Structure poisoning in childhood and treatment algorithms at present in Sumy City Children's Hospital

Acute poisoning play a significant role in the pathology of childhood

Structure poisoning in childhood and treatment algorithms at present in Sumy City Children's Hospital

Acute poisoning play a significant role in the pathology of childhood

Structure poisoning in childhood and treatment algorithms at present in Sumy City Children's Hospital

Acute poisoning play a significant role in the pathology of childhood

Structure poisoning in childhood and treatment algorithms at present in Sumy City Children's Hospital

Acute poisoning play a significant role in the pathology of childhood

Vodcast as ideating medium in STEM lesson plan in teaching heat transfer

This study attempts to link the clay soil in the locality to the topic of heat transfer as a contextualization point. It attempted to slightly modify the seven-step STEM lesson by having the part of the prototyping be first tried by the teacher, thereby having a change-of-hat to anticipate the ‘what if’ questions of the students. The teacher-researchers experimentation provided critical information to scaffold the students in the prototyping part.  The evaluation of experts shows that the modified STEM lesson can be an excellent tool and the vodcast has been found to be a very satisfactory component of the STEM lesson. It is described as a very useful material in teaching heat transfer and related thermodynamics concepts and is highly recommended for use in both distance learning and face-to-face modality. Further, the clay oven exploration has come up with a refined clay oven production process, wherein the clay oven prototype has the capacity for the contextualization of heat transfer. It is recommended that a formal implementation be conducted to refine and standardize the lesson delivery

The introduction and implementation of open dialogue in a day center in Athens, Greece: experiences and reflections of mental health professionals

IntroductionThe present study is part of a large-scale original action-research project aiming to assess the introduction and implementation of the Open Dialogue approach within the clinical practice of an established multidisciplinary team in a Day Centre in Athens, Greece. More specifically, it aimed to explore the experiences of professionals within the process of implementation both in relation to their clinical practice and their professional identity.MethodsData collection employed a focus group, which was set up to explore professional reflections of the implementation and research processes since the introduction of the model. Thematic Analysis of transcripts revealed two main themes that correspond to the impact of Open Dialogue on professionals’ clinical practice and on team dynamics, respectively.ResultsProfessionals identify several challenges in implementing OD, such as difficulties in linking theory to practice, containing uncertainty, and addressing cultural barriers to dialogical ways of working. Professionals further reflect on their own internal journey stemming from the implementation of Open Dialogue that has led them to greater openness and growth, personally and as a team.DiscussionThe role of mental health professionals is being acknowledged as being at the frontline of any meaningful psychiatric reform through the assimilation and promotion of humanistic paradigms aiming towards a change of culture in psychiatric care across different contexts. Despite variations in implementation across different contexts, the importance of consolidating and embracing Open Dialogue as a philosophical framework underpinning mental health care is being discussed

Acquired Resistance to KRAS (G12C) Inhibition in Cancer

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS(G12C)). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRAS(G12C) -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRAS(G12C) inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRAS(G12C) allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRAS(G12C) inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRAS(G12C) inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.)

c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression

Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to SMURF2 targeting the TGFβ receptor for degradation. Under these conditions, SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGFβ signalling through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGFβ receptor stabilisation. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. In vivo we show that TGFβ receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFβ and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers

Negative feedback regulation of the ERK1/2 MAPK pathway

The extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signalling pathway regulates many cellular functions, including proliferation, differentiation, and transformation. To reliably convert external stimuli into specific cellular responses and to adapt to environmental circumstances, the pathway must be integrated into the overall signalling activity of the cell. Multiple mechanisms have evolved to perform this role. In this review, we will focus on negative feedback mechanisms and examine how they shape ERK1/2 MAPK signalling. We will first discuss the extensive number of negative feedback loops targeting the different components of the ERK1/2 MAPK cascade, specifically the direct posttranslational modification of pathway components by downstream protein kinases and the induction of de novo gene synthesis of specific pathway inhibitors. We will then evaluate how negative feedback modulates the spatiotemporal signalling dynamics of the ERK1/2 pathway regarding signalling amplitude and duration as well as subcellular localisation. Aberrant ERK1/2 activation results in deregulated proliferation and malignant transformation in model systems and is commonly observed in human tumours. Inhibition of the ERK1/2 pathway thus represents an attractive target for the treatment of malignant tumours with increased ERK1/2 activity. We will, therefore, discuss the effect of ERK1/2 MAPK feedback regulation on cancer treatment and how it contributes to reduced clinical efficacy of therapeutic agents and the development of drug resistance