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Orexin Blockers’ Role in Glucose Homeostasis and Diabetic Retinopathy
Get PDFBackground:
Diabetic retinopathy (DR) is the most common complication of diabetes and can lead to blindness if untreated. Orexin is a neuropeptide produced by the hypothalamus that regulates the sleep/wake cycle. Orexin-blockers are prescribed for insomnia, which recent studies have shown to decrease blood glucose levels, suggesting a potential therapeutic for DR. This study aims to explore orexin-blockers’ role in glucose homeostasis and diabetic retinopathy through in-vitro, in-vivo, and chart-review methods.
Methods:
In-vitro: Glucose uptake by human retinal endothelial cells (HRECs) was determined by exposure to varying levels of suvorexant, a commonly prescribed orexin blocker, and orexin-A. Additionally, Orexin expression under high glucose concentrations was examined using fluorescent staining.
Pre-clinical: Diabetic (db/db) and non-diabetic (db/m) mice were injected with suvorexant daily. Mice weights and blood glucose were regularly compared with the vehicle control.
Clinical Chart-review: A review that examines individuals retrospectively to determine if orexin-blockers decrease percentages of developing vision-threatening DR or macular edema compared to patients NOT taking orexin-blockers.
Results:
In-vitro: HRECs exposed to suvorexant had increased glucose uptake, while those exposed to orexin had a decreased glucose uptake. There were no significant changes in orexin expression in HRECs exposed to high glucose.
Pre-clinical: Mice treated with suvorexant showed a downward trend in body weight, food intake, and better glucose tolerance than vehicle control diabetic mice.
Clinical Chart-review: 41 patients treated with orexin blockers were identified. Fewer patients taking suvorexant developed vision-threatening DR than those without treatment. Additionally, there was a trend of decreasing HbA1c while taking suvorexant.
Conclusion:
The results of the in-vitro, pre-clinical, and clinical chart review studies indicate suvorexant has blood glucose-lowering properties. Data will continue to be collected for the clinical chart review to further determine the effects of orexin blockers on diabetic retinopathy and HbA1c.
Sensitization of APC knock-out cells to Doxorubicin in vitro using KU55933, an ATM inhibitor
Get PDFBackground and Hypothesis:
Triple negative breast cancer (TNBC) has the lowest 5-year survival rate among breast cancer subtypes, with Adenomatous Polyposis Coli (APC) mutations/deletions found to be a leading cause of Doxorubicin (DOX) resistance. Additionally, increased expression of pATM/ATM in APC knock-out (APCKO) cells was previously observed, providing a possible explanation to chemotherapy resistance. We hypothesized that treatment with the ATM inhibitor, KU55933, would sensitize APCKO cells to DOX in vitro using γH2AX as a marker of DNA damage.
Materials and Methods:
The TNBC cell line, MDA-MB-231, was previously modified using CRISPR/Cas9 to knock out APC. The current study uses the non-targeting control (NTC) and 2 clonal knock-out cell lines (APCKO or clones 1 and 2). Cells were cultured in DMEM with 10% FBS, 1% penicillin/streptomycin, and plasmocin, and treated with either H2O, DOX, KU, or DOX+KU for 24 hours. For western blot analysis of γH2AX, membranes were blocked at room temperature in 5% nonfat dry milk and incubated with primary anti-γH2AX overnight at 4°C using actin as an internal control. Immunofluorescence studies included drug treatment of cells with the four previously mentioned treatments and probing for γH2AX using anti-γH2AX antibody.
Results:
Immunofluorescence studies displayed increased γH2AX expression, indicating DNA damage in the combination (DOX+KU) treatment group in the APCKO cell lines. Western Blot analysis showed a significant difference in the DOX treated 231 NTC and clone 2 cell lines vs H2O treated cells.
Conclusion and Potential Impact:
Data from this study will be used to pursue further research in the efficacy of KU in sensitizing APCKO cells to DOX treatment and have significant implications for the future of chemotherapy research and dosing for TNBC patients. Future studies may include testing the ability of KU to overcome DOX resistance in vivo and assessment of APCKO cell recovery after drug treatment in different growth media.
The Role of Cross-linked Actin Networks in the Proliferation and Senescence of Primary Human Trabecular Meshwork Cells
Get PDFPurpose: TGFβ2 has been found to be elevated in the trabecular meshwork (TM) of patients with primary open-angle glaucoma. TM cells treated with TGFβ2 form cross-linked actin networks (CLANs). These CLANs are a restructuring of the cells’ actin cytoskeleton that appear as web-like (2D)/spherical (3D) structures. In this study, we used TGFβ2 treated primary human TM (pHTM) cells to illuminate the relationship between CLAN formation and cell proliferation and senescence.
Methods: A characterized pHTM cell strain was seeded into a 96-well plate. Some cells were treated with 5ng/mL TGFβ2 for 1 week while the others served as a control. The cells were then fixed and immunostained for cell proliferation (Ki-67) and senescence (p21, H2AX, and β-galactosidase) markers. DAPI was also used to stain nuclei and phalloidin-Alexa-488 to stain F-actin/CLANs. Analysis was conducted through student’s t-tests.
Results: TGFβ2-treated pHTM cells formed significantly more CLANs compared to control. The cell proliferation marker Ki-67 was rarely expressed in both groups (not statistically significant) but was mostly observed in CLAN- cells and seen only in the control. Ki-67 was almost completely absent in CLAN+ cells. Among senescence markers, none were expressed significantly differently between the two groups, however TGFβ2 led to an increase in p21 and β-gal. Most CLAN+ cells expressed p21. No cells expressed H2AX.
Conclusions: TGFβ2 increases the formation of CLANs in pHTM cells. It seems that CLAN formation inhibits cell proliferation. However, the effect of CLAN formation on cell senescence is not clear. More investigation is needed to help further understand the relationship between CLAN formation and cell proliferation and senescence
Unequal Burden of Melanoma: How Socioeconomic Status is Associated with Secondary Primary Malignancy Risk and Mortality
Get PDFBackground/Objective: Melanoma is the 5th most common cancer in the U.S. There is limited literature on how socio-economic status (SES) is associated with risk of secondary primary malignancies (SPMs), despite 2.1% of population living with a melanoma history. This study examined the relationship between SES and 1) incidence of SPMs in early-stage melanoma patients, and 2) survival in metastatic melanoma patients.
Methods: A retrospective cohort study was conducted using data of 481,603 stage 0/I/II melanoma patients from 2006-2020 and 1,089 metastatic melanoma patients from 2016-2020. Patient’s SES quintile was calculated using census tract level information including median household income, median house value/rent, education index, etc. Data on primary and secondary malignancies and cancer stage at diagnosis were analyzed using binomial and ordinal logistics regression. Survival outcomes were analyzed using Kaplan Meier and multivariate Cox regression.
Results: Patients with lower SES have significantly higher risks of developing higher stage SPMs (Stage I/II Group 1-lowest SES: OR 1.39, 95% CI 1.28-1.51) and metastatic SPMs (Stage I/II Group 1: OR 1.35, 95% CI 1.2-1.52). Group 5 (highest SES) served as reference. Conversely, patients with higher SES have a higher overall incidence of SPMs compared to lower SES groups (Stage I/II Group 1: OR 0.82, 95% CI 0.78-0.86). Results were significant across all SES levels, except for Group 4 with stage 0 melanoma. Five-year survival analysis revealed metastatic melanoma patients with lowest SES are most at risk of dying (Group 1: HR 1.54, 95% CI:1.15-2.08).
Conclusion/Implications: This study shows the significance of socioeconomic disparities in melanoma outcomes. Patients with lower SES are at greater risk of developing higher stage SPMs and have poorer survival rates, whereas higher SES patients are more likely to be diagnosed with SPMs. Our findings highlight the need for targeted interventions to address SES-related disparities in melanoma prevention and care.
Collaborative Endeavors: A Team Perspective on Co-authoring Systematic Reviews with Medical Students
Get PDFIntroduction: Evidence synthesis (ES) projects have been on the rise, providing a way to work collaboratively without needing to use a lab or meet in person. ES projects are a good method for all involved to learn more about the subject, to foster meaningful collaborations among team members, and to establish and improve mentoring skills. The authors conceptualized, formulated, drafted, and published a diagnostic accuracy systematic review on rapid antigen tests used to detect COVID-19. During the review, varied challenges arose, many unanticipated. To address them the authors and team members developed effective strategies that may benefit future ES projects.
Experience: The article describes the experiences of the varied team members, which included medical students, a librarian, faculty, and a data analyst. The article addresses the collaborative process including defining roles and responsibilities. Next, the authors describe laying the foundation of the project so that as team members were recruited, the project flowed smoothly. The team then reflects on the management of the project over multiple years. As with many ES projects, the protocol needed to be revised, and the authors share their approach to these changes.
Discussion: The librarian\u27s collaboration with both students and faculty members yielded significant benefits, including improved mentoring skills, enhanced team coordination, and diverse perspectives gained through interdisciplinary collaboration. The challenges faced by navigating the literature landscape and managing the team are also described.
Takeaways: Librarians are in a unique position to advocate for multi-disciplinary teams, incorporating a data analyst early on, and judiciously using software in evidence synthesis projects. These projects help build the backbone of medical literature
It Means Everything…and It Means Nothing: New Social Worker Views on Taking the Master’s Licensure Exam
No full textIn order to call oneself a social worker in the United States, an individual must not only complete the required coursework and degree program, but also, in many states, pass a licensure exam. Recent discussion has centered around the efficacy of using an examination as a regulatory tool for licensure, particularly following the Association of Social Work Boards (ASWB) report identifying bias with the licensure exam itself, and indicating specific demographic characteristics including race, age, and English as a second language, as having an impact on the pass rate of test-takers (ASWB, 2022). This qualitative study specifically highlighted the experiences of 22 MSWs who were preparing for or had taken the licensure exam. Five themes emerged through an analysis of the data: meaning everything and nothing, hoops and barriers, emotional responses, learning the tricks, and setting aside practice wisdom. Our study reflects the ambivalence of new social workers toward the licensing exam and the disconnect between education and practice in what the test is actually measuring. Recommendations and implications for social work educators include advocating for a re-evaluation of social work licensure exams as proof of competence
Leveraging a Social Justice Focus on Social Work Education and Licensure
No full textWhile MSW students are increasingly interested in attaining social work licenses, social work educators vary in their understanding of state licensure and regulations and how to best prepare graduate students. Opportunities exist along a pathway to licensure to honor social work’s professional commitment to social justice by teaching relevant course content that includes direct clinical practice and macro level practice, ideally bridging the knowledge to collectively work to facilitate the passing of state ASWB exams and secure professional licensure. A brief overview of the challenges that exist as social work programs strive to meet CSWE requirement and competency based course content, in the content of acknowledging the disparities noted in the ABSW licensure exams simultaneously to the growing number of students striving to seek professional licensure. Opportunities for MSW programs to identify the role and use of course content, pre-service development, marketing, and recruitment content designed to support students’ efforts to pass ASWB licensure exams and obtain credentials are presented. Finally, implications and recommendations for social work programs and faculty to enhance their recruitment, teaching, and licensure preparation endeavors to best assist students and graduates
Academic and Nonprofit Partnerships Can Enhance Capacity Building
No full textA substantial body of research has examined the potential for collaborations between nonprofit or community-based organizations and entire universities or academic departments. However, there is considerably less research focusing on partnerships between individual faculty members and nonprofit organizations. During a semester-long research sabbatical, I collaborated with several community-based organizations on various capacity-building activities. This article draws on detailed field notes taken throughout the project to illustrate the types of capacity-building contributions academics can offer and to identify common challenges encountered in these partnerships. The findings are contextualized within the broader literature on academic-nonprofit collaborations
The Guiding Light: Qurʾānic Wisdom and Prophetic Examples in Chaplaincy
No full textDuring much of human history, wisdom has been a topic of interest in religion, philosophy,and, lately, psychology and the social sciences. Over the past three decades, this term’s verydefinition has been debated among scholars who study human behavior. Psychologists activelyexplore it and increasingly focus on practical wisdom, recognizing it is a complex trait thatcontains cognitive, reflective, and compassionate components. They are finding that peoplewho possess practical wisdom have better mental states and lead more purposeful lives.However, there is a growing concern about its potential decline, particularly in the context ofnavigating increasingly complex global challenges which require collective and collaborativewise responses. This perception is linked to various factors, among them the rapid pace oftechnological change, the rise of individualism, and shifts in human values (Maxwell 2007).A lack of wisdom implies an inability to discern the best course of action, understandthe consequences of choices, and apply knowledge effectively. Cultivating collective wisdomrequires a shift in how knowledge is acquired, understood, and applied so that one can movebeyond isolated facts to formulate an integrated and holistic understanding that considersspiritual, intellectual, ethical, and societal implications. Cultivating wisdom is essential foreveryone, especially for those responsible for serving and guiding others and fosteringspiritual growth, moral integrity, and a thriving society. Indeed, it is an important quality forMuslims in any leadership role, especially for those who serve as chaplains.This article explores the concept of ḥikma (wisdom) within the Qurʾān and its propheticapplication for Muslim chaplains providing holistic spiritual care. The article argues that byre-centering chaplaincy on this Qurʾānic-Prophetic model of wisdom, chaplains can offerspiritual care and enhance pastoral counseling that is both authentically Islamic andprofoundly relevant to the complex psycho-spiritual needs of Muslims today. It concludes bybriefly discussing the implications for chaplaincy training and practice, suggesting thatintegrating this wisdom-centric approach can foster greater spiritual resilience in individualsand communities, as well as strengthen the overall development of the Muslim chaplaincyprofession and beyond
Muslim Chaplains in Law Enforcement: Challenges and Opportunities
No full textThis reflection piece explores the journey of a Muslim female police chaplain navigating the complexities of identity. Highlighting moments of connection, the paper emphasizes the power of authentic engagement and empathy in breaking down barriers. The author’s narrative also touches on the broader themes of representation, advocacy fatigue, and the internal conflict experienced when one’s values diverge from institutional norms. Ultimately, this piece offers insight into the journey of a Muslim chaplain striving to be a compassionate presence while questioning the impact and limitations of her role in a space where conformity reigns