Muscularis macrophages controlled by NLRP3 maintain the homeostasis of excitatory neurons.

Peristaltic movements in gut are essential to propel ingested materials through the gastrointestinal tract. Intestinal resident macrophages play an important role in this physiological function through protecting enteric neurons. However, it is incompletely clear how individuals maintain the homeostasis of gut motility. Here we found that NLRP3 is a critical factor in controlling loss of muscularis resident macrophages (MMs), and demonstrate that MMs are involved in the homeostasis of excitatory neurons such as choline acetyltransferase (ChAT)+ and vesicular glutamate transporter 2 (VGLUT2)+ but not inhibitory neuronal nitric oxide synthase (nNOS)+ neurons. NLRP3 knockout (KO) mice had enhanced gut motility and increased neurons, especially excitatory ChAT+ and VGLUT2+ neurons. Single cell analyses showed that there had increased resident macrophages, especially MMs in NLRP3 KO mice. The MM proportion in the resident macrophages was markedly higher than those in wild-type (WT) or caspase 1/11 KO mice. Deletion of the MMs and transplantation of the NLRP3 KO bone marrow cells showed that survival of the gut excitatory ChAT+ and VGLUT2+ neurons was dependent on the MMs. Gut microbiota metabolites ß-hydroxybutyrate (BHB) could promote gut motility through protecting MMs from pyroptosis. Thus, our data suggest that MMs regulated by NLRP3 maintain the homeostasis of excitatory neurons.

LINC01572 promotes the malignant progression of lung adenocarcinoma by modulating p53 mediated by miRNA-338-5p/TTK axis.

OBJECTIVES: Lung cancer is one of the malignant tumors that threaten human health seriously. Long non-coding RNA (lncRNA) is an important factor affecting tumorigenesis and development. However, the mechanism of lncRNA in lung cancer progression remains to be further explored. METHODS: In this study, the TCGA database was analyzed, and LINC01572 was found to be increased in lung adenocarcinoma (LUAD) tissues. Thereafter, with the help of databases including lncBase, TargetScan, and mirDIP, as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, LINC01572/miRNA-338-5p/TTK regulatory axis and downstream p53 signaling pathway were excavated. qRT-PCR was adopted to detect levels of LINC01572, miRNA-338-5p, and TTK in LUAD cells. The role that LINC01572 played in LUAD cells was validated by CCK-8 assay, flow cytometry, colony formation, Transwell, and scratch healing assays. The binding ability between LINC01572/TTK and miRNA-338-5p was then verified by dual-luciferase and RIP analysis. KEY FINDINGS: The results of this study demonstrated that LINC01572 was elevated in LUAD cells compared with normal cells. The overexpression of LINC01572 promoted the proliferative and migratory properties of LUAD cells but inhibited cell apoptosis. The inhibition of LINC01572 resulted in the opposite result. In addition, rescue experiments revealed that LINC01572, as a molecular sponge of miRNA-338-5p, targeted TTK to manipulate p53 for facilitating LUAD cell malignant progression. Apart from this, we constructed a mouse xenograft model and confirmed that the knockdown of LINC01572 hindered the growth of LUAD solid tumors in vivo. CONCLUSIONS: Our findings illuminated the molecular mechanism of LINC01572 influencing LUAD and provided new insights for targeted therapy of LUAD cells.

[Identification of Protein-Coding Gene Markers in Breast Invasive Carcinoma Based on Machine Learning].

Objective To screen out the biomarkers linked to prognosis of breast invasive carcinoma based on the analysis of transcriptome data by random forest (RF),extreme gradient boosting (XGBoost),light gradient boosting machine (LightGBM),and categorical boosting (CatBoost). Methods We obtained the expression data of breast invasive carcinoma from The Cancer Genome Atlas and employed DESeq2,t-test,and Cox univariate analysis to identify the differentially expressed protein-coding genes associated with survival prognosis in human breast invasive carcinoma samples.Furthermore,RF,XGBoost,LightGBM,and CatBoost models were established to mine the protein-coding gene markers related to the prognosis of breast invasive cancer and the model performance was compared.The expression data of breast cancer from the Gene Expression Omnibus was used for validation. Results A total of 151 differentially expressed protein-coding genes related to survival prognosis were screened out.The machine learning model established with C3orf80,UGP2,and SPC25 demonstrated the best performance. Conclusions Three protein-coding genes (UGP2,C3orf80,and SPC25) were screened out to identify breast invasive carcinoma.This study provides a new direction for the treatment and diagnosis of breast invasive carcinoma.

A novel classification of posterior pelvic exenteration to assess prognosis in female patients with locally advanced primary rectal cancer: a retrospective cohort study from China PelvEx collaborative.

PURPOSE: Surgical techniques and the prognosis of posterior pelvic exenteration for locally advanced primary rectal cancer in female patients pose challenges that need to be addressed. Therefore, we investigated the short-term and survival outcomes of posterior pelvic exenteration in female patients using a novel Peking classification. METHODS: We retrospectively analysed a prospective database from China PelvEx Collaborative across three tertiary referral centres. A total of 172 patients who underwent combined resection for locally advanced primary rectal cancer were classified based on four subtypes (PPE-I [64/172], PPE-II [68/172], PPE-III [21/172], and PPE-IV [19/172]) according to the Peking classification; perioperative characteristics and short-term and oncological outcomes were analysed. RESULTS: Differences were significant among the four groups regarding colorectal reconstruction (p < 0.001), perineal reconstruction (p < 0.001), in-hospital complications (p < 0.05), and urinary retention (p < 0.05). The R0 resection rates for PPE-I, PPE-II, PPE-III, and PPE-IV were 90.6%, 89.7%, 90.5%, and 89.5%, respectively. The 5-year overall survival rates of the PPE-I, PPE-II, PPE-III, and PPE-IV groups were 73.4%, 68.8%, 54.7%, and 37.3%, respectively. Correspondingly, their 5-year disease-free survival rates were 76.0%, 62.5%, 57.7%, and 43.1%, respectively. Notably, the PPE-IV group demonstrated the lowest 5-year overall survival rate (p < 0.001) and 5-year disease-free survival rate (p < 0.001). CONCLUSION: The Peking classification can aid in determining suitable surgical techniques and conducting prognostic assessments in female patients with locally advanced primary rectal cancer.

Association between the MDR1 rs1045642 polymorphism and breast cancer risk: An updated meta­analysis.

Multidrug resistance 1 (MDR1) is a transmembrane transporter on the cell membrane. As an ATP-dependent efflux pump, MDR1 is mainly responsible for the adsorption, distribution, metabolism, excretion and transportation of anticancer drugs to cancer cells. Mutations of the MDR1 gene may be associated with the incidence of cancer. In the past decade, associations found between the MDR1 rs1045642 polymorphism and breast cancer have been inconsistent and inconclusive. Therefore, the present study performed a meta-analysis including studies published up until August 16, 2023 to systematically evaluate the association between the MDR1 rs1045642 polymorphism and breast cancer risk. A total of 21 published case studies involving 6,815 patients with breast cancer and 9,227 healthy participants were included in the meta-analysis. Overall, the MDR1 rs1045642 polymorphism was not significantly associated with breast cancer-associated risk. However, in the subgroup analysis, the MDR1 rs1045642 polymorphism was found to be notably associated with a higher risk of breast cancer among Asian populations in recessive models [TT vs. CT + CC; odds ratio (OR)=1.393; 95% confidence interval (CI), 1.143-1.698; P=0.001; I2<25%]. The MDR1 C3435T polymorphism was also associated with a notable decrease in the incidence of breast cancer in mixed ethnicity populations (TT and CT + CC; OR=0.578; 95% CI, 0.390-0.856; P=0.006; I2<25%). In Caucasian populations, the MDR1 rs1045642 polymorphism was not associated with breast cancer risk. In conclusion, the present meta-analysis demonstrated that the MDR1 rs1045642 polymorphism may increase the risk of breast cancer in Asian populations, is associated with a reduced risk of breast cancer in mixed populations but has no notable effect in Caucasian populations.

Longitudinal Profiling of Fasting Plasma Metabolome in Response to Weight-Loss Interventions in Patients with Morbid Obesity.

It is well recognized that patients with severe obesity exhibit remarkable heterogeneity in response to different types of weight-loss interventions. Those who undergo Roux-en-Y gastric bypass (RYGB) usually exhibit more favorable glycemic outcomes than those who receive adjustable gastric banding (BAND) or intensive medical intervention (IMI). The molecular mechanisms behind these observations, however, remain largely unknown. To identify the plasma metabolites associated with differential glycemic outcomes induced by weight-loss intervention, we studied 75 patients with severe obesity (25 each in RYGB, BAND, or IMI). Using untargeted metabolomics, we repeatedly measured 364 metabolites in plasma samples at baseline and 1-year after intervention. Linear regression was used to examine whether baseline metabolites or changes in metabolites are associated with differential glycemic outcomes in response to different types of weight-loss intervention, adjusting for sex, baseline age, and BMI as well as weight loss. Network analyses were performed to identify differential metabolic pathways involved in the observed associations. After correction for multiple testing (q < 0.05), 33 (RYGB vs. IMI) and 28 (RYGB vs. BAND) baseline metabolites were associated with changes in fasting plasma glucose (FPG) or glycated hemoglobin (HbA1c). Longitudinal changes in 38 (RYGB vs. IMI) and 38 metabolites (RYGB vs. BAND) were significantly associated with changes in FPG or HbA1c. The identified metabolites are enriched in pathways involved in the biosynthesis of aminoacyl-tRNA and branched-chain amino acids. Weight-loss intervention evokes extensive changes in plasma metabolites, and the altered metabolome may underlie the differential glycemic outcomes in response to different types of weight-loss intervention, independent of weight loss itself.

Targeted activation of ferroptosis in colorectal cancer via LGR4 targeting overcomes acquired drug resistance.

Acquired drug resistance is a major challenge for cancer therapy and is the leading cause of cancer mortality; however, the mechanisms of drug resistance are diverse and the strategy to specifically target drug-resistant cancer cells remains an unmet clinical issue. Here, we established a colorectal cancer-derived organoid biobank and induced acquired drug resistance by repeated low-level exposures of chemo-agents. Chemosensitivity profiling and transcriptomic analysis studies revealed that chemoresistant cancer-derived organoids exhibited elevated expression of LGR4 and activation of the Wnt signaling pathway. Further, we generated a monoclonal antibody (LGR4-mAb) that potently inhibited LGR4-Wnt signaling and found that treatment with LGR4-mAb notably sensitized drug-induced ferroptosis. Mechanistically, LGR4-dependent Wnt signaling transcriptionally upregulated SLC7A11, a key inhibitor of ferroptosis, to confer acquired drug resistance. Our findings reveal that targeting of Wnt signaling by LGR4-mAb augments ferroptosis when co-administrated with chemotherapeutic agents, demonstrating a potential opportunity to fight refractory and recurrent cancers.

Comparison of short- and long-term outcomes between laparoscopic and open multivisceral resection for clinical T4b colorectal cancer: A multicentre retrospective cohort study in China.

BACKGROUND: Laparoscopic surgery is controversial for patients with clinical T4b colorectal cancer (CRC) who require multivisceral resection (MVR). This study aims to explore and compare the safety and long-term oncological outcomes of laparoscopic surgery and open surgery for patients with clinical T4b CRC. MATERIALS AND METHODS: This study was a retrospective cohort study based on a multicentre database. According to the operation method, the patients were divided into a laparoscopic MVR group and an open MVR group. The short-term and long-term outcomes were compared. RESULTS: From January 2010 to December 2021, a total of 289 patients in the laparoscopic MVR group and 349 patients in the open MVR group were included. After propensity score matching, patients were stratified into a laparoscopic MVR group (n = 163) and an open MVR group (n = 163). Compared with the open MVR group, the laparoscopic MVR group had less blood loss (100 vs. 200, p < 0.001), a shorter time to first flatus (3 vs. 4, P < 0.001), a shorter postoperative hospital stay (10 vs. 12, P < 0.001), and a lower incidence of surgical site infection (2.5 % vs. 8.0 %, P = 0.043). The Kaplan-Meier curves showed that the two groups had similar overall survival (P = 0.283) and disease-free survival (P = 0.152). CONCLUSION: Compared with open MVR, laparoscopic MVR had less blood loss, fewer surgical site infection complications, faster recovery and a shorter hospital stay. The long-term survival outcome of laparoscopic MVR was not inferior to that of open MVR.

Research status and hotspots of autoimmune gastritis: A bibliometric analysis.

BACKGROUND: As an emerging potential risk factor for gastric cancer, autoimmune gastritis (AIG) has garnered increasing attention from researchers. AIM: To analyze the research overview and popular topics in the field of AIG using bibliometrics. METHODS: Relevant publications on AIG in the Web of Science Core Collection were collated, and data visualization and analysis of the number of publications, countries, institutions, journals, authors, keywords, and citations were performed using software such as VOSviewer, CiteSpace, and Scimago Graphic. RESULTS: In total, 316 relevant articles were included in the analysis. From 2015 to 2022, the number of publications increased annually. The countries, institutions, authors, and journals with the highest number of publications in this field were Italy, Monash University, Toh BH, and Internal Medicine. The main keywords used in this field of research were pathogenesis, Helicobacter pylori, autoantibody, parietal cell antibody, atrophic gastritis, classification, diagnosis, autoimmune disease, risk, cancer, gastric cancer, vitamin B12 deficiency, and pernicious anemia. The following directions may be popular for future research: (1) The role of Helicobacter pylori in the pathogenesis of AIG; (2) diagnostic criteria for AIG and reference values for serum antibodies; (3) comorbidity mechanisms between AIG and other autoimmune diseases; (4) specific risks of AIG complicating gastric and other cancers; and (5) the role of vitamin B12 supplementation in patients with early-stage AIG. CONCLUSION: This bibliometric analysis reported on popular topics and emerging trends in AIG, with diagnosis and prognosis being research hotspots in this field.

Composite healthy lifestyle, socioeconomic deprivation, and mental well-being during the COVID-19 pandemic: a prospective analysis.

The adverse psychological and social impacts of COVID-19 pandemic are well characterized, but the role of composite, modifiable lifestyle factors that may interact to mitigate these impacts is not. The effect of socioeconomic deprivation on these lifestyle risks also remains unclear. Based on a nationally representative, longitudinal cohort, we assessed the association between a combination of pre-pandemic lifestyle factors and mental health conditions during pandemic, and the contribution of deprivation to it. Composite lifestyle factors included BMI, smoking status, alcohol consumption, physical activity, sedentary time, sleep duration, and fruit and vegetable intake, with lifestyle scores and lifestyle categories calculated for each participant. Symptoms of depression and anxiety, and personal well-being were assessed by validated scales during the pandemic. Socioeconomic deprivation was characterized by both individual-level (income, wealth, and education) and group-level factors (Index of Multiple Deprivation). Of the 5049 eligible participants (mean [SD] age, 68.1 [10.9] years; 57.2% were female) included in the study, 41.6% followed a favorable lifestyle, 48.9% followed an intermediate lifestyle, and 9.5% followed an unfavorable lifestyle. Compared with favorable lifestyle category, participants in the intermediate and unfavorable lifestyle category were at increased risk of mental health conditions, with the hazard ratio (HR) for trend per increment change towards unfavorable category of 1.17 (95% CI 1.09-1.26) for depression, 1.23 (1.07-1.42) for anxiety, and 1.39 (1.20-1.61) for low well-being. A significant trend of lower risk for mental health conditions with increasing number of healthy lifestyle factors was observed (P < 0.001 for trend). There were no significant interactions between lifestyle factors and socioeconomic deprivation for any of the outcomes, with similar HRs for trend per one increment change in lifestyle category observed in each deprivation group. Compared with those in the least deprived group with favorable lifestyle, participants in the most deprived group adherent to unfavorable lifestyle had the highest risk of mental health outcomes. These results suggest that adherence to a broad combination of healthy lifestyle factors was associated with a significantly reduced risk of mental health conditions during the COVID-19 pandemic. Lifestyle factors, in conjunction with socioeconomic deprivation, independently contribute to the risk of mental health issues. Although further research is needed to assess causality, the current findings support public health strategies and individual-level interventions that provide enhanced support in areas of deprivation and target multiple lifestyle factors to reduce health inequalities and promote mental well-being during the ongoing COVID-19 pandemic.

MCF2L-AS1/miR-874-3p/STAT3 feedback loop contributes to lung adenocarcinoma cell growth and cisplatin resistance.

Background: Long noncoding RNA (lncRNA) is widely acknowledged for its crucial role in the biological processes of various human cancers. MCF2L antisense RNA 1 (MCF2L-AS1) is a newly identified lncRNA, which remains unexplored in the context of cancer. Methods: MCF2L-AS1 expression was examined using qRT-PCR analysis. The impact of MCF2L-AS1 on LUAD cell growth was assessed through CCK-8, colony formation, EdU, caspase-3 activity, TUNEL, Western blot, and transwell assays. The interaction between miR-874-3p and MCF2L-AS1 or STAT3 was confirmed by RIP, luciferase reporter, and RNA pull-down assays. Results: Our study demonstrated the overexpression of MCF2L-AS1 in LUAD cells. Functionally, the silencing of MCF2L-AS1 hindered cell proliferation, migration, and invasion, while promoting cell apoptosis. Notably, the depletion of MCF2L-AS1 was associated with decreased cisplatin resistance. Mechanistically, MCF2L-AS1 was identified as an upstream gene of miR-874-3p, negatively regulating its expression. Following this, STAT3, the downstream target of miR-874-3p, was identified. Additionally, the expression of STAT3 was inversely related to miR-874-3p and positively regulated by MCF2L-AS1. A restoration assay suggested that MCF2L-AS1 promoted LUAD cell growth by sponging miR-874-3p and modulating STAT3 expression. Intriguingly, STAT3 was subsequently confirmed as a transcription factor that binds to the MCF2L-AS1 promoter, thereby enhancing its transcription. Conclusions: The MCF2L-AS1/miR-874-3p/STAT3 feedback loop plays a significant role in LUAD cell growth and cisplatin resistance.

Research on the biological mechanism and potential application of CEMIP.

Cell migration-inducing protein (CEMIP), also known as KIAA1199 and hyaluronan-binding protein involved in hyaluronan depolymerization, is a new member of the hyaluronidase family that degrades hyaluronic acid (HA) and remodels the extracellular matrix. In recent years, some studies have reported that CEMIP can promote the proliferation, invasion, and adhesion of various tumor cells and can play an important role in bacterial infection and arthritis. This review focuses on the pathological mechanism of CEMIP in a variety of diseases and expounds the function of CEMIP from the aspects of inhibiting cell apoptosis, promoting HA degradation, inducing inflammatory responses and related phosphorylation, adjusting cellular microenvironment, and regulating tissue fibrosis. The diagnosis and treatment strategies targeting CEMIP are also summarized. The various functions of CEMIP show its great potential application value.

Serum Sulfur-Containing Amino Acids and Risk of Maternal Gestational Diabetes and Adverse Growth Patterns in Offspring.

BACKGROUND: To estimate associations of sulfur-containing amino acids (SAAs) in the early trimester of pregnancy and gestational diabetes mellitus (GDM) and estimate associations of maternal SAAs with adverse growth patterns in offspring. METHODS: We established a 1:1 matched case-control study (n = 486) from our cohort of pregnant women, and 401 children were followed up at ages 1 to 8 years. We conducted binary conditional logistic regression to estimate the risk associations of serum SAAs with GDM. Multinomial logistic regression was implemented to explore associations of maternal SAAs with adverse growth patterns in the offspring. RESULTS: High serum methionine and cystine were independently associated with increased GDM risk (OR: 1.92, 95%CI: 1.18-3.13 and 2.69, 1.59-4.53). Conversely, a low level of serum taurine was independently associated with increased GDM risk (2.61, 1.64-4.16). Maternal high cystine and low taurine were also associated with an increased risk of persistent obesity growth pattern (POGP) in offspring (OR: 2.79, 95%CI: 1.09-7.17 and 3.92, 1.11-13.89) and the effect was largely independent of GDM. CONCLUSIONS: High serum methionine, cystine and low serum taurine in the early trimester of pregnancy were associated with a greatly increased risk of GDM. Maternal high cystine and low taurine were associated with elevated risk of offspring POGP, largely independent of GDM.

RGS5 augments astrocyte activation and facilitates neuroinflammation via TNF signaling.

Astrocytes contribute to chronic neuroinflammation in a variety of neurodegenerative diseases, including Parkinson's disease (PD), the most common movement disorder. However, the precise role of astrocytes in neuroinflammation remains incompletely understood. Herein, we show that regulator of G-protein signaling 5 (RGS5) promotes neurodegenerative process through augmenting astrocytic tumor necrosis factor receptor (TNFR) signaling. We found that selective ablation of Rgs5 in astrocytes caused an inhibition in the production of cytokines resulting in mitigated neuroinflammatory response and neuronal survival in animal models of PD, whereas overexpression of Rgs5 had the opposite effects. Mechanistically, RGS5 switched astrocytes from neuroprotective to pro-inflammatory property via binding to the receptor TNFR2. RGS5 also augmented TNFR signaling-mediated pro-inflammatory response by interacting with the receptor TNFR1. Moreover, interrupting RGS5/TNFR interaction by either RGS5 aa 1-108 or small molecular compounds feshurin and butein, suppressed astrocytic cytokine production. We showed that the transcription of astrocytic RGS5 was controlled by transcription factor early B cell factor 1 whose expression was reciprocally influenced by RGS5-modulated TNF signaling. Thus, our study indicates that beyond its traditional role in G-protein coupled receptor signaling, astrocytic RGS5 is a key modulator of TNF signaling circuit with resultant activation of astrocytes thereby contributing to chronic neuroinflammation. Blockade of the astrocytic RGS5/TNFR interaction is a potential therapeutic strategy for neuroinflammation-associated neurodegenerative diseases.

Construction and comprehensive analysis of a novel prognostic signature associated with immunogenic cell death molecular subtypes in patients with bladder cancer.

Background: Immunogenic cell death (ICD) triggers adaptive immune responses that aid in anticancer therapy. However, the significance of ICD-associated genes (ICDAGs) in clinical applications and their potential impact on the tumor microenvironment (TME) remains unclear. Methods: The TCGA cohort was divided into different ICD clusters using the method of Consensus clustering. We assessed the clinical results and TME features of various ICD clusters. GSVA quantified the activation of hallmark gene sets. To establish an ICD molecular subtypes-related prognostic model (ICDRPM), we performed LASSO Cox regression analysis on the differentially expressed genes (DEGs) among ICD subtypes. We evaluated the assessment of risk groups by analyzing the proportion of immune cells, the TME, differences in genomic mutation, the efficacy of immunotherapy, and drug sensitivity. To enhance the clinical effectiveness of the ICDRPM, a nomograph was developed. Results: Two distinct molecular subtypes were identified, and changes in ICDRGs were associated with clinical outcomes and TME characteristics of patients. A total of 1162 differentially expressed genes (DEGs) were obtained from two ICD clusters, and an ICDRPS was then developed to predict overall survival (OS). During both internal and external validation, patients classified as high-risk exhibited significantly poorer overall survival compared to those classified as low-risk. Additionally, the ICDRPS (ICD_score) was identified as an independent prognostic indicator for patients with BC, demonstrating excellent predictive performance. Afterward, we constructed a dependable nomogram to improve the practicality of the ICD_score. Furthermore, low-risk individuals showed stronger immunocyte infiltration, higher immune checkpoint expression, and higher IPS-PD-1 combined IPS-CTLA4 scores, indicating a greater response to immune checkpoint inhibitors (ICIs). Moreover, individuals categorized as having low or high risk exhibited contrasting sensitivity to anticancer medications. Conclusions: The model constructed for genes related to ICD provided meaningful clinical implications for immunotherapy, and facilitated individualized treatment for BC patients.

The synthesis of multifunctional cellulose graft alternating copolymers of 3,4-dihydrocoumarin and epoxides in DBU/DMSO/CO2 solvent system.

Cellulose graft copolymers having well-defined structures could incorporate the characteristics of both the cellulose skeleton and side chains, providing a new method for the preparation functionalised cellulose derivatives. Herein, a series of multifunctional cellulose grafted, alternating 3,4-dihydrocoumarin (DHC) and epoxide (EPO) copolymers (cell-g-P(DHC-alt-EPO)) were prepared in a metal-free DBU/DMSO/CO2 solvent system without adding additional catalyst. Four examples of cell-g-P(DHC-alt-EPO) with tunable thermal and optical properties were synthesized by copolymerization of DHC with styrene oxide (SO), propylene oxide (PO), cyclohexene oxide (CHO) or furfuryl glycidyl ether (FGE) onto cellulose. The nonconjugated cell-g-P(DHC-alt-EPO) showed UV absorption properties with the maximum absorption peak at 282 nm and 295 nm and photoluminescence performance. A clustering-triggered emission mechanism was confirmed and consistent with DFT theoretical calculations. In DMSO solution, the copolymer (DHCSO5) with DP of 11.64 showed ACQ behaviour as the concentration increased. In addition, DHCSO5 had good antioxidant capacity with an instantaneous radical scavenging activity of 2,2-diphenyl-1-picrylhydrazine (DPPH) up to 65 % at a concentration of 40 mg/ ml and increased to 100 % after 30 min. Thus, the multifunctional cell-g-P(DHC-alt-EPO) materials had a variety of potential applications in the fields of fluorescent printing, bio-imaging, UV- shielding and antioxidants.

Long-term outcomes and failure patterns after laparoscopic intersphincteric resection in ultralow rectal cancers.

BACKGROUND: Intersphincteric resection (ISR), the ultimate anus-preserving technique for ultralow rectal cancers, is an alternative to abdominoperineal resection (APR). The failure patterns and risk factors for local recurrence and distant metastasis remain controversial and require further investigation. AIM: To investigate the long-term outcomes and failure patterns after laparoscopic ISR in ultralow rectal cancers. METHODS: Patients who underwent laparoscopic ISR (LsISR) at Peking University First Hospital between January 2012 and December 2020 were retrospectively reviewed. Correlation analysis was performed using the Chi-square or Pearson's correlation test. Prognostic factors for overall survival (OS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were analyzed using Cox regression. RESULTS: We enrolled 368 patients with a median follow-up of 42 mo. Local recurrence and distant metastasis occurred in 13 (3.5%) and 42 (11.4%) cases, respectively. The 3-year OS, LRFS, and DMFS rates were 91.3%, 97.1%, and 90.1%, respectively. Multivariate analyses revealed that LRFS was associated with positive lymph node status [hazard ratio (HR) = 5.411, 95% confidence interval (CI) = 1.413-20.722, P = 0.014] and poor differentiation (HR = 3.739, 95%CI: 1.171-11.937, P = 0.026), whereas the independent prognostic factors for DMFS were positive lymph node status (HR = 2.445, 95%CI: 1.272-4.698, P = 0.007) and (y)pT3 stage (HR = 2.741, 95%CI: 1.225-6.137, P = 0.014). CONCLUSION: This study confirmed the oncological safety of LsISR for ultralow rectal cancer. Poor differentiation, (y)pT3 stage, and lymph node metastasis are independent risk factors for treatment failure after LsISR, and thus patients with these factors should be carefully managed with optimal neoadjuvant therapy, and for patients with a high risk of local recurrence (N + or poor differentiation), extended radical resection (such as APR instead of ISR) may be more effective.

DNA methylation is differentially associated with glycemic outcomes by different types of weight-loss interventions: an epigenome-wide association study.

BACKGROUND: Alterations in DNA methylation (DNAm) have been reported to be a mechanism by which bariatric surgeries resulted in considerable metabolic improvements. Previous studies have mostly focused on change in DNAm following weight-loss interventions, yet whether DNAm prior to intervention can explain the variability in glycemic outcomes has not been investigated. Here, we aim to examine whether baseline DNAm is differentially associated with glycemic outcomes induced by different types of weight-loss interventions. METHODS: Participants were 75 adults with severe obesity who underwent non-surgical intensive medical intervention (IMI), adjustable gastric band (BAND) or Roux-en-Y gastric bypass (RYGB) (n = 25 each). Changes in fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) were measured at 1-year after intervention. DNAm was quantified by Illumina 450 K arrays in baseline peripheral blood DNA. Epigenome-wide association studies were performed to identify CpG probes that modify the effects of different weight-loss interventions on glycemic outcomes, i.e., changes in FPG and HbA1c, by including an interaction term between types of intervention and DNAm. Models were adjusted for weight loss and baseline clinical factors. RESULTS: Baseline DNAm levels at 3216 and 117 CpGs were differentially associated with changes in FPG and HbA1c, respectively, when comparing RYGB versus IMI. Of these, 79 CpGs were significant for both FPG and HbA1c. The identified genes are enriched in adaptive thermogenesis, temperature homeostasis and regulation of cell population proliferation. Additionally, DNAm at 6 CpGs was differentially associated with changes in HbA1c when comparing RYGB versus BAND. CONCLUSIONS: Baseline DNAm is differentially associated with glycemic outcomes in response to different types of weight-loss interventions, independent of weight loss and other clinical factors. Such findings provided initial evidence that baseline DNAm levels may serve as potential biomarkers predictive of differential glycemic outcomes in response to different types of weight-loss interventions.

Resolvin D1 reprograms energy metabolism to promote microglia to phagocytize neutrophils after ischemic stroke.

Neutrophil aggregation and clearance are important factors affecting neuroinflammatory injury during acute ischemic stroke. Emerging evidence suggests that energy metabolism is essential for microglial functions, especially microglial phagocytosis, which determines the degree of brain injury. Here, we demonstrate that Resolvin D1 (RvD1), a lipid mediator derived from docosahexaenic acid (DHA), promotes the phagocytosis of neutrophils by microglia, thereby reducing neutrophil accumulation in the brain and alleviating neuroinflammation in the ischemic brain. Further studies reveal that RvD1 reprograms energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS), providing sufficient energy for microglial phagocytosis. Moreover, RvD1 enhances microglial glutamine uptake and stimulates glutaminolysis to support OXPHOS to boost ATP production depending on adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation. Overall, our results reveal that RvD1 reprograms energy metabolism to promote the microglial phagocytosis of neutrophils after ischemic stroke. These findings may guide perspectives for stroke therapy from modulating microglial immunometabolism.

STING regulates the transformation of the proinflammatory macrophage phenotype by HIF1A into autoimmune myocarditis.

Macrophages play an essential role in the pathogenesis of autoimmune myocarditis, but the molecular mechanism remains largely unknown. Here, the role of Stimulator of interferon gene (Sting) in autoimmune myocarditis was investigated. Six-week-old male BALB/c mice received two subcutaneous injections of 250 µg α-MyHC peptide to establish experimental autoimmune myocarditis (EAM). With single-cell RNA sequencing analysis of cardiac immune (Cd45+) cells, Sting was found to initiate proinflammatory macrophage differentiation related to the acute EAM phase. Furthermore, proinflammatory macrophages contribute to the pathogenesis of EAM via hypoxia-inducible factor-1α (Hif1α). A higher expression level of Sting was detected in macrophages from myocarditis, which was positively correlated with Hif1α expression. Single-stranded DNA (ssDNA) accumulation in macrophages in myocarditis was observed in the hearts of EAM mice. Pharmacological blockade of STING by C-176 (a specific inhibitor) ameliorated the inflammatory response of EAM and reduced proinflammatory molecule (Ifn-ß, Tnf-α, Ccl2, and F4/80) expression and Hif1α expression. In vitro studies revealed that ssDNA activated the expression of Sting; in turn, Sting accelerated proinflammatory molecule expression in mouse macrophages. Inhibition of Hif1α expression could reduce Sting-associated cardiac inflammation and proinflammatory molecule expression. In addition, the expression of STING and ssDNA accumulation in macrophages were observed in human autoimmune myocarditis heart samples. STING activated proinflammatory macrophage via HIF1A, promoting the development of autoimmune myocarditis. The STING signaling pathway might provide a novel mechanism of autoimmune myocarditis and serve as a potential therapeutic target for autoimmune myocarditis patients.