N6-methyladenosine modified lncRNAs signature for stratification of biochemical recurrence in prostate cancer.

Nonmutational epigenetic reprogramming is a crucial mechanism contributing to the pronounced heterogeneity of prostate cancer (PCa). Among these mechanisms, N6-methyladenosine (m6A)-modified long non-coding RNAs (lncRNAs) have emerged as key players. However, the precise roles of m6A-modified lncRNAs in PCa remain to be elucidated. In this study, methylated RNA immunoprecipitation sequencing (MeRIP-seq) was conducted on primary and metastatic PCa samples, leading to the identification of 21 lncRNAs exhibiting differential methylation and expression patterns. We further established a PCa prognostic signature, named m6A-modified lncRNA score (mLs), based on 9 differential methylated lncRNAs in 4 multicenter cohorts. The high mLs score cohort exhibited a tendency for earlier biochemical recurrence (BCR) compared to the low mLs score cohort. Remarkably, the predictive performance of the mLs score surpassed that of five previously reported lncRNA-based signatures. Functional enrichment analysis underscored a negative correlation between the mLs score and lipid metabolism. Additionally, through MeRIP-qPCR, we pinpointed a hub gene, MIR210HG, which was validated through in vitro and in vivo experiments. These findings collectively illuminate the landscape of m6A-methylated lncRNAs in PCa tissue via MeRIP-seq and harness this information to prognosticate PCa outcomes using the mLs score. Furthermore, our study validates, both experimentally and mechanistically, the facilitative role of MIR210HG in driving PCa progression.

Comparison of Brain Function Between Medication-Naïve ADHD with and without Comorbidity in Chinese Children Using Resting-State fNIRS.

Background: This study used functional near-infrared spectroscopy (fNIRS) to investigate brain activation patterns in children with attention deficit hyperactivity disorder (ADHD) with and without additional comorbidities to identify disease-related biomarkers by the neuroimaging that will facilitate to make a diagnosis decision. Methods: In this study, 165 medication-naive children aged 7 to 15 years were recruited and categorized into four groups: ADHD, ADHD with learning disabilities (ADHD&LD), ADHD with oppositional defiant disorder (ADHD&ODD), and healthy controls. A multichannel fNIRS system was used to monitor hemodynamic changes at rest state in the prefrontal and temporal lobes of the brain. The amplitude of a low-frequency fluctuation (ALFF) matrix was calculated by summation and averaging of the square root of the signal power spectrum. One-way analysis of variance was used to identify statistical differences between channels. Results: All ADHD children presented significantly higher ALFF values in different brain regions when compared with the healthy controls. Patients with ADHD&LD exhibited higher ALFF values in the medial prefrontal cortex (P Ch38 = .01, P Ch48 = .01), temporal cortex (P Ch22 = .04, P Ch41 = .002, P Ch51 = .001), and the left ventrolateral prefrontal cortex (P Ch39 = .0009, P Ch50 = .001), whereas ADHD&ODD children were not significantly different to those diagnosed with ADHD. Conclusions: ADHD with learning disabilities (LD) possessed a different pathogenesis from ADHD, manifested as lower functional brain activity in the medial prefrontal cortex, temporal cortex, and the left ventrolateral prefrontal cortex, while ADHD&ODD did not present significant changes compared with ADHD. ODD-related symptoms may be part of ADHD symptoms rather than being an independent disorder.

Aberrant Super-Enhancer Landscape in Enzalutamide-Resistant Prostate Cancer Cells.

Background: Castration-resistant prostate cancer (CRPC), which has developed resistance to next-generation antiandrogens, such as enzalutamide (Enz), is a lethal disease. Furthermore, transcriptional regulation by super enhancers (SEs) is crucial for the growth and spread of prostate cancer, as well as drug resistance. The functions of SEs, a significant class of noncoding DNA cis-regulatory elements, have been the subject of numerous recent studies in the field of cancer research. Materials and Methods: The goal of this research was to identify SEs associated with Enz resistance in C4-2B cells using chromatin immunoprecipitation sequencing and cleavage under targets and tagmentation (CUT&Tag). Using HOMER analysis to predict protein/gene-binding motifs, we identified master transcription factors (TFs) that may bind to SE sites. Using small interfering RNA, WST-1 assays, and qRT-PCR, we then confirmed the associations between TFs of SEs and Enz resistance. Results: A total of 999 SEs were screened from C4-2B EnzR cells in total. Incorporating analysis with RNA-seq data revealed 41 SEs to be strongly associated with the promotion of Enz resistance. In addition, we finally predicted that master TFs bind to SE-binding regions. Subsequently, we selected zinc finger protein 467 (ZFP467) and SMAD family member 3 to confirm the functional connections of master TFs with Enz resistance through SEs (ZNF467). Conclusions: In this study, SMAD3 and ZNF467 were found to be closely related to Enz-resistant CRPC. Our research uncovered a sizable group of SEs linked to Enz resistance in prostate cancer, dissected the mechanisms underlying SE Enz resistance, and shed light on potential clinical uses for SEs.

A prognostic signature consisting of N6-methyladenosine modified mRNAs demonstrates clinical potential in prediction of biochemical recurrence and guidance on precision therapy in prostate cancer.

Novel biomarkers are urgently needed to improve the prediction of clinical outcomes and guide personalized treatment for prostate cancer (PCa) patients. However, the role of N6-methyladenosine (m6A) modifications in PCa initiation and progression remains largely elusive. In our study, we collected benign Prostate Hyperplasia (BPH), localized PCa, and metastatic PCa samples from patients and performed methylated RNA immunoprecipitation sequencing (MeRIP-Seq) to map m6A-methylated mRNAs. Furthermore, we developed a prognostic signature based on 239 differentially methylated RNAs and the TCGA-PRAD dataset, which can be used to calculate an m6A-modified mRNA (MMM) score for a PCa patient, validated by independent multi-center cohorts. Our findings revealed that differential m6A modifications were positively correlated with altered expressions of mapped m6A-modified mRNAs. Higher MMM scores were associated with shorter times to biochemical recurrence (BCR) in PCa patients, and the MMM scoring system outperformed three well-established signatures in nine independent validation cohorts, as demonstrated by Kaplan-Meier survival analysis, C-index and ROC. Patients who did not respond to androgen receptor signaling inhibitor (ARSI) therapy and immunotherapy were found to have high MMM scores. Two hub genes, TLE1 and PFKL, were confirmed to have m6A sites through MeRIP-qPCR, and their knockdown promoted PCa cell invasion. Bioinformatics analysis of single-cell databases identified cell types with high transcript abundance levels of these two genes. In summary, our study is the first to perform transcriptome-wide m6A mapping in prostate tissues. The translational potential of a prognostic signature, comprising m6A-methylated mRNAs, in predicting clinical outcomes and therapy responses for PCa patients, is demonstrated.

COVID-19 inhibits spermatogenesis in the testes by inducing cellular senescence.

Introduction: COVID-19 (SARS-CoV-2) has been linked to organ damage in humans since its worldwide outbreak. It can also induce severe sperm damage, according to research conducted at numerous clinical institutions. However, the exact mechanism of damage is still unknown. Methods: In this study, testicular bulk-RNA-seq Data were downloaded from three COVID-19 patients and three uninfected controls from GEO to evaluate the effect of COVID-19 infection on spermatogenesis. Relative expression of each pathway and the correlation between genes or pathways were analyzed by bioinformatic methods. Results: By detecting the relative expression of each pathway and the correlation between genes or pathways, we found that COVID-19 could induce testicular cell senescence through MAPK signaling pathway. Cellular senescence was synergistic with MAPK pathway, which further affected the normal synthesis of cholesterol and androgen, inhibited the normal synthesis of lactate and pyruvate, and ultimately affected spermatogenesis. The medications targeting MAPK signaling pathway, especially MAPK1 and MAPK14, are expected to be effective therapeutic medications for reducing COVID-19 damage to spermatogenesis. Conclusion: These results give us a new understanding of how COVID-19 inhibits spermatogenesis and provide a possible solution to alleviate this damage.

Characterization of the m6A-Associated Tumor Immune Microenvironment in Prostate Cancer to Aid Immunotherapy.

The aim of this study was to elucidate the correlation between m6A modification and the tumor immune microenvironment (TIME) in prostate cancer (PCa) and to identify the m6A regulation patterns suitable for immune checkpoint inhibitors (ICIs) therapy. We evaluated the m6A regulation patterns of PCa based on 24 m6A regulators and correlated these modification patterns with TIME characteristics. Three distinct m6A regulation patterns were determined in PCa. The m6A regulators cluster with the best prognosis had significantly increased METTL14 and ZC3H13 expression and was characterized by low mutation rate, tumor heterogeneity, and neoantigens. The m6A regulators cluster with a poor prognosis had markedly high KIAA1429 and HNRNPA2B1 expression and was characterized by high intratumor heterogeneity and Th2 cell infiltration, while low Th17 cell infiltration and Macrophages M1/M2. The m6Ascore was constructed to quantify the m6A modification pattern of individual PCa patients based on m6A-associated genes. We found that the low-m6Ascore group with poor prognosis had a higher immunotherapeutic response rate than the high-m6Ascore group. The low-m6Ascore group was more likely to benefit from ICIs therapy. This study was determined that immunotherapy is more effective in low-m6Ascore PCa patients with poor prognosis.

Claspin Overexpression Promotes Tumor Progression and Predicts Poor Clinical Outcome in Prostate Cancer.

Background: Claspin (CLSPN) expression is acknowledged as a poor clinical prognostic factor in various tumors. However, the clinical characteristics and biological functions of CLSPN in prostate cancer (PCa) are still to be clarified. The aim of our study was to evaluate the association of CLSPN expression during PCa progression and its potential role in prognosis. Methods: We analyzed mRNA expression of the CLSPN gene with various clinicopathological features using the Cancer Genome Atlas and GSE21032 dataset. Immunohistochemical assays were used to detect the protein expression levels of CLSPN in human PCa tissue microarrays. Furthermore, we characterized the role of CLSPN in PCa progression through in vitro experiments using a CLSPN knockout. Results: Immunohistochemistry and public datasets revealed that CLSPN expression was increased in PCa with: a high Gleason score; advanced pathological stage; and positive surgical margins. In addition, upregulation of CLSPN was correlated with shorter biochemical recurrence (BCR)-free survival and overall survival. After we knocked-out CLSPN in DU145 and LNCaP cells, the in vitro phenotypic results showed that the ability of the knockouts to proliferate, migrate, and invade was attenuated; but that apoptosis was promoted. Conclusions: Our data support an oncogenic role for CLSPN in PCa progression. Moreover, increased CLSPN expression was identified as an independent factor in predicting bCR-free survival and disease-free survival in PCa patients.