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"Charles M"
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The SWI/SNF complex in cancer — biology, biomarkers and therapy
Cancer genome-sequencing studies have revealed a remarkably high prevalence of mutations in genes encoding subunits of the SWI/SNF chromatin-remodelling complexes, with nearly 25% of all cancers harbouring aberrations in one or more of these genes. A role for such aberrations in tumorigenesis is evidenced by cancer predisposition in both carriers of germline loss-of-function mutations and genetically engineered mouse models with inactivation of any of several SWI/SNF subunits. Whereas many of the most frequently mutated oncogenes and tumour-suppressor genes have been studied for several decades, the cancer-promoting role of mutations in SWI/SNF genes has been recognized only more recently, and thus comparatively less is known about these alterations. Consequently, increasing research interest is being focused on understanding the prognostic and, in particular, the potential therapeutic implications of mutations in genes encoding SWI/SNF subunits. Herein, we review the burgeoning data on the mechanisms by which mutations affecting SWI/SNF complexes promote cancer and describe promising emerging opportunities for targeted therapy, including immunotherapy with immune-checkpoint inhibitors, presented by these mutations. We also highlight ongoing clinical trials open specifically to patients with cancers harbouring mutations in certain SWI/SNF genes.Mutations in genes encoding subunits of the SWI/SNF chromatin-remodelling complexes occur in almost 25% of all cancers. Herein, Mittal and Roberts discuss the mechanisms by which these mutations might promote cancer and describe the associated vulnerabilities that provide opportunities for targeted therapy or immunotherapy with immune-checkpoint inhibitors.
Journal Article
Novel electrode technologies for neural recordings
Neural recording electrode technologies have contributed considerably to neuroscience by enabling the extracellular detection of low-frequency local field potential oscillations and high-frequency action potentials of single units. Nevertheless, several long-standing limitations exist, including low multiplexity, deleterious chronic immune responses and long-term recording instability. Driven by initiatives encouraging the generation of novel neurotechnologies and the maturation of technologies to fabricate high-density electronics, novel electrode technologies are emerging. Here, we provide an overview of recently developed neural recording electrode technologies with high spatial integration, long-term stability and multiple functionalities. We describe how these emergent neurotechnologies can approach the ultimate goal of illuminating chronic brain activity with minimal disruption of the neural environment, thereby providing unprecedented opportunities for neuroscience research in the future.Here, Hong and Lieber review recent developments in electrode technologies for the recording of single-unit spiking activity. They focus on advances in electrodes with high spatial integration, long-term stability and multifunctional capacities.
Journal Article
Hole spin relaxation in Ge–Si core–shell nanowire qubits
Controlling decoherence is the biggest challenge in efforts to develop quantum information hardware
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,
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,
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. Single electron spins in gallium arsenide are a leading candidate among implementations of solid-state quantum bits, but their strong coupling to nuclear spins produces high decoherence rates
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,
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,
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. Group IV semiconductors, on the other hand, have relatively low nuclear spin densities, making them an attractive platform for spin quantum bits. However, device fabrication remains a challenge, particularly with respect to the control of materials and interfaces
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. Here, we demonstrate state preparation, pulsed gate control and charge-sensing spin readout of hole spins confined in a Ge–Si core–shell nanowire. With fast gating, we measure
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spin relaxation times of up to 0.6 ms in coupled quantum dots at zero magnetic field. Relaxation time increases as the magnetic field is reduced, which is consistent with a spin–orbit mechanism that is usually masked by hyperfine contributions.
Spin doublets of holes in nanowires with a germanium core and a silicon shell can be manipulated in fast-gated double quantum dots to create quantum bits with long spin lifetimes.
Journal Article
Hepatotoxicity of a Cannabidiol-Rich Cannabis Extract in the Mouse Model
The goal of this study was to investigate Cannabidiol (CBD) hepatotoxicity in 8-week-old male B6C3F1 mice. Animals were gavaged with either 0, 246, 738, or 2460 mg/kg of CBD (acute toxicity, 24 h) or with daily doses of 0, 61.5, 184.5, or 615 mg/kg for 10 days (sub-acute toxicity). These doses were the allometrically scaled mouse equivalent doses (MED) of the maximum recommended human maintenance dose of CBD in EPIDIOLEX® (20 mg/kg). In the acute study, significant increases in liver-to-body weight (LBW) ratios, plasma ALT, AST, and total bilirubin were observed for the 2460 mg/kg dose. In the sub-acute study, 75% of mice gavaged with 615 mg/kg developed a moribund condition between days three and four. As in the acute phase, 615 mg/kg CBD increased LBW ratios, ALT, AST, and total bilirubin. Hepatotoxicity gene expression arrays revealed that CBD differentially regulated more than 50 genes, many of which were linked to oxidative stress responses, lipid metabolism pathways and drug metabolizing enzymes. In conclusion, CBD exhibited clear signs of hepatotoxicity, possibly of a cholestatic nature. The involvement of numerous pathways associated with lipid and xenobiotic metabolism raises serious concerns about potential drug interactions as well as the safety of CBD.
Journal Article
The chronicle of Ireland
The Chronicle of Ireland is the principal source for the history of events not only in Ireland itself but also in what is now Scotland up to 911. It incorporated annals compiled on Iona up to c. 740 - a monastery which played a major role in the history of Ireland, of the Picts to its east and, from 635 to 664, of Northumbria. Up to c. 740 the Chronicle is thus a crucial source for both Ireland and Britain; and from c. 740 to 911 it still records some events outside Ireland. The text of the Chronicle is best preserved in the Annals of Ulster, but it was also transmitted through chronicles derived from a version made at the monastery of Clonmacnois in the Irish midlands. This translation is set out so as to show at a glance what text is preserved in both branches of the tradition and what is in only one. -- Amazon.com.
Book
Lineage plasticity in cancer: a shared pathway of therapeutic resistance
Lineage plasticity, the ability of cells to transition from one committed developmental pathway to another, has been proposed as a source of intratumoural heterogeneity and of tumour adaptation to an adverse tumour microenvironment including exposure to targeted anticancer treatments. Tumour cell conversion into a different histological subtype has been associated with a loss of dependency on the original oncogenic driver, leading to therapeutic resistance. A well-known pathway of lineage plasticity in cancer — the histological transformation of adenocarcinomas to aggressive neuroendocrine derivatives — was initially described in lung cancers harbouring an EGFR mutation, and was subsequently reported in multiple other adenocarcinomas, including prostate cancer in the presence of antiandrogens. Squamous transformation is a subsequently identified and less well-characterized pathway of adenocarcinoma escape from suppressive anticancer therapy. The increased practice of tumour re-biopsy upon disease progression has increased the recognition of these mechanisms of resistance and has improved our understanding of the underlying biology. In this Review, we provide an overview of the impact of lineage plasticity on cancer progression and therapy resistance, with a focus on neuroendocrine transformation in lung and prostate tumours. We discuss the current understanding of the molecular drivers of this phenomenon, emerging management strategies and open questions in the field.Lineage plasticity is a source of intratumoural heterogeneity and enables tumour adaptation to an adverse tumour microenvironment, eventually leading to therapeutic resistance. The authors of this Review provide an overview of the impact of lineage plasticity on cancer progression and therapy resistance, with a focus on neuroendocrine transformation in lung and prostate tumours, and discuss emerging management strategies and open questions in the field.
Journal Article