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Cancer is considered one of the leading causes of death in the United States. Although preventive strategies, early detection, and improved treatment options have been developed, novel targets and therapeutics are still needed. Since concluding that cancer is mediated by genetic and epigenetic alterations of the cell, many research groups are now focusing on other means of prevention and therapy via nutrition, epigenetic mechanisms, and non-coding RNAs which have been shown to control gene expression and have many different functions at the cellular level. With the advent of high-throughput sequencing in human cancer, the potential to identify novel biomarkers and therapeutic targets of disease has increased tremendously and led to the identification of many non-coding RNAs that are dysregulated in various cancers. Gene expression and regulation is important in maintaining the homeostasis of normal tissues and cells. Not uncommonly, up- or down-regulation of particular genes are associated with cancer as a result of increased or decreased expression of transcriptional targets. This review focuses on the role of nutrition in cancer and the dysregulation of non-coding RNAs with particular emphasis on long non-coding RNAs and microRNAs in different cancer types.

Optimity Advisors conducted the study “Health system performance assessment – Integrated Care Assessment”, commissioned by Chafea and DG SANTE, assessing: (i) the state of integrated care (IC) implementation in the EU28 Member States, Norway and Iceland; and (ii) developing an evidence-based Integrated Care Performance Assessment (ICPA) framework. The framework, supported by an Excel tool, was co-designed with stakeholders across Europe. The ICPA tool will be tested by members of the European Innovation Partnership on Active and Healthy Ageing (EIPonAHA), B3 Action Group on Integrated Care. From a review of literature in 24 languages, an extensive mapping of 560 IC initiatives in 30 countries and the maturity assessment of 12 health systems, we inferred that IC strategies, policies, models and projects are present across Europe, but their characteristics, depth and breadth of integration vary considerably. Taking this heterogeneity into account, the framework was co-designed drawing on user-centred design and agile methodologies. Following an iterative approach with regular stakeholder engagement (questionnaires, video-conferences, peer-review webinars, presentations at events, and a validation workshop), experts and practitioners helped us determine which indicators sourced from existing performance assessment frameworks were considered “core” to IC assessment, with the rest proposed as “optional” indicators in the performance assessment model. The core indicators selected were categorised under four domains -Advancement of integration; Use of care services; Health outcomes; Experiences of care- with a fifth overarching domain considering financial issues. Indicators have been re-worded and re-defined to make them applicable across the wealth of IC initiatives while offering measures for international comparison. The heterogeneity of the context in which IC initiatives operate in Europe was a key challenge for the development of a framework that had to be relevant and potentially used in all included countries. This was addressed by providing an additional Excel-based ICPA tool offering flexibility in the use of the framework and allowing users to adapt indicators to their context. The tool allows users to compare performance to a set target for each indicator in the ICPA framework. The use of the ICPA framework and tool will help healthcare systems across Europe to further develop their IC system - based on their current state and context - and could significantly help them achieve better health outcomes and care experiences. The use of user-centred design and agile methodologies are proved methods of finding useful solutions to common challenges. Our research indicates that these principles also apply in the area of health performance assessment and can support IC implementation. Without user engagement, there was a risk that the output of the study would not provide the value sought. As IC evolves, the framework will need to be updated and adapted to new circumstances. Further user engagement and testing is recommended to ensure usability. With the research concluded, the framework and tool will need to be tested in practice through the involvement of members of the B3 Action Group of the EIPonAHA. Preliminary results will be resented at ICIC19. A web-based tool could facilitate uptake and data collection and analysis.

Alternative splicing (AS), a tightly regulated process, contributes to proteome diversification essential for tissue development and identity. During brain development, splicing targets include genes involved in several cellular processes like endocytosis, cytoskeleton dynamics and vesicle-mediated transport. Deregulation of AS in cancers enables tumor cells to alter the transcriptome in favor of isoforms that drive tumor progression. Annexin A7 (ANXA7) is a hydrophilic protein that binds membranes in a calcium-dependent manner; it is important for membrane scaffolding and vesicle trafficking. ANXA7 is alternatively spliced by PTBP1 and expressed as two isoforms - unspliced ANXA7 Isoform 1 (I1), containing cassette exon 6 and spliced Isoform 2 (I2). We determined that this splicing of ANXA7 is lineage-specific in the brain - I1 is highly expressed in post-mitotic mature neurons while I2 is expressed in neural and glial precursors. In order to understand the functional impact of these isoforms, we generated GBM cell lines that express endogenous I2 (I2 cells), or endogenous I2 + exogenous I1 (I1 cells). We evaluated the influence of I1 and/or I2 expression on RTK levels, activation and downstream events using western blot and co-immunoprecipitation assays. Receptor trafficking was observed using flow cytometry and immunofluorescence assays tagging different components of the endocytic pathway. In GBM, we observed high levels of PTBP1 with a subsequent increase in I2 levels indicative of dysregulated AS. Consequently, we observed upregulated activation of several receptor tyrosine kinases (RTKs) such as EGFR, MET, PDGFRα and EGFR vIII in the I2 cells. In I1 cells, however, we observed reduced levels and activation of all aforementioned RTKs along with the diminished activation of downstream pathways. Using EGFR signaling as a model, we found that in I1 cells EGFR co-localized with markers of lysosomal degradation indicating efficient trafficking of activated EGFR for endosomal degradation; co-localization was absent in I2 cells indicative of impaired trafficking. We propose that I1, by virtue of the amino acids encoded by cassette exon 6, binds to conserved motifs within multiple RTKs and targets them for endosomal degradation thereby attenuating tumorigenic signaling in GBM. Our results show that ANXA7 I1 is tumor suppressive in GBM and that loss of I1 promotes tumorigenicity by perpetuating RTK signaling. We present a mechanism that explains, in part, how I1 mediates the degradation of multiple tumorigenic RTKs by spatio-temporally regulating their endosomal trafficking. A refined understanding of how I1 functions will provide the foundation for future, selective therapies that target dysregulated AS in GBM. Citation Format: Sindhu Nair, Rajani Rajbhandari, Centdrika Dates-Hurt, Markus Bredel. Dysregulated splicing of Annexin A7 impairs receptor tyrosine kinase trafficking in glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3747.

Purpose/Objective(s): Glioblastomas (GBM) are highly malignant tumors that arise from astrocytes. GBMs rely on signaling through receptor tyrosine kinases (RTK) to ensure tumorigenicity. EGFR, PDGFRA and MET are distinct RTKs; each is capable of binding a ligand, which promotes receptor dimerization and kinase activation. Annexin A7 (ANXA7), a protein involved in membrane binding and vesicle trafficking, is spliced into 2 isoforms - isoforms 1 (I1) and isoform 2 (I2). A normal adult brain will express both isoforms, however, in GBM, I1 expression is prevented. We determined that I1, but not I2, is tumor suppressive, in part, because it promotes the endocytic degradation of EGFR. Because I1 is typically not expressed in GBM, EGFR signaling persists unabated and tumors thrive. Recently, we extended these observations and determined that I1 also impacts additional RTKs, including PDGFRA and MET. By understanding how ANXA7 I1 impacts PDGFRA and MET signaling, we hope to target multiple tumorigenic RTKs and improve therapy for patients with GBM. Materials/Methods: To understand how and when I1 downregulates PDGFRα and MET, U251-malignant glioma (MG) cells, which only express I2 (P), were modified to express I1. Cells were serum starved overnight, and then stimulated with PDGFAA and HGF(20 ng/ml), which activate the aforementioned receptors respectively. As a positive control, cells were stimulated with EGF to activate EGFR. Total protein was then collected and analyzed by western blot analyses. Next, we sought to determine whether I1 was competent to down-regulate several RTKs coincidentally. To do this, P and I1 cells were serum starved, stimulated with EGF, PDGFAA or both, and total protein levels were evaluated. Results: The levels of activated EGFR, PDGFRα and MET are dramatically reduced in those cells that express I1 as compared to cells expressing I2 (P). Upon activation with both PDGFAA and EGF, in cells expressing I1 (I1), levels of PDGFRα and EGFR were markedly reduced 30 minutes post-stimulation as compared to cells expressing I2. Conclusion: Our results suggest I1 may be a master regulator of RTK endocytosis and degradation. Further investigations of the impact of I1 on endocytic trafficking patterns using immunofluorescence and confocal microscopy are underway. Collectively, understanding how I1 functions and targets multiple tumorigenic RTKs will provide the foundation for future selective therapies that restore I1 expression in GBM and reduce tumorigenicity. Citation Format: Zachary B. White, Centdrika Dates Hurt, Rajani Rajbhandari, Sindhu Nair, Susan Nozell, Markus Bredel. Impact of ANXA7 I1 expression on PDGFRA and MET endosomal trafficking in glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3758.

Dysregulation of receptor tyrosine kinase genes is a frequent genetic abnormality in GBM. A common genetic alteration is amplification and/or overexpression of the epidermal growth factor receptor (EGFR) gene. Annexin A7 (ANXA7) is a hydrophilic protein that binds membranes in a calcium dependent manner; it is important for membrane scaffolding and vesicle trafficking. ANXA7 is alternatively spliced and expressed as two isoforms – unspliced ANXA7 Isoform 1 (I1), containing cassette exon 6 and spliced Isoform 2 (I2). Our lab has determined that I1 is tumor suppressive in GBM and that loss of I1 promotes tumorigenicity by perpetuating EGFR signaling. However, if restored, I1 but not I2, reduces EGFR levels, activation and downstream pathways and diminishes tumorigenicity. In patients, I1 levels directly correlate with survival and prognosis. We propose that I1 inhibits EGFR signalling by binding to and promoting degradation of EGFR in a calcium dependent manner. In GBM, I1 is absent, preventing endosomal degradation of EGFR and leading to perpetual signalling. Our approach is novel; rather than address how/whether EGFR is activated, we focus on why EGFR fails to be downregulated afterwards. Herein, we present a mechanism that explains, in part, how I1 mediates endosomal degradation of EGFR. Further studies are underway to identify exactly where and how I1 modifies endosomal trafficking and degradation of EGFR. We are also exploring the role of I1 in regulating the degradation of other receptor tyrosine kinases (RTKs), such as MET and PDGFRA. Collectively, understanding how I1 functions will provide the foundation for future, selective therapies that restore I1 expression and/or function to reduce GBM tumorigenicity.

Background: Funded by the Third EU Public Health Programme, Optimity Advisors has followed up on the work carried out by the Health System Performance Assessment HSPA Expert Group in the development of an assessment framework for integrated care. The study conducted has assessed the level penetration and adoption of integrated care in the EU28, Norway and Iceland, and the level of maturity of several health systems at national, regional and local level. Through engagement with stakeholders in the integrated care field, a new, user-friendly framework for the performance assessment of integrated care has been co-developed and further validated by Optimity Advisors, DG SANTE i.e. Directorate-General for Health and Consumers of the European Union, CHAFEA Consumers, Health, Agriculture and Food Executive Agency and stakeholders across the integrated care community in the 28 Member States, Norway and Iceland. The Integrated Care Performance Assessment Framework was developed based on previously validated frameworks, such as the WHO 2015 framework People-centred and integrated health services: an overview of the evidence. Aims and Objectives: The main objective of this workshop will be to communicate the preliminary results and the experience of using the framework to assess the performance of a number of integrated care systems at local, regional and national level. Format: The agenda for the workshop will be as follows: Introduction to the methodological approach and preliminary outputs of the framework, by Optimity Advisors and DG SANTE; Presentation by one or two representatitves of integrated care projects who have contributed in the co-design of the framework explaining the design process; Demonstration of the use of the framework by representatitves of integrated care projects, who will show how to obtain a performance profile for integrated care systems; Group discussion on the different conditions in different health systems that can enhance, or limit the adoption of the framework, and on what could be done to minimise the barriers and maximise facilitating conditions; Conclusion by the facilitators on future steps to address the issues raised by the attendees, and final remarks. Target audience: We envision the target audience of the workshop to be comprised of individuals who have an integrated care performance assessment need, including health managers, policy makers, and other stakeholders that are directly involved in decision-making actions within integrated health systems. Learnings/Take away: By the end of the session, we expect attendees to i have an understanding of a new way to assess the performance of integrated care systems, ii develop a performance profile and actionable roadmap for performance improvement of an integrated care system of their choosing.

Increased aerobic glycolysis and de novo lipid biosynthesis are common characteristics of invasive cancers. UDP-glucuronosyltransferases (UGTs) are phase II drug metabolizing enzymes that in normal cells possess the ability to glucuronidate these lipids and speed their excretion; however, de-regulation of these enzymes in cancer cells can lead to an accumulation of bioactive lipids, which further fuels cancer progression. We hypothesize that UGT2B isoform expression is down-regulated in cancer cells and that exogenous re-introduction of these enzymes will reduce lipid content, change the cellular phenotype, and inhibit cancer cell proliferation. In this study, steady-state mRNA levels of UGT isoforms from the 2B family were measured using qPCR in 4 breast cancer and 5 pancreatic cancer cell lines. Expression plasmids for UGT2B isoforms known to glucuronidate cellular lipids, UGT2B4, 2B7, and 2B15 were transfected into MCF-7 and Panc-1 cells, and the cytotoxic effects of these enzymes were analyzed using trypan blue exclusion, annexin V/PI staining, TUNEL assays, and caspase-3 immunohistochemistry. There was a significant decrease in cell proliferation and a significant increase in the number of dead cells after transfection with each of the 3 UGT isoforms in both cell lines. Cellular lipids were also found to be significantly decreased after transfection. The results presented here support our hypothesis and emphasize the important role UGTs can play in cellular proliferation and lipid homeostasis. Evaluating the effect of UGT expression on the lipid levels in cancer cell lines can be relevant to understanding the complex regulation of cancer cells, identifying the roles of UGTs as “lipid-controllers” in cellular homeostasis, and illustrating their suitability as targets for future clinical therapy development.

Tamoxifen (Tam) is a selective estrogen receptor modulator used to inhibit breast tumor growth. Tam can be directly N-glucuronidated via the tertiary amine group or O-glucuronidated after cytochrome P450–mediated hydroxylation. In this study, the glucuronidation of Tam and its hydroxylated and/or chlorinated derivatives [4-hydroxytamoxifen (4OHTam), toremifene (Tor), and 4-hydroxytoremifene (4OHTor)] was examined using recombinant human UDP-glucuronosyltransferases (UGTs) from the 1A subfamily and human hepatic microsomes. Recombinant UGT1A4 catalyzed the formation of N-glucuronides of Tam and its derivatives and was the most active UGT enzyme toward these compounds. Therefore, it was hypothesized that single nucleotide polymorphisms (SNPs) in the promoter region of UGT1A4 have the ability to significantly decrease the glucuronidation rates of Tam metabolites in the human liver. In vitro activity of 64 genotyped human liver microsomes was used to determine the association between the UGT1A4 promoter and coding region SNPs and the glucuronidation rates of Tam, 4OHTam, Tor, and 4OHTor. Significant decreases in enzymatic activity were observed in microsomes for individuals heterozygous for −163G/A and −217T/G. These alterations in glucuronidation may lead to prolonged circulating half-lives and may potentially modify the effectiveness of these drugs in the treatment of breast cancer.

OBJECTIVE There is a dearth of empirical studies aimed at examining the impact of differential cultural adaptation of evidence-based clinical and prevention interventions. This prevention study consisted of a randomized controlled trial aimed at comparing the impact of 2 differentially culturally adapted versions of the evidence-based parenting intervention known as Parent Management Training, the Oregon Model (PMTOR). METHOD The sample consisted of 103 Latina/o immigrant families (190 individual parents). Each family was allocated to 1 of 3 conditions: (a) a culturally adapted PMTO (CA), (b) culturally adapted and enhanced PMTO (CE), and (c) a wait-list control. Measurements were implemented at baseline (T1), treatment completion (T2) and 6-month follow up (T3). RESULTS Multilevel growth modeling analyses indicated statistically significant improvements on parenting skills for fathers and mothers (main effect) at 6-month follow-up in both adapted interventions, when compared with the control condition. With regard to parent-reported child behaviors, child internalizing behaviors were significantly lower for both parents in the CE intervention (main effect), compared with control at 6-month follow-up. No main effect was found for child externalizing behaviors. However, a Parent × Condition effect was found indicating a significant reduction of child externalizing behaviors for CE fathers compared with CA and control fathers at posttest and 6-month follow-up. CONCLUSION Present findings indicate the value of differential cultural adaptation research designs and the importance of examining effects for both mothers and fathers, particularly when culturally focused and gender variables are considered for intervention design and implementation. (PsycINFO Database Record

The United States Department of Homeland Security has identified 16 critical infrastructure sectors that employ computing, technology and engineering students. However, most undergraduate curricula in these disciplines do not incorporate the fundamentals of critical infrastructure protection (CIP) into their curricula in a meaningful way. This paper describes the design, development, and usage of a modular curricular framework for integrating CIP into undergraduate programs via self-contained interdisciplinary course modules; a course module is a distinct curricular unit such as a lab or teaching component for use by an instructor in existing courses without requiring any course or program modifications. The framework is designed for use in multiple disciplines, and the modules are designed for presentation at different levels of the undergraduate experience, with subsequent modules built on those presented earlier. In addition, the paper discusses assessment results obtained from the validation of the framework and modules over the past three years that covered 345 students at the community college and university levels.

Water scarcity affects 1.2 billion people on a global scale, representing nearly one fifth of the human population. In some regions, current water sources are being depleted faster than they are renewed and the majority of this depletion is being used for irrigation and agricultural purposes. At any given time, the atmosphere contains 3400 trillion gallons of water vapor, which would be enough to cover the entire Earth in 1 inch of water. Herein, we describe the design of an innovative solution to water scarcity in regions with medium to high humidity — Atmospheric Water Generators (AWG). This device converts water vapor into liquid water and is designed for agricultural and irrigation purposes in regions where water scarcity exists. More specifically, two AWG concepts were developed by our team, one utilizing Peltier devices and the other a heat exchanger, in order to allow multiple design alternatives to be considered. The Peltier-based concept works by applying current to induce a temperature gradient in order to cool and condense the surrounding air. The heat exchanger concept works by cycling a coolant that is cooled by a lower ground temperature. Both AWG concepts were designed utilizing sustainable engineering principles to minimize energy consumption and cost (particularly when compared to AWGs currently on the market). The designs are estimated to create enough water daily to grow 2 fruit trees (1 gallon a week) at an example test condition of 60% relative humidity and 85°F.

Latinos constitute the largest ethnic minority group in the United States. However, the cultural adaptation and dissemination of evidence-based parenting interventions among Latino populations continues to be scarce despite extensive research that demonstrates the long-term positive effects of these interventions. The purpose of this article is threefold: (1) justify the importance of cultural adaptation research as a key strategy to disseminate efficacious interventions among Latinos, (2) describe the initial steps of a program of prevention research with Latino immigrants aimed at culturally adapting an evidence-based intervention informed by parent management training principles, and (3) discuss implications for advancing cultural adaptation prevention practice and research, based on the initial feasibility and cultural acceptability findings of the current investigation.

Tuberculosis (TB) and Human Immunodeficiency Virus (HIV) are two catastrophic diseases affecting millions of people worldwide every year, and are considered to be pandemic by the World Health Organization. This study aims to compare the recent trends in TB and HIV in the United States and Sub-Saharan African Countries. Data (incidence, prevalence and death rates of HIV and TB) for the United States, Cameroon, Nigeria, and South Africa were collected from The Joint United Nations Programme for HIV/AIDS (UNAIDS), US Census Bureau and World Health Organization (WHO) databases and analyzed using Statistical Analysis Software (SAS v 9.1). Analysis of Variance (ANOVA) was performed to compare the variables of interest between the countries and across time. Results showed that percent rates of TB cases, TB deaths, HIV cases and HIV deaths were significantly different (P P P < 0.001) in the prevalence of TB and HIV between the United States and the Sub-Saharan African countries, as well as differences within the Sub-Saharan African countries from 1993 to 2006. More analysis needs to be carried out in order to determine the prevalence and incidence of HIV and TB among multiple variables like gender, race, sexual orientation and age to get a comprehensive picture of the trends of HIV and TB.

The Assertive Community Treatment model (ACT) was developed more than 30 years ago to treat individuals with serious and persistent mental illness. This qualitative study highlights practical challenges encountered when establishing ACT teams in diverse settings serving people who are homeless with co-occurring mental and addictive disorders (COD). Program administrators and evaluators from nine programs located in seven states completed a survey on implementation challenges, fidelity, modifications to the ACT model, and program successes. Challenges encountered related largely to staffing and funding limitations as well as to difficulties with implementing the ACT model without modifications. Several modifications to the model were believed beneficial to recruiting and retaining consumers. These included emphasizing housing, adding staff positions not prescribed by ACT, implementing mini-teams within the program, delivering in-office services in a group format, and placing time-limited services by transi...

Fidelity rating of evidence-based practices ensures the implementation of interventions as intended and enhances the likelihood of replication of positive outcomes previously demonstrated. However, modifications have been necessary when a practice is adopted in settings or for populations other than those for which they were developed. This study reports fidelity findings for six programs implementing the Assertive Community Treatment model in different settings for adults who are homeless and who present with mental and addictive disorders, together with a methodology that can assist programs to achieve fidelity. Initial and final fidelity ratings using the Dartmouth Assertive Community Treatment Scale were collected from six programs. Findings indicate that while fidelity in programs can vary over time, core elements can be maintained, resulting in at least moderate fidelity in each program and modest overall increases across all programs combined with concomitant decreases in the variance of fidelity s...

An estimated 3.5 million people in the United States meet criteria for being homeless (National Law Center on Homelessness & Poverty, 2007), about 1.4% to 2% of the population (Greenberg & Rosenhec...