A5044009830- Amyotrophic Lateral Sclerosis Research
- Developmental Biology and Gene Regulation
- Neurogenetic and Muscular Disorders Research
- Prion Diseases and Protein Misfolding
- Cancer Treatment and Pharmacology
- RNA Research and Splicing
- Congenital heart defects research
- Pluripotent Stem Cells Research
- Neurological diseases and metabolism
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- CRISPR and Genetic Engineering
- Retinoids in leukemia and cellular processes
- Epigenetics and DNA Methylation
- Brain Metastases and Treatment
- Breast Cancer Treatment Studies
- Neurogenesis and neuroplasticity mechanisms
- Glioma Diagnosis and Treatment
- Genomics and Chromatin Dynamics
- Reproductive System and Pregnancy
- Reproductive Biology and Fertility
- Muscle Physiology and Disorders
- Alzheimer's disease research and treatments
- Histone Deacetylase Inhibitors Research
- Maternal and fetal healthcare
- Colorectal Cancer Treatments and Studies
MRC Prion Unit
2022-2025
University College London
2022-2025
Mary Lyon Centre at MRC Harwell
2018-2024
Medical Research Council
2023
Sanford Burnham Prebys Medical Discovery Institute
2010-2019
Discovery Institute
2015-2019
Texas Children's Hospital
2012-2014
Centre for Life
2013
Newcastle University
2013
University of Kentucky
2010
Instilled bleomycin and thoracostomy were utilized in 38 patients with malignant pleural effusions; the therapy produced a complete or partial response rate of 63%. Toxicity was minimal. In intraperitoneal effusions, instillation after drainage 36%. One patient had severe hypotension fever. Patients ovarian breast carcinoma responded best, among them, effusions controlled greater than 70%. Because its low systemic toxicity, absence marrow virtual discomfort, we think that local is indicated...
The vitamin A metabolite retinoic acid (RA) provides patterning information during vertebrate embryogenesis, but the mechanism through which RA influences limb development is unclear. During of proximodistal axis (upper to digits), avian studies suggest that a proximal signal generated in trunk antagonizes distal fibroblast growth factor (FGF) signal. However, mouse and zebrafish genetic loss suppresses forelimb initiation. Here, using pharmacological approaches, we demonstrate not...
This report is the result of an Eastern Cooperative Oncology Group (ECOG) study. Four hundred and 15 patients with inoperable metastatic malignant melanoma, excluding those cutaneous metastases only, were randomized to one three drug treatments: DTIC alone, methyl-CCNU or combination plus methyl-CCNU. Responses seen in 14% (19/127), 15% (18/119) (18/122). Duration response was same (14 weeks) for all treatment groups. There no difference among treatments achieving complete responses....
Epicardial signaling and Rxra are required for expansion of the ventricular myocardial compact zone. Here, we examine Raldh2–/– Rxra–/– mouse embryos to investigate role retinoic acid (RA) in this developmental process. The heart phenotypes Raldh2 mutants very similar characterized by a prominent defect zone growth. Although RA activity is completely lost epicardium adjacent myocardium, not hearts, suggesting that epicardium/myocardium formation. We explored possibility RA-mediated target...
Deciphering the fundamental mechanisms controlling cardiac specification is critical for our understanding of how heart formation initiated during embryonic development and applying stem cell biology to regenerative medicine disease modeling. Using systematic unbiased functional screening approaches, we discovered that Id family helix–loop–helix proteins both necessary sufficient direct mesoderm in frog embryos human cells. Mechanistically, specify fate by repressing two inhibitors...
Abstract Metabolic reprogramming is an active regulator of stem cell fate choices, and successful differentiation in different compartments requires the induction oxidative phosphorylation. However, mechanisms that promote mitochondrial respiration during are poorly understood. Here we demonstrate Stat3 promotes muscle myogenic lineage progression by stimulating mice. We identify Fam3a, a cytokine-like protein, as major downstream effector cells. Fam3a required for commitment skeletal...
Loss of function the RNA-binding protein TDP-43 (TDP-LOF) is a hallmark amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Here we describe TDP-REG, which exploits specificity cryptic splicing induced by TDP-LOF to drive expression when where disease process occurs. The SpliceNouveau algorithm combines deep learning with rational design generate customizable events within protein-coding sequences. We demonstrate that TDP-REG reporters tightly coupled in vitro vivo....
Abstract Retinoic acid (RA) is purported to be required for expression of genes controlling proximodistal ( Meis2 ) or anteroposterior Shh limb patterning. Embryos lacking RDH10, the primary enzyme synthesizing retinaldehyde during mouse development, survive until E14.5 with stunted forelimbs but apparently normal hindlimbs. Using embryos carrying RARE‐lacZ RA‐reporter transgene, we show that endogenous RA activity in Rdh10 trex/trex mutants detected neuroectoderm not limbs initiation and...
Abstract An autosomal dominant GGGGCC repeat expansion in intron 1 of the C9orf72 gene is most common genetic cause both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we set out to engineer a targeted mouse model harbouring pathogenic length humanised allele, order pathological mechanisms physiological context. In human disease, repeats typically range from hundreds thousands units length, representing considerable challenge for cellular vivo generation given...
The epizootic prion disease of cattle, bovine spongiform encephalopathy (BSE), caused variant Creutzfeldt-Jakob (vCJD) in humans following dietary exposure. Codon 129 polymorphism the human protein gene (PRNP), encoding either methionine (M) or valine (V), dictates propagation distinct strains and up to now all but one neuropathologically confirmed vCJD patients have had a 129MM genotype. Concordant with this genetic association, transgenic modelling has established that PrP 129V is...
Syntaxin-6, a SNARE protein involved in intracellular trafficking, is proposed risk factor for sporadic prion disease, progressive supranuclear palsy and Alzheimer's disease. However, no study has validated its functional role these diseases, explored the disease stage at which it acting nor mechanism of action. Here, we show that syntaxin-6 acts early stages experimental mice by increasing transmission following inoculation with low doses. Conversely, does not affect propagation kinetics or...
Significant genetic, behavioural and neuroanatomic heterogeneity is common in autism spectrum- related- neurodevelopmental disorders (NDDs). This constrains the development of effective therapies for diverse patients precision medicine paradigms. has led to search subgroups individuals having etiologic factors/biology (e.g., genetic pathways), thus creating potential uniformity prognosis and/or treatment response. Despite NDDs a strong component, only ~15-20% will present with specific rare...
<title>Abstract</title> TDP-43 is a nuclear protein encoded by the TARDBP gene, which forms pathological aggregates in various neurodegenerative diseases, collectively known as proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These diseases are characterized multiple mechanisms, with disruptions lipid regulatory pathways emerging critical factor. However, role of regulation brain homeostasis potential connection dysfunction to myelin...
To determine the incidence of early hypernatremic dehydration among residents a nursing home care unit (NHCU) presenting with significant febrile episodes (FE).Prospective cohort analytic study. FE were defined as temperature (T) > 100 degrees F oral (o) or 101 rectal (r) for = 24 hours.NHCU in Veterans Administration hospital.A total 130 NHCU monitored during 4-month study period.Blood urea nitrogen (BUN)/creatinine (Cr) (abnormal 25) and serum sodium (Na)(abnormal 146 mmol/L) drawn within...
Tight control over the segregation of endoderm, mesoderm, and ectoderm is essential for normal embryonic development all species, yet how neighboring blastomeres can contribute to different germ layers has never been fully explained. We postulated that microRNAs, which fine-tune many biological processes, might modulate response growth factors other signals govern layer fate. A systematic screen a whole-genome microRNA library revealed let-7 miR-18 families increase mesoderm at expense...
Numbness of the chin, an uncommon neurological symptom, was observed in 15 patients with cancer. Thirteen had breast This symptom usually heralded progressive involvement cranial nerves or cerebrum and denoted a poor prognosis short `tumourfree interval'. The pathogenesis is commonly related to dural Vth nerve at base brain, although metastasis mandible might sometimes be implicated. reason for peculiar predilection mandibular branch trigeminal affected by cancer not known.
Bipotent axial stem cells residing in the caudal epiblast during late gastrulation generate neuroectodermal and presomitic mesodermal progeny that coordinate somitogenesis with neural tube formation, but mechanism controls these two fates is not fully understood. Retinoic acid (RA) restricts anterior extent of fibroblast growth factor 8 (Fgf8) expression both mesoderm plate to control neurogenesis, however it remains unclear where RA acts spatial Fgf8. Here, we found mouse Raldh2-/- embryos,...