is a lncRNA overexpressed in several epithelial cancers and strongly correlated with invasion. This lncRNA was proven a pivotal element of the epithelial-to-mesenchymal transition (EMT), a ...transdifferentiation process triggering metastasis. Snail, master inducer of EMT, requires
to recruit EZH2 on specific epithelial target genes (i.e.,
, and
) and cause their repression. Here, we designed a
deletion mutant form, named
-
, including the putative Snail-binding domain but depleted of the EZH2-binding domain.
-
acted as a dominant negative of the endogenous
. In both murine and human tumor cells,
-
impaired the ability of
to bind Snail and, in turn, trigger H3K27me3/EZH2-mediated repression of Snail epithelial target genes. Notably,
-
expression was proven to reduce cellular motility, invasiveness, anchorage-independent growth, and responsiveness to TGFβ-induced EMT. These data provide evidence on a lncRNA-based strategy to effectively impair the function of a master EMT-transcriptional factor. SIGNIFICANCE: This study defines an innovative RNA-based strategy to interfere with a pivotal function of the tumor-related lncRNA
, comprising a dominant negative mutant that was computationally designed and that impairs epithelial-to-mesenchymal transition.
Sarcomas comprise a heterogeneous group of rare mesenchymal malignancies. Sarcomas can be grouped into two categories characterized by different prognosis and treatment approaches: soft tissue ...sarcoma and primary bone sarcoma. In the last years, research on novel diagnostic, prognostic or predictive biomarkers in sarcoma management has been focused on circulating tumor-derived molecules as valuable tools. Liquid biopsies that measure various tumor components, including circulating cell-free DNA and RNA, circulating tumor cells, tumor extracellular vesicles and exosomes, are gaining attention as methods for molecular screening and early diagnosis. Compared with traditional tissue biopsies, liquid biopsies are minimally invasive and blood samples can be collected serially over time to monitor cancer progression. This review will focus on circulating noncoding RNA molecules from liquid biopsies that are dysregulated in sarcoma malignancies and discuss advantages and current limitations of their employment as biomarkers in the management of sarcomas. It will also explore their utility in the evaluation of the clinical response to treatments and of disease relapse. Moreover, it will explore state-of-the-art techniques that allow for the early detection of these circulating biomarkers. Despite the huge potential, current reports highlight poor sensitivity, specificity, and survival benefit of these methods, that are therefore still insufficient for routine screening purposes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Heterogeneous nuclear ribonucleoproteins (hnRNPs) control gene expression by acting at multiple levels and are often deregulated in epithelial tumors; however, their roles in the fine regulation of ...cellular reprogramming, specifically in epithelial-mesenchymal transition (EMT), remain largely unknown. Here, we focused on the hnRNP-Q (also known as SYNCRIP), showing by molecular analysis that in hepatocytes it acts as a "mesenchymal" gene, being induced by TGFβ and modulating the EMT. SYNCRIP silencing limits the induction of the mesenchymal program and maintains the epithelial phenotype. Notably, in HCC invasive cells, SYNCRIP knockdown induces a mesenchymal-epithelial transition (MET), negatively regulating their mesenchymal phenotype and significantly impairing their migratory capacity. In exploring possible molecular mechanisms underlying these observations, we identified a set of miRNAs (i.e., miR-181-a1-3p, miR-181-b1-3p, miR-122-5p, miR-200a-5p, and miR-let7g-5p), previously shown to exert pro- or anti-EMT activities, significantly impacted by SYNCRIP interference during EMT/MET dynamics and gathered insights, suggesting the possible involvement of this RNA binding protein in their transcriptional regulation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Amyotrophic lateral sclerosis (ALS) is an adult devastating neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), resulting in progressive paralysis and death. ...Genetic animal models of ALS have highlighted dysregulation of synaptic structure and function as a pathogenic feature of ALS-onset and progression. Alternative pre-mRNA splicing (AS), which allows expansion of the coding power of genomes by generating multiple transcript isoforms from each gene, is widely associated with synapse formation and functional specification. Deciphering the link between aberrant splicing regulation and pathogenic features of ALS could pave the ground for novel therapeutic opportunities. Herein, we found that neural progenitor cells (NPCs) derived from the
hSOD1
G93A
mouse model of ALS displayed increased proliferation and propensity to differentiate into neurons. In parallel,
hSOD1
G93A
NPCs showed impaired splicing patterns in synaptic genes, which could contribute to the observed phenotype. Remarkably, master splicing regulators of the switch from stemness to neural differentiation are de-regulated in
hSOD1
G93A
NPCs, thus impacting the differentiation program. Our data indicate that
hSOD1
G93A
mutation impacts on neurogenesis by increasing the NPC pool in the developing mouse cortex and affecting their intrinsic properties, through the establishment of a specific splicing program.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Patients with HCV who achieve a sustained virological response (SVR) on direct-acting antiviral (DAA) therapy still need to be monitored for signs of liver disease progression. To this end, the ...identification of both disease biomarkers and therapeutic targets is necessary.
Extracellular vesicles (EVs) purified from plasma of 15 healthy donors (HDs), and 16 HCV-infected patients before (T0) and after (T6) DAA treatment were utilized for functional and miRNA cargo analysis. EVs purified from plasma of 17 HDs and 23 HCV-infected patients (T0 and T6) were employed for proteomic and western blot analyses. Functional analysis in LX2 cells measured fibrotic markers (mRNAs and proteins) in response to EVs. Structural analysis was performed by qPCR, label-free liquid chromatography-mass spectrometry and western blot.
On the basis of observations indicating functional differences (i.e. modulation of FN-1, ACTA2, Smad2/3 phosphorylation, collagen deposition) of plasma-derived EVs from HDs, T0 and T6, we performed structural analysis of EVs. We found consistent differences in terms of both miRNA and protein cargos: (i) antifibrogenic miR204-5p, miR181a-5p, miR143-3p, miR93-5p and miR122-5p were statistically underrepresented in T0 EVs compared to HD EVs, while miR204-5p and miR143-3p were statistically underrepresented in T6 EVs compared to HD EVs (p <0.05); (ii) proteomic analysis highlighted, in both T0 and T6, the modulation of several proteins with respect to HDs; among them, the fibrogenic protein DIAPH1 was upregulated (Log2 fold change of 4.4).
Taken together, these results highlight structural EV modifications that are conceivably causal for long-term liver disease progression in patients with HCV despite DAA-mediated SVR.
Direct-acting antivirals lead to virological cure in the majority of patients with chronic hepatitis C virus infection. However, the risk of liver disease progression or complications in patients with fibrosis and cirrhosis remains in some patients even after virological cure. Herein, we show that extracellular vesicle modifications could be linked to long-term liver disease progression in patients who have achieved virological cure; these modifications could potentially be used as biomarkers or treatment targets in such patients.
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•HCV T0/T6 EVs have been functionally and structurally compared to HD EVs.•HD EVs ameliorate LX2 cells’ fibrogenic phenotype while HCV T0/T6 EVs do not.•HCV T0/T6 EVs contain lower levels of antifibrogenic miRNAs compared to HD EVs.•HCV T0/T6 EVs’ cargo is enriched in profibrogenic proteins (e.g. DIAPH1).•SVR does not restore antifibrogenic cargo and activity in HCV EVs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Amyotrophic lateral sclerosis (ALS) is an adult devastating neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), resulting in progressive paralysis and death. ...Genetic animal models of ALS have highlighted dysregulation of synaptic structure and function as a pathogenic feature of ALS-onset and progression. Alternative pre-mRNA splicing (AS), which allows expansion of the coding power of genomes by generating multiple transcript isoforms from each gene, is widely associated with synapse formation and functional specification. Deciphering the link between aberrant splicing regulation and pathogenic features of ALS could pave the ground for novel therapeutic opportunities. Herein, we found that neural progenitor cells (NPCs) derived from the hSOD1
mouse model of ALS displayed increased proliferation and propensity to differentiate into neurons. In parallel, hSOD1
NPCs showed impaired splicing patterns in synaptic genes, which could contribute to the observed phenotype. Remarkably, master splicing regulators of the switch from stemness to neural differentiation are de-regulated in hSOD1
NPCs, thus impacting the differentiation program. Our data indicate that hSOD1
mutation impacts on neurogenesis by increasing the NPC pool in the developing mouse cortex and affecting their intrinsic properties, through the establishment of a specific splicing program.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Hereditary hemorrhagic teleangectasia (HHT, or Rendu-Osler-Weber disease) is a rare inherited syndrome, characterized by arterio-venous malformations (AVMs or Telangiectasia). The most important and ...common manifestation is nose bleeds (epistaxis). The telangiectasias (small AVMs) are most evident on the lips, tongue, buccal mucosa, face, chest, and fingers, however; large arterio-venous malformations can also occur in the lungs, liver, pancreas, or brain. Telangiectasias in the upper gastrointestinal tract are known to occur, however data regarding possible small-bowel involvement is limited due to technical difficulties in visualizing the entire gastrointestinal tract. The occurrence of AVMs in the stomach and small bowel can result in chronic bleeding and anaemia. Less frequently, this may occur due to bleeding from oesophageal varices, as patients with HHT can develop hepatic parenchymal AVMs or vascular shunts which cause hepatic cirrhosis and portal hypertension. Gastroenterologists have a crucial role in the management of these patients, however difficulties remain in the detection and management of complications of HHT in the gastrointestinal tract.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
: Emergency Department (ED) overcrowding is a health, political, and economic problem of concern worldwide. The causes of overcrowding are an aging population, an increase in chronic diseases, a lack ...of access to primary care, and a lack of resources in communities. Overcrowding has been associated with an increased risk of mortality. The establishment of a Short Stay Unit (SSU) for conditions that cannot be treated at home but require treatment and hospitalization for up to 72 h may be a solution. SSU can significantly reduce hospital length of stay (LOS) for certain conditions but does not appear to be useful for other diseases. Currently, there are no studies addressing the efficacy of SSU in the treatment of non-variceal upper gastrointestinal bleeding (NVUGIB). Our study aims to evaluate the efficacy of SSU in reducing the need for hospitalization, LOS, hospital readmission, and mortality in patients with NVUGIB compared with admission to the regular ward.
: This was a retrospective, single-center observational study. Medical records of patients presenting with NVUGIB to ED between 1 April 2021, and 30 September 2022, were analyzed. We included patients aged >18 years who presented to ED with acute upper gastrointestinal tract blood loss. The test population was divided into two groups: Patients admitted to a normal inpatient ward (control) and patients treated at SSU (intervention). Clinical and medical history data were collected for both groups. The hospital LOS was the primary outcome. Secondary outcomes were time to endoscopy, number of blood units transfused, readmission to the hospital at 30 days, and in-hospital mortality.
: The analysis included 120 patients with a mean age of 70 years, 54% of whom were men. Sixty patients were admitted to SSU. Patients admitted to the medical ward had a higher mean age. The Glasgow-Blatchford score, used to assess bleeding risk, mortality, and hospital readmission were similar in the study groups. Multivariate analysis after adjustment for confounders found that the only factor independently associated with shorter LOS was admission to SSU (
< 0.0001). Admission to SSU was also independently and significantly associated with a shorter time to endoscopy (
< 0.001). The only other factor associated with a shorter time to EGDS was creatinine level (
= 0.05), while home treatment with PPI was associated with a longer time to endoscopy. LOS, time to endoscopy, number of patients requiring transfusion, and number of units of blood transfused were significantly lower in patients admitted to SSU than in the control group.
: The results of the study show that treatment of NVUGIB in SSU can significantly reduce the time required for endoscopy, the hospital LOS, and the number of transfused blood units without increasing mortality and hospital readmission. Treatment of NVUGIB at SSU may therefore help to reduce ED overcrowding but multicenter randomized controlled trials are needed to confirm these data.
Background: Gastrointestinal bleeding (GIB) is one of most frequent and significant challenges for emergency physicians and gastroenterologists. Mortality for upper (U) GIB is high, especially in the ...elderly and comorbid patients. However, there is scant evidence in the literature concerning an assessment of warfarin (VKA) and direct oral anticoagulants (DOACs) in terms of upper gastrointestinal bleeding (UGIB) severity. Aims: Using data from two different settings (Italy and the UK), we aimed to compare the impact of VKA and DOACs on the severity of UGIB. Methods: Retrospective bicentric study on adult patients under VKA or DOACs admitted either to the emergency department at the Gemelli Hospital in Rome, Italy or University College Hospital in London, UK, with suspected UGIB from 01/01/2017 to 31/12/2018. Univariate analysis with Fisher’s exact test, and analysis of variance (ANOVA) were used. Results: 106 patients (62 M/44 F; mean age 71.2 ± 16.9 yrs) were enrolled and divided into the VKA group (N = 57; M: 56%, mean age: 64.9 ± 21.3 yrs) and the DOAC group (N = 49; M: 61%; mean age: 77.6 ± 12.5 yrs). At univariate analysis, the VKA group presented two endoscopic diagnoses more frequently than the DOAC group (26% vs. 8%, p < 0.05), were more frequently endoscopically treated (44% vs. 22%, p < 0.05), rescoped (12% vs. 2%, p = 0.048) and hospitalized (79% vs. 53%, p = 0.01) with a longer length of stay, LOS (VKA: 58% > 5 days vs. DOAC: 68% < 5 days, p = 0.01). There was no difference in terms of hemoglobin level on admission, however the requirement of blood transfusions was higher in the VKA group (60% vs. 41%, p = 0.041). One third of the VKA group showed a lower platelet count than the DOAC group (33% vs. 8%, p = 0.01). No statistically significant differences for in-hospital mortality were observed. For the ANOVA, the type of anticoagulant used was the only significant predictor of need to rescope (p = 0.041) and a significant co-predictor for a LOS > 5 days (p = 0.009; as well as cirrhosis, p = 0.013 and age, p = 0.005). Conclusions: Our outcomes revealed a more severe UGIB in patients on VKA, but the impact of comorbidities (i.e., more cirrhotic patients in the VKA group) cannot be disregarded. DOAC subgroup descriptive analysis, even though on a little cohort, showed higher bleeding severity for rivaroxaban.
The meaning of inclusion is complex and related to every form of diversity; it needs to be defined in broad horizons, within and beyond the school context, with the aim of overcoming all forms of ...exclusion and discrimination. The concept of inclusive education concerns proper and appropriately agreed terminology and meanings expressed in the 2006 UN Convention ratifying the need of recognizing the same rights for all individuals, as human beings, beyond stigma and categorising labels. In this article we examine the Italian and Lithuanian inclusive systems, within the paradigm of social constructivism and the contribution of both national and international scientific literature referring to bio-psycho-social pedagogical meanings. In order to reveal the developments towards inclusive education in two countries contexts, the methodology of this article is based on the relevant literature, document and research reports review.
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