Relationship between serum iron, zinc, calcium, and HIF-1a-comparative analysis of 2 regions and 4 ethnic groups in China.

Background: Altitude illness has serious effects on individuals who are not adequately acclimatized to high-altitude areas and may even lead to death. However, the individualized mechanisms of onset and preventive measures are not fully elucidated at present, especially the relationship between altitude illness and elements, which requires further in-depth research. Methods: Fresh serum samples were collected from individuals who underwent health examinations at the two hospitals in Xining and Sanya between November 2021 and December 2021. The blood zinc (Zn), iron (Fe), and calcium (Ca) concentrations, as well as hypoxia-inducible factor 1-alpha (HIF-1α) concentrations, were measured. This study conducted effective sample size estimation, repeated experiments, and used GraphPad Prism 9.0 and IBM SPSS version 19.0 software for comparative analysis of differences in the expression of elements and HIF-1α among different ethnic groups, altitudes, and concentration groups. Linear regression and multiple linear regression were employed to explore the relationships among elements and their correlation with HIF-1α. Results: This study included a total of 400 participants. The results from the repeated measurements indicated that the consistency of the laboratory test results was satisfactory. In terms of altitude differences, except for Fe (p = 0.767), which did not show significant variance between low and high altitude regions, Zn, Ca, and HIF-1α elements all exhibited notable differences between these areas (p < 0.0001, p = 0.004, and p < 0.0001). When grouping by the concentrations of elements and HIF-1α, the results revealed significant variations in the distribution of zinc among different levels of iron and HIF-1α (p < 0.05). The outcomes of the linear regression analysis demonstrated that calcium and zinc, iron and HIF-1α, calcium and HIF-1α, and zinc and HIF-1α displayed substantial overall explanatory power across different subgroups (p < 0.05). Finally, the results of the multiple linear regression analysis indicated that within the high-altitude population, the Li ethnic group in Sanya, and the Han ethnic group in Sanya, the multiple linear regression model with HIF-1αas the dependent variable and elements as the independent variables exhibited noteworthy overall explanatory power (p < 0.05). Conclusion: The levels of typical elements and HIF-1α in the blood differ among various altitudes and ethnic groups, and these distinctions may be linked to the occurrence and progression of high-altitude illness.

The distribution and maturation of tertiary lymphoid structures can predict clinical outcomes of patients with gastric adenocarcinoma.

Introduction: Tertiary lymphoid structures (TLSs) are analogues of secondary lymphoid organs that contain various immune cells. The spatial distribution, maturation and composition of TLSs have differential effects on prognosis, and the roles of TLSs in gastric adenocarcinoma (GA) have not been revealed. Methods: Thus, we evaluated the prognostic value of TLSs in GA through analysis of bulk RNA sequencing(RNA-seq) data from public databases and validated our findings in tumour samples from the Fudan University Shanghai Cancer Center (FUSCC) cohort. The spatial distribution,maturation, and composition of TLSs in GA were analysed by reviewing H&E-stained sections and by multiplex immunofluorescence (mIF) staining. Results: We found that TLSs, especially TLSs with germinal centres (GCs) and TLSs located in the invasive margin (IM), were correlated with prolonged overall survival (OS). Second, analysis of public RNA-seq data showed that high dendritic cell (DC) scores were a favourable prognostic factor in GA patients with high scores for both TLSs and GCs. In the FUSCC cohort, DC-LAMP+ DCs weresignificantly enriched in IM-TLSs with GCs, suggesting a potential correlation between the tumour immune activation milieu and the DC abundance. Third, compared to that in TLSs without GCs, the proportion of FOXP3+CD8+ Treg cells was significantly decreased in IM-TLSs with GCs, and the percentage of PD1+CD20+ B cells was significantly increased in TLSs with GCs. Discussion: Our results demonstrate that the spatial arrangement and maturation of TLSs significantly affect prognosis and indicate that TLSs could be a new additional factor for histopathological evaluation.

Impact mechanisms of various surfactants on the biodegradation of phenanthrene in soil: Bioavailability and microbial community responses.

The present study was conducted to systematically explore the mechanisms underlying the impact of various surfactants (CTAB, SDBS, Tween 80 and rhamnolipid) at different doses (10, 100 and 1000 mg/kg) on the biodegradation of a model polycyclic aromatic hydrocarbon (PAH) by indigenous soil microorganisms, focusing on bioavailability and community responses. The cationic surfactant CTAB inhibited the biodegradation of phenanthrene within the whole tested dosage range by decreasing its bioavailability and adversely affecting soil microbial communities. Appropriate doses of SDBS (1000 mg/kg), Tween 80 (100, 1000 mg/kg) and rhamnolipid at all amendment levels promoted the transformation of phenanthrene from the very slow desorption fraction (Fvslow) to bioavailable fractions (rapid and slow desorption fractions, Frapid and Fslow), assessed via Tenax extraction. However, only Tween 80 and rhamnolipid at these doses significantly improved both the rates and extents of phenanthrene biodegradation by 22.1-204.3 and 38.4-76.7 %, respectively, while 1000 mg/kg SDBS had little effect on phenanthrene removal. This was because the inhibitory effects of anionic surfactant SDBS, especially at high doses, on the abundance, diversity and activity of soil microbial communities surpassed the bioavailability enhancement in dominating biodegradation. In contrast, the nonionic surfactant Tween 80 and biosurfactant rhamnolipid enhanced the bioavailability of phenanthrene for degradation and also that to specific degrading bacterial genera, which stimulated their growth and increased the abundance of the related nidA degradation gene. Moreover, they promoted the total microbial/bacterial biomass, community diversity and polyphenol oxidase activity by providing available substrates and nutrients. These findings contribute to the design of suitable surfactant types and dosages for mitigating the environmental risk of PAHs and simultaneously benefiting microbial ecology in soil through bioremediation.

Vascular anomalies of the limb and trunk in children: a retrospective comparative study of endoscopic surgery and open surgery.

BACKGROUND: Endoscopic resection has been reported for vascular anomalies (VA) previously. However, there is no study comparing endoscopic resection surgery (ERS) with open resection surgery (ORS) in children. We aimed to compare clinical and cosmetic outcomes between two approaches in pediatric VA. METHODS: Between June 2018 and June 2023, 138 pediatric VA patients undergoing ERS or ORS were retrospectively reviewed. Propensity score matching (PSM) was performed to minimize selection bias. The Scar Cosmesis Assessment and Rating (SCAR) Scale and numerical rating scale (NRS) based on patient satisfaction were used for cosmetic assessment. RESULTS: After PSM for age, depth of lesion, size of lesion, and site of surgery, 72 patients (ERS = 24, ORS = 48) were analyzed. Patients undergoing ERS had longer operative time (164.25 ± 18.46 vs. 112.85 ± 14.26 min; P < 0.001), less estimated blood loss (5.42 ± 2.15 vs. 18.04 ± 1.62 ml; P < 0.001), and shorter median hospital stay (4.50 [3.00-5.00] vs. 6.00 [5.00-6.00] days; P < 0.001). The follow-up time was 8.04 ± 1.23 month for ERS group and 8.56 ± 1.57 month for ORS group. For aesthetic results, the median overall SCAR score in ERS was lower than that in ORS (2 [1-3] vs. 5 [4-5]; P < 0.001), and the subscales of "scar spread," "dyspigmentation," "track marks or suture marks," and "overall impression" were better. The median NRS score was higher (8 [7-8] vs. 6 [5-6]; P < 0.001) and length of scars was shorter (2.18 ± 0.30 vs. 8.75 ± 1.98 cm; P < 0.001) in ERS group than those in ORS group. The incidences of total complications and recurrence showed no significant difference between two groups. CONCLUSIONS: Endoscopic surgery can be a safe and effective option for pediatric VA in the limbs and trunk. It offers the advantages of improving aesthetic outcomes and reducing postoperative wound healing time.

Study on the change of global ecological distribution of Nicotiana tabacum L. based on MaxEnt model.

Nicotiana tabacum L. (tobacco) has extremely high economic value, medicinal value, scientific research value and some other uses. Though it has been widely cultivated throughout the world, classification and change of its suitable habitats is not that clear, especially in the context of global warming. In order to achieve rational cultivation and sustainable development of tobacco, current (average from 1970-2000) and future (2070, average from 2061-2080) potential suitable habitats of Nicotiana tabacum L. were forecasted with MaxEnt model and ArcGIS platform based on 854 occurrence data and 22 environmental factors in this study. The results revealed that mean temperature of warmest quarter (bio10), annual precipitation (bio12), solar radiation in September (Srad9), and clay content (CLAY) were the four decisive environment variables for the distribution of Nicotiana tabacum L. Under current climate conditions, suitable habitats of Nicotiana tabacum L. were mainly distributed in south-central Europe, south-central North America, most parts of South America, central Africa, south and southeast Asia, and southeast coast of Australia, and only 13.7% of these areas were highly suitable. By the year 2070, suitable habitats under SSP1-2.6, SSP3-7.0, and SSP5-8.5 climate scenarios would all increase with the largest increase found under SSP3-7.0 scenario, while suitable habitats would reduce under SSP2-4.5 climate scenario. Globally, the center of mass of suitable habitats would migrate to southeast to varying degrees within Libya under four different climate scenarios. The emergence of new habitats and the disappearance of old habitats would all occur simultaneously under each climate scenario, and the specific changes in each area, combined with the prediction results under current climate conditions, will provide an important reference for the adjustment of agronomic practices and rational cultivation of Nicotiana tabacum L. both currently and in the future.

Confined semiconducting polymers with boosted NIR light-triggered H2O2 production for hypoxia-tolerant persistent photodynamic therapy.

Hypoxia featured in malignant tumors and the short lifespan of photo-induced reactive oxygen species (ROS) are two major issues that limit the efficiency of photodynamic therapy (PDT) in oncotherapy. Developing efficient type-I photosensitizers with long-term ˙OH generation ability provides a possible solution. Herein, a semiconducting polymer-based photosensitizer PCPDTBT was found to generate 1O2, ˙OH, and H2O2 through type-I/II PDT paths. After encapsulation within a mesoporous silica matrix, the NIR-II fluorescence and ROS generation are enhanced by 3-4 times compared with the traditional phase transfer method, which can be attributed to the excited-state lifetime being prolonged by one order of magnitude, resulting from restricted nonradiative decay channels, as confirmed by femtosecond spectroscopy. Notably, H2O2 production reaches 15.8 µM min-1 under a 730 nm laser (80 mW cm-2). Further adsorption of Fe2+ ions on mesoporous silica not only improves the loading capacity of the chemotherapy drug doxorubicin but also triggers a Fenton reaction with photo-generated H2O2 in situ to produce ˙OH continuously after the termination of laser irradiation. Thus, semiconducting polymer-based nanocomposites enables NIR-II fluorescence imaging guided persistent PDT under hypoxic conditions. This work provides a promising paradigm to fabricate persistent photodynamic therapy platforms for hypoxia-tolerant phototheranostics.

Transcriptomic analyses reveals a diverse venom composition in Agelena limbata (Araneae: Agelenaidae).

Spider venom is a natural source of diverse biomolecules, but due to technical limitations, only a small fraction has been studied. With the advancement of omics technologies, research on spider venom has broadened, greatly promoting systematic studies of spider venom. Agelena limbata is a common spider found in vegetation, known for constructing funnel-shaped webs, and feeding on insects such as Diptera and Homoptera. However, due to its small size and the difficulty in obtaining venom, the composition of Agelena limbata venom has never been studied. In this study, a transcriptomics approach was used to analyze the toxin components in the venom of Agelena limbata, resulting in the identification of 28 novel toxin-like sequences and 24 peptidases. Based on sequence similarity and differences in cysteine motifs, the 28-novel toxin-like sequences were classified into 10 superfamilies. According to the results annotated in the database, the 24 peptidases were divided into six distinct families, with the serine protease family being the most common. A phylogenetic tree was constructed using the toxin-like sequences of Agelena limbata along with Psechrus triangulus and Hippasa lycosina. An analysis of the structural domains and motifs of Agelena limbata was also conducted. The results indicated that Agelena limbata is more distantly related to the other two species of funnel-web spiders, and that the toxin superfamily IX has a unique function compared to the other superfamilies. This study reveals the components of the Agelena limbata venom, deepening our understanding of it, and through bioinformatics analysis, has identified unique functions of the toxin superfamilies, providing a scientific basis for the development of bioactive drugs in the future.

Inborn errors of immunity and its clinical significance in children with lymphoma in China: a single-center study

Abstract Objective: To investigate the incidence, clinical and genetic characteristics of pediatric lymphoma patients of China with inborn errors of immunity (IEI)-related gene mutations, which have not been fully studied. Method: From Jan. 2020 to Mar. 2023, IEI-related genetic mutations were retrospectively explored in 108 children with lymphomas admitted to Beijing Children's Hospital by NGS. Genetic rule and clinical characteristics as well as treatment outcomes were compared between patients with or without IEI-related gene mutations. Results: A total of 17 patients (15.7 %) harbored IEI-associated mutations, including 4 cases with X-linked lymphoproliferative syndrome (XLP), 3 cases had mutations in tumor necrosis factor receptor superfamily 13B (TNFRSF13B), 2 cases with Activated p110 syndrome (APDS). Patients with IEI all had alteration of immunocompetence with decreased levels of immunoglobulin and lymphocyte subsets. Recurrent infection existed in 41.2 % of patients. The 18-month event-free survival (EFS) and the overall response rate (ORR) of patients with IEI are significantly lower than those without IEI (33.86% vs. 73.26 %, p = 0.011; 52.94% vs. 87.91 %, p = 0.002, respectively). In addition, patients with IEI had a higher progression disease (PD) rate of 23.5 % than those without IEI of 4.4% (p = 0.006). Conclusion: The present study demonstrated that IEI-associated lymphomas were much more common than originally appreciated in pediatric lymphomas, and those were insensitive to treatment and more likely to progress or relapse. The genomic analysis and a thorough review of the medical history of IEI can be used to distinguish them from pediatric lymphomas without IEI, which are beneficial for the early diagnosis and direct intervention.

Establishment of a humanized mouse model using steady-state peripheral blood-derived hematopoietic stem and progenitor cells facilitates screening of cancer-targeted T-cell repertoires.

Background: Cancer-targeted T-cell receptor T (TCR-T) cells hold promise in treating cancers such as hematological malignancies and breast cancers. However, approaches to obtain cancer-reactive TCR-T cells have been unsuccessful. Methods: Here, we developed a novel strategy to screen for cancer-targeted TCR-T cells using a special humanized mouse model with person-specific immune fingerprints. Rare steady-state circulating hematopoietic stem and progenitor cells were expanded via three-dimensional culture of steady-state peripheral blood mononuclear cells, and then the expanded cells were applied to establish humanized mice. The human immune system was evaluated according to the kinetics of dendritic cells, monocytes, T-cell subsets, and cytokines. To fully stimulate the immune response and to obtain B-cell precursor NAML-6- and triple-negative breast cancer MDA-MB-231-targeted TCR-T cells, we used the inactivated cells above to treat humanized mice twice a day every 7 days. Then, human T cells were processed for TCR ß-chain (TRB) sequencing analysis. After the repertoires had been constructed, features such as the fraction, diversity, and immune signature were investigated. Results: The results demonstrated an increase in diversity and clonality of T cells after treatment. The preferential usage and features of TRBV, TRBJ, and the V-J combination were also changed. The stress also induced highly clonal expansion. Tumor burden and survival analysis demonstrated that stress induction could significantly inhibit the growth of subsequently transfused live tumor cells and prolong the survival of the humanized mice. Conclusions: We constructed a personalized humanized mouse model to screen cancer-targeted TCR-T pools. Our platform provides an effective source of cancer-targeted TCR-T cells and allows for the design of patient-specific engineered T cells. It therefore has the potential to greatly benefit cancer treatment.

Construction and Validation of a Nomogram to Identify the Risk of Cavitation in Pulmonary Tuberculosis.

Background: The present study aimed to construct and validate a nomogram based on clinical metrics to identify CPTB. Patients and Methods: The present study retrospectively recruited pulmonary tuberculosis (PTB) patients admitted to Jiashan County First People's Hospital in China from November 2018 to September 2023. PTB patients were classified into the CPTB group and the non-CPTB group based on chest computed tomography findings, and were randomly allocated to the training set (70%) and the validation cohort (30%). The training set and validation set were used to establish and validate nomogram, respectively. Multivariate logistic regression analysis (MLSA) was used to identify the independent risk factors for CPTB in patients with PTB. Statistically significant variables in the MLSA were then used to construct a nomogram predicting CPTB in patients with PTB. The receiver operating characteristic (ROC) curve, calibration curve analysis (CCA), and decision curve analysis (DCA) were used for the evaluation of the nomogram. Results: A total of 293 PTB patients, including 208 in the training set (85 CPTB) and 85 in the validation set (33 CPTB\), were included in this study. Stepwise MLSA showed that sputum smear (≥2+), smoking(yes), glycosylated hemoglobin A1c(HbA1c), hemoglobin (HB), and systemic inflammatory response index (SIRI) were independent risk factors for the development of cavitation in patients with PTB. The nomogram identifying the high-risk CPTB patients was successfully established and showed a strong predictive capacity, with area under the curves (AUCs) of 0.875 (95% CI:0.806-0.909) and 0.848 (95% CI:0.751-0.946) in the training set and validation set respectively. In addition, the CCA and DCA corroborated the nomogram's high level of accuracy and clinical applicability within both the training and validation sets. Conclusion: The constructed nomogram, consisting of sputum smear positivity, smoking, HbA1C, HB, and SIRI, serves as a practical and effective tool for early identification and personalized management of CPTB.

An Atlas of Accessible Chromatin in Advanced Prostate Cancer Reveals the Epigenetic Evolution during Tumor Progression.

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease that resists therapy targeting androgen signaling, the primary driver of prostate cancer. mCRPC resists androgen receptor (AR) inhibitors by amplifying AR signaling or by evolving into therapy-resistant subtypes that do not depend on AR. Elucidation of the epigenetic underpinnings of these subtypes could provide important insights into the drivers of therapy resistance. In this study, we produced chromatin accessibility maps linked to the binding of lineage-specific transcription factors (TF) by performing ATAC sequencing on 70 mCRPC tissue biopsies integrated with transcriptome and whole genome sequencing. mCRPC had a distinct global chromatin accessibility profile linked to AR function. Analysis of TF occupancy across accessible chromatin revealed 203 TFs associated with mCRPC subtypes. Notably, ZNF263 was identified as a putative prostate cancer TF with a significant impact on gene activity in the double-negative (AR- neuroendocrine-) subtype, potentially activating MYC targets. Overall, this analysis of chromatin accessibility in mCRPC provides valuable insights into epigenetic changes that occur during progression to mCRPC.

Treatment of endometriosis with mifepristone mediated by nanostructured lipid carriers.

Mifepristone, a progesterone receptor antagonist, was initially used to terminate early pregnancy. As scientific research advanced, it emerged to be effective in the treatment of various tumors and tumor-like conditions such as endometriosis. Despite the therapeutic potential of mifepristone, its therapeutic effect is still far from ideal because the drug is difficult to dissolve and to accumulate in the target tissue sites. To address this issue, mifepristone-loaded nanostructured lipid carriers (Mif-NLC) were prepared by a simple solvent diffusion method and their anti-endometriosis performance and mechanisms were initially investigated. By optimizing the preparation protocol, we obtained uniform and spheroidal Mif-NLC with an average particle size of 280 nm. The encapsulation rate and drug loading capacity were 64.67% ± 0.15% and 2.7% ± 0.014%, respectively, as measured by UV spectrophotometry. The in vitro release kinetics indicated that mifepristone was released from NLC in a sustained-release manner. Compared with free mifepristone, Mif-NLC exhibited enhanced cellular uptake and inhibition of invasion activity in primary mesenchymal cells of endometriosis. A certain reduction in the size of endometriotic cysts was observed in animals compared to controls. The induction of autophagy via Mif-NLC may serve as the molecular mechanism underlying this effect. Furthermore, observation of uterine structures showed negligible toxic effects. This suggested that mifepristone encapsulated in NLC can improve its bioavailability and anti-endometriosis efficacy, which provided a new strategy for the treatment of endometriosis.

Dysregulated Wnt/ß-catenin signaling confers resistance to cuproptosis in cancer cells.

Cuproptosis is characterized by the aggregation of lipoylated enzymes of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. As dysregulation of copper homeostasis can induce cuproptosis, there is emerging interest in exploiting cuproptosis for cancer therapy. However, the molecular drivers of cancer cell evasion of cuproptosis were previously undefined. Here, we found that cuproptosis activates the Wnt/ß-catenin pathway. Mechanistically, copper binds PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/ß-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/ß-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed the ß-catenin/TCF4 transcriptional complex directly binds the ATP7B promoter, inducing its expression. ATP7B effluxes copper ions, reducing intracellular copper and inhibiting cuproptosis. Knockdown of TCF4 or pharmacological Wnt/ß-catenin blockade increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/ß-catenin pathway and cuproptosis sensitivity, and suggest a precision medicine strategy for cancer treatment through selective cuproptosis induction.

Bone Marrow Mesenchymal Stem Cell-Derived Nanovesicles Containing H8 Improve Hepatic Glucose and Lipid Metabolism and Exert Ameliorative Effects in Type 2 Diabetes.

Purpose: Nanovesicles (NVs) derived from bone mesenchymal stem cells (BMSCs) as drug delivery systems are considered an effective therapeutic strategy for diabetes. However, its mechanism of action remains unclear. Here, we evaluated the efficacy and molecular mechanism of BMSC-derived NVs carrying the curcumin analog H8 (H8-BMSCs-NVs) on hepatic glucose and lipid metabolism in type 2 diabetes (T2D). Subjects and Methods: Mouse BMSCs were isolated by collagenase digestion and H8-BMSCs-NVs were prepared by microvesicle extrusion. The effects of H8-BMSCs-NVs on hepatic glucose and lipid metabolism were observed in a T2D mouse model and a HepG2 cell insulin resistance model. To evaluate changes in potential signaling pathways, the PI3K/AKT/AMPK signaling pathway and expression levels of G6P and PEPCK were assessed by Western blotting. Results: H8-BMSCs-NVs effectively improved lipid accumulation in liver tissues and restored liver dysfunction in T2D mice. Meanwhile, H8-BMSCs-NVs effectively inhibited intracellular lipid accumulation in the insulin resistance models of HepG2 cells. Mechanistic studies showed that H8-BMSCs-NVs activated the PI3K/AKT/AMPK signaling pathway and decreased the expression levels of G6P and PEPCK. Conclusion: These findings demonstrate that H8-BMSCs-NVs improved hepatic glucose and lipid metabolism in T2D mice by activating the PI3K/AKT/AMPK signaling pathway, which provides novel evidence suggesting the potential of H8-BMSCs-NVs in the clinically treatment of T2D patients.

Environment-responsive dendrobium polysaccharide hydrogel embedding manganese microsphere as a post-operative adjuvant to boost cascaded immune cycle against melanoma.

Rationale: Surgical resection is a primary treatment for solid tumors, but high rates of tumor recurrence and metastasis post-surgery present significant challenges. Manganese (Mn2+), known to enhance dendritic cell-mediated cancer immunotherapy by activating the cGAS-STING pathway, has potential in post-operative cancer management. However, achieving prolonged and localized delivery of Mn2+ to stimulate immune responses without systemic toxicity remains a challenge. Methods: We developed a post-operative microenvironment-responsive dendrobium polysaccharide hydrogel embedded with Mn2+-pectin microspheres (MnP@DOP-Gel). This hydrogel system releases Mn2+-pectin microspheres (MnP) in response to ROS, and MnP shows a dual effect in vitro: promoting immunogenic cell death and activating immune cells (dendritic cells and macrophages). The efficacy of MnP@DOP-Gel as a post-surgical treatment and its potential for immune activation were assessed in both subcutaneous and metastatic melanoma models in mice, exploring its synergistic effect with anti-PD1 antibody. Result: MnP@DOP-Gel exhibited ROS-responsive release of MnP, which could exert dual effects by inducing immunogenic cell death of tumor cells and activating dendritic cells and macrophages to initiate a cascade of anti-tumor immune responses. In vivo experiments showed that the implanted MnP@DOP-Gel significantly inhibited residual tumor growth and metastasis. Moreover, the combination of MnP@DOP-Gel and anti-PD1 antibody displayed superior therapeutic potency in preventing either metastasis or abscopal brain tumor growth. Conclusions: MnP@DOP-Gel represents a promising drug-free strategy for cancer post-operative management. Utilizing this Mn2+-embedding and ROS-responsive delivery system, it regulates surgery-induced immune responses and promotes sustained anti-tumor responses, potentially increasing the effectiveness of surgical cancer treatments.

A novel nomogram model for lung adenocarcinoma subtypes based on RNA-modification regulatory genes.

Background: In non-small cell lung cancer (NSCLC), lung adenocarcinoma (LUAD) is the most common subtype. RNA modification has become the frontier and hotspot of current tumor research. Results: In this study, 109 genes that regulate RNA modifications were identified according to The Cancer Genome Atlas (TCGA). A differential gene expression analysis identified 46 differentially expressed RNA modification regulatory genes (DERRGs). LUAD samples were stratified into two distinct clusters based on the expression of these DERRGs. A significant correlation was observed between these clusters and patient survival rates, as well as clinical features. Furthermore, a four-DERRG signature (EIF3B, HNRNPC, IGF2BP1, and METTL3) developed using LASSO regression. According to the calculated risk scores from this signature, LUAD patients were categorized into high-risk and low-risk groups. Patients in the low-risk group exhibited a more favorable prognosis. A prognostic nomogram was crafted, integrating the four-DERRGs signature with clinical parameters. The nomogram was revealed that OS, age, clinical stage, immune cell infiltration, and immune checkpoint molecule expression were significantly linked to the OS of LUAD. GSEA analysis found that the DERRGs were primarily regulated immune pathways. Conclusions: This study developed four DERRGs signatures and formulated a nomogram model for precise prognosis estimation in LUAD patients. The study's insights are instrumental for advancing diagnosis, prognosis, and therapeutic strategies for LUAD.

Exploring drug repositioning possibilities of kinase inhibitors via molecular simulation.

Kinases, a class of enzymes controlling various substrates phosphorylation, are pivotal in both physiological and pathological processes. Although their conserved ATP binding pockets pose challenges for achieving selectivity, this feature offers opportunities for drug repositioning of kinase inhibitors (KIs). This study presents a cost-effective in silico prediction of KIs drug repositioning via analyzing cross-docking results. We established the KIs database (278 unique KIs, 1834 bioactivity data points) and kinases database (357 kinase structures categorized by the DFG motif) for carrying out cross-docking. Comparative analysis of the docking scores and reported experimental bioactivity revealed that the Atypical, TK, and TKL superfamilies are suitable for drug repositioning. Among these kinase superfamilies, Olverematinib, Lapatinib, and Abemaciclib displayed enzymatic activity in our focused AKT-PI3K-mTOR pathway with IC50 values of 3.3, 3.2 and 5.8 µM. Further cell assays showed IC50 values of 0.2, 1.2 and 0.6 µM in tumor cells. The consistent result between prediction and validation demonstrated that repositioning KIs via in silico method is feasible.

The potential of indocyanine green fluorescence detection in surgical cut margin of breast conserving surgery.

Background: Fluorescence-guided surgery (FGS) is a cutting-edge technology that uses near-infrared (NIR) fluorescence imaging to guide surgeons in surgery. Indocyanine green (ICG) is a fluorescent dye, which can be used for in vivo imaging of tumor cells. We aimed to explore the use of ICG fluorescence-guided technology as a rapid intraoperative margin assessment method for breast cancer surgery. In addition, we also compared the dose selection of ICG. Methods: This was a non-randomized prospective cohort study. Data were collected between August 2021 and October 2022 in the Division of Breast Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School, Nanjing University. Upon specimen removal, tumor margins were immediately analyzed by ICG fluorescence detection and then sent to the pathology department for intraoperative frozen section analysis and subsequent routine pathological examination. Abnormal margin rates were calculated and compared using intraoperative frozen section analysis and under the guidance of ICG fluorescence. Results: The study included 69 cases of breast cancer patients who underwent tumor resection assisted by ICG fluorescence-guided technology, including 18 patients with a 0.5 mg/kg dose and 51 patients with a 1.0 mg/kg dose. According to the study findings, the ICG test achieved a sensitivity of 81.82% and a specificity of 75.82%. At a dose of 0.5 mg/kg, the sensitivity was 66.67% whereas the specificity was 93.33%. At the dose of 1 mg/kg, the sensitivity was 87.5%, and the specificity was 74.42%. Similarly, for intraoperative frozen section analysis, the sensitivity was 81.82%, but the specificity was enhanced to 94.83%. Positive surgical cut margin was not identified in 2/69 by ICG fluorescence and frozen section analysis respectively. Conclusions: The sensitivity of ICG fluorescence detection is comparable to that of frozen section analysis, but the specificity is poor. The sensitivity increased and the specificity decreased at 1 mg/kg compared to the 0.5 mg/kg dose. ICG fluorescence can be used as a supplementary tool for frozen section analysis. These findings support further development and clinical performance assessment of ICG fluorescence.

FRAX486, a PAK inhibitor, overcomes ABCB1-mediated multidrug resistance in breast cancer cells.

The overexpression of P-glycoprotein (P-gp/ABCB1) is a leading cause of multidrug resistance (MDR). Hence, it is crucial to discover effective pharmaceuticals that counteract ABCB1-mediated multidrug resistance. FRAX486 is a p21-activated kinase (PAK) inhibitor. The objective of this study was to investigate whether FRAX486 can reverse ABCB1-mediated multidrug resistance, while also exploring its mechanism of action. The CCK8 assay demonstrated that FRAX486 significantly reversed ABCB1-mediated multidrug resistance. Furthermore, western blotting and immunofluorescence experiments revealed that FRAX486 had no impact on expression level and intracellular localization of ABCB1. Notably, FRAX486 was found to enhance intracellular drug accumulation and reduce efflux, resulting in the reversal of multidrug resistance. Docking analysis also indicated a strong affinity between FRAX486 and ABCB1. This study highlights the ability of FRAX486 to reverse ABCB1-mediated multidrug resistance and provides valuable insights for its clinical application.

[Retracted] Chelerythrine chloride induces apoptosis in renal cancer HEK­293 and SW­839 cell lines.

[This retracts the article DOI: 10.3892/ol.2016.4520.].