Clinical significance of preoperative nutritional status in elderly gastric cancer patients undergoing radical gastrectomy: A single-center retrospective study.

BACKGROUND: The population of elderly patients with gastric cancer is increasing, which is a major public health issue in China. Malnutrition is one of the greatest risk factors for adverse clinical outcomes in elderly patients with gastric cancer. AIM: To investigate the preoperative nutritional status and its association with delayed discharge of elderly gastric cancer patients following radical gastrectomy. METHODS: A total of 783 patients aged 65 years and older harboring gastric adenocarcinoma and following radical gastrectomy were retrospectively analyzed from the prospectively collected database of Zhongshan Hospital of Fudan University between January 2018 and May 2020. RESULTS: The overall rate of malnutrition was 31.8%. The incidence of postoperative complications was significantly higher in the malnourished group compared to the well-nourished group (P < 0.001). Nutritional characteristics in the malnourished group, including body mass index, prognostic nutritional index (PNI), albumin, prealbumin, and hemoglobin, were all significantly lower than those in the well-nourished group. The percentage of patients who received postoperative total nutrient admixture was lower in the malnourished group compared to the well-nourished group (22.1% vs 33.5%, P = 0.001). Age ≥ 70 years (HR = 1.216, 95%CI: 1.048-1.411), PNI < 44.5 (HR = 1.792, 95%CI: 1.058-3.032), operation time ≥ 160 minutes (HR = 1.431, 95%CI: 1.237-1.656), and postoperative complications grade III or higher (HR = 2.191, 95%CI: 1.604-2.991) were all recognized as independent risk factors associated with delayed discharge. CONCLUSION: Malnutrition is relatively common in elderly patients undergoing gastrectomy. Low PNI is an independent risk factor associated with delay discharge. More strategies are needed to improve the clinical outcome of these patients.

Study on the Aging Precipitation Behavior and Kinetics of Al-10.0Zn-3.0Mg-2.8Cu Alloy by Pre-Deformation Treatment.

In this paper, the effect of thermomechanical treatment process on the hardening behavior, grain microstructure, precipitated phase, and tensile mechanical properties of the new high-strength and high-ductility Al-10.0Zn-3.0Mg-2.8Cu alloy was studied, and the optimal thermomechanical treatment process was established. The strengthening and toughening mechanisms were revealed, which provided technical and theoretical guidance for the engineering application of this kind of high strength-ductility aluminum alloy. Al-10.0Zn-3.0Mg-2.8Cu alloy cylindrical parts with external longitudinal reinforcement were prepared by a composite extrusion deformation process (reciprocal upsetting + counter-extrusion) with a true strain up to 2.56, and the organizational evolution of the alloys during the extrusion deformation process and the influence of pre-stretching treatments on the subsequent aging precipitation behaviors and mechanical properties were investigated. The results show that firstly, the large plastic deformation promotes the fragmentation of coarse insoluble phases and the occurrence of dynamic recrystallization, which results in the elongation of the grains along the extrusion direction, and the volume fraction of recrystallization reaches 42.4%. Secondly, the kinetic study showed that the decrease in the activation energy of precipitation increased the nucleation sites, which further promoted the diffuse distribution of the second phase in the alloy and a higher number of nucleation sites, while limiting the coarsening of the precipitated phase. When the amount of pre-deformation was increased from 0% to 2%, the size of the matrix precipitated phase decreased from 5.11 µm to 4.1 µm, and when the amount of pre-deformation was increased from 2% to 7%, the coarsening of the matrix precipitated phase took place, and the size of the phase increased from 4.1 µm to 7.24 µm. The finalized heat treatment process for the deformation of the aluminum alloy tailframe was as follows: solution (475 °C/3 h) + 2% pre-stretching + aging (120 °C/24 h), at which the comprehensive performance of the alloy was optimized, with a tensile strength of 634.2 MPa, a yield strength of 571.0 MPa, and an elongation of 15.2%. The alloy was strengthened by both precipitation strengthening and dislocation strengthening. After 2% pre-stretching, the fracture surface starts to be dominated by dense tough nest structure, and most of them are small tough nests, and small and dense tough nests are the main reason for the increase in alloy toughness after 2% pre-stretching deformation.

Elucidation of the mechanism underlying the sequential catalysis of inulin by fructotransferase.

Glycoside hydrolase family 91 (GH91) inulin fructotransferase (IFTases) enables biotransformation of fructans into sugar substitutes for dietary intervention in metabolic syndrome. However, the catalytic mechanism underlying the sequential biodegradation of inulin remains unelusive during the biotranformation of fructans. Herein we present the crystal structures of IFTase from Arthrobacter aurescens SK 8.001 in apo form and in complexes with kestose, nystose, or fructosyl nystose, respectively. Two kinds of conserved noncatalytic binding regions are first identified for IFTase-inulin interactions. The conserved interactions of substrates were revealed in the catalytic center that only contained a catalytic residue E205. A switching scaffold was comprised of D194 and Q217 in the catalytic channel, which served as the catalytic transition stabilizer through side chain displacement in the cycling of substrate sliding in/out the catalytic pocket. Such features in GH91 contribute to the catalytic model for consecutive cutting of substrate chain as well as product release in IFTase, and thus might be extended to other exo-active enzymes with an enclosed bottom of catalytic pocket. The study expands the current general catalytic principle in enzyme-substrate complexes and shed light on the rational design of IFTase for fructan biotransformation.

Reactivity of Atomic Oxygen Radical Anions in Metal Oxide Clusters.

Atomic oxygen radical anion (O•-) represents an important type of reactive centre that exists in both chemical and biological systems. Gas-phase atomic clusters can be studied under isolated and well controlled conditions. Studies of O•--containing clusters in the gas-phase provide a unique strategy to interpret the chemistry of O•- radicals at a strictly molecular level. This review summarizes the research progresses made since 2013 for the reactivity of O•- radicals in the atomically precise metal oxide clusters including negatively charged, nanosized, and neutral heteronuclear clusters benefitting from the development of advanced experimental techniques. New electronic and geometric factors to control the reactivity and product selectivity of O•- radicals under dark and photo-irradiation conditions have been revealed. The detailed mechanisms of O•- generation have been discussed for the reaction systems of nanosized and heteroatom-doped metal oxide clusters. The catalytic reactions mediated by the O•- radicals in metal clusters have also been successfully established and the microscopic mechanisms about the dynamic generation and depletion of O•- radicals have been clearly understood. The studies of O•- containing metal oxide clusters in the gas-phase provided new insights into the chemistry of reactive oxygen species in related condensed-phase systems.

Nicotinamide riboside activates SIRT3 to prevent paclitaxel-induced peripheral neuropathy.

Paclitaxel (PTX) is a microtubule stabilizer that disrupts the normal cycle of microtubule depolymerization and repolymerization, leading to cell cycle arrest and cancer cell death. It is commonly used as a first-line chemotherapeutics for various malignancies, such as breast cancer, non-small cell lung cancer, and ovarian cancer. However, PTX chemotherapy is associated with common and serious side effects, including chemotherapy-induced peripheral neuropathy (CIPN). As cancer treatment advances and survival rates increase, the impact of CIPN on patients' quality of life has become more significant. To date, there is no effective treatment strategy for CIPN. Surtuin3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD+) dependent protein deacetylase located on mitochondria. It transfers the acetyl group of the lysine side chain of acetylated substrate proteins to NAD+, producing deacetylated proteins to regulate mitochondrial energy metabolic processes. SIRT3 has been found to play an important role in various diseases, including aging, neurodegenerative diseases, cancer, heart disease, metabolic diseases, etc. However, the role of SIRT3 in CIPN is still unknown. This study found for the first time that activating SIRT3 helps to improve paclitaxel-induced CIPN. Nicotinamide riboside (NR) can protect dorsal root ganglion (DRG) mitochondria against oxidative damage caused by paclitaxel through activating SIRT3-MnSOD2 and SIRT3-Nrf2 pathway. Moreover, NR can enhance the anticancer activity of paclitaxel. Together, our research provides new strategy and candidate drug for the treatment of CIPN.

Pullulanase-assisted bamboo leaf flavonoids optimize the instant properties, in vitro digestibility, and underlying mechanism in yam flour.

In this study, pullulanase-assisted bamboo leaf flavonoids (BLF) were employed to ameliorate limitations of fluidity and digestibility of cooked yam flour via physicochemical properties, digestion, structure and interaction analysis. The results showed that 1) Pullulanase-assisted BLF significantly increased the water solubility (9.02% â†’ 69.38%) and inhibited the swelling (5.54 g/g â†’ 2.29 g/g) during heating and cooling of yam flour, causing it to have liquid-like rheological properties (the tanδ tended to 1). 2) Pullulanase and BLF synergistically affected the anti-digestion of yam flour, reducing the estimated glycemic index to a lower level (58.27 â†’ 48.26, dose-dependent of BLF). 3) Pullulanase-assisted BLF mainly interacted hydrophobic with various components, especially starch, increasing the short/long-range ordered structure of starch, changing the secondary structure of proteins, and forming a tight three-dimensional network structure. This study provided a theoretical foundation for the development of functional foods using yam flour and its potential application in liquid foods.

Butyrate protects the intestinal barrier by upregulating Fut2 expression via MEK4-JNK signaling pathway activation.

BACKGROUND: Necrotizing enterocolitis (NEC) is a severe gastrointestinal inflammatory disease in neonates. Fucosyltransferase 2 (Fut2) regulates intestinal epithelial cell fucosylation. In this study, we aimed to investigate butyrate-mediated upregulation of Fut2 expression and the underlying mechanisms. METHODS: In vivo and in vitro models were established. SP600125 was used to inhibit the MEK4-JNK pathway, and anisomycin was used to activate the MEK4-JNK pathway. Fut2, occludin, and ZO-1 expressions were assessed. Furthermore, intestinal permeability was analyzed by FITC-Dextran. The expression of proteins in the MEK-4-JNK pathway was examined by western blotting. RESULTS: In vivo, the addition of exogenous butyrate notably upregulated Fut2, occludin, and ZO-1 expressions and reduced intestinal permeability in mice with NEC. Butyrate may increase the phosphorylation of MEK4, JNK, and c-jun, which are key components of the MEK4-JNK pathway. Additionally, SP600125 inhibited their phosphorylation, which was reversed by anisomycin treatment. In vitro, butyrate substantially increased occludin and ZO-1 expressions. Butyrate considerably increased Fut2 expression and markedly upregulated p-MEK4, p-JNK, and p-c-jun expressions. SP600125 administration decreased their expressions, while anisomycin administration increased their expressions. CONCLUSION: Butyrate upregulated Fut2 expression via activation of the MEK4-JNK pathway, improved intestinal barrier integrity, and protected neonatal mice from NEC. IMPACT: We found that exogenous butyrate could improve intestinal barrier integrity and protect against NEC in neonatal mice. Our data showed that exogenous butyrate supplementation upregulated Fut2 expression by activating the MEK4-JNK pathway. Our study provides novel insights into the pathogenesis of NEC, thereby laying an experimental foundation for future clinical research on the use of butyrate in NEC treatment.

Design, synthesis and biological evaluation of novel SIRT3 inhibitors targeting both NAD+ and substrate binding sites for the treatment of acute myeloid leukemia.

Acute myeloid leukemia (AML) represents a highly malignant subtype of leukemia with limited therapeutic options. In this study, we propose a novel therapeutic strategy for treating AML by inhibiting SIRT3 to regulate mitochondrial metabolism network involved in energy metabolism and epigenetic modifications essential for AML survival. A series of thieno [3,2-d]pyrimidine-6-carboxamide derivatives were designed and synthesized by structure-based strategy, 17f was documented to be a potent and acceptable selective SIRT3 inhibitor with IC50 value of 0.043 µM and exhibited profound anti-proliferative activity in MOLM13, MV4-11, and HL-60 cells. Through CETSA assay and the degree of deacetylation of intracellular SIRT3 substrates, we confirmed that 17f could effectively bind and inhibit SIRT3 activity in AML cells. Mechanistically, 17f suppressed mitochondrial function, triggered the accumulation of ROS, and significantly inhibited the production of ATP in AML cells. With the breakdown of mitochondrial function, 17f eventually induced apoptosis of AML cells. In addition, 17f also showed excellent anti-AML potential in nude mouse tumor models of HL-60-Luc. Collectively, these results demonstrate that 17f is a potent and acceptable selective SIRT3 inhibitor with promising potential to treat AML.

Comparative efficacy and safety of SGLT2is and ns-MRAs in patients with diabetic kidney disease: a systematic review and network meta-analysis.

Objectives: To evaluate the efficacy and safety of non-steroid mineralocorticoid receptor antagonists (ns-MRAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) in patients with diabetic kidney disease (DKD). Methods: Systematic literature searches were performed using PubMed, Embase and Web of Science encompassing inception until January 20, 2024. Randomized control trials (RCTs) comparing ns-MRAs and SGLT2is in DKD were selected. The efficacy outcomes of interest included kidney-specific composite outcome, cardiovascular (CV)-specific composite outcome, end-stage kidney disease (ESKD), and overall mortality. We also investigated safety outcomes, including acute kidney injury (AKI) and hyperkalemia. Results: A total of 10 randomized clinical trials with 35,786 patients applying various treatments were included. SGLT2is (SUCRA 99.84%) have potential superiority in kidney protection. SGLT2is (RR 1.41, 95%CI 1.26 to 1.57) and ns-MRAs (RR 1.17, 95% CI 1.08 to 1.27) were associated with significantly lower kidney-specific composite outcome than the placebo. Regarding the reduction in CV-specific composite outcome and ESKD, SGLT2is (SUCRA 91.61%; 91.38%) have potential superiority in playing cardiorenal protection. Concerning the CV-specific composite outcome (RR 1.27, 95%CI 1.09 to 1.43) and ESKD (RR 1.43, 95%CI 1.20 to 1.72), SGLT2is significantly reduced the risks compared to placebo. Regarding the reduction in overall mortality, SGLT2is (SUCRA 83.03%) have potential superiority in postponing mortality. Concerning the overall mortality, SGLT2is have comparable effects (RR 1.27, 95%CI 1.09 to 1.43) with placebo to reduce the risk of overall mortality compared to placebo. For AKI reduction, ns-MRAs (SUCRA 63.58%) have potential superiority. SGLT2is have comparable effects (RR 1.24, 95%CI 1.05 to 1.46) with placebo to reduce the risk of AKI. For hyperkalemia reduction, SGLT2is (SUCRA 93.12%) have potential superiority. SGLT2is have comparable effects (RR 1.24, 95%CI 1.05 to 1.46) with placebo to reduce the risk of AKI. Concerning hyperkalemia reduction, nsMRAs (RR 1.24 95%CI 0.39 to 3.72) and SGLT2is (RR 1.01 95%CI 0.40 to 3.02) did not show significant benefit compared to placebo. Conclusion: Concerning the efficacy and safety outcomes, SGLT2is may be recommended as a treatment regimen for maximizing kidney and cardiovascular protection, with a minimal risk of hyperkalemia in DKD. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023458613.

Study on the differences between Hoek-Brown parameters and equivalent Mohr-Coulomb parameters in the calculation slope critical acceleration and permanent displacement.

Mohr-Coulomb (MC) strength criterion has been widely used in many classical analytical expressions and numerical modeling due to its simple physical calculation, but the MC criterion is not suitable for describing the failure envelope of rock masses. In order to directly apply MC parameters to analytical expressions or numerical modeling in rock slope stability analysis, scholars established a criterion for converting Hoek-Brown (HB) parameters to equivalent MC parameters. However, the consistency of HB parameters and equivalent MC parameters in calculating critical acceleration of slope needs to be further explored and confirmed. Therefore, HB parameters are converted into equivalent MC parameters by considering the influence of slope angle (1# case and 2# case when slope angle is not considered and slope angle is considered respectively). Then, the lower-bound of finite element limit analysis is used for numerical modeling, and the results of calculating critical acceleration using HB parameters and equivalent MC parameters are compared, and the influence of related parameters on the calculation of critical acceleration is studied. Finally, the influence of different critical accelerations on the calculation of slope permanent displacement is further analyzed through numerical cases and engineering examples. The results show that: (1) In the 1# case, the critical acceleration obtained by the equivalent MC parameters are significantly larger than that obtained by the 2 #case and the HB parameters, and this difference becomes more obvious with the increase of slope angle. The critical acceleration obtained by the 2# case is very close to the HB parameters; (2) In the 1# case, slope height is inversely proportional to ΔAc (HB(Ac) - 1#(Ac)), and with the increase of slope height, ΔAc decreases, while in the 2# case, the difference of ΔAc (HB(Ac) - 2#(Ac)) is not significant; (3) In the 1# case, the sensitivity of the HB parameters to ΔAc is D > GSI > mi > σci, but in the 2# case, there is no sensitivity-related regularity; (4) The application of HB parameters and equivalent MC parameters in slope permanent displacement is studied through numerical cases and engineering examples, and the limitations of equivalent MC parameters in rock slope stability evaluation are revealed.

Implementation factors of tuberculosis control program in primary healthcare settings in China: a mixed-methods using the Consolidated Framework for Implementation Research framework.

BACKGROUND: Tuberculosis (TB) is a major cause of death worldwide, and Chinese TB burden ranked the second globally. Chinese primary healthcare (PHC) sectors implement the TB Control Program (TCP) to improve active case finding, referral, treatment adherence, and health education. This study aimed to identify barriers and enablers of TCP implementation in high TB burden regions of West China. METHODS: We conducted a representative study using mixed-methods in 28 counties or districts in Chongqing Municipality and Guizhou Province of West China from October 2021 to May 2022. Questionnaire surveys and semi-structured in-depth interviews were conducted with 2720 TB healthcare workers (HCWs) and 20 interviewees in PHC sectors. Descriptive statistical analysis was used to investigate TB HCWs' characteristics, and path analysis model was utilized to analyze the impact of associated factors on TCP implementation. Thematic framework analysis was developed with the guide of the adapted Consolidated Framework for Implementation Research (CFIR) on factors of TCP implementation. RESULTS: This study found that 84.6% and 94.1% of community and village HCWs had low professional titles. Based on the results of multiple regression analysis and correlation analysis, lower TB core knowledge scores (-0.09) were identified as barriers for TCP implementation in community PHC sectors, and low working satisfaction (-0.17) and low working willingness (-0.10) are barriers for TPC implementation in village PHC sectors. The results of in-depth interviews reported barriers in all domains and enablers in four domains of CFIR. There were identified 19 CFIR constructs associated with TCP implementation, including 22 barriers such as HCWs' heavy workload, and 12 enablers such as HCWs' passion towards TCP planning. CONCLUSIONS: With the guide of the CFIR framework, complex factors (barriers and enablers) of TCP implementation in PHC sectors of West China were explored, which provided important evidences to promote TB program in high TB burden regions. Further implementation studies to translate those factors into implementation strategies are urgent needed.

PrG protects postovulatory oocytes aging in mice through the putrescine pathway.

Postovulatory aging of oocytes involves a series of deleterious molecular and cellular changes, which adversely affect oocyte maturation, fertilization, and early embryonic development. Petunidin-3-O-(6-O-pcoumaroyl)-rutinoside-5-O-glucoside (PrG), the main active ingredient of anthocyanin, exerts antioxidant effects. This study investigated whether PrG supplementation could delay postovulatory oocyte aging by alleviating oxidative stress. Our results showed that PrG supplementation decreased the number of abnormal morphology oocytes and improved the oxidative stress of aged oocytes by facilitating the reduction of the reactive oxygen species, the increase in glutathione content, and the recovery of expression of antioxidant-related gene expression. In addition, PrG treatment recovered mitochondrial dysfunction, including mitochondrial distribution, mitochondrial membrane potential and adenosine triphosphate in aged oocytes. PrG-treated oocytes returned to normal levels of cytoplasmic and mitochondrial calcium. Notably, PrG inhibited early apoptosis in aged oocytes. RNA-seq and qRT-PCR results revealed that PrG ameliorated oxidative stress injury in postovulatory aging oocytes of mice via the putrescine pathway. In conclusion, in vitro PrG supplementation is a potential therapy for delaying postovulatory oocyte aging.

Natural Occurrence and Co-Occurrence of Beauvericin and Enniatins in Wheat Kernels from China.

A total of 769 wheat kernels collected from six provinces in China were analyzed for beauvericin (BEA) and four enniatins (ENNs), namely, ENA, ENA1, ENB and ENB1, using a solid phase extraction (SPE) technique with ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The results show that the predominant toxin was BEA, which had a maximum of 387.67 µg/kg and an average of 37.69 µg/kg. With regard to ENNs, the prevalence and average concentrations of ENB and ENB1 were higher than those of ENA and ENA1. The geographical distribution of BEA and ENNs varied. Hubei and Shandong exhibited the highest and lowest positive rates of BEA and ENNs (13.46% and 87.5%, respectively). However, no significant difference was observed among these six provinces. There was a co-occurrence of BEA and ENNs, and 42.26% of samples were simultaneously detected with two or more toxins. Moreover, a significant linear correlation in concentrations was observed between the four ENN analogs (r range: 0.75~0.96, p < 0.05). This survey reveals that the contamination and co-contamination of BEA and ENNs in Chinese wheat kernels were very common.

Determination of Flavonolignan Compositional Ratios in Silybum marianum (Milk Thistle) Extracts Using High-Performance Liquid Chromatography.

Milk thistle is one of the most popular ingredients in the liver protection products market. Silymarin is the main component of milk thistle and contains multiple isomers. There have been few studies focusing on the compositional ratios of silymarin isomers. In this study, we developed an HPLC method for the separation and quantification of silymarin isomers, thereby elucidating their compositional ratios. Through the analysis of more than 40 milk thistle extract products on the market, we found that the ratios, specifically Ratio 1 (the silybin B content to the silybin A content, SBNB/SBNA) and Ratio 2 (the sum of the contents of silybin B and isosilybin B to the sum of the contents of silybin A and isosilybin A, (SBNB + IBNB)/(SBNA + IBNA)), are highly consistent across milk thistle extracts, averaging approximately 1.58 and 1.28, respectively. Furthermore, such ratios were verified in milk thistle seed samples. This study introduces significant findings concerning the stable ratios among silymarin isomers in milk thistle extracts and seeds, thereby offering an innovative approach for quality assurance of milk thistle extracts.

Metabolic score for insulin resistance (METS-IR) predicts all-cause and cardiovascular mortality in the general population: evidence from NHANES 2001-2018.

BACKGROUND: The prevalence of obesity-associated insulin resistance (IR) is increasing along with the increase in obesity rates. In this study, we compared the predictive utility of four alternative indexes of IR [triglyceride glucose index (TyG index), metabolic score for insulin resistance (METS-IR), the triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio and homeostatic model assessment of insulin resistance (HOMA-IR)] for all-cause mortality and cardiovascular mortality in the general population based on key variables screened by the Boruta algorithm. The aim was to find the best replacement index of IR. METHODS: In this study, 14,653 participants were screened from the National Health and Nutrition Examination Survey (2001-2018). And TyG index, METS-IR, TG/HDL-C and HOMA-IR were calculated separately for each participant according to the given formula. The predictive values of IR replacement indexes for all-cause mortality and cardiovascular mortality in the general population were assessed. RESULTS: Over a median follow-up period of 116 months, a total of 2085 (10.23%) all-cause deaths and 549 (2.61%) cardiovascular disease (CVD) related deaths were recorded. Multivariate Cox regression and restricted cubic splines analysis showed that among the four indexes, only METS-IR was significantly associated with both all-cause and CVD mortality, and both showed non-linear associations with an approximate "U-shape". Specifically, baseline METS-IR lower than the inflection point (41.33) was negatively associated with mortality [hazard ratio (HR) 0.972, 95% CI 0.950-0.997 for all-cause mortality]. In contrast, baseline METS-IR higher than the inflection point (41.33) was positively associated with mortality (HR 1.019, 95% CI 1.011-1.026 for all-cause mortality and HR 1.028, 95% CI 1.014-1.043 for CVD mortality). We further stratified the METS-IR and showed that significant associations between METS-IR levels and all-cause and cardiovascular mortality were predominantly present in the nonelderly population aged < 65 years. CONCLUSIONS: In conjunction with the results of the Boruta algorithm, METS-IR demonstrated a more significant association with all-cause and cardiovascular mortality in the U.S. population compared to the other three alternative IR indexes (TyG index, TG/HDL-C and HOMA-IR), particularly evident in individuals under 65 years old.

Association between the use of statins and in-hospital mortality risk in patients with sepsis-induced coagulopathy during ICU stays: a study based on medical information mart for intensive care database.

BACKGROUND: The objective of this study was to explore the correlation between statin administration in the intensive care unit (ICU) setting and the in-hospital mortality risk of patients suffering from sepsis-induced coagulopathy (SIC). METHODS: Utilizing a retrospective cohort study design, this investigation collected data from the Medical Information Mart for Intensive Care (MIMIC)-IV spanning 2008 to 2019. The diagnosis of SIC was established based on a SIC score of 4 or above. Statin usage during the ICU period was extracted from the prescription records based on the keywords of statin medications. The primary endpoint analyzed was the in-hospital mortality within the ICU, characterized by any death occurring during the ICU admission. RESULTS: During the follow-up, which had a median duration of approximately 7.28 days, 18.19% of the 4,777 SIC patients died in the ICU. Statin was linked with a decrease in the risk of in-hospital mortality for SIC patients in the ICU [hazard ratio (HR): 0.73, 95% confidence interval (CI): 0.60-0.89, P = 0.002]. Relative to rosuvastatin, the use of atorvastatin (HR: 0.54, 95% CI: 0.34-0.85, P = 0.008) or simvastatin (HR: 0.55, 95% CI: 0.33-0.92, P = 0.024), as well as combinations of multiple statins (HR: 0.36, 95% CI: 0.15-0.86, P = 0.022), was associated with a reduction in ICU in-hospital mortality risk. Subgroup analysis also suggested that the use of atorvastatin, simvastatin, or a combination of statins had an advantage over rosuvastatin in reducing ICU in-hospital mortality in SIC patients older than 65 years of age or SIC patients with respiratory failure or cardiogenic shock (all P < 0.05). CONCLUSION: The present study supports the potential benefits of statin use in mortality in SIC patients during ICU stays. The study encourages clinicians to consider the benefits of statins and supports the ongoing exploration of statins for enhanced outcomes in critical care settings.

Precision targeting in oncology: The future of conjugated drugs.

Coupled drugs, especially antibody-coupled drugs (ADCs), are a hot topic in oncology. As the development of ADCs has progressed, different coupling modes have emerged, inspired by their structural design have emerged. Technological advances have led to interweaving and collision of old and new concepts of coupled drugs, and have even challenged the concepts and techniques of coupled drugs at this stage. For example, antibody-oligonucleotide conjugates are a new class of chimeric biomolecules synthesized by coupling oligonucleotides with monoclonal antibodies through linkers, offering precise targeting and improved pharmacokinetic properties. This study aimed to elucidate the mechanism of action of coupled drugs and their current development status in antitumor therapy to provide better strategies for antitumor therapy.

Crystal Structures of DNA-bound Fish IRF10 and IRF11 Reveal the Determinants of IFN Regulation.

IFN regulatory factors (IRFs) are transcription factors that mediate homeostatic mechanisms of host defense against pathogens. In addition to IRF1-9, which are conserved across vertebrates, teleost fishes have two other IRFs, IRF10 and IRF11. In zebrafish (Danio rerio), IRF10 represses the expression of IFNφ1 and IFNφ3, whereas IRF11 exerts the opposite effect. In this study, we found IRF10 could significantly inhibit the expression of IFNφ1 and IFNφ3 induced by IFN11 to synergistically regulate type I IFN expression. To clarify the synergistically regulatory mechanism of IRF10 and IRF11 in type I IFN expression, we determined and analyzed the crystal structures of the DNA-binding domains (DBDs) of zebrafish IRF10 and IRF11 bound to DNA, as well as IRF11 DBD in apo form. The interactions of IRF10-DBD and IRF11-DBD with DNA backbone were elaborated in detail. Further analysis showed that IRF10 and IRF11 have the same binding patterns and comparable affinities with the IFN-sensitive response elements of IFNφ1 and IFNφ3 promoters. Therefore, IRF10 could function as a controlling factor for IRF11 by competitive binding of the IFN-sensitive response elements to coregulate the host IFN response. Accordingly, similar to IRF1 and IRF2 in mammals, IRF10 and IRF11 act as another pair of negative and positive regulators to balance the antiviral responses in fish.

DHPS-Mediated Hypusination Regulates METTL3 Self-m6A-Methylation Modification to Promote Melanoma Proliferation and the Development of Novel Inhibitors.

Discovering new treatments for melanoma will benefit human health. The mechanism by which deoxyhypusine synthase (DHPS) promotes melanoma development remains elucidated. Multi-omics studies have revealed that DHPS regulates m6A modification and maintains mRNA stability in melanoma cells. Mechanistically, DHPS activates the hypusination of eukaryotic translation initiation factor 5A (eIF5A) to assist METTL3 localizing on its mRNA for m6A modification, then promoting METTL3 expression. Structure-based design, synthesis, and activity screening yielded the hit compound GL-1 as a DHPS inhibitor. Notably, GL-1 directly inhibits DHPS binding to eIF5A, whereas GC-7 cannot. Based on the clarification of the mode of action of GL-1 on DHPS, it is found that GL-1 can promote the accumulation of intracellular Cu2+ to induce apoptosis, and antibody microarray analysis shows that GL-1 inhibits the expression of several cytokines. GL-1 shows promising antitumor activity with good bioavailability in a xenograft tumor model. These findings clarify the molecular mechanisms by which DHPS regulates melanoma proliferation and demonstrate the potential of GL-1 for clinical melanoma therapy.

"Coir Raincoat"-Boosted Biomimetic Hydrogel for Efficient Solar Desalination and Wastewater Purification.

Solar-driven interfacial evaporation is an efficient method for purifying contaminated or saline water. Nonetheless, the suboptimal design of the structure and composition still necessitates a compromise between evaporation rate and service life. Therefore, achieving efficient production of clean water remains a key challenge. Here, a biomimetic dictyophora hydrogel based on loofah/carbonized sucrose@ZIF-8/polyvinyl alcohol is demonstrated, which can serve as an independent solar evaporator for clean water recovery. This special structural design achieves effective thermal positioning and minimal heat loss, while reducing the actual enthalpy of water evaporation. The evaporator achieves a pure water evaporation rate of 3.88 kg m-2 h-1 and a solar-vapor conversion efficiency of 97.16% under 1 sun irradiation. In comparison, the wastewater evaporation rate of the evaporator with ZIF-8 remains at 3.85 kg m-2 h-1 for 30 days, which is 16.3% higher than the light irradiation without ZIF-8. Equally important, the evaporator also showcases the capability to cleanse water from diverse sources of contaminants, including those with small molecules, oil, heavy metal ions, and bacteria, greatly improving the lifespan of the evaporator.