Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Medicinal plants are a valuable source of essential medicines and herbal products for healthcare and disease therapy. Compared with chemical synthesis and extraction, the biosynthesis of natural products is a very promising alternative for the successful conservation of medicinal plants, and its rapid development will greatly facilitate the conservation and sustainable utilization of medicinal plants. Here, we summarize the advances in strategies and methods concerning the biosynthesis and production of natural products of medicinal plants. The strategies and methods mainly include genetic engineering, plant cell culture engineering, metabolic engineering, and synthetic biology based on multiple "OMICS" technologies, with paradigms for the biosynthesis of terpenoids and alkaloids. We also highlight the biosynthetic approaches and discuss progress in the production of some valuable natural products, exemplifying compounds such as vindoline (alkaloid), artemisinin and paclitaxel (terpenoids), to illustrate the power of biotechnology in medicinal plants.

Objective To evaluate the impact of ultra-high-molecular-weight polyethylene(UHMWPE)-Ribbond fi-bers,when combined with different restorative materials,on fracture resistance and marginal adaptation of isolated pri-mary molar defects,to provide a reference for clinical practice.Methods This study was approved by the Ethics Re-view Committee.A total of 72 extracted primary molars with complete crowns were collected,and 66 primary molars were randomly assigned as experimental groups for the fracture resistance and microleakage tests.The molars were di-vided into six groups(n=11)based on the type of restorative materials and the application of Ribbond fibers:Group A1,3M Filtek Z250+Ribbond;Group A2,3M Filtek Z250;Group B1,Beautifil Ⅱ LS+Ribbond;Group B2,Beautifil Ⅱ LS;Group C1,3M Filtek Bulk Fill+Ribbond;and Group C2,3M Filtek Bulk Fill.Groups A1,B1 and C1 received the fiber-reinforcing technique,whereas Groups A2,B2 and C2 received the direct restorative technique;the remainings were in Group D(blank control group),which did not receive treatment for the fracture resistance test.The fracture re-sistance test was divided into six experimental groups and one blank control group(n=6).Primary molar teeth in each experimental group were prepared with Class Ⅱ cavities and filled.The fracture load of all samples was detected,and the fracture mode was analyzed after thermal cycling.The microleakage test was divided into six experimental groups,with five in each group.Class Ⅰ cavities with a diameter of 3 mm and depth of 2.5 mm were prepared within the mesial and distal marginal ridges on the occlusal surface and filled for primary molars in each group.Marginal microleakage was assessed after thermal cycling.Results The fracture resistance test results showed that the fracture resistance in groups that received the fiber-reinforcing technique was greater than that in groups that received the direct restorative technique:Group A1>Group A2,Group B1>Group B2,Group C1>Group C2(P<0.05).The application of Ribbond fibers increased fracture resistance to all tested restorative materials by 37.08％to 39.34％.The proportion of tooth frac-ture decreased significantly in groups A1,C1 compared with A2,C2,with a significant increase in the occurrence rate of"Repairable"(P<0.05).The fracture resistance in Group A1 was significantly greater than that in Group B1 and Group C1(P<0.05).The marginal microleakage test results showed that the microleakage depth in groups that received the fiber-reinforcing technique was smaller than that in groups that received the direct restorative technique:Group A1

With the increasing proportion of human papilloma virus(HPV)infection in the pathogenic factors of oro-pharyngeal cancer,a series of changes have occurred in the surgical treatment.While the treatment mode has been im-proved,there are still many problems,including the inconsistency between diagnosis and treatment modes,the lack of popularization of reconstruction technology,the imperfect post-treatment rehabilitation system,and the lack of effective preventive measures.Especially in terms of treatment mode for early oropharyngeal cancer,there is no unified conclu-sion whether it is surgery alone or radiotherapy alone,and whether robotic minimally invasive surgery has better func-tional protection than radiotherapy.For advanced oropharyngeal cancer,there is greater controversy over the treatment mode.It is still unclear whether to adopt a non-surgical treatment mode of synchronous chemoradiotherapy or induction chemotherapy combined with synchronous chemoradiotherapy,or a treatment mode of surgery combined with postopera-tive chemoradiotherapy.In order to standardize the surgical treatment of oropharyngeal cancer in China and clarify the indications for surgical treatment of oropharyngeal cancer,this expert consensus,based on the characteristics and treat-ment status of oropharyngeal cancer in China and combined with the international latest theories and practices,forms consensus opinions in multiple aspects of preoperative evaluation,surgical indication determination,primary tumor re-section,neck lymph node dissection,postoperative defect repair,postoperative complication management prognosis and follow-up of oropharyngeal cancer patients.The key points include:① Before the treatment of oropharyngeal cancer,the expression of P16 protein should be detected to clarify HPV status;② Perform enhanced magnetic resonance imaging of the maxillofacial region before surgery to evaluate the invasion of oropharyngeal cancer and guide precise surgical resec-tion of oropharyngeal cancer.Evaluating mouth opening and airway status is crucial for surgical approach decisions and postoperative risk prediction;③ For oropharyngeal cancer patients who have to undergo major surgery and cannot eat for one to two months,it is recommended to undergo percutaneous endoscopic gastrostomy before surgery to effectively improve their nutritional intake during treatment;④ Early-stage oropharyngeal cancer patients may opt for either sur-gery alone or radiation therapy alone.For intermediate and advanced stages,HPV-related oropharyngeal cancer general-ly prioritizes radiation therapy,with concurrent chemotherapy considered based on tumor staging.Surgical treatment is recommended as the first choice for HPV unrelated oropharyngeal squamous cell carcinoma(including primary and re-current)and recurrent HPV related oropharyngeal squamous cell carcinoma after radiotherapy and chemotherapy;⑤ For primary exogenous T1-2 oropharyngeal cancer,direct surgery through the oral approach or da Vinci robotic sur-gery is preferred.For T3-4 patients with advanced oropharyngeal cancer,it is recommended to use temporary mandibu-lectomy approach and lateral pharyngotomy approach for surgery as appropriate;⑥ For cT1-2N0 oropharyngeal cancer patients with tumor invasion depth＞3 mm and cT3-4N0 HPV unrelated oropharyngeal cancer patients,selective neck dissection of levels ⅠB to Ⅳ is recommended.For cN+HPV unrelated oropharyngeal cancer patients,therapeutic neck dissection in regions Ⅰ-Ⅴ is advised;⑦ If PET-CT scan at 12 or more weeks after completion of radiation shows intense FDG uptake in any node,or imaging suggests continuous enlargement of lymph nodes,the patient should undergo neck dissection;⑧ For patients with suspected extracapsular invasion preoperatively,lymph node dissection should include removal of surrounding muscle and adipose connective tissue;⑨ The reconstruction of oropharyngeal cancer defects should follow the principle of reconstruction steps,with priority given to adjacent flaps,followed by distal pedicled flaps,and finally free flaps.The anterolateral thigh flap with abundant tissue can be used as the preferred flap for large-scale postoperative defects.

Objective To establish an analytical method combining gas chromatography-tandem mass spectrometry(GC-MS)and liquid chromatography-tandem mass spectrometry(LC-MS)to detect diazepam residue in bait nest materials and fish samples,and improve the pretreatment steps of samples to make the experimental results accurate and the sample processing convenient and fast.Methods Taking diazepam as the research object,samples were extracted with methanol and dichloromethane/n-hexane as solvents according to the type,and the supernatant was taken for detection after centrifugation.Results The diazepam standard sample showed a good linear relationship in the range of 10～10 000 ng/mL.The retention times in methanol and mixed solvent were 13.54 min and 13.83 min,respectively,and the correlation coefficients were 0.998 and 0.999,respectively;The limit of detection(LOD)of using methanol as extraction solvent was 2 ppb,and limit of quantification(LOQ)was 6 ppb.The LOD of using mixed solvents was 5 ppb,and the LOQ was 15 ppb.When the sample is a bait nest material,the GC-MS spectrum was clear and standard,and the peak shape was sharp and prominent;When the sample is biological specimen,the GC-MS spectra are disturbed by matrix,while the LC-MS data is more accurate and faster.Conclusion It is more appropriate to use GC-MS to determine the content of bait nest materialsamples,and it is more accurate to LC-MS to determine the content of fish samples due to the complexity of the organism.

Background/Aims: Ubiquitination is widely involved in the progression of hepatocellular carcinoma (HCC) by regulating various cellular processes. However, systematic strategies for screening core ubiquitin-related genes, clarifying their functions and mechanisms, and ultimately developing potential therapeutics for patients with HCC are still lacking. Methods: Cox and LASSO regression analyses were performed to construct a ubiquitin-related gene prediction model for HCC. Loss- and gain-of-function studies, transcriptomic and metabolomics analysis were used to explore the function and mechanism of UBE2S on HCC cell glycolysis and growth. Results: Based on 1,423 ubiquitin-related genes, a four-gene signature was successfully constructed to evaluate the prognosis of patients with HCC. UBE2S was identified in this signature with the potential to predict the survival of patients with HCC. E2F2 transcriptionally upregulated UBE2S expression by directly binding to its promoter. UBE2S positively regulated glycolysis in a HIF-1α-dependent manner, thus promoting the proliferation of HCC cells. Mechanistically, UBE2S enhanced K11-linkage polyubiquitination at lysine residues 171 and 196 of VHL independent of E3 ligase, thereby indirectly stabilizing HIF-1α protein levels by mediating the degradation of VHL by the proteasome. In particular, the combination of cephalomannine, a small molecule compound that inhibits the expression of UBE2S, and PX-478, an inhibitor of HIF-1α, significantly improved the anti-tumor efficacy. Conclusions UBE2S is identified as a key biomarker in HCC among the thousands of ubiquitin-related genes and promotes glycolysis by E3 enzyme-independent ubiquitination, thus serving as a therapeutic target for the treatment of HCC.

OBJECTIVES: To compare the efficacy of needle retaining after electroacupuncture combined with cognitive training and electroacupuncture combined with cognitive training in the treatment of post-stroke cognitive impairment (PSCI). METHODS: A total of 206 patients with PSCI were randomized into a needle retaining group (103 cases, 9 cases dropped out) and an electroacupuncture group (103 cases, 6 cases dropped out). In addition to the conventional basic medical treatment and the rehabilitation treatment, in the needle retaining group, electroacupuncture at Shenting (GV 24) and Baihui (GV 20) was applied, with continuous wave of 50 Hz in the first 15 min and with disperse-dense wave of 2 Hz/50 Hz in the last 15 min, the needles were continuously retained for 1 h after electroacupuncture, during which cognitive training was adopted; in the electroacupuncture group, cognitive training was performed after the same electric stimulation exerted for 30 min, without additional needles retaining. The treatment was given once a day, 5 times a week for totally 8 weeks in the two groups. Before and after 8-week treatment, the TCM syndrome score was observed; before and after 4,8-week treatment, the scores of mini-mental state examination (MMSE), Montreal cognitive assessment (MoCA) and ability of daily living were observed in the two groups. The clinical efficacy of the two groups was evaluated after 8-week treatment. RESULTS: After 8-week treatment, the TCM syndrome scores were increased compared with those before treatment in both groups (P<0.05); the TCM syndrome score in the needle retaining group was higher than that in the electroacupuncture group (P<0.05).After 4,8-week treatment, the scores of MMSE, MoCA and ability of daily living were increased compared with those before treatment in both groups (P<0.05); MMSE, MoCA scores after 4,8-week treatment and ability of daily living score after 8-week treatment in the needle retaining group were higher than those in the electroacupuncture group (P<0.05). The total effective rate was 90.4% (85/94) in the needle retaining group, which was superior to 82.5% (80/97) in the electroacupuncture group (P<0.05). CONCLUSIONS Both needle retaining after electroacupuncture combined with cognitive training and electroacupuncture combined with cognitive training can effectively treat PSCI, improve the clinical symptom, cognitive function and ability of daily living in PSCI patients. Needle retaining after electroacupuncture combined with cognitive training has a better therapeutic effect.
Humans ; Electroacupuncture ; Acupuncture Therapy ; Cognitive Training ; Acupuncture Points ; Cognitive Dysfunction/therapy* ; Stroke/complications* ; Treatment Outcome

BACKGROUND: Several studies have reported that polygenic risk scores (PRSs) can enhance risk prediction of coronary artery disease (CAD) in European populations. However, research on this topic is far from sufficient in non-European countries, including China. We aimed to evaluate the potential of PRS for predicting CAD for primary prevention in the Chinese population. METHODS: Participants with genome-wide genotypic data from the China Kadoorie Biobank were divided into training ( n = 28,490) and testing sets ( n = 72,150). Ten previously developed PRSs were evaluated, and new ones were developed using clumping and thresholding or LDpred method. The PRS showing the strongest association with CAD in the training set was selected to further evaluate its effects on improving the traditional CAD risk-prediction model in the testing set. Genetic risk was computed by summing the product of the weights and allele dosages across genome-wide single-nucleotide polymorphisms. Prediction of the 10-year first CAD events was assessed using hazard ratios (HRs) and measures of model discrimination, calibration, and net reclassification improvement (NRI). Hard CAD (nonfatal I21-I23 and fatal I20-I25) and soft CAD (all fatal or nonfatal I20-I25) were analyzed separately. RESULTS: In the testing set, 1214 hard and 7201 soft CAD cases were documented during a mean follow-up of 11.2 years. The HR per standard deviation of the optimal PRS was 1.26 (95% CI:1.19-1.33) for hard CAD. Based on a traditional CAD risk prediction model containing only non-laboratory-based information, the addition of PRS for hard CAD increased Harrell's C index by 0.001 (-0.001 to 0.003) in women and 0.003 (0.001 to 0.005) in men. Among the different high-risk thresholds ranging from 1% to 10%, the highest categorical NRI was 3.2% (95% CI: 0.4-6.0%) at a high-risk threshold of 10.0% in women. The association of the PRS with soft CAD was much weaker than with hard CAD, leading to minimal or no improvement in the soft CAD model. CONCLUSIONS In this Chinese population sample, the current PRSs minimally changed risk discrimination and offered little improvement in risk stratification for soft CAD. Therefore, this may not be suitable for promoting genetic screening in the general Chinese population to improve CAD risk prediction.
Male ; Humans ; Female ; Coronary Artery Disease/genetics* ; Biological Specimen Banks ; East Asian People ; Risk Assessment/methods* ; Genetic Predisposition to Disease/genetics* ; Risk Factors ; Genome-Wide Association Study