Reductions in liver enzymes are associated with anti-hyperglycaemic and anti-obesity effects of tofogliflozin in people with type 2 diabetes: Post-hoc analyses.

AIMS: How the pathology of type 2 diabetes (T2D), including hyperglycaemia and obesity, affects liver enzymes has not been clinically demonstrated. Thus, we compared time courses of gamma-glutamyltransferase (GGT) and alanine aminotransferase (ALT) with those of fasting plasma glucose (FPG) and body weight (BW) during treatment with the SGLT2 inhibitor tofogliflozin for T2D. MATERIALS AND METHODS: We post-hoc analysed preexisting data on 1046 people with T2D administered tofogliflozin or placebo for 24 weeks in four tofogliflozin studies. First, time courses of percent changes in variables during the intervention were analysed using a mixed effect model to explore the similarity of the time courses and to evaluate time-treatment interactions. Second, clinical factors related to the percent changes in GGT and ALT were clarified using multivariate analyses. RESULTS: GGT levels and FPG values rapidly and significantly decreased via tofogliflozin as early as week 4, with decreases maintained until week 24. Conversely, BW and ALT decreased progressively until week 24. Time courses of FPG (p = .365, time-treatment interaction) and GGT (p = .510) reductions were parallel between tofogliflozin and placebo from weeks 4 to 24, while BW and ALT reductions (p < .001, respectively) were not. Reductions in GGT at week 24 were associated with reductions in FPG and BW at week 24, whereas ALT reductions were only associated with reductions in BW. CONCLUSIONS: Reductions in GGT and ALT were associated with the anti-hyperglycaemic and anti-obesity effects of tofogliflozin, respectively, in people with T2D. Therefore, GGT and ALT may be surrogate markers for hyperglycaemia and obesity in T2D.

Noninvasive diagnosis of significant liver inflammation in patients with chronic hepatitis B in the indeterminate phase.

The presence of significant liver inflammation is an important indication for antiviral treatment in patients with chronic hepatitis B (CHB) in the indeterminate phase. We aimed to establish a non-invasive nomogram to predict significant liver inflammation in these patients. A total of 195 CHB patients in the indeterminate phase were randomly split into training and validation sets. The least absolute shrinkage and selection operator and logistic regression were applied to identify risk factors and establish a predictive model. A calibration curve, decision curve analysis (DCA), and receiver operating characteristic (ROC) curve were applied to assess the performance of the nomogram. The median age was 42.0 y and 59.5% of the patients were male. Alkaline phosphatase, γ-glutamyl transpeptidase, and prothrombin time were independent predictors for significant liver inflammation and selected to establish the AGP-nomogram. The calibration plot demonstrated that the predicted results matched the actual values. The DCA showed a high net benefit when the threshold probability was 25-83% in the training set and 31-100% in the validation set. The areas under ROC curves of AGP-nomogram in predicting significant inflammation were significantly higher than ALT in the training set (0.744 vs. 0.642, P = 0.049) and validation set (0.766 vs. 0.660, P = 0.047). The ability of AGP-nomogram in predicting advanced inflammation was also superior to ALT. The AGP-nomogram can accurately identify significant inflammation in CHB patients in the indeterminate phase, and its application may reduce the need for liver biopsy and help identify candidates for antiviral treatment.Abbreviations: AASLD: American Association for the Study of Liver Diseases; ALB: albumin; ALP: alkaline phosphatase; ALT: alanine aminotransferase; APRI: aspartate aminotransferase-to-platelet ratio index; AST: aspartate aminotransferase; AUROC: area under the receiver operating characteristic curve; CHB: chronic hepatitis B; CI: confidence interval; DCA: decision curve analysis; FIB-4: fibrosis index based on the four factors; GLB: globulin; GGT: γ-glutamyl transpeptidase; HBcAb: hepatitis B core antibody; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HIV: human immunodeficiency virus; INR: international-normalized ratio; IQR: interquartile range; LASSO: least absolute shrinkage and selection operator; LB: liver biopsy; LR: Likelihood ratio; NAFLD: non-alcoholic fatty liver disease; NPV: negative predictive value; PLT: platelets; PPV: positive predictive value; PT: prothrombin time; ROC: receiver operating characteristic; TB: total bilirubin; TE: transient elastography; ULN: upper limit of normal.

Effectiveness of the pomegranate extract in improving hepatokines and serum biomarkers of non-alcoholic fatty liver disease: A randomized double blind clinical trial.

BACKGROUND AND AIM: Pomegranate as a functional food has various properties and effects on health. The aim of the study was to evaluate the effect of pomegranate extract on serum levels of liver enzymes, hepatokines, interleukin-6 (IL-6), and total antioxidant capacity in non-alcoholic fatty liver disease (NAFLD). METHODS: In this double-blind randomized clinical trial, 44 patients with NAFLD were divided into two groups: pomegranate extract tablets and placebo. The intervention period was 12 weeks. At the beginning and end of the study, serum levels of alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), fetuin-A, fibroblast growth factor 21 (FGF-21), interleukin-6 (IL-6), and total antioxidant capacity were assessed in both groups. RESULTS: Pomegranate extract reduced the level of ALT (P < 0.001), AST (P < 0.001), GGT (P < 0.001), fetuin-A (P < 0.001), FGF-21(P < 0.001) and IL-6 (P = 0.04) compared to the placebo. Pomegranate extract also led to an increase in total antioxidant capacity (P˂0.001) but had no effect on ALP. CONCLUSION: It seems that the pomegranate extract improves several markers of NAFLD, and can be useful as a treatment supplement. The clinical trial approved by Nutrition and Metabolic Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences (grant No. NRC-9811). TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT), IRCT20140107016123N14, https://www.irct.ir/trial/42739.

Bifunctional anti-PD-L1/TGF-ßRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial.

BACKGROUND: Dual inhibition of PD-1/PD-L1 and TGF-ß pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-ß receptor II. This first-in-human trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701. METHODS: This was a dose-escalation, dose-expansion, and clinical-expansion phase 1 study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR). RESULTS: In total, 171 patients were enrolled (dose-escalation: n=17; dose-expansion, n=33; clinical-expansion, n=121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4-36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5-73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR. CONCLUSIONS: SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03710265.

A phase Ib study of camrelizumab in combination with apatinib and fuzuloparib in patients with recurrent or metastatic triple-negative breast cancer.

BACKGROUND: Strategies to improve activity of immune checkpoint inhibitors for triple-negative breast cancer (TNBC) are needed. Preclinical studies showed that antiangiogenic agents and poly (ADP-ribose) polymerase (PARP) inhibitors might sensitize tumors to immunotherapy. Here, we investigated the tolerability, safety, and preliminary antitumor activity of camrelizumab, an anti-PD-1 antibody, in combination with apatinib, a vascular endothelial growth factor receptor-2 inhibitor, and fuzuloparib, a PARP inhibitor, in patients with recurrent or metastatic TNBC. METHODS: This phase Ib study included a dose-finding part and a dose-expansion part. In the dose-finding part, a 3 + 3 dose escalation scheme was introduced. Patients were given camrelizumab (200 mg every 2 weeks) plus apatinib (375 mg or 500 mg once daily) and fuzuloparib (starting dose 100 mg twice daily) every 28-day cycle. After evaluation of the tolerability and safety of the dosing regimens, a clinical recommended dose was determined for the dose-expansion part. The primary endpoint was dose-limiting toxicity (DLT). RESULTS: A total of 32 patients were enrolled. Three patients received camrelizumab 200 mg + apatinib 375 mg + fuzuloparib 100 mg, and 29 received camrelizumab 200 mg + apatinib 500 mg + fuzuloparib 100 mg (clinical recommended dose). No DLTs were observed in either group. The most common grade ≥ 3 treatment-related adverse events were decreased white blood cell count (20.7%), hypertension (13.8%), decreased neutrophil count (10.3%), and increased aspartate aminotransferase (10.3%). Two patients discontinued study treatment due to immune-mediated hepatitis (n = 1) and anemia, decreased platelet count, decreased white blood cell count, increased alanine aminotransferase, increased aspartate aminotransferase, and increased γ-glutamyltransferase (n = 1). One patient died of unknown cause. Two (6.9% [95% CI, 0.9-22.8]) of 29 patients with camrelizumab 200 mg + apatinib 500 mg + fuzuloparib 100 mg had objective response. The disease control rate was 62.1% (95% CI, 42.3-79.3). The median progression-free survival was 5.2 months (95% CI, 3.6-7.3), and the 12-month overall survival rate was 64.2% (95% CI, 19.0-88.8). CONCLUSIONS: Combination of camrelizumab plus apatinib and fuzuloparib showed manageable safety profile and preliminary antitumor activity in patients with recurrent or metastatic TNBC. TRIAL REGISTRATION: ClinicalTrials.gov NCT03945604 (May 10, 2019).

Integrated strategy of RNA-sequencing and network pharmacology for exploring the protective mechanism of Shen-Shi-Jiang-Zhuo formula in rat with non-alcoholic fatty liver disease.

CONTEXT: Shen-Shi-Jiang-Zhuo formula (SSJZF) exhibits a definite curative effect in the clinical treatment of non-alcoholic fatty liver disease (NAFLD). OBJECTIVE: To explore the therapeutic effect and mechanism of SSJZF on NAFLD. MATERIALS AND METHODS: Sprague Dawley rats were randomly divided into control, NAFLD, positive drug (12 mg/kg/day), SSJZF high-dose (200 mg/kg/day), SSJZF middle-dose (100 mg/kg/day), and SSJZF low-dose (50 mg/kg/day) groups. After daily intragastric administration of NAFLD rats for 8 weeks, lipid metabolism and hepatic fibrosis were evaluated by biochemical indices and histopathology. Then we uncovered the main active compounds and mechanism of SSJZF against NAFLD by integrating RNA-sequencing and network pharmacology, and PI3K/AKT pathway activity was verified by western blot. RESULTS: High dose SSJZF had the best inhibitory effect on hepatic lipid accumulation and fibrosis in rats with NAFLD, which significantly down-regulated total triglycerides (58%), cholesterol (62%), aspartate aminotransferase (57%), alanine aminotransferase (41%) andγ-glutamyl transpeptidase (36%), as well as the expression of ACC (5.3-fold), FAS (12.1-fold), SREBP1C (2.3-fold), and CD36 (4.4-fold), and significantly reduced collagen deposition (67%). Then we identified 23 compounds of SSJZF that acted on 25 key therapeutic targets of NAFLD by integrating RNA-sequencing and network pharmacology. Finally, we also confirmed that high dose SSJZF increased p-PI3K/PI3K (1.6-fold) and p-AKT/AKT (1.6-fold) in NAFLD rats. DISCUSSION AND CONCLUSION: We found for first time that SSJZF improved NAFLD in rats by activating the PI3K/Akt pathway. These findings provide scientific support for SSJZF in the clinical treatment of NAFLD and contribute to the development of new NAFLD drugs.

Wheat germ improves hepatic steatosis, hepatic enzymes, and metabolic and inflammatory parameters in patients with nonalcoholic fatty liver disease: A randomized, placebo-controlled, double-blind clinical trial.

Globally, Non-alcoholic fatty liver disease (NAFLD) has a rising prevalence with no definitive pharmacological treatments. The aim of this study was to assess the clinical effects of wheat germ in patients with NAFLD. Fifty participants with NAFLD were randomly allocated to take 40 g wheat germ (n = 25) or placebo (n = 25) in a randomized double-blind clinical trial over 12 weeks. Transient elastography (FibroScan) determined a diagnosis of NAFLD. After 12 weeks of intervention, reduction in serum alanine aminotransferase (p = 0.006) and γ-glutamyltransferase (p = 0.004), total cholesterol (p = 0.018), triglyceride (p = 0.046), and hepatic steatosis (p = 0.043) levels in the wheat germ group was significantly higher compared to the placebo group. Serum TAC levels in wheat germ group patients increased significantly higher than placebo group (p = 0.001). Reduction in serum hs-CRP level in the wheat germ group was significantly higher than in the placebo group (p = 0.031). In conclusion, our study shows that wheat germ consumption may improve total antioxidant capacity, hepatic steatosis, serum total cholesterol and triglyceride levels, alanine aminotransferase (ALT), and Gamma-glutamyl Transferase (GGT) in NAFLD patients. Longitudinal studies with larger sample sizes are needed to confirm biological effects of wheat germ on NAFLD patients.

Statin liver safety in non-alcoholic fatty liver disease: A systematic review and metanalysis.

AIMS: Statin liver safety in non-alcoholic fatty liver disease (NAFLD) patients is not well defined. We analysed differences in liver function tests, including alanine transaminase aminotransferase (ALT), aspartate transaminase (AST) and gamma-glutamyl transpeptidase (GGT) in NAFLD patients treated or not treated with statins. METHODS: We performed a systematic review of MEDLINE via PubMed and EMBASE databases and metanalysis of clinical studies investigating levels of ALT, AST and GGT in NAFLD according to statin treatment. Mean difference (MD) and percentage MD were calculated between the two groups. RESULTS: We included 22 studies with 2345 NAFLD patients. Overall, 16 were before-after interventional, five were cross-sectional and one was combined cross-sectional/interventional study. In all interventional studies, except one, patients had raised ALT, AST and GGT at baseline. Interventional studies showed reduced ALT values with an MD reduction of -27.2 U/L (95% CI -35.25/-19.15) and a percentage MD reduction of -35.41% (95% CI -44.78/-26.04). Also, AST values were reduced after statin treatment in interventional studies with an MD of -18.82 U/L (95% CI -25.63/-12.02) (percentage -31.78%, 95% CI -41.45/-22.11). Similarly, GGT levels were reduced after statin treatment with an MD of -19.93 U/L (95% CI -27.10/-12.77) (percentage -25.57%, 95% CI -35.18/-15.97). Cross-sectional studies showed no difference in AST and GGT values between patients treated with and without statins. CONCLUSION: In interventional studies, ALT, AST and GGT were reduced after statin treatment with a percentage mean difference of -35.41%, -31.78% and -25.57%, respectively, while observational studies showed a null effect, suggesting liver safety of statins in NAFLD patients.

Peripheral blood indices to predict PFS/OS with anlotinib as a subsequent treatment in advanced small-cell lung cancer.

OBJECTIVE: In the phase II ALTER-1202 (NCT03059797) trial, anlotinib significantly improved progression-free survival (PFS) and overall survival (OS) in patients with advanced small-cell lung cancer (SCLC) who underwent at least 2 previous chemotherapy cycles, when compared with a placebo group. To identify potential factors for predicting efficacy and prognosis with anlotinib treatment, we analyzed hematological indices at baseline and adverse events (AEs) over the course of anlotinib treatment. METHODS: Data were collected from March 2017 to April 2019 from a randomized, double-blind, placebo-controlled, multicenter, phase II trial of anlotinib. Eligible patients were randomly assigned 2:1 to receive anlotinib or placebo until disease progression, intolerable toxicity, or withdrawal of consent. The patients received anlotinib (12 mg) or an analogue capsule (placebo) orally once daily for 14 days every 3 weeks. The hematological indices at baseline and AEs that occurred in the initial 2 treatment cycles were recorded. The Kaplan-Meier test and Cox regression model were used to assess survival differences. RESULTS: A total of 82 patients (81 patients with complete data) were randomly assigned to receive anlotinib, with 38 receiving a placebo as a control. Multivariate analysis indicated that an elevated neutrophil to lymphocyte ratio > 7.75 and lactate dehydrogenase > 254.65 U/L at baseline were independent risk factors for PFS; basal elevated aspartate aminotransferase > 26.75 U/L, neuron specific enolase > 18.64 ng/mL, and fibrinogen > 4.645 g/L were independent risk factors for OS. During treatment, elevated γ glutamyltransferase and hypophosphatemia were independent predictors for a poor PFS, and elevated γ-glutamyl transferase and hypercholesterolemia were independent factors for OS. CONCLUSIONS: Our study preliminarily defined potential factors that affected the PFS and OS at baseline and during anlotinib treatment in patients with advanced SCLC. Our findings provide a basis for screening the dominant population and for dynamic efficacy monitoring with anlotinib therapy.

[The results of phase III multicenter open randomized controlled study REM-Chol-III-16 in patients with intrahepatic cholestasis syndrome caused by chronic diffuse liver diseases].

AIM: To assess the safety and efficacy of Remaxol, solution for infusion, compared with parenteral form of S-adenosyl-L-methionine, in the treatment of patients with intrahepatic cholestasis syndrome accompanying chronic diffuse liver diseases of various etiology. MATERIALS AND METHODS: In a multicenter open-label comparative study of the safety and efficacy of Remaxol (inosine + meglumine + methionine + nicotinamide + succinic acid) 317 patients aged 18 to 65 years were randomized into 2 groups: patients of the experimental group (n=168) received intravenous Remaxol, solution for infusion, 400 ml, and patients of the control group (n=149) Heptral (S-adenosyl-L-methionine) 800 mg. The duration of treatment was 10 days. The primary efficacy endpoint was the proportion of patients who responded to therapy, as demonstrated by dynamics of laboratory parameters of liver functional status: decrease in gamma glutamyl transpeptidase level by 40%, and/or alkaline phosphatase level by 30%, and/or decrease total bilirubin level by 30% from baseline by the end of the treatment course. RESULTS: The proportion of responders was 51% in the Remaxol group vs. 44.9% in the Heptral group (p=0.303); the lower limit of the one-sided 95% confidence interval for the difference in the proportions of responders was -4.01%, which exceeds the non-inferiority margin pre-defined by the study protocol, thus, the non-inferiority hypothesis was proven, i.e. Remaxol at a dose of 400 ml/day demonstrates similar efficacy to Heptral at a dose of 800 mg/day in patients with intrahepatic cholestasis syndrome associated with chronic diffuse liver diseases. Similar positive trends in the levels of transaminases, total bilirubin and the severity of pruritus were revealed in both treatment groups. We did not reveal statistically significant between-group differences in the frequency of adverse events definitely related to the study treatment. CONCLUSION: Administration of Remaxol as a part of the pathogenetic therapy of patients with intrahepatic cholestasis syndrome who need hepatoprotection is justified.

Impact of Serum γ-Glutamyltransferase on Overall Survival in Patients with Metastatic Renal Cell Carcinoma in the Era of Targeted Therapy.

BACKGROUND: γ-Glutamyltransferase (GGT) is a marker of oxidative stress. Elevated serum GGT is linked to poor survival in various malignancies; however, there are no data on metastatic renal cell carcinoma (mRCC). Additionally, GGT expression in cancer tissues remains largely unknown. OBJECTIVE: The present study was designed to determine the prognostic role of serum GGT in patients with mRCC and the association between systemic and local GGT levels. PATIENTS AND METHODS: Pretherapeutic serum GGT and other clinicopathological parameters were retrospectively compared with overall survival (OS) in 146 consecutive patients with mRCC receiving tyrosine kinase inhibitor therapy. GGT expression was analyzed in 65 resected specimens using immunohistochemistry. RESULTS: A total of 82 patients (56%) died during the follow-up period (median 34.9 months). Median OS was 16.0 months and 36.8 months in patients with elevated GGT levels and without elevated GGT, respectively (P < 0.001). On multivariable analysis, elevated serum GGT was an independent adverse prognostic factor (hazard ratio [HR] 4.04, P < 0.001), together with high neutrophils (HR 2.06, P = 0.041), low albumin (HR 2.00, P = 0.006), high lactate dehydrogenase (HR 2.68, P < 0.001), and high De Ritis ratio (HR 1.97, P = 0.004). Preoperative serum GGT levels were 29, 48, and 109 U/l in patients whose renal cancer cells showed negative to weak, moderate, and strong GGT expression, respectively (P = 0.004). CONCLUSIONS: Elevated serum GGT was an unfavorable prognostic factor in mRCC, and overexpression of GGT in renal cancer cells might be responsible for elevation of serum GGT.

Pre-administration of rats with Helicobacter pylori γ-glutamyl-transpeptidase alleviates osteoarthritis.

OBJECTIVE: To determine the efficacy of Helicobacter pylori γ-glutamyl-transpeptidase (GGT) in osteoarthritis (OA) therapy. RESULTS: Oral administration of rats with rGGT alleviated joint pain in the acute phase of iodoacetate (IA)-induced OA. The CXCL1/IL-6 in blood and in articular tissue as well as circulating granulocytes in the recipients of GGT, were reduced. This might be associated with the expansion of regulatory T cells in the inguinal lymph nodes and increased articular IL-10. CONCLUSION: We provide preclinical evidence that H. pylori GGT may represent a promising candidate for OA therapy.

Talidomida, peginterferón alfa-2b y ribavirina en el tratamiento de pacientes no respondedores con hepatitis crónica C genotipo 1: estudio piloto / Thalidomide with peginterferon alfa-2b and ribavirin in the treatment of non-responders genotype 1 chronic hepatitis C patients: proof of concept

Antecedentes: menos de la mitad de los pacientes con hepatitis C logra eliminar el virus de manera sostenida después de la terapia con peginterferón alfa y ribavirina (Peg-IFN/RBV). Objetivos: la talidomida posee propiedades antiinflamatorias e inmunomoduladoras a través de la inhibición del TNF-α y al efecto estimulador sobre las células T CD8+. Métodos: se inició un estudio prospectivo y abierto de re-tratamiento de pacientes con hepatitis crónica C genotipo 1, no respondedores al tratamiento con Peg-IFN/RBV, mediante triple terapia añadiendo a los mismos antivirales 200 mg/día de talidomida. Resultados: ninguno de los once pacientes que fueron incluidos en el ensayo consiguió respuesta viral completa en la semana 12 ni respuesta viral sostenida. La dinámica viral en las 12 primeras semanas de tratamiento no difirió de la dinámica viral durante el primer curso de tratamiento. La triple terapia fue bien tolerada y solo un paciente desarrolló neuropatía bilateral autolimitada. Conclusiones: añadir talidomida al tratamiento estándar fue bien tolerado pero no incrementó la tasa de respuesta viral sostenida en pacientes con hepatitis C genotipo 1 no respondedores previos(AU)

Background: fewer than half of patients infected with hepatitis C virus (HCV) achieve sustained viral clearance after peginterferon alfa/ribavirin (Peg-IFN/RBV) therapy. Aims: thalidomide posses anti-inflammatory and immunomodulatory properties through inhibition of tumor necrosis factor and costimulatory effect on human CD8+ T cells. Methods: we started a prospective, open label trial of retreatment of very-difficult-to-treat genotype 1 chronic hepatitis C patients (CHC) patients, who had failed to respond to the (Peg-IFN/RBV), with a triple therapy consisting in these same antivirals plus thalidomide 200 mg/day (the TRITAL study). Results: none of the eleven patients fulfilling the inclusion criteria and included in the trial reached complete early virological response or sustained virological response. Viral load decline after 12 weeks of triple therapy thalidomide-based retreatment did not differ from viral dynamics during the first course. The triple therapy was well tolerated and only one patient developed mild bilateral neuropathy. Conclusions: thalidomide addition to standard therapy is tolerated and did not increase the SVR rate in very-difficult-to-treat genotype 1 CHC patients. Different schedules are warranted to improve attempting retreatment of non responder CHC patients(AU)

Improvement of a potential anthrax therapeutic by computational protein design.

Past anthrax attacks in the United States have highlighted the need for improved measures against bioweapons. The virulence of anthrax stems from the shielding properties of the Bacillus anthracis poly-γ-d-glutamic acid capsule. In the presence of excess CapD, a B. anthracis γ-glutamyl transpeptidase, the protective capsule is degraded, and the immune system can successfully combat infection. Although CapD shows promise as a next generation protein therapeutic against anthrax, improvements in production, stability, and therapeutic formulation are needed. In this study, we addressed several of these problems through computational protein engineering techniques. We show that circular permutation of CapD improved production properties and dramatically increased kinetic thermostability. At 45 °C, CapD was completely inactive after 5 min, but circularly permuted CapD remained almost entirely active after 30 min. In addition, we identify an amino acid substitution that dramatically decreased transpeptidation activity but not hydrolysis. Subsequently, we show that this mutant had a diminished capsule degradation activity, suggesting that CapD catalyzes capsule degradation through a transpeptidation reaction with endogenous amino acids and peptides in serum rather than hydrolysis.

Avaliação do efeito da clorpromazina sobre a função renal de cães submetidos à isquemia e reperfusão / Evaluation of chlorpromazine effect at renal function in dogs submitted to ischemia and reperfusion

A isquemia renal está presente em diferentes situações como em cirurgias renais, vasculares e no transplante renal. O objetivo deste trabalho foi avaliar a integridade e a função renal de cães submetidos à isquemia e reperfusão com ou sem aplicação de clorpromazina. Para tanto foram utilizados 12 cães distribuídos aleatoriamente em dois grupos de seis indivíduos: grupo A com isquemia e reperfusão sem tratamento por clorpromazina e o grupo B com isquemia e reperfusão tratados previamente com clorpromazina. De cada cão foi coletado sangue e urina antes da isquemia, no inicio da reperfusão, após 120 minutos de reperfusão e semanalmente até 28º dia pós-cirúrgico para verificar possíveis efeitos tardios da isquemia/reperfusão. Avaliações da integridade e função renal foram feitas por exame físico, concentração sérica de ureia e creatinina e determinação da GGT urinária. A avaliação da relação proteína urinária/creatinina urinária (PU/CU) e atividade da GGT urinária são exames mais sensíveis para detectar lesão tubular aguda que o exame de urina de rotina, uma vez que estas variáveis apresentaram alteração mais precocemente. Não houve ação protetora da clorpromazina conforme constatado por meio da urinálise, dosagens séricas de ureia e creatinina, excreção urinária de GGT e PU/CU.

Renal ischemia may occur in different situations such as vascular or renal surgery and also in renal transplantation. This study evaluates renal function in dogs submitted to ischemia and reperfusion after chlorpromazine application. Twelve adult mongrel dogs were distributed into two groups with six animals each. Group A was composed of dogs submitted to renal ischemia and reperfusion without previous administration of chlorpromazine. Group B was composed of dogs with renal ischemia and reperfusion previously treated with chlorpromazine. In order to evaluate the possible ischemia/reperfusion late effects, blood and urine samples were sampled in four different times: Before ischemia, early stages of reperfusion, 120 minutes after reperfusion, and every week until 28th day postsurgery. Renal function was evaluated by clinical examination, serum urea and creatinine levels and urinary GGT activity. PU/CU and GGT urinary activity were more sensitive in detecting acute tubular injury than routine urine examination because these variables showed earlier changes. Based on urinalysis, urea and creatinine serum levels plus urinary excretion of GGT and PU/CU, no evidences of protective action of chlorpromazine were observed.

Nutritional amblyopia in a 32-year-ld male [abstract]

A 32-year-old Caucasian man presented with a 6 month history of gradual visual loss. He lived alone and consumed large quantities of alcohol. In addition, he smoked heavily and had only one meal per day. Examination revealed poor visual acuities bilaterally, with normal looking optic discs and retina. An MRI brain scan was normal. Visual evoked potentials showed small P100 responses. His mean corpuscular volume was elevated as was the gammaglutamyl transpeptidase. The patient was started on high dose vitamin B. His visual acuities are improving. (AU)