N6-Methyladenosine Modification of ANLN Enhances Hepatocellular Carcinoma Bone Metastasis.

Bones are categorized as the second most prevalent location of extra-hepatic metastasis in Hepatocellular Carcinoma (HCC), which is linked to an extremely poor prognosis due to limited therapeutic options. N6-methyladenosine (m6A) is a prominent modification involved in HCC, but the exact mechanisms on how m6A modifications induce HCC bone metastases (BM) remain unclear. The key modulators responsible for the abundant m6A RNA modification-induced HCC BM was found to be the METTL3 and YTHDF1. The expression of Anillin actin-binding protein (ANLN) was dramatically higher in HCC with BM tissues, and its messenger RNA (mRNA) stability was enhanced via m6A epitranscriptomic regulation by METTL3 and YTHDF1. High METTL3 and YTHDF1 expression along with nuclear ANLN protein was clinically correlated with BM in HCC patients. Furthermore, HCC BM was attributed to over-expression of nuclear ANLN forming a transcriptional complex with SP1 which enhanced KIF2C transcriptional activity to activate the mTORC1 pathway, therefore increased the expression of RANKL and disproportionated RANKL-OPG expression in bone microenvironment leading to malignant neoplasms invade bone tissue. In addition, inhibition of ANLN m6A modification by DZNeP attenuated HCC BM. This data provides meaningful understanding of the modulation and association of m6A epitranscriptomic-regulated BM in HCC, and moreover, defines potentially valuable therapeutic targets.

Clinical and pathological characteristics and prognostic analysis of upper tract urothelial carcinoma with concurrent histological variants / 中华泌尿外科杂志

Objective:To investigate the clinical and pathological characteristics and prognosis of upper tract urothelial carcinoma (UTUC) with concurrent other histological variants.Methods:The clinical data of 566 UTUC patients admitted to Peking University People's Hospital from January 2007 to April 2021 were retrospectively analyzed. Among them, 289 were males and 277 were females, with an average age of (67.3±10.0)years old. Among the patients, 97 had a history of smoking, 29 had undergone kidney transplantation, 120 had diabetes, 76 had coronary heart disease, 146 had hyperlipidemia, 271 had hypertension, and 50 had a history of chronic kidney disease. Among the UTUC cases, 366 had concurrent hydronephrosis, 55 had concurrent bladder cancer, and 43 had a history of previous bladder cancer. The distribution included 210 cases of renal pelvis carcinoma, 5 cases of carcinoma at the renal pelvis-ureter junction, 226 cases of ureteral carcinoma, and 125 cases of multifocal tumors. Patients were classified into the pure UTUC group and the UTUC with concurrent other histological variants group based on postoperative pathology, and their clinical and pathological features were compared. Logistic regression analysis was used to explore risk factors for the occurrence of histological variations in UTUC. The log-rank test was employed to compare the overall survival (OS) and cancer-specific survival (CSS) between the two groups, while Cox regression analysis was performed to investigate prognostic factors.Results:Among the 566 cases, 511 were pure UTUC and 55 were UTUC with concurrent other histological variants. Among the latter, 30 cases had squamous differentiation, 6 had glandular differentiation, 5 had mucinous differentiation, 5 had sarcomatoid carcinoma, 2 had micropapillary carcinoma, 2 had neuroendocrine carcinoma, 1 had giant cell carcinoma, and 4 had other mixed histological variations. The proportion of patients with a history of kidney transplantation was higher in the UTUC with concurrent histological variants group than that in the pure UTUC group [14.5% (8/55) vs. 4.1% (21/511)], with statistically significant difference ( P=0.003). In the UTUC with concurrent histological variants group, the proportion of postoperative high-grade tumors [98.2% (54/55) vs. 80.2% (410/511)], muscle-invasive tumors [89.1% (49/55) vs. 68.1% (348/511)], lymph node metastasis tumors [10.9% (6/55) vs. 2.3% (12/511)], and maximum tumor diameter [(3.60±2.64) cm vs. (2.96±1.98) cm] were higher than those in the pure UTUC group ( P<0.05). Multivariate logistic regression analysis showed that a history of kidney transplantation ( OR=4.991, 95% CI 1.749-13.615, P=0.002) was an independent predictive factor for the occurrence of histological variants. Follow-up was conducted for 1 to 174 months, with a median follow-up time of 32.8 months. UTUC with concurrent histological variants was significantly associated with worse OS and CSS ( P<0.05). Multivariate Cox regression analysis indicated that histological variants were an independent risk factor for OS ( HR=1.860, 95% CI 1.228-2.816, P=0.003) and CSS ( HR=2.146, 95% CI 1.349-3.412, P=0.001). Conclusions:UTUC with concurrent other histological variants exhibited higher postoperative tumor grade and stage compared to pure UTUC, and UTUC with concurrent other histological variants was an independent risk factor for worse prognosis.

Decreased Expression of Programmed Death Ligand-L1 by Seven in Absentia Homolog 2 in Cholangiocarcinoma Enhances T-Cell-Mediated Antitumor Activity.

N6-methyladenosine (m6A) has been reported as an important mechanism of post-transcriptional regulation. Programmed death ligand 1 (PD-L1) is a primary immune inhibitory molecule expressed on tumor cells that promotes immune evasion. In addition, seven in absentia homolog 2 (Siah2), a RING E3 ubiquitin ligase, has been involved in tumorigenesis and cancer progression. However, the role of m6A-METTL14-Siah2-PD-L1 axis in immunotherapy remains to be elucidated. In this study, we showed that METTL14, a component of the m6A methyltransferase complex, induced Siah2 expression in cholangiocarcinoma (CCA). METTL14 was shown to enrich m6A modifications in the 3'UTR region of the Siah2 mRNA, thereby promoting its degradation in an YTHDF2-dependent manner. Furthermore, co-immunoprecipitation experiments demonstrated that Siah2 interacted with PD-L1 by promoting its K63-linked ubiquitination. We also observed that in vitro and in vivo Siah2 knockdown inhibited T cells expansion and cytotoxicity by sustaining tumor cell PD-L1 expression. The METTL14-Siah2-PD-L1-regulating axis was further confirmed in human CCA specimens. Analysis of specimens from patients receiving anti-PD1 immunotherapy suggested that tumors with low Siah2 levels were more sensitive to anti-PD1 immunotherapy. Taken together, our results evidenced a new regulatory mechanism of Siah2 by METTL14-induced mRNA epigenetic modification and the potential role of Siah2 in cancer immunotherapy.

Corrigendum: Decreased expression of programmed death ligand-L1 by seven in absentia homolog 2 in cholangiocarcinoma enhances T-cell-mediated antitumor activity.

[This corrects the article DOI: 10.3389/fimmu.2022.845193.].

Impact of warm ischemia time during partial nephrectomy on laparoscopic postoperative renal function / 中华泌尿外科杂志

Objective:To assess the association between warm ischemia time (WIT) and renal function in patients undergoing laparoscopic partial nephrectomy.Methods:A total of 344 patients treated with laparoscopic partial nephrectomy in Peking University People’s Hospital were included. There were 240 males (69.8%) and 104 females (30.2%) with a median age of 57 (23-89) years.The median BMI was 25.6 (16.7-36.0) kg/m 2.213 cases (61.9%) were associated with hypertension.There were 66 (19.2%) patients with diabetes mellitus. There were 92 cases (26.7%) with smoking history. The median preoperative creatinine was 73 (32-170) μmol/L. The median preoperative estimated glomerular filtration rate (eGFR) was 95 (33-142) ml/(min·1.73m 2). The maximum diameter of the tumor was 2.5 (7-9) cm.314 (91.3%) patients with renal cancer stage T 1. All patients underwent warm ischemia during the operation. The patients were divided into three groups for analysis. Restricted cubic spline regression analysis was used to assess the association between WIT as a continuous variable and percentage change of eGFR. Analysis of covariance was used to compare postoperative eGFR among the three groups, and to adjust for preoperative eGFR and tumor diameter. Results:There were statistically significant differences in the percentage change of postoperative eGFR ( P=0.009) and tumor diameter ( P<0.001) among the three groups. Restricted cubic spline regression analysis showed that with the prolongation of WIT, the percentage change of postoperative eGFR gradually decreased, and the curve began to stabilize after 30 minutes (R 2=0.044, P=0.015). The results of covariance analysis showed that after adjusting for baseline preoperative eGFR and tumor size, the effect of WIT on postoperative eGFR was significantly different among the three groups ( F=3.864, P=0.022). The postoperative eGFR in the WIT<20 min group was significantly higher than that in 20 min≤WIT<30 min group( P=0.009) and WIT≥30 min group( P=0.017). There was no significant difference in postoperative eGFR between the two groups with longer WIT( P=0.806). Conclusions:In partial nephrectomy, patients with WIT less than 20 minutes had higher postoperative eGFR levels than those with WIT greater than 20 minutes. However, when WIT exceeded 20 minutes, prolonged ischemia time did not lead to further decline in renal function.

Comparison of long-term outcomes in different managements of diverticular neck in percutaneous nephrolithotomy for diverticular calculi / 北京大学学报(医学版)

OBJECTIVE@#To compare the short-term effects and long-term outcomes of incisional procedure and dilatation procedure to manage diverticular neck in percutaneous nephrolithotomy for diverticular stones.@*METHODS@#Clinical data of 61 patients with diverticular stones who underwent percutaneous nephrolithotomy from June 2009 to January 2019 were retrospectively collected and analyzed, which was as follous: (1) basic information: age, gender, body mass index (BMI), American Society of Anesthesiology (ASA) classifications and preoperative symptoms.(2)stone characteristic and procedure-related data: location and size of stone, skinned renal access length and procedure time.(3)perioperative clinical data: hemoglobin drop, Clavien's classification and stone-free rate. Long-term follow-ups were performed for more than 5 years after the patients were discharged.@*RESULTS@#Fifty-three patients were included based on the inclusion and exclusion criteria, and were divided into the dilation group (n=37) and the incision group (n=16) by the treatment methods of diverticular neck. There were 24 male patients (45.3%) and 29 female patients (54.7%), with a mean age of 39.96±12.88 years. Stones were mainly located in the upper pole (n=32, 60.38%) and posterior area (n=41, 77.4%), with a predominance of single stone (n=36, 67.9%). There was no statistically significant difference in demographic data and stone characteristics between the two groups except for age and stone burden. Forty-five patients (84.9%) reached stone-free status after surgeries, and 44 patients (83.0%) postoperative symptoms improved. Twelve patients were lost to the follow-ups, and 41 cases were followed up for an average of 77 months. One recurrence occurred 1 year after surgery. Fifteen patients underwent operations within the past 5 years and the overall 5-year recurrence rate for the remaining 26 patients was 34.6%. There was no statistically significant difference in the incidence of perioperative complications, postoperative stone-free rate and recurrence rate between the two groups, and the recurrence rate was significantly higher 5 years postoperatively than 1 year postoperatively. The proportion of the patients who remained lithotripsy-free and residual stone status decreased significantly.@*CONCLUSION@#Both incisional and dilatation procedures in percutaneous nephrolithotomy to manage diverticular neck could bring the satisfactory postoperative stone free rate. The recurrence rate was about 30% to 40% 5 years after surgery.

Peripheral blood indicators in medical radiation workers in Yangpu District of Shanghai， 2017-2019 / 上海预防医学

Objective:To explore the impact of occupational ionizing radiation exposure on blood indicators including white blood cell（ WBC）， red blood cell （RBC）， hemoglobin （Hb）， platelet （PLT） were analyzed. Methods:A total of 237 medical radiation workers in Yangpu district， Shanghai were recruited and divided into observation group and control group， according to individual average dose of external exposure. The annual effective dose in observation group was 0.357 7-4.704 3 mSv， and the median dose was 0.536 8 mSv （0.441 2-0.893 8）. The annual effective dose in control group was 0.031 2-0.350 8 mSv， and the median dose was 0.199 2 mSv （0.143 8-0.252 8）. Routine blood tests were conducted twice in the occupational health examinations from 2017 to 2019 and the results were collected. Chi-square test， Mann-Whitney U test， and generalized estimating equations （GEE） model were used for statistical analysis. Results:Compared to the first examination， the risk of having abnormal Hb increased （OR=1.029， 95%CI： 1.006-1.053）. After adjusting the factors of age， gender， seniority and exposure time， the risk of Hb abnormality in the observation group was lower than that in the control group （OR=0.422， 95%CI：0.198-0.898）. There was no significant difference between the observation and control groups in the risk of abnormal WBC， RBC， and PLT. Conclusion:Exposure to occupational ionizing radiation may increase the risk of abnormal Hb， while there is no significant change in WBC， RBC and PLT. Radiation workers should have full protection at work and be under appropriate occupational health management.

Complications and management of penile augmentation with hyaluronic acid injection / 亚洲男科学杂志(英文版)

Hyaluronic acid injection is becoming a popular way for penile augmentation. However, only few studies and follow-ups have investigated the various complications of hyaluronic acid injection and their corresponding management. In this study, a total of 230 patients who had penile augmentation with hyaluronic acid injection from January 2018 to December 2019 were examined on follow-up for penile girth, complications, and their corresponding management. At 1-month, 3-month, and 6-month postoperative follow-ups, the penile circumference had increased by 2.66 ± 1.24 cm, 2.28 ± 1.02 cm, and 1.80 ± 0.83 cm, respectively. During the entire 6-month follow-up, 4.3% had complications such as subcutaneous bleeding, subcutaneous nodules, and infection. There were no systemic or local allergic reactions among all the patients. All complications were treated accordingly, and no further deterioration or severe sequelae were observed. Although complications of hyaluronic acid injections are mild and rare, these may affect the patient's satisfaction postoperatively. Preoperative redundant prepuce may increase the incidence of penile edema or postoperative gel migration. Standardization of the surgery protocol and elucidation of the effects of other injection parameters are still lacking. Nevertheless, it still highlights the importance of preoperative preparation and surgical technique.

Effects of troxerutin on vascular inflammatory mediators and expression of microRNA-146a/NF-κB signaling pathway in aorta of healthy and diabetic rats.

This study has investigated the effect of a potent bioflavonoid, troxerutin, on diabetes-induced changes in pro-inflammatory mediators and expression of microRNA-146a and nuclear factor-kappa-B (NF-κB) signaling pathway in aortic tissue of type-I diabetic rats. Male Wistar rats were randomly divided into four groups (n = 6/each): healthy, healthy-troxerutin, diabetic, and diabetic-troxerutin. Diabetes was induced by streptozotocin injection (60 mg/kg; intraperitoneally) and lasted 10 weeks. Troxerutin (150 mg/kg/day) was administered orally for last month of experiment. Inflammatory cytokines IL-1ß, IL-6, and TNF-α, as well as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM), cyclooxygenase-II (COX-II), and inducible-nitric oxide synthase (iNOS) were measured on aortic samples by enzyme-linked immunosorbent assay. Gene expressions for transcription factor NF-κB, interleukin-1 receptor-associated kinase-1 (IRAK-1), TNF receptor-associated factor-6 (TRAF-6), and microRNA-146a were determined using real-time polymerase chain reaction. Ten-week diabetes significantly increased mRNA levels of IRAK-1, TRAF-6, NF-κB, and protein levels of cytokines IL-1ß, IL-6, TNF-α, adhesion molecules ICAM-1, VCAM, and iNOS, COX-II, and decreased expression of microRNA-146a as compared with healthy rats (p < 0.05 to p < 0.01). However, one month treatment of diabetic rats with troxerutin restored glucose and insulin levels, significantly decreased expression of inflammatory genes and pro-inflammatory mediators and increased microRNA level in comparison to diabetic group (p < 0.05 to p < 0.01). In healthy rats, troxerutin had significant reducing effect only on NF-κB, TNF-α and COXII levels (p < 0.05). Beside slight improvement of hyperglycemia, troxerutin prevented the activation of NF-κB-dependent inflammatory signaling in the aorta of diabetic rats, and this response may be regulated by microRNA-146a.

Liver Enzyme Elevation in Coronavirus Disease 2019: A Multicenter, Retrospective, Cross-Sectional Study.

INTRODUCTION: Elevated liver enzyme levels are observed in patients with coronavirus disease 2019 (COVID-19); however, these features have not been characterized. METHODS: Hospitalized patients with COVID-19 in Zhejiang Province, China, from January 17 to February 12, 2020, were enrolled. Liver enzyme level elevation was defined as alanine aminotransferase level >35 U/L for men and 25 U/L for women at admission. Patients with normal alanine aminotransferase levels were included in the control group. Reverse transcription polymerase chain reaction was used to confirm severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and patients symptomatic with SARS-CoV-2 infection were defined as patients with COVID-19. Epidemiological, demographic, clinical, laboratory, treatment, and outcome data were collected and compared. RESULTS: Of 788 patients with COVID-19, 222 (28.2%) patients had elevated liver enzyme levels (median [interquartile range {IQR}] age, 47.0 [35.0-55.0] years; 40.5% women). Being male, overweight, and smoking increased the risk of liver enzyme level elevation. The liver enzyme level elevation group had lesser pharyngalgia and more diarrhea than the control group. The median time from illness onset to admission was 3 days for liver enzyme level elevation groups (IQR, 2-6), whereas the median hospitalization time for 86 (38.7%) discharged patients was 13 days (IQR, 11-16). No differences in disease severity and clinical outcomes were noted between the groups. DISCUSSION: We found that 28.2% of patients with COVID-19 presented with elevated liver enzyme levels on admission, which could partially be related to SARS-CoV-2 infection. Male patients had a higher risk of liver enzyme level elevation. With early medical intervention, liver enzyme level elevation did not worsen the outcomes of patients with COVID-19.