Objective To elucidate the changes in the gut microbiota and molecular mechanism of huaier in enhancing the efficacy of oxaliplatin (OXA) chemotherapy in gastric cancer (GC). Methods The effects of huaier on the gut microbiota structure and intestinal barrier function in MKN45-bearing mice were analyzed by using 16S rRNA sequencing, RT-qPCR, and IHC. UPLC-MS and network pharmacology, as well as in vivo experimental approaches, were employed to investigate the key bioactive constituents of huaier systematically and elucidate the underlying mechanisms by which huaier exerts therapeutic effects against GC. The expression of the PI3K/AKT/SREBP pathway was detected in cancer cells and tissues via Western blot analysis. The safety profile of huaier combined with OXA was verified through serum biochemistry and HE-stained tissue section analyses. Results Huaier inhibited the PI3K/AKT/SREBP pathway by increasing the abundance of Akkermansia muciniphila, reduced lipid droplet deposition, and ultimately enhanced the sensitivity to OXA in the treatment of GC. Conclusion This study demonstrates the value of huaier in gastric cancer treatment by enhancing chemosensitivity and provides novel insights into its systemic therapeutic effects through molecular mechanisms and gut microbiota modulation.

BACKGROUND:Myocardial hypertrophy often leads to severe cardiovascular diseases and is difficult to diagnose due to its early stages being hard to detect.Circulating inflammatory proteins have been found to be significantly associated with cardiovascular diseases,yet the specific mechanisms linking them to myocardial hypertrophy remain unclear.OBJECTIVE:To investigate the relationship between circulating proteins and myocardial hypertrophy using multiple Mendelian randomization approaches.METHODS:Utilizing data from 91 circulating inflammatory proteins in the GWAS Catalog database and the latest myocardial hypertrophy data from the R11 FinnGen database,we employed bidirectional two-sample Mendelian randomization,multivariate Mendelian randomization,and Genome-Wide Association Studies co-localization to investigate the causal relationship between circulating inflammatory proteins and myocardial hypertrophy.The accuracy of the results was verified through sensitivity tests including MR-PRESSO,Cochran's Q test,MR-Egger intercept assessment,leave-one-out analysis,and funnel plot analysis.RESULTS AND CONCLUSION:In the results of two-sample Mendelian randomization,the primary method used for evaluation was the Inverse Variance Weighting(IVW)approach.It was found that the level of T-cell surface glycoprotein CD6 isoform(IVW:P=0.046,OR=0.74,95％Cl:0.66-1.00),level of slit chemokine(IVW:P=2.1×10-2,OR=0.74,95％CI:0.556-0.95),level of Delta and Notch-like epidermal growth factor-related receptor(IVW:P=3.7×10-4,OR=0.66,95％CI:0.49-0.87),level of interleukin-2(IVW:P=3.8×103,OR=0.667,95％CI:0.50-0.88),and sulfotransferase 1A1(IVW:P=1.42×102,OR=0.80,95％CI:0.67-0.96)had a unidirectional causal effect on cardiac hypertrophy.(2)Among the findings in multivariate Mendelian randomization,the levels of the CD6 isoform of T-cell surface glycoprotein(IVW:P=1.39×102,OR=0.81,95％CI:0.69-0.96)and the levels of Delta and Notch-like epidermal growth factor-related receptor(IVW:P=3.7×10-2,OR=0.73,95％CI:0.55-0.98)were positive,indicating that the results remained significant after excluding the effects of other circulating inflammatory proteins that had an impact on myocardial hypertrophy.(3)In colocalization,T-cell surface glycoprotein CD6 isoform levels had H3+H4=0.96,with the most significant single nucleotide polymorphism being rs59570070,suggesting an intrinsic link between T-cell surface glycoprotein CD6 isoform levels and myocardial hypertrophy.(4)Sensitivity results showed no abnormalities,indicating no heterogeneity or pleiotropic effects influencing the results.(5)These results verified that T cell surface glycoprotein CD6 isoforms,Slit chemokine,Delta and Notch-like epidermal growth factor-related receptors,interleukin-2,and sulfotransferase 1A1 had a unidirectional causal effect on myocardial hypertrophy.T cell surface glycoprotein CD6 isoforms and Delta and Notch-like epidermal growth factor-related receptors had the deepest impact,suggesting that there may be related pathways between T cell surface glycoprotein CD6 isoforms and myocardial hypertrophy.Mendelian randomization studies require large amounts of clinical data and therefore often use European samples from international databases for analysis.Since this analytical method has significant advantages in causal inference,precision medicine,and cross-population validation,its research results still hold great significance for the medical development in China.As Mendelian randomization research deepens,it also promotes the collection and analysis of clinical data in China to some extent.In the future,we can further analyze key protein mechanisms,combine multiomics and clinical validation,develop an inflammatory marker monitoring system and novel anti-inflammatory therapies,thereby promoting the prevention and control of cardiovascular diseases and the development of personalized medicine.

BACKGROUND:Myocardial hypertrophy often leads to severe cardiovascular diseases and is difficult to diagnose due to its early stages being hard to detect.Circulating inflammatory proteins have been found to be significantly associated with cardiovascular diseases,yet the specific mechanisms linking them to myocardial hypertrophy remain unclear.OBJECTIVE:To investigate the relationship between circulating proteins and myocardial hypertrophy using multiple Mendelian randomization approaches.METHODS:Utilizing data from 91 circulating inflammatory proteins in the GWAS Catalog database and the latest myocardial hypertrophy data from the R11 FinnGen database,we employed bidirectional two-sample Mendelian randomization,multivariate Mendelian randomization,and Genome-Wide Association Studies co-localization to investigate the causal relationship between circulating inflammatory proteins and myocardial hypertrophy.The accuracy of the results was verified through sensitivity tests including MR-PRESSO,Cochran's Q test,MR-Egger intercept assessment,leave-one-out analysis,and funnel plot analysis.RESULTS AND CONCLUSION:In the results of two-sample Mendelian randomization,the primary method used for evaluation was the Inverse Variance Weighting(IVW)approach.It was found that the level of T-cell surface glycoprotein CD6 isoform(IVW:P=0.046,OR=0.74,95％Cl:0.66-1.00),level of slit chemokine(IVW:P=2.1×10-2,OR=0.74,95％CI:0.556-0.95),level of Delta and Notch-like epidermal growth factor-related receptor(IVW:P=3.7×10-4,OR=0.66,95％CI:0.49-0.87),level of interleukin-2(IVW:P=3.8×103,OR=0.667,95％CI:0.50-0.88),and sulfotransferase 1A1(IVW:P=1.42×102,OR=0.80,95％CI:0.67-0.96)had a unidirectional causal effect on cardiac hypertrophy.(2)Among the findings in multivariate Mendelian randomization,the levels of the CD6 isoform of T-cell surface glycoprotein(IVW:P=1.39×102,OR=0.81,95％CI:0.69-0.96)and the levels of Delta and Notch-like epidermal growth factor-related receptor(IVW:P=3.7×10-2,OR=0.73,95％CI:0.55-0.98)were positive,indicating that the results remained significant after excluding the effects of other circulating inflammatory proteins that had an impact on myocardial hypertrophy.(3)In colocalization,T-cell surface glycoprotein CD6 isoform levels had H3+H4=0.96,with the most significant single nucleotide polymorphism being rs59570070,suggesting an intrinsic link between T-cell surface glycoprotein CD6 isoform levels and myocardial hypertrophy.(4)Sensitivity results showed no abnormalities,indicating no heterogeneity or pleiotropic effects influencing the results.(5)These results verified that T cell surface glycoprotein CD6 isoforms,Slit chemokine,Delta and Notch-like epidermal growth factor-related receptors,interleukin-2,and sulfotransferase 1A1 had a unidirectional causal effect on myocardial hypertrophy.T cell surface glycoprotein CD6 isoforms and Delta and Notch-like epidermal growth factor-related receptors had the deepest impact,suggesting that there may be related pathways between T cell surface glycoprotein CD6 isoforms and myocardial hypertrophy.Mendelian randomization studies require large amounts of clinical data and therefore often use European samples from international databases for analysis.Since this analytical method has significant advantages in causal inference,precision medicine,and cross-population validation,its research results still hold great significance for the medical development in China.As Mendelian randomization research deepens,it also promotes the collection and analysis of clinical data in China to some extent.In the future,we can further analyze key protein mechanisms,combine multiomics and clinical validation,develop an inflammatory marker monitoring system and novel anti-inflammatory therapies,thereby promoting the prevention and control of cardiovascular diseases and the development of personalized medicine.

Objective: To investigate the association between plant-based dietary patterns and gestational weight gain (GWG) among pregnant women with gestational diabetes mellitus (GDM), so as to provide the evidence for guiding the reasonable diet during pregnancy. Methods: GDM pregnant women who participated in the WeBirth project in Hangzhou Obstetrics and Gynecology Hospital were selected. Maternal age and pre-pregnancy body mass index (BMI) were collected. The Chinese version of Pregnancy Physical Activity questionnaire was used to assess the daily activity equivalent. The food frequency questionnaire was used to collect the frequency and amount of food intake in the last month before enrollment. The overall plant-based diet index (PDI), healthy plant-based diet index (HPDI), and unhealthy plant-based diet index (UPDI) were constructed based on food intake and grouped by quartiles. Multiple linear regression models were used to analyze the association between plant-based dietary patterns and GWG. Results: A total of 1 943 pregnant women with GDM, with a median age of 30.91 (interquartile range, 4.92) years. The median BMI of pre-pregnancy was 21.51 (interquartile range, 4.06) kg/m2. The medians of PDI, HPDI and UPDI were 32.42 (interquartile range, 4.60), 32.48 (interquartile range, 4.41) and 32.40 (interquartile range, 5.36), respectively. The median of GWG was 11.30 (interquartile range, 4.52) kg. Multiple linear regression analysis showed that PDI (Q3 group, β=0.674, 95%CI: 0.064-1.285; Q4 group, β=0.702, 95%CI: 0.098-1.306), UPDI (Q3 group, β=1.332, 95%CI: 0.771-1.894; Q4 group, β=1.115, 95%CI: 0.550-1.681) were positively associated with GWG after adjusting for age, pre-pregnancy BMI, daily activity equivalent and daily energy intake. No significant association was found between HPDI and GWG (all P>0.05). Conclusion UPDI was associated with a higher risk of GWG in pregnant women with GDM.

Objective:To evaluate the effect of value orientation brief therapy(VBT)combined with selective serotonin reuptake inhibitors(SSRIs)on clinical symptoms,rumination,decision-making ability,and cognitive func-tion in patients with mild to moderate depression.Methods:Eighty patients meeting the DSM-5 diagnostic criteria for mild to moderate depression were randomly assigned to either a medication(SSRIs)group(36 completed)or a VBT combined group(38 completed)for a 6-week intervention.Baseline and post-intervention assessments includ-ed the Hamilton Depression Scale(HAMD),Hamilton Anxious Scale(HAMA),Ruminative Response Scale-Chi-nese Version(RRS-CV),Iowa Gambling Test(IGT),number of eye fixation(NEF),responsive search score(RSS)in exploratory eye trajectory movement were used to evaluate patients'anxiety and depression symptoms,ru-minative thinking,decision-making function,and cognitive function.Results:The VBT combined group showed sig-nificantly better therapeutic effects than the medication group(P＜0.05).Compared to baseline and the medication group,the VBT combined group had significantly lower post-intervention scores in HAMD,HAMA,symptom rumi-nation,introspective reflection,compulsive meditation,and RRS-CV total scores after intervention(Ps＜0.05),and significantly higher scores in IGT net profit scores,NEF,and RSS scores(Ps＜0.05).Compared with the medica-tion group,the VBT combined group demonstrated a greater reduction in HAMD,HAMA,symptom rumination,in-trospective reflection,compulsive meditation,and RRS-CV total scores before and after intervention(Ps＜0.05),and a larger increase in IGT net profit scores,NEF,and RSS scores(Ps＜0.05).Conclusion:VBT combined with SSRIs effectively improves the symptoms of depression,anxiety,decision-making ability,rumination thinking,and cognitive function in patients with mild to moderate depression.

Objective:To evaluate the effect of value orientation brief therapy(VBT)combined with selective serotonin reuptake inhibitors(SSRIs)on clinical symptoms,rumination,decision-making ability,and cognitive func-tion in patients with mild to moderate depression.Methods:Eighty patients meeting the DSM-5 diagnostic criteria for mild to moderate depression were randomly assigned to either a medication(SSRIs)group(36 completed)or a VBT combined group(38 completed)for a 6-week intervention.Baseline and post-intervention assessments includ-ed the Hamilton Depression Scale(HAMD),Hamilton Anxious Scale(HAMA),Ruminative Response Scale-Chi-nese Version(RRS-CV),Iowa Gambling Test(IGT),number of eye fixation(NEF),responsive search score(RSS)in exploratory eye trajectory movement were used to evaluate patients'anxiety and depression symptoms,ru-minative thinking,decision-making function,and cognitive function.Results:The VBT combined group showed sig-nificantly better therapeutic effects than the medication group(P＜0.05).Compared to baseline and the medication group,the VBT combined group had significantly lower post-intervention scores in HAMD,HAMA,symptom rumi-nation,introspective reflection,compulsive meditation,and RRS-CV total scores after intervention(Ps＜0.05),and significantly higher scores in IGT net profit scores,NEF,and RSS scores(Ps＜0.05).Compared with the medica-tion group,the VBT combined group demonstrated a greater reduction in HAMD,HAMA,symptom rumination,in-trospective reflection,compulsive meditation,and RRS-CV total scores before and after intervention(Ps＜0.05),and a larger increase in IGT net profit scores,NEF,and RSS scores(Ps＜0.05).Conclusion:VBT combined with SSRIs effectively improves the symptoms of depression,anxiety,decision-making ability,rumination thinking,and cognitive function in patients with mild to moderate depression.

Cadmium is one of the heavy metals with severe reproductive toxicity,whose half-life lasts 20 to 40 years.Cadmium could induce dysfunction of testis and epididymis for its significant accumulation in human testis,and the amount,motility parameters and morphology of sperm change abnormally.The adverse change could also extend to male offspring and cause the impairment of their reproductive system.There has been no clear mecha-nism of how cadmium induces dysfunction of male reproductive system,and treatment for the adverse influence on male reproductive system by cadmium has not yet been found.Therefore,this problem has been discussed in repro-ductive and environmental field for a long time.A number of previous investigations showed that cadmium could damage male fertility by followed pathways,including interfering with hormone secretion,inducing oxidative stress,activating inflammation and apoptosis,and causing energy metabolism disorder,etc.In order to enlighten new ideas for therapeutic targets of male reproductive function damage induced by cadmium,we systematically reviewed and summarized the findings of previous publications in this paper.

Objective : To examine the association between dietary patterns during pregnancy and gestational diabetes mellitus (GDM), so as to provide the evidence for guiding the establishment of healthy and balanced dietary patterns and reducing the prevalence of GDM. Methods: Pregnant women who underwent oral glucose tolerance tests in Hangzhou Obstetrics and Gynecological Hospital from 2020 to 2021 were enrolled, and their demographic information were collected using questionnaires. Pregnant women's diets during the past three months were collected using Food Frequency Questionnaires (FFQs), and dietary patterns were extracted using principal component analysis. In addition, the association between dietary patterns and risk of GDM was examined using a multivariable logistic regression model. Results: A total of 1 689 pregnant women were included, with a median age of 28.53 (interquartile range, 2.47) years and a median gestational age of 26.00 (interquartile range, 2.00) weeks. Five dietary patterns were identified according to pregnant women's types of diets, including meat-based diets, dessert-fruit-refined grain diets, plant-based diets, eggs-milk-nut diets and whole-grain diets, with a cumulative contribution rate of 58.76%. The prevalence of GDM was 24.57% (415 cases) among the study subjects. Multivariable logistic regression analysis showed that pregnant women with scores in the highest quartile (Q4) of the meat-based diets had an increased risk of GDM (OR=1.372, 95%CI: 1.043-2.055) relative to those with scores in the lowest quartile (Q1), and pregnant women with Q4 scores of the dessert-fruit-refined grain diets had an increased risk of GDM (OR=1.743, 95%CI: 1.397-2.432) relative to those with Q1 scores, while pregnant women with Q4 scores of the plant-based diets had a reduced risk of GDM (OR=0.382, 95%CI: 0.346-0.613) relative to those with Q1 scores. Conclusion A plant-based dietary pattern may reduce the risk of GDM, while meat-based and dessert-fruit-refined grain dietary patterns may increase the risk of GDM.

Objective:To investigate the type and severity of skin adverse reactions induced by afatinib in the treatment of lung cancer, and to analyze their correlation with anti-lung cancer efficacy.Methods:A case-case-control study was conducted on lung cancer patients treated with afatinib in ZhongDa Hospital, Southeast University from December 2016 to January 2018. The type and severity of skin adverse reactions were evaluated in 76 patients with lung cancer based on the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.0, and these patients were divided into 3 groups according to the severity of skin lesions, including grade-0, -1, and -2/3 groups. The patients underwent chest computed tomography (CT) examination every 3 months, and the tumor response to afatinib was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) . Anti-lung cancer efficacy of afatinib was compared among the patients with different grades of skin lesions by using the Kruskal-wallis H rank sum test. Results:After treatment with afatinib, 44 of the 76 patients with lung cancer achieved stable condition or partial remission, and 32 experienced disease progression. Skin adverse reactions occurred in 69 patients, and manifested as acneiform lesions in 42 (55.3%) patients, paronychia in 35 (46.1%) , mucosal erosions in 30 (39%) , hair changes in 8 (10.5%) , and hand-foot syndrome in 6 (7.9%) . Improvement was achieved in 3, 7 and 34 cases in the grade-0, -1, and -2/3 groups ( n = 7, 19 and 50 respectively) , respectively. There was a significant difference in the response rate among the 3 groups ( χ2 = 6.117, P = 0.047) , and the response rate was significantly higher in the grade-1 and -2/3 groups than in the grade-0 group (both P < 0.001) , and higher in the grade-2/3 group than in the grade-1 group ( P < 0.001) . Conclusion:The treatment of lung cancer with afatinib can cause various types of skin lesions, such as acneiform lesions, paronychia, mucosal erosions, hair changes and hand-foot syndrome, and the higher the severity of the skin lesions, the more marked the anti-lung cancer efficacy of afatinib.

Objective:To investigate the progression pattern of acquired resistance to osimertinib and the treatment method as well as the therapeutic effect of salvage therapy in advanced lung cancer patients with epidermal growth factor receptor (EGFR) sensitive mutation or T790M mutation after the treatment of tyrosine-kinase inhibitor (TKI).Methods:The data of 145 patients with advanced lung cancer treated with osimertinib in Jiangsu Cancer Hospital between April 2017 (the approval time of osimertinib in China) and May 2019 were collected. At the last follow-up (December 2019), a total of 87 (60.0%) patients had acquired resistance to osimertinib, 61 (70.1%) of whom received salvage treatment; for patients with dramatic progression after resistance, chemotherapy was mainly given in the salvage therapy; for patients with gradual or local progression after resistance, the continuing targeted drug therapy and the local therapy were given. Imaging evaluation and Kaplan-Meier method were used to analyze the progression pattern of acquired resistance to osimertinib and the survival status, and to compare the salvage treatment results among subgroups.Results:The median follow-up time of 61 patients receiving salvage therapy was 11 months (4-32 months), among which 58 (95.1%) patients again had resistance to osimertinib, and 24 (39.3%) patients died of lung cancer. The median progression-free survival (PFS) time and overall survival (OS) time for the whole cohort was 2.5 months (95% CI 2.1-3.0 months) and 19.0 months (95% CI 13.7-26.3 months), respectively. The 1-year and 2-year OS rate was 72.1% and 41.7%, respectively. Among 61 patients receiving salvage therapy, 8 (13.1%) , 30 (49.2%) and 23 (37.7%) cases had dramatic progression, gradual progression and local progression, respectively; when given timely and proper salvage treatment, there were no statistically differences in PFS and OS of the patients in the above three subgroups (all P>0.05). There were no statistically differences in PFS and OS between patients receiving local therapy (24 cases) and patients not receiving local therapy (37 cases) after the progression occurred (all P>0.05). Among 58 patients with resistance to osimertinib again after the salvage therapy, 6 patients with gradual or local progression had more than 6-mouth PFS after the salvage therapy. Conclusions:Dramatic, gradual and local progression are the main patterns in patients with acquired resistance to osimertinib. The therapeutic efficacy of salvage therapy still shows some disappointing results.