Impact of Inherited Genetic Variants on Critically Ill Septic Children

Sepsis remains an important source of morbidity and mortality in children, despite the development of standardized care. In the last decades, there has been an increased interest in genetic and genomic approaches to early recognition and development of treatments to manipulate the host inflammatory response. This review will present a summary of the normal host response to infection and progression to sepsis, followed by highlighting studies with a focus on gene association studies, epigenetics, and genome-wide expression profiling. The susceptibility (or outcome) of sepsis in children has been associated with several polymorphisms of genes broadly involved in inflammation, immunity, and coagulation. More recently, gene expression profiling has been focused on identifying novel biomarkers, pathways and therapeutic targets, and gene expression-based subclassification. Knowledge of a patient’s individual genotype may, in the not-too-remote future, be used to guide tailored treatment for sepsis. However, at present, the impact of genomics remains far from the bedside of critically ill children.

A Multidisciplinary Approach Evaluating Soybean Meal-Induced Enteritis in Rainbow Trout Oncorhynchus mykiss

This study evaluated a diverse range of markers of feeding stress to obtain a more precise assessment of the welfare of rainbow trout in relation to inadequate husbandry conditions. A feeding stress model based on dietary soybean meal was employed to identify suitable minimally invasive “classical” stress markers, together with molecular signatures. In a 56-day feeding experiment, rainbow trout were fed diets containing different levels of soybean meal. The impact of these different soybean meal diets on rainbow trout was assessed by water quality analyses, clinical health observations, classic growth and performance parameters, gut histopathology, blood-parameter measurements and multigene-expression profiling in RNA from whole blood. Soybean meal-induced enteritis was manifested phenotypically by an inflammatory reaction in the posterior section of the intestine and by diarrhoea in some trout. These inflammatory changes were associated with decreased supranuclear vacuolation. The haematocrit values and the levels of plasma cortisol and circulating lymphocytes in the blood were increased in trout that had consumed high amounts of SBM. Notably, the increased haematocrit depended significantly on the bodyweight of the individual trout. The transcript levels of certain genes (e.g., MAP3K1, LYG, NOD1, STAT1 and HSP90AB) emerged as potentially useful indicators in the blood of rainbow trout providing valuable information about inadequate nutrition. The expression-profiling findings provide a basis for improved, minimally invasive monitoring of feeding regimens in trout farming and may stimulate the development of practical detection devices for innovative aquaculture operations.

MED10 Drives the Oncogenicity and Refractory Phenotype of Bladder Urothelial Carcinoma Through the Upregulation of hsa-miR-590

BackgroundDysfunctional transcription machinery with associated dysregulated transcription characterizes many malignancies. Components of the mediator complex, a principal modulator of transcription, are increasingly implicated in cancer. The mediator complex subunit 10 (MED10), a vital kinase module of the mediator, plays a critical role in bladder physiology and pathology. However, its role in the oncogenicity, metastasis, and disease recurrence in bladder cancer (BLCA) remains unclear.ObjectiveThus, we investigated the role of dysregulated or aberrantly expressed MED10 in the enhanced onco-aggression, disease progression, and recurrence of bladder urothelial carcinoma (UC), as well as the underlying molecular mechanism.MethodsUsing an array of multi-omics big data analyses of clinicopathological data, in vitro expression profiling and functional assays, and immunocytochemical staining, we assessed the probable roles of MED10 in the progression and prognosis of BLCA/UC.ResultsOur bioinformatics-aided gene expression profiling showed that MED10 is aberrantly expressed in patients with BLCA, is associated with high-grade disease, is positively correlated with tumor stage, and confers significant survival disadvantage. Reanalyzing the TCGA BLCA cohort (n = 454), we showed that aberrantly expressed MED10 expression is associated with metastatic and recurrent disease, disease progression, immune suppression, and therapy failure. Interestingly, we demonstrated that MED10 interacts with and is co-expressed with the microRNA, hsa-miR-590, and that CRISPR-mediated knockout of MED10 elicits the downregulation of miR-590 preferentially in metastatic UC cells, compared to their primary tumor peers. More so, silencing MED10 in SW1738 and JMSU1 UC cell lines significantly attenuates their cell proliferation, migration, invasion, clonogenicity, and tumorsphere formation (primary and secondary), with the associated downregulation of BCL-xL, MKI67, VIM, SNAI1, OCT4, and LIN28A but upregulated BAX protein expression. In addition, we showed that high MED10 expression is a non-inferior biomarker of urothelial recurrence compared with markers of cancer stemness; however, MED10 is a better biomarker of local recurrence than any of the stemness markers.ConclusionThese data provide preclinical evidence that dysregulated MED10/MIR590 signaling drives onco-aggression, disease progression, and recurrence of bladder UC and that this oncogenic signal is therapeutically actionable for repressing the metastatic/recurrent phenotypes, enhancing therapy response, and shutting down stemness-driven disease progression and relapse in patients with BLCA/UC.

Prediction of pan-solid tumor pembrolizumab benefit by integrating tumor mutation and gene expression profiling

Pembrolizumab is approved in many advanced solid tumor types, however predictive biomarkers and the proportion of pembrolizumab-benefiting patients vary. Biomarkers beyond PD-L1 immunohistochemistry, microsatellite instability (MSI) status, and tumor mutation burden (TMB) may improve benefit prediction. Here, leveraging treatment data (time to next treatment [TTNT]) and comprehensive genomic and quantitative transcriptomic profiling on routine tumor tissue from 708 patients (24 tumor types) collected in an ongoing observational trial (NCT03061305), we report a multivariate, integrative predictor of pan-solid tumor pembrolizumab benefit. The Immune Response Score (IRS) model, which includes TMB and quantitative PD-1, PD-L2, ADAM12 and CD4 RNA expression, was confirmed as predictive through comparison of pembrolizumab TTNT with previous chemotherapy TTNT in a subset of 166 patients treated with both. Applying IRS to the entire NCT03061305 cohort (n=25,770 patients), 13.2-30.7% of patients (2.2-9.6% of patients outside of pembrolizumab approved tumor types [including TMB-High and MSI-High]) are predicted to benefit substantially from pembrolizumab. Hence, if prospectively validated, the IRS model may improve pembrolizumab benefit prediction across approved tumor types including patients outside of currently approved indications.

Highly Conserved Evolution of Aquaporin PIPs and TIPs Confers Their Crucial Contribution to Flowering Process in Plants

Flowering is the key process for the sexual reproduction in seed plants. In gramineous crops, the process of flowering, which includes the actions of both glume opening and glume closing, is directly driven by the swelling and withering of lodicules due to the water flow into and out of lodicule cells. All these processes are considered to be controlled by aquaporins, which are the essential transmembrane proteins that facilitate the transport of water and other small molecules across the biological membranes. In the present study, the evolution of aquaporins and their contribution to flowering process in plants were investigated via an integration of genome-wide analysis and gene expression profiling. Across the barley genome, we found that HvTIP1;1, HvTIP1;2, HvTIP2;3, and HvPIP2;1 were the predominant aquaporin genes in lodicules and significantly upregulated in responding to glume opening and closing, suggesting the importance of them in the flowering process of barley. Likewise, the putative homologs of the above four aquaporin genes were also abundantly expressed in lodicules of the other monocots like rice and maize and in petals of eudicots like cotton, tobacco, and tomato. Furthermore, all of them were mostly upregulated in responding to the process of floret opening, indicating a conserved function of these aquaporin proteins in plant flowering. The phylogenetic analysis based on the OneKP database revealed that the homologs of TIP1;1, TIP1;2, TIP2;3, and PIP2;1 were highly conserved during the evolution, especially in the angiosperm species, in line with their conserved function in controlling the flowering process. Taken together, it could be concluded that the highly evolutionary conservation of TIP1;1, TIP1;2, TIP2;3 and PIP2;1 plays important roles in the flowering process for both monocots and eudicots.

IMPARTER, Phase 1 of an intervention to improve patients’ understanding of gene expression profiling tests in breast cancer

Purpose To compare participants’ knowledge about gene expression profiling (GEP) tests and recurrence risks after reading an information leaflet with that following viewing of an information film. Methods Using a randomised cross-over design, at time-point one (T1), women aged 45–75 years without breast cancer either read leaflets or watched information films about Oncotype DX or Prosigna tests. Participants answered nine questions assessing knowledge (maximum score 18). Next-day information in the opposite modality was provided and knowledge re-assessed. Additional questions probed which format was easiest to understand, participants’ preferences for film or leaflet and their reasons for these. Results 120 women participated (60 received OncotypeDX films and leaflets; 60 received the Prosigna versions). T1 mean knowledge scores were higher following film viewing (13.37) compared with that after reading leaflets (9.25) (mean difference 4.1; p < 0.0001; 95% CI 3.2, 5.0). When participants read leaflets first and subsequently viewed films, all increased their scores (mean + 6.08, from T1 of 9.25, p < 0.0001; 95% CI 5.44, 6.72). When films were viewed first, followed by leaflets, (36/60, 60%), participants’ scores declined (mean-1.55 from T1 of 13.37, p < 0.001; 95% CI -2.32, -0.78). A majority of participants expressed preferences for the films (88/120, 73.3%) irrespective as to whether they described OncotypeDX or Prosigna. Reasons included the clarity, ease of understanding, visual material and reassuring voice-over. Conclusion Discussions between oncologists and patients about recurrence risk results can be challenging. Information leaflets may aid understanding but often employ complex language. Information films significantly improved knowledge and were preferred by participants.