Short peptides based on the conserved regions of MIEN1 protein exhibit anticancer activity by targeting the MIEN1 signaling pathway.

Migration and invasion enhancer 1 (MIEN1) overexpression characterizes several cancers and facilitates cancer cell migration and invasion. Leveraging conserved immunoreceptor tyrosine-based activation motif and prenylation motifs within MIEN1, we identified potent anticancer peptides. Among them, bioactive peptides LA3IK and RP-7 induced pronounced transcriptomic and protein expression changes at sub-IC50 concentrations. The peptides effectively inhibited genes and proteins driving cancer cell migration, invasion, and epithelial-mesenchymal transition pathways, concurrently suppressing epidermal growth factor-induced nuclear factor kappa B nuclear translocation in metastatic breast cancer cells. Specifically, peptides targeted the same signal transduction pathway initiated by MIEN1. Molecular docking and CD spectra indicated the formation of MIEN1-peptide complexes. The third-positioned isoleucine in LA3IK and CVIL motif in RP-7 were crucial for inhibiting breast cancer cell migration. This is evident from the limited migration inhibition observed when MDA-MB-231 cells were treated with scrambled peptides LA3IK SCR and RP-7 SCR. Additionally, LA3IK and RP-7 effectively suppressed tumor growth in an orthotopic breast cancer model. Notably, mice tolerated high intraperitoneal (ip) peptide doses of 90 mg/Kg well, surpassing significantly lower doses of 5 mg/Kg intravenously (iv) and 30 mg/Kg intraperitoneally (ip) used in both in vivo pharmacokinetic studies and orthotopic mouse model assays. D-isomers of LA3IK and RP-7 showed enhanced anticancer activity compared to their L-isomers. D-LA3IK remained stable in mouse plasma for 24 h with 75% remaining, exhibiting superior pharmacokinetic properties over D/L-RP-7. In summary, our findings mark the first report of short peptides based on MIEN1 protein sequence capable of inhibiting cancer signaling pathways, effectively impeding cancer progression both in vitro and in vivo.

Mitochondrial SOS: how mtDNA may act as a stress signal in Alzheimer's disease.

BACKGROUND: Alterations in mitochondrial DNA (mtDNA) levels have been observed in Alzheimer's disease and are an area of research that shows promise as a useful biomarker. It is well known that not only are the mitochondria a key player in producing energy for the cell, but they also are known to interact in other important intracellular processes as well as extracellular signaling and communication. BODY: This mini review explores how cells use mtDNA as a stress signal, particularly in Alzheimer's disease. We investigate the measurement of these mtDNA alterations, the mechanisms of mtDNA release, and the immunological effects from the release of these stress signals. CONCLUSION: Literature indicates a correlation between the release of mtDNA in Alzheimer's disease and increased immune responses, showing promise as a potential biomarker. However, several questions remain unanswered and there is great potential for future studies in this area.

Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American's metabolic risk for developing Alzheimer's disease.

Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk. Our results show that 8oxoG levels in both buffy coat and plasma were significantly associated with population, sex, years of education, and reveal a potential association with AD. Furthermore, MAs are significantly burdened by mtDNA oxidative damage in both blood fractions, which may contribute to their metabolic vulnerability to developing AD.

Integrative Blood-Based Characterization of Oxidative Mitochondrial DNA Damage Variants Implicates Mexican Americans' Metabolic Risk for Developing Alzheimer's Disease.

Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65+) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latinx population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk. Our results show that 8oxoG levels in both buffy coat and plasma were significantly associated with population, sex, years of education, and reveal a potential association with AD. Furthermore, MAs are significantly burdened by mtDNA oxidative damage in both blood fractions, which may contribute to their metabolic vulnerability to developing AD.

Nasal Tumor Vaccination Protects against Lung Tumor Development by Induction of Resident Effector and Memory Anti-Tumor Immune Responses.

Lung metastasis is a leading cause of cancer-related deaths. Here, we show that intranasal delivery of our engineered CpG-coated tumor antigen (Tag)-encapsulated nanoparticles (NPs)-nasal nano-vaccine-significantly reduced lung colonization by intravenous challenge of an extra-pulmonary tumor. Protection against tumor-cell lung colonization was linked to the induction of localized mucosal-associated effector and resident memory T cells as well as increased bronchiolar alveolar lavage-fluid IgA and serum IgG antibody responses. The nasal nano-vaccine-induced T-cell-mediated antitumor mucosal immune response was shown to increase tumor-specific production of IFN-γ and granzyme B by lung-derived CD8+ T cells. These findings demonstrate that our engineered nasal nano-vaccine has the potential to be used as a prophylactic approach prior to the seeding of tumors in the lungs, and thereby prevent overt lung metastases from existing extra pulmonary tumors.

Surgical Primary Tumor Resection Reduces Accumulation of CD11b+ Myeloid Cells in the Lungs Augmenting the Efficacy of an Intranasal Cancer Vaccination against Secondary Lung Metastasis.

A hallmark of effective cancer treatment is the prevention of tumor reoccurrence and metastasis to distal organs, which are responsible for most cancer deaths. However, primary tumor resection is expected to be curative as most solid tumors have been shown both experimentally and clinically to accelerate metastasis to distal organs including the lungs. In this study, we evaluated the efficacy of our engineered nasal nano-vaccine (CpG-NP-Tag) in reducing accelerated lung metastasis resulting from primary tumor resection. Cytosine-phosphate-guanine oligonucleotide [CpG ODN]-conjugated nanoparticle [NP] encapsulating tumor antigen [Tag] (CpG-NP-Tag) was manufactured and tested in vivo using a syngeneic mouse mammary tumor model following intranasal delivery. We found that our nasal nano-vaccine (CpG-NP-Tag), compared to control NPs administered after primary mammary tumor resection, significantly reduced lung metastasis in female BALB/c mice subjected to surgery (surgery mice). An evaluation of vaccine efficacy in both surgery and non-surgery mice revealed that primary tumor resection reduces CD11b+ monocyte-derived suppressor-like cell accumulation in the lungs, allowing increased infiltration of vaccine-elicited T cells (IFN-γ CD8+ T cells) in the lungs of surgery mice compared to non-surgery mice. These findings suggest that the combination of the target delivery of a nasal vaccine in conjunction with the standard surgery of primary tumors is a plausible adjunctive treatment against the establishment of lung metastasis.

Religious service attendance and mortality among older Black men.

Religious institutions have been responsive to the needs of Black men and other marginalized populations. Religious service attendance is a common practice that has been associated with stress management and extended longevity. The objective of this study was to examine the relationship between religious service attendance and all-cause mortality among Black men 50 years of age and older. Data for this study were from NHANES III (1988-1994). The analytic sample (n = 839) was restricted to participants at least 50 years of age at the time of interview who self-identified as Black and male. Mortality was the primary outcome for this study and the NHANES III Linked Mortality File was used to estimate race-specific, non-injury-related death rates using a probabilistic matching algorithm, linked to the National Death Index through December 31, 2015, providing up to 27 years follow-up. The primary independent variable was religious service attendance, a categorical variable indicating that participants attended religious services at least weekly, three or fewer times per month, or not at all. The mean age of participants was 63.6±0.3 years and 36.4% of sample members reported that they attended religious services one or more times per week, exceeding those attending three or fewer times per month (31.7%), or not at all (31.9%). Cox proportional hazard logistic regression models were estimated to determine the association between religious service attendance and mortality. Participants with the most frequent religious service attendance had a 47% reduction of all-cause mortality risk compared their peer who did not attend religious services at all (HR 0.53, CI 0.35-0.79) in the fully adjusted model including socioeconomic status, non-cardiovascular medical conditions, health behaviors, social support and allostatic load. Our findings underscore the potential salience of religiosity and spirituality for health in Black men, an understudied group where elevated risk factors are often present.

Variations of a group coaching intervention to support early-career biomedical researchers in Grant proposal development: a pragmatic, four-arm, group-randomized trial.

BACKGROUND: Funded grant proposals provide biomedical researchers with the resources needed to build their research programs, support trainees, and advance public health. Studies using National Institutes of Health (NIH) data have found that investigators from underrepresented groups in the biomedical workforce are awarded NIH research grants at disproportionately lower rates. Grant writing training initiatives are available, but there is a dearth of rigorous research to determine the effectiveness of such interventions and to discern their essential features. METHODS: This 2 × 2, unblinded, group-randomized study compares the effectiveness of variations of an NIH-focused, grant writing, group coaching intervention for biomedical postdoctoral fellows and early-career faculty. The key study outcomes are proposal submission rates and funding rates. Participants, drawn from across the United States, are enrolled as dyads with a self-selected scientific advisor in their content area, then placed into coaching groups led by senior NIH-funded investigators who are trained in the intervention's coaching practices. Target enrollment is 72 coaching groups of 4-5 dyads each. Groups are randomized to one of four intervention arms that differ on two factors: [1] duration of coaching support (regular dose = 5 months of group coaching, versus extended dose = regular dose plus an additional 18 months of one-on-one coaching); and [2] mode of engaging scientific advisors with the regular dose group coaching process (unstructured versus structured engagement). Intervention variations were informed by programs previously offered by the NIH National Research Mentoring Network. Participant data are collected via written surveys (baseline and 6, 12, 18, and 24 months after start of the regular dose) and semi-structured interviews (end of regular dose and 24 months). Quantitative analyses will be intention-to-treat, using a 2-sided test of equality of the effects of each factor. An inductive, constant comparison analysis of interview transcripts will be used to identify contextual factors -- associated with individual participants, their engagement with the coaching intervention, and their institutional setting - that influence intervention effectiveness. DISCUSSION: Results of this study will provide an empirical basis for a readily translatable coaching approach to supporting the essential grant writing activities of faculty, fellows, and other research trainees, including those from underrepresented groups.

The Minority Scientists' Experience: Challenging and Overcoming Barriers to Enhancing Diversity and Career Advancement.

Minority groups face barriers in accessing quality health care, professional advancement, and representation in immunology research efforts as a result of institutional racism that if unaddressed can perpetuate a lack of diversity. In 2021, the AAI Minority Affairs Committee convened a cross section of academic and industry scientists from underrepresented groups at various stages of their professions to discuss how best to address the toll racism takes on study design and scientific careers. Panelists drew directly from their own experiences as scientists to share perspectives and strategies for countering a lack of representation in clinical research, responding to microaggressions, navigating academic advancement, and providing effective mentorship. The session reinforced the need for minority scientists to take an active role in advocating for diversity, engaging mentors, and taking responsibility to face rather than avoid institutional obstacles. Overall, increased dialogue and institutional awareness of the experience of scientists from underrepresented groups in research remain the best tools to ensure a health equity mindset and advancement of their careers.

The National Institute of Neurological Disorders and Stroke's efforts on diversifying the neuroscience research workforce.

Research innovation that leads to discovery in the battle against neurological disease and disorders requires diverse ideas. The National Institute of Neurological Disorders and Stroke, one of the National Institutes of Health's 27 institutes and centers, strives to reduce the burden of neurological disease and disorders. The National Institutes of Neurologic Disorders and Stroke is very interested in increasing the diversity of researchers by addressing the existing barriers responsible for the low numbers of underrepresented populations from traditionally minority-serving institutions (MSIs) and non-minority serving institutions (non-MSIs). This commentary provides insight on the persistent underrepresentation of racial/ethnic minorities entering neuroscience research careers paths, focusing on multiples levels within the scientific academy and the supportive role that both MSIs and non-MSIs play in increasing diversity in the biomedical research workforce.

Combination of Small Extracellular Vesicle-Derived Annexin A2 Protein and mRNA as a Potential Predictive Biomarker for Chemotherapy Responsiveness in Aggressive Triple-Negative Breast Cancer.

Small extracellular vesicles (sEVs), mainly exosomes, are nanovesicles that shed from the membrane as intraluminal vesicles of the multivesicular bodies, serve as vehicles that carry cargo influential in modulating the tumor microenvironment for the multi-step process of cancer metastasis. Annexin A2 (AnxA2), a calcium(Ca2+)-dependent phospholipid-binding protein, is among sEV cargoes. sEV-derived AnxA2 (sEV-AnxA2) protein is involved in the process of metastasis in triple-negative breast cancer (TNBC). The objective of the current study is to determine whether sEV-AnxA2 protein and/or mRNA could be a useful biomarkers to predict the responsiveness of chemotherapy in TNBC. Removal of Immunoglobulin G (IgG) from the serum as well as using the System Bioscience's ExoQuick Ultra kit resulted in efficient sEV isolation and detection of sEV-AnxA2 protein and mRNA compared to the ultracentrifugation method. The standardized method was applied to the twenty TNBC patient sera for sEV isolation. High levels of sEV-AnxA2 protein and/or mRNA were associated with stage 3 and above in TNBC. Four patients who responded to neoadjuvant chemotherapy had high expression of AnxA2 protein and/or mRNA in sEVs, while other four who did not respond to chemotherapy had low levels of AnxA2 protein and mRNA in sEVs. Our data suggest that the sEV-AnxA2 protein and mRNA could be a combined predictive biomarker for responsiveness to chemotherapy in aggressive TNBC.

The Association Between NRMN STAR Grantsmanship Self-Efficacy and Grant Submission.

BACKGROUND: Eliminating the NIH funding gap among underrepresented minorities (URMs) remains a high priority for the National Institutes of Health. In 2014, the National Research Mentoring Network1 Steps Toward Academic Research (NRMN STAR) program recruited postdoctoral, early-stage and junior faculty to participate in a 12-month grant writing and professional development program. The expectation of the program was to increase the number of grant submissions and awards to URM researchers. Although receiving a grant award is the gold standard of NRMN STAR, instilling confidence for postdocs and early-stage faculty to submit an application is a critical first step. Based on our previous study, a sustained increase in trainee self-efficacy score over a 24-month period was observed after completing NRMN STAR. METHODS: The current study sought to determine the association between self-efficacy score and grant submissions among two cohorts of trainees. Grantsmanship Self-Efficacy was measured using a 19-item questionnaire previously described by and used in our own work, which was originally adapted from an 88-item Clinical Research Appraisal Inventory.2 A binary variable was created to identify trainees who submitted an initial or revised proposal vs those who abandoned their proposal or were still writing. Trainees were assessed prior to and following program completion with subsequent assessments at 6 and 12 months beyond participation. RESULTS: As of June 20, 2019, 12 of the 21 (57%) trainees had submitted a grant proposal (eg, NIH, other federal or non-federal grant). For every point increase in 12-month post assessments, Grantsmanship Self-Efficacy scores across all domains had a 44% higher prevalence of submitting a grant after controlling for race, sex, education level, academic rank, research experience, duration of postdoctoral training, institution type, and NRMN STAR cohort. CONCLUSIONS: Our findings demonstrate that NRMN STAR had a positive impact on trainees' confidence in grant writing and professional development activities, which resulted in higher grant submission rates.

The Many Faces of Innate Immunity in SARS-CoV-2 Infection.

The innate immune system is important for initial antiviral response. SARS-CoV-2 can result in overactivity or suppression of the innate immune system. A dysregulated immune response is associated with poor outcomes; with patients having significant Neutrophil-to-Lymphocyte ratios (NLR) due to neutrophilia alongside lymphopenia. Elevated interleukin (IL)-6 and IL-8 leads to overactivity and is a prominent feature of severe COVID-19 patients. IL-6 can result in lymphopenia; where COVID-19 patients typically have significantly altered lymphocyte subsets. IL-8 attracts neutrophils; which may play a significant role in lung tissue damage with the formation of neutrophil extracellular traps leading to cytokine storm or acute respiratory distress syndrome. Several factors like pre-existing co-morbidities, genetic risks, viral pathogenicity, and therapeutic efficacy act as important modifiers of SARS-CoV-2 risks for disease through an interplay with innate host inflammatory responses. In this review, we discuss the role of the innate immune system at play with other important modifiers in SARS-CoV-2 infection.

The Perfect Storm: COVID-19 Health Disparities in US Blacks.

Coronavirus disease 2019 (COVID-19) accounts for over 180,000 deaths in the USA. Although COVID-19 affects all racial ethnicities, non-Hispanic Blacks have the highest mortality rates. Evidence continues to emerge, linking the disproportion of contagion and mortality from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a result of adverse social determinants of health. Yet, genetic predisposition may also play a credible role in disease transmission. SARS-CoV-2 enters cells by interaction between SARS-CoV-2 spike protein and the receptor molecule angiotensin converting enzyme 2 (ACE2) expressed on the surface of the target cells, such that polymorphisms and the expression level of ACE2 influence infectivity and consequent pathogenesis of SARS-CoV-2. Genetic polymorphisms in other multiple genes, such as acetylcholinesterase (AChE) and interleukin-6, are also closely associated with underlying diseases, such as hypertension and type 2 diabetes mellitus, which substantially raise SARS-CoV-2 mortality. However, it is unknown how these genetic polymorphisms contribute to the disparate mortality rates, with or without underlying diseases. Of particular interest is the potential that genetic polymorphisms in these genes may be influencing the disparity of COVID-19 mortality rates in Black communities. Here, we review the evidence that biological predisposition for high-risk comorbid conditions may be relevant to our ability to fully understand and therefore address health disparities of COVID-19 deaths in Blacks.

The Association Between Depressive Symptoms and Accumulation of Stress Among Black Men in the Health and Retirement Study.

BACKGROUND AND OBJECTIVES: Among the multiple factors posited to drive the health inequities that black men experience, the fundamental role of stress in the production of poor health is a key component. Allostatic load (AL) is considered to be a byproduct of stressors related to cumulative disadvantage. Exposure to chronic stress is associated with poorer mental health including depressive symptoms. Few studies have investigated how AL contributes to depressive symptoms among black men. The purpose of the cross-sectional study was to examine the association between AL and depressive symptoms among middle- to old age black men. RESEARCH DESIGN AND METHODS: This project used the 2010 and 2012 wave of the Health and Retirement Study enhanced face-to-face interview that included a biomarker assessment and psychosocial questionnaire. Depressive symptoms, assessed by the endorsement of 3 or more symptoms on the Center for Epidemiological Studies-Depression 8-item scale, was the outcome variable. The main independent variable, AL, score was calculated by summing the number values that were in the high range for that particular biomarker value scores ranging from 0 to 7. black men whose AL score was 3 or greater were considered to be in the high AL group. Modified Poisson regression was used to estimate prevalence ratios (PRs) and corresponding 95% confidence intervals (CIs). RESULTS: There was a larger proportion of black men in the high AL group who reported depressive symptoms (30.0% vs. 20.0%) compared with black men in the low AL group. After adjusting for age, education, income, drinking, and smoking status, the prevalence of reporting 3 or more depressive symptoms was statistically significant among black men in the high AL group (PR = 1.61 [95% CI: 1.20-2.17]) than black men in the low AL group. DISCUSSION AND IMPLICATIONS: Exposure to chronic stress is related to reporting 3 or more depressive symptoms among black men after controlling for potential confounders. Improving the social and economic conditions for which black men work, play, and pray is key to reducing stress, thereby potentially leading to the reporting of fewer depressive symptoms.

Grant application outcomes for biomedical researchers who participated in the National Research Mentoring Network's Grant Writing Coaching Programs.

BACKGROUND: A diverse research workforce is essential for catalyzing biomedical advancements, but this workforce goal is hindered by persistent sex and racial/ethnic disparities among investigators receiving research grants from the National Institutes of Health (NIH). In response, the NIH-funded National Research Mentoring Network implemented a Grant Writing Coaching Program (GCP) to provide diverse cohorts of early-career investigators across the United States with intensive coaching throughout the proposal development process. We evaluated the GCP's national reach and short-term impact on participants' proposal submissions and funding outcomes. METHODS: The GCP was delivered as six similar but distinct models. All models began with an in-person group session, followed by a series of coaching sessions over 4 to 12 months. Participants were surveyed at 6-, 12- and 18-months after program completion to assess proposal outcomes (submissions, awards). Self-reported data were verified and supplemented by searches of public repositories of awarded grants when available. Submission and award rates were derived from counts of participants who submitted or were awarded at least one grant proposal in a category (NIH, other federal, non-federal). RESULTS: From June 2015 through March 2019, 545 investigators (67% female, 61% under-represented racial/ethnic minority, URM) from 187 different institutions participated in the GCP. Among them, 324 (59% of participants) submitted at least one grant application and 134 (41% of submitters) received funding. A total of 164 grants were awarded, the majority being from the NIH (93, 56%). Of the 74 R01 (or similar) NIH research proposals submitted by GCP participants, 16 have been funded thus far (56% to URM, 75% to women). This 22% award rate exceeded the 2016-2018 NIH success rates for new R01s. CONCLUSION: Inter- and intra-institutional grant writing coaching groups are a feasible and effective approach to supporting the grant acquisition efforts of early-career biomedical investigators, including women and those from URM groups.

Understanding the Interplay Between Health Disparities and Epigenomics.

Social epigenomics has emerged as an integrative field of research focused on identification of socio-environmental factors, their influence on human biology through epigenomic modifications, and how they contribute to current health disparities. Several health disparities studies have been published using genetic-based approaches; however, increasing accessibility and affordability of molecular technologies have allowed for an in-depth investigation of the influence of external factors on epigenetic modifications (e.g., DNA methylation, micro-RNA expression). Currently, research is focused on epigenetic changes in response to environment, as well as targeted epigenetic therapies and environmental/social strategies for potentially minimizing certain health disparities. Here, we will review recent findings in this field pertaining to conditions and diseases over life span encompassing prenatal to adult stages.