Parkinson’s disease (PD) is the second most common neurodegenerative disorder. The number of cases of PD is expected to double by 2030, representing a heavy burden on the healthcare system. Clinical symptoms include the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain, which leads to striatal dopamine deficiency and, subsequently, causes motor dysfunction. Certainly, the study of the transcriptome of the various RNAs plays a crucial role in the study of this neurodegenerative disease. In fact, the aim of this study was to evaluate the transcriptome in a cohort of subjects with PD compared with a control cohort. In particular we focused on mRNAs and long non-coding RNAs (lncRNA), using the Illumina NextSeq 550 DX System. Differential expression analysis revealed 716 transcripts with padj ≤ 0.05; among these, 630 were mRNA (coding protein), lncRNA, and MT_tRNA. Ingenuity pathway analysis (IPA, Qiagen) was used to perform the functional and pathway analysis. The highest statistically significant pathways were: IL-15 signaling, B cell receptor signaling, systemic lupus erythematosus in B cell signaling pathway, communication between innate and adaptive immune cells, and melatonin degradation II. Our findings further reinforce the important roles of mitochondria and lncRNA in PD and, in parallel, further support the concept of inverse comorbidity between PD and some cancers.

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, representing the most aggressive breast cancer (BC) subtype with limited treatment options due to a lack of estrogen receptor alpha (ERα), progesterone receptor (PR), and Erb-B2 receptor tyrosine kinase 2 (HER2/neu) expression. Estrogen receptor beta (ERβ) is present in a fraction of TNBC patients, where its expression correlates with improved patient outcomes, supported by the fact that it exerts oncosuppressive effects in TNBC cell models in vitro. ERβ is involved in microRNA-mediated regulation of gene expression in hormone-responsive BC cells and could mediate its actions through small noncoding RNAs (sncRNAs) in TNBCs also. To verify this possibility, smallRNA sequencing was performed on three ERβ-expressing cell lines from different TNBC molecular subtypes. Several sncRNAs resulted modulated by ERβ, with a subset being regulated in a tumor subtype-independent manner. Interestingly, sncRNA profiling of 12 ERβ+and 32 ERβ− primary TNBC biopsies identified 7 microRNAs, 1 PIWI-interacting RNA (piRNA), and 1 transfer RNA (tRNA) differentially expressed in ERβ+ compared to ERβ− tumors and cell lines. Among them, miR-181a-5p was found to be overexpressed in ERβ+ tumors and predicted target key components of the cholesterol biosynthesis pathway previously found to be inhibited by ERβ in TNBC cells.

Immunogenic cell death (ICD) in cancer represents a functionally unique therapeutic response that can induce tumor-targeting immune responses. ICD is characterized by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which confer adjuvanticity to dying cancer cells. The spatiotemporally defined emission of DAMPs during ICD has been well described, whereas the epigenetic mechanisms that regulate ICD hallmarks have not yet been deeply elucidated. Here, we aimed to examine the involvement of miRNAs and their putative targets using well-established in vitro models of ICD. To this end, B cell lymphoma (Mino) and breast cancer (MDA-MB-231) cell lines were exposed to two different ICD inducers, the combination of retinoic acid (RA) and interferon-alpha (IFN-α) and doxorubicin, and to non ICD inducers such as gamma irradiation. Then, miRNA and mRNA profiles were studied by next generation sequencing. Co-expression analysis identified 16 miRNAs differentially modulated in cells undergoing ICD. Integrated miRNA-mRNA functional analysis revealed candidate miRNAs, mRNAs, and modulated pathways associated with Immune System Process (GO Term). Specifically, ICD induced a distinctive transcriptional signature hallmarked by regulation of antigen presentation, a crucial step for proper activation of immune system antitumor response. Interestingly, the major histocompatibility complex class I (MHC-I) pathway was upregulated whereas class II (MHC-II) was downregulated. Analysis of MHC-II associated transcripts and HLA-DR surface expression confirmed inhibition of this pathway by ICD on lymphoma cells. miR-4284 and miR-212-3p were the strongest miRNAs upregulated by ICD associated with this event and miR-212-3p overexpression was able to downregulate surface expression of HLA-DR. It is well known that MHC-II expression on tumor cells facilitates the recruitment of CD4+ T cells. However, the interaction between tumor MHC-II and inhibitory coreceptors on tumor-associated lymphocytes could provide an immunosuppressive signal that directly represses effector cytotoxic activity. In this context, MHC-II downregulation by ICD could enhance antitumor immunity. Overall, we found that the miRNA profile was significantly altered during ICD. Several miRNAs are predicted to be involved in the regulation of MHC-I and II pathways, whose implication in ICD is demonstrated herein for the first time, which could eventually modulate tumor recognition and attack by the immune system.

Background: Familial prostate cancer (PCa) accounts for nearly 20% of all PCa cases and is associated with increased genetic susceptibility and earlier disease onset. However, early detection and risk stratification in genetically predisposed individuals remain challenging. Circulating cell-free DNA (cfDNA) provides a minimally invasive source of tumor-derived genomic and epigenomic information. Integrating multi-omic cfDNA analyses may enhance the discovery of biomarkers relevant to familial PCa biology. Methods: We conducted a pilot feasibility study employing whole-genome, strand-specific sequencing of cfDNA from eight patients with familial PCa. A unified analytical pipeline was used to jointly profile genomic alterations and epigenomic features. Variant calling, methylation mapping, and allele-specific methylation (ASM) analysis were performed to identify somatic mutations, characterize epigenetic dysregulation, and explore potential interactions between genetic and epigenetic mechanisms. Results: Sequencing revealed 18,878 genetic variants, including 2276 potentially pathogenic alterations. We identified 26 recurrent high-impact mutations, such as stop-gain and start-loss variants, in genes including MUC4, MCM9, and SKA3. Epigenomic profiling demonstrated widespread gene-specific hypermethylation, consistent with transcriptional repression in these loci. ASM events were detected in TTC22, TEX51, WDR89, LAIR2, and SKA3, suggesting coordinated interactions between somatic variation and epigenetic regulation in familial PCa. Conclusions: This proof-of-concept study highlights the feasibility and potential of integrating whole-genome and epigenome profiling of cfDNA to decode the molecular architecture of familial prostate cancer. By jointly capturing genomic alterations and epigenetic signatures, including allele-specific methylation, this multi-omic liquid biopsy approach supports a high-resolution exploration of biologically relevant molecular features. Moreover, this integrated profiling strategy provides a minimally invasive and clinically scalable tool that may substantially improve risk assessment. These findings offer a promising foundation for future validation studies in larger cohorts, with the aim of advancing multi-omic cfDNA analysis as a next-generation technology in the field of precision oncologic epigenetics.