Social network analysis of the CaRE2 health equity center: Team science in full display.

Cancer health disparities that exist in the Black or African American and Hispanic or Latino/x communities are scientific challenges, yet there are limited team science approaches to mitigate these challenges. This article's purpose is to evaluate the team science collaborations of the National Institutes of Health-funded Florida-California Cancer Research, Education & Engagement (CaRE2 ) Center partnership underscoring the inclusion of multidisciplinary team members and future under-represented minority (URM) cancer researchers. To understand our collaborative efforts, we conducted a social network analysis (SNA) of the CaRE2 Center partnership among University of Florida, Florida A&M University, and University of Southern California with data collected via the dimensions.ai application programming interface. We downloaded metadata for all publications associated with dimensions.ai IDs. The CaRE2 collaboration network increased over time as evidenced by accruing more external collaborators and more publishing of collaborative works. Degree centrality of key personnel was stable in each wave of the networks. CaRE2 key personnel averaged a total of 60.8 collaborators in 2018-2019 (SD = 57.4, minimum = 3, maximum = 221), and 65.8 collaborators in 2020-2021 (SD = 56.06, minimum = 4, maximum = 222). Betweenness was largely stable across all groups and waves. We observed a steady decline in transitivity, the probability that a pair of CaRE2 co-authors shared a third co-author, from 0.74 in 2018 to 0.47 in 2022. The SNA findings suggest that the CaRE2 Center partnership's publications show growth in team science collaborations with the inclusion of multidisciplinary team members from the three partner institutions and future URM cancer researchers who were mentored as trainees and early-stage investigators.

Mentoring Minority Cancer Researchers of Tomorrow: Comparison of the Face-to-Face, Virtual, and Hybrid Training Methods of the CaRE2 Summer Cancer Research Education and Training Program.

In our previous publication, we reported a framework to develop an undergraduate cancer research training program at Florida A&M University (FAMU) under the umbrella of the Florida-California Cancer Research, Education, and Engagement (CaRE2) Health Equity Center activity by harnessing the resources available at FAMU, the University of Florida (UF), and the University of Southern California (USC) Cancer Centers. The implementation of the CaRE2 face-to-face training platform was dramatically affected by the COVID-19 pandemic during the summer of 2020 and 2021 training periods. However, a concerted effort was made to restructure the face-to-face training model into virtual and hybrid training methods to maintain the continuity of the program during the pandemic. This article compared the three methods to identify the best platform for training URM students in cancer disparity research. The program's effectiveness was measured through motivation, experiences, and knowledge gained by trainees during and one year after the completion of the program. The results showed that the participants were highly positive in their feedback about the professional and academic values of the program. Although the virtual and hybrid methods experienced significant challenges during the pandemic, the hybrid training module offered an "above average" effectiveness in performance, like the face-to-face mentoring platform in mentoring URM students in cancer disparity research.

Developing a Novel Framework for an Undergraduate Cancer Research Education and Engagement Program for Underrepresented Minority Students: the Florida-California CaRE2 Research Education Core (REC) Training Program.

Lack of substantive research experiences and technical skills mentoring during undergraduate studies leaves many underrepresented minority (URM) students unprepared to apply to competitive graduate programs. As a part of our ongoing effort to increase the pipeline for the development and training of successful URM scientists in biomedical sciences with focus on reducing cancer health disparities, the Florida-California Cancer Research Education and Engagement (CaRE2) Health Equity Center was launched in 2018. Funded through an NIH/NCI U54 grant mechanism, the CaRE2 Center is a triad partnership among Florida Agricultural and Mechanical University (FAMU), a minority-serving institution, University of Florida (UF), and University of Southern California (USC) Cancer Center. One of the objectives of the triad partnership is to promote the coordination and implementation of the training of the next generation of Black and Latinx biomedical scientists in Florida and California. An important component of the CaRE2 program is the Research and Education Core (REC) designed to coordinate the training of URM students and researchers at different levels in their academic and professional developments. The undergraduate cancer research training program under FAMU-CaRE2 Center is a 3-year (2018-2021) project to identify, train, mentor, and provide the URM undergraduate students with the support network they need to flourish in the program and beyond. In its year-1 funding cycle, the program has made significant progress in developing a novel framework for an undergraduate cancer research education and engagement program at FAMU, one of the forefront minority institutions in the nation. The mentored research program is complemented with professional development and engagement activities, including cancer research seminars, workshops, and community outreach activities. The purpose of this paper is to discuss the strategies implemented for an effective partnership, the leadership and mentoring skills, and outcomes from the year-1 experiences. In addition, we present the progress made in advancing the pool of underrepresented minority students with scientific and academic career progression paths focused on cancer health disparities.

Mitochondrial biology and prostate cancer ethnic disparity.

Prostate cancer remains the second most prevalent cancer in men. Its incidence, progression and mortality profiles vary significantly by race and ethnicity, with African-American men having the highest incidence rate and mortality rate in the world. Although these disparities can be partially explained by socioeconomic factors, the underlying molecular causes are complex and require careful research. A considerable amount of literature exists, supporting the association between mitochondrial health and the incidence, aggression and risk of prostate cancer. Genetic alterations in mitochondrial DNA are frequent in prostate cancer; therefore, the resulting mitochondrial dysfunction and metabolic dysregulation may contribute to or indicate oncogenesis. Many of the prominent features of cancer cells are also closely related to mitochondrial functions, such as resistance to apoptosis, excess reactive oxygen species production and altered oxidative phosphorylation. In addition, prostate cancer ethnic disparity is influenced by environmental and lifestyle factors, which involves differences in mitochondrial metabolism and retrograde signaling events.

The attenuating effects of 1,2,3,4,6 penta-O-galloyl-ß-d-glucose on pro-inflammatory responses of LPS/IFNγ-activated BV-2 microglial cells through NFƙB and MAPK signaling pathways.

BACKGROUND: Overactivated microglial cells exhibit chronic inflammatory response and can lead to the continuous production of pro-inflammatory cytokines, perpetuating inflammation, and ultimately resulting in neuronal injury. 1,2,3,4,6-Penta-O-Galloyl-ß-d-Glucose (PGG), which is a naturally occurring polyphenolic compound, has exhibited anti-inflammatory effect through the inhibition of many cytokines in different experimental models, but its effect on activated microglia cells was never described. In the present study, we investigated PGG effect in proteins involved in the NFƙB and MAPK signaling pathways, which play a central role in inflammation through their ability to induce transcription of pro-inflammatory genes. METHODS: PCR arrays and RT-PCR with individual primers were used to determine the effect of PGG on mRNA expression of genes involved in NFƙB and MAPK signaling pathways. Western blots were performed to confirm PCR results. RESULTS: The data obtained showed that PGG modulated the expression of 5 genes from the NFƙB (BIRC3, CHUK, IRAK1, NFƙB1, NOD1) and 2 genes from MAPK signaling pathway (CDK2 and MYC) when tested in RT-PCR assays. Western blots confirmed the PCR results at the protein level, showing that PGG attenuated the expression of total and phosphorylated proteins (CDK2, CHUK, IRAK1, and NFƙB1) involved in NFƙB and MAPK signaling. CONCLUSION: These findings show that PGG could modulate the expression of genes and proteins involved in the production of pro-inflammatory cytokines in microglia cells.

Smart thermosensitive liposomes for effective solid tumor therapy and in vivo imaging.

In numerous studies, liposomes have been used to deliver anticancer drugs such as doxorubicin to local heat-triggered tumor. Here, we investigate: (i) the ability of thermosensitive liposomal nanoparticle (TSLnp) as a delivery system to deliver poorly membrane-permeable anticancer drug, gemcitabine (Gem) to solid pancreatic tumor with the aid of local mild hyperthermia and, (ii) the possibility of using gadolinium (Magnevist®) loaded-TSLnps (Gd-TSLnps) to increase magnetic resonance imaging (MRI) contrast in solid tumor. In this study, we developed and tested gemcitabine-loaded thermosensitive liposomal nanoparticles (Gem-TSLnps) and gadolinium-loaded thermosensitive liposomal nanoparticles (Gd-TSLnps) both in in-vitro and in-vivo. The TSLnps exhibited temperature-dependent release of Gem, at 40-42°C, 65% of Gem was released within 10 min, whereas < 23% Gem leakage occurred at 37°C after a period of 2 h. The pharmacokinetic parameters and tissue distribution of both Gem-TSLnps and Gd-TSLnps were significantly greater compared with free Gem and Gd, while Gem-TSLnps plasma clearance was reduced by 17-fold and that of Gd-TSLpns was decreased by 2-fold. Area under the plasma concentration time curve (AUC) of Gem-TSLnps (35.17± 0.04 µghr/mL) was significantly higher than that of free Gem (2.09 ± 0.01 µghr/mL) whereas, AUC of Gd-TSLnps was higher than free Gd by 3.9 fold high. TSLnps showed significant Gem accumulation in heated tumor relative to free Gem. Similar trend of increased Gd-TSLnps accumulation was observed in non-heated tumor compared to that of free Gd; however, no significant difference in MRI contrast enhancement between free Gd and Gd-TSLnps ex-vivo tumor images was observed. Despite Gem-TSLnps dose being half of free Gem dose, antitumor efficacy of Gem-TSLnps was comparable to that of free Gem(Gem-TSLnps 10 mg Gem/kg compared with free Gem 20 mg/kg). Overall, the findings suggest that TSLnps may be used to improve Gem delivery and enhance its antitumor activity. However, the formulation of Gd-TSLnp needs to be fully optimized to significantly enhance MRI contrast in tumor.

Anti-inflammatory effects of thymoquinone in activated BV-2 microglial cells.

Thymoquinone (TQ), the main pharmacological active ingredient within the black cumin seed (Nigella sativa) is believed to be responsible for the therapeutic effects on chronic inflammatory conditions such as arthritis, asthma and neurodegeneration. In this study, we evaluated the potential anti-inflammatory role of TQ in lipopolysaccharide (LPS)-stimulated BV-2 murine microglia cells. The results obtained indicate that TQ was effective in reducing NO2(-) with an IC50 of 5.04µM, relative to selective iNOS inhibitor LNIL-l-N6-(1-iminoethyl)lysine (IC50 4.09µM). TQ mediated reduction in NO2(-) was found to parallel the decline of iNOS protein expression as confirmed by immunocytochemistry. In addition, we evaluated the anti-inflammatory effects of TQ on ninety-six (96) cytokines using a RayBio AAM-CYT-3 and 4 cytokine antibody protein array. Data obtained establish a baseline protein expression profile characteristic of resting BV-2 cells in the order of osteopontin>MIP-1alpha>MIP-1g>IGF-1 and MCP-I. In the presence of LPS [1ug/ml], activated BV-2 cells produced a sharp rise in specific pro-inflammatory cytokines/chemokine's IL-6, IL-12p40/70, CCL12 /MCP-5, CCL2/MCP-1, and G-CSF which were attenuated by the addition of TQ (10µM). The TQ mediated attenuation of MCP-5, MCP-1 and IL-6 protein in supernatants from activated BV-2 cells were corroborated by independent ELISA. Moreover, the data obtained from the RT(2) PCR demonstrated a similar pattern where the LPS mediated elevation of mRNA for IL-6, CCL12/MCP-5, CCL2/MCP-1 were significantly attenuated by TQ (10µM). Also, in this study, consistent data were obtained for both protein antibody array densitometry and ELISA assays. In addition, TQ was found to reduce LPS mediated elevation in gene expression of Cxcl10 and a number of other cytokines in the panel. These findings demonstrate the significant anti-inflammatory properties of TQ in LPS activated microglial cells. Therefore, the obtained results might indicate the usefulness of TQ in delaying the onset of inflammation-mediated neurodegenerative disorders involving activated microglia cells.

The role of oxidative stress, impaired glycolysis and mitochondrial respiratory redox failure in the cytotoxic effects of 6-hydroxydopamine in vitro.

The neurotoxin, 6-hydroxydopamine (6-OHDA) has been implicated in the neurodegenerative process of Parkinson's disease. The current study was designed to elucidate the toxicological effects of 6-OHDA on energy metabolism in neuroblastoma (N-2A) cells. The toxicity of 6-OHDA corresponds to the total collapse of anaerobic/aerobic cell function, unlike other mitochondrial toxins such as MPP+ that target specific loss of aerobic metabolism. The toxicity of 6-OHDA paralleled the loss of mitochondrial oxygen (O2) consumption (MOC), glycolytic activity, ATP, H+ ion gradients, membrane potential and accumulation of the autoxidative product, hydrogen peroxide (H2O2). Removing H2O2 with nonenzymatic stoichiometric scavengers, such as carboxylic acids, glutathione and catalase yielded partial protection. The rapid removal of H2O2 with pyruvate or catalase restored only anaerobic glycolysis, but did not reverse the loss of MOC, indicating mitochondrial impairment is independent of H2O2. The H2O2 generated by 6-OHDA contributed toward the loss of anaerobic glycolysis through lipid peroxidation and lactic acid dehydrogenase inhibition. The ability of 6-OHDA to maintain oxidized cytochrome c (CYT-C-OX) in its reduced form (CYT-C-RED), appears to play a role in mitohondrial impairment. The reduction of CYT-C by 6-OHDA, was extensive, occurred within minutes, preceded formation of H2O2 and was unaffected by catalase or superoxide dismutase. At similar concentrations, 6-OHDA readily altered the valence state of iron [Fe(III)] to Fe(II), which would also theoretically sustain CYT-C in its reduced form. In isolated mitochondria, 6-OHDA had negligible effects on complex I, inhibited complex II and interfered with complex III by maintaining the substrate, CYT-C in a reduced state. 6-OHDA caused a transient and potent surge in isolated cytochrome oxidase (complex IV) activity, with rapid recovery as a result of 6-OHDA recycling CYT-C-OX to CYT-C-RED. Typical mitochondrial toxins such as MPP+, azide and antimycin appeared to inhibit the catalytic activity of ETC enzymes. In contrast, 6-OHDA alters the redox of the cytochromes, resulting in loss of substrate availability and obstruction of oxidation-reduction events. Complete cytoprotection against 6-OHDA toxicity and restored MOC was achieved by combining catalase with CYT-C (horse heart). In summary, CYT-C reducing properties are unique to catecholamine neurotransmitters, and may play a significant role in selective vulnerability of dopaminergic neurons to mitochondrial insults.

Gestational Cocaine Exposure Alters Postnatal Pituitary-Adrenal Axis Activity and Stress Endurance in Ratsa.

Female pregnant Sprague-Dawley rats were injected once daily with 40 mg/kg cocaine hydrochloride or 0.9% saline from gestational day 12 (GD 12) to GD 21. From postnatal day 21 (PND 21) to PND 60, both male and female offspring were examined for stress response. Treated male and female offspring demonstrated a diminished tolerance to stress as determined by a cold water stress test performed at PND 21, 30 and 40. Base hormonal levels of adrenocorticotropin hormone (ACTH) and corticosterone were not affected by prenatal cocaine exposure in male offspring at PND 30. However, immobilization for 1 hr caused a significant sustained elevation of corticosterone levels at both PND 30 and PND 60 in male treated offspring as compared to the control group. Plasma ACTH levels were also significantly sustained after 1 hr of immobilization at PND 60 for the cocaine-treated male offspring. These results indicate both a diminished capacity to respond to stress and an abnormal heightened reactivity of the pituitary-adrenal axis in offspring exposed to cocaine in utero.