Ultrasensitive and Rapid Circulating Tumor DNA Liquid Biopsy Using Surface-Confined Gene Amplification on Dispersible Magnetic Nano-Electrodes.

Circulating tumor DNA (ctDNA) detection has been acknowledged as a promising liquid biopsy approach for cancer diagnosis, with various ctDNA assays used for early detection and treatment monitoring. Dispersible magnetic nanoparticle-based electrochemical detection methods have been proposed as promising candidates for ctDNA detection based on the detection performance and features of the platform material. This study proposes a nanoparticle surface-localized genetic amplification approach by integrating Fe3O4-Au core-shell nanoparticles into polymerase chain reactions (PCR). These highly dispersible and magnetically responsive superparamagnetic nanoparticles act as nano-electrodes that amplify and accumulate target ctDNA in situ on the nanoparticle surface upon PCR amplification. These nanoparticles are subsequently captured and subjected to repetitive electrochemical measurements to induce reconfiguration-mediated signal amplification for ultrasensitive (∼3 aM) and rapid (∼7 min) metastatic breast cancer ctDNA detection in vitro. The detection platform can also detect metastatic biomarkers from in vivo samples, highlighting the potential for clinical applications and further expansion to rapid and ultrasensitive multiplex detection of various cancers.

Comparative interactome analysis of α-arrestin families in human and Drosophila.

The α-arrestins form a large family of evolutionally conserved modulators that control diverse signaling pathways, including both G-protein-coupled receptor (GPCR)-mediated and non-GPCR-mediated pathways, across eukaryotes. However, unlike ß-arrestins, only a few α-arrestin targets and functions have been characterized. Here, using affinity purification and mass spectrometry, we constructed interactomes for 6 human and 12 Drosophila α-arrestins. The resulting high-confidence interactomes comprised 307 and 467 prey proteins in human and Drosophila, respectively. A comparative analysis of these interactomes predicted not only conserved binding partners, such as motor proteins, proteases, ubiquitin ligases, RNA splicing factors, and GTPase-activating proteins, but also those specific to mammals, such as histone modifiers and the subunits of V-type ATPase. Given the manifestation of the interaction between the human α-arrestin, TXNIP, and the histone-modifying enzymes, including HDAC2, we undertook a global analysis of transcription signals and chromatin structures that were affected by TXNIP knockdown. We found that TXNIP activated targets by blocking HDAC2 recruitment to targets, a result that was validated by chromatin immunoprecipitation assays. Additionally, the interactome for an uncharacterized human α-arrestin ARRDC5 uncovered multiple components in the V-type ATPase, which plays a key role in bone resorption by osteoclasts. Our study presents conserved and species-specific protein-protein interaction maps for α-arrestins, which provide a valuable resource for interrogating their cellular functions for both basic and clinical research.

JAK2 Loss Arising From Tumor-Spread-Through-Air-Spaces (STAS) Promotes Tumor Progression by Suppressing CD8+ T Cells in Lung Adenocarcinoma: A Machine Learning Approach.

BACKGROUND: Tumor spread through air spaces (STAS) is a recently discovered risk factor for lung adenocarcinoma (LUAD). The aim of this study was to investigate specific genetic alterations and anticancer immune responses related to STAS. By using a machine learning algorithm and drug screening in lung cancer cell lines, we analyzed the effect of Janus kinase 2 (JAK2) on the survival of patients with LUAD and possible drug candidates. METHODS: This study included 566 patients with LUAD corresponding to clinicopathological and genetic data. For analyses of LUAD, we applied gene set enrichment analysis (GSEA), in silico cytometry, pathway network analysis, in vitro drug screening, and gradient boosting machine (GBM) analysis. RESULTS: The patients with STAS had a shorter survival time than those without STAS (P < 0.001). We detected gene set-related downregulation of JAK2 associated with STAS using GSEA. Low JAK2 expression was related to poor prognosis and a low CD8+ T-cell fraction. In GBM, JAK2 showed improved survival prediction performance when it was added to other parameters (T stage, N stage, lymphovascular invasion, pleural invasion, tumor size). In drug screening, mirin, CCT007093, dihydroretenone, and ABT737 suppressed the growth of lung cancer cell lines with low JAK2 expression. CONCLUSION: In LUAD, low JAK2 expression linked to the presence of STAS might serve as an unfavorable prognostic factor. A relationship between JAK2 and CD8+ T cells suggests that STAS is indirectly related to the anticancer immune response. These results may contribute to the design of future experimental research and drug development programs for LUAD with STAS.

Cancer-Associated Fibroblasts Together with a Decline in CD8+ T Cells Predict a Worse Prognosis for Breast Cancer Patients.

BACKGROUND: Cancer-associated fibroblasts (CAFs) play a crucial role in tumor microenvironment regulation and cancer progression. This study assessed the significance and predictive potential of CAFs in breast cancer prognosis. METHODS: The study included 1503 breast cancer patients. Cancer-associated fibroblasts were identified using morphologic features from hematoxylin and eosin slides. The study analyzed clinicopathologic parameters, survival rates, immune cells, gene sets, and prognostic models using gene-set enrichment analysis, in silico cytometry, pathway analysis, in vitro drug-screening, and gradient-boosting machine (GBM)-learning. RESULTS: The presence of CAFs correlated significantly with young age, lymphatic invasion, and perineural invasion. In silico cytometry showed altered leukocyte subsets in the presence of CAFs, with decreased CD8+ T cells. Gene-set enrichment analysis showed associations with critical processes such as the epithelial-mesenchymal transition and immune modulation. Drug sensitivity analysis in breast cancer cell lines with varying fibroblast activation protein-α expression suggested that CAF-targeted therapies might enhance the efficacy of certain anticancer drugs including ARRY-520, ispinesib-mesylate, paclitaxel, and docetaxel. Integrating CAF presence with machine-learning improved survival prediction. For breast cancer patients, CAFs were independent prognostic markers for worse disease-specific survival and disease-free survival. CONCLUSION: This study highlighted the significance of CAFs in breast cancer biology and provided compelling evidence of their impact on patient outcomes and treatment response. The findings offer valuable insights into the potential of CAFs as prognostic and predictive biomarkers and support the development of CAF-targeted therapies to improve breast cancer management.

Ultrafast Synthesis of Graphene-Embedded Cyclodextrin-Metal-Organic Framework for Supramolecular Selective Absorbency and Supercapacitor Performance.

Limited by preparation time and ligand solubility, synthetic protocols for cyclodextrin-based metal-organic framework (CD-MOF), as well as subsequent derived materials with improved stability and properties, still remains a challenge. Herein, an ultrafast, environmentally friendly, and cost-effective microwave method is proposed, which is induced by graphene oxide (GO) to design CD-MOF/GOs. This applicable technique can control the crystal size of CD-MOFs from macro- to nanocrystals. CD-MOF/GOs are investigated as a new type of supramolecular adsorbent. It can selectively adsorb the dye molecule methylene green (MG) owing to the synergistic effect between the hydrophobic nanocavity of CDs, and the abundant O-containing functional groups of GO in the composites. Following high temperature calcination, the resulting N, S co-doped porous carbons derived from CD-MOF/GOs exhibit a high capacitance of 501 F g-1 at 0.5 A g-1 , as well as stable cycling stability with 90.1% capacity retention after 5000 cycles. The porous carbon exhibits good electrochemical performance due to its porous surface containing numerous electrochemically active sites after dye adsorption and carbonization. The design strategy by supramolecular incorporating a variety of active molecules into CD-MOFs optimizes the properties of their derived materials, furthering development toward the fabrication of zeitgeisty and high-performance energy storage devices.

Development of a novel histone deacetylase inhibitor unveils the role of HDAC11 in alleviating depression by inhibition of microglial activation.

Histone deacetylases (HDACs) are key epigenetic regulators and classified into four subtypes. Despite the various roles of each HDAC isoform, the lack of selective HDAC inhibitors has limited the elucidation of their roles in biological systems. HDAC11, the sole class-IV HDAC, is highly expressed in the brain, however, the role of HDAC11 in microglia is not fully understood. Based on the modification of MC1568, we developed a novel HDAC inhibitor, 5. Interestingly, 5 suppresses lipopolysaccharide-induced microglial activation by the initiation of autophagy and subsequent inhibition of nitric oxide production. Furthermore, we demonstrated that 5 significantly alleviates depression-like behavior by inhibiting microglial activation in mouse brain. Our discovery reveals that specific pharmacological regulation of HDAC11 induces autophagy and reactive nitrogen species balance in microglia for the first time, which makes HDAC11 a new therapeutic target for depressive disorder.

Efficacy and safety of Kumpe access catheter for pre-percutaneous nephrolithotomy renal access in modified supine percutaneous nephrolithotomy.

INTRODUCTION: Traditionally, a pigtail catheter (PCN) is placed for preoperative renal access before performing percutaneous nephrolithotomy (PCNL). However, PCN can hamper the passage of the guidewire to the ureter, due to which, access tract can be lost. Therefore, Kumpe Access Catheter (KMP) has been proposed for preoperative renal access before PCNL. In this study, we analyzed the efficacy and safety of KMP for surgical outcomes in modified supine PCNL compared to those in PCN. MATERIALS AND METHODS: From July 2017 to December 2020, 232 patients underwent modified supine PCNL at a single tertiary center, of which 151 patients were enrolled in this study after excluding patients who underwent bilateral surgery, multiple punctures, or combined operations. Enrolled patients were divided into two groups according to the type of pre-PCNL nephrostomy catheter used: PCN versus KMP. A pre-PCNL nephrostomy catheter was selected based on the radiologist's preference. A single surgeon performed all PCNL procedures. Patient characteristics and surgical outcomes, including stone-free rate, operation time, radiation exposure time (RET), and complications, were compared between the two groups. RESULTS: Of the 151 patients, 53 underwent PCN placement, and 98 underwent KMP placement for pre-PCNL nephrostomy. Patient baseline characteristics were comparable between the two groups, except for the renal stone type and multiplicity. The operation time, stone-free rate, and complication rate were not significantly different between the two groups; however, RET was significantly shorter in the KMP group. CONCLUSION: The surgical outcomes of KMP placement were comparable to those of PCN and showed shorter RET during modified supine PCNL. Based on our results, we recommend KMP placement for pre-PCNL nephrostomy, particularly for reducing RET during supine PCNL.

Rapid Synthesis of Oxygen-Enriched Porous Carbon through a Microwave Method and Its Application in Supercapacitors.

In this study, a strategy for the rapid and simple preparation of porous carbon (PC) using the microwave method was proposed. Oxygen-rich PC was synthesized by microwave irradiation in air, where potassium citrate and ZnCl2 served as the carbon source and microwave absorber, respectively. ZnCl2 achieves microwave absorption through dipole rotation, which uses ion conduction to convert heat energy in the reaction system. In addition, potassium salt etching improved the porosity of PCs. The PC prepared under optimal conditions had a large specific surface area (902 m2·g-1) and exhibited a significant specific capacitance (380 F·g-1) in the three-electrode system at 1 A·g-1. The energy and power densities of the assembled symmetrical supercapacitor device based on PC-375W-0.4 were 32.7 W·h·kg-1 and 0.65 kW·kg-1, respectively, at a current density of 1 A·g-1. Even after 5000 cycles at 5 A·g-1 current density, the excellent cycle life retained 94% of its initial capacitance.

Special Issue: Resistance to Targeted Therapies in Human Cancer.

Cancer is the second leading cause of death worldwide, accounting for approximately 10 million deaths in 2020 [...].

Highly Stable Sb/C Anode for K+ and Na+ Energy Storage Enabled by Pulsed Laser Ablation and Polydopamine Coating.

Potassium- and sodium-ion batteries (PIBs and SIBs) have great potential as the next-generation energy application owing to the natural abundance of K and Na. Antimony (Sb) is a suitable alloying-type anode for PIBs and SIBs due to its high theoretical capacity and proper operation voltage; yet, the severe volume variation remains a challenge. Herein, a preparation of N-doped carbon-wrapped Sb nanoparticles (L-Sb/NC) using pulsed laser ablation and polydopamine coating techniques, is reported. As the anode for PIB and SIB, the L-Sb/NC delivers superior rate capabilities and excellent cycle stabilities (442.2 and 390.5 mA h g-1 after 250 cycles with the capacity decay of 0.037% and 0.038% per cycle) at the current densities of 0.5 and 1.0 A g-1 , respectively. Operando X-ray diffraction reveals the facilitated and stable potassiation and sodiation mechanisms of L-Sb/NC enabled by its optimal core-shell structure. Furthermore, the SIB full cell fabricated with L-Sb/NC and Na3 V2 (PO4 )2 F3 shows outstanding electrochemical performances, demonstrating its practical energy storage application.

Carbon Nanofibers Based on Potassium Citrate/Polyacrylonitrile for Supercapacitors.

Wearable supercapacitors based on carbon materials have been emerging as an advanced technology for next-generation portable electronic devices with high performance. However, the application of these devices cannot be realized unless suitable flexible power sources are developed. Here, an effective electrospinning method was used to prepare the one-dimensional (1D) and nano-scale carbon fiber membrane based on potassium citrate/polyacrylonitrile (PAN), which exhibited potential applications in supercapacitors. The chemical and physical properties of carbon nanofibers were characterized by X-ray diffraction analysis, scanning electron microscopy, transmission electron microscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, and the Brunnauer-Emmett-Teller method. The fabricated carbon nanofiber membrane illustrates a high specific capacitance of 404 F/g at a current density of 1 A/g. The good electrochemical properties could be attributed to the small diameter and large specific surface area, which promoted a high capacity.

Influences of Dog Attachment and Dog Walking on Reducing Loneliness during the COVID-19 Pandemic in Korea.

The COVID-19 pandemic has changed people's lives and increased their vulnerability to physical and mental health hazards. While Korea has avoided nationwide lockdown measures since the COVID-19 outbreak, the prolonged restrictions and social isolation measures have resulted in detrimental psychological effects, such as increased anxiety, boredom, and loneliness. The present study investigated dog attachment and changes in dog walking during the COVID-19 pandemic and the effects of dog attachment and dog walking on the loneliness of Korean dog owners. An online, cross-sectional survey was conducted in the fall of 2021 in which 249 dog owners responded to questionnaires that asked questions about dog attachment, their perception of dog walking, and their feelings of loneliness during the COVID-19 pandemic. Most dog owners responded that they spent more time with their dogs and developed a stronger bond with them during the pandemic. Additionally, respondents stated that they walked their dogs more often than they did before COVID-19 and that their dogs aided in reducing loneliness. We found that dog walking directly affected attachment and indirectly influenced the loneliness of dog owners. Further research is required to determine how dog walking impacts positive psychological effects and promote dog walking.

Laser-Ablated Red Phosphorus on Carbon Nanotube Film for Accelerating Polysulfide Conversion toward High-Performance and Flexible Lithium-Sulfur Batteries.

The use of a conducting interlayer between separator and cathode is one of the most promising methods to trap lithium polysulfides (LiPSs) for enhancing the performance of lithium-sulfur (Li-S) batteries. Red phosphorus nanoparticles (RPEN )-coated carbon nanotube (CNT) film (RPEN @CF) is reported herein as a novel interlayer for Li-S batteries, which shows strong chemisorption of LiPSs, good flexibility, and excellent electric conductivity. A pulsed laser ablation method is engaged for the ultrafast production of RPEN of uniform morphology, which are deposited on the CNT film by a direct spinning method. The RPEN @CF interlayer provides pathways for effective Li+ and electron transfer and strong chemical interaction with LiPSs. The S/RPEN @CF electrode shows a superior specific capacity of 782.3 mAh g-1 (3 C-rate) and good cycling performances (769.5 mAh g-1 after 500 cycles at 1 C-rate). Density functional theory calculations reveal that the morphology and dispersibility of RPEN are crucial in enhancing Li+ and electron transfer kinetics and effective trap of LiPSs. This work demonstrates the possibility of using the RPEN @CF interlayer for the enhanced electrochemical performances of Li-S batteries and other flexible energy storage devices.

Synergies of Fe Single Atoms and Clusters on N-Doped Carbon Electrocatalyst for pH-Universal Oxygen Reduction.

Single atomic metal-N-C materials have attracted immense interest as promising candidates to replace noble metal-based electrocatalysts for the oxygen reduction reaction (ORR). The coordination environment of metal-N-C active centers plays a critical role in determining their catalytic activity and durability, however, attention is focused only on the coordination of metal atoms. Herein, Fe single atoms and clusters co-embedded in N-doped carbon (Fe/NC) that deliver the synergistic enhancement in pH-universal ORR catalysis via the four-electron pathway are reported. Combining a series of experimental and computational analyses, the geometric and electronic structures of catalytic sites in Fe/NC are revealed and the neighboring Fe clusters are shown to weaken the binding energies of the ORR intermediates on Fe-N sites, hence enhancing both catalytic kinetics and thermodynamics. This strategy provides new insights into the understanding of the mechanism of single atom catalysis.

Crystal structures of human NSDHL and development of its novel inhibitor with the potential to suppress EGFR activity.

NAD(P)-dependent steroid dehydrogenase-like (NSDHL), an essential enzyme in human cholesterol synthesis and a regulator of epidermal growth factor receptor (EGFR) trafficking pathways, has attracted interest as a therapeutic target due to its crucial relevance to cholesterol-related diseases and carcinomas. However, the development of pharmacological agents for targeting NSDHL has been hindered by the absence of the atomic details of NSDHL. In this study, we reported two X-ray crystal structures of human NSDHL, which revealed a detailed description of the coenzyme-binding site and the unique conformational change upon the binding of a coenzyme. A structure-based virtual screening and biochemical evaluation were performed and identified a novel inhibitor for NSDHL harboring suppressive activity towards EGFR. In EGFR-driven human cancer cells, treatment with the potent NSDHL inhibitor enhanced the antitumor effect of an EGFR kinase inhibitor. Overall, these findings could serve as good platforms for the development of therapeutic agents against NSDHL-related diseases.

NSD3-Induced Methylation of H3K36 Activates NOTCH Signaling to Drive Breast Tumor Initiation and Metastatic Progression.

Histone methyltransferase NSD3 is frequently dysregulated in human cancers, yet the epigenetic role of NSD3 during cancer development remains elusive. Here we report that NSD3-induced methylation of H3K36 is crucial for breast tumor initiation and metastasis. In patients with breast cancer, elevated expression of NSD3 was associated with recurrence, distant metastasis, and poor survival. In vivo, NSD3 promoted malignant transformation of mammary epithelial cells, a function comparable to that of HRAS. Furthermore, NSD3 expanded breast cancer-initiating cells and promoted epithelial-mesenchymal transition to trigger tumor invasion and metastasis. Mechanistically, the long isoform (full-length transcript) of NSD3, but not its shorter isoform lacking a catalytic domain, cooperated with EZH2 and RNA polymerase II to stimulate H3K36me2/3-dependent transactivation of genes associated with NOTCH receptor cleavage, leading to nuclear accumulation of NICD and NICD-mediated transcriptional repression of E-cadherin. Furthermore, mice harboring primary and metastatic breast tumors with overexpressed NSD3 showed sensitivity to NOTCH inhibition. Together, our findings uncover the critical epigenetic role of NSD3 in the modulation of NOTCH-dependent breast tumor progression, providing a rationale for targeting the NSD3-NOTCH signaling regulatory axis in aggressive breast cancer. SIGNIFICANCE: This study demonstrates the functional significance of histone methyltransferase NSD3 in epigenetic regulation of breast cancer stemness, EMT, and metastasis, suggesting NSD3 as an actionable therapeutic target in metastatic breast cancer.

Cancer Target Gene Screening: a web application for breast cancer target gene screening using multi-omics data analysis.

Breast cancer comprises several molecular subtypes with distinct clinical features and treatment responses, and a substantial portion of each subtype remains incurable. A comprehensive analysis of multi-omics data and clinical profiles is required in order to better understand the biological complexity of this cancer type and to identify new prognostic and therapeutic markers. Thus, there arises a need for useful analytical tools to assist in the investigation and clinical management of the disease. We developed Cancer Target Gene Screening (CTGS), a web application that provides rapid and user-friendly analysis of multi-omics data sets from a large number of primary breast tumors. It allows the investigation of genomic and epigenomic aberrations, evaluation of transcriptomic profiles and performance of survival analyses and of bivariate correlations between layers of omics data. Notably, the genome-wide screening function of CTGS prioritizes candidate genes of clinical and biological significance among genes with copy number alteration, DNA methylation and dysregulated expression by the integrative analysis of different types of omics data in customized subgroups of breast cancer patients. These features may help in the identification of druggable cancer driver genes in a specific subtype or the clinical condition of human breast cancer. CTGS is available at http://ctgs.biohackers.net.

CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1-ErbB-PI3K signaling.

Cyclin-dependent kinase 12 (CDK12) has emerged as an effective therapeutic target due to its ability to regulate DNA damage repair in human cancers, but little is known about the role of CDK12 in driving tumorigenesis. Here, we demonstrate that CDK12 promotes tumor initiation as a novel regulator of cancer stem cells (CSCs) and induces anti-HER2 therapy resistance in human breast cancer. High CDK12 expression caused by concurrent amplification of CDK12 and HER2 in breast cancer patients is associated with disease recurrence and poor survival. CDK12 induces self-renewal of breast CSCs and in vivo tumor-initiating ability, and also reduces susceptibility to trastuzumab. Furthermore, CDK12 kinase activity inhibition facilitates anticancer efficacy of trastuzumab in HER2+ tumors, and mice bearing trastuzumab-resistant HER2+ tumor show sensitivity to an inhibitor of CDK12. Mechanistically, the catalytic activity of CDK12 is required for the expression of genes involved in the activation of ErbB-PI3K-AKT or WNT-signaling cascades. These results suggest that CDK12 is a major oncogenic driver and an actionable target for HER2+ breast cancer to replace or augment current anti-HER2 therapies.

Phosphorus-doped graphene nanosheets anchored with cerium oxide nanocrystals as effective sulfur hosts for high performance lithium-sulfur batteries.

To meet the ever-increasing market requirements for energy storage devices with improved performances, lithium-sulfur (Li-S) batteries with high theoretical capacity and energy density have been extensively studied. However, to bring Li-S batteries into real life, several challenges still need to be overcome, such as dissolution of intermediate polysulfides, large volume change, and low electrical conductivity of sulfur. In this study, phosphorus-doped graphene anchored with well-dispersed cerium oxide nanocrystals (CeO2/PG) were prepared as effective sulfur host materials through a hydrothermal synthesis method followed by a thermal treatment process. The cerium oxide nanocrystals/phosphorus-doped graphene (CeO2/PG) nanocomposites can provide high electrical conductivity, sufficient spaces for the storage of sulfur, and strong chemical binding with polysulfides. In particular, well-dispersed polar CeO2 nanocrystals effectively exhibit chemical affinity with polysulfides and promote polysulfide redox reactions during the cycling. Furthermore, phosphorus dopants can offer a sufficient number of active sites for polysulfide trapping and enhance the overall electrical conductivity of graphene nanosheets. As a result, a S@CeO2/PG cathode with 72.3 wt% sulfur content exhibits a high specific capacity (1287 mA h g-1 at 0.1 C-rate) and good cycling stability (577.7 mA h g-1 at 1 C-rate after 100 cycles).

Fe3O4 nanoparticle decorated three-dimensional porous carbon/MoS2 composites as anodes for high performance lithium-ion batteries.

Molybdenum disulfide (MoS2) is a promising anode material for lithium-ion batteries owing to its high theoretical capacity and low cost. However, it exhibits low electrical conductivity and volume expansion, resulting in poor electrochemical performance. In this work, three-dimensional porous carbon/MoS2 composites with Fe3O4 nanoparticles (C-MF) are synthesized via a mix-bake-wash method. The few-layered MoS2 in the porous carbon matrix provides improved electrical conductivity and facilitates lithium ion diffusion, so the composites exhibit a high specific capacity of 939.6 mA h g-1 on average at 0.1 A g-1 and a high rate capability (515.9 mA h g-1 at 5 A g-1). Moreover, the Fe3O4 nanoparticles in C-MF, which are anchored on the composites, improve the specific capacity and effectively mitigate diffusion of lithium polysulfides during cycling, resulting in remarkable cycling stability (590.1 mA h g-1 after 500 cycles at 2 A g-1). This work suggests that not only C-MF but also C@MoS2 with other metal oxides synthesized using this facile strategy have potential for energy-related applications.