Association of UGT2B7 and CaMK4 with response of valproic acid in Chinese children with epilepsy.

Therapie. 2019 Jul 26;:

Authors: Wang Y, Li Z

Abstract
AIM OF THE STUDY: Valproic acid (VPA) is a widely used antiepileptic drug for epilepsy. However, approximately 30% of patients with epilepsy do not respond to this therapy even when it was appropriately used. In order to explore the potential genetic factors related to the VPA response, this pharmacogenetics study was conducted.
METHODS: A total of one hundred and fifty-seven Chinese children with epilepsy who were administered with by VPA for at least one year were enrolled. Thirteen single-nucleotide polymorphisms (SNPs) located in eight genes involving targets and metabolic enzymes of VPA were genotyped. The frequencies of these polymorphisms and the effect of genotypes on the efficacy of VPA were analyzed.
RESULTS: The frequencies of two SNPs, rs7668258 (uridine diphosphate glucuronosyltransferase-2B7, UGT2B7) and rs306104 (calmodulin-kinase 4, CaMK4) were associated with VPA responses. However, no association was found for the other SNPs. Furthermore, the polymorphism of UGT2B7 influenced the adjusted concentration (AC) in the responders rather than in the non-responders.
CONCLUSION: Two SNPs (UGT2B7 and CaMK4) were associated with VPA response, which may explain the pharmacological mechanism of VPA resistance to some extent.

PMID: 31474408 [PubMed - as supplied by publisher]

Cholesterol efflux responds to viral load and CD4 counts in HIV+ patients and is dampened in HIV exposed.

J Lipid Res. 2018 11;59(11):2108-2115

Authors: Tort O, Escribà T, Egaña-Gorroño L, de Lazzari E, Cofan M, Fernandez E, Gatell JM, Martinez E, Garcia F, Arnedo M

Abstract
Cholesterol efflux (CE) capacity has been inversely associated with atherosclerosis and may provide an insight on inflammation occurring in human immunodeficiency virus (HIV) individuals. We address this by studying CE in HIV patients at different stages of HIV disease progression. In this cross-sectional study, CE from ApoB-depleted plasma, lipids levels, viral load (VL), CD4+/CD8+ T-cells, high-sensitive C-reactive protein (hsCRP), and lipoprotein (a) were evaluated in untreated HIV-infected patients (UHIVs; n = 43), elite controllers (ECs; n = 8), HIV-exposed seronegative individuals (HESNs; n = 32), and healthy controls (HCs; n = 14). Among UHIVs, those with CD4+ <500 cells/mm3 presented the lowest significant CE, HDL cholesterol (HDL-C), and ApoAI levels. ECs showed similar HDL-C, ApoAI, and CE compared with HCs. Among UHIVs, CE positively correlated with CD4+ T-cell counts (Beta: 1.05; 95% CI: 1.02; 1.07), and for VL higher than 3.8 log, CE was inversely associated with VL (Beta: 0.70; 95% CI: 0.51; 0.95). Remarkably, HESNs presented higher CE (0.78 ± 0.14) than UHIVs (0.65 ± 0.17; P = 0.0005), but lower than HCs (0.90 ± 0.13; P = 0.009). hsCRP levels were highest in the UHIV group (0.45 ± 0.49). CE was sensitive to HIV disease progression. Low CE in HIV patients was associated with lower CD4+ T-cells and higher VL and hsCRP. CE was also lower in HESNs compared with HCs. Our results suggest that immune status secondary to HIV progression and exposure influence plasma HDL-CE capacity.

PMID: 30213800 [PubMed - indexed for MEDLINE]

Pharmacogenetics of drug dependence: polymorphisms of genes involved in GABA neurotransmission.

Neurosci Lett. 2019 Aug 28;:134463

Authors: Nudmamud-Thanoi S, Veerasakul S, Thanoi S

Abstract
GABA plays a critical role in brain reward pathways via projecting signals from the ventral tegmental area to the nucleus accumbens. Activation of the reward circuitry by abused drugs induces abnormalities of GABA neurotransmission. Recent studies have indicated the involvement of GABAergic genes in the mechanism of drug dependence and its consequences. The aim of this paper is to provide a brief review of association studies of GABA-related genes with drug dependence. Single nucleotide polymorphisms (SNPs) in genes involved in GABA neurotransmission such as GABA receptor genes (GABR, GABBR), and glutamic acid decarboxylase genes (GAD) are the focus of this review as potential risk factors for drug dependence and its consequence psychosis.

PMID: 31472163 [PubMed - as supplied by publisher]

Novel analytical methods to interpret large sequencing data from small sample sizes.

Hum Genomics. 2019 Aug 30;13(1):41

Authors: Lichou F, Orazio S, Dulucq S, Etienne G, Longy M, Hubert C, Groppi A, Monnereau A, Mahon FX, Turcq B

Abstract
BACKGROUND: Targeted therapies have greatly improved cancer patient prognosis. For instance, chronic myeloid leukemia is now well treated with imatinib, a tyrosine kinase inhibitor. Around 80% of the patients reach complete remission. However, despite its great efficiency, some patients are resistant to the drug. This heterogeneity in the response might be associated with pharmacokinetic parameters, varying between individuals because of genetic variants. To assess this issue, next-generation sequencing of large panels of genes can be performed from patient samples. However, the common problem in pharmacogenetic studies is the availability of samples, often limited. In the end, large sequencing data are obtained from small sample sizes; therefore, classical statistical analyses cannot be applied to identify interesting targets. To overcome this concern, here, we described original and underused statistical methods to analyze large sequencing data from a restricted number of samples.
RESULTS: To evaluate the relevance of our method, 48 genes involved in pharmacokinetics were sequenced by next-generation sequencing from 24 chronic myeloid leukemia patients, either sensitive or resistant to imatinib treatment. Using a graphical representation, from 708 identified polymorphisms, a reduced list of 115 candidates was obtained. Then, by analyzing each gene and the distribution of variant alleles, several candidates were highlighted such as UGT1A9, PTPN22, and ERCC5. These genes were already associated with the transport, the metabolism, and even the sensitivity to imatinib in previous studies.
CONCLUSIONS: These relevant tests are great alternatives to inferential statistics not applicable to next-generation sequencing experiments performed on small sample sizes. These approaches permit to reduce the number of targets and find good candidates for further treatment sensitivity studies.

PMID: 31470908 [PubMed - in process]

Exploring the microvascular impact of red blood cell transfusion in intensive care unit patients.

Crit Care. 2019 Aug 30;23(1):292

Authors: Hariri G, Bourcier S, Marjanovic Z, Joffre J, Lemarié J, Lavillegrand JR, Charue D, Duflot T, Bigé N, Baudel JL, Maury E, Mohty M, Guidet B, Bellien J, Blanc-Brude O, Ait-Oufella H

Abstract
BACKGROUND: Red blood cell (RBC) transfusion is a common treatment for hospitalized patients. However, the effects of RBC transfusion on microvascular function remain controversial.
METHODS: In a medical ICU in a tertiary teaching hospital, we prospectively included anemic patients requiring RBC transfusion. Skin microvascular reactivity was measured before and 30 min after RBC transfusion. Plasma was collected to analyze intravascular hemolysis and draw the lipidomic and cytokine profiles.
RESULTS: In a cohort of 59 patients, the median age was 66 [55-81] years and SAPS II was 38 [24-48]. After RBC transfusion, endothelium-dependent microvascular reactivity improved in 35 (59%) patients, but worsened in 24 others (41%). Comparing clinical and biological markers revealed that baseline blood leucokyte counts distinguished improving from worsening patients (10.3 [5.7; 19.7] vs. 4.6 [2.1; 7.3] × 109/L; p = 0.001) and correlated with variations of microvascular reactivity (r = 0.36, p = 0.005). Blood platelet count was also higher in improving patients (200 [97; 280] vs 160 [40; 199] × 103/mL, p = 0.03) but did not correlate with variations of microvascular reactivity. We observed no intravascular hemolysis (HbCO, heme, bilirubin, LDH), but recorded a significant increase in RBC microparticle levels specific to improving patients after transfusion (292 [108; 531] vs. 53 [34; 99] MP/μL; p = 0.03). The improvement in microvascular dilation was positively correlated with RBC microparticle levels (R = 0.83, p < 0.001) and conversion of arachidonic acid into vasodilating eicosanoids.
CONCLUSIONS: Patients displaying an improved microvascular reactivity after RBC transfusion had high blood leukocyte counts, increased RBC microparticle formation, and enhanced metabolism of arachidonic acid into vasodilating lipids. Our data suggested a contribution of recipient leukocytes to the vascular impact of RBC transfusion.

PMID: 31470888 [PubMed - in process]

Loss of Glycine N-Methyltransferase Associates with Angiopoietin-Like Protein 8 Expression in High Fat-Diet-Fed Mice.

Int J Mol Sci. 2019 Aug 29;20(17):

Authors: Huang JW, Chen CJ, Yen CH, Chen YA, Liu YP

Abstract
Imbalance of lipid metabolism is a main cause of metabolic syndrome leading to life-threatening metabolic diseases. Angiopoietin-like protein 8 (Angptl8) was recently identified as a liver and adipose tissue-released hormone that is one of the molecules involved in triglyceride metabolism. However, the regulatory mechanism of Angptl8 is largely unknown. A high fat diet (HFD)-fed mouse model, which showed high cholesterol, high triglyceride, and high insulin in the blood, revealed the upregulation of hepatic and plasma Angptl8 and the downregulation of hepatic glycine N-methyltransferase (GNMT). The inverse correlation of hepatic Angptl8 and GNMT expression in the livers of HFD-fed mice was also confirmed in a publicly available microarray dataset. The mechanistic study using primary hepatocytes showed that the Angptl8 expression could be induced by insulin treatment in a dose- and time-dependent manner. Inhibition of PI3K/Akt pathway by the specific inhibitors or the dominant-negative Akt blocked the insulin-induced Angptl8 expression. Moreover, knockout of GNMT promoted the Akt activation as well as the Angptl8 expression. These results suggested that GNMT might be involved in insulin-induced Angptl8 expression in HFD-mediated metabolic syndrome.

PMID: 31470507 [PubMed - in process]

Sequential analysis of myocardial gene expression with phenotypic change: Use of cross-platform concordance to strengthen biologic relevance.

PLoS One. 2019;14(8):e0221519

Authors: Toni LS, Carroll IA, Jones KL, Schwisow JA, Minobe WA, Rodriguez EM, Altman NL, Lowes BD, Gilbert EM, Buttrick PM, Kao DP, Bristow MR

Abstract
OBJECTIVES: To investigate the biologic relevance of cross-platform concordant changes in gene expression in intact human failing/hypertrophied ventricular myocardium undergoing reverse remodeling.
BACKGROUND: Information is lacking on genes and networks involved in remodeled human LVs, and in the associated investigative best practices.
METHODS: We measured mRNA expression in ventricular septal endomyocardial biopsies from 47 idiopathic dilated cardiomyopathy patients, at baseline and after 3-12 months of β-blocker treatment to effect left ventricular (LV) reverse remodeling as measured by ejection fraction (LVEF). Cross-platform gene expression change concordance was investigated in reverse remodeling Responders (R) and Nonresponders (NR) using 3 platforms (RT-qPCR, microarray, and RNA-Seq) and two cohorts (All 47 subjects (A-S) and a 12 patient "Super-Responder" (S-R) subset of A-S).
RESULTS: For 50 prespecified candidate genes, in A-S mRNA expression 2 platform concordance (CcpT), but not single platform change, was directly related to reverse remodeling, indicating CcpT has biologic significance. Candidate genes yielded a CcpT (PCR/microarray) of 62% for Responder vs. Nonresponder (R/NR) change from baseline analysis in A-S, and ranged from 38% to 100% in S-R for PCR/microarray/RNA-Seq 2 platform comparisons. Global gene CcpT measured by microarray/RNA-Seq was less than for candidate genes, in S-R R/NR 17.5% vs. 38% (P = 0.036). For S-R global gene expression changes, both cross-cohort concordance (CccT) and CcpT yielded markedly greater values for an R/NR vs. an R-only analysis (by 22 fold for CccT and 7 fold for CcpT). Pathway analysis of concordant global changes for R/NR in S-R revealed signals for downregulation of multiple phosphoinositide canonical pathways, plus expected evidence of a β1-adrenergic receptor gene network including enhanced Ca2+ signaling.
CONCLUSIONS: Two-platform concordant change in candidate gene expression is associated with LV biologic effects, and global expression concordant changes are best identified in an R/NR design that can yield novel information.

PMID: 31469842 [PubMed - in process]

Zinc finger proteins in psychiatric disorders and response to psychotropic medications.

Psychiatr Genet. 2019 Aug 28;:

Authors: Squassina A, Meloni A, Chillotti C, Pisanu C

Abstract
Zinc finger proteins are a large family of abundantly expressed small motifs that play a crucial role in a wide range of physiological and pathophysiological mechanisms. Findings published so far support an involvement of zinc fingers in psychiatric disorders. Most of the evidence has been provided for the zinc finger protein 804A (ZNF804A) gene, which has been suggested to be implicated in schizophrenia and bipolar disorder. This evidence has been corroborated by a wide range of functional studies showing that ZNF804A regulates the expression of genes involved in cell adhesion and plays a crucial role in neurite formation and maintenance of dendritic spines. On the other hand, far less is known on other zinc finger proteins and their involvement in psychiatric disorders. In this review, we discussed studies exploring the role of zinc finger proteins in schizophrenia, bipolar disorder, and major depressive disorder as well as in pharmacogenetics of psychotropic drugs.

PMID: 31469784 [PubMed - as supplied by publisher]

Pharmacogenomics of Cytochrome P450 of Nimodipine Metabolism After Aneurysmal Subarachnoid Hemorrhage.

J Neurosci Nurs. 2019 Aug 28;:

Authors: Peacock SH, James C, Turnbull MT, Cowart JB, Reid JM, Freeman WD

Abstract
INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH) is a type of stroke that is life threatening with high rates of mortality, and many survivors are left with permanent neurologic deficits. Nimodipine is the treatment of choice for aSAH with the goal of reduction of delayed cerebral ischemia. It is the only evidence-based medication that has been shown to have improved outcomes for delayed cerebral ischemia; therefore, it is important for neuroscience nurses to be knowledgeable of the pharmacology and pharmacogenomics properties of this medication, including cytochrome P450 (CYP450) enzymes.
METHODS AND RESULTS: This article reviews the CYP450 enzyme system including a review of the pharmacotherapy and pharmacogenomics of nimodipine for patients with aSAH illustrated with case study of a patient with abnormal drug metabolism.
CONCLUSION: CYP450 enzymes can be inhibited or induced by multiple medications resulting in clinically significant differences in drug metabolism. Food and Drug Administration-approved medication nimodipine is the only medication shown to improve outcomes in patients with aSAH. Hence, it is important to have awareness of potential drug-to-drug interactions and pharmacogenomics of nimodipine when caring for critically ill patients with aSAH.

PMID: 31469704 [PubMed - as supplied by publisher]

Effects of age, sex, race/ethnicity, and allergy status in obesity-related pediatric asthma.

Pediatr Pulmonol. 2019 Aug 30;:

Authors: Lang JE, Bunnell HT, Lima JJ, Hossain MJ, Wysocki T, Bacharier L, Dempsey A, Ulrich L, Test MR, Forrest CB

Abstract
RATIONALE: Obesity in children increases the risk for new asthma. How age, sex, race/ethnicity, and allergy status affect the relationship between obesity and asthma is unclear. This study describes the relationship between high body mass index (BMI) and incident asthma.
METHODS: We conducted a retrospective cohort study to compare asthma incidence among normal weight, overweight, and obese 2 to 6, 7 to 11, and 12 to 17 year olds to define the effects of sex, race/ethnicity, and allergy status. Weight status was determined at baseline and asthma incidence was defined as ≥2 asthma encounters and ≥1 asthma prescriptions. We used multivariable Poisson regression to estimate adjusted incident asthma rates and risk ratios.
RESULTS: Data from 192 843 2 to 6 year olds, 157 284 7 to 11 year olds, and 157 369 12 to 17 year olds were included. The relative risks (95% confidence interval [CI]) of new asthma among obese children in 2 to 6 year olds, 7 to 11 year olds, and 12 to 17 year olds were 1.25 (1.15, 1.37), 1.49 (1.32, 1.69) and 1.40 (1.21, 1.63), respectively. Among children with underlying allergic rhinitis, obesity did not increase the risk of new asthma. In children without allergic rhinitis, the risk for obesity-related asthma was highest in 7 to 11 year olds (risk ratio = 1.50 95% CI, 1.33, 1.60). Before age 12, females had a higher risk for obesity-related asthma; but after age 12, obese males had a higher asthma risk (interaction P-value < .05).
CONCLUSION: Obesity is a major preventable risk factor for pediatric asthma that appears to vary along the pediatric age continuum and depends on sex, race/ethnicity and atopy status.

PMID: 31469258 [PubMed - as supplied by publisher]

Antinociceptive Activity of Petroleum Ether Fraction of Clinacanthus nutans Leaves Methanolic Extract: Roles of Nonopioid Pain Modulatory Systems and Potassium Channels.

Biomed Res Int. 2019;2019:6593125

Authors: Zakaria ZA, Abdul Rahim MH, Roosli RAJ, Mohd Sani MH, Marmaya NH, Omar MH, Teh LK, Salleh MZ

Abstract
Methanolic extract of Clinacanthus nutans Lindau leaves (MECN) has been reported to exert antinociceptive activity. The present study aimed to elucidate the possible antinociceptive mechanisms of a lipid-soluble fraction of MECN, which was obtained after sequential extraction in petroleum ether. The petroleum ether fraction of C. nutans (PECN), administered orally to mice, was (i) subjected to capsaicin-, glutamate-, phorbol 12-myristate 13-acetate-, bradykinin-induced nociception model; (ii) prechallenged (intraperitoneal (i.p.)) with 0.15 mg/kg yohimbine, 1 mg/kg pindolol, 3 mg/kg caffeine, 0.2 mg/kg haloperidol, or 10 mg/kg atropine, which were the respective antagonist of α 2-adrenergic, β-adrenergic, adenosinergic, dopaminergic, or muscarinic receptors; and (iii) prechallenged (i.p.) with 10 mg/kg glibenclamide, 0.04 mg/kg apamin, 0.02 mg/kg charybdotoxin, or 4 mg/kg tetraethylammonium chloride, which were the respective inhibitor of ATP sensitive-, small conductance Ca2+-activated-, large conductance Ca2+-activated-, or nonselective voltage-activated-K+ channel. Results obtained demonstrated that PECN (100, 250, and 500 mg/kg) significantly (P<0.05) inhibited all models of nociception described earlier. The antinociceptive activity of 500 mg/kg PECN was significantly (P<0.05) attenuated when prechallenged with all antagonists or K+ channel blockers. However, only pretreatment with apamin and charybdotoxin caused full inhibition of PECN-induced antinociception. The rest of the K+ channel blockers and all antagonists caused only partial inhibition of PECN antinociception, respectively. Analyses on PECN's phytoconstituents revealed the presence of antinociceptive-bearing bioactive compounds of volatile (i.e., derivatives of γ-tocopherol, α-tocopherol, and lupeol) and nonvolatile (i.e., cinnamic acid) nature. In conclusion, PECN exerts a non-opioid-mediated antinociceptive activity involving mainly activation of adenosinergic and cholinergic receptors or small- and large-conductance Ca2+-activated-K+ channels.

PMID: 31467905 [PubMed - in process]

Association of caspase 8 polymorphisms -652 6N InsDel and Asp302His with progression-free survival and tumor infiltrating lymphocytes in early breast cancer.

Sci Rep. 2019 Aug 29;9(1):12594

Authors: Kuhlmann JD, Bachmann HS, Link T, Wimberger P, Kröber E, Thomssen C, Mallé B, Bethmann D, Vetter M, Kantelhardt EJ

Abstract
The caspase 8 variants CASP8 -652 6N InsDel and Asp302His have previously been identified to promote survival of T-lymphocytes and to indicate reduced breast cancer susceptibility. Besides some preliminary findings, prognostic relevance of these polymorphisms in patients with existing breast cancer has not been investigated. Considering an immunomodulatory role of these polymorphisms, we genotyped 785 early breast cancer patients and correlated caspase 8 variants with disease-free survival (DFS) and the presence of tumor infiltrating lymphocytes (TILs). Early breast cancer specimens were collected as part of the multicenter prospective PiA study. Genotyping was performed by pyrosequencing, TILs status was assessed using hematoxylin & eosin staining. The CASP8 -652Del variant was significantly associated with improved DFS in an allele-dose dependent manner (p = 0.027). Homozygosity for the -652Del variant was an independent predictor for improved DFS (HR = 0.36; 95% CI = 0.174-0.726; p = 0.005). In patients with the 302HisHis genotype, there was no event of recurrence during observation time. Combined analysis of diplotypes revealed an influence of both polymorphisms on DFS (p = 0.029). Interestingly, patients with the 302HisHis variant among the unstratified patient cohort (and among the luminal-like subtype, by trend) had tumors with lower lymphocyte infiltration (p = 0.025). We propose a prognostically favorable role of the -652Del and the 302His variant in primary breast cancer and suggest for the first time an association between polymorphisms in apoptosis-related genes and the immunophenotype in breast cancer. Our findings encourage further investigation of caspase 8 polymorphisms as biomarkers for prognostic and immunotherapeutic considerations.

PMID: 31467295 [PubMed - in process]

CSL controls telomere maintenance and genome stability in human dermal fibroblasts.

Nat Commun. 2019 Aug 29;10(1):3884

Authors: Bottoni G, Katarkar A, Tassone B, Ghosh S, Clocchiatti A, Goruppi S, Bordignon P, Jafari P, Tordini F, Lunardi T, Hoetzenecker W, Neel V, Lingner J, Paolo Dotto G

Abstract
Genomic instability is a hallmark of cancer. Whether it also occurs in Cancer Associated Fibroblasts (CAFs) remains to be carefully investigated. Loss of CSL/RBP-Jκ, the effector of canonical NOTCH signaling with intrinsic transcription repressive function, causes conversion of dermal fibroblasts into CAFs. Here, we find that CSL down-modulation triggers DNA damage, telomere loss and chromosome end fusions that also occur in skin Squamous Cell Carcinoma (SCC)-associated CAFs, in which CSL is decreased. Separately from its role in transcription, we show that CSL is part of a multiprotein telomere protective complex, binding directly and with high affinity to telomeric DNA as well as to UPF1 and Ku70/Ku80 proteins and being required for their telomere association. Taken together, the findings point to a central role of CSL in telomere homeostasis with important implications for genomic instability of cancer stromal cells and beyond.

PMID: 31467287 [PubMed - in process]

Long Non-coding RNAs in Prostate Cancer: Functional Roles and Clinical Implications.

Cancer Lett. 2019 Aug 26;:

Authors: Xu Y, Deng J, Wang G, Zhu Y

Abstract
Long noncoding RNAs (lncRNAs) are defined as RNA transcripts longer than 200 nucleotides that do not encode proteins. LncRNAs have been documented to exhibit aberrant expression in various types of cancer, including prostate cancer. Currently, screening for prostate cancer results in overdiagnosis. The consequent overtreatment of patients with indolent disease in the clinic is due to the lack of appropriately sensitive and specific biomarkers. Thus, the identification of lncRNAs as novel biomarkers and therapeutic targets for prostate cancer is promising. In the present review, we attempt to summarize the current knowledge of lncRNA expression patterns and mechanisms in prostate cancer. In particular, we focus on lncRNAs regulated by the androgen receptor and the specific molecular mechanism of lncRNAs in prostate cancer to provide a potential clinical therapeutic strategy for prostate cancer.

PMID: 31465841 [PubMed - as supplied by publisher]

A GENETIC VARIANT IN THE BCL2 GENE ASSOCIATES WITH ADALIMUMAB RESPONSE IN HIDRADENITIS SUPPURATIVA CLINICAL TRIALS AND REGULATES EXPRESSION OF BCL2.

J Invest Dermatol. 2019 Aug 26;:

Authors: Liu M, Degner J, Georgantas RW, Nader A, Mostafa NM, Teixeira HD, Williams DA, Kirsner RS, Nichols AJ, Davis JW, Waring JF

Abstract
Hidradenitis Suppurativa (HS) is a chronic skin disease with strong genetic component and prevalance from 0.5% to 4%. Adalimumab is the only treatment approved by either the European Medicines Agency (EMA) or the US Food or Drug Administration (FDA) for the management of moderate-to-severe HS. To identify genetic variants associated with adalimumab response, we performed a genome-wide association study (GWAS) from the largest two Phase 3 HS clinical trials (PIONEER I and II) to date. Through direct genotyping and imputation, we tested almost 7 million genetic variants with MAF > 5% and identified one single linkage disequilibrium (LD) block, located in the intron of the BCL2 gene, which reached genome-wide significance (lead single-nucleotide polymorphism [SNP] rs 59532114; p=2.35E-08). Bioinformatic analysis and functional genomics experiments suggested correlation of the most strongly associated SNP minor allele with increased BCL2 gene and protein expression in hair follicle tissues. In reciprocal knockdown experiments, we found that BCL2 is down-regulated by TNF inhibition. These results highlight to our knowledge previously unreported pathway that involves BCL2 in response to adalimumab. Further work is required to determine how this pathway influences adalimumab effectiveness in patients suffering with HS.

PMID: 31465739 [PubMed - as supplied by publisher]

Zinc finger proteins in psychiatric disorders and response to psychotropic medications.

Psychiatr Genet. 2019 Oct;29(5):132-141

Authors: Squassina A, Meloni A, Chillotti C, Pisanu C

Abstract
Zinc finger proteins are a large family of abundantly expressed small motifs that play a crucial role in a wide range of physiological and pathophysiological mechanisms. Findings published so far support an involvement of zinc fingers in psychiatric disorders. Most of the evidence has been provided for the zinc finger protein 804A (ZNF804A) gene, which has been suggested to be implicated in schizophrenia and bipolar disorder. This evidence has been corroborated by a wide range of functional studies showing that ZNF804A regulates the expression of genes involved in cell adhesion and plays a crucial role in neurite formation and maintenance of dendritic spines. On the other hand, far less is known on other zinc finger proteins and their involvement in psychiatric disorders. In this review, we discussed studies exploring the role of zinc finger proteins in schizophrenia, bipolar disorder, and major depressive disorder as well as in pharmacogenetics of psychotropic drugs.

PMID: 31464994 [PubMed - in process]

Discovery of HSPG2 (Perlecan) as a Therapeutic Target in Triple Negative Breast Cancer.

Sci Rep. 2019 Aug 28;9(1):12492

Authors: Kalscheuer S, Khanna V, Kim H, Li S, Sachdev D, DeCarlo A, Yang D, Panyam J

Abstract
In recent years, there have been significant advances in the treatment of breast cancer resulting in remarkably high survival rates. However, treatment options for metastatic triple negative breast cancer (TNBC) are quite limited due to a lack of identifiable, unique markers. Using a phage display-based whole cell biopanning procedure, we developed two human antibodies that bind to tumor cells with a metastatic TNBC phenotype. Our studies further identified domain 1 of HSPG2 (perlecan) protein as the cognate cell surface antigen bound by the antibody. Immunohistochemistry studies utilizing patient tissue samples revealed significant cell surface expression of HSPG2 in both primary tumors and metastatic lesions. Further, higher HSPG2 expression correlated with poor survival in TNBC. The affinity-matured antibody inhibited the growth of triple negative MDA-MB-231 tumors to a greater extent in nude mice than in NSG mice, pointing to the potential role of natural killer cell-mediated antibody-dependent cell cytotoxicity. This mechanism of action was confirmed through in vitro assays using mouse splenocytes and human peripheral blood mononuclear cells (PBMCs). These results suggest that HSPG2 is a promising target in metastatic TNBC and HSPG2-targeted antibodies could represent a potentially novel class of targeted therapeutics for TNBC.

PMID: 31462656 [PubMed - in process]

QT length during methadone maintenance treatment: Gene x dose interaction.

Fundam Clin Pharmacol. 2019 Feb;33(1):94-95

Authors: Ramoz N

PMID: 30663143 [PubMed - indexed for MEDLINE]

Anterior Cingulate Cortex Glutamatergic Metabolites and Mood Stabilizers in Euthymic Bipolar I Disorder Patients: A Proton Magnetic Resonance Spectroscopy Study.

Biol Psychiatry Cogn Neurosci Neuroimaging. 2018 12;3(12):985-991

Authors: Soeiro-de-Souza MG, Otaduy MCG, Machado-Vieira R, Moreno RA, Nery FG, Leite C, Lafer B

Abstract
BACKGROUND: Bipolar disorder is a chronic and recurrent illness characterized by depressive and manic episodes. Proton magnetic resonance spectroscopy (1H-MRS) studies have demonstrated glutamate (Glu) system abnormalities in BD, but it is unclear how Glu varies among mood states and how medications modulate it. The objective of this study was to investigate the influence of mood stabilizers on anterior cingulate cortex Glu levels using 1H-MRS during euthymia.
METHODS: One hundred twenty-eight bipolar I disorder (BDI) euthymic subjects and 80 healthy control subjects underwent 3T brain 1H-MRS imaging examination including acquisition of an anterior cingulate cortex single voxel (8 cm3) 1H-MRS, based on a point resolved spectroscopy (PRESS) sequence with an echo time of 80 ms and a repetition time of 1500 ms (BIPUSP MRS study). The Glu system was described by measuring Glu and the sum of Glu and glutamine (Glx) using creatine (Cre) as a reference.
RESULTS: Euthymic BDI subjects presented with higher ratios of Glu/Cre and Glx/Cre compared to healthy control subjects. Glu/Cre ratios were lower among patients using anticonvulsants, while Glx/Cre did not differ between the two groups. Lithium, antipsychotics, and antidepressants did not influence Glu/Cre or Glx/Cre.
CONCLUSIONS: We reported Glu/Cre and Glx abnormalities in the largest sample of euthymic BDI patients studied by 1H-MRS to date. Our data indicate that both Glu/Cre and Glx/Cre are elevated in BDI during euthymia regardless of medication effects, reinforcing the hypothesis of glutamatergic abnormalities in BD. Furthermore, we found an effect of anticonvulsants on Glu/Cre during euthymia, which might indicate a mechanism of mood stabilization in BD.

PMID: 29789269 [PubMed - indexed for MEDLINE]

Pharmacology Focus: Pharmacogenomics: Gene-directed Prescribing in the Era of Personalized Medicine.

S D Med. 2019 Jun;72(6):280-281

Authors: Baye J, Limberg C, Wall T

PMID: 31461237 [PubMed - in process]