Dysregulation of testis mRNA expression levels in hatchery-produced vs wild greater amberjack Seriola dumerili.

Reproductive dysfunctions have been recently documented in male greater amberjack Seriola dumerili caught from the wild and reared in captivity. In the present study, we compared testis transcriptome in wild fish (WILD), hatchery-produced fish with apparently normal spermatogenesis (Normal Farmed; NormalF) and hatchery-produced fish with evident reproductive dysfunction (Dysfunctional Farmed; DysF). Gene expression analysis identified 2157, 1985 and 74 differentially expressed genes (DEGs) in DysF vs WILD, NormalF vs DysF and NormalF vs WILD comparisons, respectively. In DysF, a dysregulation of several interconnected biological processes, including cell assembly, steroidogenesis and apoptosis was found. Gene enrichment of progesterone-mediated oocyte maturation, oocyte meiosis and cell cycle pathways were identified in the DysF vs NormalF comparison. Most of the DEGs involved in the enriched pathways were downregulated in DysF. The comparison of NormalF vs WILD showed that most of the DEGs were downregulated in NormalF, including a gene that encodes for a regulatory protein with a protective role in apoptosis regulation (ptpn6), indicating that spermatogenesis was dysfunctional also in the apparently "normal" hatchery-produced fish. Hence, rearing of male greater amberjack in captivity, from eggs produced by captive breeders, did not prevent the appearance of reproductive dysfunctions, and these dysfunctions involved several biological processes and metabolic pathways.

Algorithm for Reducing Overall Biological Detriment Caused by PET/CT: an Age-Based Study.

Purpose: This study is to use a simple algorithm based on patient's age to reduce the overall biological detriment associated with PET/CT. Materials and Methods: A total of 421 consecutive patients (mean age 64 ± 14 years) undergoing PET for various clinical indications were enrolled. For each scan, effective dose (ED in mSv) and additional cancer risk (ACR) were computed both in a reference condition (REF) and after applying an original algorithm (ALGO). The ALGO modified the mean dose of FDG and the PET scan time parameters; indeed, a lower dose and a longer scan time were reported in the younger, while a higher dose and a shorter scan time in the older patients. Moreover, patients were classified by age bracket (18-29, 30-60, and 61-90 years). Results: The ED was 4.57 ± 0.92 mSv in the REF condition. The ACR were 0.020 ± 0.016 and 0.0187 ± 0.013, respectively, in REF and ALGO. The ACR for the REF and ALGO conditions were significantly reduced in males and females, although it was more evident in the latter gender (all p < 0.0001). Finally, the ACR significantly reduced from the REF condition to ALGO in all three age brackets (all p < 0.0001). Conclusion: Implementation of ALGO protocols in PET can reduce the overall ACR, mainly in young and female patients.

Rethinking Tako-tsubo Cardiomyopathy: The Contribution of Myocardial Pathology and Molecular Imaging.

BACKGROUND: Despite substantial research, the mechanisms behind stress Tako-tsubo cardiomyopathy (TTC) remain rather elusive. OBJECTIVE: The purpose of this paper was to provide a detailed review of the mainstream factors underlying the pathophysiology of TTC, highlighting the novel contributions of molecular pathology and in-vivo molecular imaging. METHODS: A careful literature review selected all papers discussing TTC, specifically those providing novel insights from myocardial pathology and cardiac molecular imaging. RESULTS: Results concerning myocardial pathology, defect extension, sites and relationships between functional parameters underline the existence of a causal relationship between a determinant (e.g., the release of catecholamines induced by stress) and an outcome for TTC, which is not limited to a reversible contractile cardiomyopathy, but it includes reversible changes in myocardial perfusion and a long-lasting residual deficit in sympathetic function. Besides, they reinforce the hypothesis that sympathetic nerves may exert a complex control on cardiac contractile function, which is likely to be direct or indirect through metabolism and microvascular perfusion changes during anaerobic and aerobic conditions. CONCLUSION: TTC is characterized by acute transient left ventricular systolic dysfunction, which can be challenging to distinguish from myocardial infarction at presentation. Catecholamineinduced myocardial injury is the most established theory, but other factors, including myocardial metabolism and perfusion, should be considered of utmost importance. Each effort to clarify the numerous pathways and emerging abnormalities may provide novel approaches to treat the acute episode, avoid recurrences, and prevent major adverse cardiovascular events.

The Role of Molecular Imaging in Patients with Brain Metastases: A Literature Review.

Over the last several years, molecular imaging has gained a primary role in the evaluation of patients with brain metastases (BM). Therefore, the "Response Assessment in Neuro-Oncology" (RANO) group recommends amino acid radiotracers for the assessment of BM. Our review summarizes the current use of positron emission tomography (PET) radiotracers in patients with BM, ranging from present to future perspectives with new PET radiotracers, including the role of radiomics and potential theranostics approaches. A comprehensive search of PubMed results was conducted. All studies published in English up to and including December 2022 were reviewed. Current evidence confirms the important role of amino acid PET radiotracers for the delineation of BM extension, for the assessment of response to therapy, and particularly for the differentiation between tumor progression and radionecrosis. The newer radiotracers explore non-invasively different biological tumor processes, although more consistent findings in larger clinical trials are necessary to confirm preliminary results. Our review illustrates the role of molecular imaging in patients with BM. Along with magnetic resonance imaging (MRI), the gold standard for diagnosis of BM, PET is a useful complementary technique for processes that otherwise cannot be obtained from anatomical MRI alone.

Cumulus Cell Transcriptome after Cumulus-Oocyte Complex Exposure to Nanomolar Cadmium in an In Vitro Animal Model of Prepubertal and Adult Age.

Cadmium (Cd), a highly toxic pollutant, impairs oocyte fertilization, through oxidative damage on cumulus cells (CCs). This study analysed the transcriptomic profile of CCs of cumulus-oocyte complexes (COCs) from adult and prepubertal sheep, exposed to Cd nanomolar concentration during in vitro maturation. In both age-groups, CCs of matured oocytes underwent RNA-seq, data analysis and validation. Differentially expressed genes (DEGs) were identified in adult (n = 99 DEGs) and prepubertal (n = 18 DEGs) CCs upon Cd exposure. Transcriptomes of adult CCs clustered separately between Cd-exposed and control samples, whereas prepubertal ones did not as observed by Principal Component Analysis. The transcriptomic signature of Cd-induced CC toxicity was identified by gene annotation and literature search. Genes associated with previous studies on ovarian functions and/or Cd effects were confirmed and new genes were identified, thus implementing the knowledge on their involvement in such processes. Enrichment and validation analysis showed that, in adult CCs, Cd acted as endocrine disruptor on DEGs involved in hormone biosynthesis, cumulus expansion, regulation of cell signalling, growth and differentiation and oocyte maturation, whereas in prepubertal CCs, Cd affected DEGs involved in CC development and viability and CC-oocyte communications. In conclusion, these DEGs could be used as valuable non-invasive biomarkers for oocyte competence.

FDG PET/CT for Staging and Restaging Malignant Mesothelioma.

Malignant mesothelioma is an aggressive tumor originating from the mesothelial cells and presenting in general with a very poor prognosis. The pleural localization represents the prevailing disease site, while peritoneal involvement is commonly rare. The WHO classifies mesotheliomas into epithelioid, biphasic, and sarcomatoid histotypes, having diverse outcome with the sarcomatoid or biphasic forms showing the poorest prognosis. Given the peculiar rind-like pattern of growth, mesothelioma assessment is rather challenging for medical imagers. Conventional imaging is principally based on contrast-enhanced CT, while the role of functional and metabolic imaging is regarded as complementary. By focusing essentially on the staging and restaging role of [18F]FDG PET/CT in malignant mesotheliomas, the present review will summarize the available data present in literature and provide some hints on alternative imaging and future perspectives. Given the prevailing incidence of pleural disease, the majority of the information will be addressed on malignant pleural mesothelioma, although a summary of principal characteristics and imaging findings in patients with peritoneal mesothelioma will be also provided.

"Good Wine Makes Good Blood": An Integrated Approach to Characterize Autochthonous Apulian Grapevines as Promising Candidates for Healthy Wines.

Wine production represents an ancient human activity and one of the most economically important markets in Europe. Moreover, the health effects of grapes and related products have been largely demonstrated, and mostly depend on their richness in bioactive molecules such as flavonoid and non-flavonoid phenolic compounds. Italy has the highest global wine production and provides one of the richest grapevine germplasm in the Mediterranean area. In this paper, our attention was focused on the evaluation of the total phenol and anthocyanin content in five autochthonous Apulian grapevine cultivars, in both wines and their non-alcoholic extracts. Moreover, the potential antioxidant effects of the non-alcoholic wine extracts on the cell viability of Caco-2 and HeLa carcinoma cell lines were tested. Finally, for the most promising autochthonous selected cultivars (Negramaro, Nero di Troia and Susumaniello), comparative transcriptomic analysis in berries was performed using high-throughput sequencing technology.

The Role of Radiomics in the Era of Immune Checkpoint Inhibitors: A New Protagonist in the Jungle of Response Criteria.

Immune checkpoint inhibitors (ICI) have demonstrated encouraging results in terms of durable clinical benefit and survival in several malignancies. Nevertheless, the search to identify an "ideal" biomarker for predicting response to ICI is still far from over. Radiomics is a new translational field of study aiming to extract, by dedicated software, several features from a given medical image, ranging from intensity distribution and spatial heterogeneity to higher-order statistical parameters. Based on these premises, our review aims to summarize the current status of radiomics as a potential predictor of clinical response following immunotherapy treatment. A comprehensive search of PubMed results was conducted. All studies published in English up to and including December 2021 were selected, comprising those that explored computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) for radiomic analyses in the setting of ICI. Several studies have demonstrated the potential applicability of radiomic features in the monitoring of the therapeutic response beyond the traditional morphologic and metabolic criteria, as well as in the prediction of survival or non-invasive assessment of the tumor microenvironment. Nevertheless, important limitations emerge from our review in terms of standardization in feature selection, data sharing, and methods, as well as in external validation. Additionally, there is still need for prospective clinical trials to confirm the potential significant role of radiomics during immunotherapy.

Changes over the years in radiopharmaceutical design.

Of the many uses of radiopharmaceuticals, developing radiotracers that contribute significantly to diagnosis and therapy of patients has been a major focus. This requires a broad spectrum of expertise including that of the attending physician who lends insight to an unmet clinical need neither addressed by other imaging techniques nor by analysis of tissue, blood, and urine for diagnostics and addressed by pharmaceuticals for therapeutic applications. The design criteria have depended on radiochemistry, on matching the radiopharmaceutical with the imaging devices, and basing the design on current pharmaceuticals. The chelates of technetium-99m were based on radiochemistry rather than clinical need yet are still used today in >70% of the clinical studies. Targeted radiotracers in neurologic and psychiatric disorders, inflammation, cardiovascular disease, and oncology have all been studied with the goal of determining the change in the density of a target protein as a function of disease or treatment or, especially in oncology, detection of the total extent of disease. In the latter approach, PET in university settings leads the way; however, the use of SPECT/CT has increased the specificity of SPECT imaging to complement the cost-effective generator and instant kits already available. Remarkable advances have been achieved in radionuclide therapy using theragnostic agents, with the exclusive domain of oncology. For this application the design of radionuclide therapy follows that used for diagnostics. The increased impact of the discipline depends on the opportunity to continue the search for the most appropriate radiopharmaceutical for each individual patient.

The Alleviating Effect of Herniarin Against Ionizing Radiation-Induced Genotoxicity and Cytotoxicity in Human Peripheral Blood Lymphocytes.

BACKGROUND AND OBJECTIVE: Herniarin is a simple coumarin that is found naturally in some plant species. In this study, we aimed to evaluate the protective effect of herniarin against ionizing radiation-induced genotoxicity and cytotoxicity in human peripheral blood lymphocytes. METHODS: Herniarin was added to human lymphocytes before irradiation with a dose of 2 Gy of Xrays. The antagonistic potential of herniarin against radiation was measured by MTT [3-(4,5- dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide] assay, micronucleus assay, flow cytometry, and reactive oxygen species (ROS) level analysis. RESULTS: The maximum survival of lymphocytes against radiation was observed at a concentration of 50 µM of herniarin and a treatment time of 1 h. Pretreatment with 50 µM herniarin significantly decreased the micronuclei frequency, the percentage of apoptotic lymphocytes, and the ROS level in irradiated human lymphocytes. Moreover, 50 µM herniarin significantly increased the cytokinesis blocked proliferation index in irradiated lymphocytes. CONCLUSION: Herniarin could reduce radiation-induced cytotoxicity and genotoxicity in human lymphocytes. To complete the results of this study, it is suggested that in the future, more preclinical studies with larger samples or animal models be performed on herniarin.

From the Magic Bullet to Theragnostics: Certitudes and Hypotheses, Trying to Optimize the Somatostatin Model.

The first "theragnostic model", that of radioiodine, was first applied both in diagnosis and therapy in the 1940s. Since then, many other theragnostic models have been introduced into clinical practice. To bring about the closest pharmacokinetic connection, the radiocompound used for diagnosis and therapy should be the same, although at present this is rarely applicable. Today, a widely applied and effective model is also the "DOTA-Ga-68/Lu-177", used with success in neuroendocrine tumors (NET). In this paper, we analyze the necessary steps from the in vitro evaluation of a target to the choice of radionuclide and chelate for therapy up to in vivo transition and clinical application of most employed radiocompounds used for theragnostic purposes. Possible future applications and strategies of theragnostic models are also highlighted.

RNA Editing Detection in HPC Infrastructures.

RNA editing by A-to-I deamination is a relevant co/posttranscriptional modification carried out by ADAR enzymes. In humans, it has pivotal cellular effects and its deregulation has been linked to a variety of human disorders including neurological and neurodegenerative diseases and cancer. Despite its biological relevance, the detection of RNA editing variants in large transcriptome sequencing experiments (RNAseq) is yet a challenging computational task. To drastically reduce computing times we have developed a novel REDItools version able to identify A-to-I events in huge amount of RNAseq data employing High Performance Computing (HPC) infrastructures.Here we show how to use REDItools v2 in HPC systems.

Databases for RNA Editing Collections.

A-to-I RNA editing in humans plays a relevant role since it can influence gene expression and increase proteome diversity. In addition, its deregulation has been linked to a variety of human diseases, including neurological disorders and cancer.In the last decade, massive transcriptome sequencing through the RNAseq technology has dramatically improved the investigation of RNA editing at single nucleotide resolution. Nowadays, different bioinformatics resources to discover and/or collect A-to-I events have been released. Hereafter, we initially provide an overview of the state-of-the-art RNA editing databases and, then, we focus on REDIportal, the largest collection of A-to-I events with more than 4.5 million sites from 2660 humans GTEx samples.

Detection of A-to-I RNA Editing in SARS-COV-2.

ADAR1-mediated deamination of adenosines in long double-stranded RNAs plays an important role in modulating the innate immune response. However, recent investigations based on metatranscriptomic samples of COVID-19 patients and SARS-COV-2-infected Vero cells have recovered contrasting findings. Using RNAseq data from time course experiments of infected human cell lines and transcriptome data from Vero cells and clinical samples, we prove that A-to-G changes observed in SARS-COV-2 genomes represent genuine RNA editing events, likely mediated by ADAR1. While the A-to-I editing rate is generally low, changes are distributed along the entire viral genome, are overrepresented in exonic regions, and are (in the majority of cases) nonsynonymous. The impact of RNA editing on virus-host interactions could be relevant to identify potential targets for therapeutic interventions.

Theragnostics before we found its name.

Theragnostics embraces "gnosis" and "prognosis" and concerns a treatment strategy which combines diagnostics with therapeutics. The birth of what we call today theragnostics can be traced in 1936, with the proposal of radioiodine, the first radiopharmaceutical approved in 1951 by FDA, in USA, as 131I sodium iodide. In 1957, 89Sr was also approved as first therapeutic radiotracer for skeletal metastases, followed in the subsequent years by 186Rh, 153Sm and, more recently, 223Ra, the first alpha emitter clinically utilized, allowing curative results and not only a palliative effect. Proposed in first eighties as [131I] Metaiodobenzylguanidine (MIBG), the theragnostic couple 123I/131I MIBG is still used in neural crest tumors, while, starting from partially unsatisfactory results in 70's, models based on antibodies for radioimmunoscintigraphy/radioimmunotherapy have been subsequently upgraded thanks to the introduction of monoclonal antibodies and other significant biological and technical improvements. The "Theragnostics called with this name" can be dated to early 90's with the first proposal of the somatostatin model, actually widely operating in neuroendocrine tumors with radio-chelates usable for diagnosis and therapy. Since then, many investigators are working on new theragnostics agents, also outside of the nuclear medicine, based on peptides, antibodies and other tools to find new models applicable in the clinical practice. The fast growth is stimulated by the interest of big pharma. Theragnostic concepts are the roots of nuclear medicine and new great goals are soon to be achieved in the direction of an increasing precision and tailored medicine.

REDIportal: millions of novel A-to-I RNA editing events from thousands of RNAseq experiments.

RNA editing is a relevant epitranscriptome phenomenon able to increase the transcriptome and proteome diversity of eukaryotic organisms. ADAR mediated RNA editing is widespread in humans in which millions of A-to-I changes modify thousands of primary transcripts. RNA editing has pivotal roles in the regulation of gene expression or modulation of the innate immune response or functioning of several neurotransmitter receptors. Massive transcriptome sequencing has fostered the research in this field. Nonetheless, different aspects of the RNA editing biology are still unknown and need to be elucidated. To support the study of A-to-I RNA editing we have updated our REDIportal catalogue raising its content to about 16 millions of events detected in 9642 human RNAseq samples from the GTEx project by using a dedicated pipeline based on the HPC version of the REDItools software. REDIportal now allows searches at sample level, provides overviews of RNA editing profiles per each RNAseq experiment, implements a Gene View module to look at individual events in their genic context and hosts the CLAIRE database. Starting from this novel version, REDIportal will start collecting non-human RNA editing changes for comparative genomics investigations. The database is freely available at http://srv00.recas.ba.infn.it/atlas/index.html.