Mitochondrial DNA mutations in Malaysian female breast cancer patients.

PLoS One. 2020;15(5):e0233461

Authors: Omasanggar R, Yu CY, Ang GY, Emran NA, Kitan N, Baghawi A, Falparado Ahmad A, Abdullah MA, Teh LK, Maniam S

Abstract
Cancer development has been ascribed with diverse genetic variations which are identified in both mitochondrial and nuclear genomes. Mitochondrial DNA (mtDNA) alterations have been detected in several tumours which include lung, colorectal, renal, pancreatic and breast cancer. Several studies have explored the breast tumour-specific mtDNA alteration mainly in Western population. This study aims to identify mtDNA alterations of 20 breast cancer patients in Malaysia by next generation sequencing analysis. Twenty matched tumours with corresponding normal breast tissues were obtained from female breast cancer patients who underwent mastectomy. Total DNA was extracted from all samples and the entire mtDNA (16.6kb) was amplified using long range PCR amplification. The amplified PCR products were sequenced using mtDNA next-generation sequencing (NGS) on an Illumina Miseq platform. Sequencing involves the entire mtDNA (16.6kb) from all pairs of samples with high-coverage (~ 9,544 reads per base). MtDNA variants were called and annotated using mtDNA-Server, a web server. A total of 18 of 20 patients had at least one somatic mtDNA mutation in their tumour samples. Overall, 65 somatic mutations were identified, with 30 novel mutations. The majority (59%) of the somatic mutations were in the coding region, whereas only 11% of the mutations occurred in the D-loop. Notably, somatic mutations in protein-coding regions were non-synonymous (49%) in which 15.4% of them are potentially deleterious. A total of 753 germline mutations were identified and four of which were novel mutations. Compared to somatic alterations, less than 1% of germline missense mutations are harmful. The findings of this study may enhance the current knowledge of mtDNA alterations in breast cancer. To date, the catalogue of mutations identified in this study is the first evidence of mtDNA alterations in Malaysian female breast cancer patients.

PMID: 32442190 [PubMed - as supplied by publisher]

Pharmacogenetics of Postoperative Pain Management: A Review.

AANA J. 2020 Jun;88(3):229-236

Authors: Aroke EN, Kittelsrud JM

Abstract
Despite the opioid epidemic, up to 86% of patients experience moderate to severe pain after major surgery. Although several factors influence the amount of pain patients experience postoperatively, studies have identified genetic variations that influence pain perception and response to pain medications. The purpose of this article is to examine evidence of the genetic differences that affect patients' responses to medications frequently used in postoperative pain management. Genes of interest associated with postoperative pain management include the opioid µ1 receptor (OPRM1), cytochrome P450 (CYP) enzymes, catechol O-methyl transferase (COMT) enzyme, and adenosine triphosphate-binding cascade (ABCB1) transporter. There is moderate evidence linking the OPRM1 sequence variation and response to morphine in the postoperative period. Besides activity at the OPRM1 receptor, analgesic efficacy and adverse effects of pain medications also depend on their rate of metabolism by CYP enzymes. CYP2D6 enzymes metabolize codeine and tramadol. Codeine and tramadol are not recommended in CYP2D6 poor metabolizers and ultrarapid metabolizers and are contraindicated in children and breastfeeding mothers. Similarly, caution must be exercised when using nonsteroidal anti-inflammatory drugs in CYP2C9 intermediate metabolizers and poor metabolizers. Large-scale studies are needed to develop genotype-guided therapeutic guidelines for most medications used in postoperative pain management.

PMID: 32442101 [PubMed - as supplied by publisher]

PTSD and the klotho longevity gene: Evaluation of longitudinal effects on inflammation via DNA methylation.

Psychoneuroendocrinology. 2020 Apr 13;117:104656

Authors: Wolf EJ, Logue MW, Zhao X, Daskalakis NP, Morrison FG, Escarfulleri S, Stone A, Schichman SA, McGlinchey RE, Milberg WP, Chen C, Abraham CR, Miller MW

Abstract
BACKGROUND: Longevity gene klotho (KL) is associated with age-related phenotypes including lifespan, cardiometabolic disorders, cognition, and brain morphology, in part, by conferring protection against inflammation. We hypothesized that the KL/inflammation association might be altered in the presence of psychiatric stress and operate via epigenetic pathways. We examined KL polymorphisms, and their interaction with posttraumatic stress disorder (PTSD) symptoms, in association with KL DNA methylation in blood. We further examined KL DNA methylation as a predictor of longitudinal changes in a peripheral biomarker of inflammation (C-reactive protein; CRP).
METHODS: The sample comprised 309 white non-Hispanic military veterans (93.5 % male; mean age: 32 years, range: 19-65; 30 % PTSD per structured diagnostic interview); 111 were reassessed approximately two years later.
RESULTS: Analyses revealed a methylation quantitative trait locus at rs9527025 (C370S, previously implicated in numerous studies of aging) in association with a Cytosine-phosphate-Guanine site (cg00129557; B = -.65, p =  1.29 X 10-20), located within a DNase hypersensitivity site in the body of KL. There was also a rs9527025 x PTSD severity interaction (B = .004, p = .035) on methylation at this locus such that the minor allele was associated with reduced cg00129557 methylation in individuals with few or no PTSD symptoms while this effect was attenuated in those with elevated levels of PTSD. Path models revealed that methylation at cg00129557 was inversely associated with CRP over time (B = -.14, p = .005), controlling for baseline CRP. There was also an indirect effect of rs9527025 X PTSD on subsequent CRP via cg00129557 methylation (indirect B = -.002, p = .033).
CONCLUSIONS: Results contribute to our understanding of the epigenetic correlates of inflammation in PTSD and suggest that KL methylation may be a mechanism by which KL genotype confers risk vs. resilience to accelerated aging in those experiencing traumatic stress.

PMID: 32438247 [PubMed - as supplied by publisher]

CELLector: Genomics-Guided Selection of Cancer In Vitro Models.

Cell Syst. 2020 May 20;10(5):424-432.e6

Authors: Najgebauer H, Yang M, Francies HE, Pacini C, Stronach EA, Garnett MJ, Saez-Rodriguez J, Iorio F

Abstract
Selecting appropriate cancer models is a key prerequisite for maximizing translational potential and clinical relevance of in vitro oncology studies. We developed CELLector: an R package and R Shiny application allowing researchers to select the most relevant cancer cell lines in a patient-genomic-guided fashion. CELLector leverages tumor genomics to identify recurrent subtypes with associated genomic signatures. It then evaluates these signatures in cancer cell lines to prioritize their selection. This enables users to choose appropriate in vitro models for inclusion or exclusion in retrospective analyses and future studies. Moreover, this allows bridging outcomes from cancer cell line screens to precisely defined sub-cohorts of primary tumors. Here, we demonstrate the usefulness and applicability of CELLector, showing how it can aid prioritization of in vitro models for future development and unveil patient-derived multivariate prognostic and therapeutic markers. CELLector is freely available at https://ot-cellector.shinyapps.io/CELLector_App/ (code at https://github.com/francescojm/CELLector and https://github.com/francescojm/CELLector_App).

PMID: 32437684 [PubMed - as supplied by publisher]

Predictive model of bosentan-induced liver toxicity in Japanese patients with pulmonary arterial hypertension.

Can J Physiol Pharmacol. 2020 May 20;:

Authors: Yorifuji K, Uemura Y, Horibata S, Tsuji G, Suzuki Y, Nakayama K, Hatae T, Kumagai S, Emoto N

Abstract
Bosentan, an endothelin receptor antagonist, has been widely used as a first-line medication for the treatment of pulmonary arterial hypertension (PAH). However, liver dysfunction is a major side effect of bosentan treatment that could hamper the optimal management of patients with PAH. Previously, we demonstrated, using drug metabolism enzymes and transporters (DMET) analysis, that the carbohydrate sulfotransferase 3 (CHST3) and CHST13 alleles are significantly more frequent in patients with elevated amino-transferases during therapy with bosentan than they are in patients without liver toxicity. In addition, we constructed a pharmacogenomics model to predict bosentan-induced liver injury in patients with PAH using two single nucleotide polymorphisms (SNPs) and two non-genetic factors. The purpose of the present study was to externally validate the predictive model of bosentan-induced liver toxicity in Japanese patients. We evaluated five cases of patients treated with bosentan, and one presented with liver dysfunction. We applied mutation alleles of CHST3 and CHST13, serum creatinine, and age to our model to predict liver dysfunction. The sensitivity and specificity were calculated as 100% and 50%, respectively. Considering that PAH is a rare disease, multicenter collaboration would be necessary to validate our model.

PMID: 32433892 [PubMed - as supplied by publisher]

Clinical advances in obsessive-compulsive disorder: a position statement by the International College of Obsessive-Compulsive Spectrum Disorders.

Int Clin Psychopharmacol. 2020 May 18;:

Authors: Fineberg NA, Hollander E, Pallanti S, Walitza S, Grünblatt E, Dell'Osso BM, Albert U, Geller DA, Brakoulias V, Janardhan Reddy YC, Arumugham SS, Shavitt RG, Drummond L, Grancini B, De Carlo V, Cinosi E, Chamberlain SR, Ioannidis K, Rodriguez CI, Garg K, Castle D, Van Ameringen M, Stein DJ, Carmi L, Zohar J, Menchon JM

Abstract
In this position statement, developed by The International College of Obsessive-Compulsive Spectrum Disorders, a group of international experts responds to recent developments in the evidence-based management of obsessive-compulsive disorder (OCD). The article presents those selected therapeutic advances judged to be of utmost relevance to the treatment of OCD, based on new and emerging evidence from clinical and translational science. Areas covered include refinement in the methods of clinical assessment, the importance of early intervention based on new staging models and the need to provide sustained well-being involving effective relapse prevention. The relative benefits of psychological, pharmacological and somatic treatments are reviewed and novel treatment strategies for difficult to treat OCD, including neurostimulation, as well as new areas for research such as problematic internet use, novel digital interventions, immunological therapies, pharmacogenetics and novel forms of psychotherapy are discussed.

PMID: 32433254 [PubMed - as supplied by publisher]

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pharmacogenomics

These pubmed results were generated on 2020/05/20

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18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/05/19

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Neonatal diabetes due to potassium channel mutation: response to sulfonylurea according to the genotype.

Pediatr Diabetes. 2020 May 16;:

Authors: Garcin L, Mericq V, Fauret-Amsellem AL, Cave H, Polak M, Beltrand J

Abstract
OBJECTIVE: A precision medicine approach is used to improve treatment of patients with monogenic diabetes. Herein we searched SU efficiency according to the genotype-phenotype correlation, dosage used and side effects.
RESEARCH DESIGN AND METHODS: Systematic review conducted according the PRISMA control criteria identifying relevant studies evaluating the in vivo and in vitro sensitivity of ATP-dependent potassium channels according to the characteristics of genetic mutation.
RESULTS: 103 selected articles with complete data in 502 cases in whom 413 (82.3%) had mutations in KCNJ11 (#64) and 89 in ABCC8 (# 56). Successful transfer from insulin to SU was achieved in 91% and 86.5% patients, respectively at a mean age of 36.5 months (0-63 years). Among patients with KCNJ11 and ABCC8 mutations 64 & 46 were associated with constant success,5 & 5 to constant failure, and 10 and 4 to variable degrees of reported success rate, respectively. The glibenclamide dosage required for each genotype ranged from 0.017 to 2.8 mg / kg / day. Comparing both the in vivo and in vitro susceptibility results, some mutations appear more sensitive than others to sulfonylurea treatment. Side effects were reported in 17 /103 of the included articles: mild gastrointestinal symptoms and hypoglycaemia were the most common. One premature patient had an ulcerative necrotizing enterocolitis which association with SU is difficult to ascertain.
CONCLUSIONS: Sulfonylurea are an effective treatment for monogenic diabetes due to KCNJ11 and ABCC8 genes mutations. The success of the treatment is conditioned by differences in pharmacogenetics, younger age, pharmacokinetics, compliance and maximal dose used. This article is protected by copyright. All rights reserved.

PMID: 32418263 [PubMed - as supplied by publisher]

Propranolol suppresses the growth of colorectal cancer through simultaneously activating autologous CD8+ T cells and inhibiting tumor AKT/MAPK pathway.

Clin Pharmacol Ther. 2020 May 17;:

Authors: Liao P, Song K, Zhu Z, Liu Z, Zhang W, Li W, Hu J, Hu Q, Chen C, Chen B, McLeod HL, Pei H, Chen L, He Y

Abstract
Propranolol suppresses tumor growth in a variety of preclinical solid tumor models, with a number of proposed cell signaling and immunological mechanisms. We want to confirm the potential mechanisms, including reduced phosphorylation of AKT/MAPK pathways, as well as enhanced CD8+ T-cell-mediated antitumor immune response. To clarify the mechanism of propranolol activity in colorectal cancer, the therapeutic activity of propranolol was then assessed in CT26WT tumors engrafted in BALB/C mice. Then the effect of propranolol treatment was also examined by randomizing patients undergoing surgical resection of a previously untreated colorectal cancer to propranolol or placebo group and treated for 1 week prior to surgery. CT26WT tumor size was smaller after propranolol than vehicle control. Propranolol downregulated the expression of p-AKT/p-ERK/p-MEK in tumor tissue. The frequency of tumor CD8+ T cells was significantly elevated in propranolol-treated mice. The expression of GzmB/IFN-γ/T-bet in the CD8+ T-cell population was significantly increased in propranolol treated mice tumor tissue. In propranolol-treated surgical specimens, the expression of p-ERK was decreased and the frequency of CD8+ was significantly elevated. The expression of GzmB in the CD8+ T-cell population was significantly increased in propranolol-treated subjects. Together these data show propranolol simultaneously activating autologous CD8+ T cells and decreasing the expression of p-AKT/p-ERK/p-MEK in mouse tumor models, while inhibiting the expression of p-ERK in clinical colorectal cancer. Effort is now needed to further dissect whether both pathways are required for anti-tumor effect, as the activity of this old drug is moved forward.

PMID: 32418204 [PubMed - as supplied by publisher]

Effect of Cytochrome P450 and ABCB1 Polymorphisms on Imatinib Pharmacokinetics After Single-Dose Administration to Healthy Subjects.

Clin Drug Investig. 2020 May 15;:

Authors: Pena MÁ, Muriel J, Saiz-Rodríguez M, Borobia AM, Abad-Santos F, Frías J, Peiró AM

Abstract
BACKGROUND: Validated genomic biomarkers for oncological drugs are expanding to improve targeted therapies. Pharmacogenetics research focusing on the mechanisms underlying imatinib suboptimal response might help to explain the different treatment outcomes and drug safety profiles.
OBJECTIVE: To investigate whether polymorphisms in genes encoding cytochrome P450 (CYP) enzymes and ABCB1 transporter affect imatinib pharmacokinetic parameters.
METHODS: A prospective, multicenter, pharmacogenetic pilot study was performed in the context of two separate oral imatinib bioequivalence clinical trials, which included 26 healthy volunteers. DNA was extracted in order to analyze polymorphisms in genes CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and ABCB1. Imatinib plasma concentrations were measured by HPLC-MS/MS. Pharmacokinetic parameters were calculated by non-compartmental methods using WinNonlin software.
RESULTS: Volunteers (n = 26; aged 24 ± 3 years; 69% male) presented regular pharmacokinetic imatinib data (concentration at 24 h, 436 ± 140 ng/mL and at 72 h, 40 ± 26 ng/mL; AUC0-72 32,868 ± 10,713 ng/mL⋅h; and Cmax 2074 ± 604 ng/mL). CYP2B6 516GT carriers showed a significant reduction of imatinib concentration at 24 h (23%, 391 ng/dL vs 511 ng/dL in 516GG carriers, p = 0.005) and elimination half-life (11%, 12.6 h vs 14.1 h in 516GG carriers, p = 0.041). Carriers for CYP3A4 (*22/*22, *1/*20 and *1/*22 variants) showed a reduced frequency of adverse events compared to *1/*1 carriers (0 vs 64%, p = 0.033). The other polymorphisms analyzed did not influence pharmacokinetics or drug toxicity.
CONCLUSION: CYP2B6 G516T and CYP3A4 *20,*22 polymorphisms could influence imatinib plasma concentrations and safety profile, after single-dose administration to healthy subjects. This finding needs to be confirmed before it is implemented in clinical practice in oncological patients under treatment with imatinib.

PMID: 32415468 [PubMed - as supplied by publisher]

A Multimodal Genotoxic Anti-cancer Drug Characterized by Pharmacogenetic Analysis in Caenorhabditis elegans.

Genetics. 2020 May 15;:

Authors: Ye FB, Hamza A, Singh T, Flibotte S, Hieter P, O'Neil NJ

Abstract
New anti-cancer therapeutics require extensive in vivo characterization to identify endogenous and exogenous factors affecting efficacy, to measure toxicity and mutagenicity, and to determine genotypes that result in therapeutic sensitivity or resistance. We used Caenorhabditis elegans as a platform with which to characterize properties of the anti-cancer therapeutic CX-5461. To understand the processes that respond to CX-5461-induced damage, we generated pharmacogenetic profiles for panel of C. elegans DNA replication and repair mutants with common DNA damaging agents to compare to the profile of CX-5461. We found that multiple repair pathways, including homology directed repair, microhomology-mediated end joining, nucleotide excision repair, and translesion synthesis, were needed for CX-5461 tolerance. To determine the frequency and spectrum of CX-5461-induced mutations, we used a genetic balancer to capture CX-5461-induced mutations. We found that CX-5461 is mutagenic, resulting in both large copy number variations and a high frequency of single nucleotide variations (SNVs), which are consistent with the pharmacogenetic profile for CX-5461. Whole genome sequencing of CX-5461 exposed animals found that CX-5461-induced SNVs exhibited a distinct mutational signature. We also phenocopied the CX-5461 photo-reactivity observed in clinical trials and demonstrated that CX-5461 generates reactive oxygen species when exposed to UVA radiation. Together, the data from C. elegans demonstrate that CX-5461 is a multimodal DNA damaging anti-cancer agent.

PMID: 32414869 [PubMed - as supplied by publisher]

GSTM1 null variant associated with anthracycline-related cancer in pediatric cancer.

Cancer. 2020 May 15;:

Authors: Rassekh SR

PMID: 32413168 [PubMed - as supplied by publisher]

EHD2 is a Predictive Biomarker of Chemotherapy Efficacy in Triple Negative Breast Carcinoma.

Sci Rep. 2020 May 14;10(1):7998

Authors: Shen WW, Bièche I, Fuhrmann L, Vacher S, Vincent-Salomon A, Torrino S, Lamaze C

Abstract
EHD2 is a mechanotransducing ATPase localized in caveolae invaginations at the plasma membrane. EHD2 has recently been associated with several human cancers, however the significance of EHD2 transcript levels in cancer prognosis remains debated. Breast cancer is the most commonly occurring cancer in women and prognosis is variable depending on the subtypes. Triple negative breast cancer (TNBC) often has a poor therapeutic response. The aim of this study was to assess the prognostic significance of EHD2 transcripts and protein expression levels in breast carcinomas. We found that low EHD2 levels were associated with enhanced proliferation, migration and invasion of TNBC cells. EHD2 expression was significantly reduced in TNBC tissues and the loss of EHD2 led to higher expression of the pro-tumoral cytokine IL-8. In apparent contradiction with in vitro data, multivariate analysis of two independent cohorts of breast cancer patients revealed that low EHD2 was in fact associated with good prognosis in the highly proliferative TNBC subtype. Accordingly, TNBC low EHD2 expressers were found to benefit the most from chemotherapy when compared to all subtypes of breast cancers. Our study validates EHD2 expression level as an independent prognostic factor of metastasis-free survival and as a new predictive marker of chemotherapy efficacy in TNBC patients.

PMID: 32409676 [PubMed - in process]

An Exploratory Analysis on the Influence of Genetic Variants on Weight Gain among Etonogestrel Contraceptive Implant Users.

Contraception. 2020 May 11;:

Authors: Lazorwitz A, Dindinger E, Harrison M, Aquilante CL, Sheeder J, Teal S

Abstract
OBJECTIVE: To identify genetic variants associated with weight gain related to etonogestrel contraceptive implant use.
STUDY DESIGN: We conducted a retrospective analysis from a parent pharmacogenomic study of healthy, reproductive-aged women using etonogestrel implants. We reviewed medical records to calculate objective weight changes from implant insertion to study enrollment and asked participants about subjective weight gain (yes/no) during contraceptive implant use. We used genotyping data (99 genetic variants) from the parent study to conduct backward-stepwise generalized linear modeling to identify genetic variants associated with objective weight changes.
RESULTS: Among 276 ethnically diverse participants, median body-mass index (BMI) was 25.8kg/m2 (range 18.5-48.1). We found a median weight change of +3.2kg (range -27.6 to +26.5) from implant insertion to study enrollment. Report of subjective weight gain had minimal agreement with measured weight gain during implant use (Cohen's kappa=0.21). Our final generalized linear model contained two variables associated with objective weight change that met conservative statistical significance (p<5.0x10-4). Participants with two copies (homozygous) of the ESR1 rs9340799 variant on average gained 14.1kg more than all other participants (p=1.4x10-4). Higher enrollment BMI was also associated with objective weight gain (β= 0.54, p=9.4x10-12).
CONCLUSION: Genetic variants in the estrogen receptor 1 (ESR1) do not have known associations with obesity or metabolic syndrome, but there is physiologic plausibility for a progestin-mediated genetic association between ESR1 and weight gain. Additional genetic research is needed to substantiate our findings and elucidate further advances in individualized counseling on the risk of weight gain with exogenous steroid hormones.
IMPLICATIONS: Genetic variation in the estrogen receptor 1 gene may account for variability in weight gain among etonogestrel contraceptive implant users. If these findings can be replicated with other progestin-containing medications, we may be able to better individualize contraceptive counseling.

PMID: 32407811 [PubMed - as supplied by publisher]

Ifosfamide and etoposide in advanced-stage, relapsed or refractory primary cutaneous T-cell lymphomas.

Br J Dermatol. 2020 May 14;:

Authors: Dangien A, Ram-Wolff C, Brice P, Battistella M, Roelens M, Moins-Teisserenc H, de Latour RP, Mourah S, Bouaziz JD, Lebbé C, Bagot M, de Masson A

Abstract
Ifosfamide + etoposide (I+E) have been used to treat lymphomas, combined with platinum-based agents in Hodgkin disease or non-Hodgkin lymphomas including peripheral T-cell lymphomas. Monoclonal antibodies have induced long-term remissions in CTCL but are usually poorly effective in transformed disease. Allogeneic hematopoietic stem cell transplantation (alloHSCT) holds a potential for cure but relies on the existence of a pre-transplant CR which may require the use of chemotherapeutic regimens.

PMID: 32407544 [PubMed - as supplied by publisher]

Optimization of a Low-Cost, Sensitive PNA Clamping PCR Method for JAK2 V617F Variant Detection.

J Appl Lab Med. 2020 May 14;:

Authors: Di Francia R, Crisci S, Muto T, Giancola C, Petriccone L, Catapano O, Cummarro A, Pinto A, Frigeri F

Abstract
BACKGROUND: The JAK2 V617F variant is diagnostic for myeloproliferative neoplasms, a group of clonal disorders of hematopoietic stem and progenitor cells. Although several approaches have been developed to detect the variant, a gold standard diagnostic method has not yet been defined. We describe a simple, fast, and cost-effective PCR-based approach that enhances test specificity and sensitivity by blocking the amplification of the large excess of wild-type DNA.
METHODS: The method involves using an oligo peptide nucleic acid (PNA) perfectly matching its corresponding DNA sequence. The PCR protocol was optimized by collecting a detailed thermodynamic data set on PNA-DNA wild-type duplexes by circular dichroism melting experiments. The specificity and sensitivity of PNA clamping PCR were assessed by genotyping 50 patients with myeloproliferative neoplasm who carried the JAK2 V617F variant and 50 healthy donors.
RESULTS: The optimized protocol enabled selective amplification of the variant alleles, achieving maximum sensitivity (100%) and specificity (100%). Analytical sensitivity was 0.05% of variant alleles as assessed by serial dilutions of DNA from the HEL cell line (which carries the JAK2 V617F variant) mixed to wild-type DNA from healthy donors. The JAK2 V617F variant test performed according to this method has better diagnostic performance than its 2 main PCR-based competitors, at much lower cost.
CONCLUSIONS: High sensitivity and specificity and cost-effectiveness make PNA clamping PCR a useful testing platform for the detection of minor allele variants in small-scale diagnostic laboratories. It promises to improve patient care while enabling significant healthcare savings.

PMID: 32407536 [PubMed - as supplied by publisher]

Pharmacogenetic evaluation of metformin and sulphonylurea response in Mexican Mestizos with type 2 diabetes.

Curr Drug Metab. 2020 May 14;:

Authors: Marta M, Katy SP, Joel JS, Jazmin ME, Carolina RS, de Los Ángeles GM, Guadalupe OM

Abstract
BACKGROUND: In Mexico, approximately 25% of patients with type 2 diabetes (T2D) have adequate glycemic control. Polymorphisms in pharmacogenetic genes have been shown to have clinical consequences resulting in drug toxicity or therapeutic inefficacy.
OBJECTIVE: To evaluate the impact of variants in genes known to be involved in the response to oral hypoglycemic drugs, such as CYP2C9, OCT, MATE, ABCA1 and C11orf65, in the Mexican Mestizo population of T2D patients.
METHODS: In this study, 265 patients with T2D were enrolled from Hospital Juárez de México, Mexico City. Genotyping was performed by TaqMan® assays. SNP-SNP interactions were analyzed using the multifactor dimensionality reduction (MDR) method.
RESULTS: Carriers of the del allele of rs72552763 could achieve a better glycemic control than noncarriers. There was a significant difference in plasma glucose and HbA1c levels among rs622342 genotypes. The results suggested a SNP-SNP interaction between rs72552763 and rs622342 OCT1 and rs12943590 MATE2.
CONCLUSION: The interaction between rs72552763 and rs622342 in OCT1, and rs12943590 in MATE2 suggested an important role of these polymorphisms in metformin response in T2D Mexican Mestizo population.

PMID: 32407269 [PubMed - as supplied by publisher]

Targeting mitochondrial fusion and fission proteins for cardioprotection.

J Cell Mol Med. 2020 May 14;:

Authors: Hernandez-Resendiz S, Prunier F, Girao H, Dorn G, Hausenloy DJ, EU-CARDIOPROTECTION COST Action (CA16225)

Abstract
New treatments are needed to protect the myocardium against the detrimental effects of acute ischaemia/reperfusion (IR) injury following an acute myocardial infarction (AMI), in order to limit myocardial infarct (MI) size, preserve cardiac function and prevent the onset of heart failure (HF). Given the critical role of mitochondria in energy production for cardiac contractile function, prevention of mitochondrial dysfunction during acute myocardial IRI may provide novel cardioprotective strategies. In this regard, the mitochondrial fusion and fissions proteins, which regulate changes in mitochondrial morphology, are known to impact on mitochondrial quality control by modulating mitochondrial biogenesis, mitophagy and the mitochondrial unfolded protein response. In this article, we review how targeting these inter-related processes may provide novel treatment targets and new therapeutic strategies for reducing MI size, preventing the onset of HF following AMI.

PMID: 32406208 [PubMed - as supplied by publisher]

25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2.

Nutrients. 2020 May 09;12(5):

Authors: D'Avolio A, Avataneo V, Manca A, Cusato J, De Nicolò A, Lucchini R, Keller F, Cantù M

Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), with a clinical outcome ranging from mild to severe, including death. To date, it is unclear why some patients develop severe symptoms. Many authors have suggested the involvement of vitamin D in reducing the risk of infections; thus, we retrospectively investigated the 25-hydroxyvitamin D (25(OH)D) concentrations in plasma obtained from a cohort of patients from Switzerland. In this cohort, significantly lower 25(OH)D levels (p = 0.004) were found in PCR-positive for SARS-CoV-2 (median value 11.1 ng/mL) patients compared with negative patients (24.6 ng/mL); this was also confirmed by stratifying patients according to age >70 years. On the basis of this preliminary observation, vitamin D supplementation might be a useful measure to reduce the risk of infection. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations and to confirm our preliminary observation.

PMID: 32397511 [PubMed - indexed for MEDLINE]