Study of the link between dopamine transporter gene polymorphisms and response to paroxetin and escitalopram in patients with lifelong premature ejaculation.

Int J Impot Res. 2017 Nov;29(6):235-239

Authors: Eltonsi TK, Tawfik TM, Rashed LA, GamalEl Din SF, Mahmoud MA

Abstract
We evaluated the role of dopamine (DA) transporter gene polymorphism in lifelong premature ejaculation (LPE) and its role in determining the response to paroxetine and escitalopram. Eighty consecutive patients and controls were recruited. Sixty of them suffered from LPE. They were divided into two equal groups. One group received paroxetine 20 mg daily for 3 months and the other one received ecistalopram 20 mg daily for 3 months. Their wives were instructed to measure the intra-vaginal ejaculation latency time using stopwatch. Five milliliters of blood was withdrawn from patients and controls for PCR analysis. The present study revealed that the mean ages of the patients and controls were 41.42 and 36.4 years, respectively. The majority of the patients were of (10R/10R) genotypes of the DA transporter gene polymorphism, whereas the controls were of (6R/6R) genotypes and this revealed statistically significant result (P-value=0.001). Both paroxitine and escitalopram significantly delayed ejaculation in the responders (P-values=0.001 and 0.001, respectively). The study revealed significant association between such response and DA transporter gene polymorphism (P-values of fold increase and log FI were 0.019 and 0.010, respectively). To the best of our knowledge, this is the first report to demonstrate a highly significant association between such response and DA transporter gene polymorphism in patients with LPE.

PMID: 28904397 [PubMed - indexed for MEDLINE]

Bioinformatic Analysis of Plasma Apolipoproteins A-I and A-II Revealed Unique Features of A-I/A-II HDL Particles in Human Plasma.

Sci Rep. 2016 08 16;6:31532

Authors: Kido T, Kurata H, Kondo K, Itakura H, Okazaki M, Urata T, Yokoyama S

Abstract
Plasma concentration of apoA-I, apoA-II and apoA-II-unassociated apoA-I was analyzed in 314 Japanese subjects (177 males and 137 females), including one (male) homozygote and 37 (20 males and 17 females) heterozygotes of genetic CETP deficiency. ApoA-I unassociated with apoA-II markedly and linearly increased with HDL-cholesterol, while apoA-II increased only very slightly and the ratio of apoA-II-associated apoA-I to apoA-II stayed constant at 2 in molar ratio throughout the increase of HDL-cholesterol, among the wild type and heterozygous CETP deficiency. Thus, overall HDL concentration almost exclusively depends on HDL with apoA-I without apoA-II (LpAI) while concentration of HDL containing apoA-I and apoA-II (LpAI:AII) is constant having a fixed molar ratio of 2 : 1 regardless of total HDL and apoA-I concentration. Distribution of apoA-I between LpAI and LpAI:AII is consistent with a model of statistical partitioning regardless of sex and CETP genotype. The analysis also indicated that LpA-I accommodates on average 4 apoA-I molecules and has a clearance rate indistinguishable from LpAI:AII. Independent evidence indicated LpAI:A-II has a diameter 20% smaller than LpAI, consistent with a model having two apoA-I and one apoA-II. The functional contribution of these particles is to be investigated.

PMID: 27526664 [PubMed - indexed for MEDLINE]

Correction: Endonuclease G promotes mitochondrial genome cleavage and replication.

Oncotarget. 2018 Jun 12;9(45):27908

Authors: Wiehe RS, Gole B, Chatre L, Walther P, Calzia E, Palmer A, Gebhardt JCM, Ricchetti M, Wiesmüller L

Abstract
[This corrects the article DOI: 10.18632/oncotarget.24822.].

PMID: 29963248 [PubMed - in process]

Comparative Study of Wheatley's Trichrome Stain and In-vitro Culture against PCR Assay for the Diagnosis of Blastocystis sp. in Stool Samples.

Iran J Parasitol. 2018 Jan-Mar;13(1):127-136

Authors: Mohammad NA, Mastuki MF, Al-Mekhlafi HM, Moktar N, Anuar TS

Abstract
Background: This study evaluated the performance of routine permanent stain and cultivation method in comparison with polymerase chain reaction assay as the reference technique to detect Blastocystis sp.
Methods: A cross-sectional study was conducted among aboriginal populations that reside in Pahang, Peninsular Malaysia in Feb to Mar 2015. A total of 359 stool samples were examined using Wheatley's trichrome stain, in-vitro cultivation in Jones' medium and PCR assay. Positive amplicons were subjected to sequencing and phylogenetic analysis.
Results: Fifty-six (15.6%) samples were detected positive with Blastocystis sp. by Wheatley's trichrome stain and 73 (20.3%) by in-vitro culture, while PCR assay detected 71 (19.8%) positive samples. Detection rate of Blastocystis sp. was highest in combination of microscopic techniques (27.9%). The sensitivity and specificity of Wheatley's trichrome staining and in-vitro culture techniques compared to PCR assay were 49.3% (95% CI: 37.2-61.4) and 92.7% (95% CI: 89.1-95.4) and 39.4% (95% CI: 28.0-51.8) and 84.4% (95% CI: 79.7-88.4), respectively. However, the sensitivity [60.6% (95% CI: 48.3-71.9)] of the method increased when both microscopic techniques were performed together. False negative results produced by microscopic techniques were associated with subtype 3. The agreement between Wheatley's trichrome stain, in-vitro culture and combination of microscopic techniques with PCR assay were statistically significant by Kappa statistics (Wheatley's trichrome stain: K = 0.456, P<0.001; in-vitro culture: K = 0.236, P<0.001 and combination techniques: K = 0.353, P<0.001).
Conclusion: The combination of microscopic technique is highly recommended to be used as a screening method for the diagnosis of Blastocystis infection either for clinical or epidemiological study to ensure better and accurate diagnosis.

PMID: 29963095 [PubMed]

Temozolomide and Pituitary Tumors: Current Understanding, Unresolved Issues, and Future Directions.

Front Endocrinol (Lausanne). 2018;9:318

Authors: Syro LV, Rotondo F, Camargo M, Ortiz LD, Serna CA, Kovacs K

Abstract
Temozolomide, an alkylating agent, initially used in the treatment of gliomas was expanded to include pituitary tumors in 2006. After 12 years of use, temozolomide has shown a notable advancement in pituitary tumor treatment with a remarkable improvement rate in the 5-year overall survival and 5-year progression-free survival in both aggressive pituitary adenomas and pituitary carcinomas. In this paper, we review the mechanism of action of temozolomide as alkylating agent, its interaction with deoxyribonucleic acid repair systems, therapeutic effects in pituitary tumors, unresolved issues, and future directions relating to new possibilities of targeted therapy.

PMID: 29963012 [PubMed]

Economic Evaluation of Implementing a Novel Pharmacogenomic Test (IDgenetix®) to Guide Treatment of Patients with Depression and/or Anxiety.

Pharmacoeconomics. 2017 Dec;35(12):1297-1310

Authors: Najafzadeh M, Garces JA, Maciel A

Abstract
BACKGROUND: The response to therapeutics varies widely in patients with depression and anxiety, making selection of an optimal treatment choice challenging. IDgenetix®, a novel pharmacogenomic test, has been shown to improve outcomes by predicting the likelihood of response to different psychotherapeutic medications.
OBJECTIVE: The objective of this study was to estimate the cost effectiveness of implementing a novel pharmacogenomic test (IDgenetix®) to guide treatment choices in patients with depression and/or anxiety compared with treatment as usual from the US societal perspective.
METHODS: We developed a discrete event simulation to compare clinical events, quality-adjusted life-years, and costs of the two treatment strategies. Target patients had a Hamilton Rating Scale for Depression Score ≥ 20 and/or a Hamilton Rating Scale for Anxiety score ≥ 18 at baseline. Remission, response, and no response were simulated based on the observed rates in the IDgenetix® randomized controlled trial. Quality-adjusted life-years and direct and indirect costs attributable to depression and anxiety were estimated and compared over a 3-year time horizon. We conducted extensive deterministic and probabilistic sensitivity analyses to assess the robustness of the results.
RESULTS: The model predicted cumulative remission rates of 78 and 66% in IDgenetix® and treatment as usual groups, respectively. Estimated discounted quality-adjusted life-years were 2.09 and 1.94 per patient for IDgenetix® and treatment as usual, respectively, which resulted in 0.15 incremental quality-adjusted life-years (95% credible interval 0.04-0.28). The total costs after accounting for a US$2000 test cost were US$14,124 for IDgenetix® compared with US$14,659 for treatment as usual, suggesting a US$535 (95% credible interval - 2902 to 1692) cost saving per patient in the IDgenetix® group. Incremental quality-adjusted life-year gain (0.49) and cost savings (US$6800) were substantially larger in patients with severe depression (Hamilton Rating Scale for Depression score ≥ 25).
CONCLUSION: Using the IDgenetix® test to guide the treatment of patients with depression and anxiety may be a dominant strategy, as it improves quality-adjusted life-years and decreases overall costs over a 3-year time horizon.

PMID: 29110140 [PubMed - indexed for MEDLINE]

Environmental exposure to organophosphorus nerve agents.

Environ Toxicol Pharmacol. 2017 Dec;56:163-171

Authors: Vucinic S, Antonijevic B, Tsatsakis AM, Vassilopoulou L, Docea AO, Nosyrev AE, Izotov BN, Thiermann H, Drakoulis N, Brkic D

Abstract
Exposure to organophosphorus nerve agents, the most deadly chemical warfare agents, is possible in a variety of situations, such as destruction of chemical warfare agents, terrorist attacks, armed conflicts or accidents in research laboratories and storage facilities. Hundreds of thousands of tons of chemical munitions were disposed of at the sea in the post World War II period, with European, Russian, Japanese and US coasts being the most affected. Sulfur mustard, Lewisite and nerve agents appear to be the most frequently chemical warfare agents disposed of at the sea. Addressing the overall environmental risk, it has been one of the priorities of the world community since that time. Aside from confirming exposure to nerve agents in the alleged use for forensic purposes, the detection and identification of biological markers of exposure are also needed for the diagnosis and treatment of poisoning, in addition to occupational health monitoring for specific profiles of workers. When estimating detrimental effects of acute or potential chronic sub-lethal doses of organophosphorus nerve agents, released accidentally or intentionally into the environment, it is necessary to understand the wide spectra of physical, chemical and toxicological properties of these agents, and predict their ultimate fate in environmental systems.

PMID: 28942081 [PubMed - indexed for MEDLINE]

Long-term outcomes of elderly patients with CYP2C9 and VKORC1 variants treated with vitamin K antagonists.

J Thromb Haemost. 2017 Nov;15(11):2165-2175

Authors: Nagler M, Angelillo-Scherrer A, Méan M, Limacher A, Abbal C, Righini M, Beer JH, Osterwalder J, Frauchiger B, Aschwanden M, Matter CM, Kucher N, Cornuz J, Banyai M, Husmann M, Staub D, Mazzolai L, Hugli O, Rodondi N, Aujesky D

Abstract
Essentials The long-term effects of VKORC1 and CYP2C9 variants on clinical outcomes remains unclear. We followed 774 patients ≥65 years with venous thromboembolism for a median duration of 30 months. Patients with CYP2C9 variants are at increased risk of death and non-major bleeding. Patients with genetic variants have a slightly lower anticoagulation quality only.
SUMMARY: Background The long-term effect of polymorphisms of the vitamin K-epoxide reductase (VKORC1) and the cytochrome P450 enzyme gene (CYP2C9) on clinical outcomes remains unclear. Objectives We examined the association between CYP2C9/VKORC1 variants and long-term clinical outcomes in a prospective cohort study of elderly patients treated with vitamin K antagonists for venous thromboembolism (VTE). Methods We followed 774 consecutive patients aged ≥ 65 years with acute VTE from nine Swiss hospitals for a median duration of 30 months. The median duration of initial anticoagulant treatment was 9.4 months. The primary outcome was the time to any clinical event (i.e. the composite endpoint of overall mortality, major and non-major bleeding, and recurrent VTE. Results Overall, 604 (78%) patients had a CYP2C9 or VKORC1 variant. Three hundred and thirty-four patients (43.2%) had any clinical event, 119 (15.4%) died, 100 (12.9%) had major and 167 (21.6%) non-major bleeding, and 100 had (12.9%) recurrent VTE. After adjustment, CYP2C9 (but not VKORC1) variants were associated with any clinical event (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.08-1.66), death (HR, 1.74; 95% CI, 1.19-2.52) and clinically relevant non-major bleeding (sub-hazard ratio [SHR], 1.39; 95% CI, 1.02-1.89), but not with major bleeding (SHR, 1.03; 95% CI, 0.69-1.55) or recurrent VTE (SHR, 0.95; 95% CI, 0.62-1.44). Patients with genetic variants had a slightly lower anticoagulation quality. Conclusions CYP2C9 was associated with long-term overall mortality and non-major bleeding. Although genetic variants were associated with a slightly lower anticoagulation quality, there was no relationship between genetic variants and major bleeding or VTE recurrence.

PMID: 28834238 [PubMed - indexed for MEDLINE]

Prognostic significance of frequent CLDN18-ARHGAP26/6 fusion in gastric signet-ring cell cancer.

Nat Commun. 2018 Jun 30;9(1):2447

Authors: Shu Y, Zhang W, Hou Q, Zhao L, Zhang S, Zhou J, Song X, Zhang Y, Jiang D, Chen X, Wang P, Xia X, Liao F, Yin D, Chen X, Zhou X, Zhang D, Yin S, Yang K, Liu J, Fu L, Zhang L, Wang Y, Zhang J, An Y, Cheng H, Zheng B, Sun H, Zhao Y, Wang Y, Xie D, Ouyang L, Wang P, Zhang W, Qiu M, Fu X, Dai L, He G, Yang H, Cheng W, Yang L, Liu B, Li W, Dong B, Zhou Z, Wei Y, Peng Y, Xu H, Hu J

Abstract
Signet-ring cell carcinoma (SRCC) has specific epidemiology and oncogenesis in gastric cancer, however, with no systematical investigation for prognostic genomic features. Here we report a systematic investigation conducted in 1868 Chinese gastric cancer patients indicating that signet-ring cells content was related to multiple clinical characteristics and treatment outcomes. We thus perform whole-genome sequencing on 32 pairs of SRC samples, and identify frequent CLDN18-ARHGAP26/6 fusion (25%). With 797 additional patients for validation, prevalence of CLDN18-ARHGAP26/6 fusion is noticed to be associated with signet-ring cell content, age at diagnosis, female/male ratio, and TNM stage. Importantly, patients with CLDN18-ARHGAP26/6 fusion have worse survival outcomes, and get no benefit from oxaliplatin/fluoropyrimidines-based chemotherapy, which is consistent with the fact of chemo-drug resistance acquired in CLDN18-ARHGAP26 introduced cell lines. Overall, this study provides insights into the clinical and genomic features of SRCC, and highlights the importance of frequent CLDN18-ARHGAP26/6 fusions in chemotherapy response for SRCC.

PMID: 29961079 [PubMed - in process]

Geographic variation in molecular subtype for gastric adenocarcinoma.

Gut. 2018 Jun 29;:

Authors: Liao P, Jia F, Teer JK, Knepper TC, Zhou HH, He YJ, McLeod HL

PMID: 29960981 [PubMed - as supplied by publisher]

Clinical intervention using Bifidobacterium strains in celiac disease children reveals novel microbial modulators of TNF-α and short-chain fatty acids.

Clin Nutr. 2018 Jun 18;:

Authors: Primec M, Klemenak M, Di Gioia D, Aloisio I, Bozzi Cionci N, Quagliariello A, Gorenjak M, Mičetić-Turk D, Langerholc T

Abstract
BACKGROUND & AIMS: Celiac disease (CD) is an immune-mediated systemic disease, caused by ingestion of gluten in genetically predisposed individuals. Gut microbiota dysbiosis might play a significant role in pathogenesis of chronic enteropathies and its modulation can be used as an intervention strategy in CD as well. In this study, we aimed to identify correlations between fecal microbiota, serum tumor necrosis factor alpha (TNF-α) and fecal short-chain fatty acids (SCFAs) in healthy children and children with CD after administration of probiotic Bifidobacterium breve BR03 and B632.
METHODS: A double-blind placebo-controlled study enrolled 40 children with CD (CD) and 16 healthy children (HC). CD children were randomly allocated into two groups, of which 20 belonged to the placebo (PL) group and 20 to the Probiotic (PR) group. The PR group received a probiotic formulation containing a mixture of 2 strains, B. breve BR03 (DSM 16604) and B. breve B632 (DSM 24706) in 1:1 ratio for 3 months. Subsequently, for statistical analysis, blood and fecal samples from CD children (on enrolment - T0 and after 3 months, at the end of intervention with probiotic/placebo - T1) and HC children were used. The HC group was sampled only once (T0).
RESULTS: Verrucomicrobia, Parcubacteria and some yet unknown phyla of Bacteria and Archaea may be involved in the disease, indicated by a strong correlation to TNF-α. Likewise, Proteobacteria strongly correlated with fecal SCFAs concentration. The effect of probiotic administration has disclosed a negative correlation between Verrucomicrobia, some unknown phyla of Bacteria, Synergistetes, Euryarchaeota and some SCFAs, turning them into an important target in microbiome restoration process. Synergistetes and Euryarchaeota may have a role in the anti-inflammatory process in healthy human gut.
CONCLUSIONS: Our results highlight new phyla, which may have an important relation to disease-related parameters, CD itself and health.

PMID: 29960810 [PubMed - as supplied by publisher]

Population-Based Analysis of Cluster Headache-Associated Genetic Polymorphisms.

J Mol Neurosci. 2018 Jun 29;:

Authors: Katsarou MS, Papasavva M, Latsi R, Toliza I, Gkaros AP, Papakonstantinou S, Gatzonis S, Mitsikostas DD, Kovatsi L, Isotov BN, Tsatsakis AM, Drakoulis N

Abstract
Cluster headache is a disorder with increased hereditary risk. Associations between cluster headache and polymorphism rs2653349 of the HCRTR2 gene have been demonstrated. The less common allele (A) seems to reduce disease susceptibility. The polymorphism rs5443 of the GNB3 gene positively influences triptan treatment response. Carriers of the mutated T allele are more likely to respond positively compared to C:C homozygotes, when treated with triptans. DNA was extracted from buccal swabs obtained from 636 non-related Southeastern European Caucasian individuals and was analyzed by real-time PCR. Gene distribution for the rs2653349 was G:G = 79.1%, G:A = 19.2%, and A:A = 1.7%. The frequency of the wild-type G allele was 88.7%. The frequencies for rs5443 were C:C = 44.0%, C:T = 42.6%, and T:T = 13.4%. The frequency of the wild-type C allele was 65.3%. The frequency distribution of rs2653349 in the Southeastern European Caucasian population differs significantly when compared with other European and East Asian populations, and the frequency distribution of rs5443 showed a statistically significant difference between Southeastern European Caucasian and African, South Asian, and East Asian populations. For rs2653349, a marginal statistically significant difference between genders was found (p = 0.080) for A:A versus G:G and G:A genotypes (OR = 2.78), indicating a higher representation of male homozygotes for the protective mutant A:A allele than female. No statistically significant difference was observed between genders for rs5443. Cluster headache pathophysiology and pharmacotherapy response may be affected by genetic factors, indicating the significant role of genotyping in the overall treatment effectiveness of cluster headaches.

PMID: 29959630 [PubMed - as supplied by publisher]

Characterization of 108 Genomic DNA Reference Materials for 11 Human Leukocyte Antigen (HLA) Loci: A GeT-RM Collaborative Project.

J Mol Diagn. 2018 Jun 26;:

Authors: Bettinotti MP, Ferriola D, Duke JL, Mosbruger TL, Tairis N, Jennings L, Kalman LV, Monos D

Abstract
The highly polymorphic human leukocyte antigen (HLA) genes, located in the human major histocompatibility complex, encode the class I and II antigen-presenting molecules which are centrally involved in the immune response. HLA typing is used for several clinical applications such as transplantation, pharmacogenetics, and diagnosis of autoimmune disease. HLA typing is highly complex due to the homology of HLA genes and pseudogenes and the extensive polymorphism in the population. The Centers for Disease Control and Prevention (CDC) established the Genetic Testing Reference Materials Coordination Program (GeT-RM) in partnership with the genetics community to improve the availability of genomic DNA reference materials necessary to assure the quality of genetic laboratory testing. The GeT-RM together with three clinical laboratories and the Coriell Cell Repositories have characterized genomic DNA obtained from a panel of 108 cell lines for all HLA classical polymorphic loci: HLA-A, B, C, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1. The goal was to develop a publicly available and renewable source of well-characterized genomic DNA reference materials to support molecular HLA typing assay development, validation, and verification, quality control, and proficiency testing. These genomic DNA samples are publicly available from the National Institutes of General Medical Science (NIGMS) Repository at the Coriell Cell Repositories.

PMID: 29959025 [PubMed - as supplied by publisher]

The sample that would not clot.

Clin Chim Acta. 2018 Jun 26;:

Authors: Strickland SW, Burns E, Palkimas S, Bazydlo LAL

Abstract
BACKGROUND: Vitamin K is a vital component within both the intrinsic and extrinsic coagulation cascade as certain factors (II, VII, IX, X and protein C and S) utilize vitamin K as a cofactor during post translational modification. Deficiency of vitamin K can result in the inability to properly form blood clots, both in vivo and in vitro, due to reduced vitamin K dependent factor levels and function. Vitamin K deficiency can result from congenital causes, such as VKOR or CYP2C9 mutations, or acquired causes, such as nutritional deficiencies, antibiotic therapy, or supra-therapeutic warfarin dosing.
RESULTS: In this case we present a patient with multifactorial vitamin K deficiency (due to nutritional defects and multiple genetic mutations in VKOR and CYP2C9) that was exacerbated by antibiotic and warfarin therapy during her hospital admission.
CONCLUSION: This case displays the importance of genetic testing prior to warfarin dosing and the role antibiotics play in the coagulation cascade.

PMID: 29958892 [PubMed - as supplied by publisher]

Warfarin: The End or the End of One Size Fits All Therapy?

J Pers Med. 2018 Jun 28;8(3):

Authors: Pirmohamed M

Abstract
Oral anticoagulants are required for both treatment and prophylaxis in many different diseases. Clinicians and patients now have a choice of oral anticoagulants, including the vitamin K antagonists (of which warfarin is the most widely used and is used as the exemplar in this paper), and direct oral anticoagulants (DOACs: dabigatran, apixaban, rivaroxaban, and edoxaban). This paper explores the recent advances and controversies in oral anticoagulation. While some commentators may favour a complete switchover to DOACs, this paper argues that warfarin still has a place in therapy, and a stratified approach that enables the correct choice of both drug and dose would improve both patient outcomes and affordability.

PMID: 29958440 [PubMed]

Genetic Polymorphism on the Pharmacokinetics and Pharmacodynamics of Platelet-derived Growth Factor Receptor (PDGFR) Kinase Inhibitors.

Curr Drug Metab. 2018 Jun 28;:

Authors: Qian Y, Yu L, Zhang XH, Yuan-Zi QY, Zhao P, Sun LN, Wang YQ

Abstract
Platelet-derived Growth Factor Receptor (PDGFR) is one of the families of Receptor Tyrosine Kinases (RTKs), which have attracted increasing attention as a potential target of antitumor therapy in cancer. PDGFR family members consist of PDGFR-α, PDGFR-β, CSF-1R, KIT and FLT3. Tyrosine Kinase Inhibitors (TKIs) are a kind of small molecule inhibitors targeting RTKs. TKIs prevent and block vital pathways by targeting signaling molecules which are necessary for cell survival. At present, about 11 kinds of TKIs targeting PDGFR family members have been approved for the treatment of diseases like chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GIST), renal cell carcinoma (RCC), etc. This review focuses on 11 PDGFR kinase inhibitors, including imatinib, sunitinib, regorafenib, sorafenib, pazopanib, axitinib, dasatinib, nilotinib, lenvatinib, cabozantinib and ponatinib. This article also provides an overview of: (1) general information on PDGFR kinase inhibitors; (2) pharmacokinetic parameters of PDGFR kinase inhibitors; (3) metabolic enzymes and transporters of PDGFR kinase inhibitors; (4) main drug interactions of PDGFR kinase inhibitors; (5) adverse events of PDGFR kinase inhibitors; and (6) genetic polymorphism on pharmacokinetics and pharmacodynamics of PDGFR kinase inhibitors.

PMID: 29956623 [PubMed - as supplied by publisher]

The Pharmacogenomics of Asthma beyond its Endotypes.

Curr Drug Metab. 2018 Jun 28;:

Authors: Meng S, Chen S, Tao A

Abstract
Asthma is a heterogeneous disease that consists of different phenotypes and endotypes, driven by different mechanistic pathways. An increasing number of genetic loci and single-nucleotide polymorphisms have been associated with therapeutic responses to asthma drugs. The purpose of this review is to focus on certain susceptibility genes, gene variants and typical therapeutic drugs of the glucocorticoid, leukotriene, histamine, and β2-adrenergic receptor pathways related to asthma. Pharmacogenomics can help us better understand the genetic basis of drug responses and better define new therapeutic targets to improve treatment effectiveness.

PMID: 29956621 [PubMed - as supplied by publisher]

UGT1A1 polymorphisms associated with prolactin response in risperidone-treated children and adolescents with autism spectrum disorder.

Pharmacogenomics J. 2018 Jun 29;:

Authors: Hongkaew Y, Medhasi S, Pasomsub E, Ngamsamut N, Puangpetch A, Vanwong N, Chamnanphon M, Limsila P, Suthisisang C, Wilffert B, Sukasem C

Abstract
The aim of this study was to investigate the association of drug-metabolizing enzyme and transporter (DMET) polymorphisms with the risperidone-induced prolactin response using an overlapping gene model between serum prolactin level and hyperprolactinemia in autism spectrum disorder (ASD) patients. Eighty-four ASD patients who were receiving risperidone for at least 1 month were recruited and then assigned to either the normal prolactin group or the hyperprolactinemia group based on their serum prolactin level. The genotype profile of 1936 (1931 single nucleotide polymorphisms (SNPs) and 5 copy number variation (CNVs) drug metabolism markers was obtained using the Affymetrix DMET Plus GeneChip microarray platform. Genotypes of SNPs used to test the accuracy of DMET genotype profiling were determined using TaqMan SNP Genotyping Assay kits. Eighty-four patients were selected for the allelic association study after microarray analyses (51 in the normal prolactin group, and 33 in the hyperprolactinemia group). An overlapping allelic association analysis of both analyses discovered five DMET SNPs with a suggestive association (P < 0.05) with risperidone-induced prolactin response. Three UGT1A1 SNPs (UGT1A1*80c.-364C > T, UGT1A1*93 c.-3156G > A, and UGT1A1 c.-2950A > G, showed a suggestive association with the risperidone-induced prolactin response and found to be in complete linkage disequilibrium (D' value of 1). In this DMET microarray platform, we found three UGT1A1 variants with suggestive evidences of association with the risperidone-induced prolactin response both measured by hyperprolactinemia and by prolactin level. However, due to the lack of validation studies confirmation and further exploration are needed in future pharmacogenomic studies.

PMID: 29955115 [PubMed - as supplied by publisher]

SH003 reverses drug resistance by blocking signal transducer and activator of transcription 3 (STAT3) signaling in breast cancer cells.

Biosci Rep. 2017 Dec 22;37(6):

Authors: Seo HS, Ku JM, Lee HJ, Woo JK, Cheon C, Kim M, Jang BH, Shin YC, Ko SG

Abstract
Overcoming drug resistance is an important task for investigators and clinician to achieve successful chemotherapy in cancer patients. Drug resistance is caused by various factors, including the overexpression of P-glycoprotein (P-gp, MDR1). The development of new, useful compounds that overcome drug resistance is urgent. SH003 is extracted from the mixture of three different herbs, and its anticancer effect has been revealed in different cancer cell types. In the present study, we investigated whether SH003 is able to reverse drug resistance using paclitaxel-resistant breast cancer cells (MCF-7/PAC). In our experiments, SH003 significantly decreased cell growth and colony formation in MCF-7/PAC cells and parental MCF-7 cells. This growth inhibition was related to the accumulation of cells in the sub-G0/G1 apoptotic population and an increase in the number of apoptotic cells. SH003 reduced the mRNA expression of multidrug resistance 1 (MDR1) and multidrug resistance-associated proteins (MRPs) in MCF-7/PAC cells. SH003 also down-regulated the expression of P-gp. SH003 reversed drug efflux from MCF-7/PAC cells, resulting in rhodamine123 (Rho123) accumulation. Inhibition of drug resistance by SH003 is related to the suppression of the signal transducer and activator of transcription 3 (STAT3) signaling pathway. SH003 decreased STAT3 activation (p-STAT3) and its nuclear translocation and inhibited the secretion of VEGF and MMP-2, which are STAT3 target genes. An STAT3 inhibitor, JAK inhibitor I and an HIF-1α inhibitor decreased cell growth in MCF-7 and MCF-7/PAC cells. Taken together, these results demonstrate that SH003 can overcome drug resistance, and SH003 might be helpful for chemotherapy in cancer patients.

PMID: 28864784 [PubMed - indexed for MEDLINE]

A polymorphism in the CYP17A1 gene influences the therapeutic response to steroidogenesis inhibitors in Cushing's syndrome.

Clin Endocrinol (Oxf). 2017 Nov;87(5):433-439

Authors: Valassi E, Aulinas A, Glad CA, Johannsson G, Ragnarsson O, Webb SM

Abstract
CONTEXT: Steroidogenesis inhibitors, such as ketoconazole (KTZ) and metyrapone (MTP), are used to lower hypercortisolism in patients with Cushing's syndrome (CS). Cortisol normalization is not reached in all patients taking these medications.
OBJECTIVE: To test the hypothesis that variants in genes affecting steroidogenesis contribute to different responses to KTZ and/or MTP in patients with CS.
PATIENTS AND METHODS: Fifty-four CS patients (46 women; mean [±SD] age, 39.7±12.7; 83% with Cushing's disease [CD] and 17% with an adrenal adenoma) preoperatively treated with KTZ (20%), MTP (37%) or a combination of both (43%). Thirty-nine of these (72%) were described in a previous study investigating the outcome of preoperative treatment with KTZ or MTP in CS patients. Following single-nucleotide polymorphisms (SNPs) were analysed: rs6410 (CYP11B1 gene), rs1799998 and rs4546 (CYP11B2 gene), and rs6163 (CYP17A1 gene). The associations between SNPs and cortisol levels at the end of medical treatment were evaluated.
RESULTS: Normalization of urinary free cortisol (UFC) was achieved in 50% of patients after 5 months of treatment. Patients carrying the CC genotype of SNP rs6163 were more likely to be controlled than AC/AA (OR 0.25 [95%CI, 0.075-0.88]; P=.031). When only patients reaching eucortisolism after medical treatment were analysed, median interquartile range (IQR) duration of treatment was shorter in patients carrying the CC genotype of SNP rs6163 as compared to AA/AC carriers (4 [4.57] months vs 5.2 [6.1] months; P=.026).
CONCLUSIONS: A polymorphism in the CYP17A1 gene was associated with the response to steroidogenesis inhibitors in CS. Genetic differences in the steroidogenic enzymes might account for inter-individual variations in the responsiveness to adrenal-blocking agents.

PMID: 28665508 [PubMed - indexed for MEDLINE]