The use of tyrosine kinase inhibitors （TKI） has been an important advance in the systemic treatment of hepatocellular carcinoma， but their sustained anti-angiogenic therapy leads to increased tumor hypoxia， accelerates the development of a hypoxic microenvironment and promotes the expressions of hypoxia-inducible factors （HIF）， thereby inducing drug resistance of tumor patients to TKI. This paper summarizes the mechanism of action of HIF mediating TKI resistance in hepatocellular carcinoma in aspects of metabolic reprogramming， abnormal expressions of cancer and cancer-associated genes， and ferroptosis， and sorts resistance response strategies to provide reference for clinical solutions to TKI resistance issues. As results show， HIF/ glycolysis axis inhibitors （isoflavonoid genistein， simvastatin， etc.） can improve TKI resistance based on metabolic reprogramming mechanism； oncogene-targeted inhibitors combined with TKI （the combination of capsaicin and sorafenib） can improve TKI resistance based on abnormal expression of cancer and cancer-related genes； fatty acid synthase inhibitor （orlistat） can improve TKI resistance based on ferroptosis mechanism.

Objective To investigate the effect of computer-aided diagnosis(CAD)as a"second reader"integrated in prostate cancer(PCa)multiparametric magnetic resonance imaging(mpMRI)on the diagnostic performance.Methods Sixty-four patients were recruited retrospectively.Six readers were divided into 3 groups according to the experience.Unknown the pathologic diagnosis,readers graded according to prostate imaging reporting and data system(PI-RADS)v2.1 and accepted or rejected the revision of PI-RADS v2.1 scores by CAD.Using pathology as the gold standard,the diagnostic efficiency,diagnostic confidence and reading time of PI-RADS v2.1 were compared before and after CAD assistant.Results On the level of lesions,without CAD,the area under the curve(AUC)of reader A1 was higher than B1,C1 and C2,and the AUC of reader A2 was higher than C1 and C2,the difference was statistically significant(P＜0.05).While the difference of AUC among other readers were not significant(P＞0.05).With CAD,the difference of AUC among all readers were not significant(P＞0.05).On the level of patients,the mean AUC of all readers with CAD[0.903,95％confidence interval(CI)0.848-0.958]was higher than that without CAD(0.863,95％CI 0.800-0.929),the differ-ence was statistically significant(F=6.52,P=0.040).The difference of AUC between without and with CAD assistance was-0.040(95％CI-0.078--0.003),standard deviation was 0.016,the difference was statistically significant(t=-2.55,P=0.040).The diag-nostic confidence of readers was improved significantly with CAD(P＜0.05).Besides,the average reading time of each case required an additional 0.8 min.Conclusion After integrating CAD into PCa mpMRI diagnosis as a"second reader",the performance of less experienced readers can be improved and show similar diagnostic efficiency with experienced readers.

Objective To evaluate the influence of stress distributions on bone-anchored maxillary protraction at different protraction sites, so as to guide patients to choose an optimal protraction site in clinic. Methods A three-dimensional (3D) finite element model of child head with implant anchorages was establised. Four protraction sites were set according to the position of implant installation. Working condition 1: the alveolar bone at the intersection of distal 2 mm of primary lateral incisor crown distal surface and gingival cervical margin to 5 mm. Working condition 2: the alveolar bone at the intersection of mesial 2 mm of maxillary first primary molar crown mesial surface and gingival cervical margin to 5 mm. Working condition 3: the alveolar bone at the intersection of mesial 2 mm of maxillary first molar crown mesial surface and gingival cervical margin to 5 mm. Working condition 4: the alveolar bone at the intersection of distal 2 mm of maxillary first molar crown distal surface and gingival cervical margin to 5 mm. The finite element models were loaded with 500 g protraction force at each side with 30° forward direction to the occlusal plane. Stress distributions on each suture were analysed. Results The maximum stress of frontomaxillary suture was in working condition 2 (1 477-28 190 Pa). The maximum stress of nasomaxillary suture was in working condition 1 (5.296-924 Pa). The maximum stress of zygomaticomaxillary suture was in working condition 4(394.7-13 130 Pa). The maximum stress of zygomaticofrontalis suture was in working condition 4 (495.2-31 690 Pa). The maximum stress of zygomaticotemporal suture was in working condition 3 (1 148-15 870 Pa). The maximum stress of medianpalatine suture was in working condition I (6.479-730 Pa). Conclusions When the protraction sites are set in distal maxillary primary lateral incisor and mesial maxillary first primary molar, it is of positive significance to improve the concave profile, especially in nose root. When the protraction sites are set in mesial or distal maxillary first molar, it is of positive significance to improve the concave profile, especially in maxillary basal bone of the midface.

Objective:To investigate the factors associated with delay in anticoagulant therapy in patients with cerebral venous sinus thrombosis (CVST) and its effect on outcome.Methods:Patients with CVST admitted to Changhai Hospital, Naval Medical University from January 2010 to August 2021 were retrospectively enrolled. Patients were divided into early anticoagulation group and late anticoagulation group by the median time interval from first symptom to initiation of anticoagulation. The modified Rankin Scale was used for outcome assessment at 90 d after onset. 0-2 scores were defined as good outcome and 3-6 were defined as poor outcome. Demographic and clinical data were compared for the early versus late anticoagulation group and for the good versus poor outcome groups. Multivariable logistic regression was used to identify independent influencing factors of delay in anticoagulation and the correlation of delay in anticoagulation with poor outcome. Results:A total of 131 patients were included, their age was 40.07±15.11 years old, and 68 (51.91%) were male. Of these, 65 patients (49.62%) were in the early anticoagulation group and 14 (10.69%) were in the poor outcome group. Compared with the late anticoagulation group, the early anticoagulation group had a significantly higher proportion of patients with seizures and brain parenchymal damage as well as higher D-dimer levels on admission, while the proportion of patients with visual impairment/papilloedema was significantly lower (all P<0.05). Compared with the good outcome group, the poor outcome group had significantly higher proportions of patients with seizures, dyskinesia, impaired consciousness, low Glasgow Coma Scale score, and brain parenchymal damage as well as higher D-dimer, total cholesterol and low density lipoprotein cholesterol levels, sites of thrombus involvement were more common in the superior sagittal and straight sinuses, and significantly lower proportions of patients with headache and lower albumin levels on admission (all P<0.05). Multivariate logistic regression analysis showed that visual impairment/papilloedema (odds ratio [ OR] 0.119, 95% confidence interval [ CI] 0.030-0.473; P=0.002) and brain parenchymal damage ( OR 1.341, 95% CI 1.042-1.727; P=0.023) were independently associated with a delay in anticoagulation treatment, and a delay in anticoagulation treatment ( OR 6.102, 95% CI 1.185-30.504; P=0.030) and D-dimer level on admission ( OR 1.299, 95% CI 1.141-1.480; P<0.001) were the independent predictors of poor outcome in patients with CVST. Conclusions:Visual impairment/papilloedema and absence of brain parenchymal damage on cranial imaging are the independent risk factors for delay in anticoagulation in patients with CVST. The delay in anticoagulation is strongly associated with the poor outcome in patients with CVST.

Rett syndrome (RTT) is a progressive neurodevelopmental disorder, mainly caused by mutations in MeCP2 and currently with no cure. We report here that neurons from R106W MeCP2 RTT human iPSCs as well as human embryonic stem cells after MeCP2 knockdown exhibit consistent and long-lasting impairment in maturation as indicated by impaired action potentials and passive membrane properties as well as reduced soma size and spine density. Moreover, RTT-inherent defects in neuronal maturation could be pan-neuronal and occurred in neurons with both dorsal and ventral forebrain features. Knockdown of MeCP2 led to more severe neuronal deficits as compared to RTT iPSC-derived neurons, which appeared to retain partial function. Strikingly, consistent deficits in nuclear size, dendritic complexity and circuitry-dependent spontaneous postsynaptic currents could only be observed in MeCP2 knockdown neurons but not RTT iPSC-derived neurons. Both neuron-intrinsic and circuitry-dependent deficits of MeCP2-deficient neurons could be fully or partially rescued by re-expression of wild type or T158M MeCP2, strengthening the dosage dependency of MeCP2 on disease phenotypes and also the partial function of the mutant. Our findings thus reveal stable neuronal maturation deficits and unexpectedly, graded sensitivities of neuron-inherent and neural transmission phenotypes towards the extent of MeCP2 deficiency, which is informative for future therapeutic development.

Vascular cognitive impairment (VCI) is a progressive cognitive impairment caused by cerebrovascular disease or vascular risk factors. It is the second common type of cognitive impairment after Alzheimer's disease. VCI can be caused by a variety of signal and metabolic pathways. Its core mechanism is that cerebrovascular disease destroys the neurovascular unit composed of neurons, glial cells, and cerebrovascular endothelial cells. This article summarizes and discusses the known mechanisms of VCI, in order to deepen the understanding of the molecular pathological process of VCI and provide ideas for its prevention and treatment.

Objective:To study the relationship between somatization symptoms and body mass index (BMI), sleep and cognitive function in patients with depression.Methods:A total of 119 patients with depression were selected from January to December in 2019.According to the score of patient health questionnaire-15(PHQ15), they were divided into mild somatization group ( n=75) and moderate severe somatization group ( n=44). Hamilton depression scale-24(HAMD-24), patient health questionnaire-15, Pittsburgh sleep quality index(PSQI) and Montreal cognitive assessment(MoCA) were used to evaluate all subjects.SPSS 23.0 software was used for data analysis.Independent sample t-test was used to compare BMI, sleep and cognitive function scores between the two groups.Pearson correlation analysis was used to study the correlation between somatization symptoms and sleep quality and cognitive function. Results:There were significant differences in BMI((21.70±3.09)kg/m 2, (23.31±3.51)kg/m 2), PSQI((12.56±4.37), (14.37±3.72)), sleep quality(1.87±0.86), (2.21±0.80)), sleep disorder ((1.24±0.59), (1.65±0.53))and daytime dysfunction((2.45±0.81), (2.77±0.48)) between the two groups ( t=-3.783--2.133, all P<0.05), but no difference was found in cognition ( P>0.05). Correlation analysis showed that after controlling HAMD, PHQ-15 was positively correlated with PSQI, sleep quality, sleep disorder, daytime dysfunction and language score in MoCA ( r=0.205-0.298, all P<0.05). Conclusion:The severity of somatization in patients with depression is related to BMI, sleep quality, sleep disorder, daytime dysfunction and language function, suggesting that they may play an important role in the pathogenesis of depression with somatization.

Cognitive impairment includes several clinical processes from mild cognitive impairment to dementia, and now it has been a serious public health problem, as there is no effective treatment, it has caused a heavy economic and psychological burden on the family and society, therefore, it seems important to find effective intervention means.Vitamin D is an essential nutrient element for the human body, more and more evidences show that it also participates in many extraskeletal biological reactions, such as nervous system regulatory processes, in addition to calcium and phosphorus metabolism.Several researches have revealed that Vitamin D deficiency is associated with impaired cognition, the mechanisms mediating this link are poorly understood, what's more, for further clinical application, we need to solve the problems like choosing the suitable populations and drug dosage, therefore, this article summarizes and analyzes the effects of serum Vitamin D levels on the cognitive function of different populations, the research progress of Vitamin D intervention research and its possible mechanism of action, hoping to provide references for the clinical application of Vitamin D in the treatment of cognitive impairment.The results show that Vitamin D deficiency is related to the decline of cognitive function in different populations, and Vitamin D can improve cognitive function through reducing Aβ toxicity, anti-inflammatory and anti-oxidative stress and other mechanisms, its supplementation is expected to be an important measure of treating cognitive impairment, in the future, large-scale longitudinal cohort studies are needed to determine the optimal dosage and duration of treatment.

Objective: To analyze ¹⁸F-fluorodeoxyglucose(FDG) PET/CT imaging manifestations in patients with peritoneal carcinomatosis (PC) from colorectal cancer (CRC) and investigate its clinical significance. Methods: From May 2016 to August 2018, 46 patients (25 males, 21 females; age range: 36-82(62.0±10.4) years) with PC from CRC who underwent ¹⁸F-FDG PET/CT imaging in Affiliated Hospital of Nantong University and had complete clinical data were retrospectively analyzed. The peritoneal carcinomatosis index (PCI) grading system was used to evaluate the PC lesions. Independent-sample t test and Kruskal-Wallis H test were used for data analysis. Results: There were various CT manifestations of PC, while FDG metabolism on PET was observed in all 46 patients. Patients were divided into different groups according to the location of the primary CRC lesion. The diameter of PC lesion in the left colon group was (2.46±1.26) cm, which was significantly different from that of the rectum group ((3.19±1.72) cm; t=-2.77, P<0.01). The maximum standardized uptake value (SUV_max) in the right colon group were significantly higher than that in the left colon group (9.16±4.79 vs 6.99±3.50; t=2.92, P<0.01). The PCI score ranged from 1 to 30 in 46 patients, and there was no significant difference in PCI score distribution (≥20 vs <20) among the right colon group, left colon group and rectum group (H=0.242, P>0.05). Ten patients had abdominal and pelvic effusion. Conclusion ¹⁸F-FDG PET/CT can well display the PC in patients with CRC, and the combination of PCI and ¹⁸F-FDG PET/CT plays an important role in the diagnosis and treatment of PC.

Objective: To detect the expression of NRAGE protein in esophageal squamous cell carcinoma and investigate the relationship between NRAGE and therapeutic effect of radiotherapy. Methods: The expression level of NRAGE in 44 patients with esophageal squamous cell carcinoma was evaluated by immunohistochemistry and statistically analyzed along with clinical data by using multivariate analysis using Cox regression model. Results: The overall expression level of NRAGE protein in esophageal squamous cell carcinoma (P=0.025) and the expression level of NRAGE nuclear protein (P=0.008) were negatively correlated with short-term efficacy. In terms of the overall expression level of NRAGE protein, the 3-year survival rates in the strongly positive group and the positive weakly positive group were 16% and 36%(P=0.198). As for the expression of NRAGE nuclear protein, the 3-year survival rates in the strongly positive group and the positive+ weakly positive group were 0% and 41%(P<0.001). Multivariate analysis using Cox regression model demonstrated that as for the expression of NRAGE nuclear protein, the risk of death in the strongly positive group was significantly higher than those in the positive+ weakly positive group (P=0.002). Conclusion The overall expression level of NRAGE protein in the esophageal cancer is negatively correlated with the short-term efficacy of radiotherapy, whereas it is not correlated with long-term survival rate. The strongly positive expression level of NRAGE nuclear protein is negatively correlated with the short-term efficacy of radiotherapy and the long-term survival rate, prompting that NRAGE may be a molecular indicator for predicting radiation resistance and even the efficacy of radiotherapy for esophageal squamous cell carcinoma