Intra-arterial chemotherapy combined with BCG immunotherapy is more effective than intra-arterial chemotherapy plus intravesical chemotherapy or standard BCG immunotherapy in preventing the recurrence and progression of high-risk non-muscle-invasive bladder cancer.

BACKGROUND: Up to 45% of patients with high-risk non-muscle-invasive bladder cancer (NMIBC) will not benefit from adjuvant intravesical instillation. We aimed to introduce intra-arterial chemotherapy (IAC) to existing intravesical treatment and evaluate its feasibility and safety. MATERIALS AND METHODS: We collected data from 170 patients who had been diagnosed with high-risk NMIBC and underwent transurethral resection of bladder tumor (TURBT) over the last 5 years. Twenty-seven patients were excluded according to specific exclusion criteria. The remaining 143 patients were divided into 3 groups according to their treatment: intravesical instillation of Bacillus Calmette - Guerin (BCG), BCG+ intra-arterial chemotherapy (IAC), and intravesical chemotherapy (IVC)+IAC groups. All groups received standard intravesical instillation of BCG or chemotherapeutic agents. In contrast, both the BCG+IAC and IVC+IAC groups received four courses of IAC (injection of cisplatin [60 mg/m2] and epirubicin [50 mg/m2] in the internal iliac arteries via Seldinger's percutaneous technique). RESULTS: The median follow-up time was 47 months, ranging from 20 to 60 months. The restricted mean survival time (RMST), which represents the recurrence and progression rate of the BCG+IAC group, differed significantly when compared with the BCG group (P = 0.029 and 0.004, respectively) and the IVC+IAC group (P = 0.004 and 0.006, respectively). Kaplan-Meier plots revealed that the recurrence and progression-free survival of the BCG+IAC group were significantly higher than the BCG and IVC+IAC groups (P = 0.033 and 0.028, respectively). In contrast, the BCG and IVC+IAC groups showed similar RMST (P = 0.156 and 0.935, respectively), recurrence (P = 0.627), and progression-free (P = 0.931) survival. A small proportion of patients (20%) suffered from the adverse effects of IAC while 65% suffered from adverse reactions to intravesical instillation. Most adverse effects were ranked as grade I or II according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. CONCLUSION: Analysis showed that tumor recurrence and progression rate in the BCG+IAC group was lower than the BCG and IVC+IAC groups while patients in the IVC+IAC group suffered from milder adverse effects in cystitis and flu-like symptoms. Our findings may provide a new perspective for urologists when treating patients with high-risk NMIBC.

Highly integrated, self-powered and activatable bipedal DNA nanowalker for imaging of base excision repair in living cells.

DNA walkers have attracted considerable attention in biosensing and bioimaging. Compared with the conventional single leg-based DNA walker, the bipedal DNA walker has remarkable advantages, with improved sensitivity and fast kinetics, and can work efficiently in a crowded cellular environment. However, most reported bipedal DNA walkers are powered by exogenous supplementation, and elaborate DNA sequence designs, auxiliary additives or extra carriers are often needed. A highly integrated bipedal DNA walker that can address robustness, sensitivity and consistency issues in a single system is highly desirable but remains a great challenge. We herein report a novel bipedal DNA nanowalker system through simple assembly of a DNA substrate, hairpin functionalized-AuNPs (AuNPs-H2), and a blocked Mn2+-dependent DNAzyme hairpin (H1) on degradable MnO2 nanosheets, which holds great potential for living cell operation. Highly integrated features enable the simultaneous delivery of core components of the bipedal DNA walker, including a walking track (AuNPs-H2), a walking strand (H1 cleaved by APE1), and a driving force (Mn2+-dependent DNAzyme cleavage) as a whole, thereby enhancing the control of the spatiotemporal distribution of these components at the intracellular target sites. The redox reaction between the MnO2 nanosheets and GSH inside the cells not only consumed the intracellular GSH to improve the biostability of the walking track but also generated abundant Mn2+ as a cofactor of the DNAzyme. As a proof of concept, the developed nanowalker was demonstrated to work efficiently for monitoring base excision repair (BER)-related human apurinic/apyrimidinic endonuclease 1 (APE1) in living cells, highlighting the great potential of the bipedal DNA nanowalker in biological systems.

Unraveling the Origin of the Repulsive Interaction between Hydrogen Adsorbates on Platinum Single-Crystal Electrodes.

Hydrogen adsorption on platinum (Pt) single-crystal electrodes has been studied intensively in both experiments and computations. Yet, the precise origin and nature of the repulsive interactions observed between hydrogen adsorbates (Hads) have remained elusive. Here, we use first-principles density functional theory calculations to investigate in detail the interactions between Hads on Pt(111), Pt(100), and Pt(110) surfaces. The repulsive interaction between Hads on Pt(111) is deconvoluted into three different physical contributions, namely, (i) electrostatic interactions, (ii) surface distortion effect, and (iii) surface coordination effect. The long-range electrostatic interaction, which is generally considered the most important source of repulsive interactions in surface adsorption, was found to contribute less than 30% of the overall repulsive interaction. The remaining >70% arises from the other two contributions, underscoring the critical influence of surface-mediated interactions on the adsorption process. Surface distortion and coordination effects are found to strongly depend on the coverage and adsorption geometry: the effect of surface distortion dominates when adsorbates reside two or more Pt atoms apart; the effect of surface coordination dominates if hydrogen is adsorbed on neighboring adsorption sites. The above effects are considerably less pronounced on Pt(100) and Pt(110), therefore resulting in weaker interactions between Hads on these two surfaces. Overall, the study highlights the relevance of surface-mediated effects on adsorbate-adsorbate interactions, such as the often-overlooked surface distortion. The effect of these interactions on the hotly debated adsorption site for the adsorbed hydrogen intermediate in the hydrogen evolution reaction is also discussed.

Deciphering regulatory patterns in a mouse model of hyperoxia-induced acute lung injury.

Background: Oxygen therapy plays a pivotal role in treating critically ill patients in the intensive care unit (ICU). However, excessive oxygen concentrations can precipitate hyperoxia, leading to damage in multiple organs, with a notable effect on the lungs. Hyperoxia condition may lead to hyperoxia-induced acute lung injury (HALI), deemed as a milder form of acute respiratory distress syndrome (ARDS). Given its clinical importance and practical implications, there is a compelling need to investigate the underlying pathogenesis and comprehensively understand the regulatory mechanisms implicated in the development of HALI. Results: In this study, we conducted a mouse model with HALI and performed regulatory mechanism analysis using RNA-seq on both HALI and control group. Comprehensive analysis revealed 727 genes of significant differential expression, including 248 long non-coding RNAs (lncRNAs). Also, alternative splicing events were identified from sequencing results. Notably, we observed up-regulation or abnormal alternative splicing of genes associated with immune response and ferroptosis under hyperoxia conditions. Utilizing weighted gene co-expression network analysis (WGCNA), we ascertained that genes involved in immune response formed a distinct cluster, showcasing an up-regulated pattern in hyperoxia, consistent with previous studies. Furthermore, a competing endogenous RNA (ceRNA) network was constructed, including 78 differentially expressed mRNAs and six differentially expressed lncRNAs, including H19. These findings uncover the intricate interplay of multiple transcriptional regulatory mechanisms specifically tailored to the pulmonary defense against HALI, substantiating the importance of these non-coding RNAs in this disease context. Conclusions: Our results provide new insights into the potential mechanisms and underlying pathogenesis in the development of HALI at the post-transcriptional level. The findings of this study reveal potential regulatory interactions and biological roles of specific lncRNAs and genes, such as H19 and Sox9, encompassing driven gene expression patterns, alternative splicing events, and lncRNA-miRNA-mRNA ceRNA networks. These findings may pave the way for advancing therapeutic strategies and reducing the risk associated with oxygen treatment for patients.

Site-specific bioorthogonal regulation of bone morphogenetic protein 2 expression for effective bone regeneration.

Growth factor holds great promise for bone regeneration, and spatiotemporal control of their expressing through site-specific reactions is crucial but challenging for on-demand therapy. In this study, we present the development of a novel unnatural amino acids (UAAs)-triggered therapeutic switch (UATS) system, composed of an orthogonal aminoacyl-tRNA-synthase (aaRS)-tRNA pair and a bone morphogenetic protein 2 (BMP2) gene harboring premature stop codon, which enable in situ and on-demand initiation of the expression of BMP2. The resulting UATS system allowed specifically control of base expressing on the BMP2 mRNA that switched to the BMP2 protein with complete structure and function to facilitate bone regeneration. Our investigations showed that the UATS system exhibits remarkable attributes of rapid, sensitive, reversible, and sustained BMP2 expression both in vitro and in vivo settings. Moreover, the implantation of microencapsulated cells with UATS system is applied to a mouse femur defect model, demonstrating high effciency in controlled expressing of BMP2 protein and substantial repair of bone defect following oral administration of UAAs. Therefore, our findings underscore the great potential of UATS system for on-demand awakening of functional growth factor, thus offering promising prospects in the realm of regenerative medicine.

Fc receptor-like A promotes malignant behavior in renal cell carcinoma and correlates with tumor immune infiltration.

BACKGROUND: Our study aims to investigate the mechanisms through which Fc receptor-like A (FCRLA) promotes renal cell carcinoma (RCC) and to examine its significance in relation to tumor immune infiltration. MATERIALS AND METHODS: The correlation between FCRLA and data clinically related to RCC was explored using The Cancer Genome Atlas (TCGA), then validated using Gene Expression Omnibus (GEO) gene chip data. Enrichment and protein-protein interaction (PPI) network analyses were performed for FCRLA and its co-expressed genes. FCRLA was knocked down in RCC cell lines to evaluate its impact on biological behavior. Then the potential downstream regulators of FCRLA were determined by western blotting, and rescue experiments were performed for verification. The relevance between FCRLA and various immune cells was analyzed through GSEA, TIMER, and GEPIA tools. TIDE and ESTIMATE algorithms were used to predict the effect of FCRLA in immunotherapy. RESULTS: Fc receptor-like A was associated with clinical and T stages and could predict the M stage (AUC = 0.692) and 1-3- and 5-year survival rates (AUC = 0.823, 0.834, and 0.862) of RCC patients. Higher expression of FCLRA predicted an unfavorable overall survival (OS) in TCGA-RCC and GSE167573 datasets (p = 0.03, p = 0.04). FCRLA promoted the malignant biological behavior of RCC cells through the pERK1/2/-MMP2 pathway and was associated with tumor immune microenvironment in RCC. CONCLUSION: Fc receptor-like A is positively correlated with poor outcomes in RCC patients and plays an oncogenic role in RCC through the pERK1/2-MMP2 pathway. Patients with RCC might benefit from immunotherapy targeting FCRLA.

Daily dynamics of ground-dwelling invertebrate communities during and following an extreme high-temperature event in summer 2022, China.

The recent increase in the frequency of extreme weather events and declining soil biodiversity in global agricultural ecosystems make it crucial to assess the daily dynamics of soil communities in fields. To elucidate the daily dynamics of ground-dwelling invertebrate communities, their communities were monitored temporally using infrared camera traps in field farmland during and following an extremely high-temperature (EHT) event in summer 2022 in Ningbo City, China. Nine taxa and 1,147 individuals of the ground-dwelling invertebrate community were photographed in the 176,256 images. There were no significant differences in the taxonomic richness and abundance of the total ground-dwelling invertebrate communities during and following the EHT event. The abundance of ants was significantly decreased following the EHT event, whereas the abundance of other taxa was not. Significantly daily dynamics and obvious differences between each day in taxonomic richness, abundance of ground-dwelling invertebrate community, and abundance of each taxon were not observed during and following the EHT event. The results of this study showed that the daily dynamics of richness and abundance of the ground-dwelling invertebrate community and the abundance of each taxon were not significant during and following the EHT event. Overall, this study provides a useful monitoring method to observe the daily dynamics of ground-dwelling invertebrates in field farmlands and suggests that the daily dynamics of soil fauna communities should be further studied when assessing the effects of climate change on soil biodiversity.

Multidimensional role of adapalene in regulating cell death in multiple myeloma.

Aims: Multiple myeloma (MM) remains a challenging condition to cure, with persistent drug resistance negating the benefits of treatment advancements. The unraveling complexities in programmed cell death (PCD), inclusive of apoptosis, autophagy, and ferroptosis, have highlighted novel therapeutic avenues. Our study focuses on deciphering how adapalene (ADA), a small molecule compound, accelerates the demise of MM cells via targeting their compensatory survival mechanisms. Methods: To assess the impact of ADA on MM, we employed flow cytometry and trypan blue exclusion assays to determine cell viabilities across MM cell lines and primary patient samples post-treatment. To delineate ADA's therapeutic targets and mechanisms, we conducted RNA sequencing (RNA-seq), gene set enrichment analysis (GSEA), molecular docking, and molecular dynamics simulations. We further designed pre-clinical trials emphasizing MM, exploring the efficacy of ADA as a standalone and in combination with bortezomib (BTZ). Results: ADA elicited a dose-responsive induction of MM cell death. Building upon ADA's anti-MM capabilities as a single agent, we proposed that ADA-BTZ co-treatment might amplify this lethality. Indeed, ADA and BTZ together greatly potentiated MM cell death. ADA proved beneficial in restoring BTZ susceptibility in BTZ-resistant relapsed or refractory MM (RRMM) patient cells. Molecular simulations highlighted ADA's high affinity (-9.17 kcal/mol) for CD138, with MM-GBSA revealing a binding free energy of -27.39 kcal/mol. Detailed interaction analyses indicated hydrogen-bonding of ADA with CD138 at the Asp35 and Gln34 residues. Additionally, ADA emerged as a versatile instigator of both ferroptosis and apoptosis in MM cells. Furthermore, ADA disrupted activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway triggered by BTZ, fostering cell death in BTZ-resistant MM subsets. Conclusion: ADA demonstrates a comprehensive capability to orchestrate MM cell death, exerting pronounced anti-MM activity while disrupting NF-κB-related drug resistance. ADA sensitization of MM cells to BTZ unravels its potential as a novel therapeutic drug for MM management.

Nuclear translocation of ISG15 regulated by PPP2R2B inhibits cisplatin resistance of bladder cancer.

Cisplatin resistance is a major challenge for systemic therapy against advanced bladder cancer (BC). Little information is available on the regulation of cisplatin resistance and the underlying mechanisms require elucidation. Here, we detected that downregulation of the tumor suppressor, PPP2R2B (a serine/threonine protein phosphatase 2 A regulatory subunit), in BC promoted cell proliferation and migration. What's more, low PPP2R2B expression was correlated with cisplatin resistance. In vitro and in vivo experiments verified that PPP2R2B could promote BC sensitivity to cisplatin. In terms of mechanism, we identified a novel function of PPP2R2B as a nucleocytoplasmic transport molecule. PPP2R2B promoted ISG15 entry into the nucleus by mediating binding of IPO5 with ISG15. Nuclear translocation of ISG15 inhibited DNA repair, further increasing ISG15 expression through activation of the STING pathway. Besides, PPP2R2B was down-regulated by SUV39H1-mediated histone 3 lysine 9 trimethylation, which could be restored by the SUV39H1-specific inhibitor, chaetocin. Our data suggest that PPP2R2B expression level is a potential biomarker for chemotherapy response and that chemotherapy in combination with chaetocin may be a feasible treatment strategy for patients with BC.

Negative expression of CD117 predicted inferior OS and PFS in acute promyelocytic leukemia.

INTRODUCTION: In recent years, the correlation between CD117 antigen and the prognosis of hematological malignancies has been demonstrated. However, there is limited literature on the clinical significance of CD117 antigen in acute promyelocytic leukemia (APL). The aim of this study was to retrospectively analyze the clinical features and prognostic significance of CD117 in APL. METHODS: In this study, we retrospectively investigated the clinicopathological characteristics, outcome, and prognostic impact of negative CD117 expression (CD117-) in 169 APL patients treated with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) containing regimen. RESULTS: The median follow-up period was 63.0 months. CD117- was detected in 13 APL patients (7.7%). No significant differences were found in baseline characteristics between CD117+ and CD117- subgroups. However, compared to CD117+ APL, the incidence of early death (ED) was significantly higher in CD117- APL (p = 0.023). By multivariate analysis, CD117- was an independent adverse prognostic factor for overall survival (OS) and progression-free survival (PFS) (p = 0.022 and p = 0.014, respectively). CONCLUSIONS: To sum up, CD117- is associated with greater risk of ED and has the statistical power to predict inferior OS and PFS, this marker may be considered to build prognostic scores for risk-adapted therapeutic strategies in APL management.

Advances in Circular RNA in the Pathogenesis of Epilepsy.

Recent studies evidenced the involvement of circular RNA (circRNA) in neuroinflammation, apoptosis, and synaptic remodeling suggesting an important role for circRNA in the occurrence and development of epilepsy. This review provides an overview of circRNAs considered to be playing regulatory roles in the process of epilepsy and to be involved in multiple biological epilepsy-related processes, such as hippocampal sclerosis, inflammatory response, cell apoptosis, synaptic remodeling, and cell proliferation and differentiation. This review covers the current research status of differential expression of circRNA-mediated seizures, m6A methylation, demethylation-mediated seizures in post transcriptional circRNA modification, as well as the mechanisms of m5C- and m7G-modified circRNA. In summary, this article reviews the research progress on the relationship between circRNA in non-coding RNA and epilepsy.

Shooting area of infrared camera traps affects recorded taxonomic richness and abundance of ground-dwelling invertebrates.

Ground-dwelling invertebrates are vital for soil biodiversity and function maintenance. Contemporary biodiversity assessment necessitates novel and automatic monitoring methods because of the threat of sharp reductions in soil biodiversity in farmlands worldwide. Using infrared camera traps (ICTs) is an effective method for assessing richness and abundance of ground-dwelling invertebrates. However, the influence that the shooting area of ICTs has on the diversity of ground-dwelling invertebrates has not been strongly considered during survey design. In this study, data from six ICTs with two shooting areas (A1, 38.48 cm2; A2, 400 cm2) were used to investigate ground-dwelling invertebrates in a farm in a city on the Eastern Coast of China from 20: 00 on July 31 to 00:00 on September 29, 2022. Over the course of 59 days and 1420 h, invertebrates within 9 taxa, 2447 individuals, and 112,909 ind./m2 were observed from 222,912 images. Our results show that ICTs with relatively large shooting areas recorded relatively high taxonomic richness and abundance of total ground-dwelling invertebrates, relatively high abundance of the dominant taxon, and relatively high daily and hourly abundance of most taxa. The shooting areas of ICTs significantly affected the recorded taxonomic richness and abundance of ground-dwelling invertebrates throughout the experimental period and at fine temporal resolutions. Overall, these results suggest that the shooting areas of ICTs should be considered when designing experiments, and ICTs with relatively large shooting areas are more favorable for monitoring the diversity of ground-dwelling invertebrates. This study further provides an automatic tool and high-quality data for biodiversity monitoring and protection in farmlands.

Recent advances in functional nucleic acid decorated nanomaterials for cancer imaging and therapy.

Nanomaterials possess unusual physicochemical properties including unique optical, magnetic, electronic properties, and large surface-to-volume ratio. However, nanomaterials face some challenges when they were applied in the field of biomedicine. For example, some nanomaterials suffer from the limitations such as poor selectivity and biocompatibility, low stability, and solubility. To address the above-mentioned obstacles, functional nucleic acid has been widely served as a powerful and versatile ligand for modifying nanomaterials because of their unique characteristics, such as ease of modification, excellent biocompatibility, high stability, predictable intermolecular interaction and recognition ability. The functionally integrating functional nucleic acid with nanomaterials has produced various kinds of nanocomposites and recent advances in applications of functional nucleic acid decorated nanomaterials for cancer imaging and therapy were summarized in this review. Further, we offer an insight into the future challenges and perspectives of functional nucleic acid decorated nanomaterials.

Identification of common mechanisms and biomarkers of atrial fibrillation and heart failure based on machine learning.

AIMS: Atrial fibrillation (AF) is the most common arrhythmia. Heart failure (HF) is a disease caused by heart dysfunction. The prevalence of AF and HF were progressively increasing over time. The co-existence of AF and HF presents a significant therapeutic challenge. In order to provide new ideas for the diagnosis of AF and HF, it is necessary to carry out biomarker related studies. METHODS AND RESULTS: The training set and validation set data of AF and HF patient samples were downloaded from the GEO database, 'limma' was used to compare the differences in gene expression levels between the disease group and the normal group to screen for differentially expressed genes (DEGs). Weighted correlation network analysis (WGCNA) identified the modules with the highest positive correlation with AF and HF. Functional enrichment and PPI network construction of key genes were carried out. Biomarkers were screened by machine learning. The infiltration of immune cells in AF and HF groups was evaluated by R-packet 'CIBERSORT'. The miRNA network was constructed and potential therapeutic agents for biomarker genes were predicted through the drugbank database. Through WGCNA analysis, it was found that the modules most positively correlated with AF and HF were MEturquoise (r = 0.21, P value = 0.09) and MEbrown (r = 0.62, P value = 8e-12), respectively. We screened 25 genes that were highly correlated with both AF and HF. Lasso regression analysis results showed 7 and 20 core genes in AF and HF groups, respectively. The top 20 important genes in AF and HF groups were obtained as core genes by RF model analysis. Four biomarkers were obtained after the intersection of core genes in four groups, namely, GLUL, NCF2, S100A12, and SRGN. The diagnostic efficacy of four genes in AF validation sets was good (AUC: GLUL 0.76, NCF2 0.64, S100A12 0.68, and SRGN 0.76), as well as in the HF validation set (AUC: GLUL 0.76, NCF2 0.84, S100A12 0.92, and SRGN 0.68). The highest correlation with neutrophils was observed for GLUL, NCF2, and S100A12, while SRGN exhibited the strongest correlation with T cells CD4 memory resting in the AF group. GLUL, NCF2, S100A12, and SRGN were most associated with neutrophils in the HF group. A total of 101 miRNAs were predicted by four genes, and GLUL, NCF2, and S100A12 predicted a total of 10 potential therapeutic agents. CONCLUSIONS: We identified four biological markers that are highly correlated with AF and HF, namely, GLUL, NCF2, S100A12, and SRGN. Our findings provide theoretical basis for the clinical diagnosis and treatment of AF and HF.

Role of ferroptosis in Porphyromonas gingivalis-induced impairment of epithelial junction.

Objectives: This study aims to clarify the effect of ferroptosis by P. gingivalis on periodontal epithelium impairment and potential mechanisms. Materials and methods: The expression of epithelial junction proteins (CDH1, OCLN, ZO-1), FTL and GPX4 in healthy and periodontitis tissues was analyzed using bioinformatics analysis and validated in vivo. An in vitro model was constructed to evaluate ferroptosis by mitochondria morphology, content of iron and GSH, and level of lipid peroxidation, FTL, GPX4 and SLC7A11. The iron concentration was changed with iron chelator DFO and iron supplementation FAC. The epithelial impairment was assessed by protein expression. To investigate the mechanism, si-MYB (a negative transcription factor of SLC7A11) and GPX4 inhibitor RSL3 were employed. Results: CDH1, OCLN, ZO-1 and GPX4 expression was decreased, while FTL expression was elevated in periodontitis tissues. Infected cells showed ferroptosis change of the mitochondria with higher level of lipid peroxidation, iron, FTL and lower level of GPX4, GSH, SLC7A11. FAC augmented ferroptosis and weakened epithelial junction, while DFO exhibited a counteractive effect. Silencing MYB rescued SLC7A11, GPX4 and epithelial junction proteins, which was hindered by RSL3. Conclusions: Our study demonstrated that P. gingivalis weakened the oral epithelial barrier by causing ferroptosis via inhibiting SLC7A11/GSH/GPX4 axis.

Crosstalk of disulfidptosis-related subtypes identifying a prognostic signature to improve prognosis and immunotherapy responses of clear cell renal cell carcinoma patients.

BACKGROUND: Disulfidptosis is a novel form of programmed cell death induced by high SLC7A11 expression under glucose starvation conditions, unlike other known forms of cell death. However, the roles of disulfidptosis in cancers have yet to be comprehensively well-studied, particularly in ccRCC. METHODS: The expression profiles and somatic mutation of DGs from the TCGA database were investigated. Two DGs clusters were identified by unsupervised consensus clustering analysis, and a disulfidptosis-related prognostic signature (DR score) was constructed. Furthermore, the predictive capacity of the DR score in prognosis was validated by several clinical cohorts. We also developed a nomogram based on the DR score and clinical features. Then, we investigated the differences in the clinicopathological information, TMB, tumor immune landscapes, and biological characteristics between the high- and low-risk groups. We evaluated whether the DR score is a robust tool for predicting immunotherapy response by the TIDE algorithm, immune checkpoint genes, submap analysis, and CheckMate immunotherapy cohort. RESULTS: We identified two DGs clusters with significant differences in prognosis, tumor immune landscapes, and clinical features. The DR score has been demonstrated as an independent risk factor by several clinical cohorts. The high-risk group patients had a more complicated tumor immune microenvironment and suffered from more tumor immune evasion in immunotherapy. Moreover, patients in the low-risk group had better prognosis and response to immunotherapy, particularly in anti-PD1 and anti-CTLA-4 inhibitors, which were verified in the CheckMate immunotherapy cohort. CONCLUSION: The DR score can accurately predict the prognosis and immunotherapy response and assist clinicians in providing a personalized treatment regime for ccRCC patients.

Imbalanced EphB4/EphrinB2 Signaling Modulates Bone Resorption in Periodontitis Induced by Porphyromonas gingivalis.

Periodontitis, a chronic infectious disease in periodontal tissues, is characterized by an imbalance of alveolar bone resorption and remodeling, which eventually results in tooth loosening and even tooth loss. The etiology of periodontitis is polymicrobial synergy and dysbiosis, in which Porphyromonas gingivalis (P. gingivalis) is one of the primary pathogens responsible for periodontitis progression. The interplay of EphrinB2/EphB4 is crucial for osteoblast-osteoclast communication during bone remodeling and healing. This study investigates the mechanism of EphB4/EphrinB2 transduction modulating osteogenesis inhibition and bone resorption in periodontitis induced by P. gingivalis. An in vivo model of chronic periodontitis provoked by P. gingivalis was constructed, the inflammation and bone resorption were evaluated. The expression of EphB4 and EphrinB2 proteins in periodontal tissues was detected, which was also evaluated, respectively, in osteoblasts and osteoclasts infected with P. gingivalis in vitro. Then, a simulated coculture model of osteoblasts and osteoclasts was established to activate the forward and reverse pathways of EphB4/EphrinB2 with P. gingivalis infection. This study showed that P. gingivalis infection promoted alveolar bone resorption in rats and enhanced EphB4 and EphrinB2 expression in periodontal tissues. EphB4 and molecules associated with osteogenesis in osteoblasts infected with P. gingivalis were inhibited, while EphrinB2 and osteoclast differentiation-related markers in osteoclasts were activated. In conclusion, this study suggested that EphB4/EphrinB2 proteins were involved in alveolar bone remodeling in the process of periodontitis induced by P. gingivalis infection. Moreover, attenuated EphB4/EphrinB2 with P. gingivalis infection weakened osteoblast activity and enhanced osteoclast activity.

Clinical Efficacy Analysis of Circumferential Upper Arm Liposuction with Double Incision: A Study of 496 Cases.

BACKGROUND: In cases where the upper arm exhibits an irregular cylindrical appearance with subcutaneous fat concentrated primarily in the posterior lateral aspect, traditional localized fat suction techniques may lead to uneven or disharmonious results when addressing this concern. Many practitioners have turned to circumferential fat suction methods using multi-incision approaches to ensure effective results and fat removal. However, these methods often involve numerous incisions and complex procedures, necessitating the development of new, more efficient surgical techniques. METHODS: We collected and screened patients who underwent upper arm circumferential liposuction with a double incision technique at our hospital from October 2020 to February 2023. A total of 496 cases were included in our retrospective analysis, in which we examined factors such as the length of surgery, arm circumference before and after surgery, subcutaneous tissue thickness before and after surgery, fat suction volume, postoperative satisfaction, and postoperative complications of the patients. RESULTS: The average length of surgery was 71.7 min. 458 cases (92.3%) showed significant improvement, 23 cases (4.6%) reported satisfaction, and 10 cases (2.0%) were essentially satisfied. Additionally, 339 cases (68.3%) experienced an improvement in skin laxity. Four cases (0.8%) developed localized hard nodules with slight tenderness in the early postoperative period, which resolved without special treatment after observation and follow-up for 1-3 months. Three cases (0.6%) reported localized pain or numbness, and they were given oral medication. Their symptoms disappeared after 1-3 months of observation and follow-up. Three cases (0.6%) had localized pain or numbness, and their symptoms disappeared. All of these cases improved and resolved after one month of taking mecobalamin tablets. There were also three cases (0.6%) with mild pigmentation of the incision and two cases (0.4%) with mild limitation of unilateral upper arm abduction movement. However, upper arm activities were not affected after three months to one year of follow-up. No serious complications were reported, resulting in an overall satisfaction rate of 99.0%. CONCLUSION: The double incision upper arm liposuction is safe, effective, time-saving, with high satisfaction and fewer complications, and is worthy of clinical popularization and application. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of contents or the online Instructions to Authors www.springer.com/00266 .

Meta-analysis of MMP-9 levels in the serum of patients with epilepsy.

Background: Epilepsy's pathogenesis and progression are significantly influenced by neuroinflammation, blood-brain barrier function, and synaptic remodeling function. Matrix metalloproteinase 9 (MMP-9), as a critical factor, may contribute to the development of epilepsy through one or more of the above-mentioned pathways. This study aims to evaluate and quantify the correlation between MMP-9 levels and epilepsy. Methods: We conducted a comprehensive search of Embase, Web of Science, PubMed, Cochrane Library, WanFang DATA, VIP, and the CNKI to identify studies that investigate the potential association between MMP-9 and epilepsy. The data were independently extracted by two researchers and assessed for quality using the Cochrane Collaboration tool. The extracted data were analyzed using Stata 15 and Review Manager 5.4. The study protocol was registered prospectively at PROSPERO, ID: CRD42023468493. Results: Thirteen studies with a total of 756 patients and 611 matched controls met the inclusion criteria. Eight of these studies reported total serum MMP-9 levels, and the other five studies were used for a further subgroup analysis. The meta-analysis indicated that the serum MMP-9 level was higher in epilepsy patients (SMD = 4.18, 95% confidence interval = 2.18-6.17, p < 0.00001) compared with that in the control group. Publication bias was not detected according to Begg's test. The subgroup analysis of country indicated that the epilepsy patients in China, Poland, and Egypt had higher levels of serum MMP-9 than the control group, with the increase being more pronounced in Egypt. The subgroup analysis of the age category demonstrated that the serum MMP-9 levels of the adult patients with epilepsy were significantly higher than those of the matched controls. However, the serum MMP-9 levels did not significantly differ in children with epilepsy. The subgroup analysis of the seizure types demonstrated substantial difference in the MMP-9 levels between patients of seizure-free epilepsy (patients who have been seizure-free for at least 7 days) and the control group. Meanwhile, the serum MMP-9 level in patients with epileptic seizures was significantly higher than that in the control group. The subgroup analysis based on seizure duration in patients showed that the serum MMP-9 levels at 1-3, 24, and 72 h after seizure did not exhibit significant differences between female and male patients with epilepsy when compared with the control group. The serum MMP-9 levels at 1-3 and 24 h were significantly higher than those of the matched controls. Nevertheless, the serum MMP-9 level at 72 h was not significantly different from that in the control group. Conclusion: This meta-analysis presents the first comprehensive summary of the connection between serum MMP-9 level and epilepsy. The MMP-9 levels in epilepsy patients are elevated. Large-scale studies with a high level of evidence are necessary to determine the exact relationship between MMP-9 and epilepsy.

The Age-Male-Albumin-Bilirubin-Platelets (aMAP) Risk Score Predicts Liver Metastasis Following Surgery for Breast Cancer in Chinese Population: A Retrospective Study.

Objective: The current study is conducted to investigate the potential prognostic value of the age-male-albumin-bilirubin-platelets (aMAP) score in breast cancer patients with liver metastasis after surgery. Methods: This is a retrospective study of 178 breast cancer patients who developed liver metastasis after surgery. These patients were treated and followed up from 2000 to 2018 at our hospital. The aMAP risk score was estimated in accordance with the following formula: . The optimal cutoff value of the aMAP was evaluated via X-tile. Kaplan-Meier, Log-rank and Cox proportional hazards regression models were applied to determine the clinical influence of the aMAP score on the survival outcomes. The nomogram models were established by multivariate analyses. The calibration curves and decision curve analysis were applied to evaluate the estimated performance of the nomogram models. Results: A total of 178 breast cancer patients were divided into low aMAP score group (<47.6) and high aMAP score group (≥47.6) via X-tile plots. The aMAP score was a potential prognostic factor in multivariate analysis. The median disease free survival (p=0.0013) and overall survival (p=0.0003) in low aMAP score group were longer than in high aMAP score group. The nomograms were constructed to predict the DFS with a C-index of 0.722 (95% CI, 0.673-0.771), and the OS with a C-index of 0.708 (95% CI, 0.661-0.755). The aMAP-based nomograms had good predictive performance. Conclusion: The aMAP score is a potential prognostic factor in breast cancer with liver metastasis after surgery. The aMAP score-based nomograms were conducive to discriminate patients at high risks of liver metastasis and develop adjuvant treatment and prevention strategies.