miR-101a-3p/ROCK2 axis regulates neuronal injury in Parkinson's disease models.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). This study focuses on deciphering the role of microRNA (miR)-101a-3p in the neuronal injury of PD and its regulatory mechanism. METHODS: We constructed a mouse model of PD by intraperitoneal injection of 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine hydrochloride (MPTP), and used 1-methyl-4-phenylpyridinium (MPP+) to treat Neuro-2a cells to construct an in-vitro PD model. Neurological dysfunction in mice was evaluated by swimming test and traction test. qRT-PCR was utilized to examine miR-101a-3p expression and ROCK2 expression in mouse brain tissues and Neuro-2a cells. Western blot was conducted to detect the expression of α-synuclein protein and ROCK2 in mouse brain tissues and Neuro-2a cells. The targeting relationship between miR-101a-3p and ROCK2 was determined by dual-luciferase reporter gene assay. The apoptosis of neuro-2a cells was assessed by flow cytometry. RESULTS: Low miR-101a-3p expression and high ROCK2 expression were found in the brain tissues of PD mice and MPP+-treated Neuro-2a cells; PD mice showed decreased neurological disorders, and apoptosis of Neuro-2a cells was increased after MPP+ treatment, both of which were accompanied by increased accumulation of α-synuclein protein. After miR-101a-3p was overexpressed, the neurological function of PD mice was improved, and the apoptosis of Neuro-2a cells induced by MPP+ was alleviated, and the accumulation of α-synuclein protein was reduced; ROCK2 overexpression counteracted the protective effect of miR-101a-3p. Additionally, ROCK2 was identified as the direct target of miR-101a-3p. CONCLUSION: MiR-101a-3p can reduce neuronal apoptosis and neurological deficit in PD mice by inhibiting ROCK2 expression, suggesting that miR-101a-3p is a promising therapeutic target for PD.

Roles of ubiquitin­specific protease 13 in normal physiology and tumors (Review).

Ubiquitin-specific protease 13 (USP13) is one of the most important deubiquitinases involved in various diseases. As deubiquitinases are components of the deubiquitination process, a significant post-translational modification, they are potential treatment targets for different diseases. With recent technological developments, the structure of USP13 and its pathological and physiological functions have been investigated. However, USP13 expression and function differ in various diseases, especially in tumors, and the associated mechanisms are complex and remain to be fully investigated. The present review summarized the recent discoveries and the current understanding of the USP13 function in tumors.

Breeding of Saccharomyces cerevisiae with a High-Throughput Screening Strategy for Improvement of S-Adenosyl-L-Methionine Production.

S-adenosyl-l-methionine (SAM), a vital physiologically active substance in living organisms, is produced by fermentation over Saccharomyces cerevisiae. The main limitation in SAM production was the low biosynthesis ability of SAM in S. cerevisiae. The aim of this work is to breed an SAM-overproducing mutant through UV mutagenesis coupled with high-throughput selection. Firstly, a high-throughput screening method by rapid identification of positive colonies was conducted. White colonies on YND medium were selected as positive strains. Then, nystatin/sinefungin was chosen as a resistant agent in directed mutagenesis. After several cycles of mutagenesis, a stable mutant 616-19-5 was successfully obtained and exhibited higher SAM production (0.41 g/L vs 1.39 g/L). Furthermore, the transcript levels of the genes SAM2, ADO1, and CHO2 involved in SAM biosynthesis increased, while ergosterol biosynthesis genes in mutant 616-19-5 significantly decreased. Finally, building on the above work, S. cerevisiae 616-19-5 could produce 10.92 ± 0.2 g/L SAM in a 5-L fermenter after 96 h of fermentation, showing a 2.02-fold increase in the product yield compared with the parent strain. Paving the way of breeding SAM-overproducing strain has improved the good basis for SAM industrial production.

Effects of ulinastatin therapy in deep vein thrombosis prevention after brain tumor surgery: A single-center randomized controlled trial.

BACKGROUND: Venous thromboembolism (VTE) is a common neurosurgical complication after brain tumor resection, and its prophylaxis has been widely studied. There are no effective drugs in the clinical management of venous thromboembolism, and there is an absence of evidence-based medicine concerning the treatment of severe multiple traumas. AIM: To explore whether ulinastatin (UTI) can prevent VTE after brain tumor resection. METHODS: The present research included patients who underwent brain tumor resection. Patients received UTIs (400,000 IU) or placebos utilizing computer-based random sequencing (in a 1:1 ratio). The primary outcome measures were the incidence of VTE, coagulation function, pulmonary emboli, liver function, renal function, and drug-related adverse effects. RESULTS: A total of 405 patients were evaluated between January 2019 and December 2021, and 361 of these were initially enrolled in the study to form intention-to-treat, which was given UTI (n = 180) or placebo (n = 181) treatment in a random manner. There were no statistically significant differences in baseline clinical data between the two groups. The incidence of VTE in the UTI group was remarkably improved compared with that in the placebo group. UTI can improve coagulation dysfunction, pulmonary emboli, liver function, and renal function. No significant difference was identified between the two groups in the side effects of UTI-induced diarrhea, vomiting, hospital stays, or hospitalization costs. The incidence of allergies was higher in the UTI group than in the placebo group. CONCLUSION: The findings from the present research indicated that UTI can decrease the incidence of VTE and clinical outcomes of patients after brain tumor resection and has fewer adverse reactions.

Combination of transcatheter arterial chemoembolization and anti-PD-L1 liposomes therapy suppressed hepatocellular carcinoma progression in mice.

BACKGROUND: Hepatocellular carcinoma (HCC) is a serious life-threatened tumor with high morbidity and mortality. This study aimed to study the effects of combination TACE and anti-PD-L1 liposome drug in treating HCC in mice models. METHODS: We constructed the liposome drug with phosphatidylcholine and cholesterol and mannitol, etc. Besides, the HCC mice model was established through abdominal subcutaneous injection HepG2 cancer cells in mice, then the PE-10 polyethylene catheter was used for TACE therapy. The mice were separately received transcatheter arterial chemoembolization treatment, avelumab liposome drug therapy, and TACE combined with avelumab liposome drug therapy. Flow cytometry was used to analyze cell apoptosis. Western blot, Immunofluorescence staining, real-time PCR were performed to detect protein and gene expressions. RESULTS: The liposomes drug was successfully constructed with a diameter of (125.5 ± 15.3) nm. After the mice received TACE and (or) immunotherapy, the combined liposome drug therapy significantly reduced the volume of hepatic carcinoma tissues, besides, the apoptotic rate of hepatic carcinoma cells in the combined liposome drug treatment group was increased obviously compared with other groups. Moreover, the protein TGFßR2 located in the cellular membrane was obviously down-regulated in the combined liposome drug therapy, while the expression of SMAD7 and PTPN14 was up-regulated in the treatment groups compared with the mice without treatment, besides, the protein PTPN14 was mainly located in the nucleus. Additionally, the mRNA expression of genes SNAI1 and Vimentin was significantly down-regulated in the combined liposome drug therapy. CONCLUSION: Combination of transcatheter arterial chemoembolization and anti-PD-L1 liposome drug therapy significantly suppressed hepatocellular carcinoma proliferation and metastasis in mice models.

DCE-MRI-based radiomics in predicting angiopoietin-2 expression in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer, and the third leading cause of cancer death worldwide. Studies have shown that increased angiopoietin-2 (Ang-2) expression relative to Ang-1 expression in tumors is associated with a poor prognosis.The purpose of this study was to investigate the efficacy of predicting Ang-2 expression in HCC by preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-based radiomics. METHODS: The data of 52 patients with HCC who underwent surgical resection in our hospital were retrospectively analyzed. Ang-2 expression in HCC was analyzed by immunohistochemistry. All patients underwent preoperative upper abdominal DCE-MRI and intravoxel incoherent motion diffusion-weighted imaging scans. Radiomics features were extracted from the early and late arterial and portal phases of axial DCE-MRI. Univariate analysis and least absolute shrinkage and selection operator (LASSO) was performed to select the optimal radiomics features for analysis. A logistic regression analysis was performed to establish a DCE-MRI radiomics model, clinic-radiologic (CR) model and combined model integrating the radiomics score with CR factors. The stability of each model was verified by 10-fold cross-validation. Receiver operating characteristic (ROC) curve analysis, calibration curve analysis and decision curve analysis (DCA) were employed to evaluate these models. RESULTS: Among the 52 HCC patients, high Ang-2 expression was found in 30, and low Ang-2 expression was found in 22. The areas under the ROC curve (AUCs) for the radiomics model, CR model and combined model for predicting Ang-2 expression were 0.800, 0.874, and 0.933, respectively. The DeLong test showed that there was no significant difference in the AUC between the radiomics model and the CR model (p > 0.05) but that the AUC for the combined model was significantly greater than those for the other 2 models (p < 0.05). The DCA results showed that the combined model outperformed the other 2 models and had the highest net benefit. CONCLUSION: The DCE-MRI-based radiomics model has the potential to predict Ang-2 expression in HCC patients; the combined model integrating the radiomics score with CR factors can further improve the prediction performance.

Detection of Epstein-Barr virus infection in thymic epithelial tumors by nested PCR and Epstein-Barr-encoded RNA ISH.

BACKGROUND: Epstein-Barr virus (EBV) is well known to be associated with a lot of tumors, including lymphoma, nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and some other carcinomas with similar lymphoepithelioma-like features. However, the association between EBV and thymic epithelial tumors (TETs) is inconclusive as reports in this regard are not entirely consistent and the methods employed are of different sensitivity and specificity. The geographical difference of the patients is also one of the reasons for the different points of view. METHODS: In our study, we examined 72 thymomas, including 3 cases of type A thymomas, 27 cases of type AB, 6 cases of type B1, 26 cases of type B2 and 10 cases of type B3 thymomas, and 15 thymic carcinomas to detect the viral genome at both DNA and RNA levels. The genome DNA of fresh tissues was first screened by nested polymerase chain reaction (PCR), which could be regarded as the most sensitive method to detect small amounts of DNA. Then all the tissue blocks were further submitted for viral localization by Epstein-Barr-encoded RNA (EBER) ISH. Group parameters were assessed using the chi-square test at a significance level of p < 0.05. RESULTS: Nested PCR results showed that none of type A, eight (29.6%) type AB, one (16.7%) type B1, fifteen (57.7%) type B2, and four (40.0%) type B3 were positive for EBV genome. However, none of them detected EBER expression except for one case of type B2 thymoma. Fourteen (93.3%) thymic carcinomas were positive for EBV by nested PCR, of which three displayed weak nuclear signals within the tumor cells by EBER ISH. CONCLUSIONS: These results showed that nested PCR was a sensitive method for screening the EBV genome in thymic epithelial tumors. As the malignancy of thymoma increases, the rate of EBV infection became higher. Thymic carcinomas were well associated with the Epstein-Barr virus.There was significant association between the EBV infection rate and thymoma type (p < 0.05). We further analyzed the association between EBV infection and myasthenia gravis. However, it showed no significant difference(p = 0.2754), although the EBV infection rate was higher in the thymomas with myasthenia gravis.

Radiomics models based on multisequence MRI for predicting PD-1/PD-L1 expression in hepatocellular carcinoma.

The purpose of this study was to explore the effectiveness of radiomics based on multisequence MRI in predicting the expression of PD-1/PD-L1 in hepatocellular carcinoma (HCC). One hundred and eight patients with HCC who underwent contrast-enhanced MRI 2 weeks before surgical resection were enrolled in this retrospective study. Corresponding paraffin sections were collected for immunohistochemistry to detect the expression of PD-1 and PD-L1. All patients were randomly divided into a training cohort and a validation cohort at a ratio of 7:3. Univariate and multivariate analyses were used to select potential clinical characteristics related to PD-1 and PD-L1 expression. Radiomics features were extracted from the axial fat-suppression T2-weighted imaging (FS-T2WI) images and the arterial phase and portal venous phase images from the axial dynamic contrast-enhanced MRI, and the corresponding feature sets were generated. The least absolute shrinkage and selection operator (LASSO) was used to select the optimal radiomics features for analysis. Logistic regression analysis was performed to construct single-sequence and multisequence radiomics and radiomic-clinical models. The predictive performance was judged by the area under the receiver operating characteristic curve (AUC) in the training and validation cohorts. In the whole cohort, PD-1 expression was positive in 43 patients, and PD-L1 expression was positive in 34 patients. The presence of satellite nodules served as an independent predictor of PD-L1 expression. The AUC values of the FS-T2WI, arterial phase, portal venous phase and multisequence models in predicting the expression of PD-1 were 0.696, 0.843, 0.863, and 0.946 in the training group and 0.669, 0.792, 0.800 and 0.815 in the validation group, respectively. The AUC values of the FS-T2WI, arterial phase, portal venous phase, multisequence and radiomic-clinical models in predicting PD-L1 expression were 0.731, 0.800, 0.800, 0.831 and 0.898 in the training group and 0.621, 0.743, 0.771, 0.810 and 0.779 in the validation group, respectively. The combined models showed better predictive performance. The results of this study suggest that a radiomics model based on multisequence MRI has the potential to predict the preoperative expression of PD-1 and PD-L1 in HCC, which could become an imaging biomarker for immune checkpoint inhibitor (ICI)-based treatment.

Prognostic Correlation between Tumor Volume and Complete Resection of Thymoma at Different Masaoka-Koga Stages.

OBJECTIVE: Thymoma is a slow-growing epithelial tumor of thymus gland. Its size is associated with its prognosis. The aim of this study was to analyze the prognostic correlation of tumor volume and complete resection of thymoma at different Masaoka-Koga stages. METHODS: A retrospective study was carried out, using the data of 502 patients who underwent complete resection of thymectomy at Zhongshan Hospital, Fudan University, in Shanghai, China, from February 2009 to February 2016. The characteristics of the patients were collected. Using Masaoka-Koga staging system, patients were divided into four different subcohorts: Stage I, stage II, stage III and stage IVa/IVb. The relationship between tumor volume and postoperative recurrence was analyzed for each subcohort, using receiver operating curves, cutoff values were obtained. and patients were grouped according to the cutoff values. Survival analysis was performed with the help of Kaplan-Meier method, and the difference between the two survival curves was compared using log-rank test. Whether tumor volume could be used as an independent risk factor for thymoma prognosis was analyzed, using a univariate Cox proportional hazards model. RESULTS: The area under the curve was 0.718, 0.740, 0.798, and 0.804 for the stage I, II, III, and IVa/IVb subcohorts, respectively, and the cutoff values of tumor volume for predicting recurrence were 47.90 cm3, 53.70 cm3, 76.35 cm3, and 89.05 cm3, respectively. Patients with tumor volumes greater than the cutoff values had significantly shorter recurrence-free survival than those with tumor volumes less than the cutoff values (p < 0.001). The results of the univariate Cox proportional hazards model indicated that tumor volume was an independent risk factor for thymoma prognosis and for postoperative prognosis of thymoma in Masaoka-Koga stage I (p < 0.001). CONCLUSIONS: Tumor volume is significantly correlated with the postoperative prognosis of thymoma in Masaoka-Koga stage I and can serve as an independent risk factor for predicting postoperative tumor recurrence.

Effect of preoperative pulmonary artery pressure on the prognosis of end-stage heart failure patients after heart transplantation.

OBJECTIVE: To evaluate the effect of preoperative pulmonary artery pressure on perioperative outcome of end-stage heart failure patients undergoing heart transplantation. METHODS: Retrospective analysis was undertaken on the clinical data of patients receiving heart transplantation in the Department of Cardiovascular Surgery of our hospital from March 2017 to March 2022. A ROC curve analysis was developed between mean pulmonary artery pressure (mPAP) and postoperative mortality using mPAP as diagnostic criteria. Patients were divided into groups based on this threshold to determine the best mPAP threshold value for predicting postoperative nosocomial mortality, and the differences in preoperative and intraoperative data, postoperative complications, and clinical prognosis of patients in the two groups were compared. Patients were followed up to draw the survival curve of patients in the two groups. RESULTS: The study enlisted the participation of 105 patients. ROC curve research revealed that preoperative pulmonary artery pressure was substantially linked with death following heart transplantation, with mPAP = 30.5mmHg being the best threshold. The group with mPAP ≥ 30.5mmHg had a greater incidence of postoperative ECMO support (28.2% vs. 10.6%, P = 0.021) and a higher incidence of in-hospital mortality (15.4% vs. 1.5%, P = 0.019) than the group with mPAP < 30.5mmHg. The postoperative survival rates of 105 patients were 91.3%, 88.7%, 81.6%, and 77.5% at 1, 2, 3, and 4 years, respectively, however, there was no significant difference between the two groups of patients in the postoperative intermediate-far survival rate (P = 0.431). CONCLUSIONS: Preoperative pulmonary artery pressure in patients with end-stage heart failure is intimately correlated with perioperative prognosis of heart transplant recipients. The optimal cut-off mPAP value in predicting perioperative prognosis of heart transplant recipients is 30.5mmHg. In the high mPAP group, perioperative ECMO support rate and perioperative mortality rate are high, which do not affect the medium and long-term prognosis of the recipients undergoing heart transplantation.

A correlative study between IVIM-DWI parameters and VEGF and MMPs expression in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Angiogenic factors may be valuable indices of tumor recurrence and treatment and potentially useful markers for predicting the response to antiangiogenesis therapy. Vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) are major drivers of tumor angiogenesis. Preoperatively predicting the expression of VEGF and MMPs is crucial for treating HCC. Intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) has been successfully used in the differential diagnosis of HCC, pathological grading, and treatment response evaluation. However, the correlations between IVIM-DWI parameters and VEGF and MMP expression have not been reported. This study provides a preliminary analysis of the correlation between IVIM-DWI parameters and the expression of VEGF, MMP-2, and MMP-9 to investigate the value of IVIM-DWI in the noninvasive evaluation of angiogenesis in HCC. Methods: IVIM-DWI was performed in 61 patients with HCC 1 week before they underwent surgical resection. VEGF, MMP-2, and MMP-9 expression was detected using immunohistochemistry staining. Spearman correlation analysis was used to analyze the correlations between the IVIM-DWI parameters and VEGF, MMP-2, and MMP-9 expression in HCC. Results: The fast apparent diffusion coefficient fraction (f) value was positively correlated with the expression of VEGF (P<0.001), MMP-2 (P=0.002), and MMP-9 (P<0.001). The fast apparent diffusion coefficient (D*) was positively correlated with VEGF (P<0.001) and MMP-9 (P<0.001) expression but was not correlated with MMP-2 (P=0.659) expression. The apparent diffusion coefficient (ADC) and slow apparent diffusion coefficient (D) values were not significantly correlated with the expression of VEGF (P=0.103 and P=0.543, respectively), MMP-2 (P=0.596 and P=0.338, respectively), or MMP-9 (P=0.102 and P=0.660, respectively). Conclusions: IVIM-DWI can be used to noninvasively evaluate angiogenesis in HCC.

Girdin acts as an oncogene in gastric cancer by regulating AKT/GSK3ß/ß-catenin signaling.

ThE present work focused on exploring Girdin expression within gastric cancer (GC), examining the effect of Girdin on the cell phenotype of GC, and clarifying the underlying mechanisms. Girdin expression in GC samples was identified by immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR) assays. Girdin-targeting siRNAs were transfected into GC cells; later, we examined GC cell proliferation, migration, invasion, and apoptosis, respectively. Additionally, the protein expression was examined through Western blotting assay. Moreover, the tumor implantation experiment was conducted for examining Girdin knockdown in vivo. The results showed that Girdin expression elevated within GC samples, which was associated with the dismal prognostic outcome. Girdin knockdown suppressed GC cell proliferation, migration, and invasion, and enhanced apoptosis and cell cycle arrest. Girdin promoted the phosphorylation of AKT, GSK3ß, and ß-catenin. Moreover, Girdin inhibited the phosphorylation of ß-catenin. Girdin suppressed cell apoptosis and stimulated cell migration and invasion, while AKT inhibitor (MK2206) treatment reversed the effect of Girdin overexpression, and GSK3ß inhibitor (CHIR99021) treatment enhanced the effect of Girdin overexpression on GC cells. Besides, Girdin delayed tumor growth in vivo. In conclusion, Girdin was abnormally expressed in GC samples, which promoted the development of GC by regulating AKT/GSK3ß/ß-catenin signaling.

Radiomic Analysis Based on Magnetic Resonance Imaging for Predicting PD-L2 Expression in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the sixth most common malignant tumour and the third leading cause of cancer death in the world. The emerging field of radiomics involves extracting many clinical image features that cannot be recognized by the human eye to provide information for precise treatment decision making. Radiomics has shown its importance in HCC identification, histological grading, microvascular invasion (MVI) status, treatment response, and prognosis, but there is no report on the preoperative prediction of programmed death ligand-2 (PD-L2) expression in HCC. The purpose of this study was to investigate the value of MRI radiomic features for the non-invasive prediction of immunotherapy target PD-L2 expression in hepatocellular carcinoma (HCC). A total of 108 patients with HCC confirmed by pathology were retrospectively analysed. Immunohistochemical analysis was used to evaluate the expression level of PD-L2. 3D-Slicer software was used to manually delineate volumes of interest (VOIs) and extract radiomic features on preoperative T2-weighted, arterial-phase, and portal venous-phase MR images. Least absolute shrinkage and selection operator (LASSO) was performed to find the best radiomic features. Multivariable logistic regression models were constructed and validated using fivefold cross-validation. The area under the receiver characteristic curve (AUC) was used to evaluate the predictive performance of each model. The results show that among the 108 cases of HCC, 50 cases had high PD-L2 expression, and 58 cases had low PD-L2 expression. Radiomic features correlated with PD-L2 expression. The T2-weighted, arterial-phase, and portal venous-phase and combined MRI radiomics models showed AUCs of 0.789 (95% CI: 0.702-0.875), 0.727 (95% CI: 0.632-0.823), 0.770 (95% CI: 0.682-0.875), and 0.871 (95% CI: 0.803-0.939), respectively. The combined model showed the best performance. The results of this study suggest that prediction based on the radiomic characteristics of MRI could noninvasively predict the expression of PD-L2 in HCC before surgery and provide a reference for the selection of immune checkpoint blockade therapy.

Improving ATP availability by sod1 deletion with a strategy of precursor feeding enhanced S-adenosyl-L-methionine accumulation in Saccharomyces cerevisiae.

S-adenosyl-L-methionine (SAM), used in diverse pharmaceutical applications, was biosynthesized from L-methionine (L-met) and adenosine triphosphate (ATP). This study aims to increase the accumulation of SAM in Saccharomyces cerevisiae by promoting ATP availability. Strain ΔSOD1 was obtained from the parent strain WT15-33 (CCTCC M 2021915) by deleting gene sod1, which improved the supply of ATP. The SAM content in strain ΔSOD1 exhibited a 22.3% improvement compared to the parent strain, which reached 93.6 mg g-1. The transformation of NADH (reduced nicotinamide adenine dinucleotide) and the relative expression of ATPase essential genes were investigated, respectively. The results showed that the lack of gene sod1 benefited the generation of ATP, which positively regulated the synthesis of SAM. Besides that, the production of SAM was further enhanced by improving substrate assimilation. With the infusion of 1.44 g L-1L-met and 0.60 g L-1 adenosine at 24 h (h) and 0 h following fermentation, the optimum medium could produce 1.54 g L-1 SAM. Based on the regulations mentioned above, the SAM concentration of strain ΔSOD1 enhanced from 7.3 g L-1 to 10.1 g L-1 in a 5-L fermenter in 118 h. This work introduces a novel idea for the biosynthesis of ATP and SAM, and the strain ΔSOD1 has the potential for industrial production.

Incidence, Survival Outcome, and Prognostic Nomogram of Patients with Angioimmunoblastic T-cell Lymphoma: a Population-based Analysis.

OBJECTIVE: Due to the rarity of angioimmunoblastic T-cell lymphoma (AITL), very limited data concerning its incidence patterns and prognostic factors are available. This study aimed to explore the incidence, characteristics, survival outcomes, and prognostic factors of AITL. METHODS: Age-adjusted incidence and temporal trends were calculated based on 1247 AITL patients from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)-13 database. A total of 1525 AITL patients from the SEER-18 database and 43 patients from our single center were included for survival analysis and nomogram construction. RESULTS: The age-adjusted incidence for overall cohort was 0.123 [95% confidence interval (CI), 0.117-0.131) per 100 000 during 1992-2017. The overall incidence increased steeply at the rate of 15.3% (95%CI 11.0%-19.8%, P<0.001) per year during 1992-2004, but remained stable during 2004-2017 (P=0.200). Similar incidence trends were observed in age, sex, and stage subgroups. The final nomograms consisted of four variables: age at diagnosis, sex, Ann Arbor stage, and primary site. The concordance index (C-index) of the nomogram for 5-year overall survival prediction was 0.717, 0.690 and 0.820 in the training cohort, validation cohort-1 and cohort-2, respectively. Regarding the disease-specific survival (DSS), the nomogram also demonstrated a good discrimination level, with the C-index for predicting the probability of DSS at 5 years of 0.716, 0.682 and 0.813 for the three cohorts, respectively. The calibration displayed good concordance between the nomogram-predicted and actual observed outcomes. CONCLUSION: The age-adjusted incidence for AITL was low during 1992-2017. The incidence continuously increased during 1992-2004, but remained stable during 2004-2017. The nomograms as proposed may provide a favorable and accurate prognostic survival prediction in AITL.

Salvage 125I brachytherapy for liver metastases of colorectal cancer in anatomically challenging locations after failure of systemic chemotherapy-A retrospective study.

PURPSOE: Colorectal cancer liver metastasis (CCLM) in anatomically challenging locations is difficult to treat. This retrospective study aimed to evaluate the effectiveness and safety of permanent 125I seeds implantation (ISI) for treatment of CCLM in anatomically challenging locations after failure of systemic chemotherapy. METHODS AND MATERIALS: A total of 31 liver metastases (in 25 patients) were treated by ISI under computerized tomography guidance from January 2011 to December 2017. Post-treatment follow-up was for 40 months. Adverse events were classified using the National Cancer Institute's Common Terminology Criteria for Adverse Events. Tumor response was evaluated by the mRECIST criteria. Objective response rate, overall survival rate, and complications were retrospectively analyzed. RESULTS: All ISI procedures were performed successfully. Most patients only complained of fatigue and mild pain after ISI. Only one patient had liver rupture during the procedure. Serum alanine aminotransferase and aspartate aminotransferase levels at 1 month after ISI were not significantly different from pre-procedure levels (p > 0.05). Computed tomography at 6 months after ISI treatment showed completed response in 11 (11/31, 35.5%) lesions, partial response in 14 (14/31, 45.2%) lesions, stable disease in 4 (4/31, 12.9%) lesions, and disease progression in 2 (2/31, 6.5%) lesions; thus, the objective response rate was 80.6%. Median survival was for 12 months. The 1 and 2 year overall survival rates were 52.0% and 20.0%, respectively. CONCLUSIONS: 125I seeds implantation for CCLM in anatomically challenging locations is safe and effective. Survival benefit is limited in the salvage setting where patients have high intrahepatic tumor load after failed systemic chemotherapy.

Cervical aortic arch with aneurysm formation and an anomalous right subclavian artery and left vertebral artery: A case report.

BACKGROUND: A cervical aortic arch (CAA) refers to a high-riding aortic arch (AA) that often extends above the level of the clavicle. This condition is very rare, with an incidence of less than 1/10000. CASE SUMMARY: A 29-year-old woman was admitted to the otolaryngology department of our hospital for repeated bilateral purulent nasal discharge for the prior 3 mo. The patient was diagnosed with chronic sinusitis and chronic rhinitis at admission. A preoperative noncontrast chest computed tomography scan showed a high-riding, tortuous AA extending to the mid-upper level of the first thoracic vertebra with local cystic dilatation. A further computed tomography angiography examination showed that the brachiocephalic trunk, left common carotid artery, left vertebral artery (LVA) (slender), and left subclavian artery sequentially branched off of the aorta from the proximal end to the distal end of the AA. The proximal end of the right subclavian artery (RSCA) was tortuous and dilated. The AA showed tumor-like local expansion, with a maximum diameter of approximately 4 cm. After consultation with the department of cardiac macrovascular surgery, the patient was diagnosed with left CAA with aneurysm formation and an anomalous RSCA and LVA and was transferred to that department. The patient underwent AA aneurysm resection and artificial blood vessel replacement under general anesthesia and cardiopulmonary bypass. No abnormality was found during the 2-mo follow-up after discharge. CONCLUSION: A CAA is a rare congenital anomaly of vascular development. The present unique case of CAA with aneurysm formation and an anomalous RSCA and LVA enriches existing CAA data.

Deletion of Schizophrenia Susceptibility Gene Ulk4 Leads to Abnormal Cognitive Behaviors via Akt-GSK-3 Signaling Pathway in Mice.

OBJECTIVES: Despite of strenuous research in the past decades, the etiology of schizophrenia (SCZ) still remains incredibly controversial. Previous genetic analysis has uncovered a close association of Unc-51 like kinase 4 (ULK4), a family member of Unc-51-like serine/threonine kinase, with SCZ. However, animal behavior data which may connect Ulk4 deficiency with psychiatric disorders, particularly SCZ are still missing. METHODS: We generated Emx1-Cre:Ulk4flox/flox conditional knockout (CKO) mice, in which Ulk4 was deleted in the excitatory neurons of cerebral cortex and hippocampus. RESULTS: The cerebral cellular architecture was maintained but the spine density of pyramidal neurons was reduced in Ulk4 CKO mice. CKO mice showed deficits in the spatial and working memories and sensorimotor gating. Levels of p-Akt and p-GSK-3α/ß were markedly reduced in the CKO mice indicating an elevation of GSK-3 signaling. Mechanistically, Ulk4 may regulate the GSK-3 signaling via putative protein complex comprising of two phosphatases, protein phosphatase 2A (PP2A) and 1α (PP1α). Indeed, the reduction of p-Akt and p-GSK-3α/ß was rescued by administration of inhibitor acting on PP2A and PP1α in CKO mice. CONCLUSIONS: Our data identified potential downstream signaling pathway of Ulk4, which plays important roles in the cognitive functions and when defective, may promote SCZ-like pathogenesis and behavioral phenotypes in mice.

Progress of MRI Radiomics in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third leading cause of cancer-related death. Although the diagnostic scheme of HCC is currently undergoing refinement, the prognosis of HCC is still not satisfactory. In addition to certain factors, such as tumor size and number and vascular invasion displayed on traditional imaging, some histopathological features and gene expression parameters are also important for the prognosis of HCC patients. However, most parameters are based on postoperative pathological examinations, which cannot help with preoperative decision-making. As a new field, radiomics extracts high-throughput imaging data from different types of images to build models and predict clinical outcomes noninvasively before surgery, rendering it a powerful aid for making personalized treatment decisions preoperatively. OBJECTIVE: This study reviewed the workflow of radiomics and the research progress on magnetic resonance imaging (MRI) radiomics in the diagnosis and treatment of HCC. METHODS: A literature review was conducted by searching PubMed for search of relevant peer-reviewed articles published from May 2017 to June 2021.The search keywords included HCC, MRI, radiomics, deep learning, artificial intelligence, machine learning, neural network, texture analysis, diagnosis, histopathology, microvascular invasion, surgical resection, radiofrequency, recurrence, relapse, transarterial chemoembolization, targeted therapy, immunotherapy, therapeutic response, and prognosis. RESULTS: Radiomics features on MRI can be used as biomarkers to determine the differential diagnosis, histological grade, microvascular invasion status, gene expression status, local and systemic therapeutic responses, and prognosis of HCC patients. CONCLUSION: Radiomics is a promising new imaging method. MRI radiomics has high application value in the diagnosis and treatment of HCC.

Prenatal exposure to organophosphate esters and neonatal thyroid-stimulating hormone levels: A birth cohort study in Wuhan, China.

BACKGROUND: Increasing animal studies have indicated that organophosphate esters (OPEs) have endocrine-disruptive potential. However, human epidemiological evidence is limited, especially in susceptible populations, such as pregnant women and neonates. The purpose of this present study was to examine the trimester-specific relationships of prenatal exposure to OPEs with neonatal thyroid-stimulating hormone (TSH). METHOD: A total of 102 mother-newborn pairs were recruited from a birth cohort study between April 2015 and September 2016 in Wuhan, China. Eight OPE metabolites were detectable in urine samples from pregnant women across the different three trimesters. Neonatal TSH levels were measured using time-resolved immunofluorescence assay. The associations between maternal urinary OPE metabolites and neonatal TSH and the critical exposure windows of fetal vulnerability were estimated using multiple informant models. RESULTS: Seven OPE metabolites with detection frequency > 50% (52.9%-98.0%) were detected in repeated urine samples from different three trimesters, and the urinary OPE metabolites across pregnancy was of high variability (ICCs: 0.09-0.26). After adjusted for confounders (e.g., maternal age, prepregnancy BMI, passive smoking during pregnancy), some suggestive associations were observed between maternal urinary OPE metabolites and neonatal TSH in different trimesters. A doubling of second trimester di-o-cresyl phosphate & di-p-cresyl phosphate (DoCP & DpCP) was associated with a 7.82% increase in neonatal TSH level (95% CI: -0.70%, 17.06%, p-value = 0.07), a doubling of third trimester diphenyl phosphate (DPHP) was associated with a 4.71% decrease in neonatal TSH level (95% CI: -9.80%, 0.67%, p-value = 0.09), and a doubling of third trimester bis(2-butoxyethyl) phosphate (BBOEP) was associated with a 6.38% increase in neonatal TSH level (95% CI: -0.12%, 13.31%, p = 0.05). However, such associations did not differ materially across trimesters. When performing stratified analysis by infant sex, the associations were statistically significant and were sex-dependent.In females, maternal urinary DoCP & DpCP concentrations in each trimester were associated with increased neonatal TSH levels, and urinary DPHP concentration in the third trimester was associated with decreased neonatal TSH level. In males, maternal urinary BBOEP concentration in the first trimester was positively related to neonatal TSH level. CONCLUSION: This prospective study demonstrated that prenatal exposure to OPEs can lead to a sex-dependent change in neonatal TSH levels. Although the sex-selective effect was differed among various urinary OPE metabolites, more evidence was supported that OPE exposure was related to increased TSH levels for both males and females.