[摘 要] 目的：探究吉马酮通过叉头盒蛋白O3（FOXO3）-FOX亚类M1转录因子（FOXM1）信号通路调控人甲状腺癌细胞BCPAP和多柔比星（DOX）耐药BCPAP细胞（BCPAP/DOX）的增殖、迁移和化疗耐药。方法:常规培养BCPAP细胞，用BCPAP细胞构建BCPAP/DOX细胞，用MTT法检测不同浓度吉马酮对BCPAP和BCPAP/DOX细胞增殖的影响。将BCPAP和BCPAP/DOX细胞分为Ctrl组（空白对照）、sh-NC组（转染sh-NC质粒）、低浓度吉马酮组（0.10 mmol/L）、高浓度吉马酮组（0.15 mmol/L）、高浓度吉马酮（0.15 mmol/L） + sh-FOXO3组（转染sh-FOXO3质粒），用转染试剂将sh-NC质粒和sh-FOXO3质粒转至相应的BCPAP和BCPAP/DOX细胞中。用CCK-8法、划痕愈合实验和WB法分别检测各组细胞的增殖、迁移能力，以及FOXO3、FOXM1、BAX、MMP-9和多药耐药-1（MDR-1）蛋白的表达。结果:在BCPAP和BCPAP/DOX细胞中成功地敲减了FOXO3的表达，低浓度和高浓度吉马酮均可显著抑制BCPAP和BCPAP/DOX细胞的增殖、迁移能力，降低细胞中FOMX1、MMP-9或MDR-1（BCPAP/DOX细胞）蛋白的表达，提升FOXO3和BAX蛋白的表达（均P < 0.05），与低浓度比较，高浓度吉马酮的作用更为显著（均P < 0.05），敲减FOXO3后可部分逆转吉马酮对这两种细胞的作用（均P < 0.05）。结论:吉马酮可能通过FOXO3/FOXM1信号通路调控BCPAP和BCPAP/DOX细胞的增殖和迁移能力，降低BCPAP/DOX细胞化疗耐药性。

Objective To observe the clinical efficacy of Shen Shuai Ⅱ Granules combined with integrated Western medicine therapy in patients with primary chronic kidney disease(CKD)in stages 3-4 with the syndrome of spleen and kidney qi deficiency,dampness turbidity and blood stasis,and its effects on expression of serum autophagy related proteins.Methods Totally 88 patients were randomly divided into treatment group and control group,with 44 cases in each group.Both groups were given an integrated Western medicine therapy.On this basis,the treatment group was given Shen Shuai Ⅱ Granules,while the control group was given Shen Shuai Ⅱ placebo,1 bag at a time,twice a day,orally.The treatment for both groups lasted for 24 weeks.The clinical efficacy of the two groups was observed.The TCM symptom scores,serum creatinine(Scr),blood urea nitrogen(BUN),uric acid(UA),blood calcium(Ca2+),blood phosphorus(P3-),parathyroid hormone(PTH),and 24-hour urinary protein quantification(24 UPro)before and after treatment were compared in the two groups.The serum levels of autophagy related protein Beclin-1,Atg7,and LC3-Ⅱ were detected by ELISA before and after treatment in the two groups.Safety indexes of both groups were monitored.Results During the treatment,4 cases fell off in the treatment group and 4 cases in the control group.The total effective rate in the treatment group was 55％(22/40),while that in the control group was 30％(12/40).The therapeutic effect in the treatment group was better than that in the control group(P<0.01).Compared with before treatment,the TCM symptom scores in the treatment group decreased after treatment(P<0.01),the levels of Scr,BUN,UA,P3-,PTH,and 24 UPro decreased(P<0.05,P<0.01),while eGFR increased(P<0.01).The levels of Scr in the control group increased(P<0.05),while eGFR decreased(P<0.01).After treatment,the treatment group had lower various TCM symptom scores,Scr,BUN,UA,P3-,PTH,and 24 UPro levels than the control group(P<0.01,P<0.05),and higher eGFR than the control group(P<0.01).Compared with before treatment,the serum levels of Beclin-1,Atg7,and LC3-Ⅱ increased in the treatment group after treatment(P<0.01,P<0.05),while the serum level of Beclin-1 decreased in the control group after treatment(P<0.01).After treatment,the improvement of the above indicators in the treatment group were better than those in the control group(P<0.01,P<0.05).Correlation analysis showed that Beclin-1,Atg7,and LC3-Ⅱ were negatively correlated with Scr and BUN(P<0.05),and positively correlated with eGFR(P<0.05).There was no obvious adverse reaction in both groups.Conclusion The combination of Shen Shuai Ⅱ Granules and integrated Western medicine therapy for the treatment of primary CKD in stages 3-4 with the syndrome of spleen and kidney qi deficiency,dampness turbidity and blood stasis has confirmed efficacy,which can effectively alleviate clinical symptoms,improve renal function,and delay the progression of CKD.The mechanism may be related to improving the level of autophagy in renal.

Objective:To investigate the current status of endoscopic treatment for gastroesophageal varices in portal hypertension in China, and to provide supporting data and reference for the development of endoscopic treatment.Methods:In this study, initiated by the Liver Health Consortium in China (CHESS), a questionnaire was designed and distributed online to investigate the basic condition of endoscopic treatment for gastroesophageal varices in portal hypertension in 2022 in China. Questions included annual number and indication of endoscopic procedures, adherence to guideline for preventing esophagogastric variceal bleeding (EGVB), management and timing of emergent EGVB, management of gastric and isolated varices, and improvement of endoscopic treatment. Proportions of hospitals concerning therapeutic choices to all participant hospitals were calculated. Guideline adherence between secondary and tertiary hospitals were compared by using Chi-square test.Results:A total of 836 hospitals from 31 provinces (anotomous regions and municipalities) participated in the survey. According to the survey, the control of acute EGVB (49.3%, 412/836) and the prevention of recurrent bleeding (38.3%, 320/836) were major indications of endoscopic treatment. For primary [non-selective β-blocker (NSBB) or endoscopic therapies] and secondary prophylaxis (NSBB and endoscopic therapies) of EGVB, adherence to domestic guideline was 72.5% (606/836) and 39.2% (328/836), respectively. There were significant differences in the adherence between secondary and tertiary hospitals in primary prophylaxis of EGVB [71.0% (495/697) VS 79.9% (111/139), χ2=4.11, P=0.033] and secondary prophylaxis of EGVB [41.6% (290/697) VS 27.3% (38/139), χ2=9.31, P=0.002]. A total of 78.2% (654/836) hospitals preferred endoscopic therapies treating acute EGVB, and endoscopic therapy was more likely to be the first choice for treating acute EGVB in tertiary hospitals (82.6%, 576/697) than secondary hospitals [56.1% (78/139), χ2=46.33, P<0.001]. The optimal timing was usually within 12 hours (48.5%, 317/654) and 12-24 hours (36.9%, 241/654) after the bleeding. Regarding the management of gastroesophageal varices type 2 and isolated gastric varices type 1, most hospitals used cyanoacrylate injection in combination with sclerotherapy [48.2% (403/836) and 29.9% (250/836), respectively], but substantial proportions of hospitals preferred clip-assisted therapies [12.4% (104/836) and 26.4% (221/836), respectively]. Improving the skills of endoscopic doctors (84.2%, 704/836), and enhancing the precision of pre-procedure evaluation and quality of multidisciplinary team (78.9%, 660/836) were considered urgent needs in the development of endoscopic treatment. Conclusion:A variety of endoscopic treatments for gastroesophageal varices in portal hypertension are implemented nationwide. Participant hospitals are active to perform emergent endoscopy for acute EGVB, but are inadequate in following recommendations regarding primary and secondary prophylaxis of EGVB. Moreover, the selection of endoscopic procedures for gastric varices differs greatly among hospitals.

Randomized controlled trial (RCT) are considered the "gold standard" for evaluating the causal effects of interventions on outcome measures. However, due to high research costs and ethical constraints, conducting RCT in clinical practice, especially in the surgical field, faces numerous challenges such as difficulties in subject recruitment, implementation of blinding, and standardization of interventions. In such cases, using real-world data to perform causal inference under the framework of target trial emulation (TTE), based on the principles of RCT design, helps to identify and reduce biases arising from design flaws in traditional observational studies, such as immortal time bias, confounding, selection bias, or collider bias. This approach can produce high-quality evidence comparable to that of RCT, thereby enhancing the clinical guidance value of real-world data studies. However, TTE has limitations, such as the inability to completely eliminate confounding, high quality requirements for source data, and the current lack of reporting standards. Therefore, researchers should be fully aware of these limitations to avoid making incorrect causal inferences. This article intends to provide an overview of the TTE framework, implementation points, application scope, application cases, and advantages and disadvantages of the framework.

Objective:To assess the value of serum tumor specific protein 70 (SP70) for prognostic stratification in acute myeloid leukemia (AML).Methods:A cohort study design was adopted. 129 newly diagnosed AML patients from September 2022 to January 2024 at the Hematology Department of the First Affiliated Hospital of Nanjing Medical University were included, as well as a control group consisted of 120 healthy individuals and 7 cases with benign hematologic diseases during the same period (total 127 cases). Clinical data were collected from Electronic Medical Records. According to the 2023 edition of the Chinese Leukemia Diagnosis and Treatment Guidelines, AML patients with good or moderate prognosis were categorized as low-to-intermediate risk, while those with poor prognosis were high-risk group. Univariate and multivariate logistic regression analyses were used to identify variables significantly associated with AML prognostic risk. ROC analysis was used to evaluate diagnostic performance. A nomogram for predicting patient prognostic risk was constructed by R 4.0.2 software, and the internal validation was performed using bootstrapping.Results:Among 129 AML patients, there were 71 males (55.0%) and 58 females (45.0%), with 42 (32.6%) classified as high-risk and 87 (67.4%) as low-intermediate risk. The high-risk group had a significantly higher median age [62 (48, 67) years] compared to the low-intermediate risk group [50 (35, 63) years, Z=-2.381, P=0.017], and a significantly higher proportion of males (30 patients, 71.4%) compared to the low-intermediate risk group (41 patients, 47.1%, χ 2=6.760, P=0.009). Multivariate logistic regression analysis indicated that serum SP70 ( OR=2.54, 95% CI: 1.68-3.84, P<0.001), hemoglobin (HB) ( OR=0.96, 95% CI: 0.93-0.99, P<0.05), and bone marrow blast (BM blast) ( OR=1.07, 95% CI: 1.02-1.13, P<0.05) were independent risk factors for high-risk prognosis in AML patients. ROC analysis showed that the area under the curve (AUC) for SP70 predicting high-risk patients was 0.908 (cut-off value of 5.74 ng/ml, 95% CI: 0.845-0.952, sensitivity 90.5%, specificity 82.8%). The combined model of serum SP70, HB, and BM blasts had an AUC of 0.931 (95% CI: 0.890-0.973); C-index=0.925 (95% CI: 0.876-0.963),with no statistically significant difference compared to serum SP70 alone ( Z=1.693, P>0.05). Conclusion:Serum SP70 may be a promising non-invasive molecular biomarker for prognostic stratification in AML.

Objective:To assess the value of serum tumor specific protein 70 (SP70) for prognostic stratification in acute myeloid leukemia (AML).Methods:A cohort study design was adopted. 129 newly diagnosed AML patients from September 2022 to January 2024 at the Hematology Department of the First Affiliated Hospital of Nanjing Medical University were included, as well as a control group consisted of 120 healthy individuals and 7 cases with benign hematologic diseases during the same period (total 127 cases). Clinical data were collected from Electronic Medical Records. According to the 2023 edition of the Chinese Leukemia Diagnosis and Treatment Guidelines, AML patients with good or moderate prognosis were categorized as low-to-intermediate risk, while those with poor prognosis were high-risk group. Univariate and multivariate logistic regression analyses were used to identify variables significantly associated with AML prognostic risk. ROC analysis was used to evaluate diagnostic performance. A nomogram for predicting patient prognostic risk was constructed by R 4.0.2 software, and the internal validation was performed using bootstrapping.Results:Among 129 AML patients, there were 71 males (55.0%) and 58 females (45.0%), with 42 (32.6%) classified as high-risk and 87 (67.4%) as low-intermediate risk. The high-risk group had a significantly higher median age [62 (48, 67) years] compared to the low-intermediate risk group [50 (35, 63) years, Z=-2.381, P=0.017], and a significantly higher proportion of males (30 patients, 71.4%) compared to the low-intermediate risk group (41 patients, 47.1%, χ 2=6.760, P=0.009). Multivariate logistic regression analysis indicated that serum SP70 ( OR=2.54, 95% CI: 1.68-3.84, P<0.001), hemoglobin (HB) ( OR=0.96, 95% CI: 0.93-0.99, P<0.05), and bone marrow blast (BM blast) ( OR=1.07, 95% CI: 1.02-1.13, P<0.05) were independent risk factors for high-risk prognosis in AML patients. ROC analysis showed that the area under the curve (AUC) for SP70 predicting high-risk patients was 0.908 (cut-off value of 5.74 ng/ml, 95% CI: 0.845-0.952, sensitivity 90.5%, specificity 82.8%). The combined model of serum SP70, HB, and BM blasts had an AUC of 0.931 (95% CI: 0.890-0.973); C-index=0.925 (95% CI: 0.876-0.963),with no statistically significant difference compared to serum SP70 alone ( Z=1.693, P>0.05). Conclusion:Serum SP70 may be a promising non-invasive molecular biomarker for prognostic stratification in AML.

Objective:To compare the differences in the prevalence of mild micro-hepatic encephalopathy (MHE) among patients with cirrhosis by using the psychometric hepatic encephalopathy score (PHES) and the Stroop smartphone application (Encephal App) test.Methods:This prospective, multi-center, real-world study was initiated by the National Clinical Medical Research Center for Infectious Diseases and the Portal Hypertension Alliance and registered with International ClinicalTrials.gov (NCT05140837). 354 cases of cirrhosis were enrolled in 19 hospitals across the country. PHES (including digital connection tests A and B, digital symbol tests, trajectory drawing tests, and serial management tests) and the Stroop test were conducted in all of them. PHES was differentiated using standard diagnostic criteria established by the two studies in China and South Korea. The Stroop test was evaluated based on the criteria of the research and development team. The impact of different diagnostic standards or methods on the incidence of MHE in patients with cirrhosis was analyzed. Data between groups were differentiated using the t-test, Mann-Whitney U test, and χ2 test. A kappa test was used to compare the consistency between groups. Results:After PHES, the prevalence of MHE among 354 cases of cirrhosis was 78.53% and 15.25%, respectively, based on Chinese research standards and Korean research normal value standards. However, the prevalence of MHE was 56.78% based on the Stroop test, and the differences in pairwise comparisons among the three groups were statistically significant (kappa = -0.064, P < 0.001). Stratified analysis revealed that the MHE prevalence in three groups of patients with Child-Pugh classes A, B, and C was 74.14%, 83.33%, and 88.24%, respectively, according to the normal value standards of Chinese researchers, while the MHE prevalence rates in three groups of patients with Child-Pugh classes A, B, and C were 8.29%, 23.53%, and 38.24%, respectively, according to the normal value standards of Korean researchers. Furthermore, the prevalence rates of MHE in the three groups of patients with Child-Pugh grades A, B, and C were 52.68%, 58.82%, and 73.53%, respectively, according to the Stroop test standard. However, among the results of each diagnostic standard, the prevalence of MHE showed an increasing trend with an increasing Child-Pugh grade. Further comparison demonstrated that the scores obtained by the number connection test A and the number symbol test were consistent according to the normal value standards of the two studies in China and South Korea ( Z = -0.982, -1.702; P = 0.326, 0.089), while the other three sub-tests had significant differences ( P < 0.001). Conclusion:The prevalence rate of MHE in the cirrhotic population is high, but the prevalence of MHE obtained by using different diagnostic criteria or methods varies greatly. Therefore, in line with the current changes in demographics and disease spectrum, it is necessary to enroll a larger sample size of a healthy population as a control. Moreover, the establishment of more reliable diagnostic scoring criteria will serve as a basis for obtaining accurate MHE incidence and formulating diagnosis and treatment strategies in cirrhotic populations.

Fibrosis is a repair response initiated by tissues and organs after injury, and is a self-protection mechanism of the body. It has been found that endothelium-to-interstitial transdifferentiation (EndMT) is involved in the physiological and pathological processes of various organ fibrosis, which has become a focus of the research on fibrotic diseases. In recent years, the study has found that EndMT plays an important role in many pathological processes in cardiovascular system, lungs, kidneys, liver, pancreas fibrosis, and so on. This article summarizes EndMT regulatory mechanism and its role in each organ fibrosis, as well as the related treatment progress of EndMT targets, so as to provide new targets for prevention and control of organ fibrosis.

Objective:To investigate the diagnostic accuracy of serological indicators and evaluate the diagnostic value of a new established combined serological model on identifying the minimal hepatic encephalopathy (MHE) in patients with compensated cirrhosis.Methods:This prospective multicenter study enrolled 263 compensated cirrhotic patients from 23 hospitals in 15 provinces, autonomous regions and municipalities of China between October 2021 and August 2022. Clinical data and laboratory test results were collected, and the model for end-stage liver disease (MELD) score was calculated. Ammonia level was corrected to the upper limit of normal (AMM-ULN) by the baseline blood ammonia measurements/upper limit of the normal reference value. MHE was diagnosed by combined abnormal number connection test-A and abnormal digit symbol test as suggested by Guidelines on the management of hepatic encephalopathy in cirrhosis. The patients were randomly divided (7∶3) into training set ( n=185) and validation set ( n=78) based on caret package of R language. Logistic regression was used to establish a combined model of MHE diagnosis. The diagnostic performance was evaluated by the area under the curve (AUC) of receiver operating characteristic curve, Hosmer-Lemeshow test and calibration curve. The internal verification was carried out by the Bootstrap method ( n=200). AUC comparisons were achieved using the Delong test. Results:In the training set, prevalence of MHE was 37.8% (70/185). There were statistically significant differences in AMM-ULN, albumin, platelet, alkaline phosphatase, international normalized ratio, MELD score and education between non-MHE group and MHE group (all P<0.05). Multivariate Logistic regression analysis showed that AMM-ULN [odds ratio ( OR)=1.78, 95% confidence interval ( CI) 1.05-3.14, P=0.038] and MELD score ( OR=1.11, 95% CI 1.04-1.20, P=0.002) were independent risk factors for MHE, and the AUC for predicting MHE were 0.663, 0.625, respectively. Compared with the use of blood AMM-ULN and MELD score alone, the AUC of the combined model of AMM-ULN, MELD score and education exhibited better predictive performance in determining the presence of MHE was 0.755, the specificity and sensitivity was 85.2% and 55.7%, respectively. Hosmer-Lemeshow test and calibration curve showed that the model had good calibration ( P=0.733). The AUC for internal validation of the combined model for diagnosing MHE was 0.752. In the validation set, the AUC of the combined model for diagnosing MHE was 0.794, and Hosmer-Lemeshow test showed good calibration ( P=0.841). Conclusion:Use of the combined model including AMM-ULN, MELD score and education could improve the predictive efficiency of MHE among patients with compensated cirrhosis.

Objective: To explore the relative risks of rotavirus diarrhea after exposure to different levels of atmospheric pressure in children in Guangzhou City, so as to provide reference for improving public awareness of high atmospheric pressure exposure. Methods: The study used the China Notifiable Communicable Diseases Network System and China Meteorological Science Data Sharing Service Network to collect meteorological data and data relating to daily cases of rotavirus diarrhea in children at Guangzhou Women and Children s Medical Center from 2012 to 2020. The association between rotavirus diarrhea and atmospheric pressure was analyzed using distributed lag non linear models (DLNM). The relative risks of different sex and age sub groups exposed to different atmospheric pressures were also evaluated. Results: A total of 18 587 cases of rotavirus diarrhea were reported from 2012 to 2020, among which 11 662 cases (62.7%) were boys, and 12 582 cases (67.7%) were children aged 6 to 24 months old, which represented the highest proportion. The results of the DLNM showed that the relative risk of rotavirus diarrhea was the highest on the day of exposure to extreme high atmospheric pressure ( RR =1.50, 95% CI =1.24-1.82, P <0.05) and the effect could last for 28 days. Risk of rotavirus diarrhea was low for exposure to low pressure within 2 weeks ( P <0.05). During extremely high atmospheric pressure weather, RR was higher in girls ( RR =3.31, 95% CI =1.46-7.49， P <0.05) than that in boys ( RR =1.98, 95% CI =0.96-4.07， P >0.05). Among different age sub groups, RR was the highest in children aged 24 to 60 months after exposure to the highest level of atmospheric pressure exposure ( RR =3.36, 95% CI =1.27-8.89, P <0.05). Conclusion In Guangzhou, exposure to high pressure increases the risk of rotavirus diarrhea in children. In the future, public awareness should be raised regarding the risk after exposure to high atmospheric pressure.