Feasibility and Effectiveness of Venoarterial Extracorporeal Membrane Oxygenation Plus Intra-Aortic Balloon Pump Assisted High-Risk Percutaneous Coronary Intervention in Complex Coronary Disease.

Background: Mechanical circulatory support may facilitate high-risk percutaneous coronary intervention (PCI). This study aimed to assess the feasibility, safety and effectiveness of high-risk PCI under the support of venoarterial extracorporeal membrane oxygenation (VA-ECMO) combined with intra-aortic balloon pump (IABP). Methods: We enrolled patients who received VA-ECMO plus IABP-assisted PCI procedures at our center from April 2012 to June 2018. Major adverse cardiac events (MACEs) included all-cause death, myocardial infarction, and target vessel revascularization. Results: A total of 10 patients were included, with a mean age of 71 years, EuroSCORE II of 19.9%, and SYNTAX score of 39.8. Procedural success was achieved in nine (90%) patients. The mean duration of ECMO support was 1.5 hours, and 2.6 stents were implanted per patient. Major complications included contrast-induced nephropathy needing hemodialysis in one (10%) patient, significant hemoglobin drop requiring blood transfusion in two (20%) patients, pulmonary infection in one (10%) patient, and local surgical incision infection in one (10%) patient. The accumulative mortality rates for the nine patients with procedural success were 0, 22.2%, and 44.4% at 1, 3, and 5 years follow-up, respectively. However, cardiac death occurred in only one (11.1%) patient. In addition, two patients received repeat PCI or coronary artery bypass grafting within two years following the index procedure. The overall incidence rates of MACEs were 11.1%, 44.4%, and 66.7% at 1, 3, and 5 years follow-up, respectively. Conclusions: VA-ECMO plus IABP-assisted high-risk PCI was feasible in patients with complex coronary disease, with a high procedural success rate and acceptable mid-term clinical outcomes.

Combinations of HDAC inhibitor and PPAR agonist induce ferroptosis of leukemic stem cell-like cells in acute myeloid leukemia.

PURPOSE: Leukemia stem cells (LSCs) are responsible for leukemia initiation, relapse, and therapeutic resistance. Therefore, the development of novel therapeutic approaches targeting LSCs is urgently needed for patients with AML. METHODS: The LSCs-like cell lines (KG-1α and Kasumi-1), CD34+ primary AML cells purified from AML patients (n=23) treated with CS055 and/or chiglitazar and were analyzed for viability, death, and colony formation assay. We performed RNA-seq, Glutamate-Release, Intracellular-GSH, Lipid-ROS, transmission-electron-microscopy, Western-Blotting assay, and confirmed ferroptosis in LSCs-like cells. The luciferase-reporter, co-immunoprecipitation, HDAC3-shRNA/HDAC3/deacetylase-deficient LSCs-like cell lines, His-pull-down, and chromatin-immunoprecipitation assays performed to clarify the molecular mechanism of CS055/chiglitazar in LSCs-like cells. We also established CDX and PDX mouse models to evaluate the therapeutic efficacy of CS055/chiglitazar against-AML in vivo. RESULTS: We report that the histone deacetylase inhibitor CS055, in combination with peroxisome proliferator-activated receptor (PPAR) pan-agonist (chiglitazar), synergistically targets leukemia stem-like cells from leukemia cell lines and patient samples, while sparing normal hematopoietic progenitor cells. Mechanistically, chiglitazar enhances the inhibitory effect of CS055 on HDAC3 and induces ferroptosis in LSCs-like cells by down-regulating the expression of ferroptosis suppressor SLC7A11. In fact, the inhibition of HDAC3 increases H3K27AC levels in the promoter region of activating transcription factor 3 (ATF3), a transcriptional repressor of the SLC7A11 gene, and upregulates the expression of ATF3. In contrast, ATF4, a SLC7A11 activator, is suppressed by HDAC3 inhibition. CONCLUSIONS: Our findings suggest that treatment with CS055 combined with chiglitazar, will target LSCs by inducing ferroptosis and may confer an effective approach for the treatment of AML.

CMFHMDA: a prediction framework for human disease-microbe associations based on cross-domain matrix factorization.

Predicting associations between microbes and diseases opens up new avenues for developing diagnostic, preventive, and therapeutic strategies. Given that laboratory-based biological tests to verify these associations are often time-consuming and expensive, there is a critical need for innovative computational frameworks to predict new microbe-disease associations. In this work, we introduce a novel prediction algorithm called Predicting Human Disease-Microbe Associations using Cross-Domain Matrix Factorization (CMFHMDA). Initially, we calculate the composite similarity of diseases and the Gaussian interaction profile similarity of microbes. We then apply the Weighted K Nearest Known Neighbors (WKNKN) algorithm to refine the microbe-disease association matrix. Our CMFHMDA model is subsequently developed by integrating the network data of both microbes and diseases to predict potential associations. The key innovations of this method include using the WKNKN algorithm to preprocess missing values in the association matrix and incorporating cross-domain information from microbes and diseases into the CMFHMDA model. To validate CMFHMDA, we employed three different cross-validation techniques to evaluate the model's accuracy. The results indicate that the CMFHMDA model achieved Area Under the Receiver Operating Characteristic Curve scores of 0.9172, 0.8551, and 0.9351$\pm $0.0052 in global Leave-One-Out Cross-Validation (LOOCV), local LOOCV, and five-fold CV, respectively. Furthermore, many predicted associations have been confirmed by published experimental studies, establishing CMFHMDA as an effective tool for predicting potential disease-associated microbes.

Nickel-Catalyzed Narasaka-Heck Cyclization Carbonylation of Unsaturated Oxime Esters with Arylboronic Acids.

The Narasaka-Heck reaction is one of the most straightforward methods for constructing pyrroline derivatives. Herein, we report a novel nickel-catalyzed three-component carbonylation reaction, which cleverly realizes the continuous construction of C(sp3)-N bonds and C(sp3)-C(sp2) bonds and effectively promotes the synthesis of acyl-substituted pyrroline derivatives. Furthermore, this strategy not only expands the conversion pathway of γ,δ-unsaturated oxime esters but also provides a new method for the synthesis of nitrogen-containing heterocyclic compounds.

Selective Synthesis of Mono- and Bis-Phosphorylated (Dihydro)pyrans via TMSCl-Mediated Cascade Phosphorylation Cycloisomerization of Enynones.

A chlorotrimethylsilane (TMSCl)-mediated cascade phosphorylation and cycloisomerization of enynones with diphenylphosphine oxides is presented. This methodology enables the highly selective synthesis of monophosphorylated 2H-pyrans and bisphosphorylated dihydropyrans through precise solvent-reagent stoichiometry control. The strategy demonstrated excellent functional group compatibility and high yields (up to 96%), providing facile access to structurally diverse phosphorylated heterocycles with potential applications in medicinal chemistry and materials science.

Palladium-Catalyzed Four-Component Radical Cascade Carbonylation Access to 2,3-Disubstituted Benzofuran Derivatives.

Multicomponent radical tandem reactions have emerged as a crucial technique for synthesizing complex molecules in organic chemistry. In this study, we report a palladium-catalyzed four-component difluoroalkylative carbonylation of enynes and ethyl difluoroiodoacetate. This transformation proceeds through a multistep sequential reaction that introduces reactive difluoro and carbonyl groups while constructing the benzofuran skeleton. Moreover, a variety of valuable 2,3-disubstituted benzofuran derivatives were obtained in respectable yields with excellent functional group compatibility.

A STAT3 Degrader Demonstrates Pre-clinical Efficacy in Venetoclax resistant Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that continues to have poor prognosis despite recent therapeutic advances. Venetoclax (Ven), a BCL2-inhibitor has shown a high response rate in AML; however, relapse is invariable due to mitochondrial dysregulation that includes upregulation of the antiapoptotic protein MCL1, a central mechanism of Ven resistance (Ven-res). We have previously demonstrated that the transcription factor STAT3 is upregulated in AML hematopoietic stem and progenitor cells (HSPCs) and can be effectively targeted to induce apoptosis of these aberrant cells. We now show that overexpression of STAT3 alone is sufficient to initiate a strong AML phenotype in a transgenic murine model. Phospho-proteomic data from Ven treated AML patients show a strong correlation of high total STAT3 and phospho-STAT3 [both p-STAT3(Y705) and p-STAT3(S727)] expression with worse survival and reduced remission duration. Additionally, significant upregulation of STAT3 was observed in Ven-res cell lines, in vivo models and primary patient samples. A novel and specific degrader of STAT3 demonstrated targeted reduction of total STAT3 and resulting inhibition of its active p-STAT3(Y705) and p-STAT3(S727) forms. Treatment with the STAT3 degrader induced apoptosis in parental and Ven-res AML cell lines and decreased mitochondrial depolarisation, and thereby dependency on MCL1 in Ven-res AML cell line, as observed by BH3 profiling assay. STAT3 degrader treatment also enhanced differentiation of myeloid and erythroid colonies in Ven-res peripheral blood mononuclear cells (PBMNCs). Upregulation of p-STAT3(S727) was also associated with pronounced mitochondrial structural and functional dysfunction in Ven-res cell lines, that were restored by STAT3 degradation. Treatment with a clinical-stage STAT3 degrader, KT-333 resulted in a significant reduction in STAT3 and MCL1 protein levels within two weeks of treatment in a cell derived xenograft model of Ven-res AML. Additionally, this treatment significant improvement in the survival of a Ven-res patient-derived xenograft in-vivo study. Degradation of STAT3 resulting in downregulation of MCL1 and improvements in global mitochondrial dysfunction suggests a novel mechanism of overcoming Ven-res in AML. Statement of Purpose: Five-year survival from AML is dismal at 30%. Our prior research demonstrated STAT3 over-expression in AML HSPC's to be associated with inferior survival. We now explore STAT3 over-expression in Ven-res AML, explain STAT3 mediated mitochondrial perturbations and describe a novel therapeutic strategy, STAT3 degradation to overcome Ven-res.

Genotype Associated With Visual Prognosis in Patients With Congenital Ectopia Lentis Following Lens Surgery: A Prospective Cohort Study.

PURPOSE: To investigate the relationship between visual prognosis and genotype in patients undergoing lens surgery for congenital ectopia lentis (EL). DESIGN: Prospective clinical cohort study. METHODS: Patients with congenital EL who underwent lens removal and intraocular lens implantation received panel-based next-generation sequencing. Patients were grouped into children and adolescents/adults based on the age at surgery. The visual prognosis, including best-corrected visual acuity (BCVA) and amblyopia, was stratified into short-term and medium to long-term. RESULTS: This study included 329 probands with congenital EL, with a median age at lens surgery of 7.00 years (interquartile range [IQR] = 5.00, 12.50 years). Children with the non-FBN1 mutation exhibited inferior medium to long-term postoperative BCVA (0.26 [IQR: 0.14, 0.33] vs 0.15 [IQR: 0.10, 0.22], P = .034) and a higher prevalence of amblyopia (44.4% vs 16.8%, P = .012) compared to those with FBN1 mutation. Multivariable analysis showed that genotype (FBN1 vs non-FBN1 mutation) was significantly associated with medium to long-term postoperative BCVA (b = -0.128, 95% CI -0.214 to -0.042, P = .004) and amblyopia (OR = 0.20, 95% CI 0.05-0.78, P = .020) in children. Further classification of FBN1 genotype did not yield significant correlations with visual prognosis. However, no significant correlation was observed between genotype and short-term visual prognosis in the children. Children with less severe EL (OR = 0.13, 95% CI 0.02-0.85, P = .033) had lower risks of amblyopia in the short-term follow-up. For adolescent and adult patients with congenital EL, those with poor preoperative BCVA and long axial length should be informed of suboptimal visual prognosis. CONCLUSIONS: Genotype significantly influences the medium to long-term visual prognosis in children with congenital EL. Genotype, along with preoperative BCVA, may assist in establishing reasonable expectations for patients regarding their visual outcomes after the lens surgery.

Outcomes after open and endovascular treatment for mesenteric artery embolism patients: a retrospective inverse probability of treatment-weighted analysis.

PURPOSE: This study aims to evaluate outcomes in patients with mesenteric artery embolism (MAE) who received primary endovascular therapy (EVT) or laparotomy, and investigate risk factors for 30-day mortality. METHODS: A retrospective analysis of 94 MAE patients who underwent two different treatment strategies was undertaken. An inverse probability of treatment weighting (IPTW) method was used to balance the confounding effects of baseline clinical data. Logistic regression analysis was performed to compare the outcomes according to type of treatment regimens before and after IPTW. Univariate and multivariable analysis were conducted to determine the risk factors for 30-day mortality. RESULTS: Twenty-eight MAE patients received primary EVT, and 66 Open Surgery (OS). Logistic regression analysis showed that there was no significant difference between the EVT and OS group in 30-day mortality rate before (odds ratio [OR] 0.477, 95% confidence interval [CI] 0.170 to 1.340, P = 0.160), and after IPTW (OR 0.647, 95% CI 0.210 to 1.993, P = 0.449). After IPTW, it revealed that the rates of second-look surgery (OR 36.727, 95% CI 5.407 to 249.458, P < 0.001) and hospital stay [> 30 days] (OR 0.006, 95% CI 0.000 to 0.363, P = 0.014) were different in the two groups. D-dimer (> 4 mg/L) and procalcitonin (> 0.5 ng/mL) were the independent risk factors for 30-day mortality in MAE patients postoperatively (P < 0.05). CONCLUSION: In this retrospective study, MAE patients who performed primary EVT had no obvious difference in 30-day mortality rate compared to those who received OS; but it was conducive to reducing prolonged hospital stays. An increase in procalcitonin level and higher D-dimer were associated with short-term poor prognosis in patients with MAE.

Genetic and selective constraints on the optimization of gene product diversity.

RNA and protein expressed from the same gene can have diverse isoforms due to various post-transcriptional and post-translational modifications. For the vast majority of alternative isoforms, It is unknown whether they are adaptive or simply biological noise. As we cannot experimentally probe the function of each isoform, we can ask whether the distribution of isoforms across genes and across species is consistent with expectations from different evolutionary processes. However, there is currently no theoretical framework that can generate such predictions. To address this, we developed a mathematical model where isoform abundances are determined collectively by cis-acting loci, trans-acting factors, gene expression levels, and isoform decay rates to predict isoform abundance distributions across species and genes in the face of mutation, genetic drift, and selection. We found that factors beyond selection, such as effective population size and the number of cis-acting loci, significantly influence evolutionary outcomes. Notably, suboptimal phenotypes are more likely to evolve when the population is small and/or when the number of cis-loci is large. We also explored scenarios where modification processes have both beneficial and detrimental effects, revealing a non-monotonic relationship between effective population size and optimization, demonstrating how opposing selection pressures on cis- and trans-acting loci can constrain the optimization of gene product diversity. As a demonstration of the power of our theory, we compared the expected distribution of A-to-I RNA editing levels in coleoids and found this to be largely consistent with non-adaptive explanations.

PTBP3 Mediates IL-18 Exon Skipping to Promote Immune Escape in Gallbladder Cancer.

Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system, with poor response to current treatments. Abnormal alternative splicing has been associated with the development of a variety of tumors. Combining the GEO database and GBC mRNA-seq analysis, it is found high expression of the splicing factor polypyrimidine region- binding protein 3 (PTBP3) in GBC. Multi-omics analysis revealed that PTBP3 promoted exon skipping of interleukin-18 (IL-18), resulting in the expression of ΔIL-18, an isoform specifically expressed in tumors. That ΔIL-18 promotes GBC immune escape by down-regulating FBXO38 transcription levels in CD8+T cells to reduce PD-1 ubiquitin-mediated degradation is revealed. Using a HuPBMC mouse model, the role of PTBP3 and ΔIL-18 in promoting GBC growth is confirmed, and showed that an antisense oligonucleotide that blocked ΔIL-18 production displayed anti-tumor activity. Furthermore, that the H3K36me3 promotes exon skipping of IL-18 by recruiting PTBP3 via MRG15 is demonstrated, thereby coupling the processes of IL-18 transcription and alternative splicing. Interestingly, it is also found that the H3K36 methyltransferase SETD2 binds to hnRNPL, thereby interfering with PTBP3 binding to IL-18 pre-mRNA. Overall, this study provides new insights into how aberrant alternative splicing mechanisms affect immune escape, and provides potential new perspectives for improving GBC immunotherapy.

Post-transfer adaptation of HGT-acquired genes and contribution to guanine metabolic diversification in land plants.

Horizontal gene transfer (HGT) is a major driving force in the evolution of prokaryotic and eukaryotic genomes. Despite recent advances in distribution and ecological importance, the extensive pattern, especially in seed plants, and post-transfer adaptation of HGT-acquired genes in land plants remain elusive. We systematically identified 1150 foreign genes in 522 land plant genomes that were likely acquired via at least 322 distinct transfers from nonplant donors and confirmed that recent HGT events were unevenly distributed between seedless and seed plants. HGT-acquired genes evolved to be more similar to native genes in terms of average intron length due to intron gains, and HGT-acquired genes containing introns exhibited higher expression levels than those lacking introns, suggesting that intron gains may be involved in the post-transfer adaptation of HGT in land plants. Functional validation of bacteria-derived gene GuaD in mosses and gymnosperms revealed that the invasion of foreign genes introduced a novel bypass of guanine degradation and resulted in the loss of native pathway genes in some gymnosperms, eventually shaping three major types of guanine metabolism in land plants. We conclude that HGT has played a critical role in land plant evolution.

The GC-content at the 5' ends of human protein-coding genes is undergoing mutational decay.

BACKGROUND: In vertebrates, most protein-coding genes have a peak of GC-content near their 5' transcriptional start site (TSS). This feature promotes both the efficient nuclear export and translation of mRNAs. Despite the importance of GC-content for RNA metabolism, its general features, origin, and maintenance remain mysterious. We investigate the evolutionary forces shaping GC-content at the transcriptional start site (TSS) of genes through both comparative genomic analysis of nucleotide substitution rates between different species and by examining human de novo mutations. RESULTS: Our data suggests that GC-peaks at TSSs were present in the last common ancestor of amniotes, and likely that of vertebrates. We observe that in apes and rodents, where recombination is directed away from TSSs by PRDM9, GC-content at the 5' end of protein-coding gene is currently undergoing mutational decay. In canids, which lack PRDM9 and perform recombination at TSSs, GC-content at the 5' end of protein-coding is increasing. We show that these patterns extend into the 5' end of the open reading frame, thus impacting synonymous codon position choices. CONCLUSIONS: Our results indicate that the dynamics of this GC-peak in amniotes is largely shaped by historic patterns of recombination. Since decay of GC-content towards the mutation rate equilibrium is the default state for non-functional DNA, the observed decrease in GC-content at TSSs in apes and rodents indicates that the GC-peak is not being maintained by selection on most protein-coding genes in those species.

Hydrogen sulfide inhibits skeletal muscle ageing by up-regulating autophagy through promoting deubiquitination of adenosine 5'-monophosphate (AMP)-activated protein kinase α1 via ubiquitin specific peptidase 5.

BACKGROUND: Hydrogen sulfide (H2S), the third gasotransmitter discovered, regulates a variety of physiological functions. Whether H2S alleviates skeletal muscle ageing by regulating autophagy has not been reported. METHODS: Mice were administered 150 mg/kg/day of D-galactose (D-gal), and C2C12 myotubes were cultured in 20 g/L D-gal to induce ageing. Sodium hydrosulfide (NaHS) was employed as an exogenous donor in the treatment group. The intracellular concentration of H2S was quantified by the 7-azido-4-methylcoumarin fluorescence probe. The proteins involved in the ubiquitin-mediated degradation of AMPKα1 were detected by liquid chromatography tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation (Co-IP). S-sulfhydration of USP5 was tested by a biotin-switch assay. Associated proteins were analysed by western blot. RESULTS: NaHS was found to effectively restore the H2S content in both ageing gastrocnemius (+91.89%, P < 0.001) and C2C12 myotubes (+27.55%, P < 0.001). In comparison to the D-gal group, NaHS was observed to increase the mean cross-sectional area of muscle fibres (+44.91%, P < 0.001), to decrease the collagen volume fraction of gastrocnemius (-81.32%, P = 0.001) and to reduce the ß-galactosidase-positive area of C2C12 myotubes (-28.74%, P < 0.001). NaHS was also found to reverse the expression of muscle atrophy F box protein (MAFbx), muscle-specific RING finger protein 1 (MuRF1), Cyclin D1 and p21 in the ageing gastrocnemius tissue (MAFbx: -31.73%, P = 0.008; MuRF1: -32.37%, P = 0.003; Cyclin D1: +45.34%, P = 0.010; p21: -25.53%, P = 0.022) and C2C12 myotubes (MAFbx: -16.38%, P < 0.001; MuRF1: -16.45%, P = 0.003; Cyclin D1: +40.23%, P < 0.001; p21: -35.85%, P = 0.026). The AMPKα1-ULK1 pathway was activated and autophagy was up-regulated in NaHS-treated gastrocnemius tissue (p-AMPKα1: +61.61%, P = 0.018; AMPKα1: +30.64%, P = 0.010; p-ULK1/ULK1: +85.87%, P = 0.005; p62: -29.07%, P < 0.001; Beclin1: +24.75%, P = 0.007; light chain 3 II/I [LC3 II/I]: +55.78%, P = 0.004) and C2C12 myotubes (p-AMPKα1: +77.49%, P = 0.018; AMPKα1: +26.18%, P = 0.022; p-ULK1/ULK1: +38.34%, P = 0.012; p62: -9.02%, P = 0.014; Beclin1: +13.36%, P < 0.001; LC3 II/I: +79.38%, P = 0.017; autophagy flux: +24.88%, P = 0.034) compared with the D-gal group. The effects of NaHS on autophagy were comparable to those of acadesine and LYN-1604, and chloroquine could reverse its effects on ageing. LC-MS/MS and Co-IP experiments demonstrated that USP5 is a deubiquitinating enzyme of AMPKα1. Following the knockdown of USP5, the activation of AMPKα1 was decreased (p-AMPKα1: -42.10%, P < 0.001; AMPKα1: -43.93%, P < 0.001), autophagy was inhibited (p-ULK1/ULK1: -27.51, P = 0.001; p62: +36.00, P < 0.001; Beclin1: -22.15%, P < 0.001) and NaHS lost its ability to up-regulate autophagy. NaHS was observed to restore the expression (gastrocnemius: +62.17%, P < 0.001; C2C12 myotubes: +37.51%, P = 0.003) and S-sulfhydration (+53.07%, P = 0.009) of USP5 and reduce the ubiquitination of AMPKα1. CONCLUSIONS: H2S promotes the deubiquitination of AMPKα1 by increasing the expression and S-sulfhydration of USP5, thereby up-regulating autophagy and alleviating skeletal muscle ageing.

Correction: A robust and porous titanium metal-organic framework for gas adsorption, CO2 capture and conversion.

Correction for 'A robust and porous titanium metal-organic framework for gas adsorption, CO2 capture and conversion' by Xuze Pan, et al., Dalton Trans., 2023, 52, 3896-3906, https://doi.org/10.1039/D2DT03158B.

Imbalance of mitochondrial quality control regulated by STING and PINK1 affects cyfluthrin-induced neuroinflammation.

Nervous system diseases are a global health problem, and with the increase in the elderly population around the world, their incidence will also increase. Harmful substances in the environment are closely related to the occurrence of nervous system diseases. China is a large agricultural country, and thus the insecticide cyfluthrin has been widely used. Cyfluthrin is neurotoxic, but the mechanism of this injury is not clear. Inflammation is an important mechanism for the occurrence of nervous system diseases. Mitochondria are the main regulators of the inflammatory response, and various cellular responses, including autophagy, directly affect the regulation of inflammatory processes. Mitochondrial damage is related to mitochondrial quality control (MQC) and PTEN-induced kinase 1 (PINK1). As an anti-inflammatory factor, stimulator of interferon genes (STING) participates in the regulation of inflammation. However, the relationship between STING and mitochondria in the process of cyfluthrin-induced nerve injury is unclear. This study established in vivo and in vitro models of cyfluthrin exposure to explore the role of MQC and to clarify the mechanism of action of STING and PINK1. Our results showed that cyfluthrin can increase the reactive oxygen species (ROS) level, resulting in mitochondrial damage and inflammation. In this process, an imbalance in MQC leads to the aggravation of mitochondrial damage, and high STING expression drives the occurrence of inflammation. We established a differential expression model of STING and PINK1 to further determine the underlying mechanism and found that the interaction between STING and PINK1 regulates MQC to affect the levels of mitochondrial damage and inflammation. When STING and PINK1 expression are downregulated, mitochondrial damage and STING-induced inflammation are significantly alleviated. In summary, a synergistic effect between STING and PINK1 on cyfluthrin-induced neuroinflammation may exist, which leads to an imbalance in MQC by inhibiting mitochondrial biogenesis and division/fusion, and PINK1 can reduce STING-driven inflammation.

Mechanism of immune activation mediated by genomic instability and its implication in radiotherapy combined with immune checkpoint inhibitors.

Various genetic and epigenetic changes associated with genomic instability (GI), including DNA damage repair defects, chromosomal instability, and mitochondrial GI, contribute to development and progression of cancer. These alterations not only result in DNA leakage into the cytoplasm, either directly or through micronuclei, but also trigger downstream inflammatory signals, such as the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. Apart from directly inducing DNA damage to eliminate cancer cells, radiotherapy (RT) exerts its antitumor effects through intracellular DNA damage sensing mechanisms, leading to the activation of downstream inflammatory signaling pathways. This not only enables local tumor control but also reshapes the immune microenvironment, triggering systemic immune responses. The combination of RT and immunotherapy has emerged as a promising approach to increase the probability of abscopal effects, where distant tumors respond to treatment due to the systemic immunomodulatory effects. This review emphasizes the importance of GI in cancer biology and elucidates the mechanisms by which RT induces GI remodeling of the immune microenvironment. By elucidating the mechanisms of GI and RT-induced immune responses, we aim to emphasize the crucial importance of this approach in modern oncology. Understanding the impact of GI on tumor biological behavior and therapeutic response, as well as the possibility of activating systemic anti-tumor immunity through RT, will pave the way for the development of new treatment strategies and improve prognosis for patients.

Prophylactic Dose of Rivaroxaban Versus Warfarin for the Treatment of Isolated Calf Muscle Vein Thrombosis: A Retrospective Propensity Score-Matched Analysis.

BACKGROUND: Prophylactic dose of rivaroxaban is often used in treatment of isolated calf muscle vein thrombosis (ICMVT); nevertheless, its effect is less reported. This study aims to evaluate short-term outcomes in patients with ICMVT who received prophylactic dose of rivaroxaban or warfarin therapy. METHODS: A retrospective analysis of 472 ICMVT patients who received 2 different treatment regimens was undertaken. Propensity score matching method was used to balance the confounding effect of baseline clinical data. Chi-squared test and logistic regression analysis were used to compare outcomes (venous thromboembolism events, bleeding events, complete clot resolution) according to the type of treatment regimens before and after propensity score matching. Univariate and multivariable analysis were used to investigate risk factors for incomplete clot resolution of ICMVT after propensity score matching. RESULTS: 242 ICMVT patients received prophylactic dose of rivaroxaban (rivaroxaban group, RG), and 230 received warfarin (warfarin group, WG). After propensity score matching, 156 patients were included in each group; Venous thromboembolism (VTE) events occurred in 14 (9.0%) patients in the RG and 10 (6.4%) in the WG (P = 0.395); no major bleeding events occurred in each group, and clinically relevant nonmajor bleeding events occurred in 5 (3.2%) patients in the RG and 10 (6.4%) in the WG (P = 0.186); complete clot resolution at 3 months occurred in 80 (51.3%) patients in the RG and 100 (64.1%) in the WG (P = 0.022). Logistic regression analysis showed that there were no significant differences between RG and WG in VTE events (odds ratio 1.439, 95% confidence interval 0.619-3.347, P = 0.397) and clinically relevant nonmajor bleeding events (odds ratio 0.483, 95% confidence interval 0.161-1.449, P = 0.194); it revealed that complete clot resolution rate at 3 months was different in the 2 groups (odds ratio 0.589, 95% confidence interval 0.375-0.928, P = 0.022). Treatment regimens (prophylactic dose of rivaroxaban), thrombosis (maximum diameter >7 mm), and risk factors for VTE (nonsurgery risk factors, mainly referring to active malignancy) were risk factors for incomplete clot resolution of ICMVT (P < 0.05). CONCLUSIONS: In this retrospective study with a short-term follow-up, ICMVT patients who received prophylactic dose of rivaroxaban had no significant differences in VTE and bleeding events compared to those who received warfarin therapy (the overall INR >2.0 for >50% of the time); but it was not conducive to complete clot resolution.