A5077757906- Lung Cancer Treatments and Mutations
- Protein Kinase Regulation and GTPase Signaling
- Cancer-related Molecular Pathways
- Enzyme Structure and Function
- Cancer Immunotherapy and Biomarkers
- Advanced Proteomics Techniques and Applications
- Monoclonal and Polyclonal Antibodies Research
- Cancer, Hypoxia, and Metabolism
- Cancer therapeutics and mechanisms
- Prostate Cancer Treatment and Research
- Cytokine Signaling Pathways and Interactions
- HER2/EGFR in Cancer Research
- Colorectal Cancer Treatments and Studies
- Melanoma and MAPK Pathways
- Ubiquitin and proteasome pathways
- Molecular Biology Techniques and Applications
- PI3K/AKT/mTOR signaling in cancer
- Acute Ischemic Stroke Management
- Plant-based Medicinal Research
- Spondyloarthritis Studies and Treatments
- Hormonal and reproductive studies
- Biotin and Related Studies
- Antiplatelet Therapy and Cardiovascular Diseases
- Gender Diversity and Inequality
- Estrogen and related hormone effects
AstraZeneca (United Kingdom)
2014-2024
Leipzig University
2024
Western University
2007-2024
Eli Lilly (United States)
2023-2024
University of South Florida
2024
University College London
2010-2022
Campbell Collaboration
2021
British Heart Foundation
2017
Leeds Teaching Hospitals NHS Trust
2017
Leeds General Infirmary
2017
The extensive research examining relations between group member dissimilarity and outcome measures has yielded inconsistent results. In the present research, authors used computer simulations to examine impact that a methodological feature of such participant nonresponse, can have on dissimilarity-outcome relations. Results suggest using only survey responders calculate typically results in underestimation true effects these occur even when response rates are high.
Abstract Resistance to targeted EGFR inhibitors is likely develop in EGFR-mutant lung cancers. Early identification of innate or acquired resistance mechanisms these agents essential direct development future therapies. We describe the detection heterogeneous within populations cells (PC9 and/or NCI-H1975) with current and newly developed tyrosine kinase inhibitors, including AZD9291. report NRAS mutations, a novel E63K mutation, gain copy number WT KRAS cell resistant gefitinib, afatinib,...
Activating mutations in KRAS underlie the pathogenesis of up to 20% human tumors, and is one most frequently mutated genes cancer. Developing therapeutics block activity has proven difficult, no direct inhibitor function entered clinical trials. We describe preclinical evaluation AZD4785, a high-affinity constrained ethyl-containing therapeutic antisense oligonucleotide (ASO) targeting mRNA. AZD4785 potently selectively depleted cellular mRNA protein, resulting inhibition downstream effector...
Antisense oligonucleotides (ASOs) modulate cellular target gene expression through direct binding to complementary RNA. Advances in ASO chemistry have led the development of phosphorothioate (PS) ASOs with constrained-ethyl modifications (cEt). These next-generation cEt-ASOs can enter cells without transfection reagents. Factors involved intracellular uptake and trafficking leading successful knockdown are highly complex not yet fully understood. AZD4785 is a potent selective therapeutic...
Abstract Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins tumor regression but ultimately fail to elicit cures. As result, there is an intense interest how best combine targeted therapies with other treatments, immunotherapies. However, preclinical systems for studying the interaction tumors host immune system are inadequate, part due low mutational burden genetically engineered mouse models. Here we set out develop models...
KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based design approach led the identification of 21, AZD4625, a clinical development candidate for treatment KRASG12C positive tumors. Highlights include quinazoline tethering strategy lock out bio-relevant binding conformation and optimization focused on reduction...
OBJECTIVES: To define the clinical, neuropsychological, and radiological features of bilateral parietal lobe atrophy. METHODS: Four patients underwent a comprehensive longitudinal neuropsychological assessment, as well MRI HMPAO-SPECT. RESULTS: The consistent findings in were early visuospatial problems, agraphia predominantly peripheral (or apraxic) type, difficulty with bimanual tasks, all which outweighted deficits memory language until later course illness. As disease progressed,...
We describe the characterization of Ybp1, a novel protein, in Saccharomyces cerevisiae, that is required for oxidative stress response to peroxides. Ybp1 H2O2-induced expression antioxidant encoding gene TRX2. Our data indicate effects are mediated through Yap1 transcription factor. Indeed, forms stress-induced complex with vivo and stimulates nuclear accumulation H2O2 but not thiol-oxidizing agent diamide. The regulated by oxidation specific cysteine residues dependent on thiol peroxidase...
Abstract Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical ablation therapies have failed, therefore remains target for the treatment of progressive disease. Here, we describe biological characterization AZD3514, an orally bioavailable drug that inhibits androgen-dependent -independent AR signaling. AZD3514 modulates through two distinct mechanisms, inhibition ligand-driven nuclear translocation...
Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" has recently yielded covalent targeting small molecules that bind cysteine create allosteric pocket on GDP-bound RAS, locking it in inactive state. A weak inhibitor at this site was optimized through conformational of a piperazine-quinazoline motif linker modification. Subsequent introduction key methyl...
The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach led the identification 14, AZD4747, a clinical development candidate for treatment KRASG12C-positive tumors, including central nervous system (CNS) metastases. Building on earlier discovery C5-tethered quinazoline AZD4625, excision usually critical pyrimidine ring yielded weak...
Abstract Background/objective To explore the anti-tumour activity of combining AKT inhibition and docetaxel in PTEN protein null WT prostate tumours. Methods Mechanisms associated with capivasertib treatment cancer were examined using a panel vivo tumour models cell lines. Results Combining had increased vivo. In vitro short-term caused cycle arrest majority cells. However, sub-population docetaxel-persister cells did not undergo G2/M but upregulated phosphorylation PI3K/AKT pathway...
A genetic screen was performed in Saccharomyces cerevisiae to identify mechanisms important for the transcriptional activation of genes encoding antioxidant proteins. Thioredoxin peroxidase, Tsa1p, thioredoxin system, found be essential induction other components TRX2 (thioredoxin) andTRR1 (thioredoxin reductase), response H 2 O . The expression is known regulated by transcription factors Yap1p and Skn7p , Tsa1p-dependent regulation requires Yap1p/Skn7p pathway. data suggest that system...
Research examining relations between work group diversity and outcome measures often relies on scores that are calculated the basis of individual responses to organizational surveys. When employees fail respond a survey, however, resultant score representing their will be somewhat distorted. The authors conducted series computer simulations examine extent which correlations (derived from continuous or categorical variables) variables were attenuated by various forms random systematic...
The Notch signaling pathway has been implicated in cell fate determination and differentiation many tissues. Accumulating evidence points toward a pivotal role blood vessel formation, the importance of Delta-like ligand (Dll) 4-Notch1 ligand-receptor interaction shown both physiological tumor angiogenesis. Disruption this leads to reduction growth as result an increase nonfunctional vasculature leading poor perfusion tumor. MEDI0639 is investigational human therapeutic antibody that targets...
Background. Cardiac rehabilitation programs have evolved to become secondary prevention centers. However, the independent effect of exercise alone on coronary risk factors and body composition in patients with artery disease has not been well studied. Objective. The aim this study was determine training alone, without modification dietary intake, a population. Methods. authors studied 82 (23 females 59 males) aged 61.2 ± 12.2 years (mean SD) before after 3-month program. Outcome variables...
Background Few studies have investigated the influence of body composition, abdominal obesity, age and fitness on coronary risk factors in populations patients with heart disease (CHD). We whether obesity or generalized adiposity is a better predictor cardiovascular men artery (CAD), effects exercise training younger older CAD. Methods The study population consisted 81 male aged 33–83 years (mean ± SD 60.0 13.3 years) established studied relationships among fat distribution, dietary intake,...