The heterogeneous pathogenesis and treatment response of non-small cell lung cancer (NSCLC) has led clinical treatment decisions to be guided by NSCLC subtypes, with lung adenocarcinoma and lung ...squamous cell carcinoma being the most common subtypes. While histology-based subtyping remains challenging, NSCLC subtypes were found to be distinct at the transcriptomic level. However, unlike genomic alterations, gene expression is generally not assessed in clinical routine. Since subtyping of NSCLC has remained elusive using mutational data, we aimed at developing a neural network model that simultaneously learns from adenocarcinoma and squamous cell carcinoma samples of other tissue types and is regularized using a neural network model trained from gene expression data. While substructures of the expression-based manifold were captured in the mutation-based manifold, NSCLC classification accuracy did not significantly improve. However, performance was increased when rejecting inconclusive samples using an ensemble-based approach capturing prediction uncertainty. Importantly, SHAP analysis of misclassified samples identified co-occurring mutations indicative of both NSCLC subtypes, questioning the current NSCLC subtype classification to adequately represent inherent mutational heterogeneity. Since our model captures mutational patterns linked to clinical heterogeneity, we anticipate it to be suited as foundational model of genomic data for clinically relevant prognostic or predictive downstream tasks.
In pigs, the microbial ecosystem of the gastrointestinal tract (GIT) is influenced by various factors; however, variations in diet composition have been identified as one of the most important ...determinants. Marked changes in fermentation activities and microbial ecology may occur when altering the diet, for example, from milk to solid feed during weaning. In that way, access of pathogens to the disturbed ecosystem is alleviated, leading to infectious diseases and diarrhea. Thus, there is increasing interest in improving intestinal health by use of dietary ingredients suitable to beneficially affect the microbial composition and activity. For example, fermentable carbohydrates have been shown to promote growth of beneficial Lactobacillus species and bifidobacteria, thereby enhancing colonization resistance against potential pathogens or production of short-chain fatty acids, which can be used as energy source for epithelial cells. On the other hand, fermentation of protein results in the production of various potentially toxic products, such as amines and NH₃, and is often associated with growth of potential pathogens. In that way, excessive protein intake has been shown to stimulate the growth of potentially pathogenic species such as Clostridium perfringens, and to reduce fecal counts of beneficial bifidobacteria. Therefore, it seems to be a promising approach to support growth and metabolic activity of the beneficial microbiota by developing suitable feeding strategies. For example, a reduction of dietary CP content and, at the same time, dietary supplementation with fermentable carbohydrates have proven to successfully suppress protein fermentation. In addition, the intestinal microbiota seems to be sensible to variations in dietary protein source, such as the use of highly digestible protein sources may reduce growth of protein-fermenting and potentially pathogenic species. The objective of the present review is to assess the impact of dietary protein on microbiota composition and activity in the GIT of piglets. Attention will be given to studies designed to determine the effect of variations in total protein supply, protein source and supplementation of fermentable carbohydrates to the diet on composition and metabolic activity of the intestinal microbiota.
The Hedgehog-signaling pathway is an important target in cancer research and regenerative medicine; yet, on the cellular level, many steps are still poorly understood. Extensive studies of the bulk ...behavior of the key proteins in the pathway established that during signal transduction they dynamically localize in primary cilia, antenna-like solitary organelles present on most cells. The secreted Hedgehog ligand Sonic Hedgehog (SHH) binds to its receptor Patched1 (PTCH1) in primary cilia, causing its inactivation and delocalization from cilia. At the same time, the transmembrane protein Smoothened (SMO) is released of its inhibition by PTCH1 and accumulates in cilia. We used advanced, single molecule-based microscopy to investigate these processes in live cells. As previously observed for SMO, PTCH1 molecules in cilia predominantly move by diffusion and less frequently by directional transport, and spend a fraction of time confined. After treatment with SHH we observed two major changes in the motional dynamics of PTCH1 in cilia. First, PTCH1 molecules spend more time as confined, and less time freely diffusing. This result could be mimicked by a depletion of cholesterol from cells. Second, after treatment with SHH, but not after cholesterol depletion, the molecules that remain in the diffusive state showed a significant increase in the diffusion coefficient. Therefore, PTCH1 inactivation by SHH changes the diffusive motion of PTCH1, possibly by modifying the membrane microenvironment in which PTCH1 resides.
In 2012, recommendations for universal tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccination during pregnancy were released. Our objective was to determine if Tdap, ...influenza, and pneumococcal vaccine uptake during pregnancy changed after the release of the guidelines, and identify factors associated with receiving the Tdap and influenza vaccine after 2012. We conducted a retrospective cohort study on pregnant individuals who initiated prenatal care before 20 weeks' gestation between 11/2011-11/2012 ("pre-guideline") and 12/2012-12/2015 ("post-guideline"). Vaccine uptake dates were abstracted from medical records. The pre and post-guideline cohorts were compared to determine if Tdap vaccine uptake and timing improved after the new Tdap guidelines. We additionally examined influenza and pneumococcal vaccine uptake before and after guidelines. Factors associated with receipt of the Tdap and influenza vaccine during pregnancy in the post-guideline cohort were evaluated using multivariable logistic regression models. Of 2,294 eligible individuals, 1,610 (70.2%) received care in the post-guideline cohort. Among the pre-guideline cohort, 47.4% received Tdap, whereas Tdap uptake increased to 86.1% after the guidelines (p<0.001). Similarly, receiving the Tdap vaccine between the recommended time of 27-36 weeks gestational age improved from 52.5% to 91.8% after the guidelines (p<0.001). Vaccine frequency for influenza improved significantly from 61.2% to 72.0% (p<0.001), while frequency for pneumococcus were low and unchanged. An increased number of prenatal visits was associated with receiving the Tdap and influenza vaccines during pregnancy (respective, aOR 1.09 95% CI 1.05-1.13; aOR 1.50 95% CI 1.17-1.94). Non-Hispanic Black individuals were less likely to receive both the Tdap and influenza vaccines during pregnancy compared to non-Hispanic White individuals (respective, aOR 0.51 95% CI 0.33-0.80; aOR 0.68 95% CI 0.48-0.97). Receipt and timing of Tdap vaccine improved after implementation of the 2012 ACIP guidelines. Receipt of influenza vaccine uptake also improved during the study period, while uptake of the pneumococcal vaccine remained low. Significant racial disparities exist in receipt of Tdap and influenza vaccine during pregnancy.
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