Brief Bioinform. 2021 Mar 27:bbab024. doi: 10.1093/bib/bbab024. Online ahead of print.

ABSTRACT

Multi-omics allows the systematic understanding of the information flow across different omics layers, while single omics can mainly reflect one aspect of the biological system. The advancement of bulk and single-cell sequencing technologies and related computational methods for multi-omics largely facilitated the development of system biology and precision medicine. Single-cell approaches have the advantage of dissecting cellular dynamics and heterogeneity, whereas traditional bulk technologies are limited to individual/population-level investigation. In this review, we first summarize the technologies for producing bulk and single-cell multi-omics data. Then, we survey the computational approaches for integrative analysis of bulk and single-cell multimodal data, respectively. Moreover, the databases and data storage for multi-omics, as well as the tools for visualizing multimodal data are summarized. We also outline the integration between bulk and single-cell data, and discuss the applications of multi-omics in precision medicine. Finally, we present the challenges and perspectives for multi-omics development.

PMID:33778867 | DOI:10.1093/bib/bbab024

Cell Rep Med. 2021 Mar 23:100245. doi: 10.1016/j.xcrm.2021.100245. Online ahead of print.

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 and variants has led to significant mortality. We recently reported that an RNA-targeting CRISPR-Cas13 system, termed prophylactic antiviral CRISPR in human (PAC-MAN), offered an antiviral strategy against SARS-CoV-2 and influenza A virus. Here, we expand in silico analysis to use PAC-MAN to target a broad spectrum of human- or livestock-infectious RNA viruses with high specificity, coverage, and predicted efficiency. Our analysis reveals that a minimal set of 14 crRNAs is able to target >90% of human-infectious viruses across 10 RNA virus families. We predict that a set of 5 experimentally validated crRNAs can target new SARS-CoV-2 variant sequences with zero mismatches. We also build an online resource (crispr-pacman.stanford.edu) to support community use of CRISPR-Cas13 for broad-spectrum RNA virus targeting. Our work provides a new bioinformatic resource for using CRISPR-Cas13 to target diverse RNA viruses in order to facilitate development of CRISPR-based antivirals.

PMID:33778788 | PMC:PMC7985958 | DOI:10.1016/j.xcrm.2021.100245

Front Cell Dev Biol. 2021 Mar 11;9:647197. doi: 10.3389/fcell.2021.647197. eCollection 2021.

ABSTRACT

BACKGROUND: Increasing evidence indicates an association between the incidence of Alzheimer's disease (AD) and cancer development. Despite advances being made by comparisons from epidemiological studies, common pathways and molecular mechanisms, little is known about the identities of the circular RNAs (circRNAs) involved in the development and progression of these two pathologies and their possible correlations. The aim of this study was to explore the circRNA relationship between AD and cancer.

MATERIALS AND METHODS: In this investigation, circRNAs that were significantly dysregulated in AD or associated with AD diagnosis, clinical dementia severity, and neuropathological severity, were examined in a large panel of 28 cancer types. On the basis of shared abnormal circRNAs in AD and cancers, we constructed a circRNA-micro RNA (miRNA)-messenger RNA (mRNA) network by leveraging experimentally identified miRNA-circRNA and miRNA-mRNA interactions from crosslinking-immunoprecipitation sequencing data.

RESULTS: An inverse correlation of expression pattern was found in acute myeloid leukemia, juvenile myelomonocytic leukemia, renal cell carcinoma, and myelofibrosis. CircRNAs associated with AD diagnosis and clinical severity demonstrated negative correlation in more cancer types. Notably, differentially expressed candidate circRNAs in temporal lobe epilepsy were not associated with any cancers. Gene Ontology and KEGG pathway analysis suggested the circRNA-regulated genes are significantly associated with interleukin-12-mediated signaling and viral response. CircPICALM, circRTN4 and circMAN2A1 are the hub nodes in the circRNA-miRNA-target network.

CONCLUSION: Our results indicated the relevance of inflammation signaling as a common pathogenesis shared by cancer and AD and provided novel insight for therapeutics targeting circRNAs.

PMID:33777952 | PMC:PMC7991802 | DOI:10.3389/fcell.2021.647197

PeerJ. 2021 Mar 15;9:e10816. doi: 10.7717/peerj.10816. eCollection 2021.

ABSTRACT

BACKGROUND: Antiplasmodial drug discovery is significant especially from natural sources such as plant bacteria. This research aimed to determine antiplasmodial metabolites of Streptomyces spp. against Plasmodium falciparum 3D7 by using a metabolomics approach.

METHODS: Streptomyces strains' growth curves, namely SUK 12 and SUK 48, were measured and P. falciparum 3D7 IC50 values were calculated. Metabolomics analysis was conducted on both strains' mid-exponential and stationary phase extracts.

RESULTS: The most successful antiplasmodial activity of SUK 12 and SUK 48 extracts shown to be at the stationary phase with IC50 values of 0.8168 ng/mL and 0.1963 ng/mL, respectively. In contrast, the IC50 value of chloroquine diphosphate (CQ) for antiplasmodial activity was 0.2812 ng/mL. The univariate analysis revealed that 854 metabolites and 14, 44 and three metabolites showed significant differences in terms of strain, fermentation phase, and their interactions. Orthogonal partial least square-discriminant analysis and S-loading plot putatively identified pavettine, aurantioclavine, and 4-butyldiphenylmethane as significant outliers from the stationary phase of SUK 48. For potential isolation, metabolomics approach may be used as a preliminary approach to rapidly track and identify the presence of antimalarial metabolites before any isolation and purification can be done.

PMID:33777509 | PMC:PMC7971094 | DOI:10.7717/peerj.10816

Nano Today. 2021 Apr;37:101066. doi: 10.1016/j.nantod.2020.101066. Epub 2021 Jan 13.

ABSTRACT

Exosomes are a class of cell-secreted, nano-sized extracellular vesicles with a bilayer membrane structure of 30-150 nm in diameter. Their discovery and application have brought breakthroughs in numerous areas, such as liquid biopsies, cancer biology, drug delivery, immunotherapy, tissue repair, and cardiovascular diseases. Isolation of exosomes is the first step in exosome-related research and its applications. Standard benchtop exosome separation and sensing techniques are tedious and challenging, as they require large sample volumes, multi-step operations that are complex and time-consuming, requiring cumbersome and expensive instruments. In contrast, microfluidic platforms have the potential to overcome some of these limitations, owing to their high-precision processing, ability to handle liquids at a microscale, and integrability with various functional units, such as mixers, actuators, reactors, separators, and sensors. These platforms can optimize the detection process on a single device, representing a robust and versatile technique for exosome separation and sensing to attain high purity and high recovery rates with a short processing time. Herein, we overview microfluidic strategies for exosome isolation based on their hydrodynamic properties, size filtration, acoustic fields, immunoaffinity, and dielectrophoretic properties. We focus especially on advances in label-free isolation of exosomes with active biological properties and intact morphological structures. Further, we introduce microfluidic techniques for the detection of exosomal proteins and RNAs with high sensitivity, high specificity, and low detection limits. We summarize the biomedical applications of exosome-mediated therapeutic delivery targeting cancer cells. To highlight the advantages of microfluidic platforms, conventional techniques are included for comparison. Future challenges and prospects of microfluidics towards exosome isolation applications are also discussed. Although the use of exosomes in clinical applications still faces biological, technical, regulatory, and market challenges, in the foreseeable future, recent developments in microfluidic technologies are expected to pave the way for tailoring exosome-related applications in precision medicine.

PMID:33777166 | PMC:PMC7990116 | DOI:10.1016/j.nantod.2020.101066

Front Genet. 2021 Mar 11;12:660201. doi: 10.3389/fgene.2021.660201. eCollection 2021.

NO ABSTRACT

PMID:33777114 | PMC:PMC7990759 | DOI:10.3389/fgene.2021.660201

Front Immunol. 2021 Mar 11;12:644700. doi: 10.3389/fimmu.2021.644700. eCollection 2021.

ABSTRACT

Dendritic cells (DC) play a central role in the pathogenesis of allergic contact dermatitis (ACD), the most prevalent form of immunotoxicity in humans. However, knowledge on allergy-induced DC maturation is still limited and proteomic studies, allowing to unravel molecular effects of allergens, remain scarce. Therefore, we conducted a global proteomic analysis of human monocyte-derived dendritic cells (MoDC) treated with NiSO4, the most prominent cause of ACD and compared proteomic alterations induced by NiSO4 to the bacterial trigger lipopolysaccharide (LPS). Both substances possess a similar toll-like receptor (TLR) 4 binding capacity, allowing to identify allergy-specific effects compared to bacterial activation. MoDCs treated for 24 h with 2.5 μg/ml LPS displayed a robust immunological response, characterized by upregulation of DC activation markers, secretion of pro-inflammatory cytokines and stimulation of T cell proliferation. Similar immunological reactions were observed after treatment with 400 μM NiSO4 but less pronounced. Both substances triggered TLR4 and triggering receptor expressed on myeloid cells (TREM) 1 signaling. However, NiSO4 also activated hypoxic and apoptotic pathways, which might have overshadowed initial signaling. Moreover, our proteomic data support the importance of nuclear factor erythroid 2-related factor 2 (Nrf2) as a key player in sensitization since many Nrf2 targets genes were strongly upregulated on protein and gene level selectively after treatment with NiSO4. Strikingly, NiSO4 stimulation induced cellular cholesterol depletion which was counteracted by the induction of genes and proteins relevant for cholesterol biosynthesis. Our proteomic study allowed for the first time to better characterize some of the fundamental differences between NiSO4 and LPS-triggered activation of MoDCs, providing an essential contribution to the molecular understanding of contact allergy.

PMID:33777040 | PMC:PMC7991087 | DOI:10.3389/fimmu.2021.644700

Front Immunol. 2021 Mar 11;12:624191. doi: 10.3389/fimmu.2021.624191. eCollection 2021.

ABSTRACT

In spite of several decades of research, an effective vaccine against schistosomiasis remains elusive. The radiation-attenuated (RA) cercarial vaccine is still the best model eliciting high protection levels, although the immune mechanisms have not yet been fully characterized. In order to identify genes and pathways underlying protection we investigated patterns of gene expression in PBMC and skin draining Lymph Nodes (LN) from mice using two exposure comparisons: vaccination with 500 attenuated cercariae versus infection with 500 normal cercariae; one versus three doses. Vaccinated mice were challenged with 120 normal parasites. Integration of PBMC and LN data from the infected group revealed early up-regulation of pathways associated with Th2 skewing and polarization of IgG antibody profiles. Additionally, hemostasis pathways were downregulated in infected mice, correlating with platelet reduction, potentially a mechanism to assist parasite migration through capillary beds. Conversely, up regulation of such mechanisms after vaccination may explain parasite blockade in the lungs. In contrast, a single exposure to attenuated parasites revealed early establishment of a Th1 bias (signaling of IL-1, IFN-γ; and Leishmania infection). Genes encoding chemokines and their receptors were more prominent in vaccinated mice, indicating an enhanced capacity for inflammation, potentially augmenting the inhibition of intravascular migration. Increasing the vaccinations from one to three did not dramatically elevate protection, but there was a clear shift towards antibody-mediated effectors. However, elements of the Th1 bias were still evident. Notable features after three vaccinations were markers of cytotoxicity (including IL-6 and NK cells) together with growth factors and their receptors (FGFR/VEGF/EGF) and the apoptosis pathway. Indeed, there is evidence for the development of anergy after three vaccinations, borne out by the limited responses detected in samples after challenge. We infer that persistence of a Th1 response puts a limit on expression of antibody-mediated mechanisms. This feature may explain the failure of multiple doses to drive protection towards sterile immunity. We suggest that the secretions of lung stage parasites would make a novel cohort of antigens for testing in protection experiments.

PMID:33777004 | PMC:PMC7996093 | DOI:10.3389/fimmu.2021.624191

Front Microbiol. 2021 Mar 12;12:641440. doi: 10.3389/fmicb.2021.641440. eCollection 2021.

ABSTRACT

Prokaryotic tolerance to inorganic arsenic is a widespread trait habitually determined by operons encoding an As (III)-responsive repressor (ArsR), an As (V)-reductase (ArsC), and an As (III)-export pump (ArsB), often accompanied by other complementary genes. Enigmatically, the genomes of many environmental bacteria typically contain two or more copies of this basic genetic device arsRBC. To shed some light on the logic of such apparently unnecessary duplication(s) we have inspected the regulation-together and by separate-of the two ars clusters borne by the soil bacterium Pseudomonas putida strain KT2440, in particular the cross talk between the two repressors ArsR1/ArsR2 and the respective promoters. DNase I footprinting and gel retardation analyses of Pars1 and Pars2 with their matching regulators revealed non-identical binding sequences and interaction patterns for each of the systems. However, in vitro transcription experiments exposed that the repressors could downregulate each other's promoters, albeit within a different set of parameters. The regulatory frame that emerges from these data corresponds to a particular type of bifan motif where all key interactions have a negative sign. The distinct regulatory architecture that stems from coexistence of various ArsR variants in the same cells could enter an adaptive advantage that favors the maintenance of the two proteins as separate repressors.

PMID:33776973 | PMC:PMC7994332 | DOI:10.3389/fmicb.2021.641440

Front Neurosci. 2021 Mar 12;15:648629. doi: 10.3389/fnins.2021.648629. eCollection 2021.

ABSTRACT

Many neurodegenerative diseases are associated with chronic inflammation in the brain and periphery giving rise to a continuous imbalance of immune processes. Next to inflammation markers, activation of transposable elements, including long intrespersed nuclear elements (LINE) elements and endogenous retroviruses (ERVs), has been identified during neurodegenerative disease progression and even correlated with the clinical severity of the disease. ERVs are remnants of viral infections in the human genome acquired during evolution. Upon activation, they produce transcripts and the phylogenetically youngest ones are still able to produce viral-like particles. In addition, ERVs can bind transcription factors and modulate immune response. Being between own and foreign, ERVs are reviewed in the context of viral infections of the central nervous system, in aging and neurodegenerative diseases. Moreover, this review tests the hypothesis that viral infection may be a trigger at the onset of neuroinflammation and that ERVs sustain the inflammatory imbalance by summarizing existing data of neurodegenerative diseases associated with viruses and/or ERVs.

PMID:33776642 | PMC:PMC7994506 | DOI:10.3389/fnins.2021.648629

Front Neurosci. 2021 Mar 11;15:621121. doi: 10.3389/fnins.2021.621121. eCollection 2021.

ABSTRACT

Advances in large-scale proteomics analysis have been very useful in understanding pathogenesis of diseases and elaborating therapeutic strategies. Proteomics has been employed to study Parkinson disease (PD); however, sparse studies reported proteome investigation after cell therapy approaches. In this study, we used liquid chromatography-tandem mass spectrometry and systems biology to identify differentially expressed proteins in a translational mouse model of PD after cell therapy. Proteins were extracted from five nigrostriatal-related brain regions of mice previously lesioned with 6-hydroxydopamine in the substantia nigra. Protein expression was compared in non-grafted brain to 1 and 7 days after intranigral grafting of E12.5 embryonic ventral mesencephalon (VM). We found a total of 277 deregulated proteins after transplantation, which are enriched for lipid metabolism, oxidative phosphorylation and PD, thus confirming that our animal model is similar to human PD and that the presence of grafted cells modulates the expression of these proteins. Notably, seven proteins (Acta1, Atp6v1e1, Eci3, Lypla2, Pip4k2a, Sccpdh, and Sh3gl2) were commonly down-regulated after engraftment in all studied brain regions. These proteins are known to be involved in the formation of lipids and recycling of dopamine (DA) vesicle at the synapse. Moreover, intranigral transplantation of VM cells decreased the expression of proteins related to oxidative stress, especially in the nigrostriatal pathway containing the DA grafted neurons. In the same regions, an up-regulation of several proteins including α-synuclein and tyrosine hydroxylase was observed, whereas expression of tetraspanin 7 was shut down. Overall, these results suggest that intranigral transplantation of VM tissue in an animal model of PD may induce a decrease of oxidative stress in the nigrostriatal pathway and a restoration of the machinery of neurotransmitters, particularly DA release to promote DA transmission through a decrease of D2 DA receptors endocytosis. Identification of new mechanistic elements involved in the nigrostriatal reconstruction process, using translational animal models and systems biology, is a promising approach to enhance the repair of this pathway in PD patients undergoing cell therapy.

PMID:33776636 | PMC:PMC7991918 | DOI:10.3389/fnins.2021.621121

J Ethnopharmacol. 2021 Mar 25:114025. doi: 10.1016/j.jep.2021.114025. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Yashtimadhu choorna (powder) is prepared from the dried root of Glycyrrhiza glabra L., commonly known as licorice. The Indian Ayurvedic system classifies Yashtimadhu as a Medhya Rasayana that can enhance brain function, improves memory, and possess neuroprotective functions, which can be used against neurodegenerative diseases like Parkinson's disease (PD).

AIM OF THE STUDY: We aimed to decipher the neuroprotective effects of G. glabra L., i.e., Yashtimadhu, in a rotenone-induced PD model.

MATERIALS AND METHODS: Retinoic acid-differentiated IMR-32 cells were treated with rotenone (PD model) and Yashtimadhu, and were assessed for cellular toxicity, live-dead staining, cell cycle, oxidative stress, protein abundance, and kinase phosphorylation.

RESULTS: Yashtimadhu conferred protection against rotenone-induced cytotoxicity, countered cell death, reduced expression of pro-apoptotic proteins (cleaved-caspases-9, and 3, cleaved-PARP, BAX, and BAK) and increased anti-apoptotic protein, BCL-2. Rotenone-induced cell cycle re-entry (G2/M transition), was negated by Yashtimadhu and was confirmed with PCNA levels. Yashtimadhu countered rotenone-mediated activation of mitochondrial proteins involved in oxidative stress, cytochrome-C, PDHA1, and HSP60. Inhibition of rotenone-induced ERK-1/2 hyperphosphorylation prevented activation of apoptosis, which was confirmed with MEK-inhibitor, highlighted the action of Yashtimadhu via ERK-1/2 modulation.

CONCLUSIONS: We provide the evidence for neuroprotection conferred by G. glabra L. (Yashtimadhu) and its mechanism via inhibiting MEK-ERK-1/2 hyper-phosphorylation, prevention of mitochondrial stress, and subsequent prevention of apoptosis. The study highlights Yashtimadhu as a promising candidate with neuroprotective effects, the potential of which can be harnessed for identifying novel therapeutic targets.

PMID:33775804 | DOI:10.1016/j.jep.2021.114025

J Neurosci Methods. 2021 Mar 25:109156. doi: 10.1016/j.jneumeth.2021.109156. Online ahead of print.

ABSTRACT

Understanding a neuron's input-output relationship is a longstanding challenge. Arguably, these signalling dynamics can be better understood if studied at three levels of analysis: computational, algorithmic and implementational (Marr, 1982). But it is difficult to integrate such analyses into a single platform that can realistically simulate neural information processing. Multiscale dynamical "whole-cell" modelling, a recent systems biology approach, makes this possible. Dynamical "whole-cell" models are computational models that aim to account for the integrated function of numerous genes or molecules to behave like virtual cells in silico. However, because constructing such models is laborious, only a couple of examples have emerged since the first one, built for Mycoplasma genitalium bacterium, was reported in 2012. Here, we review dynamic "whole-cell" neuron models for fly photoreceptors and how these have been used to study neural information processing. Specifically, we review how the models have helped uncover the mechanisms and evolutionary rules of quantal light information sampling and integration, which underlie light adaptation and further improve our understanding of insect vision.

PMID:33775669 | DOI:10.1016/j.jneumeth.2021.109156

Trends Cell Biol. 2021 Mar 25:S0962-8924(21)00053-2. doi: 10.1016/j.tcb.2021.03.007. Online ahead of print.

ABSTRACT

Enhancer reprogramming lies at the heart of dynamic cellular processes such as differentiation and tumorigenesis. WNT signaling is an evolutionary conserved pathway that exploits transcriptional enhancers to control the state-specific transcriptional program. Recent evidences suggest several mechanisms that govern this state-specific enhancer regulation in stem cells and cancer.

PMID:33775538 | DOI:10.1016/j.tcb.2021.03.007

Parasitology. 2021 Mar 29:1-37. doi: 10.1017/S003118202100055X. Online ahead of print.

NO ABSTRACT

PMID:33775262 | DOI:10.1017/S003118202100055X

Hypertension. 2021 Mar 29:HYPERTENSIONAHA12016425. doi: 10.1161/HYPERTENSIONAHA.120.16425. Online ahead of print.

ABSTRACT

Various studies found an association of different renin-angiotensin system (RAS) components with gestational duration and preterm birth, as well as with preeclampsia. Approximately 25% of first-time pregnant women develop a mild to severe hypertension in pregnancy or even preeclampsia. Based on recently published single-cell RNA-sequencing, we hypothesized an alternative RAS function in placenta and furthermore, an implication in hypertensive disorders in pregnancy. Placental RAS expression and localization was analyzed via quantitative polymerase chain reaction and in situ mRNA padlock probes. Tissue was collected from first-trimester elective termination (n=198), from healthy third-trimester controls (n=54), from early-onset preeclamptic (n=54) and age-matched controls (n=29), as well as first-trimester placentae from women with a high uterine artery resistance index (high-risk for preeclampsia, n=9) and controls (n=8). Serum levels of Ang (angiotensin) I to IV from women before and after conception were measured via mass spectrometry (n=10). Placental explants were cultured in 2.5% oxygen with Ang II, candesartan, and leptin. Seahorse XF96 MitoStress assays assessed trophoblast metabolism. Here, we show that maternal angiotensin acts on placental LNPEP (leucine aminopeptidase), that is, angiotensin IV-receptor and fetal angiotensin on placental AGTR1 (angiotensin II receptor type 1). Maternal circulating RAS shifts towards Ang IV in pregnancy. Ang IV decreases trophoblastic mitochondrial respiration and increases placental leptin via placental LNPEP. Lower placental LNPEP in preeclampsia and in first-trimester patients at high-risk for preeclampsia suggests a new alternative route in maternal RAS signaling and may contribute to hypertension and disease in pregnancy. The study shows how hypertensive disorders in pregnancy may be connected metabolic alterations that finally seem to contribute to the multifactorial disease in pregnancy, preeclampsia.

PMID:33775117 | DOI:10.1161/HYPERTENSIONAHA.120.16425

Plant Biotechnol J. 2021 Mar 27. doi: 10.1111/pbi.13589. Online ahead of print.

ABSTRACT

Recent discoveries show that fungi can take up environmental RNA, which can then silence fungal genes through environmental RNA interference. This discovery prompted the development of Spray-Induced Gene Silencing (SIGS) for plant disease management. In this study, we aimed to determine the efficacy of SIGS across a variety of eukaryotic microbes. We first examined the efficiency of RNA uptake in multiple pathogenic and non-pathogenic fungi, and an oomycete pathogen. We observed efficient double-stranded RNA (dsRNA) uptake in the fungal plant pathogens Botrytis cinerea, Sclerotinia sclerotiorum, Rhizoctonia solani, Aspergillus niger, and Verticillium dahliae, but no uptake in Colletotrichum gloeosporioides, and weak uptake in a beneficial fungus, Trichoderma virens. For the oomycete plant pathogen, Phytophthora infestans, RNA uptake was limited, and varied across different cell types and developmental stages. Topical application of dsRNA targeting virulence-related genes in pathogens with high RNA uptake efficiency significantly inhibited plant disease symptoms, whereas the application of dsRNA in pathogens with low RNA uptake efficiency did not suppress infection. Our results have revealed that dsRNA uptake efficiencies vary across eukaryotic microbe species and cell types. The success of SIGS for plant disease management can largely be determined by the pathogen's RNA uptake efficiency.

PMID:33774895 | DOI:10.1111/pbi.13589

Eur J Nucl Med Mol Imaging. 2021 Mar 27. doi: 10.1007/s00259-021-05322-2. Online ahead of print.

ABSTRACT

PURPOSE: We evaluated whether biomarkers on baseline [18F]-FDG PET/CT are associated with recurrence after surgery in patients with invasive breast cancer of no special type (NST).

METHODS: In this retrospective single-center study, we included consecutive patients with non-metastatic breast cancer of NST who underwent [18F]-FDG PET/CT before treatment, including surgery, between 2011 and 2016. Clinicopathological data were collected. Tumor SUVmax, total metabolic tumor volume (TMTV), and spleen- and bone marrow-to-liver SUVmax ratios (SLR, BLR) were measured from the PET images. Cut-off values were determined using predictiveness curves to predict 5-year recurrence-free survival (5y-RFS). A multivariable prediction model was developed using Cox regression. The association with stromal tumor-infiltrating lymphocytes (TILs) levels (low if <50%) was studied by logistic regression.

RESULTS: Three hundred and three women were eligible, including 93 (31%) with triple-negative breast carcinoma. After a median follow-up of 6.2 years, 56 and 35 patients experienced recurrence and death, respectively. The 5y-RFS rate was 86%. In multivariable analyses, high TMTV (>20 cm3) and high SLR (>0.76) were associated with shorter 5y-RFS (HR 2.4, 95%CI 1.3-4.5, and HR 1.9, 95%CI 1.0-3.6). In logistic regression, high SLR was the only independent factor associated with low stromal TILs (OR 2.8, 95%CI 1.4-5.7).

CONCLUSION: High total metabolic tumor volume and high spleen glucose metabolism on baseline [18F]-FDG PET/CT were associated with poor 5y-RFS after surgical resection in patients with breast cancer of NST. Spleen metabolism was inversely correlated with stromal TILs and might be a surrogate for an immunosuppressive tumor microenvironment.

PMID:33774685 | DOI:10.1007/s00259-021-05322-2

Bioinformatics. 2021 Mar 28:btab212. doi: 10.1093/bioinformatics/btab212. Online ahead of print.

ABSTRACT

MOTIVATION: Genomic selection (GS) is currently deemed the most effective approach to speed up breeding of agricultural varieties. It has been recognized that consideration of multiple traits in GS can improve accuracy of prediction for traits of low heritability. However, since GS forgoes statistical testing with the idea of improving predictions, it does not facilitate mechanistic understanding of the contribution of particular single nucleotide polymorphisms (SNP).

RESULTS: Here we propose a L2,1-norm regularized multivariate regression model and devise a fast and efficient iterative optimization algorithm, called L2,1-joint, applicable in multi-trait GS. The usage of the L2,1-norm facilitates variable selection in a penalized multivariate regression that considers the relation between individuals, when the number of SNPs is much larger than the number of individuals. The capacity for variable selection allows us to define master regulators that can be used in a multi-trait GS setting to dissect the genetic architecture of the analyzed traits. Our comparative analyses demonstrate that the proposed model is a favorable candidate compared to existing state-of-the-art approaches. Prediction and variable selection with data sets from Brassica napus, wheat and Arabidopsis thaliana diversity panels are conducted to further showcase the performance of the proposed model.

AVAILABILITY AND IMPLEMENTATION: The model is implemented using R programming language and the code is freely available from https://github.com/alainmbebi/L21-norm-GS.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:33774677 | DOI:10.1093/bioinformatics/btab212

Bioorg Chem. 2021 Mar 10;110:104813. doi: 10.1016/j.bioorg.2021.104813. Online ahead of print.

ABSTRACT

MutT Homolog 1 (MTH1) has been proven to hydrolyze oxidized nucleotide triphosphates during DNA repair. It can prevent the incorporation of wrong nucleotides during DNA replication and mitigate cell apoptosis. In a cancer cell, abundant reactive oxygen species can lead to substantial DNA damage and DNA mutations by base-pairing mismatch. MTH1 could eliminate oxidized dNTP and prevent cancer cells from entering cell death. Therefore, inhibition of MTH1 activity is considered to be an anti-cancer therapeutic target. In this study, high-throughput screening techniques were combined with a fragment-based library containing 2,313 compounds, which were used to screen for lead compounds with MTH1 inhibitor activity. Four compounds with MTH1 inhibitor ability were selected, and compound MI0639 was found to have the highest effective inhibition. To discover the selectivity and specificity of this action, several derivatives based on the MTH1 and MI0639 complex structure were synthesized. We compared 14 complex structures of MTH1 and the various compounds in combination with enzymatic inhibition and thermodynamic analysis. Nanomolar-range IC50 inhibition abilities by enzyme kinetics and Kd values by thermodynamic analysis were obtained for two compounds, named MI1020 and MI1024. Based on structural information and compound optimization, we aim to provide a strategy for the development of MTH1 inhibitors with high selectivity and specificity.

PMID:33774493 | DOI:10.1016/j.bioorg.2021.104813