Key Results: Three Chinese radiologists had a sensitivity of 72%, 72% and 94% and specificity of 94%, 88% and 24% in differentiating 219 COVID-19 from 205 non-COVID-19 pneumonia.  Four United States radiologists had a sensitivity of 93%, 83%, 73% and 73% and specificity of 100%, 93%, 93% and 100%.  The most discriminating features for COVID-19 pneumonia included a peripheral distribution (80% vs. 57%, p<0.001), ground-glass opacity (91% vs. 68%, p<0.001) and vascular thickening (58% vs. 22%, p<0.001). Manuscript type: original researchThe total number of words of the manuscript, including entire text from title page to tables and references: 4364 This copy is for personal use only. To order printed copies, contact reprints@rsna.org I n P r e s s Performance of radiologists in differentiating COVID-19 from viral pneumonia on chest CT Summary: Radiologists had high specificity but moderate sensitivity in differentiating COVID-19 from viral pneumonia on chest CT. Key Results:  Three Chinese radiologists had sensitivities of 72%, 72% and 94% and specificities of 94%, 88% and 24% in differentiating 219 COVID-19 from 205 non-COVID-19 pneumonia.  Four United States radiologists had sensitivities of 93%, 83%, 73% and 73% and specificities of 100%, 93%, 93% and 100%.  The most discriminating features for COVID-19 pneumonia included a peripheral distribution (80% vs. 57%, p<0.001), ground-glass opacity (91% vs. 68%, p<0.001) and vascular thickening (58% vs. 22%, p<0.001). Abstract Background: Despite its high sensitivity in diagnosing COVID-19 in a screening population, chest CT appearances of COVID 19 pneumonia are thought to be non-specific. Purpose: To assess the performance of United States (U.S.) and Chinese radiologists in differentiating COVID-19 from viral pneumonia on chest CT. Methods: A total of 219 patients with both positive COVID-19 by RT-PCR and abnormal chest CT findings were retrospectively identified from 7 Chinese hospitals in Hunan Providence, China from January 6 to February 20, 2020. A total of 205 patients with positive Respiratory Pathogen Panel for viral pneumonia and CT findings consistent with or highly suspicious for pneumonia by original radiology interpretation within 7 days of each other were identified from Rhode Island Hospital in Providence, RI. Three Chinese radiologists blindly reviewed all chest CTs (n=424) to differentiate COVID-19 from viral pneumonia. A sample of 58 age-matched cases was randomly selected and evaluated by 4 U.S. radiologists in a similar fashion. Different CT features were recorded and compared between the two groups. Results: For all chest CTs, three Chinese radiologists correctly differentiated COVID-19 from non-COVID-19 pneumonia 83% (350/424), 80% (338/424), and 60% (255/424) of the time, respectively. The seven radiologists had sensitivities of 80%, 67%, 97%, 93%, 83%, 73% and 70% and specificities of 100%, 93%, 7%, 100%, 93%, 93%, 100%. Compared to non-COVID-19 pneumonia, COVID-19 pneumonia was more likely to have a peripheral distribution (80% vs. 57%, p...

NF-B is critical for determining cellular sensitivity to apoptotic stimuli by regulating both mitochondrial and death receptor apoptotic pathways. The endoplasmic reticulum (ER) emerges as a new apoptotic signaling initiator. However, the mechanism by which ER stress activates NF-B and its role in regulation of ER stress-induced cell death are largely unclear. Here, we report that, in response to ER stress, IKK forms a complex with IRE1␣ through the adapter protein TRAF2. ER stress-induced NF-B activation is impaired in IRE1␣ knockdown cells and IRE1␣ ؊/؊ MEFs. We found, however, that inhibiting NF-B significantly decreased ER stress-induced cell death in a caspase-8-dependent manner. Gene expression analysis revealed that ER stress-induced expression of tumor necrosis factor alpha (TNF-␣) was IRE1␣ and NF-B dependent. Blocking TNF receptor 1 signaling significantly inhibited ER stress-induced cell death. Further studies suggest that ER stress induces down-regulation of TRAF2 expression, which impairs TNF-␣-induced activation of NF-B and c-Jun N-terminal kinase and turns TNF-␣ from a weak to a powerful apoptosis inducer. Thus, ER stress induces two signals, namely TNF-␣ induction and TRAF2 down-regulation. They work in concert to amplify ER-initiated apoptotic signaling through the membrane death receptor.

ATP-dependent chromatin remodeling complexes are a notable group of epigenetic modifiers that use the energy of ATP hydrolysis to change the structure of chromatin, thereby altering its accessibility to nuclear factors. BAF250a (ARID1a) is a unique and defining subunit of the BAF chromatin remodeling complex with the potential to facilitate chromosome alterations critical during development. Our studies show that ablation of BAF250a in early mouse embryos results in developmental arrest (about embryonic day 6.5) and absence of the mesodermal layer, indicating its critical role in early germ-layer formation. Moreover, BAF250a deficiency compromises ES cell pluripotency, severely inhibits self-renewal, and promotes differentiation into primitive endoderm-like cells under normal feeder-free culture conditions. Interestingly, this phenotype can be partially rescued by the presence of embryonic fibroblast cells. DNA microarray, immunostaining, and RNA analyses revealed that BAF250a-mediated chromatin remodeling contributes to the proper expression of numerous genes involved in ES cell self-renewal, including Sox2, Utf1, and Oct4. Furthermore, the pluripotency defects in BAF250a mutant ES cells appear to be cell lineage-specific. For example, embryoid body-based analyses demonstrated that BAF250a-ablated stem cells are defective in differentiating into fully functional mesoderm-derived cardiomyocytes and adipocytes but are capable of differentiating into ectodermderived neurons. Our results suggest that BAF250a is a key component of the gene regulatory machinery in ES cells controlling self-renewal, differentiation, and cell lineage decisions.BAF250a (ARID1a) ͉ lineage commitment ͉ mesoderm R egulatory factors that control chromatin architecture (directly or indirectly) are potential key proteins for maintaining the pluripotent state or directing differentiation of early embryonic cells into distinct cell types (1). Such factors include ATP-dependent chromatin remodeling complexes that hydrolyze ATP to noncovalently restructure, mobilize, or eject nucleosomes to modulate transcription factor access to chromosomal DNA (2). Among the various members of the ATPdependent chromatin remodeling superfamily is the SWI/SNF subfamily, consisting of two closely related SWI/SNF remodeling complexes BAF and PBAF in mammalian cells (3, 4).BAF250a, a defining subunit of the BAF chromatin remodeling complex (5, 6), is a trithorax group (TrxG) protein (7). TrxG proteins were initially identified by their ability to antagonize the Polycomb group (PcG) proteins to maintain proper expression of many differentiation regulators during development (8). Interestingly, many PcG and TrxG proteins are chromatin modifying factors. Recent studies mapping the targets of PcG action in mouse and human ES cells suggest these proteins also play a role in sustaining a heritable epigenetic state uniquely associated with pluripotency (9, 10).Given the influence of epigenetic factors in determining developmental potential (embryonic development, cellular ...

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of many diseases and in cancer therapy. Although the unfolded protein response is known to alleviate ER stress by reducing the accumulation of misfolded proteins, the exact survival elements and their downstream signaling pathways that directly counteract ER stress-stimulated apoptotic signaling remain elusive. Here, we have shown that endogenous Akt and ERK are rapidly activated and act as downstream effectors of phosphatidylinositol 3-kinase in thapsigargin- or tunicamycin-induced ER stress. Introduction of either dominant-negative Akt or MEK1 or the inhibitors LY294002 and U0126 sensitized cells to ER stress-induced cell death in different cell types. Reverse transcription-PCR analysis of gene expression during ER stress revealed that cIAP-2 and XIAP, members of the IAP family of potent caspase suppressors, were strongly induced. Transcription of cIAP-2 and XIAP was up-regulated by the phosphatidylinositol 3-kinase/Akt pathway as shown by its reversal by dominant-negative Akt or LY294002. Ablation of these IAPs by RNA interference sensitized cells to ER stress-induced death, which was reversed by the caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone. The protective role of IAPs in ER stress coincided with Smac release from mitochondria to the cytosol. Furthermore, it was shown that mTOR was not required for Akt-mediated survival. These results represent the first demonstration that activation of endogenous Akt/IAPs and MEK/ERK plays a critical role in controlling cell survival by resisting ER stress-induced cell death signaling.

The tumor microenvironment (TME) has been increasingly recognized as a crucial contributor to tumorigenesis. Based on the unique TME for achieving tumor‐specific therapy, here a novel concept of photothermal‐enhanced sequential nanocatalytic therapy in both NIR‐I and NIR‐II biowindows is proposed, which innovatively changes the condition of nanocatalytic Fenton reaction for production of highly efficient hydroxyl radicals (•OH) and consequently suppressing the tumor growth. Evidence suggests that glucose plays a vital role in powering cancer progression. Encouraged by the oxidation of glucose to gluconic acid and H2O2 by glucose oxidase (GOD), an Fe3O4/GOD‐functionalized polypyrrole (PPy)‐based composite nanocatalyst is constructed to achieve diagnostic imaging‐guided, photothermal‐enhanced, and TME‐specific sequential nanocatalytic tumor therapy. The consumption of intratumoral glucose by GOD leads to the in situ elevation of the H2O2 level, and the integrated Fe3O4 component then catalyzes H2O2 into highly toxic •OH to efficiently induce cancer‐cell death. Importantly, the high photothermal‐conversion efficiency (66.4% in NIR‐II biowindow) of the PPy component elevates the local tumor temperature in both NIR‐I and NIR‐II biowindows to substaintially accelerate and improve the nanocatalytic disproportionation degree of H2O2 for enhancing the nanocatalytic‐therapeutic efficacy, which successfully achieves a remarkable synergistic anticancer outcome with minimal side effects.