The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet.

The ketogenic diet (KD) is used to treat refractory epilepsy, but the mechanisms underlying its neuroprotective effects remain unclear. Here, we show that the gut microbiota is altered by the KD and required for protection against acute electrically induced seizures and spontaneous tonic-clonic seizures in two mouse models. Mice treated with antibiotics or reared germ free are resistant to KD-mediated seizure protection. Enrichment of, and gnotobiotic co-colonization with, KD-associated Akkermansia and Parabacteroides restores seizure protection. Moreover, transplantation of the KD gut microbiota and treatment with Akkermansia and Parabacteroides each confer seizure protection to mice fed a control diet. Alterations in colonic lumenal, serum, and hippocampal metabolomic profiles correlate with seizure protection, including reductions in systemic gamma-glutamylated amino acids and elevated hippocampal GABA/glutamate levels. Bacterial cross-feeding decreases gamma-glutamyltranspeptidase activity, and inhibiting gamma-glutamylation promotes seizure protection in vivo. Overall, this study reveals that the gut microbiota modulates host metabolism and seizure susceptibility in mice.

Predictive nomograms based on gamma-glutamyl transpeptidase to prealbumin ratio for prognosis of hepatocellular carcinoma patients without microvascular invasion.

BACKGROUND: Hepatocellular carcinoma (HCC) presents a significant threat to individuals and healthcare systems due to its high recurrence rate. Accurate prognostic models are essential for improving patient outcomes. Gamma-glutamyl transpeptidase (GGT) and prealbumin (PA) are biomarkers closely related to HCC. This study aimed to investigate the predictive value of the GGT to PA ratio (GPR) and to construct prognostic nomograms for HCC patients without microvascular invasion. METHODS: We retrospectively analyzed data from 355 HCC patients who underwent radical hepatectomy at Shengjing Hospital of China Medical University between December 2012 and January 2021. Patients were randomly assigned to a training cohort (n = 267) and a validation cohort (n = 88). The linearity of GPR was assessed using restricted cubic spline (RCS) analysis, and the optimal cut-off value was determined by X-tile. Kaplan-Meier survival curves and log-rank tests were used to investigate the associations between GPR and both progression-free survival (PFS) and overall survival (OS). Cox multivariate regression analysis identified independent risk factors, enabling the construction of nomograms. Time-dependent receiver operating characteristic (ROC) and calibration curves were used to evaluate the accuracy of the nomograms. Decision curve analysis (DCA) assessed the predictive value of the models. RESULTS: Patients were categorized into GPR-low and GPR-high groups based on a GPR value of 333.33. Significant differences in PFS and OS were observed between the two groups (both P < 0.001). Cox multivariate analysis identified GPR as an independent risk factor for both PFS (OR = 1.80, 95% CI: 1.24-2.60, P = 0.002) and OS (OR = 1.87, 95% CI: 1.07-3.26, P = 0.029). The nomograms demonstrated good predictive performance, with C-index values of 0.69 for PFS and 0.76 for OS. Time-dependent ROC curves and calibration curves revealed the accuracy of the models in both the training and validation cohorts, with DCA results indicating notable clinical value. CONCLUSIONS: GPR emerged as an independent risk factor for both OS and PFS in HCC patients without microvascular invasion. The nomograms based on GPR demonstrated relatively robust predictive efficiency for prognosis.

Gamma-glutamyl transferase to aspartate aminotransferase ratio (GSR) predicts prognoses in patients with colorectal cancer with liver metastasis after microwave ablation.

BACKGROUND: Microwave ablation (MWA) is widely used to eliminate colorectal liver metastases (CRLM). However, the risk of tumor recurrence is difficult to predict due to lack of reliable clinical and biological markers. Elevation of gamma-glutamyl transferase (GGT) and aspartate transaminase (AST) provides signals for liver inflammation and cancer progression. The present study evaluated the association between pre-ablation GGT to AST ratio index (GSR) and hepatic recurrence in patients with CRLM after MWA. METHODS: A retrospectively analyzed 192 CRLM patients who underwent MWA from January 2013 to December 2017. Pre-ablation GSR was classified into high (≤ 2.34) or low (> 2.34) using the upper quartile value. The prognostic value of GSR and other risk factors for liver progression-free survival (LPFS) and cancer-specific survival (CSS) were evaluated by univariate and multivariate analyses. RESULTS: High GSR was significantly associated with males (P = 0.041), the presence of cholelithiasis (P = 0.012), but not pre-ablation chemotherapy (P = 0.355), which caused significantly increased levels of GGT (P = 0.015) and AST (P = 0.008). GSR showed a significant association with LPFS and CSS through univariate analysis (P = 0.002 and 0.006) and multivariate analysis (P = 0.043 and 0.037). The subgroup analysis demonstrated no interaction between GSR and all variables except for distribution in the sub-analysis of LPFS. CONCLUSIONS: Our findings suggest that the pre-ablation GSR can be considered as a promising prognostic indicator for poor prognosis of patients with CRLM underwent MWA. TRIAL REGISTRATION: Not applicable.

Value of GPR, APPRI and FIB-4 in the early diagnosis of hepatocellular carcinoma: a prospective cohort study.

OBJECTIVE: There is an urgent need for novel biomarkers that are inexpensive, effective and easily accessible to complement the early diagnosis of hepatocellular carcinoma. This study aimed to analyze the relationship between serum gamma-glutamate-transpeptidase to platelet ratio, alkaline phosphatase-to-platelet ratio index, fibrosis index based on four factors and the risk of hepatocellular carcinoma, and to determine the optimal cut-offs for predicting hepatocellular carcinoma. METHODS: Based on a prospective cohort study, 44 215 participants who were cancer-free at baseline (2011-13) were included in the study. Cox proportional hazard models and receiver operating characteristics curves were used to analyze the diagnostic value and optimal cut-off value of gamma-glutamyl-transpeptidase to platelet ratio, alkaline phosphatase-to-platelet ratio index and fibrosis index based on four factors in predicting hepatocellular carcinoma patients. RESULTS: Gamma-glutamyl-transpeptidase to platelet ratio, alkaline phosphatase-to-platelet ratio index and fibrosis index based on four factors can be used as early independent predictors of hepatocellular carcinoma risk. The risk of hepatocellular carcinoma in the fourth quantile of gamma-glutamyl-transpeptidase to platelet ratio and alkaline phosphatase-to-platelet ratio index was 4.04 times (hazard ratio = 4.04, 95% confidence interval: 2.09, 7.80) and 2.59 times (hazard ratio = 2.59, 95% confidence interval: 1.45, 4.61), respectively, compared with the first quantile. With fibrosis index based on four factors first quantile as a reference, fibrosis index based on four factors fourth quantile had the highest risk (hazard ratio = 18.58, 95% confidence interval: 7.55, 45.72). Receiver operating characteristic results showed that fibrosis index based on four factors had a stronger ability to predict the risk of hepatocellular carcinoma (area under curve = 0.81, 95% confidence interval: 0.80, 0.81), and similar results were shown for gender stratification. In the total population, the optimal cut-off values of gamma-glutamyl-transpeptidase to platelet ratio, alkaline phosphatase-to-platelet ratio index and fibrosis index based on four factors were 0.208, 0.629 and 1.942, respectively. CONCLUSIONS: Gamma-glutamyl-transpeptidase to platelet ratio, alkaline phosphatase-to-platelet ratio index and fibrosis index based on four factors were independent predictors of hepatocellular carcinoma risk. Amongst them, fibrosis index based on four factors shows a stronger predictive ability for hepatocellular carcinoma risk, and gamma-glutamyl-transpeptidase to platelet ratio and alkaline phosphatase-to-platelet ratio index can be used as complementary indicators.

Acute acalculous cholecystitis following extended administration of nirmatrelvir/ritonavir for persistent SARS-CoV-2 infection.

Immunocompromised patients with hematologic malignancies, particularly those treated with anti-CD20 antibodies such as rituximab and obinutuzumab, are known to be at risk of prolonged infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Prolonged administration or combination therapy with antiviral medications reportedly yields favorable outcomes in these patients. However, knowledge regarding the adverse events associated with such therapeutic approaches is limited. Herein, we report a case of acute acalculous cholecystitis (AAC) following extended administration of nirmatrelvir/ritonavir (NMV/r) in a 68-year-old Japanese man with persistent SARS-CoV-2 infection. The patient had received obinutuzumab and bendamustine for follicular lymphoma and was diagnosed with coronavirus disease 2019 (COVID-19) approximately one year after treatment initiation with these drugs. Subsequently, he was admitted to a different hospital, where he received antiviral drugs, monoclonal antibodies, and steroids. Despite these interventions, the patient relapsed and was subsequently transferred to our hospital due to persistent SARS-CoV-2 infection. Remdesivir administration was ineffective, leading to the initiation of extended NMV/r therapy. One week later, he exhibited elevated gamma-glutamyl transpeptidase (GGT) levels, and one month later, he developed AAC. Cholecystitis was successfully resolved via percutaneous transhepatic gallbladder drainage and administration of antibiotics. We speculate that extended NMV/r administration, in addition to COVID-19, may have contributed to the elevated GGT and AAC. During treatment of persistent SARS-CoV-2 infection with extended NMV/r therapy, patients should be carefully monitored for the appearance of findings suggestive of biliary stasis and the development of AAC.

Simple Predictive Markers and Clinicopathological Features of Primary Liver Cancer following HCV Clearance with Direct-Acting Antivirals.

INTRODUCTION: Simple predictive markers enabling even nonspecialized medical doctors and clinicopathological features of primary liver cancer (PLC) following HCV clearance with direct-acting antivirals (DAAs) are unclear. METHODS: The subjects of this retrospective study were 2,476 patients following HCV clearance with DAAs. All patients were confirmed to be PLC-free before and during DAAs. RESULTS: PLC was diagnosed in 73 patients during the follow-up, with an incidence rate per 1 000 person-years of 5.9. The annual rate of PLC during the first 6 years was 0.6%. Multivariate analysis identified gender, GGT, and FIB-4 index as the significant determinants of PLC. According to a combination of these risk factors, the cumulative PLC incidence rates were significantly different among the five subgroups based on the number of PLC risk scores. In 73 patients with PLC, the rates of abnormal AFP, PIVKAII, and serum TERT C228T positive were 37.0, 32.4, and 22.2%. PIVKAII levels in BCLC stage A and B were significantly higher than those in stage 0. In 41 patients, who underwent surgical resection for PLC, maximum tumor diameters of abnormal PIVKAII were significantly larger than those of normal PIVKAII. PLC of abnormal PIVKAII significantly indicated presence of vp more than that of normal PIVKAII, and did not contain well-differentiated HCC. CONCLUSIONS: Combination of simple markers, enabling even nonspecialized medical doctors, is useful for the evaluation of PLC risk following HCV clearance with DAAs. However, imaging studies are regularly recommended for the early detection of PLC.

Affinity purification, identification, and biochemical characterization of Gamma-glutamyl transpeptidase, a membrane anchored enzyme of Gigantocotyle explanatum.

Gamma-glutamyl transpeptidase is an enzyme that facilitates the transfer of glutamyl groups from glutamyl peptides to other peptides or water. Additionally, it also participates in important processes such as amino acid transport, cellular redox control, drug detoxification, apoptosis, and DNA fragmentation in a various organism. In the present study, GGT activity in Gigantocotyle explanatum was examined in order to characterize the enzyme in the helminth system. GGT is isolated using membrane solubilization and purified through affinity column chromatography (Con-A Sepharose column). Km and Vmax values, as well as the optimal pH, optimal temperature, and incubation period, are also determined using enzyme kinetics. The hetero-dimeric property of the enzyme is demonstrated by the purified GGT, which yielded two subunits of 65.5 and 55 kDa. The optimal pH and temperature are found to be 8.0 and 37 °C, respectively. While assessing the optimal incubation time of the enzyme, it was observed that the purified GGT not only retained its functional integrity up to 15 min but also reflected considerable thermostability at higher temperatures, by retaining 78% and 25% of its initial activities at 50 °C and 60 °C, respectively. One millimolar concentration of 6-Diazo-5-Oxo Nor-isoleucine (DON), a specific inhibitor of GGT, completely abolished GGT activity. These results suggest that GGT in these worms is a catalytically active enzyme with distinguishing characteristics that can be used for further study to comprehend its function in amphistome biology and in host-parasite relationships, especially since the potential therapeutic candidacy of the GGT enzyme has already been indicated in these groups of organisms.

Prognostic significance of gamma-glutamyl transpeptidase to albumin ratio in patients with intrahepatic cholangiocarcinoma after hepatectomy.

Inflammation has been reported to play an important role in tumour progression and prognosis. In this study, we evaluated the prognostic significance of γ-glutamyl transpeptidase (GGT) to albumin ratio (GAR) in patients with intrahepatic cholangiocarcinoma (ICC) after hepatectomy. We retrospectively analysed 650 ICC patients underwent hepatectomy at three Chinese medical centres between January 2009 and September 2017. Patients were classified into derivation cohort (n = 509) and validation cohort (n = 141). Receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value for GAR. Survival curve and cox regression analysis were applied to assess the prognostic power of GAR. The prognostic accuracy of GAR was compared with other variables by ROC curve. The optimal cut-off value for GAR was 1.3655. Preoperative high GAR was closely related to tumour number, lymph node invasion and GGT. The survival curve of derivation and validation cohorts showed that patients in the high GAR group had significantly shorter overall survival (OS) and disease-free survival (DFS) than patients in the low GAR group. Multivariate analysis in the derivation cohort confirmed that GAR was an independent prognostic factor for survival outcomes. Moreover, the ROC curve revealed that GAR had better predictive accuracy than other variables. High GAR predicted poor OS and DFS in ICC patients after hepatectomy. GAR may be a novel, simple and effective prognostic marker for ICC patients.

Gamma-glutamyl transpeptidase to platelet and gamma-glutamyl transpeptidase to lymphocyte ratio in a sample of Chinese Han population.

BACKGROUND: Gamma-glutamyl transpeptidase to platelet ratio (GPR) and gamma-glutamyl transpeptidase to lymphocyte ratio (GLR) are assumed to be prognostic factors in liver fibrosis, cirrhosis and hepatocellular carcinoma. However, the reference values of GPR and GLR were not known. OBJECTIVES: The study aimed to investigate the reference ranges of GPR and GLR in Chinese Han population in Chaoshan region in South China. METHODS: A retrospective study was conducted in the First Affiliated Hospital of Shantou University Medical College in South China. 2400 healthy adults aged 20~79 years were included. GPR and GLR were determined. RESULTS: Of 2400 healthy adults, 1200 men and 1200 women were included. The median GPR and GLR for men were 0.22 and 11.28, for women were 0.18 and 7.86, respectively. The 95% reference range of GPR in normal male and female are 0.09~0.54 and 0.08~0.55, GLR are 4.55~29.64 and 3.52~23.08, respectively. The male had a higher GPR at age 20~49 than the female while the GPR at age 60~79 was higher in the female than in the male. The GPR was affected by age, decreased with aging in male and increased in female. The GLR was higher in the male than in the female and varied with aging in the female but not in the male. CONCLUSION: The study provides reference data on GPR and GLR from different age and sex groups in South China. GPR and GLR varied with age and sex.

Design and evaluation of novel analogs of 2-amino-4-boronobutanoic acid (ABBA) as inhibitors of human gamma-glutamyl transpeptidase.

Inhibitors of gamma-glutamyl transpeptidase (GGT1, aka gamma-glutamyl transferase) are needed for the treatment of cancer, cardiovascular illness and other diseases. Compounds that inhibit GGT1 have been evaluated in the clinic, but no inhibitor has successfully demonstrated specific and systemic GGT1 inhibition. All have severe side effects. L-2-amino-4­boronobutanoic acid (l-ABBA), a glutamate analog, is the most potent GGT1 inhibitor in vitro. In this study, we have solved the crystal structure of human GGT1 (hGGT1) with ABBA bound in the active site. The structure was interrogated to identify interactions between the enzyme and the inhibitor. Based on these data, a series of novel ABBA analogs were designed and synthesized. Their inhibitory activity against the hydrolysis and transpeptidation activities of hGGT1 were determined. The lead compounds were crystalized with hGGT1 and the structures solved. The kinetic data and structures of the complexes provide new insights into the critical role of protein structure dynamics in developing compounds for inhibition of hGGT1.

Gamma-Glutamyl Transpeptidase-to-Platelet ratio predicts liver fibrosis in patients with concomitant chronic hepatitis B and nonalcoholic fatty liver disease.

OBJECTIVES: The aim of this study was to compare the correlation of gamma-glutamyl transpeptidase-to-platelet ratio (GPR), aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis index-4 (FIB-4), and liver stiffness measurement (LSM) in the diagnosis of liver fibrosis, and perform a diagnostic value of GPR for predicting fibrosis in CHB patients with NAFLD. METHODS: A retrospective study was conducted on CHB patients concurrent with NAFLD between September 2019 and December 2020. They were divided into control group (LSM ≤ 9.7 kpa) and fibrosis group (LSM ≥ 9.8 kpa). Demographic data were collected; ALT, AST, and PLT were also detected. LSM was measured by transient elastography (TE). The GPR, APRI, and FIB-4 were calculated. The correlation between GPR, APRI, FIB-4, and LSM was compared. The accuracy of predicting liver fibrosis using GPR, APRI, and FIB-4 was assessed. RESULTS: Eighty-five CHB patients with NAFLD were enrolled. Multivariate analysis showed that age (p = 0.005), GGT (p = 0.001), and PLT (p = 0.013) were the independent risk factors for LSM. The GPR (p = 0.008), APRI (p = 0.001), and FIB-4 (p = 0.001) values in fibrosis group were higher than control group. Pearson linear correlation was used to analyze the correlations between LSM and GPR, APRI, and FIB-4. LSM was correlated with GPR, APRI, and FIB-4. The AUCs of GPR, APRI, and FIB4 were 0.805, 0.766, and 0.826 in assessing liver fibrosis, respectively. No significant differences in the areas of GPR were comparable to that of APRI and FIB-4. CONCLUSION: GPR has a good correlation with LSM in assessing liver fibrosis and can be used as a noninvasive index for the assessment of liver fibrosis in patients with concomitant CHB and NAFLD.

Calcium influx and spermatogenesis in the testis and liver enzyme activities in the zebrafish are rapidly modulated by the calcium content of the water.

This study investigated the effects of varying environmental Ca2+ concentrations on the influx of Ca2+ to the testis, testicular morphology, and liver enzymes in the zebrafish. Adult zebrafish (Danio rerio) were held in water containing low (0.02 mM), control (0. 7 mM) or high (2 mM) Ca2+ concentrations for 12 h. Testes were then incubated in vitro with 0.1 µCi/mL 45Ca2+ to measure Ca2+ influx at 30 and 60 min and qualitative and quantitative testicular histological analyses were conducted. In addition, activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT), enzymes that indicate tissue damage, were evaluated in the liver. The testes from zebrafish exposed in vivo to low (0.02 mM) and high (2 mM) Ca2+ content water had a higher Ca2+ influx than the control group after 30 min of incubation, and at 60 min (high Ca2+ group only). There were morphological changes in the testes from the low and high Ca2+ groups including spermatozoa distributed in dense agglomerates and apoptotic cells. Furthermore, zebrafish exposed to high Ca2+ containing water had an increased density of haploid cells (spermatids and spermatozoa). In addition, both low and high Ca2+ water affected liver function by increasing ALT and GGT activities. Collectively, these studies show that alterations in calcium homeostasis in the testis, stimulation of the spermatogenic wave and hepatic injury were rapid responses to changes in the concentration of Ca2+ in the water.

Gamma-glutamyl transpeptidase has different efficacy on biliary atresia diagnosis in different hospital patient groups: an application of machine learning approach.

OBJECTIVES: Gamma-glutamyl transpeptidase (GGT) is the most widely used biomarker in the early diagnosis of biliary atresia (BA), but its diagnostic efficacy is questionable in different sub-populations. We aim to identify subgroups that are defined by specific variables with cut-offs and can significantly affect the diagnostic efficacy of GGT for detecting BA. METHODS: Clinical data from 1273 infants with neonatal obstructive jaundice (NOJ) diagnosed between January 2012 and December 2017 at the Children's Hospital of Fudan University were enrolled, reviewed, and analyzed. Random forest-based Virtual Twins method was used to identify potential subgroups. RESULTS: Hemoglobin (HGB) and fasting gallbladder filling were selected as defining variables. The diagnostic efficacy of GGT was significantly better (AUC = 0.855) for patients with hemoglobin (HGB) ≤ 105 g/L and a gallbladder that was not or poorly filled. Diagnostic efficacy was worst in the subgroup defined by HGB > 105 g/L (AUC = 0.722). The inclusion of interaction terms between GGT and the subgroups in a logistic regression model significantly improved (p = 0.002) prediction performance. CONCLUSIONS: This study provides evidence that the diagnostic efficacy of GGT can differ significantly across different subgroups. Therefore, a GGT diagnostic result should be interpreted cautiously when patients belong to subgroups with low diagnostic efficacy. The development of a prediction model and/or clinical diagnostic pathway for early detection of BA should also account for the heterogeneous diagnostic efficacy of GGT.

Fluorescence Imaging Using Enzyme-Activatable Probes for Detecting Diabetic Kidney Disease and Glomerular Diseases.

A clear identification of the etiology of glomerular disease is essential in patients with diabetes. Renal biopsy is the gold standard for assessing the underlying nephrotic pathology; however, it has the risk for potential complications. Here, we aimed to investigate the feasibility of urinary fluorescence imaging using an enzyme-activatable probe for differentiating diabetic kidney disease and the other glomerular diseases. Hydroxymethyl rhodamine green (HMRG)-based fluorescent probes targeting gamma-glutamyl transpeptidase (GGT) and dipeptidyl-peptidase (DPP) were used. Urinary fluorescence was compared between groups which were classified by their histopathological diagnoses (diabetic kidney disease, glomerulonephritis, and nephrosclerosis) as obtained by ultrasound-guided renal biopsy. Urinary fluorescence was significantly stronger in patients with diabetic kidney disease compared to those with glomerulonephritis/nephrosclerosis after DPP-HMRG, whereas it was stronger in patients with nephrosclerosis than in patients with glomerulonephritis after GGT-HMRG. Subgroup analyses of the fluorescence performed for patients with diabetes showed consistent results. Urinary fluorescence imaging using enzyme-activatable fluorescence probes thus represents a potential noninvasive assessment technique for kidney diseases in patients with diabetes.

A model incorporating serum C3 complement levels may be useful for diagnosing biliary atresia in infants.

INTRODUCTION: Correctly identifying patients with biliary atresia (BA), while avoiding invasive diagnostic methods is challenging. The purpose of this study was to determine the value of serum immune indicators for distinguishing BA from other causes of cholestasis in infants. PATIENTS AND METHODS: The data of infants with a surgical/histological diagnosis of BA and those with other causes of cholestatic jaundice were retrospectively analyzed. Patients were divided into a BA group and a cholestasis control (CC) group. Biochemical parameters, major lymphocyte subsets, immunoglobin and C3 and C4 complement levels were compared between the groups. RESULTS: A total of 129 infants with BA and 63 with other causes of cholestasis (CC control group) with a median age of 2.2 months were included in the analysis. The levels of CD3+ T cells, CD3+CD4+ T cells, and premature T cells and the levels of C3 and C4 were all significantly higher in the BA group compared to the CC group (all P<0.05). Pair-wise correlation analyses indicated that C3 and C4 had a significant positive correlation with γ-GT in the BA group, but not in the CC group. Five indices were found to be significantly associated with BA: stool color, globulin, γ-GT, C3 and C4. A model incorporating stool color, gamma-glutamyl transpeptidase level, and C3 level exhibited an area under the ROC curve (AUC) of 0.93, and a sensitivity of 93% and specificity of 83% for the diagnosis of BA. CONCLUSIONS: Models incorporating serum C3 levels may be useful for accurately diagnosing BA in infants.

Prognostic value of preoperative inflammatory markers in patients with hepatocellular carcinoma who underwent curative resection.

BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) is not optimistic. Our study focused on present inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), gamma-glutamyl transpeptidase-to-platelet ratio (GPR), aspartate aminotransferase-to-lymphocyte ratio (ALR) and fibrinogen-to-albumin ratio (FAR), and explored their optimal combination for the prognosis of HCC after resection. METHODS: A total of 347 HCC patients who underwent curative resection were enrolled. The optimal cutoff values of the inflammatory markers were calculated using receiver operating characteristic (ROC) curve analysis, and used to divide patients into two groups whose differences were compared by Kaplan-Meier analysis. Cox univariate and multivariate analyses were used to analyze the independent prognostic inflammatory markers. The χ2 test was chosen to determine the relationship between independent prognostic inflammatory markers and clinicopathological features. We created combined scoring models and evaluated them by Cox univariate and multivariate methods. The concordance index (C-index), Akaike information criterion (AIC) and likelihood ratio were calculated to compare the models. The selected optimal inflammatory markers and their combinations were tested in different stages of HCC by Kaplan-Meier analysis. RESULTS: The ALR and GPR were independent prognostic factors for disease-free survival (DFS); the ALR, PLR, and GPR were independent prognostic factors for overall survival (OS). The proposed GPR and ALR-GPR-PLR score models were independent predictors for DFS and OS, respectively. CONCLUSION: The preoperative GPR and ALR-GPR-PLR score models were independent predictors for DFS and OS, respectively, and performed well in stratifying patients with HCC. The higher the score in the model was, the worse the prognosis.

Ultrasound characteristics combined with gamma-glutamyl transpeptidase for diagnosis of biliary atresia in infants less than 30 days.

PURPOSE: To retrospectively assess the diagnostic performance of grey-scale ultrasound (US) characteristics and gamma-glutamyl transpeptidase (GGT) alone or combined in distinguishing biliary atresia (BA) from other cholestasis diseases in infants younger than 30 days. MATERIALS AND METHODS: Between January 2012 and October 2020, the demographic characteristics, laboratory results and US characteristics of 35 BA and 52 non-BA infants younger than 30 days were retrospectively evaluated. Areas under the receiver operating characteristic curves (AUCs) were used to estimate the probability of predicting BA, which were compared by DeLong test. RESULTS: The diagnostic performance of gallbladder classification in identifying BA was higher than that of fibrotic cord thickness (AUC 0.900 vs. 0.771, P = 0.03). With the cutoff level of 188 IU/L, serum GGT had a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 77.1%, 69.2%, 62.8%, and 81.8%, respectively. Combined with gallbladder classification and GGT, the sensitivity, specificity, PPV, NPV and accuracy were 100.0%, 63.5%, 64.8%, 100.0% and 78.2%. CONCLUSIONS: Gallbladder classification was more valuable than fibrotic cord thickness in the diagnosis of BA among infants less than 30 days. Combined with gallbladder classification and GGT, the sensitivity for the diagnosis of BA can reach 100.0%.

Serum Exosomal Gamma-Glutamyltransferase Activity Increased in Patients with Renal Cell Carcinoma with Advanced Clinicopathological Features.

BACKGROUND: There has been no clinically useful diagnostic or prognostic biomarker for renal cell carcinoma (RCC). Serum γ-glutamyltransferase (GGT) activity has been reported to be a prognostic marker for several types of cancer including RCC. Exosomes or small extracellular vesicles present in body fluids have potential as a biomarker. We have recently demonstrated that GGT activity on exosomes isolated from serum is useful for the differential diagnosis of prostate cancer and benign prostate hyperplasia. In this study, we aimed to examine if serum exosomal GGT activity could be a marker for RCC. METHODS: We examined GGT1 expression and GGT activity in cell lysates and exosomes from culture medium of HK-2 proximal tubule epithelial and RCC cell lines. GGT activity was measured using a fluorescent probe for GGT, γ-glutamyl hydroxymethyl rhodamine green. Serum and serum exosomal GGT activities were measured in patients with RCC. GGT1 expression in RCC tissues was evaluated by immunohistochemical staining. RESULTS: GGT1 levels in exosomes from KMRC-1, OS-RC-2 and 786-O cells were elevated compared with those from HK-2 cells. In exosomes, GGT1 expression correlated with GGT activity determined using a fluorescent probe for GGT. In RCC patients, serum exosomal GGT activity was elevated in those with advanced stages (III/IV vs. I/II, p = 0.037) and those with microvascular invasion (with vs. without, p = 0.034). Immunohistochemical analysis showed that membranous GGT1 expression was increased in RCC with microvascular invasion. Notably, preoperative serum exosomal GGT activity could predict the likelihood of having microvascular invasion diagnosed by pathological examination of surgically resected specimens. CONCLUSIONS: Our results suggest that serum exosomal GGT activity could be a clinically useful marker for advanced clinicopathological features of RCC patients, and its combined use with conventional diagnostic modalities may improve the diagnosis and treatment of patients.

Diagnostic value of fibrinogen to prealbumin ratio and gamma-glutamyl transpeptidase to platelet ratio in the progression of AFP-negative hepatocellular carcinoma.

BACKGROUND: This study aimed to comprehensively assess the diagnostic value of fibrinogen to prealbumin ratio (FPR) and gamma-glutamyl transpeptidase to platelet ratio (GPR) as single markers or in combination in patients with alpha-fetoprotein-negative (AFP-negative) hepatocellular carcinoma (HCC). METHODS: A total of 199 healthy controls and 515 AFP-negative patients were enrolled in this study, including 180 HCC inpatients, 151 liver cirrhosis (LC) patients, and 184 chronic hepatitis (CH) cases. Mann-Whitney U or Kruskal-Wallis H test were used to analyze differences between groups in laboratory parameters and clinicopathological features. The diagnostic value of FPR and GPR, alone or in combination, in AFP-negative HCC (AFP-NHCC) patients was determined via a receiver operating characteristic (ROC) curve. RESULTS: The levels of FPR and GPR were gradually increased in the development of AFP-NHCC and positively correlated with the tumor size and Barcelona Clinic Liver Cancer (BCLC) stages. Moreover, GPR was associated with Edmondson-Steiner grades. After univariate logistic regression analysis, FPR and GPR remained independent predictors of adverse outcomes. The combination of FPR and GPR had a good ability to detect AFP-NHCC from the control group (area under curve [AUC] = 0.977), AFP-negative CH (AUC = 0.745), and AFP-negative LC (AUC = 0.666). FPR combined with GPR possessed a larger area (0.943, 0.971) and sensitivity (87.50%, 89.81%) than FPR or GPR alone for differentiating AFP-NHCC with tumor size < 3 cm or at the BCLC-A stage. CONCLUSIONS: The pretreatment levels of FPR and GPR played vital roles in the development of AFP-NHCC, especially in patients with early or small AFP-NHCC.

Amlodipine alleviates cisplatin-induced nephrotoxicity in rats through gamma-glutamyl transpeptidase (GGT) enzyme inhibition, associated with regulation of Nrf2/HO-1, MAPK/NF-κB, and Bax/Bcl-2 signaling.

BACKGROUND: The therapeutic utility of the effective chemotherapeutic agent cisplatin is hampered by its nephrotoxic effect. We aimed from the current study to examine the possible protective effects of amlodipine through gamma-glutamyl transpeptidase (GGT) enzyme inhibition against cisplatin nephrotoxicity. METHODS: Amlodipine (5 mg/kg, po) was administered to rats for 14 successive days. On the 10th day, nephrotoxicity was induced by a single dose of cisplatin (6.5 mg/kg, ip). On the last day, blood samples were collected for estimation of kidney function, while kidney samples were used for determination of GGT activity, oxidative stress, inflammatory, and apoptotic markers, along with histopathological evaluation. RESULTS: Amlodipine alleviated renal injury that was manifested by significantly diminished serum creatinine and blood urea nitrogen levels, compared to cisplatin group. Amlodipine inhibited GGT enzyme, which participates in the metabolism of extracellular glutathione (GSH) and platinum-GSH-conjugates to a reactive toxic thiol. Besides, amlodipine diminished mRNA expression of NADPH oxidase in the kidney, while enhanced the anti-oxidant defense by activating Nrf2/HO-1 signaling. Additionally, it showed marked anti-inflammatory response by reducing expressions of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB), with subsequent down-regulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1). Moreover, amlodipine reduced Bax/Bcl-2 ratio and elevated hepatocyte growth factor (HGF), thus favoring renal cell survival. CONCLUSIONS: Effective GGT inhibition by amlodipine associated with enhancement of anti-oxidant defense and suppression of inflammatory signaling and apoptosis support our suggestion that amlodipine could replace toxic GGT inhibitors in protection against cisplatin nephrotoxicity.