ERCC overexpression associated with a poor response of cT4b colorectal cancer with FOLFOX-based neoadjuvant concurrent chemoradiation.

Oncol Lett. 2020 Nov;20(5):212

Authors: Huang MY, Lee HH, Huang CW, Huang CM, Ma CJ, Yin TC, Tsai HL, Chai CY, Chen YT, Wang JY

Abstract
Colorectal cancer (CRC) of the clinical tumor stage T4b (cT4b) refers to advanced tumors with direct invasion of adjacent structures and the tumors are considered unresectable. Despite advancements in aggressive surgery and combination chemotherapy, the prognosis of cT4b CRC remains poor. Optimizing the therapeutic sequence administered to patients with cT4b CRC to improve clinical outcomes is crucial. In the present study, patients with unresectable cT4b and nodal stage N1-2 CRC were investigated at a single institution. A total of 20 consecutive patients were treated with pre-operative concurrent chemoradiation by using 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) since February 2015 and were regularly followed up until March 2020. Due to their poor response to concurrent chemoradiation (CCRT) with FOLFOX, the chemotherapy regimen was changed to irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as the second-line neoadjuvant treatment. Genetic alterations, such as microsatellite instability (MSI), were documented, and the expression levels of excision repair cross-complementing group 1 (ERCC1) and ERCC2 were examined. Of the 20 patients, the tumors of 14 patients (70%) became resectable after FOLFIRI administration. The median duration between the last date of radiotherapy and surgery was 32.7 weeks (range, 10.1-59.3 weeks). Of note, 4 of the 14 patients with resectable tumors (28.6%) achieved a pathologic complete response. The median overall survival and progression-free survival were 27.5 months (range, 12-39 months) and 27.5 months (range, 8-39 months), respectively. The cancerous specimens of all of the patients (100%) exhibited ERCC2 overexpression and 18 specimens (90%) had ERCC1 overexpression. Only one tumor (5%) exhibited high MSI. The present study indicated that ERCC overexpression associated with the poor response of FOLFOX-based CCRT and FOLFIRI after FOLFOX-based CCRT failure may have a potential role in conversion to resectable tumors by neoadjuvant treatment in cT4b CRC. However, a further prospective study with more patients is required to improve the precision of the conclusions.

PMID: 32963618 [PubMed - as supplied by publisher]

Observational Study Comparing Efficacy and Safety between Neoadjuvant Concurrent Chemoradiotherapy and Chemotherapy for Patients with Unresectable Locally Advanced or Metastatic Gastric Cancer.

J Oncol. 2020;2020:6931317

Authors: Yeh YS, Huang MY, Ma CJ, Huang CW, Tsai HL, Chen YC, Li CC, Yu FJ, Shih HY, Wang JY

Abstract
Objective: Dismal outcomes in patients with locally advanced or metastatic gastric cancer (GC) highlight the need for effective systemic neoadjuvant treatment strategies to improve clinical results. Neoadjuvant multimodality strategies vary widely. This study compared the efficacy, safety, and clinical outcomes of neoadjuvant CCRT and chemotherapy for such patients.
Materials and Methods: Sixty-five patients with histologically confirmed locally advanced or metastatic GC following neoadjuvant CCRT or computed tomography (CT) were retrospectively enrolled between January 2010 and April 2019. Clinical outcomes included response, progression-free survival (PFS), and overall survival (OS), and toxicity was compared between the two groups.
Results: Of the 65 patients, 18 (27.7%) were in the response group (2 patients with a complete response and 16 with a partial response) and 47 (72.3%) in the nonresponse group (29 patients with a stable disease and 18 with a progressive disease). Multivariate analysis revealed no independent response predictor between CCRT and chemotherapy groups (all P > 0.05). Furthermore, results revealed no statistical differences in toxicity between the two groups (all P > 0.05). With a follow-up median of 12 months (ranging 6-48 months), 12-month OS and PFS were 39.7% and 20.4% in the CCRT group and 30.3% and 13.2% in the chemotherapy group, respectively. The median OS and PFS were 14.0 months (95% CI 9.661-18.339) and 9.0 months (95% CI 6.805-11.195) in the CCRT group and 10.0 months (95% CI 6.523-13.477) and 8.0 months (95% CI 6.927-9.073) in the chemotherapy group, respectively. Both OS (P=0.011) and PFS (P=0.008) in patients with CCRT were significantly better than those in patients with chemotherapy alone.
Conclusion: Neoadjuvant CCRT achieved more favorable OS and PFS than did neoadjuvant chemotherapy alone, without significant increases of toxicity in patients. However, prospective randomized trials comparing treatment modalities are necessary to confirm the potential advantages of neoadjuvant CCRT.

PMID: 32963531 [PubMed - as supplied by publisher]

HLA-B*39:01:01 is a novel risk factor for antithyroid drug-induced agranulocytosis in Japanese population.

Pharmacogenomics J. 2020 Sep 22;:

Authors: Nakakura S, Hosomichi K, Uchino S, Murakami A, Oka A, Inoue I, Nakaoka H

Abstract
Antithyroid drug (ATD) is a mainstay of Graves' disease (GD). About 0.1-0.5% of patients with GD treated with ATD exhibit ATD-induced agranulocytosis, which is characterized by severe reduction of circulating neutrophils. Immune-mediated responses have been proposed as a possible mechanism for the pathogenesis of ATD-induced agranulocytosis. Although it has been reported that the HLA class II allele (HLA-DRB1*08:03) was associated with ATD-induced agranulocytosis in multiple populations, the entire HLA region have not been explored in Japanese. Therefore, we performed HLA sequencing for 10 class I and 11 class II genes in 87 patients with ATD-induced agranulocytosis and 384 patients with GD who did not show ATD-induced agranulocytosis. By conducting case-control association studies at the HLA allele and haplotype levels, we replicated the association between HLA-DRB1*08:03:02 and ATD-induced agranulocytosis (P = 5.2 × 10-7, odds ratio = 2.80), and identified HLA-B*39:01:01 as an independent risk factor (P = 1.4 × 10-3, odds ratio = 3.35). To verify reproducibility of the novel association of HLA-B*39:01:01, we reanalyzed allele frequency data for HLA-B*39:01:01 from previous case-control association studies. The association of HLA-B*39:01:01 was significantly replicated in Chinese (P = 9.0 × 10-3), Taiwanese (P = 1.1 × 10-3), and European populations (P = 5.2 × 10-4). A meta-analysis combining results from the previous and current studies reinforced evidence of the association between HLA-B*39:01:01 and ATD-induced agranulocytosis (Pmeta = 1.2 × 10-9, pooled OR = 3.66, 95% CI; 2.41-5.57). The results of this study will provide a better understanding of the pathogenesis of ATD-induced agranulocytosis in the context of HLA-mediated hypersensitivity reactions.

PMID: 32963330 [PubMed - as supplied by publisher]

Validated prognostic significance of YB-1 genetic variation in metastatic prostate cancer.

Pharmacogenomics J. 2020 Sep 22;:

Authors: Shiota M, Narita S, Habuchi T, Eto M

Abstract
Genetic polymorphism in YB-1 was previously shown to be associated with the prognosis of advanced prostate cancer patients treated with primary androgen-deprivation therapy. However, the significance of this polymorphism remains invalidated. In this study, we aimed to validate the prognostic significance of the YB-1 genetic polymorphism in metastatic prostate cancer. This study included 79 Japanese patients who were diagnosed as metastatic prostate cancer between 2000 and 2016. Genomic DNA was obtained from patient whole blood samples, and genotyping on YB-1 (rs12030724) was performed by PCR-based technique. The association of genotype in YB-1 with clinicopathological parameters and oncological outcome, including progression-free survival and overall survival, was examined. Homozygous wild-type (AA), heterozygous variant (AT), and homozygous variant (TT) were identified in 47 (59.5%), 26 (32.9%) and 6 patients (7.6%), respectively. Heterozygous/homozygous variant (AT/TT) in YB-1 was significantly associated with lower progression risk compared with homozygous wild-type (AA) (hazard ratio = 0.52; 95% confidence interval = 0.30-0.88, P = 0.015). Consistent with this finding, heterozygous/homozygous variant (AT/TT) in YB-1 was significantly associated with lower risk of any-cause mortality compared with homozygous wild-type (AA) (hazard ratio = 0.46; 95% confidence interval = 0.21-0.93, P = 0.031). Gene polymorphism in YB-1 rs12030724 was validated to be a promising predictive biomarker of androgen-deprivation therapy in metastatic prostate cancer to identify patients requiring more intensive therapeutics.

PMID: 32963329 [PubMed - as supplied by publisher]

Genomics and Pharmacogenomics Knowledge, Attitude and Practice of Pharmacists Working in United Arab Emirates: Findings from Focus Group Discussions-A Qualitative Study.

J Pers Med. 2020 Sep 18;10(3):

Authors: Rahma AT, Elbarazi I, Ali BR, Patrinos GP, Ahmed LA, Al Maskari F

Abstract
(1) Background: Genomics and pharmacogenomics are relatively new fields in medicine in the United Arab Emirates (UAE). Understanding the knowledge, attitudes and current practices among pharmacists is an important pillar to establish the roadmap for implementing genomic medicine and pharmacogenomics; (2) Methods: A qualitative method was used, with focus group discussions (FGDs) being conducted among pharmacists working in public and private hospitals in Abu Dhabi Emirate. Snowball sampling was used. Thematic inductive analysis was performed by two researchers independently. NVIVO software was used to establish the themes; (3) Results: Lack of knowledge of genomics and pharmacogenomics among pharmacists was one of the most prominent findings. Therefore, the role of pharmacist in making the right decisions was highlighted to be a barrier for pharmacogenomics implementation in the UAE. Pharmacists have a positive attitude toward pharmacogenomics, but they are preoccupied with concern of confidentiality. In addition, religion and culture shadowed their attitudes toward genetic testing; (4) Conclusions: It is highly recommended to introduce new courses and training workshops for healthcare providers to improve the opportunities for genomics and pharmacogenomics application in the UAE. Pharmacists agreed that the health authorities should take the lead for improving trust and confidence in the system for a better future in the era of genomics and pharmacogenomics.

PMID: 32962013 [PubMed - as supplied by publisher]

An Exploratory Association Analysis of ABCB1 rs1045642 and ABCB1 rs4148738 with Non-Major Bleeding Risk in Atrial Fibrillation Patients Treated with Dabigatran or Apixaban.

J Pers Med. 2020 Sep 18;10(3):

Authors: Roşian AN, Iancu M, Trifa AP, Roşian ŞH, Mada C, Gocan CP, Niţă T, Istratoaie S, Boarescu PM, Buzoianu AD

Abstract
(1) Background: The approach of bleeding complications in patients treated with non-vitamin K oral anticoagulants (NOACs) represents an important issue in clinical practice. Both dabigatran and apixaban are substrates for P-glycoprotein and, therefore, ABCB1 gene variations may be useful in individualizing NOACs treatment, especially in high-risk patients. (2) Methods: ABCB1 rs1045642 and rs4148738 were determined in 218 atrial fibrillation patients treated with dabigatran or apixaban (70.94 ± 9.04 years; 51.83% men). (3) Results: Non-major bleeding appeared in 7.34% NOACs-treated patients. The logistic tested models based on the four genetic models revealed no significant association between the variant genotype of two ABCB1 SNPs and the risk of bleeding (p > 0.05). Among the four two-locus haplotypes, TA and CA haplotypes had the highest frequency in NOACs-treated patients with bleeding, involving a possible positive association with the susceptibility of bleeding complications (OR = 1.04 and OR = 1.91, respectively). The logistic model found no significant association of estimated haplotypes with bleeding (p > 0.05) except for the TG haplotype which had a trend toward statistical significance (p = 0.092). Among the risk factors for bleeding, only age > 70 years and stroke/TIA showed a tendency toward statistical significance. (4) Conclusions: We found no significant associations between the studied ABCB1 variant genotypes with non-major bleeding risk in NOACs-treated patients. A trend of association between TG haplotype with bleeding risk was observed, implying a protective role of this haplotype against bleeding in patients treated with dabigatran or apixaban.

PMID: 32961964 [PubMed - as supplied by publisher]

Pharmacogenetics of Type 2 Diabetes-Progress and Prospects.

Int J Mol Sci. 2020 Sep 18;21(18):

Authors: Nasykhova YA, Tonyan ZN, Mikhailova AA, Danilova MM, Glotov AS

Abstract
Type 2 diabetes mellitus (T2D) is a chronic metabolic disease resulting from insulin resistance and progressively reduced insulin secretion, which leads to impaired glucose utilization, dyslipidemia and hyperinsulinemia and progressive pancreatic beta cell dysfunction. The incidence of type 2 diabetes mellitus is increasing worldwide and nowadays T2D already became a global epidemic. The well-known interindividual variability of T2D drug actions such as biguanides, sulfonylureas/meglitinides, DPP-4 inhibitors/GLP1R agonists and SGLT-2 inhibitors may be caused, among other things, by genetic factors. Pharmacogenetic findings may aid in identifying new drug targets and obtaining in-depth knowledge of the causes of disease and its physiological processes, thereby, providing an opportunity to elaborate an algorithm for tailor or precision treatment. The aim of this article is to summarize recent progress and discoveries for T2D pharmacogenetics and to discuss the factors which limit the furthering accumulation of genetic variability knowledge in patient response to therapy that will allow improvement the personalized treatment of T2D.

PMID: 32961860 [PubMed - as supplied by publisher]

Identification of Glycochenodeoxycholate 3-O-Glucuronide and Glycodeoxycholate 3-O-Glucuronide as Highly Sensitive and Specific OATP1B1 Biomarkers.

Clin Pharmacol Ther. 2020 Sep 22;:

Authors: Neuvonen M, Hirvensalo P, Tornio A, Rago B, West M, Lazzaro S, Mathialagan S, Varma M, Cerny MA, Costales C, Ramanathan R, Rodrigues AD, Niemi M

Abstract
The aim of this study was to investigate the sensitivity and specificity of endogenous glycochenodeoxycholate and glycodeoxycholate 3-O-glucuronides (GCDCA-3G and GDCA-3G) as substrates for organic anion transporting polypeptide 1B1 (OATP1B1) in humans. We measured fasting levels of plasma GCDCA-3G and GDCA-3G using liquid chromatography-tandem mass spectrometry in 356 healthy volunteers. The mean plasma levels of both compounds were approximately 50% lower in women than in men (P=2.25×10-18 and P=4.73×10-9 ). In a microarray-based genome wide association study, the SLCO1B1 rs4149056 (c.521T>C, p.Val174Ala) variation showed the strongest association with the plasma GCDCA-3G (P=3.09×10-30 ) and GDCA-3G (P=1.60×10-17 ) concentrations. The mean plasma concentration of GCDCA-3G was 9.2-fold (P=8.77×10-31 ) and that of GDCA-3G was 6.4-fold (P=2.45x10-13 ) higher in individuals with the SLCO1B1 c.521C/C genotype than in those with the c.521T/T genotype. No other variants showed independent genome wide significant associations with GCDCA-3G or GDCA-3G. GCDCA-3G was highly efficacious in detecting the SLCO1B1 c.521C/C genotype with an area under the receiver operating characteristic curve of 0.996 (P<0.0001). The sensitivity (98-99%) and specificity (100%) peaked at a cut-off value of 180 ng/mL for men and 90 ng/mL for women. In a haplotype-based analysis, SLCO1B1*5 and *15 were associated with reduced and *1B, *14, and *35 with increased OATP1B1 function. In vitro, both GCDCA-3G and GDCA-3G showed at least 6 times higher uptake by OATP1B1 than OATP1B3 or OATP2B1. These data indicate that the hepatic uptake of GCDCA-3G and GDCA-3G is predominantly mediated by OATP1B1. GCDCA-3G, in particular, is a highly sensitive and specific OATP1B1 biomarker in humans.

PMID: 32961594 [PubMed - as supplied by publisher]

Effect of SLCO1B1 Polymorphisms on High-Dose Methotrexate Clearance in Children and Young Adults with Leukemia and Lymphoblastic Lymphoma.

Clin Transl Sci. 2020 Sep 22;:

Authors: Schulte RR, Choi L, Utreja N, Van Driest SL, Michael Stein C, Ho RH

Abstract
High-dose (HD) methotrexate (MTX) is a critical component of treatment for hematologic malignancies in children and young adults. Therapeutic drug monitoring is necessary due to substantial interindividual variation in MTX clearance. Common function-altering polymorphisms in SLCO1B1 (encodes OATP1B1, which transports MTX) may contribute to clearance variability. We performed pharmacokinetic modeling using data for 106 children and young adults treated with HD MTX for hematologic malignancies; of 396 total courses of HD MTX, 360 consisted of 5 g/m2 over 24 hours. We evaluated the contribution of clinical covariates and SLCO1B1 genotype (388A>G and 521T>C) to MTX clearance variability. Of the clinical covariates studied, patient weight improved the pharmacokinetic model most significantly (p<0.001). The addition of the SLCO1B1 variants individually further improved the model (p<0.05 for each). An interaction between these variants was suggested when both were included (p=0.017). SLCO1B1 genotype should be considered in efforts to personalize HD MTX dosing.

PMID: 32961024 [PubMed - as supplied by publisher]

Pharmacogenomics of Antiretroviral Drug Metabolism and Transport.

Annu Rev Pharmacol Toxicol. 2020 Sep 22;:

Authors: Yu ZJ, Mosher EP, Bumpus NN

Abstract
Antiretroviral therapy has markedly reduced morbidity and mortality for persons living with human immunodeficiency virus (HIV). Individual tailoring of antiretroviral regimens has the potential to further improve the long-term management of HIV through the mitigation of treatment failure and drug-induced toxicities. While the mechanisms underlying anti-HIV drug adverse outcomes are multifactorial, the application of drug-specific pharmacogenomic knowledge is required in order to move toward the personalization of HIV therapy. Thus, detailed understanding of the metabolism and transport of antiretrovirals and the influence of genetics on these pathways is important. To this end, this review provides an up-to-date overview of the metabolism of anti-HIV therapeutics and the impact of genetic variation in drug metabolism and transport on the treatment of HIV. Future perspectives on and current challenges in pursuing personalized HIV treatment are also discussed. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 61 is January 7, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID: 32960701 [PubMed - as supplied by publisher]

Can the degree of coronary collateralization be used in clinical routine as a valid angiographic parameter of viability?

Int J Cardiovasc Imaging. 2020 Sep 21;:

Authors: Pirnat M, Stillman AE, Rienmueller R, Noc M, Gorenjak M, Šeruga T

Abstract
The success rate of percutaneous coronary artery intervention (PCI) of chronic total occlusion (CTO) lesions have increased in the recent years. However, improvement of function is only possible when significant myocardial viability is present. One of the most important factors of maintaining myocardial viability is the opening and development of collaterals. Our hypothesis was that with a higher degree of collaterals more viable myocardium is present. In 38 patients we compared the degree of collaterals, evaluated with a conventional coronary angiogram (CCA) and graded by the Rentrop classification to transmural extent of the scar obtained in a viability study with magnetic resonance (MRI). We found a statistically significant association of the degree of collaterals determined with Rentrop method and transmural extent of the scar as measured by CMR (p = 0.001; Tau = -0.144). Additionally, associations showed an increase in the ratio between viable vs. non-viable myocardium with the degree of collaterals. Our study suggests that it may be beneficial to routinely grade the collaterals at angiography in patients with CTO as an assessment of myocardial viability.

PMID: 32959094 [PubMed - as supplied by publisher]

Impact of loading dose of caspofungin in PK/PD target attainment for severe candidiasis infections in ICU patients - the CASPOLOAD study.

Antimicrob Agents Chemother. 2020 Sep 21;:

Authors: Bailly S, Gautier-Veyret E, Lê MP, Bouadma L, Andremont O, Neuville M, Mourvillier B, Sonneville R, Magalhaes E, Lebut J, Radjou A, Smonig R, Wolff M, Massias L, Dupuis C, Timsit JF

Abstract
INTRODUCTION: This study evaluated impact of a high loading dose of caspofungin (CAS) on the pharmacokinetic of CAS and the pharmacokinetic-pharmacodynamic (PK-PD) target attainment in intensive care units (ICU) patients.
METHODS: ICU patients requiring CAS treatment were prospectively included to receive a 140 mg loading dose of CAS. Plasma CAS concentrations (0, 2, 3, 5, 7 and 24h post-infusion) were determined to develop a two-compartmental population PK model. A Monte-Carlo simulation was performed and the probabilities of target attainment (PTA) were computed using previously published minimal inhibitory concentrations (MIC). PK-PD targets were ratios of area under the curve over 24 hours over the MIC (AUC0-24h/MIC) of 250, 450 and 865 and maximal concentration over MIC (Cmax/MIC) of 5, 10, 15 and 20.
RESULTS: Among 13 included patients, CAS clearance was 0.98±0.13 L/h and distribution volumes V1=9.0±1.2 L and V2=11.9±2.9 L. Observed and simulated CAS AUC0-24h were 79.1 [55.2-108.4] and 81.3 [63.8; 102.3] mg.h/L during the first 24 hours of therapy, which is comparable to values usually observed in ICU patients at day 3 or later. PTAs were > 90% for MIC of 0.19 and 0.5 mg/L, considering respectively AUC/MIC=250 and Cmax/MIC=10 as PK-PD targets.
CONCLUSION: A high loading dose of CAS (140mg) increased CAS exposure in the first 24 hours of therapy allowing early achievement of PK-PD targets for most Candida strains. Such strategy seems to improve treatment efficacy, even if further researches are needed to assess its impact on clinical outcomes.

PMID: 32958709 [PubMed - as supplied by publisher]

Genomic analysis of germline variation associated with survival of colorectal cancer patients treated with chemotherapy plus biologics in CALGB/SWOG 80405 (Alliance).

Clin Cancer Res. 2020 Sep 21;:

Authors: Innocenti F, Sibley AB, Patil SA, Etheridge AS, Jiang C, Ou FS, Howell S, Plummer SJ, Casey G, Bertagnolli MM, McLeod HL, Auman JT, Blanke CD, Furukawa Y, Venook AP, Kubo M, Lenz HJ, Parker JS, Ratain MJ, Owzar K

Abstract
BACKGROUND: Irinotecan/5-FU (FOLFIRI) or oxaliplatin/5-FU (FOLFOX), combined with bevacizumab or cetuximab, are approved, first-line treatments for metastatic colorectal cancer (mCRC). We aimed at identifying germline variants associated with survival in mCRC patients treated with these regimens in CALGB/SWOG 80405.
METHODS: Patients with mCRC receiving either FOLFOX or FOLFIRI were randomized to either cetuximab or bevacizumab. DNA from peripheral blood was genotyped for ~700,000 single-nucleotide polymorphisms (SNPs). The association between SNPs and overall survival (OS) was tested in 613 patients of genetically-estimated European ancestry using Cox proportional hazards models.
RESULTS: The four most significant SNPs associated with OS were three haplotypic SNPs between MGST1 and LMO3 (representative hazard ratios (HR) 1.56, p-value 1.30x10-6), and rs11644916 in AXIN1 (HR 1.39, p-value 4.26x10-6). AXIN1 is a well-established tumor suppressor gene in CRC, and rs11644916 (G>A) conferred shorter OS. Median OS for patients with the AA, AG or GG genotypes was 18.4, 25.6, or 36.4 months, respectively. In 90 stage IV CRC patients from TCGA, rs11649255 in AXIN1 (in almost complete linkage disequilibrium (LD) with rs11644916), was associated with shorter OS (HR 2.24, p-value 0.0096). Using rs11648673 in AXIN1 (in very high LD with rs11644916 and with functional evidence), luciferase activity in three CRC cell lines was reduced.
CONCLUSIONS: This is the first large GWAS ever conducted in mCRC patients treated with first-line standard treatment in a randomized phase III trial. A common SNP in AXIN1 confers worse OS and the effect is replicated in TCGA. Further studies in CRC experimental models are required.

PMID: 32958699 [PubMed - as supplied by publisher]

Perioperative genetic screening: entering a new era.

Br J Anaesth. 2020 Sep 18;:

Authors: Riazi S, Kraeva N, Girard T

PMID: 32958205 [PubMed - as supplied by publisher]

Micronuclei Formation upon Radioiodine Therapy for Well-Differentiated Thyroid Cancer: The Influence of DNA Repair Genes Variants.

Genes (Basel). 2020 Sep 17;11(9):

Authors: S Santos L, M Gil O, N Silva S, C Gomes B, C Ferreira T, Limbert E, Rueff J

Abstract
Radioiodine therapy with 131I remains the mainstay of standard treatment for well-differentiated thyroid cancer (DTC). Prognosis is good but concern exists that 131I-emitted ionizing radiation may induce double-strand breaks in extra-thyroidal tissues, increasing the risk of secondary malignancies. We, therefore, sought to evaluate the induction and 2-year persistence of micronuclei (MN) in lymphocytes from 26 131I-treated DTC patients and the potential impact of nine homologous recombination (HR), non-homologous end-joining (NHEJ), and mismatch repair (MMR) polymorphisms on MN levels. MN frequency was determined by the cytokinesis-blocked micronucleus assay while genotyping was performed through pre-designed TaqMan® Assays or conventional PCR-restriction fragment length polymorphism (RFLP). MN levels increased significantly one month after therapy and remained persistently higher than baseline for 2 years. A marked reduction in lymphocyte proliferation capacity was also apparent 2 years after therapy. MLH1 rs1799977 was associated with MN frequency (absolute or net variation) one month after therapy, in two independent groups. Significant associations were also observed for MSH3 rs26279, MSH4 rs5745325, NBN rs1805794, and tumor histotype. Overall, our results suggest that 131I therapy may pose a long-term challenge to cells other than thyrocytes and that the individual genetic profile may influence 131I sensitivity, hence its risk-benefit ratio. Further studies are warranted to confirm the potential utility of these single nucleotide polymorphisms (SNPs) as radiogenomic biomarkers in the personalization of radioiodine therapy.

PMID: 32957448 [PubMed - in process]

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pharmacogenomics

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13 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 2020/09/22

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.

Research participant understanding and engagement in an institutional, self-consent biobank model.

J Genet Couns. 2020 Sep 20;:

Authors: Schmanski A, Roberts E, Coors M, Wicks SJ, Arbet J, Weber R, Crooks K, Barnes KC, Taylor MRG

Abstract
The number of institutional and governmental biobanks and the target enrollment sizes of modern biobanks are increasing, affording more opportunities for the public to participate in biobanking efforts. In parallel with these expansions are pressures to increase the efficiency of obtaining informed consent using shorter consent forms that cover a broader scope of research and increasingly include provisions for return of research or clinical genetic test results to participants. Given these changes, how well these participants understand genetics, their level of understanding of what they are consenting to, and their wishes to engage longitudinally and receive biobank results are not well understood. We surveyed participants in a large, medical system-based biobank who had enrolled through a two-page, self-consent process about their baseline knowledge of genetics, understanding and recall of the consent process, wishes for future contact and engagement, and level of interest in receiving clinical genetic testing results. A total of 856 consented persons participated in the survey (67% women; 67% white). Participants' general reported genetics knowledge was relatively high (mean 11.60 of 15 questions answered correctly) as was recall of key elements from the two-page consent form. Overall participant enthusiasm for future contact by the biobank and for receiving clinical genetic testing results was high. The use of a two-page, self-consent process in a large, institutional biobank resulted in high levels of consent recall and enthusiasm for future ongoing engagement and receipt of genetic testing results by participants.

PMID: 32951257 [PubMed - as supplied by publisher]

Integration of Genetic Variants and Gene Network for Drug Repurposing in Colorectal Cancer.

Pharmacol Res. 2020 Sep 17;:105203

Authors: Irham LM, Wong HS, Chou WH, Adikusuma W, Mugiyanto E, Huang WC, Chang WC

Abstract
Even though many genetic risk loci for human diseases have been identified and comprehensively cataloged, strategies to guide clinical research by integrating the extensive results of genetic studies and biological resources are still limited. Moreover, integrative analyses that provide novel insights into disease biology are expected to be especially useful for drug discovery. Herein, we use text mining of genetic studies on colorectal cancer (CRC) and assign biological annotations to identified risk genes in order to discover novel drug targets and potential drugs for repurposing. Risk genes for CRC were obtained from PubMed text mining, and for each gene, six functional and bioinformatic annotations were analyzed. The annotations include missense mutations, expression quantitative trait loci (eQTL), molecular pathway analyses, protein-protein interactions (PPIs), genetic overlap with knockout mouse phenotypes, and primary immunodeficiency. We then prioritized biological risk candidate genes according to a scoring system for the six functional annotations. Each functional annotation was assigned one point, and those genes with a score ≥2 were designated "biological CRC risk genes". Using this method, we revealed 82 biological CRC risk genes, which mapped to 128 genes in an expanded PPI network. Further utilizing DrugBank and the Therapeutic Target Database (TTD), we found 21 genes in our list that are targeted by 166 candidate drugs. Based on data from ClinicalTrials.gov, we found our list contains four known target genes with six drugs approved for CRC treatment, as well as three known target genes with nine drugs under preclinical investigation for CRC. Additionally, 12 genes are targeted by 32 drugs approved for other indications, which can possibly be repurposed for CRC treatment. Finally, our analysis from Connectivity Map (CMap) showed that 18 of the 41 drugs under clinical and preclinical investigation have high potential to be useful for CRC.

PMID: 32950641 [PubMed - as supplied by publisher]

Genetic polymorphisms associated with upper gastrointestinal bleeding: a systematic review.

Pharmacogenomics J. 2020 Sep 18;:

Authors: Forgerini M, Lucchetta RC, Urbano G, de Nadai TR, de Carvalho Mastroianni P

Abstract
Non-variceal upper gastrointestinal bleeding (non-variceal UGIB) is a frequent and severe adverse drug reaction. Idiosyncratic responses due to genetic susceptibility to non-variceal UGIB has been suggested. A systematic review was conducted to assess the association between genetic polymorphisms and non-variceal UGIB. Twenty-one publications and 7134 participants were included. Thirteen studies evaluated genetic polymorphism in patients exposed to non-steroidal anti-inflammatory drugs, low-dose aspirin, and warfarin. Eight studies present at least one methodological problem. Only six studies clearly defined that the outcome evaluated was non-variceal UGIB. Genetic polymorphisms involved in platelet activation and aggregation, angiogenesis, inflammatory process, and drug metabolism were associated with risk of non-variceal UGIB (NOS3, COX-1; COX-2; PLA2G7; GP1BA; GRS; IL1RN; F13A1; CDKN2B-AS1; DPP6; TBXA2R; TNF-alpha; VKORC1; CYP2C9; and AGT). Further well-designed studies are needed (e.g., clear restriction to non-variceal UGIB; proper selection of participants; and adjustment of confounding factors) to provide strong evidence for pharmacogenetic and personalized medicine.

PMID: 32948830 [PubMed - as supplied by publisher]