Gastrointestinal (GI) cancers are a leading cause of cancer morbidity and mortality worldwide. Despite advances in treatment, cancer relapse remains a significant challenge, necessitating novel therapeutic strategies. In this study, we engineered nanobody-based chimeric antigen receptor (CAR) natural killer (NK) cells targeting cadherin 17 (CDH17) for the treatment of GI tumors. In addition, to enhance the efficacy of CAR-NK cells, we also incorporated CV1, a CD47-SIRPα axis inhibitor, to evaluate the anti-tumor effect of this combination. We found that CDH17-CAR-NK cells effectively eliminated GI cancers cells in a CDH17-dependent manner. CDH17-CAR-NK cells also exhibit potent in vivo anti-tumor effects in cancer cell-derived xenograft and patient-derived xenograft mouse models. Additionally, the anti-tumor activity of CDH17-CAR-NK cells is synergistically enhanced by CD47-signal regulatory protein α (SIRPα) axis inhibitor CV1, likely through augmented macrophages activation and an increase in M1-phenotype macrophages in the tumor microenvironment. Collectively, our findings suggest that CDH17-targeting CAR-NK cells are a promising strategy for GI cancers. The combination of CDH17-CAR-NK cells with CV1 emerges as a potential combinatorial approach to overcome the limitations of CAR-NK therapy. Further investigations are warranted to speed up the clinical translation of these findings.

Objective:To determine whether insulin resistance is associated with all-cause mortality in subjects without diabetes.Methods:A total of 505 participants without diabetes, 198 with normal glucose tolerance (NGT) and 307 with impaired glucose tolerance (IGT), were recruited from the Daqing Diabetes Study. The participants were followed up for 30 years. They were stratified into three groups (tertiles) according to baseline homeostasis model assessment of insulin resistance(HOMA-IR) levels, as the HOMA-IR 0, the HOMA-IR 1 and the HOMA-IR 2 groups, to assess the predictive effect of insulin resistance on risk of all-cause mortality.Results:During the 30-year follow-up, 52, 56 and 78 participants died across the three HOMA-IR groups, respectively. The corresponding mortality per 1 000 person-years (95 %CI) were 12.12 (9.56-15.01), 13.10 (10.46-16.03) and 19.91 (16.73-23.15), respectively. Participants in the HOMA-IR 2 group had a significantly higher risk of death than those in the HOMA-IR 0 group after adjustment of age, sex and smoking status ( HR=1.97,95 %CI 1.38-2.81, P<0.001). Cox analyses showed that a one standard deviation increase in HOMA-IR was associated with a 22% increase in the mortality after adjustment of potential confounders ( HR=1.22, 95 %CI 1.08-1.39, P=0.002). Conclusions:Insulin resistance is associated with increased risk of all-cause death in Chinese people without diabetes, suggesting that improving insulin resistance could be beneficial for people without diabetic in reducing risk of long-term all-cause mortality.

Objective:To investigate the long-term effects of metabolically healthy obesity on the risks of type 2 diabetes, cardiovascular disease events, and its mortality over a 23-year follow-up.Methods:Based on the results of an oral glucose tolerance test, there were 519 participants with normal glucose tolerance and 630 with newly diagnosed type 2 diabetes enrolled in 1986 and then given to assess the long-term clinical outcomes during the 23-year follow-up in Daqing. Metabolically healthy obesity was defined as the overweight and obese individuals with no metabolic abnormalities (diabetes, hypertension, hyperlipidemia). Finally, we identified 682 participants (350 with normal glucose tolerance and 332 with newly diagnosed diabetes). They were divided into five groups: 211 individuals with metabolically healthy normal weight (MHNW group), 58 with metabolically healthy overweight and obesity (MHO group), 81, 109, 223 were metabolically unhealthy overweight and obesity with hypertension (MUHO group), type 2 diabetes (MUDO group), hypertension and diabetes (MUHDO group). Incidences of type 2 diabetes, morbidity and mortality of cardiovascular disease were compared among these groups.Results:Over 23 years, instead of the morbidity and mortality of cardiovascular disease, the incidence of type 2 diabetes in MHO group was two times higher than in MHNW group ( 24.1%, 12.5/1 000 person years vs 10.9%, 5.2/1 000 person years, P=0.01), with an age, sex, and smoking history-adjusted hazard ratio ( HR) of 2.42 (95% CI 1.24-4.74, P=0.01). The morbidity and mortality of cardiovascular disease in the groups of overweight and obesity with metabolically unhealthy were higher than in MHNW group, and increased across the subjects with MUHO, MUDO, MUHDO ( P<0.05). Conclusion:Compared with metabolically healthy normal weight participants, the metabolically healthy obese group was at increased risk of type 2 diabetes but not cardiovascular disease events and its mortality. On the contrary, the overweight and obese groups with metabolic abnormalities had significant higher incidence of type 2 diabetes, morbidity and mortality of cardiovascular diseases.

Objective To explore the influence of lifestyle intervention on long-term diabetes in subjects with impaired glucose tolerance (IGT) returned to normal glucose tolerance (NGT) within 6 years.Methods A total of 577 subjects (aged 25-74 years old) with IGT in Daqing were enrolled and randomly assigned to control,and diet,exercise and diet plus exercise groups in a six-year intervention trial in 1986.Subjects who were non-diabetic at the end of the intervention were followed up for additional 14 years.Results Among all the subjects,41.38％ of them who had returned to NGT from IGT within 6 years maintained NGT status after 20 years,and had a lower incidence of diabetes than subjects maintained IGT status (46.55％ vs.75.25％).Of note,in the intervention group,the percentage of participants developed diabetes in the NGT subjects was significantly lower than that in the IGT group (43.71％ vs.76.25％) after 20 years.There was high long-term risk for diabetes in the IGT subjects after the adjustment of age,sex and baseline glucose (HR=1.81,95％CI 1.27-2.58,P=0.001),whereas in the non-intervention group,no significant difference could be viewed in long-term diabetic risk between subjects maintained IGT status and those returned to NGT (71.43％ vs.65.22％) after adjusting of the same confounders (HR=1.03,95％CI 0.45-2.35,P=0.94).Conclusions IGT subjects who had returned to NGT in early years had lower risk for future diabetes than those who remained IGT.However,this beneficial effect could only be viewed in the intervention group,but not in the non-intervention group.

Objectives: To evaluate the effect and safety of 14-day continuous subcutaneous insulin infusion (CSII) in type 2 diabetes patients with heart diseases.
Methods: A total of 22 consecutive type 2 diabetes patients (history ≤ 5 years) with heart diseases treated in our hospital from 2011-03 to 2013-08 were studied. There were 20 male, and the with the mean age of patieuts (48.15 ± 9.80) years, all patients without standard hypoglycemic treatment before admission. The patients received 14-day CSII for enhanced treatment and the blood glucose level, insulin function and insulin sensitivity were compared before and after the treatment.
Results: After CSII treatment, the blood glucose level was obviously decreased, fasting blood glucose (FBG) and postprandial blood glucose at 30, 60 and 120 min were improved, all P<0.001. The C peptide level was higher at 60 and 120 min alter treatweut as 2.73 (1.05-7.05)ng/ml vs 3.84 (1.22-63.39)ng/ml, P=0.004 and 3.34 (1.42-9.61)ng/ml vs 6.27 (0.93-47.39)ng/ml, P=0.004. The insulin sensitivity was improved as -1.89 ± 0.29 vs -1.70±0.31, P=0.008. With CSII treatment, there were 22.73% patients (5/22) at remission by controlling the diet and excise and 77.27% (17/22) with continuing medication. The patients were followed-up for (12.4 ± 8.5) months, there were 4/5 patients with euglycemia, 1/5 with increase blood sugar and received medication at 2 months after discharge, the rest 17 patients remained oral hypoglycemic medication.
Conclusion: CSII may quickly relieve glucotoxicity and improve insulin sensitivity in type 2 diabetes patients with heart diseases. Some patients may alleviate drug burden in clinical practice.

BACKGROUND:As a lipid-lowering drug, simvastatin has been proved to be effective in promoting bone formation. Previous studies have demonstrated that local y applied simvastation accelerated fracture healing at middle phase in osteoporotic rats, while no study focuses on the influence of local y applied simvastatin on fracture healing at late period in an osteoporotic rat.
OBJECTIVE:To investigate the effect of simvastatin local y applied from a bioactive polymer coating of implants on osteoporotic fracture healing at late period.
METHODS:Female Sprague-Dawley rats were divided into sham group, osteoporotic fracture group and simvastatin group. In the sham group, the abdominal cavity was exposed without ovariectomy. Six weeks later, femur fracture models were established in normal or osteotoporotic Sprague-Dawley rats, and intramedul ary stabilization was achieved with uncoated titanium Kirschner wires in normal rats (sham group),with polylactic acid coated titanium Kirschner wires (osteoporotic fracture group) and with simvastatin/polylactic acid coated titanium Kirschner wires (simvastatin group). Femurs were harvested after 12 weeks, bone mineral density was determined with dual X-ray absorptiometry, and then radiographic and histological analysis was performed for analysis of fracture healing. Immunohistochemical evaluation was employed for bone morphogenetic protein 2 expression.
RESULTS AND CONCLUSION:The bone mineral densities of both the total fractured femur and fractured site 12 weeks after fracture in the osteoporotic fracture group and simvastatin group were markedly decreased compared to normal fractured rats. The bone mineral density of the fractured site was significantly higher in the simvastatin group than the osteoporotic fracture group. Radiographic results demonstrated completely finished cal us remodeling in the sham group;poor healing, pale cal us density and blurred fracture line were seen in the osteoporotic fracture group;disappearance of fracture line, bone defects fil ed with cal us, and deep periosteal reaction were found in the simvastatin group. X-ray scores in the sham and simvastatin groups were significantly higher than that in the osteoporotic group (P<0.05). Hematoxylin-eosin staining showed a delayed healing process in the osteoporotic group, and revealed a significantly processed cal us with regular-shaped newly formed bone trabeculae in the simvastatin group. Immunohistochemical evaluation showed no significant difference in the bone morphogenetic protein 2 expression between any two groups. These findings suggest an improved fracture healing under local application of simvastatin in osteoporotic rats.

Objective To investigate if improving or slowing the progression of glucose intolerance might be linked with the reduction of cardiovascular disease(CVD)events and mortality in a Da Qing population with prediabetes.Methods In 1986,577 subjects with impaired glucose tolerance in 33 clinics in Daqing city were randomly assigned to either the control group or one of three lifestyle intervention groups(diet,exercise,or diet plus exercise)to receive a 6 year lifestyle intervention.All the participants were followed for 14 years(1993-2006)after completion of the 6 year active interventions to assess the long-term effect of the interventions.In this post-hoc analysis,the participants were stratified into four subgroups(quartiles)based on their 2 h plasma glucose(2hPG)level after glucose loading at the end of the active intervention,in order to analyze the impact of plasma glucose level on CVD events and mortality.Results During the 20-year follow-up,there were a total of 142 deaths(68 of which were attributed to CVD)and 211 first CVD events(145 strokes and 66 myocardial infarctions).From the highest to the lowest levels of 2hPG in the 4 quartiles,the all-cause mortality(17.8,12.7,10.9,and 9.7/1 000 personyears),CVD mortality(9.1,5.9,6.1,and 4.9/1 1300 person-years)and the incidence of first CVD events(30.4.24.0,18.8,and 19.7/1 000 person-years)showed a clear trend of decline.In multivariate analyses,controlled for age,sex,body mass index,smoking habit,blood pressure,and intervention methods at baseline,the results showed that the 5 mmol/L elevation of 2hPG level after glucose loading in 1992 significantly increased the all-cause mortality(HR 1.335.P=0.005),the incidences offirst CVD events(HR 1.227,P=0.012)and stroke(HR 1.213,P=0.026).Conclusion In pre-diabetes population.if the lifestyle intenrentions are substantially efficacious in improving glucose intolerance,the CVD risk and mortality will be reduced.

A series of gene function devitalized increase gradually because of tumnr-suppressing gene endogenous deactivation while not classic mutation or absence. Unlike mutation devitalizalion, methylation devitalization is reversible.Gene silencing because of high methylation of promoter has many potential clinical uses.For example, it's in favor of early diagnosis, prognosis and therapy of tumors such as lung caneer, breast cancer,renal cancer, gastric cancer, bladder cancer and so on. RASSF1A belongs to the gene thatalways due to methylation deactivation not mutation deactivation. And this gene is similar to Ras receptor of mammalian. RASSF1A suppressed tumor growth in vivo and in vitro. This further supports it could be one tumor-suppressing gene. It plays an important role in cell cycle regulation, apoptosis, and micropipe stabilization. This review mainly summarizes information and advancement about RASSF1A tumor-suppressing gene in genetic structure, endogenous gene inactivation, and functional analysis.

Objective To investigate the clinical characteristics of primary thyroid lymphoma(PTL) and its prognostic factors.Methods Clinical and pathological data of 7 cases diagnosed as primary thyroid lymphoma were retrospectively analyzed.Results All of the 7 patients were diagnosed on thyroidectomy and presented with thyroid nodules,of whom 6 cases were middle-aged to elderly women and some had locally oppressive symptoms.Four cases were diagnosed as diffuse large B non-Hodgkin's lymphoma (DLBCL) and 3 were mucosa-associated lymphoid tissue B-cell lymphoma (MALT).Pathological subtype of mucosa-associated lymphoid tissue B-cell lymphomas and younger patients had better prognosis.Conclusion The possibility of PTL must be kept in mind in the differential diagnosis of thyroid nodules in middle-aged to elderly women.Age and pathological subtype are important prognostic factors.