Hybrid Density Functional Study on the p-Type Conductivity Mechanism in Intrinsic Point Defects and Group V Element-Doped 2D ß-TeO2.

The newly discovered two-dimensional (2D) ß-TeO2 possesses extraordinarily high p-type carrier mobility and demonstrates immense potential in the electronics field. However, current research on its p-type conductivity mechanisms and the modifications of element doping remains relatively insufficient. In this study, the intrinsic point defects and extrinsic element doping in monolayer ß-TeO2 are comprehensively analyzed to probe the potential sources of the intrinsic p-type conductivity and the extrinsic p-type doping possibility in 2D ß-TeO2 through hybrid density functional calculations. Our results reveal that the vacancy defects with low formation energies have deep transition levels and thus cannot be used as sources of unintentional p-type conductivity in 2D ß-TeO2. The investigations and discussions via Group V element doping modifications in 2D ß-TeO2 indicate that bismuth (Bi) doping can easily and significantly enhance the p-type conductivity of 2D ß-TeO2 under the presence of O-rich, which can be achieved experimentally. Furthermore, Bi doping can significantly increase carrier mobility without seriously affecting the electronic structure. The finding shows that the Bi element is an ideal dopant candidate for a p-type modification in 2D ß-TeO2. Our calculations pave an alternative strategy to achieve the realization of superior p-type conductivity in 2D ß-TeO2.

Psychometric properties of computerized adaptive testing for chronic obstructive pulmonary disease patient-reported outcome measurement.

BACKGROUND: Computerized adaptive testing (CAT) is an effective way to reduce time, repetitious redundancy, and respond burden, and has been used to measure outcomes in many diseases. This study aimed to develop and validate a comprehensive disease-specific CAT for chronic obstructive pulmonary disease (COPD) patient-reported outcome measurement. METHODS: The discrimination and difficulty of the items from the modified patient-reported outcome scale for COPD (mCOPD-PRO) were analyzed using item response theory. Then the initial item, item selection method, ability estimation method, and stopping criteria were further set based on Concerto platform to form the CAT. Finally, the reliability and validity were validated. RESULTS: The item discrimination ranged from 1.05 to 2.71, and the item difficulty ranged from - 3.08 to 3.65. The measurement reliability of the CAT ranged from 0.910 to 0.922 using random method, while that ranged from 0.910 to 0.924 using maximum Fisher information (MFI) method. The content validity was good. The correlation coefficient between theta of the CAT and COPD assessment test and modified Medical Research Council dyspnea scale scores using random method was 0.628 and 0.540 (P < 0.001; P < 0.001) respectively, while that using MFI method was 0.347 and 0.328 (P = 0.007; P = 0.010) respectively. About 11 items (reducing by 59.3%) on average were tested using random method, while about seven items (reducing by 74.1%) on average using MFI method. The correlation coefficient between theta of the CAT and mCOPD-PRO total scores using random method was 0.919 (P < 0.001), while that using MFI method was 0.760 (P < 0.001). CONCLUSIONS: The comprehensive disease-specific CAT for COPD patient-reported outcome measurement is well developed with good psychometric properties, which can provide an efficient, accurate, and user-friendly measurement for patient-reported outcome of COPD.

Sulforaphane nanoparticles coated with zein-propylene glycol alginate attenuate N-diethylnitrosamine-induced liver injury in mice.

Sulforaphane-loaded nanoparticles (NP-SF) were prepared in this study to improve their biological effects. Based on propylene glycol alginate and zein as wall materials and anthocyanin and CaCl2 as crosslinking agents, the NPs were encapsulated by the crosslinking method and freeze-dried. With the increasing contents of anthocyanin and Ca2+, the encapsulation efficiency and loading capacity of NP-SF were both increased. In vitro simulated digestion experiments showed controlled release of SF from the NPs. The pharmacokinetics confirmed that NP-SF exerted a slower release effect in rats, with improved SF bioavailability and protective effects on liver injury induced by N-diethylnitrosamine in mice. NP-SF reduced serum indicators of liver injury, increased the activities of antioxidant enzymes and GSH levels, and reduced malondialdehyde levels in the liver. In addition, SF activated the Keap1/Nrf2 signaling pathway and upregulated the expression of the Nrf2 downstream genes NQO1 and heme oxidase 1. High doses of NP-SF, in particular, had a higher therapeutic effect. In conclusion, encapsulation enhanced the biological activity of SF and promoted physiological function.

Highly Efficient Synergistic Chemotherapy and Magnetic Resonance Imaging for Targeted Ovarian Cancer Therapy Using Hyaluronic Acid-Coated Coordination Polymer Nanoparticles.

The diagnosis and treatment of ovarian cancer (OC) are still a grand challenge, more than 70% of patients are diagnosed at an advanced stage with a dismal prognosis. Magnetic resonance imaging (MRI) has shown superior results to other examinations in preoperative assessment, while cisplatin-based chemotherapy is the first-line treatment for OC. However, few previous studies have brought together the two rapidly expanding fields. Here a technique is presented using cisplatin prodrug (Pt-COOH), Fe3+, and natural polyphenols (Gossypol) to construct the nanoparticles (HA@PFG NPs) that have a stable structure, controllable drug release behavior, and high drug loading capacity. The acidic pH values in tumor sites facilitate the release of Fe3+, Pt-COOH, and Gossypol from HA@PFG NPs. Pt-COOH with GSH consumption and cisplatin-based chemotherapy plus Gossypol with pro-apoptotic effects displays a synergistic effect for killing tumor cells. Furthermore, the release of Fe3+ at the tumor sites promotes ferroptosis and enables MRI imaging of OC. In the patient-derived tumor xenograft (PDX) model, HA@PFG NPs alleviate the tumor activity. RNA sequencing analysis reveals that HA@PFG NPs ameliorate OC symptoms mainly through IL-6 signal pathways. This work combines MRI imaging with cisplatin-based chemotherapy, which holds great promise for OC diagnosis and synergistic therapy.

Structural insights into transcription activation of the Streptomyces antibiotic regulatory protein, AfsR.

The Streptomyces antibiotic regulatory proteins (SARPs) are ubiquitously distributed transcription activators in Streptomyces and control antibiotics biosynthesis and morphological differentiation. However, the molecular mechanism behind SARP-dependent transcription initiation remains elusive. We here solve the cryo-EM structure of an AfsR-loading RNA polymerase (RNAP)-promoter intermediate complex (AfsR-RPi) including the Streptomyces coelicolor RNAP, a large SARP member AfsR, and its target promoter DNA that retains the upstream portion straight. The structure reveals that one dimeric N-terminal AfsR-SARP domain (AfsR-SARP) specifically engages with the same face of the AfsR-binding sites by the conserved DNA-binding domains (DBDs), replacing σHrdBR4 to bind the suboptimal -35 element, and shortens the spacer between the -10 and -35 elements. Notably, the AfsR-SARPs also recruit RNAP through extensively interacting with its conserved domains (ß flap, σHrdBR4, and αCTD). Thus, these macromolecular snapshots support a general model and provide valuable clues for SARP-dependent transcription activation in Streptomyces.

Investigating the anti-inflammatory effects of icariin: A combined meta-analysis and machine learning study.

Objective: The objectives of this study were to define the superiority of icariin and its derivatives' anti-inflammatory activities and to create a reference framework for evaluating preclinical evidence. This method combines machine learning and meta-analysis to identify underlying biological pathways. Methods: Data came from PubMed, Embase, Web of Science, and the Cochrane Library. SYRCLE was used to evaluate the risk of bias in a subset of research. Meta-analysis and detailed subgroup analyses, categorized by species, genders, disease type, dosage, and treatment duration, were performed using R and STATA 15.0 software to derive nuanced insights. Employing R software (version 4.2.3) and the tidymodels package, the analysis focused on constructing a model and selecting features, with TNF-α as the dependent variable. This approach aims to identify significant predictors of drug efficacy. An in-depth literature facilitated the synthesis of anti-inflammatory mechanisms attributed to icariin and its constituent compounds. Results: Following a meticulous search and selection process, 19 studies, involving 370 and 260 animals were included in the meta-analysis and machine-learning assessment, respectively. The findings revealed that icariin and its derivatives markedly reduced inflammation markers, including TNF-α and IL-1ß. Additionally, machine-learning outcomes, with TNF-α as the target variable, indicated enhanced anti-inflammatory effects of icariin across respiratory, urological, neurological, and digestive disease types. These effects were more pronounced at doses exceeding 27.52 mg/kg/day and treatment durations beyond 31.22 days. Conclusion: Strong anti-inflammatory effects are exhibited by icariiin and its derivatives, which are especially beneficial in the management of digestive, neurological, pulmonary, and urinary conditions. Effective for periods longer than 31.22 days and at dosages more than 27.52 mg/kg/day. Subsequent research will involve more targeted animal experiments and safety assessments to obtain more comprehensive preclinical evidence.

Suppressed Lattice Thermal Conductivity in Haeckelite Compounds for High-Performance Thermoelectric Applications.

Traditional semiconductors are known to exhibit excellent electrical properties but oversized lattice thermal conductivities, thus limiting their thermoelectric performance. Herein, we have discovered a low-energy allotrope of those traditional semiconductors. Compared with the wurtzite structure, the lattice thermal conductivity is reduced by more than five times in the haeckelite structure. This is attributed to the softening of acoustic phonon modes and concurrently enhanced anharmonicity in the haeckelite structure. Benefiting from the suppressed lattice thermal conductivity while retaining the excellent electrical properties of wurtzite structure, haeckelite compounds have been proven to be a novel category of high-performance thermoelectric materials. As an excellent representative, haeckelite CdTe exhibits a peak figure of merit approaching 1.3 at n-type doping and high temperature, which experiences a 3-fold improvement compared with its wurtzite counterpart. This work provides an alternative pathway of engineering the lattice thermal conductivities of traditional semiconductors toward superior thermoelectric properties.

Bioinspired Surface Ligand Engineering Regulates Electron Transfers in Gold Clusterzymes to Enhance the Catalytic Activity for Improving Sensing Performance.

Metal nanoclusters feature a hierarchical structure, facilitating their ability to mimic enzyme-catalyzed reactions. However, the lack of true catalytic centers, compounded by tightly bound surface ligands hindering electron transfers to substrates, underscores the need for universal rational design methodologies to emulate the structure and mechanisms of natural enzymes. Motivated by the electron transfer in active centers with specific chemical structures, by integrating the peroxidase cofactor Fe-TCPP onto the surface of glutathione-stabilized gold nanoclusters (AuSG), we engineered AuSG-Fe-TCPP clusterzymes with a remarkable 39.6-fold enhancement in peroxidase-like activity compared to AuSG. Fe-TCPP not only mimics the active center structure, enhancing affinity to H2O2, but also facilitates the electron transfer process, enabling efficient H2O2 activation. By exemplifying the establishment of a detecting platform for trace H2O2 produced by ultrasonic cleaners, we substantiate that the bioinspired surface-ligand-engineered electron transfer can improve sensing performance with a wider linear range and lower detection limit.

Mechanistic prediction and validation of Brevilin A Therapeutic effects in Lung Cancer.

BACKGROUND: Traditional Chinese medicine (TCM) has been found widespread application in neoplasm treatment, yielding promising therapeutic candidates. Previous studies have revealed the anti-cancer properties of Brevilin A, a naturally occurring sesquiterpene lactone derived from Centipeda minima (L.) A.Br. (C. minima), a TCM herb, specifically against lung cancer. However, the underlying mechanisms of its effects remain elusive. This study employs network pharmacology and experimental analyses to unravel the molecular mechanisms of Brevilin A in lung cancer. METHODS: The Batman-TCM, Swiss Target Prediction, Pharmmapper, SuperPred, and BindingDB databases were screened to identify Brevilin A targets. Lung cancer-related targets were sourced from GEO, Genecards, OMIM, TTD, and Drugbank databases. Utilizing Cytoscape software, a protein-protein interaction (PPI) network was established. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene set enrichment analysis (GSEA), and gene-pathway correlation analysis were conducted using R software. To validate network pharmacology results, molecular docking, molecular dynamics simulations, and in vitro experiments were performed. RESULTS: We identified 599 Brevilin A-associated targets and 3864 lung cancer-related targets, with 155 overlapping genes considered as candidate targets for Brevilin A against lung cancer. The PPI network highlighted STAT3, TNF, HIF1A, PTEN, ESR1, and MTOR as potential therapeutic targets. GO and KEGG analyses revealed 2893 enriched GO terms and 157 enriched KEGG pathways, including the PI3K-Akt signaling pathway, FoxO signaling pathway, and HIF-1 signaling pathway. GSEA demonstrated a close association between hub genes and lung cancer. Gene-pathway correlation analysis indicated significant associations between hub genes and the cellular response to hypoxia pathway. Molecular docking and dynamics simulations confirmed Brevilin A's interaction with PTEN and HIF1A, respectively. In vitro experiments demonstrated Brevilin A-induced dose- and time-dependent cell death in A549 cells. Notably, Brevilin A treatment significantly reduced HIF-1α mRNA expression while increasing PTEN mRNA levels. CONCLUSIONS: This study demonstrates that Brevilin A exerts anti-cancer effects in treating lung cancer through a multi-target and multi-pathway manner, with the HIF pathway potentially being involved. These results lay a theoretical foundation for the prospective clinical application of Brevilin A.

Structural and functional insights into transcription activation of the essential LysR-type transcriptional regulators.

The enormous LysR-type transcriptional regulators (LTTRs), which are diversely distributed amongst prokaryotes, play crucial roles in transcription regulation of genes involved in basic metabolic pathways, virulence and stress resistance. However, the precise transcription activation mechanism of these genes by LTTRs remains to be explored. Here, we determine the cryo-EM structure of a LTTR-dependent transcription activation complex comprising of Escherichia coli RNA polymerase (RNAP), an essential LTTR protein GcvA and its cognate promoter DNA. Structural analysis shows two N-terminal DNA binding domains of GcvA (GcvA_DBD) dimerize and engage the GcvA activation binding sites, presenting the -35 element for specific recognition with the conserved σ70R4. In particular, the versatile C-terminal domain of α subunit of RNAP directly interconnects with GcvA_DBD, σ70R4 and promoter DNA, providing more interfaces for stabilizing the complex. Moreover, molecular docking supports glycine as one potential inducer of GcvA, and single molecule photobleaching experiments kinetically visualize the occurrence of tetrameric GcvA-engaged transcription activation complex as suggested for the other LTTR homologs. Thus, a general model for tetrameric LTTR-dependent transcription activation is proposed. These findings will provide new structural and functional insights into transcription activation of the essential LTTRs.

Rational Design of Tetrahedral Derivatives as Efficient Light-Emitting Materials Based on "Super Atom" Perspective.

Traditional semiconductor quantum dots of groups II-VI are key ingredients of next-generation display technology. Yet, the majority of them contain toxic heavy-metal elements, thus calling for alternative light-emitting materials. Herein, we have explored three novel categories of multicomponent compounds, namely, tetragonal II-III2-VI4 porous ternary compounds, cubic I2-II3-VI4 ternary compounds, and cubic I-II-III3-V4 quaternary compounds. This is achieved by judicious introduction of a "super atom" perspective and concurrently varying the solid-state lattice packing of involved super atoms or the population of surrounding counter cations. Based on first-principles calculations of 392 candidate materials with designed crystal structures, 53 highly stable materials have been screened. Strikingly, 34 of them are direct-bandgap semiconductors with emitting wavelengths covering the near-infrared and visible-light regions. This work provides a comprehensive database of highly efficient light-emitting materials, which may be of interest for a broad field of optoelectronic applications.

External Stimuli-Responsive Strategies for Surface Modification of Orthopedic Implants: Killing Bacteria and Enhancing Osteogenesis.

Bacterial infection and insufficient osteogenic activity are the main causes of orthopedic implant failure. Conventional surface modification methods are difficult to meet the requirements for long-term implant placement. In order to better regulate the function of implant surfaces, especially to improve both the antibacterial and osteogenic activity, external stimuli-responsive (ESR) strategies have been employed for the surface modification of orthopedic implants. External stimuli act as "smart switches" to regulate the surface interactions with bacteria and cells. The balance between antibacterial and osteogenic capabilities of implant surfaces can be achieved through these specific ESR manifestations, including temperature changes, reactive oxygen species production, controlled release of bioactive molecules, controlled release of functional ions, etc. This Review summarizes the recent progress on different ESR strategies (based on light, ultrasound, electric, and magnetic fields) that can effectively balance antibacterial performance and osteogenic capability of orthopedic implants. Furthermore, the current limitations and challenges of ESR strategies for surface modification of orthopedic implants as well as future development direction are also discussed.

Rotor-based image-guided therapy of glioblastoma.

Glioblastoma (GBM), deep in the brain, is more challenging to diagnose and treat than other tumors. Such challenges have blocked the development of high-impact therapeutic approaches that combine reliable diagnosis with targeted therapy. Herein, effective cyanine dyes (IRLy) with the near-infrared two region (NIR-II) adsorption and aggregation-induced emission (AIE) have been developed via an "extended conjugation & molecular rotor" strategy for multimodal imaging and phototherapy of deep orthotopic GBM. IRLy was synthesized successfully through a rational molecular rotor modification with stronger penetration, higher signal-to-noise ratio, and a high photothermal conversion efficiency (PCE) up to ∼60%, which can achieve efficient NIR-II photo-response. The multifunctional nanoparticles (Tf-IRLy NPs) were further fabricated to cross the blood-brain barrier (BBB) introducing transferrin (Tf) as a targeting ligand. Tf-IRLy NPs showed high biosafety and good tumor enrichment for GBM in vitro and in vivo, and thus enabled accurate, efficient, and less invasive NIR-II multimodal imaging and photothermal therapy. This versatile Tf-IRLy nanosystem can provide a reference for the efficient, precise and low-invasive multi-synergistic brain targeted photo-theranostics. In addition, the "extended conjugation & molecular rotor" strategy can be used to guide the design of other photothermal agents.

Theoretical Insights on the Charge State and Bifunctional OER/ORR Electrocatalyst Activity in 4d-Transition-Metal-Doped g-C3N4 Monolayers.

Exploring efficient and stable electrocatalysts for the bifunctional oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) is vital to developing renewable energy technologies. However, due to the substantial and intricate design space associated with these bifunctional OER/ORR electrocatalysts, their development presents a formidable challenge, resulting in their cost-prohibitive nature in both experimental and computational studies. Herein, using the defect physics method, we systematically investigate the formation energies and bifunctional overpotential (ηBi) of 4d-transition-metal (4d-TM, 4d-TM = Zr, Nb, Mo, Ru, Rh, Pd, and Ag)-doped monolayer supercell g-C3N4 (4d-TM@C54N72) based on the density functional theory (DFT) calculations. Under N-rich and C-rich conditions, we find that the formation energies of RhN@C54N71 (Rh occupation N) and PdN@C54N71 (Pd occupation N) are smaller than that of other 4d-TMN@C54N71 (4d-TM occupation N site); for the 4d-TMint@C54N72 (4d-TM interstitial site occupation), the lowest-formation energy defects are Pdint@C54N72. These results indicate that they have better stabilities. Interestingly, for these formation energy lower systems, Pd0int@C54N72 (ηBi = 1.00 V) and Rh1+N@C54N71 (ηBi = 0.73 V) have ultralow overpotential and can be great candidates for bifunctional OER/ORR electrocatalysts. We find the reason is that adjusting the charge states of 4d-TM@C54N72 can tune the interaction strength between the oxygenated intermediates and the 4d-TM@C54N72, which plays a crucial role in the activity of reactions. Additionally, the data obtained through machine learning (ML) application suggest that the electronegativity (Nm) and bond length of 4d-TM and coordination atoms (dTM-OOH) are primary descriptors characterizing the OER and ORR activities, respectively. The charged defect tuning of the bifunctional OER/ORR activity for 4d-TM@C54N72 would enable electrocatalytic performance optimization and the development of potential electrocatalysts for renewable energy applications.

The role of pulmonary rehabilitation in idiopathic pulmonary fibrosis: An overview of systematic reviews.

BACKGROUND: The role of pulmonary rehabilitation (PR) in idiopathic pulmonary fibrosis (IPF) has been studied in several systematic reviews (SRs), but no definitive conclusions have been drawn due to the wide variation in the quality and outcomes of the studies. And there are no studies to assess the quality of relevant published SRs. This overview aims to determine the effectiveness of PR in patients with IPF and to summarize and critically evaluate the risk of bias, methodological, and evidence quality of SRs on this related topic. METHODS: With no language restrictions, eight databases were searched from inception to March 10, 2023. The literature search, screening, and data extraction were carried out separately by two reviewers. We assessed the risk of bias using the ROBIS tool, the reporting quality using PRISMA statements, the methodological quality using AMSTAR-2, and the evidence quality using Grades of Recommendations, Assessment, Development, and Evaluation (GRADE). RESULTS: Seven SRs from 2018-2023 (including 1836 participants) on PR for the treatment of IPF were selected, all of which included patients with a definitive diagnosis of IPF. After strict evaluation by the ROBIS tool and AMSTAR-2 tool, 42.86% of the SRs had a high risk of bias and 85.71% of the SRs had critically low methodological quality in this overview. PR might be effective for patients with IPF on exercise capacity, quality of life, and pulmonary function-related outcomes, but we did not find high quality evidence to confirm the effectiveness. CONCLUSION: PR may appear to be an effective and safe treatment for patients with IPF, but the results of this overview should be interpreted dialectically and with caution. Further high-quality, rigorous studies are urgently needed to draw definitive conclusions and provide scientific evidence.

Amino-Functionalized Zirconium-Based Metal-Organic Frameworks as Bifunctional Nanomaterials to Treat Bone Tumors and Promote Osteogenesis.

Bone tumor patients often encounter challenges associated with cancer cell residues and bone defects postoperation. To address this, there is an urgent need to develop a material that can enable tumor treatment and promote bone repair. Metal-organic frameworks (MOFs) have attracted the interest of many researchers due to their special porous structure, which has great potential in regenerative medicine and drug delivery. However, few studies explore MOFs with dual antitumor and bone regeneration properties. In this study, we investigated amino-functionalized zirconium-based MOF nanoparticles (UiO-66-NH2 NPs) as bifunctional nanomaterials for bone tumor treatment and osteogenesis promotion. UiO-66-NH2 NPs loading with doxorubicin (DOX) (DOX@UiO-66-NH2 NPs) showed good antitumor efficacy both in vitro and in vivo. Additionally, DOX@UiO-66-NH2 NPs significantly reduced lung injury compared to free DOX in vivo. Interestingly, the internalized UiO-66-NH2 NPs notably promoted the osteogenic differentiation of preosteoblasts. RNA-sequencing data revealed that PI3K-Akt signaling pathways or MAPK signaling pathways might be involved in this enhanced osteogenesis. Overall, UiO-66-NH2 NPs exhibit dual functionality in tumor treatment and bone repair, making them highly promising as a bifunctional material with broad application prospects.

hsa_circ_0129047 Upregulates LYVE1 to Inhibit Hepatocellular Carcinoma Progression by Sponging miR-492.

Compelling evidence indicates the regulatory role of circular RNAs in cancers, including hepatocellular carcinoma (HCC). Our study aimed to elucidate the regulatory function of circ_0129047 in HCC progression. A reverse transcription-quantitative polymeric chain reaction was conducted to detect the expression of circ_0129047, lymphatic vessel endothelial hyaluronan receptor-1 (LYVE1), and miR-492 in HCC tissues and cells. The characteristics of circ_0129047 were determined by evaluating the nuclear and cytoplasmic fractions and by RNase R digestion assays. The cell counting kit-8 assay, scratch wound, and transwell invasion assays were used to examine the effects of circ_0129047 overexpression, miR-492 mimic, and LYVE1 overexpression on the proliferation, migration, and invasion abilities of HCC cells in vitro. A mouse xenograft model was also established. The relationship between miR-492 and circ_0129047 or LYVE1 was clarified using luciferase reporter and Argonaute-2 RNA immunoprecipitation assays. We found that circ_0129047 and LYVE1 were poorly expressed in HCC tissues and cells, whereas miR-492 was upregulated. Overexpression of circ_0129047 inhibits HCC cell proliferation, migration, and invasion and delays in vivo tumor growth. Furthermore, circ_0129047 sponged miR-492, and 3'UTR LYVE1 was a direct target of miR-492. Additionally, LYVE1 overexpression reduced the oncogenic activity of the miR-492 mimic, whereas the miR-492 mimic abolished the antimigratory, antiproliferative, and anti-invasive effects of circ_0129047 overexpression in HCC cells. These data suggest that circ_0129047 exerts a tumor-suppressive role in HCC by sponging miR-492 away from LYVE1 and that the circ_0129047/miR-492/LYVE1 axis may be a promising target for HCC treatment.

An acid-responsive MOF nanomedicine for augmented anti-tumor immunotherapy via a metal ion interference-mediated pyroptotic pathway.

Pyroptosis is an inflammatory form of programmed cell death (PCD) that is regulated by the Gasdermin protein family in response to various stimuli, playing a critical role in the development of tumor therapy strategies. However, cancers are generally known to escape from PCD via immunosuppressive pathways or other resistant mechanisms. In this study, an acid-responsive Fe/Mn bimetal-organic framework nanosystem carrying metal ions and immune adjuvant R848 (FeMn@R@H) was designed for combining pyroptosis and augmented immunotherapy. The FeMn@R@H would be triggered to disintegrate and release Fe3+ and Mn2+ ions in response to the acidic tumor microenvironment (TME), thereby initiating Fenton-like reactions for ROS-mediated pyroptosis. On the one hand, the pyroptosis-caused cell rupture would induce the release of proinflammatory cytokines and immunogenic constituents from tumor cells, further resulting in immunogenic cell death (ICD) to promote antitumor immune responses. On the other hand, the co-delivered R848 could reverse suppressive tumor immune microenvironment (TIME) and induce inflammatory responses by activating the TLR7/8 pathway. In conclusion, this tumor-specific therapy system can co-deliver metal ions and R848 to tumor tissues to perform pyroptosis-mediated PCD and augmented anti-tumor immunotherapy.

Inhibiting Osteolytic Breast Cancer Bone Metastasis by Bone-Targeted Nanoagent via Remodeling the Bone Tumor Microenvironment Combined with NIR-II Photothermal Therapy.

Bone is one of the prone metastatic sites of patients with advanced breast cancer. The "vicious cycle" between osteoclasts and breast cancer cells plays an essential role in osteolytic bone metastasis from breast cancer. In order to inhibit bone metastasis from breast cancer, NIR-II photoresponsive bone-targeting nanosystems (CuP@PPy-ZOL NPs) are designed and synthesized. CuP@PPy-ZOL NPs can trigger the photothermal-enhanced Fenton response and photodynamic effect to enhance the photothermal treatment (PTT) effect and thus achieve synergistic anti-tumor effect. Meanwhile, they exhibit a photothermal enhanced ability to inhibit osteoclast differentiation and promote osteoblast differentiation, which reshaped the bone microenvironment. CuP@PPy-ZOL NPs effectively inhibited the proliferation of tumor cells and bone resorption in the in vitro 3D bone metastases model of breast cancer. In a mouse model of breast cancer bone metastasis, CuP@PPy-ZOL NPs combined with PTT with NIR-II significantly inhibited the tumor growth of breast cancer bone metastases and osteolysis while promoting bone repair to achieve the reversal of osteolytic breast cancer bone metastases. Furthermore, the potential biological mechanisms of synergistic treatment are identified by conditioned culture experiments and mRNA transcriptome analysis. The design of this nanosystem provides a promising strategy for treating osteolytic bone metastases.

Breast cancer-related lymphedema and recurrence of breast cancer: Protocol for a prospective cohort study in China.

INTRODUCTION: The primary aim is to determine the factors associated with breast cancer-related lymphedema and to identify new associated factors for the recurrence of breast cancer and depression. The secondary objective is to investigate the incidence of breast cancer-related events (breast cancer-related lymphedema, recurrence of breast cancer, and depression). Finally, we want to explore and validate the complex relationship among multiple factors influencing breast cancer complications and breast cancer recurrence. PATIENTS AND METHODS: A cohort study of females with unilateral breast cancer will be conducted in West China Hospital between February 2023 and February 2026. Breast cancer survivors in the age range of 17-55 will be recruited before breast cancer surgery. We will recruit 1557 preoperative patients with a first invasive breast cancer diagnosis. Consenting breast cancer survivors will complete demographic information, clinicopathological factors, surgery information, baseline information, and a baseline depression questionnaire. Data will be collected at four stages: the perioperative stage, chemotherapy therapy stage, radiation therapy stage, and follow-up stage. Data including the incidence and correlation of breast cancer-related lymphedema, breast cancer recurrence, depression, and medical cost will be collected and computed through the four stages above. For every statistical analysis, the participants will be classified into two groups based on whether they develop secondary lymphedema. Incidence rates of breast cancer recurrence and depression will be calculated separately for groups. Multivariate logistic regression will be used to determine whether secondary lymphedema and other parameters can predict breast cancer recurrence. DISCUSSION: Our prospective cohort study will contribute to establishing an early detection program for breast cancer-related lymphedema and recurrence of breast cancer, which are both associated with poor quality of life and reduced life expectancy. Our study can also provide new insights into the physical, economic, treatment-related and mental burdens of breast cancer survivors.