8 research outputs found
Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma
Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight
Detectable clonal mosaicism and its relationship to aging and cancer
In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 Ă 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 Ă 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases
Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients
Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation
Activatable cellâbiomaterial interfacing with photo-caged peptides
Spatio-temporally tailoring cellâmaterial interactions is essential for developing smart delivery systems and
intelligent biointerfaces. Here we report new photo-activatable cellâmaterial interfacing systems that
trigger cellular uptake of various cargoes and cell adhesion towards surfaces. To achieve this, we
designed a novel photo-caged peptide which undergoes a structural transition from an antifouling ligand
to a cell-penetrating peptide upon photo-irradiation. When the peptide is conjugated to ligands of
interest, we demonstrate the photo-activated cellular uptake of a wide range of cargoes, including
small fluorophores, proteins, inorganic (e.g., quantum dots and gold nanostars) and organic
nanomaterials (e.g., polymeric particles), and liposomes. Using this system, we can remotely regulate
drug administration into cancer cells by functionalizing camptothecin-loaded polymeric nanoparticles
with our synthetic peptide ligands. Furthermore, we show light-controlled cell adhesion on a peptidemodified surface and 3D spatiotemporal control over cellular uptake of nanoparticles using two-photon
excitation. We anticipate that the innovative approach proposed in this work will help to establish new
stimuli-responsive delivery systems and biomaterials
Quantitative volumetric Raman imaging of three dimensional cell cultures
The ability to simultaneously image multiple biomolecules in biologically relevant
three-dimensional (3D) cell culture environments would contribute greatly to the understanding of complex cellular mechanisms and cellâmaterial interactions. Here, we present a
computational framework for label-free quantitative volumetric Raman imaging (qVRI). We
apply qVRI to a selection of biological systems: human pluripotent stem cells with their
cardiac derivatives, monocytes and monocyte-derived macrophages in conventional cell
culture systems and mesenchymal stem cells inside biomimetic hydrogels that supplied a 3D
cell culture environment. We demonstrate visualization and quantification of fine details in
cell shape, cytoplasm, nucleus, lipid bodies and cytoskeletal structures in 3D with unprecedented biomolecular specificity for vibrational microspectroscopy
Surface Dynamics and LigandâCore Interactions of Quantum Sized Photoluminescent Gold Nanoclusters
Quantum-sized metallic clusters protected by
biological ligands represent a new class of luminescent materials;
yet the understanding of structural information and photoluminescence origin of these ultrasmall clusters remains a
challenge. Herein we systematically study the surface ligand
dynamics and ligandâmetal core interactions of peptide-protected
gold nanoclusters (AuNCs) with combined experimental
characterizations and theoretical molecular simulations. We
show that the peptide sequence plays an important role in
determining the surface peptide structuring, interfacial water
dynamics and ligandâAu core interaction, which can be tailored
by controlling peptide acetylation, constituent amino acid electron donating/withdrawing capacity, aromaticity/hydrophobicity
and by adjusting environmental pH. Specifically, emission enhancement is achieved through increasing the electron density of
surface ligands in proximity to the Au core, discouraging photoinduced quenching, and by reducing the amount of surfacebound water molecules. These findings provide key design principles for understanding the surface dynamics of peptideprotected nanoparticles and maximizing the photoluminescence of metallic clusters through the exploitation of biologically
relevant ligand properties
Preventing tissue fibrosis by local biomaterials interfacing of specific cryptic extracellular matrix information
Matrix metalloproteinases (MMPs) contribute to the breakdown of tissue structures such as
the basement membrane, promoting tissue fibrosis. Here we developed an electrospun
membrane biofunctionalized with a fragment of the laminin b1-chain to modulate the
expression of MMP2 in this context. We demonstrate that interfacing of the b1-fragment with
the mesothelium of the peritoneal membrane via a biomaterial abrogates the release of active
MMP2 in response to transforming growth factor b1 and rescues tissue integrity ex vivo and
in vivo in a mouse model of peritoneal fibrosis. Importantly, our data demonstrate that the
membrane inhibits MMP2 expression. Changes in the expression of epithelial-to-mesenchymal transition (EMT)-related molecules further point towards a contribution of the modulation of EMT. Biomaterial-based presentation of regulatory basement membrane signals
directly addresses limitations of current therapeutic approaches by enabling a localized and
specific method to counteract MMP2 release applicable to a broad range of therapeutic
targets
Detectable clonal mosaicism and its relationship to aging and cancer
In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 Ă 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 Ă 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases