Abnormal amino acid metabolism promotes tumor progression by inducing malignant behaviors in tumor cells and altering the immune landscape within the tumor microenvironment. However, the underlying mechanisms remain unclear. In this study, we constructed colorectal cancer (CRC) organoids and patient-derived tumor xenograft (PDX) models, performing multifaceted validation to confirm that T-complex protein 1 subunit epsilon (CCT5), mediates the biosynthesis of aspartate and enhances sensitivity to anti-PD-L1 immunotherapy. Mechanistically, CCT5 directly binds to asparagine synthetase (ASNS) and promotes the synthesis of aspartate (Asn). The Asn-mTORC1 axis facilitates tumor cell proliferation while upregulating PD-L1 expression, which leads to a reduction in the number of effector CD8⁺ T cells. Treatment with l-asparaginase (ASNase) combined with anti-PD-L1 therapy effectively reverses the growth of CRC characterized by high CCT5 expression. In summary, we identify CCT5 as a potential biomarker to guide the combined use of ASNase and anti-PD-L1 antibodies in CRC treatment.

Objective:To evaluate the health benefits and intervention efficiency of different strategies of initiating antihypertensive therapy for the primary prevention of cardiovascular diseases in a community-based Chinese population from the Chinese electronic health records research in Yinzhou(CHERRY)study.Methods:A decision-analytic Markov model was used to simulate and compare different antihy-pertensive initiation strategies,including:Strategy 1,initiation of antihypertensive therapy for Chinese adults with systolic blood pressure(SBP)≥140 mmHg(2020 Chinese guideline on the primary preven-tion of cardiovascular diseases);Strategy 2,initiation of antihypertensive therapy for Chinese adults with SBP≥130 mmHg;Strategy 3,initiation of antihypertensive therapy for Chinese adults with SBP ≥140 mmHg,or with SBP between 130 and 140 mmHg and at high risk of cardiovascular diseases(2017 American College of Cardiology/American Heart Association guideline for the prevention,detection,evaluation,and management of high blood pressure in adults);Strategy 4,initiation of antihypertensive therapy for Chinese adults with SBP≥ 160 mmHg,or with SBP between 140 and 160 mmHg and at high risk of car-diovascular diseases(2019 United Kingdom National Institute for Health and Care Excellence guideline for the hypertension in adults:Diagnosis and management).The high 10-year cardiovascular risk was de-fined as the predicted risk over 10％based on the 2019 World Health Organization cardiovascular disease risk charts.Different strategies were simulated by the Markov model for ten years(cycles),with parame-ters mainly from the CHERRY study or published literature.After ten cycles of simulation,the numbers of quality-adjusted life years(QALY),cardiovascular events and all-cause deaths were calculated to evaluate the health benefits of each strategy,and the numbers needed to treat(NNT)for each cardiovas-cular event or all-cause death could be prevented were calculated to assess the intervention efficiency.One-way sensitivity analysis on the uncertainty of incidence rates of cardiovascular disease and probabilis-tic sensitivity analysis on the uncertainty of hazard ratios of interventions were conducted.Results:A to-tal of 213 987 Chinese adults aged 35-79 years without cardiovascular diseases were included.Com-pared with strategy 1,the number of cardiovascular events that could be prevented in strategy 2 increased by 666(95％UI:334-975),while the NNT per cardiovascular event prevented increased by 10(95％UI:7-20).In contrast to strategy 1,the number of cardiovascular events that could be prevented in strategy 3 increased by 388(95％UI:194-569),and the NNT per cardiovascular event prevented decreased by 6(95％UI:4-12),suggesting that strategy 3 had better health benefits and intervention efficiency.Compared to strategy 1,although the number of cardiovascular events that could be prevented decreased by 193(95％UI:98-281)in strategy 4,the NNT per cardiovascular event prevented decreased by 18(95％UI:13-37)with better efficiency.The results were consistent in the sensitivity analyses.Conclusion:When initiating antihypertensive therapy in an economically developed area of China,the strategy combined with cardiovascular risk assessment is more efficient than those purely based on the SBP threshold.The cardiovascular risk assessment strategy with different SBP thresholds is suggested to balance health benefits and intervention efficiency in diverse populations.

Objective: To analyze the clinical and molecular diagnostic status of Fanconi anemia (FA) in China. Methods: The General situation, clinical manifestations and chromosome breakage test and genetic test results of 107 pediatric FA cases registered in the Chinese Blood and Marrow Transplantation Registry Group (CBMTRG) and the Chinese Children Blood and Marrow Transplantation Registry Group (CCBMTRG) from August 2009 to January 2022 were analyzed retrospectively. Children with FANCA gene variants were divided into mild and severe groups based on the type of variant, and Wilcoxon-test was used to compare the phenotypic differences between groups. Results: Of the 176 registered FA patients, 69 (39.2%) cases were excluded due to lack of definitive genetic diagnosis results, and the remaining 107 children from 15 hospitals were included in the study, including 70 males and 37 females. The age at transplantation treatment were 6 (4, 9) years. The enrolled children were involved in 10 pathogenic genes, including 89 cases of FANCA gene, 7 cases of FANCG gene, 3 cases of FANCB gene, 2 cases of FANCE gene and 1 case each of FANCC, FANCD1, FANCD2, FANCF, FANCJ, and FANCN gene. Compound heterozygous or homozygous of loss-of-function variants account for 69.2% (72/104). Loss-of-function variants account for 79.2% (141/178) in FANCA gene variants, and 20.8% (37/178) were large exon deletions. Fifty-five children (51.4%) had chromosome breakage test records, with a positive rate of 81.8% (45/55). There were 172 congenital malformations in 80 children.Café-au-Lait spots (16.3%, 28/172), thumb deformities (16.3%,28/172), polydactyly (13.9%, 24/172), and short stature (12.2%, 21/172) were the most common congenital malformations in Chinese children with FA. No significant difference was found in the number of congenital malformations between children with severe (50 cases) and mild FANCA variants (26 cases) (Z=-1.33, P=0.185). Conclusions: FANCA gene is the main pathogenic gene in children with FA, where the detection of its exon deletion should be strengthened clinically. There were no phenotypic differences among children with different types of FANCA variants. Chromosome break test is helpful to determine the pathogenicity of variants, but its accuracy needs to be improved.
Male ; Female ; Humans ; Child ; Fanconi Anemia/genetics* ; Chromosome Breakage ; Retrospective Studies ; Exons ; China/epidemiology*

Objective:To explore sex and rural-urban differences in the associations of different blood pressure levels with the risk of prediabetes.Methods:We used a multi-stage stratified cluster random sampling method to investigate 21 637 residents aged ≥18 years from 10 survey areas in Hubei province in 2020. The data on questionnaire, physical measurements, and laboratory indicators of the participants were collected. The associations of different blood pressure levels with risk of prediabetes by sex and regions were analyzed using multivariate logistic regressions after complex weighting.Results:A total of 16 111 subjects were included. The prevalence (95% CI) of prediabetes, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and IFG complicated with IGT were 25.1% (14.4%-35.9%), 12.7% (3.2%-22.1%), 8.1% (6.3%-9.8%), and 4.4% (2.3%-6.5%), respectively. After multivariate adjustment, the risk of prediabetes, IFG, IGT, and IFG complicated with IGT increased with the increment of blood pressure (both P for trend <0.05). The positive dose-response relationships between blood pressure levels and risk of prediabetes were also significant among male, urban, and rural residents (both P for trend <0.05), and the interactions between sex and blood pressure showed significant associations for risk of prediabetes and IGT (both P for interaction <0.05). Conclusions:Higher blood pressure levels were associated with an increased risk of prediabetes. The association with prediabetes was stronger in males, but no significant difference was found between urban and rural residents. More distinctive and effective prevention and control strategies should be developed for different populations.

In existing vascular interventional surgical robots, it is difficult to accurately detect the delivery force of the catheter/guidewire at the slave side. Aiming to solve this problem, a real-time force detection system was designed for vascular interventional surgical (VIS) robots based on catheter push force. Firstly, the transfer process of catheter operating forces in the slave end of the interventional robot was analyzed and modeled, and the design principle of the catheter operating force detection system was obtained. Secondly, based on the principle of stress and strain, a torque sensor was designed and integrated into the internal transmission shaft of the slave end of the interventional robot, and a data acquisition and processing system was established. Thirdly, an ATI high-precision torque sensor was used to build the experimental platform, and the designed sensor was tested and calibrated. Finally, sensor test experiments under ideal static/dynamic conditions and simulated catheter delivery tests based on actual human computed tomography (CT) data and vascular model were carried out. The results showed that the average relative detection error of the designed sensor system was 1.26% under ideal static conditions and 1.38% under ideal dynamic stability conditions. The system can detect on-line catheter operation force at high precision, which is of great significance towards improving patient safety in interventional robotic surgery.
Catheters ; Equipment Design ; Humans ; Mechanical Phenomena ; Robotic Surgical Procedures/methods* ; Robotics

Objective To study the effects of Xuebijing injection,somatostatin monotherapy and their combination therapy on the improvement of inflammation and prognosis in acute severe pancreatitis.Methods A total of 90 patients with acute severe pancreatitis treated in our hospital were enrolled in this study.Patients were divided into group A,group B and group C,with 30 cases in each group.The patients in group A were treated with Xuebijing injection alone,and the patients in group B were treated with somatostatin alone,and patients in group C were treated with Xuebijing injection and somatostatin,and all the treatment was lasted for 7 days.The alleviation time of clinical symptoms,improvement of inflammation and prognosis in three groups before and after treatment were observed and compared.Results After treatment,the anal defecation recovery time,abdominal pain relief time,bowel sounds recovery time and abdominal distension time in the three groups were lower than treatment before,and group C were lower than group A and group B (P ＜ 0.05).The levels of interleukin-6 (IL-6),tumour necrosis factor-α (TNF-α) and C-reactive protein (CRP) were significantly lower in group C than those in group A and group B (P ＜0.05).The APACHE-Ⅱ scores after treatment was higher than treatment before,and C group was lower than A group,B group (P ＜0.05).Conclusion Xuebijing injection in combined with somatostatin for acute severe pancreatitis has significantly better efficacy than monotherapy,and it can improve the efficacy of inflammation treatment,and prognosis.

Objective To study the effects of Xuebijing injection,somatostatin monotherapy and their combination therapy on the improvement of inflammation and prognosis in acute severe pancreatitis.Methods A total of 90 patients with acute severe pancreatitis treated in our hospital were enrolled in this study.Patients were divided into group A,group B and group C,with 30 cases in each group.The patients in group A were treated with Xuebijing injection alone,and the patients in group B were treated with somatostatin alone,and patients in group C were treated with Xuebijing injection and somatostatin,and all the treatment was lasted for 7 days.The alleviation time of clinical symptoms,improvement of inflammation and prognosis in three groups before and after treatment were observed and compared.Results After treatment,the anal defecation recovery time,abdominal pain relief time,bowel sounds recovery time and abdominal distension time in the three groups were lower than treatment before,and group C were lower than group A and group B (P ＜ 0.05).The levels of interleukin-6 (IL-6),tumour necrosis factor-α (TNF-α) and C-reactive protein (CRP) were significantly lower in group C than those in group A and group B (P ＜0.05).The APACHE-Ⅱ scores after treatment was higher than treatment before,and C group was lower than A group,B group (P ＜0.05).Conclusion Xuebijing injection in combined with somatostatin for acute severe pancreatitis has significantly better efficacy than monotherapy,and it can improve the efficacy of inflammation treatment,and prognosis.

Within the past few years, the invention of next-generation sequencing has revealed several new genes associated with tumor formation and development, for example DNMT3a. This gene is an independent prognostic factor for acute myeloid leukemia (AML). The objective of this study was to analyze the DNMT3a mutation in childhood AML in a single center. PCR amplification of the entire coding region of DNMT3a was performed using 23 overlapping primer pairs in 57 patients who were diagnosed in Blood Disease Hospital of Chinese Academy of Medical Sciences, then the directly sequencing was underwent. The results showed that no DNMT3a mutation was found in these patients including the hotspot R882. But AML1/ETO mutation was found in 10 patients, CBFB/MYH11 mutation in 3 patients, PML/RARa mutation in 13 patients, FLT3/ITD mutation in 5 patients, FLT3/TKD mutation in 1 patient, PML/RARa and FLT3/TKD mutation coexisted in 2 patients. It is concluded that DNMT3a mutations are rare in childhood AML, and different mechanisms of myeloid leukemogenesis between childhood and adults maybe involved.
Adolescent ; Base Sequence ; Child ; Child, Preschool ; DNA (Cytosine-5-)-Methyltransferases ; genetics ; DNA Mutational Analysis ; Female ; Humans ; Infant ; Karyotyping ; Leukemia, Myeloid, Acute ; genetics ; Male ; Mutation

Objective To construct and identify the efficacy of a lentiviral vector harboring RNAi sequence targe-ting NSBP1 gene. Methods Three siRNA targeting the NSBP1 mRNA were designed, the pGCSIL-GFP-NSBP1 lentivirus vectors were constructed and confirmed by DNA sequencing. A total of 293T cells were co-transfected with pGCSIL-GFP-NSBP1, pHelper1.0 and pHelper2.0 for the virus stocks produced, the titer of the virus was test-ed. After lentivirus transfecting into DU145 ceils, Western-blot and MTT methods were used to determine the ex-pression and biological activity of NSBP1 gene, the cells were transplanted into nude mice, then inhibitive effect was observed. Results PCR analysis and DNA sequencing demonstrated that the RNAi sequence targeting the hu-man NSBP1 gene was successfully inserted into the lentiviral vector. The titer of the recombinant]entiviral vector was 2 × 10~8TU/mL. NSBP1 protein expression level in transfected cells was significantly decreased and growth rate of cells transfected with lentivirus was decreased by MTT assay, the downregulation of NSBP1 reduced growth rate of transplantated tumor, whereas tumorgenicity was not influenced. Conclusion The construction of the]entiviral vector of NSBP1 has been successfully prepared and NSBP1 plays an important regulatory role in androgen-inde-pendent prostate cancer cell proliferation.

OBJECTIVETo study the effect of 5-fluorouracil-FU in combination with astragalus membranaceus(AM) on amino acid metabolism in mice model of gastric carcinoma induced by 3-methylcholanthrene(MC).

METHODSMice gastric carcinoma models were established by 3-methylcholanthrene induction and randomly divided into different groups, and received 5-FU treatment (group A) 5-FU plus AM (group B), 5-FU plus a high dose of AM(group C), no treatment (group D). Normal mice were used as control (group N). Free amino acid in the tumor specimens were examined.

RESULTSThe levels of free Valine, Methionine, Leucine, Arginine and cystine in the tumor specimens in group D were significantly higher than that in group N(P< 0.05). The levels of free serine in group A, B, C, D were significantly higher than that in group N. The levels of free glutamic acid in group A, B were significantly higher than that in group N(P< 0.05). The levels of free proline in group C, D were significantly higher than that in group P, N(P< 0.05).

CONCLUSIONSThe increasing levels of free serine and proline in tumor specimens in gastric cancer mice model reveals metabolic disturbance of amino acid. 5-FU plus astragalus membranaceus can decrease the level of free glutamic acid in the mice models, and inhibit tumor growth.

Amino Acids ; metabolism ; Animals ; Astragalus membranaceus ; Fluorouracil ; therapeutic use ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Phytotherapy ; Stomach Neoplasms ; drug therapy ; metabolism