Contrasting roles of different mismatch repair proteins in basal-like breast cancer.

The mismatch repair (MMR) pathway is known as a tumor suppressive pathway and genes involved in MMR are commonly mutated in hereditary colorectal or other cancer types. However, the function of MMR genes/proteins in breast cancer progression and metastasis are largely unknown. We found that MSH2, but not MLH1, is highly enriched in basal-like breast cancer (BLBC) and that its protein expression is inversely correlated with overall survival time (OS). MSH2 expression is frequently elevated due to genomic amplification or gain-of-expression in BLBC, which results in increased MSH2 protein to pair with MSH6 (collectively referred to as MutSα). Genetic deletion of MSH2 or MLH1 results in a contrasting phenotype in metastasis, with MSH2-deletion leading to reduced metastasis and MLH1-deletion to enhanced liver or lung metastasis. Mechanistically, MSH2-deletion induces the expression of a panel of chemokines in BLBC via epigenetic and/or transcriptional regulation, which leads to an immune reactive tumor microenvironment (TME) and elevated immune cell infiltrations. MLH1 is not correlated with chemokine expression and/or immune cell infiltration in BLBC, but its deletion results in strong accumulation of neutrophils that are known for metastasis promotion. Our study supports the differential functions of MSH2 and MLH1 in BLBC progression and metastasis, which challenges the paradigm of the MMR pathway as a universal tumor suppressive mechanism.

CD177 modulates the function and homeostasis of tumor-infiltrating regulatory T cells.

Regulatory T (Treg) cells are one of the major immunosuppressive cell types in cancer and a potential target for immunotherapy, but targeting tumor-infiltrating (TI) Treg cells has been challenging. Here, using single-cell RNA sequencing of immune cells from renal clear cell carcinoma (ccRCC) patients, we identify two distinct transcriptional fates for TI Treg cells, Fate-1 and Fate-2. The Fate-1 signature is associated with a poorer prognosis in ccRCC and several other solid cancers. CD177, a cell surface protein normally expressed on neutrophil, is specifically expressed on Fate-1 TI Treg cells in several solid cancer types, but not on other TI or peripheral Treg cells. Mechanistically, blocking CD177 reduces the suppressive activity of Treg cells in vitro, while Treg-specific deletion of Cd177 leads to decreased tumor growth and reduced TI Treg frequency in mice. Our results thus uncover a functional CD177+ TI Treg population that may serve as a target for TI Treg-specific immunotherapy.

Evaluating the use of informational technologies by students of healthcare colleges for academic purposes over a five-year period.

This study aimed to assess the extent to which healthcare students use five informational technologies for daily academic purposes and to examine the changes in student perceptions toward these technologies over five years. This was a cross-sectional descriptive study in 10 different colleges in seven governorates. We conducted a survey using the instruments developed from the Technology Acceptance Model (TAM). The surveys were administered to convenience samples of students at the colleges of pharmacy, medicine, and dentistry in the participating universities. The survey was conducted three times over three different years: 2015, 2018, 2020. Five Information and Communication Technology components were included in the study: electronic course management (ECM), internet, computer, audio recording/commentary, and PowerPoint slides. The surveys were electronic and administered using Qualtrics Survey Software. For most respondents, the survey links were administered electronically via Facebook groups to convenience samples of students of the Bachelor programs. Kruskal-Wallis test was used to measure the difference among the three (years) surveys results. The multiple linear regression analysis was used to measure the associations between the five predictors of the TAM and the outcome variable (actual use of technology). There was a total of 3,113 valid surveys collected in 2015, 2018, and 2020. Nearly two thirds of participants were females. Most students did not have enough experience in using ECM before classes closure in March 2020. Lack of facilitating conditions and infrastructures like an expert technical support team and stable internet connections are negatively impacting students' acceptance of technology use in education. Moving from mainly face-to-face learning with partial electronic use in 2015 and 2018 to totally virtual learning in 2020 had a negative impact on the perceptions of healthcare college students of the five technologies across the five TAM domains (perceived usefulness, facilitating condition, ease of use, attitude toward use, intention to use) and the actual use of these technologies. The TAM successfully explained the factors influencing the actual use of technologies by healthcare college students. Continuing technical support and training can reduce students' electronic challenges. Technical status assessment needs to be done at the beginning, mid and end of the semester to evaluate the technical challenges facing students in online learning. The study tools are internationally adoptable to evaluate the student perceptions of the ICT implementation for research and academic annual assessment purposes.

Barriers to healthcare access for Arabic-speaking population in an English-speaking country.

OBJECTIVE: To identify barriers to healthcare access, to assess the health literacy levels of the foreign-born Arabic speaking population in Iowa, USA and to measure their prevalence of seeking preventive healthcare services. METHODS: A cross-sectional study of native Arabic speaking adults involved a focus group and an anonymous paper-based survey. The focus group and the Andersen Model were used to develop the survey questionnaire. The survey participants were customers at Arabic grocery stores, worshippers at the city mosque and patients at free University Clinic. Chi-square test was used to measure the relationship between the characteristics of survey participants and preventive healthcare services. Thematic analysis was used to analyze the focus group transcript. RESULTS: We received 196 completed surveys. Only half of the participants were considered to have good health literacy. More than one-third of the participants had no health insurance and less than half of them visit clinics regularly for preventive measures. Two participant enabling factors (health insurance and residency years) and one need factor (having chronic disease(s)) were found to significantly influence preventive physician visits. CONCLUSIONS: This theory-based study provides a tool that can be used in different Western countries where Arabic minority lives. Both the survey and the focus group agreed that lacking health insurance is the main barrier facing their access to healthcare services. The availability of an interpreter in the hospital is essential to help those with inadequate health literacy, particularly new arriving individuals. More free healthcare settings are needed in the county to take care of the increasing number of uninsured Arabic speaking patients.

Surface engineering tumor cells with adjuvant-loaded particles for use as cancer vaccines.

Cell surface engineering is an expanding field and whilst extensive research has been performed decorating cell surfaces with biomolecules, the engineering of cell surfaces with particles has been a largely unexploited area. This study reports on the assembly of cell-particle hybrids where irradiated tumor cells were surface engineered with adjuvant-loaded, biodegradable, biocompatible, polymeric particles, with the aim of generating a construct capable of functioning as a therapeutic cancer vaccine. Successfully assembled cell-particle hybrids presented here comprised either melanoma cells or prostate cancer cells stably adorned with Toll-like receptor-9 ligand-loaded particles using streptavidin-biotin cross-linking. Both cell-particle assemblies were tested in vivo for their potential as therapeutic cancer vaccines yielding promising therapeutic results for the prostate cancer model. The ramifications of results obtained for both tumor models are openly discussed.

Development and Evaluation of Biodegradable Particles Coloaded With Antigen and the Toll-Like Receptor Agonist, Pentaerythritol Lipid A, as a Cancer Vaccine.

Immune adjuvants are important components of current and prospective cancer vaccines. In this study, we aimed at evaluating the use of a synthetic lipid A derivative, pentaerythritol lipid A (PET lipid A), loaded into poly(lactic-co-glycolic acid) particles, as a potential cancer vaccine adjuvant. Poly(lactic-co-glycolic acid) particles (size range: 250-600 nm) were successfully formulated to include PET lipid A and/or the model tumor antigen, chicken ovalbumin (OVA). It was shown that particulated PET lipid A had a distinct advantage at promoting secretion of the immune potentiating cytokine, IL-12p70, and upregulating key costimulatory surface proteins, CD86 and CD40, in murine dendritic cells in vitro. In a murine tumor model, involving prophylactic vaccination with various permutations of soluble versus particulated formulations of OVA with or without PET lipid A, modest benefit was observed in terms of OVA-specific cell-mediated immune responses when PET lipid A was delivered in particles. These findings translated into a corresponding trend toward increased survival of mice challenged with OVA-expressing tumor cells (E.G7). In terms of translation of safe adjuvants into the clinic, these results promote the concept of delivering toll-like receptor-4 agonists in particles because doing so improves their adjuvant properties, while decreasing the chances of adverse effects due to off-target uptake by nonphagocytic cells.

Applying biodegradable particles to enhance cancer vaccine efficacy.

One of the primary goals of our group and our collaborators here at the University of Iowa is to develop therapeutic cancer vaccines using biodegradable and biocompatible polymer-based vectors. A major advantage of using discretely packaged immunogenic cargo over non-encapsulated vaccines is that they promote enhanced cellular immunity, a key requirement in achieving antitumor activity. We discuss the importance of co-encapsulation of tumor antigen and adjuvant, with specific focus on the synthetic oligonucleotide adjuvant, cytosine-phosphate-guanine oligodeoxynucleotides. We also discuss our research using a variety of polymers including poly(α-hydroxy acids) and polyanhydrides, with the aim of determining the effect that parameters, such as size and polymer type, can have on prophylactic and therapeutic tumor vaccine formulation efficacy. Aside from their role as vaccine vectors per se, we also address the research currently underway in our group that utilizes more novel applications of biodegradable polymer-based particles in facilitating other types of immune-based therapies.