Letermovir prophylaxis reduced cytomegalovirus reactivation and resistance post umbilical cord blood transplantation.

To explore the impact of letermovir (LET) prophylaxis on cytomegalovirus (CMV) reactivation and resistance in both adult and paediatric umbilical cord blood transplantation (UCBT) patients, we retrospectively compared 43 UCBT patients who received LET as CMV prophylaxis with a historical cohort of 207 UCBT patients without LET usage. LET was administered from Day +1 to Day +100. The 180-day cumulative incidence of CMV reactivation (47.3% vs. 74.4%, p < 0.001) and the proportion of refractory CMV reactivation (15.0% vs. 42.9%, p = 0.016) were significantly lower than those in the control group. However, more frequent late CMV infection (31.0% vs. 4.3%, p = 0.002) and the 180-day cumulative incidence of Epstein-Barr virus (EBV) reactivation (9.3% vs. 3.4%, p = 0.087) were observed in UCBT patients with LET prophylaxis. Meanwhile, older age (>15 years old) and the occurrence of pre-engraftment syndrome were identified as the significant risk factors for CMV reactivation, and in patients at high risk, the incidence of CMV reactivation in the LET group was lower than that in the control group (46.7% vs. 86.5%, p < 0.001), while this decline was less pronounced among patients at low risk (47.8% vs. 62.1%, p = 0.120).

Hypoxia is correlated with the tumor immune microenvironment: Potential application of immunotherapy in bladder cancer.

OBJECTIVE: Hypoxia, which can considerably affect the tumor microenvironment, hinders the use of immunotherapy in bladder cancer (BLCA). Therefore, we aimed to identify reliable hypoxia-related biomarkers to guide clinical immunotherapy in BLCA. METHODS: Using data downloaded from TCGA-BLCA cohort, we determined BLCA subtypes which divide 408 samples into different subtypes. Tumor immune infiltration levels of two clusters were quantified using ssGSEA, MCPcounter, EPIC, ESTIMATE, and TIMER algorithms. Next, we constructed a hypoxia score based on the expression of hypoxia-related genes. The IMvigor210 cohort and SubMap analysis were used to predict immunotherapeutic responses in patients with different hypoxia scores. Hub genes were screened using cytoscape, immunohistochemistry (IHC), and multispectral immunofluorescence were used to detect the spatial distribution of immune markers. RESULTS: Patients with BLCA were categorized into cluster1 (n = 227) and Cluster2 (n = 181). Immune infiltration and expression of immune markers were higher in Cluster1. Immune infiltration was also more obvious in the high-hypoxia score group which related to a better predicted response to immunotherapy. IHC, and multispectral immunofluorescence confirmed the importance of TLR8 in immune infiltration and immune phenotype. CONCLUSIONS: BLCA subtype can evaluate the infiltration of immune cells in the tumor microenvironment of different patients. Hypoxia score in this study could effectively predict immunotherapeutic responses in patients with BLCA. TLR8 may be a potential target for clinical immunotherapy.

Identification of Bulbocodin D and C as novel STAT3 inhibitors and their anticancer activities in lung cancer cells.

Cancer stands as one of the predominant causes of mortality globally, necessitating ongoing efforts to develop innovative therapeutics. Historically, natural products have been foundational in the quest for anticancer agents. Bulbocodin D (BD) and Bulbocodin C (BC), two bibenzyls derived from Pleione bulbocodioides (Franch.) Rolfe, have demonstrated notable in vitro anticancer activity. In human lung cancer A549 cells, the IC50s for BD and BC were 11.63 and 11.71 µmol·L-1, respectively. BD triggered apoptosis, as evidenced by an upsurge in Annexin V-positive cells and elevated protein expression of cleaved-PARP in cancer cells. Furthermore, BD and BC markedly inhibited the migratory and invasive potentials of A549 cells. The altered genes identified through RNA-sequencing analysis were integrated into the CMap dataset, suggesting BD's role as a potential signal transducer and activator of transcription 3 (STAT3) inhibitor. SwissDock and MOE analyses further revealed that both BD and BC exhibited a commendable binding affinity with STAT3. Additionally, a surface plasmon resonance assay confirmed the direct binding affinity between these compounds and STAT3. Notably, treatment with either BD or BC led to a significant reduction in p-STAT3 (Tyr 705) protein levels, regardless of interleukin-6 stimulation in A549 cells. In addition, the extracellular signal-regulated kinase (ERK) was activated after BD or BC treatment. An enhancement in cancer cell mortality was observed upon combined treatment of BD and U0126, the MEK1/2 inhibitor. In conclusion, BD and BC emerge as promising novel STAT3 inhibitors with potential implications in cancer therapy.

WGX50 mitigates doxorubicin-induced cardiotoxicity through inhibition of mitochondrial ROS and ferroptosis.

BACKGROUND: Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major impediment to its clinical application. It is indispensable to explore alternative treatment molecules or drugs for mitigating DIC. WGX50, an organic extract derived from Zanthoxylum bungeanum Maxim, has anti-inflammatory and antioxidant biological activity, however, its function and mechanism in DIC remain unclear. METHODS: We established DOX-induced cardiotoxicity models both in vitro and in vivo. Echocardiography and histological analyses were used to determine the severity of cardiac injury in mice. The myocardial damage markers cTnT, CK-MB, ANP, BNP, and ferroptosis associated indicators Fe2+, MDA, and GPX4 were measured using ELISA, RT-qPCR, and western blot assays. The morphology of mitochondria was investigated with a transmission electron microscope. The levels of mitochondrial membrane potential, mitochondrial ROS, and lipid ROS were detected using JC-1, MitoSOX™, and C11-BODIPY 581/591 probes. RESULTS: Our findings demonstrate that WGX50 protects DOX-induced cardiotoxicity via restraining mitochondrial ROS and ferroptosis. In vivo, WGX50 effectively relieves doxorubicin-induced cardiac dysfunction, cardiac injury, fibrosis, mitochondrial damage, and redox imbalance. In vitro, WGX50 preserves mitochondrial function by reducing the level of mitochondrial membrane potential and increasing mitochondrial ATP production. Furthermore, WGX50 reduces iron accumulation and mitochondrial ROS, increases GPX4 expression, and regulates lipid metabolism to inhibit DOX-induced ferroptosis. CONCLUSION: Taken together, WGX50 protects DOX-induced cardiotoxicity via mitochondrial ROS and the ferroptosis pathway, which provides novel insights for WGX50 as a promising drug candidate for cardioprotection.

Predicting liposome formulations by the integrated machine learning and molecular modeling approaches.

Liposome is one of the most widely used carriers for drug delivery because of the great biocompatibility and biodegradability. Due to the complex formulation components and preparation process, formulation screening mostly relies on trial-and-error process with low efficiency. Here liposome formulation prediction models have been built by machine learning (ML) approaches. The important parameters of liposomes, including size, polydispersity index (PDI), zeta potential and encapsulation, are predicted individually by optimal ML algorithm, while the formulation features are also ranked to provide important guidance for formulation design. The analysis of key parameter reveals that drug molecules with logS [-3, -6], molecular complexity [500, 1000] and XLogP3 (≥2) are priority for preparing liposome with higher encapsulation. In addition, naproxen (NAP) and palmatine HCl (PAL) represented the insoluble and water-soluble molecules are prepared as liposome formulations to validate prediction ability. The consistency between predicted and experimental value verifies the satisfied accuracy of ML models. As the drug properties are critical for liposome particles, the molecular interactions and dynamics of NAP and PAL liposome are further investigated by coarse-grained molecular dynamics simulations. The modeling structure reveals that NAP molecules could distribute into lipid layer, while most PAL molecules aggregate in the inner aqueous phase of liposome. The completely different physical state of NAP and PAL confirms the importance of drug properties for liposome formulations. In summary, the general prediction models are built to predict liposome formulations, and the impacts of key factors are analyzed by combing ML with molecular modeling. The availability and rationality of these intelligent prediction systems have been proved in this study, which could be applied for liposome formulation development in the future.

Shape and Shear Stress Impact on the Toxicity of Mesoporous Silica Nanoparticles: In Vitro and In Vivo Evidence.

Mesoporous silica nanoparticles (MSNs) are widely used in the biomedical field because of their unique and excellent properties. However, the potential toxicity of different shaped MSNs via injection has not been fully studied. This study aims to systematically explore the impact of shape and shear stress on the toxicity of MSNs after injection. An in vitro blood flow model was developed to investigate the cytotoxicity and the underlying mechanisms of spherical MSNs (S-MSN) and rodlike MSNs (R-MSN) in human umbilical vein endothelial cells (HUVECs). The results suggested that the interactions between MSNs and HUVECs under the physiological flow conditions were significantly different from that under static conditions. Whether under static or flow conditions, R-MSN showed better cellular uptake and less oxidative damage than S-MSN. The main mechanism of cytotoxicity induced by R-MSN was due to shear stress-dependent mechanical damage of the cell membrane, while the toxicity of S-MSN was attributed to mechanical damage and oxidative damage. The addition of fetal bovine serum (FBS) alleviated the toxicity of S-MSN by reducing cellular uptake and oxidative stress under static and flow conditions. Moreover, the in vivo results showed that both S-MSN and R-MSN caused cardiovascular toxicity in zebrafish and mouse models due to the high shear stress, especially in the heart. S-MSN led to severe oxidative damage at the accumulation site, such as liver, spleen, and lung in mice, while R-MSN did not cause significant oxidative stress. The results of in vitro blood flow and in vivo models indicated that particle shape and shear stress are crucial to the biosafety of MSNs, providing new evidence for the toxicity mechanisms of the injected MSNs.

Comparative study of extracellular vesicles derived from mesenchymal stem cells and brain endothelial cells attenuating blood-brain barrier permeability via regulating Caveolin-1-dependent ZO-1 and Claudin-5 endocytosis in acute ischemic stroke.

BACKGROUND: Blood-brain barrier (BBB) disruption is a major adverse event after ischemic stroke (IS). Caveolin-1 (Cav-1), a scaffolding protein, played multiple roles in BBB permeability after IS, while the pros and cons of Cav-1 on BBB permeability remain controversial. Numerous studies revealed that extracellular vesicles (EVs), especially stem cells derived EVs, exerted therapeutic efficacy on IS; however, the mechanisms of BBB permeability needed to be clearly illustrated. Herein, we compared the protective efficacy on BBB integrity between bone marrow mesenchymal stem cells derived extracellular vesicles (BMSC-EVs) and EVs from brain endothelial cells (BEC-EVs) after acute IS and investigated whether the mechanism was associated with EVs antagonizing Cav-1-dependent tight junction proteins endocytosis. METHODS: BMSC-EVs and BEC-EVs were isolated and characterized by nanoparticle tracking analysis, western blotting, and transmission electron microscope. Oxygen and glucose deprivation (OGD) treated b. End3 cells were utilized to evaluate brain endothelial cell leakage. CCK-8 and TRITC-dextran leakage assays were used to measure cell viability and transwell monolayer permeability. Permanent middle cerebral artery occlusion (pMCAo) model was established, and EVs were intravenously administered in rats. Animal neurological function tests were applied, and microvessels were isolated from the ischemic cortex. BBB leakage and tight junction proteins were analyzed by Evans Blue (EB) staining and western blotting, respectively. Co-IP assay and Cav-1 siRNA/pcDNA 3.1 vector transfection were employed to verify the endocytosis efficacy of Cav-1 on tight junction proteins. RESULTS: Both kinds of EVs exerted similar efficacies in reducing the cerebral infarction volume and BBB leakage and enhancing the expressions of ZO-1 and Claudin-5 after 24 h pMCAo in rats. At the same time, BMSC-EVs were outstanding in ameliorating neurological function. Simultaneously, both EVs treatments suppressed the highly expressed Cav-1 in OGD-exposed b. End3 cells and ischemic cerebral microvessels, and this efficacy was more prominent after BMSC-EVs administration. Cav-1 knockdown reduced OGD-treated b. End3 cells monolayer permeability and recovered ZO-1 and Claudin-5 expressions, whereas Cav-1 overexpression aggravated permeability and enhanced the colocalization of Cav-1 with ZO-1 and Claudin-5. Furthermore, Cav-1 overexpression partly reversed the lower cell leakage by BMSC-EVs and BEC-EVs administrations in OGD-treated b. End3 cells. CONCLUSIONS: Our results demonstrated that Cav-1 aggravated BBB permeability in acute ischemic stroke, and BMSC-EVs exerted similar antagonistic efficacy to BEC-EVs on Cav-1-dependent ZO-1 and Claudin-5 endocytosis. BMSC-EVs treatment was superior in Cav-1 suppression and neurological function amelioration.

circRNA_0067717 promotes paclitaxel resistance in nasopharyngeal carcinoma by acting as a scaffold for TRIM41 and p53.

PURPOSE: Circular RNAs (circRNAs) play important roles in tumour progression. This study aimed to explore the mechanism of hsa_circ_0067717 (termed circRNA_0067717) promoting paclitaxel resistance in nasopharyngeal carcinoma (NPC). METHODS: We assayed CNE-1 and HNE-2 parental cell lines and the corresponding paclitaxel-resistant NPC cell lines using circRNA microarrays. RNA pull-down assay, RNA immunoprecipitation, and RNA fluorescence in situ hybridization were used to identify the molecular mechanisms. RESULTS: Here, we confirm that circRNA_0067717 is significantly upregulated in NPC paclitaxel-resistant cells and is associated with paclitaxel resistance in NPC. Mechanistically, circRNA_0067717 functions as a scaffold for TRIM41 protein (a ubiquitin E3 ligase) and p53 protein. In nasopharyngeal carcinoma paclitaxel-resistant cells, the highly expressed circRNA_0067717 can bind to more TRIM41 and p53 protein, promoting TRIM41-induced p53 ubiquitination and degradation, resulting in a decrease in p53 protein level. Moreover, the 1-176 nt area of circRNA_0067717 and the 301-425 nt region of circRNA_0067717 are the binding sites for p53 and TRIM41, respectively. The resistance of NPC cells to paclitaxel can be reduced by blocking these binding regions of circRNA_0067717. CONCLUSION: We demonstrate that circRNA_0067717 acts as a scaffold for TRIM41 and p53, enhancing paclitaxel chemoresistance in NPC by promoting TRIM41-induced p53 degradation via ubiquitination.

Multi-omics analysis of the oncogenic value of copper Metabolism-Related protein COMMD2 in human cancers.

BACKGROUND: The copper metabolism MURR1 domain (COMMD) protein family is involved in tumorigenicity of malignant tumors. However, as the member of COMMD, the role of COMMD2 in human tumors remains unknown. METHODS: We used The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), Human Protein Atlas (HPA) database, Cancer Cell Line Encyclopedia (CCLE) platform, univariate Cox regression analysis, Kaplan-Meier curve, cBioPortal, UALCAN database, Sangerbox online platform, GSCA database gene set enrichment analysis (GSEA), and GeneMANIA to analyze the expression of COMMD2, its prognostic values, genomic alteration patterns, and the correlation with tumor stemness, tumor mutational burden (TMB), microsatellite instability (MSI), and immune infiltrates, drug sensitivity, and gene function enrichment in pan-cancer. qRT-PCR, CCK-8, EdU, wound healing, and transwell migration assays were performed to confirm the function of COMMD2. RESULTS: COMMD2 was strongly expressed in most cancer types. Elevated COMMD2 expression affects the prognosis, clinicopathological stage, and molecular or immune subtypes of various tumors. Moreover, promoter hypomethylation and mutations in the COMMD2 gene may be associated with its high expression and poor survival. Additionally, we discovered that COMMD2 expression was linked to tumor stemness, TMB, MSI, immune cell infiltration, immune-checkpoint inhibitors, and drug sensitivity in pan-cancer. Furthermore, the COMMD2 gene co-expression network is constructed with GSEA analysis, displaying significant interaction of COMMD2 with E2F targets, G2-M checkpoint, and mitotic spindle in bladder cancer (BLCA). Finally, RNA interference data showed suppression of COMMD2 prevented proliferation and migration of BLCA and uterine corpus endometrial carcinoma (UCEC) cells. CONCLUSION: Our findings shed light on the COMMD2 functions in human cancers and demonstrate that it is a promising prognostic biomarker and therapeutic target in pan-cancer.

Genome-wide analysis of zinc finger-homeodomain (ZF-HD) transcription factors in diploid and tetraploid cotton.

ZF-HD (zinc finger-homeodomain) gene family plays important roles in plant growth, development, and various stress responses. In the present study, 49, 50, 22, and 32 ZF-HD genes were identified in Gossypium hirsutum, Gossypium barbadense, Gossypium arboretum, and Gossypium raimondii genomes, respectively. According to their phylogenetic features, the ZF-HD genes were classified into six groups. Segmental duplication, whole genome duplication, and transposable elements provides major forces for the expansion of cotton ZF-HD gene family during the divergence of Gossypium species and the divergence between monocots and dicots. The Ka/Ks ratios of the ZF-HD segmental duplication pairs were mainly distributed around 0.12, which indicated that they have experienced strong purifying selective pressure during evolution. Transcriptome analysis showed that 6 Gossypium hirsutum and 4 Gossypium barbadense ZF-HD genes were expressed in all tested tissues. Further, expression profiles under abiotic stress exhibited that the ZF-HD genes were differentially regulated in response to various stresses. Taken together, our findings provide a valuable information on the characterization of ZF-HD gene family and lay foundation for their further function investigations in cotton.

Social Integration and Residence Intention of Foreigners in Western China: Evidence from Xi'an.

Since "Belt and Road Initiative" (BRI) of 2014, the number of foreigners in China has increased rapidly and China has become an importing country for immigrants, a change ongoing since the beginning of the 21st century. To respond to the rapidly increasing number of foreigners in China, the government frequently revised the immigration policies and issued new regulations for foreigners. However, scholars understand very little about how the foreigners perceive their integration into Chinese society or decide to pursue long-term residency or lawful permanent resident status. While some pioneering studies touch on this, with samples from the coastal megacities, no empirical evidence has been collected from smaller, inner cities. Three new findings about the foreigners in Xi'an, a major city in western China, fill this literature gap. First, the level of subjective social integration is largely influenced by the local networks. Second, the level of objective social integration depends largely on local and hometown networks. Third, the intention to obtain long-term and permanent residency in China is more evident in those foreigners who come from countries covered by the BRI and who consider China to be a better place to live than their home country.

Apoptosis-Sensing Xenograft Zebrafish Tumor Model for Anticancer Evaluation of Redox-Responsive Cross-Linked Pluronic Micelles.

A suitable animal model for preclinical screening and evaluation in vivo could vastly increase the efficiency and success rate of nanomedicine development. Compared with rodents, the transparency of the zebrafish model offers unique advantages of real-time and high-resolution imaging of the whole body and cellular levels in vivo. In this research, we established an apoptosis-sensing xenograft zebrafish tumor model to evaluate the anti-cancer effects of redox-responsive cross-linked Pluronic polymeric micelles (CPPMs) visually and accurately. First, doxorubicin (Dox)-loaded CPPMs were fabricated and characterized with glutathione (GSH)-responsive drug release. Then, the B16F10 xenograft zebrafish tumor model was established to mimic the tumor microenvironment with angiogenesis and high GSH generation for redox-responsive tumor-targeting evaluation in vivo. The high GSH generation was first verified in the xenograft zebrafish tumor model. Compared with ordinary Pluronic polymeric micelles, Dox CPPMs had a much higher accumulation in zebrafish tumor sites. Finally, the apoptosis-sensing B16F10-C3 xenograft zebrafish tumor model was established for visual, rapid, effective, and noninvasive assessment of anti-cancer effects at the cellular level in vivo. The Dox CPPMs significantly inhibited the proliferation of cancer cells and induced apoptosis in the B16F10-C3 xenograft zebrafish tumor model. Therefore, the redox-responsive cross-linked Pluronic micelles showed effective anti-cancer therapy in the xenograft zebrafish tumor model. This xenograft zebrafish tumor model is available for rapid screening and assessment of anti-cancer effects in preclinical studies.

Comprehensive development and validation of gene signature for predicting survival in patients with glioblastoma.

Glioblastoma (GBM) is the most common brain tumor, with rapid proliferation and fatal invasiveness. Large-scale genetic and epigenetic profiling studies have identified targets among molecular subgroups, yet agents developed against these targets have failed in late clinical development. We obtained the genomic and clinical data of GBM patients from the Chinese Glioma Genome Atlas (CGGA) and performed the least absolute shrinkage and selection operator (LASSO) Cox analysis to establish a risk model incorporating 17 genes in the CGGA693 RNA-seq cohort. This risk model was successfully validated using the CGGA325 validation set. Based on Cox regression analysis, this risk model may be an independent indicator of clinical efficacy. We also developed a survival nomogram prediction model that combines the clinical features of OS. To determine the novel classification based on the risk model, we classified the patients into two clusters using ConsensusClusterPlus, and evaluated the tumor immune environment with ESTIMATE and CIBERSORT. We also constructed clinical traits-related and co-expression modules through WGCNA analysis. We identified eight genes (ANKRD20A4, CLOCK, CNTRL, ICA1, LARP4B, RASA2, RPS6, and SET) in the blue module and three genes (MSH2, ZBTB34, and DDX31) in the turquoise module. Based on the public website TCGA, two biomarkers were significantly associated with poorer OS. Finally, through GSCALite, we re-evaluated the prognostic value of the essential biomarkers and verified MSH2 as a hub biomarker.

Cyclodextrin-Derived ROS-Generating Nanomedicine with pH-Modulated Degradability to Enhance Tumor Ferroptosis Therapy and Chemotherapy.

Nowadays, destruction of redox homeostasis to induce cancer cell death is an emerging anti-cancer strategy. Here, the authors utilized pH-sensitive acetalated ß-cyclodextrin (Ac-ß-CD) to efficiently deliver dihydroartemisinin (DHA) for tumor ferroptosis therapy and chemodynamic therapy in a synergistic manner. The Ac-ß-CD-DHA based nanoparticles are coated by an iron-containing polyphenol network. In response to the tumor microenvironment, Fe2+ /Fe3+ can consume glutathione (GSH) and trigger the Fenton reaction in the presence of hydrogen peroxide (H2 O2 ), leading to the generation of lethal reactive oxygen species (ROS). Meanwhile, the OO bridge bonds of DHA are also disintegrated to enable ferroptosis of cancer cells. Their results demonstrate that these nanoparticles acted as a ROS generator to break the redox balance of cancer cells, showing an effective anticancer efficacy, which is different from traditional approaches.

Restriction of voltage decay by limiting low-voltage reduction in Li-rich oxide materials.

Li-rich layered oxides are recognized as promising candidates for next-generation Li-ion batteries owing to the high capacity of >250 mAh g-1, but the severe voltage fade has prevented their commercialization. It is widely known that high-voltage charge processes result in layered-to-spinel structural evolution and voltage fade in Li-rich layered oxides. This work emphasizes that limiting the low-voltage reduction can maintain the structure and voltage stability of Li-rich layered oxides after the 4.6 V high-voltage charge processes. A strategy of limiting the low-voltage (<2.8 V) reduction by cycling at 4.6-2.8 V was performed in traditional Li1.2Ni0.13Mn0.54Co0.13O2 and high-Ni Li1.2Ni0.222Mn0.504Co0.074O2. After 300 cycles, traditional Li1.2Ni0.13Mn0.54Co0.13O2 and high-Ni Li1.2Ni0.222Mn0.504Co0.074O2 cycling at 4.6-2 V showed midpoint discharge voltages of 2.83 V and 2.97 V with high voltage fade rates of 2.25 mV/cycle and 2.24 mV/cycle, respectively. While the two materials cycling at 4.6-2.8 V can maintain discharge midpoint voltages of 3.34 V and 3.49 V, with low voltage decay rates of 0.692 mV/cycle and 0.632 mV/cycle, respectively. To better understand the voltage performance, their electric structures were calculated by density functional theory. Physical characterizations were also used to analyze their differences in structural evolution. The results suggested that limiting low-voltage reduction in Li-rich layered oxides is highly necessary for maintaining their structure and voltage stability.

Enhanced electrochemical properties of potassium-doped lithium-rich oxide@carbon as cathode material for lithium-ion batteries.

Lithium-rich layered oxides are believed to be the most competitive cathode materials for next-generation lithium-ion batteries (LIBs) due to their high specific capacity, but the poor cycle stability and voltage attenuation severely limit their commercial applications. In this paper, a simple method combining surface treatment via pyrolysis of polyvinyl alcohol (PVA) and potassium ions (K+) doping, is designed to improve the above defects of the cobalt-free Lithium-rich material Li1.2Mn0.6Ni0.2O2 (LMR). The insoluble surface byproduct Li2CO3 and amorphous carbon nanolayer derived from the pyrolysis process of PVA alleviate the corrosion of acidic species with a favorable conductivity, while a large radius of K+ can enlarge the space of the lithium (Li) layer to facilitate the diffusion of Li+, suppress voltage polarization, and synchronously restrain the transformation from a layered structure to a spinel-like structure. After modification, the LMR material exhibits a great initial discharge capacity of 266.0 mAh g-1 at 0.1C, a remarkable rate capability of 159.1 mAh g-1 at 5C and an extremely high capacity retention of 98.5% over 200 cycles at 0.5C with a small voltage drop.

Therapeutic potential of triptolide in autoimmune diseases and strategies to reduce its toxicity.

With the increasing epidemiology of autoimmune disease worldwide, there is an urgent need for effective drugs with low cost in clinical treatment. Triptolide, the most potent bioactive compound from traditional Chinese herb Tripterygium Wilfordii Hook F, possesses immunosuppression and anti-inflammatory activity. It is a potential drug for the treatment of various autoimmune diseases, but its clinical application is still restricted due to severe toxicity. In this review, the pharmacodynamic effects and pharmacological mechanisms of triptolide in autoimmune diseases are summarized. Triptolide exerts therapeutic effect by regulating the function of immune cells and the expression of cytokines through inflammatory signaling pathways, as well as maintaining redox balance and gut microbiota homeostasis. Meanwhile, the research progress on toxicity of triptolide to liver, kidney, reproductive system, heart, spleen, lung and gastrointestinal tract has been systematically reviewed. In vivo experiments on different animals and clinical trials demonstrate the dose- and time- dependent toxicity of triptolide through different administration routes. Furthermore, we focus on the strategies to reduce toxicity of triptolide, including chemical structural modification, novel drug delivery systems, and combination pharmacotherapy. This review aims to reveal the potential therapeutic prospect and limitations of triptolide in treating autoimmune diseases, thus providing guiding suggestions for further study and promoting its clinical translation.

Particle Integrity and Size Effect on the Journey of Polymeric Nanocarriers in Zebrafish Model and the Correlation with Mice.

Polymeric nanocarriers have high biocompatibility for potential drug delivery applications. After entering bloodstream, nanocarriers will circulate, interact with proteins, dissociate, or be cleared by reticuloendothelial system. Zebrafish as a visual animal model, can serve as a tool for screening nanomedicines and monitoring nanocarrier behaviors in vivo. However, a comprehensive correlation between zebrafish and rodent models is currently deficient. Here, different-sized poly(caprolactone) nanocarriers (PCL NCs) are fabricated with or without PEGylation to investigate correlation between zebrafish and mice regarding their biofate via Förster resonance energy transfer technique. Results show that PEGylated PCL NCs have higher integrity in both zebrafish and mice. Small PEG-PCL NCs have longer circulation, while large PEG-PCL NCs have dramatically higher macrophage sequestration in zebrafish and mice spleen, leading to poor circulation. PCL NCs dissociate rapidly with less macrophage sequestration. Moreover, in 7 days postfertilization (dpf) zebrafish, polymers are eliminated via hepatobiliary pathway, which is not fully functional at earlier stages of development. The effects of nanocarrier integrity on macrophage sequestration in zebrafish and good correlation with mice spleen are pioneered to be demonstrated. The findings suggest that 7 dpf zebrafish are suitable as an in vivo screening model of nanocarriers and predict their biofate in rodents.

Turning up the heat on non-immunoreactive tumors: pyroptosis influences the tumor immune microenvironment in bladder cancer.

The latest research confirms that cytotoxic lymphocytes rely on pyroptosis to kill tumor cells, suggesting that pyroptosis plays a vital role in immune response. However, the influence of pyroptosis on tumor microenvironment (TME) remodeling and immunotherapy is still unclear. We analyzed the variations in the expression of 28 pyroptosis-related molecules in pan-cancer tissues and normal tissues and the influence of genome changes. We investigated 2,214 bladder cancer samples and determined that there are three pyroptosis phenotypes in bladder cancer, and there are significant differences in cell infiltration characteristics in different pyroptosis phenotypes. Phenotypes with high expression of pyroptosis-related molecules are "hot tumors" with better immune function. We used a principal component analysis to measure the level of pyroptosis in patients with PyroScore, and confirmed that the PyroScore can predict the prognosis of bladder cancer patients, the sensitivity of the immune phenotype to chemotherapy, and the response to immunotherapy. Patients with a high PyroScore are more sensitive to chemotherapeutics such as cisplatin and gemcitabine, and have a better prognosis (HR = 0.7; 95%CI = 0.51-0.97, P = 0.041). Our study suggests a significant correlation between the expression imbalance of pyroptosis-related molecules and genome variation in various cancers and suggests pyroptosis plays an important role in modeling the TME. Evaluating pyroptosis modification patterns contributes to enhancing our understanding of TME infiltration and can guide more effective immunotherapy strategies.

CD8+ T effector and immune checkpoint signatures predict prognosis and responsiveness to immunotherapy in bladder cancer.

Immune-checkpoint blockade (ICB) has been routinely implemented to treat bladder cancer; however, most patients have little or no clinical benefit. In this study, 348 pretreated metastatic urothelial cancer samples from the IMvigor210 cohort were used to identify important genes significantly associated with CD8+ T effector and immune checkpoint signatures. The immune checkpoint inhibitor score (IMS) scoring system was constructed to predict the immunotherapy responsiveness. Transcriptome analysis confirmed that the high IMS score group had significant immune activation with better prognosis and higher immunotherapy responsiveness, which was a powerful biomarker for predicting the prognosis and responsiveness of ICB. Tumor immune dysfunction and exclusion (TIDE) scores were calculated using 2031 external bladder cancer samples for further validation. We selected the important Hub genes as potential therapeutic targets, and validated the genes using genomic, transcriptomic, immunomic, and other multi-omics methods. In addition, we construct a risk prediction model which could stratify patients with bladder cancer and predict patient prognosis and ICB treatment responsiveness. In conclusion, this study identified effective biomarkers for the prediction of immune checkpoint inhibitor treatment responsiveness in bladder cancer patients and provided new immunotherapeutic targets.