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JOURNAL ARTICLE
Reyes Jiménez-Bárcenas, Gloria García-Donas-Gabaldón, Rosa María Campos-Álvarez, María Carmen Fernández-Sánchez de Mora, Josefa Luis-Navarro, Juan Francisco Domínguez-Rodríguez, María Del Mar Nieto-Hernández, Irene Sánchez-Bazán, Maria Yera-Cobo, Rocio Cardesa-Cabrera, Francisco José Jiménez-Gonzalo, María Antonia Ruiz-Cobo, Isabel Caparrós-Miranda, Laura Entrena-Ureña, Dolores Fernández Jiménez, Dana Díaz-Canales, Gloria Moreno-Carrasco, Cristina Calderón-Cabrera, Ramiro José Núñez-Vázquez, Begoña Pedrote-Amador, María Eva Mingot-Castellano
Immune thrombocytopenia (ITP) is characterized by low platelet counts (PLTs) and an increased risk of bleeding. Fostamatinib, a spleen tyrosine kinase inhibitor, has been approved as a second-line treatment for ITP. Real-world data on fostamatinib are lacking. This observational, retrospective, multicentre study, conducted in the Andalusia region of Spain, evaluated 44 adult primary ITP patients (47.7% female; median age 58 years; newly diagnosed ITP 6.8%; persistent 13.6%; chronic 79.5%; median four prior treatments) after ≥ 4 weeks of fostamatinib therapy...
April 3, 2024: British Journal of Haematology
#2
REVIEW
Joanne Britto, Anne Holbrook, Haowei Sun, Christine Cserti-Gazdewich, Oksana Prokopchuk-Gauk, Cyrus Hsia, Karima Khamisa, Paul R Yenson, Michelle Sholzberg, Harold J Olney, Sudeep Shivakumar, David Jones, Hayley Merkeley, Jacqueline Costello, Erin Jamula, Donald M Arnold
INTRODUCTION: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts and increased risk of bleeding. After corticosteroids with or without intravenous immune globulin (first-line treatment), second-line treatment options include rituximab, splenectomy, thrombopoietin receptor agonists (TPO-RAs), and fostamatinib. In Canada, the choice of second-line therapy is influenced by access to medications. The goals of this narrative review are to 1) summarize the evidence for the use of TPO-RAs and other second-line therapies in ITP and 2) highlight differences in public funding criteria for TPO-RAs across provinces and territories in Canada...
March 1, 2024: Clinical and Investigative Medicine. Médecine Clinique et Experimentale
#3
JOURNAL ARTICLE
Qing-Qing Duan, Han Wang, Wei-Ming Su, Xiao-Jing Gu, Xiao-Fei Shen, Zheng Jiang, Yan-Ling Ren, Bei Cao, Guo-Bo Li, Yi Wang, Yong-Ping Chen
BACKGROUND: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment. METHODS: To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS...
March 5, 2024: BMC Medicine
#4
REVIEW
Drew Provan, Jecko Thachil, María Teresa Álvarez Román
INTRODUCTION: Immune thrombocytopenia (ITP), a disease that commonly presents with an increased risk of bleeding, can also paradoxically produce an increased risk of thromboembolic events. The risk of thromboembolism can be associated with patient-related factors (e.g. co-morbidities, age and history of thrombosis), disease-related factors (e.g. a greater proportion of younger, more reactive platelets, and the presence of microparticles and pro-inflammatory cytokines) and treatment-related factors (e...
2024: Expert Review of Hematology
#5
JOURNAL ARTICLE
Adam Hermawan, Herwandhani Putri, Nurul Fatimah, Heri Himawan Prasetio
Luminal A breast cancer, constituting 70 % of breast cancer cases, presents a challenge due to the development of resistance and recurrence caused by breast cancer stem cells (BCSC). Luminal breast tumors are characterized by TP53 expression, a tumor suppressor gene involved in maintaining stem cell attributes in cancer. Although a previous study successfully developed mammospheres (MS) from MCF-7 (with wild-type TP53 ) and T47D (with mutant TP53 ) luminal breast cancer cells for BCSC enrichment, their transcriptomic profiles remain unclear...
January 30, 2024: Heliyon
#6
REVIEW
Kalliopi K Gkouskou, Maria G Grammatikopoulou, Evgenia Lazou, Theodora Vasilogiannakopoulou, Despina Sanoudou, Aristides G Eliopoulos
This review discusses the landscape of personalized prevention and management of obesity from a nutrigenetics perspective. Focusing on macronutrient tailoring, we discuss the impact of genetic variation on responses to carbohydrate, lipid, protein, and fiber consumption. Our bioinformatic analysis of genomic variants guiding macronutrient intake revealed enrichment of pathways associated with circadian rhythm, melatonin metabolism, cholesterol and lipoprotein remodeling and PPAR signaling as potential targets of macronutrients for the management of obesity in relevant genetic backgrounds...
January 29, 2024: Human Genomics
#7
JOURNAL ARTICLE
Mohammad Shadab, Spencer A Slavin, Zahra Mahamed, Michelle W Millar, Rauf A Najar, Antony Leonard, Anthony Pietropaoli, David A Dean, Fabeha Fazal, Arshad Rahman
Increased endothelial cell (EC) permeability is a cardinal feature of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Tyrosine phosphorylation of VE-cadherin is a key determinant of EC barrier disruption. However, the identity and role of tyrosine kinases in this context are incompletely understood. Here we report that Spleen Tyrosine Kinase (Syk) is a key mediator of EC barrier disruption and lung vascular leak in sepsis. Inhibition of Syk by pharmacological or genetic approaches, each reduced thrombin-induced EC permeability...
December 2023: Journal of Biological Chemistry
#8
REVIEW
Amirhossein Heidari, Yekta Ghane, Nazila Heidari, Sara Sadeghi, Azadeh Goodarzi
BACKGROUNDS AND AIMS: Hidradenitis suppurativa (HS) is a challenging skin disease with an underlying inflammatory process. Substantial progress has been made in our understanding of HS over the last few years, with the advancement of novel treatment approaches. The current systematic review aims to evaluate the safety and efficacy of Janus kinase (JAK) inhibitors and spleen tyrosine kinase (Syk) inhibitors in treating HS. METHOD: A thorough systematic search was performed on PubMed/Medline, Web of Science, and Ovid Embase databases up to September 23th, 2023...
January 25, 2024: International Immunopharmacology
#9
JOURNAL ARTICLE
Frederick W K Tam, James Tumlin, Jonathan Barratt, Brad H Rovin, Ian S D Roberts, Candice Roufosse, H Terence Cook, Gurjeet Bhangal, Alison L Brown, Martin Busch, Fayaz Dudhiya, Anne-Marie Duliege, Donald J Fraser, Daniel P Gale, Chiu-Ching Huang, Ping-Chin Lai, Meng Lee, Esteban S Masuda, Stephen P McAdoo, Alexander R Rosenkranz, Claudia Sommerer, Gere Sunder-Plassmann, Cheuk-Chun Szeto, Sydney C W Tang, Don E Williamson, Lisa Willcocks, Volker Vielhauer, Min Jeong Kim, Leslie Todd, Hany Zayed, Sandra Tong-Starksen, Richard Lafayette
INTRODUCTION: We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells. METHODS: This study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors...
December 2023: KI Reports
#10
REVIEW
Robert Roskoski
Because genetic alterations including mutations, overexpression, translocations, and dysregulation of protein kinases are involved in the pathogenesis of many illnesses, this enzyme family is the target of many drug discovery programs worldwide. The FDA has approved 80 small molecule protein kinase inhibitors with 77 drugs orally bioavailable. The data indicate that 69 of these medicinals are approved for the management of neoplasms including solid tumors such as breast and lung cancer as well as non-solid tumors such as leukemia...
December 12, 2023: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
#11
REVIEW
Guillaume Moulis, Lamya Garabet
Refractory immune thrombocytopenia (ITP) is a challenging disease that can be defined by refractoriness to second-line treatments. In this review, we list and comment available evidence about clinical and biological factors associated with refractoriness to splenectomy, thrombopoietin receptor agonists (TPO-RAs), rituximab and fostamatinib, as well as those associated with multirefractory ITP (active disease with failure of rituximab, TPO-RAs and splenectomy).
October 2023: British Journal of Haematology
#12
RANDOMIZED CONTROLLED TRIAL
David J Kuter, Caroline Piatek, Alexander Röth, Asif Siddiqui, Robert P Numerof, Wolfgang Dummer
Warm antibody autoimmune hemolytic anemia (wAIHA) is characterized by hemolysis and symptomatic anemia with no approved treatment options. Fostamatinib is an oral spleen tyrosine kinase inhibitor approved in the US and Europe for treatment of adults with chronic immune thrombocytopenia. In this phase 3 study, patients with an insufficient response to ≥1 prior wAIHA treatment were randomized to fostamatinib or placebo. The primary endpoint was the proportion of patients to achieve a durable hemoglobin (Hgb) response (Hgb ≥10 g/dL and increase from baseline of ≥2 g/dL on 3 consecutive visits) during the 24-week treatment period...
January 2024: American Journal of Hematology
#13
JOURNAL ARTICLE
Akshay Flora, Rebecca Jepsen, Emily K Kozera, Jane A Woods, Geoffrey D Cains, Michael Radzieta, Slade O Jensen, Matthew Malone, John W Frew
Hidradenitis Suppurativa is a chronic inflammatory disease of which the pathogenesis is incompletely understood. Dermal fibroblasts have been previously identified as a major source of inflammatory cytokines, however information pertaining to the characteristics of subpopulations of fibroblasts in HS remains unexplored. Using in silico-deconvolution of whole-tissue RNAseq, Nanostring gene expression panels and confirmatory immunohistochemistry we identified fibroblast subpopulations in HS tissue and their relationship to disease severity and lesion morphology...
2023: PloS One
#14
REVIEW
María Eva Mingot-Castellano, Mariana Canaro Hirnyk, Blanca Sánchez-González, María Teresa Álvarez-Román, Abelardo Bárez-García, Ángel Bernardo-Gutiérrez, Silvia Bernat-Pablo, Estefanía Bolaños-Calderón, Nora Butta-Coll, Gonzalo Caballero-Navarro, Isabel Socorro Caparrós-Miranda, Laura Entrena-Ureña, Luis Fernando Fernández-Fuertes, Luis Javier García-Frade, María Del Carmen Gómez Del Castillo, Tomás José González-López, Carlos Grande-García, José María Guinea de Castro, Isidro Jarque-Ramos, Reyes Jiménez-Bárcenas, Elsa López-Ansoar, Daniel Martínez-Carballeira, Violeta Martínez-Robles, Emilio Monteagudo-Montesinos, José Antonio Páramo-Fernández, María Del Mar Perera-Álvarez, Inmaculada Soto-Ortega, David Valcárcel-Ferreiras, Cristina Pascual-Izquierdo
Primary immune thrombocytopenia (ITP) is a complex autoimmune disease whose hallmark is a deregulation of cellular and humoral immunity leading to increased destruction and reduced production of platelets. The heterogeneity of presentation and clinical course hampers personalized approaches for diagnosis and management. In 2021, the Spanish ITP Group (GEPTI) of the Spanish Society of Hematology and Hemotherapy (SEHH) updated a consensus document that had been launched in 2011. The updated guidelines have been the reference for the diagnosis and management of primary ITP in Spain ever since...
October 10, 2023: Journal of Clinical Medicine
#15
JOURNAL ARTICLE
S Samanta, M F Sk, S Koirala, P Kar
The spleen tyrosine kinase (Syk) plays a pivotal role in immune cells' signal transduction mechanism. While fostamatinib, an FDA-approved Syk inhibitor, is currently used to treat immune thrombocytopenia, the search for improved Syk-targeted medications to treat autoimmune diseases is still underway. Herein, we screened 38,493 compounds against Syk and selected eight leads based on the docking score and ADMET properties, and performed 3<mml:math xmlns:mml="https://www.w3.org/1998/Math/MathML"><mml:mo>×</mml:mo></mml:math>200 ns long molecular dynamics simulations of the apo and Syk-ligand complexes...
October 26, 2023: SAR and QSAR in Environmental Research
#16
JOURNAL ARTICLE
Akshay Flora, Rebecca Jepsen, James Pham, John W Frew
Hidradenitis Suppurativa (HS) is a disease in great need of novel therapies. Given the heterogeneous nature of the disease and the variable response to therapies, biomarkers are essential to predict response to therapies and increase our understanding of disease pathogenesis. Our recent Phase 2 clinical trial of Spleen Tyrosine Kinase antagonism using Fostamatinib in Hidradenitis Suppurativa demonstrated a 75% clinical response with the greatest benefit in individuals with elevated serum inflammation and Immunoglobulin G...
October 23, 2023: Journal of Investigative Dermatology
#17
JOURNAL ARTICLE
George Dranitsaris, Aaron Peevyhouse, Tiffany Wood, Yuliya Kreychman, Heather Neuhalfen, Mehdi Moezi
INTRODUCTION: Chronic immune thrombocytopenia purpura (ITP) in adults is a serious autoimmune disease in which platelets are prematurely destroyed, leaving the patient vulnerable to bruising and bleeding. Initial treatment is with corticosteroids. In patients who become resistant or intolerant to corticosteroids, the thrombopoietic agents (TPOs), consisting of romiplostim (ROM), eltrombopag (ELT) and avatrombopag (AVA) or the spleen tyrosine kinase inhibitor fostamatinib (FOS), are appropriate next lines of therapy...
September 29, 2023: Acta Haematologica
#18
REVIEW
Talha Badar, Yazan F Madanat, Amer M Zeidan
The majority of lower-risk myelodysplastic syndromes/neoplasms patients present with anemia. Historically, these patients were treated with erythropoiesis-stimulating agents (ESA), with modest responses. A subset of these patients with del(5q) may do better with lenalidomide. Recently, in randomized trials, luspatercept has shown better responses compared with ESAs in treatment-naive patients and imetelstat in patients refractory to ESAs. Other evaluated novel compounds (fostamatinib, H3B-880, roxadustat, pyruvate kinase receptor activator) have not yet shown meaningful efficacy...
September 26, 2023: Future Oncology
#19
REVIEW
Hanny Al-Samkari, Ellis J Neufeld
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder affecting approximately 1 in 20 000 people. While most patients with ITP are successfully managed with the current set of standard and approved therapeutics, patients who cannot be adequately managed with these therapies, considered to have refractory ITP, are not uncommon. Therefore, there remains an ongoing need for novel therapeutics and drug development in ITP. Several agents exploiting novel targets and mechanisms in ITP are presently under clinical development, with trials primarily recruiting heavily pretreated patients and those with otherwise refractory disease...
October 2023: British Journal of Haematology
#20
JOURNAL ARTICLE
Nansong Xu, Changchun Lai, Qing-Mei He, Yubo Cai, Hui Yu, Wenhao Zhong, Shulin Chen, Fang-Cai Wu, Hao Chen
AIMS: Esophageal squamous cell carcinoma (ESCC) is one of the aggressive and lethal malignancies with an extremely poor prognosis. It is necessary to explore the molecular mechanisms of ESCC invasion. MAIN METHODS: We utilized high-throughput mass spectrometry to analyze the proteomes and phosphorylation profiles of two ESCC cell lines with differing invasion capacities (HK vs TE10). Differentially expressed proteins and phosphorites were identified, followed by comprehensive bioinformatics analyses encompassing function and pathway enrichment, protein-protein interaction (PPI) network analysis, hub gene identification, co-expression analysis, kinase-substrate prediction, and drug-target network analysis...
September 19, 2023: Life Sciences
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