Fibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links to several hallmarks of cancer. Genetic ...alterations in FGF receptor (
) family members are associated with increased tumor growth, metastasis, angiogenesis, and decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases. JNJ-42756493 shows rapid uptake into the lysosomal compartment of cells in culture, which is associated with prolonged inhibition of FGFR signaling, possibly due to sustained release of the inhibitor. In xenografts from human tumor cell lines or patient-derived tumor tissue with activating FGFR alterations, JNJ-42756493 administration results in potent and dose-dependent antitumor activity accompanied by pharmacodynamic modulation of phospho-FGFR and phospho-ERK in tumors. The results of the current study provide a strong rationale for the clinical investigation of JNJ-42756493 in patients with tumors harboring FGFR pathway alterations.
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Summary
Antenatal screening/testing of pregnant women should be carried out according to the guidelines of the National Health Service (NHS) Sickle Cell and Thalassaemia Screening Programme. Newborn ...screening and, when necessary, follow‐up testing and referral, should be carried out according to the guidelines of the NHS Sickle Cell and Thalassaemia Screening Programme. All babies under 1 year of age arriving in the United Kingdom should be offered screening for sickle cell disease (SCD). Preoperative screening for SCD should be carried out in patients from ethnic groups in which there is a significant prevalence of the condition. Emergency screening with a sickle solubility test must always be followed by definitive analysis. Laboratories performing antenatal screening should utilise methods that are capable of detecting significant variants and are capable of quantitating haemoglobins A
2
and F at the cut‐off points required by the national antenatal screening programme. The laboratory must ensure a provisional report is available for antenatal patients within three working days from sample receipt.
Genetic variants at three quantitative trait loci (QTL) for fetal haemoglobin (HbF), BCL11A, HBS1L-MYB and the β-globin gene cluster, have attracted interest as potential targets of therapeutic ...strategies for HbF reactivation in sickle cell anaemia (SCA). We carried out the first systematic evaluation of critical single nucleotide polymorphisms at these disease modifier loci in Nigerian patients with SCA. Common variants for BCL11A and HBS1L-MYB were strongly associated with HbF levels. At both loci, secondary association signals were detected, illustrating the mapping resolution attainable in this population. For BCL11A, the two independent sites of association were represented by rs1427407 (primary site, p = 7.0 x 10(-10)) and rs6545816 (secondary site, conditioned on rs1427407: p = 0.02) and for HBS1L-MYB by rs9402686 (HMIP-2B, p = 1.23 x 10(-4)) and rs66650371 (HMIP-2A, p = 0.002). Haplotype analysis revealed similarities in the genetic architecture of BCL11A and HBS1L-MYB in Nigerian patients. Variants at both loci also alleviated anaemia. The variant allele for the γ globin gene promoter polymorphism XmnI-HBG2 was too infrequent in our patients to be evaluated in this relatively small study. Studying the large and diverse SCA patient populations in African countries such as Nigeria will be key for a clearer understanding of how these loci work and for the discovery of new disease modifier genes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sickle cell disease (SCD) is characterized by variable clinical outcomes, with some patients suffering life‐threatening complications during childhood, and others living relatively symptom‐free into ...old age. Because of this variability, there is an important potential role for precision medicine, in which particular different treatments are selected for different groups of patients. However, the application of precision medicine in SCD is limited by difficulties in identifying different prognostic groups and the small number of available treatments. The main genetic determinant of outcomes in SCD is the underlying β‐globin genotype, with sickle cell anemia (HbSS) and hemoglobin SC disease (HbSC) forming the 2 major forms of the disease in most populations of African origin. Although there are clear differences in clinical outcomes between these conditions, treatments approaches are very similar, with little evidence on how to treat HbSC in particular. Other genomic information, such as the co‐inheritance of α‐thalassemia, or high fetal hemoglobin (HbF) levels, is of some prognostic value but insufficient to determine treatments. Precision medicine is further limited by the fact that the 2 main drugs used in SCD, penicillin and hydroxyurea, are currently recommended for all patients. Newer treatments, such as crizanlizumab and voxelotor, raise the possibility that groups will emerge who respond best to particular drugs or combinations. Perhaps the best current example of precision medicine in SCD is the selective use of blood transfusions as primary stroke prevention in children with evidence of cerebral vasculopathy. More precise treatments may emerge as we understand more about the pathology of SCD, including problems with erythropoiesis.
This study offers a detailed and original assessment of the practices of prescription veterinary medicine use on UK dairy farms. The emergence of antimicrobial resistance as a global threat has ...necessitated an increasing focus on medicine use in agriculture. While an abundance of studies have recently emerged to demonstrate and evaluate strategies for medicine reduction, this paper seeks to understand the context and the on-farm culture within which treatment practices occur on a sample of UK dairy farms. Arguing that the experiential knowledge, on-farm culture and informal information flows are as important as ‘science’ in the practice of treatment decision making and drawing on extensive participant observation fieldwork combined with semi-structured interviews, this paper identifies and discusses three key themes that develop and, in places, challenge our current understanding of farmer treatment practices. These areas - treatment knowledge and understanding, a duty of care and autonomy of treatment practice - are seen to have complex effects on the use of veterinary medicines in dairy cattle and, as such, highlight critical areas for further research and opportunities for policy interventions aimed at improving responsible medicine use.
•Farmers construct their own narratives of disease and treatment, based on experiential and experimental knowledges.•Uncertainty remains a key element of treatment decision-making, which can manifest as risk-averse behaviour.•Farmers are strongly motivated to treat by a sense of duty to the wellbeing of the animals for which they are responsible.•A perceived lack of autonomy with regard to treatment decisions directly affected dairy farmers' medicine use behaviours.
Pyruvate kinase deficiency (PKD) is the most common enzyme defect of glycolysis and an important cause of hereditary, nonspherocytic hemolytic anemia. The disease has a worldwide geographical ...distribution but there are no verified data regarding its frequency. Difficulties in the diagnostic workflow and interpretation of PK enzyme assay likely play a role. By the creation of a global PKD International Working Group in 2016, involving 24 experts from 20 Centers of Expertise we studied the current gaps in the diagnosis of PKD in order to establish diagnostic guidelines. By means of a detailed survey and subsequent discussions, multiple aspects of the diagnosis of PKD were evaluated and discussed by members of Expert Centers from Europe, USA, and Asia directly involved in diagnosis. Broad consensus was reached among the Centers on many clinical and technical aspects of the diagnosis of PKD. The results of this study are here presented as recommendations for the diagnosis of PKD and used to prepare a diagnostic algorithm. This information might be helpful for other Centers to deliver timely and appropriate diagnosis and to increase awareness in PKD.
In sickle cell disease (SCD), a single amino acid substitution at β6 of the hemoglobin (Hb) chain replaces glutamate with valine, forming HbS instead of the normal adult HbA. Loss of a negative ...charge, and the conformational change in deoxygenated HbS molecules, enables formation of HbS polymers. These not only distort red cell morphology but also have other profound effects so that this simple etiology belies a complex pathogenesis with multiple complications. Although SCD represents a common severe inherited disorder with life-long consequences, approved treatments remain inadequate. Hydroxyurea is currently the most effective, with a handful of newer treatments, but there remains a real need for novel, efficacious therapies.
This review summarizes important early events in pathogenesis to highlight key targets for novel treatments.
A thorough understanding of early events in pathogenesis closely associated with the presence of HbS is the logical starting point for identification of new targets rather than concentrating on more downstream effects. We discuss ways of reducing HbS levels, reducing the impact of HbS polymers, and of membrane events perturbing cell function, and suggest using the unique permeability of sickle cells to target drugs specifically into those more severely compromised.
Silent cerebral infarction is the most common neurological abnormality in children with sickle cell anemia, affecting 30-40% of 14 year olds. There are no known biomarkers to identify children with ...silent cerebral infarcts, and the pathological basis is also unknown. We used an unbiased proteomic discovery approach to identify plasma proteins differing in concentration between children with and without silent cerebral infarcts. Clinical parameters and plasma samples were analysed from 51 children (mean age 11.8 years, range 6-18) with sickle cell anemia (HbSS). A total of 19 children had silent cerebral infarcts and 32 normal MRI; the children with silent infarcts had lower HbF levels (8.6
16.1%,
=0.049) and higher systolic blood pressures (115
108.6,
=0.027). Plasma proteomic analysis showed 13 proteins increased more than 1.3 fold in the SCI patients, including proteins involved in hypercoagulability (α2-antiplasmin, fibrinogen-γ chain, thrombospondin-4), inflammation (α2-macroglobulin, complement C1s and C3), and atherosclerosis (apolipoprotein B-100). Higher levels of gelsolin and retinol-binding protein 4 were also found in the population with silent infarcts, both of which have been linked to stroke. We investigated the genetic basis of these differences by studying 359 adults with sickle cell disease (199 with silent cerebral infarcts, 160 normal MRIs), who had previously undergone a genome-wide genotyping array. None of the genes coding for the differentially expressed proteins were significantly associated with silent infarction. Our study suggests that silent cerebral infarcts in sickle cell anemia may be associated with higher systolic blood pressure, lower HbF levels, hypercoagulability, inflammation and atherosclerotic lipoproteins.
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