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The OmicsFootPrint framework addresses the need for advanced multi-omics data analysis methodologies by transforming data into intuitive two-dimensional circular images and facilitating the interpretation of complex diseases. Utilizing deep neural networks and incorporating the SHapley Additive exPlanations algorithm, the framework enhances model interpretability. Tested with The Cancer Genome Atlas data, OmicsFootPrint effectively classified lung and breast cancer subtypes, achieving high area under the curve (AUC) scores-0.98 ± 0.02 for lung cancer subtype differentiation and 0.83 ± 0.07 for breast cancer PAM50 subtypes, and successfully distinguished between invasive lobular and ductal carcinomas in breast cancer, showcasing its robustness. It also demonstrated notable performance in predicting drug responses in cancer cell lines, with a median AUC of 0.74, surpassing nine existing methods. Furthermore, its effectiveness persists even with reduced training sample sizes. OmicsFootPrint marks an enhancement in multi-omics research, offering a novel, efficient and interpretable approach that contributes to a deeper understanding of disease mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Polycyclic aromatic hydrocarbon (PAH) contamination in marine environments range from low-diffusive inputs to high loads. The influence of PAH concentration on the expression of functional genes [e.g. those encoding ring-hydroxylating dioxygenases (RHDs)] has been overlooked in PAH biodegradation studies. However, understanding marker-gene expression under different PAH loads can help to monitor and predict bioremediation efficiency. Here, we followed the expression (via RNA sequencing) of Cycloclasticus pugetii strain PS-1 in cell suspension experiments under different naphthalene (100 and 30 mg L-1) concentrations. We identified genes encoding previously uncharacterized RHD subunits, termed rhdPS1α and rhdPS1β, that were highly transcribed in response to naphthalene-degradation activity. Additionally, we identified six RHD subunit-encoding genes that responded to naphthalene exposure. By contrast, four RHD subunit genes were PAH-independently expressed and three other RHD subunit genes responded to naphthalene starvation. Cycloclasticus spp. could, therefore, use genetic redundancy in key PAH-degradation genes to react to varying PAH loads. This genetic redundancy may restrict the monitoring of environmental hydrocarbon-degradation activity using single-gene expression. For Cycloclasticus pugetii strain PS-1, however, the newly identified rhdPS1α and rhdPS1β genes might be potential target genes to monitor its environmental naphthalene-degradation activity., (© The Author(s) 2024. Published by Oxford University Press on behalf of FEMS.)

Nonresponse is a common problem in survey sampling. Appropriate treatment can be challenging, especially when dealing with detailed breakdowns of totals. Often, the nearest neighbor imputation method is used to handle such incomplete multinomial data. In this article, we investigate the nearest neighbor ratio imputation estimator, in which auxiliary variables are used to identify the closest donor and the vector of proportions from the donor is applied to the total of the recipient to implement ratio imputation. To estimate the asymptotic variance, we first treat the nearest neighbor ratio imputation as a special case of predictive matching imputation and apply the linearization method of Yang and Kim (2020). To account for the non-negligible sampling fractions, parametric and generalized additive models are employed to incorporate the smoothness of the imputation estimator, which results in a valid variance estimator. We apply the proposed method to estimate expenditures detail items based on empirical data from the 2018 collection of the Service Annual Survey, conducted by the United States Census Bureau. Our simulation results demonstrate the validity of our proposed estimators and also confirm that the derived variance estimators have good performance even when the sampling fraction is non-negligible.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with low overall survival rates and high molecular heterogeneity; therefore, few targeted therapies are available. The luminal androgen receptor (LAR) is the most consistently identified TNBC subtype, but the clinical utility has yet to be established. Here, we constructed a novel genomic classifier, LAR-Sig, that distinguishes the LAR subtype from other TNBC subtypes and provide evidence that it is a clinically distinct disease. A meta-analysis of seven TNBC datasets ( n = 1086 samples) from neoadjuvant clinical trials demonstrated that LAR patients have significantly reduced response (pCR) rates than non-LAR TNBC patients (odds ratio = 2.11, 95% CI: 1.33, 2.89). Moreover, deconvolution of the tumor microenvironment confirmed an enrichment of luminal epithelium corresponding with a decrease in basal and myoepithelium in LAR TNBC tumors. Increased immunosuppression in LAR patients may lead to a decreased presence of cycling T-cells and plasma cells. While, an increased presence of myofibroblast-like cancer-associated cells may impede drug delivery and treatment. In summary, the lower levels of tumor infiltrating lymphocytes (TILs), reduced immune activity in the micro-environment, and lower pCR rates after NAC, suggest that new therapeutic strategies for the LAR TNBC subtype need to be developed., (© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Cancer.)

Aims: This study sought to compare mice bred to preferentially consume high amounts of alcohol (crossed-high alcohol preferring, cHAP) to c57BL/6 (C57) mice using a chronic-binge ethanol ingestion model to induce alcoholic liver disease (ALD)., Methods: Male C57 and cHAP mice were randomized to a Lieber-DeCarli control (LDC) diet, Lieber-DeCarli 5% (v/v) ethanol (LDE) diet or free-choice between 10% (v/v) ethanol in drinking water (EtOH-DW) and DW. After 4 weeks mice were gavaged with either 9 g/kg maltose-dextrin (LDC+MD) or 5 g/kg EtOH (LDE+Binge, EtOH-DW+Binge). Nine hours later tissue and serum were collected and analyzed., Results: cHAP mice on EtOH-DW consumed significantly more ethanol than cHAP or C57 mice maintained on LDE. However, cHAP and C57 mice on the LDE+Binge regiment had greater hepatosteatosis and overall degree of liver injury compared to EtOH-DW+Binge. Changes in pro-inflammatory gene expression was more pronounced in cHAP mice than C57 mice. Analysis of liver enzymes revealed a robust induction of CYP2E1 in C57 and cHAP mice maintained on EtOH-DW+Binge or LDE+Binge. However, while C57 mice exhibited higher basal hepatic glutathione than cHAP mice, these mice appeared more susceptible to oxidative stress following LDE+Binge than cHAP counterparts., Conclusions: Despite cHAP mice consuming more total ethanol prior to gavage when maintained on EtOH-DW, LDE followed by gavage created a more severe model of ALD in both C57 and cHAP mice. These data suggest factors other than total amount of alcohol consumed affect degree of ALD development in the chronic-binge model in cHAP mice., Short Summary: cHAP mice voluntarily consume high amounts of ethanol and exhibited hepatic injury when subject to chronic-binge ethanol feeding with the Lieber-DeCarli diet. However, hepatic injury was reduced in cHAP mice in a chronic-binge model following voluntary high ethanol consumption in drinking water., (© The Author 2017. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Background: Breast cancer patients with residual disease after neoadjuvant chemotherapy (NAC) have increased recurrence risk. Molecular characterization, knowledge of NAC response, and simultaneous generation of patient-derived xenografts (PDXs) may accelerate drug development. However, the feasibility of this approach is unknown., Methods: We conducted a prospective study of 140 breast cancer patients treated with NAC and performed tumor and germline sequencing and generated patient-derived xenografts (PDXs) using core needle biopsies. Chemotherapy response was assessed at surgery., Results: Recurrent "targetable" alterations were not enriched in patients without pathologic complete response (pCR); however, upregulation of steroid receptor signaling and lower pCR rates (16.7%, 1/6) were observed in triple-negative breast cancer (TNBC) patients with luminal androgen receptor (LAR) vs basal subtypes (60.0%, 21/35). Within TNBC, TP53 mutation frequency (75.6%, 31/41) did not differ comparing basal (74.3%, 26/35) and LAR (83.3%, 5/6); however, TP53 stop-gain mutations were more common in basal (22.9%, 8/35) vs LAR (0.0%, 0/6), which was confirmed in The Cancer Genome Atlas and British Columbia data sets. In luminal B tumors, Ki-67 responses were observed in tumors that harbored mutations conferring endocrine resistance ( p53, AKT, and IKBKE ). PDX take rate (27.4%, 31/113) varied according to tumor subtype, and in a patient with progression on NAC, sequencing data informed drug selection (olaparib) with in vivo antitumor activity observed in the primary and resistant (postchemotherapy) PDXs., Conclusions: In this study, we demonstrate the feasibility of tumor sequencing and PDX generation in the NAC setting. "Targetable" alterations were not enriched in chemotherapy-resistant tumors; however, prioritization of drug testing based on sequence data may accelerate drug development., (© The Author, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Rapid development of next generation sequencing technology has enabled the identification of genomic alterations from short sequencing reads. There are a number of software pipelines available for calling single nucleotide variants from genomic DNA but, no comprehensive pipelines to identify, annotate and prioritize expressed SNVs (eSNVs) from non-directional paired-end RNA-Seq data. We have developed the eSNV-Detect, a novel computational system, which utilizes data from multiple aligners to call, even at low read depths, and rank variants from RNA-Seq. Multi-platform comparisons with the eSNV-Detect variant candidates were performed. The method was first applied to RNA-Seq from a lymphoblastoid cell-line, achieving 99.7% precision and 91.0% sensitivity in the expressed SNPs for the matching HumanOmni2.5 BeadChip data. Comparison of RNA-Seq eSNV candidates from 25 ER+ breast tumors from The Cancer Genome Atlas (TCGA) project with whole exome coding data showed 90.6-96.8% precision and 91.6-95.7% sensitivity. Contrasting single-cell mRNA-Seq variants with matching traditional multicellular RNA-Seq data for the MD-MB231 breast cancer cell-line delineated variant heterogeneity among the single-cells. Further, Sanger sequencing validation was performed for an ER+ breast tumor with paired normal adjacent tissue validating 29 out of 31 candidate eSNVs. The source code and user manuals of the eSNV-Detect pipeline for Sun Grid Engine and virtual machine are available at http://bioinformaticstools.mayo.edu/research/esnv-detect/., (© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Manganese (Mn) is an essential nutrient with potential neurotoxic effects. Mn deposited in the nose is apparently transported to the brain through anterograde axonal transport, bypassing the blood-brain barrier. However, the role of the olfactory epithelial cells in Mn transport from the nasal cavity to the blood and brain is not well understood. We utilized the methyl bromide (MeBr) lesion model wherein the olfactory epithelium fully regenerates in a time-dependent and cell type-specific manner over the course of 6-8 weeks postinjury. We instilled (54)MnCl(2) intranasally at different recovery periods to study the role of specific olfactory epithelial cell types in Mn transport. (54)MnCl(2) was instilled at 2, 4, 7, 21, and 56 days post-MeBr treatment. (54)Mn concentrations in the blood were measured over the first 4-h period and in the brain and other tissues at 7 days postinstillation. Age-matched control rats were similarly studied at 2 and 56 days. Blood and tissue (54)Mn levels were reduced initially but returned to control values by day 7 post-MeBr exposure, coinciding with the reestablishment of sustentacular cells. Brain (54)Mn levels also decreased but returned to control levels only by 21 days, the period near the completion of neuronal regeneration/bulbar reinnervation. Our data show that Mn transport to the blood and brain temporally correlated with olfactory epithelial regeneration post-MeBr injury. We conclude that (1) sustentacular cells are necessary for Mn transport to the blood and (2) intact axonal projections are required for Mn transport from the nasal cavity to the olfactory bulb and brain.

This study examined the infleunce of three types of boot-sock systems on incidence and severity of foot blisters. Participants were 357 men undergoing U.S. Marine recruit training at Parris Island, South Carolina. Each participant was assigned to one of three treatment groups. The first group wore the standard military boot sock consisting of a wool-cotton-nylon-Spandex combination. The second group wore the standard military boot sock with a thin inner or liner sock consisting of polyester. The third group wore a very thick, dense, prototype outer sock consisting of a wool-polypropylene combination over the same liner sock as the second group. Foot blister incidence was lower among participants who wore the the prototype boot sock and liner than among those wearing the standard military sock (40 vs. 69%, p < 0.001) or among subjects wearing the standard military sock with liner (40 vs. 77%, p < 0.001). Foot blisters and cellulitis severe enough to require medical attention occurred with greater frequency in the standard military sock group compared to both the prototype boot-sock group (24 vs. 11%, p = 0.02) and the standard military sock with liner group (24 vs. 9%, p < 0.01); there was no difference between the latter two groups. Blister reduction was most apparent in the early weeks of recruit training. The standard military sock with a polyester liner reduced the incidence of severe blisters, but the dense sock with the polyester liner reduced the overall incidence of blisters as well as the incidence of severe blisters.