Gene expression and methylation profiles identified CXCL3 and CXCL8 as key genes for diagnosis and prognosis of colon adenocarcinoma.

J Cell Physiol. 2019 Nov 10;:

Authors: Zhao QQ, Jiang C, Gao Q, Zhang YY, Wang G, Chen XP, Wu SB, Tang J

Abstract
Colon adenocarcinoma (COAD) is one of the most common malignant tumors with high morbidity and mortality rates worldwide. Due to the poor clinical outcomes, it is indispensable to investigate novel biomarkers for the diagnosis and prognosis of COAD. The aim of this study is to explore key genes as potential biomarkers for the diagnosis and prognosis of COAD for clinical utility. Gene expression profiles (GSE44076 and GSE44861) and gene methylation profile (GSE29490) were analyzed to identify the aberrantly methylated-differentially expressed genes by R language and Perl software. Function enrichments were performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Moreover, hub genes were identified through protein-protein interaction (PPI) network. Besides, key genes were found by the module analysis and The Cancer Genome Atlas (TCGA) survival analysis. Finally, TCGA data and quantitative real-time polymerase chain reaction (RT-qPCR) was used to validate the key genes involved in COAD. Our study found two hypomethylation-high-expression genes (CXCL3 and CXCL8) in COAD tissues compared with the adjacent normal tissues. These results were also confirmed by RT-qPCR with 25 pairs of COAD and adjacent normal tissues. Meanwhile, low expression of the two genes was associated with poor survival in patients with COAD. CXCL3 and CXCL8 may serve as key genes in the diagnosis and prognosis for COAD.

PMID: 31709538 [PubMed - as supplied by publisher]

Clinical Pharmacology Education - The Decade Ahead.

Clin Pharmacol Ther. 2019 Nov 10;:

Authors: Brouwer KLR, Schmidt S, Floren LC, Johnson JA

PMID: 31709518 [PubMed - as supplied by publisher]

Projected Cost-Effectiveness for 2 Gene-Drug Pairs Using a Multigene Panel for Patients Undergoing Percutaneous Coronary Intervention.

Value Health. 2019 Nov;22(11):1231-1239

Authors: Hart MR, Garrison LP, Doyle DL, Jarvik GP, Watkins J, Devine B

Abstract
BACKGROUND: For patients undergoing percutaneous coronary intervention, gene-drug associations exist relevant to first-line treatment options-antiplatelet agent, clopidogrel, and pain medication, tramadol. Knowledge of genotype information may allow for avoidance of adverse drug events during critical clinical windows.
OBJECTIVE: This evaluation estimated cost-effectiveness associated with a multi-gene panel pre-emptively testing two genes providing CYP2C19 genotype-guided strategy for antiplatelet therapy, with CYP2D6 genotype-guided pain management, compared to single gene test for CYP2C19 with random assignment for pain treatment, and to no testing (empiric clopidogrel with random assignment for pain treatment).
METHODS: Decision analysis modeling was used to project costs from a payer perspective and patient quality-adjusted life years (QALYs) from the three strategies. The model captured composite risks of major adverse cardiovascular events and pain therapy-related adverse drug events and associated utility estimates. We conducted sensitivity analyses to assess influential input parameters.
RESULTS: Over 15 months, multi-gene testing was least costly and yielded more QALYs compared to both single gene and no testing; total incremental costs were $1646 lower with incremental gains of 0.04 QALYs for multi-gene compared with single gene and $11 368 lower with 0.17 QALY gains compared to no test. Base case analyses revealed multi gene was dominant compared to both single gene and no test, as it demonstrated cost savings with increased QALYs.
CONCLUSIONS: For these patients, a multi-gene-guided strategy yields a favorable incremental cost-effectiveness ratio compared to the other two treatment strategies. Pre-emptively ascertaining additional gene-drug pair information can inform clinical and economic decision-making at the point of care.

PMID: 31708059 [PubMed - in process]

Corrigendum to "Drug-drug interactions in breast cancer patients treated with CDK4/6 inhibitors" [Cancer Treatm. Rev. 74 (2019) 21-28].

Cancer Treat Rev. 2019 Nov 06;:101913

Authors: Fogli S, Del Re M, Curigliano G, van Schaik RH, Lancellotti P, Danesi R

PMID: 31706687 [PubMed - as supplied by publisher]

Quantitative determination of human IgA subclasses and their Fc-glycosylation patterns in plasma by using peptide analogue internal standard and ultra-high-performance liquid chromatography-triple quadrupole mass spectrometry.

Rapid Commun Mass Spectrom. 2019 Nov 08;:

Authors: Chen HF, Shiao CY, Wu MY, Lin YC, Chen HH, Chang WC, Wu MS, Kao CC, Tsai IL

Abstract
RATIONALE: Glycosylation on immunoglobulins is important for immune function. In this study, we developed and validated a method for absolute quantification of IgA subclasses and relative quantification of IgA-Fc glycopeptides by using affinity purification and UHPLC-MS/MS. Only micro-volumes of plasma were required from each sample and we also applied the method to discover IgA and IgA-glycopeptides profiles in patients with chronic kidney diseases and IgA nephropathy.
METHODS: Peptide M affinity bead was used to purify IgA, and a cost effective peptide analog was added as internal standard. With an efficient on-bead digestion process, purified samples were analyzed by UHPLC-MS/MS with multiple reaciont monitoring mode.
RESULTS: Correlation coefficients were greater than 0.999 for the IgA1 and IgA2 calbration curves and greater than 0.994 for glycopeptide regression curves. Intraday and interday precisions for IgA1 and IgA2 were <1.6% and <5.1% RSD, respectively. Intraday and interday accuracies ranged from 102.6-114.9% and 103.5-113.5% for IgA1 and IgA2. Stabilities of IgA1 and IgA2 at -80 °C for 7 to 15 days ranged from 96.0-109.4%. The Pearson's correlation coefficient was 0.916 when comparing the IgA quantification results of the 30 clinical samples by using ELISAs and the developed UHPLC-MS/MS method. Compared to healthy controls, IgA and IgA-glycopeptides showed different profiles in patients with chronic kidney diseases and IgA nephropathy.
CONCLUSIONS: The developed method showed good validation results, and the absolute quantification results of IgA correlated to those from ELISA. Th pilot application study showed that IgA and IgA glycopeptides can be potential biomarker candidates for kidney diseases, and more clinical samples application are worth of investigation.

PMID: 31705576 [PubMed - as supplied by publisher]

Biomarker-Guided Tailored Therapy.

Adv Exp Med Biol. 2019;1192:199-224

Authors: Lydiard J, Nemeroff CB

Abstract
Personalized medicine aims to integrate a number of characteristics such as genetic and epigenetic variations, other biomarkers, clinical symptoms, and environmental factors in order to predict susceptibility to disease, aid in diagnosis, and identify efficacious treatments with maximum likelihood of favorable response and minimal chance of adverse effects. The use of personalized medicine approaches in psychiatry is underdeveloped, but has a profound potential for improving prevention and treatment. There are a number of studies that have found promising associations between a variety of biomarkers and clinical response to psychopharmacological treatment in various psychiatric disorders. These biomarkers include neuroimaging, electrophysiology, peripheral serum, and plasma biomarkers, and variations in genomics, epigenetics, proteomics, and metabolomics. Ultimately, the best model for precision medicine in complex, multifactorial diseases such as psychiatric illnesses will likely involve integrated methodology that combines information from multiple sources including biologic, clinical, and environmental data. While much progress has been made in the development of valid biomarkers in psychiatric disorders, there is much work to be done in determining their clinical utility.

PMID: 31705496 [PubMed - in process]

Management of Attention-Deficit/Hyperactivity Disorder in Primary Care.

Nurs Clin North Am. 2019 Dec;54(4):517-532

Authors: McCoy KT, Pancione K, Hammonds LS, Costa CB

Abstract
Management of attention-deficit/hyperactivity disorders require provider skill, rapport, and referral acumen to treat patients across the life span. Incidence and prevalence have increased in the United States and globally. There are innovative models of evidence-informed screening techniques, treatment strategies to help providers work with patients and their families. Diplomatic management of highly charged treatment controversies, drug diversion, and risk factor reduction helps to ethically address this growing public health phenomenon. This article examines risk factors and treatment considerations in the United States for evidence-informed care, with a focus on affordable and readily accessible treatment in primary care settings.

PMID: 31703777 [PubMed - in process]

Anticipating Changes for Depression Management in Primary Care.

Nurs Clin North Am. 2019 Dec;54(4):457-471

Authors: McCoy KT, Costa CB, Pancione K, Hammonds LS

Abstract
Depression management in primary care settings is the norm, in the United States and globally. As incidence and prevalence of depression continue to mount, there are innovative models of treatment, newer understandings, more open philosophies, and evidence-informed treatments that may address this troubling public health issue. This article attempts to succinctly examine the evidence in identifying and treating this in the United States in an expedient, evidence-informed manner to assist those in need of have care that is patient centered, of high quality, affordable, and readily accessible across the lifespan.

PMID: 31703773 [PubMed - in process]

Rhino-Orbital-Cerebral Mucormycosis after Allogeneic Hematopoietic Stem Cell Transplantation and Isavuconazole Therapeutic Drug Monitoring during Intestinal Graft versus Host Disease.

Mediterr J Hematol Infect Dis. 2019;11(1):e2019061

Authors: Andreani G, Fadda G, Gned D, Dragani M, Cavallo G, Monticone V, Morotti A, De Gobbi M, Guerrasio A, Barbui AM, D'Avolio A, Cilloni D

Abstract
A diagnosis of rhino-orbital-cerebral mucormycosis was made in a 59-year-old man with a secondary acute myeloid leukemia a few days after hematopoietic stem cell transplantation. Prompt treatment with combined antifungal therapy (liposomal amphotericin B and isavuconazole) followed by a procedure of endoscopic sinus surgery resulted in the resolution of the infection. Therapeutic drug monitoring of isavuconazole was performed during the year of treatment showing an increment of plasma concentrations in correspondence with the improvement of intestinal GvHD, thus suggesting that in this or similar conditions TDM for isavuconazole can be of value. A literature review of cases of rhino-orbital-cerebral and rhino-cerebral mucormycosis in allogeneic hematopoietic stem cell transplant recipients was carried out.

PMID: 31700586 [PubMed]

CYP2C19 Phenotype and Risk of Proton Pump Inhibitor-Associated Infections.

Pediatrics. 2019 Nov 07;:

Authors: Bernal CJ, Aka I, Carroll RJ, Coco JR, Lima JJ, Acra SA, Roden DM, Van Driest SL

Abstract
OBJECTIVES: Proton pump inhibitors (PPIs) are often used in pediatrics to treat common gastrointestinal disorders, and there are growing concerns for infectious adverse events. Because CYP2C19 inactivates PPIs, genetic variants that increase CYP2C19 function may decrease PPI exposure and infections. We tested the hypothesis that CYP2C19 metabolizer phenotypes are associated with infection event rates in children exposed to PPIs.
METHODS: This retrospective biorepository cohort study included individuals aged 0 to 36 months at the time of PPI exposure. Respiratory tract and gastrointestinal tract infection events were identified by using International Classification of Diseases codes in the year after the first PPI mention. Variants defining CYP2C19 *2, *3, *4, *8, *9, and *17 were genotyped, and all individuals were classified as CYP2C19 poor or intermediate, normal metabolizers (NMs), or rapid or ultrarapid metabolizers (RM/UMs). Infection rates were compared by using univariate and multivariate analyses.
RESULTS: In all, 670 individuals were included (median age 7 months; 44% girls). CYP2C19 NMs (n = 267; 40%) had a higher infection rate than RM/UMs (n = 220; 33%; median 2 vs 1 infections per person per year; P = .03). There was no difference between poor or intermediate (n = 183; 27%) and NMs. In multivariable analysis of NMs and RM/UMs adjusting for age, sex, PPI dose, and comorbidities, CYP2C19 metabolizer status remained a significant risk factor for infection events (odds ratio 0.70 [95% confidence interval 0.50-0.97] for RM/UMs versus NMs).
CONCLUSIONS: PPI therapy is associated with higher infection rates in children with normal CYP2C19 function than in those with increased CYP2C19 function, highlighting this adverse effect of PPI therapy and the relevance of CYP2C19 genotypes to PPI therapeutic decision-making.

PMID: 31699831 [PubMed - as supplied by publisher]

Genomic interrogation of familial short stature contributes to the discovery of the pathophysiological mechanisms and pharmaceutical drug repositioning.

J Biomed Sci. 2019 Nov 07;26(1):91

Authors: Wong HS, Lin YJ, Lu HF, Liao WL, Chen CH, Wu JY, Chang WC, Tsai FJ

Abstract
BACKGROUND: Genetic factors, dysregulation in the endocrine system, cytokine and paracrine factors are implicated in the pathogenesis of familial short stature (FSS). Nowadays, the treatment choice for FSS is limited, with only recombinant human growth hormone (rhGH) being available.
METHODS: Herein, starting from the identification of 122 genetic loci related to FSS, we adopted a genetic-driven drug discovery bioinformatics pipeline based on functional annotation to prioritize crucial biological FSS-related genes. These genes were suggested to be potential targets for therapeutics.
RESULTS: We discovered five druggable subnetworks, which contained seven FSS-related genes and 17 druggable targerts.
CONCLUSIONS: This study provides a valuable drug repositioning accompanied by corresponding targetable gene clusters for FSS therapy.

PMID: 31699087 [PubMed - in process]

NAT2 slow acetylator is associated with anti-tuberculosis drug-induced liver injury severity in indonesian population.

Pharmacogenomics. 2019 Nov 08;:

Authors: Yuliwulandari R, Prayuni K, Susilowati RW, Sofro ASM, Tokunaga K, Shin JG

Abstract
Aim: We investigated the contribution of NAT2 variants and acetylator status to anti-tuberculosis drug-induced liver injury (AT-DILI) severity. Materials & methods: 100 patients with clinically severe AT-DILI and 210 non-AT-DILI controls were subjected to NAT2 genotyping by direct DNA sequencing. Results: NAT2 slow acetylator was significantly associated with AT-DILI risk (p = 2.7 × 10-7; odds ratio [95% CI]= 3.64 [2.21-6.00]). Subgroup analysis of NAT2 ultra-slow acetylator revealed a stronger association with AT-DILI risk (p = 4.3 × 10-6; odds ratio [95% CI]= 3.37 [2.00-5.68]). Subset analysis of NAT2 acetylator status and severity grade confirmed these results in AT-DILI patients with more severe disease whereas fast and intermediate acetylator phenotypes were associated with a decreased AT-DILI risk. Conclusion: We elucidated the role of NAT2 phenotypes in AT-DILI in Indonesian population, suggesting that NAT2 genotype and phenotype determination are important to reduce AT-DILI risk.

PMID: 31699005 [PubMed - as supplied by publisher]

Cell-free DNA and the monitoring of lymphoma treatment.

Pharmacogenomics. 2019 Nov 08;:

Authors: Camus V, Jardin F

Abstract
The technique of cell-free DNA (cfDNA) analysis, also called liquid biopsy, has been developed over the past several years to serve as a minimal residual disease tool, as has already been done with reliability and robustness in acute leukemias. This technique has important theoretical advantages, including the simplicity of acquiring blood samples, which can easily be repeated over time, its noninvasive and quantitative nature, which provides results consistent with the results obtained from tumor genomic DNA, and its speed and low cost. cfDNA analysis, as the leading tool to quantify somatic mutations, is a major technological leap in the noninvasive management of lymphomas. This technology may empower monitoring and treatment adjustment in real time and enable the quick detection of refractory lymphomas and resistance to routine therapies. Here, we summarize the results that have established the clinical relevance of cfDNA in diagnostic and prognostic stratification and the monitoring of lymphoma treatments.

PMID: 31698998 [PubMed - as supplied by publisher]

Combination of germline variations associated with survival of folinic acid, fluorouracil and irinotecan-treated metastatic colorectal cancer patients.

Pharmacogenomics. 2019 Nov 08;:

Authors: Labriet A, Lévesque É, Mattia E, Cecchin E, Jonker D, Couture F, Simonyan D, Buonadonna A, D'Andrea M, Villeneuve L, Toffoli G, Guillemette C

Abstract
Aim: Germline variants could modify survival of metastatic colorectal cancer patients (mCRC). Patients & methods: The association of 285 haplotype-tagging single nucleotide polymorphisms in 11 candidate genes and overall survival (OS) was tested in two cohorts totalizing 417 FOLFIRI-treated mCRC. Gene expression was investigated in vitro and in public datasets. Results: In the combined cohort, CES1 rs9921399T>C was associated with prolonged OS (hazard ratio [HR] = 0.40) whereas ABCC1 rs17501011G>A (HR = 2.08) and UGT1 rs1113193G>A (HR = 2.12) were associated with shorter OS (p ≤ 0.005). A combined effect of these polymorphisms was observed with HR of 1.98-2.97 (p < 0.05). The ABCC1 rs17501011A variant reduced reporter-gene activity (p < 0.05) whereas ABCC1 tumor expression was associated with shorter survival (p ≤ 0.013). Conclusion: We identified a combination of genetic determinants that could predict mCRC survival.

PMID: 31698983 [PubMed - as supplied by publisher]

Clinical pharmacology of monoclonal antibodies targeting anti-PD-1 axis in urothelial cancers.

Crit Rev Oncol Hematol. 2019 Sep 26;144:102812

Authors: Rofi E, Del Re M, Arrigoni E, Rizzo M, Fontanelli L, Crucitta S, Gianfilippo G, Restante G, Fogli S, Porta C, Danesi R, Schmidinger M

Abstract
Chemotherapy is the reference treatment for patients with advanced urothelial carcinoma, both in the neo-adjuvant and adjuvant settings; however, the overall outcome remains poor in this patient population. In the last few years, the addition of immune checkpoint inhibitors into the therapeutic armamentarium has changed the therapeutic landscape of several tumor types, including urothelial carcinoma. Many different molecules have been introduced on the market and several questions about immunotherapies are currently open and deserve a critical analysis. The current review article is aimed at describing the clinical pharmacology of monoclonal antibodies targeting PD-1 axis in urothelial malignancies to underline possible pharmacodynamic and pharmacokinetic differences among them.

PMID: 31698313 [PubMed - as supplied by publisher]

Increased short- and long-term risk of sleep disorders in people with traumatic brain injury.

Neuropsychol Rehabil. 2019 Nov 07;:1-20

Authors: Wang YJ, Chang WC, Wu CC, Chiang YH, Chiu WT, Chen KY, Chang WP

Abstract
This study aims to evaluate the relationship between traumatic brain injury (TBI) and sleep disorders (SDs). We first initiated a questionnaire-based clinical survey to assess sleep problems in the early stage after a TBI, followed by a population-based cohort study to evaluate the long-term risk of SDs in TBI patients. For short-term clinical survey, mild (m)TBI patients and healthy controls were recruited to evaluate the sleep quality and daytime sleepiness using the Pittsburg Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) within two weeks after a TBI. For long-term observation, a 5-year nationwide population-based cohort study that utilized a large administrative database was conducted. In the short-term survey, 236 mTBI patients and 223 controls were analyzed. Total scores of the PSQI and ESS were significantly higher in mTBI patients than in the controls. In the long-term cohort study, 6932 TBI cases and 34,660 matched controls were included. TBI cases had a 1.36-fold greater risk of SDs compared to the non-TBI controls during the 5-year follow-up period. Results showed that patients with TBI had a significantly higher risk of SDs than did controls both in the early stage and during a 5-year follow-up period.

PMID: 31696782 [PubMed - as supplied by publisher]

Association between infliximab concentrations and clinical response in psoriasis: a prospective cohort study.

J Dermatolog Treat. 2019 Nov 07;:1-27

Authors: Colls-Gonzalez M, Notario-Rosa J, Bas-Minguet J, Padullés-Zamora A, Morandeira-Rego F, Valentí-Medina F, Colom-Codina H, Padullés-Zamora N

Abstract
BACKGROUND: Infliximab (IFX) trough concentrations (Cmin) have been linked to treatment efficacy in psoriatic patients. Inter-individual IFX Cmin variability and factors influencing IFX pharmacokinetics could explain differences in treatment response.OBJECTIVE: To evaluate the association between IFX Cmin and clinical outcomes in psoriatic patients.METHODS: Prospective study of 33 patients with moderate to severe psoriasis receiving IFX at Bellvitge University Hospital, between October 2013-November 2016. IFX Cmin and antibodies toward infliximab (ATI) were measured.RESULTS: We collected 155 IFX Cmin and ATI values (mean age, 46 (14) years; 11 (33.3%) women). Mean IFX Cmin was 2.5 (2.4) mg/L and ATIs were detected in six patients, resulting in undetectable IFX Cmin. IFX Cmin were significantly associated with ATI and BMI (β -2.51, 95% CI -3.56 to -1.4 and β -0.05, 95% CI -0.09 to -0.01). PASI score and PASI 90/100 response were significantly associated with IFX Cmin (IRR 0.80, 95% CI 0.70 to 0.92; OR 1.79, 95% CI 1.18 to 2.71 and OR 1.79, 95% CI 1.14 to 2.81).CONCLUSION: IFX Cmin significantly influences PASI 90/100 response rates. IFX Cmin were significantly associated with ATI and BMI. The observed inter-individual variability in IFX Cmin supports the need for IFX drug monitoring.

PMID: 31696747 [PubMed - as supplied by publisher]

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