A5009602470- Cancer-related Molecular Pathways
- Chronic Lymphocytic Leukemia Research
- PI3K/AKT/mTOR signaling in cancer
- Cancer Genomics and Diagnostics
- RNA modifications and cancer
- Chronic Myeloid Leukemia Treatments
- Epigenetics and DNA Methylation
- Immunotherapy and Immune Responses
- Monoclonal and Polyclonal Antibodies Research
- Lung Cancer Treatments and Mutations
- vaccines and immunoinformatics approaches
- Quinazolinone synthesis and applications
- Genomics and Chromatin Dynamics
- Cancer Immunotherapy and Biomarkers
- Genomics and Phylogenetic Studies
- Molecular Biology Techniques and Applications
- Chronic Kidney Disease and Diabetes
- Synthesis and Reactions of Organic Compounds
- Innovative Microfluidic and Catalytic Techniques Innovation
- Renal and related cancers
- MicroRNA in disease regulation
- Acute Myeloid Leukemia Research
- Cancer Treatment and Pharmacology
- Protein Degradation and Inhibitors
- Biochemical and Molecular Research
Novartis (Switzerland)
2011-2024
Novartis Institutes for BioMedical Research
2011-2020
Foundation for Biomedical Research
2018
Novartis (United States)
2018
Pathways Behavioral Services
2012
Sanofi (France)
2012
GlaxoSmithKline (Belgium)
2001-2008
Inserm
2000
Institut Necker Enfants Malades
2000
Friedrich Miescher Institute
1997
Mutations in Notch3 cause CADASIL (cerebral autosomal dominant adult onset arteriopathy), which leads to stroke and dementia humans. arteriopathy is characterized by major alterations of vascular smooth muscle cells the presence specific granular osmiophilic deposits. Patients carry highly stereotyped mutations that lead an odd number cysteine residues within EGF-like repeats receptor extracellular domain. Such may alter processing or trafficking this receptor, favor its oligomerization. In...
Abstract The functional interaction between fibroblast growth factor 23 (FGF-23) and Klotho in the control of vitamin D phosphate homeostasis is manifested by largely overlapping phenotypes Fgf23- Klotho-deficient mouse models. However, to date, targeted inactivation FGF receptors (FGFRs) has not provided clear evidence for an analogous function FGFRs this process. Here, means pharmacologic inhibition FGFRs, we demonstrate their involvement renal FGF-23/Klotho signaling elicit role...
The pan-phosphoinositide 3-kinase (PI3K) inhibitor BKM120 was found, at high concentrations, to cause cell death in various cellular systems, irrespective of their level PI3K addiction. Transcriptional and biochemical profiling studies were used identify the origin these unexpected apparently PI3K-independent effects. At 5- 10-fold, concentration needed half-maximally inhibit signaling. treatment caused changes expression mitotic genes induction a robust G(2)-M arrest. Tubulin polymerization...
Acute kidney injury (AKI) and chronic diseases are associated with high mortality morbidity. Although the underlying mechanisms determining transition from acute to not completely understood, immune-mediated processes critical in renal injury. We have performed a comparison of 2 mouse models leading either regeneration or fibrosis. Using global gene expression profiling we could identify immune-related pathways accounting for majority observed transcriptional changes during Unbiased...
Biomarkers for patient selection are essential the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report discovery a novel strategy p53–HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By intersecting high-throughput cell line sensitivity data with genomic data, have identified gene expression signature consisting 13 up-regulated genes that predicts to NVP-CGM097 both lines patient-derived tumor xenograft models....
Abstract Activation of p53 by inhibitors the p53–MDM2 interaction is being pursued as a therapeutic strategy in wild-type cancers. Here, we report distinct mechanisms which novel, potent, and selective inhibitor HDM201 elicits efficacy when applied at various doses schedules. Continuous exposure led to induction p21 delayed accumulation apoptotic cells. By comparison, high-dose pulses were associated with marked PUMA rapid onset apoptosis. shRNA screens identified mediator response...
Abstract Transcription factor networks shape the gene expression programs responsible for normal cell identity and pathogenic state. Using Core Regulatory Circuitry analysis (CRC), we identify PAX8 as a candidate oncogene in Renal Cell Carcinoma (RCC) cells. Validation of large-scale functional genomic screens confirms that silencing leads to decreased proliferation RCC lines. Epigenomic analyses PAX8-dependent cistrome demonstrate largely occupies active enhancer elements controlling genes...
9045 Background: Gene expression profiling by microarrays was used to identify markers predictive of the clinical activity MAGE-A3 Antigen-Specific Cancer Immunotherapeutic (ASCI) recorded in a phase II study metastatic melanoma. Methods: 75 patients with progressive, unresectable stage III or IV M1a (+) melanomas, were randomized as 1st-line therapy between immunization protein combined GSK proprietary Adjuvant Systems AS15 AS02B. performed on tumor biopsies taken prior any immunization....
Argyrins, produced by myxobacteria and actinomycetes, are cyclic octapeptides with antibacterial antitumor activity. Here, we identify elongation factor G (EF-G) as the cellular target of argyrin B in bacteria, via resistant mutant selection whole genome sequencing, biophysical binding studies crystallography. Argyrin binds a novel allosteric pocket EF-G, distinct from known EF-G inhibitor antibiotic fusidic acid, revealing new mode protein synthesis inhibition. In eukaryotic cells, was...
Spatiotemporal regulation of gene expression is controlled by transcription factor (TF) binding to regulatory elements, resulting in a plethora cell types and states from the same genetic information. Due importance various sequencing methods have been developed localise them genomes, for example using ChIP-seq profiling histone mark H3K27ac that marks active regions. Moreover, multiple tools predict TF these elements based on DNA sequence. As altered hallmark disease phenotypes, identifying...
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurring suppurating lesions of the intertriginous areas, resulting in substantial impact on patients' QOL. HS pathogenesis remains poorly understood. An autoimmune component has been proposed, but disease-specific autoantibodies, autoantigens, or autoreactive T cells have yet to be described. In this study, we identify high prevalence IgM, IgG, and IgA antibodies directed against Nε-carboxyethyl lysine...
We have previously purified and characterized a 5-methylcytosine (5-MeC)-DNA glycosylase from 12 day old chick embryos [Jost,J.P. et al. (1995) J. Biol. Chem. 270, 9734-9739]. The activity of the enzyme is abolished upon treatment with proteinase K ribonuclease A. RNA copurifies 5-MeC-DNA throughout all chromatographic steps preparative gel electrophoresis. length approximately 300-500 nucleotides was isolated enzyme. Upon extensive K, eluted labeled did not show any significant change in...
The histone 3 lysine 79 (H3K79) methyltransferase (HMT) DOT1L is known to play a critical role for growth and survival of MLL-rearranged leukemia. Serendipitous observations during high-throughput drug screens indicated that the use inhibitors might be expandable multiple myeloma (MM). Through pharmacologic genetic experiments, we could validate essential viability subset MM cell lines, in line with recent report from another team. In vivo activity against established xenografts was observed...
Abstract Spatiotemporal regulation of gene expression is controlled by transcription factor (TF) binding to regulatory elements, resulting in a plethora cell types and states from the same genetic information. Due importance various sequencing methods have been developed localise them genomes, for example using ChIP-seq profiling histone mark H3K27ac that marks active regions. Moreover, multiple tools predict TF these elements based on DNA sequence. As altered hallmark disease phenotypes,...
Abstract p53 is a transcription factor that plays central role in guarding genomic stability of the cell through cycle arrest or induction apoptosis. It has also been reported participates regulation tumor immunity and homeostatic immune responses. However, immunomodulatory effect microenvironment not well understood. From gene expression immunohistochemical analysis pre- post-treatment biopsies from patients treated with MDM2 inhibitor NVP-CGM097, we observed upregulation checkpoint...
Abstract Patient selection biomarkers are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study we have identified a novel patient strategy NVP-CGM097, p53-Mdm2 inhibitor currently in Phase I clinical trial (NCT01760525). We analyzed sensitivity over 500 cell lines from “Cancer Cell Line Encyclopedia” to viability assays, intersected response data with information on gene expression genomic alterations. This analysis has led...
Abstract NVP-BKM120 is a pan class I PI3K inhibitor that has recently entered phase II clinical trials. The compound was shown to inhibit cell proliferation and survival of cancer models displaying pathway dependency, in dose-dependent manner, proportionally the extent inhibition. To further characterize NVP-BKM120, we have investigated its mechanism action across broad range relevant concentrations molecule compared it other inhibitors (e.g. GDC0941 ZSTK474). effects observed on...
<div>Abstract<p>Activation of p53 by inhibitors the p53–MDM2 interaction is being pursued as a therapeutic strategy in wild-type cancers. Here, we report distinct mechanisms which novel, potent, and selective inhibitor HDM201 elicits efficacy when applied at various doses schedules. Continuous exposure led to induction p21 delayed accumulation apoptotic cells. By comparison, high-dose pulses were associated with marked PUMA rapid onset apoptosis. shRNA screens identified mediator...