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Copper, an essential element for various biological processes, demands precise regulation to avert detrimental health effects and potential cell toxicity. This paper explores the mechanisms of copper-induced cell death, known as cuproptosis, and its potential health and disease implications, including cancer therapy. Copper ionophores, such as elesclomol and disulfiram, increase intracellular copper levels. This elevation triggers oxidative stress and subsequent cell death, offering potential implications in cancer therapy. Additionally, copper ionophores disrupt mitochondrial respiration and protein lipoylation, further contributing to copper toxicity and cell death. Potential targets and biomarkers are identified, as copper can be targeted to those proteins to trigger cuproptosis. The role of copper in different cancers is discussed to understand targeted cancer therapies using copper nanomaterials, copper ionophores, and copper chelators. Furthermore, the role of copper is explored through diseases such as Wilson and Menkes disease to understand the physiological mechanisms of copper. Exploring cuproptosis presents an opportunity to improve treatments for copper-related disorders and various cancers, with the potential to bring significant advancements to modern medicine.

Abstract Disclosure: C. Springer: None. T. Janas: None. K.H. Stopsack: None. D.R. Schmidt: None. D. Ma: None. Z. Li: None. M.G. Vander Heiden: None. K.L. Penny: None. P.A. Scheet: None. T.L. Lotan: None. A. Amon: None. L.A. Mucci: None. X. Su: None. Prostate cancer (PCa) remains the second leading cause of cancer-related mortality among men in the United States. Aneuploidy, characterized by imbalanced chromosome numbers, correlates with lethal PCa progression. Chromosome 8q (chr8q) gain is one of the most frequent aneuploidy events, occurring in 23% of PCa cases. Recently, we ranked odds ratio (OR) for each chr8q gene to assess the long-term risk of metastases and death from PCa (lethal disease) within 403 patients in the HPFS and PHS cohorts. We observed that the squalene monooxygenase (SQLE) is one of the top ranked genes on chr8q, with an OR of 2.2. SQLE, encoding the key enzyme in cholesterol biosynthesis pathway, has been shown to be associated with poor prognosis in PCa, suggesting it as a potential target to treat aggressive PCa. Datasets such as The Cancer Genome Atlas (TCGA) and the Prostate Cancer Atlas were used to correlate the copy number and mRNA expression levels and the progression of PCa. We focused on mouse prostate organoids (both normal and cancer-like) and human metastatic prostate cell line, VCaP cell, expressing TMPRSS2-ERG gene, which approximately 50% of PCa cases harbors. We used lentiviral transduction to introduce either SQLE overexpression in prostate organoids (which harbor euploid SQLE) or SQLE shRNA in VCaP cells (which harbor increased SQLE). Molecular and cellular approaches were employed to study the influences of altered SQLE levels on target prostate cells. Ultra performance liquid chromatography (UPLC) with mass spectrometry (MS) was used to analyze the changed levels of squalene and lipid profiles when SQLE levels were altered. Overexpression of SQLE in cancer-like mouse prostate organoid models led to increased invasive structures and proliferation. RNA sequencing data suggested that alteration in SQLE levels changes gene signatures related to lipid metabolisms. Interestingly, SQLE overexpression decreased TMPRSS2-ERG protein levels in the organoids. In contrast, SQLE knockdown in VCaP cells resulted in significantly increased TMPRSS2-ERG protein levels. ERG is associated with fatty acid metabolism in PCa cohorts. Our findings suggest that aneuploidy-associated overexpression of SQLE drives PCa aggressiveness by modulating lipid metabolism, particularly through its impact on cholesterol biosynthesis and TMPRSS2-ERG regulation. Targeting SQLE could present a novel therapeutic approach to treat aggressive PCa. Presentation: Saturday, July 12, 2025

The widespread transmission and evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) call for rapid nucleic acid diagnostics that are easy to use outside of centralized clinical laboratories. Here we report the development and performance benchmarking of Cas13-based nucleic acid assays leveraging lyophilised reagents and fast sample inactivation at ambient temperature. The assays, which we named SHINEv.2 (for ‘streamlined highlighting of infections to navigate epidemics, version 2’), simplify the previously reported RNA-extraction-free SHINEv.1 technology by eliminating heating steps and the need for cold storage of the reagents. SHINEv.2 detected SARS-CoV-2 in nasopharyngeal samples with 90.5% sensitivity and 100% specificity (benchmarked against the reverse transcription quantitative polymerase chain reaction) in less than 90 min, using lateral-flow technology and incubation in a heat block at 37 °C. SHINEv.2 also allows for the visual discrimination of the Alpha, Beta, Gamma, Delta and Omicron SARS-CoV-2 variants, and can be run without performance losses by using body heat. Accurate, easy-to-use and equipment-free nucleic acid assays could facilitate wider testing for SARS-CoV-2 and other pathogens in point-of-care and at-home settings. SARS-CoV-2 and its variants can be visually detected via easy-to-use Cas13-based nucleic acid tests leveraging lyophilised reagents and fast sample inactivation at ambient temperature.

INTRODUCTION:We determined steatotic liver disease (SLD) incidence in a prospective cohort of men with HIV (MWH) and men without HIV (MWOH).METHODS:Incident SLD was defined using paired noncontrast computed tomography scans performed during 2010-2013 and repeated during 2015-2017.RESULTS:Of 268 men, 173 MWH and 95 MWOH, 33 had incident SLD (11.1%, incidence rate 2.4 and 2.7/100 person-years for MWH and MWOH, respectively). Overall, higher abdominal visceral adipose tissue was independently associated with increased SLD risk. In MWH, increased visceral adipose tissue, insulin resistance, chronic hepatitis B, and cumulative etravirine use were associated with SLD.DISCUSSION:Metabolic factors, but not HIV, were associated with incident SLD. The high incidence rate suggests that SLD will continue to increase in PWH.

Background African-Americans (AAs) have higher rates of inactivity, obesity, and cardiometabolic risk compared to other races/ethnicities. Romantic partners can positively influence health habits, yet whether or not couples have to exercise together in order to adopt regular exercise remains unclear. This study examined whether exercising together influences exercise adherence and cardiometabolic risk in AA couples. Methods Nine AA romantic couples (age 62.8 ± 7.7 years; body mass index 31.0 ± 4.4 kg/m 2 ; 6105 ± 1689 average steps/day) completed a 12-week walking (≥ 30 min, 3 days/week) plus resistance training (RT; 2 days/week) pilot intervention. Couples were randomized to either exercise together (ET) or separately (ES). Waist and hip circumferences, iDXA-measured body composition, blood pressure, and blood biomarkers (glucose, hemoglobin A1c (HbA1c), total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, C-reactive protein, and fibrinogen) were assessed pre- and post-intervention. Independent-sample t tests and generalized linear mixed models, controlling for gender, were used to analyze data. Significance was accepted at P  < 0.05. Results There were no significant group × time interactions for any outcome. However, ET trended toward more walking (86.5 ± 57.7 min/week) than ES (66.1 ± 31.7 min/week). There were also significant overall time effects for waist circumference ( P  < 0.001), body fat ( P  = 0.020), fat mass ( P  = 0.007), gynoid fat ( P  = 0.041), HbA1c ( P  = 0.020), and HDL ( P  = 0.047), where all variables decreased. Conclusions Trends showed exercising together may promote walking prescription adherence, although more research is needed in a larger sample. This intervention may also improve cardiometabolic risk factors in this population. These pilot data will inform the current investigators’ future exercise intervention research in AA adult dyads.

Loss-of-function mutations in the genes encoding PINK1 and PRKN result in early-onset Parkinson disease (EOPD). Together the encoded enzymes direct a neuroprotective pathway that ensures the elimination of damaged mitochondria via autophagy. We performed a genome-wide high content imaging miRNA screen for inhibitors of the PINK1-PRKN pathway and identified all three members of the miRNA family 29 (miR-29). Using RNAseq we identified target genes and found that siRNA against ATG9A phenocopied the effects of miR-29 and inhibited the initiation of PINK1-PRKN mitophagy. Furthermore, we discovered two rare, potentially deleterious, missense variants (p.R631W and p.S828L) in our EOPD cohort and tested them experimentally in cells. While expression of wild-type ATG9A was able to rescue the effects of miR-29a, the EOPD-associated variants behaved like loss-of-function mutations. Together, our study validates miR-29 and its target gene ATG9A as novel regulators of mitophagy initiation. It further serves as proof-of-concept of finding novel, potentially disease-causing EOPD-linked variants specifically in mitophagy regulating genes. The nomination of genetic variants and biological pathways is important for the stratification and treatment of patients that suffer from devastating diseases, such as EOPDCompeting Interest StatementMayo Clinic, FCF and WS have filed a patent related to PRKN activators. WEG is an employee of Revvity, formerly known as Perkin Elmer (Waltham, MA, USA). ZKW serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206) and Vigil Neuroscience, Inc. (VGL101-01.002, VGL101-01.201, PET tracer development protocol, Csf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) projects/grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research, as an external advisory board member for the Vigil Neuroscience, Inc., and as a consultant on neurodegenerative medical research for Eli Lilly & Company. All other authors declare they have no competing interests. This research was conducted in compliance with Mayo Clinic conflict of interest policies.