Teacher’s role in early identification of developmental delays

Rama*, two and a half-years-old, is the second of three siblings. Her parents cultivate vegetables on a farm on the outskirts of Bengaluru. A neighbourhood alternative school enrolled her and her elder sister in school. Her parents had begun to realize that there was some kind of hearing loss Rama was experiencing. However, their hope to see her develop as all other children led them to believe that she was one of those who would develop oral language a little later than usual. Rama’s family represents a culture where there is little or no conversation among adults and children. Conversations, if at all, are more functional in nature

Novel Role of ErbB-2 in Inhibition of Jagged-1-Mediated Trans-Activation of Notch in Breast Cancer

The ErbB-2 gene is amplified and the resulting protein product overexpressed in 15-30% of breast tumors, and associated with aggressive behavior and poor overall survival. Currently, there are two FDA approved therapies targeting ErbB-2 for the treatment of ErbB-2 positive breast cancer: trastuzumab, a humanized monoclonal antibody is directed against the extracellular domain of ErbB-2 and lapatinib, a dual EGFR/ErbB-2 tyrosine kinase inhibitor. Unfortunately, anti-ErbB-2 therapy resistance remains a major problem in metastatic breast cancer. Our data suggested that gene amplification or overexpression of ErbB-2 inhibits Notch-1 transcriptional activity and trastuzumab or lapatinib increased Notch-1 transcriptional activity. Furthermore, Notch-1 is a breast oncogene and a novel target for the treatment of trastuzumab resistant ErbB-2 positive breast cancer in vitro. The Notch-1 receptor is overexpressed with its ligand Jagged-1 in breast cancers with the poorest overall survival. We showed that ErbB-2 inhibition activates Notch-1 which results in a compensatory increase in Notch-1-mediated proliferation. However, we do not yet know the mechanism by which ErbB-2 overexpression suppresses Notch-1 activity and whether inhibition of Notch-1 would reverse resistance to trastuzumab in vivo. Our results demonstrated that trastuzumab or lapatinib treatment of SKBr3 cells increased the cell surface protein expression of Jagged-1 by flow cytometry and cell surface biotinylation. Moreover, confocal studies indicated that Jagged-1 and Notch-1 co-localized possibly in early endosomal antigen-1 (EEA-1) positive vesicles. However, upon treatment with trastuzumab, Jagged-1 and Notch-1 don\u27t co-localize. Jagged-1 is present at the plasma membrane and Notch-1 is distributed throughout the cell. In SKBr3 and MCF-7/HER-2 breast cancer cells, ErbB-2 stabilizes the protein levels of Jagged-1. We demonstrated for the first time that Jagged-1 inhibits Notch in cis. More interestingly, ErbB-2 prevents Jagged-1-mediated trans-activation of Notch signaling by limiting the association of Jagged-1 and Mib-1 and subsequent ubiquitylation of Jagged-1. Moreover, Mib-1 is the E3 ubiquitin ligase required for lapatinib-mediated ubiquitylation of Jagged-1 and induction of Notch activity. Additionally, ErbB-2 promotes an association between Jagged-1 and PKCá. Further, PKCá inhibits Notch transcriptional activity. Importantly combined inhibition of Jagged-1 by siRNA and ErbB-2 by trastuzumab significantly growth arrested SKBr3, BT474 HS, and BT474 HR cells in G1 phase of the cell cycle and induced cell death in vitro. Combined inhibition of Notch and ErbB-2 signaling pathways could decrease recurrence rates for ErbB-2 positive breast tumors and may be beneficial in the treatment of recurrent trastuzumab resistant disease. Our studies will elucidate the mechanism by which ErbB-2 and Notch pathways crosstalk in ErbB-2 positive breast cancer cells. Mechanisms underlying transactivation and cis-inhibition of Notch by its ligand even though not well characterized yet are critical processes regulating Notch activity. These findings will provide a mechanism and functional relevance of Jagged-1-Notch interactions in ErbB-2 positive breast cancer cells. Furthermore, these studies will identify Jagged-1 as a novel and better therapeutic target for the treatment of ErbB-2 positive breast cancer. Finally, these studies will provide a preclinical proof of concept for future clinical trials using combination of trastuzumab or lapatinib and a Notch pathway inhibitor (GSI or Jagged-1 targeted therapy) for the treatment of ErbB-2 positive breast cancer

Early childhood education - coming out of the flux

In this article, we sketch the status of Early Childhood Education (ECE) programs in the country and discuss the various levels at which professionals are engaged in the delivery of ECE programs. We further recommend some core theoretical understandings that professionals working in ECE ought to know with the assumption that ECE as a domain of study in Higher Education has the potential to change the quality of ECE programs offered to children on the ground. We recommend and hope that with the national thrust on ECCE there will be more rigorous efforts to offer Higher Education programs to ECE professionals

NOTCH-1 and NOTCH-4 are novel gene targets of PEA3 in breast cancer: novel therapeutic implications

INTRODUCTION: Women with triple-negative breast cancer have the worst prognosis, frequently present with metastatic tumors and have few targeted therapy options. Notch-1 and Notch-4 are potent breast oncogenes that are overexpressed in triple-negative and other subtypes of breast cancer. PEA3, an ETS transcription factor, is also overexpressed in triple-negative and other breast cancer subtypes. We investigated whether PEA3 could be the critical transcriptional activator of Notch receptors in MDA-MB-231 and other breast cancer cells. METHODS: Real-time PCR and Western blot analysis were performed to detect Notch-1, Notch-2, Notch-3 and Notch-4 receptor expression in breast cancer cells when PEA3 was knocked down by siRNA. Chromatin immunoprecipitation was performed to identify promoter regions for Notch genes that recruited PEA3. TAM-67 and c-Jun siRNA were used to identify that c-Jun was necessary for PEA3 enrichment on the Notch-4 promoter. A Notch-4 luciferase reporter was used to confirm that endogenous PEA3 or AP-1 activated the Notch-4 promoter region. Cell cycle analysis, trypan blue exclusion, annexin V flow cytometry, colony formation assay and an in vivo xenograft study were performed to determine the biological significance of targeting PEA3 via siRNA, Notch signaling via a γ-secretase inhibitor, or both. RESULTS: Herein we provide new evidence for transcriptional regulation of Notch by PEA3 in breast cancer. PEA3 activates Notch-1 transcription in MCF-7, MDA-MB-231 and SKBr3 breast cancer cells. PEA3 activates Notch-4 transcription in MDA-MB-231 cells where PEA3 levels are endogenously high. In SKBr3 and BT474 breast cancer cells where PEA3 levels are low, overexpression of PEA3 increases Notch-4 transcripts. Chromatin immunoprecipitation confirmed the enrichment of PEA3 on Notch-1 and Notch-4 promoters in MDA-MB-231 cells. PEA3 recruitment to Notch-1 was AP-1-independent, whereas PEA3 recruitment to Notch-4 was c-JUN-dependent. Importantly, the combined inhibition of Notch signaling via a γ-secretase inhibitor (MRK-003 GSI) and knockdown of PEA3 arrested growth in the G(1 )phase, decreased both anchorage-dependent and anchorage-independent growth and significantly increased apoptotic cells in vitro. Moreover, either PEA3 knockdown or MRK-003 GSI treatment significantly reduced tumor growth of MDA-MB-231 xenografts in vivo. CONCLUSIONS: Taken together, the results from this study demonstrate for the first time that Notch-1 and Notch-4 are novel transcriptional targets of PEA3 in breast cancer cells. Targeting of PEA3 and/or Notch pathways might provide a new therapeutic strategy for triple-negative and possibly other breast cancer subtypes

Protection of early phase hepatic ischemia-reperfusion injury by cholinergic agonists

BACKGROUND: Cytokine production is critical in ischemia/reperfusion (IR) injury. Acetylcholine binds to macrophages and inhibits cytokine synthesis, through the cholinergic anti-inflammatory pathway. This study examined the role of the cholinergic pathway in cytokine production and hepatic IR- injury. METHODS: Adult male mice underwent 90-min of partial liver ischemia followed by reperfusion. The AChR agonists (1,1-dimethyl-4-phenyl-L-pioperazinium-iodide [DMPP], and nicotine) or saline-vehicle were administered i.p. before ischemia. Plasma cytokine tumor necrosis factor (TNF)-α, macrophage inflammatory protein-2, and Interleukin-6 were measured. Liver injury was assessed by plasma alanine transaminase (ALT) and liver histopathology. RESULTS: A reperfusion time-dependent hepatocellular injury occurred as was indicated by increased plasma-ALT and histopathology. The injury was associated with marked elevation of plasma cytokines/chemokines. Pre-ischemic treatment of mice with DMPP or nicotine significantly decreased plasma-ALT and cytokines after 3 h of reperfusion. After 6 h of reperfusion, the protective effect of DMPP decreased and reached a negligible level by 24 h of reperfusion, despite significantly low levels of plasma cytokines. Histopathology showed markedly diminished hepatocellular injury in DMPP- and nicotine-pretreated mice during the early-phase of hepatic-IR, which reached a level comparable to saline-treated mice at late-phase of IR. CONCLUSION: Pharmacological modulation of the cholinergic pathway provides a means to modulate cytokine production and to delay IR-induced heaptocellular injury

Teacher’s role in early identification of developmental delays

Rama*, two and a half-years-old, is the second of three siblings. Her parents cultivate vegetables on a farm on the outskirts of Bengaluru. A neighbourhood alternative school enrolled her and her elder sister in school. Her parents had begun to realize that there was some kind of hearing loss Rama was experiencing. However, their hope to see her develop as all other children led them to believe that she was one of those who would develop oral language a little later than usual. Rama’s family represents a culture where there is little or no conversation among adults and children. Conversations, if at all, are more functional in nature

Play | Central to Foundational Stage Learning

The National Curriculum Framework for Foundational Stage (NCF-FS) 2022 is a landmark document that provides comprehensive guidelines – goals, pedagogical ideas and learning standards that the school system in India should strive to achieve in the first five years of children’s schooling. This article focuses on - How Children Learn, Importance of Play, Learning through Play and the relationship of play with learning goals and standards for 3- to 8-year-old children – aspects outlined in sections 1, 2 and 4 of the curriculum framework

Early childhood education - coming out of the flux

In this article, we sketch the status of Early Childhood Education (ECE) programs in the country and discuss the various levels at which professionals are engaged in the delivery of ECE programs. We further recommend some core theoretical understandings that professionals working in ECE ought to know with the assumption that ECE as a domain of study in Higher Education has the potential to change the quality of ECE programs offered to children on the ground. We recommend and hope that with the national thrust on ECCE there will be more rigorous efforts to offer Higher Education programs to ECE professionals

Early Learner Assessment (ELA): A handbook for developmental assessment of children 3-5 years

The Integrated Child Development Services programme (ICDS) is the largest Early Childhood Care and Education initiative in India since 1975 . While women and child nutrition programmes have been immensely successful, the quality of the pre-school education component of the ICDS is still low (Kaul, Chaudhary & Sharma, 2014; Singh & Mukherji, 2018; Vennam, Komanduri, Cooper, Crivello, Woodhead, 2009) . As a part of the Azim Premji Foundation’s Early Childhood Education Initiative, the Foundation has partnered with the anganwadis of Sangareddy district, in South India's Telangana state, to support the ICDS programme in providing quality pre-school education . An intervention of this kind requires a deeper understanding of the anganwadi pre-school context and growth and development of the children of anganwadis in Sangareddy . This information will help in planning a cultural and contextual quality pre-school programme . In order to do so, multiple forms of assessments that provide a valid, contextual and comprehensive understanding of what constitutes a quality pre-school programme as well as the development of children would be required