OBJECTIVE To systematically evaluate the efficacy and safety of different chemotherapy combination regimens for first-line treatment of metastatic colorectal cancer （mCRC）. METHODS PubMed， Cochrane Library， Embase and Web of Science were electronically searched to collect randomized controlled clinical trial （RCT） on first-line treatment for mCRC from January 1， 2000 to February 16， 2025. Two reviewers independently screened literature， extracted data and assessed the risk of bias of the included studies. Network meta-analysis was performed by using R4.4.3 and Stata 17.0 software. RESULTS A total of 28 RCTs， involving 16 intervention measures， were included. In terms of prolonging progression-free survival （PFS） and overall survival （OS）， FOLFOX （5-fluorouracil+oxaliplatin+calcium folinate regimen）+cetuximab had the highest probability of ranking first. In terms of improving objective response rate （ORR）， FOLFOXIRI （5-fluorouracil+oxaliplatin+irinotecan+calcium folinate regimen）+ bevacizumab and FOLFOX+bevacizumab+nivolumab had the highest probability of ranking first； in terms of the incidence of grade 3 or higher adverse reactions， FOLFOXIRI+panitumumab had the highest probability of ranking first； in subgroup analysis of KRAS wild-type patients， FOLFIRI （5-fluorouracil+irinotecan+calcium folinate regimen）+panitumumab and FOLFIRI+bevacizumab had the highest probability of ranking first in terms of prolonging PFS and OS， respectively； in terms of ORR， FOLFOXIRI+ cetuximab had the highest probability of ranking first. CONCLUSIONS In first-line treatment for mCRC， FOLFOX combined with targeted therapy has advantages in terms of efficacy and safety. However， individualized treatment strategies should be formulated based on the KRAS gene status and tumor location of patients.

This study investigates the mechanism by which Xintong Granules improve myocardial ischemia-reperfusion injury(MIRI) through the regulation of gut microbiota and their metabolites, specifically short-chain fatty acids(SCFAs). Rats were randomly divided based on body weight into the sham operation group, model group, low-dose Xintong Granules group(1.43 g·kg~(-1)·d~(-1)), medium-dose Xintong Granules group(2.86 g·kg~(-1)·d~(-1)), high-dose Xintong Granules group(5.72 g·kg~(-1)·d~(-1)), and metoprolol group(10 mg·kg~(-1)·d~(-1)). After 14 days of pre-administration, the MIRI rat model was established by ligating the left anterior descending coronary artery. The myocardial infarction area was assessed using the 2,3,5-triphenyltetrazolium chloride(TTC) staining method. Apoptosis in tissue cells was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL) assay. Pathological changes in myocardial cells and colonic tissue were observed using hematoxylin-eosin(HE) staining. The levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6), creatine kinase MB isoenzyme(CK-MB), and cardiac troponin T(cTnT) in rat serum were quantitatively measured using enzyme-linked immunosorbent assay(ELISA) kits. The activities of lactate dehydrogenase(LDH), creatine kinase(CK), and superoxide dismutase(SOD) in myocardial tissue, as well as the level of malondialdehyde(MDA), were determined using colorimetric assays. Gut microbiota composition was analyzed by 16S rDNA sequencing, and fecal SCFAs were quantified using gas chromatography-mass spectrometry(GC-MS). The results show that Xintong Granules significantly reduced the myocardial infarction area, suppressed cardiomyocyte apoptosis, and decreased serum levels of pro-inflammatory cytokines(TNF-α, IL-1β, and IL-6), myocardial injury markers(CK-MB, cTnT, LDH, and CK), and oxidative stress marker MDA. Additionally, Xintong Granules significantly improved intestinal inflammation in MIRI rats, regulated gut microbiota composition and diversity, and increased the levels of SCFAs(acetate, propionate, isobutyrate, etc.). In summary, Xintong Granules effectively alleviate MIRI symptoms. This study preliminarily confirms that Xintong Granules exert their inhibitory effects on MIRI by regulating gut microbiota imbalance and increasing SCFA levels.
Animals ; Gastrointestinal Microbiome/drug effects* ; Rats ; Male ; Myocardial Reperfusion Injury/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Rats, Sprague-Dawley ; Apoptosis/drug effects* ; Humans ; Tumor Necrosis Factor-alpha/metabolism* ; Interleukin-6/genetics* ; Malondialdehyde/metabolism*

Poly(ADP-ribosyl)ation (PARylation) is a specific form of post-translational modification (PTM) predominantly triggered by the activation of poly-ADP-ribose polymerase 1 (PARP1). However, the role and mechanism of PARylation in the advancement of acute kidney injury (AKI) remain undetermined. Here, we demonstrated the significant upregulation of PARP1 and its associated PARylation in murine models of AKI, consistent with renal biopsy findings in patients with AKI. This elevation in PARP1 expression might be attributed to trimethylation of histone H3 lysine 4 (H3K4me3). Furthermore, a reduction in PARylation levels mitigated renal dysfunction in the AKI mouse models. Mechanistically, liquid chromatography-mass spectrometry indicated that PARylation mainly occurred in receptor for activated C kinase 1 (RACK1), thereby facilitating its subsequent phosphorylation. Moreover, the phosphorylation of RACK1 enhanced its dimerization and accelerated the ubiquitination-mediated hypoxia inducible factor-1α (HIF-1α) degradation, thereby exacerbating kidney injury. Additionally, we identified a PARP1 proteolysis-targeting chimera (PROTAC), A19, as a PARP1 degrader that demonstrated superior protective effects against renal injury compared with PJ34, a previously identified PARP1 inhibitor. Collectively, both genetic and drug-based inhibition of PARylation mitigated kidney injury, indicating that the PARylated RACK1/HIF-1α axis could be a promising therapeutic target for AKI treatment.

Objective To explore the molecular mechanism of miR-125b promoting invasion,metastasis and epithelial-mesenchymal transition(EMT)of gastric cancer cells.Methods The expression of miR-125b in gastric cancer and its adjacent tissues was studied by qRT-PCR.After upregulating or downregulating miR-125b in gastric cancer cells,the protein expressions of DKK3 and SERPINA4 were detected by Western blotting.Dual luciferase reporting assay was used to verify whether miR-125b can target DKK3 and SERPINA4.MKN45 cells were co-transfected with miR-125b inhibitor and target gene siRNA.Migration and invasion experiments were conducted to explore whether miR-125b can regulate the biological function of MKN45 cells through DKK3 and SERPINA4.Then,the regulatory mechanism of SRF on miR-125b was investigated.Finally,by in vivo experiments,the expression of SRF in gastric cancer cells was upregulated or downregulated by lentivirus transfection;the number of lung metastases in nude mice was detected to explore the effect of SRF on gastric cancer cell metastasis.Results In this study,the expression of miR-125b increased in gastric cancer tissues,which was correlated with clinical stage and lymph node metastasis.Dual luciferase reporting experiments showed that DKK3 and SERPINA4 were the direct targets of miR-125b in gastric cancer cells,and could activate the Wnt/β-catenin signaling pathway,thereby promoting the transcription process of EMT-related transcription factors Twist1 and Slug,inducing the occurrence of EMT,and promoting the metastasis of gastric cancer.In vitro and in vivo experiments confirmed that SRF promoted the invasion and metastasis of gastric cancer cells by positively regulating the expression of miR-125b.Conclusion Taken together,SRF/miR-125b axis promotes the EMT and metastasis of gastric cancer cells,and these regulators represent new potential therapeutic targets or biomarkers for gastric cancer.

Purpose::Traumatic brain injury (TBI), currently a major global public health problem, imposes a significant economic burden on society and families. We aimed to quantify and predict the incidence and severity of TBI by analyzing its incidence, prevalence, and years lived with disability (YLDs). The epidemiological changes in TBI from 1990 to 2019 were described and updated to provide a reference for developing prevention, treatment, and incidence-reducing measures for TBI.Methods::A secondary analysis was performed on the incidence, prevalence, and YLDs of TBI by sex, age group, and region ( n =21,204 countries and territories) between 1990 and 2019 using the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. Proportions in the age-standardized incidence rate due to underlying causes of TBI and proportions of minor and moderate or severe TBI were also reported. Results::In 2019, there were 27.16 million (95% uncertainty intervals ( UI): 23.36 -31.42) new cases of TBI worldwide, with age-standardized incidence and prevalence rates of 346 per 100,000 population (95% UI: 298 -401) and 599 per 100,000 population (95% UI: 573 -627), respectively. From 1990 to 2019, there were no significant trends in global age-standardized incidence (estimated annual percentage changes: -0.11%, 95% UI: -0.18% --0.04%) or prevalence (estimated annual percentage changes: 0.01%, 95% UI: -0.04% -0.06%). TBI caused 7.08 million (95% UI: 5.00 -9.59) YLDs in 2019, with age-standardized rates of 86.5 per 100,000 population (95% UI: 61.1 -117.2). In 2019, the countries with higher incidence rates were mainly distributed in Central Europe, Eastern Europe, and Australia. The 2019 global age-standardized incidence rate was higher in males than in females. The 2019 global incidence of moderate and severe TBI was 182.7 per 100,000 population, accounting for 52.8% of all TBI, with falls and road traffic injuries being the main causes in most regions. Conclusions::The incidence of moderate and severe TBI was slightly higher in 2019, and TBI still accounts for a significant portion of the global injury burden. The likelihood of moderate to severe TBI and the trend of major injury under each injury cause from 1990 to 2019 and the characteristics of injury mechanisms in each age group are presented, providing a basis for further research on injury causes in each age group and the future establishment of corresponding policies and protective measures.

Objective:To summarize the clinical and prognostic features of children with opsoclonus-myoclonus-ataxia syndrome (OMAS).Methods:A total of 46 patients who met the diagnostic criteria of OMAS in the Department of Neurology, Beijing Children′s Hospital from June 2015 to June 2023 were retrospectively analyzed. Centralized online consultations or telephone visits were conducted between June and August 2023. The data of the children during hospitalization and follow-up were collected, including clinical manifestations, assistant examination, treatment and prognosis. According to the presence or absence of tumor, the patients were divided into two groups. The chi-square test or Mann-Whitney U test was used to compare the differences between the two groups. Univariate Logistic regression was used to analyze the factors related to OMAS recurrence and prognosis. Results:There were 46 patients, with 25 males and the onset age of 1.5 (1.2, 2.4) years. Twenty-six (57%) patients were diagnosed with neuroblastoma during the course of the disease, and no patients were categorized into the high-risk group. A total of 36 patients (78%) were followed up for≥6 months, and all of them were treated with first-line therapy with glucocorticoids, gammaglobulin and (or) adrenocorticotrophic hormone. Among the 36 patients, 9 patients (25%) were treated with second-line therapy for ≥3 months, including rituximab or cyclophosphamide, and 17 patients (47%) received chemotherapy related to neuroblastoma. At the follow-up time of 4.2 (2.2, 5.5) years, 10 patients (28%) had relapsed of OMAS. The Mitchell and Pike OMS rating scale score at the final follow-up was 0.5 (0, 2.0). Seven patients (19%) were mildly cognitively behind their peers and 6 patients (17%) were severely behind. Only 1 patient had tumor recurrence during follow-up. The history of vaccination or infection before onset was more common in the non-tumor group than in the tumor group (55%(11/20) vs. 23%(6/26), χ2=4.95, P=0.026). Myoclonus occurred more frequently in the non-tumor group (40%(8/20) vs. 4%(1/26), χ2=7.23, P=0.007) as the onset symptom. Univariate Logistic regression analysis showed that the tumor group had less recurrence ( OR=0.19 (0.04-0.93), P=0.041). The use of second-line therapy or chemotherapy within 6 months of the disease course had a better prognosis ( OR=11.64 (1.27-106.72), P=0.030). Conclusions:OMAS in children mostly starts in early childhood, and about half are combined with neuroblastoma. Neuroblastoma in combination with OMAS usually has a low risk classification and good prognosis. When comparing patients with OMAS with and without tumors, the latter have a more common infection or vaccination triggers, and myoclonus, as the onset symptom, is more common. Early addition of second-line therapy is associated with better prognosis in OMAS.

OBJECTIVE: To investigate the effect of holmium laser ω-shaped pre-transection of the prostate apex (PTPA) with preservation of the bladder neck on the urinary continence and sexual function of the patients with BPH after transurethral holmium laser enucleation of the prostate (HoLEP). METHODS: This retrospective study included 165 cases of BPH undergoing holmium laser ω-shaped PTPA with preservation of the bladder neck following HoLEP from January 2018 to January 2023. We recorded and compared the baseline, perioperative and 12-month follow-up data on the patients, and evaluated their urination function using IPSS, maximum urinary flow rate (Qmax), postvoid residual urine volume (PVR), and quality of life (QOL) scores. For those who had had sexual activity and normal ejaculation before surgery, we further assessed their erectile and ejaculatory functions postoperatively. RESULTS: The mean surgical time was (70.35±12.27) min, the intraoperative blood loss (60.12±19.54) ml, and the weight of the excised gland (56.37±13.71) g. The hospital stay and postoperative catheter-indwelling time averaged (5.13±2.34) and (3.21±1.37) d, respectively. Significant improvements were observed in IPSS, QOL, PVR and Qmax at 3, 6 and 12 months after surgery compared with the baseline (P<0.05), which all remained stable throughout the follow-up period. At 3 months after surgery, stress urinary incontinence was found in 10.91% of the patients, and all but 1 case (0.6%) recovered within 12 months. There were no significant changes in the IIEF-5 and Erectile Hardness Scale (EHS) scores postoperatively (P>0.05). Retrograde ejaculation occurred in 19 (11.52%) of the patients, but none experienced painful ejaculation after surgery. CONCLUSION Holmium laser ω-shaped PTPA with preservation of the bladder neck is safe and effective for the treatment of BPH, which can effectively improve the urinary continence and protect the sexual function of the patient.
Humans ; Male ; Prostatic Hyperplasia/surgery* ; Lasers, Solid-State/therapeutic use* ; Retrospective Studies ; Quality of Life ; Urinary Bladder ; Urinary Incontinence ; Transurethral Resection of Prostate/methods* ; Prostate/surgery* ; Ejaculation ; Aged ; Middle Aged

Diabetic peripheral neuropathy (DPN) is one of the most common microvascular complications occurring in both type 1 and type 2 diabetes mellitus patients, which often results in patients suffering from severe hyperalgesia and allodynia. Up to now, the clinical therapeutic effect of DPN is still unsatisfactory. Metformin is an anti-diabetic drug that has been safely and widely used for the treatment of type 2 diabetes for decades. Studies have shown that metformin can improve pain caused by DPN, but its effects on the nerve conduction velocity and morphology of the sciatic nerve of DPN, and the mechanism for improving DPN are not clear. Therefore, the STZ-induced model of type 1 DPN in SD rats was used to study the effects of metformin on DPN, and to preliminarily explore its mechanism in this study. All animal experiments were carried out with approval of the Experimental Animal Welfare Ethics Committee of the Institute of Materia Medica (Chinese Academy of Medical Sciences and Peking Union Medical College). After the model was established successfully, STZ diabetic rats were randomly divided into a model group and a metformin treatment group, and 10 normal SD rats were selected as the normal control group, and the rats were intragastrically administered for 12 weeks. The results showed that metformin significantly reduced blood glucose, glycosylated hemoglobin, food consumption and water consumption in STZ rats. Metformin markedly increased the motor nerve conduction velocity and mechanical stabbing pain threshold, prolonged the hot plate latency threshold, and improved the pathological morphological abnormalities of the sciatic nerve in STZ rats. In addition, metformin increased the content of glutathione (GSH), enhanced the activities of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), and reduced the content of malondialdehyde (MDA) in serum and sciatic nerve of STZ diabetic rats, as well as regulating the expression of genes related to oxidative stress in the sciatic nerve. Metformin obviously reduced the levels of pro-inflammatory factors such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 in the serum in STZ rats, and inhibited the gene expression of these inflammatory factors in the sciatic nerve. In summary, metformin significantly increased nerve conduction velocity, improved sciatic nerve morphological abnormalities and pain in DPN rats, which may be related to its effect in improving oxidative stress and reducing inflammation.

Humans ; RNA, Long Noncoding/genetics* ; MicroRNAs/genetics* ; Cell Line, Tumor ; Inflammation/genetics* ; Apolipoproteins E ; Apoptosis