Lin Cheng

HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions in Han Chinese patients: a multicentre retrospective case-control clinical study.

DEAR EDITOR, Severe cutaneous adverse drug reactions (SCARs) are rare but life-threatening conditions, which can even be fatal in some patients. These include drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Over one hundred drugs have been associated with SCARs, one of which is allopurinol, a drug widely used to treat hyperuricaemia and its complications. Allopurinol-induced DRESS/SJS/TEN has previously been shown to occur almost exclusively in individuals positive for the human leucocyte antigen allele HLA-B*58:01 and of Han Chinese or Thai descent; this variant allele is commonly found in these specific Asian subpopulations. However, in Japanese and white populations, where the presence of HLAB*58:01 is less frequent, only a moderate association between allopurinol-induced SCARs and HLA-B*58:01 has been seen. To elucidate this relationship we conducted a multicentre retrospective case–control study of Han Chinese patients. This study was registered in the Chinese Clinical Trial Registry with number ChiCTR-RCC-12002927 and was approved by the independent ethics committee of the Institute of Clinical Pharmacology, Central South University (CTXY-1100112). Each participant was subjected to HLA-B sequencing to guarantee an accurate genotype. In total 92 patients with allopurinol-induced SCARs, 75 allopurinol-tolerant patients and 99 healthy volunteers from 19 centres across China were enrolled in this study. The inclusion criteria were as follows. All participants had to be of Han Chinese descent. Patients with allopurinolinduced SCARs were diagnosed with DRESS, SJS, SJS/TEN overlap or TEN by dermatologists according to the RegiSCAR or Roujeau criteria. SCARs had to occur within 3 months of allopurinol use, with diminished or relieved symptoms upon withdrawal. DRESS was defined according to the RegiSCAR criteria: rash in combination with fever, lymphadenopathy and haematological abnormalities (e.g. eosinophilia, atypical lymphocytes, leucocytosis, thrombocytopenia), along with involvement of at least one internal organ (e.g. hepatitis, nephritis). SJS and TEN are more severe reactions and commonly overlap in the clinic. SJS/TEN was characterized by fever and mucocutaneous lesions (mouth, lips, genital and anal regions), which led to epidermal death and sloughing. SJS was defined as skin detachment < 10% of the total body surface area, SJS/TEN overlap as 10–30% and TEN as > 30% skin detachment. Allopurinol-tolerant individuals were defined as patients using allopurinol for at least 3 months without any evidence of cutaneous adverse events. Healthy volunteers were Han Chinese individuals without clinical diseases in their medical history, and who had never received allopurinol treatment. The exclusion criteria were patients with a medical history of bone marrow transplantation, chemotherapy or cancer. Genomic DNA was extracted from the study participants’ blood samples for HLA-B genotyping by sequence-based typing. The odds ratio (OR), 95% confidence interval (CI), Pvalue, corrected P-value (Pc), positive predictive value and negative predictive value were calculated. The Pc-values were adjusted using Bonferroni’s post hoc correction for multiple comparisons to account for the observed alleles (48 HLA-B alleles were identified in three groups). The Pc-values were therefore multiplied by a factor of 48. The demographic characteristics of the participants are listed in Table 1. The clinical features of a patient with TEN are presented in Figure 1a. In the allopurinol-induced SCAR group, the subgroups of patients with DRESS, SJS, SJS/TEN overlap and TEN contained 41 (44%), 33 (36%), seven (8%) and 11 (12%) patients, respectively (Fig. 1b). Higher prevalences of allopurinol-induced SCARs (65%) and allopurinol tolerance (95%) were seen in male patients than in female patients (Fig. 1c). This can be explained by the high incidence of gout and hyperuricaemia in elderly men. The age distribution was about equal between groups (Fig. 1c). The group with allopurinol-induced SCARs received a shorter period of treatment with allopurinol, varying from 1 day to 64 days (mean 22 1), compared with 98–8760 days (mean 1153 303) in the allopurinol-tolerant group. Some patients exhibited higher sensitivity to allopurinol and had skin eruptions at day 1. Two patients experienced a second SCAR due to re-exposure to allopurinol (patients 3 and 81, Table S1; see Supporting Information). One patient had multidrug sensitivity (patient 3, Table S1). The mean given dose of allopurinol in the SCAR group was lower than in the tolerant group (186 5 vs. 289 8 mg), because most of the patients with SCARs had insufficient renal function. In terms of additional medications, 81% (57 of 70) of the patients used other drugs together with

Up-Regulation of Long Non-Coding RNA AB073614 Predicts a Poor Prognosis in Patients with Glioma

Dysregulated long noncoding RNAs (lncRNAs) have been found in human diseases, especially in cancer. Emerging evidence indicates that dysregulated lncRNAs are implicated in tumorigenesis and cancer progression. LncRNA AB073614 characterized as a new candidate lncRNA promotes the development of ovarian cancer. However, the role of lncRNA AB073614 in human gliomas remains unknown. The expression of AB073614 was detected in 65 glioma tissues and 13 normal brain tissues by qRT-PCR, showing that lncRNA AB073614 expression was significantly up-regulated in cancerous tissues compared with normal brain tissues (p < 0.001), and it was positively correlated with tumor grade (I–II grades vs. III–IV grades, p = 0.013) in glioma patients. Kaplan-Meier analysis demonstrated that increased AB073614 expression contributed to poor overall survival (HR (hazard ratio) = 1.952, 95%CI: 1.202–3.940, p = 0.0129). Further, univariate Cox regression analysis indicated that lncRNA AB073614 overexpression was an unfavorable prognostic factor in gliomas (HR = 1.997, 95%CI: 1.135–3.514, p = 0.016), regardless of the tumor grade (I–II grades vs. III–IV grades, HR = 1.902, 95%CI: 1.066–3.391, p = 0.029). Finally, after adjustment with age, sex, tumor grade and tumor location, multivariate Cox regression analysis suggested that both highly expressed lncRNA AB073614 (HR = 2.606, 95%CI: 1.408–4.824, p = 0.002) and high tumor grade (III–IV grades, HR = 2.720, 95%CI: 1.401–5.282, p = 0.003) could be considered independent poor prognostic indicators for glioma patients. In conclusion, our study suggested that increased lncRNA AB073614 expression may be identified as a poor prognostic biomarker in gliomas.

Postnatal onset of retinal degeneration by loss of embryonic Ezh2 repression of Six1.

Some adult-onset disorders may be linked to dysregulated embryonic development, yet the mechanisms underlying this association remain poorly understood. Congenital retinal degenerative diseases are blinding disorders characterized by postnatal degeneration of photoreceptors, and affect nearly 2 million individuals worldwide, but ∼50% do not have a known mutation, implicating contributions of epigenetic factors. We found that embryonic deletion of the histone methyltransferase (HMT) Ezh2 from all retinal progenitors resulted in progressive photoreceptor degeneration throughout postnatal life, via derepression of fetal expression of Six1 and its targets. Forced expression of Six1 in the postnatal retina was sufficient to induce photoreceptor degeneration. Ezh2, although enriched in the embryonic retina, was not present in the mature retina; these data reveal an Ezh2-mediated feed-forward pathway that is required for maintaining photoreceptor homeostasis in the adult and suggest novel targets for retinal degeneration therapy.

Clinical Significance of Long Non-Coding RNA CASC8 rs10505477 Polymorphism in Lung Cancer Susceptibility, Platinum-Based Chemotherapy Response, and Toxicity

Long non-coding RNA (lncRNA) CASC8 rs10505477 polymorphism has been identified to be related to risk of many kinds of cancers, such as colorectal cancer, gastric cancer, and invasive ovarian cancer, and it may be involved in the prognosis of gastric cancer patients who have received platinum-based chemotherapy after surgical treatment. So far, there is no study investigating the clinical significance of lncRNA CASC8 rs10505477 in lung cancer susceptibility and treatment. In this study, we genotyped 498 lung cancer patients and 213 healthy control subjects to explore the correlation between the rs10505477 polymorphism and lung cancer risk in a Chinese population. Among the 498 patients, 467 were selected for the chemotherapy response and toxicity study. We found that the single nucleotide polymorphisms (SNP) rs10505477 was greatly related to lung cancer risk in male and adenocarcinoma subgroups in recessive model (adjusted OR = 0.51, 95%CI = 0.29–0.90, p = 0.02; adjusted OR = 0.52, 95%CI = 0.30–0.89, p = 0.02, respectively). It was also closely correlated with platinum-based chemotherapy response in dominant model (adjusted OR = 1.58, 95%CI = 1.05–2.39, p = 0.03). Additionally, we observed that CASC8 rs10505477 polymorphism was significantly relevant to severe hematologic toxicity in non-small-cell lung cancer (NSCLC) subgroup in dominant model (adjusted OR = 0.59, 95%CI = 0.35–0.98, p = 0.04) and in additive model (adjusted OR = 0.62, 95%CI = 0.43–0.90, p = 0.01). Furthermore, it was found that rs10505477 polymorphism was greatly associated with gastrointestinal toxicity in SCLC and cisplatin subgroups in dominant model (adjusted OR = 7.82, 95%CI = 1.36–45.07, p = 0.02; adjusted OR = 1.94, 95%CI = 1.07–3.53, p = 0.03, respectively). Thus, lncRNA CASC8 rs10505477 could serve as a possible risk marker for diagnosing lung cancer, and could be used to forecast the response and toxicity of platinum-based treatment in lung cancer patients.

Mechanism-based inhibition of Alantolactone on human cytochrome P450 3A4 in vitro and activity of hepatic cytochrome P450 in mice

ETHNOPHARMACOLOGICAL RELEVANCEnAlantolactone (AL), one of the main active ingredients in Inula helenium L., has been included in various prescriptions of traditional Chinese medicine. The effects of AL on cytochrome P450 (CYP450) were still unclear. This study evaluated the inhibitory effect of AL on cytochrome P450s in vitro and in vivo.nnnMATERIALS AND METHODSnThe inhibitory effects of AL on the CYPs activity were evaluated in human liver microsomes (HLMs) and recombinant cDNA-expressed enzymes incubation system, and then determined by LC-MS/MS based CYPs probe substrate assay. C57BL/6 mice were treated AL orally (0, 25, 50, 100 mg/kg) for 15 days. The inhibitory effects of AL on major Cyps in mice were examined at both the mRNA and enzyme activity levels.nnnRESULTSnAL showed a potent inhibitory effect on CYP3A4 activity with IC50 values of 3.599 (HLMs) and 3.90 (recombinant CYP3A4) μM, respectively. AL strongly decreased CYP3A4 activity in a dose-dependent but not time-dependent way in HLMs. Results from typical Lineweaver-Burk plots showed that AL could inhibit CYP3A4 activity noncompetitively, with a Ki value of 1.09 μM in HLMs. Moreover, activity of CYP2C19 could also be inhibited by AL with IC50 of 36.82 μM. Other CYP450 isoforms were not markedly affected by AL. The inhibition was also validated by in vivo study of mice. AL significantly decreased mRNA expression of Cyp2c and 3a family.nnnCONCLUSIONnThe study indicates that herb-drug interaction should be paid more attention between AL and drugs metabolized by CYP3A4.

Genetic variation of CYP3A5 influences paclitaxel/carboplatin‐induced toxicity in Chinese epithelial ovarian cancer patients

Combination chemotherapy with platinum and taxane is the first‐line treatment for ovarian cancer. The dose‐limiting toxicities of these drugs include neuropathy, leukopenia, and neutropenia, but they exhibit substantial interindividual variability. This study investigated the relationship between CYP3A5 polymorphisms and paclitaxel/carboplatin‐induced toxicity in Chinese epithelial ovarian cancer patients. Seventy‐five patients with epithelial ovarian cancer were recruited. After combination chemotherapy, genotype analysis was conducted, and toxic effects were evaluated according to the Common Toxicity Criteria. A significant association was found between myelosuppression and the CYP3A5*3 genotype. CYP3A5*3/*1 patients showed a significantly higher risk of developing leukopenia (Pu2009<u2009.001; Pearsons χ2 test) and neutropenia (Pu2009<u2009.001; Pearsons χ2 test) than CYP3A5*3*3 patients. CYP3A5*3/*3 patients had significantly higher median leukocyte and neutrophil nadir counts than CYP3A5*3*1 patients (Pu2009<u2009.001, Mann–Whitney U test). However, we did not observe an association between neuropathy and CYP3A5*3 in this study (Pu2009=.64; Pearsons χ2 test). This is the first study to verify the influence of CYP3A5 polymorphisms on paclitaxel/carboplatin‐induced toxicity in Chinese epithelial ovarian cancer patients. Our findings suggest that interindividual variability in paclitaxel/carboplatin‐induced myelosuppression can be predicted by CYP3A5*3 genotyping and that incorporation of CYP3A5*3 genetic data in treatment selection could help to reduce myelosuppression events, thereby individualizing paclitaxel/carboplatin pharmacotherapy.

Multimodal Regulation Orchestrates Normal and Complex Disease States in the Retina

Regulation of biological processes occurs through complex, synergistic mechanisms. In this study, we discovered the synergistic orchestration of multiple mechanisms regulating the normal and diseased state (age related macular degeneration, AMD) in the retina. We uncovered gene networks with overlapping feedback loops that are modulated by nuclear hormone receptors (NHR), miRNAs, and epigenetic factors. We utilized a comprehensive filtering and pathway analysis strategy comparing miRNA and microarray data between three mouse models and human donor eyes (normal and AMD). The mouse models lack key NHRS (Nr2e3, RORA) or epigenetic (Ezh2) factors. Fifty-four total miRNAs were differentially expressed, potentially targeting over 150 genes in 18 major representative networks including angiogenesis, metabolism, and immunity. We identified sixty-eight genes and 5 miRNAS directly regulated by NR2E3 and/or RORA. After a comprehensive analysis, we discovered multimodal regulation by miRNA, NHRs, and epigenetic factors of three miRNAs (miR-466, miR1187, and miR-710) and two genes (Ell2 and Entpd1) that are also associated with AMD. These studies provide insight into the complex, dynamic modulation of gene networks as well as their impact on human disease, and provide novel data for the development of innovative and more effective therapeutics.

Effect on multifocal electroretinogram in persistently elevated intraocular pressure by erigeron breviscapus extract.

AIMnTo observe the effect on multifocal electroretinogram (mfERG) in persistently elevated intraocular pressure (IOP) by erigeron breviscapus extract (also named Dengzhanhua in Chinese) in rat models.nnnMETHODSnThe rat models with persistently elevated IOP were established by the method of Akira. Then, erigeron breviscapus extract was given for one month to observe the effect on mfERG in persistently elevated IOP in rats.nnnRESULTSnAs elevated IOP went on, the mfERG changes were mainly in weaken of reaction density with progressive development. After intervention of erigeron breviscapus extract, the total peak latency of P1 wave had recovered to some extent and the difference was significant when compared with control group (P<0.05); the total response density and P1 wave response density in second circle had risen noticeably, which had significant differences than those of control group (P<0.05).nnnCONCLUSIONnErigeron breviscapus extract can improve the impaired visual function of persistently elevated IOP in rats, suggesting that this extract is the effective part of erigeron breviscapus for optic neuroprotection.

Hypoxia-Inducible Factor-1α Target Genes Contribute to Retinal Neuroprotection

Hypoxia-inducible factor (HIF) is a transcription factor that facilitates cellular adaptation to hypoxia and ischemia. Long-standing evidence suggests that one isotype of HIF, HIF-1α, is involved in the pathogenesis of various solid tumors and cardiac diseases. However, the role of HIF-1α in retina remains poorly understood. HIF-1α has been recognized as neuroprotective in cerebral ischemia in the past two decades. Additionally, an increasing number of studies has shown that HIF-1α and its target genes contribute to retinal neuroprotection. This review will focus on recent advances in the studies of HIF-1α and its target genes that contribute to retinal neuroprotection. A thorough understanding of the function of HIF-1α and its target genes may lead to identification of novel therapeutic targets for treating degenerative retinal diseases including glaucoma, age-related macular degeneration, diabetic retinopathy, and retinal vein occlusions.

The P450 oxidoreductase (POR) rs2868177 and cytochrome P450 (CYP) 2B6*6 polymorphisms contribute to the interindividual variability in human CYP2B6 activity

AimTo investigate whether single-nucleotide polymorphisms (SNPs) in the P450 oxidoreductase (POR) gene were correlated with interindividual variations in cytochrome P450 (CYP) 2B6 activity.MethodsThirty-six healthy volunteers who tested CYP2B6 and POR polymorphisms were enrolled in the study. CYP2B6 activity was measured by bupropion hydroxylation with LC/MS/MS. The ratio of hydroxybupropion versus bupropion (AUC_hyd/AUC_bup) in terms of area under the time-concentration curve (AUC) was used to represent the CYP2B6 activity.ResultsThe volunteers carrying CYP2B6*1/*1 showed a significantly higher mean AUC_hyd/ AUC_bup than those CYP2B6*1/*6 and CYP2B6*6/*6 variants (15.66xa0±xa01.65 vs. 9.25xa0±xa01.92, Pxa0=xa00.008 and 15.66xa0±xa01.65 vs. 8.21xa0±xa01.74, Pxa0=xa00.006, respectively). POR rs2868177 (6593xa0Axa0>xa0G) AA homozygotes showed a significantly lower mean AUC_hyd/ AUC_bup than that of POR rs2868177 AG heterozygotes or GG homozygotes (8.13xa0±xa01.37 vs. 12.15xa0±xa02.97, Pxa0=xa00.005 and 8.13xa0±xa01.37 vs. 17.59xa0±xa03.25, Pxa0=xa00.001, respectively). Moreover, POR rs2868177 AG heterozygotes and GG homozygotes showed a significantly increased mean AUC_hyd/AUC_bup than AA homozygotes in the CYP2B6*1/*1 and CYP2B6*6 carriers (16.40xa0±xa02.01 vs. 12.40xa0±xa01.45, Pxa0=xa00.006 and 10.65xa0±xa01.47 vs. 6.54xa0±xa01.25, Pxa0=xa00.004, respectively). Meanwhile, a strong correlation between the genetic variations (POR rs2868177 and CYP2B6*6) and AUC_hyd/ AUC_bup was found (Pxa0=xa00.009 and Pxa0=xa00.001, respectively). There was no significant difference in the mean AUC_hyd/AUC_bup among different POR *28 genotypes (Pxa0>xa00.05).ConclusionPOR rs2868177 and CYP2B6*6 variants contribute to the interindividual variability in human CYP2B6 activity, which may affect the disposition and interaction of other CYP2B6 substrate drugs.