In recent years, gastrointestinal stromal tumors (GIST) have increased incidence and mortality, and most GIST is caused by the activation mutation of the c-KIT gene. Therefore, c-KIT has become a promising therapeutic target of GIST. At present, the drugs approved for the treatment of GIST including imatinib, sunitinib, regorafenib and ripretinib, are mostly prone to developing resistance and accompanied by various degrees of adverse reactions. Therefore, there is an urgent need to develop new c-KIT inhibitors to solve the problem of resistance. In this study, we investigated the anti-tumor effect of a novel c-KIT inhibitor PN17-1 on gastrointestinal stromal tumor GIST-882 cells in vitro. We found that PN17-1 significantly inhibited the proliferation, colony formation and migration ability of GIST-882 cells, and significantly downregulated the protein expression levels of p-c-KIT and its downstream signals p-AKT, p-STAT5 and p-ERK in GIST-882 cells. In addition, PN17-1 induced apoptosis in GIST-882 cells, and the apoptosis may be mainly related to the mitochondrial-dependent endogenous pathway. In conclusion, the novel c-KIT inhibitor PN17-1 is a promising anti-GIST drug, and this study provides new ideas for further development of c-KIT inhibitors in the future.

This study aimed to explore the therapeutic mechanisms of Colquhounia Root Tablets(CRT) in treating diabetic kidney disease(DKD) by integrating biomolecular network mining with animal model verification. By analyzing clinical transcriptomics data, an interaction network was constructed between candidate targets of CRT and DKD-related genes. Based on the topological eigenvalues of network nodes, 101 core network targets of CRT against DKD were identified. These targets were found to be closely related to multiple pathways associated with type 2 diabetes, immune response, and metabolic reprogramming. Given that immune-inflammatory imbalance driven by metabolic reprogramming is one of the key pathogenic mechanisms of DKD, and that many core network targets of CRT are involved in this pathological process, receptor for advanced glycation end products(RAGE)-reactive oxygen species(ROS)-phosphatidylinositol 3-kinase(PI3K)-protein kinase B(AKT)-nuclear factor-κB(NF-κB)-NOD-like receptor family pyrin domain containing 3(NLRP3) signaling axis was selected as a candidate target for in-depth research. Further, a rat model of DKD induced by a high-sugar, high-fat diet and streptozotocin was established to evaluate the pharmacological effects of CRT and verify the expression of related targets. The experimental results showed that CRT could effectively correct metabolic disturbances in DKD, restore immune-inflammatory balance, and improve renal function and its pathological changes by inhibiting the activation of the RAGE-ROS-PI3K-AKT-NF-κB-NLRP3 signaling axis. In conclusion, this study reveals that CRT alleviates the progression of DKD through dual regulation of metabolic reprogramming and immune-inflammatory responses, providing strong experimental evidence for its clinical application in DKD.
Animals ; Diabetic Nephropathies/metabolism* ; Receptor for Advanced Glycation End Products/genetics* ; NF-kappa B/genetics* ; Signal Transduction/drug effects* ; Rats ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Proto-Oncogene Proteins c-akt/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Phosphatidylinositol 3-Kinases/genetics* ; Reactive Oxygen Species/metabolism* ; Humans ; Plant Roots/chemistry* ; Rats, Sprague-Dawley ; Tablets/administration & dosage*

OBJECTIVE: To investigate the effect of irradiation dose rate of ⁶⁰Co γ-ray on hematopoietic and immune cells in total body irradiation (TBI) mice. METHODS: After TBI with 8 Gy ⁶⁰Co γ-ray at three irradiation dose rates of 0.027, 0.256 and 0.597 Gy/min, the survival and change of body weight of C57BL/6J mice were observed within 30 days. The peripheral blood parameters were examined at each time point within 30 days post-irradiation. The hematopoietic stem/progenitor cell counts of mice were examined on the 10^th and 30^th day post-irradiation by flow cytometry, as well as the proportions of immune cells in peripheral blood, bone marrow and spleen of mice on the 30^th day post-irradiation. RESULTS: After TBI with 8 Gy ⁶⁰Co γ-ray, the 30-day survival rate of high dose-rate group was 0, which was significantly lower than 90% of medium dose-rate group and 100% of low dose-rate group (both P < 0.001). The peripheral blood parameters of all three groups showed a sharp decline → low value → gradually recovering trend. The count of white blood cell, neutrophil, lymphocyte, red blood cell, platelet and hemoglobin level in the high dose-rate and medium dose-rate groups were significantly lower than those in the low dose-rate group on day 7-18 post-irradiation (all P < 0.05), but there were no significant differences between the high dose-rate and medium dose-rate groups (P >0.05). On the 10^th day after irradiation, the proportion and number of bone marrow hematopoietic stem/progenitor cells (including LK, LSK, LT-HSC, ST-HSC, and MPP cells) in the low dose-rate and medium dose-rate groups were significantly decreased compared to those in the normal group (all P < 0.05), but there were no significant differences between the two groups (P >0.05). On the 30^th day after irradiation, LSK, LT-HSC, ST-HSC and MPP cells in the low dose-rate group recovered to normal levels, while those in the medium dose-rate group were still significantly lower than those in the low dose-rate group (all P < 0.001). The results of bone marrow and peripheral immune cell tests on the 30^th day after irradiation showed that the ratios of T and B lymphocytes in the low dose-rate and medium dose-rate groups were reduced compared to that in the normal group (both P < 0.05), while the ratio of neutrophils was increased (P < 0.01). The trend of changes in the spleen and peripheral blood was consistent. CONCLUSION The degree of hematopoietic and immune cell damage in mice after TBI with 8 Gy ⁶⁰Co γ-ray is related to the dose rate, and low dose-rate irradiation can reduce the damage in the animal model. Therefore, choosing the appropriate dose rate of irradiation is a key factor in establishing an objective and reliable experimental animal model of irradiation.
Animals ; Mice ; Whole-Body Irradiation ; Gamma Rays ; Mice, Inbred C57BL ; Hematopoietic Stem Cells/radiation effects* ; Cobalt Radioisotopes ; Dose-Response Relationship, Radiation ; Male

The cooccurrence of NPM1, FLT3-ITD, and DNMT3A mutations (i.e., triple mutation) is related to dismal prognosis in patients with acute myeloid leukemia (AML) receiving chemotherapy alone. In this multicenter retrospective cohort study, we aimed to identify whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) could overcome the poor prognosis of DNMT3A^mutNPM1^mutFLT3-ITD^mut AML across four transplant centers in China. Fifty-three patients with triple-mutated AML receiving allo-HSCT in complete remission were enrolled. The 1.5-year probabilities of relapse, leukemia-free survival, and overall survival after allo-HSCT were 11.9%, 80.3%, and 81.8%, respectively. Multivariate analysis revealed that more than one course of induction chemotherapy and allo-HSCT beyond CR1 were associated with poor survival. To our knowledge, this work is the largest study to explore the up-to-date undefined role of allo-HSCT in patients with triple-mutated AML. Our real-world data suggest that allo-HSCT could overcome the poor prognosis of DNMT3A^mutNPM1^mutFLT3-ITD^mut in AML.
Humans ; Nucleophosmin ; Leukemia, Myeloid, Acute/mortality* ; Hematopoietic Stem Cell Transplantation/methods* ; Male ; Female ; DNA Methyltransferase 3A ; Adult ; China ; Retrospective Studies ; DNA (Cytosine-5-)-Methyltransferases/genetics* ; Middle Aged ; Prognosis ; fms-Like Tyrosine Kinase 3/genetics* ; Mutation ; Young Adult ; Transplantation, Homologous ; Nuclear Proteins/genetics* ; Adolescent ; Aged

OBJECTIVE: To investigate the association between ABO blood types and gestational diabetes mellitus (GDM) risk. METHODS: A prospective birth cohort study was conducted. ABO blood types were determined using the slide method. GDM diagnosis was based on a 75-g, 2-h oral glucose tolerance test (OGTT) according to the criteria of the International Association of Diabetes and Pregnancy Study Groups. Logistic regression was applied to calculate the odds ratios ( ORs) and 95% confidence intervals ( CIs) between ABO blood types and GDM risk. RESULTS: A total of 30,740 pregnant women with a mean age of 31.81 years were enrolled in this study. The ABO blood types distribution was: type O (30.99%), type A (26.58%), type B (32.20%), and type AB (10.23%). GDM was identified in 14.44% of participants. Using blood type O as a reference, GDM risk was not significantly higher for types A ( OR = 1.05) or B ( OR = 1.04). However, women with type AB had a 19% increased risk of GDM ( OR = 1.19, 95% CI = 1.05-1.34; P < 0.05), even after adjusting for various factors. This increased risk for type AB was consistent across subgroup and sensitivity analyses. CONCLUSION The ABO blood types may influence GDM risk, with type AB associated with a higher risk. Incorporating it-either as a single risk factor or in combination with other known factors-could help identify individuals at risk for GDM before or during early pregnancy.
Humans ; Female ; Pregnancy ; Diabetes, Gestational/etiology* ; ABO Blood-Group System ; Adult ; Prospective Studies ; Risk Factors ; Young Adult

Objective To investigate the protective effect and mechanism of CDK4/6 inhibitor palbociclib against radiation-induced injury in rats'small intestinal crypt epithelial cell line(IEC-6).Methods(1)Using CCK-8 colorimetric assay,colony formation assay,the PI staining method,Annexin V-FITC/PI dual staining and Western blot,the impact of palbociclib on proliferation,cell cycle dynamics,apoptosis,DNA damage,as well as phosphorylation events at Rb-780 and 795 sites in irradiated IEC-6 cells was investigated.(2)An IEC-6 cell line overexpressing Rb was established,and the effects of Rb overexpression on proliferation,cell cycle,and apoptosis in the IEC-6 cell line were assessed using the CCK-8 colorimetric assay,PI staining method,Annexin V-PE/7-AAD dual staining and Western blot.Additionally,the impact of Rb overexpression on the protective effect of palbociclib against radiation damage was verified in the Rb-overexpressing IEC-6 cell line.Results(1)Administration of palbociclib was demonstrated to enhance the proliferative capacity of IEC-6 cells following exposure to 10 Gy X-ray irradiation,increase colony formation ability post 4-8 Gy X-ray exposure while concomitantly reducing the proportion of cells in the G2/M phase after 10 Gy irradiation and diminishing apoptosis in irradiated IEC-6 cells.Protein expression analysis revealed that palbociclib inhibited phosphorylation at Rb-780 and 795 sites and attenuated the production of γ-H2AX in IEC-6 cells following irradiation.(2)After transfection of IEC-6 cells with Rb overexpression lentivirus,there was a significant increase in the total protein expression of Rb.The phosphorylation levels at Rb-780 and 795 sites were markedly elevated.Consequently,cell proliferation was accelerated,the proportion of cells in the S phase of the cell cycle increased,and the apoptotic rate significantly rose after exposure to 10 Gy X-ray irradiation.(3)Treatment with a lower dose of palbociclib(0.05 μmol/L)was found to suppress the phosphorylation of Rb at 780 and 795 sites in IEC-6 cells overexpressing Rb.Additionally,it reduced apoptosis in IEC-6 cells overexpressing Rb following exposure to 10 Gy X-ray irradiation.However,this treatment did not inhibit the phosphorylation of Rb at 780 and 795 sites in IEC-6 cells transfected with the empty vector,nor did it exert a protective effect against radiation-induced damage in these cells.Conclusion The CDK4/6 inhibitor palbociclib demonstrates significant protective effects against radiation-induced damage in rats'intestinal crypt epithelial cell line(IEC-6),with the Rb protein potentially playing a crucial role in mediating this radioprotective response.

Objective:Survival analysis of cancers' incidence data in Tianjin from 2010 to 2016 was conducted to provide the basis for formulating and evaluating regional health policies on cancer prevention and treatment.Methods:Registration data in Tianjin were used between January 1, 2010 to December 31, 2016 and patients were followed-up till 31 December, 2021. Life-table method was used to calculate the observed survival rate and Edered Ⅱ was used to calculate the relative survival rate. The data were stratified by year, gender, age group and cancer sites. Difference in survival curves between group was analyzed by Kaplan-Meier method and Log rank test. Joinpoint regression model was used to analyze the trend change.Results:The 5-year relative survival rates of cancer were 41.92% to 53.65% from 2010 to 2016 for residents in Tianjin, with an increasing trend ( t=4.81 ,P=0.005), and the average was 48.56%. The survival rate of females was higher than that of males (57.71%vs. 39.20%), and the survival rate of urban residents was higher than that of rural residents (49.38% vs. 47.24%). The 5-year relative survival rates were 63.14%, 78.39%, 58.25% and 32.67% in 0-14, 15-44, 45-64 and 65 and above age groups, respectively. The median relative survival times of all cancer were 2.34 to 6.00 years from 2010 to 2016 in Tianjin, with an increasing trend ( t=3.86, P=0.012). The average of median relative survival times was 4.11 years. The median survival time of females was longer than that of males (11.99 years vs. 2.03 years), and the time of urban residents were longer than that of rural residents (4.60 years vs. 3.43 years). The median relative survival time were 12.07, 11.92 and 1.34 years in 15-44, 45-64 and 65 and above age groups, respectively. Conclusions:The cumulative survival rate of cancer increased significantly from 2010 to 2016 in Tianjin, indicating that the prevention and treatment effect of cancer is obvious. The focus should be on male, rural areas, higher age group, and targeted prevention and treatment measures should be taken to lung, esophagus, liver, gallbladder and pancreatic cancer.

Objective:To explore the trends and distribution of liver cancer between sexes, ages, and urban-rural areas in Tianjin, China from 1999 to 2021, and provide data for targeted prevention and control strategies of liver cancer in Tianjin.Methods:Liver cancer mortality data of Tianjin during 1999-2021 were from the Tianjin population based mortality surveillance system maintained by the Tianjin Centers for Disease Control and Prevention (CDC), and the population data of permanent Tianjin residents were from Tianjin Municipal Public Security Bureau. Liver cancer mortality, years of life lost (YLL), years lived with disability (YLD), and disability adjusted life years (DALY) were calculated using the cause of death surveillance data collected by Tianjin Centers for Disease Control and Prevention. The distributions of these data among residents of different sexes, ages, and regions were analyzed. Segi's world standard population was used for standardization. Joinpoint regression was used for trend analysis on the mortality rate of liver cancer and the disease burden.Results:The liver cancer mortality rate in Tianjin decreased by 46.75% from 1999 to 2021, with distinct phased characteristics. From 1999 to 2010, the age-sex-standardized mortality rate (SMR) decreased from 12.62/100 000 to 11.64/100 000 with an annual percent change (APC) of -1.32% ( P=0.003). From 2010 to 2021, the SMR decreased from 11.64/100 000 to 6.72/100 000 (APC=-3.89%, P＜0.001). The age-sex-standardized DALY rates(SDR) decreased by 50.63% from 1999 to 2021, also with distinct phased characteristics. From 1999 to 2010, the SDR decreased from 388.67/100 000 to 349.38/100 000 (APC=-1.35%, P=0.002). From 2010 to 2021, the SDR decreased from 349.38/100 000 to 191.88/100 000 (APC=-4.43%, P＜0.001). The liver cancer mortality rate declined most rapidly in the age group under 45 years; the APC for those under 35 years was -5.07% ( P＜0.001), and for those aged 35-44 years, the APC was 0.63% ( P=0.707) and -8.21% ( P＜0.001) before and after 2007, respectively. Both SMR and SDR were significantly higher in males than in females ( P＜0.01). Both SMR and SDR were significantly higher in urban areas than in rural areas from 1999 to 2007 ( P＜0.05), but they became similar after 2008. Liver cancer DALY are predominantly YLL, accounting for 99%. The median age of liver cancer deaths in Tianjin during 1999-2021 was 64-68 years old, with males lower than females ( P＜0.05), and rural areas lower than urban areas ( P＜0.05), generally showing an increasing trend (1999-2014: APC=0.11%, P=0.047; 2014-2021: APC=0.51%, P=0.005). Conclusions:Liver cancer mortality rate and disease burden decreased from 1999 to 2021 in Tianjin, with an especially accelerated decline after 2010. Further efforts to reduce liver cancer mortality in Tianjin are needed, and special attention should be focused on the elderly, male, and rural residents.

Objective:To analyze the whole genome sequence and key site mutations of hepatitis B virus (HBV) in patients with different stages of disease progression, and to understand the relationship between HBV genetic characteristics and disease progression.Methods:Serum samples and basic information of hepatitis B patients with asymptomatic HBV carrier, chronic hepatitis B patients, cirrhosis patients and primary hepatocellular carcinoma patients were collected. Nested PCR was used to amplify the samples to obtain HBV whole gene sequences. Phylogenetic trees were constructed to determine the genotype of the samples, and gene mutations of the samples were analyzed combined with reference sequences of each type.Results:A total of 256 samples were successfully amplified, including 68 asymptomatic HBV carrier patients, 118 CHB patients, 15 LC patients and 55 HCC patients, and five genotypes (B, C, D, I and C/D) were detected. The result of comparative analysis showed that the mutation rate of 56 nucleotide sites was significantly different among the four groups ( P<0.05). In addition to the discovery of C105T, A1762T/G1764A and G1899A and other previously reported key site mutations, the mutation rates of T53A, C1485T and C1628T in newly diagnosed HCC group were significantly higher than those in other groups, and the mutation rates of T2150G and T2151C in asymptomatic HBV infection group were significantly higher than those in other groups. A total of 26 sequences were deleted, mainly distributed in the pre-C and pre-S regions. The deletion mutation rate in the HCC group was significantly higher than that in the other groups. Conclusions:The data of this study indicate that some nucleotide substitution mutations and deletion mutations may be closely related to the occurrence and development of HBV-related diseases, and HCC patients are more likely to have gene mutations than non-HCC patients. These result provide a reference for understanding the relationship between viral mutation and the progression of HBV infection-related diseases.