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Background Recent characterization of stress-induced promoter-associated antisense lncRNAs (si-paancRNAs) suggests that they modulate transcription and cellular responses to oxidative, metabolic and genotoxic stress and may participate in critical cancer pathways. KDM7A divergent transcript (KDM7A-DT) is one of such stress-induced lncRNAs, whose expression is found deregulated in breast cancer (BC). The mechanisms leading to aberrant KDM7A-DT transcription, biogenesis, and downstream functions in BC types and subtypes have not been studied. Methods Cell lines, biochemical methods, and profiling experiments were used for KDM7A-DT overexpression and knockdown. Integration of experimental models, bioinformatics, and massive BRCA patient metadata analyses were performed to investigate the mechanisms and functions of KDM7A-DT. Results Stable KDM7A-DT overexpression in nonmalignant cells upregulates p53, CDKN1A, and γH2AX signaling, resulting in a prolonged cell growth retardation phenotype. Importantly, KDM7A-DT induction by acute oxidative stress in semi-transformed fibroblasts is p53-dependent. According to BC clinical metadata, KDM7A-DT gene alterations are preferentially associated with TP53 missense mutations and highly aggressive, invasive, basal-like (BL) subtype BC poor outcomes. Overall, KDM7A-DT affects DNA repair via the nonhomologous end-joining pathway, inhibits tumor suppressors involved in epithelial-to-mesenchymal transition, induces oncogenic metabolic changes and G2/M checkpoint arrest, and correlates with histology, aneuploidy, hypoxia and BC-associated proteins. Conclusion KDM7A-DT is a TP53 mutation–associated and copy number–dependent pro-oncogene si-paancRNA that contributes to genome instability and modulates BC initiation, progression, invasiveness and outcomes.

Background: Recent characterisation of stress-induced promoter-associated antisense lncRNAs (si-paancRNAs) suggests that these lncRNAs modulate transcription, cellular responses to oxidative, metabolic and genotoxic stress, and may be part of the pathways critical in cancer. KDM7A divergent transcribed (KDM7A-DT) is among the top overexpressed genes encoded by such lncRNAs. The mechanisms leading to aberrant KDM7A-DT transcription, transcript biogenesis, and downstream functions of KDM7A-DT isoforms in breast cancer (BC) types and subtypes have not been studied. Methods: Cell line models, biochemistry methods and microarrays experiments for overexpression and knockdown of KDM7A-DT were used. Next, integration of experimental models, bioinformatics, and massive BRCA patient metadata analyses were performed to investigate the mechanisms and functions of KDM7A-DT.Results: The stable KDM7A-DT overexpression in non-malignant cells upregulates p53, CDKN1A, and γH2AX signalling, resulting in a prolonged cell growth retardation phenotype and preferential depletion of epithelial-to-mesenchymal transition (EMT) pathway–associated tumour suppressor genes. Importantly, KDM7A-DT induction by acute oxidative stress of semi-transformed fibroblasts is p53-dependent. According to BC clinical metadata, KDM7A-DT is overexpressed in poor survival basal-like BC (BLBC) subtype. The KDM7A-DT overexpression is associated with the overexpression of the TP53-missense mutated gene and KDM7A-DT full-length copy number amplification. KDM7A-DT overexpression affects DNA repair via the non-homologous end-joining (NHEJ) pathway, inhibits tumor suppressors involved in EMT, induces pro-oncogenic metabolic changes, and correlates with histologic grades, aneuploidy, hypoxia, cancer-associated proteins, clinical and molecular markers.Conclusion: KDM7A-DT is the TP53 mutation–associated and copy number–dependent pro-oncogene si-paancRNAs that contributes to genome instability, initiation, progression, invasiveness, and BLBC outcomes.

Lactobacillus is a diverse genus that includes species of industrial and biomedical interest. Lactiplantibacillus pentosus, formerly known as Lactobacillus pentosus, is a recently reclassified species, that contains strains isolated from diverse environmental niches, ranging from fermented products to mammalian gut microbiota. Importantly, several L. pentosus strains present health-promoting properties, such as immunomodulatory and antiproliferative activities, and are regarded as potential probiotic strains. In this study, we present the draft genome sequence of the potential probiotic strain L. pentosus L33, originally isolated from fermented sausages. Comprehensive bioinformatic analysis and whole-genome annotation were performed to highlight the genetic loci involved in host-microbe interactions and the probiotic phenotype. Consequently, we found that this strain codes for bile salt hydrolases, adhesins and moonlighting proteins, and for Class IIb bacteriocin peptides lacking the GxxxG and GxxxG-like motifs, crucial for their inhibitory activity. Its adhesion ability was also validated in vitro, on human cancer cells. Furthermore, L. pentosus L33 contains an exopolysaccharide (EPS) biosynthesis cluster, and it does not carry transferable antibiotic resistance genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and CAZymes analyses showed that L. pentosus L33 possesses biosynthetic pathways for seven amino acids, while it can degrade a wide array of carbohydrates. In parallel, Clusters of Orthologous Groups (COGs) and KEGG profiles of L. pentosus L33 are similar to those of 26 L. pentosus strains, as well as of two well documented L. plantarum probiotic strains. Conclusively, L. pentosus L33 exhibits good probiotic potential, although further studies are needed to elucidate the extent of its biological properties.

Aldehyde dehydrogenase 1B1 (ALDH1B1) has been correlated with colorectal tumorigenesis and is considered a potential biomarker for colon cancer. Its expression has been associated with attenuation of the cell cycle in the G2/M phase and resistance to DNA damaging agents. The present study examines the role of ALDH1B1 in DNA damage response (DDR) in human colorectal adenocarcinoma. To this end, we utilized an isogenic HT29 cell line pair differing in the expression of ALDH1B1. The overexpression of ALDH1B1 was related to the translational upregulation of the total and phosphorylated (at ser15) p53. Comet and apoptosis assays revealed that the expression of ALDH1B1 protected HT29 cells from etoposide-induced DNA damage as well as apoptosis, and its overexpression led to increased constitutive phosphorylation of H2AX (at ser139). Furthermore, the expression profile of a variety of DNA damage signaling (DDS)-related genes was investigated by utilizing the RT2 profiler™ PCR array. Our results demonstrated that ALDH1B1 triggered a transcriptional activation of several DNA repair-related genes (MRE11A, PMS1, RAD18 and UNG). Finally, Spearman’s rank correlation coefficient analysis in 531 publicly available colorectal adenocarcinoma clinical samples indicated the statistically significant positive correlation between ALDH1B1 and DDR and repair genes or proteins, such as APEX1, FEN1, MPG, UNG, XRCC1, DDB1, XPC, CIB1, MRE11, PRKDC, RAD50, RAD21, TP53BP1, XRCC6 and H2AX. Collectively, our results suggest that ALDH1B1 may play an essential role in the DDR and DNA repair processes. Further studies on ALDH1B1 will elucidate its precise role in DDR.

Purpose Understanding the healthy brain aging process is key to uncover the mechanisms that lead to pathologic age-related neurodegeneration, including progression to Alzheimer disease (AD). We aimed to address the issue of pathologic heterogeneity that often underlies a clinical AD diagnosis. Methods We performed a deep whole-genome sequencing study aiming to identify variants that are associated specifically with healthy brain aging. Patients We examined samples from the community-based longitudinal Vienna Transdanubian Aging study comparing neuropathologically "healthy" aging in individuals above 80 years of age with pure AD patients of the same age. Results Focusing on potentially functional variants, we discovered a single variant (rs10149146) that lies on the autophagy-associated TECPR2 gene and was carried by 53.6% of the "healthy" brain elderly individuals (15/28). An additional nonsynonymous variant on the CINP gene (encoding a cell cycle checkpoint protein) was also found in 46% of healthy controls. Both variants are absent from all AD cases. TECPR2 and CINP appear to be "partner" genes in terms of regulation and their associated transcription factors have been previously implicated in AD and neurodegeneration. Conclusions Our study underlines the strength of neuropathology-driven definitions in genetic association studies and points to a potentially neuroprotective effect of key molecules of autophagy and cell cycle control.