Objective:To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China.Methods:Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed.Results:6 893 patients in CP ( n=6 453, 93.6%) or AP ( n=440, 6.4%) receiving initial imatinib ( n=4 906, 71.2%), nilotinib ( n=1 157, 16.8%), dasatinib ( n=298, 4.3%) or flumatinib ( n=532, 7.2%) -therapy. With the median follow-up of 43 ( IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance ( n=1 055, 15.3%), intolerance ( n=248, 3.6%), pursuit of better efficacy ( n=168, 2.4%), economic or other reasons ( n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph + ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph + ACA, poorer TFS; Ph + ACA, poorer OS. Conclusion:At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

Objective:To compare the value of Liaoning scoring system, model for end-stage liver disease (MELD), model for end-stage liver disease-Na (MELD-Na) and Blatchford score in predicting high-risk esophageal varices (EVs), hemorrhage or re-hemorrhage within 1 year and blood transfusion treatment in cirrhotic patients.Methods:Clinical data of 170 patients with esophageal varices confirmed by endoscopy from January 2018 to September 2019 were recorded. Liaoning score, MELD, MELD-Na score and Blatchford score were calculated when the first endoscopy was performed. These patients were followed up, and hemorrhage or re-hemorrhage within 1 year was recorded. Receiver operating characteristic (ROC) curve was drawn and the area under curve (AUC) was used to evaluate the accuracy of 4 scoring systems in predicting high-risk EVs, hemorrhage or re-hemorrhage within 1 year after the first endoscopy and blood transfusion. Cut-off values were obtained, and groups divided by cut-off values were compared for the proportion of high-risk EVs and hemorrhage or re-hemorrhage.Results:The cut-off value of high-risk EVs in patients with cirrhosis predicted by Liaoning score was 0.45, and the AUC was 0.702 (95% CI:0.612-0.781, P<0.01), superior to MELD, MELD-Na and Blatchford score (AUC were 0.593, 0.648, 0.610, respectively). The proportion of high-risk EVs in Liaoning score ≥0.45 and <0.45 were 71.8% (89/124) and 34.8% (16/46) with significant differences ( χ2=19.442, P<0.01). The AUC of Liaoning score for predicting hemorrhage or re-hemorrhage within 1 year was 0.680 (95% CI: 0.595-0.765, P<0.01), superior to MELD, MELD-Na and Blatchford score (AUC were 0.605,0.615,0.598, respectively). AUC of Blatchford score for predicting blood transfusion was 0.775 (95% CI:0.687-0.863, P<0.01), superior to MELD, MELD-Na and Liaoning score (AUC were 0.653, 0.719, 0.631, respectively). Conclusion:Liaoning score can predict high-risk EVs, hemorrhage or re-hemorrhage within 1 year after the first endoscopy in patients with cirrhosis and is superior to MELD, MELD-Na and Blatchford score. Blatchford score can effectively predict whether cirrhosis patients with EVs need blood transfusion.

Objective:To examine the possibility of the differentiation into islet-like cell clusters from the co-culture system of bone marrow mesenchymal stem cells (BMSCs) and islet cells.Methods:Rat BMSCs from the femur and tibia of Wistar rats were isolated and purified taken under aseptic conditions; the surface markers CD 44 and CD 90 expressions of BMSCs were detected by flow cytometry; and alizarin red staining and oil red O staining were used to identify the cells induced in the osteogenic direction and adipogenic direction, respectively. Rat islet cells from the pancreas of Wistar rats were isolated and purified; and dithiazone staining was performed for validation. The basal insulin level of the culture was detected by ELISA method. 5.6mmol/L (low glucose) and 25.0 mmol/L (high glucosa) glucose were added to the culture, respectively, and insulin release was detected by ELISA. 5-generation BMSCs and islet cells were collected and divided randomly into stem cell culture alone group (stem cell group), stem cell-islet co-culture group (co-culture group), and islet culture alone group (islet group). The morphological changes of BMSCs during co-culture were observed using an inverted phase contrast microscope; basal insulin secretion and insulin secretion stimulated by low and high glucose were tested by ELISA. Insulin protein expression in induced islet-like cell masses in co-culture group were detected by immunocytochemical staining. The ultrastructure of islet-like cells was observed by using transmission electron microscopy. Results:The positive rates of CD 44 and CD 90 were 99.48% and 99.50%, respectively; BMSCs were induced the formation of multiple calcium nodules outside the differentiation cells in the osteogenic direction, and many lipid droplets in the cytoplasm of differentiated cells in the adipogenic direction. Dithiazone staining showed that β cells in pancreatic islet were brown red and about 450 islets could be obtained per pancreas with a mean purity up to 80%. The insulin release in the low sugar group and the high sugar group were (7.105±1.551) mIU/ml and (20.231±1.592) mIU/ml, respectively, with a statistically significant difference ( P<0.05). It can be seen that local stem cells began to gather and grow upward into small clumps in the budding manner until finally forming a spherical islet-like cell cluster structure after 7 days of culture in the co-culture group. The basal insulin secretion in the stem cell group was <0.5 mIU/L. In the islet group, insulin secretion peaked on the 5th day and then gradually decreased to about 20% of the highest value on the 13th day. The insulin level of the co-culture group peaked on the 5th day, and the 13th day remained at about 40% of the peak level. There were statistically significant differences on basal insulin secretion on the 8th, 10th and 13th day between islet group and co-culture group (all P value >0.05). There was no statistically significant difference between the insulin release by islet in islet group under the stimulation of low and high sugar and that by islet-like cell cluster in co-culture group. There were a large number of brownish-yellow granules in the islet-like cell clusters after the co-culture for 14 days; and there were more secretory granules and coarse endoplasmic reticulum in the ultrastructure, showing more active protein secretion functions. Conclusions:The co-culture system of BMSCs and islet cells could induce BMSCs into differentiating into islet-like cell clusters, which can express insulin protein and had relatively mature function of insulin secretion.

Objective: To assess the relationship between body mass index (BMI) and mortality in adults of Shanxi, China. Methods: Baseline data were from the '2002 China Nutrition and Health Survey’ in Shanxi province. All the death-related investigation and follow-up visits were carried out from December 2015 to March 2016. The follow-up program covered 5 360 people from all the 7 007 participants aged 18 years and over that having complete core information, with a rate as 76.5%. Participants of this study were divided into eight groups, according to the appearance of BMI. Taking the group with the lowest mortality density as the reference group, Cox regression model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of deaths by the whole population, gender and age groups (≥60 years, <60 years). Results were then adjusted by age, gender, smoking, alcohol use and education level from the baseline survey. Sensitivity analysis was also conducted. Results: Results from the study showed that among the total number of 67 129 person- years from the average period of 12.5 years, there were 615 deaths occurred, with the mortality density as 916 per 100 000 person-years. Taking the BMI range of 26.0-27.9 kg/m² as the reference, the aHRs of death increased to 1.90 (95%CI: 1.26-2.86), 1.68 (95%CI: 1.15-2.45), 1.49 (95%CI: 1.08-2.06) and 1.72 (95%CI: 1.07-2.76) after the multivariate adjustment, in these four groups (BMI<18.5, 18.5-19.9, 22.0-23.9 and ≥30.0 kg/m²), respectively. Low body weight (BMI<18.5 kg/m²) was associated with higher risks of death in the elderly of ≥60 years, with the aHR of death as 1.94 (95%CI: 1.20-3.15). Conclusions When BMI appeared as ≤19.9 kg/m², 22.0-23.9 kg/m² and ≥30.0 kg/m², the risks of death would increase. In addition to programs that focusing on obesity, special attention should be paid to the high risk of mortality which was caused by low-weight and malnutrition in the elderly.

The correct differentiation of oligodendrocyte precursor cells (OPCs) is essential for the myelination and remyelination processes in the central nervous system. Determining the regulatory mechanism is fundamental to the treatment of demyelinating diseases. By analyzing the RNA sequencing data of different neural cells, we found that cyclin-dependent kinase 18 (CDK18) is exclusively expressed in oligodendrocytes. In vivo studies showed that the expression level of CDK18 gradually increased along with myelin formation during development and in the remyelination phase in a lysophosphatidylcholine-induced demyelination model, and was distinctively highly expressed in oligodendrocytes. In vitro overexpression and interference experiments revealed that CDK18 directly promotes the differentiation of OPCs, without affecting their proliferation or apoptosis. Mechanistically, CDK18 activated the RAS/mitogen-activated protein kinase kinase 1/extracellular signal-regulated kinase pathway, thus promoting OPC differentiation. The results of the present study suggest that CDK18 is a promising cell-type specific target to treat demyelinating disease.

Objective To observe the effects of adenosine preconditioning on the intestinal inflammatory response,the damaged mucosal tissue and apoptosis of intestinal epithelial cells in rats with abdominal open injury coupled with seawater immersion.Methods Sixty male Wistar rats with abdominal open injury were randomly divided into 3 groups,each consisting of 20 animals.The animals in group A had 0.9％ sodium chloride solution immersion + caudal vein injection of sterilization water (3 mg/kg).The animals in group B received seawater immersion + caudal vein injection of sterile water (3 mg/kg) and the animals in group C were given seawater immersion + caudal vein injection of adenosine pretreatment (3 mg/kg).All animals were sacrificed 6 hours after immersion.Pathological changes in intestinal mucosa were closely observed by histopathology.Levels of TNF-α and IL-6 were detected by enzyme-linked immunosorbent assay (ELISA).Caspase-3 protein was detected by immunohistochemistry.Apoptosis of the cells in intestinal mucosa were monitored by TUNEL method.Results The intestinal pathological scores of TNF-α and IL-6 for the animals in group B(3.98 ±0.41)were significantly higher than those in group A (2.46 ±0.39) (P ＜0.01).The TNF-α and IL-6 levels for the animals in group B [(2.38 ±0.39) μg/L and(883.11 ±34.22) ng/L] were significantly increased,as compared with those in group A [(1.01 ± 0.06) μg/L and (258.09 ± 6.52) ng/L] (P ＜ 0.01).The TNF-α and IL-6 levels for the animals in group C[(1.88 ± 0.21)pg/L and (582.13 ±19.44)ng/L] were significantly decreased,as compared with those in group B (P ＜ 0.01).The level of Caspase-3 and percentage of apoptotic cells in the intestinal mucosa of the animals in group B [(27.9 ± 4.3) ％ and (24.5 ± 3.1) ％]were significantly higher than those of the animals in group A [(13.8 ± 2.6) ％ and (16.4 ± 2.3) ％] (P ＜0.01),and the expression level of Caspase-3 and percentage of apoptotic cells of the animals in group C [(20.2 ± 3.4) ％ and (19.9 ± 2.9) ％] were significantly lower than those of the animals in group B (P ＜ 0.01).Conclusions Adenosine pretreatment could significantly improve intestinal mucosal inflammatory response in seawater immersion rats coupled with open abdominal open injury,alleviate the destruction of intestinal epithelial structure,and reduce apoptosis of intestinal mucosal epithelial cells.

Objective To observe the effects of adenosine preconditioning on gastric mucosal tissue destruction,inflammatory response and apoptosis of epithelial cells in rats with abdominal open injury coupled with seawater immersion.Methods Sixty male Wistar rats with abdominal open injury were randomly divided into 3 groups,each consisting of 20 animals.The animals in group A were treated with abdominal open injury + caudal vein injection of sterile water (3 mg/kg).The animals with abdominal open injury in group B received seawater immersion + caudal vein injection of sterile water (3 mg/kg),and the animals with abdominal open injury in group C were given seawater immersion + caudal vein injection of adenosine (3 mg/kg).All the animals were treated either with caudal vein injection of sterile water or adenosine at a dosage of 3 mg/kg 60 minutes before surgery,and were sacrificed 6 hours after immersion.Gastric mucosal ulcer index (UI) was calculated in the animals of all the groups.Pathological changes in gastric mucosa were closely observed under light microscopy.The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in the gastric mucosa of various groups were detected by enzyme-linked immunosorbent assay (ELISA),the expression levels of Caspase-3 in gastric mucosa were detected by immunohistochemistry,and apoptosis of the cells in intestinal mucosa were monitored by TUNEL method.Results The UI,the levels of TNF-α and IL-6,and the pathological damage of gastric mucosa in group B were all significantly higher than those in group A (P＜0.01) and group C (P ＜0.05).The expression level of Caspase-3 (25.2％ ±3.6％) and the percentage of apoptosis cells (27.3％ ± 2.4％) in group B were significantly higher than those in group A (10.3％ ±1.4％ and 9.4％ ± 1.8％) (P ＜0.01),and the expression level of Caspase-3 of group C (19.4％ ±2.6％ and 21.9％ ± 2.6％) were signficantly lower than those of group B (P ＜0.05).Conclusions Adenosine pretreatment could effectively protect gastric mucosal epithelial inflammatory response in seawater immersion rats coupled with open abdominal injury,inhibit the secretion of inflammatory factors,alleviate gastric mucosal inflammatory response and reduce apoptosis of gastric mucosal epithelial cells.

Objective To observe the effects of adenosine preconditioning on the intestinal inflammatory response,the damaged mucosal tissue and apoptosis of intestinal epithelial cells in rats with abdominal open injury coupled with seawater immersion.Methods Sixty male Wistar rats with abdominal open injury were randomly divided into 3 groups,each consisting of 20 animals.The animals in group A had 0.9％ sodium chloride solution immersion + caudal vein injection of sterilization water (3 mg/kg).The animals in group B received seawater immersion + caudal vein injection of sterile water (3 mg/kg) and the animals in group C were given seawater immersion + caudal vein injection of adenosine pretreatment (3 mg/kg).All animals were sacrificed 6 hours after immersion.Pathological changes in intestinal mucosa were closely observed by histopathology.Levels of TNF-α and IL-6 were detected by enzyme-linked immunosorbent assay (ELISA).Caspase-3 protein was detected by immunohistochemistry.Apoptosis of the cells in intestinal mucosa were monitored by TUNEL method.Results The intestinal pathological scores of TNF-α and IL-6 for the animals in group B(3.98 ±0.41)were significantly higher than those in group A (2.46 ±0.39) (P ＜0.01).The TNF-α and IL-6 levels for the animals in group B [(2.38 ±0.39) μg/L and(883.11 ±34.22) ng/L] were significantly increased,as compared with those in group A [(1.01 ± 0.06) μg/L and (258.09 ± 6.52) ng/L] (P ＜ 0.01).The TNF-α and IL-6 levels for the animals in group C[(1.88 ± 0.21)pg/L and (582.13 ±19.44)ng/L] were significantly decreased,as compared with those in group B (P ＜ 0.01).The level of Caspase-3 and percentage of apoptotic cells in the intestinal mucosa of the animals in group B [(27.9 ± 4.3) ％ and (24.5 ± 3.1) ％]were significantly higher than those of the animals in group A [(13.8 ± 2.6) ％ and (16.4 ± 2.3) ％] (P ＜0.01),and the expression level of Caspase-3 and percentage of apoptotic cells of the animals in group C [(20.2 ± 3.4) ％ and (19.9 ± 2.9) ％] were significantly lower than those of the animals in group B (P ＜ 0.01).Conclusions Adenosine pretreatment could significantly improve intestinal mucosal inflammatory response in seawater immersion rats coupled with open abdominal open injury,alleviate the destruction of intestinal epithelial structure,and reduce apoptosis of intestinal mucosal epithelial cells.

Objective To observe the effects of adenosine preconditioning on gastric mucosal tissue destruction,inflammatory response and apoptosis of epithelial cells in rats with abdominal open injury coupled with seawater immersion.Methods Sixty male Wistar rats with abdominal open injury were randomly divided into 3 groups,each consisting of 20 animals.The animals in group A were treated with abdominal open injury + caudal vein injection of sterile water (3 mg/kg).The animals with abdominal open injury in group B received seawater immersion + caudal vein injection of sterile water (3 mg/kg),and the animals with abdominal open injury in group C were given seawater immersion + caudal vein injection of adenosine (3 mg/kg).All the animals were treated either with caudal vein injection of sterile water or adenosine at a dosage of 3 mg/kg 60 minutes before surgery,and were sacrificed 6 hours after immersion.Gastric mucosal ulcer index (UI) was calculated in the animals of all the groups.Pathological changes in gastric mucosa were closely observed under light microscopy.The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in the gastric mucosa of various groups were detected by enzyme-linked immunosorbent assay (ELISA),the expression levels of Caspase-3 in gastric mucosa were detected by immunohistochemistry,and apoptosis of the cells in intestinal mucosa were monitored by TUNEL method.Results The UI,the levels of TNF-α and IL-6,and the pathological damage of gastric mucosa in group B were all significantly higher than those in group A (P＜0.01) and group C (P ＜0.05).The expression level of Caspase-3 (25.2％ ±3.6％) and the percentage of apoptosis cells (27.3％ ± 2.4％) in group B were significantly higher than those in group A (10.3％ ±1.4％ and 9.4％ ± 1.8％) (P ＜0.01),and the expression level of Caspase-3 of group C (19.4％ ±2.6％ and 21.9％ ± 2.6％) were signficantly lower than those of group B (P ＜0.05).Conclusions Adenosine pretreatment could effectively protect gastric mucosal epithelial inflammatory response in seawater immersion rats coupled with open abdominal injury,inhibit the secretion of inflammatory factors,alleviate gastric mucosal inflammatory response and reduce apoptosis of gastric mucosal epithelial cells.