Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
276
result(s) for
"March, Michael"
Sort by:
من الفكرة إلى الريادة : تحويل الأفكار المبتكرة إلى مشاريع ريادية ناجحة
صمم هذا الدليل لمساعدة المختصين في خلق تحديات الابتكار ودعمها، فهو يجمع ما بين عمليات اختيارية أو موازية عدة، أو عمليات يكمل بعضها بعضا وستجد في كل فص المراحل التي يمكنك اتباعها في كل عملية ويساعد الكتاب القراء على تحديد فرص الابتكار، وترتيب الأولويات، واختيار خطة تنفيذ لفرصة مستهدفة وبنائها بواسطة إرشادات مصورة توفر مثل، رؤية واضحة للخطوات الأساسية في عملية الابتكار، وإرشادات لصياغة الأفكار الأولية وتقييم مدى فاعليتها، وآليات تيسير الاجتماعات وورش العمل في أثناء عملية الابتكار، والقدرة على تحديد الطريقة الفعالة لتوليد الأفكار بناء على حالة معينة.
Book
Kaposiform lymphangiomatosis effectively treated with MEK inhibition
Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly primarily affecting the mediastinum with high mortality rate. We present a patient with KLA and significant disease burden harboring a somatic point mutation in the
Casitas B lineage lymphoma
(
CBL
) gene. She was treated with MEK inhibition with complete resolution of symptoms, near‐complete resolution of lymphatic fluid burden, and remodeling of her lymphatic system. While patients with KLA have been reported to harbor mutations in
NRAS
, here we report for the first time a causative mutation in the
CBL
gene in a patient with KLA, successfully treated with Ras pathway inhibition.
Synopsis
Report of a patient with the rare lymphatic anomaly, Kaposiform lymphangiomatosis (KLA). CBL proto‐oncogene mutation was identified and she was successfully treated by targeting the MAP kinase pathway.
Identification of CBL mutation driving KLA.
Patient successfully treated with MEK inhibition.
Graphical Abstract
Report of a patient with the rare lymphatic anomaly, Kaposiform lymphangiomatosis (KLA). CBL proto‐oncogene mutation was identified and she was successfully treated by targeting the MAP kinase pathway.
Journal Article
Superman Action Comics : the Oz effect
\"Shrouded in mystery for years, the puppetmaster known as Mr. Oz has finally shown his hand. His agents have begun to move as the Man of Steel works to stop the chaos they unleash in Metropolis and across the globe. But when Mr. Oz steps from the shadows, his identity rocks the Last Son of Krypton to his core. Who is he? The answer will change Superman forever. A mystery that has weaved through the pages of DC UNIVERSE: REBIRTH, DETECTIVE COMICS, ACTION COMICS and even Geoff Johns' SUPERMAN: THE MEN OF TOMORROW, is finally resolved here in SUPERMAN - ACTION COMICS: THE OZ EFFECT! Written by legendary scribe Dan Jurgens and illustrated by a team of superstar artists led by Ryan Sook and Viktor Bogdonavic, this graphic novel features a lenticular motion cover only available in the first print run!\"-- Provided by publisher.
Book
ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor
The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations
1
. Identifying the causal genes will allow for developing affordable therapies in keeping with precision medicine implementation
2
. Here we identified a recurrent gain-of-function
ARAF
mutation (c.640T>C:p.S214P) in a 12-year-old boy with advanced anomalous lymphatic disease unresponsive to conventional sirolimus therapy and in another, unrelated, adult patient. The mutation led to loss of a conserved phosphorylation site. Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions, which were rescued using the MEK inhibitor trametinib. The functional relevance of the mutation was also validated by recreating a lymphatic phenotype in a zebrafish model, with rescue of the anomalous phenotype using a MEK inhibitor. Subsequent therapy of the lead proband with a MEK inhibitor led to dramatic clinical improvement, with remodeling of the patient’s lymphatic system with resolution of the lymphatic edema, marked improvement in his pulmonary function tests, cessation of supplemental oxygen requirements and near normalization of daily activities. Our results provide a representative demonstration of how knowledge of genetic classification and mechanistic understanding guides biologically based medical treatments, which in our instance was life-saving.
A recurrent gain-of-function mutation in
ARAF
causes lymphatic anomaly in two unrelated patients, and treating one of the patients with an FDA-approved MEK inhibitor resulted in a remarkable recovery, exemplifying the power of precision medicine.
Journal Article
Wild target
\" ... Rose [is] a free-spirited thief who finds herself in the crosshairs of a world-class assassin named Victor ... But when Victor spares Rose's life, the lonely-hearted hitman sets off an outrageous chain of events that turn both their worlds upside down. Joined by a gun-toting apprentice ..., the unlikely trio teams up to thwart the murderous intentions of Victor's unhappy client\"--Container.
DVD
Phenotype wide association study links bronchopulmonary dysplasia with eosinophilia in children
Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Despite this, genetic drivers of BPD are poorly understood. The objective of this study is to better understand the impact of single nucleotide polymorphisms (SNPs) previously associated with BPD by examining associations with other phenotypes. We drew pediatric subjects from the biorepository at the Center for Applied Genomics to identify associations between these SNPs and 2,146 imputed phenotypes. Methylation data, external cohorts, and in silico validation methods were used to corroborate significant associations. We identified 60 SNPs that were previously associated with BPD. We found a significant association between rs3771150 and rs3771171 and mean eosinophil percentage in a European cohort of 6,999 patients and replicated this in external cohorts. Both SNPs were also associated with asthma, COPD and FEV1/FVC ratio. These SNPs displayed associations with methylation probes and were functionally linked to ST2 (IL1RL1) levels in blood and lung tissue. Our findings support a genetic justification for the epidemiological link between BPD and asthma. Given the well-established link between ST2 and type 2 inflammation in asthma, these findings provide a rationale for future studies exploring the role of type 2 inflammation in the pathogenesis of BPD.
Journal Article
Intragenic Deletions of GNAS in Pseudohypoparathyroidism Type 1A Identify a New Region Affecting Methylation of Exon A/B
Abstract
Context
Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are caused by inactivating mutations in the exons of GNAS that encode the alpha-subunit of the stimulatory G protein (Gsα). In some cases abnormal methylation of exon A/B of GNAS, a hallmark of PHP1B, has been reported.
Objective
To identify the underlying genetic basis for PHP1A/PPHP in patients in whom molecular defects were not detected by GNAS sequencing and microarray-based analysis of copy number variations.
Methods
Whole genome sequencing (WGS) and pyrosequencing of differentially methylated regions (DMRs) of GNAS using genomic deoxyribonucleic acid from affected patients.
Results
We identified 2 novel heterozygous GNAS deletions: a 6.4 kb deletion that includes exon 2 of GNAS in the first proband that was associated with normal methylation (57%) of exon A/B DMR, and a 1438 bp deletion in a second PHP1A patient that encompasses the promoter region and 5′ untranslated region of Gsα transcripts, which was inherited from his mother with PPHP. This deletion was associated with reduced methylation (32%) of exon A/B DMR.
Conclusions
WGS can detect exonic and intronic mutations, including deletions that are too small to be identified by microarray analysis, and therefore is more sensitive than other techniques for molecular analysis of PHP1A/PPHP. One of the deletions we identified led to reduced methylation of exon A/B DMR, further refining a region needed for normal imprinting of this DMR. We propose that deletion of this region can explain why some PHP1A patients have reduced of methylation of the exon A/B DMR.
Journal Article
Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition
Background
Kaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly involving most commonly the mediastinum, lung, skin and bones with few effective treatments. In recent years, RAS-MAPK pathway mutations were shown to underlie the pathogenesis of several complex lymphatic anomalies. Specifically, an activating NRAS mutation (p.Q61R) was found in the majority of KLA patients. Recent reports demonstrated promising results of treatment with the MEK inhibitor, Trametinib, in patients with complex lymphatic anomalies harboring gain of function mutations in ARAF and SOS1, as well as loss of function mutation in the CBL gene, a negative regulator of the RAS-MAPK pathway. We present a 9-year-old child with a severe case of KLA harboring the typical NRAS (p.Q61R) mutation detected by plasma-derived cell free DNA, responsive to trametinib therapy.
Methods
The NRAS somatic mutation was detected from plasma cfDNA using droplet digital PCR. Concurrent in-vitro studies of trametinib activity on mutant NRAS affected lymphatic endothelial cells were performed using a three-dimensional spheroid sprouting assay.
Results
Trametinib treatment lead to resolution of lifelong thrombocytopenia, improvement of pulmonary function tests and wellbeing, as well as weaning from prolonged systemic steroid treatment. Concurrent studies of mutant NRAS-expressing cells showed enhanced lymphangiogenic capacity along with over activation of the RAS-MAPK and PI3K-AKT-mTOR pathways, both reversed by trametinib.
Conclusions
Trametinib treatment can substantially change the prognosis of patients with RAS pathway associated lymphatic anomalies.
Impact
This is the first description of successful trametinib treatment of a patient with KLA harboring the most characteristic NRAS p.Q61R mutation.
Treatment can significantly change the prognosis of patients with RAS pathway-associated lymphatic anomalies.
We devised an in vitro model of KLA enabling a reproducible method for the continued study of disease pathogenesis.
Mutated NRAS p.Q61R cells demonstrated increased lymphangiogenic capacity.
Journal Article
Integration of GWAS, QTLs and keratinocyte functional assays reveals molecular mechanisms of atopic dermatitis
Atopic dermatitis is a highly heritable and common inflammatory skin condition affecting children and adults worldwide. Multi-ancestry approaches to atopic dermatitis genetic association studies are poised to boost power to detect genetic signal and identify loci contributing to atopic dermatitis risk. Here, we present a multi-ancestry GWAS meta-analysis of twelve atopic dermatitis cohorts from five ancestral populations totaling 56,146 cases and 602,280 controls. We report 101 genomic loci associated with atopic dermatitis, including 16 loci that have not been previously associated with atopic dermatitis or eczema. Fine-mapping, QTL colocalization, and cell-type enrichment analyses identified genes and cell types implicated in atopic dermatitis pathophysiology. Functional analyses in keratinocytes provide evidence for genes that could play a role in atopic dermatitis through epidermal barrier function. Our study provides insights into the etiology of atopic dermatitis by harnessing multiple genetic and functional approaches to unveil the mechanisms by which atopic dermatitis-associated variants impact genes and cell types.
Atopic dermatitis is a highly heritable skin condition. Here, the authors perform a GWAS meta-analysis of atopic dermatitis and carry out downstream analyses and functional experiments to understand the impact of the variants they identify.
Journal Article
Integrative analysis of genome-wide association studies identifies novel loci associated with neuropsychiatric disorders
Neuropsychiatric disorders, such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), bipolar disorder (BIP), and major depressive disorder (MDD) share common clinical presentations, suggesting etiologic overlap. A substantial proportion of SNP-based heritability for neuropsychiatric disorders is attributable to genetic components, and genome-wide association studies (GWASs) focusing on individual diseases have identified multiple genetic loci shared between these diseases. Here, we aimed at identifying novel genetic loci associated with individual neuropsychiatric diseases and genetic loci shared by neuropsychiatric diseases. We performed multi-trait joint analyses and meta-analysis across five neuropsychiatric disorders based on their summary statistics from the Psychiatric Genomics Consortium (PGC), and further carried out a replication study of ADHD among 2726 cases and 16299 controls in an independent pediatric cohort. In the multi-trait joint analyses, we found five novel genome-wide significant loci for ADHD, one novel locus for BIP, and ten novel loci for MDD. We further achieved modest replication in our independent pediatric dataset. We conducted fine-mapping and functional annotation through an integrative multi-omics approach and identified causal variants and potential target genes at each novel locus. Gene expression profile and gene-set enrichment analysis further suggested early developmental stage expression pattern and postsynaptic membrane compartment enrichment of candidate genes at the genome-wide significant loci of these neuropsychiatric disorders. Therefore, through a multi-omics approach, we identified novel genetic loci associated with the five neuropsychiatric disorders which may help to better understand the underlying molecular mechanism of neuropsychiatric diseases.
Journal Article