Abstract
Pervasive hybridization and whole-genome duplications (WGDs) influenced genome evolution in several eukaryotic lineages. Although frequent and recurrent hybridizations may result in ...reticulate phylogenies, the evolutionary events underlying these reticulations, including detailed structure of the ancestral diploid and polyploid genomes, were only rarely reconstructed. Here, we elucidate the complex genomic history of a monophyletic clade from the mustard family (Brassicaceae), showing contentious relationships to the early-diverging clades of this model plant family. Genome evolution in the crucifer tribe Biscutelleae (∼60 species, 5 genera) was dominated by pervasive hybridizations and subsequent genome duplications. Diversification of an ancestral diploid genome into several divergent but crossable genomes was followed by hybridizations between these genomes. Whereas a single genus (Megadenia) remained diploid, the four remaining genera originated by allopolyploidy (Biscutella, Lunaria, Ricotia) or autopolyploidy (Heldreichia). The contentious relationships among the Biscutelleae genera, and between the tribe and other early diverged crucifer lineages, are best explained by close genomic relatedness among the recurrently hybridizing ancestral genomes. By using complementary cytogenomics and phylogenomics approaches, we demonstrate that the origin of a monophyletic plant clade can be more complex than a parsimonious assumption of a single WGD spurring postpolyploid cladogenesis. Instead, recurrent hybridization among the same and/or closely related parental genomes may phylogenetically interlink diploid and polyploid genomes despite the incidence of multiple independent WGDs. Our results provide new insights into evolution of early-diverging Brassicaceae lineages and elucidate challenges in resolving the contentious relationships within and between land plant lineages with pervasive hybridization and WGDs.
We aimed to identify novel markers for aggressive prostate cancer in a STAT3-low proteomics-derived dataset of mitochondrial proteins by immunohistochemical analysis and correlation with ...transcriptomic data and biochemical recurrence in a STAT3 independent PCa cohort. Formalin-fixed paraffin-embedded tissue (FFPE) sample selection for proteomic analysis and tissue-microarray (TMA) generation was conducted from a cohort of PCa patients. Retrospective data analysis was performed with the same cohort. 153 proteins differentially expressed between STAT3-low and STAT3-high samples were identified. Out of these, 46 proteins were associated with mitochondrial processes including oxidative phosphorylation (OXPHOS), and 45 proteins were upregulated, including NDUFS1/ATP5O. In a STAT3 independent PCa cohort, high expression of NDUFS1/ATP5O was confirmed by immunocytochemistry (IHC) and was significantly associated with earlier biochemical recurrence (BCR). mRNA expression levels for these two genes were significantly higher in intra-epithelial neoplasia and in PCa compared to benign prostate glands. NDUFS1/ATP5O levels are increased both at the mRNA and protein level in aggressive PCa. Our results provide evidence that NDUFS1/ATP5O could be used to identify high-risk PCa patients.
Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one ...of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.
Background
Catheter ablation (CA) of atrial fibrillation (AF) is indicated in patients with recurrent and symptomatic AF episodes. Despite the strict inclusion/exclusion criteria, AF recurrence after ...CA remains high. Identification of a novel biomarker that would predict AF recurrence would help to stratify the patients. The aim of the study was to seek novel biomarkers among the plasmatic microRNAs (miRNAs, miRs).
Methods
A prospective monocentric study was conducted. A total of 49 consecutive AF patients indicated for CA were included. Blood sampling was performed prior to CA. RNA was isolated from plasma using commercial kits. In the exploration phase, small RNA sequencing was performed in ten AF patients (five with and five without AF recurrence) using Illumina instrument. In the validation phase, levels of selected miRNAs were determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in all participants.
Results
Altogether, 22 miRNAs were identified as altered between the groups by next-generation sequencing (using the DESeq2 algorithm). Using qRT-PCR, levels of the five most altered miRNAs (miR-190b/206/326/505-5p/1296-5p) were verified in the whole cohort. Plasma levels of hsa-miR-206 were significantly higher in patients with early (within 6 months) AF recurrence and showed an increase of risk recurrence,2.65 times by every increase in its level by 1 unit in the binary logistic regression.
Conclusion
We have identified a set of 22 plasmatic miRNAs that differ between the patients with and without AF recurrence after CA and confirmed hsa-miR-206 as a novel miRNA associated with early AF recurrence. Results shall be verified in a larger independent cohort.
Graphical Abstract
Graphical abstract summarizing the study design and results
The increased interest in assisted reproduction through in vitro fertilization (IVF) leads to an urgent need to identify biomarkers that reliably highly predict the success of pregnancy. Despite ...advances in diagnostics, treatment, and IVF approaches, the 30% success rate of IVF seems insurmountable. Idiopathic infertility does not have any explanation for IVF failure especially when a patient is treated with a healthy competitive embryo capable of implantation and development. Since appropriate intercellular communication is essential after embryo implantation, the emergence of the investigation of embryonic secretome including short non-coding RNA (sncRNA) molecules is crucial. That’s why biomarker identification, sncRNAs secreted during the IVF process into the blastocyst’s cultivation medium, by the implementation of artificial intelligence opens the door to a better understanding of the bidirectional communication between embryonic cells and the endometrium and so the success of the IVF. This study presents a set of promising new sncRNAs which are revealed to predictively distinguish a high-quality embryo, suitable for an embryo transfer in the IVF process, from a low-quality embryo with 86% accuracy. The identified exact combination of miRNAs/piRNAs as a non-invasively obtained biomarker for quality embryo determination, increasing the likelihood of implantation and the success of pregnancy after an embryo transfer.
Frequent truncation mutations of the histone lysine N-methyltransferase KMT2C have been detected by whole exome sequencing studies in various cancers, including malignancies of the prostate. However, ...the biological consequences of these alterations in prostate cancer have not yet been elucidated.
To investigate the functional effects of these mutations, we deleted the C-terminal catalytic core motif of Kmt2c specifically in mouse prostate epithelium. We analysed the effect of Kmt2c SET domain deletion in a Pten-deficient PCa mouse model in vivo and of truncation mutations of KMT2C in a large number of prostate cancer patients.
We show here for the first time that impaired KMT2C methyltransferase activity drives proliferation and PIN formation and, when combined with loss of the tumour suppressor PTEN, triggers loss of senescence, metastatic dissemination and dramatically reduces life expectancy. In Kmt2c-mutated tumours we show enrichment of proliferative MYC gene signatures and loss of expression of the cell cycle repressor p16
. In addition, we observe a striking reduction in disease-free survival of patients with KMT2C-mutated prostate cancer.
We identified truncating events of KMT2C as drivers of proliferation and PIN formation. Loss of PTEN and KMT2C in prostate cancer results in loss of senescence, metastatic dissemination and reduced life expectancy. Our data demonstrate the prognostic significance of KMT2C mutation status in prostate cancer patients. Inhibition of the MYC signalling axis may be a viable treatment option for patients with KMT2C truncations and therefore poor prognosis.
Purpose
Head and neck squamous cell carcinomas (HNSCCs) are a molecularly, histologically, and clinically heterogeneous set of tumors originating from the mucosal epithelium of the oral cavity, ...pharynx, and larynx. This heterogeneous nature of HNSCC is one of the main contributing factors to the lack of prognostic markers for personalized treatment. The aim of this study was to develop and identify multi-omics markers capable of improved risk stratification in this highly heterogeneous patient population.
Methods
In this retrospective study, we approached this issue by establishing radiogenomics markers to identify high-risk individuals in a cohort of 127 HNSCC patients. Hybrid
in vivo
imaging and whole-exome sequencing were employed to identify quantitative imaging markers as well as genetic markers on pathway-level prognostic in HNSCC. We investigated the deductibility of the prognostic genetic markers using anatomical and metabolic imaging using positron emission tomography combined with computed tomography. Moreover, we used statistical and machine learning modeling to investigate whether a multi-omics approach can be used to derive prognostic markers for HNSCC.
Results
Radiogenomic analysis revealed a significant influence of genetic pathway alterations on imaging markers. A highly prognostic radiogenomic marker based on cellular senescence was identified. Furthermore, the radiogenomic biomarkers designed in this study vastly outperformed the prognostic value of markers derived from genetics and imaging alone.
Conclusion
Using the identified markers, a clinically meaningful stratification of patients is possible, guiding the identification of high-risk patients and potentially aiding in the development of effective targeted therapies.
Graphical abstract
Central nervous system (CNS) malignancies include primary tumors that originate within the CNS as well as secondary tumors that develop as a result of metastatic spread. Circulating microRNAs ...(miRNAs) were found in almost all human body fluids including cerebrospinal fluid (CSF), and they seem to be highly stable and resistant to even extreme conditions. The overall aim of our study was to identify specific CSF miRNA patterns that could differentiate among brain tumors. These new biomarkers could potentially aid borderline or uncertain imaging results onto diagnosis of CNS malignancies, avoiding most invasive procedures such as stereotactic biopsy or biopsy. In total, 175 brain tumor patients (glioblastomas, low-grade gliomas, meningiomas and brain metastases), and 40 non-tumor patients with hydrocephalus as controls were included in this prospective monocentric study. Firstly, we performed high-throughput miRNA profiling (Illumina small RNA sequencing) on a discovery cohort of 70 patients and 19 controls and identified specific miRNA signatures of all brain tumor types tested. Secondly, validation of 9 candidate miRNAs was carried out on an independent cohort of 105 brain tumor patients and 21 controls using qRT-PCR. Based on the successful results of validation and various combination patterns of only 5 miRNA levels (miR-30e, miR-140, let-7b, mR-10a and miR-21-3p) we proposed CSF-diagnostic scores for each tumor type which enabled to distinguish them from healthy donors and other tumor types tested. In addition to this primary diagnostic tool, we described the prognostic potential of the combination of miR-10b and miR-196b levels in CSF of glioblastoma patients. In conclusion, we performed the largest study so far focused on CSF miRNA profiling in patients with brain tumors, and we believe that this new class of biomarkers have a strong potential as a diagnostic and prognostic tool in these patients.
Growing evidence suggests that miR-215-5p is a tumor suppressor in colorectal cancer (CRC); however, its role in metastasis remains unclear. This study evaluates the effects of miR-215 overexpression ...on the metastatic potential of CRC. Methods: CRC cell lines were stably transfected with miR-215-5p and used for in vitro and in vivo functional analyses. Next-generation sequencing and RT-qPCR were performed to study changes on the mRNA level.
: Overexpression of miR-215-5p significantly reduced the clonogenic potential, migration, and invasiveness of CRC cells in vitro and tumor weight and volume, and liver metastasis in vivo. Transcriptome analysis revealed mRNAs regulated by miR-215-5p and RT-qPCR confirmed results for seven selected genes. Significantly elevated levels of CTNNBIP1 were also observed in patients' primary tumors and liver metastases compared to adjacent tissues, indicating its direct regulation by miR-215-5p. Gene Ontology and KEGG pathway analysis identified cellular processes and pathways associated with miR-215-5p deregulation.
: MiR-215-5p suppresses the metastatic potential of CRC cells through the regulation of divergent molecular pathways, including extracellular-matrix-receptor interaction and focal adhesion. Although the specific targets of miR-215-5p contributing to the formation of distant metastases must be further elucidated, this miRNA could serve as a promising target for CRC patients' future therapeutic strategies.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and aggressive cancers with a less than 6% five-year survival rate. Circulating microRNAs (miRNAs) are emerging as a useful tool for ...non-invasive diagnosis and prognosis estimation in the various cancer types, including PDAC. Our study aimed to evaluate whether miRNAs in the pre-operative blood plasma specimen have the potential to predict the prognosis of PDAC patients. In total, 112 PDAC patients planned for surgical resection were enrolled in our prospective study. To identify prognostic miRNAs, we used small RNA sequencing in 24 plasma samples of PDAC patients with poor prognosis (overall survival (OS) < 16 months) and 24 plasma samples of PDAC patients with a good prognosis (OS > 20 months). qPCR validation of selected miRNA candidates was performed in the independent cohort of PDAC patients (n = 64). In the discovery phase of the study, we identified 44 miRNAs with significantly different levels in the plasma samples of the group of good and poor prognosis patients. Among these miRNAs, 23 showed lower levels, and 21 showed higher levels in plasma specimens from PDAC patients with poor prognosis. Eleven miRNAs were selected for the validation, but only miR-99a-5p and miR-365a-3p were confirmed to have significantly lower levels and miR-200c-3p higher levels in plasma samples of poor prognosis cases. Using the combination of these 3-miRNA levels, we were able to identify the patients with poor prognosis with sensitivity 85% and specificity 80% (Area Under the Curve = 0.890). Overall, 3-miRNA prognostic score associated with OS was identified in the pre-operative blood plasma samples of PDAC patients undergoing surgical resection. Following further independent validations, the detection of these miRNA may enable identification of PDAC patients who have no survival benefit from the surgical treatment, which is associated with the high morbidity rates.
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