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Abstract Background There is evidence indicating that chemoresistance in tumor cells is mediated by the reconfiguration of the tricarboxylic acid cycle, leading to heightened mitochondrial activity and oxidative phosphorylation (OXPHOS). Previously, we have shown that ovarian cancer cells that are resistant to chemotherapy display increased OXPHOS, mitochondrial function, and metabolic flexibility. To exploit this weakness in chemoresistant ovarian cancer cells, we examined the effectiveness of the mitochondrial inhibitor CPI-613 in treating preclinical ovarian cancer. Methods Chemosensitive OVCAR3, and chemoresistant CAOV3 and F2 ovarian cancer cells lines and their xenografts in nude mice were used. Functional metabolic studies were performed using Seahorse instrument. Metabolite quantification was performed using LC/MS/MS. Results Mice treated with CPI-613 exhibited a notable increase in overall survival and a reduction in tumor development and burden in OVCAR3, F2, and CAOV3 xenografts. CPI-613 suppressed the activity of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complex, which are two of its targets. This led to a reduction in OXPHOS and tricarboxylic acid cycle activity in all 3 xenografts. The addition of CPI-613 enhanced the responsiveness of chemotherapy in the chemoresistant F2 and CAOV3 tumors, resulting in a notable improvement in survival rates and a reduction in tumor size as compared to using chemotherapy alone. CPI-613 reduced the chemotherapy-induced OXPHOS in chemoresistant tumors. The study revealed that the mechanism by which CPI-613 inhibits tumor growth is through mitochondrial collapse. This is evidenced by an increase in superoxide production within the mitochondria, a decrease in ATP generation, and the release of cytochrome C, which triggers mitochondria-induced apoptosis. Conclusion Our study demonstrates the translational potential of CPI-613 against chemoresistant ovarian tumors.

Several protein expression platforms exist for a wide variety of biopharmaceutical needs. A substantial proportion of research and development into protein expression platforms and their optimization since the mid-1900s is a result of the production of viral antigens for use in subunit vaccine research. This review discusses the seven most popular forms of expression systems used in the past decade—bacterial, insect, mammalian, yeast, algal, plant and cell-free systems—in terms of advantages, uses and limitations for viral antigen production in the context of subunit vaccine research. Post-translational modifications, immunogenicity, efficacy, complexity, scalability and the cost of production are major points discussed. Examples of licenced and experimental vaccines are included along with images which summarize the processes involved.

Abstract The design of cereblon-binding molecular glues (MGs) that selectively recruit a desired protein while excluding teratogenic SALL4 is an area of significant interest when designing therapeutic agents. Previous studies show that SALL4 is degraded in the presence of IKZF1 degraders pomalidomide, and to a lesser extent by CC-220. To expand our understanding of the molecular basis for the interaction of SALL4 with cereblon, we performed biophysical and structural studies demonstrating that SALL4 zinc finger domains one and two (ZF1-2) interact with cereblon (CRBN) in a unique manner. ZF1 interacts with the N-terminal domain of cereblon and ZF2 binds as expected in the C-terminal IMiD-binding domain. Both ZF1 and ZF2 contribute to the potency of the interaction of ZF1-2 with CRBN:MG complexes and the affinities of SALL4 ZF1-2 for the cereblon:CC-220 complex are less potent than for the corresponding pomalidomide complex. Structural analysis provides a rationale for understanding the reduced affinity of SALL4 for cereblon in the presence of CC-220, which engages both ZF1 and ZF2. These studies further our understanding of the molecular glue-mediated interactions of zinc finger-based proteins with cereblon and may provide structural tools for the prospective design of compounds with reduced binding and degradation of SALL4.

Several pieces of literature have been written on the status of heterosexual college student attitudes toward homosexuality, homosexual students, and homophobia (D'Augelli, 1989; D'Augelli & Rose, 1990; Ficarrotto,1990; Goldberg, 1982; Grieger & Ponterotto, 1988; McDevitt, 1987; Spees, 1987; Wells & Franken, 1987; Yarber & Yee, 1983). Conversely, limited research outlines the impact that this heterosexual perspective has on homosexual (gay/lesbian) students. Furthermore, little research has been presented in the specific area of addressing the needs of homosexual and bisexual students (Baker, 1991; Scott, 1988). Due to the minimal attention focusing on gay/lesbian/bisexual students, and more specifically the issues that they face on our college campuses, this study attempts to extend the existing research. This article originally appeared in the CSPA Journal in 1994 and presented literature on LGBT students, particularly noting the lack of research at that time. It also presents findings from a qualitative project talking to LGBT students at that time about their experience.

Introduction: This study evaluates the feasibility of using a volunteer research associate (RA) to administer two separate health literacy assessment tools in the emergency department (ED), specifically in an older population of patients. The outcomes measured were administration time and interruptions.Methods: Using a prospective, cross-sectional study with a convenience sample, adult patients over the age of 55 presenting between June–August 2018 to one urban, academic ED were evaluated by a volunteer RA using either the Newest Vital Sign (NVS) or the Short Assessment of Health Literacy (SAHL). All patients 55 years of age or older who consented to participate were included. We excluded from this study the following: patients with dementia or other disability involving reading, speech, or cognitive function, as noted in their medical record or by their attending physician; prisoners; and those subjectively deemed in extremis or too ill to participate by their attending physician.Results: Health literacy was assessed in 202 patients using either the NVS or SAHL. Mean time of administration was 214.0 seconds for the NVS, and 206.8 for the SAHL. The maximum time of administration for the NVS was 563 seconds, compared to 607 seconds for the SAHL. We found that 95.2% of NVS and 93.9% of SAHL tests incurred no interruptions during administration.Conclusion: No significant difference was found between the length of time needed to administer the NVS or SAHL to older patients in the ED. Both tools averaged an administration time of around three to four minutes, and neither incurred regular interruptions to its administration by a volunteer RA. Further study is needed to assess validity of these tools in an ED setting.

Abstract: Whether an ecological community is controlled from above or below remains a popular framework that continues generating interesting research questions and takes on especially important meaning in agroecosystems. We describe the regulation from above of three coffee herbivores, a leaf herbivore (the green coffee scale, Coccus viridis), a seed predator (the coffee berry borer, Hypothenemus hampei), and a plant pathogen (the coffee rust disease, caused by Hemelia vastatrix) by various natural enemies, emphasizing the remarkable complexity involved. We emphasize the intersection of this classical question of ecology with the burgeoning field of complex systems, including references to chaos, critical transitions, hysteresis, basin or boundary collision, and spatial self-organization, all aimed at the applied question of pest control in the coffee agroecosystem.

Abstract Background Transgender and gender diverse (TGD) individuals disproportionately experience disparate health outcomes compared to their cisgender peers. This study aimed to collect qualitative data from a sample of TGD community health center patients on health research priorities to inform future TGD-centered research in the field of TGD health. Methods Between September–November of 2018, four focus groups (two groups in Boston MA, two in New York NY; n = 28 individuals) were held to evaluate community-identified TGD health research priorities with a sample of patients from two community health centers. Thematic analyses were conducted and restricted to social factors impacting health. Findings were incorporated into the development of The LEGACY Project, a longitudinal cohort of TGD patients, assessing the impact of gender-affirming care on health outcomes. Results Cross-cutting themes about TGD research priorities pertaining to social factors and health included: (1) Embodiment: understanding and investigating the complex and intersectional lived experiences of TGD individuals; (2) Social determinants of health: the impact of structural and interpersonal stigma on TGD health; and (3) Resiliency and health promoting factors: the need to expand public health research beyond disparities to assess resiliency and health promotion in TGD communities. Conclusions Participants identified investigating the impact of social influences on health as a research priority for TGD patients. Recalibrating field norms from individual researcher priorities to TGD population-driven research will help ensure investigators address topics that may otherwise be missed or overlooked and may optimize the reach and impact of research in TGD health.

We developed a dataset consisting of outbreak data collected from official, open-source surveillance reports representing more than 170 pathogens, 237 countries and territories, and more than 3300 events that occurred primarily between 1963 and 2023. Here we present and analyze a subset of these data, comprising a dataset of human epidemic events with onset between 2015 and 2020. Structuring of epidemiological data in the dataset follows a specific methodology to ensure consistency across all events. This methodology has been designed to produce the most reliable spatiotemporal view of an outbreak as possible. To ensure data are true-to-source, the structured data undergoes multiple rounds of both manual and automated review and validation. The extensive and standardized nature of the dataset makes it well-suited for both descriptive epidemiology and exploring outbreak dynamics and disease emergence. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review summarizes recent evidence linking experiences of discrimination and anticipated discrimination with cardiovascular health outcomes. Recent Findings: Experiences of discrimination were consistently associated with increased risk of nicotine exposure, poor sleep health, obesity, diabetes, hypertension, and subclinical cardiovascular disease. Evidence is mixed for cardiovascular disease diagnoses and cardiovascular mortality. Although research is limited, anticipated discrimination is an independent risk factor for poor sleep health and subclinical cardiovascular disease. Key methodological limitations included the limited use of gold-standard objective measures of health behaviors and well-validated self-report measures, inadequate consideration of intersectionality, and lack of robust examinations of psychological, behavioral, and physiological mechanisms linking discrimination with cardiovascular health outcomes. Summary: There is substantial evidence linking experiences of discrimination with cardiovascular outcomes. Yet, before translating these findings into clinical practice, more rigorous studies are needed to address methodological limitations and uncover mechanisms by which discrimination influences cardiovascular health. There is a need for studies to inform the development of evidence-based interventions focused on reducing the influence of discrimination-related stressors on cardiovascular health outcomes. Findings have important implications for future work to advance cardiovascular health equity. [ABSTRACT FROM AUTHOR]

A 27-year-old woman presented with bilateral blurry vision for 2 weeks. She had a presumed diagnosis of idiopathic intracranial hypertension given her bilateral disc edema; however, bilateral disc and retinal infiltration was noted on ophthalmoscopy. This report presents a rare case of chronic myelogenous leukemia (CML) in the non-blast phase presenting as bilateral optic disc infiltration, indicating central nervous system involvement at the time of diagnosis. The patient had no other clinical symptoms at the time of diagnosis and was promptly treated with orbital radiation and a tyrosine kinase inhibitor, resulting in 20/20 vision in both eyes. [Ophthalmic Surg Lasers Imaging Retina 2025;56:102–107.] [ABSTRACT FROM AUTHOR]

BackgroundThere has been a dramatic shift in use of bariatric procedures, but little is known about their long-term comparative effectiveness.ObjectiveTo compare weight loss and safety among bariatric procedures.DesignRetrospective observational cohort study, January 2005 to September 2015. (ClinicalTrials.gov: NCT02741674).Setting41 health systems in the National Patient-Centered Clinical Research Network.Participants65 093 patients aged 20 to 79 years with body mass index (BMI) of 35 kg/m2 or greater who had bariatric procedures.Intervention32 208 Roux-en-Y gastric bypass (RYGB), 29 693 sleeve gastrectomy (SG), and 3192 adjustable gastric banding (AGB) procedures.MeasurementsEstimated percent total weight loss (TWL) at 1, 3, and 5 years; 30-day rates of major adverse events.ResultsTotal numbers of eligible patients with weight measures at 1, 3, and 5 years were 44 978 (84%), 20 783 (68%), and 7159 (69%), respectively. Thirty-day rates of major adverse events were 5.0% for RYGB, 2.6% for SG, and 2.9% for AGB. One-year mean TWLs were 31.2% (95% CI, 31.1% to 31.3%) for RYGB, 25.2% (CI, 25.1% to 25.4%) for SG, and 13.7% (CI, 13.3% to 14.0%) for AGB. At 1 year, RYGB patients lost 5.9 (CI, 5.8 to 6.1) percentage points more weight than SG patients and 17.7 (CI, 17.3 to 18.1) percentage points more than AGB patients, and SG patients lost 12.0 (CI, 11.6 to 12.5) percentage points more than AGB patients. Five-year mean TWLs were 25.5% (CI, 25.1% to 25.9%) for RYGB, 18.8% (CI, 18.0% to 19.6%) for SG, and 11.7% (CI, 10.2% to 13.1%) for AGB. Patients with diabetes, those with BMI less than 50 kg/m2, those aged 65 years or older, African American patients, and Hispanic patients lost less weight than patients without those characteristics.LimitationPotential unobserved confounding due to nonrandomized design; electronic health record databases had missing outcome data.ConclusionAdults lost more weight with RYGB than with SG or AGB at 1, 3, and 5 years; however, RYGB had the highest 30-day rate of major adverse events. Small subgroup differences in weight loss outcomes were observed.Primary funding sourcePatient-Centered Outcomes Research Institute.

BackgroundIn the United States, problematic stimulant use is a prevalent and difficult to treat problem among men who have sex with men (MSM), as well as a major driver of HIV transmission through the large number of sexual partners and concomitant condomless anal sex (CAS). Evidence-based behavioral studies that address problematic stimulant use in MSM at risk for HIV infection are also lacking. In this paper, we describe the design of a behavioral intervention trial to reduce sexual risk behavior and stimulant use in HIV-uninfected MSM.MethodsThis study, funded by the National Institute on Drug Abuse (NIDA), is a randomized controlled trial (RCT) testing an integrated HIV risk reduction and behavioral activation counseling intervention (IMPACT) for HIV-uninfected, stimulant using MSM in Boston, MA, and Miami, FL. Participants are randomized (2:2:1) to either (1) the IMPACT intervention; (2) a relaxation condition, an active therapy time- and intensity-matched control; or (3) a standard of care risk reduction counseling comparison. At enrollment, all participants receive an HIV test and pre- and post-test counseling. The primary outcome is the difference in the rate of change in the number of self-reported condomless anal sex acts without the protection of consistent Pre-Exposure Prophylaxis (PrEP) use, as well as reductions in stimulant use during the prior 4-months. Major assessments are conducted at baseline, 4-, 8-, and 12-month follow-up visits.DiscussionEffective and sustainable behavioral interventions are sorely needed to reduce HIV acquisition in stimulant using MSM at risk for HIV infection. In this study, we will evaluate the evidence of efficacy of the IMPACT intervention to reduce HIV acquisition in HIV-uninfected, stimulant-using MSM. If found effective, the intervention tested here holds promise for being readily integrated into real-world clinical settings.Trial registrationClinicalTrials.gov number NCT03175159 , registered June 5, 2017.

Combining cytarabine and mitoxantrone with the tricarboxylic acid cycle inhibitor devimistat has been reported in a phase I clinical trial with relapsed or refractory acute myeloid leukaemia (AML). Here, the authors report the outcomes of a phase II study, analyse samples from both phases and perform preclinical analyses that show mitochondrial fission or autophagy inhibition sensitizes AML cells to devimistat.

BackgroundThe sexual health of transmasculine (TM) people—those who identify as male, men, or nonbinary and were assigned a female sex at birth—is understudied. One barrier to conducting HIV- and sexually transmitted infection (STI)–related research with this population is how to best capture sexual risk data in an acceptable, gender-affirming, and accurate manner. ObjectiveThis study aimed to report on the community-based process of developing, piloting, and refining a digitally deployed measure to assess self-reported sexual behaviors associated with HIV and STI transmission for research with TM adults. MethodsA multicomponent process was used to develop a digital-assisted self-interview to assess HIV and STI risk in TM people: gathering input from a Community Task Force; working with an interdisciplinary team of content experts in transgender medicine, epidemiology, and infectious diseases; conducting web-based focus groups; and iteratively refining the measure. We field-tested the measure with 141 TM people in the greater Boston, Massachusetts area to assess HIV and STI risk. Descriptive statistics characterized the distribution of sexual behaviors and HIV and STI transmission risk by the gender identity of sexual partners. ResultsThe Transmasculine Sexual Health Assessment (TM-SHA) measures the broad range of potential sexual behaviors TM people may engage in, including those which may confer risk for STIs and not just for HIV infection (ie, oral-genital contact); incorporates gender-affirming language (ie, genital or frontal vs vaginal); and asks sexual partnership characteristics (ie, partner gender). Among 141 individual participants (mean age 27, SD 5 years; range 21-29 years; n=21, 14.9% multiracial), 259 sexual partnerships and 15 sexual risk behaviors were reported. Participants engaged in a wide range of sexual behaviors, including fingering or fisting (receiving: n=170, 65.6%; performing: n=173, 66.8%), oral-genital sex (receiving: n=182, 70.3%; performing: n=216, 83.4%), anal-genital sex (receptive: n=31, 11.9%; insertive: n=9, 3.5%), frontal-genital sex (receptive: n=105, 40.5%; insertive: n=46, 17.8%), and sharing toys or prosthetics during insertive sex (n=62, 23.9%). Overall barrier use for each sexual behavior ranged from 10.9% (20/182) to 81% (25/31). Frontal receptive sex with genitals and no protective barrier was the highest (21/42, 50%) with cisgender male partners. In total, 14.9% (21/141) of participants reported a lifetime diagnosis of STI. The sexual history tool was highly acceptable to TM participants. ConclusionsThe TM-SHA is one of the first digital sexual health risk measures developed specifically with and exclusively for TM people. TM-SHA successfully integrates gender-affirming language and branching logic to capture a wide array of sexual behaviors. The measure elicits sexual behavior information needed to assess HIV and STI transmission risk behaviors. A strength of the tool is that detailed partner-by-partner data can be used to model partnership-level characteristics, not just individual-level participant data, to inform HIV and STI interventions.

Abstract Background The purpose of this formative study was to assess barriers and facilitators to participation of transgender and gender diverse (TGD) patients in clinical research to solicit specific feedback on perceived acceptability and feasibility of research methods to inform creation of a multisite longitudinal cohort of primary care patients engaged in care at two community health centers. Method Between September–November 2018, four focus groups (FGs) were convened at two community health centers in Boston, MA and New York, NY (N = 28 participants across all 4 groups; 11 in Boston and 17 in New York). FG guides asked about patient outreach, acceptability of study methods and measures, and ideas for study retention. FGs were facilitated by TGD study staff, lasted approximately 90 min in duration, were audio recorded, and then transcribed verbatim by a professional transcription service. Thematic analyses were conducted by two independent analysts applying a constant comparison method. Consistency and consensus were achieved across code creation and application aided by Dedoose software. Results Participants were a mean age of 33.9 years (SD 12.3; Range 18–66). Participants varied in gender identity with 4 (14.3%) men, 3 (10.7%) women, 8 (28.6%) transgender men, 10 (35.7%) transgender women, and 3 (10.7%) nonbinary. Eight (26.6%) were Latinx, 5 (17.9%) Black, 3 (10.7%) Asian, 3 (10.7%) another race, and 5 (17.9%) multiracial. Motivators and facilitators to participation were: research creating community, research led by TGD staff, compensation, research integrated into healthcare, research applicable to TGD and non-TGD people, and research helping TGD communities. Barriers were: being research/healthcare averse, not identifying as TGD, overlooking questioning individuals, research coming from a ‘cisgender lens”, distrust of how the research will be used, research not being accessible to TGD people, and research being exploitative. Conclusion Though similarities emerged between the perspectives of TGD people and research citing perspectives of other underserved populations, there are barriers and facilitators to research which are unique to TGD populations. It is important for TGD people to be involved as collaborators in all aspects of research that concerns them.

Several protein expression platforms exist for a wide variety of biopharmaceutical needs. A substantial proportion of research and development into protein expression platforms and their optimization since the mid-1900s is a result of the production of viral antigens for use in subunit vaccine research. This review discusses the seven most popular forms of expression systems used in the past decade—bacterial, insect, mammalian, yeast, algal, plant and cell-free systems—in terms of advantages, uses and limitations for viral antigen production in the context of subunit vaccine research. Post-translational modifications, immunogenicity, efficacy, complexity, scalability and the cost of production are major points discussed. Examples of licenced and experimental vaccines are included along with images which summarize the processes involved. [ABSTRACT FROM AUTHOR]

Background: There is evidence indicating that chemoresistance in tumor cells is mediated by the reconfiguration of the tricarboxylic acid cycle, leading to heightened mitochondrial activity and oxidative phosphorylation (OXPHOS). Previously, we have shown that ovarian cancer cells that are resistant to chemotherapy display increased OXPHOS, mitochondrial function, and metabolic flexibility. To exploit this weakness in chemoresistant ovarian cancer cells, we examined the effectiveness of the mitochondrial inhibitor CPI-613 in treating preclinical ovarian cancer. Methods: Chemosensitive OVCAR3, and chemoresistant CAOV3 and F2 ovarian cancer cells lines and their xenografts in nude mice were used. Functional metabolic studies were performed using Seahorse instrument. Metabolite quantification was performed using LC/MS/MS. Results: Mice treated with CPI-613 exhibited a notable increase in overall survival and a reduction in tumor development and burden in OVCAR3, F2, and CAOV3 xenografts. CPI-613 suppressed the activity of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complex, which are two of its targets. This led to a reduction in OXPHOS and tricarboxylic acid cycle activity in all 3 xenografts. The addition of CPI-613 enhanced the responsiveness of chemotherapy in the chemoresistant F2 and CAOV3 tumors, resulting in a notable improvement in survival rates and a reduction in tumor size as compared to using chemotherapy alone. CPI-613 reduced the chemotherapy-induced OXPHOS in chemoresistant tumors. The study revealed that the mechanism by which CPI-613 inhibits tumor growth is through mitochondrial collapse. This is evidenced by an increase in superoxide production within the mitochondria, a decrease in ATP generation, and the release of cytochrome C, which triggers mitochondria-induced apoptosis. Conclusion: Our study demonstrates the translational potential of CPI-613 against chemoresistant ovarian tumors. [ABSTRACT FROM AUTHOR]

Patterns of cohort decline are key demographic traits that provide a unique temporal perspective vital to understanding population dynamics. The discovery of multidecadal lifespans in tropical surgeonfishes in the 1990s created a paradigm shift to the notion that they are highly vulnerable species with low population recovery rates; however, research into the mortality patterns of surgeonfishes (Acanthuridae) has been sparse until recently. Recent studies on this family have demonstrated an unusual (possibly unique), two‐phase pattern of adult catch‐at‐age, whereby there is a population‐level shift from higher‐than‐expected rates of decline early in life to lower‐than‐expected decline rates for the remainder of the lifespan. To examine the geographic and phylogenetic ubiquity of this pattern, we compiled age‐based information from demographic samples of 70 populations of 25 tropical species spanning the Indo‐Central Pacific and Central‐Western Atlantic. Overall, we found that 79% of populations exhibited strong biphasic patterns, including 88% of populations across the Indo‐Central Pacific. By accounting for empirical relationships instead of using linear catch curves or classical assumptions of natural population decay based on lifespan, we demonstrate that surgeonfishes have turnover times that are two to four times faster than previously believed. Faster turnover times may suggest a higher level of sustainability for surgeonfish fisheries throughout the global tropics than previously estimated. [ABSTRACT FROM AUTHOR]