Current Views on the Interplay between Tyrosine Kinases and Phosphatases in Chronic Myeloid Leukemia

Simple SummaryThe chromosomal alteration t(9;22) generating the BCR-ABL1 fusion protein represents the principal feature that distinguishes some types of leukemia. An increasing number of articles have focused the attention on the relevance of protein phosphatases and their potential role in the control of BCR-ABL1-dependent or -independent signaling in different areas related to the biology of chronic myeloid leukemia. Herein, we discuss how tyrosine and serine/threonine protein phosphatases may interact with protein kinases, in order to regulate proliferative signal cascades, quiescence and self-renewals on leukemic stem cells, and drug-resistance, indicating how BCR-ABL1 can (directly or indirectly) affect these critical cells behaviors. We provide an updated review of the literature on the function of protein phosphatases and their regulation mechanism in chronic myeloid leukemia.Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by BCR-ABL1 oncogene expression. This dysregulated protein-tyrosine kinase (PTK) is known as the principal driver of the disease and is targeted by tyrosine kinase inhibitors (TKIs). Extensive documentation has elucidated how the transformation of malignant cells is characterized by multiple genetic/epigenetic changes leading to the loss of tumor-suppressor genes function or proto-oncogenes expression. The impairment of adequate levels of substrates phosphorylation, thus affecting the balance PTKs and protein phosphatases (PPs), represents a well-established cellular mechanism to escape from self-limiting signals. In this review, we focus our attention on the characterization of and interactions between PTKs and PPs, emphasizing their biological roles in disease expansion, the regulation of LSCs and TKI resistance. We decided to separate those PPs that have been validated in primary cell models or leukemia mouse models from those whose studies have been performed only in cell lines (and, thus, require validation), as there may be differences in the manner that the associated pathways are modified under these two conditions. This review summarizes the roles of diverse PPs, with hope that better knowledge of the interplay among phosphatases and kinases will eventually result in a better understanding of this disease and contribute to its eradication

ANALISIS PENJADWALAN PENERBANGAN PESAWAT WINGS AIR DALAM MENGOPTIMASI WAKTU KEBERANGKATAN DAN KEDATANGAN PESAWAT DARI DAN MENUJU BANDAR UDARA SULTAN MUHAMMAD SALAHUDDIN BIMA

Penjadwalan penerbangan begitu penting untuk maskapai dan penumpang, tidak hanya dalam hal ketepatan waktu penerbangan secara operasional tetapi juga pada optimalisasi pendapatan. Salah satu caranya adalah dengan mengoptimasi waktu keberangkatan dan kedatangan pesawat dengan menggunakan metode Hungarian. Penulisan ini bertujuan untuk mendapatkan hasil optimalisasi waktu antara waktu keberangkatan dan kedatangan pesawat Wings Air di Bandar Udara Sultan Muhammad Salahuddin Bima. Penelitian ini menggunakan metode mix method. Metode pengumpulan data menggunakan metode observasi, wawancara, dan dokumentasi. Dalam menganalisis data tersebut menggunakan metode Hungarian. Hasil penelitian ini menunjukkan bahwa dengan menggunakan metode Hungarian, selisih waktu keberangkatan dan kedatangan pesawat Wings Air di Bandar Udara Sultan Muhammad Salahuddin Bima dapat dioptimalkan. Dari yang sebelumnya berjumlah 1550 menit menjadi 1150 menit. Dengan demikian selisih waktu optimal yang dapat dipersingkat sebanyak 400 menit

A Comprehensive Review of Receptor-Type Tyrosine-Protein Phosphatase Gamma (PTPRG) Role in Health and Non-Neoplastic Disease

Protein tyrosine phosphatase receptor gamma (PTPRG) is known to interact with and regulate several tyrosine kinases, exerting a tumor suppressor role in several type of cancers. Its wide expression in human tissues compared to the other component of group 5 of receptor phosphatases, PTPRZ expressed as a chondroitin sulfate proteoglycan in the central nervous system, has raised interest in its role as a possible regulatory switch of cell signaling processes. Indeed, a carbonic anhydrase-like domain (CAH) and a fibronectin type III domain are present in the N-terminal portion and were found to be associated with its role as [HCO 3 − ] sensor in vascular and renal tissues and a possible interaction domain for cell adhesion, respectively. Studies on PTPRG ligands revealed the contactins family (CNTN) as possible interactors. Furthermore, the correlation of PTPRG phosphatase with inflammatory processes in different normal tissues, including cancer, and the increasing amount of its soluble form (sPTPRG) in plasma, suggest a possible role as inflammatory marker. PTPRG has important roles in human diseases; for example, neuropsychiatric and behavioral disorders and various types of cancer such as colon, ovary, lung, breast, central nervous system, and inflammatory disorders. In this review, we sum up our knowledge regarding the latest discoveries in order to appreciate PTPRG function in the various tissues and diseases, along with an interactome map of its relationship with a group of validated molecular interactors

Factors influencing the choice of anaesthesia as a field of specialty in University of Ghana School of Medicine and Dentistry, Korle-Bu Teaching Hospital

Background: Specialisation is perceived as essential for success, and affects the availability and distribution of medical personnel and the quality of service the health system is able to deliver. In Ghana, some areas of medical specialties have a relatively good number of practitioners and are constantly attracting prospective doctors into these fields. Anaesthesia, which is an essential and integral part of the health care system, is one field with an inadequate workforce and has been attracting few doctors into the specialty.Method: A cross-sectional study was conducted among 183 undergraduate final-year students of the University of Ghana School of Medicine and Dentistry. A total of 183 self-reporting questionnaires were distributed among the students during tutorials for their final exams. Of these, 146 questionnaires were completed and returned.Results: General surgery was the most desirable specialty 26 (17.8%), paediatrics was the second most desirable specialty 24 (16.4%), whilst anaesthesia 2 (1.4%) ranked seventh.Conclusions: The results of this survey suggest that duration of exposure during clinical clerkship influences career decision among undergraduate medical students. Most of the students prioritise their choice of specialty based on interest and exposure during rotation through the specialty.Keywords: anaesthesia, medical students, specialtie

Amélioration des conditions d’hygiène et d’assainissement dans la commune de Zè au Bénin

La présente étude vise à évaluer les effets des interventions mises en œuvre de 2017 à 2018 relatives à la promotion de l'hygiène et de l'assainissement dans la commune de Zè. Réalisée en Septembre 2019, l’étude a mobilisé la recherche documentaire, l’observation et l’entretien. La collecte a été effectuée dans les arrondissements bénéficiaires des interventions et de celles non bénéficiaires. Les résultats après interventions montrent que la proportion des personnes ayant de bonnes pratiques d’hygiène et d’assainissement est passée de 31,01% à 73,08%. La proportion des groupements de femmes associés aux activités IEC/WASH est passée de 0% à 87%. Le taux de morbidité liée aux maladies hydro-fécales a régressé de 1,20% à 0,78%. La prévalence des géohelminthiases a diminué de 7,10% à 0,75%. Par ailleurs, l’observation a permis de constater la réduction de la défécation à l’air libre, la réduction de la distance séparant les ménages d’un point d’eau, la diminution de la corvée d’eau pour les femmes et les filles, la réduction de la prévalence des maladies courantes dans les localités bénéficiaires. Malgré les résultats positifs obtenus, il reste des défis à relever pour pérenniser les acquis et passer à l’échelle supérieure notamment l’implication effective des autorités locales dans le suivi des ouvrages d’hygiène et d’assainissement.   The study aims to assess the effects of the interventions implemented from 2017 to 2018 relating to the promotion of hygiene and sanitation in the municipality of Zè. Conducted in September 2019, the study involved documentary research, observation and interview. Collection was carried out in the districts benefiting from the interventions and those not benefiting. Postintervention results show that the proportion of people with good hygiene and sanitation practices increased from 31.01% to 73.08%. The proportion of women's groups involved in IEC / WASH activities increased from 0% to 87%. The morbidity rate linked to hydro-fecal diseases fell from 1.20% to 0.78%. The prevalence of soil-transmitted helminthiasis decreased from 7.10% to 0.75%. In addition, the observation made it possible to note the reduction in open defecation, the reduction in the distance separating households from a water point, the reduction in the drudgery of water for women and girls, reducing the prevalence of common diseases in beneficiary localities and empowering women in groups through the manufacture and sale of soap

Etat Des Lieux et Facteurs Associés en Matière D’eau, D’hygiène Et D’assainissement Dans la Commune d’Abomey-Calavi Au Bénin

Pour apprécier l’accès à l’eau, l’hygiène et à l’assainissement dans la commune d’Abomey-Calavi, un état des lieux a été réalisé et les facteurs associés en matière d’eau, d’hygiène et d’assainissement ont été étudiés. De mai 2016 à janvier 2017, une étude transversale et analytique a permis d’administrer un questionnaire structuré à 630 individus. SPSS et Epi Info ont servi à analyser les facteurs associés. Les focus groupes ont permis de collecter les données qualitatives au sein d’un arrondissement urbain et rural. Un échantillonnage par commodité a permis de sélectionner, à partir des ménages enquêtés, dix participants par arrondissement. La méthode de l’analyse du contenu a été utilisée pour traiter les données qualitatives. L’analyse des résultats obtenus révèle que 61,9% des ménages utilisent une source d’eau améliorée, 87,3% disposent d’installation d’assainissement améliorée, 58,3% et 4,03% disposant respectivement de toilette à chasse mécanique et de toilettes sèches ont une installation d’hygiène améliorée. Le milieu de résidence (OR : 0,3, IC 95% : [0,61-0,42]) explique l’état de la source d’eau de boisson. Le niveau d’instruction (OR : 1,18 ; IC 95% :[0,61-2,25]) et la source d’eau de boisson (OR, 5,62, IC 95% :[2,66-11,85]) expliquent l’état de l’hygiène. La dépense journalière (OR, 0,22, IC 95% : [0,11-0,42]), le milieu de résidence (OR : 0,05 ; IC 95% : [0,02-0,20]), le niveau d’instruction (OR, 0,27 ; IC 95% : [0,16-0,47]) et les traits caractéristiques du relief (OR, 0,27 ; IC 95% : [0,07-1,14]) expliquent l’état de l’assainissement. Il ressort de tout ce qui précède que l’accès à l’eau, l’hygiène et à l’assainissement est acceptable dans la commune d’Abomey-Calavi malgré les disparités entre milieu rural et urbain. Les facteurs associés sont : le niveau d’instruction, la source d’eau de boisson, le niveau économique, le milieu de résidence et les traits caractéristiques du relief. To appreciate the access to water, hygiene and sanitation in the commune of Abomey-Calavi, the inventory was carried out and the associated factors in terms of water, hygiene and sanitation have been studied. FromMay 2016 to January 2017, a cross-sectional and analytical study was used to administer a structured questionnaire to 630 individuals. SPSS and Epi Info were used to analyze the associated factors. The focus groups were used to collect qualitative data in an urban and rural district. A convenience sample were used to select, fromthe households surveyed, ten participants per district. The content analysis method was used to process the qualitative data. The analysis of the results obtained reveals that 61.9% of households use an improved water source, 87.3% have improved sanitation facilities, 58.3% and 4.03% have respectively a flush toilet and dry toilets have an improved hygiene facility. The place of residence (OR: 0.3, 95% CI: [0, 61-0, 42]) explains the state of the drinking water source. The level of education (OR: 1,18, 95% CI: :[0,61-2,25]) and the source of drinking water (OR, 5,62, 95% CI: [2,66-11,85]) explain the state of hygiene. Daily expenditure (OR, 0, 22, 95% CI: [0,11-0,42]), place of residence (OR: 0.05, 95% CI [0,02-0,20]), level of education (OR, 0.27, 95% CI: [0,16-0,47]) and the characteristics of the relief (OR, 0.27, 95% CI: [0,07-1,14]) explain the state of sanitation. From all the foregoing, it is clear that access to water, hygiene and sanitation is acceptable in the commune of Abomey-Calavi despite the disparities between rural and urban areas. Associated factors are: educational level, drinking water source, economic level, place of residence, and characteristics of relief

Relationship between serum total magnesium and serum potassium in emergency surgical patients in a tertiary hospital in Ghana

Introduction: Potassium and magnesium are the two most abundant intra cellular cations. They play pivotal roles in many essential biological processes. Deficiencies of these electrolytes are of clinical importance in hospitalised patients.Aim: To determine the relationship between serum total magnesium and potassium levels in adult patients requiring an emergency intra-abdominal surgery and the clinical utility of this relationship in the care of patients.Methods: A cross sectional study was conducted over a five month period at the Korle-Bu Teaching Hospital. All 101 adult patients admitted for emergency intra abdominal surgery, who met the inclusion criteria and gave informed consent, were consecutively recruited and enrolled into the study. Patients’ characteristics preoperative total serum magnesium, serum potassium and albumin levels were determined. Regression analysis and correlation coefficients were used to determine the relation between serum magnesium and potassium. Analysis was done using SPSS version 20.Results: Mean serum total magnesium and serum potassium were 0.66±0.20mmol/L and 3.79±0.65mmol/L respectively. There was a significant but weak positive correlation between serum hypokalaemia and serum magnesium levels. Pearson’s correlation coefficient (2 tailed) was 0.21, R2= 0.04, p = value 0.038. Analysis generated a regression model: [Mg] = 0.06[K] + 0.42mmol/L, with a p-value = 0.038.Conclusion: A mathematical relationship was found between serum total magnesium and serum potassium among adult patients who require emergency intra-abdominal surgery. However, it had limited clinical utility.Funding: None declaredKeywords: Potassium, magnesium, electrolyte, preoperative perio

Successful Preservation of Native BCR::ABL1 in Chronic Myeloid Leukemia Primary Leukocytes Reveals a Reduced Kinase Activity

Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the acquisition of t(9;22) generating the fusion tyrosine kinase BCR::ABL1. However, despite the crucial role of this protein in the dysregulation of numerous signal transduction pathways, a direct measure of BCR::ABL1 kinase activity in chronic phase (CP) CML was never accomplished due to intense degradative activity present in mature leukocytes. Therefore, we developed a procedure suitable to preserve BCR::ABL1 protein under non-denaturing, neutral pH conditions in primary, chronic phase (CP)-CML samples. As a result, specific kinase activity was detected utilizing a biotinylated peptide substrate highly selective for c-ABL1. Furthermore, through this approach, BCR::ABL1 kinase activity was barely detectable in CP-CML compared to Ph+ acute lymphoblastic leukemia primary samples, where kinase activity is comparable to those measured in Ph+ cell lines. These in vitro findings provide the first direct measure of BCR::ABL1 kinase activity in primary CP-CML and reveal the presence of a still uncharacterized inhibitory mechanism that maintains BCR::ABL1 in a low activity state in CP-CML despite its overexpression

Regulative Loop between \u3b2-catenin and Protein Tyrosine Receptor Type \u3b3 in Chronic Myeloid Leukemia

Protein tyrosine phosphatase receptor type \u3b3 (PTPRG) is a tumor suppressor gene, down-regulated in Chronic Myeloid Leukemia (CML) cells by the hypermethylation of its promoter region. \u3b2-catenin (CTNNB1) is a critical regulator of Leukemic Stem Cells (LSC) maintenance and CML proliferation. This study aims to demonstrate the antagonistic regulation between \u3b2-catenin and PTPRG in CML cells. The specific inhibition of PTPRG increases the activation state of BCR-ABL1 and modulates the expression of the BCR-ABL1- downstream gene \u3b2-Catenin. PTPRG was found to be capable of dephosphorylating \u3b2-catenin, eventually causing its cytosolic destabilization and degradation in cells expressing PTPRG. Furthermore, we demonstrated that the increased expression of \u3b2-catenin in PTPRG-negative CML cell lines correlates with DNA (cytosine-5)-methyl transferase 1 (DNMT1) over-expression, which is responsible for PTPRG promoter hypermethylation, while its inhibition or down-regulation correlates with PTPRG re-expression. We finally confirmed the role of PTPRG in regulating BCR-ABL1 and \u3b2-catenin phosphorylation in primary human CML samples. We describe here, for the first time, the existence of a regulative loop occurring between PTPRG and \u3b2-catenin, whose reciprocal imbalance affects the proliferation kinetics of CML cells

Rapid and sustained improvements in Generalized Pustular Psoriasis Physician Global Assessment scores with spesolimab for treatment of generalized pustular psoriasis flares in the randomized, placebo-controlled Effisayil 1 study

BACKGROUND: Effisayil 1 was a randomized, placebo-controlled study of spesolimab, which is an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular psoriasis flare. OBJECTIVE: To assess the effects of spesolimab over the 12-week study. METHODS: The primary endpoint of the study was Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 at week 1. Patients (N = 53) were randomized (2:1) to receive a single intravenous dose of 900 mg spesolimab or placebo on day 1. Patients could receive open-label spesolimab for persistent flare symptoms on day 8. RESULTS: Most patients receiving spesolimab achieved a GPPGA pustulation subscore of 0 (60.0%) and GPPGA total score of 0 or 1 (60.0%) by week 12. In patients randomized to placebo who received open-label spesolimab on day 8, the proportion with GPPGA pustulation subscore of 0 increased from 5.6% at day 8 to 83.3% at week 2. No factors predictive of spesolimab response were identified in patient demographics or clinical characteristics. LIMITATIONS: The effect of initial randomization was not determined conventionally beyond week 1 due to patients receiving open-label spesolimab. CONCLUSION: Rapid control of generalized pustular psoriasis flare symptoms with spesolimab was sustained over 12 weeks, further supporting its potential use as a therapeutic option for patients