Clinical relevance of exosome-derived microRNAs in Ovarian Cancer: Looking for new tumor biological fingerprints.

Specific tumor-derived extracellular vesicles, called exosomes, are considered as potential key players in cross-talk between immune system and tumor microenvironment in several solid tumors. Different studies highlighted the clinical relevance of exosomes in ovarian cancer (OC) for their role in early diagnosis, prognosis, chemoresistance, targeted therapy. The exosomes are nanosize vesicles carrying lipids, proteins, and nucleic acids. In particular, exosomes shuttle a wide spectrum of microRNAs (miRNAs) able to induce phenotypic reprogramming of target cells, contributing to tumor progression. In this review, we will discuss the promising role of miRNAs shuttled by exosomes, called exosomal miRNAs (exo-miRNAs), as potential biomarkers for early detection, tumour progression and metastasis, prognosis, and response to therapy in OC women, in order to search for new potential biological fingerprints able to better characterize the evolution of this malignancy and provide a clinically relevant non-invasive approach useful for adopting, in future, personalized therapeutic strategies.

Curation of causal interactions mediated by genes associated with autism accelerates the understanding of gene-phenotype relationships underlying neurodevelopmental disorders.

Autism spectrum disorder (ASD) comprises a large group of neurodevelopmental conditions featuring, over a wide range of severity and combinations, a core set of manifestations (restricted sociality, stereotyped behavior and language impairment) alongside various comorbidities. Common and rare variants in several hundreds of genes and regulatory regions have been implicated in the molecular pathogenesis of ASD along a range of causation evidence strength. Despite significant progress in elucidating the impact of few paradigmatic individual loci, such sheer complexity in the genetic architecture underlying ASD as a whole has hampered the identification of convergent actionable hubs hypothesized to relay between the vastness of risk alleles and the core phenotypes. In turn this has limited the development of strategies that can revert or ameliorate this condition, calling for a systems-level approach to probe the cross-talk of cooperating genes in terms of causal interaction networks in order to make convergences experimentally tractable and reveal their clinical actionability. As a first step in this direction, we have captured from the scientific literature information on the causal links between the genes whose variants have been associated with ASD and the whole human proteome. This information has been annotated in a computer readable format in the SIGNOR database and is made freely available in the resource website. To link this information to cell functions and phenotypes, we have developed graph algorithms that estimate the functional distance of any protein in the SIGNOR causal interactome to phenotypes and pathways. The main novelty of our approach resides in the possibility to explore the mechanistic links connecting the suggested gene-phenotype relations.

Theranostic biomarkers and PARP-inhibitors effectiveness in patients with non-BRCA associated homologous recombination deficient tumors: Still looking through a dirty glass window?

Breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) deleterious variants were the first and, still today, the main biomarkers of poly(ADP)ribose polymerase (PARP)-inhibitors (PARPis) benefit. The recent, increased, numbers of individuals referred for counseling and multigene panel testing, and the remarkable expansion of approved PARPis, not restricted to BRCA1/BRCA2-Pathogenic Variants (PVs), produced a strong clinical need for non-BRCA biomarkers. Significant limitations of the current testing and assays exist. The different approaches that identify the causes of Homologous Recombination Deficiency (HRD), such as the germline and somatic Homologous Recombination Repair (HRR) gene PVs, the testing showing its consequences, such as the genomic scars, or the novel functional assays such as the RAD51 foci testing, are not interchangeable, and should not be considered as substitutes for each other in clinical practice for guiding use of PARPi in non-BRCA, HRD-associated tumors. Today, the deeper knowledge on the significant relationship among all proteins involved in the HRR, not limited to BRCA, expands the possibility of a successful non-BRCA, HRD-PARPi synthetic lethality and, at the same time, reinforces the need for enhanced definition of HRD biomarkers predicting the magnitude of PARPi benefit.

Potential agnostic role of BRCA alterations in patients with several solid tumors: One for all, all for one?

Germline BRCA1/2 alterations in the Homologous Recombination (HR) pathway are considered as main susceptibility biomarkers to Hereditary Breast and Ovarian Cancers (HBOC). The modern molecular biology technologies allowed to characterize germline and somatic BRCA1/2 alterations in several malignancies, broadening the landscape of BRCA1/2-alterated tumors. In the last years, BRCA genetic testing, beyond the preventive value, also assumed a predictive and prognostic significance for patient management. The approval of molecules with agnostic indication is leading to a new clinical model, defined "mutational". Among these drugs, the Poly (ADP)-Ribose Polymerase inhibitors (PARPi) for BRCA1/2-deficient tumors were widely studied leading to increasing therapeutic implications. In this Review we provided an overview of the main clinical studies describing the association between BRCA-mutated tumors and PARPi response, focusing on the controversial evidence about the potential agnostic indication based on BRCA1/2 alterations in several solid tumors.

SIGNOR 3.0, the SIGnaling network open resource 3.0: 2022 update.

The SIGnaling Network Open Resource (SIGNOR 3.0, https://signor.uniroma2.it) is a public repository that captures causal information and represents it according to an 'activity-flow' model. SIGNOR provides freely-accessible static maps of causal interactions that can be tailored, pruned and refined to build dynamic and predictive models. Each signaling relationship is annotated with an effect (up/down-regulation) and with the mechanism (e.g. binding, phosphorylation, transcriptional activation, etc.) causing the regulation of the target entity. Since its latest release, SIGNOR has undergone a significant upgrade including: (i) a new website that offers an improved user experience and novel advanced search and graph tools; (ii) a significant content growth adding up to a total of approx. 33,000 manually-annotated causal relationships between more than 8900 biological entities; (iii) an increase in the number of manually annotated pathways, currently including pathways deregulated by SARS-CoV-2 infection or involved in neurodevelopment synaptic transmission and metabolism, among others; (iv) additional features such as new model to represent metabolic reactions and a new confidence score assigned to each interaction.

Risk Factors for Anaplastic Thyroid Carcinoma: A Case Series From a Tertiary Referral Center for Thyroid Surgery and Literature Analysis.

Anaplastic thyroid carcinoma (ATC) is a very rare and extremely aggressive disease with a very poor prognosis. Several risk factors have been hypothesized, but there is no clear-cut literature data on it. We reviewed the literature concerning risk factors for ATC and analyzed the institutional database from 2005 to 2022. In total, 15 papers were suitable for review, while the retrospective data collection search, conducted on our institutional database, provided 13 results. In our experience, in agreement with literature data, ATC seems to be a neoplasm peculiar to old age (in our database, mean age is 72 years), with a higher prevalence in subjects with a low level of education and a long history of multinodular goiter (MNG). The role of cigarette smoking and blood group, hypothesized on some literature data, was more uncertain, although the small sample size evaluated probably had a great influence on these results. The higher incidence of the disease in individuals with a history of MNG could suggest more aggressive choices in the treatment of a benign disease, in contrast to current practice. However, this may be a highly questionable point considering that ATC accounts for no more than 2% of all thyroid neoplasms in surgical departments, even those dedicated to endocrine neck surgery. Further studies are therefore necessary for a step forward in this direction.

Interpretation of intraoperative parathyroid hormone monitoring according to the Rome criterion in primary hyperparathyroidism.

Intraoperative parathyroid hormone dosage allows real-time monitoring of the decrease in PTH levels during parathyroidectomy and verify procedure's efficacy. Currently, none of the interpretative criteria used has absolute accuracy. The aim of this study is to evaluate diagnostic accuracy of the Rome criterion verifying diagnostic significance of the individual assays. A total of 205 patients with primary hyperparathyroidism from a single adenoma were retrospectively evaluated and monitored with baseline PTH, PTH at 10 min and PTH at 20 min after adenoma excision. The accuracy of the latter two assays compared with baseline was compared by ROC curves. In addition, was evaluated the influence on these data of localization diagnostics (ultrasounds and scintigraphy), definitive histology, and type of surgery performed. The ratio of 20-min sampling to baseline in the Rome criterion showed highest diagnostic significance. This finding was not influenced by the type of surgery performed, definitive histologic examination, or intraoperative localization of the adenoma. The Rome criterion has shown its high reliability in detecting persistence. The ratio of sampling at 20 min to baseline is by far the best performing. Further studies are needed to evaluate whether sampling at 10 min after adenoma excision can be considered not mandatory.

Exploring the Dynamic Crosstalk between the Immune System and Genetics in Gastrointestinal Stromal Tumors.

Gastrointestinal Stromal Tumors (GISTs) represent a paradigmatic model of oncogene addiction. Despite the well-known impact of the mutational status on clinical outcomes, we need to expand our knowledge to other factors that influence behavior heterogeneity in GIST patients. A growing body of studies has revealed that the tumor microenvironment (TME), mostly populated by tumor-associated macrophages (TAMs) and lymphocytes (TILs), and stromal differentiation (SD) have a significant impact on prognosis and response to treatment. Interestingly, even though the current knowledge of the role of immune response in this setting is still limited, recent pre-clinical and clinical data have highlighted the relevance of the TME in GISTs, with possible implications for clinical practice in the near future. Moreover, the expression of immune checkpoints, such as PD-L1, PD-1, and CTLA-4, and their relationship to the clinical phenotype in GIST are emerging as potential prognostic biomarkers. Looking forward, these variables related to the underlying tumoral microenvironment in GIST, though limited to still-ongoing trials, might lead to the potential use of immunotherapy, alone or in combination with targeted therapy, in advanced TKI-refractory GISTs. This review aims to deepen understanding of the potential link between mutational status and the immune microenvironment in GIST.

Value of Neurostimulation Plus Laryngeal Palpation to Predict Postoperative Vocal Fold Motility.

BACKGROUND: The aim of this study was to evaluate the reliability of intraoperative neuromonitoring through recurrent laryngeal nerve stimulation and simultaneous laryngeal palpation (NSLP) in predicting postoperative vocal cord palsy and in providing useful information in the decision to perform a staged surgery in initially planned total thyroidectomy. MATERIALS AND METHODS: A retrospective review was performed involving 552 patients for whom a total thyroidectomy was planned. In all patients, preoperative and postoperative laryngoscopy was performed. The incidence of vocal cord palsy was calculated on 1104 nerves at risk. RESULTS: Sensitivity and specificity of NSLP were 0.9411 and 0.9925 respectively. The positive predictive value was 0.7804, the negative predictive value was 0.9981, the false positive rate was 0.8%. In 41 patients (7.4%) the initial surgical strategy was changed into a staged procedure. Nine patients (21.9%) were false positive, 32 patients (78.1%) were true positive. Finally, a two-stage thyroidectomy was performed in 27 of 41 patients. CONCLUSIONS: High sensitivity and specificity confirm the validity of NSLP in predicting postoperative vocal cord palsy and in driving a possible staged thyroidectomy, both in benign thyroid disease and in differentiated thyroid carcinoma.