovarian metastasis. We hypothesize that microarray analysis of global gene expression patterns in primary ovarian cancer and metastatic omental implants can identify genes that underlie the metastatic process in epithelial ovarian cancer. We utilized Affymetrix U95Av2 microarrays to characterize the molecular alterations that underlie omental metastasis from 47 epithelial ovarian cancer samples collected from multiple sites in 20 patients undergoing primary surgical cytoreduction for advanced-stage (IIIC/IV) serous ovarian cancer. Fifty-six genes demonstrated differential expression between ovarian and omental samples (P \u3c 0.01), and twenty of these 56 differentially expressed genes have previously been implicated in metastasis, cell motility, or cytoskeletal function. Ten of the 56 genes are involved in p53 gene pathways. A Bayesian statistical tree analysis was used to identify a 27-gene expression pattern that could accurately predict the site of tumor (ovary versus omentum). This predictive model was evaluated using an external data set. Nine of the 27 predictive genes have previously been shown to be involved in oncogenesis and/or metastasis, and 10/27 genes have been implicated in p53 pathways. Microarray findings were validated by real-time quantitative PCR. We conclude that gene expression patterns that distinguish omental metastasis from primary epithelial ovarian cancer can be identified and that many of the genes have functions that are biologically consistent with a role in oncogenesis, metastasis, and p53 gene networks

Book of Abstracts: 2019 Health Equity Summer Research Summit Organized by the Center of Excellence in Health Equity, Training and Research, Baylor College of Medicine, Houston, Texas 77030, USA on June 18th, 2019

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