The potential role of human HIV-1 TAT-Interactive Protein 2 levels in the pathogenesis of contact dermatitis

Background/aim: Human HIV-1 TAT interactive protein 2 (HTATIP2/TIP30) is a gene that is extensively expressed in human tissues as well as in tumor tissues. This study aimed to explore the potential role of HTATIP2/TIP30 in contact dermatitis (CD), which is one of the most common inflammatory cutaneous conditions. Materials and methods: This cross-sectional study involved adult patients with acute contact dermatitis who were admitted to the outpatient dermatology clinic of a tertiary hospital and healthy adult volunteers without any cutaneous or systemic diseases. The blood concentration of HTATIP2/TIP30 was measured using ELISA kits. Results: The research sample consisted of 31 patients with CD (18 males, 13 females) and 20 healthy control subjects (14 males, 6 females). The mean ages of the patients with CD and healthy volunteers were 37 and 30 years, respectively (p > 0.05). The mean value of serum HTATIP2/TIP30 levels in patients with CD was 1.65 ng ml­1, which is 0.60 ng ml­1 in the control group (p = 0.02) Conclusion: In this study, serum levels of HTATIP2/TIP30 were statistically significantly higher in patients with CD when compared to healthy controls. This outcome may indicate possible role of HTATIP2/TIP30 in the pathogenesis of CD.

Clinical significance of changes in AFP, HTATIP2/TIP30, B7-H4 and inflammatory cytokines after transcatheter arterial chemoembolization.

PURPOSE: To explore the clinical significance of changes in alpha-fetoprotein (AFP), HIV-1 TAT interactive protein 2/TAT interactive protein 30 (HTATIP2/TIP30), B7-H4 and inflammatory cytokines after transcatheter arterial chemoembolization (TACE). METHODS: A total of 84 hepatocellular carcinoma (HCC) patients admitted to the Department of Hepatobiliary Surgery and the Department of Interventional Radiology of our hospital from January 1, 2017 to December 31, 2018 were randomly enrolled and divided into an experimental group and a control group according to treatment methods. The expression levels of AFP mRNA, HTATIP2/TIP30, B7-H4 and inflammatory cytokines were detected before and after treatment, the short-term efficacy was followed up and analyzed, and the correlation between the two was statistically analyzed. RESULTS: The AFP expression level in the two groups of patients was lower after treatment than before treatment, this reduction being more obvious in the experimental group (receiving TACE) than in the control group. Although the levels of serum HTATIP2/TIP30 and B7-H4 were decreased after treatment in both groups, and they were lower after treatment than those before treatment in the control group, lower levels were registered in the control group. Both groups of patients had lower expression levels of tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) after treatment compared with those before treatment, this decrease being more significant in the experimental group than in the control group. Moreover, the total short-term efficacy rate and the improvement rate of the quality of life were higher in the experimental group than in the control group, although no statistical difference in the survival rate was found between the two groups after 1-year follow-up. The serum level of B7-H4 in the group with good efficacy was lower than in the group with poor efficacy before treatment, and it declined in both groups after treatment, with a lower level in the former than in the latter. Furthermore, the group with good efficacy had a lower level of serum HTATIP2/TIP30 than the group with poor efficacy, while both groups had a decreased level after treatment, with a lower level in the former than in the latter. CONCLUSION: Interventional therapy for primary HCC has good short-term efficacy. It can reduce the levels of serum HTATIP2/TIP30, B7-H4, AFP and inflammation-related indexes, improve the liver function and the patients' quality of life.

Combined detection of AFP-L3, GP73 and TIP30 enhances diagnostic accuracy for HBV-related cirrhosis and hepatocellular carcinoma.

OBJECTIVE: To investigate the value of combined tests of serum Golgi protein-73, alpha-fetoprotein- L3 and Tat-interacting protein-30 in the diagnosis of hepatitis B virus related cirrhosis and hepatocellular carcinoma. METHODS: The cross-sectional study was conducted at Yuebei People's Hospital, Guangdong, China, from January to October 2017, and comprised hepatitis B patients and healthy controls. Serum Golgi protein-73, alpha-fetoprotein-L3 and Tat-interacting protein-30 levels in both groups were detected by enzyme-linked immunosorbent assay (ELISA). Alpha-fetoprotein-L3 was separated and quantified by electrochemiluminescence immunoas says and the percentage of alpha-fetoprotein-L3 to alphafetoprotein was calculated. RESULTS: Of the 721 subjects, 525(%) were patients and 196(%) were healthy controls. Among the patients, 271(%) had chronic hepatitis B, 161(%) had liver cirrhosis and 93(%) had hepatocellular carcinoma. Serum Golgi protein-73, alpha-fetoprotein-L3 and Tat-interacting protein-30 levels were significantly different in the hepatocellular carcinoma patients compared to controls, and those with chronic hepatitis and liver cirrhosis (p<0.01 each). The sensitivity and specificity of the combined detection of the three serum levels for diagnosing cirrhosis were 78.26% and 86.72%. The corresponding values for diagnosing hepatocellular carcinoma were 86.02% and 92.51%. CONCLUSIONS: Combined detection of Golgi protein-73, alpha fetoprotein-L3 and Tat-interacting protein was found to have the potential to improve diagnostic accuracy.

The effects of interventional therapy on serum HTATIP2/TIP30, B7-H4 and short-term curative effect in primary hepatocellular carcinoma.

OBJECTIVE: To explore the effects of interventional therapy on human immunodeficiency virus (HIV)-1 Tat interactive protein 2/Tat interactive protein 30 (HTATIP2/TIP30), B7-H4 and short-term curative effect in primary hepatocellular carcinoma. PATIENTS AND METHODS: 62 patients with primary hepatocellular carcinoma admitted in our hospital from June 2015 to June 2016 were enrolled in this study and divided into observation group (n = 31) and control group (n = 31) according to the random number table. The patients in the control group were treated with radiofrequency ablation, and the patients in the observation group were treated with transcatheter arterial chemoembolization (TACE). The patients in both groups received liver protection therapy, hydration, antiemetic and stomach protection. The curative effects, the serum HTATIP2/TIP30, B7-H4, alanine aminotransferase (ALT) and total bilirubin in serum (TBIL), life quality before and after treatment, and survival during the 1-year follow-up, were compared. RESULTS: The total short-term effective rate (70.97%) was higher than the control group (38.71%) (p < 0.05). The serum levels of HTATIP2/TIP30 and B7-H4 were decreased after treatment in both groups (observation group: t = 17.1838, 18.9795, control group: t = 8.3787, 10.6393, p < 0.05). The serum levels of HTATIP2/TIP30 and B7-H4 after treatment in the observation group were lower than the control group (t = 12.2975, 10.5361, p < 0.05). The levels of ALT and TBIL were decreased after treatment (observation group: t = 15.1716, 34.5771, control group: t = 8.3374, 17.3015, p < 0.05). The levels of ALT and TBIL were lower in the observation groups than the control group (t = 15.2697, 16.8592, p < 0.05). The improvement rate of life quality in the observation group (80.65%) was higher than the control group (54.84%) (p < 0.05). The survival rates of the two groups after 1-year follow-up were not statistically different (p > 0.05). CONCLUSIONS: The short-term curative effect of interventional therapy of primary hepatocellular carcinoma is good. It can decrease serum HTATIP2/TIP30 and B7-H4, improves the liver function and the life quality of patients, prolonging the survival time. It has a high research value and it is worthy of further application.

Role of disturbed fatty acids metabolism in the pathophysiology of diabetic erectile dysfunction.

BACKGROUND: Vasculogenic erectile dysfunction (VED) is considered as a common complication among people with type 2 diabetes (T2D). We tested whether changes in fatty acid (FAs) classes measured in erythrocytes are associated with increased risk of diabetic VED along with related risk factors. METHODS: We assessed erythrocyte FAs composition, lipid peroxidation parameters and inflammatory cytokines among 72 T2D men with VED, 78 T2D men without VED and 88 healthy volunteers with similar age. Biochemical, hepatic, lipid and hormonal profiles were measured. RESULTS: T2D people with VED had significant decrease in the indexes of Δ6-desaturase and elongase activities compared to the other studied groups. The same group of participants displayed lower erythrocytes levels of dihomo-γ-linolenic acid (C20:3n-6) (P < .001), precursor of the messenger molecule PGE1 mainly involved in promoting erection. Moreover, absolute SFAs concentration and HOMA IR levels were higher in T2D people with VED when compared to controls and associated with impaired NO concentration (1.43 vs 3.30 ng/L, P < .001). Our results showed that IL-6 and TNF-α were significantly increased and positively correlated with MDA levels only in T2D people with VED (r = 0.884, P = .016 and r = 0.753, P = .035; respectively) suggesting a decrease in the relative availability of vasodilator mediators and an activation of vasoconstrictors release. CONCLUSION: Our findings show that the deranged FAs metabolism represents a potential marker of VED in progress, or at least an indicator of increased risk within men with T2D.

Mycothiol acetyltransferase (Rv0819) of Mycobacterium tuberculosis is a potential biomarker for direct diagnosis of tuberculosis using patient serum specimens.

Mycobacterium tuberculosis infection constitutes a global threat that results in significant morbidity and mortality worldwide. Efficient and early diagnosis of tuberculosis (TB) is of paramount importance for successful treatment. The aim of the current study is to investigate the mycobacterial mycothiol acetyltransferase Rv0819 as a potential novel biomarker for the diagnosis of active TB infection. The gene encoding Rv0819 was cloned and successfully expressed in Escherichia coli. The recombinant Rv0819 was purified using metal affinity chromatography and was used to raise murine polyclonal antibodies against Rv0819. The raised antibodies were employed for direct detection of Rv0819 in patient serum samples using dot blot assay and competitive enzyme-linked immunosorbent assay (ELISA). Serum samples were obtained from 68 confirmed new TB patients and 35 healthy volunteers as negative controls. The dot blot assay showed sensitivity of 64·7% and specificity of 100%, whereas the competitive ELISA assay showed lower sensitivity (54·4%) and specificity (88·57%). The overall sensitivity of the combined results of the two tests was found to be 89·7%. Overall, the mycobacterial Rv0819 is a potential TB serum biomarker that can be exploited, in combination with other TB biomarkers, for efficient and reliable diagnosis of active TB infection. SIGNIFICANCE AND IMPACT OF THE STUDY: The early and accurate diagnosis of tuberculosis infection is of paramount importance for initiating treatment and avoiding clinical complications. Most current diagnostic tests have poor sensitivity and/or specificity and in many cases they are too expensive for routine diagnostic testing in resource-limited settings. In the current study, we examined a novel mycobacterial serum biomarker, namely mycothiol acetyltransferase Rv0819. The antigen was detectable in serum specimens of a significant number of tuberculosis patients. This article proves the importance of Rv0819 and paves the way towards its future use as a useful diagnostic marker for tuberculosis infection.

MCM2 and TIP30 are prognostic markers in squamous cell/adenosquamous carcinoma and adenocarcinoma of the gallbladder.

The clinicopathological and biological characteristics of squamous cell/adenosquamous carcinoma (SC/ASC) of the gallbladder remain to be fully elucidated, due to the fact that it is a rare gallbladder cancer subtype. In the current study, the expression of minichromosome maintenance complex component 2 (MCM2) and HIV­1 tat interactive protein 2 (TIP30) was measured in 46 cases of SC/ASC and 80 adenocarcinomas (AC) using immunohistochemistry. Positive MCM2 and negative TIP30 expression were significantly associated with large tumor size, high TNM stage, invasion, lymph node metastasis and lack of surgical curability in SC/ASC and AC. Positive MCM2 and negative TIP30 expression were significantly associated with poor differentiation in AC, whereas only MCM2 was correlated with differentiation in SC/ASC. Univariate Kaplan­Meier analysis demonstrated that positive MCM2 and negative TIP30 expression, the degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis and surgical curability were significantly associated with post­operative survival in patients with SC/ASC and AC. Multivariate Cox regression analysis demonstrated that positive MCM2 and negative TIP30 expression, the degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis and lack of surgical curability were also independent predictors of poor prognosis in patients with SC/ASC and AC. These data suggest that positive MCM2 and negative TIP30 expression are closely correlated with the clinical, pathological and biological parameters, in addition to poor prognosis in patients with gallbladder cancer.

Cancer-Specific Production of N-Acetylaspartate via NAT8L Overexpression in Non-Small Cell Lung Cancer and Its Potential as a Circulating Biomarker.

In order to identify new cancer-associated metabolites that may be useful for early detection of lung cancer, we performed a global metabolite profiling of a non-small cell lung cancer (NSCLC) line and immortalized normal lung epithelial cells from the same patient. Among several metabolites with significant cancer/normal differences, we identified a unique metabolic compound, N-acetylaspartate (NAA), in cancer cells-undetectable in normal lung epithelium. NAA's cancer-specific detection was validated in additional cancer and control lung cells as well as selected NSCLC patient tumors and control tissues. NAA's cancer specificity was further supported in our analysis of NAA synthetase (gene symbol: NAT8L) gene expression levels in The Cancer Genome Atlas: elevated NAT8L expression in approximately 40% of adenocarcinoma and squamous cell carcinoma cases (N = 577), with minimal expression in all nonmalignant lung tissues (N = 74). We then showed that NAT8L is functionally involved in NAA production of NSCLC cells through siRNA-mediated suppression of NAT8L, which caused selective reduction of intracellular and secreted NAA. Our cell culture experiments also indicated that NAA biosynthesis in NSCLC cells depends on glutamine availability. For preliminary evaluation of NAA's clinical potential as a circulating biomarker, we developed a sensitive NAA blood assay and found that NAA blood levels were elevated in 46% of NSCLC patients (N = 13) in comparison with age-matched healthy controls (N = 21) among individuals aged 55 years or younger. Taken together, these results indicate that NAA is produced specifically in NSCLC tumors through NAT8L overexpression, and its extracellular secretion can be detected in blood. Cancer Prev Res; 9(1); 43-52. ©2015 AACR.

Protective effects of vitamin E against liver damage caused by renal ischemia reperfusion.

Recent studies have reported that remote organs are affected by renal ischemia reperfusion (IR). The present study investigates the role of vitamin E on the liver damage after renal IR. First, male mice were subjected to three groups (n = 9): 1) sham-operated, (2) renal IR (45 min ischemia), (3) renal IR + Vitamin E (150 mg/kg trough feeding tube for 28 d). After 24 h of reperfusion, animal were anesthetized for sample collections. Liver tissues malondialdehyde (MDA) increased and total glutathione (GSH) concentration decreased in the IR group compared to the sham group. Vitamin E consumption diminished the IR-induced increase in plasma AST and ALT. In addition, Vitamin E inhibited the IR-induced decrease in GSH activity and diminished IR-induced increase in MDA concentration. These findings showed that vitamin E consumption partly inhibited the IR-induced liver damage.

High serum HTATIP2/TIP30 level in serous ovarian cancer as prognostic or diagnostic marker.

BACKGROUND: Human HIV-1 TAT interactive protein 2 (HTATIP2/TIP30) is an evolutionarily conserved gene that is expressed ubiquitously in human tissues and some tumor tissues. This protein has been found to be associated with some gynecological cancers; as such, this study aimed to investigate blood HTATIP2/TIP30 levels in patients with ovarian cancer. METHODS: Twenty-three women with ovarian cancer and 18 patients with various non-cancerous gynecological complaints (for example, dysfunctional uterine bleeding, fibroids, and urinary incontinence) were included in the study. The pathological diagnosis of ovarian cancer was adenocarcinoma. HTATIP2/TIP30 concentration in the patients' blood samples was determined using ELISA kits. RESULTS: The HTATIP2/TIP30 level was significantly higher in the cancer group than in the control group (1.84 ± 0.82 versus 0.57 ± 0.13 ng/ml, mean ± SD). CONCLUSIONS: We demonstrated the potential role of HTATIP2/TIP30 in ovarian cancer for the first time, thereby enlightening future studies targeting HTATIP2/TIP30 in ovarian cancer treatment, diagnosis, and prevention.

Platelet activating factor levels and metabolism in Tangier disease: a case study.

BACKGROUND: Tangier disease (TD) is a phenotypic expression of rare familial syndrome with mutations in the ABCA1 transporter. The risk of coronary artery disease in patients with TD is variable. On the other hand the pivotal role of Platelet-Activating Factor (PAF) mediator in atheromatosis was found. Plasma lipoproteins are transporters of the PAF acetylhydrolase (PAF-AH) in cells and known as lipoprotein-phospholipase A2 (Lp-PLA2) in plasma and regulators of PAF levels in blood. In addition, PAF can be biosynthesized from the remodeling and the de novo pathways in which Lyso-platelet activating factor-acetyltransferase (Lyso-PAF-AT) and platelet activating factor-cholinephosphotransferase (PAF-CPT) are the regulatory enzymes. The aim of this study is to investigate in a TD patient with a unique mutation (C2033A), the concentration of PAF in blood, the Equivalent Concentration for 50% aggregation (EC50) values of platelet rich plasma (PRP) toward PAF, adenosine diphosphate (ADP) and thrombin, and the activities of PAF metabolic enzymes Lp-PLA2, PAF-AH, Lyso-PAF-AT and PAF-CPT. METHODS: The EC50 value of PRP was measured by an aggregometer. The determination of the specific activity of PAF-CPT and Lyso-PAF-AT was made after in vitro enzymatic assay, chromatographic separation and measurement of the produced PAF in a biological assay with washed rabbit platelets. The determination of PAF-AH and Lp-PLA2 was made after an in vitro enzymatic assay from the decay of radioactive PAF. RESULTS: The TD patient had lower bound-PAF values in blood, decreased specific activity of PAF-CPT and Lyso-PAF-AT, increased specific activity of PAF-AH in platelets and leukocytes and Lp-PLA2 activity in plasma compared to healthy women. The EC50 of PAF and Thrombin were higher compared to healthy women. CONCLUSION: The increased Lp-PLA2 activity, as well as, the decreased activities of PAF-CPT and Lyso-PAF-AT, explain the decreased bound-PAF level in TD patient and the EC50 of PAF. However, total PAF is in a normal range and this probably can explain one of the reasons this TD patient has no CAD.

Bimodal distribution of polyunsaturated fatty acids in schizophrenia suggests two endophenotypes of the disorder.

BACKGROUND: There is conflicting evidence of whether polyunsaturated fatty acids (PUFA) in red blood cells are bimodally distributed in schizophrenia. The purpose of this study was to examine the distribution of PUFA, as well as its links to plausible causal factors. METHODS: A 16-week cohort study and a case-control study as part of a randomized controlled trial. Ninety-nine patients with DSM-IV schizophrenia, schizoaffective disorder, or schizophreniform disorder, aged 18 to 39, were consecutively included at admission to psychiatric departments of nine Norwegian hospitals. Fatty acids were measured in 97 of these patients and in 20 healthy control subjects. The primary outcome measure was the bimodality test statistic T, assessed by a χ(2) test of the likelihood of one or two normal distributions of PUFA. RESULTS: At baseline, levels of polyunsaturated fatty acids were highly significantly bimodally distributed among patients. One third of patients constituted a group (low PUFA) who had PUFA levels at one fifth (p < .001) of those in high PUFA patients and healthy control subjects, which did not differ. Bimodality was mainly accounted for by docosahexaenoic acid and arachidonic acid. Bimodality was confirmed after 16 weeks. α-tocopherol was a robust predictor of PUFA at both occasions. Desaturase and elongase indexes differed between PUFA groups. Smoking, gender, antipsychotic medication, and dietary factors did not explain the bimodal distribution. CONCLUSIONS: Red blood cell PUFA were bimodally distributed among acutely ill patients with schizophrenia and schizoaffective disorder. Endogenous deficiencies of redox regulation or synthesis of long-chain PUFA in the low PUFA group may explain our findings.

Peptide mimic isolated by autoantibody reveals human arrest defective 1 overexpression is associated with poor prognosis for colon cancer patients.

Tumor-associated antigens, which induce the generation of autoantibodies, are useful as cancer biomarkers in early detection and prognostic prediction of cancer. To isolate a novel cancer marker, we used serum antibodies from colon cancer patients to screen a phage display peptide library. A positive peptide 249C (VPLYSNTLRYGF) that could specifically react with serum from colon cancer patients was isolated, and the corresponding antigen-human arrest defective 1 (ARD1A), which shares an identical LYSNTL motif with 249C, was identified. Both immunological assays and three-dimensional structure analysis showed that the LYSNTL region is an epitope of ARD1A. Using ELISA and immunohistochemistry, we found anti-ARD1A antibody levels in serum from patients with colon cancer were significantly higher than those in healthy volunteers (P < 0.001), and ARD1A expression was detected in 84.1% (227/270) of colon cancer tissues compared with 22.7% (55/242) of matched noncancerous tissues (P < 0.001) and 4.8% (2/42) of benign lesions (P < 0.001). Furthermore, multivariate analysis with Cox proportional hazards regression models revealed that ARD1A-positive patients had significantly shortened overall survival (OS) (HR, 1.91, P = 0.039) and borderline significantly shortened disease-free survival (DFS) (HR, 1.70; P = 0.068). Kaplan-Meier survival curves also showed that ARD1A expression was associated significantly with shortened DFS (P = 0.037) and OS (P = 0.019). These results indicate that ARD1A is a novel tumor-associated antigen and a potential prognostic factor for colon cancer.

Expression of polyamine and SSAT (spermidine/spermine N-1 acetyl transferase) levels following surgical trauma and sepsis.

Polyamines have counterregulatory effects against inflammation, and whole blood polyamine concentrations reflect whole body polyamine levels. The purpose of this study was to investigate changes in blood polyamine concentrations during sublethal surgical damage and sepsis. Eight-week-old CDF1 male mice were used. Sepsis was induced by intraperitoneal injection of lipopolysaccharide, surgical trauma was induced by cecal ligation, and control mice were sham-operated. At 1, 2, 4, 6, and 12 hours following each procedure, polyamine concentrations, tumor necrosis factor (TNF), interleukin 6 (IL-6), and expression of spermidine/spermine N-acetyl transferase (SSAT) in blood cells were measured. Increases in serum TNF and IL-6 were noted in all groups. These increases were most prominent in the sepsis group, followed by the cecal ligation group. The increase in SSAT levels was noted in the sepsis and cecal ligation groups 2 hours after treatment. SSAT expression declined to lowest levels at the sixth hour and slightly re-increased at the 12th hour. Blood levels of putrescine, spermidine, and spermine were stable in all groups. We conclude that blood concentrations of metabolically active polyamines show an early decrease during inflammation. We further conclude that their levels are strictly controlled and are stable after surgical trauma and under septic conditions.

The role of calreticulin transacetylase in the activation of human platelet nitrite reductase by polyphenolic acetates.

Our earlier investigations demonstrated the remarkable activation of cytochrome P-450 reductase and nitric oxide synthase by 7,8-diacetoxy-4-methylcoumarin, a model polyphenolic acetate by way of acetylation, catalyzed by the Calreticulin. Protein acetyltransferase action of Calreticulin was hence termed Calreticulin transacetylase (CRTAase). Nitric oxide synthase and nitrite reductase are now considered as parts of nitric oxide cycle. The activation of platelets nitric oxide synthase by 7,8-diacetoxy-4-methylcoumarin has already been demonstrated by us. Also, there are reports that certain proteins such as cytochrome P-450 reductase and cytochrome P-450 are endowed with the nitrite reductase activity in mammalian cells. Keeping these facts in view, we turned our attention to probe whether 7,8-diacetoxy-4-methylcoumarin could alter the levels of nitric oxide independent of the action of nitric oxide synthase in the human platelets model. The incubation of 7,8-diacetoxy-4-methylcoumarin and nitrite with platelets caused significant elevation of nitric oxide and cyclic guanosine monophosphate levels possibly due to the activation of nitrite reductase. Several polyphenolic acetates were similarly found to activate the nitrite reductase in tune with their affinities as substrate to CRTAase. N-omega-Nitro-L-arginine methyl ester, the inhibitor of nitric oxide synthase, failed to reverse such an effect of 7,8-diacetoxy-4-methylcoumarin. Clotrimazole which is known to be an inhibitor of nitrite reductase, effectively abolished the 7,8-diacetoxy-4-methylcoumarin mediated enhancement of nitric oxide levels in platelets as well as the nitric oxide mediated effects; such as cyclic guanosine monophosphate levels as well as adenosine diphospate induced platelets aggregation due to nitrite.

Hepatic toxicity caused by adjuvant CMF/CNF in breast cancer patients and reversal by tamoxifen.

The purpose of the study was to determine the effect of adjuvant chemotherapy on liver enzymes in breast cancer patients. Furthermore, the effect of tamoxifen on liver enzymes was analyzed. Liver function tests from 194 breast cancer patients who received adjuvant chemotherapy with or without tamoxifen (TAM) were reviewed. Statistically very significant increases were seen in alkaline phosphatase, aspartate acetyl transferase, and gamma glutamyl transferase levels in these patients receiving adjuvant chemotherapy. No statistical changes were noticed in bilirubin levels. If tamoxifen was given together with adjuvant chemotherapy, no changes in liver function tests were detected. Hepatic toxicity was induced in breast cancer patients by adjuvant CMF/CNF therapy (cyclophosphamide, methotrexate, 5-fluorouracil, mitoxantrone). These changes were mostly mild. Adjuvant tamoxifen reduced the increase in liver enzymes caused by adjuvant chemotherapy.

Inhibition of lysoPAF acetyltransferase activity by flavonoids.

OBJECTIVE AND DESIGN: Several kinds of flavonoids, widely distributed natural products of the vegetable kingdom which possess anti-inflammatory activity, were examined for inhibitory effects on the acetyl-CoA: 1-alkyl-2-lyso-sn-glycero-3-phosphocholine (lysoPAF) acetyltransferase activity. METHODS: Acetyl-CoA:lysoPAF acetyltransferase activity was determined using homogenates of a rat mucosal-type mastocytoma cell line, RBL-2H3 as an enzyme source. The production of platelet-activating factor (PAF) in rat peripheral white blood cells stimulated with the calcium ionophore A23187 was studied. RESULTS: Of the flavonoids tested, luteolin and quercetin exhibited significant inhibitory effects (IC50, 45 microM and 80 microM, respectively), whereas other structurally-related flavonoids failed to affect the lysoPAF acetyltransferase activity. Luteolin did not suppress the activity of choline acetyltransferase, suggesting that the inhibition observed here was specific. Luteolin also inhibited the production of PAF in rat peripheral white blood cells. CONCLUSIONS: These results indicate that luteolin could become a leading compound for developing a novel type of anti-inflammatory, anti-allergic drugs that target lysoPAF acetyltransferase.

Increased N-acetylglucosamine-1-phosphotransferase activity in sera from patients with leukemia.

In human cancer, lysosomal hydrolases contain increased amounts of phosphorylated sugar chains. Sugar chains of the hydrolases undergo post-translational processing which is catalyzed by N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) at the first step. In the present study we estimated serum GlcNAc-phosphotransferase in 50 adults suffering from leukemia and myelodysplastic syndrome. The serum GlcNAc-phosphotransferase was increased to moderate or high levels in patients with acute nonlymphocytic leukemia (ANLL), acute lymphoblastic leukemia and chronic myelogenous leukemia, suggesting that the serum transferase is released from leukemic cells. In many cases of ANLL examined, activity of the transferase was decreased concomitantly with reduction of peripheral blastic cells by effective chemotherapy.

An anti-inflammatory protein secreted from the rat seminal vesicle epithelium inhibits the synthesis of platelet-activating factor and the release of arachidonic acid and prostacyclin.

Platelet-activating factor (PAF), a 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, is a mediator of inflammation and endotoxic shock produced by a variety of stimulated cells. Since the main biosynthetic pathway of PAF involves acetylation of 1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF) generated from 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine by phospholipase A2, we suggest a general physiological role played by steroid-induced anti-(phospholipase A2) proteins in the modulation of PAF synthesis. The results of the present study support this hypothesis since an androgen-induced anti-inflammatory protein, SV-IV, secreted from rat seminal vesicles, inhibits PAF synthesis in stimulated polymorphonuclear neutrophils, macrophages and endothelial cells. SV-IV impairs PAF synthesis by inhibiting the activation of phospholipase A2, that also results in the inhibition of arachidonic acid and prostacyclin release, and of acetyl-CoA:lyso-PAF acetyltransferase.

In vivo priming of human normal neutrophils by granulocyte-macrophage colony stimulating factor: effect on the production of platelet activating factor.

The effect of granulocyte-macrophage colony stimulating factor (GM-CSF) (recombinant, mammalian, glycosylated, Sandoz, Schering Plough; 4 micrograms/kg every 12 h for 3 d, s.c.) on platelet activating factor (PAF, 1-O-alkyl-2-acetyl-sn glycero-3 phosphorylcholine) production from neutrophils was studied in five cancer patients with normal haemopoiesis. Peripheral blood counts, PAF production and lyso-PAF: acetyl transferase (EC 2.3.1.67) (AT) activity in neutrophils were evaluated before treatment, during treatment and 3 d after treatment had been discontinued. GM-CSF induced a three-fold increase in the number of circulating neutrophils. Neutrophils obtained during treatment produced about twice as much PAF than before treatment in response to a variety of stimuli (N-formyl-methionyl-leucyl-phenylalanine, tumour necrosis factor-alpha, phagocytosis of baker's yeast spores opsonized with C3b). This increased PAF synthesis and release is concomitant with a 2-3-fold increase in AT activity. Moreover, lower concentrations of stimuli are sufficient to induce PAF synthesis from neutrophils obtained during GM-CSF treatment. Three days after treatment had been discontinued, stimulus induced PAF production had returned to baseline levels. Since GM-CSF induces a marked shift to the left in the Arneth score, the increased PAF release might have been due to the presence of younger granulocytes. This was, however, ruled out by experiments showing that normal neutrophils primed in vitro with GM-CSF produce more PAF when challenged with the same stimuli. The potential relevance of this effect of GM-CSF treatment lies on the crucial role of PAF in inflammatory reactions and its intervention in some immune reactions, including delayed hypersensitivity, and in endotoxic shock. Lastly, increased PAF production from neutrophils may explain some toxicities observed during treatment with high doses of GM-CSF.