Since the launch of lithium-ion batteries, elements (such as silicon, tin, or aluminum) that can be alloyed with lithium have been expected as anode materials, owing to larger capacity. However, ...their successful application has not been accomplished because of drastic structural degradation caused by cyclic large volume change during battery reactions. To prolong lifetime of alloy anodes, we must circumvent the huge volume strain accompanied by insertion/extraction of lithium. Here we report that by using aluminum-foil anodes, the volume expansion during lithiation can be confined to the normal direction to the foil and, consequently, the electrode cyclability can be markedly enhanced. Such a unidirectional volume-strain circumvention requires an appropriate hardness of the matrix and a certain tolerance to off-stoichiometry of the resulting intermetallic compound, which drive interdiffusion of matrix component and lithium along the normal-plane direction. This metallurgical concept would invoke a paradigm shift to future alloy-anode battery technologies.
EGFR-mutated lung cancers account for a significant subgroup of non-small cell lung cancers overall. Third-generation EGFR tyrosine kinase inhibitors (TKI) are mutation-selective inhibitors with ...minimal effects on wild-type EGFR. Acquired resistance develops to these agents, however, the mechanisms are as yet uncharacterized. In this study, we report that the Src-AKT pathway contributes to acquired resistance to these TKI. In addition, amplification of EGFR wild-type alleles but not mutant alleles was sufficient to confer acquired resistance. These findings underscore the importance of signals from wild-type EGFR alleles in acquiring resistance to mutant-selective EGFR-TKI. Our data provide evidence of wild-type allele-mediated resistance, a novel concept of acquired resistance in response to mutation-selective inhibitor therapy in cancer treatment.
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Rice consumption is a major source of cadmium and arsenic for the population of Asia. We investigated the effects of water management in rice paddy on levels of cadmium and arsenic in Japanese rice ...grains. Flooding increased arsenic concentrations in rice grains, whereas aerobic treatment increased the concentration of cadmium. Flooding for 3 weeks before and after heading was most effective in reducing grain cadmium concentrations, but this treatment increased the arsenic concentration considerably, whereas aerobic treatment during the same period was effective in reducing arsenic concentrations but increased the cadmium concentration markedly. Flooding treatment after heading was found to be more effective than flooding treatment before heading in reducing rice grain cadmium without a concomitant increase in total arsenic levels, although it increased inorganic arsenic levels. Concentrations of dimethylarsinic acid (DMA) in grain were very low under aerobic conditions but increased under flooded conditions. DMA accounted for 3−52% of the total arsenic concentration in grain grown in soil with a lower arsenic concentration and 10−80% in soil with a higher arsenic concentration. A possible explanation for the accumulation of DMA in rice grains is that DMA translocates from shoots/roots to the grains more readily than does inorganic arsenic.
Genetic mutations in tumor cells cause several unique metabolic phenotypes that are critical for cancer cell proliferation. Mutations in the tyrosine kinase epidermal growth factor receptor (EGFR) ...induce oncogenic addiction in lung adenocarcinoma (LAD). However, the linkage between oncogenic mutated EGFR and cancer cell metabolism has not yet been clearly elucidated. Here we show that EGFR signaling plays an important role in aerobic glycolysis in EGFR-mutated LAD cells. EGFR-tyrosine kinase inhibitors (TKIs) decreased lactate production, glucose consumption, and the glucose-induced extracellular acidification rate (ECAR), indicating that EGFR signaling maintained aerobic glycolysis in LAD cells. Metabolomic analysis revealed that metabolites in the glycolysis, pentose phosphate pathway (PPP), pyrimidine biosynthesis, and redox metabolism were significantly decreased after treatment of LAD cells with EGFR-TKI. On a molecular basis, the glucose transport carried out by glucose transporter 3 (GLUT3) was downregulated in TKI-sensitive LAD cells. Moreover, EGFR signaling activated carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), which catalyzes the first step in de novo pyrimidine synthesis. We conclude that EGFR signaling regulates the global metabolic pathway in EGFR-mutated LAD cells. Our data provide evidence that may link therapeutic response to the regulation of metabolism, which is an attractive target for the development of more effective targeted therapies to treat patients with EGFR-mutated LAD.
Background: Genetic mutations in cancer-driver genes induce specific metabolic alterations in cancer cells.
Results: EGF receptor signaling has an important role for glycolysis, pentose phosphate pathway, and pyrimidine biosynthesis in EGFR-mutated lung cancer.
Conclusion: Our work reveals the relationship between the EGFR signaling axis and key metabolic changes.
Significance: These data implicate a possible link between therapeutic response and regulation of metabolism in EGFR-mutated LAD.
Cryoprobe is a novel transbronchial biopsy (TBB) tool that yields larger tissue samples than forceps. Pathological diagnosis and biomarker analysis, such as genetic alterations and programmed ...death‐ligand 1 (PD‐L1) expression, are paramount for precision medicine against lung cancer. We evaluated the safety and usefulness of cryoprobe TBB for lung cancer diagnosis and biomarker analysis. In this single‐center, prospective single‐arm study, patients suspected of having or diagnosed with primary lung cancer underwent cryoprobe TBB using flexible bronchoscopy after conventional forceps TBB from the same lesion. Cryoprobe TBB was performed in 121 patients. The incidence rate of severe bleeding and serious adverse events (4% 90% confidence interval: 2%‐9%) was significantly lower than the expected rate (20% with 30% threshold, P < 0.01). Combining both central and peripheral lesions, the diagnostic yield rate of cryoprobe samples was 76% and that of forceps samples was 84%. Compared with forceps TBB samples, cryoprobe TBB samples were larger (cryoprobe 15 mm2 vs forceps 2 mm2) and resulted in a larger proportion of definite histomorphological diagnosis (cryoprobe 86% vs forceps 74%, P < 0.01), larger amounts of DNA extracted from samples (median: cryoprobe, 1.60 µg vs forceps, 0.58 µg, P = 0.02) and RNA (median: cryoprobe, 0.62 µg vs forceps, 0.17 µg, P < 0.01) extracted from samples, and tended to yield greater rates of PD‐L1 expression >1% (51% vs 42%). In conclusion, cryoprobe is a safe and useful tool for obtaining lung cancer tissue samples of adequate size and quality, which allow morphological diagnosis and biomarker analysis for precision medicine against lung cancer.
In this study, cryoprobe biopsy was performed in 121 patients. The incidence rate of severe bleeding and serious adverse events was 4%. Compared with forceps biopsy samples, cryoprobe biopsy samples were larger and resulted in a larger proportion of definite histomorphological diagnoses and larger amounts of DNA/RNA extracted from samples.
Objectives In this study, we have investigated the effects of cannabidiol (CBD) on myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, ...using a mouse model of type I diabetic cardiomyopathy and primary human cardiomyocytes exposed to high glucose. Background Cannabidiol, the most abundant nonpsychoactive constituent of Cannabis sativa (marijuana) plant, exerts anti-inflammatory effects in various disease models and alleviates pain and spasticity associated with multiple sclerosis in humans. Methods Left ventricular function was measured by the pressure-volume system. Oxidative stress, cell death, and fibrosis markers were evaluated by molecular biology/biochemical techniques, electron spin resonance spectroscopy, and flow cytometry. Results Diabetic cardiomyopathy was characterized by declined diastolic and systolic myocardial performance associated with increased oxidative-nitrative stress, nuclear factor-κB and mitogen-activated protein kinase (c-Jun N-terminal kinase, p-38, p38α) activation, enhanced expression of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), tumor necrosis factor-α, markers of fibrosis (transforming growth factor-β, connective tissue growth factor, fibronectin, collagen-1, matrix metalloproteinase-2 and -9), enhanced cell death (caspase 3/7 and polyadenosine diphosphate-ribose polymerase activity, chromatin fragmentation, and terminal deoxynucleotidyl transferase dUTP nick end labeling), and diminished Akt phosphorylation. Remarkably, CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen species generation, nuclear factor-κB activation, and cell death in primary human cardiomyocytes. Conclusions Collectively, these results coupled with the excellent safety and tolerability profile of CBD in humans, strongly suggest that it may have great therapeutic potential in the treatment of diabetic complications, and perhaps other cardiovascular disorders, by attenuating oxidative/nitrative stress, inflammation, cell death and fibrosis.
Next‐generation sequencing (NGS) enables the diagnosis of large numbers of gene aberrations during one examination, and precision medicine has been developed for patients with advanced non–small cell ...lung cancer (NSCLC). However, peripheral lung lesions account for the majority of advanced lung cancers, especially lung adenocarcinoma. In these cases, it is difficult to obtain tissue samples which contain sufficient tumor cells by transbronchial biopsy (TBB) with forceps. Even when the target lesions are quite small, bronchial brushing can obtain enough tumor cells by endobronchial ultrasonography using guide sheath (EBUS‐GS). In this study, we investigate the suitability of bronchial brushing cytology specimens obtained by EBUS‐GS‐TBB to evaluate the correlation between the success rate of NGS and extracted DNA/RNA yields according to biopsy method. We prospectively collected 222 tumor samples obtained from patients with advanced lung cancer. All patients were enrolled in a prospective nationwide genomic screening project for lung cancer (LC‐SCRUM‐Japan/Asia). Genomic data were obtained from the clinico‐genomic database of LC‐SCRUM‐Japan/Asia. The extraction yields of DNA/RNA from samples obtained by EBUS‐GS‐TBB were relatively low compared with tissue samples. The success rate of DNA sequencing for EBUS‐GS‐TBB was 97.9%, with no significant differences between biopsy methods. The success rate of RNA sequencing for EBUS‐GS‐TBB was 80.4%, which was relatively low compared with surgical biopsy samples (P = 0.069). However, some rare oncogenic driver aberrations were detected from these specimens. This study demonstrated that cytology samples obtained by transbronchial brushing with EBUS‐GS‐TBB were suitable for NGS analysis.
This study demonstrated that cytology samples obtained by transbronchial brushing with endobronchial ultrasonography using guide sheath (EBUS‐GS) were suitable for next‐generation sequencing (NGS) analysis. We believe the new knowledge of this study can contribute to the best practice and further research for patients with advanced non–small cell lung cancer (NSCLC).
Background: Both pre-existing atrial fibrillation (AF) and new-onset AF (NOAF) are observed in patients with coronavirus disease 2019 (COVID-19); however, the effect of AF on clinical outcomes is ...unclear. This study aimed to investigate the effect of AF, especially NOAF, on the outcomes of hospitalized patients with COVID-19.Methods and Results: This study analyzed 673 COVID-19 patients with cardiovascular diseases and risk factors (CVDRF). Patients were divided into 3 groups; pre-existing AF (n=55), NOAF (n=28), and sinus rhythm (SR) (n=590). The baseline characteristics and in-hospital outcomes were evaluated. The mean age of the patients was 68 years, 65.4% were male, and the in-hospital mortality rate was 15.6%. The NOAF group demonstrated a higher in-hospital mortality rate (42.9%) than the pre-existing AF (30.9%) and SR (11.2%) groups (P<0.001). Patients with NOAF had a higher incidence of acute respiratory syndrome, multiple organ disease, hemorrhage, and stroke than those with pre-existing AF and NOAF. NOAF was independently associated with in-hospital mortality after adjusting for pre-existing AF and 4C mortality score (odds ratio 95% confidence interval: 4.71 1.63–13.6, P<0.001).Conclusions: Patients with NOAF had significantly worse outcomes as compared to patients with pre-existing AF and SR. The incidence of NOAF would be a useful predictor of clinical outcomes during hospitalization.
Oncogenic epidermal growth factor receptor (EGFR) signaling plays an important role in regulating global metabolic pathways, including aerobic glycolysis, the pentose phosphate pathway (PPP), and ...pyrimidine biosynthesis. However, the molecular mechanism by which EGFR signaling regulates cancer cell metabolism is still unclear. To elucidate how EGFR signaling is linked to metabolic activity, we investigated the involvement of the RAS/MEK/ERK and PI3K/AKT/mammalian target of rapamycin (mTOR) pathways on metabolic alteration in lung adenocarcinoma (LAD) cell lines with activating EGFR mutations. Although MEK inhibition did not alter lactate production and the extracellular acidification rate, PI3K/mTOR inhibitors significantly suppressed glycolysis in EGFR-mutant LAD cells. Moreover, a comprehensive metabolomics analysis revealed that the levels of glucose 6-phosphate and 6-phosphogluconate as early metabolites in glycolysis and PPP were decreased after inhibition of the PI3K/AKT/mTOR pathway, suggesting a link between PI3K signaling and the proper function of glucose transporters or hexokinases in glycolysis. Indeed, PI3K/mTOR inhibition effectively suppressed membrane localization of facilitative glucose transporter 1 (GLUT1), which, instead, accumulated in the cytoplasm. Finally, aerobic glycolysis and cell proliferation were down-regulated when GLUT1 gene expression was suppressed by RNAi. Taken together, these results suggest that PI3K/AKT/mTOR signaling is indispensable for the regulation of aerobic glycolysis in EGFR-mutated LAD cells.
Background: EGFR signaling maintains aerobic glycolysis, but the molecular mechanism is still undefined.
Results: Drug inhibition studies reveal that downstream signaling via the PI3K pathway is critical for glucose transport and metabolism.
Conclusion: The PI3K signaling regulates key metabolic activities in EGFR-mutant lung adenocarcinoma.
Significance: These data may guide the development of chemotherapeutic options, including targeting of the PI3K pathway and glucose transporter machinery.
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