Correction: Liu et al. Endostatin 33 Peptide Is a Deintegrin α6ß1 Agent That Exerts Antitumor Activity by Inhibiting the PI3K-Akt Signaling Pathway in Prostate Cancer. J. Clin. Med. 2023, 12, 1861.

In the original publication [...].

Multi-omics analysis and experimental validation of the value of monocyte-associated features in prostate cancer prognosis and immunotherapy.

Background: Monocytes play a critical role in tumor initiation and progression, with their impact on prostate adenocarcinoma (PRAD) not yet fully understood. This study aimed to identify key monocyte-related genes and elucidate their mechanisms in PRAD. Method: Utilizing the TCGA-PRAD dataset, immune cell infiltration levels were assessed using CIBERSORT, and their correlation with patient prognosis was analyzed. The WGCNA method pinpointed 14 crucial monocyte-related genes. A diagnostic model focused on monocytes was developed using a combination of machine learning algorithms, while a prognostic model was created using the LASSO algorithm, both of which were validated. Random forest and gradient boosting machine singled out CCNA2 as the most significant gene related to prognosis in monocytes, with its function further investigated through gene enrichment analysis. Mendelian randomization analysis of the association of HLA-DR high-expressing monocytes with PRAD. Molecular docking was employed to assess the binding affinity of CCNA2 with targeted drugs for PRAD, and experimental validation confirmed the expression and prognostic value of CCNA2 in PRAD. Result: Based on the identification of 14 monocyte-related genes by WGCNA, we developed a diagnostic model for PRAD using a combination of multiple machine learning algorithms. Additionally, we constructed a prognostic model using the LASSO algorithm, both of which demonstrated excellent predictive capabilities. Analysis with random forest and gradient boosting machine algorithms further supported the potential prognostic value of CCNA2 in PRAD. Gene enrichment analysis revealed the association of CCNA2 with the regulation of cell cycle and cellular senescence in PRAD. Mendelian randomization analysis confirmed that monocytes expressing high levels of HLA-DR may promote PRAD. Molecular docking results suggested a strong affinity of CCNA2 for drugs targeting PRAD. Furthermore, immunohistochemistry experiments validated the upregulation of CCNA2 expression in PRAD and its correlation with patient prognosis. Conclusion: Our findings offer new insights into monocyte heterogeneity and its role in PRAD. Furthermore, CCNA2 holds potential as a novel targeted drug for PRAD.

Identification of metastasis-related genes for predicting prostate cancer diagnosis, metastasis and immunotherapy drug candidates using machine learning approaches.

BACKGROUND: Prostate cancer (PCa) is the second leading cause of tumor-related mortality in men. Metastasis from advanced tumors is the primary cause of death among patients. Identifying novel and effective biomarkers is essential for understanding the mechanisms of metastasis in PCa patients and developing successful interventions. METHODS: Using the GSE8511 and GSE27616 data sets, 21 metastasis-related genes were identified through the weighted gene co-expression network analysis (WGCNA) method. Subsequent functional analysis of these genes was conducted on the gene set cancer analysis (GSCA) website. Cluster analysis was utilized to explore the relationship between these genes, immune infiltration in PCa, and the efficacy of targeted drug IC50 scores. Machine learning algorithms were then employed to construct diagnostic and prognostic models, assessing their predictive accuracy. Additionally, multivariate COX regression analysis highlighted the significant role of POLD1 and examined its association with DNA methylation. Finally, molecular docking and immunohistochemistry experiments were carried out to assess the binding affinity of POLD1 to PCa drugs and its impact on PCa prognosis. RESULTS: The study identified 21 metastasis-related genes using the WGCNA method, which were found to be associated with DNA damage, hormone AR activation, and inhibition of the RTK pathway. Cluster analysis confirmed a significant correlation between these genes and PCa metastasis, particularly in the context of immunotherapy and targeted therapy drugs. A diagnostic model combining multiple machine learning algorithms showed strong predictive capabilities for PCa diagnosis, while a transfer model using the LASSO algorithm also yielded promising results. POLD1 emerged as a key prognostic gene among the metastatic genes, showing associations with DNA methylation. Molecular docking experiments supported its high affinity with PCa-targeted drugs. Immunohistochemistry experiments further validated that increased POLD1 expression is linked to poor prognosis in PCa patients. CONCLUSIONS: The developed diagnostic and metastasis models provide substantial value for patients with prostate cancer. The discovery of POLD1 as a novel biomarker related to prostate cancer metastasis offers a promising avenue for enhancing treatment of prostate cancer metastasis.

Common immunological and prognostic features of lung and bladder cancer via smoking-related genes: PRR11 gene as potential immunotherapeutic target.

Smoking is a well-known risk factor for non-small-cell lung cancer (NSCLC) and bladder urothelial carcinoma (BLCA). Despite this, there has been no investigation into a prognostic marker based on smoking-related genes that could universally predict prognosis in these cancers and correlate with immune checkpoint therapy. This study aimed to identify smoking-related differential genes in NSCLC and BLCA, analyse their roles in patient prognosis and immune checkpoint therapy through subgroup analyses, and shed light on PRR11 as a crucial prognostic gene in both cancers. By examining PRR11 co-expressed genes, a prognostic model was constructed and its impact on immunotherapy for NSCLC and BLCA was evaluated. Molecular docking and tissue microarray analyses were conducted to explore the correlation between PRR11 and its reciprocal gene SPDL1. Additionally, miRNAs associated with PRR11 were analysed. The study confirmed a strong link between smoking-related genes, prognosis, and immune checkpoint therapy in NSCLC and BLCA. PRR11 was identified as a key smoking-associated gene that influences the efficacy of immune checkpoint therapy by modulating the stemness of these cancers. A prognostic model based on PRR11 co-expressed genes in BLCA was established and its prognostic value was validated in NSCLC. Furthermore, it was found that PRR11 regulates PDL1 via SPDL1, impacting immunotherapeutic efficacy in both cancers. The involvement of hsa-miR-200b-3p in the regulation of SPDL1 expression by PRR11 was also highlighted. Overall, the study elucidates that PRR11 modulates patient immunotherapy by influencing PDL1 expression through its interaction with SPDL1, with potential upstream regulation by hsa-miR-200b-3p.

Evaluating the predictive value of angiogenesis-related genes for prognosis and immunotherapy response in prostate adenocarcinoma using machine learning and experimental approaches.

Background: Angiogenesis, the process of forming new blood vessels from pre-existing ones, plays a crucial role in the development and advancement of cancer. Although blocking angiogenesis has shown success in treating different types of solid tumors, its relevance in prostate adenocarcinoma (PRAD) has not been thoroughly investigated. Method: This study utilized the WGCNA method to identify angiogenesis-related genes and assessed their diagnostic and prognostic value in patients with PRAD through cluster analysis. A diagnostic model was constructed using multiple machine learning techniques, while a prognostic model was developed employing the LASSO algorithm, underscoring the relevance of angiogenesis-related genes in PRAD. Further analysis identified MAP7D3 as the most significant prognostic gene among angiogenesis-related genes using multivariate Cox regression analysis and various machine learning algorithms. The study also investigated the correlation between MAP7D3 and immune infiltration as well as drug sensitivity in PRAD. Molecular docking analysis was conducted to assess the binding affinity of MAP7D3 to angiogenic drugs. Immunohistochemistry analysis of 60 PRAD tissue samples confirmed the expression and prognostic value of MAP7D3. Result: Overall, the study identified 10 key angiogenesis-related genes through WGCNA and demonstrated their potential prognostic and immune-related implications in PRAD patients. MAP7D3 is found to be closely associated with the prognosis of PRAD and its response to immunotherapy. Through molecular docking studies, it was revealed that MAP7D3 exhibits a high binding affinity to angiogenic drugs. Furthermore, experimental data confirmed the upregulation of MAP7D3 in PRAD, correlating with a poorer prognosis. Conclusion: Our study confirmed the important role of angiogenesis-related genes in PRAD and identified a new angiogenesis-related target MAP7D3.

Unveiling the role of YARS1 in bladder cancer: A prognostic biomarker and therapeutic target.

YARS is responsible for catalysing the binding of tyrosine to its cognate tRNA and plays a crucial role in basic biosynthesis. However, its biological functions in bladder cancer remains to be proven. We analysed variations in YARS1 expression and survival in bladder cancer using multiple data sets, including TCGA-BLCA, GSE13507 and bladder cancer-specific tissue microarrays. Furthermore, we explored the biological functions of YARS1 using transcriptome data. Our findings revealed a noteworthy correlation between YARS1 and immune infiltration in bladder cancer, as determined using the XCELL algorithm and single-cell analysis. In addition, we employed the TIDE algorithm to evaluate the responsiveness of different cohorts to immune checkpoint therapy. We investigated the regulatory associations between YARS1 and various aspects of bladder cancer, including senescence, ferroptosis and stemness. Finally, we established a ceRNA network that is directly linked to the overall prognosis, YARS1 can serve as a prognostic biomarker for bladder cancer; its interaction with MYC has implications for bladder cancer cell senescence, ferroptosis and stemness. Moreover, the identified ceRNA network has potential as a therapeutic target in bladder cancer.

Multi-omics comprehensive analysis reveals the predictive value of N6-methyladenosine- related genes in prognosis and immune escape of bladder cancer.

BACKGROUND: N6-methyladenosine (m6A) is the most frequent RNA modification in mammals, and its role in bladder cancer (BC) remains rarely revealed. OBJECTIVE: To predict the value of m6A-related genes in prognosis and immunity in BC. METHODS: We performed multiple omics analysis of 618 TCGA and GEO patients and used principal component analysis (PCA) to calculate the m6A score for BC patients. RESULTS: We described the multiple omics status of 23 m6A methylation-related genes (MRGs), and four m6A clusters were identified, which showed significant differences in immune infiltration and biological pathways. Next, we intersected the differential genes among m6A clusters, and 11 survival-related genes were identified, which were used to calculate the m6A score for the patients. We found that the high-score (HS) group showed lower tumor mutation burden (TMB) and TP53 mutations and better prognosis than the low-score (LS) group. Lower immune infiltration, higher expression of PD-L1, PD-1, and CTLA4, and higher immune dysfunction and immune exclusion scores were identified in the LS group, suggesting a higher possibility of immune escape. Finally, the experimental verification shows that the m6A related genes, such as IGFBP1, plays an important role in the growth and metastasis of bladder cancer. CONCLUSIONS: These findings revealed the important roles of m6A MRGs in predicting prognosis, TMB status, TP53 mutation, immune functions and immunotherapeutic response in BC.

Adaptive foraging behaviours in the Horn of Africa during Toba supereruption.

Although modern humans left Africa multiple times over 100,000 years ago, those broadly ancestral to non-Africans dispersed less than 100,000 years ago1. Most models hold that these events occurred through green corridors created during humid periods because arid intervals constrained population movements2. Here we report an archaeological site-Shinfa-Metema 1, in the lowlands of northwest Ethiopia, with Youngest Toba Tuff cryptotephra dated to around 74,000 years ago-that provides early and rare evidence of intensive riverine-based foraging aided by the likely adoption of the bow and arrow. The diet included a wide range of terrestrial and aquatic animals. Stable oxygen isotopes from fossil mammal teeth and ostrich eggshell show that the site was occupied during a period of high seasonal aridity. The unusual abundance of fish suggests that capture occurred in the ever smaller and shallower waterholes of a seasonal river during a long dry season, revealing flexible adaptations to challenging climatic conditions during the Middle Stone Age. Adaptive foraging along dry-season waterholes would have transformed seasonal rivers into 'blue highway' corridors, potentially facilitating an out-of-Africa dispersal and suggesting that the event was not restricted to times of humid climates. The behavioural flexibility required to survive seasonally arid conditions in general, and the apparent short-term effects of the Toba supereruption in particular were probably key to the most recent dispersal and subsequent worldwide expansion of modern humans.

Multidimensional pan-cancer analysis of HSPA5 and its validation in the prognostic value of bladder cancer.

Endoplasmic reticulum (ER) stress-related genes are closely related to the occurrence, development, and immunotherapy response of tumors. This study provides a comprehensive assessment of HSPA5 from a pan-cancer perspective using multi-omics data. We analyzed the function of HSPA5 in multiple tumor types using multiple databases. Finally, immunohistochemistry was used to examine the relationship between HSPA5 expression in tissue microarrays from 100 patients with bladder cancer and the prognosis of patients with bladder cancer. Using the TCGA database, we were able to determine that HSPA5 is significantly elevated in a number of common malignancies and is linked with a bad prognosis. Cox regression analysis showed that the high expression of HSPA5 was correlated with OS, progression free survival (PFS), disease free survival (DFS), and disease special survival (DSS) of adrenocortical carcinoma (ACC). In addition, we discovered significant disparities in HSPA5 methylation and phosphorylation levels between various malignancies and normal tissues. HSPA5 expression was significantly correlated with the levels of infiltrating cells and immune checkpoint genes. HSPA5 is highly expressed in bladder cancer and patients with high HSPA5 expression have a poor prognosis. Our study provides a basis for further understanding of the role of ER stress-related gene HSPA5 in different tumor genesis and development. HSPA5 has also been shown to be a prognostic biomarker for bladder cancer patients.

JAM3: A prognostic biomarker for bladder cancer via epithelial-mesenchymal transition regulation.

Understanding the intricate relationship between prognosis, immune function, and molecular markers in bladder cancer (BC) demands sophisticated analytical methods. To identify novel biomarkers for predicting prognosis and immune function in BC patients, we combined weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression analysis. This was conducted using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Ultimately, we screened the junctional adhesion molecule 3 (JAM3) as an independent risk factor in BC. High levels of JAM3 were linked to adverse clinical parameters, such as higher T and N stages. Additionally, a JAM3-based nomogram model accurately predicted 1-, 3- and 5-year survival rates of BC patients, indicating potential clinical utility. Functional enrichment analysis revealed that high JAM3 expression activated the calcium signaling pathway, the extracellular matrix (ECM)-receptor interaction, and the PI3K-Akt signaling pathway, and was positively correlated with genes associated with epithelial-mesenchymal transition (EMT). Subsequently, we found that overexpression of JAM3 promoted the migration and invasion abilities in BC cells, regulating the expression levels of N-cadherin, matrix metallopeptidase 2 (MMP2), and Claudin-1 thereby promoting EMT levels. Additionally, we showed that JAM3 was negatively correlated with anti-tumor immune cells such as CD8+ T cells, while positively correlated with pro-tumor immune cells such as M2 macrophages, suggesting its involvement in immune cell infiltration. The immune checkpoint CD200 also showed a positive correlation with JAM3. Our findings revealed that elevated JAM3 levels are predictive of poor prognosis and immune cell infiltration in BC patients by regulating the EMT process.

SERCA2 dysfunction triggers hypertension by interrupting mitochondrial homeostasis and provoking oxidative stress.

BACKGROUND AND AIM: Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) is critical in maintaining Ca2+ homeostasis. The cysteine 674 (C674) is the key redox regulatory cysteine in regulating SERCA2 activity, which is irreversibly oxidized in the renal cortex of hypertensive mice. We have reported that the substitution of C674 by serine causes SERCA2 dysfunction and increases blood pressure by induction of endoplasmic reticulum stress (ERS). This study is to explore whether the dysfunction of SERCA2 causes hypertension by interrupting mitochondrial homeostasis and inducing oxidative stress. METHODS & RESULTS: We used heterozygous SERCA2 C674S gene mutation knock-in (SKI) mice, where one copy of C674 was substituted by serine to represent partial C674 oxidation. In renal proximal tubule (RPT) cells, the substitution of C674 by serine decreased mitochondrial Ca2+ content, increased mitochondrial membrane potential, ATP content, and reactive oxygen species (ROS), which could be reversed by ERS inhibitor 4-phenylbutyric acid or SERCA2 agonist CDN1163. In SKI RPT cells, the redox modulator Tempol alleviated oxidative stress, downregulated the protein expression of ERS markers and soluble epoxide hydrolase, upregulated the protein expression of dopamine D1 receptor, and reduced Na+/K+- ATPase activity. In SKI mice, SERCA2 agonists CDN1163 and [6]-Gingerol, or the redox modulator Tempol increased urine output and lowered blood pressure. CONCLUSION: The irreversible oxidation of C674 is not only an indicator of increased ROS, but also further inducing oxidative stress to cause hypertension. Activation of SERCA2 or inhibition of oxidative stress is beneficial to alleviate hypertension caused by SERCA2 dysfunction.

A new immune-related gene signature predicts the prognosis and immune escape of bladder cancer.

BACKGROUND: The biological roles of immune-related genes (IRGs) in bladder cancer (BC) need to be further elucidated. OBJECTIVE: To elucidate the predictive value of IRGs for prognosis and immune escape in BC. METHODS: We comprehensively analyzed the transcriptomic and clinical information of 430 cases, including 19 normal and 411 BC patients from the TCGA database, and verified 165 BC cases in the GSE13507 dataset. The risk model was constructed based on IRGs by applying LASSO Cox regression and exploring the relationship between the risk score and prognosis, gene mutations, and immune escape in BC patients. RESULTS: We identified 4 survival-related genes (PSMC1, RAC3, ROBO2 and ITGB3) among 6,196 IRGs in both the TCGA and GES13507 datasets,, which were used to establish a gene risk model by applying LASSO Cox regression. The results showed that the high-risk (HR) group was closely associated with poor survival or advanced pathological stage of BC. Furthermore, the risk score was found to be an independent risk factor for prognosis of BC patients. In addition, high-risk individuals showed a greater prevalence of TP53 mutations lower CD8+ T-cell and NK cell infiltration, higher Treg cell infiltration, higher expression of PD-L1, and higher immune exclusion scores than those in the low-risk (LR) group. Finally, the experimental verification shows that the model construction gene, especially PMSC1, plays an important role in the growth and metastasis of bladder cancer. CONCLUSIONS: These evidences revealed the vital role of IRGs in predicting prognosis, TP53 mutation and immune escape in BC patients.

Enamel remineralization potential of bioactive glass air abrasion studied via elemental and surface morphology analysis.

Background: This study evaluates the remineralization potential of enamel after bioactive glass (BAG) air abrasion, using Scanning Electron Microscopy with Energy Dispersive X-ray Spectroscopy Analysis (SEM-EDS), Electron Probe Microanalysis (EPMA), and Atomic Force Microscopy (AFM). Material and Methods: Forty extracted human third molars were divided into four groups with ten samples each. Three groups were subjected to a demineralizing solution of 2.2 mM calcium chloride, 2.2 mM monopotassium phosphate, and 0.05 mM acetic acid, adjusted to a pH of 4.4 using 1 M potassium hydroxide at an intraoral temperature of 37°C for 96 hours. Of the three groups, two were subjected to air abrasion with BAG. One of the air abrasion groups was then further remineralized in 1.5 mM calcium chloride, 0.9 mM sodium phosphate, and 0.15 M potassium chloride, adjusted to a pH of 7.0 at 37°C. The teeth were then evaluated via SEM-EDS and EPMA to measure the calcium-to-phosphorous (Ca:P) ratios, and the surface morphology was investigated using AFM. Results: A measurable decrease in the Ca:P ratio was found after demineralization, which subsequently increased after remineralization. A thin layer of demineralized enamel was removed by the BAG air abrasion. AFM image analysis showed the presence of pits on the surface, which decreased in depth after demineralization, and further after BAG abrasion. Remineralized samples, in contrast, showed a slight increase in pit depth. While the observation of remineralization was statistically significant throughout our study, we could not find any evidence for BAG retention on the surface of the enamel. Conclusions: It is demonstrated that BAG, when delivered via air abrasion, indeed contributes to remineralization of the enamel; however, it does not seem to be a direct result of the presence of retained glass beads on the enamel surface. Given the increase of the Ca:P ratio after remineralization, a possible therapeutic benefit was observed, potentially reducing the probability of fractures in weakened enamel. Key words:Enamel, Demineralization, Remineralization, White Spot Lesions, Bioactive Glass, Air Abrasion, Energy Dispersive X-ray Spectroscopy, Electron Probe Microanalysis, Atomic Force Microscopy, Ca:P ratio, surface morphology.

Comprehensive analysis of PRPF19 immune infiltrates, DNA methylation, senescence-associated secretory phenotype and ceRNA network in bladder cancer.

Background: Pre-mRNA processing factor 19 (PRPF19) is an E3 ligase that plays a crucial role in repairing tumor-damaged cells and promoting cell survival. However, the predictive value and biological function of PRPF19 in bladder urothelial carcinoma (BLCA) require further investigation. Methods: In this study, we utilized transcriptomic data and bladder cancer tissue microarrays to identify the high expression of PRPF19 in BLCA, suggesting its potential as a prognostic biomarker. To gain a better understanding of the role of PRPF19 in the immune microenvironment of BLCA, we performed single cell analysis and employed the LASSO method. Additionally, we examined the methylation profiles of PRPF19 using the SMART website. Our investigation confirmed the correlation between PRPF19 and BLCA cell senescence and stemness. Furthermore, we constructed a PRPF19-miR-125a-5p-LINC02693-MIR4435-2HG ceRNA network using the ENCORI and miRWALK databases. Results: Our comprehensive analysis reveals that PRPF19 can serve as a prognostic marker for BLCA and is significantly associated with various immune-infiltrating cells in BLCA. Moreover, our findings suggest that PRPF19 influences cellular senescence through the regulation of stemness. Finally, we developed a ceRNA network that has the potential to predict the prognosis of BLCA patients. Conclusion: We confirmed the prognostic value and multiple biological functions of PRPF19 in BLCA. Furthermore, the specific ceRNA network can be used as a potential therapeutic target for BLCA.

Comprehensive analysis of integrin αvß3/α6ß1 in prognosis and immune escape of prostate cancer.

Integrin αvß3/α6ß1 are crucial in the transduction of intercellular cancer information, while their roles in prostate cancer (PCa) remain poorly understood. Here, we systematically analyzed the transcriptome, single nucleotide polymorphisms (SNPs) and clinical data of 495 PCa patients from the TCGA database and verified them in 220 GEO patients, and qPCR was used to validate the expression of the model genes in our patients. First, we found that integrin αvß3/α6ß1 was negatively correlated with most immune cell infiltration and immune functions and closely associated with poor survival in TCGA patients. Then, we divided these patients into two groups according to the expression level of αvß3/α6ß1, intersected differentially expressed genes of the two groups with the GEO dataset and identified eight biochemical recurrence-related genes (BRGs), and these genes were verified by qPCR in our patients. Next, these BRGs were used to construct a prognostic risk model by applying LASSO Cox regression. We found that the high-risk (HR) group showed poorer OS, PFS, biochemical recurrence and clinical characteristics than the low-risk (LR) group. In addition, the HR group was mainly enriched in the cell cycle pathway and had a higher TP53 mutation rate than the LR group. More importantly, lower immune cell infiltration and immune function, higher expression of PD-L1, PD-1, and CTLA4, and higher immune exclusion scores were identified in the HR group, suggesting a higher possibility of immune escape. These findings suggested the key role of integrin αvß3/α6ß1 in predicting prognosis, TP53 mutation and immune escape in PCa.

Oldhamite: a new link in upper mantle for C-O-S-Ca cycles and an indicator for planetary habitability.

In the solar system, oldhamite (CaS) is generally considered to be formed by the condensation of solar nebula gas. Enstatite chondrites, one of the most important repositories of oldhamite, are believed to be representative of the material that formed Earth. Thus, the formation mechanism and the evolution process of oldhamite are of great significance to the deep understanding of the solar nebula, meteorites, the origin of Earth, and the C-O-S-Ca cycles of Earth. Until now, oldhamite has not been reported to occur in mantle rock. However, here we show the formation of oldhamite through the reaction between sulfide-bearing orthopyroxenite and molten CaCO3 at 1.5 GPa/1510 K, 0.5 GPa/1320 K, and 0.3 GPa/1273 K. Importantly, this reaction occurs at oxygen fugacities within the range of upper-mantle conditions, six orders of magnitude higher than that of the solar nebula mechanism. Oldhamite is easily oxidized to CaSO4 or hydrolysed to produce calcium hydroxide. Low oxygen fugacity of magma, extremely low oxygen content of the atmosphere, and the lack of a large amount of liquid water on the celestial body's surface are necessary for the widespread existence of oldhamite on the surface of a celestial body otherwise, anhydrite or gypsum will exist in large quantities. Oldhamites may exist in the upper mantle beneath mid-ocean ridges. Additionally, oldhamites may have been a contributing factor to the early Earth's atmospheric hypoxia environment, and the transient existence of oldhamites during the interaction between reducing sulfur-bearing magma and carbonate could have had an impact on the changes in atmospheric composition during the Permian-Triassic Boundary.

Heat shock protein family A member 8 is a prognostic marker for bladder cancer: Evidences based on experiments and machine learning.

Heat shock protein member 8 (HSPA8) is one of the most abundant chaperones in eukaryotic cells, but its biological roles in bladder cancer (BC) are largely unclear. First, we observed that HSPA8 was abundant in both cell lines and tissues of BC, and the HSPA8-high group had poorer T stages and overall survival (OS) than the HSPA8-low group in the TCGA patients. Next, when we knocked down HSPA8 in BC cells, the growth and migration abilities were significantly decreased, the apoptosis rates were significantly increased, and the Ki67 fluorescence intensity was decreased in BC cells. Moreover, caspase 3 was significantly decreased with overexpression of HSPA8 in BC cells. After that, a machine learning prognostic model was created based on the expression of HSPA8 by applying LASSO Cox regression in TCGA and GEO patients. The model indicated that the low-risk (LR) group with BC had better tumour stages, lymphovascular invasion, and OS than the high-risk (HR) group. Additionally, the risk score was demonstrated to be an independent risk factor for the prognosis of BC by univariate and multivariate Cox analyses. Moreover, the HR group showed a greater rate of TP53 mutations and was mostly enriched in the ECM-receptor interaction pathway than the LR group. Importantly, lower CD8+ T-cell and NK cell infiltration, higher immune exclusion scores, higher expression of PD-L1 and CTLA4 and poorer immune checkpoint therapy effects were found in the HR group. These findings demonstrated how crucial HSPA8 plays a role in determining the prognosis of bladder cancer.

Endostatin 33 Peptide Is a Deintegrin α6ß1 Agent That Exerts Antitumor Activity by Inhibiting the PI3K-Akt Signaling Pathway in Prostate Cancer.

BACKGROUND: Prostate cancer (PCa) is the leading cause of death in men and has poor therapeutic outcomes. METHODS: A novel endostatin 33 peptide was synthesized by adding a specific QRD sequence on the basis of the endostatin 30 peptide (PEP06) with antitumor activity. Then, bioinformatic analysis and subsequent experiments were performed to validate the antitumor function of this endostatin 33 peptide. RESULTS: We found that the 33 polypeptides significantly inhibited growth, invasion and metastasis and promoted the apoptosis of PCa in vivo or vitro, which is more significant than PEP06 under the same conditions. According to 489 cases from the TCGA data portal, the α6ß1 high expression group was closely associated with the poor prognosis (Gleason score, pathological N stage, etc.) of PCa and was mainly enriched in the PI3K-Akt pathway. Subsequently, we demonstrated that endostatin 33 peptide can down-regulate the PI3K-Akt pathway via the targeted inhibition of α6ß1, thereby inhibiting the epithelial-mesenchymal transition and matrix metalloproteinase in C42 cell lines. CONCLUSION: The endostatin 33 peptide can exert antitumor effects by inhibiting the PI3K-Akt pathway, especially in tumors with a high expression of the integrin α6ß1 subtype, such as prostate cancer. Therefore, our study will provide a new method and theoretical basis for the treatment of prostate cancer.

[Research progress on markers related to angiogenesis and stemness characteristics in prostate cancer].

Recurrence, metastasis and drug resistance in patients with prostate cancer (PCa) are still important causes of high mortality in patients. Two important features of solid tumors, including PCa, are tumor angiogenesis and the emergence of cancer stemness. Studies have found that cancer stem cells can promote tumor angiogenesis, and the highly vascularized tumor microenvironment further supports the growth of these stem cells, forming a harmful cycle that leads to tumor recurrence, metastasis, and drug resistance. This article summarizes the regulatory factors of tumor angiogenesis and tumor stemness characteristics in PCa and deeply explores their role in promoting the development of PCa.

The predictive value of pyroptosis for the prognosis and immune escape of bladder cancer.

OBJECTIVE: To evaluate the predictive value of pyroptosis-related genes for the prognosis and immune escape of bladder cancer (BC). METHODS: Transcriptomic and single nucleotide polymorphisms (SNPs) data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) portal. Least absolute shrinkage and selection operator (LASSO) analysis was carried out to construct a prognostic risk model for BC patients. RESULTS: Based on the expression of 50 pyroptosis-related genes, BC patients from TCGA database were divided into two clusters, which showed significant differences in overall survival and disease specific survival. Furthermore, we intersected the differentially expressed genes between these two clusters with those identified from the GSE13507 dataset and finally identified eight survival related genes, which was used to construct a prognostic risk model by LASSO Cox regression. According to the model, the high-risk (HR) group was closely associated with poor survival or the advanced pathological stage of BC. In addition, the HR group was mainly enriched in cell cycle and immune-related pathways and had a higher TP53 mutation rate than the low-risk (LR) group. Furthermore, these two risk groups were significantly related to immune cell composition, immune cell infiltration, and immune response. Importantly, a higher expression of PD-1, PD-L1, and CTLA4 as well as higher immune exclusion scores were found in the HR group, suggesting a higher possibility of immune escape. CONCLUSION: Our studies revealed the key role of pyroptosis in predicting the prognosis, TP53 mutation, and immune escape of patients with BC.