Genetic biomarkers to guide poly (ADP-ribose) polymerase inhibitor precision treatment of prostate cancer.

Pharmacogenomics. 2020 Oct 06;:

Authors: Varnai R, Sipeky C

Abstract
Precision therapy for a subgroup of genetically defined metastatic castration-resistant prostate cancer patients may become a reality in the near future. DNA damage repair gene mutated prostate cancer might be vulnerable to treatment with PARP inhibitors (PARPi). PARPi clinical trials for prostate cancer investigate both germline and somatic genomic alterations of 43 genes for the applicability as genomic biomarker of PARPi sensitivity. Clinical trials with preliminary results show that BRCA2 and BRCA1, but also ATM, additionally BRIP1, FANCA, CDK12 and PALB2 may affect clinical end points, and may be potential candidates for genome guided patient selection in PARP inhibitor treatment of prostate cancer.

PMID: 33021139 [PubMed - as supplied by publisher]

Pan-cancer pharmacogenetics: targeted sequencing panels or exome sequencing?

Pharmacogenomics. 2020 Oct 06;:

Authors: Tilleman L, Heindryckx B, Deforce D, van Nieuwerburgh F

Abstract
Aim: This study provides clinicians and researchers with an informed choice between current commercially available targeted sequencing panels and exome sequencing panels in the context of pan-cancer pharmacogenetics. Materials & methods: Nine contemporary commercially available targeted pan-cancer panels and the xGen Exome Research Panel v2 were investigated to determine to what extent they cover the pharmacogenetic variant-drug interactions in five available cancer knowledgebases, and the driver mutations and fusion genes in The Cancer Genome Atlas. Results: xGen Exome Research Panel v2 and TrueSight Oncology 500 target 71.0 and 68.9% of the pharmacogenetic interactions in the available knowledgebases, and 93.7 and 86.0% of the driver mutations in The Cancer Genome Atlas, respectively. All other studied panels target lower percentages. Conclusion: Exome sequencing outperforms pan-cancer targeted sequencing panels in terms of covered cancer pharmacogenetic variant-drug interactions and pharmacogenetic cancer variants.

PMID: 33019866 [PubMed - as supplied by publisher]

(2R,3S)-Dihydroxybutanoic Acid Synthesis as a Novel Metabolic Function of Mutant Isocitrate Dehydrogenase 1 and 2 in Acute Myeloid Leukemia.

Cancers (Basel). 2020 Oct 01;12(10):

Authors: Idle JR, Seipel K, Bacher U, Pabst T, Beyoğlu D

Abstract
Acute myeloid leukemia (AML) frequently harbors mutations in isocitrate 1 (IDH1) and 2 (IDH2) genes, leading to the formation of the oncometabolite (2R)-hydroxyglutaric acid (2R-HG) with epigenetic consequences for AML proliferation and differentiation. To investigate if broad metabolic aberrations may result from IDH1 and IDH2 mutations in AML, plasma metabolomics was conducted by gas chromatography-mass spectrometry (GC-MS) on 51 AML patients, 29 IDH1/2 wild-type (WT), 9 with IDH1R132, 12 with IDH2R140 and one with IDH2R172 mutations. Distinct metabolic differences were observed between IDH1/2 WT, IDH1R132 and IDH2R140 patients that comprised 22 plasma metabolites that were mainly amino acids. Only two plasma metabolites were statistically significantly different (p < 0.0001) between both IDH1R132 and WT IDH1/2 and IDH2R140 and WT IDH1/2, specifically (2R)-hydroxyglutaric acid (2R-HG) and the threonine metabolite (2R,3S)-dihydroxybutanoic acid (2,3-DHBA). Moreover, 2R-HG correlated strongly (p < 0.0001) with 2,3-DHBA in plasma. One WT patient was discovered to have a D-2-hydroxyglutarate dehydrogenase (D2HGDH) A426T inactivating mutation but this had little influence on 2R-HG and 2,3-DHBA plasma concentrations. Expression of transporter genes SLC16A1 and SLC16A3 displayed a weak correlation with 2R-HG but not 2,3-DHBA plasma concentrations. Receiver operating characteristic (ROC) analysis demonstrated that 2,3-DHBA was a better biomarker for IDH mutation than 2R-HG (Area under the curve (AUC) 0.861; p < 0.0001; 80% specificity; 87.3% sensitivity). It was concluded that 2,3-DHBA and 2R-HG are both formed by mutant IDH1R132, IDH2R140 and IDH2R172, suggesting a potential role of 2,3-DHBA in AML pathogenesis.

PMID: 33019704 [PubMed]

The TOMATO Study (Tacrolimus Metabolization in Kidney Transplantation): Impact of the Concentration-Dose Ratio on Death-censored Graft Survival.

Transplantation. 2020 06;104(6):1263-1271

Authors: Jouve T, Fonrose X, Noble J, Janbon B, Fiard G, Malvezzi P, Stanke-Labesque F, Rostaing L

Abstract
BACKGROUND: Tacrolimus trough concentrations (mean/variability), as well as concentration-to-dose ratio (C/D ratio), affect kidney allograft outcomes. We investigated the link between the C/D ratio and death-censored kidney graft survival (DCGS).
METHODS: We performed a retrospective study on 1029 kidney transplant patients (2004-2016) with the following criteria: tacrolimus-based immunosuppression, >1-year graft survival, no initial use of everolimus, and available anti-human leukocyte antigen antibody data. We analyzed the impact of the time-varying C/D ratio on DCGS. Fast metabolizers were defined by a C/D ratio < 1.05. We also investigated the effect of an early (mo 3 to mo 6 post transplantation) C/D ratio below 1.05. Cox survival analyses were performed, adjusting for potential confounders (tacrolimus trough, variability of tacrolimus trough, de novo donor-specific antibody development, cytochrome P450 3A5 genotype, pregraft sensitization, mo 3 glomerular filtration rate).
RESULTS: Time-varying C/D ratio was significantly associated with DCGS (hazard ratio [HR], 2.35; P < 0.001) in a univariate model, on the full analysis set comprising 1029 patients. In the multivariate time-varying model, based on 666 patients with available cytochrome P450 3A5 genotypes, the effect of the C/D ratio remained significant (HR, 2.26; P = 0.015); even when glomerular filtration rate at month 3 < 30 mL/min/1.73 m (HR, 2.61; P = 0.011), de novo donor-specific antibody development (HR, 4.09; P < 0.001) and continued steroid prescription (HR=2.08, P = 0.014) were taken into account (other covariates, including tacrolimus trough concentrations, were nonsignificant). In the same multivariate model, the effect of early C/D ratio (median at mo 3 and mo 6) remained significantly associated with DCGS (HR, 2.25; P = 0.041).
CONCLUSIONS: C/D ratio is an independent and early predictor of DCGS. Identification of fast metabolizers could be a strategy to improve graft survival, for example, by optimizing tacrolimus formulation. Mechanistic studies to understand the C/D ratio effect are required.

PMID: 31415035 [PubMed - indexed for MEDLINE]

Methods and implementation of a pediatric asthma pharmacogenomic study in the emergency department setting.

Pharmacogenet Genomics. 2020 Dec;30(9):201-207

Authors: Fishe JN, Higley RK, Casey D, Hogans L, Wylie TW, Hendry PL, Henson M, Bertrand A, Blake KV

Abstract
OBJECTIVES: The emergency department (ED) is a challenging setting to conduct pharmacogenomic studies and integrate that data into fast-paced and potentially life-saving treatment decisions. Therefore, our objective is to present the methods and feasibility of a pilot pharmacogenomic study set in the ED that measured pediatric bronchodilator response (BDR) during acute asthma exacerbations.
METHODS: This is an exploratory pilot study that collected buccal swabs for DNA and measured BDR during ED encounters for pediatric asthma exacerbations. We evaluated the study's feasibility with a qualitative analysis of ED provider surveys and quantitatively by the proportion of eligible patients enrolled.
RESULTS: We enrolled 59 out of 90 patients (65%) that were identified and considered eligible during a 5-month period (target enrollment 60 patients over 12 months). The median patient age was 7 years (interquartile range 4-9 years), 61% (N = 36) were male, and 92% (N = 54) were African American. Quality DNA collection was successful for all 59 patients. The ED provider survey response rate was 100%. Most ED providers reported that the study did not impact their workflow (98% of physicians, 88% of nurses, and 90% of respiratory therapists). ED providers did report difficulties with spirometry in the younger age group.
CONCLUSIONS: Pharmacogenomic studies can be conducted in the ED setting, and enroll a younger patient population with a high proportion of minority participants. By disseminating this study's methods and feasibility analysis, we aim to increase interest in pharmacogenomic studies set in the ED and aimed toward future ED-based pharmacogenomic decision-making.

PMID: 33017130 [PubMed - as supplied by publisher]

Patient insights on features of an effective pharmacogenomics patient portal.

Pharmacogenet Genomics. 2020 Dec;30(9):191-200

Authors: Truong TM, Lipschultz E, Schierer E, Danahey K, Ratain MJ, O'Donnell PH

Abstract
OBJECTIVES: We built a novel mock pharmacogenomics web portal to deliver pharmacogenomic information and results to patients. Utilizing a patient focus group, we then sought to understand patient insights on desired features of an effective pharmacogenomics patient portal.
METHODS: The mock YourPGx Portal delivered four sample pharmacogenomic results (omeprazole, simvastatin, clopidogrel, and codeine). Patients from our existing institutional, prospective pharmacogenomics implementation study were recruited to pilot the mock portal and then asked to participate in a focus group discussion led by two facilitators. All patients had been previously genotyped, but none had been directly provided access to their own genotyping results and none had previously used the YourPGx portal. The focus group discussion explored nine domains: (1) factors influencing drug response, (2) concerns about drug effects, (3) understanding of genomics and pharmacogenomics, (4) reasons to undergo pharmacogenomic testing, (5) sources of pharmacogenomic information for patient education, (6) attributes of pharmacogenomic sources of information, (7) considerations about privacy and personal pharmacogenomic information, (8) sharing of pharmacogenomic information, and (9) features of an effective patient portal.
RESULTS: The median age of patients (n = 10) was 65.5 years old (range 38-72), 70% female, 50% Caucasian/30% Black, and 60% held a bachelor/advanced degree. When asked about resources for seeking pharmacogenomic information, patients preferred consulting their providers first, followed by self-education, then using information provided by university research organizations. A theme emerged regarding attributes of these sources, namely a desire for understandability and trust. Patients said that the effectiveness of a pharmacogenomics patient portal is improved with use of symbolisms/graphics and clear and concise content. Effective use of colors, quantifying information, consistency, and use of layperson's language were additional important facets. Patients communicated the appeal of secured phone/app-enabled access and said that they would desire linking to their electronic medical records to allow sharing of information with different members of their healthcare team.
CONCLUSIONS: Patients named providers as their primary source of pharmacogenomic information, but a pharmacogenomics patient portal that is carefully constructed to incorporate desired features may be a favorable tool to effectively deliver pharmacogenomic information and results to patients.

PMID: 33017129 [PubMed - as supplied by publisher]

Allele Frequency of ACE2 Intron Variants and Its Association with Blood Pressure.

DNA Cell Biol. 2020 Oct 05;:

Authors: Lozano-Gonzalez K, Padilla-Rodríguez E, Texis T, Gutiérrez MN, Rodríguez-Dorantes M, Cuevas-Córdoba B, Ramírez-García E, Mino-León D, Sánchez-García S, Gonzalez-Covarrubias V

Abstract
Angiotensin-converting enzyme 2 (ACE2) is known as the counter-regulator of the renin-angiotensin system, it cleaves angiotensin II to render Ag 1-7, a potent vasodilator with multiple roles in cardiovascular protection. A few studies have pinpointed ACE2 polymorphisms and their relationship with heart function and hypertension in a sex-dependent manner. These observations still lack replication mostly for admixed populations. This study aimed to report minor allele frequencies of four ACE2 intron variants, rs2285666, rs2048683, rs2106809, and rs4240157, derived from previous research using the GSA, v1.0, microarray in 1231 hypertensive and nonhypertensive patients. Logistic and multiple linear regression models were developed to identify potential associations with hypertension status and systolic and diastolic blood pressure (SBP and DBP). Allele frequency differences were identified for ACE2 rs2048683 and rs4240157 in populations with European ancestry and people of the Americas. Regression analyses identified a significant association of ACE2 rs2048683 and rs4240157 with SBP/DBP in males or females. Our observations confirm sex differences in ACE2 genetic associations with SBP and DBP and contribute to the collection of genetic variation in ACE2 for admixed populations.

PMID: 33016778 [PubMed - as supplied by publisher]

The search for personalized antidepressant treatments: what have we learned and where are we going.

Pharmacogenomics. 2020 Oct 05;:

Authors: Serretti A, Fabbri C

Abstract
Over 20 years after the initial report of gene variants within the central nervous system modulating antidepressant response, we are now facing for the first time routine clinical pharmacogenetic applications. The scientific community is divided between enthusiasm and skepticism. It seems clear that the benefit of existing tools is not huge, at least for the central nervous system gene variants, while it is generally accepted for the metabolic gene variants. Findings from large international consortia suggest for the first time in psychiatric genetic research history that cumulative scores comprising many variants across the whole genome may reliably constitute liability factors for psychiatric disorders, this approach will most likely improve also present pharmacogenetic tools. A composite genetic score complemented with clinical risk factors for each patient is the most promising approach for a more effective method of targeted treatment for patients with depression.

PMID: 33016213 [PubMed - as supplied by publisher]

Circulating miRNA-23b and miRNA-143 Are Potential Biomarkers for In-Stent Restenosis.

Biomed Res Int. 2020;2020:2509039

Authors: Saavedra N, Rojas G, Herrera J, Rebolledo C, Ruedlinger J, Bustos L, Bobadilla B, Pérez L, Saavedra K, Zambrano T, Lanas F, Salazar LA

Abstract
In-stent restenosis (ISR) is one of the main complications in patients undergoing percutaneous coronary angioplasty, and microRNAs participate in the contractile-to-synthetic phenotypic switch of vascular smooth muscle cells, a hallmark of restenosis development. MicroRNAs (miRNAs) can be released into circulation from injured tissues, enticing a potential role as noninvasive biomarkers. We aimed to evaluate circulating levels of miRNA-23b, miRNA-143, and miRNA-145 as diagnostic markers of ISR. 142 patients with coronary artery disease undergoing successful angioplasty and a follow-up angiography were included. Subjects were classified according to the degree of obstruction at the angioplasty site into cases (≥50%) or controls (<50%). Total RNA was isolated from plasma to quantify circulating miRNAs levels, and the ROC curves were constructed. Among circulating miRNAs assessed, miRNA-23b and miRNA-143 were significantly lower in cases (miRNA-23b: 18.4x10-5 and miRNA-143: 13.7x10-5) than controls (miRNA-23b: 5.2x10-5, p < 0.0001; miRNA-143: 4.0x10-5, p < 0.0001). Plasma levels of miRNA-145 showed no significant differences. The analysis of the ROC curves showed an area under the curve for miRNA-23b of 0.71 (95% CI: 0.62-0.80, p < 0.0001) and 0.69 for miRNA-143 (95% CI: 0.60-0.78; p < 0.0001). Our data suggest that plasma levels of miRNA-23b and miRNA-143 could be useful as noninvasive biomarkers of ISR.

PMID: 33015157 [PubMed - in process]

Discoidin Domain Receptors in Melanoma: Potential Therapeutic Targets to Overcome MAPK Inhibitor Resistance.

Front Oncol. 2020;10:1748

Authors: Reger de Moura C, Prunotto M, Sohail A, Battistella M, Jouenne F, Marbach D, Lebbé C, Fridman R, Mourah S

Abstract
Melanoma is a highly malignant skin cancer with high propensity to metastasize and develop drug resistance, making it a difficult cancer to treat. Current therapies targeting BRAF (V600) mutations are initially effective, but eventually tumors overcome drug sensitivity and reoccur. This process is accomplished in part by reactivating alternate signaling networks that reinstate melanoma proliferative and survival capacity, mostly through reprogramming of receptor tyrosine kinase (RTK) signaling. Evidence indicates that the discoidin domain receptors (DDRs), a set of RTKs that signal in response to collagen, are part of the kinome network that confer drug resistance. We previously reported that DDR1 is expressed in melanomas, where it can promote tumor malignancy in mouse models of melanoma, and thus, DDR1 could be a promising target to overcome drug resistance. In this review, we summarize the current knowledge on DDRs in melanoma and their implication for therapy, with emphasis in resistance to MAPK inhibitors.

PMID: 33014862 [PubMed]

Integrative analyses identify a DNA damage repair gene signature for prognosis prediction in lower grade gliomas.

Future Oncol. 2020 Mar;16(8):367-382

Authors: Pang FM, Yan H, Mo JL, Li D, Chen Y, Zhang L, Liu ZQ, Zhou HH, Wu J, Li X

Abstract
Background: The DNA damage repair (DDR) pathways play important roles for regulating cancer progression and therapeutic response. IDH mutations, well-known prognosis biomarkers for glioma, lead to hypermethylation of tumor cells and affect genes' expression. Whether IDH mutations affect glioma prognosis through influencing the expression of DDR genes remains unclear. Methods: A total of 272 DDR genes were selected for differential expression and survival analysis. The identified genes were then utilized to construct the prognosis predicting model. Results: PARPBP, PLK3, POLL and WEE1 were found differential expressed between IDH mutations carriers and wild-type carriers, and were associated with survival of low grade glioma (LGG) patients. The predicting algorithm can predicts the prognosis of LGG patients. Conclusion: IDH mutations may affect LGG prognosis through regulation of DDR pathways.

PMID: 32065545 [PubMed - indexed for MEDLINE]

Molecular characterization of Mycoplasma pneumoniae infections in Moscow from 2015 to 2018.

Eur J Clin Microbiol Infect Dis. 2020 Feb;39(2):257-263

Authors: Voronina EN, Gordukova MA, Turina IE, Mishukova OV, Dymova MA, Galeeva EV, Korsunskiy AA, Filipenko ML

Abstract
The aim of this study was to assess which Mycoplasma pneumoniae genotypes were present in Moscow during the years 2015-2018 and whether the proportion between detected genotypes changed over time. We were also interested in the presence of macrolide resistance (MR)Mycoplasma pneumoniae. We performed multilocus variable-number tandem-repeat (VNTR) analysis (MLVA), SNP typing, and mutation typing in the 23S rRNA gene from 117 M. pneumoniae clinical isolates. Our analysis suggests two major MLVA types: 4572 and 3562. In 2017-2018, MLVA type 4572 gradually became predominant. In general, the SNP type range is the same as described earlier for European countries. The analysis of MR mutations showed that 7% of the isolates had an A2063G mutation in the 23S rRNA gene with no isolates carrying an A2064G mutation. In 2017-2018, MLVA type 4572 (SNP type 1) begins to spread in Moscow, which was widespread globally, especially in Asian countries. SNP typing of our sample showed higher discriminatory power than MLVA typing.

PMID: 31655931 [PubMed - indexed for MEDLINE]

Genome-wide association study of cardiovascular disease in testicular cancer patients treated with platinum-based chemotherapy.

Pharmacogenomics J. 2020 Oct 03;:

Authors: Steggink LC, Boer H, Meijer C, Lefrandt JD, Terstappen LWMM, Fehrmann RSN, Gietema JA

Abstract
Genetic variation may mediate the increased risk of cardiovascular disease (CVD) in chemotherapy-treated testicular cancer (TC) patients compared to the general population. Involved single nucleotide polymorphisms (SNPs) might differ from known CVD-associated SNPs in the general population. We performed an explorative genome-wide association study (GWAS) in TC patients. TC patients treated with platinum-based chemotherapy between 1977 and 2011, age ≤55 years at diagnosis, and ≥3 years relapse-free follow-up were genotyped. Association between SNPs and CVD occurrence during treatment or follow-up was analyzed. Data-driven Expression Prioritized Integration for Complex Trait (DEPICT) provided insight into enriched gene sets, i.e., biological themes. During a median follow-up of 11 years (range 3-37), CVD occurred in 53 (14%) of 375 genotyped patients. Based on 179 SNPs associated at p ≤ 0.001, 141 independent genomic loci associated with CVD occurrence. Subsequent, DEPICT found ten biological themes, with the RAC2/RAC3 network (linked to endothelial activation) as the most prominent theme. Biology of this network was illustrated in a TC cohort (n = 60) by increased circulating endothelial cells during chemotherapy. In conclusion, the ten observed biological themes highlight possible pathways involved in CVD in chemotherapy-treated TC patients. Insight in the genetic susceptibility to CVD in TC patients can aid future intervention strategies.

PMID: 33011741 [PubMed - as supplied by publisher]

Remdesivir and COVID-19.

Lancet. 2020 Oct 03;396(10256):953-954

Authors: Wang LY, Cui JJ, Ouyang QY, Zhan Y, Guo CX, Yin JY

PMID: 33010833 [PubMed - as supplied by publisher]

Correction: ERCC2 gene single-nucleotide polymorphism as a prognostic factor for locally advanced head and neck carcinomas after definitive cisplatin-based radiochemotherapy.

Pharmacogenomics J. 2020 Oct 02;:

Authors: Guberina M, Sak A, Pöttgen C, Tinhofer-Keilholz I, Budach V, Balermpas P, Von der Grün J, Rödel CM, Gkika E, Grosu AL, Abdollahi A, Debus J, Belka C, Pigorsch S, Combs SE, Mönnich D, Zips D, De-Colle C, Welz S, Linge A, Lohaus F, Baretton G, Gauler T, Baumann M, Krause M, Schuler M, Bankfalvi A, Höing B, Lang S, Stuschke M

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PMID: 33009516 [PubMed - as supplied by publisher]

Gene expression signatures of BRCAness and tumor inflammation define subgroups of early-stage hormone receptor-positive breast cancer patients.

Clin Cancer Res. 2020 Oct 02;:

Authors: Schroth W, Büttner FA, Kandabarau S, Hoppe R, Fritz P, Kumbrink J, Kirchner T, Brauer HA, Ren Y, Henderson DA, Madden SF, Sauer G, Fehm T, Wallwiener D, Fasching PA, Mürdter TE, Schwab M, Tamoxifen Ai Clinicians Group G, Brauch H

Abstract
PURPOSE: Patients with estrogen and/or progesterone receptor-positive, early breast cancer benefit from hormonal treatment, yet high global death burdens due to high prevalence and long-term recurrence risk call for biomarkers to guide additional treatment approaches.
EXPERIMENTAL DESIGN: From a prospective, observational study of postmenopausal early breast cancer patients treated with tamoxifen or aromatase inhibitors gene expression analyses of 612 tumors was performed using the NanoString® Breast Cancer 360 panel to interrogate 23 breast cancer pathways. Candidate signatures associated with disease subtype and event-free survival (EFS) were obtained by cluster analysis, Cox modeling and conditional inference trees, and were independently tested in 613 patients from BreastMark. Tumor-infiltrating lymphocytes (TIL) were assessed on tissue sections, and mutational burden was assessed in 36 tumors by whole-exome sequencing.
RESULTS: PAM50-derived classification distinguished lower-risk (Luminal A) from higher-risk subtypes (Luminal B, P=.04; HER2, P=.006; Basal, P=.008). In higher-risk patients shorter EFS was associated with low androgen receptor (HR=3.61; 95%CI 1.72-7.56; P=.001) or high BRCAness signature expression (HR=3.58; 95%CI 1.19-10.7; P=.023). BRCAness was independently confirmed as a predictor of shorter EFS (HR=2.64; 95%CI 1.31-5.34; P=.007). About 13-15% of patients, enriched for high-grade, higher-risk subtypes (P<.0001), had strong expression of the Tumor Inflammation Signature (TIS) suggestive of an inhibited anti-tumor immune response. TIS scores were strongly associated with TIL numbers (P <1e-30) but not with tumor mutation status.
CONCLUSIONS: BRCA-related DNA repair deficiency and suppressed tumor immune responses may be clinically relevant predictors of endocrine therapy complementing treatment options in subgroups of hormone-sensitive early breast cancer.

PMID: 33008814 [PubMed - as supplied by publisher]

Pathogenesis of Eosinophilic Esophagitis: A Comprehensive Review of the Genetic and Molecular Aspects.

Int J Mol Sci. 2020 Sep 30;21(19):

Authors: Ryu S, Lee KH, Tizaoui K, Terrazzino S, Cargnin S, Effenberger M, Shin JI, Kronbichler A

Abstract
Eosinophilic esophagitis (EoE) is a relatively new condition described as an allergic-mediated disease of the esophagus. Clinically, it is characterized by dysphagia, food impaction, and reflux-like symptoms. Multiple genome-wide association studies (GWAS) have been conducted to identify genetic loci associated with EoE. The integration of numerous studies investigating the genetic polymorphisms in EoE and the Mendelian diseases associated with EoE are discussed to provide insights into the genetic risk of EoE, notably focusing on CCL26 and CAPN14. We focus on the genetic loci investigated thus far, and their classification according to whether the function near the loci is known. The pathophysiology of EoE is described by separately presenting the known function of each cell and molecule, with the major contributors being eosinophils, Th2 cells, thymic stromal lymphopoietin (TSLP), transforming growth factor (TGF)-β1, and interleukin (IL)-13. This review aims to provide detailed descriptions of the genetics and the comprehensive pathophysiology of EoE.

PMID: 33008138 [PubMed - as supplied by publisher]

Biopathological Significance of PIWI-piRNA Pathway Deregulation in Invasive Breast Carcinomas.

Cancers (Basel). 2020 Sep 30;12(10):

Authors: Meseure D, Vacher S, Boudjemaa S, Laé M, Nicolas A, Leclere R, Chemlali W, Champenois G, Schnitzler A, Lesage L, Dubois T, Bieche I

Abstract
The PIWI proteins emerging in the development of human cancers, edify PIWI-piRNA ribonucleoproteic complexes acting as pivotal regulators of genome integrity, differentiation and homeostasis. The aim of this study is to analyze the four PIWILs gene expression in invasive breast carcinomas (IBCs): at RNA level using quantitative RT-PCR (n = 526) and protein level using immunohistochemistry (n = 150). In normal breast tissue, PIWILs 2 and 4 were solely expressed, whereas an abnormal emergence of PIWIL1 and 3 was observed in respectively 30% and 6% of IBCs. Conversely, PIWIL2 was underexpressed in 48.3% and PIWIL4 downregulated in 43.3% of IBCs. Significant positive associations were observed between PIWIL4 underexpression, HR+ status and HR+ ERBB2+ molecular subtype and PIWIL2 underexpression, PR- status, ERBB2- status and molecular subtype. Similar patterns of PIWIL deregulation were observed in a multitumoral panel, suggesting a generic mechanism in most cancers. PIWIL2-4 underexpression was mainly regulated at epigenetic or post-transcriptional levels. PIWIL2 underexpression was significantly associated with DNA methylation and strong cytotoxic immune response. PIWIL2-4 were mainly associated with genes implicated in cell proliferation. As a result of this study, characterization of the PIWIL-piRNA pathway in IBCs opens interesting therapeutic perspectives using piRNAs, hypomethylating drugs, checkpoints immunotherapies and anti-PIWIL 1-3 antibodies.

PMID: 33008024 [PubMed - as supplied by publisher]

Genetic Variation and Autism: A Field Synopsis and Systematic Meta-Analysis.

Brain Sci. 2020 Sep 30;10(10):

Authors: Lee J, Son MJ, Son CY, Jeong GH, Lee KH, Lee KS, Ko Y, Kim JY, Lee JY, Radua J, Eisenhut M, Gressier F, Koyanagi A, Stubbs B, Solmi M, Rais TB, Kronbichler A, Dragioti E, Vasconcelos DFP, Silva FRPD, Tizaoui K, Brunoni AR, Carvalho AF, Cargnin S, Terrazzino S, Stickley A, Smith L, Thompson T, Shin JI, Fusar-Poli P

Abstract
This study aimed to verify noteworthy findings between genetic risk factors and autism spectrum disorder (ASD) by employing the false positive report probability (FPRP) and the Bayesian false-discovery probability (BFDP). PubMed and the Genome-Wide Association Studies (GWAS) catalog were searched from inception to 1 August, 2019. We included meta-analyses on genetic factors of ASD of any study design. Overall, twenty-seven meta-analyses articles from literature searches, and four manually added articles from the GWAS catalog were re-analyzed. This showed that five of 31 comparisons for meta-analyses of observational studies, 40 out of 203 comparisons for the GWAS meta-analyses, and 18 out of 20 comparisons for the GWAS catalog, respectively, had noteworthy estimations under both Bayesian approaches. In this study, we found noteworthy genetic comparisons highly related to an increased risk of ASD. Multiple genetic comparisons were shown to be associated with ASD risk; however, genuine associations should be carefully verified and understood.

PMID: 33007889 [PubMed - as supplied by publisher]

Significant Decreased Expressions of CaN, VEGF, SLC39A6 and SFRP1 in MDA-MB-231 Xenograft Breast Tumor Mice Treated with Moringa oleifera Leaves and Seed Residue (MOLSr) Extracts.

Nutrients. 2020 Sep 30;12(10):

Authors: Lim WF, Mohamad Yusof MI, Teh LK, Salleh MZ

Abstract
Moringa oleifera is a miracle plant with many nutritional and medicinal properties. Chemopreventive values of the combined mixture of moringa leaves and seed residue (MOLSr) at different ratios (M1S9, M1S1 and M9S1) were investigated. MOLSr extracts were subjected to phytochemical screening, antioxidant assays, metabolite profiling and cytotoxic activity on the primary mammary epithelial cells (PMECs), non-malignant Chang's liver cells and various human cancer cell lines (including breast, cervical, colon and liver cancer cell lines). The MOLSr ratio with the most potent cytotoxic activity was used in xenograft mice injected with MDA-MB-231 cells for in vivo tumorigenicity study as well as further protein and gene expression studies. M1S9, specifically composed of saponin and amino acid, retained the lowest antioxidant activity but the highest glucosinolate content as compared to other ratios. Cell viability decreased significantly in MCF-7 breast cancer cells and PMECs after treatment with M1S9. Solid tumor from MDA-MB-231 xenograft mice was inhibited by up to 64.5% at third week after treatment with high-dose M1S9. High-dose M1S9 significantly decreased the expression of calcineurin (CaN) and vascular endothelial cell growth factor (VEGF) proteins as well as the secreted frizzled-related protein 1 (SFRP1) and solute carrier family 39 member 6 (SLC39A6) genes. This study provides new scientific evidence for the chemoprevention potential of MOLSr extracts in a breast cancer model; however, the precise mechanism warrants further investigation.

PMID: 33007803 [PubMed - as supplied by publisher]