A5024034145- Hemoglobinopathies and Related Disorders
- Iron Metabolism and Disorders
- Erythrocyte Function and Pathophysiology
- Blood groups and transfusion
- Neonatal Health and Biochemistry
- Porphyrin Metabolism and Disorders
- Prenatal Screening and Diagnostics
- Chemical Synthesis and Analysis
- Heme Oxygenase-1 and Carbon Monoxide
- Fibroblast Growth Factor Research
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Folate and B Vitamins Research
- Neuropeptides and Animal Physiology
- Computational Drug Discovery Methods
- Melanoma and MAPK Pathways
- Parvovirus B19 Infection Studies
- Methemoglobinemia and Tumor Lysis Syndrome
- Metabolism and Genetic Disorders
- Photosynthetic Processes and Mechanisms
- Synthesis and biological activity
- Receptor Mechanisms and Signaling
- Pharmacological Receptor Mechanisms and Effects
- Biochemical and Molecular Research
- Bone and Joint Diseases
- Hematological disorders and diagnostics
King's College Hospital
2016-2025
King's College London
2016-2025
King's College Hospital NHS Foundation Trust
2015-2024
SickKids Foundation
2023
University of Toronto
2023
Novartis (India)
2023
University of Alabama at Birmingham
2023
King's College - North Carolina
2006-2022
University College London
1993-2022
Great Ormond Street Hospital
2018-2022
Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation (ALA) and porphobilinogen, is central to the pathogenesis acute attacks chronic symptoms in porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression.In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients porphyria receive either subcutaneous givosiran (2.5 mg per kilogram body weight) or placebo monthly for 6 months. The primary...
Crystals of the reaction center (RC) from Rhodopseudomonas sphaeroides with space group P2(1)2(1)2(1), have been studied by x-ray diffraction. The Patterson search (molecular replacement) technique was used to analyze data, structure viridis as a model system. A preliminary electron density map R. has obtained. Comparison RC that showed following conserved features: five membrane-spanning helices in each L and M subunits, single helix H subunit, 2-fold symmetry axis, similar positions...
Here, we describe the identification of a clinical candidate via structure-based optimization ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play key role in regulation mitosis and recent years have become attractive targets for treatment cancer. X-ray crystallographic structures were generated using novel soakable form A used to drive toward potent (IC(50) approximately 3 nM) dual A/Aurora B inhibitors. These compounds inhibited growth survival HCT116 cells produced...
Abstract Generalized lymphatic dysplasia (GLD) is a rare form of primary lymphoedema characterized by uniform, widespread affecting all segments the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces pericardial effusions. This may present prenatally non-immune hydrops. Here we report homozygous and compound heterozygous mutations in PIEZO1 , resulting an autosomal recessive GLD high incidence hydrops fetalis childhood onset...
Fibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links several hallmarks of cancer. Genetic alterations FGF receptor (FGFR) family members are associated with increased tumor growth, metastasis, angiogenesis, decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule potent tyrosine kinase inhibitory activity against all four FGFR selectivity versus other highly related...
Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and subsequent optimization two hits into leads with inhibitory activities low nanomolar range. This paper describes structure guided 2,4-dihydroxybenzamide lead molecule 1 details some drug discovery...
Induction of delta aminolevulinic acid synthase 1 (ALAS1) gene expression and accumulation neurotoxic intermediates result in neurovisceral attacks disease manifestations patients with acute intermittent porphyria, a rare inherited heme biosynthesis. Givosiran is an investigational RNA interference therapeutic agent that inhibits hepatic ALAS1 synthesis.
Hereditary hemolytic anemias are a group of disorders with variety causes, including red cell membrane defects, blood enzyme disorders, congenital dyserythropoietic anemias, thalassemia syndromes and hemoglobinopathies. As damaged cells passing through the pulp spleen removed by splenic macrophages, splenectomy is one possible therapeutic approach to management severely affected patients. However, except for hereditary spherocytosis which effectiveness has been well documented, efficacy in...
Background and Aims Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, long‐term complications. There is lack multinational, prospective data characterizing the disease current treatment practices severely affected patients. Approach Results EXPLORE prospective, natural history study activity clinical management patients with who...
Membrane-exposed residues are more hydrophobic than buried interior in the transmembrane regions of photosynthetic reaction center from Rhodobacter sphaeroides . This organization is opposite to that water-soluble proteins. The relative polarities and surface membrane water soluble proteins not simply reversed, however. hydrophobicities both comparable, whereas bilayer-exposed residues, aqueous-exposed hydrophilic residues. A method sequence analysis described, based on periodicity residue...
Genomic DNA from 106 cases of adult de novo acute myeloid leukaemia (AML) was screened by polymerase chain reaction (PCR) and gel electrophoresis for FLT3 internal tandem duplication (ITD) mutations within the juxtamembrane (JM) domain. were detected in 14 (13.2%) occurred FAB types M1 (4 out cases), M3 (1 10 M4 (5 37 cases) M5 11 cases). Sequence analysis four with abnormal PCR electrophoretic patterns revealed frame duplications region exon between 27 111 base pairs. Three are predicted to...