638 research outputs found
Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma
Published in final edited form as: Sci Transl Med. 2017 May 10; 9(389). https://doi.org/10.1126/scitranslmed.aal2668.Multiple myeloma (MM) is a frequently incurable hematological cancer in which overactivity of MYC plays a central role, notably through up-regulation of ribosome biogenesis and translation. To better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small-molecule library for anti-MM activity. The most potent hits identified were rocaglate scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, the most promising rocaglate. Proteome-wide reversion correlated with selective depletion of short-lived proteins that are key to MM growth and survival, most notably MYC, MDM2, CCND1, MAF, and MCL-1. The efficacy of CMLD010509 in mouse models of MM confirmed the therapeutic relevance of these findings in vivo and supports the feasibility of targeting the oncogenic MYC-driven translation program in MM with rocaglates
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Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.
Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist
3D Cascaded U-Net with a Squeeze-and-Exicitation Block for Semantic Segmentation on Kidney and Renal Cell Carcinoma in Abdonimal Volumetric CT
Segmentation is a fundamental process in medical image analysis. Recently, convolutional neural networks (CNNs) has allowed for automatic segmentation; however, segmentaiton of complex organs and diseases including the kidney or renal cell carcinoma (RCC) remains a different task due to limited data and labor-intensive labeling work. The purpose of this study is to segment kideny and RCC in CT using cascaded 3D U-Net with a squeeze-and-excitation (SE) block using a cascaded method. 210 kidneys and their RCC in abdominal CT images were used as training and validation sets. The Dice similarity coefficients (DSCs) of kidney and RCC in test set were 0.963 and 0.734 respectively. The cascaded semantic segmentation can potentially reduce segmentation efforts and increase the efficiency in clinical workflow
The Howl - Fall 2016
The Howl is a magazine that is planned, researched, written, photographed and designed by Otterbein University\u27s ESL and international students. The magazine serves to give them a safe space in which to use their voice to share their cultures, experiences and lives. If you are interested in submitting to The Howl, please email your writing or photography to [email protected]://digitalcommons.otterbein.edu/the_howl/1001/thumbnail.jp
Water-Gated Charge Doping of Graphene Induced by Mica Substrates
We report on the existence of water-gated charge doping of graphene deposited
on atomically flat mica substrates. Molecular films of water in units of ~0.4
nm-thick bilayers were found to be present in regions of the interface of
graphene/mica hetero-stacks prepared by micromechanical exfoliation of kish
graphite. The spectral variation of the G and 2D bands, as visualized by Raman
mapping, shows that mica substrates induce strong p-type doping in graphene,
with hole densities of {-2}$. The ultrathin water
films, however, effectively block interfacial charge transfer, rendering
graphene significantly less hole-doped. Scanning Kelvin probe microscopy
independently confirmed a water-gated modulation of the Fermi level by 0.35 eV,
in agreement with the optically determined hole density. The manipulation of
the electronic properties of graphene demonstrated in this study should serve
as a useful tool in realizing future graphene applications.Comment: 15 pages, 4 figures; Nano Letters, accepted (2012
Slitrk5 Mediates BDNF-Dependent TrkB Receptor Trafficking and Signaling
SummaryRecent studies in humans and in genetic mouse models have identified Slit- and NTRK-like family (Slitrks) as candidate genes for neuropsychiatric disorders. All Slitrk isotypes are highly expressed in the CNS, where they mediate neurite outgrowth, synaptogenesis, and neuronal survival. However, the molecular mechanisms underlying these functions are not known. Here, we report that Slitrk5 modulates brain-derived neurotrophic factor (BDNF)-dependent biological responses through direct interaction with TrkB receptors. Under basal conditions, Slitrk5 interacts primarily with a transsynaptic binding partner, protein tyrosine phosphatase δ (PTPδ); however, upon BDNF stimulation, Slitrk5 shifts to cis-interactions with TrkB. In the absence of Slitrk5, TrkB has a reduced rate of ligand-dependent recycling and altered responsiveness to BDNF treatment. Structured illumination microscopy revealed that Slitrk5 mediates optimal targeting of TrkB receptors to Rab11-positive recycling endosomes through recruitment of a Rab11 effector protein, Rab11-FIP3. Thus, Slitrk5 acts as a TrkB co-receptor that mediates its BDNF-dependent trafficking and signaling
Challenges in QCD matter physics - The Compressed Baryonic Matter experiment at FAIR
Substantial experimental and theoretical efforts worldwide are devoted to
explore the phase diagram of strongly interacting matter. At LHC and top RHIC
energies, QCD matter is studied at very high temperatures and nearly vanishing
net-baryon densities. There is evidence that a Quark-Gluon-Plasma (QGP) was
created at experiments at RHIC and LHC. The transition from the QGP back to the
hadron gas is found to be a smooth cross over. For larger net-baryon densities
and lower temperatures, it is expected that the QCD phase diagram exhibits a
rich structure, such as a first-order phase transition between hadronic and
partonic matter which terminates in a critical point, or exotic phases like
quarkyonic matter. The discovery of these landmarks would be a breakthrough in
our understanding of the strong interaction and is therefore in the focus of
various high-energy heavy-ion research programs. The Compressed Baryonic Matter
(CBM) experiment at FAIR will play a unique role in the exploration of the QCD
phase diagram in the region of high net-baryon densities, because it is
designed to run at unprecedented interaction rates. High-rate operation is the
key prerequisite for high-precision measurements of multi-differential
observables and of rare diagnostic probes which are sensitive to the dense
phase of the nuclear fireball. The goal of the CBM experiment at SIS100
(sqrt(s_NN) = 2.7 - 4.9 GeV) is to discover fundamental properties of QCD
matter: the phase structure at large baryon-chemical potentials (mu_B > 500
MeV), effects of chiral symmetry, and the equation-of-state at high density as
it is expected to occur in the core of neutron stars. In this article, we
review the motivation for and the physics programme of CBM, including
activities before the start of data taking in 2022, in the context of the
worldwide efforts to explore high-density QCD matter.Comment: 15 pages, 11 figures. Published in European Physical Journal
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FOXO protects against age‐progressive axonal degeneration
Summary Neurodegeneration resulting in cognitive and motor impairment is an inevitable consequence of aging. Little is known about the genetic regulation of this process despite its overriding importance in normal aging. Here, we identify the Forkhead Box O (FOXO) transcription factor 1, 3, and 4 isoforms as a guardian of neuronal integrity by inhibiting age‐progressive axonal degeneration in mammals. FOXO expression progressively increased in aging human and mouse brains. The nervous system‐specific deletion of Foxo transcription factors in mice accelerates aging‐related axonal tract degeneration, which is followed by motor dysfunction. This accelerated neurodegeneration is accompanied by levels of white matter astrogliosis and microgliosis in middle‐aged Foxo knockout mice that are typically only observed in very old wild‐type mice and other aged mammals, including humans. Mechanistically, axonal degeneration in nerve‐specific Foxo knockout mice is associated with elevated mTORC1 activity and accompanying proteotoxic stress due to decreased Sestrin3 expression. Inhibition of mTORC1 by rapamycin treatment mimics FOXO action and prevented axonal degeneration in Foxo knockout mice with accelerated nervous system aging. Defining this central role for FOXO in neuroprotection during mammalian aging offers an invaluable window into the aging process itself
Comparison of the outcomes between sorafenib and lenvatinib as the first-line systemic treatment for HBV-associated hepatocellular carcinoma: a propensity score matching analysis
In a randomized controlled trial, lenvatinib was non-inferior to sorafenib in overall survival (OS) of patients with unresectable hepatocellular carcinoma (uHCC). This study aimed to compare the effects of sorafenib and lenvatinib as first-line systemic therapy against uHCC with real-world data in chronic hepatitis B patients.
This retrospective single-center study involved 132 patients with HBV-related uHCC. Propensity score matching (PSM) was used to balance the baseline characteristics, including age, sex, serum alpha-fetoprotein levels, Child–Pugh class, tumor size, and tumor stage. The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), time to progression (TTP), and tumor response.
After PSM, the final analysis included 44 patients treated with lenvatinib and 88 with sorafenib. The OS (7.0 vs 9.2months, p = 0.070) and PFS (4.6 vs 2.4months, p = 0.134) were comparable between the two drugs. Multivariable analysis showed that lenvatinib and sorafenib were not independent prognostic factors of OS (adjusted hazard ratio = 1.41, 95% confidence interval = 0.96–2.08, p = 0.077) after adjustment for baseline alpha-fetoprotein levels, total bilirubin levels, alanine aminotransferase level, performance status, tumor stage, and tumor size. However, the lenvatinib group had a significantly prolonged TTP (5.2 vs 2.5months, p = 0.018) and a higher objective response rate (18.2% vs 4.5%, p = 0.020) and disease control rate (77.3% vs 47.7%, p = 0.001) than the sorafenib group.
Our study demonstrated that lenvatinib had a comparable OS and PFS but longer TTP and better tumor response compared to sorafenib in patients with HBV-related uHCC
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