Cancer Stem Cell Gene Variants in CD44 Predict Outcome in Stage II and Stage III Colon Cancer Patients.

Anticancer Res. 2017 Apr;37(4):2011-2018

Authors: Stotz M, Herzog SA, Pichler M, Smolle M, Riedl J, Rossmann C, Bezan A, Stöger H, Renner W, Berghold A, Gerger A

Abstract
BACKGROUND/AIM: Growing evidence suggests that human cancers are stem cell diseases and recent data support the existence of cancer stem cells (CSCs) in a variety of malignancies, including colon cancer. These CSCs were shown to be capable of initiating tumor development and progression. Several studies have suggested CD133, CD26 and CD44 as markers of tumor-initiating cells of colon cancer. The purpose of the present study was to assess the impact of single-nucleotide polymorphisms (SNPs) in stem cell-related genes on clinical outcome in a large cohort of colon cancer patients with clinical stage II and III.
PATIENTS AND METHODS: Data from 599 consecutive patients with colon cancer stage II and III, treated between 1995 and 2011 at a single centre, were retrospectively evaluated. Genomic DNA was extracted from paraffin-embedded normal tissue distant from the tumor to obtain germline DNA. Allelic distribution of polymorphisms was tested for deviation from Hardy-Weinberg equilibrium using χ(2)-test. The association of polymorphisms with time to recurrence (TTR) and overall survival (OS) was analyzed using Kaplan-Meier curves and compared by the log-rank test. Case-wise deletion for missing polymorphisms was used in univariable and multivariable analyses.
RESULTS: CD44 rs187115 showed a statistically significant association with TTR; patients carrying at least one G allele had a significant reduced risk of recurrence compared to patients with the homozygous A/A variant (hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.48-0.94, p=0.019). CD44 rs13347 showed a statistically significant association with OS. Patients carrying at least one T allele in rs13347 had a significantly reduced risk of death compared to patients with the homozygous C/C variant (HR=0.61, 95% CI=0.41-0.92, p=0.019). None of the other investigated polymorphisms (CD44 rs187116, CD44 rs7116432, CD44 rs353639, DPP4 rs2268889, DPP4 rs3788979, DPP4 rs7608798 and CD133 rs2240688) were associated with either TTR or OS.
CONCLUSION: Germline variants rs13347 and rs187115 in the stem cell gene CD44 are prognostically relevant in stage II and III colon cancer patients.

PMID: 28373475 [PubMed - in process]

bFGF Polymorphism Is Associated with Disease Progression and Response to Chemotherapy in Multiple Myeloma Patients.

Anticancer Res. 2017 Apr;37(4):1799-1803

Authors: Wróbel T, Butrym A, Łacina P, Rybka J, Gębura K, Mazur G, Bogunia-Kubik K

Abstract
BACKGROUND/AIM: Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) play an important role in the initiation of angiogenesis. We aimed to assess whether polymorphisms within the genes coding for these angiogenic activators (VEGF (rs3025039;C>T) and bFGF (rs308395;G>C)) contribute to susceptibility and/or progression in multiple myeloma patients (MM) and to chemotherapy.
PATIENTS AND METHODS: One hundred and thirty-two patients with MM and 122 controls were genotyped for the VEGF and bFGF alleles by the PCR-RFLP technique. Genotyping results were compared regarding progression, risk of disease and response to treatment.
RESULTS: Patients in stage I-II disease (Durie-Salmon criteria) more frequently carried the bFGF -921G allele compared to patients in stage III (p=0.053) and healthy controls (OR=2.010, p=0.040). Progression after first-line chemotherapy was more frequent among patients carrying this variant (p=0.022).
CONCLUSION: Our results imply that the course of disease in MM patients is associated with a polymorphism within the bFGF gene.

PMID: 28373444 [PubMed - in process]

Historical root of precision medicine: an ancient concept concordant with the modern pharmacotherapy.

Daru. 2017 Apr 04;25(1):7

Authors: Moeini R, Memariani Z, Pasalar P, Gorji N

Abstract
Pharmacogenomics and pharmacoproteomics are new sciences that their goal is achieving therapeutics with maximum results and minimal side effects for each individual due to the pattern of his genome and proteome.Although they considered new and high technology sciences but in distant past, Persian sages like Avicenna also knew about importance of "personalized medicine" and used specific patterns to detect individual differences in order to select suitable medication.Based on experience and analogy they divided individuals into different categories considering characteristics like body color, body temperature, sleep-awake pattern and skeletal structure.They also paid attention to effect of environmental conditions such as climate, job and the change of seasons on the influence of medication.Considering the low cost and ease of use of these experiences, it seems that researching their opinions can uncover the historical roots of modern pharmacoproteomics and can possibly infuse new ideas in this field.

PMID: 28372571 [PubMed - in process]

Acute Nonspecific Mesenteric Lymphadenitis: More Than "No Need for Surgery".

Biomed Res Int. 2017;2017:9784565

Authors: Helbling R, Conficconi E, Wyttenbach M, Benetti C, Simonetti GD, Bianchetti MG, Hamitaga F, Lava SA, Fossali EF, Milani GP

Abstract
Acute nonspecific, or primary, mesenteric lymphadenitis is a self-limiting inflammatory condition affecting the mesenteric lymph nodes, whose presentation mimics appendicitis or intussusception. It typically occurs in children, adolescents, and young adults. White blood count and C-reactive protein are of limited usefulness in distinguishing between patients with and without mesenteric lymphadenitis. Ultrasonography, the mainstay of diagnosis, discloses 3 or more mesenteric lymph nodes with a short-axis diameter of 8 mm or more without any identifiable underlying inflammatory process. Once the diagnosis is established, supportive care including hydration and pain medication is advised. Furthermore, it is crucial to reassure patients and families by explaining the condition and stating that affected patients recover completely without residuals within 2-4 weeks.

PMID: 28261620 [PubMed - indexed for MEDLINE]

Pharmacoepigenetics: an element of personalized therapy?

Expert Opin Drug Metab Toxicol. 2017 Apr;13(4):387-398

Authors: Majchrzak-Celińska A, Baer-Dubowska W

Abstract
INTRODUCTION: Epigenetics is a rapidly growing field describing heritable alterations in gene expression that do not involve DNA sequence variations. Advances in epigenetics and epigenomics have influenced pharmacology, leading to the development of a new specialty, pharmacoepigenetics, the study of the epigenetic basis for the individual variation in drug response. Areas covered: We present an overview of the major epigenetic mechanisms and their effects on the expression of drug metabolizing enzymes and drug transporters, as well as the epigenetic status of drug protein targets affecting therapy response. Recent advances in the development of pharmacoepigenetic biomarkers and epidrugs are also discussed. Expert opinion: There is growing evidence that pharmacoepigenetics has the potential to become an important element of personalized medicine. Epigenetic modifications influence drug response, but they can also be modulated by drugs. Moreover, they can be monitored not only in the affected tissue, but also in body fluids. Nevertheless, there are very few examples of epigenetic biomarkers implemented in the clinical setting. Explanation of the interplay between genomic and epigenomic changes will contribute to the personalized medicine approach. Ultimately, both genetic biomarkers and epigenetic mechanisms should be taken into consideration in predicting drug response in the course of successful personalized therapy.

PMID: 27860490 [PubMed - indexed for MEDLINE]

Association of polymorphisms within the Renin-Angiotensin System with metabolic syndrome in a cohort of Chilean subjects.

Arch Endocrinol Metab. 2016 Feb 23;60(3):190-8

Authors: Herrera CL, Castillo W, Estrada P, Mancilla B, Reyes G, Saavedra N, Guzmán N, Serón P, Lanas F, Salazar LA

Abstract
OBJECTIVE: Metabolic syndrome (MetS) is associated with hypertension, obesity and dyslipidemia. Thus, genetic variants related with these conditions may modulate its development. We evaluated the effect of polymorphisms in the renin-angiotensin system (RAS) on metabolic syndrome risk in a cohort of Chilean subjects.
SUBJECTS AND METHODS: A total of 152 subjects, 83 with MetS (51.2 ± 9.6 years) and 69 without MetS (49.5 ± 9.3 years) of both genders were included, according to the ATP III update criteria. The rs4340 Insertion/Deletion (I/D), rs699 (T>C) and rs5186 (A>C) of the ACE, AGT and AGTR1 genes, respectively, were genotyped.
RESULTS: After adjusting for age and gender, we observed the DD genotype of rs4340 associated with MetS (p = 0.02). Specifically, the DD genotype was associated with MetS risk in women (OR = 4.62, 95%CI, 1.41 - 15.04; p < 0.01). In males, the AA genotype for rs5186 variant was associated with an increased risk for developing MetS when compared with women carrying the same genotype (OR = 3.2; 95%CI, 1.03 - 9.89; p = 0.04). In subjects without MetS, DD genotype was associated with increased waist circumference (p = 0.023) while subjects with MetS carrying the rs5186 TT genotype showed higher levels of HDL-cholesterol (p = 0.031).
CONCLUSION: The present study contributes data highlighting the role for RAS polymorphisms in predisposing to metabolic syndrome in Chilean subjects.

PMID: 26910623 [PubMed - indexed for MEDLINE]

The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent.

Gastroenterology. 2016 05;150(5):1219-1230.e6

Authors: Mancina RM, Dongiovanni P, Petta S, Pingitore P, Meroni M, Rametta R, Borén J, Montalcini T, Pujia A, Wiklund O, Hindy G, Spagnuolo R, Motta BM, Pipitone RM, Craxì A, Fargion S, Nobili V, Käkelä P, Kärjä V, Männistö V, Pihlajamäki J, Reilly DF, Castro-Perez J, Kozlitina J, Valenti L, Romeo S

Abstract
BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7-TMC4 is a susceptibility locus for the development and progression of NAFLD.
METHODS: We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-Sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study also underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-Sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity.
RESULTS: The genotype rs641738 at the MBOAT7-TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared with subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function.
CONCLUSIONS: We provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling.

PMID: 26850495 [PubMed - indexed for MEDLINE]

A Simulation Study to Compare the Treatment Effect of Tamoxifen by CYP2D6 Genotypes and Third-Generation Aromatase Inhibitors.

J Clin Pharmacol. 2017 Apr 03;:

Authors: Park GC, Jung JA, Bae KS, Lim HS

Abstract
Some prospective, randomized clinical trials, including ATAC and BIG 1-98, demonstrated superior treatment effect of third-generation aromatase inhibitors (AIs) versus tamoxifen in postoperative therapy for patients with breast cancer. In retrospective genotyping analyses of the 2 studies using tumor samples, no difference in the treatment effect of tamoxifen was observed by CYP2D6 genotypes. However, those analyses did not consider loss of heterozygosity that could have occurred when genotyping using tumor tissue. The present simulation study aimed to comparatively evaluate the treatment effect of tamoxifen versus AIs of anastrozole and letrozole by CYP2D6 genotypes. A meta-analysis was conducted to estimate disease-free survival (DFS) hazard ratios of CYP2D6 genotypes representing extensive metabolizers (EMs), HRW/W,TAM , versus intermediate metabolizers (IMs)/poor metabolizers (PMs), HRV/W,TAM , using previous study results in which genotypes were determined using blood samples. Based on known allele frequencies, the CYP2D6 genotype distribution of participants in ATAC and BIG 1-98 trials were simulated. Subseqyuently, DFS HRs of AIs versus tamoxifen by CYP2D6 genotypes (HRAI/TAM,W for EMs, HRAI/TAM,V for IMs/PMs) were estimated via regression analyses using NONMEM, based on the simulated genotype distributions, HRV/W,TAM , and HRs, of AIs versus tamoxifen (HRAI/TAM ) reported in the ATAC and BIG 1-98 trials. Median HRAI/TAM,V (95% prediction interval [PI]) was 0.43 (0.23-0.79) and 0.40 (0.22-0.73) for the ATAC and BIG 1-98 trials, respectively. However, the corresponding HRAI/TAM,W values were 0.97 (0.84-1.11) and 0.91 (0.77-1.08), respectively. These results suggest that in patients with the CYP2D6 genotype representing EMs, the treatment effect of tamoxifen is comparable to that of AIs.

PMID: 28369967 [PubMed - as supplied by publisher]

System pharmacogenomics application in infectious diseases.

Brief Funct Genomics. 2017 Mar 21;:

Authors: Mandlik V, Kabra R, Singh S

Abstract
The new era in systems pharmacology has revolutionized the human biology. Its applicability, precise treatment, adequate response and safety measures fit into all the paradigm of medical/clinical practice. The importance of mathematical models in understanding the disease pathology and epideomology is now being realized. The advent of high-throughput technologies and the emergence of systems biology have resulted in the creation of systems pharmacogenomics and the focus is now on personalized medicine. However, there are some regulatory issues that need to be addresssed; are we ready for this universal adoption? This article details some of the infectious disease pharmacogenomics to the developments in this area.

PMID: 28369182 [PubMed - as supplied by publisher]

Classics in Chemical Neuroscience: Aripiprazole.

ACS Chem Neurosci. 2017 Apr 03;:

Authors: Casey AB, Canal CE

Abstract
Aripiprazole was the first antipsychotic developed to possess agonist properties at dopamine D2 autoreceptors, a groundbreaking strategy that presented a new vista for schizophrenia drug discovery. The dopamine D2 receptor is the crucial target of all extant antipsychotics, and all developed prior to aripiprazole were D2 receptor antagonists. Extensive blockade of these receptors, however, typically produces extrapyramidal (movement) side effects which plagued first-generation antipsychotics, such as haloperidol. Second-generation antipsychotics, such as clozapine, with unique polypharmacology and D2 receptor binding kinetics, have significantly lower risk of movement side effects, but can cause myriad additional ones, such as severe weight gain and metabolic dysfunction. Aripiprazole's polypharmacology-characterized by its unique agonist activity at dopamine D2, D3 and serotonin 5-HT1A receptors as well as antagonist activity at serotonin 5-HT2A receptors-translates to successful reduction of positive, negative, and cognitive symptoms of schizophrenia, while also mitigating risk of weight gain and movement side effects. New observations, however, link aripiprazole to compulsive behaviors in a small group of patients, an unusual side effect for antipsychotics. In this review, we discuss the chemical synthesis, pharmacology, pharmacogenomics, drug metabolism, and adverse events of aripiprazole, and we present a current understanding of aripiprazole's neurotherapeutic mechanisms, as well as the history and importance of aripiprazole to neuroscience.

PMID: 28368577 [PubMed - as supplied by publisher]

Do polymorphisms in MDR1 and CYP3A5 genes influence the risk of cytogenetic relapse in patients with chronic myeloid leukemia on imatinib therapy?

Leuk Lymphoma. 2017 Apr 03;:1-9

Authors: Harivenkatesh N, Kumar L, Bakhshi S, Sharma A, Kabra M, Velpandian T, Gogia A, Shastri SS, Gupta YK

Abstract
Influence of polymorphisms in the genes coding for imatinib transporters and metabolizing enzymes on cytogenetic relapse in patients with chronic myeloid leukemia (CML) is not known. One hundred and four patients (52 cases with cytogenetic relapse and 52 controls without relapse) with chronic-phase CML on imatinib therapy and have completed 5 years of follow-up were enrolled. The following single nucleotide polymorphisms (SNPs) were genotyped; C1236T, C3435T, G2677T/A in MDR1 gene and A6986G in CYP3A5 gene, using PCR-RFLP method and validated by direct gene sequencing. Imatinib trough levels were measured using LC-MS/MS. Patients with CC genotype for MDR1-C1236T polymorphism were at significantly higher risk for cytogenetic relapse [OR =4.382, 95% CI (1.145, 16.774), p = .022], while those with TT genotype for MDR1-C3435T polymorphism had significantly lower risk of relapse [OR =0.309, 95% CI (0.134, 0.708), p = .005]. Imatinib trough levels were lower in patients with relapse compared to those without relapse (1551.4 ± 1324.1 vs. 2154.2 ± 1358.3 ng/mL; p = .041). MDR1-C3435T genotype [adjusted-OR: 0.266; 95% CI (0.111, 0.636); p = .003] and trough levels (p = .014) were independent predictors of relapse in multivariate analysis. To conclude, C1236T and C3435T polymorphisms in MDR1 gene and trough levels significantly influence the risk of cytogenetic relapse. MDR1-C3435T genotype might emerge as a potential biomarker to predict the risk of cytogenetic relapse in patients with CML.

PMID: 28367681 [PubMed - as supplied by publisher]

Potential protective function of the sterol regulatory element binding factor 1-fatty acid desaturase 1/2 axis in early-stage age-related macular degeneration.

Heliyon. 2017 Mar;3(3):e00266

Authors: Ashikawa Y, Nishimura Y, Okabe S, Sato Y, Yuge M, Tada T, Miyao H, Murakami S, Kawaguchi K, Sasagawa S, Shimada Y, Tanaka T

Abstract
Age-related macular degeneration (AMD) is the most common cause of vision loss in elderly individuals throughout the developed world. Inhibitors of vascular endothelial growth factor have been successfully used to treat choroidal neovascularization in late-stage AMD. The pathogenesis of early-stage AMD, however, remains largely unknown, impairing efforts to develop effective therapies that prevent progression to late-stage AMD. To address this, we performed comparative transcriptomics of macular and extramacular retinal pigmented epithelium-choroid (RPE-choroid) tissue from early-stage AMD patients. We found that expression of fatty acid desaturase 1 (FADS1), FADS2, and acetyl-CoA acetyltransferase 2 (ACAT2) is increased in macular but not extramacular tissue, possibly through activation of sterol regulatory element binding factor 1 (SREBF1). Consistent with this, we also found that expression of Fads1 is increased in RPE-choroid in a mouse model of early-stage AMD. In zebrafish, deletion of fads2, which encodes a protein that functions as both Fads1 and Fads2 in other species, enhanced apoptosis in the retina upon exposure to intense light. Similarly, pharmacological inhibition of Srebf1 enhanced apoptosis and reduced fads2 expression in zebrafish exposed to intense light. These results suggest that the SREBF1-FADS1/2 axis may be activated in macular RPE-choroid as a protective response during early-stage AMD and could thus be a therapeutic target for early-stage AMD.

PMID: 28367511 [PubMed - in process]

Medication Risk Mitigation: Coordinating and Collaborating with Health Care Systems, Universities, and Researchers to Facilitate the Design and Execution of Practice-Based Research.

Clin Geriatr Med. 2017 May;33(2):257-281

Authors: Bain KT, Knowlton CH, Turgeon J

Abstract
The high prevalence of inappropriate polypharmacy in geriatric populations is unacceptable. Traditional medication risk mitigation (MRM) strategies have proven to be effective at improving polypharmacy, but these strategies have not consistently translated into positive health outcomes. Enhanced MRM strategies, such as using pharmacogenomics information, are needed, and these strategies need to be tested. A formidable challenge is successfully integrating pharmacogenomic information into clinical practice. As the medication experts on health care teams, pharmacists have a clear role to play in developing, integrating, and assessing enhanced MRM strategies to improve therapeutic outcomes for geriatric patients.

PMID: 28364995 [PubMed - in process]

Development and Validation of Liquid Chromatography/Tandem Mass Spectrometry Analysis for Therapeutic Drug Monitoring of Risperidone and 9-Hydroxyrisperidone in Pediatric Patients with Autism Spectrum Disorders.

J Clin Lab Anal. 2016 Nov;30(6):1236-1246

Authors: Vanwong N, Prommas S, Puangpetch A, Hongkaew Y, Nuntamool N, Nakorn CN, Ngamsamut N, Limsila P, Sukasem C

Abstract
BACKGROUND: Risperidone (RIS) is a widely used atypical antipsychotic drug. We developed and validated a sensitive and accurate LC-MS/MS method, which requires a small-volume of plasma and small-volume injection for measurement of RIS levels in ASD pediatric patients. We also investigated the relationship between RIS levels and RIS dosages, including prolactin levels.
METHOD: Blood samples were processed by protein precipitation extraction. Only 1 μl of sample was injected. Plasma samples were separated on a C18 column (4.6 cm × 50 mm; 1.8 μm particle size). Detection was by MS-MS with an analytical run time of 6 min.
RESULTS: The inter-day accuracy of RIS was 101.33-107.68% and 95.24-103.67% for 9-OH-RIS. The inter-day precision of RIS was ≤7.27% CV and ≤7.41% CV for 9-OH-RIS. The extraction recovery of RIS and 9-OH-RIS were 95.01 ± 7.31-112.62 ± 7.50% and 90.27 ± 11.15-114.00 ± 10.35%, respectively. This method was applied in the therapeutic drug monitoring of ASD pediatric patients. Higher RIS dosage has a tendency to produce higher RIS plasma levels. The high RIS plasma levels have a tendency to produce hyperprolactinemia.
CONCLUSION: The determination of RIS in individual patients might be clinically useful for monitoring and prediction of treatment response.

PMID: 27346210 [PubMed - indexed for MEDLINE]

Pharmacokinetic study of representative anti-oxidative compounds from Denshen-Chuanxiong-Honghua following oral administration in rats.

J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Mar 23;1052:82-90

Authors: Zhang X, Zheng W, Xu H, Huang X, Ren P, Zou H, Liu G, Wang J, Ma X

Abstract
Almost no pharmacokinetic compounds to date have been precisely linked with the activity of their herbal or Traditional Chinese Medicine (TCM) formula. This creates challenges for pharmacokinetic significance and application of the TCM. In our study, a sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to quantitatively or qualitatively determine multiple-components (tanshinol, ferulic acid, protocatechuic acid, rosmarinic acid, salvianolic acid B, baicalin and 9'-methyl lithospermate B) in rat plasma following the oral administration of Denshen-Chuanxiong-Honghua (DCH) extract (20g/kg). Chromatographic separation was carried out on a 300SB-C18 column using a gradient elution with a mobile phase composed of acetonitrile-water (containing 0.1% formic acid) at a flow rate of 1.0mL/min. Determination by mass spectrometry (MS) was conducted in multiple reaction monitoring (MRM) mode with negative electrospray ionization. The validated method exhibited good linearity, with correlation coefficients greater than 0.9949 over a wide concentration range, and the lower limits of quantification were 2.09-12.2ng/mL for the 5 analytes. This assay was successfully applied to investigate the pharmacokinetics of 5 compounds in rat plasma after the oral administration of DCH extracts. In addition, the anti-oxidant capacities of the 5 active ingredients of DCH extract in vitro and the total absorbed DCH extract in vivo were investigated at different concentrations during pharmacokinetic studies.

PMID: 28364700 [PubMed - as supplied by publisher]

Tissue-specific signaling networks rewired by major somatic mutations in human cancer revealed by proteome-wide discovery.

Cancer Res. 2017 Mar 31;:

Authors: Zhao J, Cheng F, Zhao Z

Abstract
Massive somatic mutations discovered by large cancer genome sequencing projects provide unprecedented opportunities in the development of precision oncology. However, deep understanding of functional consequences of somatic mutations and identifying actionable mutations and the related drug responses currently remain formidable challenges. Dysfunction of protein post-translational modification plays critical roles in tumorigenesis and drug responses. In this study, we proposed a novel computational oncoproteomics approach, named kinome-wide network module for cancer pharmacogenomics (KNMPx), for identifying actionable mutations that rewired signaling networks and further characterized tumorigenesis and anticancer drug responses. Specifically, we integrated 746,631 missense mutations in 4,997 tumor samples across 16 major cancer types/subtypes from The Cancer Genome Atlas into over 170,000 carefully curated non-redundant phosphorylation sites covering 18,610 proteins. We found 47 mutated proteins (e.g., ERBB2, TP53, and CTNNB1) that had enriched missense mutations at their phosphorylation sites in pan-cancer analysis. In addition, tissue-specific kinase-substrate interaction modules altered by somatic mutations identified by KNMPx were significantly associated with patient survival. We further reported a kinome-wide landscape of pharmacogenomic interactions by incorporating somatic mutation-rewired signaling networks in 1,001 cancer cell lines via KNMPx. Interestingly, we found that cell lines could highly reproduce oncogenic phosphorylation site mutations identified in primary tumors, supporting the confidence in their associations with sensitivity/resistance of inhibitors targeting EGF, MAPK, PI3K, mTOR, and Wnt signaling pathways. In summary, this systematic oncoproteomics analysis of kinome phosphorylation site mutations illustrates new capabilities to speed the development of precision oncology.

PMID: 28364002 [PubMed - as supplied by publisher]

A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors.

Mol Genet Genomic Med. 2017 Mar;5(2):130-140

Authors: Mitra AK, Dodge J, Van Ness J, Sokeye I, Van Ness B

Abstract
BACKGROUND: Kleefstra syndrome (KS) is a rare autosomal dominant developmental disability, caused by microdeletions or intragenic mutations within the epigenetic regulator gene EHMT1 (euchromatic histone lysine N-methyltransferase 1). In addition to common features of autism, young adult regressive behaviors have been reported. However, the genetic downstream effects of the reported deletions or mutations on KS phenotype have not yet been completely explored. While genetic backgrounds affecting drug metabolism can have a profound effect on therapeutic interventions, pharmacogenomic variations are seldom considered in directing psychotropic therapies.
METHODS: In this report, we used next-generation sequencing (exome sequencing and high-throughput RNA sequencing) in a patient and his parents to identify causative genetic variants followed by pharmacogenomics-guided clinical decision-making for making positive changes toward his treatment strategies. The patient had an early autism diagnosis and showed significant regressive behaviors and physical aberrations at age 23.
RESULTS: Exome sequencing identified a novel, de novo splice site variant NM_024757.4: c.2750-1G>T in EHMT1, a candidate gene for Kleefstra syndrome, in the patient that results in exon skipping and downstream frameshift and termination. Gene expression results from the patient showed, when compared to his parents, there was a significant decreased expression of several reported gene variants associated with autism risk. Further, using a pharmacogenomics genotyping panel, we discovered that the patient had the CYP2D6 nonfunctioning variant genotype *4/*4 that results in very low metabolic activity on a number of psychotropic drugs, including fluvoxamine which he was prescribed. As reported here, a change in psychotropic drugs and intense behavior therapies resulted in a significant reversal of the regressive behaviors and physical aberrations.
CONCLUSION: These results demonstrate an individualized approach that integrated genetic information and behavior therapies, resulting in a dramatic improvement in regressive behaviors associated with KS.

PMID: 28361099 [PubMed - in process]

Building a family network from genetic testing.

Mol Genet Genomic Med. 2017 Mar;5(2):122-129

Authors: Leppig KA, Thiese HA, Carrel D, Crosslin DR, Dorschner MO, Gordon AS, Hartzler A, Ralston J, Scrol A, Larson EB, Jarvik GP

Abstract
BACKGROUND: Genetic testing has multigenerational and familial repercussions. However, the "trickle-down effect" of providing genetic counseling and testing to family members at risk after an initial identification of a pathogenic variant in a medically actionable gene has been poorly understood.
METHODS: Three probands were identified during the pharmacogenetics research phase of eMERGEII (electronic MEdical Record and Genomics, phase II) to have variants in genes associated with autosomal dominant adult-onset disorders determined to be actionable by the American College of Medical Genetics (ACMG). Two of the three probands had variants that were classified as pathogenic and the third proband had a variant ultimately classified of uncertain significance, but of concern due to the proband's own phenotype. All probands had additional family members at risk for inheriting the variant. Two of the three probands had family members who received their medical care from the same health care system, Group Health Cooperative (GHC). It was recommended that the proband contact their family members at risk to be referred to genetic counseling for consideration of genetic testing.
RESULTS: The two probands with pathogenic variants contacted some of their family members at risk. Individuals contacted included children and adult grandchildren, particularly if they received their medical care at GHC. To the best of our knowledge, siblings and more distant relatives at risk were not informed by the proband of their genetic risk.
CONCLUSIONS: Establishing a family network is essential to disseminate knowledge of genetic risk. These three initial cases describe our experience of contacting eMERGE participants with identified variants, providing the probands with appropriate genetic counseling and care coordination, and recommendations for contacting family members at risk. Greater challenges were observed for coordinating genetics care for family members and extending the family network to include other relatives at risk.

PMID: 28361098 [PubMed - in process]

Refining Pharmacologic Research to Prevent and Treat Spontaneous Preterm Birth.

Front Pharmacol. 2017;8:118

Authors: Manuck TA

PMID: 28360854 [PubMed - in process]

[TRPM7 and tumor].

Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2016 Mar 28;41(3):333-6

Authors: Zhao M, Luo C, Wang Y, Wang J

Abstract
The transient receptor potential (TRP) family is a superfamily of cation channels located on the cell membrane. Transient receptor potential melastatin (TRPM) 7, a member of the TRPM subgroup of TRP channels, and was the most representative biofunctional membrane protein. It conducts calcium and monovalent cations to depolarize cells and increase intracellular calcium. It is capable of phosphorylating TRPM7 and other substrates. TRPM7 can mediate sensory transmission, regulate cellular Ca2+ and Mg2+ homeostasis and affect embryonic development. Abnormal expression and/or activity of the TRPM7 channel kinase is involved in a variety of diseases, particularly the development and progression of cancer. TRPM7 channel-kinase is essential for cellular processes, such as proliferation, survival, differentiation, growth, and migration.

PMID: 27033800 [PubMed - indexed for MEDLINE]