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While the International Classification of Functioning, Disability, and Health (ICF) has significantly contributed to educational research supporting inclusive initiatives worldwide, its application in special education contexts across the African continent remains unclear. This study aims to explore how the ICF is currently used in the field of education in Africa, with an emphasis on children with disabilities, although not restricted to this group. The Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) diagram shows that the 11 African-specific databases that were searched yielded 256 records. These records were uploaded to Rayyan, an online collaborative review platform. First, 158 duplicates were removed. Following title and abstract level screening, six records were eligible at full-text level, of which four were excluded, as they focused on the health context. The findings from the remaining two studies were compared and discussed in terms of similarities and differences. Both articles addressed the interactive nature between an individual's activities and participation and environmental factors, agreeing on the importance of addressing societal barriers to inclusion. The use of the ICF in educational settings across Africa is still scarce, thus requiring strategies that could drive inclusive education for children with disabilities on the African continent. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer and is expected to soon become the second leading cause of cancer-associated death. The high mortality rate is due to the clinical features that allow asymptomatic progression to advanced stages, a period when current therapeutic treatments have limited efficacy. To address these challenges, researchers are focused on identifying new molecular and circulating markers for early PDAC detection and precision medicine. In this mini-review, we report the most well-known and recently identified molecular and circulating biomarkers. This study aimed to emphasize the need for continued innovative research to develop diagnostic algorithms and therapies to improve the management of patients with PDAC. [ABSTRACT FROM AUTHOR]

Simple Summary: Protein Induced by Vitamin K Absence (PIVKA II), also known as Des-γ-Carboxy prothrombin (DCP), is an established tumor marker for hepatocellular carcinoma (HCC) and a good diagnostic performance has also been demonstrated for Pancreatic Ductal Adenocarcinoma (PDAC). Circulating PIVKA II has been recently associated in vitro with epithelial-to-mesenchymal transition (EMT) activation in pancreatic origin cells PANC-1. The aim of this manuscript is to investigate whether this association is also detectable in vivo. The matter of this research lies in the fact that the diagnostic performance of PIVKA II in PDAC, along with its association with the EMT program, suggests that this molecule could be considered an indirect indicator of EMT and, therefore, a marker of the acquisition of an aggressive phenotype. "Background/Aim": the current inability to diagnose Pancreatic Cancer Adenocarcinoma (PDAC) at an early stage strongly influences therapeutic strategies. Protein Induced by Vitamin K Absence (PIVKA II) showed an accurate diagnostic performance for PDAC. Since circulating PIVKA II has been recently associated with pancreatic origin cells with Vimentin, an epithelial-to-mesenchymal transition (EMT) early activation marker, the aim of this study was to investigate in vivo the combination between the two proteins. "Materials and Methods": we assayed the presence of PIVKA II and Vimentin proteins by using different diagnostic methods. A total of 20 PDAC patients and 10 healthy donors were tested by Western Blot analysis; 74 PDAC patient and 46 healthy donors were assayed by ECLIA and Elisa. "Results": Western Blot analysis showed the concomitant expression of PIVKA II and Vimentin in PDAC patient sera. Immunometric assay performed on a larger cohort of patients demonstrated that 72% of PIVKA II-positive PDAC patients were Vimentin-positive. Additionally, in a group of PDAC patients with PIVKA II levels ≥2070 ng/mL, the percentage of Vimentin-positive subjects reached 84%. "Conclusion": the association between PIVKA II protein and the EMT suggests that this molecule could be considered a marker of the acquisition of an aggressive phenotype. [ABSTRACT FROM AUTHOR]

Aims: Inherited or somatic mutations in the MRE11, RAD50 and NBN genes increase the incidence of tumours, including medulloblastoma (MB). On the other hand, MRE11, RAD50 and NBS1 protein components of the MRN complex are often overexpressed and sometimes essential in cancer. In order to solve the apparent conundrum about the oncosuppressive or oncopromoting role of the MRN complex, we explored the functions of NBS1 in an MB‐prone animal model. Materials and methods: We generated and analysed the monoallelic or biallelic deletion of the Nbn gene in the context of the SmoA1 transgenic mouse, a Sonic Hedgehog (SHH)‐dependent MB‐prone animal model. We used normal and tumour tissues from these animal models, primary granule cell progenitors (GCPs) from genetically modified animals and NBS1‐depleted primary MB cells, to uncover the effects of NBS1 depletion by RNA‐Seq, by biochemical characterisation of the SHH pathway and the DNA damage response (DDR) as well as on the growth and clonogenic properties of GCPs. Results: We found that monoallelic Nbn deletion increases SmoA1‐dependent MB incidence. In addition to a defective DDR, Nbn+/− GCPs show increased clonogenicity compared to Nbn+/+ GCPs, dependent on an enhanced Notch signalling. In contrast, full NbnKO impairs MB development both in SmoA1 mice and in an SHH‐driven tumour allograft. Conclusions: Our study indicates that Nbn is haploinsufficient for SHH‐MB development whereas full NbnKO is epistatic on SHH‐driven MB development, thus revealing a gene dosage‐dependent effect of Nbn inactivation on SHH‐MB development. [ABSTRACT FROM AUTHOR]

Individual educational planning (IEP) in inclusive settings in mainstream schools is a challenging task that needs the multi-professional cooperation of teachers, parents and specialists for special educational needs (SEN). This article describes ongoing research and the concepts and tools developed so far for multi-professional IEP on the basis of the international classification of functioning, disability and health (ICF) in inclusive settings in Switzerland. The aim of the research reported in this overview is to describe and analyse the process of IEP on both theoretical and practical levels, to understand its impacts on inclusive special education and to develop useful instruments and tools to support the professionals involved in IEP. As current findings, the importance and role of useful diagnostic information and meaningful goal setting in IEP is emphasised and tools supporting a multi-professional IEP-process are presented. [ABSTRACT FROM AUTHOR]

Cell proliferation is a metabolically demanding process. It requires active reprogramming of cellular bioenergetic pathways towards glucose metabolism to support anabolic growth. NF-?B/Rel transcription factors coordinate many of the signals that drive proliferation during immunity, inflammation and oncogenesis, but whether NF-?B regulates the metabolic reprogramming required for cell division during these processes is unknown. Here, we report that NF-?B organizes energy metabolism networks by controlling the balance between the utilization of glycolysis and mitochondrial respiration. NF-?B inhibition causes cellular reprogramming to aerobic glycolysis under basal conditions and induces necrosis on glucose starvation. The metabolic reorganization that results from NF-?B inhibition overcomes the requirement for tumour suppressor mutation in oncogenic transformation and impairs metabolic adaptation in cancer in vivo. This NF-?B-dependent metabolic pathway involves stimulation of oxidative phosphorylation through upregulation of mitochondrial synthesis of cytochrome c oxidase 2 (SCO2; ref. ). Our findings identify NF-?B as a physiological regulator of mitochondrial respiration and establish a role for NF-?B in metabolic adaptation in normal cells and cancer. [ABSTRACT FROM AUTHOR]

There is a lack of knowledge on the possible influence of systemic conditions on peri-implantitis. The aim of this case-control study is to evaluate the difference in terms of oral pathogens' concentrations in the peri-implant sulcus of a group of patients affected by metabolic syndrome (Mets) compared to healthy subjects. For each patient, peri-implant sulcular biofilm samples were obtained by inserting two sterile endodontic paper points in the deepest aspect of the peri-implant sulcus for 30 s. The quantitative real-time polymerase chain reaction was performed to evaluate total bacterial counts of six pathogens. Patients were screened for peri-implant diseases and clinical and radiographic parameters were recorded. A total of 50 patients was enrolled in the study, 25 affected by Mets and 25 healthy. Significantly higher bacterial counts were discovered for Aggregatibacter actinomycetemcomitans (p = 0.0008), Prevotella intermedia (p = 0.0477) and Staphylococcus aureus (p = 0.034) in MetS patients compared to healthy subjects. Performing a sub-group analysis, considering peri-implant status and dividing patients by MetS diagnosis, no statistically significant (p < 0.05) differences were found. For the first time, a correlation between MetS presence and a greater prevalence of some bacterial species in the peri-implant sulcus was reported, irrespectively from peri-implant status (health vs. disease). [ABSTRACT FROM AUTHOR]

An obituary is presented for Cesare Moretti, a glassmaker and researcher and president of Italian committee of the Association Internationale pour l’Histoire du Verre (AIHV).

Pharmacological Hedgehog (Hh) pathway inhibition has emerged as a valuable anticancer strategy. A number of small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector glioma-associated oncogene 1 (Gli1) has been designed and developed. In a recent study, we exploited the high versatility of the natural isoflavone scaffold for targeting the Hh signaling pathway at multiple levels showing that the simultaneous targeting of Smo and Gli1 provided synergistic Hh pathway inhibition stronger than single administration. This approach seems to effectively overcome the drug resistance, particularly at the level of Smo. Here, we combined the pharmacophores targeting Smo and Gli1 into a single and individual isoflavone, compound 22, which inhibits the Hh pathway at both upstream and downstream level. We demonstrate that this multitarget agent suppresses medulloblastoma growth in vitro and in vivo through antagonism of Smo and Gli1, which is a novel mechanism of action in Hh inhibition. [ABSTRACT FROM AUTHOR]

Development of the cerebellum is characterized by rapid proliferation of cerebellar granule cell precursors (GCPs) induced by paracrine stimulation of Sonic hedgehog (Shh) signaling from Purkinje cells, in the external granular layer (EGL). Then, granule cell precursors differentiate and migrate into the inner granular layer (IGL) of the cerebellum to form a terminally differentiated cell compartment. Aberrant activation of Sonic hedgehog signaling leads to granule cell precursors hyperproliferation and the onset of Sonic hedgehog medulloblastoma (MB), the most common embryonal brain tumor. β-arrestin1 (ARRB1) protein plays an important role downstream of Smoothened, a component of the Sonic hedgehog pathway. In the medulloblastoma context, β-arrestin1 is involved in a regulatory axis in association with the acetyltransferase P300, leading to the acetylated form of the transcription factor E2F1 (E2F1-ac) and redirecting its activity toward pro-apoptotic gene targets. This axis in the granule cell precursors physiological context has not been investigated yet. In this study, we demonstrate that β-arrestin1 has antiproliferative and pro-apoptotic functions in cerebellar development. β-arrestin1 silencing increases proliferation of Sonic hedgehog treated-cerebellar precursor cells while decreases the transcription of E2F1-ac pro-apoptotic targets genes, thus impairing apoptosis. Indeed, chromatin immunoprecipitation experiments show a direct interaction between β-arrestin1 and the promoter regions of the pro-apoptotic E2F1 target gene and P27 , indicating the double role of β-arrestin1 in controlling apoptosis and cell cycle exit in a physiological context. Our data elucidate the role of β-arrestin1 in the early postnatal stages of cerebellar development, in those cell compartments that give rise to medulloblastoma. This series of experiments suggests that the physiological function of β-arrestin1 in neuronal progenitors is to directly control, cooperating with E2F1 acetylated form, transcription of pro-apoptotic genes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Abballe, Alfano, Antonacci, Cefalo, Cacchione, Del Baldo, Pezzullo, Po, Moretti, Mastronuzzi, De Smaele, Ferretti, Locatelli and Miele.)

Contrasting evidence is present regarding the contribution of stem/progenitor cell populations to pancreatic regeneration in diabetes. Interestingly, a cell compartment with stem/progenitor cell features has been identified in the pancreatic duct glands (PDGs). The aims of the present study were to evaluate pancreatic islet injury and regeneration, and the participation of the PDG compartment in type 2 diabetic mellitus (T2DM) and in an experimental model of diabetes. Human pancreata were obtained from normal (N = 5) or T2DM (N = 10) cadaveric organ donors. Experimental diabetes was generated in mice by intraperitoneal injection of 150 mg/kg of streptozotocin (STZ, N = 10); N = 10 STZ mice also received daily intraperitoneal injections of 100 µg of human recombinant PDX1 peptide (STZ + PDX1). Samples were examined by immunohistochemistry/immunofluorescence or RT-qPCR. Serum glucose and c-peptide levels were measured in mice. Islets in T2DM patients showed β-cell loss, signs of injury and proliferation, and a higher proportion of central islets. PDGs in T2DM patients had a higher percentage of proliferating and insulin + or glucagon + cells compared to controls; pancreatic islets could be observed within pancreatic duct walls of T2DM patients. STZ mice were characterized by reduced islet area compared to controls. PDX1 treatment increased islet area and the percentage of central islets compared to untreated STZ mice but did not revert diabetes. In conclusion, T2DM patients show signs of pancreatic islet regeneration and involvement of the PDG niche. PDX1 administration could support increased endocrine pancreatic regeneration in STZ. These findings contribute to defining the role and participation of stem/progenitor cell compartments within the pancreas., Competing Interests: The Italian Federation of Juvenile Diabetes (FDG) holds a patent related to the recombinant Pdx1 utilized in this study. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Overi, Carpino, Moretti, Franchitto, Nevi, Onori, De Smaele, Federici, Santorelli, Maroder, Reid, Cardinale, Alvaro and Gaudio.)

MYCN drives aggressive behavior and refractoriness to chemotherapy, in several tumors. Since MYCN inactivation in clinical settings is not achievable, alternative vulnerabilities of MYCN-driven tumors need to be explored to identify more effective and less toxic therapies. We previously demonstrated that PARP inhibitors enhance MYCN-induced replication stress and promote mitotic catastrophe, counteracted by CHK1. Here, we showed that PARP and CHK1 inhibitors synergized to induce death in neuroblastoma cells and in primary cultures of SHH-dependent medulloblastoma, their combination being more effective in MYCN amplified and MYCN overexpressing cells compared to MYCN non-amplified cells. Although the MYCN amplified IMR-32 cell line carrying the p.Val2716Ala ATM mutation showed the highest sensitivity to the drug combination, this was not related to ATM status, as indicated by CRISPR/Cas9-based correction of the mutation. Suboptimal doses of the CHK1 inhibitor MK-8776 plus the PARP inhibitor olaparib led to a MYCN-dependent accumulation of DNA damage and cell death in vitro and significantly reduced the growth of four in vivo models of MYCN-driven tumors, without major toxicities. Our data highlight the combination of PARP and CHK1 inhibitors as a new potential chemo-free strategy to treat MYCN-driven tumors, which might be promptly translated into clinical trials., (© 2021. The Author(s).)

The Hedgehog (Hh) signaling pathway plays a crucial role in normal embryonic development and adult tissue homeostasis. On the other end, dysregulated Hh signaling triggers a prolonged mitogenic response that may prompt abnormal cell proliferation, favoring tumorigenesis. Indeed, about 30% of medulloblastomas (MBs), the most common malignant childhood cerebellar tumors, exhibit improper activation of the Hh signaling. The oncosuppressor KCASH2 has been described as a suppressor of the Hh signaling pathway, and low KCASH2 expression was observed in Hh-dependent MB tumor. Therefore, the study of the modulation of KCASH2 expression may provide fundamental information for the development of new therapeutic approaches, aimed to restore physiological KCASH2 levels and Hh inhibition. To this end, we have analyzed the TATA-less KCASH2 proximal promoter and identified key transcriptional regulators of this gene: Sp1, a TF frequently overexpressed in tumors, and the tumor suppressor p53. Here, we show that in WT cells, Sp1 binds KCASH2 promoter on several putative binding sites, leading to increase in KCASH2 expression. On the other hand, p53 is involved in negative regulation of KCASH2. In this context, the balance between p53 and Sp1 expression, and the interplay between these two proteins determine whether Sp1 acts as an activator or a repressor of KCASH2 transcription. Indeed, in p53 -/- MEF and p53 mutated tumor cells, we hypothesize that Sp1 drives promoter methylation through increased expression of the DNA methyltransferase 1 (DNMT1) and reduces KCASH2 transcription, which can be reversed by Sp1 inhibition or use of demethylating agents. We suggest therefore that downregulation of KCASH2 expression in tumors could be mediated by gain of Sp1 activity and epigenetic silencing events in cells where p53 functionality is lost. This work may open new venues for novel therapeutic multidrug approaches in the treatment of Hh-dependent tumors carrying p53 deficiency., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Angrisani, Di Fiore, Di Trani, Fonte, Petroni, Lospinoso Severini, Bordin, Belloni, Ferretti, Canettieri, Moretti and De Smaele.)

Target gene silencing is a strategy that can be used to turn off pathways or genes which are difficult to turn off pharmacologically, both because of lack of targeting drugs, or because of the risk of wider off-target effects. Here we describe the design and use of short hairpin RNA (ShRNA) and lentiviral vectors as an efficient technique for silencing NF-kappaB (NF-κB) pathway in cultured cells. This method can be used also in hard to transfect primary cell cultures.

Numb is an intracellular protein with multiple functions. The two prevalent isoforms, Numb p66 and Numb p72, are regulators of differentiation and proliferation in neuronal development. Additionally, Numb functions as cell fate determinant of stem cells and cancer stem cells and its abnormal expression has been described in several types of cancer. Involvement of deregulated Numb expression has been described in the malignant childhood brain tumor medulloblastoma, while Numb isoforms in these tumors and in cancer stem-like cells derived from them, have not been studied to date. Here we show that medulloblastoma stem-like cells and cerebellar neuronal stem cells (NSCs) express Numb p66 where its expression tampers stemness features. Furthermore, medulloblastoma samples evaluated in this study express decreased levels of Numb p66 while overexpressed Numb p72 compared with normal tissues. Our results uncover different roles for the two major Numb isoforms examined in medulloblastoma and a critical role for Numb p66 in regulating stem-like cells and NSCs maintenance.

Cerebellar neural stem cells (NSCs) require Hedgehog-Gli (Hh-Gli) signalling for their maintenance and Nanog expression for their self-renewal. To identify novel molecular features of this regulatory pathway, we used next-generation sequencing technology to profile mRNA and microRNA expression in cerebellar NSCs, before and after induced differentiation (Diff-NSCs). Genes with higher transcript levels in NSCs (vs. Diff-NSCs) included Foxm1, which proved to be directly regulated by Gli and Nanog. Foxm1 in turn regulated several microRNAs that were overexpressed in NSCs: miR-130b, miR-301a, and members of the miR-15~16 and miR-17~92 clusters and whose knockdown significantly impaired the neurosphere formation ability. Our results reveal a novel Hh-Gli-Nanog-driven Foxm1-microRNA network that controls the self-renewal capacity of NSCs.

This article presents the outcome of a systematic literature review exploring the applicability of the International Classification of Functioning, Disability, and Health (ICF) and its Children and Youth version (ICF-CY) at various levels and in processes within the education systems in different countries. A systematic database search using selected search terms has been used. The selection of studies was then refined further using four protocols: inclusion and exclusion protocols at abstract and full text and extraction levels along with a quality protocol. Studies exploring the direct relationship between education and the ICF/ICF-CY were sought.As expected, the results show a strong presence of studies from English-speaking countries, namely from Europe and North America. The articles were mainly published in noneducational journals. The most used ICF/ICF-CY components are activity and participation, participation, and environmental factors. From the analysis of the papers included, the results show that the ICF/ICF-CY is currently used as a research tool, theoretical framework, and tool for implementing educational processes. The ICF/ICF-CY can provide a useful language to the education field where there is currently a lot of disparity in theoretical, praxis, and research issues. Although the systematic literature review does not report a high incidence of the use of the ICF/ICF-CY in education, the results show that the ICF/ICF-CY model and classification have potential to be applied in education systems.

In developed countries, establishing eligibility for persons with disabilities is a requirement for accessing specialized services or benefits. The underlying conceptualizations of disability are often problematic because they concentrate on deficits but try to promote social participation and focus on dependence while trying to strengthen independence. In addition, such conceptualizations are unable to respond to the rights-based approach of the UN Convention on the Rights of Persons with Disabilities. The International Classification of Functioning, Disability and Health Version for Children and Youth provides a model and classification that allows relating disease- or impairment-specific information to participation in the life domains relevant for a specific policy area. Establishing eligibility in education systems needs to be compatible with the principles of inclusive education, participation, and social justice. In addition, the overall goals of education and individualized goals for a specific child with disabilities need to be taken into account. Using the International Classification of Functioning, Disability and Health Version for Children and Youth as a model and classification, the different factors influencing eligibility-related decisions (impairments, activity/participation, environment, personal factors) can be made transparent to provide the basis for a decision-making process to which parents and the child actively contribute.