Survival outcomes and treatment experience of 124 patients with primary central nervous system lymphoma.

PURPOSE: Primary central nervous system lymphoma (PCNSL) is a rare malignancy of the central nervous system with high invasiveness. There is little consensus on the treatment of PCNSL. This study retrospectively studied data from PCNSL patients in a single center to summarize treatment experience and explore prognostic factors. METHODS: Survival curves were drawn using the Kaplan-Meier method and prognostic factors were analyzed using Cox's hazards model. RESULTS: In multivariate analysis, cerebrospinal fluid lactic acid dehydrogenase (CSF LDH; p = 0.005 and p = 0.002), neutrophil to lymphocyte ratio (NLR; p = 0.014 and p = 0.038), and completion of four cycles of induction therapy (p < 0.001and p < 0.001) were significant and independent predictors of overall survival (OS) and progression-free survival (PFS), respectively. CONCLUSION: On the basis of this study, we propose that PCNSL patients should receive early induction therapy with sufficient cycles. Subsequent consolidation therapy can prevent relapses and improve survival. In patients with PCNSL, the independent prognostic factors for OS and PFS were CSF LDH level, NLR, and full cycles of induction therapy.

Long-term ozone exposure and all-cause mortality: Cohort evidence in China and global heterogeneity by region.

BACKGROUND: Cohort evidence linking long-term ozone (O3) exposure to mortality remained largely mixed worldwide and was extensively deficient in densely-populated Asia. This study aimed to assess the long-term effects of O3 exposure on all-cause mortality among Chinese adults, as well as to examine potential regional heterogeneity across the globe. METHODS: A national dynamic cohort of 42153 adults aged 16+ years were recruited from 25 provinces across Chinese mainland and followed up during 2010-2018. Annual warm-season (April-September) O3 and year-round co-pollutants (i.e., nitrogen dioxide [NO2] and fine particulate matter [PM2.5]) were simulated through validated spatial-temporal prediction models and were assigned to each enrollee in each calendar year. Cox proportional hazards models with time-varying exposures were employed to assess the O3-mortality association. Concentration-response (C-R) curves were fitted by natural cubic spline function to investigate the potential nonlinear association. Both single-pollutant model and co-pollutant models additionally adjusting for PM2.5 and/or NO2 were employed to examine the robustness of the estimated association. The random-effect meta-analysis was adopted to pool effect estimates from the current and prior population-based cohorts (n = 29), and pooled C-R curves were fitted through the meta-smoothing approach by regions. RESULTS: The study population comprised of 42153 participants who contributed 258921.5 person-years at risk (median 6.4 years), of whom 2382 death events occurred during study period. Participants were exposed to an annual average of 51.4 ppb (range: 22.7-74.4 ppb) of warm-season O3 concentration. In the single-pollutant model, a significantly increased hazard ratio (HR) of 1.098 (95% confidence interval [CI]: 1.023-1.179) was associated with a 10-ppb rise in O3 exposure. Associations remained robust to additional adjustments of co-pollutants, with HRs of 1.099 (95% CI: 1.023-1.180) in bi-pollutant model (+PM2.5) and 1.093 (95% CI: 1.018-1.174) in tri-pollutant model (+PM2.5+NO2), respectively. A J-shaped C-R relationship was identified among Chinese general population, suggesting significant excess mortality risk at high ozone exposure only. The combined C-R curves from Asia (n = 4) and North America (n = 17) demonstrated an overall increased risk of all-cause mortality with O3 exposure, with pooled HRs of 1.124 (95% CI: 0.966-1.307) and 1.023 (95% CI: 1.007-1.039) per 10-ppb rise, respectively. Conversely, an opposite association was observed in Europe (n = 8, HR: 0.914 [95% CI: 0.860-0.972]), suggesting significant heterogeneity across regions (P < 0.01). CONCLUSIONS: This study provided national evidence that high O3 exposure may curtail long-term survival of Chinese general population. Great between-region heterogeneity of pooled O3-mortality was identified across North America, Europe, and Asia.

Gender differences in GRK2 in cardiovascular diseases and its interactions with estrogen.

G protein-coupled receptor kinase 2 (GRK2) is a multifunctional protein involved in regulating G protein-coupled receptor (GPCR) and non-GPCR signaling in the body. In the cardiovascular system, increased expression of GRK2 has been implicated in the occurrence and development of several cardiovascular diseases (CVDs). Recent studies have found gender differences in GRK2 in the cardiovascular system under physiological and pathological conditions, where GRK2's expression and activity are increased in males than in females. The incidence of CVDs in premenopausal women is lower than in men of the same age, which is related to estrogen levels. Given the shared location of GRK2 and estrogen receptors, estrogen may interact with GRK2 by modulating vital molecules such as calmodulin (CaM), caveolin, RhoA, nitrate oxide (NO), and mouse double minute 2 homolog (Mdm2), via signaling pathways mediated by estrogen's genomic (ERα and ERß), and non-genomic (GPER) receptors, conferring cardiovascular protection in females. Highlighting the gender differences in GRK2 and understanding its interaction with estrogen in the cardiovascular system is pertinent in treating gender-related CVDs. As a result, this article explores the gender differences of GRK2 in the cardiovascular system and its relationship with estrogen during disease conditions. Estrogen's protective and therapeutic effects and its mechanism on GRK2-related cardiovascular diseases have also been discussed.

Residential greenness mitigates mortality risk from short-term airborne particulate exposure: An individual-level case-crossover study.

BACKGROUND: Studies suggested that greenness could reduce death risks related to ambient exposure to particulate matter (PM), while the available evidence was mixed across the globe and substantially exiguous in low- and middle-income countries. By conceiving an individual-level case-crossover study in central China, this analysis primarily aimed to quantify PM-mortality associations and examined the modification effect of greenness on the relationship. METHODS: We investigated a total of 177,058 nonaccidental death cases from 12 counties in central China, 2008-2012. Daily residential exposures to PM2.5 (aerodynamic diameter <2.5 µm), PMc (aerodynamic diameter between 2.5 and 10 µm), and PM10 (aerodynamic diameter <10 µm) were assessed at a 1 × 1-km resolution through satellite-derived machine-learning models. Residential surrounding greenness was assessed using satellite-derived enhanced vegetation index (EVI) and normalized difference vegetation index (NDVI) at multiple buffer sizes (250, 500, and 1000 m). To quantify the acute mortality risks associated with short-term exposure to PM2.5, PMc, and PM10, a time-stratified case-crossover design was utilized in conjunction with a conditional logistic regression model in our main analyses. To investigate the effect modification of greenness on PM-mortality associations, we grouped death cases into low, medium, and high greenness levels using cutoffs of 25th and 75th percentiles of NDVI or EVI exposure, and examined potential effect heterogeneity in PM-related mortality risks among these groups. RESULTS: Mean concentrations (standard deviation) on the day of death were 73.8 (33.4) µg/m3 for PM2.5, 43.9 (17.3) µg/m3 for PMc, and 117.5 (44.9) µg/m3 for PM10. Size-fractional PM exposures were consistently exhibited significant associations with elevated risks of nonaccidental and circulatory mortality. For every increase of 10-µg/m3 in PM exposure, percent excess risks of nonaccidental and circulatory mortality were 0.271 (95% confidence interval [CI]: 0.010, 0.533) and 0.487 (95% CI: 0.125, 0.851) for PM2.5 at lag-01 day, 0.731 (95% CI: 0.108, 1.359) and 1.140 (95% CI: 0.267, 2.019) for PMc at lag-02 day, and 0.271 (95% CI: 0.010, 0.533) and 0.386 (95% CI: 0.111, 0.662) for PM10 at lag-01 day, respectively. Compared to participants in the low-level greenness areas, those being exposed to higher greenness were found to be at lower PM-associated risks of nonaccidental and circulatory mortality. Consistent evidence for alleviated risks in medium or high greenness group was observed in subpopulations of female and younger groups (age <75). CONCLUSIONS: Short-term exposure to particulate air pollution was associated with elevated risks of nonaccidental and circulatory death, and individuals residing in higher neighborhood greenness possessed lower risk of PM-related mortality. These findings emphasized the potential public health advantages through incorporating green spaces into urban design and planning.

Petunia hybrida is a New Host of Pectobacterium brasiliense Associated with Soft Rot Disease in China.

Petunia hybrida is commonly cultivated for ornamental use in urban parks greening and street embellishment in China. In March 2022, 60% of P. hybrida plants cv. Wave Purple (n≈1800) from an ornamental plant nursery under natural conditions in Tianhe district (N 113°21'21", E 23°9'3.5"), Guangzhou, Guangdong Province, China, were affected with soft rot disease. The distribution of the disease was generally uniform. Infected plants initially exhibit small water-soaked lesions at the base of the stem, which then extended to the leaves. Eventually the diseased plant collapsed and died. Nine diseased plants were collected, and affected tissues cut into small fragments (5 × 5 mm), which were disinfested in 75% ethanol (30 s) and 2% sodium hypochlorite (60 s), followed by three rinses with sterile distilled water. The sterilized sections were macerated in 200 µl sterile water, and streaked on Luria-Bertani (LB) agar medium and incubated at 28°C for 48 h. Single colonies were restreaked three times to obtain purified isolation. Sixteen bacterial strains with similar morphology were isolated, and their colonies were yellowish white, round, and convex with smooth surfaces on LB agar plate. The representative strain BDQ1 was selected for further analyses and the 16S rDNA gene (GenBank Accession ON982467) were amplified using primer pair 27F/1492R, revealed above 99% sequence identity with some Pectobacterium brasiliense isolates (GenBank Accession Nos. CP046380(1421/1422), MN393966(1419/1422), and CP020350(1419/1422)) using BLASTn. A multilocus phylogenetic analysis by neighbor-joining method (1,000 bootstrap values) based on six housekeeping gene sequences of gyrA (GenBank Accession No. ON995454), icdA (ON995455), mdh (ON995456), mtlD (ON995457), proA (ON995458), and rpoS genes (ON995459) (Ma et al. 2007; Waleron et al., 2008). The results of phylogenetic analysis showed BDQ1 strain belong to the P. brasiliense clade. Pathogenicity tests were performed on ten healthy P. hybrida cv. Wave Purple plants by injecting 10 µl of bacterial suspensions of BDQ1 (108 CFU/ml) into the stems; another 10 healthy control plants were injected with 10 µl of sterile water. All plants were grown at 25-30°C and 60% humidity in natural light/dark cycle. After 3 d, all inoculated plants showed soft rot symptoms resembling to those observed in the nursery, while control plants remained healthy. Bacteria were successfully reisolated from the symptomatic tissues and identified to be P. brasiliense by PCR mentioned above. P. brasiliense is considered a very aggressive pathogen, which has been reported in Eurasia and Africa (Oulghazi et al. 2021). To our knowledge, this is the first report of P. brasiliense causing bacterial soft rot on P. hybrida in China. This pathogen may pose threat to P. hybrida production in area with warmand humid climate in China. The current study expands the known host range of P. brasiliense and helped raise attention on controlling pathogen spread.

Longitudinal association of edentulism with cognitive impairment, sarcopenia and all-cause mortality among older Chinese adults.

BACKGROUND: Tooth loss may be a surrogate for systemic health and aging. However, no previous studies have systematically assessed multiple outcomes relevant to aging trajectory in this area, and many important confounders were not adjusted in most previous studies. This study aims to prospectively evaluate the associations of complete tooth loss (edentulism) with broad markers of sarcopenia, cognitive impairment and mortality. METHODS: Data were derived from the China Health and Retirement Longitudinal Study, a nationally representative household study of the Chinese population aged 45 years and older. Multivariate Weibull proportional hazards regression was used to assess the association between edentulism with sarcopenia and all-cause mortality. Average changes in cognitive function by edentulism was estimated by mixed-effects linear regression models. RESULTS: During the 5-year follow-up, the prevalence of edentulism among adults aged 45 and over was 15.4%. Participants with edentulism had a greater decline in cognitive function compared to those without (ß=-0.70, 95%CI:-1.09, -0.31, P < 0.001). The association of edentulism and all-cause mortality for 45-64 age group (HR = 7.50, 95%CI: 1.99, 28.23, P = 0.003), but not statistically significant for the ≥ 65 age group (HR = 2.37, 95%CI: 0.97, 5.80, P = 0.057). Effects of edentulism on sarcopenia are statistically significant for all age groups (45-64 age group: HR = 2.15, 95%CI: 1.27, 3.66, P = 0.005; ≥65 age group: HR = 2.15, 95%CI: 1.27, 3.66, P = 0.002). CONCLUSIONS: These findings could have important clinical and public health implications, as tooth loss is a quick and reproducible measurement that could be used in clinical practice for identifying persons at risk of accelerated aging and shortened longevity, and who may benefit most from intervention if causality is established.

ox-LDL induces autophagy-mediated apoptosis by suppressing secretagogin-regulated autophagic flux in pancreatic ß-cells.

Lipotoxicity has been shown to induce the loss of functional ß-cell mass and lead to type 2 diabetes, but the mechanism remains unknown. In this study, we aim to explore the role of secretagogin (SCGN) in lipotoxicity-induced ß-cell injury. Our results indicate that ox-LDL treatment leads to autophagic cell death, as evidenced by decreased cell viability, aggravated cell apoptosis, and the accumulation of the p62 protein in MIN6 cells. LysoTracker Red staining, TEM and mRFP-GFP-LC3 assays demonstrate that autophagic flux is blocked in ox-LDL-treated MIN6 cells. Intriguingly, SCGN is significantly decreased in MIN6 cells under lipotoxic conditions. Additionally, siRNA-guided SCGN knockdown blocks autophagic flux triggered by rapamycin, while SCGN restoration alleviates autophagic flux retardation and mitigates cell apoptosis. The physical interaction between SCGN and SNAP29 is validated by bioinformatics analysis, coimmunoprecipitation assay and SCGN knockdown test. Downregulation of SCGN expression reduces the interaction of these two proteins. Taken together, our results indicate that ox-LDL treatment induces apoptotic ß-cell death by blocking autophagic flux dependent on SCGN downregulation. SCGN administration prevents lipotoxic ß-cell injury and may be a potential therapeutic strategy to promote ß-cell expansion in type 2 diabetes.

Early-life adversity and edentulism among Chinese older adults.

BACKGROUND: Emerging evidence indicate the relationship between ELA with oral health problems. However, most focus on single types of adversity. The association of cumulative ELA with edentulism, the final marker of disease burden for oral health, remains unclear. METHODS: Data came from 17,610 elderly participants in the China Health and Retirement Longitudinal Study (CHARLS). In 2014, the Life History Survey Questionnaire was utilized to evaluate the experience of threat and deprivation. Information on edentulism was evaluated through self-report from the follow-up in 2013, 2015, and 2018. By controlling for age, education, hukou residence, marital status, and disease history, logistic regression analyses were used to evaluate the relationships between distinct dimensions of ELA and risk of edentulism. RESULTS: Nearly half (49.8%) of the 17,610 older persons (mean [SD] age at baseline: 63.6 [9.4] years) reported experiencing early adversity due to threat-related ELA, and 77.9% reported having deprivation-related ELA. ELA characterised by threat was associated with edentulism in both male and female participants. Two forms of threat-related ELA exposure were linked to a 1.65-fold and 1.73-fold higher risk for edentulism in both male (95% CI 1.23, 2.21) and female participants (95% CI 1.31, 2.29), compared to no threat-related ELA exposure. Both male (95% CI 2.34, 4.24) and female participants (95% CI 2.49, 4.56) had a 3.15-fold and 3.37-fold higher risk for edentulism when exposed to three or more threat-related ELAs. CONCLUSION: Our findings suggest that ELA marked by threat is linked to an increased risk of edentulism. The biological pathways between different dimensions of ELA and teeth loss should be clarified by future research.

A novel secretagogin/ATF4 pathway is involved in oxidized LDL-induced endoplasmic reticulum stress and islet ß-cell apoptosis.

Excessive accumulation of cholesterol in ß cells initiates endoplasmic reticulum (ER) stress and associated apoptosis. We have reported that excessive uptake of cholesterol by MIN6 cells decreases the expression of secretagogin (SCGN) and then attenuates insulin secretion. Here, we aimed to determine whether cholesterol-induced SCGN decrease is involved in the modulation of ER stress and apoptosis in pancreatic ß cells. In this study, MIN6 cells were treated with oxidized low-density lipoprotein (ox-LDL) for 24 h, and then intracellular lipid droplets and cell apoptosis were quantified, and SCGN and ER stress markers were identified by western blot analysis. Furthermore, small interfer RNA (siRNA)-mediated SCGN knockdown and recombinant plasmid-mediated SCGN restoration experiments were performed to confirm the role of SCGN in ER stress and associated cell apoptosis. Finally, the interaction of SCGN with ATF4 was computationally predicted and then validated by a co-immunoprecipitation assay. We found that ox-LDL treatment increased the levels of ER stress markers, such as phosphorylated protein kinase-like endoplasmic reticulum kinase, phosphorylated eukaryotic initiation factor 2 alpha, activating transcription factor 4 (ATF4), and transcription factor CCAAT-enhancer-binding protein homologous protein, and promoted MIN6 cell apoptosis; in addition, the expression of SCGN was downregulated. siRNA-mediated SCGN knockdown exacerbated ß-cell ER stress by increasing ATF4 expression. Pretreatment of MIN6 cells with the recombinant SCGN partly antagonized ox-LDL-induced ER stress and apoptosis. Furthermore, a co-immunoprecipitation assay revealed an interaction between SCGN and ATF4 in MIN6 cells. Taken together, these results demonstrated that pancreatic ß-cell apoptosis induced by ox-LDL treatment can be attributed, in part, to an SCGN/ATF4-dependent ER stress response.

ROS-mediated glucose metabolic reprogram induces insulin resistance in type 2 diabetes.

Oxidative stress is known to contribute to insulin resistance in diabetes, however the mechanism is not clear. Here we show that reactive oxygen species (ROS) could reprogram the glucose metabolism through upregulating the pentose pathway so as to induce insulin resistance in type 2 diabetes (T2DM). By using streptozotocin-high fat diet (STZ-HFD) induced T2DM in rats, we show that diabetic rats exhibited high level of oxidative stress accompanied with insulin resistance. Hypoxia inducible factor (HIF-1α) protein expression as well as its downstream target glucokinase (GK), were upregulated; The glycogen synthesis increased accordingly; However the glycolysis was inhibited as indicated by decreased phosphofructokinase-1 (PFK-1), pyruvate kinase (PK), phospho-PFK-2/PFK-2 (p-PFK-2/PFK-2) ratio, lactate dehydrogenase (LDH) and pyruvate dehydrogenase kinase (PDK); Pyruvate dehydrogenase (PDH) which promotes pyruvate to generate acetyl-CoA declined as well. While phospho-acetyl-CoA carboxylase/acetyl-CoA carboxylase (p-ACC/ACC) ratio increased, meaning that lipid beta-oxidation increased. The pentose pathway was activated as indicated by increased G6PD activity and NADPH level. Our results suggest that diabetic rats countervail ROS stress through increasing pentose pathway, and reprogram the energy metabolic pathway from glycolysis into lipid oxidation in order to compensate the ATP requirement of the body, which causes insulin resistance.

Attenuated Salmonella typhimurium L forms suppress tumor growth and promote apoptosis in murine ovarian tumors.

To study the effects of attenuated Salmonella typhimurium L forms on the in vivo tumorigenicity and apoptosis of murine epithelial ovarian cancer cells, as well as the related mechanisms. Attenuated Salmonella typhimurium VNP20009 was induced into bacterial L forms by using antibiotic ceftriaxone. CCK-8 cell proliferation assay showed that attenuated S. typhimurium L forms can inhibit the proliferation of murine ovarian epithelial cancer ID8 cells. Attenuated ST L forms can induce apoptosis and inhibit invasion ability of epithelial ovarian cancer cells in vitro. TUNEL assay showed that attenuated ST L forms can induce apoptosis of ID8 cells in murine ovarian tumors. Meanwhile, attenuated ST L forms inhibit tumor growth in murine ovarian tumors. The tumorigenicity-related proteins of xenograft tumors detected by immunohistochemistry and fluorescence quantitative RT-PCR assays showed that attenuated ST L forms can reduce the expression of proteins that promote tumor growth and metastasis, such as Lgals9 and MMP9. This study confirmed that attenuated ST L forms can suppress tumor growth and promote apoptosis in murine ovarian tumors. Attenuated ST L forms may serve as a novel biological agent for bacterial-mediated tumor therapy in epithelial ovarian cancer.

Assessing long-term effects of gaseous air pollution exposure on mortality in the United States using a variant of difference-in-differences analysis.

Long-term mortality effects of particulate air pollution have been investigated in a causal analytic frame, while causal evidence for associations with gaseous air pollutants remains extensively lacking, especially for carbon monoxide (CO) and sulfur dioxide (SO2). In this study, we estimated the causal relationship of long-term exposure to nitrogen dioxide (NO2), CO, SO2, and ozone (O3) with mortality. Utilizing the data from National Morbidity, Mortality, and Air Pollution Study, we applied a variant of difference-in-differences (DID) method with conditional Poisson regression and generalized weighted quantile sum regression (gWQS) to investigate the independent and joint effects. Independent exposures to NO2, CO, and SO2 were causally associated with increased risks of total, nonaccidental, and cardiovascular mortality, while no evident associations with O3 were identified in the entire population. In gWQS analyses, an interquartile range-equivalent increase in mixture exposure was associated with a relative risk of 1.067 (95% confidence interval: 1.010-1.126) for total mortality, 1.067 (1.009-1.128) for nonaccidental mortality, and 1.125 (1.060-1.193) for cardiovascular mortality, where NO2 was identified as the most significant contributor to the overall effect. This nationwide DID analysis provided causal evidence for independent and combined effects of NO2, CO, SO2, and O3 on increased mortality risks among the US general population.

Herbal small molecule-based low/medium internal phase supramolecular gel emulsion for diabetic wound healing.

It remains a big challenge to fabricate low / medium internal phase gel emulsion for the safe wound dressing with low stimulation to the skin. Herein, utilizing the self-assembly and gelation of amphiphilic herbal small molecule-glycyrrhizic acid (GA) derived from traditional Chinese medicine, a new type of supramolecular gel emulsion (SGE) with antibacterial activity and low / medium internal phase was proposed. In the SGE, the oil droplets were stabilized by the nanofibers self-assembled from GA, and the SGE was formed by the supramolecular assembly of GA nanofibers in the presence of Pickering emulsions. As a result, under low / medium internal phase (φ = 30-50 %), SGEs could be readily prepared. Antibacterial tests demonstrated that the growth of gram-positive Staphylococcus aureus (S. aureus) and gram-negative Escherichia coli (E. coli) could be effectively inhibited by the SGE. Additionally, compared to high internal phase SGE, SGE with φ = 50 % displayed lower cytotoxicity and a positive impact on the healing process of infectious diabetic wounds. This work provided a novel approach for constructing low / medium internal phase gel emulsion via herbal small molecule-based supramolecular assembly.

Estradiol contributes to sex differences in resilience to sepsis-induced metabolic dysregulation and dysfunction in the heart via GPER-1-mediated PPARδ/NLRP3 signaling.

BACKGROUND AND AIM: Clinically, septic males tend to have higher mortality rates, but it is unclear if this is due to sex differences in cardiac dysfunction, possibly influenced by hormonal variations. Cardiac dysfunction significantly contributes to sepsis-related mortality, primarily influenced by metabolic imbalances. Peroxisome proliferator-activated receptor delta (PPARδ) is a key player in cardiac metabolism and its activation has been demonstrated to favor sepsis outcomes. While estradiol (E2) is abundant and beneficial in females, its impact on PPARδ-mediated metabolism in the heart with regards to sex during sepsis remains unknown. METHODS AND RESULTS: Here, we unveil that while sepsis diminishes PPARδ nuclear translocation and induces metabolic dysregulation, oxidative stress, apoptosis and dysfunction in the heart thereby enhancing mortality, these effects are notably more pronounced in males than females. Mechanistic experiments employing ovariectomized(OVX) mice, E2 administration, and G protein-coupled estrogen receptor 1(GPER-1) knockout (KO) mice revealed that under lipopolysaccharide (LPS)-induced sepsis, E2 acting via GPER-1 enhances cardiac electrical activity and function, promotes PPARδ nuclear translocation, and subsequently ameliorates cardiac metabolism while mitigating oxidative stress and apoptosis in females. Furthermore, PPARδ specific activation using GW501516 in female GPER-1-/- mice reduced oxidative stress, ultimately decreasing NLRP3 expression in the heart. Remarkably, targeted GPER-1 activation using G1 in males mirrors these benefits, improving cardiac electrical activity and function, and ultimately enhancing survival rates during LPS challenge. By employing NLRP3 KO mice, we demonstrated that the targeted GPER-1 activation mitigated injury, enhanced metabolism, and reduced apoptosis in the heart of male mice via the downregulation of NLRP3. CONCLUSION: Our findings collectively illuminate the sex-specific cardiac mechanisms influencing sepsis mortality, offering insights into physiological and pathological dimensions. From a pharmacological standpoint, this study introduces specific GPER-1 activation as a promising therapeutic intervention for males under septic conditions. These discoveries advance our understanding of the sex differences in sepsis-induced cardiac dysfunction and also present a novel avenue for targeted interventions with potential translational impact.

Emergency Department Visits in Children Associated with Exposure to Ambient PM1 within Several Hours.

BACKGROUND: Emerging evidence has integrated short-term exposure to PM1 with children's morbidity and mortality. Nevertheless, most available studies have been conducted on a daily scale, ignoring the exposure variations over the span of a day. OBJECTIVE: The main intention of this study was to examine the association between pediatric emergency department visits (PEDVs) and intra-day exposures to PM1 and PM2.5. We also aimed to investigate whether a high PM1/PM2.5 ratio elevated the risk of PEDVs independent from PM2.5 exposure within several hours. METHODS: We collected hourly data on aerial PM1 and PM2.5 concentrations, all-cause PEDVs, and meteorological factors from two megacities (i.e., Guangzhou and Shenzhen) in southern China during 2015-2016. Time-stratified case-crossover design and conditional logistic regression analysis were used to assess the associations of PEDVs with exposures to PM1 and PM2.5 at different lag hours. The contribution of PM1 to PM2.5-associated risk was quantified by introducing PM1/PM2.5 ratio as an additional exposure indicator in the analysis adjusting for PM2.5. Subgroup analyses were performed stratified by sex, age, and season. RESULTS: During this study period, 97,508 and 101,639 children were included from Guangzhou and Shenzhen, respectively. PM1 and PM2.5 exposures within several hours were both remarkably related to an increased risk of PEDVs. Risks for PEDVs increased by 3.9% (95% confidence interval [CI]: 2.7-5.0%) in Guangzhou and 3.2% (95% CI: 1.9-4.4%) in Shenzhen for each interquartile range (Guangzhou: 21.4 µg/m3, Shenzhen: 15.9 µg/m3) increase in PM1 at lag 0-3 h, respectively. A high PM1/PM2.5 ratio was substantially correlated with increased PEDVs, with an excess risk of 2.6% (95% CI: 1.2-4.0%) at lag 73-96 h in Guangzhou and 1.2% (95% CI: 0.4-2.0%) at lag 0-3 h in Shenzhen. Stratified analysis showed a clear seasonal pattern in PM-PEDVs relationships, with notably stronger risks in cold months (October to March of the following year) than in warm months (April to September). CONCLUSIONS: Exposures to ambient PM1 and PM2.5 within several hours were related to increased PEDVs. A high PM1/PM2.5 ratio may contribute an additional risk independent from the short-term impacts of PM2.5. These findings highlighted the significance of reducing PM1 in minimizing health risks due to PM2.5 exposure in children.

Discovery of bipyridine amide derivatives targeting pRXRα-PLK1 interaction for anticancer therapy.

Retinoid X receptor alpha (RXRα) is an important therapeutic target of cancer. Recently, small molecules (e.g.,XS-060 and its derivatives), which can significantly induce RXRα-dependent mitotic arrest by inhibiting pRXRα-PLK1 interaction, have been demonstrated as excellent anticancer agents. To further obtain novel RXR-targeted antimitotic agents with excellent bioactivity and drug-like properties, we herein synthesized two new series of bipyridine amide derivatives with XS-060 as the lead compound. In the reporter gene assay, most synthesized compounds showed antagonistic activity against RXRα. The most active compound, bipyridine amide B9 (BPA-B9), showed better activity than XS-060, with excellent RXRα-binding affinity (KD = 39.29 ± 1.12 nM) and anti-proliferative activity against MDA-MB-231 (IC50 = 16 nM, SI > 3). Besides, a docking study revealed a proper fitting of BPA-B9 into the coactivator binding site of RXRα, rationalizing its potent antagonistic effect on RXRα transactivation. Further, the mechanism studies revealed that the anticancer activity of BPA-B9 was dependent on its cellular RXRα-targeted mechanism, such as inhibiting pRXRα-PLK1 interaction and inducing RXRα-dependent mitotic arrest. Besides, BPA-B9 displayed better pharmacokinetics than the lead XS-060. Further, animal assays indicated BPA-B9 had significant anticancer efficacy in vivo with no considerable side effects. Together, our study reveals a novel RXRα ligand BPA-B9 targeting the pRXRα-PLK1 interaction, with great potential as a promising anticancer drug candidate for further development.

16α-OHE1, a novel oestrogen metabolite, attenuates dysfunction of left ventricle contractility via regulation of autophagy after myocardial ischemia and reperfusion.

BACKGROUND: Myocardial ischemia-reperfusion (MI/R) can exacerbate the initial cardiac damage in the myocardial functional changes, including dysfunction of left ventricular contractility. Oestrogen has been proven to protect the cardiovascular system. However, whether the oestrogen or its metabolites play the main role in attenuating dysfunction of left ventricular contractility is unknown. METHODS AND RESULTS: This study used the LC-MS/MS to detect oestrogen and its metabolites in clinical serum samples (n = 62) with heart diseases. After correlation analysis with markers of myocardial injury including cTnI (P < 0.01), CK-MB (P < 0.05), and D-Dimer (P < 0.001), 16α-OHE1 was identified. The result from LC-MS/MS in female and ovariectomised (OVX) rat serum samples (n = 5) matched the findings in patients. In MI/R model of animal, the recovery of left ventricular developed pressure (LVDP), rate pressure product (RPP), dp/dtmax and dp/dtmin after MI/R in OVX or male group were worsened than those in female group. Also, the infarction area of OVX or male group was larger than that in females (n = 5, p < 0.01). Furthermore, LC3 II in the left ventricle of OVX and male group was lower than that in females (n = 5, p < 0.01) by immunofluorescence. In H9C2 cells, after the application of 16α-OHE1, the number of autophagosomes was further increased and other organelles improved in MI/R. Simultaneously, LC3 II, Beclin1, ATG5, and p-AMPK/AMPK were increased, and p-mTOR/mTOR was decreased (n = 3, p < 0.01) by Simple Western. CONCLUSION: 16α-OHE1 could attenuate left ventricle contractility dysfunction via autophagy regulation after MI/R, which also offered fresh perspectives on therapeutical treatment for attenuating MI/R injury.

Cost-Effectiveness Analysis of Sintilimab Combined with Chemotherapy Versus Chemotherapy Alone as the First-Line Treatment for Advanced Esophageal Cancer.

Background: Esophageal cancer has a poor prognosis and currently ranks sixth in global cancer mortality rates. The ORIENT-15 trial showed sintilimab plus chemotherapy significantly improved survival when compared to chemotherapy alone. This study aimed to evaluate the cost-effectiveness of sintilimab, a programmed death-ligand 1 (PD-L1) inhibitor, plus chemotherapy in treating patients with esophageal cancer compared with chemotherapy alone. Methods: A Markov model with a 10-year horizon was developed based on the perspective of the Chinese healthcare payers. We conducted a cost-effectiveness analysis for sintilimab combined with chemotherapy based on a questionnaire. Patients were grouped into the sintilimab group based on a positive score of 10 or more (combined positive score (CPS) ≥ 10 groups), and those with any other PD-L1 expression were randomized into patient groups. We estimated the cost and the effectiveness of sintilimab on the quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) was computed. One-way and probabilistic sensitivity analyses were conducted to explore the impact of uncertainties on the cost-effectiveness results. Results: In the base-case analysis, compared with chemotherapy alone, the ICER of sintilimab plus chemotherapy for all patients was $21024.05 per QALY, and in the CPS≥10 group, it was $20974.23 per QALY. This was lower than $37653 per QALY. One-way sensitivity analysis demonstrated that ICERs were most sensitive to the price of sintilimab. Conclusion: The study demonstrated that sintilimab plus chemotherapy for advanced esophageal cancer as its first-line treatment would be more cost-effective than chemotherapy alone in Chinese patients.

Cost-effectiveness of nivolumab plus ipilimumab as first-line treatment for American patients with unresectable malignant pleural mesothelioma.

Background: The treatment paradigm of unresectable malignant pleural mesothelioma (MPM) has changed in recent years. Checkmate 743 demonstrate that nivolumab plus ipilimumab showed good clinical benefits compared with chemotherapy in the treatment of MPM. The study is aim to evaluate the cost-effectiveness of Nivolumab plus ipilimumab vs. platinum plus chemotherapy for the first-line treatment of unresectable MPM. Methods: A Markov model was developed to compare the cost and quality-adjusted life-year (QALY) of nivolumab plus ipilimumab and chemotherapy over a 10-year time horizon. Clinical efficacy and safety data were extracted from the CheckMate 743 trials. Health state utilities were obtained from published literature. Costs were collected from an US payer perspective. One-way and probabilistic sensitivity analyses were conducted to explore the impact of uncertainties on the cost-effectiveness's results. Results: In the base case analysis, the incremental healthcare costs and QALYs for Nivolumab plus Ipilimumab vs. chemotherapy are $196,604.22 and 0.53, respectively, resulting an incremental cost-effectiveness ratio (ICER) of $372,414.28/QALYs for the model cohort of patients with locally advanced or metastatic MPM. However, Probabilistic sensitivity analysis showed that there was no probability that Nivolumab plus ipilimumab was cost-effective within the fluctuation range of other model parameters in first-line in unresectable MPM. The results of one-way sensitivity analysis showed that the cost of Nivolumab was the most sensitive parameter. Conclusions: The ICER of Nivolumab plus ipilimumab is above the theoretical willingness-to-pay threshold in the U.S, which suggests that first-line nivolumab plus ipilimumab for unresectable MPM may be not a cost-effective choice.

Conductive silk fibroin hydrogel with semi-interpenetrating network with high toughness and fast self-recovery for strain sensors.

Regenerated silk fibroin (RSF) hydrogels have been extensively studied in the fields of biomedicine and wearable devices in recent years due to their outstanding biocompatibility. However, the pure RSF hydrogels usually exhibited frangibility and low ductility, limiting their application in many aspects severely. Herein, we demonstrate a tough RSF/poly (N, N-dimethylallylamine) hydrogel with semi-interpenetrating network, which possesses good mechanical properties with high stretchability (εb = 900%), tensile strength (σb = 101.7 kPa), toughness (Wf = 516.7 kJ/m3) and tearing fracture energy (T = 407.3 J/m2). Besides, the gels show low residual strain in the cyclic tests and rapid self-recovery (80% toughness recovery within 5 min with the maximum strain of 400%). Moreover, the gels also show high ionic conductivity due to the incorporation of the NaCl and the hydrogel can act as an ideal candidate for strain sensor with high sensitivity (GF = 1.84), admirable linearity, and good durability (1000 cycles with the strain of 100%). When used as a wearable strain sensor for monitoring human movements, it also can detect small and large deformations with high sensitivity. It is expected that this work can provide a new strategy for the fabrication of smart RSF-based hydrogels and expand their application in multiple scenarios.