Molecular mechanisms of disruption of E-cadherin adhesion induced by Arf6 and Rac small GTPases

Epithelial cells are characterised by a tight intercellular adhesion. Disassembly of E-cadherin-mediated cell-cell adhesion can induce a transition from a benign epithelial phenotype to an invasive mesenchymal phenotype. Therefore, understanding the underlying mechanisms leading to adherens junction disruption will provide insights into potential therapeutic agents to prevent tumour metastasis. The small GTPases Arf6 and Rac can each disassemble E-cadherin-based junctions, upon which epithelial cells scatter. Preliminary results in our lab showed that Rae requires PAK function during junction disassembly and that Arf6 disrupts keratinocyte junctions in a process dependent on Rac signalling. Crosstalk between Arf6 and Rac has been described previously, but.the exact molecular mechanisms involved during Arf6-induced junction disassembly are not known. A good candidate molecule to provide the link between Arf6 and Rac is GIT1. GIT1 interacts with active Arf6 by an Arf6GAP domain and induces Rac activation via binding to the RacGEF 0PIX. Rac regulates many cellular. processes in which no effector proteins have been yet identified, inclUding perturbation of cell-cell contacts. Using a keratinocyte eDNA library screen with active Rac as bait, a new Rac binding protein named Armus has been isolated previously.. This protein is interesting as in addition to binding specifically to active Rac, it contains a TBC/RabGAP domain at its C-terminus, which is predicted to inactivate Rab small GTPases. Armus function is currently unknown. The aim of my PhD project was to test the involvement of GIT1, PAK and Armus in the disassembly of E-cadherin junctions induced by active Arf6 and Rac. I found that GIT1 and D-PIX might provide the link towards Rac signalling during Arf6induced junction disassembly. Furthermore, expression of the TBC/RabGAP domain of Armus can block Arf6-induced junction disruption by inactivating Rab7. In contrast, the Rac effector PAK1 does not playa role in Arf6-dependent junction disassembly. Moreover, I found that Armus and GIT1 are distributed on similar vesicular structures, suggesting that these proteins are spatially and functionally linked.Imperial Users onl

PENERAPAN MODEL PROBLEM BASED LEARNING BERBANTUAN GIMKIT UNTUK MENINGKATKAN KETERAMPILAN BERPIKIR KRITIS SISWA PADA MATERI SISTEM EKSKRESI KELAS XI SMA

Penelitian ini bertujuan untuk mengetahui perbedaan peningkatan antara kedua kelas dengan penerapan model Problem based learning berbantuan Gimkit untuk meningkatkan keterampilan berpikir kritis peserta didik. Jenis penelitian yang dilakukan adalah dengan desain quasi-eksperimen pendekatan nonequivalent control group. Teknik analisis data menggunakan uji prasyarat dan uji hipotesis. Penelitian ini dilaksanakan di SMAN 1 Plumbon dengan polulasi penelitian yaitu kelas XI dan sampel penelitian adalah kelas XI-5 dan XI-6. Berdasarkan hasil penelitian aktivitas peserta didik dilakukan selama dua kali pertemuan, terdapat peningkatan nilai antara pertemuan pertama dan kedua sebesar 1,24%. Pengolahan data terkait peningkatan keterampilan berpikir kritis peserta didik dihitung berdasarkan nilai pretest dan posttest pada kedua kelas. Perbandingan nilai diperoleh berdasarkan nilai n-gain, terdapat peningkatan nilai rata-rata n-gainyang lebih tinggi pada kelas eksperimen sebesar 0,55 daripada kelas kontrol dengan nilai rata-rata n-gain sebesar 0,46. Angket respon siswa menunjukkan rata-rata nilai 71,76% yang termasuk dalam kategori positif atau kuat. Dapat disimpulkan bahwa penerapan model Problem based learning berbantuan Gimkit tergolong efektif untuk meningkatkan keterampilan berpikir kritis peserta didik, dengan rata-rata peningkatan nilai sebesar 6,89

Correction to:Fecal Immunochemical Test Positivity Thresholds: An International Survey of Population-Based Screening Programs (Digestive Diseases and Sciences, (2024), 10.1007/s10620-024-08664-7)

In this article, Fig. 1 appeared incorrectly without the x-axis labels and have now been corrected in the original publication. For completeness and transparency, the old incorrect and correct Fig. 1 are displayed below: Incorrect Fig. 1: The frequency of thresholds in use across the screening sites Correct Fig. 1: The frequency of thresholds in use across the screening sites.</p

Fecal Immunochemical Test Positivity Thresholds:An International Survey of Population-Based Screening Programs

BackgroundThe fecal immunochemical test for hemoglobin (FIT) is now a widely used non-invasive test in population-based organized screening programs for colorectal neoplasia. The positivity thresholds of tests currently in use are based on the fecal hemoglobin concentration (f-Hb), but the rationale for the adopted thresholds are not well documented. To understand current global usage of FIT in screening programs we conducted an international survey of the brands of FIT used, the f-Hb positivity threshold applied and the rationale for the choice.MethodsAll members of the World Endoscopy Organization CRC Screening Committee were invited to complete an eight-element initial electronic survey exploring the key aims. Responses were obtained from 63 individuals, representing 38 specific locations in 28 countries. A follow-up survey on technical issues was offered to the 38 locations, with replies from 17 sites in 13 countries.ResultsIn-use quantitative FIT were provided by four main manufacturers; Minaris Medical (2 countries), Eiken Chemical Company/Polymedco (21), Alfresa Pharma (2) and Sentinel Diagnostics (4). Of the 38 screening sites, 15 used the threshold of 20 µg hemoglobin/g feces, while thresholds ranged between 8.5 and 120 ug/g in the remainder. Seven explanations were given for adopted FIT thresholds; maximizing the sensitivity for colorectal neoplasia (n = 23) was the most common followed by the availability of colonoscopy resources (n = 18). Predictive value, specificity, and cost effectiveness were less frequently reported as the rationale. Nine sites found it necessary to change the threshold that they had initially selected.ConclusionsThis international survey has documented the wide range of FIT positivity thresholds that are in current use. Quantitative FITs enable programs to achieve the desired program outcomes within available resource constraints by adjusting the positivity threshold. This supports the need for enabling positivity threshold adjustment of emerging new screening tests based on novel predictive biomarkers, rather than providing inflexible test endpoints

Incidence of Interval Colorectal Cancer After Negative Results From First-Round Fecal Immunochemical Screening Tests, by Cutoff Value and Participant Sex and Age

Background & Aims: We evaluated the incidence of interval cancers between the first and second rounds of colorectal cancer (CRC) screening with the FOB-Gold fecal immunochemical test (FIT), and the effects of different cutoff values and patient sex and age. Methods: We collected data from participants in a population-based