The efficient clinical treatment of oral squamous cell carcinoma(OSCC)is still a challenge that demands the development of effective new drugs.Phenformin has been shown to produce more potent anti-tumor activities than metformin on different tumors,however,not much is known about the influence of phenformin on OSCC cells.We found that phenformin suppresses OSCC cell proliferation,and promotes OSCC cell autophagy and apoptosis to significantly inhibit OSCC cell growth both in vivo and in vitro.RNA-seq analysis revealed that autophagy pathways were the main targets of phenformin and identified two new targets DDIT4(DNA damage inducible transcript 4)and NIBAN1(niban apoptosis regulator 1).We found that phenformin significantly induces the expression of both DDIT4 and NIBAN1 to promote OSCC autophagy.Further,the enhanced expression of DDIT4 and NIBAN1 elicited by phenformin was not blocked by the knockdown of AMPK but was suppressed by the knockdown of transcription factor ATF4(activation transcription factor 4),which was induced by phenformin treatment in OSCC cells.Mechanistically,these results revealed that phenformin triggers endoplasmic reticulum(ER)stress to activate PERK(protein kinase R-like ER kinase),which phosphorylates the transitional initial factor eIF2,and the increased phosphorylation of eIF2 leads to the increased translation of ATF4.In summary,we discovered that phenformin induces its new targets DDIT4 and especially NIBAN1 to promote autophagic and apoptotic cell death to suppress OSCC cell growth.Our study supports the potential clinical utility of phenformin for OSCC treatment in the future.

【Objective】 To investigate the practice and benefit of national standardized management of type 2 diabetes in Yulin City. 【Methods】 We recruited the adult type 2 diabetes patients who sought medical help at our hospital from May 2020 to October 2022 as subjects. We collected their basic information (sex and age); measured height, weight, waist and hip circumference, and blood pressure; calculated body mass index (BMI); and detected blood glucose, c-peptide, HbA1c, biomarkers, urinary microalbumin, sensory nerve conduction velocity of lower limbs, ABI, and subcutaneous and visceral fat at the time of MMC recruited and the end of six months. T test and Mann-Whitney U rank sum test were used for measurement data and χ² test or Fisher’s exact probability method for counting data to analyze the data. 【Results】 After 6 months, the levels of fasting blood glucose, postprandial blood glucose, HbA1c, and visceral and subcutaneous fat in all the patients decreased, but the level of fasting c-peptide increased compared with the baseline (all P<0.05). Secondly, compared with the baseline, the control rate of HbA1c (35.21% vs. 13.71% ) and the comprehensive control rate (13.97% vs. 7.26% ) were both significantly increased at six months (P<0.05). Thirdly, after 6 months, the levels of fasting blood glucose, postprandial blood glucose, HbA1c, TG, TC, and UA were decreased more, while the fasting c-peptide and postprandial c-peptide were increased more in the patients of the HbA1c standard group (HbA1c<7% ) than those of the non-standard group. 【Conclusion】 The multiple benefits of blood glucose, blood lipid, uric acid and islet function can be achieved by taking type 2 diabetes patients into MMC. Meanwhile, the rates of HbA1c control and comprehensively reaching the standard are significantly increased. Therefore, MMC can explore a new way for the management of type 2 diabetic patients in this area.

Objective:To investigate the mechanism underlying the inhibiting effect of low-glucose combined with palmitic acid on human colon cancer cells and its influence on the radiosensitivity.Methods:Under the treatment of low-glucose, palmitic acid and low-glucose combined with palmitic acid, the treatment condition that significantly inhibited the proliferation of SW480 was screened by CCK-8 assay. The reactive oxygen species (ROS) level, mitochondrial membrane potential and apoptosis rate were detected by flow cytometry. The changes in the radiosensitivity were detected by immunofluorescence-based γ-H 2AX quantification and colony formation assay. The protein expression level was detected by Western blot. Results:Compared with the control group, the condition of low-glucose combined with 120μmol/L palmitic acid significantly inhibited the proliferation of SW480 cells ( P<0.01). The expression levels of CPT1a, PFKFB3 and PKM were significantly up-regulated, the expression levels of NDUFV1, NDUFV2 and NDUFS1 were remarkably down-regulated, the ROS level was significantly increased and the ATP level was considerably reduced in the cells under metabolic stress (all P<0.01). After irradiation, the number of γ-H 2AX foci was significantly increased ( P<0.05), and the D 0 value was significantly reduced ( P<0.01), the ROS level was considerably increased ( P<0.001), the apoptosis rate was significantly increased ( P<0.001) and the expression level of γ-H 2AX protein was remarkably up-regulated ( P<0.01) in the low-glucose combined with 120μmol/L palmitic acid group. Pretreatment with NAC could reverse the changes of ROS, apoptosis and γ-H 2AX protein expression. Conclusions:The combination of low-glucose and palmitic acid can induce metabolic stress in SW480 cells, inhibit tumor proliferation and increase the radiosensitization when combined with radiotherapy by inducing the generation of ROS and DNA damage.

Objective:To investigate the expression of Pyruvate dehydrogenase kinase 1(PDK1), phosphorylated Pyruvate dehydrogenase (p-PDH) and Pyruvate kinase isozyme type M2 (PKM2) based on Warburg effect pathway in cervical cancer tissues, and explore the roles of these molecules on prognosis and recurrence after postoperative radiation.Methods:The expressions of PDK1, p-PDH and PKM2 in primary tissues of 102 patients with cervical cancer were detected by immunohistochemistry, including 63 patients receiving postoperative radiation. The expression of the three molecules on prognosis and the efficacy of postoperative radiation on cervical cancer were analyzed separately and corporately.The level of mRNA were verified by using the 300 patients from GEO database. Kaplan-Meier method and COX proportional hazards regression model were used for univariate and multivariate analysis.Results:High expression of PDK1 and all the three indicators (PDK1 high/p-PDH high/PKM2 high) were positively correlated with pelvic lymphnode metastasis ( χ2=10.890, 7.407, P<0.05). PDK1 high/p-PDH high/PKM2 high, Federation International of Gynecology and Obstetrics (FIGO) staging, pelvic lymph node metastasis and postoperative radiation could affect the overall survival (OS) and disease-free survival (DFS) ( P<0.05). Multivariate analysis showed that PDK1 high /PDH high/PKM2 high, FIGO staging and postoperative radiation were the independent prognosis factors for OS and DFS( P<0.05). The verification result of the GEO dataset showed that PDK1 high/PDH high/PKM2 high was the risk factor for DFS( P<0.05). Pathological type, pelvic lymph node metastasis and PDK1 high/p-PDH high/PKM2 high could affect the DFS of those patients with postoperative radiation ( P<0.05). In addition, the multivariate analysis showed that pathological type and PDK1 high /p-PDH high/PKM2 high were the independent prognosis factors for DFS( P<0.05). Conclusions:The patients of PDK1 high /p-PDH high/PKM2 high phenotype have poor prognosis and DFS with postoperative radiation, which may be a high-risk group with poor prognosis and high recurrence rate after postoperative radiotherapy of stageⅠ-Ⅱ B cervical cancer.This study provides a novel strategy for stratified treatment of cervical cancer.

Objective: To investigate the relationship between systemic inflammatory markers such as neutrophil/lymphocyte ratio (NLR) and C-reactive protein/albumin ratio (CAR), and lymph node metastasis in patients with cN0 gastric cancer. To establish a nomogram model to predict the risk of lymph node metastasis in patients with cN0 gastric cancer. Methods: The preoperative systemic inflammatory markers and clinical data of 134 patients with cN0 gastric cancer were retrospectively analyzed, and these markers of patients with negative (pN0) or positive (pN+ ) lymph node metastasis in postoperative pathological diagnosis were compared. The receiver operating characteristic (ROC) curve was used to evaluate the predictive effect of preoperative systemic inflammatory markers on lymph node metastasis. The influencing factors for lymph node metastasis were assessed by univariate analysis and multivariate logistic regression analysis. A nomogram subsequently established by R software was validated by Bootstrap resampling as internal validation. Results: Compared with pN0 group, NE (P=0.022), CRP (P<0.001), NLR (P<0.001), PLR (P=0.003) and CAR (P<0.001) were higher, LY (P=0.003) and Alb (P=0.042) were lower in pN+ group. ROC curve analysis showed that the area under the curve (AUC) of postoperative pathological lymph node metastasis in patients with cN0 gastric cancer diagnosed by NLR, PLR and CAR were 0.687, 0.651 and 0.694, respectively, and the best cutoff values were 2.12, 113.59 and 0.02, respectively. The corresponding sensitivity and specificity were 62.9% and 72.2%, 77.4% and 48.6%, 74.2% and 58.3%, respectively. Univariate analysis showed that tumor size, depth of invasion, NLR, PLR and CAR were associated with lymph node metastasis in cN0 gastric cancer patients (all P<0.05). Multivariate analysis showed that depth of invasion, NLR and CAR were independent influencing factors of lymph node metastasis in patients with cN0 gastric cancer. OR were 8.084, 3.540 and 3.092, respectively (all P<0.05). The C-index of the nomogram model was 0.847 (95% CI: 0.782-0.915). The predicting calibration curve was properly fit with the ideal curve in calibration chart. Conclusion Combination of NLR and CAR to establish a nomogram model has a good consistency and can accurately predict the risk of lymph node metastasis in patients with cN0 gastric cancer.

Objective To investigate the expression of microrchidia 2(MORC2) in glioblastoma patients and to evaluate its prognostic value of MORC2 expression combined with IDH1 mutation status for chemoradiotherapy efficacy and new molecular subtype.Methods The expression level of MORC2 in 45 glioblastoma tissues was measured by immunohistochemical staining and its correlation with clinicopathological characteristics and clinical prognosis after chemoradiotherapy was analyzed.Further more,the prognostic values of the expression of MORC2 combined with the status of IDH1 were assessed in a glioblastoma CGGA mRNA dataset.Results High expression of MORC2 was observed in 76％ of glioblastoma patients,which was negatively correlated with overall survival (HR=2.928,95％CI:1.582-5.418,P=0.002;recurrence-free survival (HR=2.204,95％CI:1.186-4.095,P=0.022).Moreover,according to the prognosis value of MORC2 expression and IDH1 mutation status,glioblastoma patients were divided into 3 molecular subtypes.Patients with the subtype of IDH1mt/MORC2low obtained the best clinical prognosis with a median survival of 22 months (95％CI:13.98-30.02),whereas those with the subtype of IDH1wt/MORC2high obtained the worst clinical prognosis with a median survival of 5.63 months (95％CI:3.92-7.34,HR=4.15,95％CI:3.92-7.34,P=0.002).Among IDH1wt glioblastoma patients,MORC2high patients had worse clinical prognosis compared with MORC2low counterparts,prompting that IDH1wt/ MORC2high glioblastoma tissues yielded higher capability of DNA injury repairing and resistance to chemoradiotherapy.Conclusions The high expression of MORC2 can be used as a potential indicator of poor prognosis of glioblastoma patients after chemoradiotherapy.IDH 1 mutation status combined with MORC2 expression can establish a novel molecular subtyping,which provide evidence for stratified therapy for glioblastoma patients.

Objective To observe the improving effect of Hypericum Perforatum L Extracts (HPLES)on depression induced by chronic unpredictable mild stress in mice. Methods The depression model was established by the method of chronic unpredictable mild stress. Fifty depression model mice were divided into model control group,fluoxetine hydrochloride group (2. 6 mg / kg),Hypericum perforatum ex-tract low,medium and high (0. 2 g / kg,0. 4 g / kg,0. 8 g / kg) dose groups according to the random num-ber table method. Another 10 normal mice matched with body weight were taken as the normal control group. The mice in normal control group and the model control group were given pure water by gavage every day,and the mice in other groups were given corresponding solution by gavage for 4 weeks. In addition to the normal control group,the mice in other groups continued to undergo chronic unpredictable mild stress during gavage. The sugar water preference test and forced swimming test were performed after the last administration. Blood samples were collected from the posterior orbital venous plexus,and the levels of dopamine (DA) and brain-derived neurotrophic factor (BDNF) were measured by Elisa. The hippocampal tissues of mice were exam-ined by HE staining. Results Compared with the normal control group,the body mass of mice in the model control group decreased significantly at the first,second,third and fourth weeks ( t=2. 739,4. 162,4. 082, 3. 957;all P<0. 05). At the first,second,third and fourth weeks,the body mass of mice in the low,middle and high dose group of Hypericum perforatum extract were not significantly different from those in the model control group (all P>0. 05). Compared with the normal control group,the sugar water preference index of mice in the model control group was significantly reduced((61. 3± 4. 5)%,(52. 6± 5. 2)%; t=2. 721,P<0. 05),the swimming immobility time was prolonged(( 44. 3± 20. 00) s,(101. 8± 50. 8) s;t=2. 939,P<0. 05),the difference were statistically significant. Compared with the model control group,the sugar water preference index of mice in the low,middle and high dose group of Hypericum perforatum extract increased ((61. 8±4. 7)%,(65. 2±4. 1)%,(62. 6±5. 6)%,t=-3. 005,5. 073,-2. 928,all P<0. 05),the swimming immobility time decreased ((47. 2±17. 9) s,(54. 8±50. 3) s,(61. 3±44. 2) s; t=2. 803,1. 921,1. 903,all P<0. 05). The results of Elisa showed that compared with the normal control group,the levels of serum DA and BDNF of mice in the model control group were significantly lower (t=3. 031,8. 507,all P<0. 05); com-pared with the model control group,the levels of serum DA of mice in the low dose and high dose group of Hypericum perforatum were significantly higher (t=5. 025,3. 414,P<0. 05),and the serum BDNF of mice in the high dose group of Hypericum perforatum was also significantly higher (t=6. 098,P<0. 05),the differ-ence was statistically significant. HE staining showed that compared with the normal control group,the neu-rons in CA3 area of hippocampus in the model control group mice were seriously damaged,suggesting the es-tablishment of the mouse model. Compared with the model control group,the atrophy and degeneration of hippocampal CA3 cells in the three dose groups were significantly reduced. The atrophy and deformation of hippocampal CA3 neurons in the low,middle and high dose groups of Hypericum perforatum extract were re-lieved. Conclusion HPLES have obvious improving and antidepressant effects on the depression model mice induced by chronic unpredictable stress. The above effects may be related to the improvement of serum DA,DBNF level and reduce neuronal damage in CA3 area.

Objective: To observe the improving effect of Hypericum Perforatum L Extracts (HPLES)on depression induced by chronic unpredictable mild stress in mice. Methods: The depression model was established by the method of chronic unpredictable mild stress. Fifty depression model mice were divided into model control group, fluoxetine hydrochloride group (2.6 mg / kg), Hypericum perforatum extract low, medium and high (0.2 g / kg, 0.4 g / kg, 0.8 g / kg) dose groups according to the random number table method. Another 10 normal mice matched with body weight were taken as the normal control group. The mice in normal control group and the model control group were given pure water by gavage every day, and the mice in other groups were given corresponding solution by gavage for 4 weeks. In addition to the normal control group, the mice in other groups continued to undergo chronic unpredictable mild stress during gavage.The sugar water preference test and forced swimming test were performed after the last administration. Blood samples were collected from the posterior orbital venous plexus, and the levels of dopamine (DA) and brain-derived neurotrophic factor (BDNF) were measured by Elisa. The hippocampal tissues of mice were examined by HE staining. Results: Compared with the normal control group, the body mass of mice in the model control group decreased significantly at the first, second, third and fourth weeks (t=2.739, 4.162, 4.082, 3.957; all P<0.05). At the first, second, third and fourth weeks, the body mass of mice in the low, middle and high dose group of Hypericum perforatum extract were not significantly different from those in the model control group (all P>0.05). Compared with the normal control group, the sugar water preference index of mice in the model control group was significantly reduced((61.3±4.5)%, (52.6±5.2)%; t=2.721, P<0.05), the swimming immobility time was prolonged((44.3±20.00) s, (101.8±50.8) s; t=2.939, P<0.05), the difference were statistically significant. Compared with the model control group, the sugar water preference index of mice in the low, middle and high dose group of Hypericum perforatum extract increased((61.8±4.7)%, (65.2±4.1)%, (62.6±5.6)%, t=-3.005, 5.073, -2.928, all P<0.05), the swimming immobility time decreased ((47.2±17.9) s, (54.8±50.3) s, (61.3±44.2) s; t=2.803, 1.921, 1.903, all P<0.05). The results of Elisa showed that compared with the normal control group, the levels of serum DA and BDNF of mice in the model control group were significantly lower (t=3.031, 8.507, all P<0.05); compared with the model control group, the levels of serum DA of mice in the low dose and high dose group of Hypericum perforatum were significantly higher (t=5.025, 3.414, P<0.05), and the serum BDNF of mice in the high dose group of Hypericum perforatum was also significantly higher (t=6.098, P<0.05), the difference was statistically significant. HE staining showed that compared with the normal control group, the neurons in CA3 area of hippocampus in the model control group mice were seriously damaged, suggesting the establishment of the mouse model. Compared with the model control group, the atrophy and degeneration of hippocampal CA3 cells in the three dose groups were significantly reduced. The atrophy and deformation of hippocampal CA3 neurons in the low, middle and high dose groups of Hypericum perforatum extract were relieved. Conclusion HPLES have obvious improving and antidepressant effects on the depression model mice induced by chronic unpredictable stress.The above effects may be related to the improvement of serum DA, DBNF level and reduce neuronal damage in CA3 area.

Objective To investigate the relationship between systemic inflammatory markers such as neutrophil／lymphocyte ratio ( NLR) and C?reactive protein／albumin ratio ( CAR ), and lymph node metastasis in patients with cN0 gastric cancer. To establish a nomogram model to predict the risk of lymph node metastasis in patients with cN0 gastric cancer. Methods The preoperative systemic inflammatory markers and clinical data of 134 patients with cN0 gastric cancer were retrospectively analyzed, and these markers of patients with negative ( pN0 ) or positive ( pN+) lymph node metastasis in postoperative pathological diagnosis were compared. The receiver operating characteristic ( ROC ) curve was used to evaluate the predictive effect of preoperative systemic inflammatory markers on lymph node metastasis. The influencing factors for lymph node metastasis were assessed by univariate analysis and multivariate logistic regression analysis. A nomogram subsequently established by R software was validated by Bootstrap resampling as internal validation. Results Compared with pN0 group, NE (P＝0.022), CRP (P＜0.001), NLR (P＜0.001), PLR (P＝0.003) and CAR ( P＜0.001) were higher, LY ( P＝0.003) and Alb ( P＝0.042) were lower in pN+ group. ROC curve analysis showed that the area under the curve ( AUC) of postoperative pathological lymph node metastasis in patients with cN0 gastric cancer diagnosed by NLR, PLR and CAR were 0.687, 0.651 and 0.694, respectively, and the best cutoff values were 2.12, 113.59 and 0.02, respectively. The corresponding sensitivity and specificity were 62.9% and 72.2%, 77.4% and 48.6%, 74.2% and 58.3%, respectively. Univariate analysis showed that tumor size, depth of invasion, NLR, PLR and CAR were associated with lymph node metastasis in cN0 gastric cancer patients ( all P＜0.05). Multivariate analysis showed that depth of invasion, NLR and CAR were independent influencing factors of lymph node metastasis in patients with cN0 gastric cancer. OR were 8.084, 3.540 and 3.092, respectively ( all P＜0.05). The C?index of the nomogram model was 0.847 (95% CI: 0.782?0.915). The predicting calibration curve was properly fit with the ideal curve in calibration chart.Conclusion Combination of NLR and CAR to establish a nomogram model has a good consistency and can accurately predict the risk of lymph node metastasis in patients with cN0 gastric cancer.

Objective To investigate the relationship between systemic inflammatory markers such as neutrophil／lymphocyte ratio ( NLR) and C?reactive protein／albumin ratio ( CAR ), and lymph node metastasis in patients with cN0 gastric cancer. To establish a nomogram model to predict the risk of lymph node metastasis in patients with cN0 gastric cancer. Methods The preoperative systemic inflammatory markers and clinical data of 134 patients with cN0 gastric cancer were retrospectively analyzed, and these markers of patients with negative ( pN0 ) or positive ( pN+) lymph node metastasis in postoperative pathological diagnosis were compared. The receiver operating characteristic ( ROC ) curve was used to evaluate the predictive effect of preoperative systemic inflammatory markers on lymph node metastasis. The influencing factors for lymph node metastasis were assessed by univariate analysis and multivariate logistic regression analysis. A nomogram subsequently established by R software was validated by Bootstrap resampling as internal validation. Results Compared with pN0 group, NE (P＝0.022), CRP (P＜0.001), NLR (P＜0.001), PLR (P＝0.003) and CAR ( P＜0.001) were higher, LY ( P＝0.003) and Alb ( P＝0.042) were lower in pN+ group. ROC curve analysis showed that the area under the curve ( AUC) of postoperative pathological lymph node metastasis in patients with cN0 gastric cancer diagnosed by NLR, PLR and CAR were 0.687, 0.651 and 0.694, respectively, and the best cutoff values were 2.12, 113.59 and 0.02, respectively. The corresponding sensitivity and specificity were 62.9% and 72.2%, 77.4% and 48.6%, 74.2% and 58.3%, respectively. Univariate analysis showed that tumor size, depth of invasion, NLR, PLR and CAR were associated with lymph node metastasis in cN0 gastric cancer patients ( all P＜0.05). Multivariate analysis showed that depth of invasion, NLR and CAR were independent influencing factors of lymph node metastasis in patients with cN0 gastric cancer. OR were 8.084, 3.540 and 3.092, respectively ( all P＜0.05). The C?index of the nomogram model was 0.847 (95% CI: 0.782?0.915). The predicting calibration curve was properly fit with the ideal curve in calibration chart.Conclusion Combination of NLR and CAR to establish a nomogram model has a good consistency and can accurately predict the risk of lymph node metastasis in patients with cN0 gastric cancer.