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"Ahn, S"
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Interleukin-33/ST2 axis promotes epithelial cell transformation and breast tumorigenesis via upregulation of COT activity
Cytokines of the interleukin-1 (IL-1) family, such as IL-1α/β and IL-18, have pleiotropic activities in innate and adaptive immune responses in host defense and diseases. Insight into their biological functions helped develop novel therapeutic approaches to treat human inflammatory diseases. IL-33 is an important member of the IL-1 family of cytokines and is a ligand of the ST2 receptor, a member of the IL-1 receptor family. However, the role of the IL-33/ST2 axis in tumor growth and metastasis of breast cancer remains unclear. Here, we demonstrate that IL-33 is a critical tumor promoter during epithelial cell proliferation and tumorigenesis in the breast. IL-33 dose- and time-dependently increased Cancer Osaka Thyroid (COT) phosphorylation via ST2-COT interaction in normal epithelial and breast cancer cells. The IL-33/ST2/COT cascade induced the activation of the MEK-ERK (MEK-extracellular signal-regulated kinase), JNK-cJun (cJun N-terminal kinase-cJun) and STAT3 (signal transducer and activator of transcription 3) signaling pathways, followed by increased AP-1 and
stat3
transcriptional activity. When small interfering RNAs of ST2 and COT were introduced into cells, IL-33-induced AP-1 and
stat3
activity were significantly decreased, unlike that in the control cells. The inhibition of COT activity resulted in decreased IL-33-induced epithelial cell transformation, and knockdown of IL-33, ST2 and COT in breast cancer cells attenuated tumorigenicity of breast cancer cells. Consistent with these observations, ST2 levels were positively correlated with COT expression in human breast cancer. These findings provide a novel perspective on the role of the IL-33/ST2/COT signaling pathway in supporting cancer-associated inflammation in the tumor microenvironment. Therapeutic approaches that target this pathway may, therefore, effectively inhibit carcinogenesis in the breast.
Journal Article
Toxin-Induced Necroptosis Is a Major Mechanism of Staphylococcus aureus Lung Damage
Staphylococcus aureus USA300 strains cause a highly inflammatory necrotizing pneumonia. The virulence of this strain has been attributed to its expression of multiple toxins that have diverse targets including ADAM10, NLRP3 and CD11b. We demonstrate that induction of necroptosis through RIP1/RIP3/MLKL signaling is a major consequence of S. aureus toxin production. Cytotoxicity could be prevented by inhibiting either RIP1 or MLKL signaling and S. aureus mutants lacking agr, hla or Hla pore formation, lukAB or psms were deficient in inducing cell death in human and murine immune cells. Toxin-associated pore formation was essential, as cell death was blocked by exogenous K+ or dextran. MLKL inhibition also blocked caspase-1 and IL-1β production, suggesting a link to the inflammasome. Rip3(-/-) mice exhibited significantly improved staphylococcal clearance and retained an alveolar macrophage population with CD200R and CD206 markers in the setting of acute infection, suggesting increased susceptibility of these leukocytes to necroptosis. The importance of this anti-inflammatory signaling was indicated by the correlation between improved outcome and significantly decreased expression of KC, IL-6, TNF, IL-1α and IL-1β in infected mice. These findings indicate that toxin-induced necroptosis is a major cause of lung pathology in S. aureus pneumonia and suggest the possibility of targeting components of this signaling pathway as a therapeutic strategy.
Journal Article
Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer
Alectinib, a potent ALK tyrosine kinase inhibitor, was more effective and somewhat less toxic than crizotinib when used as primary therapy in patients with
ALK
-positive non–small-cell lung cancer. Importantly, it reduced the risk of CNS relapse.
Journal Article
NEOCENT: a randomised feasibility and translational study comparing neoadjuvant endocrine therapy with chemotherapy in ER-rich postmenopausal primary breast cancer
Neoadjuvant endocrine therapy is an alternative to chemotherapy for women with oestrogen receptor (ER)-positive early breast cancer (BC). We aimed to assess feasibility of recruiting patients to a study comparing chemotherapy versus endocrine therapy in postmenopausal women with ER-rich primary BC, and response as well as translational endpoints were assessed. Patients requiring neoadjuvant therapy were randomised to chemotherapy: 6 × 3-weekly cycles FE
100
C or endocrine therapy: letrozole 2.5 mg, daily for 18–23 weeks. Primary endpoints were recruitment feasibility and tissue collection. Secondary endpoints included clinical, radiological and pathological response rates, quality of life and translational endpoints. 63/80 patients approached were eligible, of those 44 (70, 95 % CI 57–81) were randomised. 12 (54.5, 95 % CI 32.2–75.6) chemotherapy patients showed radiological objective response compared with 13 (59.1, 95 % CI 36.4–79.3) letrozole patients. Compared with baseline, mean Ki-67 levels fell in both groups at days 2–4 and at surgery [fold change: 0.24 (95 % CI 0.12–0.51) and 0.24; (95 % CI 0.15–0.37), respectively]. Plasma total cfDNA levels rose from baseline to week 8 [fold change: chemotherapy 2.10 (95 % CI 1.47–3.00), letrozole 1.47(95 % CI 0.98–2.20)], and were maintained at surgery in the chemotherapy group [chemotherapy 2.63; 95 % CI 1.56–4.41), letrozole 0.95 (95 % CI 0.71–1.26)]. An increase in plasma let-7a miRNA was seen at surgery for patients with objective radiological response to chemotherapy. Recruitment and tissue collection endpoints were met; however, a larger trial was deemed unfeasible due to slow accrual. Both regimens were equally efficacious. Dynamic changes were seen in Ki-67 and circulating biomarkers in both groups with increases in cfDNA and let-7a miRNA persisting until surgery for chemotherapy patients.
Journal Article
Analytical estimation of the signal to noise ratio efficiency in axion dark matter searches using a Savitzky-Golay filter
A
bstract
The signal to noise ratio efficiency
ϵ
SNR
in axion dark matter searches has been estimated using large-statistic simulation data reflecting the background information and the expected axion signal power obtained from a real experiment. This usually requires a lot of computing time even with the assistance of powerful computing resources. Employing a Savitzky-Golay filter for background subtraction, in this work, we estimated a fully analytical
ϵ
SNR
without relying on large-statistic simulation data, but only with an arbitrary axion mass and the relevant signal shape information. Hence, our work can provide
ϵ
SNR
using minimal computing time and resources prior to the acquisition of experimental data, without the detailed information that has to be obtained from real experiments. Axion haloscope searches have been observing the coincidence that the frequency independent scale factor
ξ
is approximately consistent with the
ϵ
SNR
. This was confirmed analytically in this work, when the window length of the Savitzky-Golay filter is reasonably wide enough, i.e., at least 5 times the signal window.
Journal Article
Highly efficient oxygen evolution reaction via facile bubble transport realized by three-dimensionally stack-printed catalysts
Despite highly promising characteristics of three-dimensionally (3D) nanostructured catalysts for the oxygen evolution reaction (OER) in polymer electrolyte membrane water electrolyzers (PEMWEs), universal design rules for maximizing their performance have not been explored. Here we show that woodpile (WP)-structured Ir, consisting of 3D-printed, highly-ordered Ir nanowire building blocks, improve OER mass activity markedly. The WP structure secures the electrochemically active surface area (ECSA) through enhanced utilization efficiency of the extended surface area of 3D WP catalysts. Moreover, systematic control of the 3D geometry combined with theoretical calculations and various electrochemical analyses reveals that facile transport of evolved O
2
gas bubbles is an important contributor to the improved ECSA-specific activity. The 3D nanostructuring-based improvement of ECSA and ECSA-specific activity enables our well-controlled geometry to afford a 30-fold higher mass activity of the OER catalyst when used in a single-cell PEMWE than conventional nanoparticle-based catalysts.
Improved design of three-dimensionally nanostructured catalysts for oxygen evolution reaction (OER) can play a key role in maximizing the catalytic performance. Here, the authors show that woodpile-structured iridium consisting of 3D-printed, highly-ordered nanowire building blocks significantly improve OER mass activity.
Journal Article
Mitochondria as biosynthetic factories for cancer proliferation
Unchecked growth and proliferation is a hallmark of cancer, and numerous oncogenic mutations reprogram cellular metabolism to fuel these processes. As a central metabolic organelle, mitochondria execute critical biochemical functions for the synthesis of fundamental cellular components, including fatty acids, amino acids, and nucleotides. Despite the extensive interest in the glycolytic phenotype of many cancer cells, tumors contain fully functional mitochondria that support proliferation and survival. Furthermore, tumor cells commonly increase flux through one or more mitochondrial pathways, and pharmacological inhibition of mitochondrial metabolism is emerging as a potential therapeutic strategy in some cancers. Here, we review the biosynthetic roles of mitochondrial metabolism in tumors and highlight specific cancers where these processes are activated.
Journal Article
A Computationally Efficient p-Refinement Finite Element Method Approach for the Fracture Analysis of Axially Cracked Pipes with Composite Patch Reinforcement
Cylindrical shells are widely used in pipelines, pressure vessels, and aircraft fuselages due to their efficient internal pressure distribution. However, axial cracks caused by fatigue, environmental effects, or mechanical loading compromise structural integrity, requiring effective reinforcement. This study presents a finite element modeling approach integrating p-refinement techniques for the efficient analysis of axially cracked pipes reinforced with composite patches. The proposed method unifies equivalent single-layer and layer-wise theories into a single finite element type, improving computational efficiency and eliminating the need for multiple element types in transition elements. Benchmark studies show that the proposed model accurately predicts mechanical behavior, with maximum displacement and stress intensity factors (SIFs) deviating by less than 5% from reference solutions. Fracture analysis using the virtual crack closure technique confirms the accuracy of the SIF calculations. In patched cracked pipes, the proposed model achieves a 67% reduction in degrees of freedom compared to conventional p-refinement layer-wise models, while maintaining computational accuracy. Additionally, boron–epoxy composite patches reduce SIFs by up to 40%, demonstrating effective crack reinforcement. These findings support computationally efficient damage-tolerant design strategies for pressurized cylindrical structures in aerospace, marine, and mechanical engineering.
Journal Article
Prolonged hydrogen production by engineered green algae photovoltaic power stations
Interest in securing energy production channels from renewable sources is higher than ever due to the daily observation of the impacts of climate change. A key renewable energy harvesting strategy achieving carbon neutral cycles is artificial photosynthesis. Solar-to-fuel routes thus far relied on elaborately crafted semiconductors, undermining the cost-efficiency of the system. Furthermore, fuels produced required separation prior to utilization. As an artificial photosynthesis design, here we demonstrate the conversion of swimming green algae into photovoltaic power stations. The engineered algae exhibit bioelectrogenesis, en route to energy storage in hydrogen. Notably, fuel formation requires no additives or external bias other than CO
2
and sunlight. The cellular power stations autoregulate the oxygen level during artificial photosynthesis, granting immediate utility of the photosynthetic hydrogen without separation. The fuel production scales linearly with the reactor volume, which is a necessary trait for contributing to the large-scale renewable energy portfolio.
Cost, scalability, and durability are critical factors determining the application of artificial photosynthesis systems. Here, the authors address these problems by inserting a carbon nanofiber into the chloroplast of green algae to transfer of electrons for photosynthesis and demonstrate H2 production up to 50 days.
Journal Article