Androgen receptor gain in circulating free DNA and splicing variant 7 in exosomes predict clinical outcome in CRPC patients treated with abiraterone and enzalutamide.

Prostate Cancer Prostatic Dis. 2021 Jan 26;:

Authors: Del Re M, Conteduca V, Crucitta S, Gurioli G, Casadei C, Restante G, Schepisi G, Lolli C, Cucchiara F, Danesi R, De Giorgi U

Abstract
BACKGROUND: Androgen receptor (AR) signaling inhibitors represent the standard treatment in metastatic castration resistance prostate cancer (mCRPC) patients. However, some patients display a primary resistance, and several studies investigated the role of the AR as a predictive biomarker of response to treatment. This study is aimed to evaluate the role of AR in liquid biopsy to predict clinical outcome to AR signaling inhibitors in mCRPC patients.
METHODS: Six milliliters of plasma samples were collected before first-line treatment with abiraterone or enzalutamide. Circulating free DNA (cfDNA) and exosome-RNA were isolated for analysis of AR gain and AR splice variant 7 (AR-V7), respectively, by digital droplet PCR.
RESULTS: Eighty-four mCRPC patients received abiraterone (n = 40) or enzalutamide (n = 44) as first-line therapy. Twelve patients (14.3%) presented AR gain and 30 (35.7%) AR-V7+ at baseline. Median progression-free survival (PFS) and overall survival (OS) were significantly longer in AR-V7- vs AR-V7+ patients (24.3 vs 5.4 months, p < 0.0001; not reached vs 16.2 months, p = 0.0001, respectively). Patients carrying the AR gain had a median PFS of 4.8 vs 24.3 months for AR normal patients (p < 0.0001). Median OS was significantly longer in AR normal vs patients with AR gain (not reached vs 8.17 months, p < 0.0001). A significant correlation between AR-V7 and AR gain was observed (r = 0.28; p = 0.01). The AR gain/AR-V7 combined analysis confirmed a strong predictive effect for biomarkers combination vs patients without any AR aberration (PFS 3.8 vs 28 month, respectively; OS 6.1 vs not reached, respectively; p < 0.0001).
CONCLUSIONS: The present study demonstrates that cfDNA and exosome-RNA are both a reliable source of AR variants and their combined detection in liquid biopsy predicts resistance to AR signaling inhibitors.

PMID: 33500577 [PubMed - as supplied by publisher]

Breast cancer risk factors and survival by tumor subtype: pooled analyses from the Breast Cancer Association Consortium.

Cancer Epidemiol Biomarkers Prev. 2021 Jan 26;:

Authors: Morra A, Jung AY, Behrens S, Keeman R, Ahearn TU, Anton-Cluver H, Arndt V, Augustinsson A, Auvinen PK, Beane Freeman LE, Becher H, Beckmann MW, Bloomqvist C, Bojesen SE, Bolla MK, Brenner H, Briceno I, Brucker SY, Camp NJ, Campa D, Canzian F, Castelao JE, Chanock SJ, Choi JY, Clarke CL, Couch FJ, Cox A, Cross SS, Czene K, Dӧrk T, Dunning AM, Dwek M, Easton DF, Eccles DM, Egan KM, Evans DG, Fasching PA, Flyger H, Gago-Dominguez M, Gapstur SM, Garcia-Saenz JA, Gaudet MM, Giles GG, Grip M, Guénel P, Haiman CA, Håkansson N, Hall P, Hamann U, Han SN, Hart SN, Hartman M, Heyworth JS, Hoppe R, Hopper JL, Hunter DJ, Ito H, Jager A, Jakimovska M, Jakubowska A, Janni W, Kaaks R, Kang D, Middha Kapoor P, Kitahara CM, Koutros S, Kraft P, Kristensen VN, Lacey JV, Lambrechts D, Le Marchand L, Li J, Lindblom A, Lubiński J, Lush M, Mannermaa A, Manoochehri M, Margolin S, Mariapun S, Matsuo K, Mavroudis D, Milne RL, Muranen TA, Newman WG, Noh DY, Nordestgaard BG, Obi N, Olshan AF, Olsson H, Park-Simon TW, Petridis C, Pharoah PDP, Plaseska-Karanfilska D, Presneau N, Rashid MU, Rennert G, Rennert HS, Rhenius V, Romero A, Saloustros E, Sawyer EJ, Schneeweiss A, Schwentner L, Scott CG, Shah M, Shen CY, Shu XO, Southey MC, Stram DO, Tamimi RM, Tapper W, Tollenaar RAEM, Tomlinson I, Torres D, Troester MA, Truong T, Vachon CM, Wang Q, Wang SS, Williams JA, Winqvist R, Wolk A, Wu AH, Yoo KY, Yu JC, Zheng W, Ziogas A, Yang XR, Eliassen AH, Holmes MD, Garcia-Closas M, Teo SH, Schmidt MK, Chang-Claude J

Abstract
BACKGROUND: It is not known if modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype.
METHODS: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer-specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.
RESULTS: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (adjusted p>0.30). The strongest associations were between all-cause mortality and BMI {greater than or equal to}30 vs 18.5-25 kg/m2 (HR (95%CI): 1.19 (1.06,1.34)); current vs never smoking (1.37 (1.27,1.47)), high vs low physical activity (0.43 (0.21,0.86)), age {greater than or equal to}30 years vs <20 years at first pregnancy (0.79 (0.72,0.86)); >0 to <5 years vs {greater than or equal to}10 years since last full term birth (1.31 (1.11,1.55)); ever vs never use of oral contraceptives (0.91 (0.87,0.96)); ever vs never use of menopausal hormone therapy, including current estrogen-progestin therapy (0.61 (0.54,0.69)). Similar associations with breast cancer mortality were weaker; e.g. 1.11 (1.02,1.21) for current vs never smoking.
CONCLUSIONS: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype.
IMPACT: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

PMID: 33500318 [PubMed - as supplied by publisher]

Synthetic Transition from Thiourea-Based Compounds to Tetrazole Derivatives: Structure and Biological Evaluation of Synthesized New N-(Furan-2-ylmethyl)-1H-tetrazol-5-amine Derivatives.

Molecules. 2021 Jan 10;26(2):

Authors: Szulczyk D, Bielenica A, Roszkowski P, Dobrowolski MA, Olejarz W, Kmiecik S, Podsiad M, Struga M

Abstract
Twelve novel derivatives of N-(furan-2-ylmethyl)-1H-tetrazol-5-amine were synthesized. For obtained compound 8, its corresponding substrate single crystals were isolated and X-ray diffraction experiments were completed. In the initial stage of research, in silico structure-based pharmacological prediction was conducted. All compounds were screened for their antibacterial and antimycobacterial activities using standard and clinical strains. The cytotoxic activity was evaluated against a panel of human cancer cell lines, in contrast to normal (HaCaT) cell lines, by using the MTT method. All examined derivatives were found to be noncytotoxic against normal cell lines. Within the studied group, compound 6 showed the most promising results in antimicrobial studies. It inhibited four hospital S. epidermidis rods' growth, when applied at the amount of 4 µg/mL. However, the most susceptible to the presence of compound 6 was S. epidermidis T 5501 851/19 clinical strain, for which the MIC value was only 2 µg/mL. Finally, a pharmacophore model was established based on lead compounds from this and our previous work.

PMID: 33435194 [PubMed - indexed for MEDLINE]

Genetics and treatment of gastrointestinal stromal tumors with immune checkpoint inhibitors: what do we know?

Pharmacogenomics. 2020 03;21(4):231-234

Authors: Indio V, Astolfi A, Urbini M, Nannini M, Pantaleo MA

PMID: 31973655 [PubMed - indexed for MEDLINE]

Prioritizing rs7294 as a mirSNP contributing to warfarin dosing variability.

Pharmacogenomics. 2020 03;21(4):257-267

Authors: Koshy L, Harikrishnan S, Sudhakaran PR

Abstract
Aim: The role of mirSNPs in the 3'UTR of VKORC1, CYP2C9 and CYP4F2 genes that could influence warfarin dose variability via a discrete miRNA-mediated mechanism remains unexplained. Methods: Genotypic data in the 1000 Genomes dataset were analyzed for pair-wise linkage disequilibrium and allelic enrichment. Results: MirSNP rs7294 in the 3'UTR of VKORC1 gene displayed varying strengths of linkage disequilibrium with rs9923231 and rs9934438 across populations, albeit consistently associated with higher warfarin dose requirements based on genome-wide association studies, meta-analysis and population-based association studies. In silico analysis predicted altered hybrid stability for the hsa-miR-133a-3p conserved binding site, providing evidence for miRNA-mediated gene regulation. Conclusion: The results support the inclusion of rs7294 as a functional variable for population-specific dosing algorithms to improve dosing accuracy.

PMID: 31973625 [PubMed - indexed for MEDLINE]

Targeting OCT3 attenuates doxorubicin-induced cardiac injury.

Proc Natl Acad Sci U S A. 2021 Feb 02;118(5):

Authors: Huang KM, Zavorka Thomas M, Magdy T, Eisenmann ED, Uddin ME, DiGiacomo DF, Pan A, Keiser M, Otter M, Xia SH, Li Y, Jin Y, Fu Q, Gibson AA, Bonilla IM, Carnes CA, Corps KN, Coppola V, Smith SA, Addison D, Nies AT, Bundschuh R, Chen T, Lustberg MB, Wang J, Oswald S, Campbell MJ, Yan PS, Baker SD, Hu S, Burridge PW, Sparreboom A

Abstract
Doxorubicin is a commonly used anticancer agent that can cause debilitating and irreversible cardiac injury. The initiating mechanisms contributing to this side effect remain unknown, and current preventative strategies offer only modest protection. Using stem-cell-derived cardiomyocytes from patients receiving doxorubicin, we probed the transcriptomic landscape of solute carriers and identified organic cation transporter 3 (OCT3) (SLC22A3) as a critical transporter regulating the cardiac accumulation of doxorubicin. Functional validation studies in heterologous overexpression models confirmed that doxorubicin is transported into cardiomyocytes by OCT3 and that deficiency of OCT3 protected mice from acute and chronic doxorubicin-related changes in cardiovascular function and genetic pathways associated with cardiac damage. To provide proof-of-principle and demonstrate translational relevance of this transport mechanism, we identified several pharmacological inhibitors of OCT3, including nilotinib, and found that pharmacological targeting of OCT3 can also preserve cardiovascular function following treatment with doxorubicin without affecting its plasma levels or antitumor effects in multiple models of leukemia and breast cancer. Finally, we identified a previously unrecognized, OCT3-dependent pathway of doxorubicin-induced cardiotoxicity that results in a downstream signaling cascade involving the calcium-binding proteins S100A8 and S100A9. These collective findings not only shed light on the etiology of doxorubicin-induced cardiotoxicity, but also are of potential translational relevance and provide a rationale for the implementation of a targeted intervention strategy to prevent this debilitating side effect.

PMID: 33495337 [PubMed - in process]

StellarPGx: A Nextflow pipeline for calling star alleles in cytochrome P450 genes.

Clin Pharmacol Ther. 2021 Jan 25;:

Authors: Twesigomwe D, Drögemöller BI, Wright GEB, Siddiqui A, da Rocha J, Lombard Z, Hazelhurst S

Abstract
Bioinformatics pipelines for calling star alleles (haplotypes) in Cytochrome P450 (CYP) genes are important for the implementation of precision medicine. Genotyping CYP genes using high throughput sequencing data is complicated e.g. by being highly polymorphic, not to mention the structural variations especially in CYP2D6, CYP2A6 and CYP2B6. Genome graph-based variant detection approaches have been shown to be reliable for genotyping HLA alleles. However, their application to enhancing star allele calling in CYP genes has not been extensively explored. We present StellarPGx, a Nextflow pipeline for accurately genotyping CYP genes by combining genome graph-based variant detection, read coverage information from the original reference-based alignments, and combinatorial diplotype assignments. The implementation of StellarPGx using Nextflow facilitates its portability, reproducibility and scalability on various user platforms. StellarPGx is currently able to genotype 12 important pharmacogenes belonging to the CYP1, 2, and 3 families. For purposes of validation, we use CYP2D6 as a model gene owing to its high degree of polymorphisms (over 130 star alleles defined to date, including complex structural variants) and clinical importance. We applied StellarPGx and 3 existing callers to 109 whole genome sequenced samples for which the Genetic Testing Reference Material Coordination Program (GeT-RM) has recently provided consensus truth CYP2D6 diplotypes. StellarPGx had the highest CYP2D6 diplotype concordance (99%) with GeT-RM compared to Cyrius (98%), Aldy (82%) and Stargazer (84%). This exemplifies the high accuracy of StellarPGx and highlights its importance for both research and clinical pharmacogenomics (PGx) applications. The StellarPGx pipeline is open-source and available from https://github.com/SBIMB/StellarPGx.

PMID: 33492672 [PubMed - as supplied by publisher]

Race and Pharmacogenomics-Personalized Medicine or Misguided Practice?

JAMA. 2021 Jan 25;:

Authors: Goodman CW, Brett AS

PMID: 33492362 [PubMed - as supplied by publisher]

Pharmacogenomics of Medication-Induced Weight Gain and Antiobesity Medications.

Obesity (Silver Spring). 2021 Feb;29(2):265-273

Authors: Singh S, Ricardo-Silgado ML, Bielinski SJ, Acosta A

Abstract
Obesity is a chronic, multifactorial disease associated with a large number of comorbidities. The clinical management of obesity involves a stepwise integrated approach, beginning with behavioral and lifestyle modification, followed by antiobesity medications, endobariatric procedures, and bariatric surgery. Weight gain and subsequent obesity are common side effects of medications, such as prednisone or antipsychotics. In this era of precision medicine, it is essential to identify patients at the highest risk of weight gain as a result of medication use. Pharmacogenomics could play an important role in obesity management by optimizing use of antiobesity medications as well as minimizing adverse weight gain. This review aims to provide a comprehensive analysis of the current literature on the role of pharmacogenomics in obesity and medication-induced weight gain. In summary, there are more robust studies of medication associated with weight gain and pharmacogenomics, and more studies are needed to understand the role of pharmacogenomics in antiobesity medications.

PMID: 33491309 [PubMed - in process]

Haplotype structure defines effects of common DPYD variants c.85T>C (rs1801265) and c.496A>G (rs2297595) on DPD activity: implication for 5-fluorouracil toxicity.

Br J Clin Pharmacol. 2021 Jan 24;:

Authors: Hamzic S, Schärer D, Offer S, Meulendijks D, Nakas C, Diasio R, Fontana S, Wehrli M, Schürch S, Amstutz U, Largiadèr CR

Abstract
AIM: The aim of this study was to identify risk variants and haplotypes that impair dihydropyrimidine dehydrogenase (DPD) activity and are, therefore, candidate risk variants for severe toxicity to 5-fluorouracil (5-FU) chemotherapy.
METHOD: Plasma dihydrouracil/uracil (UH2 /U) ratios were measured as a population marker for DPD activity in a total of 1'382 subjects from four independent studies. Genotype and haplotype correlations with UH2 /U ratios were assessed.
RESULTS: Significantly lower UH2 /U ratios (panova <2e-16) were observed in carriers of the four well-studied 5-FU toxicity risk variants with mean differences (MD) of -43.7% for DPYD-c.1905+1G>A (rs3918290), -46.0% for DPYD-c.1679T>G (rs55886062), -37.1%, for DPYD-c.2846A>T (rs67376798), and -13.2% for DPYD-c.1129-5923C>G (rs75017182). An additional variant, DPYD c.496A>G (rs2297595), was also associated with lower UH2 /U ratios (p<0.0001, MD: -12.6%). A haplotype analysis was performed for variants in linkage disequilibrium (LD) with c.496A>G, which consisted of the common variant c.85T>C (rs1801265) and the risk variant c.1129-5923C>G. Both haplotypes carrying c.496A>G were associated with decreased UH2 /U ratios (H3, p=0.003, MD: -9.6%; H5, p=0.002, MD: -16.9%). A haplotype carrying only the variant c.85T>C (H2) was associated with elevated ratios (p=0.004, MD: +8.6%).
CONCLUSION: Based on our data, DPYD-c.496A>G is a strong candidate risk allele for 5-FU toxicity. Our data suggest that DPYD-c.85T>C might be protective; however, the deleterious impacts of the linked alleles c.496A>G and c.1129-5923C>G likely limit this effect in patients. The possible protective effect of c.85T>C and LD with c.496A>G and c.1129-5923C>G may have hampered prior association studies and should be considered in future clinical studies.

PMID: 33491253 [PubMed - as supplied by publisher]

Integrating Liquid Biopsy and Radiomics to Monitor Clonal Heterogeneity of EGFR-Positive Non-Small Cell Lung Cancer.

Front Oncol. 2020;10:593831

Authors: Cucchiara F, Del Re M, Valleggi S, Romei C, Petrini I, Lucchesi M, Crucitta S, Rofi E, De Liperi A, Chella A, Russo A, Danesi R

Abstract
Background: EGFR-positive Non-small Cell Lung Cancer (NSCLC) is a dynamic entity and tumor progression and resistance to tyrosine kinase inhibitors (TKIs) arise from the accumulation, over time and across different disease sites, of subclonal genetic mutations. For instance, the occurrence of EGFR T790M is associated with resistance to gefitinib, erlotinib, and afatinib, while EGFR C797S causes osimertinib to lose activity. Sensitive technologies as radiomics and liquid biopsy have great potential to monitor tumor heterogeneity since they are both minimally invasive, easy to perform, and can be repeated over patient's follow-up, enabling the extraction of valuable information. Yet, to date, there are no reported cases associating liquid biopsy and radiomics during treatment.
Case presentation: In this case series, seven patients with metastatic EGFR-positive NSCLC have been monitored during target therapy. Plasma-derived cell free DNA (cfDNA) was analyzed by a digital droplet PCR (ddPCR), while radiomic analyses were performed using the validated LifeX® software on computed tomography (CT)-images. The dynamics of EGFR mutations in cfDNA was compared with that of radiomic features. Then, for each EGFR mutation, a radiomic signature was defines as the sum of the most predictive features, weighted by their corresponding regression coefficients for the least absolute shrinkage and selection operator (LASSO) model. The receiver operating characteristic (ROC) curves were computed to estimate their diagnostic performance. The signatures achieved promising performance on predicting the presence of EGFR mutations (R2 = 0.447, p <0.001 EGFR activating mutations R2 = 0.301, p = 0.003 for T790M; and R2 = 0.354, p = 0.001 for activating plus resistance mutations), confirmed by ROC analysis.
Conclusion: To our knowledge, these are the first cases to highlight a potentially promising strategy to detect clonal heterogeneity and ultimately identify patients at risk of progression during treatment. Together, radiomics and liquid biopsy could detect the appearance of new mutations and therefore suggest new therapeutic management.

PMID: 33489892 [PubMed]

Relevance of Immune Infiltration and Clinical Outcomes in Pancreatic Ductal Adenocarcinoma Subtypes.

Front Oncol. 2020;10:575264

Authors: Liu R, Liao YZ, Zhang W, Zhou HH

Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with high heterogeneity and dismal survival rates. Tumor immune microenvironment plays a critical role in sensitive to chemotherapy and prognosis. Herein, we determined the relevance of the composition of tumor-infiltrating immune cells to clinical outcomes in PDACs, and we evaluated these effects by molecular subtype.
Experimental Design: Data of 1,274 samples from publically available datasets were collected. Molecular subtypes were predicted with support vector machine. Twenty-two subsets of immune cells were estimated with CIBERSORTx. The associations between each cell subset and overall survival (OS), relapse free survival (RFS), and complete response (CR) to chemotherapy were evaluated, modelling cellular proportions as quartiles.
Results: An immune-related cluster was identified with unsupervised hierarchical clustering of hallmark pathways. Of the immune cells investigated, M0 macrophages emerged as closely associated with worse OS (HR =1.23, 95% CI = 1.15-1.31, p=1.57×10-9) and RFS (HR = 1.14, 95% CI =1.04-1.25, p=2.93×10-3), regardless of molecular subtypes. The CD8+ T cells conferred favorable survival. The neutrophils conferred poor OS overall (HR=1.17, 95% CI=1.10-1.23, p=1.74×10-7) and within the classical subtype. In the basal-like subtype, activated mast cells were associated with worse OS. Consensus clustering revealed six immune subgroups with distinct survival patterns and CR rates. The higher expression of PD1 was associated with better OS.
Conclusions: The immune cellular composition infiltrate in PDAC are likely to have effects on prognosis. Further exploration of the cellular immune response has the potential to identify candidates for immunotherapy.

PMID: 33489882 [PubMed]

Precision Medicine in Childhood Asthma: Omic Studies of Treatment Response.

Int J Mol Sci. 2020 Apr 21;21(8):

Authors: Perez-Garcia J, Herrera-Luis E, Lorenzo-Diaz F, González M, Sardón O, Villar J, Pino-Yanes M

Abstract
Asthma is a heterogeneous and multifactorial respiratory disease with an important impact on childhood. Difficult-to-treat asthma is not uncommon among children, and it causes a high burden to the patient, caregivers, and society. This review aims to summarize the recent findings on pediatric asthma treatment response revealed by different omic approaches conducted in 2018-2019. A total of 13 studies were performed during this period to assess the role of genomics, epigenomics, transcriptomics, metabolomics, and the microbiome in the response to short-acting beta agonists, inhaled corticosteroids, and leukotriene receptor antagonists. These studies have identified novel associations of genetic markers, epigenetic modifications, metabolites, bacteria, and molecular mechanisms involved in asthma treatment response. This knowledge will allow us establishing molecular biomarkers that could be integrated with clinical information to improve the management of children with asthma.

PMID: 32326339 [PubMed - indexed for MEDLINE]

Serum insulin-like factor 3 quantification by LC-MS/MS in male patients with hypogonadotropic hypogonadism and Klinefelter syndrome.

Endocrine. 2021 Jan 22;:

Authors: Johannsen TH, Ljubicic ML, Young J, Trabado S, Petersen JH, Linneberg A, Albrethsen J, Juul A

Abstract
PURPOSE: Insulin-like factor 3 (INSL3) is an emerging testicular marker, yet larger studies elucidating the clinical role of INSL3 in patients with hypogonadism are lacking. The aim was to describe serum INSL3 concentrations analyzed by LC-MS/MS methodology in males with hypogonadotropic hypogonadism (HH) and Klinefelter syndrome (KS).
METHODS: This was a combined study from two tertiary centers in Denmark and France analyzing INSL3 concentrations by LC-MS/MS. In total, 103 patients with HH and 82 patients with KS were grouped into treated (HH: n = 96; KS: n = 71) or untreated (HH: n = 7; KS: n = 11). Treatment modalities included testosterone and hCG. Serum concentrations and standard deviation (SD) scores of INSL3, total testosterone, and LH according to age and treatment were evaluated.
RESULTS: In both HH and KS, INSL3 concentrations were low. In HH, INSL3 was low regardless of treatment, except for some hCG-treated patients with normal concentrations. In untreated HH, testosterone was low, while normal to high in most testosterone- and hCG-treated patients. In untreated KS, INSL3 and testosterone concentrations were low to normal, while in testosterone-treated KS, serum INSL3 was low in most patients. INSL3 SD scores were significantly lower in untreated HH than in untreated KS (p = 0.01).
CONCLUSIONS: The dichotomy between lower INSL3 and higher testosterone concentrations, particularly observed in hCG-treated patients with HH, confirms that INSL3 is a different marker of Leydig cell function than testosterone. However, the clinical application of INSL3 in males with hypogonadism remains unclear.

PMID: 33483888 [PubMed - as supplied by publisher]

Transcriptome network analyses in human coronavirus infections suggest a rational use of immunomodulatory drugs for COVID19 therapy.

Genomics. 2021 Jan 19;:

Authors: Wong HS, Guo CL, Lin GH, Lee KY, Okada Y, Chang WC

Abstract
The recent outbreak of coronavirus disease 2019 (COVID-19) by SARS-CoV-2 has led to uptodate 24.3 M cases and 0.8 M deaths. It is thus in urgent need to rationalize potential therapeutic targets against the progression of diseases. An effective, feasible way is to use the pre-existing ΔORF6 mutant of SARS-CoV as a surrogate for SARS-CoV-2, since both lack the moiety responsible for interferon antagonistic effects. By analyzing temporal profiles of upregulated genes in ΔORF6-infected Calu-3 cells, we prioritized 55 genes and 238 ligands to reposition currently available medications for COVID-19 therapy. Eight of them are already in clinical trials. Of particular importance is the emergence of immune checkpoint inhibitors targeting PD-L1 that have not been used in COVID-19 treatment. We also pinpointed 16 drug groups from the Anatomical Therapeutic Chemical classification system, with the potential to mitigate symptoms of SARS-CoV-2 infection and thus to be repositioned for COVID-19 therapy.

PMID: 33482326 [PubMed - as supplied by publisher]

Optimized RNA-targeting CRISPR/Cas13d technology outperforms shRNA in identifying functional circRNAs.

Genome Biol. 2021 Jan 21;22(1):41

Authors: Zhang Y, Nguyen TM, Zhang XO, Wang L, Phan T, Clohessy JG, Pandolfi PP

Abstract
Short hairpin RNAs (shRNAs) are used to deplete circRNAs by targeting back-splicing junction (BSJ) sites. However, frequent discrepancies exist between shRNA-mediated circRNA knockdown and the corresponding biological effect, querying their robustness. By leveraging CRISPR/Cas13d tool and optimizing the strategy for designing single-guide RNAs against circRNA BSJ sites, we markedly enhance specificity of circRNA silencing. This specificity is validated in parallel screenings by shRNA and CRISPR/Cas13d libraries. Using a CRISPR/Cas13d screening library targeting > 2500 human hepatocellular carcinoma-related circRNAs, we subsequently identify a subset of sorafenib-resistant circRNAs. Thus, CRISPR/Cas13d represents an effective approach for high-throughput study of functional circRNAs.

PMID: 33478577 [PubMed - in process]

TBC1D16 predicts chemosensitivity and prognosis in adult acute myeloid leukemia (AML) patients.

Eur J Pharmacol. 2021 Jan 18;:173894

Authors: Liu H, Chen P, Yang YL, Zhu KW, Wang T, Tang L, Liu YL, Cao S, Zhou G, Zeng H, Zhao XL, Zhang W, Chen XP

Abstract
Acute myeloid leukemia (AML) is a hematopoietic disease with poor survival. Chemotherapy resistance is one of the determinant factors influencing AML prognosis. To identify genes possibly affecting the drug responses in AML, the Illumina Infinium MethylationEPIC (850K) was used to screen for differential DNA methylation loci between patients achieved complete remission (CR) or not (non-CR) after induction therapy in 37 AML patients. Then, 32 differentially methylated sites (DMS) were selected for replication in another 86 AML patients by next-generation sequencing. Nine sites including cg03988660, cg16804603, cg18166936, cg11308319, cg09095403, cg18493214, cg01443536, cg16030878 and cg10143426 were replicated. Analysis of the Gene Expression Omnibus (GEO) database showed that mRNA expression of TBC1D16 and HDAC4 was associated with AML prognosis. Methylation level of the cg16030878 in TBC1D16 3'-UTR correlated positively with TBC1D16 mRNA expression in samples both in the TCGA database and clinically collected in the study. Both higher cg16030878 methylation and higher TBC1D16 mRNA expression were associated with increased risk of non-CR and worse overall survival (OS) in AML patients. In AML cells, knockdown of TBC1D16 decreased cell proliferation and ERK phosphorylation levels, as well as increased sensitivity to mitoxantrone and decitabine indicated by IC50. In patients with combined use of decitabine, those patients with CR showed significantly lower TBC1D16 mRNA expression. On the contrary, knockdown of TBC1D16 resulted in decreased sensitivity to cytarabine in U937 cells. Our findings implicated that TBC1D16 is a potential predictor for chemical sensitivity and prognosis in adult AML patients.

PMID: 33476656 [PubMed - as supplied by publisher]

Use of Pharmacogenomics to Guide Proton Pump Inhibitor Therapy in Clinical Practice.

Dig Dis Sci. 2021 Jan 21;:

Authors: Harris DM, Stancampiano FF, Burton MC, Moyer AM, Schuh MJ, Valery JR, Bi Y

Abstract
Prescribing the right medication, at the right dose, to the right patient is the goal of every physician. Pharmacogenomic information is an emerging tool that can be used to deliver precision medicine. In this review, we discuss the pharmacogenomics of available PPIs, racial differences of CYP2C19 and how PPI pharmacogenomics affects the treatment of common gastrointestinal diseases. We also provide practical guidance on when to order pharmacogenomic testing, which test to order, and how to modify treatment based on published guidelines.

PMID: 33475867 [PubMed - as supplied by publisher]

Integrating pharmacogenetic testing via medication therapy management in an outpatient family medicine clinic.

Pharmacogenomics. 2021 Jan 20;:

Authors: Brown JT, MacDonald D, Yapel A, Luczak T, Hanson A, Stenehjem DD

Abstract
Introduction: Pharmacogenetic (PGx) implementation has lagged behind the development of drug/gene pair guidelines. Materials & methods: This was a prospective study assessing the integration of PGx through medication therapy management in an outpatient clinic. Variables collected included patient diagnosis, current medications, failed or discontinued medications, PGx results/recommendations, turnaround time and pre/post clinical ratings. Results: A total of 91 participants completed study procedures with an average enrollment of approximately one consult per week. Participants were referred for testing primarily for guidance for current and future medications. The average number of recommendations per participant was 0.93. Conclusion: Integrating PGx testing into medication therapy management is feasible with PGx results available in under a week resulting in clinical recommendations in over half of patients tested.

PMID: 33470873 [PubMed - as supplied by publisher]

Review on Databases and Bioinformatic Approaches on Pharmacogenomics of Adverse Drug Reactions.

Pharmgenomics Pers Med. 2021;14:61-75

Authors: Tong H, Phan NVT, Nguyen TT, Nguyen DV, Vo NS, Le L

Abstract
Pharmacogenomics has been used effectively in studying adverse drug reactions by determining the person-specific genetic factors associated with individual response to a drug. Current approaches have revealed the significant importance of sequencing technologies and sequence analysis strategies for interpreting the contribution of genetic variation in developing adverse reactions. Advance in next generation sequencing and platform brings new opportunities in validating the genetic candidates in certain reactions, and could be used to develop the preemptive tests to predict the outcome of the variation in a personal response to a drug. With the highly accumulated available data recently, the in silico approach with data analysis and modeling plays as other important alternatives which significantly support the final decisions in the transformation from research to clinical applications such as diagnosis and treatments for various types of adverse responses.

PMID: 33469342 [PubMed]