Post-operative albumin-bilirubin grade predicts long-term outcomes among Child–Pugh grade A patients with hepatocellular carcinoma after curative resection

Background: Although Child–Pugh grade A patients with hepatocellular carcinoma(HCC) are candidates for curative resection, some may have a poor prognosis. The albumin-bilirubin(ALBI) grade, a measure of liver function based on albumin and bilirubin, has the potential to detect Child–Pugh grade A HCC patients with poor prognosis. Because components of the ALBI grade can be measured easily even after surgery, we explored the predictive values of ALBI in patient prognosis after HCC resection. Methods: In this retrospective case-control study, we included 136 HCC patients who underwent curative resection between January 2004 and December 2013 at our hospital. ALBI grade was calculated from laboratory data recorded the day before surgery and at post-operative day 5. Results: Pre-and post-operative ALBI grade predicted patients' long-term outcomes( P = 0.020 and P 0.001, respectively, for overall survival, and P = 0.012 and P = 0.015, respectively, for recurrence-free survival). Post-operative ALBI grade was associated with patients' surgical factors of repeated hepatic resection( P = 0.012), intra-operative bleeding( P = 0.006), and surgery duration( P = 0.033). Furthermore, post-operative ALBI grade, rather than pre-operative ALBI grade, was an independent predictive factor of long-term outcome of Child–Pugh grade A patients with HCC. Conclusions: Post-operative ALBI grade is useful to predict the prognosis in patients after HCC resection.     

葡萄糖醛酸转移酶1A基因的组织差异性表达及多态调节

目的从mRNA、蛋白质及细胞水平分析尿苷二磷酸葡萄糖醛酸转移酶（UGT）1A基因的组织差异性表达及多态凋节。方法采用逆转录聚合酶链反应分析结直肠癌组40例、正常人群肠道黏膜20例、正常肝组织10例的UGT 1A mRNA表达；免疫印迹检测各组UGT 1A蛋白表达；高效液相色谱法测定各组UGT 1A酶的催化活性。结果①结直肠癌组织中UGT 1A mRNA表达量明显低于其周围正常黏膜，而后者低于正常人群肠黏膜组织，正常人群结直肠黏膜中UGT 1A mRNA表达量总体低于肝组织，P〈0．01。结直肠癌组、正常人群结直肠黏膜组织呈现个体差异表达，而肝组织的表达较均质。②癌组织、癌周正常黏膜及正常人群肠道黏膜中UGT 1A各同工酶的表达例数均不相同。③UGT 1A蛋白表达在癌组织显著低于癌周正常组织，后者又低于正常人肠黏膜（P〈0．01），各组蛋白表达量亦各不相同。而肝组织呈均质表达。④癌组织的UGT 1A酶活性低于癌周正常黏膜．而后者的微粒体酶活性低于正常人群肠黏膜微粒体蛋白，P〈0．01。结论①UGT 1A基因位点呈组织差异性表达。②结直肠黏膜上皮UGT 1A基因位点在转录水平及功能水平均存在多态调节，不同个体对致癌物的易感性不同可能是这种差异表达的结果。     

Association between promoter and coding region mutations of UDP-glucuronosyltransferase 1A1 and beta-thalassemia/Hb E with cholelithiasis

Background and objectives:  Cholelithiasis has been observed with high incidence in beta‐thalassemia/hemoglobin E (β‐thal/Hb E). Recent studies have shown that a variant TATA‐box in the promoter region of the UDP‐glucuronosyltransferase 1A1 (UGT1A1) gene is associated with the development of cholelithiasis. The coding region mutation (G71R) of the UGT1A1 gene was higher in Asians than those in Caucasians. The relationship between the variant UGT1A1 promoter and coding region gene and cholelithiasis in β‐thal/Hb E subjects were investigated. Methods:  One hundred and seventeen β‐thal/Hb E subjects entered this study. The TATA‐box and G71R mutations were analyzed by fragment size analysis and restriction fragment length polymorphism methods, respectively. Results:  The incidence of cholelithiasis was higher in heterozygous (68.3%) and homozygous (100%) subjects compared with normal UGT1A1 haplotype (61.4%). Total bilirubin level (6.0 ± 2.03 mg/dL) in the homozygous group was significantly higher than that of wild type (3.31 ± 1.83 ng/dL). Prevalence of cholelithiasis increased with age (OR = 1.1, 95% CI = 1.03–1.12, P < 0.001). Female gender (OR = 3.7, 95% CI = 1.3–10.6, P < 0.01) and elevated liver enzyme (OR = 1.02, 95%CI = 1.0–1.04, P < 0.02) were two other risk factors for cholethiasis in β‐thal/Hb E. Conclusion:  This study shows that the combined TATA‐box variants and G71R mutations of the UGT1A1 is associated with cholelithiasis in β‐thal/Hb E.     

白蛋白对肾小管上皮细胞血管紧张素转换酶2表达的抑制作用

目的观察白蛋白对人近端肾小管上皮细胞株（HK_2）血管紧张素转换酶2（ACE2）mRNA和蛋白表达的影响,探讨蛋白尿激活肾脏局部RAs的机制。方法采用不同浓度的牛血清白蛋白（BSA）作用HK-2细胞不同时间。以实时RT-PCR和Western印迹检测ACE2mRNA和蛋白的表达。采用放射免疫法检测细胞上清液中血管紧张素Ⅱ（ATⅡ）含量。采用激光共聚焦显微镜观察ACE2蛋白的表达。结果与对照组（相对表达量为O）相比,BSA使ACE2mRNA表达显著减少（2．5mg／ml：-1．05土0．12;5mg／ml：-1．30±0．11;10mg／ml：-2．54土0．44;P均〈0．05）。同时,BSA使ACE2蛋白表达显著降低（对照组：0．90±0．10;2．5mg／ml：0．66士0．09;5mg／ml：0．50士0．07;10mg／ml：0．35±0．05;P均〈0．05）。其中BSA（10mg／ml）使ACE2mRNA及蛋白表达减少呈时间依赖性（P均〈0．05）。与对照组相比,不同浓度BSA组的细胞上清液中的ATⅡ均显著升高（P均〈0．05）。激光共聚焦显微镜可见ACE2主要分布于细胞膜。结论BSA可显著抑制HK-2细胞ACE2 mRNA和蛋白的表达,此作用所导致的近曲小管间质液ATⅡ浓度升高可能与间质纤维化相关。     

Red cell distribution width to serum albumin ratio as an early prognostic marker for severe acute pancreatitis: A retrospective study

Background and study aimsThe ability to predict severe acute pancreatitis (SAP) at an early stage is crucial for reducing the associated complications and mortality. In this study, we compared the ratio of red cell distribution width to albumin (RDW-to-ALB) using predictive scoring systems, such as the Ranson score, BISAP, and MCTSI, to develop a simple and accurate method of predicting SAP.Patients and methodsWe included 212 patients with mild acute pancreatitis (MAP) and 89 with SAP between January 2013 and December 2018. The differences in the general characteristics and biochemical analysis as well as the various predictive scores were compared between the two groups. We evaluated the sensitivity and specificity between the RDW-to-ALB ratio, RDW, ALB, and multiple predictive scores in patients with early acute pancreatitis (AP) by using the receiver operating characteristic (ROC) curve.ResultsThe RDW-to-ALB ratio (%) of patients with SAP was higher than that of patients with MAP (0.43 ± 0.08 vs. 0.32 ± 0.04, p < 0.001). Patients with SAP had higher Ranson, BISAP, and MCTSI scores than those with MAP. The ROC curve revealed that, when the RDW-to-ALB ratio (%) was >0.36, the sensitivity and specificity of the predicted SAP were 80.0% and 80.7%, respectively. Further statistical analysis found that the RDW-to-ALB ratio and Ranson, BISAP, and MCTSI scores were consistent in predicting SAP effectiveness (P > 0.05).ConclusionsThe RDW-to-ALB ratio has a promising predictive power for SAP, and its effectiveness is comparable with those of Ranson, BISAP, and MCTSI scores.     

Munc18-1 binds directly to the neuronal SNARE complex

Both SM proteins (for Sec1/Munc18-like proteins) and SNARE proteins (for soluble NSF-attachment protein receptors) are essential for intracellular membrane fusion, but the general mechanism of coupling between their functions is unclear, in part because diverse SM protein/SNARE binding modes have been described. During synaptic vesicle exocytosis, the SM protein Munc18-1 is known to bind tightly to the SNARE protein syntaxin-1, but only when syntaxin-1 is in a closed conformation that is incompatible with SNARE complex formation. We now show that Munc18-1 also binds tightly to assembled SNARE complexes containing syntaxin-1. The newly discovered Munc18-1/SNARE complex interaction involves contacts of Munc18-1 with the N-terminal H(abc) domain of syntaxin-1 and the four-helical bundle of the assembled SNARE complex. Together with earlier studies, our results suggest that binding of Munc18-1 to closed syntaxin-1 is a specialization that evolved to meet the strict regulatory requirements of neuronal exocytosis, whereas binding of Munc18-1 to assembled SNARE complexes reflects a general function of SM proteins involved in executing membrane fusion.     

Long-term albumin infusion in decompensated cirrhosis: A review of current literature

Decompensated cirrhosis is characterized by chronic inflammation and severe portal hypertension leading to systemic circulatory dysfunction. Albumin infusion has been widely used in decompensated cirrhosis in patients with spontaneous bacterial peritonitis, large-volume paracentesis and hepatorenal syndrome. Emerging data suggest long-term albumin infusion has both oncotic and non-oncotic properties which may improve the clinical outcomes in decompensated cirrhosis patients. We review the current literature on both the established and potential role of albumin, and specifically address the controversies of long-term albumin infusion in decompensated cirrhosis patients.     

Measuring the albumin excretion rate: agreement between methods and biological variability.

A timed urine collection is necessary to determine the excretion rate of albumin (AER) but such specimens are tedious to collect and frequently inaccurate. Albumin excretion can also be quantified by the use of the albumin:creatinine ratio in randomly obtained specimens. In the present study the agreement between AER as measured on a 24-h urine collection and as estimated from the albumin:creatinine ratio is determined. Previously published studies have examined the correlation rather than the agreement between these methods and not taken into account the biological variability of AER. Thirty patients with diabetes who had normal renal function, but varying degrees of albuminuria, produced two 24-h specimens and two random daytime specimens of urine. AER was measured on the former and estimated from the latter by multiplying the albumin:creatinine ratio by an estimate of that individual's creatinine excretion rate. Agreement between the methods and the biological variability was determined by using appropriate statistical methodology, the main outcome measure being the limits of agreement between repeat values for both measurements and both estimates of AER, and between the averages of the measurements and the estimates. The limits of agreement between repeated 24-h measurements were wide, the second specimen being 33 to 490% of the first. The estimates of AER gave values numerically similar to the measurements. The limits of agreement between the two estimates did not differ significantly from those of the measurements, nor did the limits of agreement when the average of the measurements and the average of the estimates were compared (all NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

大量放腹水后输注人体白蛋白疗效的 Meta 分析

目的：评估肝硬化合并腹水患者经腹腔大量穿刺放液后（LVP）输注人体白蛋白的疗效。方法检索Cochrane 图书馆、PubMed、Embase、High Wire Press、web of Science、中国生物医学文献数据库、中国知网、维普数据库和万方数据库,收集用人体白蛋白治疗肝硬化腹水的随机对照试验的论文。根据纳入标准对文献进行筛选和评估,采用RevMan 5．2软件进行统计分析,计算相对危险度（RR）和95％置信区间（CI ）,试验组静脉输注人体白蛋白,对照组静脉滴注人工胶体或者血管加压素,比较试验组与对照组 LVP 后 PCD、低钠血症、肾损伤、住院病死率的情况。结果最终纳入文献13篇,均为英文文献。Meta 分析结果显示,试验组穿刺后循环障碍（PCD）发生率为14．76％,低于对照组的31．98％,差异有统计学意义（RR ＝0．48,95％ CI ：0．364～0．63,P ＜0．01）。试验组低钠血症发生率（8．12％）低于对照组（15．28％）,差异有统计学意义（RR＝0．57,95％CI ：0．37～0．87,P ＝0．009）。试验组肾损伤发生率（5．62％）低于对照组（7．03％）,差异无统计学意义（RR ＝0．88,95％CI ：0．53～1．44,P ＝0．61）。试验组住院病死率（9．56％）低于对照组（12．55％）,差异有统计学意义（RR＝0．58,95％CI ：0．364～0．93,P ＝0．02）。结论输注人体白蛋白在预防肝硬化腹水患者 LVP 后 PCD、低钠血症方面有优势,且住院病死率降低。     

Serum albumin strongly influences SDF-1 dependent migration

Stem cell migration is largely regulated by the chemokine SDF-1 and its receptor CXCR4. In the present study, we analyzed the effect of protein on SDF-1 dependent chemotaxis using CXCR4 expressing primary CD34+ hematopoietic progenitor cells for transwell migration assays. We show that migration towards SDF-1 is abolished in the absence of protein, while addition of serum albumin rescues SDF-1 dependent migration. Acid hydrolyzation or tryptic digest of protein eliminates its migration supporting effect, showing that the intact protein is necessary. We demonstrate that gradients of human serum albumin (HSA) that are physiologically present in vivo between human plasma and interstitial fluid (bone marrow) greatly influence SDF-1 dependent migration of hematopoietic progenitor cells. While SDF-1 dependent migration is strongly enhanced in the presence of a HSA gradient from 4% (plasma) towards 1% (interstitial fluid), reversion of the protein concentrations inhibits SDF-1 dependent chemotaxis. Furthermore, migration is induced to lower serum albumin concentrations in the presence of equal SDF-1 concentration, while albumin gradients in the absence of SDF-1 have no effect. Our results suggest that physiological gradients of serum albumin between blood and bone marrow support SDF-1 dependent homing of hematopoietic progenitor cells to the stem cell niche.     

尿苷二磷酸葡萄糖醛酸转移酶1A6基因多态性与抗结核药致肝损害的相关性

目的 探讨尿苷二磷酸葡萄糖醛酸转移酶1A6(UGT1A6)基因多态性与中国唐山地区结核患者抗结核药致肝损害的相关性.方法采用病例对照研究,以抗结核治疗导致肝损害患者202例为病例组,无肝损害者239例为对照组,收集环境因素暴露情况及静脉血.UGT1A6基因多态性分析采用聚合酶链反应限制性片段长度多态方法,利用Hha Ⅰ、Dpn Ⅱ和NsiⅠ内切酶分析其基因多态性,以SPSS13.0软件对各危险因素进行单因素和多因素非条件Logistic回归分析.结果 UGT1A6的19T/G、308C/A和541A/G多态性位点均存在3种基因型,UGT1A6-19T/T、UGT1A6-19T/G和UGT1A6-19G/G在病例组和对照组的频率分别为51.5%、39.6%、8.9%和71.1%、25.5%、3.3%;UGT1A6-308C/C、UGT1A6-308C/A和UGT1A6-308A/A在病例组和对照组的频率分别为52.0%、40.6%、7.4%和79.1%、19.2%、1.7%; UGT1A6-541AA、UGT1A6-541A/G和UGT1A6-541G/G在病例组和对照组的频率分别为57.9%、33.7%、8.4%和79.5%、19.2%、1.3%,两组间差异均有统计学意义(x2值分别为17.956、37.385和24.095,P值均＜0.01).单因素和多因素分析均显示UGT1A6-19T/G、-308C/A、-541A/G 3个位点基因多态性与抗结核药致肝损害的发生有关(P值均＜0.05).结论 UGT1A6基因多态性可能与汉族人抗结核药致肝损害的发病有关,且各基因型存在相互作用.

Abstract：

Objective To investigate the relationship between the polymorphisms of UGT1A6 genes and anti-tuberculosis drug induced hepatic-injury (ADIH). Methods 202 cases and 239 controls were collected and a case-control study was conducted. Information on related risk factors of tuberculosis was collected. The genotypes of UGT1A6-19T/G, UGT1A6-308C/A and UGT1A6-541A/G genetic polymorphisms were detected by polymerase chain reaction and restriction fragment length polymorphism technique (PCRRFLP) in patients received anti-tuberculosis therapy. The Hha Ⅰ, Dpn Ⅱ and NsiⅠenzyme were employed.Univariate and multivariate conditional logistic analyses were conducted using SPSS13.0 for windows software.Results The allele frequency of gene UGT1A6-19T/T, UGT1A6-19T/G, UGT1A6-19G/G, GT1A6-308C/C, UGT1A6-308C/A, UGT1A6-308A/A, UGT1A6-541AA, UGT1A6-541A/G and UGT1A6-541G/G in ADIH group were 51.5%, 39.6%, 8.9%, 52.0%, 40.6%, 7.4%, 57.9%, 33.7%, 8.4% and 71.1%, 25.5%, 3.3%,79.1%, 19.2%, 1.7%, 79.5%, 19.2%, 1.3% in control group, respectively. Univariate analysis demonstrated that the frequency of UGT1A6-19T/G, UGT1A6-308C/A and UGT1A6-541A/G genotype in cases were significantly higher than that in controls (P ＜ 0.05). Conclusion A positive association is found between UGT1A6 genotype and the occurrence of ADIH. The synergetic effect is proved on susceptibility to pulmonary tuberculosis between UGT1A6 mutant genotypes.     

HTLV-I Tax directly binds the Cdc20-associated anaphase-promoting complex and activates it ahead of schedule

Expression of the human T lymphotropic virus type I (HTLV-I) transactivator/oncoprotein, Tax, leads to faulty mitosis as reflected by chromosome aneuploidy, cytokinesis failure, and formation of micro- and multinucleated cells. Here we show that HTLV-I-transformed T cells progress through S/G(2)/M phases of the cell cycle with a delay. This delay is correlated with a decrease in the levels of cyclin A, cyclin B1, and securin. In tax-expressing cells, the Cdc20-associated anaphase promoting complex (APC(Cdc20)), an E3 ubiquitin ligase that controls metaphase to anaphase transition, becomes active before cellular entry into mitosis as evidenced by premature cyclin B1 polyubiquitination and degradation during S/G(2). Consistent with the notion that Tax activates APC(Cdc20) directly, Tax is found to coimmunoprecipitate with Cdc20 and Cdc27/APC3. The APC(Cdc20) activity prematurely activated by Tax remains sensitive to spindle checkpoint inhibition. Unscheduled activation of APC(Cdc20) by Tax provides an explanation for the mitotic abnormalities in HTLV-I-infected cells and is likely to play an important role in the development of adult T cell leukemia.     

Current position of vasoconstrictor and albumin infusion for type 1 hepatorenal syndrome

Spontaneous bacterial peritonitis(SBP),refractory ascites,hepatorenal syndrome(HRS),hyponatremia and hepatic encephalopathy are complicationswhich frequently happen during a clinical course of decompensated cirrhosis.Splanchnic and peripheral vasodilatation,increased intrarenal vasoconstriction and impaired cardiac responsive function are pathological changes causing systemic and hemodynamic derangement.Extreme renal vasoconstriction leads to severe reduction of renal blood flow and glomerular filtration rate,which finally evolves into the clinical feature of HRS.Clinical manifestations of type 1 and type 2 HRS come to medical attention differently.Patients with type1 HRS present as acute kidney injury whereas those with type 2 HRS will have refractory ascites as the leading problem.Prompt diagnosis of type 1 HRS can halt the progression of HRS to acute tubular necrosis if the combined treatment of albumin infusion and vasoconstrictors is started timely.HRS reversal was seen in 34%-60%of patients,followed with decreasing mortality.Baseline serum levels of creatinine less than5 mg/dL,bilirubin less than 10 mg/dL,and increased mean arterial pressure of over 5 mmHg by day 3 of the combined treatment of vasoconstrictor and albumin are the predictors of good response.Type 1 HRS can be prevented in some conditions such as albumin infusion in SBP,prophylactic antibiotics for upper gastrointestinal hemorrhage,albumin replacement after large volume paracentesis in cirrhotic patients with massive ascites.The benefit of albumin infusion in infection with primary source other than SBP requires more studies.     

Midodrine and albumin for prevention of complications in patients with cirrhosis awaiting liver transplantation. A randomized placebo-controlled trial

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The p53 protein is an unusually shaped tetramer that binds directly to DNA.

We have analyzed the size and structure of native immunopurified human p53 protein. By using a combination of chemical crosslinking, gel filtration chromatography, and zonal velocity gradient centrifugation, we have determined that the predominant form of p53 in such preparations is a tetramer. The behavior of purified p53 in gels and sucrose gradients implies that the protein has an extended shape. Wild-type p53 has been shown to bind specifically to sites in cellular and viral DNA. We show in this study by Southwestern ligand blotting and by analysis of DNA-bound crosslinked p53 that p53 monomers, dimers, and tetramers can bind directly to DNA.     

Baseline level and change in serum albumin concentration and the risk of incident type 2 diabetes

Aims

We aimed to determine whether baseline level and change in serum albumin concentration are predictive of future development of type 2 diabetes (T2D).

The platelet protein kinase C substrate pleckstrin binds directly to SDPR protein

Pleckstrin is a modular platelet protein consisting of N- and C-terminal pleckstrin homology (PH) domains, a central dishevelled egl10 and pleckstrin (DEP) domain and a phosphorylation region. Following agonist-induced platelet stimulation, dimeric pleckstrin translocates to the plasma membrane, is phosphorylated and then monomerizes. A recent study found that pleckstrin null platelets from a knockout mouse have a defect in granule secretion, actin polymerization and aggregation. However, the mechanism of pleckstrin signaling for this function is unknown. Our recent studies have led to the identification of a novel pleckstrin-binding protein, serum deprivation response protein (SDPR), by co-immunoprecipitation, GST-pulldowns and nanospray quadruple time of flight mass spectrometry. We show that this interaction occurs directly through N-terminal sequences of pleckstrin. Both pleckstrin and SDPR are phosphorylated by protein kinase C (PKC), but the interaction between pleckstrin and SDPR was shown to be independent of PKC inhibition or activation. These results suggest that SDPR may facilitate the translocation of nonphosphorylated pleckstrin to the plasma membrane in conjunction with phosphoinositides that bind to the C-terminal PH domain. After binding of pleckstrin to the plasma membrane, its phosphorylation by PKC exerts downstream effects on platelet aggregation/secretion.     

Oligosaccharyltransferase directly binds to ribosome at a location near the translocon-binding site

Oligosaccharyltransferase (OT) transfers high mannose-type glycans to the nascent polypeptides that are translated by the membrane-bound ribosome and translocated into the lumen of the endoplasmic reticulum through the Sec61 translocon complex. In this article, we show that purified ribosomes and OT can form a binary complex with a stoichiometry of ≈1 to 1 in the presence of detergent. We present evidence that OT may bind to the large ribosomal subunit near the site where nascent polypeptides exit. We further show that OT and the Sec61 complex can simultaneously bind to ribosomes in vitro. Based on existing data and our findings, we propose that cotranslational translocation and N-glycosylation of nascent polypeptides are mediated by a ternary supramolecular complex consisting of OT, the Sec61 complex, and ribosomes.