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Wild species of crops serve as a valuable germplasm resource for breeding of modern cultivars. Rice (Oryza sativa L.) is a vital global staple food. However, research on genome evolution and diversity of wild rice species remains limited. Here, we present nearly complete genomes of 13 representative wild rice species. By integrating with four previously published genomes for pangenome analysis, a total of 101,723 gene families are identified across the genus, including 9834 (9.67%) core gene families. Additionally, 63,881 gene families absent in cultivated rice species but present in wild rice species are discovered. Extensive structural rearrangements, sub-genomes exchanges, widespread allelic variations, and regulatory sequence variations are observed in wild rice species. Interestingly, expanded but less diverse disease resistance genes in the genomes of cultivated rice, likely due to the loss of some resistance genes and the fixing and amplification of genes encoding resistance genes to specific diseases during domestication and artificial selection. This study not only reveals natural variations valuable for gene-level studies and breeding selection but also enhances our understanding on rice evolution and domestication. The Oryza genus comprise two cultivated rice species and 20 extant wild species. Here the authors assemble genomes of 13 representative wild rice species, construct a super pangenome by integrating them with four previously reported genomes in the genus, and reveal the genome evolution and diversity within the genus. [ABSTRACT FROM AUTHOR]

Aneuploidy, a deviation of the chromosome number from euploidy, is one of the hallmarks of cancer. High levels of aneuploidy are generally correlated with metastasis and poor prognosis in cancer patients. However, the causality of aneuploidy in cancer metastasis remains to be explored. Here we demonstrate that teratomas derived from aneuploid murine embryonic stem cells (ESCs), but not from isogenic diploid ESCs, disseminated to multiple organs, for which no additional copy number variations were required. Notably, no cancer driver gene mutations were identified in any metastases. Aneuploid circulating teratoma cells were successfully isolated from peripheral blood and showed high capacities for migration and organ colonization. Single-cell RNA sequencing of aneuploid primary teratomas and metastases identified a unique cell population with high stemness that was absent in diploid ESCs-derived teratomas. Further investigation revealed that aneuploid cells displayed decreased proteasome activity and overactivated endoplasmic reticulum (ER) stress during differentiation, thereby restricting the degradation of proteins produced from extra chromosomes in the ESC state and causing differentiation deficiencies. Noticeably, both proteasome activator Oleuropein and ER stress inhibitor 4-PBA can effectively inhibit aneuploid teratoma metastasis. Aneuploidy is associated with cancer metastasis, but the causal relationship between them is unclear. Here the authors show that aneuploid murine embryonic stem cells lead to teratomas that can spread to multiple organs without requiring additional driver gene mutations and identify unique cell populations with high stemness in aneuploid teratomas. [ABSTRACT FROM AUTHOR]

Prostate-Specific Antigen (PSA) based screening of prostate cancer (PCa) needs refinement. The aim of this study was the identification of urinary biomarkers to predict the Prostate Imaging—Reporting and Data System (PI-RADS) score and the presence of PCa prior to prostate biopsy. Urine samples from patients with elevated PSA were collected prior to prostate biopsy (cohort = 99). The re-analysis of mass spectrometry data from 45 samples was performed to identify urinary biomarkers to predict the PI-RADS score and the presence of PCa. The most promising candidates, i.e. SPARC-like protein 1 (SPARCL1), Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), Alpha-1-microglobulin/bikunin precursor (AMBP), keratin 13 (KRT13), cluster of differentiation 99 (CD99) and hornerin (HRNR), were quantified by ELISA and validated in an independent cohort of 54 samples. Various biomarker combinations showed the ability to predict the PI-RADS score (AUC = 0.79). In combination with the PI-RADS score, the biomarkers improve the detection of prostate carcinoma-free men (AUC = 0.89) and of those with clinically significant PCa (AUC = 0.93). We have uncovered the potential of urinary biomarkers for a test that allows a more stringent prioritization of mpMRI use and improves the decision criteria for prostate biopsy, minimizing patient burden by decreasing the number of unnecessary prostate biopsies. [ABSTRACT FROM AUTHOR]

Prostate-Specific Antigen (PSA) based screening of prostate cancer (PCa) needs refinement. The aim of this study was the identification of urinary biomarkers to predict the Prostate Imaging—Reporting and Data System (PI-RADS) score and the presence of PCa prior to prostate biopsy. Urine samples from patients with elevated PSA were collected prior to prostate biopsy (cohort = 99). The re-analysis of mass spectrometry data from 45 samples was performed to identify urinary biomarkers to predict the PI-RADS score and the presence of PCa. The most promising candidates, i.e. SPARC-like protein 1 (SPARCL1), Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), Alpha-1-microglobulin/bikunin precursor (AMBP), keratin 13 (KRT13), cluster of differentiation 99 (CD99) and hornerin (HRNR), were quantified by ELISA and validated in an independent cohort of 54 samples. Various biomarker combinations showed the ability to predict the PI-RADS score (AUC = 0.79). In combination with the PI-RADS score, the biomarkers improve the detection of prostate carcinoma-free men (AUC = 0.89) and of those with clinically significant PCa (AUC = 0.93). We have uncovered the potential of urinary biomarkers for a test that allows a more stringent prioritization of mpMRI use and improves the decision criteria for prostate biopsy, minimizing patient burden by decreasing the number of unnecessary prostate biopsies. [ABSTRACT FROM AUTHOR]

Cybersecurity has emerged as a critical global concern. Intrusion Detection Systems (IDS) play a critical role in protecting interconnected networks by detecting malicious actors and activities. Machine Learning (ML)-based behavior analysis within the IDS has considerable potential for detecting dynamic cyber threats, identifying abnormalities, and identifying malicious conduct within the network. However, as the number of data grows, dimension reduction becomes an increasingly difficult task when training ML models. Addressing this, our paper introduces a novel ML-based network intrusion detection model that uses Random Oversampling (RO) to address data imbalance and Stacking Feature Embedding based on clustering results, as well as Principal Component Analysis (PCA) for dimension reduction and is specifically designed for large and imbalanced datasets. This model's performance is carefully evaluated using three cutting-edge benchmark datasets: UNSW-NB15, CIC-IDS-2017, and CIC-IDS-2018. On the UNSW-NB15 dataset, our trials show that the RF and ET models achieve accuracy rates of 99.59% and 99.95%, respectively. Furthermore, using the CIC-IDS2017 dataset, DT, RF, and ET models reach 99.99% accuracy, while DT and RF models obtain 99.94% accuracy on CIC-IDS2018. These performance results continuously outperform the state-of-art, indicating significant progress in the field of network intrusion detection. This achievement demonstrates the efficacy of the suggested methodology, which can be used practically to accurately monitor and identify network traffic intrusions, thereby blocking possible threats. [ABSTRACT FROM AUTHOR]

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Background: Pancreatic adenocarcinoma, recognized for its aggressive behavior and frequent late-stage diagnosis, imposes significant challenges in early detection and prognosis. This study aimed to evaluate the diagnostic and prognostic potential by measuring the expression levels of long non-coding RNA HOTAIR and the glycolytic enzyme hexokinase 2 (HK2) mRNA in both tumorous and adjacent non-tumorous pancreatic tissue samples (n = 25 each) using RT-qPCR. Results Both lncRNA HOTAIR and HK2 expression levels significantly increased in tumorous pancreatic tissues compared to non-tumorous tissue (P = 0.001). However, their levels in stage T2 and T3 showed no statistically significant difference (P = 0.01). lncRNA HOTAIR and HK2 expression levels positively correlated with each other (P = 0.001; r = 0.95); however, no significant associations were found with serum tumor markers CA19-9 and CEA (P = 0.01; r = 005; p = 0.1, r = 0.2). ROC analysis demonstrated the significant abilities of both lncRNA HOTAIR and HK2 expression levels to discriminate between tumorous and non-tumorous pancreatic tissues (AUC = 0.92 and 0.84, respectively) with 96% and 88% sensitivity, and 72% and 40% specificity, respectively, at optimal cut-off values of 1.12 and 0.84 relative expression units. Patients with elevated lncRNA HOTAIR and HK2 expression had shorter median survival (8 and 7 months, respectively), increasing the risk of adverse outcomes or recurrence 4–4.8 times (HR = 4.08, p = 0.07; HR = 4.8, p = 0.01), thus emphasizing their prognostic potential in pancreatic cancer. Conclusion: lncRNA HOTAIR and HK2 expression levels exhibit diagnostic potential in pancreatic tumors. Elevated levels of both markers correlate strongly with adverse outcomes, underscoring their prognostic value. [ABSTRACT FROM AUTHOR]

The drivers of recurrence and resistance in ovarian high grade serous carcinoma remain unclear. We investigate the acquisition of resistance by collecting tumour biopsies from a cohort of 276 women with relapsed ovarian high grade serous carcinoma in the BriTROC-1 study. Panel sequencing shows close concordance between diagnosis and relapse, with only four discordant cases. There is also very strong concordance in copy number between diagnosis and relapse, with no significant difference in purity, ploidy or focal somatic copy number alterations, even when stratified by platinum sensitivity or prior chemotherapy lines. Copy number signatures are strongly correlated with immune cell infiltration, whilst diagnosis samples from patients with primary platinum resistance have increased rates of CCNE1 and KRAS amplification and copy number signature 1 exposure. Our data show that the ovarian high grade serous carcinoma genome is remarkably stable between diagnosis and relapse and acquired chemotherapy resistance does not select for common copy number drivers. 'Treatment resistance is common in ovarian high grade serous carcinoma, often leading to relapse. Here, the authors leverage shallow whole genome and panel sequencing of 276 patients with available diagnostic and relapse samples and show high concordance of copy number and mutation status. [ABSTRACT FROM AUTHOR]

Background: Even in the novel immunotherapy era, Merkel cell carcinoma (MCC) remains challenging in its treatment. Apart from Merkel cell polyomavirus (MCPyV) associated MCC, this cancer is linked in about 20% of cases to ultraviolet-induced mutational burden frequently causing aberrations in Notch and PI3K/AKT/mTOR signalling pathways. The recently developed agent GP-2250 is capable to inhibit growth of cells of different cancers, including pancreatic neuroendocrine tumors. The objective of the present study was to investigate the effects of GP-2250 on MCPyV-negative MCC cells. Methods: Methods We employed three cell lines (MCC13, MCC14.2, MCC26) which were exposed to different GP-2250doses. GP-2250's effects on cell viability, proliferation, and migration were evaluated by means of MTT, BrdU, and scratch assays, respectively. Flow cytometry was performed for the evaluation of apoptosis and necrosis. Western blotting was implemented for the determination of AKT, mTOR, STAT3, and Notch1 protein expression. Results: Cell viability, proliferation, and migration decreased with increasing GP-2250 doses. Flow cytometry revealed a dose response to GP-2250 in all three MCC cell lines. While the viable fraction decreased, the share of necrotic and in a smaller amount the apoptotic cells increased. Regarding Notch1, AKT, mTOR, and STAT3 expression a comparatively time- and dose-dependent decrease of protein expression in the MCC13 and MCC26 cell lines was observed. By contrast, Notch1, AKT, mTOR, and STAT3 expression in MCC14.2 was scarcely altered or even increased by the three dosages of GP-2250 applied. Conclusions: The present study indicates GP-2250 having anti-neoplastic effects in MCPyV-negative tumor cells in regard to viability, proliferation, and migration. Moreover, the substance is capable of downregulating protein expression of aberrant tumorigenic pathways in MCPyV-negative MCC cells. [ABSTRACT FROM AUTHOR]

Radiologists routinely analyze hippocampal asymmetries in magnetic resonance (MR) images as a biomarker for neurodegenerative conditions like epilepsy and Alzheimer's Disease. However, current clinical tools rely on either subjective evaluations, basic volume measurements, or disease-specific models that fail to capture more complex differences in normal shape. In this paper, we overcome these limitations by introducing NORHA, a novel NORmal Hippocampal Asymmetry deviation index that uses machine learning novelty detection to objectively quantify it from MR scans. NORHA is based on a One-Class Support Vector Machine model learned from a set of morphological features extracted from automatically segmented hippocampi of healthy subjects. Hence, in test time, the model automatically measures how far a new unseen sample falls with respect to the feature space of normal individuals. This avoids biases produced by standard classification models, which require being trained using diseased cases and therefore learning to characterize changes produced only by the ones. We evaluated our new index in multiple clinical use cases using public and private MRI datasets comprising control individuals and subjects with different levels of dementia or epilepsy. The index reported high values for subjects with unilateral atrophies and remained low for controls or individuals with mild or severe symmetric bilateral changes. It also showed high AUC values for discriminating individuals with hippocampal sclerosis, further emphasizing its ability to characterize unilateral abnormalities. Finally, a positive correlation between NORHA and the functional cognitive test CDR-SB was observed, highlighting its promising application as a biomarker for dementia. [ABSTRACT FROM AUTHOR]

The drivers of recurrence and resistance in ovarian high grade serous carcinoma remain unclear. We investigate the acquisition of resistance by collecting tumour biopsies from a cohort of 276 women with relapsed ovarian high grade serous carcinoma in the BriTROC-1 study. Panel sequencing shows close concordance between diagnosis and relapse, with only four discordant cases. There is also very strong concordance in copy number between diagnosis and relapse, with no significant difference in purity, ploidy or focal somatic copy number alterations, even when stratified by platinum sensitivity or prior chemotherapy lines. Copy number signatures are strongly correlated with immune cell infiltration, whilst diagnosis samples from patients with primary platinum resistance have increased rates of CCNE1 and KRAS amplification and copy number signature 1 exposure. Our data show that the ovarian high grade serous carcinoma genome is remarkably stable between diagnosis and relapse and acquired chemotherapy resistance does not select for common copy number drivers. 'Treatment resistance is common in ovarian high grade serous carcinoma, often leading to relapse. Here, the authors leverage shallow whole genome and panel sequencing of 276 patients with available diagnostic and relapse samples and show high concordance of copy number and mutation status. [ABSTRACT FROM AUTHOR]

Purpose: Early biochemical recurrence (eBCR) indicated a high risk for potential recurrence and metastasis in prostate cancer. The N6-methyladenosine (m6A) methylation modification played an important role in prostate cancer progression. This study aimed to develop a m6A lncRNA signature to accurately predict eBCR in prostate cancer. Methods: Pearson correlation analysis was first conducted to explore m6A lncRNAs and univariate Cox regression analysis was further performed to identify m6A lncRNAs of prognostic roles for predicting eBCR in prostate cancer. The m6A lncRNA signature was constructed by least absolute shrinkage and selection operator analysis (LASSO) in training cohort and further validated in test cohort. Furthermore, half maximal inhibitory concentration (IC50) values were utilized to explore potential effective drugs for high-risk group in this study. Results: Five hundred and thirty-eighth m6A lncRNAs were searched out through Pearson correlation analysis and 25 out of 538 m6A lncRNAs were identified to pose prediction roles for eBCR in prostate cancers. An m6A lncRNA signature including 5 lncRNAs was successfully built in training cohort. The high-risk group derived from m6A lncRNA signature could efficiently predict eBCR occurrence in both training (p < 0.001) and test cohort (p = 0.002). ROC analysis also confirmed that lncRNA signature in this study posed more accurate prediction roles for eBCR occurrence when compared with PSA, TNM stages and Gleason scores. Drug sensitivity analysis further discovered that various drugs could be potentially utilized to treat high-risk samples in this study. Conclusions: The m6A lncRNA signature in this study could be utilized to efficiently predict eBCR occurrence, various clinical characteristic and immune microenvironment for prostate cancer. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming has been recognised as a hallmark in solid tumours. Malignant modification of the tumour's bioenergetics provides energy for tumour growth and progression. Otto Warburg first reported these metabolic and biochemical changes in 1927. In prostate cancer (PCa) epithelial cells, the tumour metabolism also changes during development and progress. These alterations are partly driven by the androgen receptor, the key regulator in PCa development, progress, and survival. In contrast to other epithelial cells of different entities, glycolytic metabolism in prostate cells sustains physiological citrate secretion in the normal prostatic epithelium. In the early stages of PCa, citrate is utilised to power oxidative phosphorylation and fuel lipogenesis, enabling tumour growth and progression. In advanced and incurable castration-resistant PCa, a metabolic shift towards choline, amino acid, and glycolytic metabolism fueling tumour growth and progression has been described. Therefore, even if the metabolic changes are not fully understood, the altered metabolism during tumour progression may provide opportunities for novel therapeutic strategies, especially in advanced PCa stages. This review focuses on the main differences in PCa's metabolism during tumourigenesis and progression highlighting glutamine's role in PCa. [ABSTRACT FROM AUTHOR]

Background: Periodic surges of COVID-19 patients seeking care in the hospital environment overwhelm systems reduce the availability of resources for treatment of non-COVID-19 cases (Zheng et al. in J Hosp Infect 106:325–329, 2020). Hospital flow and resource management could be greatly enhanced by differentiating patients who are likely at risk of adverse clinical outcomes from those who could safely be discharged after evaluation and managed outside of the hospital setting (Sun et al. in J Infect Dis 223:38–46, 2021). Herein, we propose a prognostic score named PEGALUS (Predictivity of Elderly age, arterial blood Gas Analysis and Lung UltraSound) that could potentially help clinicians properly and rapidly choose the appropriate allocation of COVID-19 patients admitted to the emergency department (ED). Methods: This observational prospective study enrolled COVID-19 patients who were admitted to the ED of IRCCS San Raffaele Hospital (HSR). Results: 230 COVID-19 patients were enrolled and 30-day follow-up data was collected. Composite outcome was death or need for oro-tracheal intubation (OTI). 50 patients (21.5%) reached the outcome during the observational period. In multivariate Cox analysis, age, PO2/FiO2 ratio, pCO2, duration of symptoms, and lung ultrasound evaluation were significantly associated with the adverse outcome. We obtained a new scorecard (PEGALUS) according to the hazard ratio of the identified predictors. PEGALUS score performed well in predicting the composite outcome (AUC 0.866, 95% IC 0.812–0.921; p < 0.001). Kaplan–Meier showed that a PEGALUS score < 7 was associated with a good 30-day prognosis (survival rate 97.5%), compared to a PEGALUS score of 7–11 (survival rate 85.9%; p log-rank 0.009) and PEGALUS score > 11 (survival rate 49.3%; p log-rank < 0.001). Conclusions: PEGALUS score performed at the admission can predict adverse outcomes in patients with COVID-19. The systematic application of this score might permit a more accurate and rapid treatment allocation in this setting. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the protein expression characteristics of genes employed in a recently introduced prognostic gene expression assay for patients with cutaneous melanoma (CM). Methods: We studied 37 patients with CM and 10 with benign (melanocytic) nevi (BN). Immunohistochemistry of primary tumor tissue was performed for eight proteins: COL6A6, DCD, GBP4, KLHL41, KRT9, PIP, SCGB1D2, SCGB2A2. Results: The protein expression of most markers investigated was relatively low (e.g., DCD, KRT9, SCGB1D2) and predominantly cytoplasmatic in melanocytes and keratinocytes. COL6A6, GBP4, and KLHL41 expression was significantly enhanced in CM when compared to BN. DCD protein expression was significantly correlated with COL6A6, GBP4, and KLHL41. GBP4 was positively correlated with KLHL41 and inversely correlated with SCGB2B2. The latter was also inversely correlated with serum S100B levels at time of initial diagnosis. The presence of SCGB1D2 expression was significantly associated with ulceration of the primary tumor. KRT9 protein expression was significantly more likely found in acral lentiginous melanoma. The presence of DCD expression was less likely associated with superficial spreading melanoma subtype but significantly associated with non-progressive disease. The absence of SCGB2A2 expression was significantly more often observed in patients who did not progress to stage III or IV. Conclusions: The expression levels observed were relatively low but differed in part with those found in BN. Even though we detected some significant correlations between the protein expression levels and clinical parameters (e.g., CM subtype, course of disease), there was no major concordance with the protective or risk-associated functions of the corresponding genes included in a recently introduced prognostic gene expression assay. [ABSTRACT FROM AUTHOR]

Live cancer is the sixth most prevalent diagnosed malignant tumor and the fourth leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the main histological type of liver cancer. Here, we attempt to evaluate the role of long non coding RNA NEAT1 in HCC, and explore its potential mechanism in this disease. Initially, we detected the expression of NEAT1 in HCC cell lines (SMMC-7721 and Huh7 cells) using qRT-PCR. Then we transfected si-NC or si-NEAT1 into SMMC-7721 and Huh7 cells by RNA interference. CCK-8 assay, transwell assay, flow cytometry, qRT-PCR and western blotting were used to evaluate the role of NEAT1 in the biological behavior of SMMC-7721 and Huh7 cells. The rescue experiment, RIP assay and MeRIP were devoted to the underlying mechanism. NEAT1 expression level was significantly elevated in SMMC-7721 and Huh7 cells. Knockdown of NEAT1 inhibited proliferation and migration, induced apoptosis of HCC cell lines. NEAT1 serves as a sponge for miR-214. Besides, PSMB8 was a direct target of miR-214. Furthermore, ALKBH5 could up-regulate NEAT1 expression by inhibiting m6A enrichment. ALKBH5-induced NEAT1 promoted cell proliferation and migration of HCC by sponging miR-214 in vitro, which may provide a potential therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

Melanomas and other solid tumors commonly have increased ploidy, with near-tetraploid karyotypes being most frequently observed. Such karyotypes have been shown to arise through whole-genome doubling events that occur during early stages of tumor progression. The generation of tetraploid cells via whole-genome doubling is proposed to allow nascent tumor cells the ability to sample various pro-tumorigenic genomic configurations while avoiding the negative consequences that chromosomal gains or losses have in diploid cells. Whereas a high prevalence of whole-genome doubling events has been established, the means by which whole-genome doubling arises is unclear. Here, we find that BRAFV600E, the most common mutation in melanomas, can induce whole-genome doubling via cytokinesis failure in vitro and in a zebrafish melanoma model. Mechanistically, BRAFV600E causes decreased activation and localization of RhoA, a critical cytokinesis regulator. BRAFV600E activity during G1/S phases of the cell cycle is required to suppress cytokinesis. During G1/S, BRAFV600E activity causes inappropriate centriole amplification, which is linked in part to inhibition of RhoA and suppression of cytokinesis. Together these data suggest that common abnormalities of melanomas linked to tumorigenesis – amplified centrosomes and whole-genome doubling events – can be induced by oncogenic BRAF and other mutations that increase RAS/MAPK pathway activity. Whole-genome doubling (WGD) commonly occurs in many solid tumors. Here the authors use a zebrafish model of melanoma and in vitro models to show that BRAFV600E induces WGD via inhibition of RhoA and cytokinesis failure. [ABSTRACT FROM AUTHOR]

Melanoma is commonly driven by activating mutations in the MAP kinase BRAF; however, oncogenic BRAF alone is insufficient to promote melanomagenesis. Instead, its expression induces a transient proliferative burst that ultimately ceases with the development of benign nevi comprised of growth-arrested melanocytes. The tumor suppressive mechanisms that restrain nevus melanocyte proliferation remain poorly understood. Here we utilize cell and murine models to demonstrate that oncogenic BRAF leads to activation of the Hippo tumor suppressor pathway, both in melanocytes in vitro and nevus melanocytes in vivo. Mechanistically, we show that oncogenic BRAF promotes both ERK-dependent alterations in the actin cytoskeleton and whole-genome doubling events, which independently reduce RhoA activity to promote Hippo activation. We also demonstrate that functional impairment of the Hippo pathway enables oncogenic BRAF-expressing melanocytes to bypass nevus formation and rapidly form melanomas. Our data reveal that the Hippo pathway enforces the stable arrest of nevus melanocytes and represents a critical barrier to melanoma development. Activating mutations of BRAF alone are inadequate to drive melanoma formation. Here the authors show that activation of Hippo signalling by oncogenic BRAF represents an additional safeguard to limit BRAF-dependent human melanocyte growth and melanoma formation. [ABSTRACT FROM AUTHOR]

Over the last decade, the increasing interest in long non-coding RNAs (lncRNAs) has led to the discovery of these transcripts in multiple organisms. LncRNAs tend to be specifically, and often lowly, expressed in certain tissues, cell types and biological contexts. Although lncRNAs participate in the regulation of a wide variety of biological processes, including development and disease, most of their functions and mechanisms of action remain unknown. Poor conservation of the DNA sequences encoding for these transcripts makes the identification of lncRNAs orthologues among different species very challenging, especially between evolutionarily distant species such as flies and humans or mice. However, the functions of lncRNAs are unexpectedly preserved among different species supporting the idea that conservation occurs beyond DNA sequences and reinforcing the potential of characterising lncRNAs in animal models. In this review, we describe the features and roles of lncRNAs in the fruit fly Drosophila melanogaster, focusing on genomic and functional comparisons with human and mouse lncRNAs. We also discuss the current state of advances and limitations in the study of lncRNA conservation and future perspectives. [ABSTRACT FROM AUTHOR]

MCC (Merkel cell carcinoma) is an aggressive neuroendocrine cutaneous neoplasm. Integration of the Merkel cell polyomavirus (MCPyV) is observed in about 80% of the cases, while the remaining 20% are related to UV exposure. Both MCPyV-positive and -negative MCCs—albeit by different mechanisms—are associated with RB1 inactivation leading to overexpression of SOX2, a major contributor to MCC biology. Moreover, although controversial, loss of RB1 expression seems to be restricted to MCPyV-negative cases. The aim of the present study was to assess the performances of RB1 loss and SOX2 expression detected by immunohistochemistry to determine MCPyV status and to diagnose MCC, respectively. Overall, 196 MCC tumors, 233 non-neuroendocrine skin neoplasms and 70 extra-cutaneous neuroendocrine carcinomas (NEC) were included. SOX2 and RB1 expressions were assessed by immunohistochemistry in a tissue micro-array. Diagnostic performances were determined using the likelihood ratio (LHR). RB1 expression loss was evidenced in 27% of the MCC cases, 12% of non-neuroendocrine skin tumors and 63% of extra-cutaneous NEC. Importantly, among MCC cases, RB1 loss was detected in all MCPyV(-) MCCs, while MCPyV(+) cases were consistently RB1-positive (p < 0.001). SOX2 diffuse expression was observed in 92% of the MCC cases and almost never observed in non-neuroendocrine skin epithelial neoplasms (2%, p < 0.0001, LHR + = 59). Furthermore, SOX2 diffuse staining was more frequently observed in MCCs than in extra-cutaneous NECs (30%, p < 0.001, LHR + = 3.1). These results confirm RB1 as a robust predictor of MCC viral status and further suggest SOX2 to be a relevant diagnostic marker of MCC. [ABSTRACT FROM AUTHOR]

Our work aims to investigate long non-coding RNA (lncRNA) N6-methyladenosine (m6A) modification and its role in infantile hemangioma (IH). The mRNA and protein expression levels were assessed using quantitative real-time polymerase chain reaction, western blot and immunohistochemistry. Me-RIP assay was performed to evaluate lncRNA NEAT1 m6A levels. Cell proliferation, migration and invasion were evaluated using cell counting kit-8 assay, transwell migration and invasion assay, respectively. Photo-activatable ribonucleoside-enhanced crosslinking and immunoprecipitation assay was conducted to verify the binding relationship between lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) and ALKBH5 (an RNA demethylase). The binding relationship between lncRNA NEAT1, microRNA (miR)-378b and FOS-like antigen 1 (FOSL1) was verified using dual-luciferase reporter gene assay and/or RNA immunoprecipitation assay. ALKBH5, lncRNA NEAT1 and FOLS1 expression was elevated in IH tissues, while miR-378b was downregulated. ALKBH5 knockdown suppressed cell proliferation, migration and invasion of IH cells, while promoting cell apoptosis. ALKBH5 promoted lncRNA NEAT1 expression by reducing the m6A modification of lncRNA NEAT1. In addition, miR‐378b was the target of lncRNA NEAT1, and its overexpression reversed the promotion effect of lncRNA NEAT1 overexpression on IH cell tumor-like behaviors. Moreover, FOLS1 was the target of miR-378b, and its overexpression reversed the inhibitory effect of miR-378b overexpression on IH cell tumor-like behaviors in vitro. ALKBH5 might have great potential as therapeutic target for IH, since ALKBH5 silencing suppressed IH progression by regulation of the NEAT1/miR-378b/FOSL1 axis. [ABSTRACT FROM AUTHOR]

Tracking small laboratory animals such as flies, fish, and worms is used for phenotyping in neuroscience, genetics, disease modelling, and drug discovery. An imaging system with sufficient throughput and spatiotemporal resolution would be capable of imaging a large number of animals, estimating their pose, and quantifying detailed behavioural differences at a scale where hundreds of treatments could be tested simultaneously. Here we report an array of six 12-megapixel cameras that record all the wells of a 96-well plate with sufficient resolution to estimate the pose of C. elegans worms and to extract high-dimensional phenotypic fingerprints. We use the system to study behavioural variability across wild isolates, the sensitisation of worms to repeated blue light stimulation, the phenotypes of worm disease models, and worms' behavioural responses to drug treatment. Because the system is compatible with standard multiwell plates, it makes computational ethological approaches accessible in existing high-throughput pipelines. A multiplexed machine-vision-based tracking system enables the high-content analysis of C. elegans behavior in several 96-well plates at a time and shows its utility for comparisons across multiple genotypes and upon drug treatment, tackling the bottlenecks in behavioural quantification. [ABSTRACT FROM AUTHOR]

Purpose of Review: Liquid biopsies, including circulating tumour DNA (ctDNA), can inform a variety of clinical questions. This review examines the potential role of ctDNA as a clinical tool to inform clinical decision-making from early to late stage cutaneous melanoma. Recent Findings: In pre-clinical studies, ctDNA has been shown to detect minimal residual disease and molecular relapse; predict and monitor response to therapy; and identify key resistance mechanisms. Here, we examine the potential utility of ctDNA and discuss its limitations for use in patients with melanoma. We present novel clinical trials, which are testing its value as a tool to augment clinical decision-making. Finally, we discuss the steps that are needed to ensure that ctDNA is used optimally in order to improve outcomes for patients with melanoma. Summary: Preclinical studies have shown that ctDNA has huge potential to provide real-time information about disease status in patients with melanoma. It is now time to test it rigorously within clinical trials to assess how it can be optimally used to benefit patients in the clinic. [ABSTRACT FROM AUTHOR]

Background: Merkel cell polyomavirus (MCPyV) is associated with the development of Merkel cell carcinoma (MCC). Antibody (MCPyV-Ab) titers may have prognostic implications. This study evaluated the impact of the presence or absence of MCPyV-Ab on the 2-year overall survival (OS) and disease-free survival (DFS) of MCC patients. Methods: This single-center, IRB-approved, retrospective cohort study evaluated 51 adult patients with MCC from 2014 to 2021 using a prospectively maintained database. Patients were compared by MCPyV-Ab status, and Kaplan-Meier analysis was used to evaluate 2-year OS and DFS. Results: Of the 51 patients, 13 (25.4%) were seropositive, 41 (80.4%) underwent wide excision, 40 (80.0%) received radiotherapy, and 43 (84.3%) received multimodal therapy. The median follow-up period was 15.5 months (range 1–69.5 months). The median 2-year OS of the entire cohort was not reached. The median 2-year OS was not reached for either the seronegative or the seropositive patients. The difference in 2-year OS between the groups was not statistically significant (p = 0.37). Eight patients, all seronegative, were never rendered disease-free and were removed from recurrence analysis. The seropositive patients experienced no recurrences. Of the 30 seronegative patients, 9 (30.0%) experienced recurrence. The median 2-year DFS of the entire cohort was not reached. The median 2-year DFS of the seronegative group was 22.2 months. The 2-year DFS was not reached for the seropositive cohort. Seropositivity conferred a significantly better 2-year DFS than seronegativity (p = 0.04). Conclusion: The MCPyV-Ab seropositive patients demonstrated improved 2-year DFS. The seropositive patients showed a strong trend toward improved 2-year OS, although the difference not statistically significant. This study substantiated the value of MCPyV-Ab assessment for MCC. [ABSTRACT FROM AUTHOR]

Fungal pathogens, from phytopathogenic fungus to human pathogens, are able to alternate between the yeast-like form and filamentous forms. This morphological transition (dimorphism) is in close connection with their pathogenic lifestyles and with their responses to changing environmental conditions. The mechanisms governing these morphogenetic conversions are still not fully understood. Therefore, we studied the filamentous growth of the less-known, non-pathogenic dimorphic fission yeast, S. japonicus, which belongs to an ancient and early evolved branch of the Ascomycota. Its RNA sequencing revealed that several hundred genes were up- or down-regulated in the hyphae compared to the yeast-phase cells. These genes belonged to different GO categories, confirming that mycelial growth is a rather complex process. The genes of transport- and metabolic processes appeared especially in high numbers among them. High expression of genes involved in glycolysis and ethanol production was found in the hyphae, while other results pointed to the regulatory role of the protein kinase A (PKA) pathway. The homologues of 49 S. japonicus filament-associated genes were found by sequence alignments also in seven distantly related dimorphic and filamentous species. The comparative genomic analyses between S. japonicus and the closely related but non-dimorphic S. pombe shed some light on the differences in their genomes. All these data can contribute to a better understanding of hyphal growth and those genomic rearrangements that underlie it. [ABSTRACT FROM AUTHOR]

Objective: To externally validate a Genomic Classifier (GC) based risk-stratification nomogram identifying candidates who would benefit from adjuvant radiation (aRT) therapy after radical prostatectomy (RP). Methods: We identified 350 patients who underwent RP, between 2013 and 2018, and had adverse pathological features (positive margin, and/or pT3a or higher) on final pathology. Genomic profile was available for all these men. The clinical recurrence-free survival was estimated using the Kaplan–Meier method. The external validity of the nomogram was tested using the concordance index (c-index), calibration plot, and decision curve analysis. Results: The median follow-up of the cohort was 26.5 months. Overall, 14% of the patients received aRT. During the follow-up period, 3.4% of the patients developed metastasis. Overall 3-year metastasis-free survival was 95% (95% CI 0.92–0.98). The c-index of the nomogram was 0.84. The calibration of the model was favorable. Decision-curve analysis showed a positive net benefit for probabilities ranging between 0.01 and 0.09, with the highest difference at threshold probability around 0.05. At that threshold, the net benefit is 0.06 for the model and 0 for treating all the patients. Conclusion: Our report is the first to confirm the validity of this genomic-based risk-stratification tool in identifying men who might benefit from aRT after RP. As such, it can be a useful instrument to be incorporated in shared decision making on whether administration of aRT will lead to a clinically meaningful benefit. Such a model can also be useful for patients' classification in future clinical trials. [ABSTRACT FROM AUTHOR]

Immunotherapy, so promising in many neoplasms, still does not have a precise role in the treatment of neuroendocrine neoplasms (NENs). In this article, we provide an overview on the current knowledge about immunotherapy with immune checkpoint inhibitors (ICIs) applied to NENs, evaluating future perspectives in this setting of tumors. Evidence so far available for ICIs in gastroenteropancreatic (GEP)-NENs is definitively not as robust as for other tumors such as Small Cell Lung Cancer or Merkel Cell Carcinoma. In fact, with regard to the well-differentiated forms of NENs (NETs), the results obtained nowadays have been disappointing. However, the near future, might reserve interesting results for ICIs in GEP-NEN from a total of nine different ICI drugs, used throughout 19 randomised controlled trials. Such numbers highlight the growing attention gathering around NENs and ICIs, in response to the need of stronger evidences supporting such therapy. For the future, the most important aspect will be to study strategies that can make NETs more susceptible to response to ICI and, thus, enhance the effectiveness of these treatments. Therefore, the combination of conventional therapy, target therapy and immunotherapy deserve attention and warrant to be explored. A sequential chemotherapy, possibly inducing an increase in tumor mutational burden and tested before immunotherapy, could be a hypothesis deserving more consideration. A radiation treatment that increases tumor-infiltrating lymphocytes, could be another approach to explore before ICIs in NENs. Equally essential will be the identification of biomarkers useful for selecting patients potentially responsive to this type of treatment. [ABSTRACT FROM AUTHOR]

Microbial fuel cells (MFC) have been foreseen as a sustainable renewable energy resource to meet future energy demand. In the past, several studies have been executed in both benchtop and pilot scale to produce electrical energy from wastewater. The key role players in this technology that leads to the operation are microbes, mainly bacteria. The dominant among them is termed as "exoelectrogens" that have the capability to produce and transport electron by utilizing waste source. The current review focuses on such electrogenic bacteria's involvement for enhanced power generation of MFC. The pathway of electron transfer in their cell along and its conduction to the extracellular environment of the MFC system are critically discussed. The interaction of the microbes in various MFC operational conditions, including the role of substrate and solid electron acceptors, i.e., anode, external resistance, temperature, and pH, was also discussed in depth along with biotechnological advancement and future research perspective. [ABSTRACT FROM AUTHOR]

Introduction and objectives: ISL1 serves as a biomarker of metastasis and neuroendocrine neoplasia in multiple tumors. However, the expression and relation of ISL1 to other biomarkers in prostate cancer have not been fully elucidated. Here, we characterize the expression of ISL1 and its partners in PCa and document its association to disease progression and post castration resistance neuroendocrine differentiation. Methods: The expression of ISL1 was interrogated in > 6000 primary samples from the Decipher GRID registry and 250 mCRPC samples to assess its prognostic value and relation to neuroendocrine differentiation. Results: ISL1 was highly correlated to MEIS genes and other genes related to cell motility. ISL1 down-regulation in PCa was associated with cancer progression, aggressive primary tumors, and metastatic outcome. We found that ISL1 is highly correlated to MEIS genes across multiple primary PCa and mCRPC cohorts. The expression of ISL1 and MEIS genes were significantly and inversely related to metastasis-free survival and lethal disease, and were downregulated in CRPC and hormone naïve metastatic tumors but showed upregulation in neuroendocrine tumors. Co-immunoprecipitation showed MEIS2 and ISL1 interacting with each supporting their role in modulating transcriptional regulation and nominating this complex for potential targeted therapy. Conclusions: ISL1 complex with MEIS2 serves a critical role in prostate tumor progression and its upregulation in mCRPC/NE provides a rationale for assessing the role of ISL1 and its associated protein in treatment resistance. [ABSTRACT FROM AUTHOR]

Background: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cutaneous malignancy with poor prognosis. In Europe, approved systemic therapies are limited to the PD-L1 inhibitor avelumab. For avelumab-refractory patients, efficient and safe treatment options are lacking. Methods: At three different sites in Germany, clinical and molecular data of patients with metastatic MCC being refractory to the PD-L1 inhibitor avelumab and who were later on treated with combined IPI/NIVO were retrospectively collected and evaluated. Results: Five patients treated at three different academic sites in Germany were enrolled. Three out of five patients investigated for this report responded to combined IPI/NIVO according to RECIST 1.1. Combined immunotherapy was well tolerated without any grade II or III immune-related adverse events. Two out of three responders to IPI/NIVO received platinum-based chemotherapy in between avelumab and combined immunotherapy. Conclusion: In this small retrospective study, we observed a high response rate and durable responses to subsequent combined immunotherapy with IPI/NIVO in avelumab-refractory metastatic MCC patients. In conclusion, our data suggest a promising activity of second- or third-line PD-1- plus CTLA-4-blockade in patients with anti-PD-L1-refractory MCC. [ABSTRACT FROM AUTHOR]

Introduction: Metastatic prostate cancer (mPCa) is responsible for most prostate cancer (PCa) deaths worldwide. The present study aims to explore the molecular differences between mPCa and PCa.Methods: The authors downloaded GSE6752, GSE6919, and GSE32269 from the Gene Expression Omnibus and employed integrated analysis to identify differentially expressed genes (DEGs) between mPCa and PCa. Functional and pathway-enrichment analyses were performed, and a protein-protein interaction (PPI) network and modules were constructed. Clinical mPCa specimens were collected to verify the results by performing RT-qPCR. The Cancer Genome Atlas database was used to conduct a survival analysis, and an immunohistochemical assay was performed. The invasion ability of PCa cells was verified by Transwell assay.Results: One-hundred six consistently DEGs were found in mPCa compared with PCa. DEGs significantly enriched the positive regulation of cell proliferation, cell division, and cell adhesion in small cell lung cancer and PCa. Cell division, nucleoplasm, and cell cycle were selected from the PPI network, and the top 10 hub genes were selected. CDC20 and PTTG1 with genetic alterations were significantly associated with poorer disease-free survival. Immunohistochemical assay results showed that the expression levels of CDC20 and PTTG1 in mPCa were higher than those in PCa. The results of the migration assay indicated that CDC20 and PTTG1 could enhance the migration ability of PCa cells.Conclusion: The present study revealed that CDC20 and PTTG1 contribute more to migration, progression, and poorer prognoses in mPCa compared with PCa. CDC20 and PTTG1 could represent therapeutic targets in mPCa medical research and clinical studies. [ABSTRACT FROM AUTHOR]

Background: Merkel cell carcinoma (MCC) is an aggressive malignancy, associated with poor outcomes in patients with metastatic disease (mMCC). Management has been dramatically altered as a result of incorporating immune checkpoint blockade agents. MCC data from Latin America (LATAM) come from case-series or individual records. Regional registries are lacking. A need for better registries to improve current knowledge about MCC is highlighted. Our objectives were to describe a real-world experience with avelumab as a second-line (or first-line in unfit patients) treatment in a subset of LATAM participants enrolled in a global Expanded Access Program (EAP) for patients with mMCC, and to evaluate its contribution to the resolution of the concerns described in a recent regional experts review. Materials and methods: We reviewed data of LATAM participants in an avelumab EAP for mMCC treatment (NCT03089658). EAP patient had unresectable or mMCC with progressive disease after one line of chemotherapy, and were ineligible for clinical trials or unfit for chemotherapy. Results: 46 patients (median age: 71.6 years; 60.9% males; median treatment duration: 7.9 months) were included in the LATAM EAP. Physician-assessed objective responses were available for 19 patients. Complete response rate was 15.8% and partial response rate reached 42.1%, summarizing an objective response rate of 57.9%. Stable disease rate was 10.5%, with a disease control response of 68.4%. Conclusion: Avelumab showed robust efficacy and a safety profile consistent with global EAP data. Results are aimed to improve current knowledge about mMCC treatment and access to immunooncologic strategies for treating LATAM patients. [ABSTRACT FROM AUTHOR]

Many long non-coding RNAs (lncRNA) are highly dysregulated in cancer and are emerging as therapeutic targets. One example is NEAT1, which consists of two overlapping lncRNA isoforms, NEAT1_1 (3.7 kb) and NEAT1_2 (23 kb), that are functionally distinct. The longer NEAT1_2 is responsible for scaffolding gene-regulatory nuclear bodies termed paraspeckles, whereas NEAT1_1 is involved in paraspeckle-independent function. The NEAT1 isoform ratio is dependent on the efficient cleavage and polyadenylation of NEAT1_1 at the expense of NEAT1_2. Here, we developed a targeted antisense oligonucleotide (ASO) approach to sterically block NEAT1_1 polyadenylation processing, achieving upregulation of NEAT1_2 and abundant paraspeckles. We have applied these ASOs to cells of the heterogeneous infant cancer, neuroblastoma, as we found higher NEAT1_1:NEAT1_2 ratio and lack of paraspeckles in high-risk neuroblastoma cells. These ASOs decrease NEAT1_1 levels, increase NEAT1_2/paraspeckles and concomitantly reduce cell viability in high-risk neuroblastoma specifically. In contrast, overexpression of NEAT1_1 has the opposite effect, increasing cell proliferation. Transcriptomic analyses of high-risk neuroblastoma cells with altered NEAT1 ratios and increased paraspeckle abundance after ASO treatment showed an upregulation of differentiation pathways, as opposed to the usual aggressive neuroblastic phenotype. Thus, we have developed potential anti-cancer ASO drugs that can transiently increase growth-inhibiting NEAT1_2 RNA at the expense of growth-promoting NEAT1_1 RNA. These ASOs, unlike others that degrade lncRNAs, provide insights into the importance of altering lncRNA polyadenylation events to suppress tumorigenesis as a strategy to combat cancer. [ABSTRACT FROM AUTHOR]

Chromatin remodeler complexes regulate gene transcription, DNA replication and DNA repair by changing both nucleosome position and post-translational modifications. The chromatin remodeler complexes are categorized into four families: the SWI/SNF, INO80/SWR1, ISWI and CHD family. In this review, we describe the subunits of these chromatin remodeler complexes, in particular, the recently identified members of the ISWI family and novelties of the CHD family. Long non-coding (lnc) RNAs regulate gene expression through different epigenetic mechanisms, including interaction with chromatin remodelers. For example, interaction of lncBRM with BRM inhibits the SWI/SNF complex associated with a differentiated phenotype and favors assembly of a stem cell-related SWI/SNF complex. Today, over 50 lncRNAs have been shown to affect chromatin remodeler complexes and we here discuss the mechanisms involved. [ABSTRACT FROM AUTHOR]

Objective: To review the current body of evidence surrounding non-imaging biomarkers in patients with known or suspected prostate cancer. Results: Several non-imaging biomarkers have been developed and are available that aim to improve risk estimates at several clinical junctures. For patients with suspicion of prostate cancer who are considering first-time or repeat biopsy, blood- and urine-based assays can improve the prediction of harboring clinically significant disease and may reduce unnecessary biopsy. Blood- and urine-based biomarkers have been evaluated in association with prostate MRI, offering insights that might augment decision-making in the pre and post-MRI setting. Tissue-based genomic and proteomic assays have also been developed that provide independent assessments of prostate cancer aggressiveness that can complement imaging. Conclusion: A growing number of non-imaging biomarkers are available to assist in clinical decision-making for men with known or suspected prostate cancer. An appreciation for the intersection of imaging and biomarkers may improve clinical care and resource utilization for men with prostate cancer. [ABSTRACT FROM AUTHOR]

"Radiomics," as it refers to the extraction and analysis of a large number of advanced quantitative radiological features from medical images using high-throughput methods, is perfectly suited as an engine for effectively sifting through the multiple series of prostate images from before, during, and after radiotherapy (RT). Multiparametric (mp)MRI, planning CT, and cone beam CT (CBCT) routinely acquired throughout RT and the radiomics pipeline are developed for extraction of thousands of variables. Radiomics data are in a format that is appropriate for building descriptive and predictive models relating image features to diagnostic, prognostic, or predictive information. Prediction of Gleason score, the histopathologic cancer grade, has been the mainstay of the radiomic efforts in prostate cancer. While Gleason score (GS) is still the best predictor of treatment outcome, there are other novel applications of quantitative imaging that are tailored to RT. In this review, we summarize the radiomics efforts and discuss several promising concepts such as delta-radiomics and radiogenomics for utilizing image features for assessment of the aggressiveness of prostate cancer and its outcome. We also discuss opportunities for quantitative imaging with the advance of instrumentation in MRI-guided therapies. [ABSTRACT FROM AUTHOR]

Purpose: To review available prostate cancer biomarkers and their performance in a clinical order, from prostate cancer detection, to treatment of localized and advanced disease. Methods: We used an electronic literature search of the PubMed database using the key words "prostate biomarkers," "genomic markers," and "prostate cancer screening," as well as specific biomarkers, until March 2019. Results: Prostate-specific antigen (PSA) lacks sensitivity for prostate cancer detection, and PSA derivatives have slightly improved its specificity, but have not resolved the limitations of PSA screening. Prostate cancer biomarkers have emerged as an ancillary tool to guide the clinical decision-making in different clinical scenarios. Urine-based tests can identify patients who may benefit from a prostate biopsy, and issue-based markers are helpful in guiding the decision regarding a second biopsy, stratifying patient with newly diagnosed prostate cancer to active surveillance or treatment, and identifying patients who may benefit from adjuvant treatment after surgery. Conclusions: New biomarkers have improved risk stratification in diagnosing and treating prostate cancer. Many of these markers are still considered experimental, and their efficacy and cost utility have not been determined. [ABSTRACT FROM AUTHOR]

The human DNA damage response (DDR) is a complex signaling network constituting many factors responsible for the preservation of genomic integrity. Human polyomaviruses (HPyVs) are able to harness the DDR machinery during their infectious cycle by expressing an array of tumor (T) antigens. These molecular interactions between human polyomavirus T antigens and the DDR create conditions that promote viral replication at the expense of host genomic stability to cause disease as well as carcinogenesis in the cases of the Merkel cell polyomavirus and BK polyomavirus. This review focuses on the six HPyVs with disease association, emphasizing strain-dependent differences in their selective manipulation of the DDR. Appreciation of the HPyV–DDR interface at a molecular scale is conducive to the development of novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

The principle of dynamic liver function breath tests is founded on the administration of a 13C-labeled drug and subsequent monitoring of 13CO2 in the breath, quantified as time series delta over natural baseline 13CO2 (DOB) liberated from the drug during hepatic CYP-dependent detoxification. One confounding factor limiting the diagnostic value of such tests is that only a fraction of the liberated 13CO2 is immediately exhaled, while another fraction is taken up by body compartments from which it returns with delay to the plasma. The aims of this study were to establish a novel variant of the methacetin-based breath test LiMAx that allows to estimate and to eliminate the confounding effect of systemic 13CO2 distribution on the DOB curve and thus enables a more reliable assessment of the hepatic detoxification capacity compared with the conventional LiMAx test. We designed a new test variant (named "2DOB") consisting of two consecutive phases. Phase 1 is initiated by the intravenous administration of 13C-bicarbonate. Phase 2 starts about 30 min later with the intravenous administration of the 13C-labelled test drug. Using compartment modelling, the resulting 2-phasic DOB curve yields the rate constants for the irreversible elimination and the reversible exchange of plasma 13CO2 with body compartments (phase 1) and for the detoxification and exchange of the drug with body compartments (phase 2). We carried out the 2DOB test with the test drug 13C-methacetin in 16 subjects with chronic liver pathologies and 22 normal subjects, who also underwent the conventional LiMAx test. Individual differences in the systemic CO2 kinetics can lead to deviations up to a factor of 2 in the maximum of DOB curves (coefficient of variation CV ≈ 0.2) which, in particular, may hamper the discrimination between subjects with normal or mildly impaired detoxification capacities. The novel test revealed that a significant portion of the drug is not immediately metabolized, but transiently taken up into a storage compartment. Intriguingly, not only the hepatic detoxification rate but also the storage capacity of the drug, turned out to be indicative for a normal liver function. We thus used both parameters to define a scoring function which yielded an excellent disease classification (AUC = 0.95) and a high correlation with the MELD score (RSpearman = 0.92). The novel test variant 2DOB promises a significant improvement in the assessment of impaired hepatic detoxification capacity. The suitability of the test for the reliable characterization of the natural history of chronic liver diseases (fatty liver—fibrosis—cirrhosis) has to be assessed in further studies. [ABSTRACT FROM AUTHOR]

Nuclear-enriched abundant transcript 1 (NEAT1), a vital long noncoding RNA (lncRNA), exhibits the functions in disparate cancers. Nevertheless, the influences of NEAT1 in congenital heart disease (CHD) remain unreported. The research delves into whether NEAT1 affects H9c2 cells apoptosis and autophagy under the hypoxia condition. Overexpressed NEAT1 vector was transfected into H9c2 cells; then, functions of NEAT1 in cell viability, apoptosis, autophagy, PI3K/AKT/mTOR and JAK1/STAT3 pathways were detected in H9c2 cells under hypoxia condition. Expression of NEAT1 and miR-181b in hypoxia and blood samples from CHD was evaluated. After miR-181b inhibitor transfection, functions of miR-181b repression in the above-mentioned cell behavior and PI3K/AKT/mTOR and JAK1/STAT3 pathways were reassessed. Overexpressed NEAT1 clearly allayed hypoxia-triggered H9c2 cells apoptosis and autophagy. The decreased NEAT1 and miR-181b were showcased in hypoxia and blood samples from CHD; meanwhile, elevated miR-181b evoked by overexpressed NEAT1 was observed in hypoxia-managed H9c2 cells. More importantly, miR-181b inhibition obviously overturned the influences of NEAT1 in hypoxia-affected H9c2 cells apoptosis and autophagy. Besides, overexpressed NEAT1 facilitated PI3K/AKT/mTOR and JAK1/STAT3 activations via enhancing miR-181b. The research exposed that NEAT1 eased hypoxia-triggered H9c2 cells apoptosis and autophagy by expediting PI3K/AKT/mTOR and JAK1/STAT3 pathways via elevating miR-181b. [ABSTRACT FROM AUTHOR]

Surgery with or without radiation has always been the mainstay of treatment for patients with non-melanoma skin cancers, including basal cell carcinoma, squamous cell carcinoma, and Merkel cell carcinoma. Until recently, there were no effective systemic therapies for patients with advanced disease. This review will focus on the landmark clinical trials that led to Food and Drug Administration (FDA) approval of Vismodegib for advanced basal cell carcinoma (ERIVANCE BCC) and pembrolizumab for advanced Merkel cell carcinoma (KEYNOTE-017). These trials have not only changed the landscape for patients with metastatic disease but also notably for patients with locally advanced disease that is either unresectable or resectable with high morbidity. Additional mention is made for the clinical trial that led to FDA approval of cemiplimab for advanced cutaneous squamous cell carcinoma (EMPOWER-CSCC-1), which is already changing practice patterns, but for which longer-term data are still needed. [ABSTRACT FROM AUTHOR]

Visualizing regions of conserved synteny between two genomes is supported by numerous software applications. However, none of the current applications allow researchers to select genome features to display or highlight in blocks of synteny based on the annotated biological properties of the features (e.g., type, function, and/or phenotype association). To address this usability gap, we developed an interactive web-based conserved synteny browser, The Jackson Laboratory (JAX) Synteny Browser. The browser allows researchers to highlight or selectively display genome features in the reference and/or the comparison genome according to the biological attributes of the features. Although the current implementation for the browser is limited to the reference genomes for the laboratory mouse and human, the software platform is intentionally genome agnostic. The JAX Synteny Browser software can be deployed for any two genomes where genome coordinates for syntenic blocks are defined and for which biological attributes of the features in one or both genomes are available in widely used standard bioinformatics file formats. The JAX Synteny Browser is available at: http://syntenybrowser.jax.org/. The code base is available from GitHub: https://github.com/TheJacksonLaboratory/syntenybrowser and is distributed under the Creative Commons Attribution license (CC BY). [ABSTRACT FROM AUTHOR]

Recent genome-wide association studies (GWAS) in European descent population have identified more than 30 independent single-nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD). In the present study, we genotyped 39 AD-risk SNPs in 499 sporadic AD patients and 760 matched healthy controls of Mongolian ethnicity from the Inner Mongolia, China. Further, we investigated whether genetic risk score (GRS) combining multiple AD-risk loci confirmed in our study population could improve AD prediction. Two approaches were used for GRS calculation: a simple risk allele count (cGRS) and a weighted approach (wGRS). The area under the receiver operating characteristic curve (AUC) was used to compare the discriminatory ability of the GRS models. Seven SNPs were confirmed associated with AD and four SNPs were associated with AD risk independent of APOE genotypes in our population. GRS based on either seven SNPs or four APOE-independent SNPs were significantly associated with AD risk (P = 2.3E−17~2.0E−6). The AUC for wGRS was significantly greater than for cGRS (0.6416 versus 0.6339, P = 0.0049 for seven SNPs; 0.5857 versus 0.5765, P = 0.0047 for four APOE-independent SNPs). Furthermore, we found that wGRS combining four APOE-independent SNPs and APOE E4 genotypes reached AUC 0.7023, significantly better than the discriminate ability of APOE E4 genotypes alone (AUC = 0.6699, P = 0.0379). The combined model, with an AUC of 0.6989, significantly higher than that of APOE E4 alone (0.6529) (P = 0.0284), for subjects in a validation cohort comprising 250 cases and 380 controls, randomly selected from our original cohort. In summary, we found that wGRS based on four APOE-independent AD risk SNPs may supplement APOE E4 for better assessing individual risk for AD in Mongolian population in China. [ABSTRACT FROM AUTHOR]

Geobacter sulfurreducens pili enable extracellular electron transfer and play a role in secretion of c-type cytochromes such as OmcZ. PilA-deficient mutants of G. sulfurreducens have previously been shown to accumulate cytochromes within their membranes. This cytochrome retaining phenotype allowed for enhanced growth of PilA-deficient mutants in electron donor and carbon-limited conditions where formate and fumarate are provided as the sole electron donor and acceptor with no supplementary carbon source. Conversely, wild-type G. sulfurreducens, which has normal secretion of cytochromes, has comparative limited growth in these conditions. This growth is further impeded for OmcZ-deficient and OmcS-deficient mutants. A PilB-deficient mutant which prevents pilin production but allows for secretion of OmcZ had moderate growth in these conditions, indicating a role for cytochrome localization to enabling survival in the electron donor and carbon-limited conditions. To determine which pathways enhanced growth using formate, Sequential Window Acquisition of all Theoretical Mass Spectra mass spectrometry (SWATH-MS) proteomics of formate adapted PilA-deficient mutants and acetate grown wild type was performed. PilA-deficient mutants had an overall decrease in tricarboxylic acid (TCA) cycle enzymes and significant upregulation of electron transport chain associated proteins including many c-type cytochromes and [NiFe]-hydrogenases. Whole genome sequencing of the mutants shows strong convergent evolution and emergence of genetic subpopulations during adaptation to growth on formate. The results described here suggest a role for membrane constrained c-type cytochromes to the enhancement of survival and growth in electron donor and carbon-limited conditions. [ABSTRACT FROM AUTHOR]

Objectives: We sought to evaluate the correlation between MRI phenotypes of prostate cancer as defined by PI-RADS v2 and the Decipher Genomic Classifier (used to estimate the risk of early metastases).Methods: This single-center, retrospective study included 72 nonconsecutive men with prostate cancer who underwent MRI before radical prostatectomy performed between April 2014 and August 2017 and whose MRI registered lesions were microdissected from radical prostatectomy specimens and then profiled using Decipher (89 lesions; 23 MRI invisible [PI-RADS v2 scores ≤ 2] and 66 MRI visible [PI-RADS v2 scores ≥ 3]). Linear regression analysis was used to assess clinicopathologic and MRI predictors of Decipher results; correlation coefficients (r) were used to quantify these associations. AUC was used to determine whether PI-RADS v2 could accurately distinguish between low-risk (Decipher score < 0.45) and intermediate-/high-risk (Decipher score ≥ 0.45) lesions.Results: MRI-visible lesions had higher Decipher scores than MRI-invisible lesions (mean difference 0.22; 95% CI 0.13, 0.32; p < 0.0001); most MRI-invisible lesions (82.6%) were low risk. PI-RADS v2 had moderate correlation with Decipher (r = 0.54) and had higher accuracy (AUC 0.863) than prostate cancer grade groups (AUC 0.780) in peripheral zone lesions (95% CI for difference 0.01, 0.15; p = 0.018).Conclusions: MRI phenotypes of prostate cancer are positively correlated with Decipher risk groups. Although PI-RADS v2 can accurately distinguish between lesions classified by Decipher as low or intermediate/high risk, some lesions classified as intermediate/high risk by Decipher are invisible on MRI.Key Points: • MRI phenotypes of prostate cancer as defined by PI-RADS v2 positively correlated with a genomic classifier that estimates the risk of early metastases. • Most but not all MRI-invisible lesions had a low risk for early metastases according to the genomic classifier. • MRI could be used in conjunction with genomic assays to identify lesions that may carry biological potential for early metastases. [ABSTRACT FROM AUTHOR]

Non-functioning pituitary adenomas (NFPAs) are locally invasive with high morbidity. The objective of this study was to diagnose important genes and pathways related to the invasiveness of NFPAs and gain more insights into the underlying molecular mechanisms of NFPAs. The gene expression profiles of GSE51618 were downloaded from the Gene Expression Omnibus database with 4 non-invasive NFPA samples, 3 invasive NFPA samples, and 3 normal pituitary gland samples. Differentially expressed genes (DEGs) are screened between invasive NFPA samples and normal pituitary gland samples, followed by pathway and ontology (GO) enrichment analyses. Subsequently, a protein–protein interaction (PPI) network was constructed and analyzed for these DEGs, and module analysis was performed. In addition, a target gene–miRNA network and target gene–TF (transcription factor) network were analyzed for these DEGs. A total of 879 DEGs were obtained. Among them, 439 genes were upregulated and 440 genes were downregulated. Pathway enrichment analysis indicated that the upregulated genes were significantly enriched in cysteine biosynthesis/homocysteine degradation (trans-sulfuration) and PI3K-Akt signaling pathway, while the downregulated genes were mainly associated with docosahexaenoate biosynthesis III (mammals) and chemokine signaling pathway. GO enrichment analysis indicated that the upregulated genes were significantly enriched in animal organ morphogenesis, extracellular matrix, and hormone activity, while the downregulated genes were mainly associated with leukocyte chemotaxis, dendrites, and RAGE receptor binding. Subsequently, ESR1, SOX2, TTN, GFAP, WIF1, TTR, XIST, SPAG5, PPBP, AR, IL1R2, and HIST1H1C were diagnosed as the top hub genes in the upregulated and downregulated PPI networks and modules. In addition, HS3ST1, GPC4, CCND2, and SCD were diagnosed as the top hub genes in the upregulated and downregulated target gene–miRNA networks, while CISH, ISLR, UBE2E3, and CCNG2 were diagnosed as the top hub genes in the upregulated and downregulated target gene–TF networks. The new important DEGs and pathways diagnosed in this study may serve key roles in the invasiveness of NFPAs and indicate more molecular targets for the treatment of NFPAs. [ABSTRACT FROM AUTHOR]

Stroke can lead to the serious long-term neurological disability. The dysregulation of long non-coding RNAs (lncRNAs) has been proven to be a pivotal factor for the progression of ischemic stroke. However, it is largely unknown whether lncRNAs regulated the OGD/R injury of cerebral microglial cells. In this study, we designed experiments to reveal the role of lncRNA Nuclear Enriched Abundant Transcript 1 (NEAT1) in the OGD/R injury of microglial cells. We found that NEAT1 contributed to the OGD/R injury and neuroinflammation damage in microglial cells. Moreover, the molecular mechanism involved in the NEAT1-mediated OGD/R injury. Mechanism investigation revealed that NEAT1 was upregulated by the transcription factor YY1. Moreover, Western blot analysis suggested that NEAT1 enhance the protein levels of core factors of Wnt/β-catenin signaling pathway, indicating that NEAT1 contributed to the activation of Wnt/β-catenin signaling pathway. Rescue assays were carried out in the microglial cells treated with OGD/R. The results showed that NEAT1 regulated the OGD/R injury and neuroinflammation damage via Wnt/β-catenin signaling pathway. In conclusion, our findings suggested that YY1-induced upregulation of NEAT1 contributed to the OGD/R injury and neuroinflammation damage of microglial cells via Wnt/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]