Unraveling links between aging, circadian rhythm and cancer: Insights from evidence-based analysis.

Aging and circadian rhythms have been connected for decades, but their molecular interaction has remained unknown, especially for cancers. In this situation, we summarized the current research actuality and problems in this field using the bibliometric analysis. Publications in the PubMed and Web of Science databases were retrieved. Overall, there is a rising trend in the publication volume regarding aging and circadian rhythms in the field of cancer. Researchers from USA, Germany, Italy, China and England have greater studies than others. Top three publication institutions are University of California System, UDICE-French Research Universities and University of Texas System. Current research hotspots include oxidative stress, breast cancer, melatonin, cell cycle, calorie restriction, prostate cancer and NF-KB. In conclusion, results generated by bibliometric analysis indicate that many approaches involve in the complex interactions between aging and circadian rhythm in cancer. These established and emerging research directions guide our exploration of the regulatory mechanisms of aging and circadian rhythms in cancer and provide a reference for developing new research avenues.

Relationship between clonal evolution and drug resistance in bladder cancer: A genomic research review.

Bladder cancer stands as a prevalent global malignancy, exhibiting notable sex-based variations in both incidence and prognosis. Despite substantial strides in therapeutic approaches, the formidable challenge of drug resistance persists. The genomic landscape of bladder cancer, characterized by intricate clonal heterogeneity, emerges as a pivotal determinant in fostering this resistance. Clonal evolution, encapsulating the dynamic transformations within subpopulations of tumor cells over time, is implicated in the emergence of drug-resistant traits. Within this review, we illuminate contemporary insights into the role of clonal evolution in bladder cancer, elucidating its influence as a driver in tumor initiation, disease progression, and the formidable obstacle of therapy resistance.

Interactions between oxidative stress and senescence in cancer: Mechanisms, therapeutic implications, and future perspectives.

BACKGROUND: Recently, numerous studies have reported the interaction between senescence and oxidative stress in cancer. However, there is a lack of a comprehensive understanding of the precise mechanisms involved. AIM: Therefore, our review aims to summarize the current findings and elucidate by presenting specific mechanisms that encompass functional pathways, target genes, and related aspects. METHODS: Pubmed and Web of Science databases were retrieved to search studies about the interaction between senescence and oxidative stress in cancer. Relevant publications in the reference list of enrolled studies were also checked. RESULTS: In carcinogenesis, oxidative stress-induced cellular senescence acts as a barrier against the transformation of stimulated cells into cancer cells. However, the senescence-associated secretory phenotype (SASP) is positively linked to tumorigenesis. In the cancer progression stage, targeting specific genes or pathways that promote oxidative stress-induced cellular senescence can suppress cancer progression. In terms of treatment, many current clinical therapies combine with novel drugs to overcome resistance and reduce side effects by attenuating oxidative stress-induced senescence. Notably, emerging drugs control cancer development by enhancing oxidative stress-induced senescence. These studies highlight the complacted effects of the interplay between oxidative stress and senescence at different cancer stages and among distinct cell populations. Future research should focus on characterizing the roles of distinct senescent cell types in various tumor stages and identifying the specific components of SASP. CONCLUDSION: We've summarized the mechanisms of senescence and oxidative stress in cancer and provided illustrative figures to guide future research in this area.

Exploring the crosstalk of immune cells: The impact of dysregulated RUNX family genes in kidney renal clear cell carcinoma.

Background: Abnormally expressed Runt-associated transcription factor (RUNX) family has been reported in multiple tumors. Nevertheless, the immunological role of RUNX family in kidney renal clear cell carcinoma (KIRC) remains unknown. Methods: We studied the RNA-seq data regarding tumor and healthy subjects from several public databases in detail for evaluating the prognostic and immunological functions owned by three RUNX genes in cancer patients. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical (IHC) staining served for detecting their expressions in tumor and normal samples. Results: We observed that KIRC patients presented high expressions of RUNX1, RUNX2, and RUNX3. The expressions of three genes were validated by qRT-PCR, which was same as bioinformatical results. Prognostic analysis indicated that the overexpression of RUNX1 and RUNX2 negatively affects the outcomes in patients with KIRC. Related functional predictions indicated that the RUNXs and co-expression genes were significantly related to the immune response pathway. Moreover, three RUNX members were associated with immune infiltration cells and their related gene markers. The expression of RUNX family in several immune cells is positively or negatively correlated, and its dysregulation is obviously associated with the differential distribution of immune cells. RUNX family genes were abnormally expressed in KIRC patients, and were closely related to the crosstalk of immune cells. Conclusions: Our findings may help to understand the pathogenesis and immunologic roles of the RUNX family in KIRC patients from new perspectives.

Prognostic significance and immune landscape of a cell cycle progression-related risk model in bladder cancer.

BACKGROUND: A greater emphasis has been placed on the part of cell cycle progression (CCP) in cancer in recent years. Nevertheless, the precise connection between CCP-related genes and bladder cancer (BCa) has remained elusive. This study endeavors to establish and validate a reliable risk model incorporating CCP-related factors, aiming to predict both the prognosis and immune landscape of BCa. METHODS: Clinical information and RNA sequencing data were collected from the GEO and TCGA databases. Univariate and multivariate Cox regression analyses were conducted to construct a risk model associated with CCP. The performance of the model was assessed using ROC and Kaplan-Meier survival analyses. Functional enrichment analysis was employed to investigate potential cellular functions and signaling pathways. The immune landscape was characterized using CIBERSORT algorithms. Integration of the risk model with various clinical variables led to the development of a nomogram. RESULTS: To build the risk model, three CCP-related genes (RAD54B, KPNA2, and TPM1) were carefully chosen. ROC and Kaplan-Meier survival analysis confirm that our model has good performance. About immunological infiltration, the high-risk group showed decreased levels of regulatory T cells and dendritic cells coupled with increased levels of activated CD4 + memory T cells, M2 macrophages, and neutrophils. Furthermore, the nomogram showed impressive predictive power for OS at 1, 3, and 5 years. CONCLUSION: This study provides new insights into the association between the CCP-related risk model and the prognosis of BCa, as well as its impact on the immune landscape.

Chronobiology of the Tumor Microenvironment: Implications for Therapeutic Strategies and Circadian-Based Interventions.

Numerous research works have emphasized the critical role that circadian rhythm plays in the tumor microenvironment (TME). The goal of clarifying chrono-pharmacological strategies for improving cancer treatment in clinical settings is a continuous endeavor. Consequently, to enhance the use of time-based pharmaceutical therapies in oncology, combining existing knowledge on circadian rhythms' roles within the TME is essential. This perspective elucidates the functions of circadian rhythms in the TME across various stages of cancer development, progression, and metastasis. Specifically, aging, angiogenesis, and inflammation are implicated in modulating circadian rhythm within the TME. Furthermore, circadian rhythm exerts a profound influence on current cancer treatments and thereby generates chronotheray to manage tumors. From a TME perspective, circadian rhythm offers promising opportunities for cancer prevention and treatment; nevertheless, further study is needed to address unanswered scientific problems.

An endothelial-related prognostic index for bladder cancer patients.

BACKGROUND: Within the tumor microenvironment, endothelial cells hold substantial sway over bladder cancer (BC) prognosis. Herein, we aim to elucidate the impact of endothelial cells on BC patient outcomes by employing an integration of single-cell and bulk RNA sequencing data. METHODS: All data utilized in this study were procured from online databases. R version 3.6.3 and relevant packages were harnessed for the development and validation of an endothelial-associated prognostic index (EPI). RESULTS: EPI was formulated, incorporating six genes (CYTL1, FAM43A, GSN, HSPG2, RBP7, and SLC2A3). EPI demonstrated significant prognostic value in both The Cancer Genome Atlas (TCGA) and externally validated dataset. Functional results revealed a profound association between EPI and endothelial cell functionality, as well as immune-related processes. Our findings suggest that patients with low-risk EPI scores are more likely to respond positively to immunotherapy, as indicated by immune checkpoint activity, immune infiltration, tumor mutational burden, stemness index, TIDE, and IMvigor210 analyses. Conversely, individuals with high-risk EPI scores exhibited heightened sensitivity to cisplatin, docetaxel, and gemcitabine treatment regimens. CONCLUSION: We have effectively discerned pivotal genes from the endothelial cell perspective and constructed an EPI for BC patients, thereby offering promising prospects for precision medicine.

A pan-cancer analysis of the oncogenic and immunological roles of transglutaminase 1 (TGM1) in human cancer.

BACKGROUND: There is currently a limited number of studies on transglutaminase type 1 (TGM1) in tumors. The objective of this study is to perform a comprehensive analysis across various types of cancer to determine the prognostic significance of TGM1 in tumors and investigate its role in the immune environment. METHOD: Pan-cancer and mutational data were retrieved from the TCGA database and analyzed using R (version 3.6.4) and its associated software package. The expression difference and prognosis of TGM1 were examined, along with its correlation with tumor heterogeneity, stemness, mutation landscape, and RNA modification. Additionally, the relationship between TGM1 expression and tumor immunity was investigated using the TIMER method. RESULTS: TGM1 is expressed differently in various tumors and normal samples and is associated with the overall survival and progression-free time of KIRC, ACC, SKCM, LIHC, and STES. In LICH, we found a negative correlation between TGM1 expression and 6 indicators of tumor stemness. The mutation frequencies of BLCA, LIHC, and KIRC were 1.7%, 0.3%, and 0.3% respectively. In BLCA and BRCA, there was a significant correlation between TGM1 expression and the infiltration of CD4 + T cells, CD8 + T cells, neutrophils, and dendritic cells. CONCLUSION: TGM1 has the potential to serve as both a prognostic marker and a drug target.

Natural products and derivatives in renal, urothelial and testicular cancers: Targeting signaling pathways and therapeutic potential.

BACKGROUND: Natural products have demonstrated significant potential in cancer drug discovery, particularly in renal cancer (RCa), urothelial carcinoma (UC), and testicular cancer (TC). PURPOSE: This review aims to examine the effects of natural products on RCa, UC and TC. STUDY DESIGN: systematic review METHODS: PubMed and Web of Science databases were retrieved to search studies about the effects of natural products and derivatives on these cancers. Relevant publications in the reference list of enrolled studies were also checked. RESULTS: This review highlighted their diverse impacts on key aspects such as cell growth, apoptosis, metastasis, therapy response, and the immune microenvironment. Natural products not only hold promise for novel drug development but also enhance the efficacy of existing chemotherapy and immunotherapy. Importantly, we exert their effects through modulation of critical pathways and target genes, including the PI3K/AKT pathway, NF-κB pathway, STAT pathway and MAPK pathway, among others in RCa, UC, and TC. CONCLUSION: These mechanistic insights provide valuable guidance for researchers, facilitating the selection of promising natural products for cancer management and offering potential avenues for further gene regulation studies in the context of cancer treatment.

Identification of cell differentiation trajectory-related gene signature to reveal the prognostic significance and immune landscape in prostate cancer based on multiomics analysis.

Background: In the context of prostate cancer (PCa), the occurrence of biochemical recurrence (BCR) stands out as a pivotal factor significantly impacting prognosis, potentially leading to metastasis and mortality. However, the early detection of BCR poses a substantial challenge for PCa patients. There is an urgent need to pinpoint hub genes that can serve as predictive indicators for BCR in PCa patients. Methods: Our primary goal was to identify cell differentiation trajectory-related gene signature in PCa patients by pseudo-time trajectory analysis. We further explored the functional enrichment of overlapped marker genes and probed clinically relevant modules and BCR-related genes using Weighted Gene Co-expression Network Analysis (WGCNA) in PCa patients. Key genes predicting recurrence-free survival were meticulously identified through univariate and multivariate Cox regression analyses. Subsequently, these genes were utilized to construct a prognostic gene signature, the expression, predictive efficacy, putative functions, and immunological landscape of which were thoroughly validated. Additionally, we employed immunohistochemistry (IHC) and a western blotting assay to quantify the expression of PYCR1 in clinical samples. Results: Our single-cell RNA (scRNA) sequencing analysis unveiled three subgroups characterized by distinct differentiation trajectories, and the marker genes associated with these groups were extracted from PCa patients. These marker genes successfully classified the PCa sample into two molecular subtypes, demonstrating a robust correlation with clinical characteristics and recurrence-free survival. Through WGCNA and Lasso analysis, we identified four hub genes (KLK3, CD38, FASN, and PYCR1) to construct a risk profile of prognostic genes linked to BCR. Notably, the high-risk patient group exhibited elevated levels of B cell naive, Macrophage M0, and Macrophage M2 infiltration, while the low-risk group displayed higher levels of T cells CD4 memory activated and monocyte infiltration. Furthermore, IHC and western blotting assays confirmed the heightened expression of PYCR1 in PCa tissues. Conclusion: This study leveraged the differentiation trajectory and genetic variability of the microenvironment to uncover crucial prognostic genes associated with BCR in PCa patients. These findings present novel perspectives for tailoring treatment strategies for PCa patients on an individualized basis.

Pan-cancer analysis of RNA 5-methylcytosine reader (ALYREF).

The increasing interest in RNA modifications has significantly advanced epigenomic and epitranscriptomic technologies. This study focuses on the immuno-oncological impact of ALYREF in human cancer through a pan-cancer analysis, enhancing understanding of this gene's role in cancer. We observed differential ALYREF expression between tumor and normal samples, correlating strongly with prognosis in various cancers, particularly kidney renal papillary cell carcinoma (KIRP) and liver hepatocellular carcinoma (LIHC). ALYREF showed a negative correlation with most tumor-infiltrating cells in lung squamous cell carcinoma (LUSC) and lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), while positive correlations were noted in LIHC, kidney chromophobe (KICH), mesothelioma (MESO), KIRP, pheochromocytoma and paraganglioma (PARD), and glioma (GBMLGG). Additionally, ALYREF expression was closely associated with tumor heterogeneity, stemness indices, and a high mutation rate in TP53 across these cancers. In conclusion, ALYREF may serve as an oncogenic biomarker in numerous cancers, meriting further research attention.

SKA3 targeted therapies in cancer precision surgery: bridging bench discoveries to clinical applications - review article.

Spindle and kinetochore-associated complex subunit 3 (SKA3) is a microtubule-binding subcomplex of the outer kinetochore, which plays a vital role in proper chromosomal segregation and cell division. Recently, SKA3 have been demonstrated its oncogenic role of tumorigenesis and development in cancers. In this review, the authors comprehensively deciphered SKA3 in human cancer from various aspects, including bibliometrics, pan-cancer analysis, and narrative summary. The authors also provided the top 10 predicted drugs targeting SKA3. The authors proposed that SKA3 was a potential target and brought new therapeutic opportunities for cancer patients.

Establishment of novel ferroptosis-related prognostic subtypes correlating with immune dysfunction in prostate cancer patients.

Background: We aimed to identify two new prognostic subtypes and create a predictive index for prostate cancer (PCa) patients based on ferroptosis database. Methods: The nonnegative matrix factorization approach was used to identify molecular subtypes. We investigate the differences between cluster 1 and cluster 2 in terms of clinical features, functional pathways, tumour stemness, tumour heterogeneity, gene mutation and tumour immune microenvironment score after identifying the two molecular subtypes. Colony formation assay and flow cytometry assay were performed. Results: The stratification of two clusters was closely connected to BCR-free survival using the nonnegative matrix factorization method, which was validated in the other three datasets. Furthermore, multivariate Cox regression analysis revealed that this classification was an independent risk factor for patients with PCa. Ribosome, aminoacyl tRNA production, oxidative phosphorylation, and Parkinson's disease-related pathways were shown to be highly enriched in cluster 1. In comparison to cluster 2, patients in cluster 1 exhibited significantly reduced CD4+ T cells, CD8+ T cells, neutrophils, dendritic cells and tumor immune microenvironment scores. Only HHLA2 was more abundant in cluster 1. Moreover, we found that P4HB downregulation could significantly inhibit the colony formation ability and contributed to cell apoptosis of C4-2B and DU145 cell lines. Conclusions: We discovered two new prognostic subtypes associated with immunological dysfunction in PCa patients based on ferroptosis-related genes and found that P4HB downregulation could significantly inhibit the colony formation ability and contributed to cell apoptosis of PCa cell lines.

Dysregulated ANLN reveals immune cell landscape and promotes carcinogenesis by regulating the PI3K/Akt/mTOR pathway in clear cell renal cell carcinoma.

Background: Abnormal anillin (ANLN) expression has been observed in multiple tumours and is closely associated with patient prognosis and clinical features. In this study, we systematically elucidated the clinical significance and biological roles of ANLN in patients with clear cell renal cell carcinoma (ccRCC). Methods: We obtained transcriptome and clinical data of patients with ccRCC from public databases. Multi-omics data and clinical samples were combined to analyse the correlation between ANLN expression and the clinical characteristics of patients with renal cancer. Additionally, the immune cell landscape of ANLN expression was evaluated using different immune algorithms in the tumour microenvironment. The tumour-promoting potential of ANLN was confirmed using in vitro assays, including CCK8 and Transwell assays. Results: Bioinformatics analysis showed that ANLN is over-expressed in patients with ccRCC, as validated by clinical samples. Publicly available clinical data suggest that high ANLN expression may indicate poor outcomes in patients with ccRCC. Moreover, biological function analysis revealed a marked enrichment of the cell cycle and PI3K-Akt pathways. The distribution of immune cells, particularly M2 macrophages, differed in patients with ccRCC. Furthermore, ANLN silencing inhibited the proliferation, migration, and invasion of renal cancer cells in vitro. After ANLN expression was knocked down in 786-O cells, the protein levels of important PI3K signalling pathway components, including PI3K, Akt, and mTOR, drastically decreased. Conclusions: These findings suggest that ANLN is dysregulated in renal cancer tissues and promotes tumour progression by activating the PI3K/Akt/mTOR signalling pathway.

Targeting Prolyl 4-Hydroxylase Subunit Beta (P4HB) in Cancer: New Roads to Travel.

Prolyl 4-hydroxylase subunit beta (P4HB) can catalyze the formation, breakage and rearrangement of disulfide bonds through two thioredoxin domains, which is important for the maintenance of oxidizing environment in endoplasmic reticulum. Recently, P4HB has been demonstrated its oncogenic role of tumorigenesis and development in cancers. Therefore, we comprehensively deciphered P4HB in human cancer from various aspects, including pan-cancer analysis and narrative summary. We also provided some possible interacted molecules and the top 10 predicted drugs targeting P4HB to contribute to future research. We proposed that P4HB was a potential target and brought new therapeutic opportunities for cancer patients.

Development and validation of a kidney renal clear cell carcinoma prognostic model relying on pyroptosis-related LncRNAs-A multidimensional comprehensive bioinformatics exploration.

BACKGROUND: Renal cell carcinoma (RCC) is a malignant tumour that may develop in the kidney. RCC is one of the most common kinds of tumours of this sort, and its most common pathological subtype is kidney renal clear cell carcinoma (KIRC). However, the aetiology and pathogenesis of RCC still need to be clarified. Exploring the internal mechanism of RCC contributes to diagnosing and treating this disease. Pyroptosis is a critical process related to cell death. Recent research has shown that pyroptosis is a critical factor in the initiation and progression of tumour formation. Thus far, researchers have progressively uncovered evidence of the regulatory influence that long noncoding RNAs (lncRNAs) have on pyroptosis. METHODS: In this work, a comprehensive bioinformatics approach was used to produce a predictive model according to pyroptosis-interrelated lncRNAs for the purpose of predicting the overall survival and molecular immune specialties of patients diagnosed with KIRC. This model was verified from multiple perspectives. RESULTS: First, we discovered pyroptosis-associated lncRNAs in KIRC patients using the TCGA database and a Sankey diagram. Then, we developed and validated a KIRC patient risk model based on pyroptosis-related lncRNAs. We demonstrated the grouping power of PLnRM through PCA and used PLnRM to assess the tumour immune microenvironment and response to immunotherapy. Immunological and molecular traits of diverse PLnRM subgroups were evaluated, as were clinical KIRC patient characteristics and predictive risk models. On this basis, a predictive nomogram was developed and analyzed, and novel PLnRM candidate compounds were identified. Finally, we investigated possible medications used by KIRC patients. CONCLUSIONS: The results demonstrate that the model generated has significant value for KIRC in clinical practice.

Three-port approach vs conventional laparoscopic radical cystectomy with orthotopic neobladder: a single-center retrospective study.

BACKGROUND: This study aimed to compare the clinical outcomes of patients who underwent three-port laparoscopic radical cystectomy (LRC) with orthotopic neobladder (ONB) and traditional five-port method. METHODS: From January 2017 to November 2020, 100 patients underwent LRC + ONB at a third-level grade A hospital. RESULTS: Our study included 55 patients who underwent three-port LRC and 45 patients who underwent the five-port method. There were no significant differences in perioperative data such as operation time (253.00 ± 43.89 vs. 259.07 ± 52.31 min, P = 0.530), estimated blood loss (EBL)(97.64 ± 59.44 vs. 106.67 ± 55.35 min, P = 0.438), day to flatus (2.25 ± 1.49 vs. 2.76 ± 1.77 days, P = 0.128), day to regular diet (7.07 ± 2.99 vs. 7.96 ± 3.32 days, P = 0.165), day to pelvic drain removal (9.58 ± 3.25 vs. 10.53 ± 3.80 days, P = 0.180), and hospital stay after operation (11.62 ± 3.72 vs. 11.84 ± 4.37 days, P = 0.780) between the two groups. The only significant difference was in the treatment cost (P = 0.035). Similarly, postoperative complications, quality of life, and tumor outcomes were not significantly different between the two groups (P > 0.05). CONCLUSIONS: The three-port method is safe and feasible for patients suitable for traditional five-port LRC with an orthotopic neobladder.

ORC6, a novel prognostic biomarker, correlates with T regulatory cell infiltration in prostate adenocarcinoma: a pan-cancer analysis.

BACKGROUND: The origin recognition complex (ORC), a six-subunit DNA-binding complex, participates in DNA replication in cancer cells. Specifically in prostate cancers, ORC participates the androgen receptor (AR) regulated genomic amplification and tumor proliferation throughout the entire cell cycle. Of note, ORC6, the smallest subunit of ORC, has been reported to be dysregulated in some types of cancers (including prostate cancer), however, its prognostic and immunological significances remain yet to be elucidated. METHODS: In the current study, we comprehensively investigated the potential prognostic and immunological role of ORC6 in 33 human tumors using multiple databases, such as TCGA, Genotype-Tissue Expression, CCLE, UCSC Xena, cBioPortal, Human Protein Atlas, GeneCards, STRING, MSigDB, TISIDB, and TIMER2 databases. RESULTS: ORC6 expression was significantly upregulated in 29 types of cancers compared to the corresponding normal adjacent tissues. ORC6 overexpression correlated with higher stage and worse prognostic outcomes in most cancer types analyzed. Additionally, ORC6 was involved in the cell cycle pathway, DNA replication, and mismatch repair pathways in most tumor types. A negative correlation was observed between the tumor endothelial cell infiltration and ORC6 expression in almost all tumors, whereas the immune infiltration of T regulatory cell was noted to be statistically positively correlated with the expression of ORC6 in prostate cancer tissues. Furthermore, in most tumor types, immunosuppression-related genes, especially TGFBR1 and PD-L1 (CD274), exhibited a specific correlation with the expression of ORC6. CONCLUSIONS: This comprehensive pan-cancer analysis revealed that ORC6 expression serves as a prognostic biomarker and that ORC6 is involved in the regulation of various biological pathways, the tumor microenvironment, and the immunosuppression status in several human cancers, suggesting its potential diagnostic, prognostic, and therapeutic value in pan-cancer, especially in prostate adenocarcinoma.