Downregulation of DANCR acts as a potential biomarker for papillary thyroid cancer diagnosis.

Biosci Rep. 2019 Mar 25;:

Authors: Zhang K, Lv J, Peng XW, Liu JQ, Li CL, Li J, Yin NW, Li H, Li Z

Abstract
Long non-coding RNAs (lncRNAs) have been reported dysregulated and play crucial role in the progression of cancer. LncRNA DANCR has recently been revealed that involved in tumorigenesis of numerous types of cancer, including osteosarcoma, gastric cancer, breast cancer, hepatocellular carcinoma and colorectal cancer. However, the expression profiles and biological relevance of DANCR in papillary thyroid cancer (PTC) have not yet been reported. In the present study, the expression level of DANCR in PTC tissues and adjacent normal tissues was detected by reverse transcription-quantitative polymerase chain reaction in papillary thyroid cancer patients, then we analyzed the association with clinical pathological characteristics of patients and DANCR expressions. These results demonstrated that the expression of DANCR was notably decreased in tumor tissues in comparison with adjacent normal tissues (P<0.001). Furthermore, the present study found DANCR expression level was correlated to T grade (P<0.01) and TNM stage (P=0.017). The present study demonstrated that DANCR was associated with PTC aggressive clinical features and may serve as a diagnostic biomarker for detecting PTC patients.

PMID: 30910839 [PubMed - as supplied by publisher]

Quantification of Panax notoginseng saponins metabolites in rat plasma with in vivo gut microbiota-mediated biotransformation by HPLC-MS/MS.

Chin J Nat Med. 2019 Mar;17(3):231-240

Authors: Guo YP, Chen MY, Shao L, Zhang W, Rao T, Zhou HH, Huang WH

Abstract
Panax notoginseng saponins (PNS) are the major components of Panax notoginseng, with multiple pharmacological activities but poor oral bioavailability. PNS could be metabolized by gut microbiota in vitro, while the exact role of gut microbiota of PNS metabolism in vivo remains poorly understood. In this study, pseudo germ-free rat models were constructed by using broad-spectrum antibiotics to validate the gut microbiota-mediated transformation of PNS in vivo. Moreover, a high performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) was developed for quantitative analysis of four metabolites of PNS, including ginsenoside F1 (GF1), ginsenoside Rh2 (GRh2), ginsenoside compound K (GCK) and protopanaxatriol (PPT). The results showed that the four metabolites could be detected in the control rat plasma, while they could not be determined in pseudo germ-free rat plasma. The results implied that PNS could not be biotransformed effectively when gut microbiota was disrupted. In conclusion, gut microbiota plays an important role in biotransformation of PNS into metabolites in vivo.

PMID: 30910060 [PubMed - in process]

Neuropsychiatric manifestations among HIV-1 infected African patients receiving efavirenz-based cART with or without tuberculosis treatment containing rifampicin.

Eur J Clin Pharmacol. 2018 Nov;74(11):1405-1415

Authors: Mugusi S, Ngaimisi E, Janabi M, Mugusi F, Minzi O, Aris E, Bakari M, Bertilsson L, Burhenne J, Sandstrom E, Aklillu E

Abstract
PURPOSE: Efavirenz-based combination antiretroviral therapy (cART) is associated with neuropsychiatric adverse events. We investigated the time to onset, duration, clinical implications, impact of pharmacogenetic variations, and anti-tuberculosis co-treatment on efavirenz-associated neuropsychiatric manifestations.
METHODS: Prospective cohort study of cART naïve HIV patients with or without tuberculosis (HIV-TB) co-infection treated with efavirenz-based cART. Rifampicin-based anti-tuberculosis therapy was initiated 4 weeks prior to efavirenz-based cART in HIV-TB patients. Data on demographic, clinical, laboratory, and a 29-item questionnaire on neuropsychiatric manifestations were collected for 16 weeks after cART initiation. Genotyping for CYP2B6, CYP3A5, SLCO1B1, and ABCB1 and quantification of efavirenz plasma concentration were done on the 4th and 16th week.
RESULTS: Data from 458 patients (243 HIV-only and 215 HIV-TB) were analyzed. Overall incidence of neuropsychiatric manifestations was 57.6% being higher in HIV-only (66.7%) compared to HIV-TB patients (47.4%) (p < 0.01). HIV-only patients were more symptomatic, with proportionately higher grades of manifestations compared to HIV-TB patients. Median time to manifestations was 1 week after cART initiation in HIV-only and 6 weeks after anti-TB (i.e., 2 weeks after cART initiation) in HIV-TB patients. HIV-only patients had significantly higher efavirenz plasma concentrations at 4 weeks after cART compared to HIV-TB patients. No association of sex or genotype was seen in relation to neuropsychiatric manifestations. Risk for neuropsychiatric manifestations was three times more in HIV-only patients compared to HIV-TB (p < 0.01).
CONCLUSIONS: Incidence of neuropsychiatric manifestations during early initiation of efavirenz-based cART is high in Tanzanian HIV patients. Risk of neuropsychiatric manifestations is lower in HIV patients co-treated with rifampicin containing anti-TB compared to those treated with efavirenz-based cART only.

PMID: 30003275 [PubMed - indexed for MEDLINE]

Epidemiology of Childhood Hyperthyroidism in France: A Nationwide Population-Based Study.

J Clin Endocrinol Metab. 2018 08 01;103(8):2980-2987

Authors: Simon M, Rigou A, Le Moal J, Zeghnoun A, Le Tertre A, De Crouy-Chanel P, Kaguelidou F, Leger J

Abstract
Context: Hyperthyroidism affects all age groups, but epidemiological data for children are scarce.
Objective: To perform a nationwide epidemiological survey of hyperthyroidism in children and adolescents.
Design: A cross-sectional descriptive study.
Setting: Identification of entries corresponding to reimbursements for antithyroid drugs in the French national insurance database.
Participants: All cases of childhood hyperthyroidism (6 months to 17 years of age) in 2015.
Main Outcome Measures: National incidence rate estimated with a nonlinear Poisson model and spatial distribution of cases.
Results: A total of 670 cases of childhood hyperthyroidism were identified. Twenty patients (3%) had associated autoimmune or genetic disease, with type 1 diabetes and Down syndrome the most frequent. The annual incidence for 2015 was 4.58/100,000 person-years (95% CI 3.00 to 6.99/100,000). Incidence increased with age, in both sexes. This increase accelerated after the age of 8 in girls and 10 in boys and was stronger in girls. About 10% of patients were affected before the age of 5 years (sex ratio 1.43). There was an interaction between age and sex, the effect of being female increasing with age: girls were 3.2 times more likely to be affected than boys in the 10 to 14 years age group and 5.7 times more likely to be affected in the 15 to 17 years age group. No conclusions about spatial pattern emerged.
Conclusion: These findings shed light on the incidence of hyperthyroidism and the impact of sex on this incidence during childhood and adolescence. The observed incidence was higher than expected from the results published for earlier studies in Northern European countries.

PMID: 29846622 [PubMed - indexed for MEDLINE]

Relevance of CYP2B6 and CYP2D6 genotypes to methadone pharmacokinetics and response in the OPAL study.

Br J Clin Pharmacol. 2019 Mar 25;:

Authors: Victorri-Vigneau C, Verstuyft C, Bouquié R, Laforgue EJ, Hardouin JB, Leboucher J, Le Geay B, Dano C, Challet-Bouju G, Grall-Bronnec M

Abstract
Our study aimed to evaluate the impacts of the CYP2B6 G516T and CYP2D6 genetic polymorphisms on pharmacokinetic and clinical parameters in patients receiving methadone maintenance treatment. OPAL was a clinical survey of sociodemographic characteristics, history and consequences of pathology, response to treatment, current addictive comorbidities. A subgroup of 72 methadone patients was genotyped. When comparing the three CYP2B6 genotype groups, both methadone (R) and (S)-enantiomers concentration/dose were different (p=0.029, p=0.0019). The CYP2D6 phenotypes seemed to be not relevant with regards to methadone levels. By multivariate analysis, neither CYP2B6 genotype nor the CYP2D6 phenotype explained (i) the (R)-methadone concentration/dose values (p=0.92; p=0.86), (ii) the (S)-methadone concentration/dose values (p=0.052; p=0.95), nevertheless there was a difference between TT group and GT and GG groups (p=0.019), (iii) the opiate cessation (p=0.12; p=0.90). Genotyping of the CYP2B6 G516T could be an interesting tool to explore methadone intervariability.

PMID: 30907440 [PubMed - as supplied by publisher]

ABCB1 2677G>T single nucleotide polymorphism influences warfarin dose requirement for warfarin maintenance therapy.

Br J Biomed Sci. 2019 Mar 25;

Authors: Gopisankar MG, Hemachandren M, Surendiran A

Abstract
This work represents an advance in biomedical science because it shows, in a singlecentre study of 210 patients, an association between ABCB1 2677 G>T genetic polymorphism and the maintenance dose requirement of warfarin for patients who have achieved a stable INR. Hence incorporation of this polymorphism to algorithms for dose prediction of warfarin may improve the accuracy of dose prediction.

PMID: 30907254 [PubMed - as supplied by publisher]

Genetic implications in the pathogenesis of rheumatoid arthritis; an updated review.

Gene. 2019 Mar 20;:

Authors: Karami J, Aslani S, Jamshidi A, Garshasbi M, Mahmoudi M

Abstract
Three important factors, including genetics, environment factors and autoimmunity play a role in the pathogenesis of rheumatoid arthritis (RA). The heritability of RA has been accounted to be 50-60%, while the HLA involvement in heritability of the disease has been accounted to be 10-40%. It has been documented that shared epitope (SE) alleles, such as HLA-DRB1*01 and DRB1*04, some HLA alleles like HLA-DRB1*13 and DRB1*15 are connected to RA susceptibility. An advanced classification of SE categorizes SE alleles into four main groups namely, S1, S2, S3D, and S3P. The S2 and S3P groups have been linked to susceptibility of seropositive RA. Various genome-wide association studies (GWAS) have discovered many susceptibility loci implicated in pathogenesis of RA. Some of the important single nucleotide polymorphisms (SNPs) linked to RA are TRAF1, STAT4, CTLA4, IRF5, CCR6, PTPN22, IL23R, and PADI4. HLA and non-HLA genes may discriminate anti-cyclic citrullinated peptide (anti-CCP) antibody-positive and anti-CCP-negative RA groups. Furthermore, risk of the disease has also been linked to environmental agents, mainly cigarette smoking. Pharmacogenomics has also confirmed SNPs or genetic patterns that might be linked to drugs responses. Different aspects of genetic involvement in the pathogenesis, etiology, and RA complications are reviewed in this article.

PMID: 30904715 [PubMed - as supplied by publisher]

Population-scale genomics-Enabling precision public health.

Adv Genet. 2019;103:119-161

Authors: Sivadas A, Scaria V

Abstract
The current excitement for affordable genomics technologies and national precision medicine initiatives marks a turning point in worldwide healthcare practices. The last decade of global population sequencing efforts has defined the enormous extent of genetic variation in the human population resulting in insights into differential disease burden and response to therapy within and between populations. Population-scale pharmacogenomics helps to provide insights into the choice of optimal therapies and an opportunity to estimate, predict and minimize adverse events. Such an approach can potentially empower countries to formulate national selection and dosing policies for therapeutic agents thereby promoting public health with precision. We review the breadth and depth of worldwide population-scale sequencing efforts and its implications for the implementation of clinical pharmacogenetics toward making precision medicine a reality.

PMID: 30904093 [PubMed - in process]

Use of a Bile Salt Export Pump Knockdown Rat Susceptibility Model to Interrogate Mechanism of Drug Induced Liver Toxicity.

Toxicol Sci. 2019 Mar 23;:

Authors: Li Y, Evers R, Hafey MJ, Cheon K, Duong H, Lynch D, LaFranco-Scheuch L, Pacchione S, Tamburino A, Tanis K, Geddes K, Holder D, Rena Zhang N, Kang W, Gonzalez RJ, Galijatovic-Idrizbegovic A, Pearson K, Lebron J, Glaab WE, Sistare FD

Abstract
Inhibition of the Bile Salt Export Pump (BSEP) may be associated with clinical drug-induced liver injury, but is poorly predicted by preclinical animal models. Here we present the development of a novel rat model using siRNA knockdown (KD) of Bsep that displayed differentially enhanced hepatotoxicity to 8 Bsep inhibitors and not to 3 Bsep non-inhibitors when administered at maximally tolerated doses for 7 days. Bsep KD alone resulted in 3- and 4.5-fold increases in liver and plasma levels, respectively, of the sum of the 3 most prevalent taurine conjugated bile acids (T3-BA), approximately 90% decrease in plasma and liver glycocholic acid, and a distinct bile acid regulating gene expression pattern, without resulting in hepatotoxicity. Among the Bsep inhibitors, only asunaprevir and TAK-875 resulted in serum transaminase and total bilirubin increases associated with increases in plasma T3-BA that were enhanced by Bsep KD. Benzbromarone, lopinavir, and simeprevir caused smaller increases in plasma T3-BA, but did not result in hepatotoxicity in Bsep KD rats. Bosentan, cyclosporine A, and ritonavir, however, showed no enhancement of T3-BA in plasma in Bsep KD rats, as well as Bsep non-inhibitors acetaminophen, MK-0974, or clarithromycin. T3-BA findings were further strengthened through monitoring TCA-d4 converted from cholic acid-d4 overcoming inter-animal variability in endogenous bile acids. Bsep KD also altered liver and/or plasma levels of asunaprevir, TAK-875, TAK-875 acylglucuronide, benzbromarone, and bosentan. The Bsep KD rat model has revealed differences in the effects on bile acid homeostasis among Bsep inhibitors that can best be monitored using measures of T3-BA and TCA-d4 in plasma. However, the phenotype caused by Bsep inhibition is complex due to the involvement of several compensatory mechanisms.

PMID: 30903168 [PubMed - as supplied by publisher]

Current Progress in Pharmacogenetics of Second-Line Antidiabetic Medications: Towards Precision Medicine for Type 2 Diabetes.

J Clin Med. 2019 Mar 21;8(3):

Authors: Heo CU, Choi CI

Abstract
Precision medicine is a scientific and medical practice for personalized therapy based on patients' individual genetic, environmental, and lifestyle characteristics. Pharmacogenetics and pharmacogenomics are also rapidly developing and expanding as a key element of precision medicine, in which the association between individual genetic variabilities and drug disposition and therapeutic responses are investigated. Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by hyperglycemia mainly associated with insulin resistance, with the risk of clinically important cardiovascular, neurological, and renal complications. The latest consensus report from the American Diabetes Association and European Association for the Study of Diabetes (ADA-EASD) on the management of T2D recommends preferential use of glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and some dipeptidyl peptidase-4 (DPP-4) inhibitors after initial metformin monotherapy for diabetic patients with established atherosclerotic cardiovascular or chronic kidney disease, and with risk of hypoglycemia or body weight-related problems. In this review article, we summarized current progress on pharmacogenetics of newer second-line antidiabetic medications in clinical practices and discussed their therapeutic implications for precision medicine in T2D management. Several biomarkers associated with drug responses have been identified from extensive clinical pharmacogenetic studies, and functional variations in these genes have been shown to significantly affect drug-related glycemic control, adverse reactions, and risk of diabetic complications. More comprehensive pharmacogenetic research in various clinical settings will clarify the therapeutic implications of these genes, which may be useful tools for precision medicine in the treatment and prevention of T2D and its complications.

PMID: 30901912 [PubMed]

Limited Sensitivity of Circulating Tumor DNA Detection by Droplet Digital PCR in Non-Metastatic Operable Gastric Cancer Patients.

Cancers (Basel). 2019 Mar 21;11(3):

Authors: Cabel L, Decraene C, Bieche I, Pierga JY, Bennamoun M, Fuks D, Ferraz JM, Lefevre M, Baulande S, Bernard V, Vacher S, Mariani P, Proudhon C, Bidard FC, Louvet C

Abstract
This study was designed to monitor circulating tumor DNA (ctDNA) levels during perioperative chemotherapy in patients with non-metastatic gastric adenocarcinoma. Plasma samples were prospectively collected in patients undergoing perioperative chemotherapy for non-metastatic gastric adenocarcinoma (excluding T1N0) prior to the initiation of perioperative chemotherapy, before and after surgery (NCT02220556). In each patient, mutations retrieved by targeted next-generation sequencing (NGS) on tumor samples were then tracked in circulating cell-free DNA from 4 mL of plasma by droplet digital PCR. Thirty-two patients with a diagnosis of non-metastatic gastric adenocarcinoma were included. A trackable mutation was identified in the tumor in 20 patients, seven of whom experienced relapse during follow-up. ctDNA was detectable in four patients (N = 4/19, sensitivity: 21%; 95% confidence interval CI = 8.5⁻43%, no baseline plasma sample was available for one patient), with a median allelic frequency (MAF) of 1.6% (range: 0.8⁻2.3%). No patient with available plasma samples (N = 0/18) had detectable ctDNA levels before surgery. After surgery, one of the 13 patients with available plasma samples had a detectable ctDNA level with a low allelic frequency (0.7%); this patient experienced a very short-term distant relapse only 3 months after surgery. No ctDNA was detected after surgery in the other four patients with available plasma samples who experienced a later relapse (median = 14.4, range: 9.3⁻26 months). ctDNA monitoring during preoperative chemotherapy and after surgery does not appear to be a useful tool in clinical practice for non-metastatic gastric cancer to predict the efficacy of chemotherapy and subsequent relapse, essentially due to the poor sensitivity of ctDNA detection.

PMID: 30901876 [PubMed]

Liraglutide Exerts an Anti-Inflammatory Action in Obese Patients with Type 2 Diabetes.

Rom J Intern Med. 2019 Jan 01;:

Authors: Kaidashev I, Savchenko LG, Digtiar NI, Selikhova LG, Kaidasheva EI, Shlykova OA, Vesnina LE

Abstract
INTRODUCTION: Liraglutide (L) is the analogue of human glucagon-like peptide 1 which stimulates glucose-dependent insulin secretion and can modify a level of inflammatory biomarkers. L can influence NF-kB inflammatory cascade, but the mechanisms of anti-inflammatory activities of L remain to be determined. In animal models L influenced an activity of Sirtuin 1(SIRT1). Moreover, recent evidences strongly suggest that SIRT1 up-regulation may serve as a potent therapeutic approach against development and progression of diabetic complications . The aim of this study was to investigate L effects directed on pro-inflammatory NF-kB pathway and expression of SIRT1 in obese patients with type 2 diabetes mellitus (DM).
MATERIALS AND METHODS: 15 obese patients with type 2 diabetes were studied, all using metformin (1-2 g/day) and sulfonylurea (glimiperide). All patients received L 1.2 mg daily add-on to stable therapy for 6 weeks. Blood samples were collected before, 6 weeks after start of treatment and after an overnight fast 6 weeks after stopping L, mononuclear cells (MNC) were isolated. The mRNA expression of TNF-α, TLR2, TLR4, NOD1, IL-2 and SIRT1 were measured in MNC by RT-PCR. Ceruloplasmin concentration was measured in plasma by photometric method.
RESULTS: In this add-on pilot clinical investigation we received new data that L can inhibit proinflammatory NF-kB pathway by increased SIRT1 expression in obese patients with type 2 DM improving metabolic profile. The mRNA expression in MNC of TNF-α, IkB, TLR2, TLR4, and plasma ceruloplasmin fell after 6 weeks of L. Expressions of IL-2 and NOD-1 were stable. There was a significant increase of SIRT1 mRNA expression. The mRNA expression in MNC of TNF-α, IkB, TLR2, TLR4, NOD1, SIRT1 and ceruloplasmin concentrations didn't reverse to baseline levels after 6 weeks stopping of L treatment. IL-2 expression decreased in comparison with basic level.
CONCLUSIONS: L has a potent anti-inflammatory effect as do GLP-1 agonists due to inhibition of NF-kB pathways and up-regulate SIRT1 expression, down-regulating pro-inflammatory factors including cytokines (TNF-α), extra- and intracellular receptors (TLR2, TLR4), and inflammation markers such as ceruloplasmin. Long lasting effects of L can be mediated by epigenetic regulation of NF-kB pathway by SIRT-1.

PMID: 30901315 [PubMed - as supplied by publisher]

Commercial Pharmacogenetic Tests in Psychiatry: Do they Facilitate the Implementation of Pharmacogenetic Dosing Guidelines?

Pharmacopsychiatry. 2019 Mar 21;:

Authors: Fan M, Bousman CA

Abstract
INTRODUCTION: Expert groups have created dosing guidelines to facilitate the implementation of pharmacogenetic knowledge into clinical practice and commercial pharmacogenetic tests are becoming increasingly accessible. However, the extent to which these commercial tests facilitate the implementation of dosing guidelines is not clear.
METHODS: Gene-drug pairs included on 22 commercial pharmacogenetic test panels were extracted and cross-referenced with the 74 gene-drug pairs with dosing guidelines in the Pharmacogenetics Knowledgebase, with particular attention given to the 28 gene-drug pairs relevant to psychiatry.
RESULTS: On average, 70% of the 28 gene-drug pairs most relevant to psychiatry were covered by the examined tests. Six gene-drug pairs (CYP2D6-venlafaxine, CYP2D6-paroxetine, CYP2D6-amitriptyline, CYP2C19-sertraline, CYP2C19-citalopram, CYP2C19-amitriptyline) were included by all tests. Gene-drug pairs included on less than half of the test panels included HLA-B-phenytoin (14%), HLA-A-carbamazepine (24%), HLA-B-carbamazepine (29%), and CYP2D6-zuclopenthixol (43%).
DISCUSSION: Most commercial pharmacogenetic tests we examined are well-equipped to facilitate implementation of the majority of dosing guidelines relevant to psychiatry but are limited in their ability to facilitate implementation of the full spectrum of dosing guidelines currently available.

PMID: 30900236 [PubMed - as supplied by publisher]

TNF-α G-308A genetic variants, serum CRP-hs concentration and DNA damage in obese women.

Mol Biol Rep. 2019 Mar 21;:

Authors: Marta W, Michał C, Grażyna N

Abstract
Obesity is associated with inflammation, which can disturb genome stability. Tumor necrosis factor (TNF-α) polymorphism was found to affect TNF-α protein production and inflammation. Therefore, the present study illustrates the relationship between TNF-α polymorphism, the degree of inflammation assessed by serum high sensitivity C-reactive protein concentration (CRP-hs) and basal DNA damage in patients with obesity (BMI 30-34.9 kg/m2) and control subjects with proper body mass (BMI < 25 kg/m2). A total of 115 participants (75 obese premenopausal women; and 40 age-, and gender-matched controls) were included. Biochemical parameters (serum concentrations of total-cholesterol, HDL-cholesterol, LDL- cholesterol, triglycerides, glucose, apolipoprotein AI, CRP-hs) and endogenous DNA damage (determined by comet assay) were measured. TNF-α G-308A polymorphism (rs1800629) was analyzed by PCR-RFLP (PCR-restriction fragments length polymorphism). An effect of TNF-α genotype on serum CRP-hs concentration was noted (p = 0.031). In general, carriers of the rare A allele of the TNF-α G-308A polymorphism had significantly lower endogenous DNA damage and serum CRP-hs concentrations than GG homozygotes, however, the protective effect of the A allele was especially visible in non-obese women. Serum CRP-hs concentrations and levels of DNA damage (% DNA in tail) were significantly higher in obese than in controls (p = 0.001 and p < 0.0001, respectively). The adjusted multiple linear regression analyses revealed a significant, independent impact of obesity on DNA damage (p = 0.00000) and no effect of other covariates i.e. age, TNF-α genotype and serum CRP-hs concentration. Our study showed that obesity has a significant impact on the levels of endogenous DNA damage. Obesity abolished the protective effect of A allele of the TNF-α G-308A polymorphism on DNA damage and on inflammation development observed in non-obese A allele carriers.

PMID: 30900134 [PubMed - as supplied by publisher]

A targeted genomic alteration analysis predicts survival of melanoma patients under BRAF inhibitors.

Oncotarget. 2019 Mar 01;10(18):1669-1687

Authors: Louveau B, Delyon J, De Moura CR, Battistella M, Jouenne F, Golmard L, Sadoux A, Podgorniak MP, Chami I, Marco O, Caramel J, Dalle S, Feugeas JP, Dumaz N, Lebbe C, Mourah S

Abstract
Several mechanisms have been described to elucidate the emergence of resistance to MAPK inhibitors in melanoma and there is a crucial need for biomarkers to identify patients who are likely to achieve a better and long-lasting response to BRAF inhibitors therapy. In this study, we developed a targeted approach combining both mRNA and DNA alterations analysis focusing on relevant gene alterations involved in acquired BRAF inhibitor resistance. We collected baseline tumor samples from 64 melanoma patients at BRAF inhibitor treatment initiation and showed that the presence, prior to treatment, of mRNA over-expression of genes' subset was significantly associated with improved progression free survival and overall survival. The presence of DNA alterations was in favor of better overall survival. The genomic analysis of relapsed-matched tumor samples from 20 patients allowed us to uncover the largest landscape of resistance mechanisms reported to date as at least one resistance mechanism was identified for each patient studied. Alterations in RB1 have been most frequent and hence represent an important additional acquired resistance mechanism. Our targeted genomic analysis emerges as a relevant tool in clinical practice to identify those patients who are more likely to achieve durable response to targeted therapies and to exhaustively describe the spectrum of resistance mechanisms. Our approach can be adapted to new targeted therapies by including newly identified genetic alterations.

PMID: 30899440 [PubMed]

Vitamin D serum levels in women using contraception containing drospirenone - a preliminary study.

Arch Med Sci. 2019 Mar;15(2):554-557

Authors: Ciebiera M, Włodarczyk M, Słabuszewska-Jóźwiak A, Ciebiera M, Nowicka G, Jakiel G

PMID: 30899309 [PubMed]

Age at onset of obesity, transcription factor 7-like 2 (TCF7L2) rs7903146 polymorphism, adiponectin levels and the risk of type 2 diabetes in obese patients.

Arch Med Sci. 2019 Mar;15(2):321-329

Authors: Wrzosek M, Sawicka A, Wrzosek M, Piątkiewicz P, Tałałaj M, Nowicka G

Abstract
Introduction: Interaction between obesity and genetic factors involved in the regulatory pathways of glucose homeostasis may play a significant role in diabetes development in the obese. The aim of this study was to investigate the associations between the TCF7L2 rs7903146 polymorphism, adiponectin levels, age at onset of obesity and the occurrence of type 2 diabetes (T2D) in a sample of obese Polish adults.
Material and methods: A total of 474 unrelated obese subjects were included in this study. Real-time PCR was used to detect the TCF7L2 rs7903146 polymorphism. Serum level of adiponectin was determined by the ELISA method. Standard assays were used to measure total cholesterol, HDL cholesterol, triglycerides, glucose and HbA1c concentrations. We used multiple logistic regression to identify factors associated with type 2 diabetes.
Results: We found that the T allele of rs7903146 was significantly associated with T2D risk (odds ratio of 1.59 for T allele, p = 0.005). This association persisted after adjusting for confounders in the recessive model (odds ratio of 3.54 for TT genotype, p = 0.011). Serum adiponectin levels were significantly lower in diabetic subjects than in nondiabetic individuals (3.6 vs. 5.6 µg/ml, p < 0.001). Participants who were obese at age ≥ 20 years had significantly higher odds of having T2D (OR = 4.94) than those with the onset of obesity before 20 years (p < 0.001).
Conclusions: Our study highlights the significance of the relationship between the TCF7L2 polymorphism, a person's age at onset of obesity and the prevalence of T2D, and confirms lower adiponectin levels in obese diabetics in comparison to obese nondiabetics.

PMID: 30899283 [PubMed]

A Bibliometric Analysis of Scientific Production on Second-Generation Anti-Psychotic Drugs in Malaysia.

Malays J Med Sci. 2018 May;25(3):40-55

Authors: López-Muñoz F, Povedano-Montero FJ, Chee KY, Shen WW, Fernández-Martín P, García-Pacios J, Rubio G, Álamo C

Abstract
Objective: We carried out a bibliometric study on the scientific papers related to second-generation antipsychotic drugs (SGAs) in Malaysia.
Methods: With the SCOPUS database, we selected those documents made in Malaysia whose title included descriptors related to SGAs. We applied bibliometric indicators of production and dispersion, as Price's law and Bradford's law, respectively. We also calculated the participation index of the different countries. The bibliometric data were also been correlated with some social and health data from Malaysia (total per capita expenditure on health and gross domestic expenditure on R&D).
Results: We found 105 original documents published between 2004 and 2016. Our results fulfilled Price's law, with scientific production on SGAs showing exponential growth (r = 0.401, vs. r = 0.260 after linear adjustment). The drugs most studied are olanzapine (9 documents), clozapine (7), and risperidone (7). Division into Bradford zones yields a nucleus occupied by the Medical Journal of Malaysia, Singapore Medical Journal, Australian and New Zealand Journal of Psychiatry, and Pharmacogenomics. Totally, 63 different journals were used, but only one in the top four journals had an impact factor being greater than 3.
Conclusion: The publications on SGAs in Malaysia have undergone exponential growth, without evidence a saturation point.

PMID: 30899186 [PubMed]

Clioquinol: To harm or heal.

Pharmacol Ther. 2019 Mar 18;:

Authors: Perez DR, Sklar LA, Chigaev A

Abstract
Clioquinol, one of the first mass-produced drugs, was considered safe and efficacious for many years. It was used as an antifungal and an antiprotozoal drug until it was linked to an outbreak of subacute myelo-optic neuropathy (SMON), a debilitating disease almost exclusively confined to Japan. Today, new information regarding clioquinol targets and its mechanism of action, as well as genetic variation (SNPs) in efflux transporters in the Japanese population, provide a unique interpretation of the existing phenomena. Further understanding of clioquinol's role in the inhibition of cAMP efflux and promoting apoptosis might offer promise for the treatment of cancer and/or neurodegenerative diseases. Here, we highlight recent developments in the field and discuss possible connections, hypotheses and perspectives in clioquinol-related research.

PMID: 30898518 [PubMed - as supplied by publisher]

A Disinhibitory Microcircuit Mediates Conditioned Social Fear in the Prefrontal Cortex.

Neuron. 2019 Mar 08;:

Authors: Xu H, Liu L, Tian Y, Wang J, Li J, Zheng J, Zhao H, He M, Xu TL, Duan S, Xu H

Abstract
Fear behavior is under tight control of the prefrontal cortex, but the underlying microcircuit mechanism remains elusive. In particular, it is unclear how distinct subtypes of inhibitory interneurons (INs) within prefrontal cortex interact and contribute to fear expression. We employed a social fear conditioning paradigm and induced robust social fear in mice. We found that social fear is characterized by activation of dorsal medial prefrontal cortex (dmPFC) and is largely diminished by dmPFC inactivation. With a combination of in vivo electrophysiological recordings and fiber photometry together with cell-type-specific pharmacogenetics, we further demonstrated that somatostatin (SST) INs suppressed parvalbumin (PV) INs and disinhibited pyramidal cells and consequently enhanced dmPFC output to mediate social fear responses. These results reveal a previously unknown disinhibitory microcircuit in prefrontal cortex through interactions between IN subtypes and suggest that SST INs-mediated disinhibition represents an important circuit mechanism in gating social fear behavior.

PMID: 30898376 [PubMed - as supplied by publisher]