Ubiquitin-specific protease 7 (USP7), a deubiquitinase, is involved in tumor progression. However, its roles in pancreatic neuroendocrine neoplasms (pNENs) remain unclear. The main objective of this study was therefore to investigate the molecular mechanism of how USP7 promoted pNEN progression. Proteomics and ubiquitin-omics were used to identify the substrates for USP7. We investigated the roles of USP7 and histone H1.2 in DNA repair in pNEN cells using comet assays and γ-H2AX immunofluorescence. The synergistic effects of cisplatin and the USP7 inhibitor, P005091, were evaluated using CCK-8, colony formation, and EdU assays. Western blot analysis was conducted to characterize the PI3K/AKT/mTOR signaling pathway. In vivo, the efficacy of the combination therapy was tested in xenograft models. The results showed a significant increase in USP7 levels in the tissues and cells of pNENs. Furthermore, USP7 was found to promote the proliferation, migration, and invasion of pNENs both in vitro and in vivo. Mechanistically, USP7 facilitated DNA repair through its interaction with histone H1.2 and the activation of the PI3K/AKT/mTOR pathway. The combination of cisplatin and P005091, a USP7 inhibitor, synergistically inhibited tumor growth and DNA repair in both in vitro and in vivo models, without exhibiting significant toxicity. In conclusion, USP7 was a key regulator of DNA repair in pNENs. The combination of cisplatin and P005091 therefore holds promise as a therapeutic strategy for pNENs.

N6-methyladenosine (m6A) is considered the most prevalent RNA epigenetic regulator in cancer. FTO, an m6A demethylase, has been implicated in contributing to the progression of various cancers by up-regulating the expression of multiple oncogenes. However, studies exploring its impact on lipid metabolism in cancer, especially in pNENs, remain scarce. In this study, we demonstrated that FTO was up-regulated in pNENs and played a critical role in tumor growth and lipid metabolism. Mechanistically, we discovered that FTO over-expression increased the expression of APOE in an m6A-IGF2BP2-dependent manner, leading to dysregulation of lipid metabolism. Furthermore, we found APOE could activate the PI3K/AKT/mTOR signaling pathway, thereby enhancing lipid metabolism and proliferative capabilities, by orchestrating the state of FASN ubiquitination. In conclusion, our study reveals the FTO/IGF2BP2/APOE/FASN/mTOR axis as a mechanism underlying aberrant m6A modification in lipid metabolism and provides new insights into the molecular basis for developing therapeutic strategies for pNENs treatment.

Background: Roxadustat is commonly used to treat renal anemia. However, the potential effects of roxadustat on metabolism and organs other than the kidneys have recently attracted increased attention. Objective: This study aimed to examine the regulatory effects of roxadustat on thyroid hormones and blood lipid metabolism in patients with end-stage kidney disease (ESKD) undergoing hemodialysis. Methods: Eighty ESKD patients on hemodialysis and taking roxadustat were enrolled. Hemoglobin, thyroid hormones (TSH, FT3, FT4), and blood lipid profiles (TC, LDL-C, TG, HDL-C) were assessed before and after treatment. Changes in these parameters were compared, and relevant causative factors were analyzed. Results: Roxadustat significantly increased Hb, lowered TSH, FT4, TC, and LDL-C levels (all P<0.001). Patients were categorized into three groups based on post-treatment TSH inhibition percentage: Q1(≥70%), Q2(30%-70%), Q3(≤30%). Pre-treatment TSH decreased with reduced TSH inhibition (P<0.05). Post-treatment, TC, LDL-C, TSH, FT3, and FT4 increased with reduced TSH inhibition (all P<0.05).TC and LDL-C significantly decreased post-treatment in Q1 and Q2 (P<0.05). Correlation analysis showed a positive correlation between ΔTSH and pre-treatment TSH levels (r=0.732, P<0.001). The proportion of patients with ≥70% TSH inhibition increased with higher pre-treatment TSH levels (P for trend <0.05). ΔLDL-C and ΔTSH were positively correlated (r=0.278, P<0.05), with ΔTSH identified as an influencing factor in multiple linear regression (β=0.133, 95% CI [0.042, 0.223], P<0.05). Conclusion: Roxadustat effectively improves anemia in ESKD patients while inhibiting TSH and FT4 secretion and reducing TC and LDL-C levels. Decreases in TSH levels correlate with baseline TSH levels, and lowered blood lipid levels are associated with decreased TSH levels.

Increasing evidence indicates that long non-coding RNA (lncRNA) is one of the most important RNA regulators in the pathogenesis of neuroblastoma (NB). Here, we found that FAM201A was low expressed in NB and a variety of gain and loss of function studies elucidated the anti-tumor effects of FAM201A on the regulation of proliferation, migration and invasion of NB cells. Intriguingly, we identified the ability of FAM201A to encode the tumor-suppressing protein, NBASP, which interacted with FABP5 and negatively regulated its expression. In vivo assays also revealed NBASP repressed NB growth via inactivating MAPK pathway mediated by FABP5. In conclusion, our findings demonstrated that NBASP encoded by FAM201A played a tumor-suppressor role in NB carcinogenesis via down-regulating FABP5 to inactivate the MAPK pathway. These results extended our understanding of the relationship of lncRNA-encoded functional peptides and plasticity of tumor progression.

Background It has been manifested in several studies that age-related metabolic reprogramming is associated with tumor progression, in particular, colorectal cancer (CRC). Here we investigated the role of upregulated metabolites of the aged serum, including methylmalonic acid (MMA), phosphoenolpyruvate (PEP), and quinolinate (QA), in CRC. Methods Functional assays including CCK-8, EdU, colony formation and transwell experiments were used to ascertain which upregulated metabolite of elderly serum was related to tumor progression. RNA-seq analysis was conducted to explore the potential mechanisms of MMA-induced CRC progression. Subcutaneous tumorigenesis and metastatic tumor models were constructed to verify the function of MMA in vivo. Results Among three consistently increased metabolites of the aged sera, MMA was responsible for tumorigenesis and metastasis in CRC, according to functional assays. The promotion of Epithelial–mesenchymal transition (EMT) was observed in CRC cells treated with MMA, on the basis of protein expression of EMT markers. Moreover, combined with transcriptome sequencing, Wnt/β-catenin signaling pathway was activated in CRC cells treated with MMA, which was verified by western blot and qPCR experiments. Furthermore, animal assays demonstrated the pro-proliferation and promotion of metastasis role of MMA in vivo. Conclusion We have identified that age-dependent upregulation of MMA in serum promoted the progression of CRC via Wnt/β-catenin signaling pathway mediated EMT. These collective findings provide valuable insights into the vital role of age-related metabolic reprogramming in CRC progression and propose a potential therapeutic target for elderly CRC.

偏侧舞蹈或投掷症( hemiballism-hemichorea, HB-HC)是基底核区病变引起的锥体外系症状,可由多种疾病引起,包括脑血管疾病、代谢疾病、神经退行性疾病、感染性疾病、病毒性疾病、免疫性疾病等,少见于老年非酮症高血糖伴基底神经节功能障碍病人[1] ,即非酮症高血糖性偏侧舞蹈症( HCNH ).该症由Bedwell于1960年首次报道[2] ,常急性起病,以非酮症性高血糖、HB-HC、对侧基底核区CT高密度或MRI T1加权像高信号为临床特征,近年来常有报道.但酮症高血糖性偏侧舞蹈症在临床上罕见,现将2021年11月我科收治的 1 例老年酮症高血糖性偏侧舞蹈症报道如下.

本文报道了1例缺氧诱导因子脯氨酰羟化酶抑制剂罗沙司他治疗肾性贫血导致的可逆性血清低促甲状腺激素性甲状腺功能减退。患者88岁，因2型糖尿病合并慢性肾脏病、肾性贫血接受罗沙司他口服治疗，用药3个月后偶查甲状腺功能发现血清促甲状腺激素低下和游离甲状腺素、游离三碘甲状腺原氨酸低下，停用罗沙司他1周后甲状腺功能逐渐恢复正常。建议对接受罗沙司他治疗的患者，用药后关注患者的甲状腺功能。

Abstract Increasing evidence indicates that long non-coding RNA (lncRNA) is one of the most important RNA regulators in the pathogenesis of neuroblastoma (NB). However, limited studies have addressed the possibility that lncRNAs possess the ability of encoding functional peptides, which could affect the initiation and development of tumors by participating in signal pathway transduction, immune regulation, and tumor metabolism. Here, we found that downregulation of lncRNA FAM201A was associated with NB malignant progression and a poor prognosis. A variety of gain- and loss-of-function studies elucidated the anti-tumor effects of lncFAM201A on the regulation of growth and metastasis of NB cells. Surprisingly, combined with database predictions and experimental verifications, we found that significantly down-regulating lncRNA FAM201A in NB identified the ability to encode the tumor-suppressing micropeptide, NBASP, which negatively regulated the expression of FABP5. Mechanistically, our transcriptomics analyses confirmed that the regulatory role between NBASP and FABP5 was mediated by activation of the ERK pathway. In conclusion, our findings revealed that NBASP encoded by lncRNA FAM201A played a tumor-suppressor role in NB carcinogenesis via down-regulating FABP5 to inactivate the ERK pathway. These results extended our understanding of the relationship of lncRNA-encoded functional peptides and plasticity of tumor progression.

Objective:To assess the correlation between hyperuricaemia and normoalbuminuric diabetic kidney disease(NADKD) in elderly type 2 diabetic patients.Methods:This retrospective case-control study enrolled 910 patients with type 2 diabetes mellitus who were hospitalized in the Geriatric Department of Nanjing Drum Tower Hospital from 2015 to 2020. The patients were divided into NADKD group [urinary albumin/creatinine(UACR)<30 mg/g and estimated glomerular filtration rate(eGFR) <60 mL·min -1·(1.73 m 2) -1, n=169)], albuminuria DKD group [UACR ≥30 mg/g and eGFR <60 mL·min -1·(1.73 m 2) -1, n=234], and control group [UACR <30 mg/g and eGFR≥60 mL·min -1·(1.73 m 2) -1, n=507]. Medical history, physical examination, and laboratory tests were collected. Results:The proportion of women in the NADKD group was significantly higher than that in the albuminuric DKD group(50.89% vs 40.60%, P<0.05). Duration of diabetes, HbA 1C, fasting plasma glucose(FPG), the prevalences of hypertension and hyperuricaemia, blood urea nitrogen, blood creatinine, and blood uric acid were significantly lower in the NADKD group than those in the albuminuric DKD group(all P<0.05). Blood urea nitrogen, serum creatinine, triglycerides, serum uric acid and the prevalence of hyperuricemia were significantly higher in the NADKD group compared the control group(all P<0.001) while the proportion of hypertension, systolic blood pressure, LDL-C, HbA 1C, and FPG were lower(all P<0.05). Multivariate linear regression analysis showed that eGFR was negatively associated with urea nitrogen and serum uric acid while positively associated with HbA 1C in normoalbuminuric elderly type 2 diabetic patients(all P<0.001). Logistic regression analysis revealed that hyperuricaemia was a risk factor for NADKD in elderly type 2 diabetic patients after adjusting for BMI, blood pressure, lipids, and glucose( OR=1.963, 95% CI 1.157-3.332, P=0.012). Conclusion:Hyperuricaemia is significantly associated with NADKD in elderly patients with type 2 diabetes.

Objective To investigate the relationship between serum lutein and type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD) in elderly individuals. Methods A total of 60 T2DM patients over 60 years were subgrouped into a DKD group and a non-DKD group according to their urinary microalbumin-to-creatinine ratio (UACR), while 30 age-matched non-T2DM patients were recruited in the control group. Baseline characteristics, laboratory examination results, and serum lutein levels were compared, and their correlations were analyzed. Receiver operating characteristic (ROC) curves were plotted to identify the diagnostic potential of lutein in T2DM and DKD. Results The lutein level in the T2DM group was significantly lower than that in the control group and was also significantly lower in the DKD group than in the non-DKD group (p < 0.001). Lutein levels were negatively correlated with body mass index, glycosylated hemoglobin, fasting blood glucose, triglyceride, and UACR and positively correlated with high-density lipoprotein cholesterol (p < 0.05). T2DM patients were divided into four groups according to the quartile of their lutein level. The proportion of T2DM and DKD gradually decreased with increasing lutein levels (p < 0.001). The area under the ROC curve of serum lutein in diagnosing T2DM and DKD was 0.880 and 0.779, respectively, with corresponding cut-off values of 0.433 mu mol/L and 0.197 mu mol/L (p < 0.001). Conclusion The serum level of lutein is negatively correlated with the incidence of T2DM and DKD in the elderly and can serve as a diagnostic marker for T2DM and DKD.

PURPOSE:To develop a simple and clinically useful assessment tool for osteoporosis in older women with type 2 diabetes mellitus (T2DM).METHODS:A total of 601 women over 60 years of age with T2DM were enrolled in this study. The levels of serum sex hormones and bone metabolism markers were compared between the osteoporosis and non-osteoporosis groups. The least absolute shrinkage and selection operator regularization (LASSO) model was applied to generate a risk assessment tool. The risk score formula was evaluated using receiver operating characteristic analysis and the relationship between the risk score and the bone mineral density (BMD) and T-value were investigated.RESULTS:Serum sex hormone-binding globulin (SHBG), cross-linked C-telopeptide of type 1 collagen (CTX), and osteocalcin (OC) were significantly higher in the osteoporosis group. After adjustment for age and body mass index (BMI), SHBG was found to be correlated with the T-value or BMD. Then, a risk score was specifically generated with age, BMI, SHBG, and CTX using the LASSO model. The risk score was significantly negatively correlated with the T-value and BMD of the lumbar spine, femoral neck, and total hip (all P<0.05).CONCLUSION:A risk score using age, BMI, SHBG, and CTX performs well for identifying osteoporosis in older women with T2DM.

目的 探讨影响≥75岁老年病人国际华法林药物基因组协会(IWPC)预测模型准确性的相关因素,为≥75岁病人更合理地应用华法林提供参考.方法 收集≥75岁口服华法林抗凝治疗的老年病人的临床资料,根据预测剂量与实际剂量间的差异率分为差异轻微组、差异一般组和差异显著组,比较各组性别、年龄、BMI、血压、心率、合并疾病及合并用药等临床指标差异,并分析各指标与剂量差异率的相关性.结果 73例病人分为差异轻微组42例,差异一般组21例,差异显著组10例.3组病人性别、年龄、肝功能等指标及各基因型分布差异无统计学意义(P＞0.05).差异轻微组心力衰竭(心衰)病史及应用利尿剂比例明显低于差异显著组,血清肌酐明显低于差异一般组及差异显著组,估算的肾小球率过滤(eGFR)明显高于差异一般组及差异显著组,差异有统计学意义(均P＜O.05).差异轻微组华法林实际剂量明显高于差异显著组(P＜0.05).有序多元Logistic回归分析显示,心衰病史及是否应用利尿剂对病人剂量差异率无显著影响(P＞0.05).将eGFR按四分位数分为低水平[(＜59.5 mL/(min.1.73m2)]、中低水平[59.5～76.3 mL/(min-1.73m2)]、中高水平[76.4～96.5 mL/(min ?1.73m2)]、高水平[＞96.5 mL/(min-1.73m2)]4个等级,eGFR低水平病人引起华法林实际与预测剂量间明显差异的OR值是eGFR高水平病人的4.455倍;eGFR中低水平病人引起华法林实际与预测剂量间明显差异的OR值是eGFR高水平病人的5.135倍.结论 中国汉族≥75岁病人华法林平均实际稳定剂量＜2.5 mg/d;实际剂量越低,与IWPC模型公式预测剂量差异越大;eGFR与剂量差异大小有显著相关性.

Objective:To explore the clinical characteristics of perioperative euglycemic diabetic ketoacidosis (euDKA) induced by sodium-glucose cotransporter 2 (SGLT2) inhibitors.Methods:The case reports of perioperative euDKA caused by SGLT2 inhibitors published up to June 30, 2019 were collected by searching the relevant databases and the following information of patients including demographic characteristics, types of diabetes, use of SGLT2 inhibitors, onset time and clinical manifestation of euDKA, the blood glucose and pH, serum bicarbonate and anion gap, β-hydroxybutyric acid and ketone body concentration in urine when diagnosing euDKA, predisposing factors of euDKA, as well as the treatments and outcomes were collected. The clinical characteristics of perioperative euDKA induced by SGLT2 inhibitors were analyzed descriptively.Results:A total of 27 patients (from 20 articles) were collected, including 13 males and 14 females with an age of (58±12) years; 26 patients were with type 2 diabetes mellitus and 1 with type 1 diabetes mellitus. Of them, 15 cases were treated with canagliflozin, 6 cases were treated with dapagliflozin, and 6 cases were treated with empagliflozin; the onset time of euDKA was 10 hours to 10 days after operation and within 3 days after operation in 21 cases (77.8%); 24 cases had similar symptoms as ketoacidosis and 3 cases had no obvious symptoms; the blood glucose was (9.5±2.2) mmol/L when diagnosing euDKA and the other laboratory test results were similar to those of ketoacidosis. The main factors inducing euDKA were operation and low carbohydrate diet. After the occurrence of euDKA, all patients received insulin and rehydration therapy, and then 26 cases (96.3%) got better and 1 (3.7%) died.Conclusions:The perioperative euDKA mainly occurred within 3 days after operation. The main inducing factors of euDKA were operation and low carbohydrate diet. After insulin and rehydration therapy, most patients had a good prognosis.