Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

Long-term outcomes of intraoperative chemotherapy with 5-FU for colorectal cancer patients receiving curative resection (IOCCRC): a randomized, multicenter, prospective, phase III trial.

BACKGROUND: We aimed to compare combined intraoperative chemotherapy and surgical resection with curative surgical resection alone in colorectal cancer patients. METHODS: We performed a multicenter, open-label, randomized, phase III trial. All eligible patients were randomized and assigned to intraoperative chemotherapy and curative surgical resection or curative surgical resection alone (1:1). Survival actualization after long-term follow-up was performed in patients analyzed on an intention-to-treat basis. RESULTS: From January 2011 to January 2016, 696 colorectal cancer patients were enrolled and randomly assigned to intraoperative chemotherapy and radical surgical resection (n=341) or curative surgical resection alone (n=344). Intraoperative chemotherapy with surgical resection showed no significant survival benefit over surgical resection alone in colorectal cancer patients (3-year DFS: 91.1% vs. 90.0%, P=0.328; 3-year OS: 94.4% vs. 95.9%, P=0.756). However, colon cancer patients benefitted from intraoperative chemotherapy, with a relative 4% reduction in liver and peritoneal metastasis (HR=0.336, 95% CI: 0.148-0.759, P=0.015) and a 6.5% improvement in 3-year DFS (HR=0.579, 95% CI: 0.353-0.949, P=0.032). Meanwhile, patients with colon cancer and abnormal pretreatment CEA levels achieved significant survival benefits from intraoperative chemotherapy (DFS: HR=0.464, 95% CI: 0.233-0.921, P=0.029 and OS: (HR=0.476, 95% CI: 0.223-1.017, P=0.049). CONCLUSIONS: Intraoperative chemotherapy showed no significant extra prognostic benefit in total colorectal cancer patients who underwent radical surgical resection; however, in colon cancer patients with abnormal pretreatment serum CEA levels (> 5 ng/ml), intraoperative chemotherapy could improve long-term survival.

[Impact of chaperone-mediated autophagy on bilirubin-induced damage of mouse microglial cells]. / åˆ†å­ä¼´ä¾£ä»‹å¯¼çš„è‡ªå™¬å¯¹èƒ†çº¢ç´ è¯±å¯¼çš„å°é¼ å°èƒ¶è´¨ç»†èƒžæŸä¼¤çš„å½±å“.

OBJECTIVES: To investigate the effect of chaperone-mediated autophagy (CMA) on the damage of mouse microglial BV2 cells induce by unconjugated bilirubin (UCB). METHODS: The BV2 cell experiments were divided into two parts. (1) For the CMA activation experiment: control group (treated with an equal volume of dimethyl sulfoxide), QX77 group (treated with 20 µmol/L QX77 for 24 hours), UCB group (treated with 40 µmol/L UCB for 24 hours), and UCB+QX77 group (treated with both 20 µmol/L QX77 and 40 µmol/L UCB for 24 hours). (2) For the cell transfection experiment: LAMP2A silencing control group (treated with an equal volume of dimethyl sulfoxide), LAMP2A silencing control+UCB group (treated with 40 µmol/L UCB for 24 hours), LAMP2A silencing group (treated with an equal volume of dimethyl sulfoxide), and LAMP2A silencing+UCB group (treated with 40 µmol/L UCB for 24 hours). The cell viability was assessed using the modified MTT method. The expression levels of p65, nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), and cysteinyl aspartate specific proteinase-1 (caspase-1) were detected by Western blot. The relative mRNA expression levels of the inflammatory cytokines interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α) were determined by real-time quantitative polymerase chain reaction. Levels of IL-6 and TNF-α in the cell culture supernatant were measured using ELISA. The co-localization of heat shock cognate protein 70 with p65 and NLRP3 was detected by immunofluorescence. RESULTS: Compared to the UCB group, the cell viability in the UCB+QX77 group increased, and the expression levels of inflammation-related proteins p65, NLRP3, and caspase-1, as well as the mRNA relative expression levels of IL-1ß, IL-6, and TNF-α and levels of IL-6 and TNF-α decreased (P<0.05). Compared to the control group, there was co-localization of heat shock cognate protein 70 with p65 and NLRP3 in both the UCB and UCB+QX77 groups. After silencing the LAMP2A gene, compared to the LAMP2A silencing control+UCB group, the LAMP2A silencing+UCB group showed increased expression levels of inflammation-related proteins p65, NLRP3, and caspase-1, as well as increased mRNA relative expression levels of IL-1ß, IL-6, and TNF-α and levels of IL-6 and TNF-α (P<0.05). CONCLUSIONS: CMA is inhibited in UCB-induced BV2 cell damage, and activating CMA may reduce p65 and NLRP3 protein levels, suppress inflammatory responses, and counteract bilirubin neurotoxicity.

Material and microbial perspectives on understanding the role of biochar in mitigating ammonia inhibition during anaerobic digestion.

With the increasing adoption of carbon-based strategies to enhance methanogenic processes, there is a growing concern regarding the correlation between biochar properties and its stimulating effects on anaerobic digestion (AD) under ammonia inhibition. This study delves into the relevant characteristics and potential mechanisms of biochar in the context of AD system under ammonia inhibition. The introduction of optimized biochar, distinguished by rich CO bond, abundant defect density, and high electronic capacity, resulted in a significant reduction in the lag period of anaerobic digestion system under 5.0 g/L ammonia stress, approximately by around 63 % compared to the control one. Biochar helps regulate the community structure, promotes the accumulation of acetate-consuming bacteria, in the AD system under ammonia inhibition. More examinations show that biochar promotes direct interspecies electron transfer in AD system under ammonia inhibition, as evidenced by diminished levels of bound electroactive extracellular polymeric substances, increased abundance of electroactive bacteria, and notably, the up-regulation of direct interspecies electron transfer associated genes, including the conductive pili and Cytochrome C genes, as revealed by meta-transcriptomic analysis. Additionally, gene expression related to proteins associated with ammonium detoxification were found to be up-regulated in systems supplemented with biochar. These findings provide essential evidence and insights for the selection and potential engineering of effective biochar to enhance AD performance under ammonia inhibition.

Fe-N co-doped biochar derived from biomass waste triggers peracetic acid activation for efficient water decontamination.

In this study, the porous carbon material (FeN-BC) with ultra-high catalytic activity was obtained from waste biomass through Fe-N co-doping. The prominent degradation rate (> 96.8%) of naproxen (NAP) was achieved over a wide pH range (pH 3.0-9.0) in FeN-BC/PAA system. Unlike previously reported iron-based peracetic acid (PAA) systems with •OH or RO• as the dominated reactive species, the degradation of contaminants was attributed to singlet oxygen (1O2) produced by organic radicals (RO•) decomposition, which was proved to be thermodynamically feasible and favorable by theoretical calculations. Combining the theoretical calculations, characteristic and experimental analysis, the synergistic effects of Fe and N were proposed and summarized as follows: i) promoted the formation of extensive defects and Fe0 species that facilitated electron transfer between FeN-BC and PAA and continuous Fe(II) generation; ii) modified the specific surface area (SSA) and the isoelectric point of FeN-BC in favor of PAA adsorption on the catalyst surface. This study provides a strategy for waste biomass reuse to construct a heterogeneous catalyst/PAA system for efficient water purification and reveals the synergistic effects of typical metal-heteroatom for PAA activation.

Characteristics and literature review of ETV6::ABL1 fusion gene-positive acute myeloid leukemia.

OBJECTIVE: To describe the features of ETV6::ABL1 AML as well as the clinical treatment and outcomes. METHODS: Clinical data were collected from three patients diagnosed with ETV6::ABL1 AML at Hebei Yanda Lu Daopei Hospital and Beijing Lu Daopei Hospital. Their clinical and laboratory features were analyzed, and the treatment process and outcomes were described. Ten reported cases of ETV6::ABL1 AML from the literature were also included for analysis. RESULTS: The median age of the patients was 34 years, and 2 patients were male. No patient had a history of blood disorders before diagnosis. After relapse, they were referred to our hospital, where the ETV6::ABL1 gene was detected. Unfortunately, Patient 1 died rapidly after leukemia relapse due to severe infection. Patients 2 and 3 received salvage therapy with a dasatinib-containing regimen, followed by allo-HSCT, and are currently alive and disease-free. CONCLUSION: ETV6::ABL1 is a rare but recurrent genetic aberration in AML, and the combined use of fluorescence in situ hybridization and PCR can better identify this fusion gene. Patients carrying ETV6::ABL1 have a high relapse rate and a poor prognosis. TKIs are a reasonable treatment option for this group, and allo-HSCT may be curative.

Long-Term Outcomes of dMMR/MSI-H Rectal Cancer Treated With Anti-PD-1-Based Immunotherapy as Curative-Intent Treatment.

BACKGROUND: Neoadjuvant anti-PD-1 therapy has shown encouraging efficacy in patients with deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) locally advanced rectal cancer (LARC), which suggests its potential as a curative-intent therapy and a promising treatment option for organ preservation. We aimed to investigate the long-term outcomes of patients with dMMR/MSI-H LARC who experienced clinical complete response (cCR) after anti-PD-1 therapy. METHODS: We retrospectively analyzed patients with dMMR/MSI-H LARC who achieved cCR and received nonoperative management following neoadjuvant anti-PD-1-based treatment from 4 Chinese medical centers. Patients were followed up for at least 1 year after they achieved cCR, their clinical data were collected, and survival outcomes were analyzed using the Kaplan-Meier method. RESULTS: A total of 24 patients who achieved cCR and received nonoperative management from March 2018 to May 2022 were included, with a median age of 51.0 years (range, 19.0-77.0 years). The median treatment course to reach cCR was 6.0 (range, 1.0-12.0). Fifteen patients (62.5%) continued their treatments after experiencing cCR, and the median treatment course was 17.0 (range, 3.0-36.0). No local regrowth or distant metastasis was observed in a median follow-up time of 29.1 months (range, 12.6-48.5 months) after cCR. The 3-year disease-free and overall survivals were both 100%. CONCLUSIONS: Patients with dMMR/MSI-H locally advanced or low-lying rectal cancer who achieved cCR following anti-PD-1-based therapy had promising long-term outcomes. A prospective clinical trial with a larger sample size is required to further validate these findings.

Network pharmacology and pharmacological evaluation of Wenzheng Jiedu Powder Modified Formula for neuropathic pain relief.

This study aimed to elucidate the mechanism of Wenzheng Jiedu Powder Modified Formula (WJPMF) in treating neuropathic pain (NP). Network pharmacology and experimental verification were integrated to explore the therapeutic effects and key targets of WJPMF. Active components, corresponding target genes, and absorption, distribution, metabolism, and excretion (ADME) genes of WJPMF against NP were screened from public databases. Network analysis and molecular docking were conducted to identify key targets and verify binding abilities. In vivo experiments were performed on spared nerve injury (SNI) rats to assess the analgesic effects and regulatory mechanisms of WJPMF. WJPMF significantly improved pain behaviors in SNI rats by regulating ATP-binding cassette transporter A1 (ABCA1), peroxisome proliferator-activated receptor alpha (PPARA), peroxisome proliferator-activated receptor gamma (PPARG), and superoxide dismutase 2 (SOD2) expression, which were key targets involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. WJPMF shows promising therapeutic potential for NP through the modulation of specific targets, offering a novel therapeutic strategy for managing NP.

Asymmetric Synthesis of Trisubstituted Vicinal Diols through Copper(I)-Catalyzed Diastereoselective and Enantioselective Allylation of Ketones with Siloxypropadienes.

Chiral trisubstituted vicinal diols are a type of important organic compounds, serving as both common structure units in bioactive natural products and chiral auxiliaries in asymmetric synthesis. Herein, by using siloxypropadienes as the precursors of allyl copper(I) species, a copper(I)-catalyzed diastereoselective and enantioselective reductive allylation of ketones was achieved, providing both syn-diols and anti-diols in good to excellent enantioselectivity. DFT calculations show that cis-γ-siloxy-allyl copper species are generated favorably with either 1-TBSO-propadiene or 1-TIPSO-propadiene. Moreover, the steric difference of TBS group and TIPS group distinguishes the face selectivity of acetophenone, leading to syn-selectivity for 1-TBSO-propadiene and anti-selectivity for 1-TIPSO-propadiene. Easy transformations of the products were performed, demonstrating the synthetic utility of the present method. Moreover, one chiral diol prepared in the above transformations was used as a suitable organocatalyst for the catalytic asymmetric reductive self-coupling of aldimines generated in situ with B2(neo)2.

Advances in the study of endocannabinoid receptors in experimental acupuncture analgesia. / å† æºæ€§å¤§éº»ç´ å—ä½“åœ¨é’ˆåˆºé•‡ç—›æœºåˆ¶ä¸­çš„ç ”ç©¶è¿›å±•.

The endocannabinoid system, an important biological network for maintaining and balancing various functions of the human body, is involved in many physiological functions such as pain, emotion, learning and memory, etc. Among which the endocannabinoid receptors ï¼»including type I (CB1) and type II (CB2) receptorsï¼½ play an important role in the regulation of pain and have become an important target in the mechanism research of acupuncture analgesia. CB1 is mainly distributed in the central nervous system, including the spinal cord, cerebral cortex, amygdala, insular cortex, and basal ganglia, etc. CB2 is mainly distributed in peripheral immune tissues, such as spleen, bone, skin, etc. In the central and peripheral nervous systems, acupuncture can activate CB1 and CB2 receptors respectively, which is involved in the transmission of central nociceptive signals and related transmitters as well as the peri-pheral pro-nociceptive inflammatory response, thereby alleviating the nociceptive hypersensitivity in animal models. In this paper, we systematically summarize the roles of the above mechanisms in different types of animal models (inflammatory pain, neuropathological pain, visceral pain, etc.), so as to provide new ideas for the study of the underlying mechanisms of acupuncture analgesia.

Epigenetic upregulation of MNAT1 by SMYD2 is linked to PI3K/AKT activation and tumorigenesis of pancreatic adenocarcinoma.

Dysregulation of histone methyltransferase SET and MYND domain-containing protein 2 (SMYD2) has been correlated with human developmental disorders and cancers. This research aims to investigate the roles of SMYD2 and its interacted molecules in pancreatic adenocarcinoma (PAAD). Two PAAD-related gene expression datasets were downloaded to screen key molecules involved in tumor progression. SMYD2 was expressed at high levels in PAAD tissues and cells. SMYD2 silencing suppressed while its overexpression promoted proliferation, invasiveness, migration, apoptosis resistance, and cell cycle progression of PAAD cells. Target molecules of SMYD2 were predicted by online tools and validated by chromatin immunoprecipitation and luciferase assays. SMYD2 catalyzed H3K36me2 modification at the promoter region of MNAT1 component of CDK activating kinase (MNAT1), to promote its transcription. MNAT1 was correlated with an unfavorable clinical outcome of PAAD patients. Alteration of MNAT1 alone also affected the malignant behavior of PAAD cells. Moreover, MNAT1 overexpression in cells rescued the malignant phenotype of cells suppressed by SMYD2 silencing. MNAT1 activated the phosphatidyl inositol 3-kinase/protein kinase B (PI3K/AKT) signaling. In vivo, SMYD2 silencing decreased the growth rate and weight of xenograft tumors in nude mice. Overall, this paper demonstrates that SMYD2-mediated MNAT1 upregulation is linked to PAAD tumorigenesis via PI3K/AKT pathway activation.

A large-scale microRNA transcriptome-wide association study identifies two susceptibility microRNAs, miR-1307-5p and miR-192-3p, for colorectal cancer risk.

Transcriptome-wide association studies (TWAS) have identified many putative susceptibility genes for colorectal cancer (CRC) risk. However, susceptibility miRNAs, critical dysregulators of gene expression, remain unexplored. We genotyped DNA samples from 313 CRC East Asian patients and performed small RNA sequencing in their normal colon tissues distant from tumors to build genetic models for predicting miRNA expression. We applied these models and data from genome-wide association studies (GWAS) including 23 942 cases and 217 267 controls of East Asian ancestry to investigate associations of predicted miRNA expression with CRC risk. Perturbation experiments separately by promoting and inhibiting miRNAs expressions and further in vitro assays in both SW480 and HCT116 cells were conducted. At a Bonferroni-corrected threshold of P < 4.5 × 10-4, we identified two putative susceptibility miRNAs, miR-1307-5p and miR-192-3p, located in regions more than 500 kb away from any GWAS-identified risk variants in CRC. We observed that a high predicted expression of miR-1307-5p was associated with increased CRC risk, while a low predicted expression of miR-192-3p was associated with increased CRC risk. Our experimental results further provide strong evidence of their susceptible roles by showing that miR-1307-5p and miR-192-3p play a regulatory role, respectively, in promoting and inhibiting CRC cell proliferation, migration, and invasion, which was consistently observed in both SW480 and HCT116 cells. Our study provides additional insights into the biological mechanisms underlying CRC development.

Copper(I)-Catalyzed Asymmetric Allylation of Ketones with 2-Aza-1,4-Dienes.

Catalytic asymmetric allylation of ketones under proton-transfer conditions is a challenging issue due to the limited pronucleophiles and the electrophilic inertness of ketones. Herein, a copper(I)-catalyzed asymmetric allylation of ketones with 2-aza-1,4-dienes (N-allyl-1,1-diphenylmethanimines) is disclosed, which affords a series of functionalized homoallyl tertiary alcohols in high to excellent enantioselectivity. Interestingly, N-allyl-1,1-diphenylmethanimines work as synthetic equivalents of propanals. Upon the acidic workup, a formal asymmetric ß-addition of propanals to ketones is achieved. An investigation on KIE effect indicates that the deprotonation of N-allyl-1,1-diphenylmethanimines is the rate-determining step, which generates nucleophilic allyl copper(I) species. Finally, the synthetic utility of the present method is demonstrated by the asymmetric synthesis of (R)-boivinianin A and (R)-gossonorol.

Effects of Mineralocorticoid Receptor Antagonists for Chronic Kidney Disease: A Systemic Review and Meta-Analysis.

BACKGROUND: Mineralocorticoid receptor blockade could be a potential approach for the inhibition of chronic kidney disease (CKD) progression. The benefits and harms of different mineralocorticoid receptor antagonists (MRAs) in CKD are inconsistent. OBJECTIVES: The aim of the study was to summarize the benefits and harms of MRAs for CKD patients. METHODS: We searched MEDLINE, EMBASE, and the Cochrane databases for trials assessing the effects of MRAs on non-dialysis-dependent CKD populations. Treatment and adverse effects were summarized using meta-analysis. RESULTS: Fifty-three trials with 6 different MRAs involving 22,792 participants were included. Compared with the control group, MRAs reduced urinary albumin-to-creatinine ratio (weighted mean difference [WMD], -90.90 mg/g, 95% CI, -140.17 to -41.64 mg/g), 24-h urinary protein excretion (WMD, -0.20 g, 95% CI, -0.28 to -0.12 g), estimated glomerular filtration rate (eGFR) (WMD, -1.99 mL/min/1.73 m2, 95% CI, -3.28 to -0.70 mL/min/1.73 m2), chronic renal failure events (RR, 0.86, 95% CI, 0.79-0.93), and cardiovascular events (RR, 0.84, 95% CI, 0.77-0.92). MRAs increased the incidence of hyperkalemia (RR, 2.04, 95% CI, 1.73-2.40) and hypotension (RR, 1.80, 95% CI, 1.41-2.31). MRAs reduced the incidence of peripheral edema (RR, 0.65, 95% CI, 0.56-0.75) but not the risk of acute kidney injury (RR, 0.94, 95% CI, 0.79-1.13). Nonsteroidal MRAs (RR, 0.66, 95% CI, 0.57-0.75) but not steroidal MRAs (RR, 0.20, 95% CI, 0.02-1.68) significantly reduced the risk of peripheral edema. Steroidal MRAs (RR, 5.68, 95% CI, 1.26-25.67) but not nonsteroidal MRAs (RR, 0.52, 95% CI, 0.22-1.22) increased the risk of breast disorders. CONCLUSIONS: In the CKD patients, MRAs, particularly in combination with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, reduced albuminuria/proteinuria, eGFR, and the incidence of chronic renal failure, cardiovascular and peripheral edema events, whereas increasing the incidence of hyperkalemia and hypotension, without the augment of acute kidney injury events. Nonsteroidal MRAs were superior in the reduction of more albuminuria with fewer peripheral edema events and without the augment of breast disorder events.

Efficacy and safety of aspirin antiplatelet therapy within 48 h of symptom onset in patients with acute stroke.

BACKGROUND: Aspirin is a widely used antiplatelet agent that reduces the risk of recurrent ischemic stroke and other vascular events. However, the optimal timing and dose of aspirin initiation after an acute stroke remain controversial. AIM: To evaluate the efficacy and safety of aspirin antiplatelet therapy within 48 h of symptom onset in patients with acute stroke. METHODS: We conducted a randomized, open-label, controlled trial in 60 patients with acute ischemic or hemorrhagic stroke who were admitted to our hospital within 24 h of symptom onset. Patients were randomly assigned to receive either aspirin 300 mg daily or no aspirin within 48 h of stroke onset. The primary outcome was the occurrence of recurrent stroke, myocardial infarction, or vascular death within 90 d. The secondary outcomes were functional outcomes at 90 d measured using the modified Rankin Scale (mRS), incidence of bleeding complications, and mortality rate. RESULTS: The mean age of the patients was 67.8 years and 55% of them were male. The median time from stroke onset to randomization was 12 h. The baseline characteristics were well balanced between the two groups. The primary outcome occurred in 6.7% of patients in the aspirin group and 16.7% of patients in the no aspirin group (relative risk = 0.40, 95% confidence interval: 0.12-1.31, P = 0.13). The mRS score at 90 d was significantly lower in the aspirin group than in the no aspirin group (median, 2 vs 3, respectively; P = 0.04). The incidence of bleeding complications was similar between the groups (6.7% vs 6.7%, P = 1.00). The mortality rates were also comparable between the two groups (10% vs 13.3%, P = 0.69). CONCLUSION: Aspirin use is associated with favorable functional outcomes but does not significantly reduce the risk of recurrent vascular events. Its acceptable safety profile is comparable to that of no aspirin. Further studies with larger sample sizes and longer follow-up periods are needed to confirm these findings.

Danggui Buxue Decoction exerts its therapeutic effect on rheumatoid arthritis through the inhibition of Wnt/ß-catenin signaling pathway.

BACKGROUND: Danggui Buxue Decoction (DBD) is a traditional Chinese medicine prescription, which has the functions of benefiting Qi, generating blood and regulating the immune system. At present, various clinical reports suggest that DBD has some efficacy in Rheumatoid arthritis (RA), but its mechanism of action is still unclear. Thus, the present study explored mechanism of this preparation on RA. METHODS: The effect of DBD was evaluated by tumor necrosis factor (TNF)-α-induced Human fibroblast-like synoviocyte of rheumatoid arthritis (HFLS-RA) cell model and collagen-induced arthritis (CIA) rat model, respectively. Inflammatory factors including TNF-ɑ, IL-1ß, IL-6 and IL-10 in the culture supernatants or rat serum were measured using ELISA. The related indexes including fur luster, mental state and activity of rat and the symptoms including swelling and deformation of toes and ankles were also measured. RESULTS: In vitro results showed that DBD cannot only inhibit the proliferation of HFLS-RA cells but also reduce the levels of pro-inflammatory factors while increasing the level of anti-inflammatory factors. Similar results were obtained from in vivo experiments. Rats receiving DBD showed a decrease in the severity of rheumatoid arthritis in rat models. Moreover, the protein levels of c-myc and ß-catenin decreased significantly, while the protein level of SFRP4 increased, which indicated that DBD might inhibit the inflammatory reaction by regulating Wnt/ß-catenin signaling pathway, thus alleviating the symptoms of RA. CONCLUSION: Our findings not only provide insights for understanding the molecular mechanism of DBD in treating RA, but also provide the theoretical basis for further clinical prevention and treatment.

Mechanism of Rhodiola rosea-Euonymus alatus drug pair against rheumatoid arthritis: Network pharmacology and experimental validation.

PURPOSE: The present study aimed to explore the potential components and mechanisms of Rhodiola rosea-Euonymus alatus drug pair (TY) that ameliorate rheumatoid arthritis (RA). METHODS: The main active components, core targets, and important pathways of TY against RA were predicted by network pharmacology analysis. The binding activity between the main active components and the core targets was verified by the molecular docking technique. Collagen-induced arthritis (CIA) rat model and tumor necrosis factor (TNF)-α-induced fibroblast-like synovial cells in human RA (HFLS-RA) model were established, respectively. The core targets were verified by cell counting kit-8 assay, hematoxylin eosin, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and Western blot analysis, and the therapeutic effect of TY was evaluated. RESULTS: A total of 18 possible components and 34 core targets were obtained by network pharmacology, among which inflammatory response, phosphatidylinositide 3-kinases (PI3K)-AKT and MAPK pathways were involved in the therapeutic effect of TY on RA. The results of molecular docking showed that kaempferol and quercetin had high binding affinity to interleukin (IL)-1ß, IL-6, matrix metalloproteinase (MMP)9, and TNF-α. In vivo and in vitro experiments showed that TY dose-dependently inhibited the proliferation of HFLS-RA cells induced by TNF-α, and significantly reduced the paw swelling and arthritis scores in CIA rats. At the same time, TY inhibited the production of inflammatory factors in CIA rat serum and TNF-α-induced HFLS-RA cells. It also decreased the expression of PI3K, phospho-protein kinase B, MMP1, MMP3, MMP9, and increased the protein and mRNA levels of tissue inhibitors of MMPs (TIMP)1 in synovial tissue. CONCLUSION: TY can inhibit the PI3K/AKT signaling pathway and regulate the balance between MMPs and TIMP, thus playing a therapeutic role in RA.

Long-term effects of the COVID-19 pandemic on five mental and psychological disorders: in terms of the number of disease visits, drug consumption, and scale scores.

BACKGROUND: COVID-19 caused mild to severe infections in humans. The long-term epidemic environment harms people's mental health. To explore the impact of the epidemic on people's mental and psychological conditions, we surveyed in Wenzhou. METHODS: We collected the data of people who visited the First Affiliated Hospital of Wenzhou Medical University for five types of mental and psychological diseases from January 2018 to December 2021. Then, taking December 2019 as the cut-off point, the 48-month data were divided into the pre-epidemic group and the dur-epidemic group. Based on the above data, statistical analysis was done. RESULTS: From 2018 to 2021, the number of initial diagnoses, the number of disease visits, and drug consumption for these five types of mental and psychological diseases were all on the rise. Compared with the number of disease visits for all disorders in both psychiatry and neurology departments, it was found that the growth rate of these five diseases was higher than the growth rate of all disorders. We found that the number of disease visits, drug consumption, and scale scores after the COVID-19 outbreak were significantly different from those before the outbreak (P < 0.05). And the number of disease visits positively correlated with drug consumption (P < 0.0001, r = 0.9503), which verified the stability of the data. CONCLUSION: The epidemic environment has had a long-term and negative impact on people's mental and psychological conditions. Therefore, whether or not the epidemic is receding, we still need to be concerned about the impact of COVID-19 on mental and psychological health.

Validation of a modified Chinese-language version of the Davos Assessment of Cognitive Biases Scale (MCL-DACOBS) in a sample of Chinese patients with schizophrenia.

INTRODUCTION: The Davos Assessment of Cognitive Biases Scale (DACOBS) is widely used to assess cognitive biases in patients who have schizophrenia. However, the lack of a modified Chinese-language version of the DACOBS (MCL-DACOBS) precludes Chinese schizophrenic patients from treatment aimed at normalizing cognitive biases, impacting their prognosis. Here, we aimed to produce a DACOBS for China and test the validity and reliability of the resultant MCL-DACOBS. METHODS: Eighteen researchers collaborated to develop the MCL-DACOBS: A total of 15 researchers modified and translated the English version of the DACOBS, 1 native-English-speaking researcher back-translated the scale, and 2 Chinese sinologists localized and optimized the language of the MCL-DACOBS. Forty-two volunteers checked the scale items' comprehensibility, and the two sinologists performed further localization and optimization based on their feedback. The final version of the MCL-DACOBS used in this study was thus derived from the harmonized English-language version of the scale. Confirmatory factor analyses (CFAs) were used to examine the best latent structure of the MCL-DACOBS. Cronbach's α and intraclass correlation coefficients (ICCs) were used to check the reliability. The discriminative ability of the MCL-DACOBS was assessed according to the area under the receiver operating characteristic curve. RESULTS: The CFA showed that all items loaded onto factors with loadings >0.400. A two-factor structure showed a good model fit (root mean square error of approximation = .018, Tucker-Lewis index = .978, comparative fit index = .984). Promax rotation demonstrated that each item had a high factor load (0.432-0.774). Cronbach's α coefficient and ICC for the MCL-DOCABS were .965 and .957, respectively, indicating that the scale has ideal reliability. CONCLUSION: The MCL-DACOBS has good validity and good reliability, and its psychometric properties indicate that it is a valid tool for measuring cognitive biases in Chinese patients with schizophrenia.

Efficacy of PD-1 inhibitors for colorectal cancer and polyps in Lynch syndrome patients.

BACKGROUND: Programmed death-1 (PD-1) inhibitor is effective for colorectal cancer (CRC) with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). We aimed to explore its effects on CRCs and colonic polyps in Lynch syndrome (LS) patients. METHODS: LS patients with CRC who had evaluable tumours and received at least 2 cycles of PD-1 inhibitors were retrospectively included. PD-1 inhibitors were given as a monotherapy or in combination with other therapies, including anticytotoxic T-lymphocyte-associated antigen-4 treatment, radiotherapy, chemotherapy, and targeted therapy. Correlations of treatment responses with clinicopathological characteristics and genomic profiles were analysed. RESULTS: A total of 75 LS patients were included, with a median age of 39 years. The median duration of follow-up was 27 months (range, 3-71). The objective response rate (ORR) was 70.7%, including 28.0% (n = 21) complete responses and 42.7% (n = 32) partial responses. Four of five cases of LS CRCs displaying proficient MMR (pMMR) or microsatellite stable (MSS) were not responsive. Mucinous/signet-ring cell differentiation was associated with a lower ORR (P = 0.013). The 3-year overall survival and progression-free survival were 91.2% and 82.2%, respectively. A polyp was detected in 26 patients during surveillance. Seven adenomas disappeared after treatment, and they were all larger than 7 mm. CONCLUSION: PD-1 inhibitors are highly effective for dMMR and MSI-H LS CRCs, but not for pMMR or MSS LS CRCs or mucinous/signet-ring cell CRC. Large LS adenomas may also be eliminated by anti-PD-1 treatment. DATA AVAILABILITY STATEMENT: Due to the privacy of patients, the related data cannot be available for public access but can be obtained from Pei-Rong Ding (dingpr@sysucc.org.cn) upon reasonable request. The key raw data have been uploaded to the Research Data Deposit public platform (www.researchdata.org.cn).