Factors influencing bilirubin elevation and its correlation with UGT1A1 gene polymorphism in the early postoperative period of transjugular intrahepatic portosystemic shunt / 中华肝脏病杂志

Objective: To investigate the factors influencing total bilirubin elevation and its correlation with UGT1A1 gene polymorphism in the early postoperative period of transjugular intrahepatic portosystemic shunt (TIPS). Methods: 104 cases with portal hypertension and esophageal variceal hemorrhage (EVB) treated with elective TIPS treatment were selected as the study subjects and were divided into a bilirubin-elevated group and a normal bilirubin group according to the total bilirubin elevation level during the early postoperative period. Univariate analysis and logistic regression were used to analyze the factors influencing total bilirubin elevation in the early postoperative period. PCR amplification and first-generation sequencing technology were used to detect the polymorphic loci of the UGT1A1 gene promoter TATA box, enhancer c.-3279 T > G, c.211G > A, and c.686C > A. Logistic regression was used to analyze the correlation of four locus alleles and genotypes with elevated total bilirubin in the early postoperative period. Results: Among the 104 cases, 47 patients were in the bilirubin elevated group, including 35 males (74.5%) and 12 females (25.5%), aged (50.72 ± 12.56) years. There were 57 cases in the normal bilirubin group, including 42 males (73.7%) and 15 females (26.3%), aged (51.63 ± 11.10) years. There was no statistically significant difference in age (t = -0.391, P = 0.697) and gender (χ(2) = 0.008, P = 0.928) between the two groups of patients. Univariate analysis revealed that preoperative alanine transaminase (ALT) level (χ(2) = 5.954, P = 0.015), total bilirubin level (χ(2) = 16.638, P < 0.001), MELD score (χ(2) = 10.054, P = 0.018), Child-Pugh score (χ(2) = 6.844, P = 0.022), and postoperative portal vein branch development (χ(2) = 6.738, P = 0.034) were statistically significantly different between the two groups. Logistic regression analysis showed that preoperative ALT level, total bilirubin level, and portal vein branch development after TIPS were correlated with the elevated total bilirubin in the early postoperative period. The polymorphism of the c.211G > A locus of the UGT1A1 gene correlation had elevated total bilirubin in the early postoperative period of TIPS. The risk of elevated total bilirubin was increased in the population carrying allele A (P = 0.001, OR = 4.049) in the early postoperative period. Allelic polymorphisms in the TATA box promoter region and enhancer c.-3279 T > G and c.686C > A had no statistically significant difference between the bilirubin-elevated group and the normal bilirubin group. Conclusion: The preoperative ALT level, total bilirubin level, and portal vein branch development are correlated with the elevated total bilirubin in early postoperative patients. The polymorphisms of the UGT1A1 gene and enhancer c.211G > A are correlated with the occurrence of elevated total bilirubin in the early postoperative period of TIPS. Allele A carrier may have a higher risk of elevated total bilirubin in the early postoperative period.

UGT1A1 gene mutations in Chinese Dong neonates in Sanjiang, Guangxi / 中国当代儿科杂志

OBJECTIVES@#To study the characteristics of UGT1A1 gene mutations in Dong neonates in Sanjiang County of Liuzhou and its association with the pathogenesis of hyperbilirubinemia in Dong neonates.@*METHODS@#A prospective analysis was performed on 84 neonates who were diagnosed with unexplained hyperbilirubinemia in the Department of Neonatology, Sanjiang County People's Hospital, from January 2021 to January 2022. Sixty healthy neonates born during the same period were enrolled as the control group. Peripheral blood genomic DNA was extracted for both groups, and UGT1A1 exon 1 was amplified by PCR and sequenced.@*RESULTS@#In the case group, 33 neonates were found to have G71R missense mutation, with a mutation rate of 39%. The case group had a significantly higher frequency of A allele than the healthy control group (21% vs 10%, P<0.05). The risk of hyperbilirubinemia in Dong neonates carrying G71R missense mutation was 2.588 times as high as that in healthy neonates carrying wild-type UGT1A1 gene (P<0.05). Hardy-Weinberg equilibrium testing showed that the UGT1A1 G71R locus was in genetic equilibrium in both groups (P>0.05).@*CONCLUSIONS@#UGT1A1 G71R mutation is a high-frequency gene mutation type in Dong neonates in Sanjiang County, and G71R missense mutation is associated with hyperbilirubinemia in Dong neonates.

Characteristics and Clinical Implication of UGT1A1 Heterozygous Mutation in Tumor / 中国肺癌杂志

BACKGROUND@#The literature recommends that reduced dosage of CPT-11 should be applied in patients with UGT1A1 homozygous mutations, but the impact of UGT1A1 heterozygous mutations on the adverse reactions of CPT-11 is still not fully clear.@*METHODS@#A total of 107 patients with UGT1A1 heterozygous mutation or wild-type, who were treated with CPT-11 from January 2018 to September 2021 in Peking University Third Hospital, were retrospectively enrolled. The adverse reaction spectra of patients with UGT1A1*6 and UGT1A1*28 mutations were analyzed. Adverse reactions were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 5.0. The efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The genotypes of UGT1A1*6 and UGT1A1*28 were detected by digital fluorescence molecular hybridization.@*RESULTS@#There were 43 patients with UGT1A1*6 heterozygous mutation, 26 patients with UGT1A1*28 heterozygous mutation, 8 patients with UGT1A1*6 and UGT1A1*28 double heterozygous mutations, 61 patients with heterozygous mutation at any gene locus of UGT1A1*6 and UGT1A1*28. Logistic regression analysis showed that the presence or absence of vomiting (P=0.013) and mucositis (P=0.005) was significantly correlated with heterozygous mutation of UGT1A1*28, and the severity of vomiting (P<0.001) and neutropenia (P=0.021) were significantly correlated with heterozygous mutation of UGT1A1*6. In colorectal cancer, UGT1A1*6 was significantly correlated to diarrhea (P=0.005), and the other adverse reactions spectrum was similar to that of the whole patient cohort, and efficacy and prognosis were similar between patients with different genotypes and patients treated with reduced CPT-11 dosage or not.@*CONCLUSIONS@#In clinical use, heterozygous mutations of UGT1A1*6 and UGT1A1*28 are related to the risk and severity of vomiting, diarrhea, neutropenia and mucositis in patients with Pan-tumor and colorectal cancer post CPT-11 therpy. In colorectal cancer, UGT1A1*6 is significantly related to diarrhea post CPT-11 use, efficacy and prognosis is not affected by various genotypes or CPT-11 dosage reduction.

Study on metabolic dynamics,metabolic enzyme phenotype and species difference of hepatic and intestinal microsome of psoralidin / 中国中药杂志

This study aims to investigate metabolic activities of psoralidin in human liver microsomes( HLM) and intestinal microsomes( HIM),and to identify cytochrome P450 enzymes( CYPs) and UDP-glucuronosyl transferases( UGTs) involved in psoralidin metabolism as well as species differences in the in vitro metabolism of psoralen. First,after incubation serial of psoralidin solutions with nicotinamide adenine dinucleotide phosphate( NADPH) or uridine 5'-diphosphate-glucuronic acid( UDPGA)-supplemented HLM or HIM,two oxidic products( M1 and M2) and two conjugated glucuronides( G1 and G2) were produced in HLM-mediated incubation system,while only M1 and G1 were detected in HIM-supplemented system. The CLintfor M1 in HLM and HIM were 104. 3,and57. 6 μL·min~(-1)·mg~(-1),respectively,while those for G1 were 543. 3,and 75. 9 μL·min~(-1)·mg~(-1),respectively. Furthermore,reaction phenotyping was performed to identify the main contributors to psoralidin metabolism after incubation of psoralidin with NADPH-supplemented twelve CYP isozymes( or UDPGA-supplemented twelve UGT enzymes),respectively. The results showed that CYP1 A1( 39. 5 μL·min~(-1)·mg~(-1)),CYP2 C8( 88. 0 μL·min~(-1)·mg~(-1)),CYP2 C19( 166. 7 μL·min~(-1)·mg~(-1)),and CYP2 D6( 9. 1 μL·min~(-1)·mg~(-1)) were identified as the main CYP isoforms for M1,whereas CYP2 C19( 42. 0 μL·min~(-1)·mg~(-1)) participated more in producing M2. In addition,UGT1 A1( 1 184. 4 μL·min~(-1)·mg~(-1)),UGT1 A7( 922. 8 μL·min~(-1)·mg~(-1)),UGT1 A8( 133. 0 μL·min~(-1)·mg~(-1)),UGT1 A9( 348. 6 μL·min~(-1)·mg~(-1)) and UGT2 B7( 118. 7 μL·min~(-1)·mg~(-1)) played important roles in the generation of G1,while UGT1 A9( 111. 3 μL·min~(-1)·mg~(-1)) was regarded as the key UGT isozyme for G2. Moreover,different concentrations of psoralidin were incubated with monkey liver microsomes( MkLM),rat liver microsomes( RLM),mice liver microsomes( MLM),dog liver microsomes( DLM) and mini-pig liver microsomes( MpLM),respectively. The obtained CLintwere used to evaluate the species differences.Phase Ⅰ metabolism and glucuronidation of psoralidinby liver microsomes showed significant species differences. In general,psoralidin underwent efficient hepatic and intestinal metabolisms. CYP1 A1,CYP2 C8,CYP2 C19,CYP2 D6 and UGT1 A1,UGT1 A7,UGT1 A8,UGT1 A9,UGT2 B7 were identified as the main contributors responsible for phase Ⅰ metabolism and glucuronidation,respectively. Rat and mini-pig were considered as the appropriate model animals to investigate phase Ⅰ metabolism and glucuronidation,respectively.

A case of Gilbert syndrome caused by gene compound heterozygous mutations / 浙江大学学报·医学版

A case of Gilbert syndrome (GS) with a heterozygous mutation in the gene is reported. The patient had no symptoms except for recurrent sclera icterus since childhood. Laboratory examinations revealed an elevated unconjugated bilirubin. Biliary obstruction, hemolysis and other diseases that might cause jaundice were excluded. *28 and c.211G>A heterozygous mutations in gene were found, which may be another type of mutation causing GS in Chinese population.

Correlation of UGT2B7 Polymorphism with Cardiotoxicity in Breast Cancer Patients Undergoing Epirubicin/Cyclophosphamide-Docetaxel Adjuvant Chemotherapy

PURPOSE: The present study aimed to investigate correlations between uridine glucuronosyltransferase 2B7 (UGT2B7) -161 single nucleotide polymorphism C to T (C>T) and the occurrence of cardiotoxicity in Chinese breast cancer (BC) patients undergoing epirubicin/cyclophosphamide-docetaxel (EC-D) adjuvant chemotherapy. MATERIALS AND METHODS: 427 BC patients who had underwent surgery were consecutively enrolled in this prospective cohort study. All patients were scheduled to receive EC-D adjuvant chemotherapy regimen, and they were divided into UGT2B7 -161 CC (n=141), UGT2B7 -161 CT (n=196), and UGT2B7 -161 TT (n=90) groups according to their genotypes. Polymerase chain reaction was performed for determination of UGT2B7 -161 genotypes. Cardiotoxicity was defined as an absolute decline in left ventricular ejection fraction (LVEF) of at least 10% points from baseline to a value less than 53%, heart failure, acute coronary artery syndrome, or fatal arrhythmia. RESULTS: LVEF values were lower at cycle (C) 4, C8, 3 months after chemotherapy (M3), M6, M9, and M12 compared to C0 (all p < 0.001), in BC patients undergoing EC-D adjuvant chemotherapy. Cardiotoxicity was recorded for 4.2% of the overall population and was lowest in the UGT2B7 -161 TT group (1.1%), compared to UGT2B7 -161 CT (3.1%) and UGT2B7 -161 CC (7.8%) group (p=0.026). Multivariate logistic regression revealed that UGT2B7 -161 T allele could independently predict a low occurrence of cardiotoxicity in BC patients undergoing EC-D adjuvant chemotherapy (p=0.004). CONCLUSION: A UGT2B7 -161 T allele serves as a potential biomarker for predicting a low occurrence of cardiotoxicity in BC patients undergoing EC-D adjuvant chemotherapy.

Study on hepatotoxicity of physcion based on liver metabolism in vitro / 中国中药杂志

To evaluate the hepatotoxicity risks of physcion on the basis of the bilirubin metabolism mediated by glucuronidation of UDP-glucuronosyltransferases 1A1(UGT1A1 enzyme). The monomers were added into the rat liver microsomes to test the hepatotoxicity by using bilirubin as UGT1A1 enzyme substrate, with apparent inhibition constant K_i as the evaluation index. Liver microsome incubation in vitro was adopted to initiate phase Ⅱ metabolic reaction and investigate the inhibitory effect of physcion. Then the phase Ⅰ and Ⅱ metabolic reactions were initiated to investigate the comprehensive inhibition of metabolites and prototype components. The results showed that when only the phase Ⅱ reaction was initiated, physcion directly acted on the UGT1A1 enzyme in a prototype form, exhibited weak inhibition and the inhibition type was mixed inhibition; When the phase Ⅰ and Ⅱ reactions were initiated simultaneously, the inhibitory effects of physcion on UGT1A1 enzyme became strong and the inhibition type was mixed inhibition, suggesting that physcion had phase Ⅰ and Ⅱ metabolic processes, and the metabolites had strong inhibitory effect on UGT1A1 enzyme. This experiment preliminarily proved that the metabolites of physcion may be the main components to induce hepatotoxicity.

The metabolism and hepatotoxicity of ginkgolic acid (17 : 1) in vitro / 中国天然药物

Pharmacological activities and adverse side effects of ginkgolic acids (GAs), major components in extracts from the leaves and seed coats of Ginkgo biloba L, have been intensively studied. However, there are few reports on their hepatotoxicity. In the present study, the metabolism and hepatotoxicity of GA (17 : 1), one of the most abundant components of GAs, were investigated. Kinetic analysis indicated that human and rat liver microsomes shared similar metabolic characteristics of GA (17 : 1) in phase I and II metabolisms. The drug-metabolizing enzymes involved in GA (17 : 1) metabolism were human CYP1A2, CYP3A4, UGT1A6, UGT1A9, and UGT2B15, which were confirmed with an inhibition study of human liver microsomes and recombinant enzymes. The MTT assays indicated that the cytotoxicity of GA (17 : 1) in HepG2 cells occurred in a time- and dose-dependent manner. Further investigation showed that GA (17 : 1) had less cytotoxicity in primary rat hepatocytes than in HepG2 cells and that the toxicity was enhanced through CYP1A- and CYP3A-mediated metabolism.

The metabolism and hepatotoxicity of ginkgolic acid (17 : 1) in vitro / 中国天然药物

Pharmacological activities and adverse side effects of ginkgolic acids (GAs), major components in extracts from the leaves and seed coats of Ginkgo biloba L, have been intensively studied. However, there are few reports on their hepatotoxicity. In the present study, the metabolism and hepatotoxicity of GA (17 : 1), one of the most abundant components of GAs, were investigated. Kinetic analysis indicated that human and rat liver microsomes shared similar metabolic characteristics of GA (17 : 1) in phase I and II metabolisms. The drug-metabolizing enzymes involved in GA (17 : 1) metabolism were human CYP1A2, CYP3A4, UGT1A6, UGT1A9, and UGT2B15, which were confirmed with an inhibition study of human liver microsomes and recombinant enzymes. The MTT assays indicated that the cytotoxicity of GA (17 : 1) in HepG2 cells occurred in a time- and dose-dependent manner. Further investigation showed that GA (17 : 1) had less cytotoxicity in primary rat hepatocytes than in HepG2 cells and that the toxicity was enhanced through CYP1A- and CYP3A-mediated metabolism.

Enhanced absorption and inhibited metabolism of emodin by 2, 3, 5, 4'-tetrahydroxystilbene-2-O-β-D-glucopyranoside: Possible mechanisms for Polygoni Multiflori Radix-induced liver injury / 中国天然药物

Polygoni Multiflori Radix (PMR) has been commonly used as a tonic in China for centuries. However, PMR-associated hepatotoxicity is becoming a safety issue. In our previous in vivo study, an interaction between stilbenes and anthraquinones has been discovered and a hypothesis is proposed that the interaction between stilbene glucoside-enriching fraction and emodin may contribute to the side effects of PMR. To further support our previous in vivo results in rats, the present in vitro study was designed to evaluate the effects of 2, 3, 5, 4'-tetrahydroxystilbene-2-O-β-D-glucopyranoside (TSG) on the cellular absorption and human liver microsome metabolism of emodin. The obtained results indicated that the absorption of emodin in Caco-2 cells was enhanced and the metabolism of emodin in human liver microsomes was inhibited after TSG treatment. The effects of the transport inhibitors on the cellular emodin accumulation were also examined. Western blot assay suggested that the depressed metabolism of emodin could be attributed to the down-regulation of UDP-glucuronosyltransferases (UGTs) 1A8, 1A10, and 2B7. These findings definitively demonstrated the existence of interaction between TSG and emodin, which provide a basis for a better understanding of the underlying mechanism for PMR-induced liver injury.

Identification of human cytochrome P450 and UGT enzymes involved in the metabolism of ferulic acid, a major bioactive component in traditional Chinese medicines / 中国天然药物

Ferulic acid (FA) is an active component of herbal medicines. One of the best documented activities of FA is its antioxidant property. Moreover, FA exerts antiallergic, anti-inflammatory, and hepatoprotective effects. However, the metabolic pathways of FA in humans remain unclear. To identify whether human CYP or UGT enzymes are involved in the metabolism of FA, reaction phenotyping of FA was conducted using major CYP-selective chemical inhibitors together with individual CYP and UGT Supersomes. The CYP- and/or UGT-mediated metabolism kinetics were examined simultaneously or individually. Relative activity factor and total normalized rate approaches were used to assess the relative contributions of each major human CYPs towards the FA metabolism. Incubations of FA with human liver microsomes (HLM) displayed NADPH- and UDPGA-dependent metabolism with multiple CYP and UGT isoforms involved. CYPs and UGTs contributed equally to the metabolism of FA in HLM. Although CYP1A2 and CYP3A4 appeared to be the major contributors in the CYP-mediated clearance, their contributions to the overall clearance are still minor (< 25%). As a constitute of many food and herbs, FA poses low drug-drug interaction risk when co-administrated with other herbs or conventional medicines because multiple phase I and phase II enzymes are involved in its metabolism.

Repeated yellowing of the skin and sclera for 2 years / 中国当代儿科杂志

A two-year-old girl was admitted due to repeated yellowing of the skin and sclera for 2 years and had no other specific symptoms or signs. The use of phenobarbital could relieve the symptoms of jaundice. Multiple examinations showed increased indirect bilirubin levels, and the results of aminotransferases and liver imaging were normal. There was no evidence of hemolysis. The analysis of UGT1A1 gene in her family found that this child had double homozygous mutation of c.211G>A(G71R) and c.1456T>G(Y486D), which had been reported as the pathogenic mutation for Gilbert syndrome. Her parents carried double heterozygous mutation of G71R and Y486D and had no symptom of jaundice. The child was diagnosed as having Gilbert syndrome. It is concluded that as for patients with unconjugated hyperbilirubinemia which cannot be explained by liver damage and hemolysis, their family history should be investigated in detail and gene analysis should be performed as early as possible, in order to identify congenital bilirubin metabolic disorders.

Research Progress on Abused Drugs Metabolic in vivo / 法医学杂志

Under the catalysis of a variety of metabolic enzymes in vivo, such as UDP-glucuronyl transferases, cytochrome P450, carboxylesterase, sulfotransferase, butyrylcholinesterase, catechol-O-methyl transferase and 6-morphine dehydrogenase, the drugs perform glucuronidation, hydrolysis, oxidation, sulfonation and other reactions, then translate into active or inactive metabolites, which are excreted through urination, bile or the other pathways at last. Different drugs own their different metabolic pathways. This paper introduces the studies about the metabolism of drugs in human and animal in recent years, such as morphine-like drugs, amphetamine, ketamine, cannabis and cocaine, and reviews the research progress about the sites of metabolism, metabolic enzymes, metabolites and physiological activity of those drugs metabolic in vivo.

Effects of diammonium glycyrrhizinate on hepatic and intestinal UDP-Glucuronosyltransferases in rats: Implication in herb-drug interactions / 中国天然药物

Glycyrrhizin is a major bioactive component of liquorice, which exerts multiple biochemical and pharmacological activities and is frequently used in combination with other drugs in the clinic. Mycophenolate mofetil (MMF), an immunosuppressant widely used in transplant patients, is metabolized by UDP-glucuronyltransferases (UGTs). Although significant evidence supports that glycyrrhizin could interact with the cytochrome P450s (CYPs), few studies have addressed its effects on UGTs. The present study aimed at investigating the regulatory effects of diammonium glycyrrhizinate (GLN) on UGTs in vitro and in vivo. We found that long-term administration of GLN in rats induced overall metabolism of MMF, which might be due to the induction of UGT1A protein expression. Hepatic UGT1A activity and UGT1A mRNA and protein expression were significantly increased in GLN-treated rats. UGT1A expression levels were also increased in the intestine, contradicting with the observed decrease in intestinal UGT1A activities. This phenomenon may be attributed to different concentrations of glycyrrhetinic acid (GA) in liver and intestine and the inhibitory effects of GA on UGT1A activity. In conclusion, our study revealed that GLN had multiple effects on the expression and activities of UGT1A isoforms, providing a basis for a better understanding of interactions between GLN and other drugs.

Isochlorogenic acid A affects P450 and UGT enzymes in vitro and in vivo / 中国天然药物

Isochlorogenic acid A (ICQA), which has anti-inflammatory, hepatoprotective, and antiviral properties, is commonly presented in fruits, vegetables, coffee, plant-based food products, and herbal medicines. These herbal medicines are usually used in combination with other medicines in the clinic. However, little is known about the regulatory effects of ICQA on drug-metabolizing enzymes and the herb-drug interactions. In the present study, we evaluated the inhibitory potentials of ICQA on CYP1A2, CYP2C9, CYP2C19, CYP3A4, CYP2D6, and CYP2E1 in vitro based on a cocktail approach. The P450 and UGT activities in mice treated with ICQA for a prolonged period were also determined. Our results demonstrated that ICQA exhibited a weak inhibitory effect on CYP2C9 in human liver microsomes with IC being 57.25 μmol·L and Ki being 26.77 μmol·L. In addition, ICQA inhibited UGT1A6 activity by 25%, in the mice treated with ICQA (i.p.) at 30 mg·kg for 14 d, compared with the control group. Moreover, ICQA showed no mechanism-based inhibition on CYP2C9 or UGT1A6. In conclusion, our results further confirm a safe use of ICQA in clinical practice.

Genetic analysis of a child affected with Crigler-Najjar syndrome type II / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To detect potential mutation of the UGT1A1 gene in a child affected with Crigler-Najjar syndrome type II.</p><p><b>METHODS</b>Blood samples were collected from the patient and his parents for the extraction of genomic DNA. Potential mutation of the UGT1A1 gene was detected with polymerase chain reaction (PCR) and direct sequencing. The child was followed up until the age of 3 years and 6 months.</p><p><b>RESULTS</b>The patient showed persistent unconjugated hyperbilirubinemia. Sequencing of the UGT1A1 gene has detected a rare heterozygous c.610 A>G (p.Met204Val) mutation in the exon 1, in addition with a heterozygous c.1091 C>T (p.Pro364Leu) mutation in exon 4. The two mutations were inherited from his father and mother, respectively. The patient was diagnosed with Crigler-Najjar syndrome type II and received oral phenobarbital treatment.</p><p><b>CONCLUSION</b>The compound UGT1A1 gene mutation probably accounts for the disease in the patient manifesting persistent mild unconjugated hyperbilirubinemia. Genetic counseling and prenatal diagnosis should be provided for his family.</p>

Hyaluronidases and hyaluronan synthases expression is inversely correlated with malignancy in lung/bronchial pre-neoplastic and neoplastic lesions, affecting prognosis

We collected a series of 136 lung/bronchial and 56 matched lung parenchyma tissue samples from patients who underwent lung/bronchial biopsies and presented invasive carcinoma after lung surgery. The lung/bronchial samples included basal cell hyperplasia, squamous metaplasia, moderate dysplasia, adenomatous hyperplasia, severe dysplasia, squamous cell carcinoma and adenocarcinoma. Matched lung parenchyma tissue samples included 25 squamous cell carcinomas and 31 adenocarcinomas. Immunohistochemistry was performed to analyze for the distribution of hyaluronidase (Hyal)-1 and −3, and hyaluronan synthases (HAS)-1, −2, and −3. Hyal-1 showed significantly higher expression in basal cell hyperplasia than in moderate dysplasia (P=0.01), atypical adenomatous hyperplasia (P=0.0001), or severe dysplasia (P=0.03). Lower expression of Hyal-3 was found in atypical adenomatous hyperplasia than in basal cell hyperplasia (P=0.01) or moderate dysplasia (P=0.02). HAS-2 was significantly higher in severe dysplasia (P=0.002) and in squamous metaplasia (P=0.04) compared with basal cell hyperplasia. HAS-3 was significantly expressed in basal cell hyperplasia compared with atypical adenomatous hyperplasia (P=0.05) and severe dysplasia (P=0.02). Lower expression of HAS-3 was found in severe dysplasia compared with squamous metaplasia (P=0.01) and moderate dysplasia (P=0.01). Epithelial Hyal-1 and −3 and HAS-1, −2, and −3 expressions were significantly higher in pre-neoplastic lesions than in neoplastic lesions. Comparative Cox multivariate analysis controlled by N stage and histologic tumor type showed that patients with high HAS-3 expression in pre-neoplastic cells obtained by lung/bronchial biopsy presented a significantly higher risk of death (HR=1.19; P=0.04). We concluded that localization of Hyal and HAS in lung/bronchial pre-neoplastic and neoplastic lesions was inversely related to malignancy, which implied that visualizing these factors could be a useful diagnostic procedure for suspected lung cancer. Finalizing this conclusion will require a wider study in a randomized and prospective trial.

The expression and clinical significance of hyaluronan synthase in nasal polyps / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#To study the expression of hyaluronan synthasel-3 (HAS1-3) in nasal polyps, and discuss their clinical significance.@*METHOD@#The expression of HA, HAS1, HAS2 and HAS3 in nasal polyps group (25 cases) and inferior turbinate group (15 cases) was detected by immunohistochemistry and semi-quantitative RT-PCR.@*RESULT@#Compared with the control, the expression of HA, HAS1 and HAS3 was higher in nasal polyps (P0. 05).@*CONCLUSION@#The increase of HASI and HAS3 expression may be the main cause of the excessive deposition of HA in nasal polyps, which may play an important role in the pathogenic process of nasal polyps, and become a potential target for therapy of nasal polyps.

Association of UGT1A1 (*28, *60 and * 93) polymorphism with the adverse reactions of irinotecan chemotherapy in extensive stage small cell lung cancer / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To explore the correlation between UGT1A1 (*28, *60 and * 93) polymorphism and the adverse reactions in small cell lung cancer patients after irinotecan chemotherapy.</p><p><b>METHODS</b>Clinical data of 58 small cell lung cancer patients in extensive stage treated in our hospital were retrospectively analyzed. Polymerase chain reaction was used to amplify the UTG, and direct sequencing was performed to determine the UGT polymorphism. The adverse reactions ≥ grade 3 after irinotecan chemotherapy in patients with different UGT genotype were analyzed.</p><p><b>RESULTS</b>Amongthe 58 patients with extensive stage small cell lung cancer, there were 45 (77.6%) cases of wild type UGT1A1*28, 40 (69.0%) cases of wild type UGT1A1* 93, 38 (65.5%) cases of wild type UGT1A1*60, 18 cases of mutation in UGT1A1* 93 and 20 cases of mutation in UGT1A1*60. In UGT1A1 promoter position 28, there were 8 (13.8%) cases of TA5 mutation and 5 (8.6%) cases of TA7 mutation. Among the patients with TA5 mutation, 5 cases had ≥ grade 3 diarrhea, 3 cases had ≥ grade 3 leucopenia and 3 cases had ≥ grade 3 neutropenia, while among the patients with UGT1A1 * 93 mutation, 7 cases had ≥ grade 3 diarrhea, 6 cases had ≥ grade 3 leucopenia and 4 cases had ≥ grade 3 neutropenia.</p><p><b>CONCLUSIONS</b>TA5 and UGT1A1* 93 mutation increase the risk of diarrhea and ≥ grade 3 leukopenia and neutropenia, however, wild type UGT1A1 (*28, * 93, *60) and mutant UGT1A1*60 do not increase those risks. Further prospective study in a larger number of patients is needed to clarify the association between UGT1A1*28, UGT1A1* 93 and UGT1A1*60 polymorphism and adverse reactions of irinotecan, and to help clinicians in choosing a better therapeutic modality for personalized chemotherapy to improve curative effect and reduce adverse reactions.</p>