Arginine methylation is a critical post-translational modification that plays multifaceted biological functions. However, the manipulation of protein arginine methylation largely depends on genetic or pharmaceutic inhibition of the regulatory enzymes, protein arginine methyltransferases (PRMTs), or non-methylation substitution of corresponding arginine residue to lysine or alanine of protein of interest (POI), which inevitably affects other substrates, or disrupts the structure of POI. Thus, it urges an approach to specifically modulate the arginine methylation of a POI under physiological conditions. To this end, we report the discovery of a methylation tagging system (MeTAG), that enables targeted modification of protein arginine methylation. Through bridging the methyltransferase PRMT5 proximity to a POI, MeTAG facilitates the arginine methylation of POIs, including known arginine methylated proteins, androgen receptor (AR) and protein kinase B (AKT), as well as a neo-substrate E1A binding protein (p300), in a reversible and PRMT5-dependent manner. Moreover, MeTAG can regulate downstream signaling in a methylation dependent manner, leading to downregulation of PSMA mRNA level and activation of AKT. Therefore, MeTAG represents a feasible approach to modulate protein methylation and thereby perturbs protein function in biological and therapeutic contexts.

Objective:To investigate the clinicopathological and genetic characteristics of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL).Methods:The forty-two MEITL cases diagnosed in the Department of Pathology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China from 2016 to 2022 was retrospectively analyzed. Clinical data were collected, and follow-up was performed. Morphological characteristics were observed. Immunohistochemistry, Epstein-Barr virus (EBV) in situ hybridization, clonal rearrangement analysis of T-cell receptor (TCR) genes, and targeted next-generation sequencing (NGS) were performed.Results:Among the 42 patients (male/female ratio of 2.8∶1.0), the age range was 32-77 years with a median age of 59.5 (52.0-65.0) years. Grossly, the tumors were presented as ulcerative or exophytic lesions, with a maximum diameter of 2-18 cm. There were 34 cases with a single lesion and 8 cases with more than 1 lesion. The tumor cells in all 42 cases were relatively monotonous in histology and small or medium in size. They had round or oval nuclei, moderately pale or clear cytoplasm, evenly distributed nuclear chromatin, inconspicuous nucleoli, and frequent mitotic figures. In one of the cases, there were moderately large cells, vacuolated nuclei, and clear nucleoli. Lymphoepithelial lesions were observed in 36 (85.7%) of the 42 cases, tumor necrosis in 4 (9.5%) cases, scattered eosinophils and/or plasma cell infiltration in the background in 9 (21.4%) cases, and a "starry sky" phenomenon in 1 (2.4%) case. The tumor cells in all cases exhibited high expression of CD3, CD2, CD7, CD8, CD56, TIA1, Granzyme B, and Perforin, while some also expressed CD4 (5/41, 12.2%), CD5 (3/41, 7.3%), CD20 (4/41, 11.9%), CD79α (2/37, 5.4%), and CD30 (1/34, 2.9%). The Ki-67 proliferation index ranged from 40% to 90%. EBER in situ hybridization tests were negative in all cases. TCR gene clonal rearrangement was detected in 96.4% (27/28) of the tested cases. Targeted NGS revealed commonly mutated genes including SETD2, STAT5B, JAK3, TP53, and CREBBP. The primary treatment was chemotherapy, with 2 cases undergoing autologous hematopoietic stem cell transplantation. Follow-up information was obtained for 29 cases, with a follow-up period of 1-73 months. The mortality was 93.1% (27/29).Conclusions:MEITL is a rare and highly aggressive peripheral T-cell lymphoma. Its clinical manifestations are diverse, and diagnosis primarily relies on a comprehensive assessment of pathological morphology, immunohistochemical profiles, and EBV infection status, supplemented by genetic testing if necessary. At present, there is no effective treatment, and its overall prognosis is poor.

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare familial autosomal dominant genetic disease with primary hyperparathyroidism, jaw tumors, kidney tumors and uterine tumors caused by cell division cycle 73 (CDC73) germline mutations. A 42-year-old male patient was admitted for pancreatitis and further examination revealed elevated PTH at 54.00pmol/L and a history of jaw tumors. This patient was diagnosed as HPT-JT finally and underwent upper right, lower right, and upper left parathyroid glands resection and genetic testing. Postoperative pathology revealed that atypical adenomatous nodules of parathyroid glands with extensive atypia and nucleus division and parathyroid hyperplasia and whole exome sequencing suggested that the CDC73 mutation.

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare familial autosomal dominant genetic disease with primary hyperparathyroidism, jaw tumors, kidney tumors and uterine tumors caused by cell division cycle 73 (CDC73) germline mutations. A 42-year-old male patient was admitted for pancreatitis and further examination revealed elevated PTH at 54.00pmol/L and a history of jaw tumors. This patient was diagnosed as HPT-JT finally and underwent upper right, lower right, and upper left parathyroid glands resection and genetic testing. Postoperative pathology revealed that atypical adenomatous nodules of parathyroid glands with extensive atypia and nucleus division and parathyroid hyperplasia and whole exome sequencing suggested that the CDC73 mutation.

Objective:To investigate the clinicopathological and genetic characteristics of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL).Methods:The forty-two MEITL cases diagnosed in the Department of Pathology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China from 2016 to 2022 was retrospectively analyzed. Clinical data were collected, and follow-up was performed. Morphological characteristics were observed. Immunohistochemistry, Epstein-Barr virus (EBV) in situ hybridization, clonal rearrangement analysis of T-cell receptor (TCR) genes, and targeted next-generation sequencing (NGS) were performed.Results:Among the 42 patients (male/female ratio of 2.8∶1.0), the age range was 32-77 years with a median age of 59.5 (52.0-65.0) years. Grossly, the tumors were presented as ulcerative or exophytic lesions, with a maximum diameter of 2-18 cm. There were 34 cases with a single lesion and 8 cases with more than 1 lesion. The tumor cells in all 42 cases were relatively monotonous in histology and small or medium in size. They had round or oval nuclei, moderately pale or clear cytoplasm, evenly distributed nuclear chromatin, inconspicuous nucleoli, and frequent mitotic figures. In one of the cases, there were moderately large cells, vacuolated nuclei, and clear nucleoli. Lymphoepithelial lesions were observed in 36 (85.7%) of the 42 cases, tumor necrosis in 4 (9.5%) cases, scattered eosinophils and/or plasma cell infiltration in the background in 9 (21.4%) cases, and a "starry sky" phenomenon in 1 (2.4%) case. The tumor cells in all cases exhibited high expression of CD3, CD2, CD7, CD8, CD56, TIA1, Granzyme B, and Perforin, while some also expressed CD4 (5/41, 12.2%), CD5 (3/41, 7.3%), CD20 (4/41, 11.9%), CD79α (2/37, 5.4%), and CD30 (1/34, 2.9%). The Ki-67 proliferation index ranged from 40% to 90%. EBER in situ hybridization tests were negative in all cases. TCR gene clonal rearrangement was detected in 96.4% (27/28) of the tested cases. Targeted NGS revealed commonly mutated genes including SETD2, STAT5B, JAK3, TP53, and CREBBP. The primary treatment was chemotherapy, with 2 cases undergoing autologous hematopoietic stem cell transplantation. Follow-up information was obtained for 29 cases, with a follow-up period of 1-73 months. The mortality was 93.1% (27/29).Conclusions:MEITL is a rare and highly aggressive peripheral T-cell lymphoma. Its clinical manifestations are diverse, and diagnosis primarily relies on a comprehensive assessment of pathological morphology, immunohistochemical profiles, and EBV infection status, supplemented by genetic testing if necessary. At present, there is no effective treatment, and its overall prognosis is poor.

Objective To explore the causal relationship between educational attainment and chronic kidney disease(including chronic glomerulonephritis,nephrotic syndrome,diabetic nephropathy,chronic renal failure,and other clinical diagnoses of chronic kidney disease),and provide targeted guidance support for different populations in the prevention and treatment of chronic kidney disease.Methods The study used four regression models,random-effects inverse-variance weighted(IVW),MR-Egger regression,weighted median method,and weighted model,to perform Mendelian randomization analysis of the causal relationship between educational attainment and chronic kidney disease.Results All four regression models showed no statistical significance for the three models of chronic kidney disease,chronic glomerulonephritis,and nephrotic syndrome with P>0.05.The diabetic nephropathy model was seen to be statistically significant as the results of the three methods except IVW method(OR=0.520,P<0.05)were not significant,while the scatter plot showed that the direction of the total effect value was the same for all methods.Chronic renal failure model IVW method(OR=0.487,P<0.001),weighted median method(OR=0.503,P<0.001)showed a significant effect and the scatter plot showed that the direction of the total effect value was the same in all methods,which was statistically significant.Conclusion Using two-sample Mendelian randomization method to exclude confounding factors and reverse causal associations,unbiased estimation results were obtained to get that the education level is not related to the overall chronic kidney disease incidence,but has reverse causality for diabetic nephropathy and chronic renal failure among them.

OBJECTIVE: To investigate the safety of laparoscopic pancreaticoduodenectomy (LPD) in elderly patients and the related risk factors admitted to the intensive care unit (ICU) after LPD. METHODS: The perioperative data of patients who underwent LPD in Tianjin Medical University General Hospital from February 2017 to June 2023 were retrospectively collected, including basic data, preoperative laboratory indicators, intraoperative and postoperative indicators, pathological results (tumor size, lymph node dissection and pathological type), postoperative complications, ICU postoperative management and prognosis. The patients were divided into the elderly group (≥ 65 years) and the non-elderly group (< 65 years) according to age. Perioperative data between two groups were compared. Kaplan-Meier survival curve was drawn to analyze the survival rate of the elderly group and the non-elderly group, and the pancreatic head carcinoma group and other type of tumors group after LPD. Logistic regression was used to analyze the risk factors of ICU stay (length of ICU stay > 1 day) after LPD in elderly patients. The receiver operator characteristic curve (ROC curve) was drawn to analyze the predictive value of this risk factor for ICU stay after LPD in elderly patients. RESULTS: A total of 160 patients were enrolled, including 57 cases in the elderly group (17 cases of vascular reconstruction) and 103 cases in the non-elderly group (40 cases of vascular reconstruction). All patients underwent R0 resection and were transferred to the comprehensive ICU for treatment. The follow-up time of patients with malignant tumors was 43 (6, 72) months. The elderly group had significantly longer surgery time, postoperative hospital stay and oral feeding time than the non-elderly group, and the incidence of delayed gastric emptying (DGE) was significantly higher than that in the non-elderly group. There were no significant differences in intraoperative blood transfusion rate, intraoperative blood loss, pathological results, short-term and severe postoperative complications, reoperation rate and 90-day mortality between the two groups. In patients with vascular resection reconstruction, the intraoperative blood loss in the elderly group was significantly higher than that in the non-elderly group, and the operation time and postoperative hospital stay were significantly longer. During ICU, the acute physiology and chronic health evaluation II [APACHE II: 12 (9, 14) vs. 8 (7, 10)], sequential organ failure assessment [SOFA: 6 (4, 8) vs. 3 (2, 5)] within 24 hours after admission to ICU were significantly increased in the elderly group (both P < 0.05), the time of mechanical ventilation [hours: 12 (10, 15) vs. 9 (5, 13)] and the length of ICU stay [days: 2 (1, 2) vs. 1 (1, 1)] were significantly increased in the elderly group (both P < 0.05), and the proportion of multi-disciplinary team (MDT) was also significantly increased in the elderly group (33.3% vs. 17.4%, P < 0.05), there were no significant differences in the levels of hemoglobin (Hb), albumin, and blood lactic acid between the two groups. Logistic regression analysis showed that the APACHE II score was an independent risk factor for ICU stay after LPD in elderly patients (β = 1.737, P = 0.028). ROC curve showed that the prediction performance was the best when the APACHE II score was 13, with the sensitivity of 72.41% and the specificity of 96.43%, and the area under the ROC curve (AUC) of 0.884. The Kaplan-Meier survival curve showed that there were no significant difference in median survival time (months: 24.1 vs. 24.7) and 5-year survival rate (19.01% vs. 19.02%) between the elderly group (52 cases) and the non-elderly group (92 cases) among the 144 patients with malignant tumors (both P > 0.05). The median survival time in the pancreatic head carcinoma group was significantly shorter than that in the other tumors group (63 cases; months: 20.2 vs. 40.1, P < 0.05), 5-year survival rate was significantly lower than that in the other tumors group (21.98% vs. 30.91%, P < 0.05). CONCLUSIONS LPD is a safe and feasible treatment for elderly patients. APACHE II score has a certain predictive value for ICU stay after LPD in elderly patients.
Humans ; Aged ; Middle Aged ; Sepsis/therapy* ; ROC Curve ; Pancreaticoduodenectomy/adverse effects* ; Retrospective Studies ; Blood Loss, Surgical ; Prognosis ; Pancreatic Neoplasms/surgery* ; Postoperative Complications ; Intensive Care Units

Objective:To investigate the effect of ANXA on biological behavior of papillary thyroid carcinoma (PTC) cells by interfering with the expression of annexin A1 (ANXA1) in PTC cell lines by short hairpin RNA (shRNA) .Methods:The shRNA with specific and high efficiency was designed to specifically interfere with the expression of ANXA1 in TPC-1 and BCPAP cell lines, and transfect the TPC-1 and BCPAP cell lines respectively, including specific ANXA1 interference and negative control virus transfection, and they were divided into shANXA1 group and negative control virus group. Semi-quantitative reverse transcription PCR (Q-PCR) and Western Blot were employed to verify gene expression. The shANXA1 group was used as the experimental group, the untransfected virus group and the negative control virus group were set as the control groups. The expression levels of ANXA1 in the three groups were compared and the shRNA interference efficiency was verified. The effects of ANXA1 knockdown on the proliferation, migration and invasion of TPC-1 and BCPAP cell lines were investigated by scratch, CCK8 and Transwell invasion experiments. Independent sample t test was used to compare the means between the two groups, and one-way analysis of variance was employed to compare multiple groups, with P<0.05 as statistically significant. Results:shRNA could efficiently silence the expression of ANXA1 at the transcription and translation level in PTC cell lines. Compared with the negative control cells, the cells proliferated after successful lentiviral transfection of TPC-1 and BCPAP (BCPAP, 24h: F= 25.15, P<0.001; 48h: F=6.44, P<0.001; 48h: F=46.94, P<0.001; TPC-1, 24h: F=207.50, P<0.001; 48h: F=202.45, P<0.001; 48h: F=55.89, P<0.001) , its migration (BCPAP, F=12511.10, P<0.001; TPC-1, F=3966.10, P<0.001) and invasion ability (BC-PAP: F=94.65, P<0.001; TPC-1: F=681.74, P<0.001) significantly decreased. Conclusion:After shRNA knock-down of ANXA1 gene, the proliferation, migration and invasion ability of TPC-1 and BCPAP cell lines decreased significantly, indicating that silencing this gene can reduce tumor aggressiveness, and initially reveals that ANXA1 may be an important potential in PTC biotherapy Target.

Thyroid carcinoma is the most common malignancy in the endocrine system.Most patients cannot be cured with operation alone.The concept and implementation of multidisciplinary team (MDT) in clinical oncology attributes to improved diagnosis and treatment of cancer.MDT plays an important role in diagnosis,treatment,and post operational management of thyroid carcinoma,as well as in the application of novel techniques and translational medicine.MDT can maximize the expertise of various disciplines,strengthen inter disciplinary cooperation,and provide standardized and individualized comprehensive treatment for patients with thyroid cancer.The most important benefit of MDT is that individual patient gets the most appropriate treatment decision made by a team of experts,including endocrinologists,nuclear medicine specialists,pathologists,radiologists,radiation therapists,and surgeons.This will be of great significance to improve quality of life and prognosis,at the same time,avoid over-treatment of thyroid cancer.

Objective To explore the anomalous expression of HDAC1 in cervical intraepithelial neoplasia(CIN)and cervical carcinoma and its relationship with the infection of HPV16/18. Methods The expressions of HDAC1 protein and HDAC1 infection were detected by in situ hybridiza?tion(ISH)and immunohistochemistry staining(SP)in tissues from patient with chronic cervicitis(the chronic cervicitis group),CIN(the CINⅠgroup,the CINⅡgroup and the CINⅢgroup)and cervical squamous carcinoma(the cervical carcinoma group). Results The infection rate of HPV16/18 was 8.33%,34.78%,48.00%,65.21%,78.00%in patients with chronic cervicitis,CINⅠ,CINⅡ,CINⅢand cervical carcinoma re?spectively. There was significant difference between groups(P<0.05). The positive expression rate of HDAC1 was 0,13.04%,32.00%,47.82%and 76.00%in chronic cervicitis,CINⅠ,CINⅡ,CINⅢand cervical carcinoma,respectively. The differences were statistically significant(P<0.05). The positive expression of HDAC1 in the HPV16/18 infected patients was significantly higher than those uninfected with HPV16/18(P<0.05). The HDAC1 positive expression had no relationship with clinical stages of cervical carcinoma,however,it was related to the tissue differentia?tion,stromal invasion and pelvic lymph node metastasis(all P<0.05). Conclusion The infection of HPV16/18 may play an important role in the carcinongenesis of SCC through increasing the expression of HDAC1.