DHX9 helicase impacts on splicing decisions by modulating U2 snRNP recruitment in Ewing sarcoma cells.

Ewing sarcomas (ESs) are biologically aggressive tumours of bone and soft tissues caused by chromosomal translocations yielding in-frame fusion proteins driving the neoplastic transformation. The DNA/RNA helicase DHX9 is an important regulator of cellular processes often deregulated in cancer. Using transcriptome profiling, our study reveals cancer-relevant genes whose splicing is modulated by DHX9.

LCM-RNAseq Highlights Intratumor Heterogeneity and a lncRNA Signature from Archival Tissues of GH-Secreting PitNETs.

Background: This study explores the potential for hidden variations within seemingly uniform regions of growth hormone-secreting pituitary neuroendocrine tumors (GH-PitNETs). We employed archived tissue samples using Laser Capture Microdissection Sequencing (LCM-RNAseq) to probe the molecular landscape of these tumors at a deeper level.

Methods: A customized protocol was developed to extract, process, and sequence small amounts of RNA from formalin-fixed, paraffin-embedded (FFPE) tissues derived from five patients with GH-secreting PitNETs and long-term follow-up (≥10 years).

High Expression of SMN circ4-2b-3 in SMA I Children Treated with Nusinersen is Associated with Improved Motor Outcomes.

Spinal muscular atrophy (SMA) is a neuromuscular disorder resulting in the loss of α-motor neurons. Nusinersen is an antisense oligonucleotide administered intrathecally to SMA patients that corrects the splicing defect of SMN2. Not all SMA patients respond equally to the therapy and work is in progress to identify biomarkers that may help stratify to SMA patients.

RACK1 contributes to the upregulation of embryonic genes in a model of cardiac hypertrophy.

Receptors for activated C kinases (RACKs) have been shown to coordinate PKC-mediated hypertrophic signalling in mice. However, little information is available on its participation in embryonic gene expression. This study investigated the involvement of RACK1 in the expression of embryonic genes in a zebrafish (ZF) ex vivo heart culture model by using phenylephrine (PE) or a growth factors cocktail (GFs) as a prohypertrophic/regeneration stimulus.

The DNA/RNA helicase DHX9 orchestrates the KDM2B-mediated transcriptional regulation of YAP1 in Ewing sarcoma.

Ewing sarcomas (ES) are aggressive paediatric tumours of bone and soft tissues. Resistance to chemotherapy and high propensity to metastasize remain the main causes of treatment failure. Thus, identifying novel targets for alternative therapeutic approaches is urgently needed.

Dual inhibition of CDK12 and CDK13 uncovers actionable vulnerabilities in patient-derived ovarian cancer organoids.

Background: High grade serous ovarian cancer (HGSOC) is highly lethal, partly due to chemotherapy resistance and limited availability of targeted approaches. Cyclin dependent kinases 12 and 13 (CDK12/13) are promising therapeutic targets in human cancers, including HGSOC. Nevertheless, the effects of their inhibition in HGSOC and the potential synergy with other drugs are poorly known.

Regionally restricted modulation of expression and alternative splicing in the hippocampus of a murine model of multiple sclerosis.

Multiple sclerosis (MS) and its preclinical models are characterized by marked changes in neuroplasticity, including excitatory/inhibitory imbalance and synaptic dysfunction that are believed to underlie the progressive cognitive impairment (CI), which represents a significant clinical hallmark of the disease. In this study, we investigated several parameters of neuroplasticity in the hippocampus of the experimental autoimmune encephalomyelitis (EAE) SJL/J mouse model, characterized by rostral inflammatory and demyelinating lesions similar to Relapsing-Remitting MS. By combining morphological and molecular analyses, we found that the hippocampus undergoes extensive inflammation in EAE-mice, more pronounced in the CA3 and dentate gyrus (DG) subfields than in the CA1, associated with changes in GABAergic circuitry, as indicated by the increased expression of the interneuron marker Parvalbumin selectively in CA3.

Spatially resolved transcriptomics reveals innervation-responsive functional clusters in skeletal muscle.

Striated muscle is a highly organized structure composed of well-defined anatomical domains with integrated but distinct assignments. So far, the lack of a direct correlation between tissue architecture and gene expression has limited our understanding of how each unit responds to physio-pathologic contexts. Here, we show how the combined use of spatially resolved transcriptomics and immunofluorescence can bridge this gap by enabling the unbiased identification of such domains and the characterization of their response to external perturbations.

Can Blebbistatin block the hypertrophy status in the zebrafish ex vivo cardiac model?

Ex-vivo simple models are powered tools to study cardiac hypertrophy. It is possible to control the activation of critical genes and thus test the effects of drug therapies before the in vivo tests. A zebrafish cardiac hypertrophy developed by 500 μM phenylephrine (PE) treatment in ex vivo culture has been demonstrated to activate the essential expression of the embryonal genes.

Immunohistochemical detection of "ex novo" HLA-DR in tumor cells determines clinical outcome in laryngeal cancer patients.

There are controversial results about the role of "ex novo" HLA-DR expression by tumor cells and its correlation with the oncological outcomes. Unfortunately, little is known about HLA-DR expression in laryngeal cancer tumor cells. The main purpose of this retrospective study is to strengthen the usefulness of studying "ex novo" HLA-DR expression on tumor cells from primary laryngeal squamous cell carcinoma (LSCC) patients and investigate its correlation with clinical outcome.

Gene Expression Profiling of Pancreas Neuroendocrine Tumors with Different Ki67-Based Grades.

Pancreatic neuroendocrine tumors (PanNETs) display variable aggressive behavior. A major predictor of survival is tumor grade based on the Ki67 proliferation index. As information on transcriptomic profiles of PanNETs with different tumor grades is limited, we investigated 29 PanNETs (17 G1, 7 G2, 5 G3) for their expression profiles, mutations in 16 PanNET relevant genes and LINE-1 DNA methylation profiles.

GLI1 and AXIN2 Are Distinctive Markers of Human Calvarial Mesenchymal Stromal Cells in Nonsyndromic Craniosynostosis.

All skeletal bones house osteogenic stem cell niches, in which mesenchymal stromal cells (MSC) provide progenitors for tissue growth and regeneration. They have been widely studied in long bones formed through endochondral ossification. Limited information is available on the composition of the osteogenic niche in flat bones (i.

A Dynamic Splicing Program Ensures Proper Synaptic Connections in the Developing Cerebellum.

Tight coordination of gene expression in the developing cerebellum is crucial for establishment of neuronal circuits governing motor and cognitive function. However, transcriptional changes alone do not explain all of the switches underlying neuronal differentiation. Here we unveiled a widespread and highly dynamic splicing program that affects synaptic genes in cerebellar neurons.

The RNA binding protein Sam68 controls T helper 1 differentiation and anti-mycobacterial response through modulation of miR-29.

Polarization of naive T cells into interferon (IFN)-γ-producing T helper 1 (Th1) cells is an essential event in the inflammatory response to pathogens. Herein, we identify the RNA binding protein Sam68 as a specific modulator of Th1 differentiation. Sam68-knockout (ko) naive T cells are strongly defective in IL-12-mediated Th1 polarization and express low levels of T-bet and Eomes.

Micro RNAs are involved in activation of epicardium during zebrafish heart regeneration.

Zebrafish could be an interesting translational model to understand and improve the post-infarction trial and possible regeneration in humans. The adult zebrafish is able to regenerate efficiently after resecting nearly 20% of the ventricular apex. This process requires the concert activation of the epicardium and endocardium, as well as trans-differentiation of pre-existing cardiomyocytes that together replace the lost tissue.

Alternative splicing of human insulin receptor gene (INSR) in type I and type II skeletal muscle fibers of patients with myotonic dystrophy type 1 and type 2.

INSR, one of those genes aberrantly expressed in myotonic dystrophy type 1 (DM1) and type 2 (DM2) due to a toxic RNA effect, encodes for the insulin receptor (IR). Its expression is regulated by alternative splicing generating two isoforms: IR-A, which predominates in embryonic tissue, and IR-B, which is highly expressed in adult, insulin-responsive tissues (skeletal muscle, liver, and adipose tissue). The aberrant INSR expression detected in DM1 and DM2 muscles tissues, characterized by a relative increase of IR-A versus IR-B, was pathogenically related to the insulin resistance occurring in DM patients.

The neuroprotective and neurogenic effects of neuropeptide Y administration in an animal model of hippocampal neurodegeneration and temporal lobe epilepsy induced by trimethyltin.

The effects of intracerebroventricular administration of neuropeptide Y (NPY), which is believed to play an important role in neuroprotection against excitotoxicity and in the modulation of adult neurogenesis, were evaluated in an animal model of hippocampal neurodegeneration and temporal lobe epilepsy represented by trimethyltin (TMT) intoxication. A single TMT injection (8 mg/kg) causes, in the rat brain, massive neuronal death, selectively involving pyramidal neurons, accompanied by glial activation and enhanced hippocampal neurogenesis. Our data indicate that intracerebroventricular administration of exogenous NPY (at the dose of 2 μg/2 μL, 4 days after TMT-administration), in adult rats, exerts a protective role in regard to TMT-induced hippocampal damage and a proliferative effect on the hippocampal neurogenic niche through the up-regulation of Bcl-2, Bcl2l1, Bdnf, Sox-2, NeuroD1, Noggin and Doublecortin genes, contributing to delineate more clearly the role of NPY in in vivo neurodegenerative processes.

Lack of association between inherited thrombophilic risk factors and idiopathic sudden sensorineural hearing loss in Italian patients.

Objectives: We investigated the presence of congenital thrombophilic risk factors in a population of consecutive Italian patients affected by idiopathic sudden sensorineural hearing loss (SSNHL).

Methods: We investigated 48 patients with idiopathic SSNHL for the presence of congenital thrombophilic risk factors. The factor V Leiden G1691A, the prothrombin G20210A allele, and methylenetetrahydrofolate reductase (MTHFR) C677T genotypes were investigated.