Type I Interferons Enhance the Repair of Ultraviolet Radiation-Induced DNA Damage and Regulate Cutaneous Immune Suppression.

Type I interferons (IFNs) are important enhancers of immune responses which are downregulated in human cancers, including skin cancer. Solar ultraviolet (UV) B radiation is a proven environmental carcinogen, and its exposure contributes to the high prevalence of skin cancer. The carcinogenic effects of UV light can be attributed to the formation of cyclobutane pyrimidine dimers (CPD) and errors in the repair and replication of DNA. Treatment with a single dose of UVB (100 mJ/cm2) upregulated IFNα and IFNß in the skin of C57BL/6 mice. IFNα and IFNß were predominantly produced by CD11b+ cells. In mice lacking the type I IFN receptor 1 (IFNAR1), the repair of CPD following cutaneous exposure to a single dose of UVB (100 mJ/cm2) was decreased. UVB induced the expression of the DNA repair gene xeroderma pigmentosum A (XPA) in wild-type (WT) mice. In contrast, such treatment in IFNAR1 (IFNAR1-/-) mice downregulated XPA. A local UVB regimen consisting of UVB radiation (150 mJ/cm2) for 4 days followed by sensitization with hapten 2,4, dinitrofluorobenzene (DNFB) resulted in significant suppression of immune responses in both WT and IFNAR1-/- mice. However, there were significantly higher CD4+CD25+Foxp3+ regulatory T-cells in the draining lymph nodes of IFNAR1-/- mice in comparison to WT mice. Overall, our studies reveal a previously unknown action of type I IFNs in the repair of photodamage and the prevention of UVB-induced immune suppression.

Learning from Black/African American Participants: Applying the Integrated Behavioral Model to Assess Recruitment Strategies for a Glaucoma Genetic Study.

The underrepresentation of African American (AA) participants in medical research perpetuates racial health disparities in the United States. Open-ended phone interviews were conducted with 50 AA adults from Philadelphia who had previously participated in a genetic study of glaucoma that included complimentary ophthalmic screenings. Recruitment for the genetic study was done in partnership with a Black-owned radio station. Thematic analysis of interview transcripts, guided by the integrated behavior model (IBM), identified self-reported motivations for participating in this care-focused and community-promoted research program. Findings revealed that decisions to enroll were influenced by strong instrumental attitudes regarding learning more about personal health and contributing to future care options for others. Notable normative influences that factored into participants' decisions to enroll in the study included hearing about the study from a respected community media outlet, friends, and family. About one-third of respondents discussed past and current racial discrimination in medical research as an important sociocultural frame within which they thought about participation, suggesting that experiential attitudes play a continuing role in AA's decisions to enroll in medical research studies. Medical researchers seeking to recruit AA participants should collaborate with community partners, combine enrollment opportunities with access to health services, and emphasize the potential for new research to mitigate racial inequalities.

Evaluation of a multimedia marketing campaign to engage African American patients in glaucoma screening.

Our objective was to determine which messaging approaches from a marketing campaign were most effective in recruiting African American individuals to a glaucoma screening and research study. We conducted a multimedia marketing campaign in Philadelphia from 01/31/2018 to 06/30/2018. Messaging approaches included radio advertisements and interviews (conducted in partnership with a local radio station with a large African American listener base), print materials, event tables, and online postings. Participants received free glaucoma screenings and the opportunity to enroll in our glaucoma genetics study. These screenings allowed individuals with glaucoma to receive a full examination and treatment plan with a glaucoma specialist, as well as to contribute to future efforts to identify genetic variants underlying this disease. We compared inquiry, enrollment, and cost yield for each messaging approach. Our campaign resulted in 154 unique inquiries, with 98 patients receiving glaucoma screenings (64%) and 60 patients enrolling in our study (39%). Commercials on WURD radio yielded the highest number of inquiries (62%) and enrollments (62%), but at relatively high cost ($814/enrolled patient). The most inexpensive approach that yielded more than five enrollments was postcards ($429/enrolled patient). Our campaign suggests that high-frequency commercials and postcards distributed at targeted healthcare locations are particularly effective and affordable options for connecting with the African American community. Our findings can help to inform recruitment efforts for other understudied diseases in minority populations.

Evidence for biochemical barrier restoration: Topical solenopsin analogs improve inflammation and acanthosis in the KC-Tie2 mouse model of psoriasis.

Psoriasis is a chronic inflammatory skin disease affecting 2.5-6 million patients in the United States. The cause of psoriasis remains unknown. Previous human and animal studies suggest that patients with a susceptible genetic background and some stimulus, such as barrier disruption, leads to a coordinated signaling events involving cytokines between keratinocytes, endothelial cells, T cells, macrophages and dendritic cells. Ceramides are endogenous skin lipids essential for maintaining skin barrier function and loss of ceramides may underlie inflammatory and premalignant skin. Ceramides act as a double-edged sword, promoting normal skin homeostasis in the native state, but can be metabolized to sphingosine-1-phosphate (S1P), linked to inflammation and tumorigenesis. To overcome this difficulty, we synthesized solenopsin analogs which biochemically act as ceramides, but cannot be metabolized to S1P. We assess their in vivo bioactivity in a well-established mouse model of psoriasis, the KC-Tie2 mouse. Topical solenopsin derivatives normalized cutaneous hyperplasia in this model, decreased T cell infiltration, interleukin (IL)-22 transcription, and reversed the upregulation of calprotectin and Toll-like receptor (TLR) 4 in inflamed skin. Finally, they stimulated interleukin (IL)-12 production in skin dendritic cells. Thus suggesting barrier restoration has both a biochemical and physical component, and both are necessary for optimal barrier restoration.

SIN3A and SIN3B differentially regulate breast cancer metastasis.

SIN3 corepressor complexes play important roles in both normal development and breast cancer. Mammalian cells have two paralogs of SIN3 (SIN3A and SIN3B) that are encoded by distinct genes and have unique functions in many developmental processes. However, specific roles for SIN3A and SIN3B in breast cancer progression have not been characterized. We generated stable knockdown cells of SIN3 paralogs individually and in combination using three non-overlapping shRNA. Stable knockdown of SIN3B caused a significant decrease in transwell invasion through Matrigel and decreased the number of invasive colonies when grown in a 3D extracellular matrix. Conversely, stable knockdown of SIN3A significantly increased transwell invasion and increased the number of invasive colonies. These results were corroborated in vivo in which SIN3B knockdown significantly decreased and SIN3A knockdown increased experimental lung metastases. RNA sequencing was used to identify unique targets and biological pathways that were altered upon knockdown of SIN3A compared to SIN3B. Additionally, we analyzed microarray data sets to identify correlations of SIN3A and SIN3B expression with survival in patients with breast cancer. These data sets indicated that high mRNA expression of SIN3A as well as low mRNA expression of SIN3B correlates with longer relapse free survival specifically in patients with triple negative breast cancer which corresponds with our in vitro and in vivo data. These results demonstrate key functional differences between SIN3 paralogs in regulating the process of breast cancer metastasis and suggest metastasis suppressive roles of SIN3A and metastasis promoting roles of SIN3B.

Increased autophagic response in a population of metastatic breast cancer cells.

Breast cancer cells are heterogeneous in their ability to invade and fully metastasize, and thus also in their capacity to survive the numerous stresses encountered throughout the multiple steps of the metastatic cascade. Considering the role of autophagy as a survival response to stress, the present study hypothesized that distinct populations of breast cancer cells may possess an altered autophagic capacity that influences their metastatic potential. It was observed that a metastatic breast cancer cell line, MDA-MB-231, that was sensitive to autophagic induction additionally possessed the ability to proliferate following nutrient deprivation. Furthermore, a selected subpopulation of these cells that survived multiple exposures to starvation conditions demonstrated a heightened response to autophagic induction compared to their parent cells. Although this subpopulation maintained a more grape-like pattern in three-dimensional culture compared to the extended spikes of the parent population, autophagic induction in this subpopulation elicited an invasive phenotype with extended spikes. Taken together, these results suggest that autophagic induction may contribute to the ability of distinct breast cancer cell populations to survive and invade.

Globular adiponectin enhances invasion in human breast cancer cells.

Every year, a large number of women succumb to metastatic breast cancer due to a lack of curative approaches for this disease. Adiponectin (AdipoQ) is the most abundant of the adipocyte-secreted adipokines. In recent years, there has been an interest in the use of AdipoQ and AdipoQ receptor agonists as therapeutic agents for the treatment of breast cancer. However, while multiple epidemiological studies have previously indicated that low levels of circulating plasma AdipoQ portend poor prognosis in patients with breast cancer, recent studies have reported that elevated expression levels of AdipoQ in breast tissue are correlated with advanced stages of the disease. Thus, the aim of the present study was to clarify the mechanism by which AdipoQ in breast tissue acts directly on tumor cells to regulate the early steps of breast cancer metastasis. In the present study, the effects of different AdipoQ isoforms on the metastatic potential of human breast cancer cells were investigated. The results revealed that globular adiponectin (gAd) promoted invasive cell morphology and significantly increased the migration and invasion abilities of breast cancer cells, whereas full-length adiponectin (fAd) had no effect on these cells. Additionally, gAd, but not fAd, increased the expression levels of microtubule-associated protein 1 light chain 3 beta (LC3B)-II and intracellular LC3B puncta, which are indicators of autophagosome formation, thus suggesting autophagic induction by gAd. Furthermore, the inhibition of autophagic function by autophagy-related protein 7 knockdown attenuated the gAd-induced increase in invasiveness in breast cancer cells. Therefore, the results of the present study suggested that a specific AdipoQ isoform may enhance breast cancer invasion, possibly via autophagic induction. Understanding the roles of the different AdipoQ isoforms as microenvironmental regulatory molecules may aid the development of effective AdipoQ-based treatments for breast cancer.

Executive control functioning and functional ability in older adults.

The manner in which executive control functioning exerts its influence on functional tasks was investigated. Sixty older adults were administered neuropsychological tasks tapping into four domains of executive control function, including working memory, planning, fluency, and flexibility. A test of performance-based functional ability also was administered. Correlational analyses demonstrated that working memory was most strongly associated with performance-based functional ability; however, impairment in planning appeared to best predict performance-based functional decrement in simultaneous regression models. Results highlight the role of planning in the maintenance of functional ability, as measured by performance-based functional measures.

Elevated methylmalonic acid is related to cognitive impairement in older adults enrolled in an elderly nutrition program.

Vitamin B12 status has been linked to cognitive impairment among older adults. Deficit in methylmalonic acid (MMA) may be reflective of cognitive impairment because it is a biochemically sensitive marker of B12 deficiency. In a cross-sectional study the contributions of different indices of B12 status, including serum B12, MMA and total homocysteine (tHcy), were measured in relation to cognitive functioning. B12 deficiency as measured by elevated MMA concentrations appeared to be most reflective of cognitive impairment and appeared to contribute unique variance to cognitive measures after controlling for other biochemical variables. Demographic variables, particularly education and age, were more strongly associated with cognitive measures than was MMA. Monitoring and reducing serum MMA concentrations by increasing the intake of vitamin B12 may provide protection against cognitive decline in this and other older populations.