ABSTRACT
Diverse mechanisms have been established to understand the chemoresistance of hepatocellular carcinoma (HCC), but the contribution of non-coding RNAs is not surveyed well. Here, we aimed to explore the lncRNA-miRNA axis in Hepatitis C and B virus (HCV and HBV) infected HCC to investigate the molecular mechanism of chemoresistance and to identify a potential therapeutic target for HCC. The small RNA transcriptome analysis followed by qRT-PCR validation with the liver tissues of both HCV and HBV infected HCC patients revealed that miR-424-5p, miR-136-3p, miR-139-5p, miR-223-3p, and miR-375-3p were the most downregulated miRNAs in HCC compared to normal (log2 fold change ≤-1.5, Padj ≤ 0.05). In silico pathway analysis with the validated targets of each miRNA revealed that the signalling pathway regulating pluripotency of stem cells is commonly targeted by these five miRNAs. Subsequent validation by 3'UTR-luciferase assay and western blot analysis unveiled that these five miRNAs impeded either same or diverse genes, but all linked to BMP signalling pathway such as BMPR1A/BMPR1B by miR-139-5p, miR-136-3p, and miR-375-3p, and ACVR2A/ACVR2B by miR-424-5p and miR-223-3p. Furthermore, restoration of each miRNA in Huh7/SNU449 cells inhibited phosphorylation of downstream SMAD1/5 and ERK1/2, and attenuated Epithelial-mesenchymal transition, stemness, spheroid formation, chemoresistance, invasion and migration of cells. To investigate the mechanism of suppression of these miRNAs, "DIANA" tool was employed and lncRNA-KCNQ1OT1 was retrieved as interacting partner of all the five miRNAs. In vitro RNA pull-down assay revealed that lncRNA-KCNQ1OT1 physically interacted and sequestered these five miRNAs in the cytoplasm. Hence, KCNQ1OT1 was suppressed in Huh7/SNU449 cells using CRISPR technology and observed regression of oncogenic properties with enhanced chemosensitivity and reduced metastasis in cancer cells. Shrinkage of tumour size and volume in NOD-SCID mice injected with KCNQ1OT1-sgRNA cells further strengthened our observations. Thus, lncRNA-KCNQ1OT1 is the main regulator, which reduces the level of beneficiary miRNAs in the tumour milieu and modulates BMP signalling pathway to promote chemoresistance in HCC, suggesting lncRNA-KCNQ1OT1 might have robust potential to be a therapeutic target in HCC.
ABSTRACT
Background: In the Asia-Pacific region, around one-third of the children who are out-of-school have a disability and given that teacher readiness and capability are key contributors for inclusive education, it is high time for a mapping of disability inclusive teacher professional development (TPD) interventions in this region. Objectives: The key objective of this evidence and gap map (EGM) is to locate evidence on interventions for in-service TPD focussing on education for the inclusion of students with a disability in low- and middle-income countries (LMICs) in the Asia-Pacific region. Search Methods: A broad range of bibliographic databases and repositories were searched electronically to identify the evidence published between January 2000 and December 2021. Key search platforms included the British Education Index (BEI), Education Research Complete (ERC), Education Resources Information Center (ERIC), SCOPUS, 3ie Development Evidence Portal (Evidence Hub) and the Campbell Collaborations Systematic Reviews and EGMs portal (Better evidence for a better world). In addition, potential program evaluations/impact reports, reviews, case studies, and program descriptions/summaries were sought through 'snowballing' based on searching bibliographies and reference lists of papers located during the search process, as well as specific searches of relevant grey literature. Selection Criteria: To be eligible for inclusion, studies had to contain sufficient details about TPD interventions that support early childhood educators and kindergarten to Year 12 teachers to understand the needs of students with disabilities and aid them to create inclusive mainstream classrooms and/or provide improved support for students with disabilities in special education settings. Data Collection and Analysis: A total of 820 records were entered into the MS Excel file in which the entire data extraction process was managed. All records were screened against the predefined inclusion and exclusion criteria. Data were extracted independently by two reviewers and any differences were resolved through consultations. All included studies and their characteristics were extracted from the MS Excel file and uploaded to the ACER server in.csv file format. The interactive, online EGM is available here: https://datavis.acer.org/gem/disability-inclusion-TPD/. Main Results: Fifty studies from 16 countries out of the 41 LMICs in the Asia-Pacific region were identified, whereby Thailand had the largest number of studies with evidence (7) followed by China, Vietnam, and India (5 each). Two main gaps in research about professional learning were identified. First, only three studies reported interventions aimed at supporting mental health among students with a disability. Second, no studies were found that reported on how teachers could support positive student behaviour. These gaps are important because research has persistently suggested that experiencing disability is an important risk factor for young people developing mental health conditions. Authors' Conclusions: This report illustrates the critical value of evaluating and publishing evidence from disability inclusive TPD interventions in LMICs, including any that are ongoing, or are components of highly resource intensive large-scale education sector programs.
ABSTRACT
Hepatitis B virus (HBV) infection has a multi-dimensional effect on the host, which not only alters the dynamics of immune response but also persists in the hepatocytes to predispose oncogenic factors. The virus exists in multiple forms of which the nuclear localized covalently closed circular DNA (cccDNA) is the most stable and the primary reason for viral persistence even after clearance of surface antigen and viral DNA. The second reason is the existence of pregenomic RNA (pgRNA) containing virion particles. On the other hand, the integration of the viral genome in the host chromosome also leads to persistent production of viral proteins along with the chromosomal instabilities. The interferon treatment or administration of nucleot(s)ide analogs leads to reduction in the viral DNA load, but the pgRNA and surface antigen clearance are a slow process and complete loss of serological HBsAg is rare. The prolonged exposure of immune cells to the viral antigens, particularly HBs antigen, in the blood circulation results in T-cell exhaustion, which disrupts immune clearance of the virus and virus-infected cells. In addition, it predisposes immune-tolerant microenvironment, which facilitates the tumor progression. Thus cccDNA, pgRNA, and HBsAg along with the viral DNA could be the therapeutic targets in the early disease stages that may improve the quality of life of chronic hepatitis B patients by impeding the progression of the disease toward hepatocellular carcinoma.
ABSTRACT
According to prior research, teacher readiness and capability are key contributors for successful transition towards disability inclusive education, yet in-service teacher professional development for disability inclusion remains an under-researched area. The key objective of this evidence and gap map (EGM) is to locate evidence on interventions for disability inclusion focused teacher professional development (TPD) in low-to-middle-income-countries (LMICs) in the Asia-Pacific region. As such, it will illustrate different levels of evidence for TPD interventions as well as where there is no evidence (i.e., gaps). In other words, the EGM can make agencies aware where they might be operating in an area that is evidence-free or evidence-weak so they can take up interventions that are evidence-based or collect evidence for the intervention they are presently supporting. Thus, the ultimate goal for the EGM is to assist funders and implementing agencies when making decisions as to how to support LMICs in the region to reach their aim of developing quality teachers for the global inclusive education agenda (target SDG 4.c).
