miR-15a targets the HSP90 co-chaperone Morgana in chronic myeloid leukemia.

Morgana is a ubiquitous HSP90 co-chaperone protein coded by the CHORDC1 gene. Morgana heterozygous mice develop with age a myeloid malignancy resembling human atypical myeloid leukemia (aCML), now renamed MDS/MPN with neutrophilia. Patients affected by this pathology exhibit low Morgana levels in the bone marrow (BM), suggesting that Morgana downregulation plays a causative role in the human malignancy. A decrease in Morgana expression levels is also evident in the BM of a subgroup of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) patients showing resistance or an incomplete response to imatinib. Despite the relevance of these data, the mechanism through which Morgana expression is downregulated in patients' bone marrow remains unclear. In this study, we investigated the possibility that Morgana expression is regulated by miRNAs and we demonstrated that Morgana is under the control of four miRNAs (miR-15a/b and miR-26a/b) and that miR-15a may account for Morgana downregulation in CML patients.

Lentils pasta by-product in a complete extruded diet for dogs and its effect on extrusion, digestibility, and carbohydrate metabolism.

Introduction: Recently, increasing effort has been directed toward environmental sustainability in pet food. The aim of this study was to evaluate the extrusion parameters, nutrient digestibility, fecal characteristics, palatability and insulinemic and glycaemic curves of a complete diet for dogs in which the main carbohydrate source was a red lentil pasta by-product (LP). Methods: Five experimental diets were formulated: a basal diet (CO) based on rice and a poultry by-product meal; three experimental diets where LP substituted rice at 33, 66, or 100% (LP33, LP66, and LP100, respectively); and a diet formulated on 70% of the basal diet (CO) plus 30% LP (LPS) to evaluate the digestibility of LP ingredient. Results and discussion: The extruder pressure, hardness and bulk density of the kibble increased in a linear manner with increasing LP percentage (P < 0.05), without affecting starch gelatinization. According to polynomial contrast analysis, rice replacement with LP at 33 and 66% caused no reduction in apparent total tract digestibility coefficient (ATTDC), with similar or higher values compared with the CO diet. Nitrogen balance did not change (P > 0.05), but we observed a linear increase in feces production and moisture content as the LP inclusion rate rose and a linear decrease in feces pH (P < 0.05). Nevertheless, the fecal score was unaffected. Fecal acetate, propionate, total short-chain fatty acids (SCFA), branched-chain fatty acids, and lactate all increased linearly as the LP inclusion rate increased (P < 0.05), without altering ammonia concentration in feces. Feces concentrations of cadaverine, tyramine, histamine, and spermidine also increased in a linear manner with increasing LP inclusion (P < 0.05). The fermentation of LP dietary fiber by the gut microbiota increased the concentration of desirable fermentation by-products, including SCFA and spermidine. The post-prandial glucose and insulin responses were lower in the dogs fed the LP100 diet compared with CO, suggesting the possible use of this ingredient in diets designed to generate a low glycaemic response. Finally, the palatability study results showed a preference for the LP100 ration in both the "first choice" and the "consumption rate" evaluation (P < 0.05). This trial reveals how a by-product discarded from the human-grade food chain retains both its nutritional and organoleptic properties.

RNA-binding protein transcripts as potential biomarkers for detecting Primary Sclerosing Cholangitis and for predicting its progression to Cholangiocarcinoma.

Primary Sclerosing Cholangitis (PSC) is a persistent inflammatory liver condition that affects the bile ducts and is commonly diagnosed in young individuals. Despite efforts to incorporate various clinical, biochemical and molecular parameters for diagnosing PSC, it remains challenging, and no biomarkers characteristic of the disease have been identified hitherto. PSC is linked with an uncertain prognosis, and there is a pressing need to explore multiomics databases to establish a new biomarker panel for the early detection of PSC's gradual progression into Cholangiocarcinoma (CCA) and for the development of effective therapeutic interventions. Apart from non-coding RNAs, other components of the Ribonucleoprotein (RNP) complex, such as RNA-Binding Proteins (RBPs), also hold great promise as biomarkers due to their versatile expression in pathological conditions. In the present review, an update on the RBP transcripts that show dysregulated expression in PSC and CCA is provided. Moreover, by utilizing a bioinformatic data mining approach, we give insight into those RBP transcripts that also exhibit differential expression in liver and gall bladder, as well as in body fluids, and are promising as biomarkers for diagnosing and predicting the prognosis of PSC. Expression data were bioinformatically extracted from public repositories usingTCGA Bile Duct Cancer dataset for CCA and specific NCBI GEO datasets for both PSC and CCA; more specifically, RBPs annotations were obtained from RBP World database. Interestingly, our comprehensive analysis shows an elevated expression of the non-canonical RBPs, FANCD2, as well as the microtubule dynamics regulator, ASPM, transcripts in the body fluids of patients with PSC and CCA compared with their respective controls, with the same trend in expression being observed in gall bladder and liver cancer tissues. Consequently, the manipulation of tissue expression of RBP transcripts might be considered as a strategy to mitigate the onset of CCA in PSC patients, and warrants further experimental investigation. The analysis performed herein may be helpful in the identification of non-invasive biomarkers for the early detection of PSC and for predicting its progression into CCA. In conclusion, future clinical research should investigate in more depth the full potential of RBP transcripts as biomarkers for human pathologies.

Sterile inflammation via TRPM8 RNA-dependent TLR3-NF-kB/IRF3 activation promotes antitumor immunity in prostate cancer.

Inflammation is a common condition of prostate tissue, whose impact on carcinogenesis is highly debated. Microbial colonization is a well-documented cause of a small percentage of prostatitis cases, but it remains unclear what underlies the majority of sterile inflammation reported. Here, androgen- independent fluctuations of PSA expression in prostate cells have lead us to identify a prominent function of the Transient Receptor Potential Cation Channel Subfamily M Member 8 (TRPM8) gene in sterile inflammation. Prostate cells secret TRPM8 RNA into extracellular vesicles (EVs), which primes TLR3/NF-kB-mediated inflammatory signaling after EV endocytosis by epithelial cancer cells. Furthermore, prostate cancer xenografts expressing a translation-defective form of TRPM8 RNA contain less collagen type I in the extracellular matrix, significantly more infiltrating NK cells, and larger necrotic areas as compared to control xenografts. These findings imply sustained, androgen-independent expression of TRPM8 constitutes as a promoter of anticancer innate immunity, which may constitute a clinically relevant condition affecting prostate cancer prognosis.