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Jakafi (Ruxolitinib) Research

00:45 EST 24th February 2020 | BioPortfolio

Landscape of Combination Therapy Trials in Breast Cancer Brain Metastasis.

Combination therapy has become a cornerstone in cancer treatment to potentiate therapeutic effectiveness and overcome drug resistance and metastasis. In this work, we explore combination trials in breast cancer brain metastasis (BCBM), highlighting deficiencies in trial design and underlining promising combination strategies. On October 31, 2019, we examined ClinicalTrials.gov for interventional a...

Urolithin C increases glucose-induced ERK activation which contributes to insulin secretion.

Polyphenols exert pharmacological actions through protein-mediated mechanisms and by modulating intracellular signalling pathways. We recently showed that a gut-microbial metabolite of ellagic acid named urolithin C is a glucose-dependent activator of insulin secretion acting by facilitating L-type Ca channel opening and Ca influx into pancreatic β-cells. However, it is still unknown whether urol...

Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.

Bruton's tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors is limited to oncology indications based on their suboptimal kinase selectivity. We describe the discovery and preclinical profile of LOU064 (remibrutinib, ), a potent, highly s...

Catecholaminergic modulation of the cost of cognitive control in healthy older adults.

Catecholamines have long been associated with cognitive control and value-based decision-making. More recently, we have shown that catecholamines also modulate value-based decision-making about whether or not to engage in cognitive control. Yet it is unclear whether catecholamines influence these decisions by altering the subjective value of control. Thus, we tested whether tyrosine, a catecholami...

Mechanisms of Cardiovascular Toxicity of BCR-ABL1 Tyrosine Kinase Inhibitors in Chronic Myelogenous Leukemia.

Oral tyrosine kinase inhibitors have revolutionized the treatment of chronic myelogenous leukemia, with many patients achieving major clinical and molecular responses without complications. While typically well-tolerated, clinical experience with tyrosine kinase inhibitors (particularly those of the second and third generations) has highlighted unanticipated associations with serious non-cancer ad...

Inhibition of striatal-enriched protein tyrosine phosphatase by targeting computationally revealed cryptic pockets.

Cryptic pockets, which are not apparent in crystallographic structures, provide promising alternatives to traditional binding sites for drug development. However, identifying cryptic pockets is extremely challenging and the therapeutic potential of cryptic pockets remains unclear. Here, we reported the discovery of novel inhibitors for striatal-enriched protein tyrosine phosphatase (STEP), a poten...

Insights on the heparan sulphate-dependent externalisation of transglutaminase-2 (TG2) in glucose-stimulated proximal-like tubular epithelial cells.

The extracellular matrix crosslinking enzyme transglutaminase 2 (TG2) is highly implicated in tissue fibrosis that precedes end-stage kidney failure. TG2 is unconventionally secreted through extracellular vesicles in a way that depends on heparan sulphate (HS) proteoglycan syndecan-4 (Sdc4), the deletion of which reduces experimental kidney fibrosis as a result of lower extracellular TG2 in the tu...

Protein Tyrosine Phosphatase Nonreceptor Type 2 Expression Does Not Correlate with Viral Load or Response to Direct-Acting Antiviral Therapy in Hepatitis C Virus Infections-Infected Patients.

The hepatitis C virus nonstructural 3/4A protease has been shown to cleave protein tyrosine phosphatase nonreceptor type 2 (PTPN2, also known as T cell protein tyrosine phosphatase), thereby inducing a shift from a Th1 toward a nonantiviral Th2 immunity. Ribavirin therapy reverses these effects and supports direct-acting antiviral (DAA) therapy as an immunomodulatory compound and ultimately improv...

B-Cell Precursor-Acute Lymphoblastic Leukemia With EBF1-PDGFRB Fusion Treated With Hematopoietic Stem Cell Transplantation and Imatinib: A Case Report and Literature Review.

A 9-year-old girl was diagnosed with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL). Although she entered remission after induction therapy, she relapsed 15 months after maintenance therapy cessation. Since further investigation revealed EBF1-PDGFRB fusion, her condition was treated as BCR-ABL1-like acute lymphoblastic leukemia. She was started on a tyrosine kinase inhibitor, imatinib, an...

Birth weight related blood concentrations of the neurotransmission amino acids glutamine plus glutamate, phenylalanine and tyrosine in full-term breastfed infants perinatally.

Background The amino acids glutamine plus glutamate, phenylalanine and tyrosine are implicated in neurotransmission. We aimed to evaluate these amino acid blood concentrations in full-term breastfed infants with different birth weight (BW) perinatally. Methods Breastfed full-term infants (n = 6000, males 3000, females 3000) BW 2000-4000 g were divided into four equal groups. Both males and fem...

Control of clathrin-mediated endocytosis by NIMA family kinases.

Endocytosis, the process by which cells internalize plasma membrane and associated cargo, is regulated extensively by posttranslational modifications. Previous studies suggested the potential involvement of scores of protein kinases in endocytic control, of which only a few have been validated in vivo. Here we show that the conserved NIMA-related kinases NEKL-2/NEK8/9 and NEKL-3/NEK6/7 (the NEKLs)...

Tyrosine kinase signaling in and on the endoplasmic reticulum.

Tyrosine kinases are signaling molecules that are common to all metazoans and are involved in the regulation of many cellular processes such as proliferation and survival. While most attention has been devoted to tyrosine kinases signaling at the plasma membrane and the cytosol, very little attention has been dedicated to signaling at endomembranes. In this review, I will discuss recent evidence t...

Chemoenzymatic Semisynthesis of Phosphorylated α-Synuclein Enables Identification of a Bidirectional Effect on Fibril Formation.

Post-translational modifications (PTMs) impact the pathological aggregation of α-synuclein (αS), a hallmark of Parkinson's disease (PD). Here, we synthesize αS phosphorylated at tyrosine 39 (pY) through a novel route using enzymatic phosphorylation of a fragment followed by ligation to form the full-length protein. We can execute this synthesis in combination with unnatural amino acid mutagene...

ASK1 inhibition: a therapeutic strategy with multi-system benefits.

p38 mitogen-activated protein kinases (P38α and β) and c-Jun N-terminal kinases (JNK1, 2, and 3) are key mediators of the cellular stress response. However, prolonged P38 and JNK signalling is associated with damaging inflammatory responses, reactive oxygen species-induced cell death, and fibrosis in multiple tissues, such as the kidney, liver, central nervous system, and cardiopulmonary systems...

The GLP-2 analogue elsiglutide reduces diarrhoea caused by the tyrosine kinase inhibitor lapatinib in rats.

Lapatinib is a small molecule tyrosine kinase inhibitor used to treat breast cancer, often in combination with chemotherapy. Diarrhoea commonly occurs in up to 78% of patients undertaking lapatinib treatment. The mechanism of this diarrhoea is currently unknown. Elsiglutide is a GLP-2 analogue known to increase cell proliferation and reduce apoptosis in the intestine.

Mechanisms regulating PIF transcription factor activity at the protein level.

Plant growth and development are precisely regulated by transcription factors (TFs) such as the PHYTOCHROME INTERACTING FACTORs (PIFs). PIFs regulate growth in response to various internal and external stimuli, and, accordingly, are regulated by a variety of different factors and mechanisms. Canonically, PIF activity is inhibited by light through the sequential phosphorylation, ubiquitination, and...

Tyrosine-Based Signals Regulate the Assembly of Daple⋅PARD3 Complex at Cell-Cell Junctions.

Polarized distribution of organelles and molecules inside a cell is vital for a range of cellular processes and its loss is frequently encountered in disease. Polarization during planar cell migration is a special condition in which cellular orientation is triggered by cell-cell contact. We demonstrate that the protein Daple (CCDC88C) is a component of cell junctions in epithelial cells which serv...

Comprehensive Proteomic Characterization Reveals Subclass-Specific Molecular Aberrations within Triple-negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer lacking targeted therapies. This is attributed to its high heterogeneity that complicates elucidation of its molecular aberrations. Here, we report identification of specific proteome expression profiles pertaining to two TNBC subclasses, basal A and basal B, through in-depth proteomics analysis of breast cancer c...

Anti-Proliferative Role of the Tyrosine Kinase Inhibitors TKI-258 on Oral Squamous Cell Carcinoma In Vitro.

Identification of the antitumor role of tyrosine kinase inhibitors, such as TKI-258, may lead to novel therapeutics for Oral Squamous Cell Carcinoma (OSCC), which has high mortality rates. TKI-258 blocks Fibroblast Growth Factor Receptors (FGFRs), Platelet-Derived Growth Factor Receptors (PDGFRs), and Endothelial Growth Factor Receptor (VEGFRs).

Cataloguing the dead: breathing new life into pseudokinase research.

Pseudoenzymes are present within many, but not all, known enzyme families, and lack one or more conserved canonical amino acids that help define their catalytically-active counterparts. Recent findings in the pseudokinase field confirm that evolutionary re-purposing of the structurally-defined bilobal protein kinase fold permits distinct biological functions to emerge, many of which rely on confor...

AMPKα Subunit Ssp2 and Glycogen Synthase Kinases Gsk3/Gsk31 are involved in regulation of sterol regulatory element-binding protein (SREBP) activity in fission yeast.

Sterol regulatory element-binding protein (SREBP), a highly conserved family of membrane-bound transcription factors, is an essential regulator for cellular cholesterol and lipid homeostasis in mammalian cells. Sre1, the homolog of SREBP in the fission yeast Schizosaccharomyces pombe (S. pombe), regulates genes involved in the transcriptional responses to low sterol as well as low oxygen. Previous...

Expression of Receptor Tyrosine Kinases on Peripheral Blood Mononuclear Cells and Tumor-Infiltrating Lymphocytes in Patients with Renal Cell Carcinoma and Healthy Donors.

Very little is known about receptor tyrosine kinase (RTK) expression on peripheral blood mononuclear cells (PBMC) in humans including renal cell carcinoma (RCC) patients.

Regulation of lung endothelial permeability by NEK kinases.

Dysregulation of lung endothelial barrier function may lead to lethal outcomes, as demonstrated in the case of the acute respiratory distress syndrome (ARDS). p53 participates in the regulation of the lung endothelial barrier, and it has been associated both in vivo and in vitro with protective effects against the LPS-induced hyperpermeability. Family members of the never in mitosis A-related kina...

Uncommon nornardosinane, seconeolemnane and related sesquiterpenoids from Xisha soft coral Litophyton nigrum.

Three new nardosinane-type sesquiterpenoids linardosinenes A-C (1-3) and four new neolemnane-type sesquiterpenoids lineolemnenes A-D (4-7), together with the related known compound 4-acetoxy-2,8-neolemnadien-5-one (8), were isolated from the Xisha soft coral Litophyton nigrum. The structures of these new compounds were elucidated by comprehensive analyses of spectroscopic data, in association with...

Potential tripeptides against the tyrosine kinase domain of human epidermal growth factor receptor (HER) 2 through computational and kinase assay approaches.

An abnormal activation of human epidermal growth factor receptor (HER) 2 has been found to associate with several types of human cancer, and thus the protein is a prominent target for cancer therapy. Although several small chemical molecules targeting the tyrosine kinase (TK) of HER family have been identified, the development of a new class of inhibitors, i.e., small peptides inhibiting the funct...

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