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Background: The interplay between exosomes and the tumor microenvironment (TME) remains unclear. We investigated the influence of exosomes on the TME in hepatocellular carcinoma (HCC), focusing on their mRNA expression profile. Methods: mRNA expression profiles of exosomes were obtained from exoRBase. RNA sequencing data from HCC patients’ tumors were acquired from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). An exosome mRNA-related risk score model of prognostic value was established. The patients in the two databases were divided into high- and low-risk groups based on the median risk score value, and used to validate one another. Functional enrichment analysis was performed based on a differential gene prognosis model (DGPM). CIBERSORT was used to assess the abundance of immune cells in the TME. The correlation between the expression levels of immune checkpoint-related genes and DGPM was analyzed alongside the prediction value to drug sensitivity. Results: A prognostic exosome mRNA-related 4-gene signature (DYNC1H1, PRKDC, CCDC88A, and ADAMTS5) was constructed and validated. A prognostic nomogram had prognostic ability for HCC. The genes for this model are involved in extracellular matrix, extracellular matrix (ECM)-receptor interaction, and the PI3K-Akt signaling pathway. Expression of genes here had a positive correlation with immune cell infiltration in the TME. Conclusions: Our study results demonstrate that an exosome mRNA-related risk model can be established in HCC, highlighting the functional significance of the molecules in prognosis and risk stratification. [ABSTRACT FROM AUTHOR]

Differentiating between pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) is crucial for the appropriate course of treatment, especially with advancements in the role of neoadjuvant chemotherapies for PDAC, compared to CCA. Furthermore, benign pancreaticobiliary diseases can mimic malignant disease, and indeterminate lesions may require repeated investigations to achieve a diagnosis. As bile flows in close proximity to these lesions, we aimed to establish a bile-based microRNA (miRNA) signature to discriminate between malignant and benign pancreaticobiliary diseases. We performed miRNA discovery by global profiling of 800 miRNAs using the NanoString nCounter platform in prospectively collected bile samples from malignant (n = 43) and benign (n = 14) pancreaticobiliary disease. Differentially expressed miRNAs were validated by RT-qPCR and further assessed in an independent validation cohort of bile from malignant (n = 37) and benign (n = 38) pancreaticobiliary disease. MiR-148a-3p was identified as a discriminatory marker that effectively distinguished malignant from benign pancreaticobiliary disease in the discovery cohort (AUC = 0.797 [95% CI 0.68–0.92]), the validation cohort (AUC = 0.772 [95% CI 0.66–0.88]), and in the combined cohorts (AUC = 0.752 [95% CI 0.67–0.84]). We also established a two-miRNA signature (miR-125b-5p and miR-194-5p) that distinguished PDAC from CCA (validation: AUC = 0.815 [95% CI 0.67–0.96]; and combined cohorts: AUC = 0.814 [95% CI 0.70–0.93]). Our research stands as the largest, multicentric, global profiling study of miRNAs in the bile from patients with pancreaticobiliary disease. We demonstrated their potential as clinically useful diagnostic tools for the detection and differentiation of malignant pancreaticobiliary disease. These bile miRNA biomarkers could be developed to complement current approaches for diagnosing pancreaticobiliary cancers. [ABSTRACT FROM AUTHOR]

Keywords: LMTK3; Kinase inhibitor; Breast cancer; Tubulin; NUSAP1 EN LMTK3 Kinase inhibitor Breast cancer Tubulin NUSAP1 1 6 6 12/02/21 20211201 NES 211201 The original online version of this article was revised: There are errors in Figures 2a and 2d. In addition, to confirm the involvement of NUSAP1 in the C28-mediated effect on microtubule stability and cell cycle arrest, we investigated the levels of cyclin-dependent kinase 1 (CDK1), a previously described NUSAP1-regulated protein [[12]], and phospho- III tubulin (S172). Taken together, although C28 can potentially bind tubulin, its relatively low binding affinity to purified tubulin dimer and the lack of any observable effect on tubulin polymerization suggest that C28 does not confer its effects by direct inhibition of tubulin polymerization. Considering the role of kinase inhibitors on microtubules [[4]], we investigated the possibility that C28 is a direct tubulin-targeting agent by employing an in vitro tubulin polymerization assay. [Extracted from the article]

Keywords: COVID-19; CXCL9; Cytokine; Dexamethasone; Inflammation; Serology EN COVID-19 CXCL9 Cytokine Dexamethasone Inflammation Serology 1 3 3 09/12/22 20220908 NES 220908 Supplementary Information The online version contains supplementary material available at https://doi.org/10.1186/s12967-022-03583-5. " I" or " C" refers to analytes measured by Olink Inflammation I panel or Cardiovascular II panel, respectively Focusing on markers differentially regulated in COVID-19 patients, we observed a unique biomarker profile in patients depending on their therapeutic journey. 1 A (lower) Heatmap analysis comparing fold change for protein biomarker levels in baseline samples of COVID-19 patients versus age/sex-matched healthy controls (HC). [Extracted from the article]

In addition, to confirm the involvement of NUSAP1 in the C28-mediated effect on microtubule stability and cell cycle arrest, we investigated the levels of cyclin-dependent kinase 1 (CDK1), a previously described NUSAP1-regulated protein [[12]], and phospho- III tubulin (S172). Taken together, although C28 can potentially bind tubulin, its relatively low binding affinity to purified tubulin dimer and the lack of any observable effect on tubulin polymerization suggest that C28 does not confer its effects by direct inhibition of tubulin polymerization. Considering the role of kinase inhibitors on microtubules [[4]], we investigated the possibility that C28 is a direct tubulin-targeting agent by employing an in vitro tubulin polymerization assay. Keywords: LMTK3; Kinase inhibitor; Breast cancer; Tubulin; NUSAP1 EN LMTK3 Kinase inhibitor Breast cancer Tubulin NUSAP1 1 6 6 04/12/21 20210409 NES 210409 The original online version of this article was revised: There are errors in Figures 2a and 2d. [Extracted from the article]

Taken together, although C28 can potentially bind tubulin, its relatively low binding affinity to purified tubulin dimer and the lack of any observable effect on tubulin polymerization suggest that C28 does not confer its effects by direct inhibition of tubulin polymerization. Keywords: LMTK3; Kinase inhibitor; Breast cancer; Tubulin; NUSAP1 EN LMTK3 Kinase inhibitor Breast cancer Tubulin NUSAP1 1 6 6 03/19/21 20210317 NES 210317 Supplementary Information The online version contains supplementary material available at https://doi.org/10.1186/s12943-021-01345-3. Following, the effect of C28 on microtubule stability was confirmed using a cell-based microtubule polymerization assay, where we observed a dose dependent decrease of the insoluble polymerized tubulin fraction. Considering the role of kinase inhibitors on microtubules [[4]], we investigated the possibility that C28 is a direct tubulin-targeting agent by employing an in vitro tubulin polymerization assay. [Extracted from the article]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

Background: Small RNAs include different classes essential for endogenous gene regulation and cellular defence against genomic parasites. However, a comprehensive analysis of the small RNA pathways in the germline of the mosquito Anopheles gambiae has never been performed despite their potential relevance to reproductive capacity in this malaria vector. Results: We performed small RNA deep sequencing during larval and adult gonadogenesis and find that they predominantly express four classes of regulatory small RNAs. We identified 45 novel miRNA precursors some of which were sex-biased and gonad-enriched , nearly doubling the number of previously known miRNA loci. We also determine multiple genomic clusters of 24-30 nt Piwi-interacting RNAs (piRNAs) that map to transposable elements (TEs) and 3'UTR of protein coding genes. Unusually, many TEs and the 3'UTR of some endogenous genes produce an abundant peak of 29-nt small RNAs with piRNA-like characteristics. Moreover, both sense and antisense piRNAs from TEs in both Anopheles gambiae and Drosophila melanogaster reveal novel features of piRNA sequence bias. We also discovered endogenous small interfering RNAs (endo-siRNAs) that map to overlapping transcripts and TEs. Conclusions: This is the first description of the germline miRNome in a mosquito species and should prove a valuable resource for understanding gene regulation that underlies gametogenesis and reproductive capacity. We also provide the first evidence of a piRNA pathway that is active against transposons in the germline and our findings suggest novel piRNA sequence bias. The contribution of small RNA pathways to germline TE regulation and genome defence in general is an important finding for approaches aimed at manipulating mosquito populations through the use of selfish genetic elements. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most aggressive type of primary brain tumours. Anti-angiogenic therapies (AAT), such as bevacizumab, have been developed to target the tumour blood supply. However, GBM presents mechanisms of escape from AAT activity, including a speculated direct effect of AAT on GBM cells. Furthermore, bevacizumab can alter the intercellular communication of GBM cells with their direct microenvironment. Extracellular vesicles (EVs) have been recently described as main acts in the GBM microenvironment, allowing tumour and stromal cells to exchange genetic and proteomic material. Herein, we examined and described the alterations in the EVs produced by GBM cells following bevacizumab treatment. Interestingly, bevacizumab that is able to neutralise GBM cells-derived VEGF-A, was found to be directly captured by GBM cells and eventually sorted at the surface of the respective EVs. We also identified early endosomes as potential pathways involved in the bevacizumab internalisation by GBM cells. Via MS analysis, we observed that treatment with bevacizumab induces changes in the EVs proteomic content, which are associated with tumour progression and therapeutic resistance. Accordingly, inhibition of EVs production by GBM cells improved the anti-tumour effect of bevacizumab. Together, this data suggests of a potential new mechanism of GBM escape from bevacizumab activity. [ABSTRACT FROM AUTHOR]