Pharmacogenomics on the Treatment Response in Patients with Psoriasis: An Updated Review.

The efficacy and the safety of psoriasis medications have been proved in trials, but unideal responses and side effects are noted in clinical practice. Genetic predisposition is known to contribute to the pathogenesis of psoriasis. Hence, pharmacogenomics gives the hint of predictive treatment response individually. This review highlights the current pharmacogenetic and pharmacogenomic studies of medical therapy in psoriasis. HLA-Cw*06 status remains the most promising predictive treatment response in certain drugs. Numerous genetic variants (such as ABC transporter, DNMT3b, MTHFR, ANKLE1, IL-12B, IL-23R, MALT1, CDKAL1, IL17RA, IL1B, LY96, TLR2, etc.) are also found to be associated with treatment response for methotrexate, cyclosporin, acitretin, anti-TNF, anti-IL-12/23, anti-IL-17, anti-PDE4 agents, and topical therapy. Due to the high throughput sequencing technologies and the dramatic increase in sequencing cost, pharmacogenomic tests prior to treatment by whole exome sequencing or whole genome sequencing may be applied in clinical in the future. Further investigations are necessary to manifest potential genetic markers for psoriasis treatments.

Comparative Immunohistochemical Study of Hidroacanthoma Simplex and Clonal Seborrheic Keratosis With GATA3 and p63.

ABSTRACT: Histopathologically both hidroacanthoma simplex (HS) and clonal seborrheic keratosis (CSK) are characterized by intraepidermal nests of tumor cells. Although they show subtle microscopic differences, they can be difficult to accurately differentiate. Previous immunohistochemical studies have been inconclusive. We conducted an immunohistochemical study with GATA3 and p63 on cases of HS and CSK tentatively identified by their microscopic appearances and cases of eccrine poroma and seborrheic keratosis as their respective controls. The clinical, histopathological, and dermoscopic findings of these cases were also reviewed. All cases of HS and poroma were negative for GATA3, whereas all cases of CSK and seborrheic keratosis were positive for GATA3. HS, CSK, and their controls were all positive for p63. Microscopic, clinical, and dermoscopic differences were also found between HS and CSK. Our study demonstrated that GATA3 is useful for differentiating HS from CSK. Our initial microscopic observations also proved to be reliable, but immunostaining with GATA3 is helpful for confirming the diagnosis or establishing the diagnosis of uncertain cases. Awareness of the clinical and dermoscopic features of these 2 entities could also avoid misdiagnosis based solely on pathological observation.

Impact of ABCG2 Gene Polymorphism on the Predisposition to Psoriasis.

Psoriasis is a chronic inflammatory disease which is caused by the interaction between genetic and environmental factors. Evidence shows an association of psoriasis with co-morbidities including cardiovascular diseases, metabolic syndrome and hyperuricemia. Genome-wide association studies have revealed that the ABCG2 gene encoding ATP-binding cassette G2 protein was associated with inflammation and higher serum urate concentrations. In this study, we aimed to evaluate the role of ABCG2 gene polymorphisms on the susceptibility to psoriasis. The genotype distribution of two ABCG2 single nucleotide polymorphisms (SNPs), rs2231142 and rs2231137, was examined in 410 psoriasis patients and 1,089 gender-matched non-psoriasis controls. We found that heterozygotes (GT) for rs2231142 was associated with a decreased risk of psoriasis (p = 0.001; adjusted OR = 0.532; 95% CI, 0.370-0.765) after adjusting for age, as compared with homozygotes for the major allele (GG). Subjects who carried at least one polymorphic allele (homozygote or heterozygote for the minor allele) were less susceptible to psoriasis (p = 0.002; adjusted OR = 0.594; 95% CI, 0.249-0.823) and bearing higher serum urate levels (p = 0.026) than those homozygous for the major allele. Our results indicated that the ABCG2 gene polymorphism was associated with the risk of psoriasis.

Detecting Lesional Granulysin Levels for Rapid Diagnosis of Cytotoxic T lymphocyte-Mediated Bullous Skin Disorders.

BACKGROUND: Bullous skin disorders are induced by different pathomechanisms and several are emergent, including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Rapid diagnostic methods for SJS/TEN or cytotoxic T-lymphocyte (CTL)-mediated bullous disorders are crucial for early treatment. Granulysin, primarily expressed by CTLs, is a specific cytotoxic protein responsible for SJS/TEN and similar skin reactions. OBJECTIVE: To assess granulysin levels in blister fluids to differentiate SJS/TEN and similar CTL-mediated bullous reactions from other autoimmune bullous disorders. METHODS: Using ELISA, we measured granulysin in blister fluids from patients with bullous skin disorders, including SJS/TEN, erythema multiforme major, bullous fixed-drug eruption, bullous lupus erythematosus, paraneoplastic pemphigus, pemphigus vulgaris, bullous pemphigoid, purpura fulminans-related bullae, and hand-foot syndrome/hand-foot-skin reactions. We compared serum and blister granulysin levels in patients with SJS/TEN presenting varying severity, monitoring serial granulysin levels from acute to late stages. RESULTS: Overall, 144 patients presenting with bullous skin disorders were enrolled. Blister granulysin levels (mean ± SD) in CTL-mediated disorders, including TEN (n = 28; 3938.7 ± 3475.7), SJS-TEN overlapping (n = 22; 1440.4 ± 1179.6), SJS (n = 14; 542.0 ± 503.2), erythema multiforme major (n = 7; 766.3 ± 1073.7), generalized bullous fixed-drug eruption (n = 10; 720.4 ± 858.3), and localized bullous fixed-drug eruption (n = 16; 69.0 ± 56.4), were significantly higher than in non-CTL-mediated bullous disorders (P < .0001), including bullous lupus erythematosus (n = 3; 22.7 ± 20.1), paraneoplastic pemphigus (n = 3; 20.3 ± 8.6), pemphigus vulgaris (n = 3; 4.4 ± 2.8), bullous pemphigoid (n = 18; 4.0 ± 2.7), purpura fulminans (n = 4; 5.9 ± 5.5), and hand-foot syndrome/hand-foot-skin reactions (n = 6; 4.6 ± 3.5). Blister granulysin levels correlated with clinical severity of SJS/TEN (P < .0001). CONCLUSIONS: Determination of blister granulysin levels is a noninvasive and useful tool for rapid differential diagnosis of SJS/TEN and other similar CTL-mediated bullous skin disorders for treatment selection.

Discovery of Novel Agents on Spindle Assembly Checkpoint to Sensitize Vinorelbine-Induced Mitotic Cell Death Against Human Non-Small Cell Lung Cancers.

Non-small cell lung cancer (NSCLC) accounts about 80% of all lung cancers. More than two-thirds of NSCLC patients have inoperable, locally advanced or metastatic tumors. Non-toxic agents that synergistically potentiate cancer-killing activities of chemotherapeutic drugs are in high demand. YL-9 was a novel and non-cytotoxic compound with the structure related to sildenafil but showing much less activity against phosphodiesterase type 5 (PDE5). NCI-H460, an NSCLC cell line with low PDE5 expression, was used as the cell model. YL-9 synergistically potentiated vinorelbine-induced anti-proliferative and apoptotic effects in NCI-H460 cells. Vinorelbine induced tubulin acetylation and Bub1-related kinase (BUBR1) phosphorylation, a necessary component in spindle assembly checkpoint. These effects, as well as BUBR1 cleavage, were substantially enhanced in co-treatment with YL-9. Several mitotic arrest signals were enhanced under combinatory treatment of vinorelbine and YL-9, including an increase of mitotic spindle abnormalities, increased cyclin B1 expression, B-cell lymphoma 2 (Bcl-2) phosphorylation and increased phosphoproteins. Moreover, YL-9 also displayed synergistic activity in combining with vinorelbine to induce apoptosis in A549 cells which express PDE5. In conclusion. the data suggest that YL-9 is a novel agent that synergistically amplifies vinorelbine-induced NSCLC apoptosis through activation of spindle assembly checkpoint and increased mitotic arrest of the cell cycle. YL-9 shows the potential for further development in combinatory treatment against NSCLC.

Hypersensitivity and Cardiovascular Risks Related to Allopurinol and Febuxostat Therapy in Asians: A Population-Based Cohort Study and Meta-Analysis.

The safety of newer xanthine oxidase inhibitor febuxostat compared to allopurinol remains unclear. To compare the risks of allopurinol hypersensitivity and febuxostat hypersensitivity and cardiovascular diseases (CVDs) in Asians, we conducted a population-based cohort study enrolling patients receiving allopurinol or febuxostat from Chang Gung Memorial Hospital Health System across Taiwan during 2012-2016 and further performed a meta-analysis incorporating two recent studies. Among the 61,539 users, a corresponding 12,007 and 5,680 patients were identified as new users. The overall incidence of febuxostat hypersensitivity was significantly lower than allopurinol hypersensitivity (0.2 vs. 2.7 per 1,000 new users; P < 0.001). There were 33 allopurinol-hypersensitivity reactions (including 18 severe cutaneous adverse drug reactions), and only one patient developed febuxostat-maculopapular exanthema. Moreover, febuxostat did not statistically increase the risk of CVD (hazard ratio (HR), 1.16; P = 0.152) and related death (HR, 1.49; P = 0.496) compared to allopurinol. The result of the meta-analysis also showed a consistent result. In conclusion, the incidence and severity of febuxostat-hypersensitivity are lower than with allopurinol. Febuxostat did not show an increased risk of CVD and related death.

The Medication Risk of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Asians: The Major Drug Causality and Comparison With the US FDA Label.

Specific ethnic genetic backgrounds are associated with the risk of Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) especially in Asians. However, there have been no large cohort, multiple-country epidemiological studies of medication risk related to SJS/TEN in Asian populations. Thus, we analyzed the registration databases from multiple Asian countries who were treated during 1998-2017. A total 1,028 SJS/TEN cases were identified with the algorithm of drug causality for epidermal necrolysis. Furthermore, those medications labeled by the US Food and Drug Administration (FDA) as carrying a risk of SJS/TEN were also compared with the common causes of SJS/TEN in Asian countries. Oxcarbazepine, sulfasalazine, COX-II inhibitors, and strontium ranelate were identified as new potential causes. In addition to sulfa drugs and beta-lactam antibiotics, quinolones were also a common cause. Only one acetaminophen-induced SJS was identified, while several medications (e.g., oseltamivir, terbinafine, isotretinoin, and sorafenib) labeled as carrying a risk of SJS/TEN by the FDA were not found to have caused any of the cases in the Asian countries investigated in this study.

Anticancer Drugs Induced Severe Adverse Cutaneous Drug Reactions: An Updated Review on the Risks Associated with Anticancer Targeted Therapy or Immunotherapies.

Cutaneous adverse drug reactions are commonly seen in patients with anticancer drug treatment. Anticancer drugs, including chemotherapy, target therapy, and recent immunotherapy causing skin reactions ranging from mild skin rash to life-threatening severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) with increase morbidity and mortality while they are receiving cancer treatments, have been proposed to be a result of direct skin toxicity or drug hypersensitivity reactions (these are proposed mechanism, not definite). Differentiating SCARs from other more commonly seen reactions with a better outcome help prevent discontinuation of therapy and inappropriate use of systemic immunosuppressants for presumable allergic reactions, of which will affect the clinical outcome. In this article, we have reviewed published articles from 1950 to August 2017 for SJS/TEN associated with anticancer drugs, including chemotherapy, targeted therapy, and immunotherapy. We aimed to provide an overview of SJS/TEN associated with anticancer drugs to increase clinician recognition and accelerate future studies on the pathomechanism and managements.

Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions.

BACKGROUND: Cytotoxic T lymphocyte-mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-α and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial. We aimed to evaluate the efficacy, safety, and therapeutic mechanism of a TNF-α antagonist in CTL-mediated SCARs. METHODS: We enrolled 96 patients with SJS-TEN in a randomized trial to compare the effects of the TNF-α antagonist etanercept versus traditional corticosteroids. RESULTS: Etanercept improved clinical outcomes in patients with SJS-TEN. Etanercept decreased the SCORTEN-based predicted mortality rate (predicted and observed rates, 17.7% and 8.3%, respectively). Compared with corticosteroids, etanercept further reduced the skin-healing time in moderate-to-severe SJS-TEN patients (median time for skin healing was 14 and 19 days for etanercept and corticosteroids, respectively; P = 0.010), with a lower incidence of gastrointestinal hemorrhage in all SJS-TEN patients (2.6% for etanercept and 18.2% for corticosteroids; P = 0.03). In the therapeutic mechanism study, etanercept decreased the TNF-α and granulysin secretions in blister fluids and plasma (45.7%-62.5% decrease after treatment; all P < 0.05) and increased the Treg population (2-fold percentage increase after treatment; P = 0.002), which was related to mortality in severe SJS-TEN. CONCLUSIONS: The anti-TNF-α biologic agent etanercept serves as an effective alternative for the treatment of CTL-mediated SCARs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01276314. FUNDING: Ministry of Science and Technology of Taiwan.

Characteristics of Decreased Pulmonary Function and Clinical Symptoms in Nickel Electroplating Workers.

OBJECTIVE: To investigate health problems, especially pulmonary function, among electroplating workers exposed to nickel. METHODS: We recruited 153 nickel-exposed and 74 control workers from electroplating shops in printed circuit board production plants. Questionnaires were conducted to collect basic information. Symptoms and pulmonary function were ascertained. RESULTS: The average urine nickel level of the 79 high-exposure, 74 low-exposure, and 74 control workers were 7.38 ±â€Š5.96, 5.79 ±â€Š4.75, and 5.27 ±â€Š3.89 µg/g Cr, respectively. Nickel-exposed workers had a significantly higher incidence of skin- and airway-based symptoms. A significant relationship between impaired pulmonary function and high (more than5.2 µg/g Cr) urine nickel level was observed. CONCLUSIONS: Nickel-exposed workers had significantly higher urine nickel levels with more skin-, airway-based symptoms, as well as impaired pulmonary function. A dose-response relationship between decreased pulmonary function and nickel exposure status was observed.

Metabolic parameters in psoriatic patients treated with interleukin-12/23 blockade (ustekinumab).

The associations between psoriasis, metabolic syndrome and cardiovascular events are increasingly recognized. Studies have shown decreased cardiovascular events with the treatment of methotrexate and anti-tumor necrosis factor, however, effects of interleukin (IL)-12/23 blockade remain debatable. Our study investigated the effect of IL-12/23 blockade on the metabolic parameters in patients with psoriasis. We performed a retrospective cohort study to assess 93 consecutive patients with moderate to severe plaque type psoriasis who received IL-12/23 blockade (ustekinumab) for 24 weeks between January 2012 and May 2016. Metabolic parameters and disease activity (Psoriasis Area and Severity Index [PASI] score) at baseline and 24 weeks of treatment were collected. At week 24, the disease activity improved significantly (P < 0.0001), with a significant reduction of erythrocyte sedimentation rate. Conversely, body mass index was significantly elevated in PASI-75 responders at week 24 of treatment and was independent of disease severity. Fasting sugar and triglyceride levels were also elevated at week 24 in both PASI-75 responders and PASI-75 non-responders. Cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) remained unchanged. These metabolic parameters were not correlated with the improvement in disease severity after ustekinumab treatment. Nonetheless, the atherogenic index, LDL/HDL ratio and cholesterol/HDL ratio remained unchanged. Male sex and cigarette smoking are predictors of elevated plasma triglyceride levels. Our results suggest that despite tremendous improvement in disease activity after ustekinumab treatment, obesity, fasting sugar and hypertriglyceridemia still present in these patients. Regular screening of lipid profile, obesity control and smoking cessation are advised during the treatment of ustekinumab especially in male psoriatic patients with predisposing cardiovascular risks.

Quantitative Analysis of Face and Neck Skin Tightening by Microfocused Ultrasound With Visualization in Asians.

BACKGROUND: Previous studies of microfocused ultrasound with visualization (MFU-V) on facial and neck laxity were largely based on masked physician assessments, histological analysis, and safety profile. More quantitative studies are needed. OBJECTIVE: To evaluate the 800 treatment lines of MFU-V on skin tightening effect of face and neck in Asians using 2 quantitative analysis systems at 0, 90, and 180 days after treatment. MATERIALS AND METHODS: Total 25 subjects were recruited in this prospective study. Subjects were treated with MFU-V to the face and neck using 2 different transducers: 4 MHz, 4.5-mm focal depth and 7 MHz, 3.0-mm focal depth with total 800 lines. The subjects were evaluated by skin complexion analysis and 3-dimensional imaging system at 0, 90, and 180 days. Mean brow height lift and submental lift were calculated. RESULTS: All 25 subjects completed treatment and received the follow-up examinations at 90 and 180 days. Two of the 25 subjects were male. Mean patient age was 53.3 years (range: 39.8-61.1 years). Wrinkles, texture, and pores were 3 variables relevant to analysis of skin laxity. Only mean wrinkles score reduction at 90 days was statistically significant (p = .0222). There was a mean 0.47 mm brow lift at 90 days (p = .0165), but there was a 0.12 mm decrease in brow height compared to baseline at 180 days (p = .6494). At 90 days, a mean 26.44 mm submental lift was noted (p = .0217). And at 180 days, a mean 13.76 mm submental lift was noted (p = .243). CONCLUSION: This study showed that the most prominent change after the 800-line MFU-V treatments in Asians was the significant submental lift at 90 days. Other noninvasive or minimally invasive treatment modalities can be considered to combine with MFU-V for the optimal treatment response. Additional MFU-V treatments can be considered 3 months after the first treatment.

TGF-ß1 stimulates cyclooxygenase-2 expression and PGE2 production of human dental pulp cells: Role of ALK5/Smad2 and MEK/ERK signal transduction pathways.

BACKGROUND/PURPOSES: TGF-ß1 is an important growth factor that may influence the odontoblast differentiation and matrix deposition in the reactionary/reparative dentinogenesis to dental caries or other tooth injuries. TGF-ß1 exerts its effects through various signaling pathways, such as Smads and MAPKs. Cyclooxygenase-2 (COX-2) is a membrane-associated enzyme that produces prostaglandin E2 (PGE2) at sites of pulpal injury and inflammation, which leads to tissue swelling, redness and pain. The purposes of this study were to investigate the differential signal transduction pathways of TGF-ß1 that mediate COX-2 stimulation and PGE2 production in dental pulp cells. METHODS: Pulp cells were exposed to TGF-ß1 with/without SB431542 (an ALK5/Smad2 inhibitor) and U0126 (a MEK/ERK inhibitor). MTT assay was used to estimate cell viability. Enzyme-linked immunosorbent assay (ELISA) was used for measurement of PGE2 levels. RT-PCR and western blot were used to determined COX-2 mRNA and protein, respectively. RESULTS: Exposure to TGF-ß1 (1-10 ng/ml) increased the COX-2 mRNA and protein level of cultured pulp cells. Exposure to TGF-ß1 (0.1-10 ng/mL) significantly stimulated PGE2 production of dental pulp cells. Under the pretreatment of SB431542, the stimulatory effect of TGF-ß1 on COX-2 level of pulp cells was inhibited. Similarly, U0126 also partly inhibited the TGF-ß1-induced COX-2 expression. CONCLUSION: TGF-ß1 increased the COX-2 and PGE2 level of cultured pulp cells. The effect of TGF-ß1 on COX-2 protein expression was associated with ALK5/Smad2/3 and MEK/ERK pathways. These events are important in the early inflammation, repair and regeneration of dental pulp in response to injury.

Treatment of sudden hearing loss using electro-acupuncture.

OBJECTIVES: Sudden neurosensory deafness is the second debilitating disease in China. In fact, the current treatment is limited to hearing aids, assistive devices and cochlear implants. However, some patients might not be suitable for surgery or even hearing aids. METHODS: Hereby, we report a pediatric case of sudden sensorineural hearing loss accompanied by otalgia and blocked ear sensation. RESULTS: He firstly failed with conventional treatment but later his hearing symptoms were improved with our electro-acupuncture therapy according to pure tone audiometry findings and clinical responses. CONCLUSIONS: It may be worth trying in patients with sudden neurosensory deafness, who do not respond to routine medical treatment. In line with previous studies, the current report indicates that future observational studies or even clinical trials are needed to prove the efficacy of acupuncture on hearing loss and the accompanying symptoms.

Risk and association of HLA with oxcarbazepine-induced cutaneous adverse reactions in Asians.

OBJECTIVE: To investigate the risk and genetic association of oxcarbazepine-induced cutaneous adverse reactions (OXC-cADRs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), in Asian populations (Chinese and Thai). METHODS: We prospectively enrolled patients with OXC-cADRs in Taiwan and Thailand from 2006 to 2014, and analyzed the clinical course, latent period, drug dosage, organ involvement, complications, and mortality. We also investigated the carrier rate of HLA-B*15:02 and HLA-A*31:01 of patients with OXC-cADRs and compared to OXC-tolerant controls. The incidence of OXC-SJS/TEN was compared with carbamazepine (CBZ)-induced SJS/TEN according to the nationwide population dataset from the Taiwan National Health Insurance Research Database. RESULTS: We enrolled 50 patients with OXC-cADRs, including 20 OXC-SJS/TEN and 6 drug reaction with eosinophilia and systemic symptoms, of Chinese patients from Taiwan and Thai patients from Thailand. OXC-cADRs presented with less clinical severity including limited skin detachment (all ≦5%) and no mortality. There was a significant association between HLA-B*15:02 and OXC-SJS (p = 1.87 × 10-10; odds ratio 27.90; 95% confidence interval [CI] 7.84-99.23) in Chinese and this significant association was also observed in Thai patients. The positive and negative predictive values of HLA-B*15:02 for OXC-SJS/TEN were 0.73% and 99.97%, respectively. HLA-A*31:01 was not associated with OXC-cADRs. The incidence and mortality of OXC-SJS/TEN was lower than CBZ-STS/TEN in new users (p = 0.003; relative risk 0.212; 95% CI 0.077-0.584). CONCLUSIONS: Our findings suggest that HLA-B*15:02 is significantly associated with OXC-SJS in Asian populations (Chinese and Thai). However, the severity and incidence of OXC-SJS/TEN are less than that of CBZ-SJS/TEN. The need for preemptive HLA-B*15:02 screening should be evaluated further.

7-Ketocholesterol induces ATM/ATR, Chk1/Chk2, PI3K/Akt signalings, cytotoxicity and IL-8 production in endothelial cells.

Cardiovascular diseases (atherosclerosis, stroke, myocardiac infarction etc.) are the major systemic diseases of elder peoples in the world. This is possibly due to increased levels of oxidized low-density lipoproteins (oxLDLs) such as 7-ketocholesterol (7-KC) and lysophosphatidylcholine (LPC) that damage vascular endothelial cells, induce inflammatory responses, to elevate the risk of cardiovascular diseases, Alzheimer's disease, and age-related macular degeneration. However the toxic effects of 7-KC on endothelial cells are not known. In this study, 7-KC showed cytotoxicity to endothelial cells at concentrations higher than 10 µg/ml. 7-KC stimulated ATM/Chk2, ATR-Chk1 and p53 signaling pathways in endothelial cells. 7-KC also induced G0/G1 cell cycle arrest and apoptosis with an inhibition of Cyclin dependent kinase 1 (Cdk1) and cyclin B1 expression. Secretion and expression of IL-8 in endothelial cells were stimulated by 7-KC. 7-KC further induced intracellular ROS production as shown by increase in DCF fluorescence and Akt phosphorylation. LY294002 attenuated the 7-KC-induced apoptosis and IL-8 mRNA expression of endothelial cells. These results indicate that oxLDLs such as 7-KC may contribute to the pathogenesis of atherosclerosis, thrombosis and cardiovascular diseases by induction of endothelial damage, apoptosis and inflammatory responses. These events are associated with ROS production, activation of ATM/Chk2, ATR/Chk1, p53 and PI3K/Akt signaling pathways.

Impact of the HLA-B(*)58:01 Allele and Renal Impairment on Allopurinol-Induced Cutaneous Adverse Reactions.

Allopurinol, a common drug for treating hyperuricemia, is associated with cutaneous adverse drug reactions ranging from mild maculopapular exanthema to life-threatening severe cutaneous adverse reactions, including drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. We have previously reported that HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions in Han Chinese, but the associations of the HLA-B*58:01 genotype in an allopurinol-induced hypersensitivity phenotype remain unclear. To investigate the comprehensive associations of HLA-B*58:01, we enrolled 146 patients with allopurinol-induced cutaneous adverse drug reactions (severe cutaneous adverse reactions, n = 106; maculopapular exanthema, n = 40) and 285 allopurinol-tolerant control subjects. Among these allopurinol-induced cutaneous adverse drug reactions, HLA-B*58:01 was strongly associated with severe cutaneous adverse reactions (odds ratio [OR] = 44.0; 95% confidence interval = 21.5-90.3; P = 2.6 × 10(-41)), and the association was correlated with disease severity (OR = 44.0 for severe cutaneous adverse reactions, OR = 8.5 for maculopapular exanthema). The gene dosage effect of HLA-B*58:01 also influenced the development of allopurinol-induced cutaneous adverse drug reactions (OR = 15.25 for HLA-B*58:01 heterozygotes and OR = 72.45 for homozygotes). Furthermore, coexistence of HLA-B*58:01 and renal impairment increased the risk and predictive accuracy of allopurinol-induced cutaneous adverse drug reactions (heterozygous HLA-B*58:01 and normal renal function: OR = 15.25, specificity = 82%; homozygous HLA-B*58:01 and severe renal impairment: OR = 1269.45, specificity = 100%). This HLA-B*58:01 correlation study suggests that patients with coexisting HLA-B*58:01 and renal impairment (especially estimated glomerular filtration rate < 30ml/minute/1.73 m(2)) should be cautious and avoid using allopurinol.

Areca nut components stimulate ADAM17, IL-1α, PGE2 and 8-isoprostane production in oral keratinocyte: role of reactive oxygen species, EGF and JAK signaling.

Betel quid (BQ) chewing is an etiologic factor of oral submucous fibrosis (OSF) and oral cancer. There are 600 million BQ chewers worldwide. The mechanisms for the toxic and inflammatory responses of BQ are unclear. In this study, both areca nut (AN) extract (ANE) and arecoline stimulated epidermal growth factor (EGF) and interleukin-1α (IL-1α) production of gingival keratinocytes (GKs), whereas only ANE can stimulate a disintegrin and metalloproteinase 17 (ADAM17), prostaglandin E2 (PGE2) and 8-isoprostane production. ANE-induced EGF production was inhibited by catalase. Addition of anti-EGF neutralizing antibody attenuated ANE-induced cyclooxygenase-2 (COX-2), mature ADAM9 expression and PGE2 and 8-isoprostane production. ANE-induced IL-1α production was inhibited by catalase, anti-EGF antibody, PD153035 (EGF receptor antagonist) and U0126 (MEK inhibitor) but not by α-naphthoflavone (cytochrome p450-1A1 inhibitor). ANE-induced ADAM17 production was inhibited by pp2 (Src inhibitor), U0126, α-naphthoflavone and aspirin. AG490 (JAK inhibitor) prevented ANE-stimulated ADAM17, IL-1α, PGE2 production, COX-2 expression, ADAM9 maturation, and the ANE-induced decline in keratin 5 and 14, but showed little effect on cdc2 expression and EGF production. Moreover, ANE-induced 8-isoprostane production by GKs was inhibited by catalase, anti-EGF antibody, AG490, pp2, U0126, α-naphthoflavone, Zinc protoporphyrin (ZnPP) and aspirin. These results indicate that AN components may involve in BQ-induced oral cancer by induction of reactive oxygen species, EGF/EGFR, IL-1α, ADAMs, JAK, Src, MEK/ERK, CYP1A1, and COX signaling pathways, and the aberration of cell cycle and differentiation. Various blockers against ROS, EGF, IL-1α, ADAM, JAK, Src, MEK, CYP1A1, and COX can be used for prevention or treatment of BQ chewing-related diseases.

The (CCTTT) n pentanucleotide repeat polymorphism in the inducible nitric oxide synthase gene promoter and the risk of psoriasis in Taiwanese.

Recently, genome-wide association studies identified a novel psoriasis susceptibility locus tagged by two single-nucleotide polymorphisms (SNPs) rs4795067 and rs28998802, both of which are in the intronic region of inducible nitric oxide synthase (iNOS) gene. This study aimed to assess the role of (CCTTT) n pentanucleotide repeat polymorphisms in the promoter region of iNOS gene in Chinese-Taiwanese patients with psoriasis. In total, 280 patients with psoriasis and 512 control subjects were analyzed for the presence of the iNOS microsatellite polymorphism by polymerase chain reactions. The alleles were classified as S and L alleles according to the number of (CCTTT) n repeats, with the alleles with ≤13 repeats designated as S and alleles with ≥14 repeats designated as L alleles. The distribution of allele frequencies and genotypes was significantly different between the control and psoriasis groups (P = 0.040, and 0.014, respectively). After adjustment for age, sex, body mass index, smoking, diabetes, and hypertension, carriers of the LL genotype were 0.38 (95% confidence interval 0.16-0.95) times less likely than non-carriers to have psoriasis (P = 0.038). The promoter assays demonstrated that the iNOS promoter activity increases in parallel with the repeat number of (CCTTT) n in HaCaT cells. Approximately 70% of the study subjects were genotyped for rs4795067 and rs28998802. The rs4795067 is in linkage disequilibrium with the microsatellite L/S allelic classification. The association of iNOS microsatellite with psoriasis is independent of these known iNOS variants. Our results suggest that the iNOS microsatellite may contribute to the genetic background of psoriasis in Chinese-Taiwanese patients.