Catechol compounds as dual-targeting agents for fish protection against Ichthyophthirius multifiliis infections.

Aquaculture is one of the fastest growing sectors in global food production, recognized as a significant contributor to poverty alleviation, food security, and income generation. However, the frequent occurrence of diseases caused by pathogen infections result in reduced yields and economic losses, posing a substantial constraint to the sustainable development of aquaculture. Here, our study identified that four catechol compounds, quercetin, luteolin, caffeic acid, and chlorogenic acid, exhibited potent antiparasitic effects against Ichthyophthirius multifiliis in both, in vitro and in vivo. The parasite is recognized as one of the most pathogenic to fish worldwide. Using a combination of in silico methods, the dipeptidyl peptidase (DPP) was identified as a critical target for catechol compounds. The two hydroxyl radicals of the catechol group were essential for its binding to and interacting with the DPP protein. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that catechol compounds disrupt pathways associated with the metabolism and growth of I. multifiliis, thereby exerting antiparasitic effects. Furthermore, these compounds attenuated the expression of proinflammatory cytokines in vivo in fish and promoted macrophage polarization toward M2 phenotype by inhibiting the STAT1 signaling pathway. The dual activity of catechol compounds, acting as both direct antiparasitic and anti-inflammatory agents in fish, offers a promising therapeutic approach for combating I. multifiliis infections in aquaculture.

Is neoadjuvant immunotherapy necessary in patients with programmed death ligand 1 expression-negative resectable non-small cell lung cancer? A systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to investigate the clinical benefit and necessity of neoadjuvant programmed cell death (or ligand) (PD-(L)1) blockades in resectable non-small cell lung cancer (NSCLC) patients with negative PD-L1 expression. MATERIALS AND METHODS: Randomized control trials (RCTs) that compared event-free survival (EFS), overall survival (OS), major pathological response (MPR), and/or pathological complete response (pCR) between neoadjuvant chemo-immunotherapy (nCIT) and neoadjuvant chemotherapy (nCT) for patients with resectable NSCLC stratified by PD-L1 expression were eligible for inclusion in the study. Data regarding the pathological response and EFS were evaluated by the odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (CI) using random and fixed models. RESULTS: A total of six RCTs involving 3,194 patients with resectable NSCLC with or without neoadjuvant immunotherapy were included. Compared with nCT alone, nCIT significantly improved pCR (18.3 % vs. 3.0 %; OR, 5.64; 95 % CI, 3.22-9.89; P < 0.001), MPR (38.9 % vs. 15.5 %; OR, 3.57; 95 % CI, 2.10-6.05; P < 0.001), and EFS (HR, 0.75; 95 % CI, 0.62-0.90; P = 0.002) in PD-L1 <1 % NSCLC patients. In addition, PD-L1 ≥1 % was associated with higher rates of pCR (32.8 % vs. 18.3 %; OR, 2.28; 95 % CI, 1.40-3.73; P = 0.001) and MPR (53.9 % vs. 38.9 %; OR, 1.84; 95 % CI, 1.22-2.79; P = 004) and longer EFS (HR, 0.44 vs. 0.75) in the setting of nCIT compared with PD-L1 <1 %. nCIT improved only OS in NSCLC patients with PD-L1 ≥1 % but not in patients with PD-L1 <1 %. CONCLUSIONS: The use of nCIT should be recommended for resectable NSCLC patients with negative PD-L1 expression, as nCIT significantly improved the pathological response and EFS in these patients. The benefit to PD-L1-negative patients treated with nCIT on OS remains to be validated.

Rational application of EGFR-TKI adjuvant therapy in patients with completely resected stage IB-IIIA EGFR-mutant NSCLC: a systematic review and meta-analysis of 11 randomized controlled trials.

PURPOSE: To determine the role and rational application of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) adjuvant therapy in patients with completely resected stage IB-IIIA EGFR-mutant non-small-cell lung cancer (NSCLC). METHOD: Randomized controlled trials (RCTs) that compared the survival outcomes between adjuvant EGFR-TKIs and adjuvant chemotherapy or a placebo, or between different EGFR-TKI treatment durations for resected NSCLC, were eligible for inclusion. Disease-free survival (DFS) and overall survival (OS) with hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated as effective measures using random-effect or fixed-effect models. Subgroup analysis was also performed. RESULTS: Eleven RCTs involving 2102 EGFR-mutant NSCLC patients with or without EGFR-TKI adjuvant therapy were included. For all stage IB-IIIA NSCLC patients, EGFR-TKIs adjuvant therapy could not only significantly improve DFS (HR 0.43, 95% CI 0.30-0.63, P < 0.001) and 2- and 3-year DFS rates, but also improve OS (HR 0.72, 95% CI, 0.54-0.96, P = 0.024), compared with chemotherapy or the placebo. Further subgroup analyses indicated prolonged OS from first-generation EGFR-TKI adjuvant therapy in stage III patients, compared with chemotherapy or the placebo (HR for OS, 0.34; 95% CI, 0.18-0.63; P = 0.001). Of note, osimertinib adjuvant therapy led to the OS benefit expanding from stage III to stage II-III patients, with significantly improved DFS and a lower risk of brain recurrence, compared with the placebo. A 2-year treatment duration with EGFR-TKI adjuvant therapy showed a significantly lower recurrence risk than a ≤ 1-year duration. CONCLUSION: The DFS advantage from first-generation EGFR-TKI adjuvant therapy can translate into an OS benefit in stage III NSCLC patients. Osimertinib might be more suitable for adjuvant therapy than first-generation EGFR-TKIs, because of the lower recurrence rate and the potential OS benefit even in early-stage patients. The optimal treatment duration for EGFR-TKIs at different stages of disease needs to be validated.

Dual antitumor immunomodulatory effects of PARP inhibitor on the tumor microenvironment: A counterbalance between anti-tumor and pro-tumor.

Poly (ADP-ribose)-polymerases (PARPs) play an essential role in the maintenance of genome integrity, DNA repair, and apoptosis. PARP inhibitors (PARPi) exert antitumor effects via synthetic lethality and PARP trapping. PARPi impact the antitumor immune response by modulating the tumor microenvironment, and their effect has dual properties of promoting and inhibiting the antitumor immune response. PARPi promote M1 macrophage polarization, antigen presentation by dendritic cells, infiltration of B and T cells and their killing capacity and inhibit tumor angiogenesis. PARPi can also inhibit the activation and function of immune cells by upregulating PD-L1. In this review, we summarize the dual immunomodulatory effects and possible underlying mechanisms of PARPi, providing a basis for the design of combination regimens for clinical treatment and the identification of populations who may benefit from these therapies.

Efficacy and mechanisms of Dingxian pill combined with valproic acid on pentylenetetrazol-induced chronic epilepsy in rats.

OBJECIVE: To investigate the efficacy and mechanisms of Dingxian pill combined with valproic acid (VPA) on pentylenetetrazol-induced chronical epilepsy in rats. METHODS: A rat model of epilepsy was established by administering pentylenetetrazol (PTZ) water solution (35 mg/kg). Rats were divided into 4 groups, among which three groups were treated with different drugs once a day for 28 d including Dingxian pill (2.4 g/kg), VPA (0.2 g/kg), or a combination of Dingxian pill (2.4 g/kg) and VPA (0.2 g/kg) respectively, and the control group was given the same volume of saline. Rats in different groups were compared based on animal behavior, electroencephalograms, Morris water maze, immunohistochemistry, transcriptomics and real-time polymerase chain reaction. RSULTS: The combination therapy of Dingxian pill and VPA inhibited PTZ-induced seizure-like behavior and reduced seizure grades more significantly than VPA alone. Compared with the control group, the learning and memory ability of chronic PTZ-induced epileptic rats was improved in all the drug treatment groups, especially in the group that received both Dingxian pill and VPA. Similar to the results of MWM tests, expression of the neuroexcitability marker gene c-Fos was reduced after Dingxian pill and/or VPA treatment, and the effect was most pronounced in the combined treatment group. Transcriptomic analysis revealed that gene expression in the rodent hippocampus, which is involved in epilepsy, was upregulated by combined treatment with Dingxian pill and VPA, compared with VPA treatment alone. CONCLUSION: Our results not only highlight the anti-epileptic effects of combined Dingxian pill and VPA treatment, but also shed light on the underlying molecular mechanisms and provide a way to apply Traditional Chinese Medicine in the treatment of epilepsy.

Obeticholic acid protects against methamphetamine-induced anxiety-like behavior by ameliorating microbiota-mediated intestinal barrier impairment.

Methamphetamine (Meth) abuse can cause severe anxiety disorder and interfere with gut homeostasis. Obeticholic acid (OCA) has emerged as a protective agent against diet-related anxiety that improves gut homeostasis. The potential for OCA to ameliorate Meth-induced anxiety, and the microbial mechanisms involved, remain obscure. Here, C57/BL6 mice were intraperitoneally injected with Meth (15 mg/kg) to induce anxiety-like behavior. 16 S rRNA sequence analysis and fecal microbiome transplantation (FMT) were used to profile the gut microbiome and evaluate its effects, respectively. Orally administered OCA was investigated for protection against Meth-induced anxiety. Results indicated that Meth mediated anxiety-like behavior, aroused hippocampal neuroinflammation through activation of the TLR4/MyD88/NF-κB pathway, weakened intestinal barrier and disturbed the gut microbiome. Specifically, abundance of anxiety-related Rikenella was increased. FMT from Meth-administrated mice also weakened intestinal barrier and elevated serum LPS, inducing hippocampal neuroinflammation and anxiety-like behavior in recipient mice. Finally, OCA pretreatment ameliorated Meth-induced impairment of gut homeostasis by reshaping the microbial composition and improving the intestinal barrier. Meth-induced anxiety-like behavior and hippocampal neuroinflammation were also ameliorated by OCA pretreatment. These preliminary findings reveal the crucial role of gut microbiota in Meth-induced anxiety-like behavior and neuroinflammation, highlighting OCA as a potential candidate for the prevention of Meth-induced anxiety.

Evaluation of autogenous arteriovenous fistula insufficiency by ultrasound monitoring of brachial artery resistance index / 中华超声影像学杂志

Objective:To evaluate the autogenous arteriovenous fistula(AVF) insufficiency by ultrasound monitoring of brachial artery resistance index(RI).Methods:The brachial artery RI and blood flow volume(FV) data of 828 patients who underwent color-Doppler ultrasound detection after AVF in the General Hospital of Western Theater Command from January 2019 to June 2021 were retrospectively analyzed. The patients were grouped according to the adequacy of clinical dialysis, including 668 patients in the group with normal AVF function and 160 patients in the group with insufficient AVF function. The general information and ultrasonic measurement parameters were compared between the two groups. The correlation between brachial artery FV and RI was analyzed. The evaluation of brachial artery flow RI for AVF insufficiency was analyzed by ROC curve.Results:There were statistically significant differences between the two groups in brachial artery RI and FV(both P<0.001). The results of Pearson correlation analysis showed that brachial artery FV was negatively correlated to RI ( r=-0.657, P<0.001). The area under ROC curve for assessing AVF function by brachial artery RI was 0.970, with 95% CI was 0.955-0.986, the optimal cut-off value was 0.665, and the sensitivity and specificity were 0.888 and 0.955, respectively. Conclusions:Brachial artery RI in patients with AVF insufficiency is significantly higher than that in patients with normal AVF function. The optimal cutoff value of brachial artery RI can be used as an evaluation parameter for rapid screening of AVF function.

Clinical characteristics of choledocholithiasis combined with periampullary diverticulum and influencing factor analysis for difficult cannulation of endoscopic retrograde cholangiopan-creatography: a report of 1 920 cases / 中华消化外科杂志

Objective:To investigate the clinical characteristics of choledocholithiasis com-bined with periampullary diverticulum and influencing factor for difficult cannulation of endoscopic retrograde cholangiopancreatography (ERCP).Methods:The retrospective case-control study was conducted. The clinical data of 1 920 patients who underwent ERCP for choledocholithiasis in 15 medical centers, including the First Hospital of Lanzhou University, et al, from July 2015 to December 2017 were collected. There were 915 males and 1 005 females, aged (63±16)years. Of 1 920 patients, there were 228 cases with periampullary diverticulum and 1 692 cases without periampullary diverticulum. Observation indicators: (1) clinical characteristics of patients with choledocholithiasis; (2) intraoperative and postoperative situations of patients undergoing ERCP for choledocholithiasis; (3) influencing factor analysis for difficult cannulation in patients undergoing ERCP for choledocholithiasis. Measurement data with normal distribution were represented as Mean±SD, and comparison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M(range) or M( Q1, Q3), and com-parison between groups was conducted using the Wilcoxon rank sum test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test or Fisher exact probability. The Logistic regression model was used for univariate and multivariate analyses. Results:(1) Clinical characteristics of patients with choledocholithiasis. Age, body mass index, cases with complications as chronic obstructive pulmonary disease, diameter of common bile duct, cases with diameter of common bile duct as <8 mm, 8?12 mm, >12 mm, diameter of stone, cases with number of stones as single and multiple were (69±12)years, (23.3±3.0)kg/m 2, 16, (14±4)mm, 11, 95, 122, (12±4)mm, 89, 139 in patients with choledocholithiasis combined with periampullary diverticulum, versus (62±16)years, (23.8±2.8)kg/m 2, 67, (12±4)mm, 159, 892, 641, (10±4)mm, 817, 875 in patients with choledocholithiasis not combined with periampullary diver-ticulum, showing significant differences in the above indicators between the two groups ( t=?7.55, 2.45, χ2=4.54, t=?4.92, Z=4.66, t=?7.31, χ2=6.90, P<0.05). (2) Intraoperative and postoperative situations of patients undergoing ERCP for choledocholithiasis. The balloon expansion diameter, cases with intraoperative bleeding, cases with hemorrhage management of submucosal injection, hemostatic clip, spray hemostasis, electrocoagulation hemostasis and other treatment, cases with endoscopic plastic stent placement, cases with endoscopic nasal bile duct drainage, cases with mechanical lithotripsy, cases with stone complete clearing, cases with difficult cannulation, cases with delayed intubation, cases undergoing >5 times of cannulation attempts, cannulation time, X-ray exposure time, operation time were 10.0(range, 8.5?12.0)mm, 56, 6, 5, 43, 1, 1, 52, 177, 67, 201, 74, 38, 74, (7.4±3.1)minutes, (6±3)minutes, (46±19)minutes in patients with choledocholithiasis combined with periampullary diverticulum, versus 9.0(range, 8.0?11.0)mm, 243, 35, 14, 109, 73, 12, 230, 1 457, 167, 1 565, 395, 171, 395, (6.6±2.9)minutes, (6±5)minutes, (41±17)minutes in patients with choledocholithiasis not combined with periampullary diverticulum, showing significant differences in the above indicators between the two groups ( Z=6.31, χ2=15.90, 26.02, 13.61, 11.40, 71.51, 5.12, 9.04, 8.92, 9.04, t=?3.89, 2.67, ?3.61, P<0.05). (3) Influencing factor analysis for difficult cannulation in patients undergoing ERCP for choledocholithiasis. Results of multivariate analysis showed total bilirubin >30 umol/L, number of stones >1, combined with periampullary diverticulum were indepen-dent risk factors for difficult cannulation in patients with periampullary diverticulum who underwent ERCP for choledocholithiasis ( odds ratio=1.31, 1.48, 1.44, 95% confidence interval as 1.06?1.61, 1.20?1.84, 1.06?1.95, P<0.05). Results of further analysis showed that, of 1 920 patients undergoing ERCP for choledocholithiasis, the incidence of postoperative pancreatitis was 17.271%(81/469) and 8.132%(118/1 451) in the 469 cases with difficult cannulation and 1 451 cases without difficult cannula-tion, respectively, showing a significant difference between them ( χ2=31.86, P<0.05). In the 1 692 patients with choledocholithiasis not combined with periampullary diverticulum, the incidence of postopera-tive pancreatitis was 17.722%(70/395) and 8.250%(107/1 297) in 395 cases with difficult cannula-tion and 1 297 cases without difficult cannulation, respectively, showing a significant difference between them ( χ2=29.00, P<0.05). In the 228 patients with choledocholithiasis combined with peri-ampullary diverticulum, the incidence of postoperative pancreatitis was 14.865%(11/74) and 7.143%(11/154) in 74 cases with difficult cannulation and 154 cases without difficult cannulation, respectively, showing no significant difference between them ( χ2=3.42, P>0.05). Conclusions:Compared with patients with choledocholithiasis not combined with periampullary divertioulum, periampullary divertioulum often occurs in choledocholithiasis patients of elderly and low body mass index. The proportion of chronic obstructive pulmonary disease is high in choledocholithiasis patients with periampullary diverticulum, and the diameter of stone is large, the number of stone is more in these patients. Combined with periampullary diverticulum will increase the difficult of cannulation and the ratio of patient with mechanical lithotripsy, and reduce the ratio of patient with stone complete clearing without increasing postoperative complications of choledocholithiasis patients undergoing ERCP. Total bilirubin >30 μmol/L, number of stones >1, combined with periampullary diverticulum are independent risk factors for difficult cannulation in patients of periampullary diverticulum who underwent ERCP for choledocholithiasis.

Efficacy and safety of combined immunotherapy and antiangiogenesis with or without chemotherapy for advanced non-small-cell lung cancer: A systematic review and pooled analysis from 23 prospective studies.

Purpose: Immune checkpoint and antiangiogenic inhibitors have a potentially synergistic antitumor effect. We aimed to assess the efficacy and safety of immunotherapy in combination with antiangiogenesis therapy with or without chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Methods: PubMed, Embase, the Cochrane library, Google Scholar, Ovid, Scopus, and Web of Science were searched for eligible trials. ClinicalTrials.gov and meeting abstracts were also searched for qualified clinical studies. The inclusion criteria were as follows: prospective studies (including single-arm studies) that evaluated efficacy and/or toxicity of immunotherapy combined with antiangiogenic agents (A + I) with or without chemotherapy (A + I + chemo) in patients with advanced or metastatic NSCLC; and primary outcome of each study reported at least one of these endpoints: progression-free survival (PFS), overall survival, objective response rate (ORR), disease control rate (DCR), or adverse events (AEs). Results: Twenty three prospective studies comprising 1,856 patients with advanced NSCLC were included. The pooled ORR, median PFS and estimated overall survival were 39%, 6.8 months [95% confidence interval (CI), 5.53-8.13], and 18.6 months in the overall group. Similar ORR and median PFS with A + I + chemo versus A + I were observed in patients treated in first-line setting [59% and 9.47 months (95% CI, 6.45-12.49) versus 52% and 10.9 months (95% CI, 1.81-19.98), respectively]. We also observed improved ORR and mPFS with A + I + chemo versus A + I in subsequent-line setting [56% and 8.1 months (95% CI, 5.00-11.26) versus 22% and 5.1 months (95% CI, 4.01-6.15), respectively]. Efficacy of A + I + chemo therapy was evident across different PD-L1 subgroups, especially in patients with EGFR mutations [ORR: 59%; mPFS: 8.13 months (95% CI: 5.00-11.26)] or baseline liver metastases. The incidence of AEs with a major grade of ≥3 in the overall, A + I, and A + I + chemo groups were 4.1% vs. 5.5% vs. 3.4% for proteinuria, 13.7% vs. 16.2% vs. 9.7% for hypertension, and 1.9% vs. 1.2% vs. 2.8% for rash, respectively. No new safety signals were identified in this pooled analysis. Conclusion: Immunotherapy combined with antiangiogenic agents with or without chemotherapy showed encouraging antitumor activity and an acceptable toxicity profile in treatment-naïve or pretreated patients with advanced NSCLC. Doublet treatment with immunotherapy and antiangiogenic agents might be a new option for patients with advanced NSCLC, especially those who are treatment-naive or cannot tolerate chemotherapy.

Efficacy of Osimertinib in EGFR-Mutated Advanced Non-small-Cell Lung Cancer With Different T790M Status Following Resistance to Prior EGFR-TKIs: A Systematic Review and Meta-analysis.

Purpose: Epidermal growth factor receptor (EGFR) T790M-negative/unknown advanced non-small cell lung cancer (NSCLC) patients lack subsequent approved targeted therapies. This meta-analysis aimed to assess the efficacy of osimertinib in advanced NSCLC patients with different T790M status after resistance to prior first- or second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and to predict the subgroups that may benefit beside T790M-positive disease. Methods: PubMed, Embase, Web of Science, and Cochrane Library databases were searched for relevant trials. Meeting abstracts were also reviewed to identify appropriate studies. Studies evaluating the efficacy and/or survival outcomes of osimertinib in patients with different T790M status (positive, negative, or unknown) after resistance to prior first- or second-generation EGFR-TKIs were enrolled, and data were pooled to assess hazard ratios (HRs) or relative risk ratios (RRs) in terms of overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Results: A total of 1,313 EGFR-mutated NSCLC patients from 10 retrospective and one prospective studies treated with osimertinib after resistance to first- or second-generation EGFR-TKIs were included. In overall groups, T790M-positive patients showed an improved OS (HR=0.574, p=0.015), PFS (HR = 0.476, p = 0.017), and ORR (RR = 2.025, p = 0.000) compared with T790M-negative patients. In the brain metastases subgroup, no significant difference in OS was observed between T790M-positive and T790M-negative patients (HR = 0.75, p = 0.449) or between T790M-positive and T790M-unknown patients (HR = 0.90, p = 0.673). In the plasma genotyping subgroup, PFS was similar between T790M-positive and T790M-negative patients (HR = 1.033, p = 0.959). Conclusion: Patients with progressive brain metastases on first- or second-generation EGFR-TKIs can benefit from subsequent osimertinib therapy regardless of T790M status. Patients with plasma T790M-negative status and lack of tissue genotyping should be allowed to receive osimertinib treatment.

Impact of EGFR exon 19 deletion subtypes on clinical outcomes in EGFR-TKI-Treated advanced non-small-cell lung cancer.

OBJECTIVE: Exon 19 deletion (19del) is a sensitive mutation of epidermal growth factor receptor (EGFR) observed in non-small cell lung cancer (NSCLC), and consists of a large number of variants. It remains unclear whether 19del subtype impacts clinical outcomes following EGFR tyrosine kinase inhibitor (TKI) therapy. METHODS: We systematically searched web databases and identified eligible studies comparing the clinical outcomes of various EGFR 19del subtypes with EGFR-TKIs. The hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS),as well as the risk ratio (RR) for objective response rate and the frequency of acquired T790M mutation were used as study endpoints. RESULTS: A total of eleven retrospective studies and one prospective study involving 1,630 NSCLC patients with EGFR 19del were included in this meta-analysis. Most of studies were from Asia, and the 19del subtypes in these studies were grouped differently. Patients harboring deletions starting from E746 had significantly longer OS than those with deletions starting from L747 (HR, 0.79; 95% CI: 0.65 to 0.96, P = 0.019), and relatively but not significantly longer PFS (HR, 0.86; 95% CI: 0.69 to 1.06, P = 0.160). Patients with E746_A750del, the most common 19del subtype, had a significantly higher frequency of acquired T790M mutation when treated with first- or second-generation EGFR-TKIs compared to those with other 19del subtypes (RR, 0.76; 95% CI: 0.64-0.89, P = 0.001). There were no differences in PFS between the E746_A750del group and the uncommon group, or between the 15-nucleotide deletion group and other patients. CONCLUSION: This is the first meta-analysis to present survival outcomes and acquired T790M mutation frequency in the context of EGFR 19del subtype with EGFR-TKI therapy. Patients with a deletion starting from E746 show better OS than those with other subtypes, and patients with E746_A750del subtype have a higher frequency of acquired T790M mutation.

Efficacy and influencing factors of anlotinib in treatment of elderly patients with small cell lung cancer after second-line treatment failure / 国际肿瘤学杂志

Objective:To investigate the efficacy and influencing factors of anlotinib in treatment of elderly patients with small cell lung cancer after second-line treatment failure.Methods:A total of 56 elderly patients with small cell lung cancer who were diagnosed and treated in the Tumor Hospital Affiliated to Xinjiang Medical University from September 2018 to February 2020 were collected. All patients were treated with anlotinib capsule after failure of second-line chemotherapy, objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were calculated, and ORR, DCR and PFS of patients with different clinical characteristics were compared. Cox proportional hazards model was used to analyze the factors influencing PFS in elderly patients with small cell lung cancer, and adverse drug reactions were observed.Results:After 2 cycles of treatment, the ORR and DCR of 56 elderly patients with small cell lung cancer were 10.7% (6/56) and 53.6% (30/56) respectively. Among them, the ORR and DCR of patients without brain metastasis were 20.8% (5/24) and 75.0% (18/24), which were higher than 3.1% (1/32) and 37.5% (12/32) in patients with brain metastasis, with statistically significant differences ( χ2=4.496, P=0.034; χ2=7.754, P=0.005). The ORR and DCR of patients with Eastern Cooperative Oncology Group (ECOG) score of 0-1 were 21.7% (5/23) and 69.6% (16/23), which were higher than those of patients with ECOG score of 2-3 [3.0% (1/33), 42.4% (14/33)], with statistically significant differences ( χ2=4.959, P=0.026; χ2=4.014, P=0.045). ORR and DCR were not related to gender, age, clinical stage or smoking status (all P>0.05). The median PFS of 56 patients was 3.8 months. The median PFS of patients aged ≤70 years was 5.0 months, and that of patients aged >70 years was 3.4 months, with a statistically significant difference ( χ2=5.452, P=0.020). The median PFS of patients without brain metastasis was 5.1 months, and that of patients with brain metastasis was 3.2 months, with a statistically significant difference ( χ2=8.895, P=0.003). The median PFS of patients with ECOG score of 0-1 was 5.0 months, and that of patients with ECOG score of 2-3 was 2.9 months, with a statistically significant difference ( χ2=5.923, P=0.015). The median PFS of patients with limited stage was 5.0 months, and that of patients with extensive stage was 3.1 months, with a statistically significant difference ( χ2=5.141, P=0.023). Cox multivariate analysis showed that ECOG score ( HR=2.522, 95% CI: 1.378-4.615, P=0.003) and brain metastasis or not ( HR=0.323, 95% CI: 0.168-0.622, P=0.001) were independent prognostic factors of PFS. During the treatment of anlotinib, the main adverse reactions were grade Ⅰ-Ⅱ, grade Ⅲ-Ⅳ adverse reactions were mainly hypertension and hand-foot syndrome, which improved after drug reduction and symptomatic treatment, and could be tolerated later. The incidence of drug reduction was 3.6% (2/56), and there were no patients with drug interruption or termination of treatment. Conclusion:Anlotinib has good short-term efficacy and survival benefits in the treatment of elderly patients with small cell lung cancer after second-line treatment failure. It has good therapeutic effect for patients with low ECOG score and without brain metastasis, and has tolerable adverse reactions and high safety.

Comprehensive minimally invasive treatment for biliary anastomotic stenosis after orthotopic liver transplantation: a single center analysis of 60 cases / 器官移植

Objective To evaluate the clinical efficacy of endoscopic retrograde cholangiopancreatography (ERCP)-based comprehensive minimally invasive treatment for biliary anastomotic stenosis (BAS) after liver transplantation. Methods Clinical data of 60 BAS recipients after liver transplantation were retrospectively analyzed, 54 male and 6 female, aged (48±10) years. ERCP was initially carried out. If it succeeded, plastic or metallic stents were placed into the biliary tract. If it failed, percutaneous transhepatic cholangial drainage (PTCD) or single-operator cholangioscopy (SpyGlass) was adopted to pass through the stenosis. If all these procedures failed, magnetic anastomosis or other special methods were delivered. The incidence and treatment of BAS after liver transplantation were summarized. The efficacy, stent removal and recurrence were observed. Results The median time of incidence of BAS after liver transplantation was 8 (4, 13) months. Within postoperative 1 year, 1-2 years and over 2 years, 39, 16 and 5 recipients were diagnosed with BAS, respectively. All 60 BAS recipients after liver transplantation were successfully treated, including 56 cases initially receiving ERCP, and 41 completing BAS treatment, with a success rate of 73%. The failure of guide wire was the main cause of ERCP failure. The success rates of PTCD, SpyGlass and magnetic anastomosis were 5/9, 5/7 and 7/8, respectively. Two recipients were successfully treated by percutaneous choledochoscope-assisted blunt guide wire technique and stent placement in the biliary and duodenal fistula. After 3 (3, 4) cycles of ERCP and 13 (8, 18) months of stent indwelling, 38 recipients reached the stent removal criteria, including 25 plastic stents and 13 metallic stents. The indwelling time of plastic stents was longer than that of metallic stents (P < 0.05). Six cases suffered from stenosis recurrence at 12 (8, 33) months after stent removal, and the recurrence rate was 16%. Six patients were treated with ERCP, and 5 of them did not recur after the stents were successfully removed. Multivariate analysis showed that delayed diagnosis of stenosis and frequent ERCP before stent removal were the independent risk factors for BAS recurrence (both P < 0.05). Conclusions ERCP-based comprehensive minimally invasive treatment may improve the success rate of BAS treatment after liver transplantation and yield satisfactory long-term efficacy. Delayed diagnosis of BAS and high frequent ERCP required for stent removal are the independent risk factors for BAS recurrence.

Comprehensive analysis of an immune infiltrate-related competitive endogenous RNA network reveals potential prognostic biomarkers for non-small cell lung cancer.

Globally, non-small cell lung cancer (NSCLC) is the most common malignancy and its prognosis remains poor because of the lack of reliable early diagnostic biomarkers. The competitive endogenous RNA (ceRNA) network plays an important role in the tumorigenesis and prognosis of NSCLC. Tumor immune microenvironment (TIME) is valuable for predicting the response to immunotherapy and determining the prognosis of NSCLC patients. To understand the TIME-related ceRNA network, the RNA profiling datasets from the Genotype-Tissue Expression and The Cancer Genome Atlas databases were analyzed to identify the mRNAs, microRNAs, and lncRNAs associated with the differentially expressed genes. Weighted gene co-expression network analysis revealed that the brown module of mRNAs and the turquoise module of lncRNAs were the most important. Interactions among microRNAs, lncRNAs, and mRNAs were prognosticated using miRcode, miRDB, TargetScan, miRTarBase, and starBase databases. A prognostic model consisting of 13 mRNAs was established using univariate and multivariate Cox regression analyses and validated by the receiver operating characteristic (ROC) curve. The 22 immune infiltrating cell types were analyzed using the CIBERSORT algorithm, and results showed that the high-risk score of this model was related to poor prognosis and an immunosuppressive TIME. A lncRNA-miRNA-mRNA ceRNA network that included 69 differentially expressed lncRNAs (DElncRNAs) was constructed based on the five mRNAs obtained from the prognostic model. ROC survival analysis further showed that the seven DElncRNAs had a substantial prognostic value for the overall survival (OS) in NSCLC patients; the area under the curve was 0.65. In addition, the high-risk group showed drug resistance to several chemotherapeutic and targeted drugs including cisplatin, paclitaxel, docetaxel, gemcitabine, and gefitinib. The differential expression of five mRNAs and seven lncRNAs in the ceRNA network was supported by the results of the HPA database and RT-qPCR analyses. This comprehensive analysis of a ceRNA network identified a set of biomarkers for prognosis and TIME prediction in NSCLC.

Efficacy and Safety of Fusion Imaging in Radiofrequency Ablation of Hepatocellular Carcinoma Compared to Ultrasound: A Meta-Analysis.

Background: Radiofrequency ablation (RFA), generally performed under real-time guidance of ultrasound which is safe and effective, is a common minimally invasive therapy for treating hepatocellular carcinoma. Fusion imaging (FI) is a newly developed imaging method, which integrates CT/MRI accurate imaging and matches the characteristics of real-time ultrasound imaging, thereby providing a new approach to guide tumor ablation therapy. However, the efficacy and safety of FI as opposed to ultrasound in tumor ablation remains unclear. Objective: The present study sought to evaluate the difference in the efficacy and safety between FI and ultrasound in radiofrequency surgery for the treatment of hepatocellular carcinoma through a metaanalysis. Materials and Methods: Searching for studies comparing the efficacy and safety of FI and ultrasound in radiofrequency of hepatocellular carcinoma in PubMed, Embase, and Cochrane Library databases for articles published until April 2021. Random or fixed effect models were used for statistical analysis. Metaanalysis and sensitivity analysis were used on the included studies. Results: A total of six studies met predefined inclusion criteria, and were finally included in the analysis. Sensitivity and subgroup analyses, based on predetermined patient characteristics, allowed minimization of bias. In the RFA of hepatocellular carcinoma, FI decreased 1-year overall survival (OS) when compared with ultrasound. But FI was not significantly different from ultrasound in terms of technical efficiency, 1-, 2-, and 3-year local tumor progression (LTP), complications, as well as 2-year OS. Subgroup analysis, based on tumor mean diameter, showed that FI reduced the rate of 1- and 2-year LTP in patients with tumors of mean diameter ≥15 mm when compared with ultrasound. Moreover, operative complications could be reduced in patients with tumor mean diameter <15 mm using FI, compared with ultrasound. Conclusion: Overall, these results showed that FI may have some effects on improving efficacy and safety of thermal ablation in HCC patients, relative to ultrasound. However, it may be a more effective method for managing large lesions, as well as those that are difficult to ablate. Further large-scale and well-designed randomized controlled trials are needed to validate these findings.

Antibiotics Attenuate Methamphetamine-Induced Hepatotoxicity by Regulating Oxidative Stress and TLR4/MyD88/Traf6 Axis.

Methamphetamine (METH) is a major psychostimulant drug of abuse worldwide, and its neurotoxicity has been studied extensively. In addition to neurotoxicity, METH can also induce hepatotoxicity. The underlying mechanism of intestinal microorganisms in METH-induced hepatotoxicity remains unclear. In this study, mice have received antibiotics intragastrically or PBS once each day for 1 week, followed by METH or saline. The antibiotics attenuated METH-induced hepatotoxicity as evidenced by histopathological observation and biochemical analysis; furthermore, they alleviated METH-induced oxidative stress. The effect of antibiotics on METH-induced hepatotoxicity was investigated using RNA-sequencing (RNA-seq). The RNA-seq results demonstrated that antibiotics could regulate 580 differentially expressed genes (DEGs), of which 319 were upregulated after METH treatment and then downregulated with antibiotic pretreatment and 237 were first downregulated after METH administration and then upregulated after antibiotic pretreatment, in addition to 11 upregulated and 13 downregulated ones simultaneously in METH and antibiotic-pretreated groups. RNA-seq analyses revealed that TLR4 is one of the hub genes. Western blot analysis indicated that antibiotics inhibited the increase of TLR4, MyD88 and Traf6 induced by METH. This research suggests that antibiotics may play an important role in preventing METH-induced liver injury by regulating oxidative stress and TLR4/MyD88/Traf6 axis, though further investigation is required.

Short-term outcomes and safety of radiotherapy for immediate breast reconstruction with autologous flap transfer following breast-conserving surgery.

BACKGROUND: The outcomes of immediate autologous breast reconstruction (IABR) after partial mastectomy followed by postoperative radiotherapy (RT) in terms of aesthetics, treatment-related complications, and local control are unclear. In this study, we evaluated the efficacy of IABR after partial mastectomy with or without breast RT, and thus the impact of radiation on autologous flap transfer. METHOD: A retrospective cohort study involving consecutive breast cancer patients who underwent IABR after partial mastectomy between July 2011 and December 2017 at Shengjing Hospital was performed. Patients were divided into two groups based on whether or not they received RT after IABR. We compared aesthetic outcomes and changes in the flap size over the three-dimensional coordinates at various timepoints (pre-RT, 1, 6, and 12 months post-RT), as well as postoperative complications, survival, and recurrence rates between the two groups. RESULTS: In total, 84 breast cancer patients were enrolled, with 32 patients in the RT group and 52 in the non-RT group. At a median follow-up time of 33.3 months, no significant difference was found in the rate of regional recurrence between the two groups (3.13% vs. 3.85%, P = 1.00), and no local recurrences occurred in either group. At the timepoints pre-RT, 1, and 6 months post-RT (approximately 4, 7, and 12 months after IABR, respectively), 77 (91.7%), 70 (83.3%), and 83 (98.8%) patients, respectively, had achieved very good or good cosmetic outcomes, and only changes in breast skin color at 1 month after RT significantly differed between the RT and non-RT groups, with very good or good cosmetic result rates of 62.5% vs. 96.2%, respectively (P < 0.001). No significant difference in the reduction of flap size was observed at any timepoint between the two groups. There were no significant differences between the two groups in the rates of postoperative complications including necrosis of the flap, infection, hematoma, or seroma (all P > 0.05). Additionally, no grade 3 or greater RT-associated adverse events occurred during or after RT. CONCLUSION: RT following IABR provides aesthetically satisfactory results without intolerable adverse complications and may safely be performed in patients who underwent IABR after partial mastectomy.

Rational Application of First-Line EGFR-TKIs Combined with Antiangiogenic Inhibitors in Advanced EGFR-Mutant Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: A meta-analysis of randomized controlled trials (RCTs) was conducted to compare the difference in efficacy and safety between epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) with antiangiogenic inhibitors (A + T) and EGFR-TKI monotherapy in patients with treatment-naïve advanced EGFR-mutant non-small-cell lung cancer (NSCLC). METHODS: PubMed, Embase, Web of Science, and Cochrane electronic databases were searched for relevant RCTs. Meeting abstracts were also reviewed to identify appropriate studies. The endpoints included progression-free survival (PFS), overall survival (OS), 1- and 2-year OS rates, objective response rate (ORR), and grade ≥ 3 adverse events. All pooled outcomes were expressed using hazard ratios (HRs) or relative risk ratios (RRs). RESULTS: Data were collected from six eligible RCTs, which included 1,244 participants (619 in the A + T group and 625 in the TKI alone group). PFS was significantly improved with A + T compared to TKI alone (HR = 0.60; P < 0.01) regardless of EGFR mutation types (exon 19 deletion or L858R) and brain metastasis status (with or without brain metastases). There was no significant difference in median OS between the A + T and TKI alone groups (HR = 0.933; P = 0.551) regardless of EGFR mutation type. The ORR for A + T combination therapy was significantly increased compared to TKI monotherapy in exon 19 deletion subgroups (RR = 0.774; P = 0.008). There was no difference in the positive rates of acquired T790M mutation between the two groups (RR = 0.967; P = 0.846). More patients in the TKI alone group received a variety of subsequent systemic treatments than those in the A + T group (RR = 0.881; P = 0.002). CONCLUSION: Addition of antiangiogenic inhibitors to first-line EGFR-TKI therapy significantly reduced the risk of disease progression for patients with advanced EGFR-mutant NSCLC regardless of EGFR mutation type and brain metastasis status. The lack of OS benefit may be explained by differences in subsequent treatments rather than drug resistance mechanisms.

Robust tunable plasmon induced transparency in coupled-resonance finite array of metasurface nanostructure.

Robust and dynamically polarization-controlled tunable plasmon induced transparency (PIT) resonance in designed finite-array nanostructures metasurface is demonstrated, where sharp resonance is guaranteed by design and protected against large geometrical imperfections even for micro-zone sub-array. By employing the explicit analysis of near-field characteristic in the reciprocal-space based on the momentum matching, and the far-field radiation features with point-scattering approach in real-space sparked from Huygens's principles, the physics of interference resonance for plane-wave optical transmission and reflection of the metasurface is theoretically and thoroughly investigated. The distinctive polarization-selective and Q-tunable PIT shows robust features to performance degradations in traditional PIT system caused by inadvertent fabrication flaws or geometry asymmetry-variations, which paves way for the development of reconfigurable and flexible metasurface and, additionally, opens new avenues in robust and multifunctional controllable nanophotonics device design and applications.

Role of phosphoglycerate mutase 5 in myocardial ischemia-reperfusion injury in diabetic rats: relationship with mitochondrial quality / 中华麻醉学杂志

Objective:To evaluate the role of phosphoglycerate mutase 5 (phosphoglycerate mutase family member 5, PGAM5) in myocardial ischemia-reperfusion (I/R) injury in diabetic rats and the relationship with mitochondrial quality.Methods:SPF healthy male Sprague-Dawley rats, aged 6-8 weeks, weighing 200-220 g, were used in this study.Type 1 diabetes mellitus was induced by 1% streptozotocin diluted in citrate buffer solution 60 mg/kg.The rats were continuously fed for 8 weeks after successful establishment of the model.Seventy-two rats with type 1 diabetes mellitus were divided into 4 groups ( n=18 each) by a random number table method: diabetic sham operation group (DS group), diabetic myocardial I/R group (DIR group), diabetic myocardial I/R plus AAV9-PGAM5 shRNA group (DIR+ PGAM5 shRNA group), and diabetic myocardial I/R plus AAV9-GFP group (DIR+ GFP group). The myocardial I/R model was established by ligation of the left anterior descending coronary artery for 30 min followed by reperfusion for 2 h starting from 8 weeks after establishment of type 1 diabetes mellitus model.AAV9-PGAM5 shRNA and AAV9-GFP 2×10 12 μg/kg were slowly injected via tail vein 3 weeks before ischemia.In group AAV9-PGAM5 shRNA, left ventricular systolic pressure (LVSP) and the maximum rate of increase or decrease in left ventricular systolic pressure (±dp/dt max) were monitored and recorded at the end of reperfusion, and then blood samples from the the right carotid artery were collected for determination of serum troponin Ⅰ(cTnI), creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) levels (by enzyme-linked immunosorbent assay). The animals were sacrificed and hearts were obtained for determination of myocardial infarct size (by Evans Blue plus TTC double staining method) and expression of PGAM5, autophagy-related proteins (LC3B, p62), dynamin-related protein 1 (Drp1), and mitochondrial autophagy receptor protein (FUNDC1) (by Western blot) and for microscopic examination of pathological changes of myocardial tissues (by HE staining). Results:Compared with group DS, the LVSP and ±dp/dt max were significantly decreased, the serum levels of cTnI, CK-MB and LDH were increased, myocardial infarct size was increased, the expression of PGAM5, LC3B, Drp1 and FUNDC1 was up-regulated, and the expression of p62 was down-regulated in group DIR and group DIR+ GFP ( P<0.05). Compared with group DIR, LVSP and ±dp/dt max were significantly increased, the serum levels of cTnI, CK-MB and LDH were decreased, myocardial infarct size was decreased, the expression of PGAM5, LC3B, Drp1 and FUNDC1 was down-regulated, and the expression of p62 was up-regulated in group DIR+ PGAM5 shRNA ( P<0.05), and no significant change was found in the parameters mentioned above in group DIR+ GFP ( P>0.05). Conclusion:PGAM5 is involved in the myocardial I/R injury in diabetic rats, which is related to the reduction of mitochondrial quality.