Cancer therapy-related cognitive impairment (CTRCI) is a debilitating neurotoxic condition adversely impacting cancer patients during and post-cancer treatments. The cancer treatments linked to CTRCI include chemotherapy, hormone therapy, targeted therapy, and immunotherapy. Despite CTRCI severely affecting the psychological and social, cognitive functions, and the overall quality of life of cancer survivors, no effective medications are available currently. Our prior studies have indicated hippocampal tyrosine phosphatase protein tyrosine phosphatase receptor type O (PTPRO) as a putative target for CTRCI. However, phosphatase is historically considered undruggable, and delivering drugs across the blood-brain barrier (BBB) is challenging. Here, we developed a novel delivery system using neuron-targeted extracellular vesicles (EVs) engineered with a neuron-specific peptide rabies virus glycoprotein (RVG) to transport a small activating RNA (saRNA) targeting Ptpro (RVG-EVs-saPtpro). We evaluated the stability, dynamic distribution, cytotoxicity, and brain specificity of RVG-EVs-saPtpro in cellular and animal models. A single intravenous injection of RVG-EVs-saPtpro resulted in sustained elevation of PTPRO in the brain for at least 28 days in CTRCI mice. More importantly, RVG-EVs-saPtpro significantly alleviated CTRCI symptoms by enhancing neuronal survival, neurogenesis, and synaptic plasticity. These findings highlight the potential of RVG-EVs-saPtpro system for targeted treatment of CTRCI.

Background:The optimal protocol for intermittent androgen deprivation therapy (IAD) in managing biochemical recurrence (BCR) and persistent prostate-specific antigen (PSA) levels after radical prostatectomy (RP) remains undefined. This study aimed to introduce a novel IAD protocol, conduct an initial assessment of the protocol's effectiveness in real-world settings, and develop a risk-based model to identify patients most likely to benefit from this approach. Methods:This study included 175 post-RP patients receiving IAD, with a median follow-up of 44.77 months [interquartile range (IQR), 31.87-69.50 months] post-androgen deprivation therapy (ADT). The IAD protocol used a PSA threshold of 0.2 ng/mL to define progression during the first intermittent phase. Key clinical and pathological parameters, including PSA kinetics and testosterone levels, were analyzed. Cox regression assessed the duration of the first intermittent phase, while logistic regression analyses identified factors associated with the efficacy of ADT in the second treatment phase. Nomograms were developed for clinical applications. Results:Cox regression analysis revealed that the duration of the first intermittent phase was significantly associated with castration-resistant prostate cancer (CRPC)-free survival. Pathological Gleason grade group 5 (GGG 5) was a risk factor for a shorter first intermittent phase, while PSA doubling time (PSADT) ≥3.32 months and testosterone doubling time (TDT) ≥5.03 months were protective factors. Logistic regression identified combined metformin use, testosterone recovery to normal levels during the first intermittent phase, and a PSA response rate ≥90% after the first luteinizing hormone-releasing hormone (LHRH) injection in the first treatment cycle as protective factors against a PSA response rate <90% during salvage ADT in the second treatment phase [area under the curve (AUC) =0.84]. Conclusions:The duration of the first intermittent phase was a significant predictor of CRPC-free survival. PSADT, TDT, and pathological GGG 5 were independent predictors of this duration. Furthermore, combined metformin use appeared to preserve ADT sensitivity in patients with PSA progression during the first intermittent phase.

The testosterone (TT)/androgen receptor axis plays a crucial role in the initiation and progression of prostate cancer (PCa). We aimed to investigate the predictive value of serum TT levels on metastatic PCa progression. A total of 219 patients with metastatic PCa were included in this study. Analyses performed included Pearson’s correlation test, Wilcoxon rank test, Chi-square test, Cox regression, and Kaplan-Meier analysis. High serum TT levels (> 405 ng/dL) before ADT treatment, deep testosterone reduction (DTR) within the first year of ADT, rapid DTR within 3 months of ADT, and sustained DTR in the first year of ADT are associated with longer CRPC progression-free time. Low serum TT levels before abiraterone treatment are a risk factor for early PSA progression. We constructed a nomogram model based on the DTR within the first year of ADT. Calibration curve and decision curve analyses suggest the model has a high predictive ability for 1-, 1.5-, and 2-year CRPC progression and well clinical utility. Serum TT levels before and during ADT, as well as before abiraterone treatment, can predict metastatic PCa progression. Monitoring serum TT levels throughout the entire course of treatment is crucial for patient follow-up and prognosis.

PURPOSE:Exosomal RNAs are emerging as cancer signatures, and saliva is a noninvasive biospecimen. Given the high mortality of patients with esophageal squamous cell carcinoma (ESCC) and limited early detection tools, we investigated a salivary exosome‑based Tri-signature for its diagnostic and prognostic potential. MATERIALS AND METHODS:The salivary exosome‑based signature (ie, a chimeric RNA seG-NchiRNA, a tRNA fragment GlyGCC-5, and a novel sRESE RNA) was quantified by qRT-PCR in a multicenter observational study across two ESCC-endemic regions. Model development and validation were performed in the training (n = 359) and validation (n = 225) cohorts using logistic regression, survival analyses, and Shapley Additive exPlanations-based feature interpretation. RESULTS:The Tri-signature showed excellent diagnostic accuracy (training cohort: AUC, 0.987; validation cohort: AUC, 0.964) and robust prognostic value (training cohort: overall survival [OS] hazard ratio [HR], 5.52, progression-free survival [PFS] HR, 4.46; validation cohort: OS HR, 4.76, PFS HR, 2.79). In the high Combined Risk Score for Prognosis (CRSP) subgroup, patients with relatively lower CRSP derived significant benefit from adjuvant therapy (training cohort: OS HR, 0.54, PFS HR, 0.47; validation cohort: OS HR, 0.38, PFS HR = 0.32), whereas no such benefit was observed in low Tri-signature patients. The Tri-signature exhibited strong early diagnostic performance, distinguishing early-stage ESCC without lymph node metastasis from healthy controls (training cohort: AUC = 0.975; validation cohort: AUC = 0.950). Patients with early-stage ESCC and high CRSP had significantly worse outcomes (training cohort: OS HR, 5.09, RFS HR, 3.80; validation cohort: OS HR, 8.79, RFS HR, 4.55). CONCLUSION:The salivary exosome-based tri-RNA signature showed robust multicenter reproducibility and strong diagnostic, prognostic, and treatment response-predictive performance, supporting its translational potential as a noninvasive biomarker panel for ESCC management.

Background:Accurate risk stratification of renal cell carcinoma (RCC) is critical for selecting the most appropriate treatment options. Existing prognostic systems, which incorporate various clinical and pathological parameters, have limitations in terms of accuracy. However, it remains unclear whether integrating molecular data with clinicopathological features can enhance the identification of high-risk tumors. The objective of this study was to establish a model to predict RCC recurrence by integrating molecular data with clinicopathological features and to evaluate circulating tumor DNA (ctDNA) as a non-invasive prognostic marker. Methods:Next-generation sequencing (NGS) was performed on 73 RCC patients, including 54 with clear-cell RCC (ccRCC). A prognostic model for disease-free survival (DFS) in non-metastatic ccRCC (NMCCRCC) was constructed and validated with two external datasets. The prognostic potential of ctDNA was assessed by its detection rates, mutation concordance with tumor tissue DNA, and association with clinical outcomes. Results:Frequently altered genes in ccRCC included VHL (72.22%), PBRM1 (25.93%), BAP1 (20.37%), TP53 (11.11%), KDM5C (11.11%), and SETD2 (16.67%). Advanced T stage, BAP1, and SETD2 mutations were independent risk factors for recurrence in NMCCRCC patients. The model achieved a concordance index (C-index) of 0.833 and demonstrated area under the receiver operating characteristic (ROC) curve (AUC) values ranging from 0.900 to 0.821 for 1- to 5-year outcomes. In external validation, the model also demonstrated reliable performance in the external validation cohorts, with AUC values ranging from 0.688 to 0.751 and 0.721 to 0.768, respectively. The mutation concordance between ctDNA and tumor tissue DNA was 61.54%, with higher ctDNA detection rates observed in patients with distant metastasis. Conclusions:Our prognostic model, factoring in T stage and genetic mutations in BAP1 and SETD2, effectively predicted recurrence in NMCCRCC patients. The potential of ctDNA as a non-invasive prognostic biomarker was underscored by its high detection rates and mutation concordance.

Given the well-established role of organic cation transporter 2 (OCT2) in cisplatin uptake to the inner ear cells, and the fact that cimetidine is an FDA-approved drug with well-established inhibitory activity against OCT2, we hypothesized that inhibiting OCT2-mediated cisplatin uptake with cimetidine could eliminate or alleviate cisplatin-mediated ototoxicity. Our preliminary data showed that cisplatin can reduce the viability of House Ear Institute-Organ of Corti 1 (HEI-OC1) cells in a dose-dependent manner, and cimetidine can effectively counteract this cisplatin-induced toxicity without affecting cisplatin's effect on cancer cells. Therefore, combined application of these drugs could ameliorate cisplatin ototoxicity with minimal impact on their anti-cancer effect.

PURPOSE:Upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) share histomorphological and therapeutic features but distinct epidemiologic and clinicopathologic characteristics. We examined alterations of chromatin regulatory genes in molecular subtypes, clonal relatedness, and T-cell receptor (TCR) diversity in UTUC and UCB. MATERIALS AND METHODS:Targeted next-generation sequencing or whole-exome DNA sequencing and TCR sequencing were conducted with 34 UTUC and 49 UCB specimens from 63 patients. Tumors were subtyped based on the expression of CK5 and GATA3. Results of tissue microarray of 78 muscle-invasive bladder cancer (MIBC) samples were used as prognostic factors of different subtypes of MIBC. RESULTS:Chromatin regulatory genes were frequently mutated in both UTUC and UCB. Rapid relapse and progression of non-MIBC are correlated with alterations of KMT2C and EP300. Frequency of alterations in chromatin regulatory genes is higher in UTUC patients with SBS22 and SBS2 signatures and lower in UCB patients with SBS2 and SBS6 signatures. GATA3 and CK5 double-positive patients with higher frequencies of SMARCA4, ARID1A, and EP300 mutations have better prognoses than patients with basal subtypes. Although UTUC and UCB in the same patient can be either clonally related or developed independently, mutated genes in chromatin pathway were enriched in the related clones. Compared to UTUC, UCB had more deleterious mutations in DNA damage repair (DDR) genes, higher levels of tumor mutation burden (TMB) and copy number variations (CNVs), as well as higher TCR clonality and lower TCR diversity. CONCLUSIONS:Since genetic alterations of the chromatin pathway genes are important in both UTUC and UCB, they could serve as potential biomarkers for predicting disease progression and therapeutic targets. Differences in mutation frequencies of DDR pathway, TMB, CNV, and TCR might be the contributing factors for the distinct responses to immune checkpoint inhibitor (ICI) between UTUC and UCB.

Aims Resistance to targeted therapy is one of the critical obstacles in cancer management. Resistance to trastuzumab frequently develops in the treatment for HER2+ cancers. The role of protein tyrosine phosphatases (PTPs) in trastuzumab resistance is not well understood. In this study, we aim to identify pivotal PTPs affecting trastuzumab resistance and devise a novel counteracting strategy. Methods Four public datasets were used to screen PTP candidates in relation to trastuzumab responsiveness in HER2+ breast cancer. Tyrosine kinase (TK) arrays were used to identify kinases that linked to protein tyrosine phosphate receptor type O (PTPRO)-enhanced trastuzumab sensitivity. The efficacy of small activating RNA (saRNA) in trastuzumab-conjugated silica nanoparticles was tested for PTPRO upregulation and resistance mitigation in cell models, a transgenic mouse model, and human cancer cell line-derived xenograft models. Results PTPRO was identified as the key PTP which influences trastuzumab responsiveness and patient survival. PTPRO de-phosphorated several TKs, including the previously overlooked substrate ERBB3, thereby inhibiting multiple oncogenic pathways associated with drug resistance. Notably, PTPRO, previously deemed “undruggable,” was effectively upregulated by saRNA-loaded nanoparticles. The upregulated PTPRO simultaneously inhibited ERBB3, ERBB2, and downstream SRC signaling pathways, thereby counteracting trastuzumab resistance. Conclusions Antibody-conjugated saRNA represents an innovative approach for targeting “undruggable” PTPs.

Metastasis is the primary culprit behind cancer-related fatalities in multiple cancer types, including prostate cancer. Despite great advances, the precise mechanisms underlying prostate cancer metastasis are far from complete. By using a transgenic mouse prostate cancer model (TRAMP) with and without Phf8 knockout, we have identified a crucial role of PHF8 in prostate cancer metastasis. By complexing with E2F1, PHF8 transcriptionally upregulates SNAI1 in a demethylation-dependent manner. The upregulated SNAI1 subsequently enhances epithelial-to-mesenchymal transition (EMT) and metastasis. Given the role of the abnormally activated PHF8/E2F1-SNAI1 axis in prostate cancer metastasis and poor prognosis, the levels of PHF8 or the activity of this axis could serve as biomarkers for prostate cancer metastasis. Moreover, targeting this axis could become a potential therapeutic strategy for prostate cancer treatment. (c) 2024 The Pathological Society of Great Britain and Ireland.

[This corrects the article DOI: 10.3389/fonc.2022.826778.].

Background: Cancer cells are intimately intertwined with tumor microenvironment (TME), fostering symbiotic relationship propelling cancer progression. However, the interaction between cancer cells and tumor-associated macrophages (TAMs) in urothelial bladder cancer (UBC) remains poorly understood. Methods: UBC cell lines (5637, T24 and SW780), along with a monocytic cell line (U937) capable of differentiating into macrophage, were used in a co-culture system for cell proliferation and stemness by MTT, sphere formation assays. VEZF1/SPOP/STAT3/CCL2/ IL-6 axis was determined by luciferase reporter, ChIP, RNA-seq, co-IP, in vitro ubiquitination, RT-qPCR array and ELISA analyses. Results: We observed the frequent downregulation of SPOP, an E3 ubiquitin ligase, was positively associated with tumor progression and TAM infiltration in UBC patients and T24 xenografts. Cancer cell-TAM crosstalk promoting tumor aggressiveness was demonstrated dependent on SPOP deficiency: 1) In UBC cells, STAT3 was identified as a novel substrate of SPOP, and SPOP deficiency increased STAT3 protein stability, elevated chemokine CCL2 secretion, which induced chemotaxis and M2 polarization of macrophage; 2) In co-cultured macrophages, IL-6 secretion enhanced UBC cell proliferation and stemness. Additionally, transcription factor VEZF1 could directly activate SPOP transcription, and its overexpression suppressed the above effects in UBC cells. Conclusions: A pivotal role of SPOP in maintaining UBC stemness and remodeling immunosuppressive TME was revealed. Both the intrinsic signaling (dysregulated VEZF1/SPOP/STAT3 axis) and the extrinsic cues from TME (CCL2-IL-6 axis based on macrophages) promoted UBC progression. Targeting this crosstalk may offer a promising therapeutic strategy for UBC patients with SPOP deficiency.

BACKGROUND/AIM:Protein arginine methyltransferase 5 (PRMT5), a member of the arginine methyltransferases, is an enzyme catalyzing the methylation of arginine residuals of histones and non-histone proteins to serve as one of many critical posttranslational modifications (PTMs). Phosphorylated P21-activated kinase 1 (p-PAK1), a serine/threonine protein kinase family member, is a cytoskeletal protein that plays a critical role in metastasis. We examined the expression of PRMT5 and PAK1 in esophageal squamous cell carcinoma (ESCC) and evaluated the correlation between PRMT5/p-PAK1 and both clinicopathological parameters and prognosis of ESCC patients.MATERIALS AND METHODS:106 tumor tissues collected from ESCC patients were assessed for PRMT5 and PAK1 expression using immunohistochemistry. Pearson's correlation and Kaplan-Meier analysis were used to estimate the correlation with the clinicopathological parameters and effect on patient survival. Western blot analysis was used to determine the PRMT5/p-PAK1 protein expression. The wound healing assay was performed to assess the effect of PRMT5 on the migration of ESCC cells.RESULTS:PRMT5 is upregulated in ESCC and the level of PRMT5 is correlated with metastasis and can serve as an independent prognostic factor for overall survival (OS). PRMT5 knockdown remarkably inhibited ESCC cell migration with concomitantly reduced levels of phosphorylated PAK1 (p-PAK1) but not total PAK1. Kaplan-Meier analysis showed that the OS of the subgroup of patients with PRMT5high/p-PAK1high is remarkably shorter than those of other subgroups (i.e., PRMT5high/p-PAK1low, PRMT5low/p-PAK1low and PRMT5low/p-PAK1high).CONCLUSION:PRMT5-PAK1 signaling participates in ESCC metastasis and can predict patients' outcomes.

Background: Gleason grade group (GG) upgrading is associated with increased biochemical recurrence (BCR), local progression, and decreased cancer-specific survival (CSS) in prostate cancer (PCa). However, descriptions of the risk factors of GG upgrading are scarce. The objective of this study was to identify risk factors and establish a model to predict GG upgrading. Methods: There were 361 patients with PCa who underwent radical prostatectomy between May 2011 and February 2022 enrolled. Univariate and multivariate logistic regression analyses were identified and nomogram further narrowed down the contributing factors in GG upgrading. The correction curve and decision curve were used to assess the model. Results: In the overall cohort, 141 patients had GG upgrading. But the subgroup cohort (GG <= 2) showed that 68 patients had GG upgrading. Multivariate logistic regression analysis showed that in the overall cohort, total prostate-specific antigen (tPSA) >= 10 ng/mL, systemic immune-inflammation index (SII) >379.50, neutrophil-lymphocyte ratio (NLR) >2.13, the GG of biopsy >= 3, the number of positive cores >3 were independent risk factors in GG upgrading. In the cohort of biopsy GG <= 2, multivariate logistic regression showed that the tPSA >= 10 ng/mL, SII >379.50 and the number of positive cores >3 were independent risk factors in GG upgrading. A novel model predicting GG upgrading was established based on these three parameters. The area under the curve (AUC) of the prediction model was 0.759. The C-index of the nomogram was 0.768. The calibration curves of the model showed good predictive performance. Clinical decision curves indicated clinical benefit in the interval of 20% to 90% of threshold probability and good clinical utility. Conclusions: Combined levels of tPSA, SII and the positive biopsy cores distinguish patients with high-risk GG upgrading in the group of biopsy GG <= 2 and are helpful in the decision of treatment plans.

BackgroundThe prevalence of lung cancer, a major type of malignant tumor, has been increasing over the years greatly impacting the health of Chinese residents. This study investigates the epidemiological characteristics of lung cancer among healthcare workers in the Hunan Province, as well as the occupational risk factors.MethodsThe data analyzed in this study was collected from the largest tumor hospital in the province: the Hunan Provincial Tumor Hospital affiliated with Central South University, School of Medicine. The data collected encompasses input collected between the years of 2004 to 2013 of the population of healthcare workers who were hospitalized for lung cancer treatments. Information was obtained through statistical analysis and telephonic interviews.ResultsThe prevalence of lung cancer among healthcare workers was much higher than that of the general population, as revealed by the difference between number of healthcare worker cases per 1,000 cases and number of healthcare workers per 1,000 population in the decade from 2004 to 2013. Analysis of the data further demonstrates that lung cancer prevalence among healthcare workers increases exponentially with age. Although smoking has been shown to increase the incidence of lung cancer to some extent, it is most likely not the main cause of lung cancer. In addition, it appears that the highest rates of lung cancer incidence occurs in mainly in primary general practitioners, medical radiologists, and nurses. The lack of awareness of personal safety measures may place healthcare workers at a greater risk of lung cancer.

Our understanding of the DNA damage responses of human cells to radiation has increased remarkably over the recent years although some notable signaling events remain to be discovered. Here we provide a brief account of the key molecular events of the responses to reflect the current understanding of the key underlying mechanisms involved.

Abstract Background Protein arginine methyltransferase 5 (PRMT5), a member of protein arginine methyltransferases, is an enzyme catalyzing the methylation of arginine residuals of histones and non-histone proteins to serve as one of many critical posttranslational modifications (PTMs). Phosphorylated P21-activated kinase 1 (p-PAK1), a member of serine/threonine protein kinases family, is a cytoskeletal protein playing a critical role in metastasis. This study aimed to explore the potential therapeutic value of PRMT5 and p-PAK1 in esophageal squamous cell carcinoma (ESCC). Methods and results PRMT5 expression in 106 primary human ESCC tissues with their adjacent non-cancerous tissues was detected by immunohistochemistry (IHC). Cell migration was detected by wound healing assays. Finally, we evaluated the clinical significance of PRMT5 combined with PAK1 and p-PAK1 by IHC staining. PRMT5 is upregulated in ESCC and the level of PRMT5 is not only correlated with metastasis but also can serve as an independent prognostic factor for overall survival (OS). PRMT5 knockdown remarkably inhibited ESCC cell migration with concomitantly reduced levels of phosphorylated PAK1 (p-PAK1). IHC assay of human ESCC tissue revealed that the levels of PRMT5 are highly correlated with that of p-PAK1. Kaplan-Meier analysis showed that the OS of patients with PRMT5high/p-PAK1high are significantly shorter than the others (PRMT5high/p-PAK1low, PRMT5low/p-PAK1low, and PRMT5low/p-PAK1high). Conclusions Targeting the PRMT5-p-PAK1 axis is of potential values in ESCC stratification and treatment.

Protein tyrosine phosphatase receptor-type O (PTPRO) is a membrane-bound tyrosine phosphatase. Notably, epigenetically silenced PTPRO due to promoter hypermethylation is frequently linked to malignancies. In this study, we used cellular and animal models, and patient samples to demonstrate that PTPRO can suppress the metastasis of esophageal squamous cell carcinoma (ESCC). Mechanistically, PTPRO can inhibit MET-mediated metastasis by dephosphorylating Y1234/1235 in the kinase activation loop of MET. Patients with PTPROlow/ p-METhigh had significantly poor prognosis, suggesting that PTPROlow/p-METhigh can serve as an independent prognostic factor for patients with ESCC.

EDITORIAL article Front. Cell Dev. Biol., 19 July 2023Sec. Signaling Volume 11 - 2023 | https://doi.org/10.3389/fcell.2023.1254961

Abstract Cancer stem-like cells (CSC) play pivotal roles in both chemoresistance and recurrence of many cancer types, including urothelial bladder cancer (UBC). In addition to intrinsic signaling pathways, extracellular cues from the tumor microenvironment (TME) are indispensable for the maintenance of CSCs. To better understand the mechanisms involved in TME-mediated generation and support of UBC CSCs, we focused on the role of cancer-associated fibroblasts (CAF) in this study. Overexpression of miR-146a-5p in CAFs promoted CAF-to-UBC cell interactions, cancer stemness, and chemoresistance to treatment with gemcitabine and cisplatin. Mechanistically, miR-146–5p upregulated SVEP1 in CAFs by enhancing the recruitment of transcriptional factor YY1. Meanwhile, by targeting the 3′UTR of mRNAs of ARID1A and PRKAA2 (also known as AMPKα2) in UBC cells, CAF-secreted miR-146a-5p promoted cancer stemness and chemoresistance. Downregulation of ARID1A resulted in the inhibition of SOCS1 and subsequent STAT3 activation, and downregulated PRKAA2 led to the activation of mTOR signaling. Elevated levels of exosomal miR-146a-5p in the serum of patients with UBC were correlated with both tumor stage and relapse risk. These findings altogether indicate that CAF-derived miR-146a-5p can promote stemness and enhance chemoresistance in UBC. Exosomal miR-146a-5p may be a biomarker of UBC recurrence and a potential therapeutic target. Significance: The tumor–stromal cross-talk mediated by cancer-associated fibroblast–derived miR-146a-5p fosters cancer stem cell niche formation and cancer stemness to drive chemoresistance in urothelial bladder cancer.