Rev Endocr Metab Disord. 2021 Mar 12. doi: 10.1007/s11154-021-09637-1. Online ahead of print.

ABSTRACT

We present current knowledge concerning the pharmacogenomics of growth hormone therapy in children with short stature. We consider the evidence now emerging for the polygenic nature of response to recombinant human growth hormone (r-hGH). These data are related predominantly to the use of transcriptomic data for prediction. The impact of the complex interactions of developmental phenotype over childhood on response to r-hGH are discussed. Finally, the issues that need to be addressed in order to develop a clinical test are described.

PMID:33712998 | DOI:10.1007/s11154-021-09637-1

Pharmacogenomics J. 2021 Mar 12. doi: 10.1038/s41397-021-00230-y. Online ahead of print.

ABSTRACT

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells and does not have sufficient prognostic indicators. Interferon gamma inducible protein 16 (IFI16) plays a crucial role in B-cell differentiation. Several studies have shown that IFI16 predicted prognosis in many cancers. However, the relationship between MM prognosis and IFI16 expression has not been studied. In our study, we analyzed the prognostic role of IFI16 expression and explored the possible mechanism in MM progression by using 4498 myeloma patients and 52 healthy donors from 13 independent gene expression omnibus (GEO) datasets. The IFI16 expression increased with myeloma progression, ISS stage, 1q21 amplification, and relapse (all P < 0.01). MM patients with higher IFI16 expression had shorter survival in six datasets (all P < 0.05). Furthermore, multivariate analysis indicated that enhanced IFI16 expression was an independent poor prognostic factor for EFS and OS (P = 0.007, 0.009, respectively). And PPI, GO, KEGG, and GSEA also confirmed that IFI16 promoted MM progression by participating in tumor-related pathways. In conclusion, our study confirmed that IFI16 was a poor prognostic biomarker in MM.

PMID:33712724 | DOI:10.1038/s41397-021-00230-y

Cytokine. 2021 Mar 6;142:155492. doi: 10.1016/j.cyto.2021.155492. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: The interferon-induced transmembrane protein 3 (IFITM3) plays an important role in the adaptive and innate immune response by inhibiting viral membrane hemifusion between the host and viral cell cytoplasm. Single nucleotide polymorphisms (SNPs) in the gene IFITM3 have been associated with susceptibility and severity of influenza or other viral infections. We aimed to analyze the role of SNPs in the gene IFITM3 in SARS-CoV-2 infection.

METHODS: We performed genotyping of the SNPs rs12252 and rs34481144 in the gene IFITM3 in 239 SARS-CoV-2-positive and 253 SARS-CoV-2-negative patients. We analyzed the association of the SNPs with susceptibility to SARS-CoV-2 infection and severity of COVID-19.

RESULTS: SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding demographics. Neither IFITM3 rs12252 nor rs34481144 polymorphisms were related to SARS-CoV-2 infection risk or severity of COVID-19. Interestingly, we observed the putative deleterious rs12252 CC genotype only in SARS-CoV-2-positive patients (N = 2). Also, we found a non-significant higher frequency of rs34481144 A-allele carriers in the patients with 'serious' COVID-19.

CONCLUSIONS: In summary, we could not confirm the recently reported influence of polymorphisms in the gene IFITM3 on SARS-CoV-2 infection risk or severity of COVID-19 in a German cohort. Additional studies are needed to clarify the influence of the rs12252 CC genotype on SARS-CoV-2 infection risk and the rs34481144 A-allele on course of COVID-19.

PMID:33711707 | DOI:10.1016/j.cyto.2021.155492

ESMO Open. 2021 Mar 9;6(2):100064. doi: 10.1016/j.esmoop.2021.100064. Online ahead of print.

ABSTRACT

BACKGROUND: Checkpoint inhibitors in melanoma can lead to self-immune side-effects such as vitiligo-like depigmentation (VLD). Beyond the reported association with favorable prognosis, there are limited data regarding VLD patient features and their echo on the therapeutic outcomes.

METHODS: To assess the association between VLD and a series of clinical and biological features as well as therapeutic outcomes, we built an observational cohort study by recruiting patients who developed VLD during checkpoint inhibitors.

RESULTS: A total of 148 patients from 15 centers (101 men, median age 66 years, BRAF mutated 23%, M1c 42%, Eastern Cooperative Oncology Group (ECOG) status 0/1 99%, normal lactate dehydrogenase 74%) were enrolled. VLD was induced by ipilimumab, programmed cell death-1 (PD-1) inhibitors, and their combination in 32%, 56%, and 12%, respectively. The median onset was 26 weeks and it was associated with other skin and nonskin toxicities in 27% and 28%, respectively. After 3 years of VLD onset, 52% (95% confidence interval 39% to 63%) were progression free and 82% (95% confidence interval 70% to 89%) were still alive. The overall response rate was 73% with 26% complete response. Univariable analysis indicated that BRAF V600 mutation was associated with a better overall survival (P = 0.028), while in multivariable analysis a longer progression-free survival was associated with BRAF V600 (P = 0.093), female sex (P = 0.008), and M stage other than 1a (P = 0.024). When VLD occurred, there was a significant decrease of white blood cell (WBC) count (P = 0.05) and derived WBC-to-lymphocytes ratio (dWLR; P = 0.003). A lower monocyte count (P = 0.02) and dWLR (P = 0.01) were also reported in responder patients.

CONCLUSIONS: Among VLD population, some features might help to identify patients with an effective response to immunotherapy, allowing clinicians to make more appropriate choices in terms of therapeutic options and duration.

PMID:33711672 | DOI:10.1016/j.esmoop.2021.100064

Mol Cell Endocrinol. 2021 Mar 9:111221. doi: 10.1016/j.mce.2021.111221. Online ahead of print.

ABSTRACT

As the most frequent women's cancer, breast cancer causes the second most cancer-related death in women worldwide. Majority of the breast cancers are hormone receptor-positive and commonly treated by hormone therapy. Thus, the expression levels of hormone receptors signaling pathways are pivotal in the development and therapy of breast cancer. The expression of hormone receptors signaling pathways is not only regulated at the transcription level but also at the post-transcription level by both proteins and RNAs. In addition to that, the function of hormone receptors can also be regulated by RNAs. In this review, we summarize the roles of RNAs in hormone receptor-positive breast cancer. We introduce how mRNA stability and protein function of genes in hormone receptors signaling pathways are regulated by RNA-binding proteins, miRNAs, and lncRNAs. We believe these proteins and RNAs can be potential therapeutic targets of breast cancer.

PMID:33711334 | DOI:10.1016/j.mce.2021.111221

Ther Drug Monit. 2021 Apr 1;43(2):150-200. doi: 10.1097/FTD.0000000000000871.

ABSTRACT

When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.

PMID:33711005 | DOI:10.1097/FTD.0000000000000871

EMBO Mol Med. 2021 Mar 11:e13366. doi: 10.15252/emmm.202013366. Online ahead of print.

ABSTRACT

Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A-priori identification of platinum resistance is therefore crucial to improve on standard first-line carboplatin-paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum-induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK-compliant study of pre-treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR-proficient cancers (Myriad HRDscore < 42). Interestingly, overexpression of RAD51 modified expression of immune-regulatory pathways in vitro, while RAD51-High tumours showed exclusion of cytotoxic T cells in situ. Our findings highlight RAD51 expression as a determinant of platinum resistance and suggest possible roles for therapy to overcome immune exclusion in RAD51-High EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression.

PMID:33709473 | DOI:10.15252/emmm.202013366

Indian J Crit Care Med. 2021 Feb;25(2):228-230. doi: 10.5005/jp-journals-10071-23738.

ABSTRACT

Thiopurines by their glucocorticoid-sparing property help in maintaining remission for patients with inflammatory bowel disease (IBD), when glucocorticoids are reduced and withdrawn. However, due to bone marrow suppression, it cannot be used in various conditions where it is indicated. A 17-year-old patient presented with pancytopenia with neutropenic sepsis and alopecia after 3 weeks of starting azathioprine for her underlying Crohn's disease. Thiopurine S-methyltransferase (TPMT;*2, *3A, *3C) analysis resulted in a wild-type genotype, whereas homozygous Nudix hydrolase 15 (NUDT 15 C415T) variant was positive. Azathioprine was stopped immediately, and she was started on broad-spectrum antibiotics that led to some clinical improvements initially, but later on, the patient developed intestinal obstruction along with postoperative complications leading to death. In this report, we highlight a case of serious hematological toxicity associated with azathioprine use in a patient with Crohn's disease with homozygous NUDT 15 variant, thus favoring the implementation of a pharmacogenomic approach before starting azathioprine, particularly in the Asian population.

HOW TO CITE THIS ARTICLE: Debnath P, Nair S, Jain S, Udgirkar S, Contractor Q, Rathi P. Thiopurine-induced Myelosuppression with Severe Sepsis in a Patient with Crohn's Disease: A Case Report. Indian J Crit Care Med 2021;25(2):228-230.

PRIOR PRESENTATION OF CASE REPORT AT PROFESSIONAL MEETING: The case was presented in abstract form at the American College of Gastroenterology Annual Scientific Meeting, held at San Antonio, TX, USA 2019.

INFORMED CONSENT FOR PUBLICATION OF CASE DETAILS: Obtained from patient's relatives.

PMID:33707905 | PMC:PMC7922446 | DOI:10.5005/jp-journals-10071-23738

Sci Rep. 2021 Mar 11;11(1):5662. doi: 10.1038/s41598-021-84960-w.

ABSTRACT

OATP1B3 is expressed de novo in primary prostate cancer tissue and to a greater degree in prostate cancer metastases. Gadoxetate disodium is a substrate of OATP1B3, and its uptake has been shown to correlate with OATP1B3 expression in other cancers. We aimed to evaluate use of gadoxetate disodium to image prostate cancer and to track its utility as a biomarker. A single center open-label non-randomized pilot study recruited men with (1) localized, and (2) metastatic castration resistant prostate cancer (mCRPC). Gadoxetate disodium-enhanced MRI was performed at four timepoints post-injection. The Wilcoxon signed rank test was used to compare MRI contrast enhancement ratio (CER) pre-injection and post-injection. OATP1B3 expression was evaluated via immunohistochemistry (IHC) and a pharmacogenomic analysis of OATP1B3, NCTP and OATP1B1 was conducted. The mCRPC subgroup (n = 9) demonstrated significant enhancement compared to pre-contrast images at 20-, 40- and 60-min timepoints (p < 0.0078). The localized cancer subgroup (n = 11) demonstrated earlier enhancement compared to the mCRPC group, but no retention over time (p > 0.05). OATP1B3 expression on IHC trended higher contrast enhancement between 20-40 min (p ≤ 0.064) and was associated with contrast enhancement at 60 min (p = 0.0422). OATP1B1 haplotype, with N130D and V174A substitutions, impacted enhancement at 40-60 min (p ≤ 0.038). mCRPC lesions demonstrate enhancement after injection of gadoxetate disodium on MRI and retention over 60 min. As inter-individual variability in OATP1B3 expression and function has both predictive and prognostic significance, gadoxetate disodium has potential as a biomarker in prostate cancer.

PMID:33707581 | DOI:10.1038/s41598-021-84960-w

Sci Rep. 2021 Mar 11;11(1):5696. doi: 10.1038/s41598-021-85086-9.

ABSTRACT

A subset of prostate cancer displays a poor clinical outcome. Therefore, identifying this poor prognostic subset within clinically aggressive groups (defined as a Gleason score (GS) ≧8) and developing effective treatments are essential if we are to improve prostate cancer survival. Here, we performed a bioinformatics analysis of a TCGA dataset (GS ≧8) to identify pathways upregulated in a prostate cancer cohort with short survival. When conducting bioinformatics analyses, the definition of factors such as "overexpression" and "shorter survival" is vital, as poor definition may lead to mis-estimations. To eliminate this possibility, we defined an expression cutoff value using an algorithm calculated by a Cox regression model, and the hazard ratio for each gene was set so as to identify genes whose expression levels were associated with shorter survival. Next, genes associated with shorter survival were entered into pathway analysis to identify pathways that were altered in a shorter survival cohort. We identified pathways involving upregulation of GRB2. Overexpression of GRB2 was linked to shorter survival in the TCGA dataset, a finding validated by histological examination of biopsy samples taken from the patients for diagnostic purposes. Thus, GRB2 is a novel biomarker that predicts shorter survival of patients with aggressive prostate cancer (GS ≧8).

PMID:33707553 | DOI:10.1038/s41598-021-85086-9

Pediatr Allergy Immunol. 2021 Mar 11. doi: 10.1111/pai.13494. Online ahead of print.

ABSTRACT

BACKGROUND: Some children with asthma experience exacerbations despite long-acting beta2-agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome-wide study until now has investigated which genetic factors associate with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium.

METHODS: A meta-analysis of genome-wide association studies (meta-GWAS) was performed in 1,425 children and young adults with asthma (age 6-21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma.

RESULTS: Genome-wide association results for a total of 82,996common SNPs (MAF ≥ 1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (p-value threshold ≤ 5x10-6 ) associated with exacerbations despite LABA use.

CONCLUSION: No strong effects of SNPs on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7), that were previously implicated in the response to short-acting beta2-agonists (SABA). These loci merit further investigation in response to LABA and SABA use.

PMID:33706416 | DOI:10.1111/pai.13494

Cancer Sci. 2021 Mar 11. doi: 10.1111/cas.14872. Online ahead of print.

ABSTRACT

Lung cancer is the leading cause of cancer related death worldwide. In spite of the identification of epidermal growth factor receptor (EGFR) driver mutations has improved the therapeutics for lung cancer, patients harboring EGFR mutations usually display shorter overall survival and a higher tendency to develop distant metastasis compared with those carrying wild-type EGFR. Nevertheless, the way to control mutated EGFR signaling remains unclear. Here, we performed membrane proteomic analysis to determine potential components that may act with EGFR mutations to promote lung cancer malignancy. The results show that the expressions of transmembrane glycoprotein non-metastatic melanoma protein B (GPNMB) is positively correlated with the status of mutated EGFR in non-small cell lung cancer (NSCLC). It is not only overexpressed but also highly glycosylated in EGFR-mutated, especially the EGFR-L858R mutated, NSCLC cells. Further examinations indicate that GPNMB could activate mutated EGFR without ligand stimulation. It could bind to the C-terminus of EGFR, facilitate its' phosphorylation at Y845, turn on the downstream STAT3 signaling, and promote cancer metastasis. Moreover, we also found that the Asn134 (N134) glycosylation of GPNMB plays a crucial role in this ligand-independent regulation. Depleting the N134-glycosylation of GPNMB could dramatically inhibit the binding of GPNMB to mutated EGFR, block its downstream signaling, and ultimately inhibit cancer metastasis in NSCLC. Clarifying the role of N-glycosylated GPNMB in regulating the ligand-independent activation of mutated EGFR may provide a new insight for developing novel therapeutics for NSCLC in the near future.

PMID:33706413 | DOI:10.1111/cas.14872

Neurosci Lett. 2021 Mar 8:135802. doi: 10.1016/j.neulet.2021.135802. Online ahead of print.

ABSTRACT

In view of inconsistencies in the association studies of alpha synuclein (SNCA) rs7684318 (chr4: 90655003 T > C) with Parkinson's disease (PD), we conducted a meta-analysis to establish the association of this variant with PD and examined changes in transcription factor binding. SNCA rs7684318 C-allele was identified as genetic risk factor for PD in fixed (OR: 1.53, 95% CI: 1.40 - 1.68, p < 0.0001) and random effect (OR: 1.65, 95% CI: 1.30 - 2.09, p = 0.0003) models. Heterogeneity was observed in association (Tau2: 0.0576, H: 2.32, I2: 0.815, Q: 21.64, p = 0.0002). Egger's test showed no evidence of publication bias (p = 0.37). Subgroup analysis showed that rs7684318 is contributing to PD risk in Japanese (OR: 1.46, 95% CI: 1.30 - 1.64) and Indian (OR: 2.63, 95% CI: 1.79 - 3.86) populations while showing no significant association in Chinese population (OR: 1.68, 95% CI: 0.93 - 3.02). Sensitivity analysis showed that exclusion of any one of the studies has no significant impact on the association, which justifies the robustness of the analysis. Tissue-specific DNase foot print analysis revealed that this variant contributes to increased transcription factor binding in midbrain, putamen and caudate nucleus. The substitution of T > C increased binding of RBPJ and GATA-family transcription factors; and decreased binding of NKX2 family, SNAI2, SNAI3, DMRT1, HOXA13, HOXB13, HOXC13, HOXD13, WT1, POU4F1, POU4F2, POU4F3 transcriptional factors. TRANSFAC and DNA curvature analyses substantiate the association of this variant with increased binding of GATA1 that contribute to intensity of DNA curvature peaks and splitting pattern. These studies along with the meta-analysis strongly suggest that the rs7684318 variant contributes to the pathophysiology of PD by modulating binding of transcription factors related to Notch and Wnt signalling pathways that are likely to impair dopmanergic transmission.

PMID:33705925 | DOI:10.1016/j.neulet.2021.135802

Pharmacol Res. 2021 Mar 8:105538. doi: 10.1016/j.phrs.2021.105538. Online ahead of print.

ABSTRACT

Undoubtedly, pharmacogenomics (PGx) aims in optimizing drug treatment responses whilst also improving the patients' quality of life, either via a reduction of adverse drug reactions and/or an enhancement of drug treatment efficacy. To achieve this, PGx guidance is provided by the two major regulatory bodies in a worldwide level, specifically the U.S. Food and Drug Administration (FDA) and the European Medicine Agency (EMA), and occasionally some research consortia, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) or the Dutch Pharmacogenomics Working Group (DPWG). However, so far, there is a limited number of studies focusing on the delineation of the similarities and more importantly, the discrepancies in the PGx guidance by the different regulatory bodies and consortia. Herein, we use real-life clinical PGx data to highlight such discrepancies and similarities for genome-guided interventions in psychiatric disorders, thus demonstrating the need for harmonization of the guidelines and recommendations. More precisely, we used the PharmCAT genome-informed drug treatment reports from 304 Greek individuals with psychiatric disorders in order to emphasize on the discrepancies in the PGx guidance/guidelines between FDA vs EMA and CPIC vs DPWG, respectively. For example, CYP2D6-pimozide pair is characterized as 'Testing Required' according to FDA and is accompanied by a DPWG PGx guideline, whilst no EMA or CPIC PGx guidance is found for this drug-gene pair. Moreover, discrepancies are observed regarding the type of PGx guidance for CYP2C19-doxepin pair, with 89 individuals from our study cohort requiring a dose prescribing change based on FDA, whilst only 5 individuals have to receive genome-guided treatment adjustment according to CPIC. To our knowledge, this is the first study, in which discrepancies regarding the type of PGx guidance and the number of actionable drug-gene pairs amongst FDA and EMA, as well as CPIC and DPWG, are brought to light with an emphasis on psychiatric disorders.

PMID:33705851 | DOI:10.1016/j.phrs.2021.105538

Am J Health Syst Pharm. 2021 Mar 10:zxab084. doi: 10.1093/ajhp/zxab084. Online ahead of print.

ABSTRACT

In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

PMID:33693532 | DOI:10.1093/ajhp/zxab084

Nat Rev Urol. 2021 Mar 10. doi: 10.1038/s41585-021-00442-8. Online ahead of print.

ABSTRACT

Prostate cancer is a global health problem, but incidence varies considerably across different continents. Asia is traditionally considered a low-incidence area, but the incidence and mortality of prostate cancer have rapidly increased across the continent. Substantial differences in epidemiological features have been observed among different Asian regions, and incidence, as well as mortality-to-incidence ratio, is associated with the human development index. Prostate cancer mortality decreased in Japan and Israel from 2007 to 2016, but mortality has increased in Thailand, Kyrgyzstan and Uzbekistan over the same period. Genomic analyses have shown a low prevalence of ERG oncoprotein in the East Asian population, alongside a low rate of PTEN loss, high CHD1 enrichments and high FOXA1 alterations. Contributions from single-nucleotide polymorphisms to prostate cancer risk vary with ethnicity, but germline mutation rates of DNA damage repair genes in metastatic prostate cancer are comparable in Chinese and white patients from the USA and UK. Pharmacogenomic features of testosterone metabolism might contribute to disparities seen in the response to androgen deprivation between East Asian men and white American and European men. Overall, considerable diversity in epidemiology and genomics of prostate cancer across Asia defines disease characteristics in these populations, but studies in this area are under-represented in the literature. Taking into account this intracontinental and intercontinental heterogeneity, translational studies are required in order to develop ethnicity-specific treatment strategies.

PMID:33692499 | DOI:10.1038/s41585-021-00442-8

Sci Rep. 2021 Mar 10;11(1):5554. doi: 10.1038/s41598-020-72892-w.

ABSTRACT

Dengue virus causes dengue hemorrhagic fever (DHF) and has been associated to fatal cases worldwide. The liver is one of the most important target tissues in severe cases, due to its intense viral replication and metabolic role. microRNAs role during infection is crucial to understand the regulatory mechanisms of DENV infection and can help in diagnostic and anti-viral therapies development. We sequenced the miRNome of six fatal cases and compared to five controls, to characterize the human microRNAs expression profile in the liver tissue during DHF. Eight microRNAs were differentially expressed, including miR-126-5p, a regulatory molecule of endothelial cells, miR-122-5p, a liver specific homeostasis regulator, and miR-146a-5p, an interferon-regulator. Enrichment analysis with predicted target genes of microRNAs revealed regulatory pathways of apoptosis, involving MAPK, RAS, CDK and FAS. Immune response pathways were related to NF- kB, CC and CX families, IL and TLR. This is the first description of the human microRNA and isomicroRNA profile in liver tissues from DHF cases. The results demonstrated the association of miR-126-5p, miR-122-5p and miR-146a-5p with DHF liver pathogenesis, involving endothelial repair and vascular permeability regulation, control of homeostasis and expression of inflammatory cytokines.

PMID:33692368 | DOI:10.1038/s41598-020-72892-w

Pac Symp Biocomput. 2021;26:184-195.

ABSTRACT

Pharmacogenetics studies how genetic variation leads to variability in drug response. Guidelines for selecting the right drug and right dose for patients based on their genetics are clinically effective, but are widely unused. For some drugs, the normal clinical decision making process may lead to the optimal dose of a drug that minimizes side effects and maximizes effectiveness. Without measurements of genotype, physicians and patients may adjust dosage in a manner that reflects the underlying genetics. The emergence of genetic data linked to longitudinal clinical data in large biobanks offers an opportunity to confirm known pharmacogenetic interactions as well as discover novel associations by investigating outcomes from normal clinical practice. Here we use the UK Biobank to search for pharmacogenetic interactions among 200 drugs and 9 genes among 200,000 participants. We identify associations between pharmacogene phenotypes and drug maintenance dose as well as differential drug response phenotypes. We find support for several known drug-gene associations as well as novel pharmacogenetic interactions.

PMID:33691016

ACS Nano. 2021 Mar 9. doi: 10.1021/acsnano.1c00076. Online ahead of print.

ABSTRACT

NIR-II (1000-1700 nm) fluorescence imaging is continually attracting strong research interest. However, current NIR-II imaging materials are limited to small molecules with fast blood clearance and inorganic nanomaterials and organic conjugated polymers of poor biodegradability and low biocompatibility. Here, we report a highly biodegradable polyester carrying tandem NIR-II fluorophores as a promising alternative. The polymer encapsulated a platinum intercalator (56MESS, (5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane) platinum(II)) and was conjugated with both a cell-targeting RGD peptide and a caspase-3 cleavable peptide probe to form nanoparticles for simultaneous NIR-II and apoptosis imaging. In vitro, the nanoparticles were approximately 4-1000- and 1.5-10-fold more potent than cisplatin and 56MESS, respectively. Moreover, in vivo, they significantly inhibited tumor growth on a multidrug-resistant patient-derived mouse model (PDXMDR). Finally, through label-free laser desorption-ionization mass spectrometry imaging (MALDI-MSI), in situ 56MESS release in the deeper tumors was observed. This work highlighted the use of biodegradable NIR-II polymers for monitoring drugs in vivo and therapeutic effect feedback in real-time.

PMID:33689300 | DOI:10.1021/acsnano.1c00076

Gut. 2021 Mar 8:gutjnl-2020-323426. doi: 10.1136/gutjnl-2020-323426. Online ahead of print.

ABSTRACT

OBJECTIVE: Our goals were to evaluate the antitumour efficacy of Lactobacillus rhamnosus GG (LGG) in combination with immune checkpoint blockade (ICB) immunotherapies on tumour growth and to investigate the underlying mechanisms.

DESIGN: We used murine models of colorectal cancer and melanoma to evaluate whether oral administration of LGG improves the efficacy of ICB therapies. We performed the whole genome shotgun metagenome sequencing of intestinal contents and RNA sequencing of dendritic cells (DCs). In a series of in vitro and in vivo experiments, we further defined the immunological and molecular mechanisms of LGG-mediated antitumour immunity.

RESULTS: We demonstrate that oral administration of live LGG augmented the antitumour activity of anti-programmed cell death 1 (PD-1) immunotherapy by increasing tumour-infiltrating DCs and T cells. Moreover, the combination treatment shifted the gut microbial community towards enrichment in Lactobacillus murinus and Bacteroides uniformis, that are known to increase DC activation and CD8+tumour recruitment. Mechanistically, treatment with live LGG alone or in combination with anti-PD-1 antibody triggered type I interferon (IFN) production in DCs, enhancing the cross-priming of antitumour CD8+ T cells. In DCs, cyclic GMP-AMP synthase (cGAS)/stimulator of IFN genes (STING) was required for IFN-β induction in response to LGG, as evidenced by the significant decrease in IFN-β levels in cGAS or STING-deficient DCs. LGG induces IFN-β production via the cGAS/STING/TANK binding kinase 1/interferon regulatory factor 7 axis in DCs.

CONCLUSION: Our findings have offered valuable insight into the molecular mechanisms of live LGG-mediated antitumour immunity and establish an empirical basis for developing oral administration of live LGG as a combination agent with ICB for cancer therapies.

PMID:33685966 | DOI:10.1136/gutjnl-2020-323426