Mild traumatic brain injury is associated with reduced cortical thickness in those at risk for Alzheimer's disease.

Brain. 2017 Mar 01;140(3):813-825

Authors: Hayes JP, Logue MW, Sadeh N, Spielberg JM, Verfaellie M, Hayes SM, Reagan A, Salat DH, Wolf EJ, McGlinchey RE, Milberg WP, Stone A, Schichman SA, Miller MW

Abstract
Moderate-to-severe traumatic brain injury is one of the strongest environmental risk factors for the development of neurodegenerative diseases such as late-onset Alzheimer's disease, although it is unclear whether mild traumatic brain injury, or concussion, also confers risk. This study examined mild traumatic brain injury and genetic risk as predictors of reduced cortical thickness in brain regions previously associated with early Alzheimer's disease, and their relationship with episodic memory. Participants were 160 Iraq and Afghanistan War veterans between the ages of 19 and 58, many of whom carried mild traumatic brain injury and post-traumatic stress disorder diagnoses. Whole-genome polygenic risk scores for the development of Alzheimer's disease were calculated using summary statistics from the largest Alzheimer's disease genome-wide association study to date. Results showed that mild traumatic brain injury moderated the relationship between genetic risk for Alzheimer's disease and cortical thickness, such that individuals with mild traumatic brain injury and high genetic risk showed reduced cortical thickness in Alzheimer's disease-vulnerable regions. Among males with mild traumatic brain injury, high genetic risk for Alzheimer's disease was associated with cortical thinning as a function of time since injury. A moderated mediation analysis showed that mild traumatic brain injury and high genetic risk indirectly influenced episodic memory performance through cortical thickness, suggesting that cortical thinning in Alzheimer's disease-vulnerable brain regions is a mechanism for reduced memory performance. Finally, analyses that examined the apolipoprotein E4 allele, post-traumatic stress disorder, and genetic risk for schizophrenia and depression confirmed the specificity of the Alzheimer's disease polygenic risk finding. These results provide evidence that mild traumatic brain injury is associated with greater neurodegeneration and reduced memory performance in individuals at genetic risk for Alzheimer's disease, with the caveat that the order of causal effects cannot be inferred from cross-sectional studies. These results underscore the importance of documenting head injuries even within the mild range as they may interact with genetic risk to produce negative long-term health consequences such as neurodegenerative disease.

PMID: 28077398 [PubMed - indexed for MEDLINE]

H2S-Donating Doxorubicins May Overcome Cardiotoxicity and Multidrug Resistance.

J Med Chem. 2016 May 26;59(10):4881-9

Authors: Chegaev K, Rolando B, Cortese D, Gazzano E, Buondonno I, Lazzarato L, Fanelli M, Hattinger CM, Serra M, Riganti C, Fruttero R, Ghigo D, Gasco A

Abstract
Doxorubicin (DOXO) is one of the most effective antineoplastic agents in clinical practice. Its use is limited by acute and chronic side effects, in particular by its cardiotoxicity and by the rapid development of resistance to it. As part of a program aimed at developing new DOXO derivatives endowed with reduced cardiotoxicity, and active against DOXO-resistant tumor cells, a series of H2S-releasing DOXOs (H2S-DOXOs) were obtained by combining DOXO with appropriate H2S donor substructures. The resulting compounds were studied on H9c2 cardiomyocytes and in DOXO-sensitive U-2OS osteosarcoma cells, as well as in related cell variants with increasing degrees of DOXO-resistance. Differently from DOXO, most of the products were not toxic at 5 μM concentration on H9c2 cells. A few of them triggered high activity on the cancer cells. H2S-DOXOs 10 and 11 emerged as the most interesting members of the series. The capacity of 10 to impair Pgp transporter is also discussed.

PMID: 27120394 [PubMed - indexed for MEDLINE]

Incidence and triggers of Stevens-Johnson syndrome and toxic epidermal necrolysis in a large cancer patient cohort.

J Invest Dermatol. 2017 May 23;:

Authors: Gillis NK, Hicks JK, Bell GC, Daly AJ, Kanetsky PA, McLeod HL

PMID: 28549953 [PubMed - as supplied by publisher]

Pharmacogenomic findings from clinical whole exome sequencing of diagnostic odyssey patients.

Mol Genet Genomic Med. 2017 May;5(3):269-279

Authors: Cousin MA, Matey ET, Blackburn PR, Boczek NJ, McAllister TM, Kruisselbrink TM, Babovic-Vuksanovic D, Lazaridis KN, Klee EW

Abstract
BACKGROUND: We characterized the pharmacogenomics (PGx) results received by diagnostic odyssey patients as secondary findings during clinical whole exome sequencing (WES) testing as a part of their care in Mayo Clinic's Individualized Medicine Clinic to determine the potential benefits and limitations to this cohort.
METHODS: WES results on 94 patients included a subset of PGx variants in CYP2C19,CYP2C9, and VKORC1 if identified in the patient. Demographic, phenotypic, and medication usage information was abstracted from patient medical data. A pharmacist interpreted the PGx results in the context of the patients' current medication use and made therapeutic recommendations.
RESULTS: The majority was young with a median age of 10 years old, had neurological involvement in the disease presentation (71%), and was currently taking medications (90%). Of the 94 PGx-evaluated patients, 91% had at least one variant allele reported and 20% had potential immediate implications on current medication use.
CONCLUSION: Due to the disease complexity and medication needs of diagnostic odyssey patients, there may be immediate benefit obtained from early life PGx testing for many and most will likely find benefit in the future. These results require conscientious interpretation and management to be actionable for all prescribing physicians throughout the lifetime of the patient.

PMID: 28546997 [PubMed - in process]

Gut microbiota and hepatitis-B-virus-induced chronic liver disease: implications for faecal microbiota transplantation therapy.

J Hosp Infect. 2017 Apr 15;:

Authors: Kang Y, Cai Y

Abstract
Hepatitis B is one of the most common infectious diseases globally. It has been estimated that there are 350 million chronic hepatitis B virus (HBV) carriers worldwide. The liver is connected to the small intestine by the bile duct, which carries bile formed in the liver to the intestine. Nearly all of the blood that leaves the stomach and intestines must pass through the liver. Human intestines contain a wide diversity of microbes, collectively termed the 'gut microbiota'. Gut microbiota play a significant role in host metabolic processes and host immune modulation, and influence host development and physiology (organ development). Altered gut microbiota is a common complication in liver disease. Changes in intestinal microbiota seem to play an important role in induction and promotion of HBV-induced chronic liver disease progression, and specific species among the intestinal commensal bacteria may play either a pathogenic or a protective role in the development of HBV-induced chronic liver disease. Thus, the gut microbiome may represent fertile targets for prevention or management of HBV-induced chronic liver disease. Faecal microbiota transplantation (FMT) may be a useful therapy for HBV-related disease in the future. However, the data available in this field remain limited, and relevant scientific work has only just commenced. New technologies have enabled systematic studies of gut microbiota, and provided more realistic information about its composition and pathological variance. This review summarizes the cutting edge of research into the relationship between gut microbiota and HBV-induced chronic liver disease, and the future prospects of FMT therapy.

PMID: 28545829 [PubMed - as supplied by publisher]

State of Art of Cancer Pharmacogenomics in Latin American Populations.

Int J Mol Sci. 2017 May 23;18(6):

Authors: López-Cortés A, Guerrero S, Redal MA, Alvarado AT, Quiñones LA

Abstract
Over the past decades, several studies have shown that tumor-related somatic and germline alterations predicts tumor prognosis, drug response and toxicity. Latin American populations present a vast geno-phenotypic diversity due to the great interethnic and interracial mixing. This genetic flow leads to the appearance of complex characteristics that allow individuals to adapt to endemic environments, such as high altitude or extreme tropical weather. These genetic changes, most of them subtle and unexplored, could establish a mutational profile to develop new pharmacogenomic therapies specific for Latin American populations. In this review, we present the current status of research on somatic and germline alterations in Latin America compared to those found in Caucasian and Asian populations.

PMID: 28545225 [PubMed - in process]

Widespread Down-Regulation of Cardiac Mitochondrial and Sarcomeric Genes in Patients With Sepsis.

Crit Care Med. 2017 Mar;45(3):407-414

Authors: Matkovich SJ, Al Khiami B, Efimov IR, Evans S, Vader J, Jain A, Brownstein BH, Hotchkiss RS, Mann DL

Abstract
OBJECTIVES: The mechanism(s) for septic cardiomyopathy in humans is not known. To address this, we measured messenger RNA alterations in hearts from patients who died from systemic sepsis, in comparison to changed messenger RNA expression in nonfailing and failing human hearts.
DESIGN: Identification of genes with altered abundance in septic cardiomyopathy, ischemic heart disease, or dilated cardiomyopathy, in comparison to nonfailing hearts.
SETTING: ICUs at Barnes-Jewish Hospital, St. Louis, MO.
PATIENTS: Twenty sepsis patients, 11 ischemic heart disease, nine dilated cardiomyopathy, and 11 nonfailing donors.
INTERVENTIONS: None other than those performed as part of patient care.
MEASUREMENTS AND MAIN RESULTS: Messenger RNA expression levels for 198 mitochondrially localized energy production components, including Krebs cycle and electron transport genes, decreased by 43% ± 5% (mean ± SD). Messenger RNAs for nine genes responsible for sarcomere contraction and excitation-contraction coupling decreased by 43% ± 4% in septic hearts. Surprisingly, the alterations in messenger RNA levels in septic cardiomyopathy were both distinct from and more profound than changes in messenger RNA levels in the hearts of patients with end-stage heart failure.
CONCLUSIONS: The expression profile of messenger RNAs in the heart of septic patients reveals striking decreases in expression levels of messenger RNAs that encode proteins involved in cardiac energy production and cardiac contractility and is distinct from that observed in patients with heart failure. Although speculative, the global nature of the decreases in messenger RNA expression for genes involved in cardiac energy production and contractility suggests that these changes may represent a short-term adaptive response of the heart in response to acute change in cardiovascular homeostasis.

PMID: 28067713 [PubMed - indexed for MEDLINE]

Population pharmacokinetics of Daunorubicin in adult patients with acute myeloid leukemia.

Cancer Chemother Pharmacol. 2016 Nov;78(5):1051-1058

Authors: Varatharajan S, Panetta JC, Abraham A, Karathedath S, Mohanan E, Lakshmi KM, Arthur N, Srivastava VM, Nemani S, George B, Srivastava A, Mathews V, Balasubramanian P

Abstract
PURPOSE: Chemotherapy drug resistance and relapse of the disease have been the major factors limiting the success of acute myeloid leukemia (AML) therapy. Several factors, including the pharmacokinetics (PK) of Cytarabine (Ara-C) and Daunorubicin (Dnr), could contribute to difference in treatment outcome in AML.
METHODS: In the present study, we evaluated the plasma PK of Dnr, the influence of genetic polymorphisms of genes involved in transport and metabolism of Dnr on the PK, and also the influence of these factors on clinical outcome. Plasma levels of Dnr and its major metabolite, Daunorubicinol (DOL), were available in 70 adult de novo AML patients. PK parameters (Area under curve (AUC) and clearance (CL)) of Dnr and DOL were calculated using nonlinear mixed-effects modeling analysis performed with Monolix. Genetic variants in ABCB1, ABCG2, CBR1, and CBR3 genes as well as RNA expression of CBR1, ABCB1, and ABCG2 were compared with Dnr PK parameters.
RESULTS: The AUC and CL of Dnr and DOL showed wide inter-individual variation. Patients with an exon1 variant of rs25678 in CBR1 had significantly higher plasma Dnr AUC [p = 0.05] compared to patients with wild type. Patients who achieved complete remission (CR) had significantly lower plasma Dnr AUC, Cmax, and higher CL compared to patients who did not achieve CR.
CONCLUSION: Further validation of these findings in a larger cohort of AML patients is warranted before establishing a therapeutic window for plasma Dnr levels and targeted dose adjustment.

PMID: 27738808 [PubMed - indexed for MEDLINE]

Interleukin 1 receptor type 2 gene polymorphism is associated with reduced risk of preterm birth.

J Matern Fetal Neonatal Med. 2016 Oct;29(20):3347-50

Authors: Langmia IM, Apalasamy YD, Omar SZ, Mohamed Z

Abstract
OBJECTIVE: Interleukin 1 receptor type 2 (IL1R2) regulates the inflammatory pathway that results in preterm delivery. We aim to investigate the impact of IL1R2 gene polymorphisms on the risk of preterm delivery.
METHOD: A total of 664 women with spontaneous preterm and term deliveries were genotyped for IL1R2 gene polymorphisms (rs2072476A/G, rs2071008G/T, rs2072474C/T) using Sequenom MassARRAY platform.
RESULTS: Ethnic-specific analysis revealed a significant association between the G allele of IL1R2 rs2072476 polymorphism and reduced risk of PTB in the Indian ethnic subgroup (OR: 3.7, 95% CI: 1.3-11.3, p = 0.017). The odds of G allele occurring among Indian women with term delivery (>37 weeks) was three times higher than those with preterm delivery (<37 weeks). Genotype analysis showed a significant association between the GG genotype of IL1R2 rs2072476 polymorphism and term delivery in the Indian women.
CONCLUSION: This study shows disparity in the occurrence of preterm birth due to the differences in the genotype of the women. Particularly, Indian women with the minor allele of IL1R2 rs2072476 polymorphisms were more likely to deliver at term (>37 weeks). These findings suggest the possible influence of maternal IL1R2 gene polymorphism on the risk of preterm delivery.

PMID: 26607028 [PubMed - indexed for MEDLINE]

Genetic determination of body fat distribution and the attributive influence on metabolism.

Obesity (Silver Spring). 2017 May 25;:

Authors: Fehlert E, Wagner R, Ketterer C, Böhm A, Machann J, Fritsche L, Machicao F, Schick F, Staiger H, Stefan N, Häring HU, Fritsche A, Heni M

Abstract
OBJECTIVE: Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with estimates of body fat distribution. Using predefined risk allele scores, the correlation of these scores with precisely quantified body fat distribution assessed by magnetic resonance (MR) imaging techniques and with metabolic traits was investigated.
METHODS: Data from 4,944 MR scans from 915 subjects of European ancestry were analyzed. Body fat distribution was determined by MR imaging and liver fat content by (1) H-MR spectroscopy. All subjects underwent a five-point 75-g oral glucose tolerance test. A total of 65 SNPs with reported genome-wide significant associations regarding estimates of body fat distribution were genotyped. Four genetic risk scores were created by summation of risk alleles.
RESULTS: A higher allelic load of waist-to-hip ratio SNPs was associated with lower insulin sensitivity, higher postchallenge glucose levels, and more visceral and less subcutaneous fat mass.
CONCLUSIONS: GWAS-derived polymorphisms estimating body fat distribution are associated with distinct patterns of body fat distribution exactly measured by MR. Only the risk score associated with the waist-to-hip ratio in GWAS showed an unhealthy pattern of metabolism and body fat distribution. This score might be useful for predicting diseases associated with genetically determined, unhealthy obesity.

PMID: 28544651 [PubMed - as supplied by publisher]

The role of ITPA and ribavirin transporter genes polymorphisms in prediction of ribavirin-induced anemia in chronic hepatitis C Egyptian patients.

Clin Exp Pharmacol Physiol. 2017 May 24;:

Authors: El Desoky ES, Abdelhafez AT, Cusato J, Kamel SI, Hussein AMR, De Nicolo A, Di Perri G, D'Avolio A

Abstract
Few data are available concerning the roles of polymorphisms of inosine triphosphatase (ITPA) gene and ribavirin (RBV) transporter genes in the prediction of RBV-induced anemia among Egyptians with chronic hepatitis C (CHC). Genotyping of 3 ITPA gene variants and 2 variants of RBV transporter genes has been performed in 123 patients under pegylated interferon-α/ribavirin treatment. The baseline hemoglobin and ITPA rs1127354 CA/AA have been found as predictors of anemia at 4, 8 and 12 weeks of RBV therapy. In addition, ITPA rs7270101 AC/CC and age predicted anemia after 12 weeks of therapy. In conclusion, the ITPA variant rs1127354C>A significantly predict RBV-induced anemia during the first 3 months of treatment and it is recommended to be assessed before RBV administration. This article is protected by copyright. All rights reserved.

PMID: 28543275 [PubMed - as supplied by publisher]

Evaluation of connectivity map-discovered celastrol as a radiosensitizing agent in a murine lung carcinoma model: Feasibility study of diffusion-weighted magnetic resonance imaging.

PLoS One. 2017;12(5):e0178204

Authors: Jun HY, Kim TH, Choi JW, Lee YH, Lee KK, Yoon KH

Abstract
This study was designed to identify potential radiosensitizing (RS) agents for combined radio- and chemotherapy in a murine model of human lung carcinoma, and to evaluate the in vivo effect of the RS agents using diffusion-weighted magnetic resonance imaging (DW-MRI). Radioresistance-associated genes in A549 and H460 cells were isolated on the basis of their gene expression profiles. Celastrol was selected as a candidate RS by using connectivity mapping, and its efficacy in lung cancer radiotherapy was tested. Mice inoculated with A549 carcinoma cells were treated with single ionizing radiation (SIR), single celastrol (SC), or celastrol-combined ionizing radiation (CCIR). Changes in radiosensitization over time were assessed using DW-MRI before and at 3, 6, and 12 days after therapy initiation. The tumors were stained with hematoxylin and eosin at 6 and 12 days after therapy. The percentage change in the apparent diffusion coefficient (ADC) value in the CCIR group was significantly higher than that in the SC and SIR group on the 12th day (Mann-Whitney U-test, p = 0.05; Kruskal-Wallis test, p < 0.05). A significant correlation (Spearman's rho correlation coefficient of 0.713, p = 0.001) was observed between the mean percentage tumor necrotic area and the mean ADC values after therapy initiation. These results suggest that the novel radiosensitizing agent celastrol has therapeutic effects when combined with ionizing radiation (IR), thereby maximizing the therapeutic effect of radiation in non-small cell lung carcinoma. In addition, DW-MRI is a useful noninvasive tool to monitor the effects of RS agents by assessing cellularity changes and sequential therapeutic responses.

PMID: 28542649 [PubMed - in process]

Genotype-specific methylation of HPV in cervical intraepithelial neoplasia.

J Gynecol Oncol. 2017 Jul;28(4):e56

Authors: Hsu YW, Huang RL, Su PH, Chen YC, Wang HC, Liao CC, Lai HC

Abstract
OBJECTIVE: Hypermethylation of human papillomavirus (HPV) and host genes has been reported in cervical cancer. However, the degree of methylation of different HPV types relative to the severity of the cervical lesions remains controversial. Studies of the degree of methylation associated with the host gene and the HPV genome to the severity of cervical lesions are rare. We examined the association of methylation status between host genes and late gene 1 (L1) regions of HPV16, 18, 52, and 58 in cervical brushings.
METHODS: Cervical brushings from 147 HPV-infected patients were obtained. The samples comprised normal (n=28), cervical intraepithelial neoplasia (CIN) 1 (n=45), CIN2 (n=13), and CIN3/carcinoma in situ (n=61). The methylation status of HPV and host genes was measured using bisulfite pyrosequencing and quantitative methylation-specific polymerase chain reaction (PCR).
RESULTS: The degree of methylation of L1 in HPV16, 18, and 52 was associated with the severity of the cervical lesion. In HPV52, C-phosphate-G (CpG) sites 6368m, 6405m, and 6443m showed significantly higher methylation in lesions ≥CIN3 (p=0.005, 0.003, and 0.026, respectively). Methylation of most HPV types except HPV52 (r<-0.1) was positively correlated with the degree of methylation of host genes including PAX1 and SOX1 (0.4≤r≤0.7). Combining HPV methylation with PAX1 methylation improved the clustering for ≥CIN2.
CONCLUSION: Our study showed that the degree of L1 methylation of HPV16, 18, and 52 but not 58 is associated with the severity of cervical lesions. The association between HPV methylation and host gene methylation suggests different responses of host cellular epigenetic machinery to different HPV genotypes.

PMID: 28541643 [PubMed - in process]

Long Fragment Polymerase Chain Reaction.

Methods Mol Biol. 2017;1620:65-74

Authors: Chua EW, Maggo S, Kennedy MA

Abstract
Polymerase chain reaction (PCR) is an oft-used preparatory technique in amplifying specific DNA regions for downstream analysis. The size of an amplicon was initially limited by errors in nucleotide polymerization and template deterioration during thermal cycling. A variant of PCR, designated long-range PCR, was devised to counter these drawbacks and enable the amplification of large fragments exceeding a few kb. In this chapter we describe a protocol for long-range PCR, which we have adopted to obtain products of 6.6, 7.2, 13, and 20 kb from human genomic DNA samples.

PMID: 28540699 [PubMed - in process]

Correlation of HAMP gene polymorphisms and expression with the susceptibility and length of hospital stays in Taiwanese children with Kawasaki disease.

Oncotarget. 2017 May 08;:

Authors: Huang YH, Yang KD, Hsu YW, Lu HF, Wong HS, Yu HR, Kuo HC, Huang FC, Lo MH, Hsieh KS, Chen SF, Chang WC, Kuo HC

Abstract
Kawasaki disease (KD) is a form of systemic vasculitis. Regarding its pathogenesis, HAMP gene encoding hepcidin, which is significant for iron metabolism, has a vital function. In this study, we recruited a total of 381 KD patients for genotyping. Data from 997 subjects (500 subjects from cohort 1; 497 subjects from cohort 2) were used for analysis. Using TaqMan allelic discrimination, we determined five tag SNPs (rs916145, rs10421768, rs3817623, rs7251432, and rs2293689). Treatment outcome data related to such clinical phenotypes as coronary artery lesions (CAL), coronary artery aneurysms (CAA), and intravenous immunoglobulin (IVIG) effects were also collected. Furthermore, we measured plasma hepcidin levels with an enzyme-linked immunosorbent assay. We found that HAMP gene polymorphism (rs7251432, and rs2293689) was significantly correlated with KD risk and that plasma hepcidin levels both before and after IVIG treatment had a significantly positive correlation with length of hospital stays (R = 0.217, p = 0.046 and R = 0.381, p < 0.0001, respectively). In contrast, plasma hepcidin levels has a negative correlation with KD patients' albumin levels (R = -0.27, p < 0.001) prior to IVIG treatment. This study's findings indicate that HAMP might have a role in the disease susceptibility, as well as its expressions correlated length of hospital stays, and albumin levels in Taiwanese children with KD.

PMID: 28538210 [PubMed - as supplied by publisher]

UHPLC-MS/MS method with sample dilution to test therapeutic adherence through quantification of ten antihypertensive drugs in urine samples.

J Pharm Biomed Anal. 2017 May 13;142:279-285

Authors: De Nicolò A, Avataneo V, Rabbia F, Sciandra M, Tosello F, Cusato J, Perlo E, Mulatero P, Veglio F, Di Perri G, D'Avolio A

Abstract
Nowadays, hypertension represents an important health problem, particularly in developed countries. In some cases the standard therapeutic approaches are not able to reestablish the normal blood pressure values: this condition is called "resistant hypertension". However, a fraction of cases of resistant hypertension are actually due to poor adherence to the prescribed therapy. Therapeutic Drug Monitoring could represent a direct and useful tool to correctly identify non-compliant patients. Nevertheless, high throughput methods for the simultaneous monitoring of a wide panel of drugs in the same analysis are lacking and, furthermore, there is not a generally acknowledged "standard" matrix for this test (plasma or urine). In this work, we validated a UHPLC-MS/MS assay to quantify ten among the most used antihypertensive agents in urine samples, covering all the current classes: amlodipine, atenolol, clonidine, chlortalidone, doxazosin, hydrochlorothiazide, nifedipine, olmesartan, ramipril and telmisartan. Both standards and quality controls were prepared in urine matrix. Only 100μL of each sample were added with 40μL of internal standard and 860μL of water:acetonitrile 90:10, acidified with 0.05% formic acid. Chromatographic separation was performed on an Acquity(®) UPLC HSS T3 1.8μm 2.1×150mm column, with a gradient of water and acetonitrile, both added with 0.05% formic acid. Accuracy, intra-day and inter-day precision fitted FDA guidelines for all analytes, while matrix effects resulted reproducible among different urine lots. Method performances were tested on urine samples from hypertensive patients with good results. This simple analytical method could represent a useful tool for the management of antihypertensive therapy.

PMID: 28538203 [PubMed - as supplied by publisher]

Spectrum of genomic alterations in FGFR3: current appraisal of the potential role of FGFR3 in advanced urothelial carcinoma.

BJU Int. 2016 Nov;118(5):681-691

Authors: Sethakorn N, O'Donnell PH

Abstract
Molecular analysis has identified subsets of urothelial carcinoma (UC) expressing distinct genetic signatures. Genomic alterations in the oncogenic fibroblast growth factor receptor 3 (FGFR3) pathway are among the most well described in UC and have led to extensive and ongoing investigation of FGFR3-targeted therapies in this disease, although no new drugs have yet been approved. Given the unmet need for effective treatments in advanced and metastatic UC, a better understanding of the known molecular alterations of FGFR3 and of the previous and ongoing clinical investigations of this promising target in UC deserves attention. The objective of the present review is to describe the landscape of alterations and biology of FGFR3 in UC, comprehensively summarize the current state of UC clinical trials of FGFR3 inhibitors, and discuss future therapeutic applications. Using the Pubmed and Clinicaltrials.gov databases, articles describing the spectrum and biological activity of FGFR3 genomic alterations and trials of FGFR3 inhibitors in UC were identified. Search terms included 'FGFR3 genomic alterations' and 'urothelial cancer' or 'bladder cancer'. Genomic alterations, including translocations and activating mutations, are increasingly described in advanced and metastatic UC. The majority of clinical trials have been performed in unselected populations; however, recent studies have reported encouraging preliminary data. We argue that routine use of molecular genomic tumour analysis in UC may inform selection of patients for appropriate trials and we further investigate the potential of FGFR3 as a meaningful clinical target for this difficult disease.

PMID: 27271022 [PubMed - indexed for MEDLINE]

Pharmacokinetic Pharmacogenetic Prescribing Guidelines for Antidepressants: A Template for Psychiatric Precision Medicine.

Mayo Clin Proc. 2016 Jul;91(7):897-907

Authors: Nassan M, Nicholson WT, Elliott MA, Rohrer Vitek CR, Black JL, Frye MA

Abstract
Antidepressants are commonly prescribed medications in the United States, and there is increasing interest in individualizing treatment selection for more than 20 US Food and Drug Administration-approved treatments for major depressive disorder. Providing greater precision to pharmacotherapeutic recommendations for individual patients beyond the large-scale clinical trials evidence base can potentially reduce adverse effect toxicity profiles and increase response rates and overall effectiveness. It is increasingly recognized that genetic variation may contribute to this differential risk to benefit ratio and thus provides a unique opportunity to develop pharmacogenetic guidelines for psychiatry. Key studies and concepts that review the rationale for cytochrome P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19) genetic testing can be delineated by serum levels, adverse events, and clinical outcome measures (eg, antidepressant response). In this article, we report the evidence that contributed to the implementation of pharmacokinetic pharmacogenetic guidelines for antidepressants primarily metabolized by CYP2D6 and CYP2C19.

PMID: 27289413 [PubMed - indexed for MEDLINE]

TRPC6 G757D Loss-of-Function Mutation Associates with FSGS.

J Am Soc Nephrol. 2016 Sep;27(9):2771-83

Authors: Riehle M, Büscher AK, Gohlke BO, Kaßmann M, Kolatsi-Joannou M, Bräsen JH, Nagel M, Becker JU, Winyard P, Hoyer PF, Preissner R, Krautwurst D, Gollasch M, Weber S, Harteneck C

Abstract
FSGS is a CKD with heavy proteinuria that eventually progresses to ESRD. Hereditary forms of FSGS have been linked to mutations in the transient receptor potential cation channel, subfamily C, member 6 (TRPC6) gene encoding a nonselective cation channel. Most of these TRPC6 mutations cause a gain-of-function phenotype, leading to calcium-triggered podocyte cell death, but the underlying molecular mechanisms are unclear. We studied the molecular effect of disease-related mutations using tridimensional in silico modeling of tetrameric TRPC6. Our results indicated that G757 is localized in a domain forming a TRPC6-TRPC6 interface and predicted that the amino acid exchange G757D causes local steric hindrance and disruption of the channel complex. Notably, functional characterization of model interface domain mutants suggested a loss-of-function phenotype. We then characterized 19 human FSGS-related TRPC6 mutations, the majority of which caused gain-of-function mutations. However, five mutations (N125S, L395A, G757D, L780P, and R895L) caused a loss-of-function phenotype. Coexpression of wild-type TRPC6 and TRPC6 G757D, mimicking heterozygosity observed in patients, revealed a dominant negative effect of TRPC6 G757D. Our comprehensive analysis of human disease-causing TRPC6 mutations reveals loss of TRPC6 function as an additional concept of hereditary FSGS and provides molecular insights into the mechanism responsible for the loss-of-function phenotype of TRPC6 G757D in humans.

PMID: 26892346 [PubMed - indexed for MEDLINE]

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