A highly chem‐ and regioselective synthesis of diversely substituted benzoacarbazoles and indolo2,1‐a‐isoquinolines through Rh(III)‐catalyzed cascade reactions of 2‐arylindoles with sulfoxonium ...ylides is presented. To be specific, treatment of 2‐arylindoles, 2‐arylindole‐3‐carbaldehydes, 2‐arylindole‐3‐carbonitriles or 2‐aryl‐3‐methylindoles with sulfoxonium ylides under the catalysis of Rh(III) led to the selective formation of 6‐aryl/alkyl benzoacarbazoles, 5‐acylbenzoacarbazoles, 6‐amino‐5‐acylbenzoacarbazoles or 12‐methylindolo2,1‐aisoquinolines, respectively. Mechanistically, the formation of the title compounds involves a cascade process including metalation of the inert C(sp2)−H bond, migratory insertion of ylide into the carbon‐metal bond via an in situ carbenoid formation, protodemetalation, and condensation. To our knowledge, this is the first example in which β‐carbonyl sulfoxonium ylides were used as stable carbene precursors and bifunctional C2 synthons to afford benzoacarbazoles and indolo2,1‐aisoquinolines.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Transcutaneous auricular vagus nerve stimulation (taVNS) is a relatively non-invasive alternative treatment for patients suffering from major depressive disorder (MDD). It has been postulated that ...acupuncture may achieve its treatment effects on MDD through suppression of vagal nerve inflammatory responses. Our previous research established that taVNS significantly increases amygdala-dorsolateral prefrontal cortex connectivity, which is associated with a reduction in depression severity. However, the relationship between taVNS and the central/peripheral functional state of the immune system, as well as changes in brain neural circuits, have not as yet been elucidated. In the present paper, we outline the anatomic foundation of taVNS and emphasize that it significantly modulates the activity and connectivity of a wide range of neural networks, including the default mode network, executive network, and networks involved in emotional and reward circuits. In addition, we present the inflammatory mechanism of MDD and describe how taVNS inhibits central and peripheral inflammation, which is possibly related to the effectiveness of taVNS in reducing depression severity. Our review suggests a link between the suppression of inflammation and changes in brain regions/circuits post taVNS.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
In glioblastoma (GBM), promoter methylation of the DNA repair gene O‐methylguanine‐DNA methyltransferase (MGMT) is associated with beneficial chemotherapy.
Purpose/Hypothesis
To analyze ...radiomics features for utilizing the full potential of medical imaging as biomarkers of MGMT promoter methylation.
Study Type
Retrospective.
Population/Subjects
In all, 98 GBM patients with known MGMT (48 methylated and 50 unmethylated tumors).
Field Strength/Sequence
3.0T magnetic resonance (MR) images, containing T1‐weighted image (T1WI), T2‐weighted image (T2WI), and enhanced T1WI.
Assessment
A region of interest (ROI) of the tumor was delineated. A total of 1665 radiomics features were extracted and quantized, and were reduced using least absolute shrinkage and selection operator (LASSO) regularization.
Statistical Testing
After the support vector machine construction, accuracy, sensitivity, and specificity were computed for different sequences. An independent validation cohort containing 20 GBM patients was utilized to further evaluate the radiomics model performance.
Results
Radiomics features of T1WI reached an accuracy of 67.54%. Enhanced T1WI features reached an accuracy of 82.01%, while T2WI reached an accuracy of 69.25%. The best classification system for predicting MGMT promoter methylation status originated from the combination of 36 T1WI, T2WI, and enhanced T1WI images features, with an accuracy of 86.59%. Further validation on the independent cohort of 20 patients produced similar results, with an accuracy of 80%.
Data Conclusion
Our results provide further evidence that radiomics MR features could predict MGMT methylation status in preoperative GBM. Multiple imaging modalities together can yield putative noninvasive biomarkers for the identification of MGMT.
Level of Evidence: 4
Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1380–1387.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The MEN1 gene, a tumor suppressor gene that encodes the protein menin, is mutated at high frequencies in neuroendocrine (NE) tumors; however, the biological importance of this gene in NE-type lung ...cancer in vivo remains unclear. Here, we established an ATII-specific Kras
/Men1
driven genetically engineered mouse model and show that deficiency of menin results in the accumulation of DNA damage and antagonizes oncogenic Kras-induced senescence and the epithelial-to-mesenchymal transition during lung tumorigenesis. The loss of menin expression in certain human primary lung cancers correlates with elevated NE profiles and reduced overall survival.
Phosphoglycerate mutase 1 (PGAM1) plays a pivotal role in cancer metabolism and tumor progression via its metabolic activity and interaction with other proteins like α-smooth muscle actin (ACTA2). ...Allosteric regulation is considered to be an innovative strategy to discover a highly selective and potent inhibitor targeting PGAM1. Here, we identified a novel PGAM1 allosteric inhibitor, HKB99, via structure-based optimization. HKB99 acted to allosterically block conformational change of PGAM1 during catalytic process and PGAM1-ACTA2 interaction. HKB99 suppressed tumor growth and metastasis and overcame erlotinib resistance in non-small-cell lung cancer (NSCLC). Mechanistically, HKB99 enhanced the oxidative stress and altered multiple signaling pathways including the activation of JNK/c-Jun and suppression of AKT and ERK. Collectively, the study highlights the potential of PGAM1 as a therapeutic target in NSCLC and reveals a distinct mechanism by which HKB99 inhibits both metabolic activity and nonmetabolic function of PGAM1 by allosteric regulation.
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•A PGAM1 allosteric inhibitor HKB99 is developed via structure-based optimization•HKB99 modulates PGAM1 both in its catalytic process and ACTA2 interaction•HKB99 suppresses NSCLC growth and metastasis through allosteric PGAM1 regulation•PGAM1 is a potential therapeutic target in NSCLC
PGAM1 plays a critical role in cancer cell metabolism. Huang et al. discovered a novel PGAM1 inhibitor HKB99, which allosterically blocks the structure of PGAM1, impacting both its catalytic activity and ACTA2 interaction. HKB99 significantly inhibits NSCLC tumor growth and metastasis in vivo by impacting both PGAM1’s metabolic activity and nonmetabolic function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Major depressive disorder (MDD) is a leading cause of disability worldwide. After the first episode, patients with remitted MDD have a 60% chance of experiencing a second episode. Consideration of ...therapy continuation should be viewed in terms of the balance between the adverse effects of medication and the need to prevent a possible relapse. Relapse during the early stages of MDD could be prevented more efficiently by conducting individual risk assessments and providing justification for continuing therapy. Our previous work established the neuroimaging markers of relapse by comparing patients with recurrent major depressive disorder (rMDD) in depressive and remitted states. However, it is not known which of these markers are trait markers that present before initial relapse and, consequently, predict disease course. Here, we first describe how inflammation can be translated to subtype-specific clinical features and suggest how this could be used to facilitate clinical diagnosis and treatment. Next, we address the central and peripheral functional state of the immune system in patients with MDD. In addition, we emphasize the important link between the number of depressive episodes and rMDD and use neuroimaging to propose a model for the latter. Last, we address how inflammation can affect brain circuits, providing a possible mechanism for rMDD. Our review suggests a link between inflammatory processes and brain region/circuits in rMDD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Resolving atomic site‐specific electronic properties and correlated substrate–molecule interactions is challenging in real space. Now, mapping of sub‐10 nm sized Pt nanoislands on a Au(111) surface ...was achieved by tip‐enhanced Raman spectroscopy, using the distinct Raman fingerprints of adsorbed 4‐chlorophenyl isocyanide molecules. A spatial resolution better than 2.5 nm allows the electronic properties of the terrace, step edge, kink, and corner sites with varying coordination environments to be resolved in real space in one Pt nanoisland. Calculations suggest that low‐coordinate atomic sites have a higher d‐band electronic profile and thus stronger metal–molecule interactions, leading to the observed blue‐shift of Raman frequency of the N≡C bond of adsorbed molecules. An experimental and theoretical study on Pt(111) and mono‐ and bi‐atomic layer Pt nanoislands on a Au(111) surface reveals the bimetallic effect that weakens with the increasing number of deposited Pt adlayer.
With a spatial resolution better than 2.5 nm, tip‐enhanced Raman spectroscopic imaging reveals unprecedented site‐specific electronic properties of different atomic sites with varying coordination numbers within a single, sub‐10 nm sized Pt nanoisland, using the distinct Raman fingerprints of adsorbed molecules. The work pushes forward the atomic‐ and molecular‐level characterization of heterogeneous catalysts.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
•PEO with Ce salt sealing and LDHs composite coating was produced via hydrothermal treatment and was then modified by phytic acid.•PEO-Ce-LDH showed two different surface morphologies.•Due to the ...compact insoluble precipitate covered the entire defect, PEO-Ce-LDH-P had the best self-healing ability.
A composite coating was produced via (i) plasma electrolytic oxidation (PEO) with Ce salt sealing, on which layered double hydroxides (LDHs) were deposited via a hydrothermal treatment, and (ii) then modified by phytic acid (PA) via an ion-exchange reaction. The final coating (characterized using XRD, XPS, FT-IR, SEM, EDS and GDOES) consisted of LDHs/Mg(OH)2/CeO2/Ce(OH)3 with a non-uniform Ce distribution. The corrosion protection and self-healing ability were investigated using polarization curves, EIS, immersion tests and SVET. The composite coating modified with PA showed the most superior corrosion protection and self-healing ability, attributed to the synergistic effect between Ce species and phosphate.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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