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ObjectiveTo establish an early predictive model using serological markers based on LASSO regression for predicting the possibility of HBsAg clearance in HBeAg-negative chronic hepatitis B （CHB） patients treated with pegylated interferon α-2b （PEG-IFNα-2b）， and to investigate the diagnostic value of the model. MethodsA total of 136 HBeAg-negative CHB patients who received PEG-IFNα-2b treatment in the Affiliated Hospital of Xuzhou Medical University from April 2020 to October 2021 were enrolled， among whom 47 received PEG-IFNα-2b for the first time （previously untreated） and 89 received PEG-IFNα-2b after 48 weeks of treatment with nucleos（t）ide analogues （treatment-experienced）. The patients were randomly assigned to a training set with 95 patients and a validation set with 41 patients at a ratio of 7∶3， and related data were collected for both groups， including virological markers， routine blood test results， and liver function at baseline and week 12 of treatment. According to HBsAg status at week 48 of treatment， the patients were divided into seroconversion group with 38 patients and non-seroconversion group with 98 patients. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous data between two groups； the chi-square test was used for comparison of categorical variables between two groups. The LASSO regression analysis and univariate and multivariate logistic regression analyses were used to establish a nomogram model； the receiver operating characteristic （ROC） curve was used to assess its predictive ability， and the area under the ROC curve （AUC） was used for comparison of predictive value. ResultsIn the training set， 95 HBeAg-negative CHB patients were treated with PEG-IFNα-2b for 48 weeks， among whom there were 27 patients in the seroconversion group and 68 in the non-seroconversion group. The univariate Logistic regression analysis， with P<0.2 as the criterion for screening， showed that 9 indicators were included in the LASSO regression analysis， i.e.， sex， baseline HBV DNA level， the reduction in HBV DNA in 0 — 12 weeks， baseline HBsAg level， the reduction in HBsAg in 0 — 12 weeks， baseline aspartate aminotransferase （AST） level， the reduction in AST in 0 — 12 weeks， baseline alanine aminotransferase （ALT） level， and the reduction in ALT in 0 — 12 weeks. The LASSO regression analysis showed that sex， baseline HBsAg level， the reduction in HBsAg in 0 — 12 weeks， and the reduction in ALT in 0 — 12 weeks were non-zero variables and were included in the multivariate Logistic regression analysis. The multivariate Logistic regression analysis obtained 4 independent predictive factors， i.e.， sex （odds ratio ［OR］=5.38， 95% confidence interval ［CI］： 1.11 — 34.21， P=0.049）， baseline HBsAg level （OR=0.12， 95%CI： 0.04 — 0.26， P<0.001）， the reduction in HBsAg in 0 — 12 weeks （OR=5.54， 95%CI： 1.97 — 19.18， P=0.003）， and the reduction in ALT in 0 — 12 weeks （OR=0.99， 95%CI： 0.97 — 1.00， P=0.039）. A nomogram model was established based on the results of the multivariate Logistic regression analysis， and the ROC curve was used to assess the predictive value of this nomogram model. This nomogram model had an AUC of 0.934 （95%CI： 0.886 — 0.981） in the training set and an AUC of 0.921 （95%CI： 0.838 — 1.000） in the validation set. In addition， the results of calibration curve and decision curve analyses showed that the model had good consistency and accuracy. ConclusionBased on general information and serological markers， the LASSO regression analysis is used to establish a nomogram model using sex， baseline HBsAg level， the reduction in HBsAg in 0 — 12 weeks， and the reduction in ALT in 0 — 12 weeks， and this model can be used to predict the probability of achieving HBsAg clearance in HBeAg-negative CHB patients treated with PEG-IFNα-2b， which provides important reference and theoretical support for the clinical treatment of patients.
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N 6-methyladenosine (m 6A) modification, as the most prevalent epigenetic modification of RNA, plays a crucial role in the initiation and development of malignancies. Methyltransferase like protein 14 (METTL14) is a major methylase catalyzing m 6A modification and regulating biological processes such as RNA splicing, translation and degradation. Recent studies have demonstrated that METTL14 not only regulates the growth, invasion and metastasis of tumors through various molecular mechanisms, but also is closely correlated with the prognosis of tumor patients and clinical efficacy of anti-tumor therapies. In-depth understanding of the mechanism of METTL14 in breast, digestive system and urinary system tumors is helpful to provide new clinical markers and drug targets for the prevention and treatment of tumors based on m 6A modification.
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Objective:To evaluate the effects of proton pump inhibitors (PPIs) on the clinical outcomes for advanced solid tumor patients treated with immune checkpoint inhibitors (ICIs).Methods:A total of 204 patients with advanced solid tumors who received ICIs in the Affiliated Hospital of Yangzhou University from November 2016 to December 2020 were retrospectively analyzed. The patients were divided into PPIs group ( n=73) and Non-PPIs group ( n=131) according to whether they received PPIs within 1 month before or after the initiation of ICIs treatment. The correlations between the uses of PPIs and the clinical characteristics of patients were explored, and the clinical efficacy of the two groups was evaluated. Kaplan-Meier survival curve was applied to analyze the effects of PPIs uses on overall survival (OS) and progression-free survival (PFS) of patients. The Cox proportional hazards model was used to clarify whether PPIs was an independent indicator of patients′ prognosis. Results:During ICIs treatment of advanced solid tumors, the use of PPIs was not correlated with the patients′ gender, age, tumor type, the score of the United States Eastern Collaborative Group, types of immunotherapy drugs and treatment strategy (all P>0.05). The objective response rate of the Non-PPIs group was better than that of the PPIs group (45.0% vs. 24.7%, χ2=8.286, P=0.004). The disease control rate of the Non-PPIs group was better than that of the PPIs group (75.6% vs. 52.0%, χ2=11.755, P=0.001). In patients with advanced solid tumors, the median OS (3.4 months vs. 6.1 months) and median PFS (2.8 months vs. 4.0 months) in the PPIs group were shorter than those in the Non-PPIs group ( χ2=9.563, P=0.002; χ2=5.761, P=0.016). Univariate analysis showed that among patients with advanced solid tumors treated with ICIs, PPIs uses was significantly correlated with OS ( HR=1.85, 95% CI: 1.24-2.76, P=0.003); PPIs uses( HR=1.65, 95% CI: 1.09-2.51, P=0.019) and age ( HR=1.56, 95% CI: 1.05-2.32, P=0.029) were significantly correlated with PFS. Multivariate analysis showed that PPIs uses was an independent prognostic factor affecting OS ( HR=1.90, 95% CI: 1.27-2.85, P=0.002) and PFS ( HR=1.73, 95% CI: 1.12-2.65, P=0.013). Meanwhile, subgroup analysis discovered that in the course of ICIs treatment of lung cancer patients, the median OS (3.2 months vs. 6.2 months) and median PFS (2.2 months vs. 3.8 months) in the PPIs group ( n=64) were shorter than those in the Non-PPIs group ( n=34) ( χ2=16.187, P<0.001; χ2=5.106, P=0.020). Univariate analysis showed that PPIs uses was associated with OS ( HR=2.97, 95% CI: 1.70-5.22, P<0.001) and PFS ( HR=1.97, 95% CI: 1.09-3.55, P=0.025) in lung cancer patients treated with ICIs. Multivariate analysis showed that PPIs uses was an independent prognostic factor for OS ( HR=3.38, 95% CI: 1.87-6.11, P<0.001) and PFS ( HR=2.31, 95% CI: 1.22-4.38, P=0.010) in lung cancer patients treated with ICIs. Conclusion:The use of PPIs reduces the effect of ICIs in the treatment of advanced solid tumor, especially in lung cancer. PPIs should be used cautiously in patients with advanced solid tumors treated with ICIs.
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Nonalcoholic steatohepatitis (NASH) can cause end-stage liver diseases such as liver cirrhosis and liver cancer, and therefore, it is urgent to treat NASH, reverse hepatic steatosis, and delay the onset of end-stage liver diseases. NASH has a complex pathogenesis and there are currently no effective drugs for treatment. At present, new drugs still have huge market potential and are the research hotspots of various pharmaceutical companies in China and globally. This article mainly reviews and summarizes the clinical research status, drug types, mechanism of action, and future market prospects of the new drugs for NASH in existing phase Ⅲ studies.
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In recent years, immunotherapy with immune checkpoint inhibitor (ICI) as the representative drug has become an important treatment method for advanced malignant tumors. Preclinical studies have found that disorders of the gut microbiota can reduce the clinical benefit of patients treated with ICI. The latest data indicate that antibiotics may further affect the occurrence and development of tumors and the efficacy of immunotherapy by changing the abundance and composition of intestinal microbiota. To sum up the role of anti-biotics in the immunotherapy of advanced malignant tumor may provide a new idea for the optimization of treatment strategies for patients with advanced cancer.
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N 6-methyladenosine (m 6A) methylation modification is defined as the methylation at the N 6 position of adenosine. This dynamic process is regulated by writer, eraser and reader. Accumulating evidence indicates that m 6A methylation modification is involved in the initiation and development of various digestive system neoplasms including proliferation, invasion, metastasis and chemoresistance. A further understanding about the role of m 6A methylation modification in digestive system neoplasms will benefit the development of a novel precise diagnostic and therapeutic strategy and finally improve the overall prognosis of patients.
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In the treatment of non-small cell lung cancer (NSCLC), immunotherapies represented by immune checkpoint inhibitors are developing rapidly. It is the premise of precise treatment to clarify the influencing factors of NSCLC immunotherapy. In the course of immunotherapy for advanced NSCLC, elderly patients can obtain specific effect from immunotherapy; male patients benefit more from monotherapy; when steroid hormones are used for related symptoms caused by tumors, they are poor prognostic factors for patients. The occurrence of immune-related adverse events is a favorable prognostic factor while driving gene mutations and the use of antibiotics will reduce the efficacy of immunotherapy.
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ObjectiveTo investigate the etiology of liver diseases with negative hepatotropic virus, and to provide ideas for the clinical diagnosis and treatment of liver diseases. MethodsA retrospective analysis was performed for the clinical data and liver biopsy results of 113 patients with negative hepatotropic virus who were admitted to The Affiliated Hospital of Xuzhou Medical University from July 2018 to December 2019. According to sex, they were divided into male group with 41 patients and female group with 72 patients, and according to age, they were divided into youth group with 42 patients, middle-aged group with 56 patients, and elderly group with 15 patients. The chi-square test was used for comparison of categorical data between groups. ResultsAmong the 113 patients with negative hepatotropic virus, 111(98.23%) were given a confirmed diagnosis, among whom 43 (38.05%) were diagnosed with nonalcoholic fatty liver disease (NAFLD), 40(35.40%) were diagnosed with drug-induced liver injury (DILI), 16(14.15%) had autoimmune liver disease (AILD), 8(7.08%) had alcoholic liver disease, 3(2.65%) had biliary disease, and 1(0.88%) had diseases in other systems which involved the liver. Among the male patients, 53.49% had NAFLD, 100% had ALD, and 15% had DILI, while among the female patients, 85% had DILI, 46.51% had NAFLD, and 93.75% had AILD. For DILI, there were significantly more female patients than male patients (χ2=40000, P＜0.001), and for AILD, there were also significantly more female patients than male patients (χ2=12.250, P＜0.001). In the youth group, NAFLD (55.81%), DILI (20%), and ALD (75%) were the main causes of disease, and DILI was the main cause in the middle-aged group and the elderly group. Among the patients with NAFLD, there were significantly more patients in the youth group than in the elderly group (χ2=16.333, P＜0.001); among the patients with DILI, there were significantly more patients in the middle-aged group than in the youth group (χ2=8.000, P=0.005); among the patients with AILD, there were significantly more patients in the middle-aged group than in the youth group (χ2=8.333, P=0.004). ConclusionMost liver diseases with negative hepatotropic virus can be diagnosed by liver biopsy, and NAFLD, DILI, and AILD are the main causes. Patients with different sexes and ages have different etiologies.
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Objective To investigate the beneficial role of synbiotics in the intestinal microbiota of patients with chronic functional constipation (CFC).Methods According to the inclusion and exclusion criteria,6 patients with CFC were enrolled with their fresh fecal samples collected,after a continuous treatment of one month their fresh fecal samples collected again.Meanwhile,6 healthy volunteers were enrolled as the control group with their fresh fecal samples collected.All samples were transported with ice and stored in -80 ℃ refrigerator,and were analyzed by metagenomics sequencing.Results After 4 weeks of symbiotic treatment,the intestinal microbiota had changed in species in patients with CFC.Bacteria of Escherichia_ coli,Clostridium_ sp._ SS2/1 and Clostridium_ sp._ 7_ 3_ 54FAA,which were rich in the people with constipation,decreased in abundance after the treatment.Bacteria of Lactobacillus_ oris and Bifidobacterium _ animalis,which were rich in the healthy people,increased in content after the treatment.Bacteria of Veillonella_ parvula,Veillonella_ sp._ 6_ 1_ 27,Veillonella_ sp._ 3 _ 1_ 44 which were rich in the healthy people,decreased in content after the treatment.LEfSe analysis showed that Parabacteroides distaso nis,Escherichia_ coli and Enterobacter-cloacae were the specific species of the three groups respectively.Conclusion Synbiotics can change the intestinal microbiota showing therapeutic effect,thus can be used as a novel clinical treatment method.
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60 curved root canals of permanent teeth with angles of curvature ranging from 15°to 40°(Schneider's methodology)were prepared using the instruments of Hyflex CM(HC) and ProTaper(PT) Universal respectively(n=30).Using standardized pre-and post-instrumentation paralleling periapical radiographs,canal curvature was determined by image analysis software and the clinical shaping effect of Hyflex CM and ProTaper rotary NiTi files were compared.The canal curvature in group HC and PT decreased by 4.54°±3.25° and 5.63°±3.84° respectively(between pre-and post-treatment in both groups,P0.05).Hyflex CM can meet the clinical necessity for the instrumentation of curved root canals.
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Cancer stem cells (CSCs) markers are specific molecules to identify CSCs.Recent findings demonstrate that CSCs markers associated with colorectal cancer mainly include CD133,CD29,CD166,CD44,Nanog,etc.These markers can take park in the initiation and progression of cancers by various molecular mechanisms,which have the potential to be used as therapeutic targets as well as prognostic indicators.
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As a member of T-box family,Tbx3 (T-box3) is widely expressed in multiple organs and involves in the development of breast,limb,heart,eye,lung and pancreas during embryonic development stage.Moreover,Tbx3 plays an important role in maintaining the embryonic stem cells.Recent studies show that Tbx3 can work as a transcription factor to participate in the initiation and progression of tumor by epithelialmesenchymal transition,induction tumor stemness and methylation.A better understanding of Tbx3 will provide new insights into genetic diagnosis and targeted treatment of tumor.
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Objective To investigate the correlation between the Periostin and Epithelial-Mesenchymal Transition(EMT) markers(E-cadheirn and N-cadheirn) in colorectal cancer(CRC),and analyze the relationship between the expression of Periostin and clinicopathological parameters.Methods The expression of Periostin,Ecadheirn and N-cadheirn in 106 cases with primary CRC tumors and corresponding normal tissues were detected by Immunohistoehemistry and the results were analyzed.Results The expression of Periostin,E-cadheirn and N-cad-heirn in tumors were significantly high expression than those in corresponding normal tissues(62/106 vs 21/106,x2 =34.027,P ＜ 0.05 ;43/106 vs 89/106,x2 =42.480,P ＜ 0.05 ; 66/106 vs 19/106,x2 =43.382,P ＜ 0.05).The expression of Periostin in tumors was associated significantly with tumor differentiation,tumor invasion,lymph node metastasis and distance metastasis (x2 =7.752,P =0.007; x2 =5.008,P =0.031 ; x2 =10.227,P =0.002;x2 =8.001,P =0.006).It was negatively correlated with E-cadherin expression (r =-0.435,P ＜ 0.001),but positively correlated with N-cadherin expression (r =0.213,P =0.028).Conclusion Periostin may promote the occurrence and development of CRC by participating in EMT program.
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Objective To detect the expressions of Y-box-binding protein-1(YB-1)and epithelial-mesenchymal transition(EMT)markers(E-cadherin and N-cadherin)in colorectal cancer(CRC),to analyze the relationship between the expression of YB-1 and clinicopathological parameters,to evaluate the correlations among YB-1,E-cadherin and N-cadherin. Methods The expressions of YB-1,E-cadherin and N-cadherin in 120 primary CRC tumors and corresponding normal tissues were detected by western blot and immunohistochem-istry and the results were analyzed. Results The expressions of YB-1,E-cadherin and N-cadherin in tumors were significantly different from those in corresponding normal tissues(χ2 = 47. 373,P ﹤ 0. 05;χ2 = 83. 145, P ﹤ 0. 05;χ2 = 41. 832,P ﹤ 0. 05). The expression of YB-1 in tumors was associated significantly with tumor differentiation,tumor invasion,lymph node metastasis and distance metastasis(χ2 = 8. 077,P = 0. 008;χ2 =8. 178,P = 0. 006;χ2 = 15. 152,P ﹤ 0. 001;χ2 = 7. 368,P = 0. 011). It was negatively correlated with E-cadherin expression(r = - 0. 238,P = 0. 009),but positively correlated with N-cadherin expression(r =0. 361,P ﹤ 0. 001). Conclusion YB-1 may promote the occurrence and development of CRC by participating in EMT program.
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Objective To clarify the anatomical and pathlogical implications of Denonvilliers' fascia.Method In this study,thirty pelvic specimens (17 males and 13 females) were incised through the median sagittal plane and carried for regional anatomy study; Denonvilliers' fascia was identified by immunohistochemistry.Results Denonvilliers' fascia could be found in all male specimens:it had an anterior leaf and a posterior leaf,with the anterior one attaching to seminal vesicle,seminiferous duct,prostate and the bottom of bladder firmly.The fascia originated at the fold of the peritoneum and ended at the perineum fascia,fusing into the pelvic parietal fascia laterally.It was not obvious in females,only to find a thin and transparent membrane between vagina and rectum.The maximum height of Denonvilliers' fascia in left pelvis was (3.2 ± 0.3) cm,compared with (3.3 ± 0.3) cm in the right pelvis (t =0.965,P ＞ 0.05).Immunohistochemistry study revealed that there was no lymph node in the fascia and its lateral parts were enriched of nerve fibers,which were few in its middle part.Conclusions The unique anatomical and pathlogical characteristics of Denonvilliers' fascia are of vital importance to the avoidance of nerve injury during rectal surgery.
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In the process of epithelial-mesenchymal transition (EMT),cell-cell adherence is disrupted,apico-basal polarity is lost,the ability of anti-apoptosis,migration and invasion is acquired.Y-box-binding protein 1 (YB-1) is a member of the cold-shock protein superfamily,containing a structurally and functionally conserved cold shock domain.Studies indicate that YB-1 can promote the occurrence and development of tumors by regulating EMT.In the process of EMT mediated by YB-1,various transcription factors and signal pathways play important roles.
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Objective To explore the correlativity between liver shear-wave velocities and liver fibrosis stages in chronic hepatitis B patients.Methods One hundred and twelve patients with chronic hepatitis B accepted virtual touch tissue quantification (VTQ) testing to obtain shear-wave speed and compared to histological stages.Each patient received VTQ measurements in right lobe of liver.The standards of histological examination of the stages of fibrosis refered to the Hepatitis Pathology Diagnostic Standard Xi'an formulated in 2000.Results Of 112 patients,S0,S1,S2,S3 and S4 were 15,17,15,23 and 42 respectively.There was no significant statistically difference of the mean values of liver shear-wave speed between S0 and S1,while among the rest subgroup had significant statistically differences by multiple comparisons.The areas under the ROC curves were 0.94 for S2,0.87 for S3,and 0.95 for S4.The cut-off values of the shear wave velocity were as follows:1.27 m/s for S2(sensitivity 80.0％,specificity 89.5％),1.43 m/s for S3 (sensitivity 71.8 ％,specificity 87.7 ％ ) and 1.79 m/s for S4 (sensitivity 83.3 ％,specificity 89.4％).Hepatic fibrosis expressed by the histological scale correlated well with the VTQ values of all patients ( r =0.92).Conclusions Along with the increase of liver fibrosis degree,the hepatic parenchyma shear wave velocities increase gradually.The more advanced the degree of fibrosis,the higher the shear wave velocities.
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Objective To study the function of core protein (CORE) of genotype 1b hepatitis C virus (HCV) of different strains (T: derived from tumor tissues; NT: derived from non-tumor tissues; C191: HCV-J6) and different domains (1-172, 1-126, 1-58, 59-126, 127-172 AA) of T CORE in the pathogenesis of HCV infection and to find the therapy target. Methods Different truncated genotype 1b HCV CORE eukaryotic expression plasmids (T, NT, C191) and different domains of T CORE were constructed and transfected to HepG2 cells. Cell apoptosis and necrosis were quantified by flow cytometry. Cell growth curves were observed with real time cell growth instrument. Results COREs from different strains of genotype 1b and different domains of CORE induced cell apoptosis and necrosis, and inhibited HepG2 cell growth at different levels. CORE derived from T induced apoptosis and necrosis and inhibited cell growth higher than that derived NT and C191. N terminal 1-58 AA of CORE derived from T induced cell apoptosis and necrosis and inhibited cell growth higher than any other domains. Conclusion COREs from different strains of genotype 1b HCV and different domains of CORE from the same HCV strain play different roles in their molecular pathogenesis of HCV. Among different domains of CORE, N terminal 1-58 AA might play an important role in its pathogenesis and be one target of gene therapy.
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Objective To study the pathogenesis mechanism of hepatitis C vires (HCV) core protein (CORE), the subcellular localization of different truncated genotype 1b HCV CORE was observed. Methods HepG2 cells were transiently transfected with the enhanced green fluorescence protein (EGFP-CORE) recombinant plasmids, which expresses EGFP and COREs from three different genotype lb HCV strains and different truncated COREs from one HCV strain. The localizations of different truncated COREs was analyzed by the laser scanning confocal microscope and fluorescence microscope. Results N terminal 1-172 an of different HCV strains of genotype 1b expressed mainly in cytoplasm. Among the different truncated COREs, the longer of the CORE containing N terminal, the more expressed in cytoplasm. The N terminal 1-58 aa mainly expressed in nucleus. CORE of 59-126 aa and 127-172 aa expressed both in cytoplasm and nucleus. Conclusion The different localizations of different truncated COREs might have some relationships with their functions in pathogenesis.
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Objective To compare the clinical efficacy and tolerability of 0 75% ropivacaine(8～10ml) versus 1% lidocaine plus 0 2% dicaine in epidural anesthesia cesarean section.Method Parturients for elective cesarean were randomly designed to receive 0 75% ropivacaine(groupⅠ,n=15) or 1%lidocaine plus 0 2% dicaine(groupⅡ,n=15) epidural anesthesia. Sensory block,intraoperative pain(VAS score) and abdominal wall relaxation were assessed together with adverse reaction. Results The percentage of sensory block to reach T6 level was higher in groupⅠ than that in groupⅡ(P