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Bulk cancer cells and cancer stem cells (CSCs) harbor efficient and adaptive redox systems to help them resist oxidative insults arising from diverse therapeutic modalities. Herein, a tumor microenvironment (TME)‐activatable nano‐modulator capable of disrupting adaptive redox homeostasis, prepared by integrating FDA‐approved xCT inhibitor sulfasalazine (SSZ) into pH‐responsive hydroxyethyl starch‐doxorubicin conjugate stabilized copper peroxide nanoparticles (HSCPs) is reported. Compared to poly(vinylpyrrolidone) (PVP)‐stabilized copper peroxide nanoparticles, HSCPs exhibit superior physiological stability, longer circulation half‐life, and higher tumor enrichment. Under an acidic TME, the active components inside HSCPs are productively released along with the disintegration of HSCPs. The specifically generated hydrogen peroxide (H2O2) from copper peroxide nanoparticles furnishes a constant power source for copper‐mediated hydroxyl radical (•OH) production, serving as a wealthy supplier for oxidative stress. Meanwhile, the tumor‐specific release of Cu2+ and SSZ can induce long‐lasting glutathione (GSH) depletion via copper‐mediated self‐cycling valence transitions and SSZ‐blocked GSH biosynthesis, thereby reducing the offsetting action of the antioxidant GSH against oxidative stress. As a result, this sustained oxidative stress potently restrains the growth of aggressive orthotopic breast tumors while suppressing pulmonary metastasis by eradicating CSC populations. The reported smart nanomedicine provides a new paradigm for redox imbalance‐triggered cancer therapy. [ABSTRACT FROM AUTHOR]

Tumor starvation induced by intratumor glucose depletion emerges as a promising strategy for anticancer therapy. However, its antitumor potencies are severely compromised by intrinsic tumor hypoxia, low delivery efficiencies, and undesired off‐target toxicity. Herein, a multifunctional cascade bioreactor (HCG), based on the self‐assembly of pH‐responsive hydroxyethyl starch prodrugs, copper ions, and glucose oxidase (GOD), is engineered, empowered by hyperbaric oxygen (HBO) for efficient cooperative therapy against aggressive breast cancers. Once internalized by tumor cells, HCG undergoes disassembly and releases cargoes in response to acidic tumor microenvironment. Subsequently, HBO activates GOD‐catalyzed oxidation of glucose to H2O2 and gluconic acid by ameliorating tumor hypoxia, fueling copper‐catalyzed •OH generation and pH‐responsive drug release. Meanwhile, HBO degrades dense tumor extracellular matrix, promoting tumor accumulation and penetration of HCG. Moreover, along with the consumption of glucose and the redox reaction of copper ions, the antioxidant capacity of tumor cells is markedly reduced, collectively boosting oxidative stress. As a result, the combination of HCG and HBO can not only remarkably suppress the growth of orthotopic breast tumors but also restrain pulmonary metastases by inhibiting cancer stem cells. Considering the clinical accessibility of HBO, this combined strategy holds significant translational potentials for GOD‐based therapies. [ABSTRACT FROM AUTHOR]

Glutathione (GSH), the main redox buffer, has long been recognized as a pivotal modulator of tumor initiation, progression and metastasis. It is also implicated in the resistance of platinum-based chemotherapy and radiation therapy. Therefore, depleting intracellular GSH was considered a potent solution to combating cancer. However, reducing GSH within cancer cells alone always failed to yield desirable therapeutic effects. In this regard, the convergence of GSH-scavenging agents with therapeutic drugs has thus been pursued in clinical practice. Unfortunately, the therapeutic outcomes are still unsatisfactory due to untargeted drug delivery. Advanced nanomedicine of synergistic GSH depletion and cancer treatment has attracted tremendous interest because they promise to deliver superior therapeutic benefits while alleviating life-threatening side effects. In the past five years, the authors and others have demonstrated that numerous nanomedicines, by simultaneously delivering GSH-depleting agents and therapeutic components, boost not only traditional chemotherapy and radiotherapy but also multifarious emerging treatment modalities, including photodynamic therapy, sonodynamic therapy, chemodynamic therapy, ferroptosis, and immunotherapy, to name a few, and achieved decent treatment outcomes in a large number of rodent tumor models. In this review, we summarize the most recent progress in engineering nanomedicine for GSH depletion-enhanced cancer therapies. Biosynthesis of GSH and various types of GSH-consuming strategies will be briefly introduced. The challenges and perspectives of leveraging nanomedicine for GSH consumption-augmented cancer therapies will be discussed at the end. [ABSTRACT FROM AUTHOR]

• The line element method is presented for the prediction of free surface seepage in fractured rocks. • The solutions provided by the method agree well with the solutions of the literature. • The new method achieves accurate results with less computational time and memory storage and less iterations. In this paper, an equivalent line element method is established to analyze seepage problems with free surface through two-dimensional rock mass, including fracture networks. Low-permeablity rock matrix is characterized by the line elements as well as the high-permeablity fracture networks. Unlike the conventional equivalent continuum model, water flow in a rock mass is restricted to the line elements, and the equivalent hydraulic conductivity is determined according to Darcy's law and flux equivalence principle. As a result, uniform expressions of governing equations and boundary conditions are formulated, and the corresponding numerical procedure is developed by introducing the local coordinate and continuous Heaviside function. Satisfactory agreements with the existing test and numerical data verify this proposed line element method. The numerical solutions on the fractured slope indicate that the geological features of fractures have a substantial effect on locating the free surface. In addition, the proposed line element method can efficiently achieve accurate results with less computing time, iteration, and storage. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • CuS nanoparticles were synthesized using versatile polydopamine as bio-template. • Without additional surfactant, the nanocomposite shows favorable biocompatibility. • The integration of MRI and photothermal therapy enables more effective treatment. • The nanocomposite possesses high stability and excellent photothermal property. Abstract Copper sulfide nanoparticles(CuS NPs) have attracted considerable interest in the field of photothermal therapy(PTT) due to its low cost, easy preparation and favorable photothermal effect. However, lack of reliable visualization and relatively poor biocompatibility restrict its further bio-application. To overcome these limitations, polydopamine(PDA, a melanin-like biopolymer) stabilized CuS NPs and further chelated with iron ions (denoted as CuPDF) were designed as a versatile nanoplatform for T 1 -weighted MR imaging-guided PTT. In this system, PDA served as both bio-template to synthesis CuS NPs and an active platform to give MRI diagnostic capability. The as-prepared CuPDF NPs demonstrated strong absorption at NIR region, nearly three times higher than that of pure PDA NPs at 808 nm. Moreover, toxicity studies and histology evalution verified that CuPDF NPs possess excellent biocompatibility. In addition, CuPDF NPs showed significant MRI signal enhancement with high longitudinal relaxivity (r 1 = 4.59 mM−1 s−1). In vivo MRI and biodistribution test confirmed the efficient accumulation of CuPDF NPs in the tumor region. After intravenous injection of CuPDF, irreversible tumor ablation was successfully achieved without inducing any obvious side effects by using 808-nm laser irradiation. All in all, these results indicated that the developed CuPDF NPs hold great potential as an effective theranostic agent for MR imaging guided PTT in vivo. [ABSTRACT FROM AUTHOR]

Neural topic models have triggered a surge of interest in extracting topics from text automatically since they avoid the sophisticated derivations in conventional topic models. However, most of these models only utilize word count information, which will result in low coherent topics. To address this issue, we explore the way to incorporate word relatedness in word embeddings into the topic modeling process and propose the novel Variational Gaussian Topic Model (VaGTM). Based on the variational auto-encoder, the proposed VaGTM models each topic with a multivariate Gaussian in the decoder to group the semantically similar words together and obtains more coherent topics. Moreover, to address the limitation that pre-trained word embedding of topic-associated words does not exactly follows Gaussian, we extend the VaGTM and propose the Variational Gaussian Topic Model with Invertible neural Projections (VaGTM-IP). Extensive experiments have been conducted on three benchmark text corpora, and the experimental results show that VaGTM and VaGTM-IP outperform several competitive baselines in terms of four topic coherence metrics. Besides, the proposed approaches could also mine topic correlations between extracted topics with topic-associated Gaussian distributions. [ABSTRACT FROM AUTHOR]

We use a trigonometric identity and elementary calculus to obtain simple proofs of the following identities: and. [ABSTRACT FROM AUTHOR]

We use freshman calculus to prove thatfor θ ∈ (0, π) andn= 0, 1, 2, … ; in particular, we obtain a simple unified method for evaluating the following infinite series: [ABSTRACT FROM PUBLISHER]

• The novel triple cation Organic-inorganic hybrid perovskites (OHPs) Cs 0.05 (FA x MA 1-x) 0.95 PbBr y I 3-y based optoelectronic coupling memristors were fabricated. • Capacitive coupling behaviors are observed. • By changing voltage and light, the device can evolve from capacitive behavior to pure memristive behavior. • The corresponding physical mechanisms is investigated. Memristors are new type of circuit element with the characteristics of both integrated computing and storage, which can promote the development of artificial intelligence and memory- computing fusion technology. In this manuscript, a novel triple cation Organic-inorganic hybrid perovskite (OHP) based optoelectronic coupling memristors with structure of FTO/TiO 2 /Cs 0.05 (FA x MA 1−x) 0.95 PbBr y I 3−y /Al were fabricated, hysteresis loops with low power consumption, high HRS/LRS ratio and obvious light response are presented. Besides, capacitive coupling behaviors are observed in current curves. By changing voltage or light condition, memristors can evolve from capacitive behavior to pure memristive behavior. Physical mechanisms are discussed to explain this phenomenon. This work opens up a way in improving the resistive switching performances of OHP memristors, and can be of great benefit to the potential application in neuromorphological analysis. [ABSTRACT FROM AUTHOR]

• Multifunctional Bi 2 S 3 /FeS 2 @BSA-FA NHs were synthesized via a facile one-pot strategy. • BSA was tactfully introduced as both the reaction nanocages and sulfur provider. • The obtained nanohybrids enables complementary MR/CT imaging of tumors. • The conjugation of targeting ligands (FA) can enhance specific uptake by tumor cells. • The nanohybrids can valid suppressed growth of tumors under laser irradiation. Constructing versatile theranostic nanoplatforms that combine diagnostic and therapeutic moieties has shown great promise in the area of precision nanomedicine. However, the limitations on biosecurity, efficiency, and accessibility still need to be addressed. Herein, Bi 2 S 3 /FeS 2 nanohybrids (NHs) were fabricated by a facile and biomimetic one-pot strategy using bovine serum albumin (BSA) as both the sulfur provider to achieve the nucleation and reaction nanocages to regulate the growth of NHs. Upon modification with folic acid (FA), the final obtained Bi 2 S 3 /FeS 2 @BSA-FA NHs could successfully target folate receptor α overexpressed 4T1 tumor cells. Moreover, CCK-8 assay and histopathologic evaluation confirmed the favorable biocompatibility of Bi 2 S 3 /FeS 2 @BSA-FA NHs, which is the premise of subsequent research. In addition, both in vitro and in vivo tests demonstrated that the Bi 2 S 3 /FeS 2 @BSA-FA NHs can serve as computed tomography (CT)/magnetic resonance (MR) dual mode imaging contrast agents, which possess a high X-ray absorption coefficient of 8.02 HU mM−1 and transverse relaxivity (53.9 mM−1s−1). And these two clinical imaging modes could complement each other. After intravenous injection, Bi 2 S 3 /FeS 2 @BSA-FA NHs exhibited efficient tumor homing, as shown by imaging and biodistribution measurement. Notably, when irradiated with 808 nm NIR laser (1.5 W.cm−2), the tumor growth of Bi 2 S 3 /FeS 2 @BSA-FA-treated group could be suppressed effectively, proving the high efficacy of photothermal therapy with these NHs. Thus, our research represents a facile and "green" approach for the construction of multifunctional theranostic reagents. [ABSTRACT FROM AUTHOR]

Organic–inorganic halide perovskites (OHPs) have been proven to possess unique optical and electrical properties, and achieved more extensive application as excellent materials for memristors in recent years. Based on the traditional OHP-based memristors, the intermediate layer of the memristor was prepared using yttrium oxide (Y2O3)/OHP stacking structure in this manuscript. The potential barrier between Y2O3 and perovskite is relatively high (ΔEC = 2.13 eV) which leads to comparatively low current of the memristor, thus the power consumption can be reduced. Besides, by changing the external light conditions, one can realize sharp or slow switch between high resistance state (HRS) and low resistance state (LRS), so as to meet the requirement of multilevel data storage, which indicates its promising application prospect in information storage and biological simulation. In addition, based on characteristics of photoelectric coupling, the Y2O3/OHP memristor can also achieve the advantage of adjustable threshold voltage. The transition of HRS and LRS can be realized by changing the illumination condition at any voltage, which means the set and reset voltage are not fixed, so that the memristor with adjustable threshold voltage can adapt to various working conditions. [ABSTRACT FROM AUTHOR]

Abstract Mitochondria, which are a major source of adenosine triphosphate (ATP) and apoptosis regulators, are the key organelles that promote tumor cell proliferation, and their dysfunction affects tumor cell behavior. Additionally, mitochondria have been shown to play a central role in the biosynthesis of protoporphyrin IX (PpIX), which is a widely used photosensitizer that has been used for tumor detection, monitoring and photodynamic therapy. Nevertheless, photosensitizers administrated exogenously are often restricted by limited bioavailability.δ-Aminolevulinic acid (δ-ALA) is a naturally occurring delta amino acid that can be converted in situ to PpIX via the heme biosynthetic pathway in mitochondria. Because δ-ALA is the precursor for PpIX, δ-ALA-based photodynamic therapy (PDT) shows promise in treating cancer. However, the accumulation of δ-ALA within endosomal system limits the production of PpIX and eventually impedes its effectiveness. Theranostic nanoparticles (NPs) capable of endosomal escape are expected to optimize the endogenous biosynthetic yield. In this study, δ-ALA was improved with triphenylphosphoniumcation (TPP+), a high net position cation that functions in endosomal escape and as a mitochondria-targeting ligand, and was further modified with bovine serum albumin stabilized manganese dioxide (MnO 2). The tumor microenvironment (TME) responsive MnO 2 in this system can elevate oxygen content to relieve hypoxia. Both enhanced photosensitizer yield and elevated oxygen contributing to the final therapeutic effect. Moreover, the enhancement of magnetic resonance imaging (MRI) (r 1 = 5.410 s−1mM−1) stemming from the degradation of MnO 2 by the TME could serve as a guide prior to treatment for accurate location, while in situ hysteretic photoluminescence imaging derived from PpIX can be utilize as a supervisor for prognosis evaluation. This systematic design could broaden the biomedical application and highlight the considerable therapeutic promise of PDT. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs), enabled to self-renew, differentiate, and initiate the bulk tumor, are recognized as the culprit of treatment resistance, metastasis, and recurrence. Simultaneously eradicating CSCs and bulk cancer cells is crucial for successful cancer therapy. Herein, we reported that doxorubicin (Dox) and erastin co -loaded hydroxyethyl starch-polycaprolactone nanoparticles (DEPH NPs) eliminated CSCs and cancer cells by regulating redox status. We found that an excellently synergistic effect existed when Dox and erastin were co-delivered by DEPH NPs. Specifically, erastin could deplete intracellular glutathione (GSH), thereby inhibiting the efflux of intracellular Dox and boosting Dox-induced reactive oxygen species (ROS) to amplify redox imbalance and oxidative stress. The high ROS levels restrained CSCs self-renewal via downregulating Hedgehog pathways, promoted CSCs differentiation, and rendered differentiated cancer cells vulnerable to apoptosis. As such, DEPH NPs significantly eliminated not only cancer cells but more importantly CSCs, contributing to suppressed tumor growth, tumor-initiating capacity, and metastasis, in various tumor models of triple negative breast cancer. This study demonstrates that the combination of Dox and erastin is potent in elimination of both cancer cells and CSCs, and that DEPH NPs represent a promising treatment against CSCs-rich solid tumors. DEPH nanoparticles eliminate cancer stem cells (CSCs) by destroying the redox equilibrium to suppress CSCs self-renewal pathway, promote differentiation and induce apoptosis. [Display omitted] • DEPH NPs simultaneously and precisely release erastin and Dox for synergistic effect. • Erastin enhances Dox tumor accumulation and aggrandizes Dox-induced oxidative stress. • DEPH NPs potently suppress both CSCs and cancer cells by regulating redox balance. • This study provides novel insights on combination therapy and anti-CSCs therapy. [ABSTRACT FROM AUTHOR]

High reactive oxygen species (ROS) levels provide a therapeutic opportunity to eradicate cancer stem cells (CSCs), a population of cells responsible for tumorigenesis, progression, metastasis, and recurrence. However, enhanced antioxidant systems in this population of cells attenuate ROS-inducing therapies. Here, we developed a nanoparticle-assisted combination therapy to eliminate CSCs by employing photodynamic therapy (PDT) to yield ROS while disrupting ROS defense with glutaminolysis inhibition. Specifically, we leveraged an oleic acid-hemicyanine conjugate (CyOA) as photosensitizer, a new entity molecule HYL001 as glutaminolysis inhibitor, and a biocompatible folic acid-hydroxyethyl starch conjugate (FA-HES) as amphiphilic surfactant to construct cellular and mitochondrial hierarchical targeting nanomedicine (COHF NPs). COHF NPs inhibited glutaminolysis to reduce intracellular ROS scavengers, including glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH), and to blunt oxidative phosphorylation (OXPHOS) for oxygen-conserved PDT. Compared to COLF NPs without glutaminolysis inhibitor, COHF NPs exhibited higher phototoxicity to breast cancer stem cells (BCSCs) both in vitro and in vivo. More importantly, we corroborated that marketed glutaminolysis inhibitors, such as CB839 and V9302, augment the clinically used photosensitizer (Hiporfin) for BCSCs elimination. This study develops a potent CSCs targeting strategy by combining glutaminolysis inhibition with PDT and provides significant implications for cancer therapy. This study reports a hierarchical targeting nanoparticle with high drug loading efficiency, consisting of an oleic acid modified photosensitizer and a glutaminolysis inhibitor, which amplifies oxidative stress by reducing intracellular ROS scavengers and enabling oxygen conserving photodynamic therapy, resulting in potent eradication of cancer stem cells. [Display omitted] • COHF NPs is a cellular and mitochondrial hierarchical targeting nano-formulation. • COHF NPs engage in two-way cross-talk to synergistically amplify oxidative stress for CSCs elimination. • This study develops a potent CSCs elimination strategy by combining glutaminolysis inhibition with photodynamic therapy. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A simple method is presented for the preparation of novel ECOD nanoparticles. • The oxidative DA precursor with rough surface is prepared by Cu2+ catalysis. • The roughening extent of the ECOD nanoparticles will further aggravate. • The ECOD nanoparticles have an efficient accumulate at the tumor site. • This nanoagent show a highly potential use in clinical diagnosis and treatment. Abstract A simple method is presented for the preparation of novel europium complexes-grafted-oxidative dopamine (ECOD) nanoparticles with uniform sizes (ca. 220 nm), as a high-performance nanotheranostic agent guided by X-ray computed tomography (CT) and photoluminescence (PL). Here, an oxidative dopamine precursor with a rough surface is first prepared by copper (II) ionic catalysis. Then, europium complexes are successfully grafted onto the oxidative dopamine precursor by surface-initiated atom transfer radical polymerization (ATRP). Interestingly, as the additional amount of europium (III) complexes increases, the roughening extent of the ECOD nanoparticles is increased, and the roughening surface expands to a porous network structure. This nanoagent with a rough surface exhibits not only excellent X-ray attenuation properties, but also prominent eminent near-infrared (NIR) absorbance and strong optical imaging efficiency. In addition, ECOD can provide an effective photothermal therapy (PTT) effect, and 39% photothermal conversion efficiency can be achieved. Furthermore, there is no widely detectable toxicity induced in vivo/vitro , and blood circulation can last for a long time in the presence of ECOD nanoparticles, leading to efficient accumulation at the tumor site by a persistently of enhanced permeability and retention (EPR) effect. With the combination of NIR laser irradiation (1.5 W/cm2) for 10 min at 808 nm, effective photothermal ablation of a tumor in vivo can be achieved. Thus, ECOD nanoparticles can be used for effective antitumor treatment and may further exhibit potential as a nanotheranostic agent for clinical diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) have been blamed as the main culprit of tumor initiation, progression, metastasis, chemoresistance, and recurrence. However, few anti-CSCs agents have achieved clinical success so far. Here we report a novel derivative of lonidamine (LND), namely HYL001, which selectively and potently inhibits CSCs by targeting mitochondria, with 380-fold and 340-fold lower IC 50 values against breast cancer stem cells (BCSCs) and hepatocellular carcinoma stem cells (HCSCs), respectively, compared to LND. Mechanistically, we reveal that HYL001 downregulates glutaminase (GLS) expression to block glutamine metabolism, blunt tricarboxylic acid cycle, and amplify mitochondrial oxidative stress, leading to apoptotic cell death. Therefore, HYL001 displays significant antitumor activity in vivo , both as a single agent and combined with paclitaxel. Furthermore, HYL001 represses CSCs of fresh tumor tissues derived from liver cancer patients. This study provides critical implications for CSCs biology and development of potent anti-CSCs drugs. [Display omitted] • This work develops a potent cancer stem cell inhibitor by targeting mitochondia. • This work demonstrates that HYL001 represses CSCs in fresh tumor tissues derived from HCC patients. • This work indicates that it is feasible to selectively eliminate CSCs by regulating glutamine metabolism. [ABSTRACT FROM AUTHOR]

• The RS characteristics of the memristors with W/OTP/Al structure are determined by the ionic migration in the OTP layers and the SBH of the OTP/Metal interface. • Adding ZnO films and applying 2 mW/cm2 light made the maximum power of the devices from 9.8 × 10−9 W to 2.48 × 10−11 W. • It can be considered that the device has the potential of an ultra-low power large-scale integrated circuit. Due to its unique I-V property, memristor is considered to be the key device for artificial intelligence application. Among the alternative memristor materials, organometal trihalide perovskite (OTP) follow with interest in photoelectric coupling area with excellent light absorption ability. However, the power consumption of OTP memristor still remains to be reduced. Here, Cs 0.05 (FA x MA 1−x) 0.95 PbI y Br 3−y (CsFAMAPbIBr) with prominent photoresponse property is used as the functional layer of the memristor. Maximum high resistance state (HRS)/low resistance state (LRS) (~100) and maximum power of 9.8 × 10−9 W is reached under small voltage (−1 V~1 V) with W/OTP/Al structure. Since the oxide modification layer acts as a series resistance for the device, when 90 nm thickness of zinc oxide layer is added to the W/OTP interface, the power consumption of the device is reduced by an order of magnitude. Then, the maximum power of the device decreases by two orders of magnitude (to 2.5 × 10−11 W) under 2 mW/cm2 light condition, and the phenomenon called negative photoconductance (NPC) effect that defined as an increase in resistance upon exposure to illumination. Through the optical and oxide modification, OTP memristor with low power consumption is achieved. [ABSTRACT FROM AUTHOR]