Glucoregulatory efficiency and ATP production are key regulators for neuronal plasticity and memory formation. Besides its chemotactic and neuroinflammatory functions, the CC chemokine--CCL5 displays ...neurotrophic activity. We found impaired learning-memory and cognition in CCL5-knockout mice at 4 months of age correlated with reduced hippocampal long-term potentiation and impaired synapse structure. Re-expressing CCL5 in knockout mouse hippocampus restored synaptic protein expression, neuronal connectivity and cognitive function. Using metabolomics coupled with FDG-PET imaging and seahorse analysis, we found that CCL5 participates in hippocampal fructose and mannose degradation, glycolysis, gluconeogenesis as well as glutamate and purine metabolism. CCL5 additionally supports mitochondrial structural integrity, purine synthesis, ATP generation, and subsequent aerobic glucose metabolism. Overexpressing CCL5 in WT mice also enhanced memory-cognition performance as well as hippocampal neuronal activity and connectivity through promotion of de novo purine and glutamate metabolism. Thus, CCL5 actions on glucose aerobic metabolism are critical for mitochondrial function which contribute to hippocampal spine and synapse formation, improving learning and memory.
Tumour hypoxia plays an important role in modulating tumorigenesis, angiogenesis, invasion, immunosuppression, resistance to treatment, and even maintenance of the stemness of cancer stem cells ...(CSCs). Moreover, the targeting and treatment of hypoxic cancer cells and CSCs to reduce the influence of tumor hypoxia on cancer therapy remains an imperative clinical problem that needs to be addressed. Since cancer cells upregulate the expression of glucose transporter 1 (GLUT1) through the Warburg effect, we considered the possibility of GLUT1-mediated transcytosis in cancer cells and developed a tumor hypoxia-targeting nanomedicine. Our experimental results indicate that glucosamine-labeled liposomal ceramide can be efficiently transported between cancer cells by GLUT1 transporters and substantially accumulated in the hypoxic area in in vitro CSC spheroids and in vivo tumor xenografts. We also verified the effects of exogenous ceramide on tumor hypoxia, including important bioactivities such as upregulation of p53 and retinoblastoma protein (RB), downregulation of hypoxia-inducible factor-1 alpha (HIF-1α) expression, disruption of the OCT4-SOX2 network of stemness, and inhibition of CD47 and PD-L1 expression. To achieve an ideal therapeutic outcome, we combined treatment of glucosamine-labeled liposomal ceramide with paclitaxel and carboplatin, and we found an excellent synergistic effect, with tumor clearance being noted in three-fourths of the mice. Overall, our findings provide a potential therapeutic strategy for the treatment of cancer.
A well-established lung-cancer-survival-prediction model that relies on multiple data types, multiple novel machine-learning algorithms, and external testing is absent in the literature. This study ...aims to address this gap and determine the critical factors of lung cancer survival. We selected non-small-cell lung cancer patients from a retrospective dataset of the Taipei Medical University Clinical Research Database and Taiwan Cancer Registry between January 2008 and December 2018. All patients were monitored from the index date of cancer diagnosis until the event of death. Variables, including demographics, comorbidities, medications, laboratories, and patient gene tests, were used. Nine machine-learning algorithms with various modes were used. The performance of the algorithms was measured by the area under the receiver operating characteristic curve (AUC). In total, 3714 patients were included. The best performance of the artificial neural network (ANN) model was achieved when integrating all variables with the AUC, accuracy, precision, recall, and F1-score of 0.89, 0.82, 0.91, 0.75, and 0.65, respectively. The most important features were cancer stage, cancer size, age of diagnosis, smoking, drinking status, EGFR gene, and body mass index. Overall, the ANN model improved predictive performance when integrating different data types.
In this paper, we present a copper(I)-catalyzed nitrile-addition/
-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6
-indolo3,2-
quinolin-6-ones from 2-(2-bromophenyl)-
...-(2-cyanophenyl)acetamides. Using CuBr and
-BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis2-(dimethylamino)ethyl-5,12-dihydro-6
-1,3dioxolo4',5':5,6indolo3,2-
quinolin-6-one (
), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound
actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of
with the Top-DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6
-indolo3,2-
quinolin-6-ones as topoisomerase-I inhibitors.
The immune cells in the local environments surrounding non-small cell lung cancer (NSCLC) implicate the balance of pro- and antitumor immunity; however, their transcriptomic profiles remain poorly ...understood.
A transcriptomic microarray study of bronchoalveolar lavage (BAL) cells harvested from tumor-bearing lung segments was performed in a discovery group. The findings were validated (1) in published microarray datasets, (2) in an independent group by RT-qPCR, and (3) in non-diseased and tumor adjacent non-neoplastic lung tissue by immunohistochemistry and in BAL cell lysates by immunoblotting.
The differential expression of 129 genes was identified in the discovery group. These genes revealed functional enrichment in Fc gamma receptor-dependent phagocytosis and circulating immunoglobulin complex among others. Microarray datasets analysis (
= 607) showed that gene expression of BAL cells of tumor-bearing lung segment was also the unique transcriptomic profile of tumor adjacent non-neoplastic lung of early stage NSCLC and a significantly gradient increase of immunoglobulin genes' expression for non-diseased lungs, tumor adjacent non-neoplastic lungs, and tumors was identified (ANOVA,
< 2 × 10
). A 53-gene signature was determined with significant correlation with inhibitory checkpoint
(
= 0.59,
= 0.0078) among others, where the nine top genes including
and
were RT-qPCR validated with high diagnostic performance (AUC: 0.920, 95% CI: 0.831-0.985,
= 2.98 × 10
). Increased staining and expression of IGKC revealed by immunohistochemistry and immunoblotting in tumor adjacent non-neoplastic lung tissues (Wilcoxon signed-rank test,
< 0.001) and in BAL cell lysates (
< 0.01) of NSCLC, respectively, were noted.
The BAL cells of tumor-bearing lung segments and tumor adjacent non-neoplastic lung tissues present a unique gene expression characterized by IGKC in relation to inhibitory checkpoints. Further study of humoral immune responses to NSCLC is warranted.
The efficacy and safety of maternal tenofovir disoproxil fumarate (TDF) in reducing mother‐to‐infant hepatitis B virus (HBV) transmissions is not clearly understood. We conducted a prospective, ...multicenter trial and enrolled 118 hepatitis B surface antigen (HBsAg)– and hepatitis B e antigen–positive pregnant women with HBV DNA ≥7.5 log10 IU/mL. The mothers received no medication (control group, n = 56, HBV DNA 8.22 ± 0.39 log10 IU/mL) or TDF 300 mg daily (TDF group, n = 62, HBV DNA 8.18 ± 0.47 log10 IU/mL) from 30‐32 weeks of gestation until 1 month postpartum. Primary outcome was infant HBsAg at 6 months old. At delivery, the TDF group had lower maternal HBV DNA levels (4.29 ± 0.93 versus 8.10 ± 0.56 log10 IU/mL, P < 0.0001). Of the 121/123 newborns, the TDF group had lower rates of HBV DNA positivity at birth (6.15% versus 31.48%, P = 0.0003) and HBsAg positivity at 6 months old (1.54% versus 10.71%, P = 0.0481). Multivariate analysis revealed that the TDF group had lower risk (odds ratio = 0.10, P = 0.0434) and amniocentesis was associated with higher risk (odds ratio 6.82, P = 0.0220) of infant HBsAg positivity. The TDF group had less incidence of maternal alanine aminotransferase (ALT) levels above two times the upper limit of normal for ≥3 months (3.23% versus 14.29%, P = 0.0455), a lesser extent of postpartum elevations of ALT (P = 0.007), and a lower rate of ALT over five times the upper limit of normal (1.64% versus 14.29%, P = 0.0135) at 2 months postpartum. Maternal creatinine and creatinine kinase levels, rates of congenital anomaly, premature birth, and growth parameters in infants were comparable in both groups. At 12 months, one TDF‐group child newly developed HBsAg positivity, presumably due to postnatal infection and inefficient humoral responses to vaccines. Conclusions: Treatment with TDF for highly viremic mothers decreased infant HBV DNA at birth and infant HBsAg positivity at 6 months and ameliorated maternal ALT elevations. (Hepatology 2015;62:375–386
In this paper, we present a copper(I)-catalyzed nitrile-addition/N-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6H-indolo3,2-cquinolin-6-ones from ...2-(2-bromophenyl)-N-(2-cyanophenyl)acetamides. Using CuBr and t-BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis2-(dimethylamino)ethyl-5,12-dihydro-6H-1,3dioxolo4′,5′:5,6indolo3,2-cquinolin-6-one (2k), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound 2k actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of 2k with the Top–DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6H-indolo3,2-cquinolin-6-ones as topoisomerase-I inhibitors.
Designed from combining the structural features of Raf inhibitory azastilbene 7 and EGFR/VEGFR inhibitory 4-anilinoquinazolines 1–3, 4-(3-hydroxyanilino)-6-(1H-1,2,3-triazol-4-yl)quinazoline 9m ...exhibited potent and selective inhibitory activity toward B-Raf (IC50: 57 nM) and B-RafV600E (IC50: 51 nM) over C-Raf (IC50: 1.0 μM). Compound 9m also actively inhibited EGFR (IC50: 73 nM) and VEGFR2 (IC50: 7.0 nM) but not EGFRT790M and PDGFR-β (IC50 > 10 μM).
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•4-Anilinoquinazoline 9m is a selective B-Raf/B-RafV600E kinase inhibitor.•The IC50 of 9m for B-Raf and B-RafV600E are 57 and 51 nM, respectively.•9m is less active for C-Raf with IC50 of 1.0 μM (~20 × selectivity).•9m potently inhibits EGFR (IC50: 73 nM) and VEGFR2 (IC50: 7.0 nM).•9m binds to the inactive conformations of B-Raf kinases.
This paper presents the design and synthesis of 4-(3-hydroxyanilino)-6-(1H-1,2,3-triazol-4-yl)quinazolines of scaffold 9 as selective B-Raf/B-RafV600E and potent EGFR/VEGFR2 kinase inhibitors. Total 14 compounds of scaffold 9 having different side chains at the triazolyl group with/without fluoro substituents at the anilino group were synthesized and investigated. Among them, 9m with a 2-carbamoylethyl side chain and C-4′/C-6′ difluoro substituents was the most potent, which selectively inhibited B-Raf (IC50: 57 nM) and B-RafV600E (IC50: 51 nM) over C-Raf (IC50: 1.0 μM). Compound 9m also actively inhibited EGFR (IC50: 73 nM) and VEGFR2 (IC50: 7.0 nM) but not EGFRT790M and PDGFR-β (IC50: >10 μM). Despite having good potency for B-Raf and B-RafV600E in the enzymatic assays, 9m was less active to inhibit melanoma A375 cells which proliferate due to constitutively activated B-Raf600E. The inferior activity of 9m for A375 was similar to that of sorafenib (6), suggesting that 9m might bind to the inactive conformations of B-Raf and B-RafV600E. Docking simulations could thus be performed to reveal the binding poses of 9m in B-Raf, B-RafV600E, and VEGFR2 kinases.
This paper presents the design and synthesis of 4-(3-hydroxyanilino)-6-(1H-1,2,3-triazol-4-yl)quinazolines of scaffold 9 as selective B-Raf/B-Raf
and potent EGFR/VEGFR2 kinase inhibitors. Total 14 ...compounds of scaffold 9 having different side chains at the triazolyl group with/without fluoro substituents at the anilino group were synthesized and investigated. Among them, 9m with a 2-carbamoylethyl side chain and C-4'/C-6' difluoro substituents was the most potent, which selectively inhibited B-Raf (IC
: 57 nM) and B-Raf
(IC
: 51 nM) over C-Raf (IC
: 1.0 μM). Compound 9m also actively inhibited EGFR (IC
: 73 nM) and VEGFR2 (IC
: 7.0 nM) but not EGFR
and PDGFR-β (IC
: >10 μM). Despite having good potency for B-Raf and B-Raf
in the enzymatic assays, 9m was less active to inhibit melanoma A375 cells which proliferate due to constitutively activated B-Raf
. The inferior activity of 9m for A375 was similar to that of sorafenib (6), suggesting that 9m might bind to the inactive conformations of B-Raf and B-Raf
. Docking simulations could thus be performed to reveal the binding poses of 9m in B-Raf, B-Raf
, and VEGFR2 kinases.
An innovative non-invasive Zigbee-base wireless controller is proposed in this study for energy saving control of split and package air-conditioning units. The controller needs only be connected to ...the temperature sensor of an air-conditioner, therefore is non-invasive to the control circuitry of the air-conditioner. The primary function of the controller is to effect the on/off functions of the air-conditioner unit, according to the readings from the Zigbee based wireless sensors. Energy saving can be achieved both by the control of comfort condition at the space at use, and also proper scheduling when connected to remote central control system. It has been found by experiments that this control method can be made a part of the wireless sensors network, and can be deployed at a low cost. Moreover, this control method can be used with presently installed package or split units. The energy saving measured for a split air-conditioner with this control method exceeds 50%. Therefore this non-invasive control method has a potential of saving energy in air-conditioning.
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