BACKGROUND Multiple acyl-CoA dehydrogenase deficiency(MADD)is a disease of rare autosomal recessive disorder.There are three types of MADD.Type I is a neonatalonset form with congenital anomalies.Type II is a neonatal-onset form without congenital anomalies.Type III is considered to a milder form and usually responds to riboflavin.However,late-onset form could also be fatal and not responsive to treatments.CASE SUMMARY We report a severe case of a young man with onset type III MADD induced by drugs and strenuous exercise characterized by rhabdomyolysis and liver dysfunction.Urine analysis indicated 12 out of 70 kinds of organic acids like glutaric acid-2 were detected.Serum analysis in genetic metabolic diseases revealed 24 out of 43 tested items were abnormal,revealing the elevation of several acylcarnitines and the reduction of carnitine in the patient.By next generation sequencing technology for gene sequencing related to fatty acid oxidation and carnitine cycle defects,a rare ETFDH gene variant was identified:NM_004453:4:C.1448C>T(p.Pro483 Leu).The patient was diagnosed with lateonset GAII.He was not responsive to riboflavin and progressively worsened into multiple organ failure that finally led to death.CONCLUSION Type III MADD can also be fatal and not responsive to treatments.
Immobilization of D-amino acid dehydrogenase(DAADH)by the assembly of peptide linker was studied for the biosynthesis of Dphenylalanine.Hybrid material of zeolitic imidazolate framework-8(ZIF-8)combined with reduced graphene oxide(RGO)was applied for the immobilization of DAADH from Ureibacillus thermosphaericus.The recovery rate of DAADH/ZIF-8/RGO was 165.6%.DAADH/ZIF-8/RGO remained 53.4%of its initial activity at 50°C for 10 h while the free enzyme was inactivated.DAADH/ZIF-8/RGO maintained 70.5%activity in hyperalkaline solution with pH 12.Kinetic parameters indicated that DAADH/ZIF-8/RGO had greater affinity of phenylpyruvate as V_(max)/K_(m)of DAADH/ZIF-8/RGO was 1.27-fold than free enzyme.After seven recycles,the activity of DAADH/ZIF-8/RGO remained 64.3%.Furthermore,one-step separation and in situ immobilization of DAADH by ZIF-8/RGO/Ni was carried out with 1.5-fold activity enhancement.Combining peptide linker and metal-organic framework(MOF)immobilization,thermostability and activity of the immobilized DAADH were significantly improved.
Hangbin LeiQian ZhangXiaoyan XiangLiang JiangShiyan WangLingxuan DuanShizhen Wang
The activation of spinal astrocytes accounts for opioid-induced hyperalgesia(OIH),but the underlying mechanisms remain elusive.The presence of astrocyte-neuron lactate shuttle(ANLS)makes astrocytes necessary for some neural function and communication.The aim of this study was to explore the role of ANLS in the occurrence and maintenance of OIH.After 7 days consecutive morphine injection,a mice OIH model was established and astrocytic pyruvate dehydrogenase kinase 4(PDK4),phosphorylated pyruvate dehydrogenase(p-PDH)and accumulation of L-lactate was elevated in the spinal dorsal horn.Intrathecally administration of inhibitors of PDK,lactate dehydrogenase 5 and monocarboxylate transporters to decrease the supply of L-lactate on neurons was observed to attenuate hypersensitivity behaviors induced by repeated morphine administration and downregulate the expression of markers of central sensitization in the spinal dorsal horns.The astrocyte line and the neuronal line were co-cultured to investigate the mechanisms in vitro.In this study,we demonstrated that morphine-induced hyperalgesia was sustained by lactate overload consequent upon aberrant function of spinal ANLS.In this process,PDK-p-PDH-lactate axis serves a pivotal role,which might therefore be a new target to improve long-term opioid treatment strategy in clinical practice.
目的 探讨乳酸脱氢酶(LDH)等血液参数和生化指标对初次接受免疫检查点抑制剂(ICIs)治疗的晚期非小细胞肺癌(NSCLC)患者疗效及其预后的预测价值。方法 回顾性分析2019-03-01-2021-10-30在山东省肿瘤医院首次接受ICIs治疗的136例晚期NSCLC患者临床资料。收集患者初次接受ICIs治疗前的临床基本特征,采用Kaplan-Meier法绘制生存率曲线,log-rank检验比较组间生存率。单因素和多因素Cox回归分析各临床特征及血液生化参数与无进展生存期(PFS)和总生存期(OS)的关系。结果 136例患者中疾病稳定39例,因疾病进展死亡84例,失访13例。患者的中位随访时间为39.01个月(95%CI:38.19~39.83),中位PFS(mPFS)为7.14个月(95%CI:6.06~8.22),中位OS(mOS)为19.24个月(95%CI:14.54~23.94)。Kaplan-Meier生存分析结果显示,与无肝转移组相比,肝转移组PFS和OS均更短[mPFS:(8.26 vs 3.87)个月,P=0.001;mOS:(21.75 vs 11.54)个月,P=0.011];与低LDH组(<209.5 U/L)相比,高LDH组(≥209.5 U/L)PFS和OS均更短[mPFS:(8.33 vs 5.88)个月,P=0.002;mOS:(32.89 vs 15.01)个月,P=0.001];与高白蛋白(ALB)组(≥42.95 g/L)相比,低ALB组(<42.95 g/L)OS更差[mOS:(23.37 vs 12.89)个月,P=0.007]。单因素Cox回归结果示,LDH、既往放疗史、LDH/白蛋白比值(LAR)、肝转移和抗血管药物治疗是患者PFS的影响因素,均P<0.05;多因素分析表明,LDH与肝转移是影响PFS的独立预后因素(LDH:HR=1.748,95%CI:1.181~2.587,P=0.005;肝转移:HR=1.885,95%CI:1.235~2.877,P=0.003)。单因素Cox回归结果示,肝转移、绝对单核细胞计数(AMC)、LDH、ALB、中性粒细胞/淋巴细胞比值(NLR)、LAR、单核细胞/淋巴细胞比值(MLR)及全身炎症反应指数(SIRI)是患者OS的影响因素,均P<0.05。多因素分析表明,LDH、肝转移和ALB是影响患者OS的独立预后因素(LDH:HR=2.087,95%CI:1.298~3.354,P=0.002;肝转移:HR=1.909,95%CI:1.164~3.130,P=0.010;ALB:HR=0.514,95%CI:0.331~0.801,P=0.003)。结论 基线LDH可作为一种无创且易获取�
Background: Glycine dehydrogenase(GLDC) plays an important role in the initiation and proliferation of several human cancers. In this study, we aimed to detect the methylation status of GLDC promoter and its diagnostic value for hepatitis B virus-associated hepatocellular carcinoma(HBV-HCC). Methods: We enrolled 197 patients, 111 with HBV-HCC, 51 with chronic hepatitis B(CHB), and 35 healthy controls(HCs). The methylation status of GLDC promoter in peripheral mononuclear cells(PBMCs) was identified by methylation specific polymerase chain reaction(MSP). The mRNA expression was examined using real-time quantitative polymerase chain reaction(q PCR). Results: The methylation frequency of the GLDC promoter was significantly lower in HBV-HCC patients(27.0%) compared to that in CHB patients(68.6%) and HCs(74.3%)( P < 0.001). The methylated group had lower alanine aminotransferase level( P = 0.035) and lower rates of tumor node metastasis(TNM) Ⅲ/Ⅳ( P = 0.043) and T3/T4( P = 0.026). TNM stage was identified to be an independent factor for GLDC promoter methylation. GLDC mRNA levels in CHB patients and HCs were significantly lower than those in HBV-HCC patients( P = 0.022 and P < 0.001, respectively). GLDC mRNA levels were significantly higher in HBV-HCC patients with unmethylated GLDC promoters than those with methylated GLDC promoters( P = 0.003). The diagnostic accuracy of alpha-fetoprotein(AFP) combined with GLDC promoter methylation for HBV-HCC was improved compared with that of AFP alone(AUC: 0.782 vs. 0.630, P < 0.001). In addition, GLDC promoter methylation was an independent predictor for overall survival of HBV-HCC patients( P = 0.038). Conclusions: The methylation frequency of GLDC promoter was lower in PBMCs from HBV-HCC patients than that from patients with CHB and HCs. The combination of AFP and GLDC promoter hypomethylation significantly improved the diagnostic accuracy of HBV-HCC.
Li-Li MiaoJing-Wen WangHui-Hui LiuShuai GaoYu-Chen FanKai Wang
