Efficacy and safety of robotic versus laparoscopic liver resection for hepatocellular carcinoma: a propensity score-matched retrospective cohort study.

BACKGROUND: Evidence concerning long-term outcome of robotic liver resection (RLR) and laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) patients is scarce. METHODS: This study enrolled all patients who underwent RLR and LLR for resectable HCC between July 2016 and July 2021. Propensity score matching (PSM) was employed to create a 1:3 match between the RLR and LLR groups. A comprehensive collection and analysis of patient data regarding efficacy and safety have been conducted, along with the evaluation of the learning curve for RLR. RESULTS: Following PSM, a total of 341 patients were included, with 97 in the RLR group and 244 in the LLR group. RLR group demonstrated a significantly longer operative time (median [IQR], 210 [152.0-298.0] min vs. 183.5 [132.3-263.5] min; p = 0.04), with no significant differences in other perioperative and short-term postoperative outcomes. Overall survival (OS) was similar between the two groups (p = 0.43), but RLR group exhibited improved recurrence-free survival (RFS) (median of 65 months vs. 56 months, p = 0.006). The estimated 5-year OS for RLR and LLR were 74.8% (95% CI: 65.4-85.6%) and 80.7% (95% CI: 74.0-88.1%), respectively. The estimated 5-year RFS for RLR and LLR were 58.6% (95% CI: 48.6-70.6%) and 38.3% (95% CI: 26.4-55.9%), respectively. In the multivariate Cox regression analysis, RLR (HR: 0.586, 95% CI (0.393-0.874), p = 0.008) emerged as an independent predictor of reducing recurrence rates and enhanced RFS. The operative learning curve indicates that approximately after the 11th case, the learning curve of RLR stabilized and entered a proficient phase. CONCLUSIONS: OS was comparable between RLR and LLR, and while RFS was improved in the RLR group. RLR demonstrates oncological effectiveness and safety for resectable HCC.

Salivary metabolites are promising noninvasive biomarkers of drug-induced liver injury.

BACKGROUND: Drug-induced liver injury (DILI) is one of the most common adverse events of medication use, and its incidence is increasing. However, early detection of DILI is a crucial challenge due to a lack of biomarkers and noninvasive tests. AIM: To identify salivary metabolic biomarkers of DILI for the future development of noninvasive diagnostic tools. METHODS: Saliva samples from 31 DILI patients and 35 healthy controls (HCs) were subjected to untargeted metabolomics using ultrahigh-pressure liquid chromatography coupled with tandem mass spectrometry. Subsequent analyses, including partial least squares-discriminant analysis modeling, t tests and weighted metabolite coexpression network analysis (WMCNA), were conducted to identify key differentially expressed metabolites (DEMs) and metabolite sets. Furthermore, we utilized least absolute shrinkage and selection operato and random fores analyses for biomarker prediction. The use of each metabolite and metabolite set to detect DILI was evaluated with area under the receiver operating characteristic curves. RESULTS: We found 247 differentially expressed salivary metabolites between the DILI group and the HC group. Using WMCNA, we identified a set of 8 DEMs closely related to liver injury for further prediction testing. Interestingly, the distinct separation of DILI patients and HCs was achieved with five metabolites, namely, 12-hydroxydodecanoic acid, 3-hydroxydecanoic acid, tetradecanedioic acid, hypoxanthine, and inosine (area under the curve: 0.733-1). CONCLUSION: Salivary metabolomics revealed previously unreported metabolic alterations and diagnostic biomarkers in the saliva of DILI patients. Our study may provide a potentially feasible and noninvasive diagnostic method for DILI, but further validation is needed.

Deciphering the pharmacological mechanisms of Shenlingbaizhu formula in antibiotic-associated diarrhea treatment: Network pharmacological analysis and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Shenlingbaizhu (SLBZ) formula, a classical traditional Chinese medicinal (TCM) formula, has been widely used for treating antibiotic-associated diarrhea (AAD). However, the underlying pharmacological mechanisms have not yet been investigated thoroughly. AIM OF THE STUDY: To explore the remission mechanism of SLBZ in the treatment of AAD, we conducted network pharmacological analysis and experimental validation in vitro and in vivo. MATERIALS AND METHODS: In this study, the main compounds of SLBZ were identified by ultra-high-performance liquid chromatography-mass spectroscopy (UHPLC-MS) and online databases. The targets of the active components and AAD-related targets were predicted by network pharmacology, and the potential targets of SLBZ against AAD were obtained. Then the core targets were recognized after Protein-Protein Interaction (PPI) analysis. Based on these, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analyses were conducted, and the key pathway was screened. Subsequently, molecular docking was performed using Auto Dock Vina to find the key components that played a crucial role in that pathway. Molecular dynamics simulation was performed by Gromacs software to detect the binding mode. Finally, the results were confirmed by in vitro and in vivo experiments. RESULTS: A total of 66 active ingredients of SLBZ were detected by UHPLC-MS, and 128 active ingredients were screened out by network pharmacological analysis. Additionally, 935 drug targets and 1686 AAD-related targets were obtained. Seventy-eight intersected genes were selected as potential therapeutic targets and 19 genes were excavated as core targets. Enrichment analysis revealed PI3K-AKT signaling pathway was the key pathway in SLBZ against AAD. Topological analysis further revealed that JAK2, MTOR, TLR4, and SYK were the key targets affected by SLBZ on the PI3K-AKT pathway, and 52 components of SLBZ were associated with them. Molecular docking and dynamics simulation revealed strong binding affinities between MTOR and diosgenin. Subsequently, after SLBZ treatment, the expression levels of JAK2, MTOR, TLR4, and SYK were found significantly upregulated in the AAD model rats (p < 0.05). The cell experiment further validated the good binding ability between MTOR and diosgenin. CONCLUSION: We demonstrate that the therapeutic effect of SLBZ on AAD was achieved in part by inhibiting the PI3K-AKT pathway.

"Internet+Nursing Service" Mobile Apps in China App Stores: Functionality and Quality Assessment Study.

Background: As the Chinese society ages and the concern for health and quality of life grows, the demand for care services in China is increasing. The widespread use of internet technology has greatly improved the convenience and efficiency of web-based services. As a result, the Chinese government has been implementing "Internet+Nursing Services" since 2019, with mobile apps being the primary tools for users to access these services. The quality of these apps is closely related to user experience and the smooth use of services. Objective: This study aims to evaluate the functionality, services, and quality of "Internet+Nursing Service" apps; identify weaknesses; and provide suggestions for improving service programs and the research, development, improvement, and maintenance of similar apps. Methods: In December 2022, two researchers searched for "Internet+Nursing Service" apps by applying the search criteria on the Kuchuan mobile app monitoring platform. After identifying the apps to be included based on ranking criteria, they collected information such as the app developer, app size, version number, number of downloads, user ratings, and number and names of services. Afterward, 5 trained researchers independently evaluated the quality of the apps by using the Chinese version of the user version of the Mobile App Rating Scale (uMARS-C). The total uMARS-C score was based on the average of the five evaluators' ratings. Results: A total of 17 "Internet+Nursing Service" apps were included. Among these, 12 (71%) had been downloaded more than 10,000 times, 11 (65%) had user ratings of 4 or higher, the median app size was 62.67 (range 22.71-103; IQR 37.51-73.47) MB, 16 (94%) apps provided surgical wound dressing change services, 4 (24%) covered first-tier cities, and only 1 (6%) covered fourth-tier cities. The median total uMARS-C score was 3.88 (range 1.92-4.92; IQR 3.71-4.05), which did not correlate with app store user ratings (r=0.003; P=.99). The quality of most apps (11/17, 65%) was average. Most apps (12/17, 71%) were rated as "good" or above (≥4 points) in terms of information quality, layout, graphics, performance, and ease of use; however, the vast majority of apps were rated as "fair" or even "poor" (<4 points) in terms of credibility (14/17, 82%) and demand (16/17, 94%). Conclusions: "Internet+Nursing Service" apps need to broaden their service coverage, increase service variety, and further optimize their service structure. The overall quality of these apps is generally poor. App developers should collaborate with medical professionals and communicate with target users before launching their products to ensure accurate content, complete functionality, and good operation that meets user needs.

STING guides the STX17-SNAP29-VAMP8 complex assembly to control autophagy.

The stimulator of interferon genes (STING) plays a pivotal role in orchestrating innate immunity, and dysregulated activity of STING has been implicated in the pathogenesis of autoimmune diseases. Recent findings suggest that bacterial infection activates STING, relieving ER stress, and triggers non-canonical autophagy by spatially regulating STX17. Despite these insights, the precise mechanism governing the dynamics of autophagosome fusion elicited by STING remains unclear. In this study, we demonstrate that dynamic STING activation guides the autophagy flux, mirroring the trajectory of canonical autophagy adaptors. STING engages in a physical interaction with STX17, and agonist-induced phosphorylation or degradation alleviates STING's inhibitory effects on the assembly of the STX17-SNAP29-VAMP8 complex. Consistent with these findings, degradation-deficient mutants hinder autophagy flux by impeding STX17-mediated autophagosome-lysosome fusion. Moreover, STING mutants associated with lupus disrupt the assembly of the STX17-SNAP29-VAMP8 complex and autophagy process, which lead to persistent STING activation and elevated IFN-ß production. Our results highlight that the intracellular trajectory of STING, coupled with autophagy flux, guides the assembly and membrane fusion of the STX17-SNAP29-VAMP8 complex, ensuring the accurate regulation of innate immunity.

Novel Natural Carrier-Free Self-Assembled Nanoparticles for Treatment of Ulcerative Colitis by Balancing Immune Microenvironment and Intestinal Barrier.

Ulcerative colitis (UC) is a chronic inflammatory illness affecting the colon and rectum, with current treatment methods being unable to meet the clinical needs of ulcerative colitis patients. Although nanomedicines are recognized as promising anti-inflammatory medicines, their clinical application is limited by their high cost and unpredictable safety risks. This study reveals that two natural phytochemicals, berberine (BBR) and hesperetin (HST), self-assemble directly to form binary carrier-free multi-functional spherical nanoparticles (BBR-HST NPs) through noncovalent bonds involving electrostatic interactions, π-π stacking, and hydrogen bonding. Because of their synergistic anti-inflammatory activity, berberine-hesperetin nanoparticles (BBR-HST NPs) exhibit significantly better therapeutic effects on UC and inhibitory effects on inflammation than BBR and HST at the same dose by regulating the immune microenvironment and repairing the damaged intestinal barrier. Furthermore, BBR-HST NPs exhibit good biocompatibility and biosafety. Thus, this study proves the potential of novel natural anti-inflammatory nanoparticles as therapeutic agents for UC, which could promote the progress of drug development for UC and eventually benefit patients who suffering from it.

Identification and Validation of a Metabolism-Related Prognostic Signature Associated with M2 Macrophage Infiltration in Gastric Cancer.

High levels of M2 macrophage infiltration invariably contribute to poor cancer prognosis and can be manipulated by metabolic reprogramming in the tumor microenvironment. However, the metabolism-related genes (MRGs) affecting M2 macrophage infiltration and their clinical implications are not fully understood. In this study, we identified 173 MRGs associated with M2 macrophage infiltration in cases of gastric cancer (GC) using the TCGA and GEO databases. Twelve MRGs were eventually adopted as the prognostic signature to develop a risk model. In the high-risk group, the patients showed poorer survival outcomes than patients in the low-risk group. Additionally, the patients in the high-risk group were less sensitive to certain drugs, such as 5-Fluorouracil, Oxaliplatin, and Cisplatin. Risk scores were positively correlated with the infiltration of multiple immune cells, including CD8+ T cells and M2 macrophages. Furthermore, a difference was observed in the expression and distribution between the 12 signature genes in the tumor microenvironment through single-cell sequencing analysis. In vitro experiments proved that the M2 polarization of macrophages was suppressed by Sorcin-knockdown GC cells, thereby hindering the proliferation and migration of GC cells. These findings provide a valuable prognostic signature for evaluating clinical outcomes and corresponding treatment options and identifying potential targets for GC treatment.

Soluble forms of PD-1 and sPD-L1/2 in serum and urine of patients with head and neck cancer and their clinical significance.

This study explored the soluble forms of PD-1 and sPD-L1/2 in serum and urine of patients with head and neck cancer (HNCs) and associated the data with clinical state and 5-year survival. The sPD-1 and sPD-L1/2 levels were evaluated by ELISA in sufferers (N=110) and normal controls (N=82). Patients in the case group were more likely to be male smokers or former smokers. Compared with the normal control group, the serum levels of sPD-1, sPD-L1 and sPD-L2 and the urine level of sPD-L1 in patients with HNCs were increased. Furthermore, sPD-1 and sPD-L1 serum levels existed a positive connection, and sPD-1 and sPD-L2 serum levels positively correlated in HNCs sufferers. The urine sPD-1 and sPD-L1 had a positive relationship. sPD-1 serum levels had a positive connection with urine sPD-1, sPD-L1 urine levels had a positive relationship with sPD-L1, and sPD-L2 serum levels positively connected to urine sPD-L2. Lower serum sPD-1 and sPD-L1/L2 were associated with disease progression and survival at the examination time. sPD-1 and sPD-L1/L2 serum levels above median were markedly related to a decreased probability of 5-years OS in patients with HNCs. The sPD-1 and sPD-L1/2 were complementary markers representing clinical condition and illness outcomes for HNCs patients. The sPD-L1 might accelerate the characterization of high-risk patients with disapproving illness outcomes. sPD-1 and sPD-L1/2 could be easily accessed through liquid biopsy. The incorporation of them as indicators for risk evaluation throughout treatment scheduling and follow-up seems to be an appreciated method.

Efficacy and safety of Weifuchun tablet for chronic atrophic gastritis: A systematic review and meta-analysis.

BACKGROUND: Chronic atrophic gastritis is a significant premalignant lesion of gastric carcinoma. There is a great need to prevent the progression to gastric carcinoma through early intervention and treatment for chronic atrophic gastritis. Weifuchun, a famous Chinese patent drug, has been widely used for chronic atrophic gastritis in China. However, it remains unclear whether Weifuchun is effective for atrophic gastritis. OBJECTIVE: To determine the effectiveness and safety of Weifuchun for chronic atrophic gastritis. METHODS: We systematically retrieved seven databases (Cochrane Library, EMBASE, PubMed, China National Knowledge Infrastructure, Wanfang database, Chinese Scientific Journals Database, and Chinese Biological Medical Database) from their inception to October 5, 2022. Methodological quality was examined using the Cochrane Risk of bias tool. We also used RevMan 5.4 software for statistical analysis to examine the effectiveness and safety of Weifuchun. RESULTS: Fifteen studies with 1,488 patients were enrolled in this meta-analysis. The study indicated that Weifuchun was more effective (RR 1.52; 95% CI 1.41, 1.63; p<0.00001) than Western medicine and other Chinese patent medicine. In addition, Weifuchun was more effective in improving gastric mucosal under gastroscopy, improving histopathologic changes of gastric mucosal, and inhibiting Helicobacter pylori. However, no significant difference in safety was examined between Weifuchun and the control group (RR 2.83; 95% CI 0.85, 9.38; P = 0.09). CONCLUSIONS: The meta-analysis revealed a significant statistical difference with Weifuchun in effectiveness compared to the control group. However, there was no significant difference in safety. Thus, more high-quality clinical studies are needed in the future. TRIAL REGISTRATION: Registration number CRD42022365703.

Epidemiological characteristics, virulence potential, antimicrobial resistance profiles, and phylogenetic analysis of Aeromonas caviae isolated from extra-intestinal infections.

Objective: Aeromonas caviae (A. caviae) is one of the major etiological agents in human intestinal infections reported to be associated with a broad spectrum of extra-intestinal infections with increasing incidence over recent years. Although previous studies have established its significance as a causative agent of both bloodstream and gastrointestinal infections, the characteristics of A. caviae that cause extra-intestinal infections remain unilluminated.In this single-center retrospective study, we investigated epidemiological characteristics, antimicrobial resistance genes and phenotypes, virulence genes, and phyloevolution of 47 clinical A. caviae isolated from patients with extra-intestinal infections from 2017 to 2020. Methods: A. caviae strains were identified by biochemical tests and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF/MS), ultimately confirmed to species level by whole-genome sequencing (WGS). Antimicrobial resistance and virulence genes were identified using the Comprehensive Antibiotic Resistance Database (CARD) and the virulence factor database (VFDB), respectively. Phylogenetic analysis of 47 clinical strains was performed by combining with 521 A. caviae strains from NCBI database. Results: A. caviae was an opportunistic pathogen in immunocompromised patients, especially those with underlying hepatobiliary diseases and malignancies. 19 out of 47 isolates were identified as multidrug resistance (MDR) strains. Piperacillin-tazobactam, levofloxacin, gentamicin, amikacin with a resistance rate of less than 10% remained as options to treat extra-intestinal infections. 24 out of 47 isolates exhibited non-susceptibility to cephalosporins and cephamycins, all of which carried ß-lactamase gene, including bla MOX, bla PER-3, bla OXA, bla NDM, and bla CphA. Most stains (98%, 46/47) carried at least one of the virulence genes, but extra-intestinal infections had a low mortality rate. Phylogenetic analysis indicated the risk of nosocomial transmission but revealed no outbreak. However, the emergence of MDR and ß-lactamase resistance genes in extra-intestinal isolates of A. caviae is becoming an increasing risk to public health and requires attention. Conclusions: This study strengthen our understanding of A.caviae isolated from extra-intestinal infections. It may contribute to the management of extra-intestinal infections as well as the prevention and control of drug resistance.

Research on the experience of National Master of Traditional Chinese Medicine Professor Lu ZhiZheng in treating chronic atrophic gastritis based on data mining technology.

BACKGROUND: The purpose of this research is to summarize the academic expertise of Professor Lu Zhizheng in the treatment of Chronic Atrophic Gastritis, and to explain his clinical reasoning and common prescriptions in the treatment of CAG. METHODS: Professor Lu's outpatient cases of CAG from January 2008 to December 2021 were selected, and the PageRank algorithm was applied on the FangNet platform to analyze the usage frequencies of herbs, their four natures and five flavors according to Traditional Chinese Medicine, core herbs, and herb clustering patterns, with the goal of summarizing the distinguishing features of Professor Lu's academic and clinical approach to CAG. A total of 170 patients from 252 consultations were included in this study. The prescriptions involved a total of 239 herbs, which occurred a cumulative 4339 times. The herb natures were mainly warm, neutral, and slightly cold, and the herb flavors were predominantly sweet, bitter, and pungent. The channel tropism of the selected herbs primarily targeted the spleen, stomach, and lung meridians. Herb rank analysis showed that 34 herbs, including Gancao, Taizishen, Banxia, Huanglian, Shengjiang, Baizhu, Yiyiren, Maiya, Cangzhu, and Kuxingren, were the driver herbs used by Professor Lu for the treatment of CAG. RESULTS: Herb-herb co-occurrence/exclusivity analysis revealed 10 sets of frequently used herb pairs; herb cluster analysis yielded 10 herb clusters. These results reflected the emphasis Professor Lu placed on protecting Qi and Yin while clearing damp-heat. Professor Lu Zhizheng utilized dialectics reinforced with flexible thinking in the treatment of CAG, and emphasized that identifying the pathogenesis and addressing the syndrome should be prioritized. CONCLUSIONS: The characteristic treatment strategy aimed to replenish Qi and nourish Yin, clear away damp-heat, and treat CAG patients comprehensively under the guidance of established principles.

Choroidal structural changes following vitrectomy performed with phacoemulsification in unilateral idiopathic epiretinal membrane.

BACKGROUND: This study aims to determine the influence of vitrectomy combined with macular epiretinal membrane dissection and internal limiting membrane (ILM) peeling and phacoemulsification on choroidal vasculature in patients with unilateral idiopathic epiretinal membrane (IERM) and concurrent cataract using optical coherence tomography (OCT). METHODS: This retrospective study included 26 eyes of 26 patients (8 males and 18 females) with unilateral IERM without vitreomacular traction (VMT) (group 1) and the patients' fellow eyes (n = 26, group 2). Three-port 25-G pars plana vitrectomy (PPV) combined with macular epiretinal membrane dissection and ILM peeling and phacoemulsification was performed on all patients. The comprehensive ophthalmologic examinations of all patients involved OCT measurements at every visit before and after surgery, and the choroidal thickness (CT), central macular thickness (CMT) and choroidal vascularity index (CVI) were calculated. RESULTS: The mean age of the IERM patients was 66.58 ± 7.06 years. Postoperatively, best corrected visual acuity (BCVA) was significantly greater than baseline (P = 0.023). The CVI of the IERM eyes was significantly lower (P < 0.01) than that of the fellow eyes at baseline. The subfoveal CT in the IERM eyes was lower than that in the fellow eyes (P = 0.023), but there was, no significant difference in the average CT between the two groups at baseline (P = 0.071). In eyes with IERM, the CVI significantly increased at 1 week, 1 month (P < 0.001), and 3 months (P = 0.049) postoperatively, the subfoveal CT was markedly thickened 1 month after surgery (P = 0.001), the temporal 3 mm and nasal CT significantly increased at 1 week and 1 month postoperatively (P = 0.041, P = 0.022 for temporal 3 mm; P < 0.001, P = 0.047 for nasal 1.5 mm; P = 0.01, P = 0.001 for nasal 3 mm), and only the temporal 3 mm CT increased significantly at 3 months postoperatively (P = 0.017). The baseline CMT of the IERM eyes was significantly thicker than that of the fellow eyes (P < 0.001). CMT significantly decreased at 3 months postoperatively in IERM eyes(P = 0.033). CONCLUSIONS: The increase in the CVI in the IERM eyes without VMT after combined PPV with ILM peeling and phacoemulsification persists for at least 3 months.

Dipping Pattern and 1-year stroke functional outcome in ischemic stroke or transient ischemic attack.

AIMS: This study aimed to explore whether a relationship exists between dipping patterns and 1-year functional outcome in patients with acute ischemic stroke (IS) or transient ischemic attack (TIA). METHODS: Data from the Blood Pressure and Clinical Outcome in TIA or Ischemic Stroke Study (BOSS), a nationwide, hospital-based, longitudinal cohort study, was used for this study. Patients with acute IS or TIA were recruited within 7 days after onset and ambulatory blood pressure monitoring was performed during hospitalization. Patients were defined as dippers if nocturnal systolic blood pressure fell by ≥10%, non-dippers if 0-10%, and reverse dippers if < 0%. Poor functional outcome was defined as a modified Rankin Scale (mRS) score of 3-5. Logistic regression analysis was used to test the association between dipping patterns and 1-year functional outcome. RESULTS: Among the 1808 IS/TIA patients, 19.19% were dippers, 53.21% were non-dippers, and 27.60% were reverse dippers. Poor functional outcome occurred in 22.44% of reverse dippers, which was significantly higher than that of dippers (16.14%) and non-dippers (16.53%) (P = .014). A univariate analysis revealed that reverse dipping was a risk factor for poor functional outcome (Odds ratio 1.504, 95% confidence interval 1.055-2.145, P = .024). However, this significance disappeared after adjusting for confounders. CONCLUSIONS: Reverse dipping was prevalent in patients with IS/TIA. The higher incidence of 1-year poor functional outcome in reverse dippers warrants further investigation.

Efficacy of femoral periarterial block in preventing thigh tourniquet pain: a randomized controlled trial.

BACKGROUND: Tourniquet pain, described as a dull, tight, poorly localized aching sensation, is common in conscious patients. Although various pain-reduction methods have been implemented, none are completely effective. Femoral periarterial block (FAB) has been shown to attenuate tourniquet-induced hypertension in patients undergoing general anesthesia. We aimed to test the feasibility of FAB in inhibiting thigh tourniquet pain in orthopedic patients under conscious sedation. METHODS: Forty-two patients (aged 18-64 years and ASA I-II) scheduled for below-knee orthopedic surgeries with an anticipated tourniquet duration of more than 40 min were recruited and received FAB (Group 1) or not (Group 2). The primary outcome was the occurrence of tourniquet pain. The onset time and severity of the tourniquet pain were recorded. Total doses of sedatives and analgesics administered intraoperatively and hemodynamic changes were documented. The occurrence of local anesthetic systemic toxicity was recorded. RESULTS: Kaplan-Meier time-to-event curves indicated an improved tourniquet tolerance and delayed pain onset. Tourniquet pain occurrence was lower in Group 1 than in Group 2 (30% vs. 95.5%, P=0.02). Tourniquet pain onset was delayed in Group 1 (80[67,84] min vs. 58[51.5,60] min, P<0.01). Fewer patients in Group 1 experienced severe pain (3(15%) vs. 18(81.8%), P<0.01), and less hemodynamic changes (2(10%) vs. 12(54.5%), P<0.01). Local anesthetic systemic toxicity was absent. CONCLUSIONS: FAB, applied with regional anesthesia in patients undergoing below-knee orthopedic surgeries, could reduce thigh tourniquet pain, stabilize blood pressure and heart rate, and prolong tourniquet duration.

Pathogenesis from Inflammation to Cancer in NASH-Derived HCC.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the deadliest cancers worldwide. As opposed to the majority of patients with HCC, approximately 20-30% of cases of non-alcoholic steatohepatitis (NASH)-derived HCC develop malignant tumours in the absence of liver cirrhosis. NASH is characterized by metabolic dysregulation, chronic inflammation and cell death in the liver, which provide a favorable setting for the transformation of inflammation into cancer. This review aims to describe the pathogenesis and the underlying mechanism of the transition from inflammation to cancer in NASH.

A two-step mechanism governing PARP1-DNA retention by PARP inhibitors.

PARP inhibitors (PARPi) have emerged as promising cancer therapeutics capable of targeting specific DNA repair pathways, but their mechanism of action with respect to PARP1-DNA retention remains unclear. Here, we developed single-molecule assays to directly monitor the retention of PARP1 on DNA lesions in real time. Our study reveals a two-step mechanism by which PARPi modulate the retention of PARP1 on DNA lesions, consisting of a primary step of catalytic inhibition via binding competition with NAD+ followed by an allosteric modulation of bound PARPi. While clinically relevant PARPi exhibit distinct allosteric modulation activities that can either increase retention of PARP1 on DNA or induce its release, their retention potencies are predominantly determined by their ability to outcompete NAD+ binding. These findings provide a mechanistic basis for improved PARPi selection according to their characteristic activities and enable further development of more potent inhibitors.

Qu-Du-San-Jie decoction induces growth inhibition and vascular normalization in NF2-associated vestibular schwannoma.

Background: Neurofibromatosis type 2 (NF2) is a rare genetic syndrome that predisposes individuals to develop bilateral vestibular schwannomas (VSs) causing a high risk of life-threatening neurological complications. Traditional treatment options for NF2-associated VS usually cause neurological damage, and to date, there are no FDA-approved pharmacotherapies for NF2. The aim of this study was to evaluate the antitumor efficacy of Qu-Du-San-Jie (QDSJ) decoction, a traditional Chinese medicine formula, on NF2-associated VS and to investigate the potential underlying mechanisms. Methods: Ultra high-performance liquid chromatography-mass spectroscopy (UHPLC-MS) analysis was performed to identify the components of QDSJ and their targets. To determine the relationships between the putative targets of QDSJ and the differential genes of NF2-associated VS, the drug-disease crossover genes were screened using the UHPLC-MS data combined with our previous gene expression profiling data. The differentially expressed genes were imported into the STRING database to generate a PPI network. Differentially expressed gene targets and pathways were identified using GO and KEGG pathway enrichment analyses. The in vitro and in vivo drug efficacy of QDSJ decoction was tested using a patient-derived schwannoma cell line and a patient-derived xenograft mouse model, respectively. H&E staining, immunochemistry, and immunofluorescence staining were used to evaluate the cell proliferation and tumor vessels. Results: A total of 133 compounds were identified in QDSJ decoction using UHPLC-MS analysis. Network pharmacology showed that the regulation of necroptosis, apoptosis, cell cycle, angiogenesis, adherens junction, and neuroactive ligand-receptor interaction could be associated with the efficacy of QDSJ in treating NF2-associated VS. Treatment with QDSJ induced necrotic cell death and apoptosis of schwannoma cells in vitro and suppressed the tumor growth in vivo. Histopathological analysis revealed areas of cell necrosis and enlarged tumor blood vessels in the QDSJ-treated tumors. The numbers of cells positive for Cyclin D1 and Ki-67 were significantly reduced in QDSJ-treated tumors compared to control tumors. Immunofluorescence staining of CD31 and αSMA showed a decreased number and density of tumor vessels and normalized vessel structure in QDSJ-treated tumors. Conclusion: Our study demonstrates that QDSJ decoction shows significant antitumor activity against NF2-associated schwannoma and is a possible candidate for future clinical trials.

Design, synthesis and cytotoxic evaluation of novel betulonic acid-diazine derivatives as potential antitumor agents.

With the purpose to improve antiproliferative activity, 26 new betulonic acid-diazine derivatives were designed and synthesized from betulinic acid. The anticancer activity of these semi-synthetic compounds was evaluated by MTT assay in both tumor cell lines and normal cell line. The results indicated that majority of new compounds exhibited improved antitumor activity compared with the parent compound betulonic acid. Compound BoA2C, in particular, had the most significant action with IC50 value of 3.39 µM against MCF-7 cells, while it showed lower cytotoxicity on MDCK cell line than cisplatin. Furthermore, we discovered that BoA2C strongly increased MCF-7 cell damage mostly by influencing arginine and fatty acid metabolism. In addition, the structure-activity relationships were briefly discussed. The results of this study suggested that the introduction of different diazines at C-28 could selectively inhibit different kinds of cancer cells and might be an effective way to synthesize potent anticancer lead compound from betulonic acid.

Manpixiao Decoction Halted the Malignant Transformation of Precancerous Lesions of Gastric Cancer: From Network Prediction to In-Vivo Verification.

Manpixiao decoction (MPX), a traditional Chinese medicine formula, is mainly used to improve the gastric mucosal pathology and stomach discomfort in patients with gastric precancerous lesions. Precancerous lesion of gastric cancer (PLGC) refers to intestinal metaplasia and/or dysplasia based on gastric mucosal atrophy. Effective prevention and treatment of PLGC is of great significance to reduce the incidence of gastric cancer. Because of the complexity of the etiology and pathogenesis of PLGC, there is no unified and effective treatment plan in western medicine. In recent years, traditional Chinese medicine has shown obvious advantages in the treatment of PLGC and the prevention of its further progression to gastric cancer, relying on its multi-approach and multi-target comprehensive intervention characteristics. This study is designed to examine the protective effect of MPX against PLGC and further to reveal the engaged mechanism via integrating network pharmacology and in vivo experimental evidence. Network pharmacology results demonstrated that inflammation, immune responses, and angiogenesis might be associated with the efficacy of MPX in the treatment of PLGC, in which the PI3K-Akt, cellular senescence, P53 and protein processing in endoplasmic reticulum were involved. Then, we established a rat model of PLGC using a combination of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), sodium salicylate, irregular fasting, and ranitidine, and observed the effects after MPX treatment. Our result showed that MPX improved the pathological condition of gastric mucosa in PLGC rats and reduced the incidence of gastric cancer. Next, the analysis of serum inflammatory cytokines showed that MPX reduced the inflammation-related cytokines (such as IL-1α, IL-7, CSF-1, and CSF-3) in the serum. Additionally, MPX also had a regulation effect on the "protein/protein phosphorylation-signaling pathway" network in the core region of the PLGC rats. It is showed that MPX can inhibit the phosphorylation of PI3K-AKT, and downregulates the EGFR, ß-catenin, and N-cadherin protein levels. These results indicate that MPX halted the PLGC progression through inhibiting EGFR-PI3K-AKT related epithelial-mesenchymal transition process.