Drp1 splice variants regulate ovarian cancer mitochondrial dynamics and tumor progression.

Aberrant mitochondrial fission/fusion dynamics are frequently associated with pathologies, including cancer. We show that alternative splice variants of the fission protein Drp1 (DNM1L) contribute to the complexity of mitochondrial fission/fusion regulation in tumor cells. High tumor expression of the Drp1 alternative splice variant lacking exon 16 relative to other transcripts is associated with poor outcome in ovarian cancer patients. Lack of exon 16 results in Drp1 localization to microtubules and decreased association with mitochondrial fission sites, culminating in fused mitochondrial networks, enhanced respiration, changes in metabolism, and enhanced pro-tumorigenic phenotypes in vitro and in vivo. These effects are inhibited by siRNAs designed to specifically target the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the pathophysiological importance of Drp1 alternative splicing, highlight the divergent functions and consequences of changing the relative expression of Drp1 splice variants in tumor cells, and strongly warrant consideration of alternative splicing in future studies focused on Drp1.

GPX3 supports ovarian cancer tumor progression in vivo and promotes expression of GDF15.

OBJECTIVE: We previously reported that high expression of the extracellular glutathione peroxidase GPX3 is associated with poor patient outcome in ovarian serous adenocarcinomas, and that GPX3 protects ovarian cancer cells from oxidative stress in culture. Here we tested if GPX3 is necessary for tumor establishment in vivo and to identify novel downstream mediators of GPX3's pro-tumorigenic function. METHODS: GPX3 was knocked-down in ID8 ovarian cancer cells by shRNA to test the role of GPX3 in tumor establishment using a syngeneic IP xenograft model. RNA sequencing analysis was carried out in OVCAR3 cells following shRNA-mediated GPX3 knock-down to identify GPX3-dependent gene expression signatures. RESULTS: GPX3 knock-down abrogated clonogenicity and intraperitoneal tumor development in vivo, and the effects were dependent on the level of GPX3 knock-down. RNA sequencing showed that loss of GPX3 leads to decreased gene expression patterns related to pro-tumorigenic signaling pathways. Validation studies identified GDF15 as strongly dependent on GPX3. GDF15, a member of the TGF-ß growth factor family, has known oncogenic and immune modulatory activities. Similarly, GPX3 expression positively correlated with pro-tumor immune cell signatures, including regulatory T-cell and macrophage infiltration, and displayed significant correlation with PD-L1 expression. CONCLUSIONS: We show for the first time that tumor produced GPX3 is necessary for ovarian cancer growth in vivo and that it regulates expression of GDF15. The immune profile associated with GPX3 expression in serous ovarian tumors suggests that GPX3 may be an alternate marker of ovarian tumors susceptible to immune check-point inhibitors.

Urine cadmium and urolithiasis: A systematic review and meta-analysis.

Exposure to cadmium may increase risk of urolithiasis, but the results remain inconclusive. This systematic review and meta-analysis aimed to access the association between cadmium exposure and urolithiasis. We searched Medline/PubMed, Embase, Web of Science Core Collection, and Cochrane Central for studies. The primary outcome was the incidence of urolithiasis compared to reference groups. We used relative risk as the summary effect measure. This meta-analysis included eight observational studies and divided into 39 study populations. Among 63,051 subjects, 5018 (7.96%) individuals had urolithiasis. The results indicated that people with an increment of 0.1 µg/g creatinine in urinary cadmium had a 2% increased risk of urolithiasis (pooled relative risk [RR], 1.02; 95% confidence interval [CI], 1.01-1.03) and there is no difference in the risk of urolithiasis in high and low cadmium exposure levels. Meanwhile, people with an increment of 0.1 µg/L in urinary cadmium had a 4% increased risk of urolithiasis (pooled RR, 1.04; 95% CI, 1.02-1.07). Our findings also showed similar associations in both sex, different region (Sweden, China, and Thailand), general and occupational population. The results indicate that cadmium exposure was significantly associated with an elevated risk of urolithiasis. Therefore, it is imperative to take steps to minimize cadmium exposure.

Triage body temperature and its influence on patients with acute myocardial infarction.

BACKGROUND: Fever can occur after acute myocardial infarction (MI). The influence of body temperature (BT) after hospital arrival on patients with acute MI has rarely been investigated. METHODS: Patients who were diagnosed with acute MI in the emergency department (ED) of a tertiary teaching hospital between 1 January 2020 and 31 December 2020 were enrolled. Based on the tympanic temperature obtained at the ED triage, patients were categorized into normothermic (35.5°C-37.5°C), hypothermic (< 35.5°C), or hyperthermic (> 37.5°C) groups. The primary outcome was in-hospital cardiac arrest (IHCA), while the secondary outcomes were adverse events. Statistical significance was set at p < 0.05. RESULTS: There were 440 enrollees; significant differences were found among the normothermic (n = 369, 83.9%), hypothermic (n = 27, 6.1%), and hyperthermic (n = 44, 10.0%) groups in the triage respiratory rate (median [IQR]) (20.0 [4.0] cycles/min versus 20.0 [4.0] versus 20.0 [7.5], p = 0.009), triage heart rate (88.0 [29.0] beats/min versus 82.0 [28.0] versus 102.5 [30.5], p < 0.001), presence of ST-elevation MI (42.0% versus 66.7% versus 31.8%, p = 0.014), need for cardiac catheterization (87.3% versus 85.2% versus 72.7%, p = 0.034), initial troponin T level (165.9 [565.2] ng/L versus 49.1 [202.0] versus 318.8 [2002.0], p = 0.002), peak troponin T level (343.8 [1405.9] ng/L versus 218.7 [2318.2] versus 832.0 [2640.8], p = 0.003), length of ICU stay (2.0 [3.0] days versus 3.0 [8.0] versus 3.0 [9.5], p = 0.006), length of hospital stay (4.0 [4.5] days versus 6.0 [15.0] versus 10.5 [10.8], p < 0.001), and infection during hospitalization (19.8% versus 29.6% versus 63.6%, p < 0.001) but not in IHCA (7.6% versus 14.8% versus 11.4%, p = 0.323) or any adverse events (50.9% versus 48.1% versus 63.6%, p = 0.258). Multivariable analysis showed no significant association of triage BT with IHCA or any major complication. CONCLUSION: Triage BT did not show a significant association with IHCA or adverse events in patients with acute MI. However, triage BT could be associated with different clinical presentations and should warrant further investigation.

Assessing anti-doping knowledge among Taiwanese pharmacists.

BACKGROUND: Taiwan's unique health behaviour, such as extensive exposure to Chinese Herbal Medicine (CHM), has introduced a risk of inadvertent doping among competing athletes. Pharmacy professionals have an imperative role in advising athletes on the safe use of medicines. This study provides an overview of anti-doping knowledge and educational needs among pharmacists in Taiwan and examines influencing factors. METHODS: A cross-sectional online questionnaire survey consisting of five domains, namely demographic characteristics, source of prohibited substances, identification of prohibited substances, understanding of doping control, and education needs on anti-doping, was distributed to the registered pharmacists in Taiwan. In total, 491 responses were included in the analyses. RESULTS: Respondents (65% female, aged 41.9 ± 11.4 years, with 68% having a Bachelor's degree) reported a moderate anti-doping knowledge score of 37.2 ± 4.9, ranging from 21 to 48 (out of 51). Fifteen per cent of them had the experience of being counselled about drug use in sports. Higher knowledge scores were observed in younger respondents, showing an age-dependent effect (p < 0.001). Individuals practising in southern Taiwan (compared to northern Taiwan) and those working at clinics (compared to hospitals) exhibited lower knowledge. Most of the respondents (90%) knew that stimulant ephedrine is prohibited in sports, but few had recognised diuretic furosemide (38%) and CHM (7%) containing ß2-agonist higenamine. Approximately 90% of respondents agreed with the need for anti-doping education. CONCLUSIONS: This study highlights the heterogeneity of anti-doping knowledge among pharmacy professionals and provides practical relevance in organising future educational topics and research-based activities.

Serotonin receptor HTR6-mediated mTORC1 signaling regulates dietary restriction-induced memory enhancement.

Dietary restriction (DR; sometimes called calorie restriction) has profound beneficial effects on physiological, psychological, and behavioral outcomes in animals and in humans. We have explored the molecular mechanism of DR-induced memory enhancement and demonstrate that dietary tryptophan-a precursor amino acid for serotonin biosynthesis in the brain-and serotonin receptor 5-hydroxytryptamine receptor 6 (HTR6) are crucial in mediating this process. We show that HTR6 inactivation diminishes DR-induced neurological alterations, including reduced dendritic complexity, increased spine density, and enhanced long-term potentiation (LTP) in hippocampal neurons. Moreover, we find that HTR6-mediated mechanistic target of rapamycin complex 1 (mTORC1) signaling is involved in DR-induced memory improvement. Our results suggest that the HTR6-mediated mTORC1 pathway may function as a nutrient sensor in hippocampal neurons to couple memory performance to dietary intake.

Development and validation of the dialysis dementia risk score: A retrospective, population-based, nested case-control study.

BACKGROUND: Dementia is prevalent and underdiagnosed in the dialysis population. We aimed to develop and validate a simple dialysis dementia scoring system to facilitate identification of individuals who are at high risk for dementia. METHODS: We applied a retrospective, nested case-control study design using a national dialysis cohort derived from the National Health Insurance Research Database in Taiwan. Patients aged between 40 and 80 years were included and 2940 patients with incident dementia were matched to 29,248 non-dementia controls. All subjects were randomly divided into the derivation and validation sets with a ratio of 4:1. Conditional logistic regression models were used to identify factors contributing to the risk score. The cutoff value of the risk score was determined by Youden's J statistic and the graphic method. RESULTS: The dialysis dementia risk score (DDRS) finally included age and 10 comorbidities as risk predictors. The C-statistic of the model was 0.71 (95% confidence interval [CI] 0.70-0.72). Calibration revealed a strong linear relationship between predicted and observed dementia risk (R2  = 0.99). At a cutoff value of 50 points, the high-risk patients had an approximately three-fold increased risk of having dementia compared to those with low risk (odds ratio [OR] 3.03, 95% CI 2.78-3.31). The DDRS performance, including discrimination (C-statistic 0.71, 95% CI 0.69-0.73) and calibration (p value of Hosmer-Lemeshow test for goodness of fit = 0.18), was acceptable during validation. The OR value (2.82, 95% CI 2.37-3.35) was similar to those in the derivation set. CONCLUSION: The DDRS system has the potential to serve as an easily accessible screening tool to determine the high-risk groups who deserve subsequent neurological evaluation in daily clinical practice.

Physiological changes and symptoms associated with short-term exposure to electromagnetic fields: a randomized crossover provocation study.

BACKGROUND: The biological association between electromagnetic fields (EMF) and idiopathic environmental intolerance attributed to EMF (IEI-EMF) has not been established. To assess the physiological changes and symptoms associated with exposure to EMF, we conducted a randomized crossover provocation study. METHODS: We recruited 58 individuals with IEI-EMF (IEI-EMF group) and 92 individuals without IEI-EMF (control group). In a controlled environment, all participants received EMF signals mimicking those from mobile phone base stations in a randomized sequence under the blinded condition. During the course, participants reported their symptoms and whether they perceived EMF, and we monitored their physiological parameters, including blood pressure (BP), heart rate (HR), and HR variability. RESULTS: The IEI-EMF and control groups reported similar frequencies of symptoms during both the provocation and sham sessions. No participant could accurately identify the provocation. In both groups, physiological parameters were similar between the two sessions. The control group, but not the IEI-EMF group, had elevated HR when they perceived EMF exposure. CONCLUSIONS: No symptoms or changes in physiological parameters were found to be associated with short-term exposure to EMF, and no participant could accurately detect the presence of EMF. Moreover, the participants in the control group, but not those in the IEI-EMF group, had elevated HR when they perceived EMF.

Establishment of disaster medical assistance team standards and evaluation of the teams' disaster preparedness: An experience from Taiwan.

BACKGROUND/PURPOSE: Taiwan set up disaster medical assistance teams (DMATs) after the Chi-Chi earthquake, but these teams lack unified standards. METHODS: This study was divided into two phases. Phase I was a Delphi study conducted in 2019 with 26 experts who were invited to establish Taiwan's DMAT standards by modifying the World Health Organization Emergency Medical Team (WHO EMT) type I fixed standards. Phase II was a cross-sectional study conducted in 2020. A questionnaire was used to evaluate the disaster preparedness of DMATs by standards set in phase I. RESULTS: In phase I, Taiwan's DMAT standards were established after three rounds of Delphi consensus, with a response rate of 88.5%. The major departures from the WHO EMT standards were the exclusion of obstetric care, mental health, rehabilitation, and laboratory and blood transfusion standards and the addition of an ultrasound standard. During phase II, a total of 32 teams were invited, and the response rate was 96.9%. The overall standard achievement rate was 56.9%, and the three lowest achievement rates corresponded to sanitation (22.6%), medical malpractice insurance (25.8%), and pharmacy and drug supply (25.8%). The national DMATs, official DMATs, DMATs funded by government, and DMATs with ≥10 years of experience had significantly higher achievement rates for partial or overall standards. CONCLUSION: Using localized standards to evaluate the disaster preparedness of each team, DMATs were found to have many shortcomings mainly due to the lack of unified government announcement standards, legal protection, and adequate financial support.

Micro- and Nanosized Substances Cause Different Autophagy-Related Responses.

With rapid industrialization, humans produce an increasing number of products. The composition of these products is usually decomposed. However, some substances are not easily broken down and gradually become environmental pollutants. In addition, these substances may cause bioaccumulation, since the substances can be fragmented into micro- and nanoparticles. These particles or their interactions with other toxic matter circulate in humans via the food chain or air. Whether these micro- and nanoparticles interfere with extracellular vesicles (EVs) due to their similar sizes is unclear. Micro- and nanoparticles (MSs and NSs) induce several cell responses and are engulfed by cells depending on their size, for example, particulate matter with a diameter ≤2.5 µm (PM2.5). Autophagy is a mechanism by which pathogens are destroyed in cells. Some artificial materials are not easily decomposed in organisms. How do these cells or tissues respond? In addition, autophagy operates through two pathways (increasing cell death or cell survival) in tumorigenesis. Many MSs and NSs have been found that induce autophagy in various cells and tissues. As a result, this review focuses on how these particles interfere with cells and tissues. Here, we review MSs, NSs, and PM2.5, which result in different autophagy-related responses in various tissues or cells.

Identification of carbonylated proteins in a bactericidal process induced by curcumin with blue light irradiation on imipenem-resistant Acinetobacter baumannii.

RATIONALE: Antimicrobial photodynamic treatment is potentially an alternative to antibiotics and is also effective against viruses, fungi and some cancers. Our previous studies have shown that blue light combined with curcumin, a chemical from the turmeric plant, exerted effective antimicrobial activity via photodynamic treatment. The study reported in this paper investigates which target proteins are affected after the treatment. METHODS: We treated imipenem-resistant Acinetobacter baumannii with blue light and curcumin and used protein carbonylation as a marker for oxidative damage. After treatment, the bacterial proteins were extracted and the protein carbonyls marked using dinitrophenylhydrazide. After enzyme digestion, we used liquid chromatography/nano-electrospray ionization (LC/nano-ESI) ion trap mass spectrometry to identify bacterial peptides from a customized database. The functional enrichment analyses of the identified proteins were performed using gene ontology annotation and the STRING protein-protein interaction network. RESULTS: The application of curcumin with blue light showed good antibacterial activity against imipenem-resistant A. baumannii. Using a shotgun proteomics approach, the carbonylated proteins in A. baumannii caused by the photolytic curcumin were identified. The results showed that the proteins related to membrane structures, translation and response to oxidative stress were preferentially modified. CONCLUSIONS: The photolytic curcumin treatment could be a potential alternative to antibiotics for bacterial infection. In this study, the shotgun proteomics strategy allows us to explore the possible bactericidal mechanisms under this oxidative stress. The result provides a reference for future studies on the enhancement of the action of photolytic curcumin.

The Relationship Between Occupational Exposure to Low-dose Ionizing Radiation and Changes in Thyroid Hormones in Hospital Workers.

BACKGROUND: The effects of ionized radiation on the thyroid have been extensively studied. However, most studies have focused on high-dose radiation received accidentally or through therapy, and few were on low-dose occupational exposure. METHODS: Using a retrospective cohort study design, we collected health examination reports from employees who worked on jobs with occupational exposure to radiation at a hospital to evaluate possible changes in the serum thyroid hormones and determine whether there is a dose-response effect. After excluding those with diseases that may affect thyroid function and who were pregnant at any given examination during the study periods we followed the remaining 326 workers for 12 years and evaluated the associations between radiation exposure and changes in serum thyroid hormones using the generalized estimating equation for repeated measures. Data from an external comparison cohort were used to adjust for changes over time. RESULTS: We observed declines in triiodothyronine (T3) and thyroxine (T4) over the study period, but not in thyroid-stimulating hormone (TSH). In addition, we found negative dose-response relationships between exposure duration and declines in the serum levels of T3 (a change of -0.037 ng/ml/year after adjusting for sex and age at the beginning of follow-up; 95% confidence interval [CI] = -0.042, -0.032 ng/ml/year) and T4 (-0.115 µg/dl/year; 95% CI = -0.140, -0.091 µg/dl/year). We also observed an increase in the TSH level (0.683 µIU/ml/year; 95% CI = 0.151, 1.214 µIU/ml/year) after the ninth year of follow-up. CONCLUSIONS: We concluded that despite low exposure doses, occupational exposure to ionizing radiation in healthcare workers still may be associated with the declines in the serum levels of T3 and T4.

Extrication time and earthquake-related mortality in the 2016 Taiwan earthquake.

BACKGROUND/PURPOSE: People with different age distributions and extrication times might have distinct injury characteristics and outcomes in earthquakes. METHODS: A retrospective study was conducted to analyze the casualties in the 2016 Taiwan earthquake using data from the incident registry system and the field disaster operation system. The study subjects were assigned to 4 groups by age: preschool (<5 years), school (5-17 years), adult (18-64 years), and elderly (>64 years). Classification and regression tree analysis and receiver-operating characteristic curves were utilized to examine several factors, including extrication time, age group, floor height, and structural damage, for earthquake-related mortality. A two-sided p value less than 0.05 was considered statistically significant. RESULTS: A total of 238 enrollees were assigned to the preschool (n = 18, 7.6%), school (n = 45, 18.9%), adult (n = 169, 71.0%), or elderly (n = 6, 2.5%) groups. Among the parameters, the extrication time exhibited the strongest association with mortality. Regarding the association between the extrication time and mortality hazard in multivariate models, we found significant odds ratios (ORs) at the extrication time cutoffs of 12, 24 and 72 h (OR = 42.61, 95% confidence interval [CI]: 13.92-130.37; OR = 37.58, 95% CI: 14.77-95.60; OR = 95.16, 95% CI: 23.02-393.48, respectively, all p < 0.001). The optimal extrication time cutoff for mortality was 12 h in the preschool group and 24 h in the school and adult groups. CONCLUSION: Extrication time is strongly associated with earthquake-related mortality. These findings may facilitate strategic approaches for patients entrapped in damaged buildings and can contribute to future training for field search and rescues after earthquakes.

Association of injury pattern and entrapment location inside damaged buildings in the 2016 Taiwan earthquake.

BACKGROUND/PURPOSE: To explore the association of patient injury patterns and entrapped locations inside damaged buildings in the 2016 Taiwan earthquake. METHODS: A retrospective analysis was conducted using the Tainan incident registry system. Residents inside nine conjunctive, 16-story (49.3 m in height) reinforced concrete buildings were categorized as non-injured, injured, and dead. Residents were classified into different groups according to their entrapped locations in height and the severity of building damage. The field triage acuity and trauma severity among groups were compared. Statistical significance was set at the level of 0.05. RESULTS: There were 309 enrollees with 76 (24.6%) non-injured, 118 (38.2%) injured, and 115 (37.2%) dead. Residents either in the high floors (odds ratio [OR] = 2.9, 95% CI: 1.5-5.8, p = 0.003) or in the collapsed buildings (OR = 18.2, 95% CI: 7.6-43.6, p < 0.001) were more likely to be dead. Injured patients who were located in the high floors were more likely to have severe field triage acuities (adjusted OR = 14.7, 95% CI: 1.8-118.0, p = 0.012); intracranial hemorrhage (12.5%), intrathoracic injury (18.8%), or intra-abdominal damage (12.5%) (All p < 0.05); the need for emergency surgical intervention (31.3%, p = 0.035); and major trauma (18.8%, p = 0.001). Residents in the collapsed buildings were more likely to have a crush injury (80.0%, p < 0.001) or crush syndrome (80.0%, p < 0.001). CONCLUSION: People entrapped at different heights of floors or in differently damaged buildings could have a distinct pattern of injury. Our findings may facilitate strategic approaches of patients entrapped in damaged buildings and may contribute to future training for field searches and rescues after earthquakes.

Astaxanthin Ameliorates Ischemic-Hypoxic-Induced Neurotrophin Receptor p75 Upregulation in the Endothelial Cells of Neonatal Mouse Brains.

Ischemic stroke is a leading cause of human death in present times. Two phases of pathological impact occur during an ischemic stroke, namely, ischemia and reperfusion. Both periods include individual characteristic effects on cell injury and apoptosis. Moreover, these conditions can cause severe cell defects and harm the blood-brain barrier (BBB). Also, the BBB components are the major targets in ischemia-reperfusion injury. The BBB owes its enhanced protective roles to capillary endothelial cells, which maintain BBB permeability. One of the nerve growth factor (NGF) receptors initiating cell signaling, once activated, is the p75 neurotrophin receptor (p75NTR). This receptor is involved in both the survival and apoptosis of neurons. Although many studies have attempted to explain the role of p75NTR in neurons, the mechanisms in endothelial cells remain unclear. Endothelial cells are the first cells to encounter p75NTR stimuli. In this study, we found the upregulated p75NTR expression and reductive expression of tight junction proteins after in vivo and in vitro ischemia-reperfusion injury. Moreover, astaxanthin (AXT), an antioxidant drug, was utilized and was found to reduce p75NTR expression and the number of apoptotic cells. This study verified that p75NTR plays a prominent role in endothelial cell death and provides a novel downstream target for AXT.

Association Between Dioxin and Metabolic Syndrome by Age and Sex in an Endemic Area of Exposure in Taiwan.

BACKGROUND: Some of the effects of dioxins seem to be different between men and women, and exposures starting at an early age seem to have more prominent effects. Therefore, we conducted a study in Taiwan to evaluate the associations between exposure to polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and metabolic syndrome (MetS) starting at different ages in both sexes. METHODS: We recruited participants from an area where residents were exposed to PCDD/Fs released from a factory and defined serum PCDD/Fs levels ≥20 pg WHO98-TEQDF/g lipid as high dioxin levels. MetS was defined as meeting three of the following criteria: fasting glucose ≥100 mg/dl or under treatment for diabetes, waist circumference ≥90 cm in men or ≥80 cm in women, triglycerides ≥150 mg/dl or under treatment for elevated triglycerides, high-density lipoprotein <40 mg/dl in men or <50 mg/dl in women, and blood pressures ≥130/85 mmHg or under treatment for hypertension. RESULTS: Of the 2758 participants, 785 patients with MetS were identified, and we observed positive associations between a high dioxin level and MetS. After adjusting for sex, age, and age at starting exposure, we found that a high dioxin level was an independent predictor for MetS (adjusted odds ratio =1.38; 95% confidence interval = 1.11, 1.72). When we stratified the participants by gender, we found that a high dioxin level remained an independent predictor of MetS in men, but not in women, regardless of the age at starting exposure. CONCLUSIONS: Exposure to PCDD/Fs was associated with MetS in men, independent of age and age at starting exposure.

Investigating the role of social inhibition in enduring involvement in online synchronous exercise classes: A use and gratification perspective.

With the advancement of communication technology, online synchronous exercise courses become more common in recent years due to their ability to transcend time and space. Based on uses and gratifications theory (U&G), this study proposes a conceptual model for online synchronized exercise classes and examines the relationships among social inhibition, motivation, satisfaction, and continued involvement. After 322 valid questionnaires were collected and analyzed by partial least squares (PLS), this study confirmed the significant positive effects of hedonic, identified, and integrative motivation on online synchronous exercise satisfaction and the significant negative effect of social inhibition on online synchronous exercise satisfaction. Moreover, online synchronous exercise satisfaction has a positive effect on enduring involvement. This study not only contributes by extending the application of U&G theory to dynamic online synchronized exercise and addressing the interaction and pressure of online users in cyberspace but also provides novel marketing strategies for fitness and sports organizations.

GPX3 supports ovarian cancer tumor progression in vivo and promotes expression of GDF15.

Objective: We previously reported that high expression of the extracellular glutathione peroxidase GPX3 is associated with poor patient outcome in ovarian serous adenocarcinomas, and that GPX3 protects ovarian cancer cells from oxidative stress in culture. Here we tested if GPX3 is necessary for tumor establishment in vivo and to identify novel downstream mediators of GPX3's pro-tumorigenic function. Methods: GPX3 was knocked-down in ID8 ovarian cancer cells by shRNA to test the role of GPX3 in tumor establishment using a syngeneic IP xenograft model. RNA sequencing analysis was carried out in OVCAR3 cells following shRNA-mediated GPX3 knock-down to identify GPX3-dependent gene expression signatures. Results: GPX3 knock-down abrogated clonogenicity and intraperitoneal tumor development in vivo, and the effects were dependent on the level of GPX3 knock-down. RNA sequencing showed that loss of GPX3 leads to decreased gene expression patterns related to pro-tumorigenic signaling pathways. Validation studies identified GDF15 as strongly dependent on GPX3. GDF15, a member of the TGF-ß growth factor family, has known oncogenic and immune modulatory activities. Similarly, GPX3 expression positively correlated with pro-tumor immune cell signatures, including regulatory T-cell and macrophage infiltration, and displayed significant correlation with PD-L1 expression. Conclusions: We show for the first time that tumor produced GPX3 is necessary for ovarian cancer growth in vivo and that it regulates expression of GDF15. The immune profile associated with GPX3 expression in serous ovarian tumors suggests that GPX3 may be an alternate marker of ovarian tumors susceptible to immune check-point inhibitors.

Alternative splice variants of the mitochondrial fission protein DNM1L/Drp1 regulate mitochondrial dynamics and tumor progression in ovarian cancer.

Aberrant mitochondrial fission/fusion dynamics have been reported in cancer cells. While post translational modifications are known regulators of the mitochondrial fission/fusion machinery, we show that alternative splice variants of the fission protein Drp1 (DNM1L) have specific and unique roles in cancer, adding to the complexity of mitochondrial fission/fusion regulation in tumor cells. Ovarian cancer specimens express an alternative splice transcript variant of Drp1 lacking exon 16 of the variable domain, and high expression of this splice variant relative to other transcripts is associated with poor patient outcome. Unlike the full-length variant, expression of Drp1 lacking exon 16 leads to decreased association of Drp1 to mitochondrial fission sites, more fused mitochondrial networks, enhanced respiration, and TCA cycle metabolites, and is associated with a more metastatic phenotype in vitro and in vivo. These pro-tumorigenic effects can also be inhibited by specific siRNA-mediated inhibition of the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the significance of the pathophysiological consequences of Drp1 alternative splicing and divergent functions of Drp1 splice variants, and strongly warrant consideration of Drp1 splicing in future studies.

Air pollution associate with advanced hepatic fibrosis among patients with chronic liver disease.

We aimed to investigate the association between air pollution and advanced fibrosis among patients with metabolic associated fatty liver disease (MAFLD) and chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. A total of 1376 participants who were seropositive for HBV surface antigen (HBsAg) or antibodies to HCV (anti-HCV) or had abnormal liver function in a community screening program from 2019 to 2021 were enrolled for the assessment of liver fibrosis using transient elastography. Daily estimates of air pollutants (particulate matter ≤2.5 µm in diameter [PM2.5 ], nitrogen dioxide [NO2 ], ozone [O3 ] and benzene) were aggregated into mean estimates for the previous year based on the date of enrolment. Of the 1376 participants, 767 (52.8%) and 187 (13.6) had MAFLD and advanced fibrosis, respectively. A logistic regression analysis revealed that the factors associated with advanced liver fibrosis were HCV viremia (odds ratio [OR], 3.13; 95% confidence interval [CI], 2.05-4.77; p < 0.001), smoking (OR, 1.79; 95% CI, 1.16-2.74; p = 0.01), age (OR, 1.04; 95% CI, 1.02-1.05; p < 0.001) and PM2.5 (OR, 1.10; 95% CI, 1.05-1.16; p < 0.001). Linear regression analysis revealed that LSM was independently correlated with PM2.5 (ß: 0.134; 95% CI: 0.025, 0.243; p = 0.02). There was a dose-dependent relationship between different fibrotic stages and the PM2.5 level (the PM2.5 level in patients with fibrotic stages 0, 1-2 and 3-4: 27.9, 28.4, and 29.3 µg/m3 , respectively; trend p < 0.001). Exposure to PM2.5 , as well as HBV and HCV infections, is associated with advanced liver fibrosis in patients with MAFLD. There was a dose-dependent correlation between PM2.5 levels and the severity of hepatic fibrosis.