Omics sciences and precision medicine in melanoma

Background: This article provides an overview of the application of omics sciences in melanoma research. The name omics sciences refers to the large-scale analysis of biological molecules like DNA, RNA, proteins, and metabolites. Methods: In the course of this review, we have adopted a focu-sed research strategy, meticulously selecting the most pertinent and emblematic articles related to the topic. Our methodology included a systematic examination of the scientific literature to guarantee a thorough and precise synthesis of the existing sources. Results: With the advent of high-throughput technologies, omics have become an essential tool for understanding the complexity of melanoma. In this article, we discuss the different omics approaches used in melanoma research, including genomics, transcriptomics, proteomics, and metabolomics. We also highlight the major findings and insights gained from these studies, including the identification of new therapeutic targets and the development of biomarkers for diagnosis and prognosis. Finally, we discuss the challenges and future directions in omics-based melanoma research, including the integration of multiple omics data and the development of personalized medicine approaches. Conclusions: Overall, this article emphasizes the importance of omics science in advancing our understanding of melanoma and its potential for improving patient outcomes

Towards a Long-Read Sequencing Approach for the Molecular Diagnosis of RPGRORF15 Genetic Variants

Sequencing of the low-complexity ORF15 exon of RPGR, a gene correlated with retinitis pigmentosa and cone dystrophy, is difficult to achieve with NGS and Sanger sequencing. False results could lead to the inaccurate annotation of genetic variants in dbSNP and ClinVar databases, tools on which HGMD and Ensembl rely, finally resulting in incorrect genetic variants interpretation. This paper aims to propose PacBio sequencing as a feasible method to correctly detect genetic variants in low-complexity regions, such as the ORF15 exon of RPGR, and interpret their pathogenicity by structural studies. Biological samples from 75 patients affected by retinitis pigmentosa or cone dystrophy were analyzed with NGS and repeated with PacBio. The results showed that NGS has a low coverage of the ORF15 region, while PacBio was able to sequence the region of interest and detect eight genetic variants, of which four are likely pathogenic. Furthermore, molecular modeling and dynamics of the RPGR Glu-Gly repeats binding to TTLL5 allowed for the structural evaluation of the variants, providing a way to predict their pathogenicity. Therefore, we propose PacBio sequencing as a standard procedure in diagnostic research for sequencing low-complexity regions such as RPGRORF15, aiding in the correct annotation of genetic variants in online databases

The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology

Background & Aims: Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF. Methods: A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded. Results: Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC). Conclusions: Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. ClinicalTrials.gov number: NCT03056612. Lay summary: Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death – termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD – patients in this group rarely require hospital admission and have a much lower 1-year mortality risk

KCNJ5 gene somatic mutations affect cardiac remodelling but do not preclude cure of high blood pressure and regression of left ventricular hypertrophy in primary aldosteronism.

OBJECTIVE:: Aldosterone exerts detrimental cardiovascular effects, and patients with an aldosterone-producing adenoma (APA) carrying somatic mutations in the KCNJ5 K channel (mutAPA) have higher plasma aldosterone concentration than wild-type APA (wtAPA) patients. We therefore investigated whether mutAPA patients develop a more prominent cardiovascular damage than wtAPA patients

GPER-1 and estrogen receptor-\u3b2 ligands modulate aldosterone synthesis

Fertile women have lower blood pressure and cardiovascular risk than age-matched men, which suggests that estrogens exert cardiovascular protective effects. However, whether 17 \u3b2-estradiol (E2) blunts aldosterone secretion, and thereby affects the gender dimorphism of blood pressure, is unknown. We therefore sought for the estrogen receptor (ER) subtypes in human adrenocortical tissues ex vivo by performing gene and protein expression studies. We also investigated the effect of E2 on aldosterone synthesis and the involved receptors through in vitro functional experiments in the adrenocortical cells HAC15. We found that in the human adrenal cortex and aldosterone-producing adenoma cells, the most expressed ERs were the ER\u3b2 and the G protein-coupled receptor-1 (GPER-1), respectively. After selective ER\u3b2 blockade, E2 (10 nmol/L) markedly increased both the expression of aldosterone synthase and the production of aldosterone (+5- to 7-fold vs baseline, P < .001). Under the same condition, the GPER-1 receptor agonist 1-[4-(6-bromo-benzo (1, 3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c] quinolin-8-yl]-ethanone (G-1) (10 nmol/L) mimicked this effect, which was abrogated by cotreatment with either the GPER-1 receptor antagonist (3aS*,4R*,9bR*)-4-(6-Bro-mo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta[c]quinoline (G-15), or a selective protein kinase A inhibitor 8-Bromo-2-monobutyryladenosine-3,5-cyclic mono-phosphorothioate, Rp-isomer. Silencing of the ER\u3b2 significantly raised aldosterone synthase expression and aldosterone production. Conversely, silencing of the GPER-1 lowered aldosterone synthase gene and protein expression. Moreover, it blunted the stimulatory effect of E2 on aldosterone synthase that was seen during ER\u3b2 blockade. These results support the conclusion that in humans, E2 inhibits aldosterone synthesis by acting via ER\u3b2. Pharmacologic disinhibition of ER\u3b2 unmasks a potent secretagogue effect of E2 that involves GPER-1 and protein kinase A signaling

The Role of Olive Tree Polyphenols In The Prevention of COVID-19: A Scoping Review Part 2

Abstract: The recent COVID-19 pandemic caused by SARS-CoV-2 affected hundreds of millions of people and caused millions of deaths. There are few effective medications against SARS-CoV-2, and several stud-ies attempted to make drugs based on natural components, such as olive leaves. Olive leaves are rich in polyphenolic compounds, which were proposed as a viable co-therapy supplement to treat and improve clinical symptoms in COVID-19 patients. Polyphenols have renown anti-inflammatory and multitarget antiviral effects on several virus families, which could be among the reasons of the beneficial effects of the Mediterranean diet against COVID-19. This scoping review is focused on the effect of olive tree polyphenols as a natural remedy to inhibit SARS-CoV-2, mainly discussing their influence on the process of viral entry into host cells by endocytosis

Omics sciences and precision medicine in kidney cancer

: In the last decade, renal carcinoma has become more prevalent in European and North American regions. Kidney tumors are usually categorized based on histological features, with renal cell carcinoma being the most common subtype in adults. Despite conventional diagnostic and therapeutic strategies, a rise in cancer incidence and recurrence necessitates a fresh approach to diagnosing and treating kidney cancer. This review focuses on novel multi-omics approaches, such as genomics, transcriptomics, proteomics, metabolomics, and microbiomics, to better understand the molecular and clinical features of renal cell carcinoma. Studies integrating omics sciences have shown early promise in enhancing prognostic and therapeutic outcomes for various kidney cancer subtypes and providing insight into fundamental pathophysiological mechanisms occurring at different molecular levels. This review highlights the importance of utilizing omics sciences as a revolutionary concept in diagnostics and therapeutics and the clinical implications of renal cell carcinoma. Finally, the review presents the most recent findings from large-scale multi-omics studies on renal cell carcinoma and its associations with patient subtyping and drug development

Omics sciences and precision medicine in thyroid cancer

Background: Thyroid cancer, a heterogeneous disease originating from the thyroid gland, stands as the predominant endocrine malignan-cy worldwide. Despite advances in diagnosis and treatment, some patients still experience recurrence and mortality, which highlights the need for more personalized approaches to treatment. Omics sciences, encompassing genomics, transcriptomics, proteomics, and metabolomics, offer a high-throughput and impartial methodology for investigating the molecular signatures of thyroid cancer. Methods: In the course of this review, we have adopted a focu-sed research strategy, meticulously selecting the most pertinent and emblematic articles related to the topic. Our methodology included a systematic examination of the scientific literature to guarantee a thorough and precise synthesis of the existing sources. Results: These techniques enable the identification of molecular markers that can aid in diagnosis, prognosis, and treatment selection. As an illustration, through genomics studies, numerous genetic alterations commonly discovered in thyroid cancer have been identified, such as mutations in the BRAF and RAS genes. Through transcriptomics studies, distinctively expressed genes in thyroid cancer have been uncovered, playing roles in diverse biological processes, including cell proliferation, invasion, and metastasis. These genes can serve as potential targets for novel therapies. Proteomics studies have unveiled differentially expressed proteins intricately involved in thyroid cancer pathogenesis, presenting promising biomarkers for early detection and disease progression monitoring. Metabolomics studies have identified alterations in metabolic pathways linked to thyroid cancer, offering promising avenues for potential therapeutic targets. Conclusions: Precision medicine in thyroid cancer involves the integration of omics sciences with clinical data to develop personalized treatment plans for patients. Employing targeted therapies guided by molecular markers has exhibited promising outcomes in enhancing the prognosis of thyroid cancer patients. Notably, those with advanced hyroid cancer carrying BRAF mutations have displayed substantial responses to specific targeted therapies, such as vemurafenib and dabrafenib

Omics sciences and precision medicine in Urothelial Carcinoma

: This comprehensive review explores the potential of omics sciences - such as genomics, transcriptomics, proteomics, and metabolomics - in advancing the diagnosis and therapy of urothelial carcinoma (UC), a prevalent and heterogeneous cancer affecting the urinary tract. The article emphasizes the significant advancements in understanding the molecular mechanisms underlying UC development and progression, obtained through the application of omics approa-ches. Genomic studies have identified recurrent genetic alterations in UC, while transcriptomic analyses have revealed distinct gene expression profiles associated with different UC subtypes. Proteomic investigations have recognized protein biomarkers with diagnostic and prognostic potential, and metabolomic profiling has found metabolic alterations that are specific to UC. The integration of multi-omics data holds promises in refining UC subtyping, identifying therapeutic targets, and predicting treatment response. However, challenges like the standardization of omics technologies, validation of biomarkers, and ethical considerations need to be addressed to successfully translate these findings into clinical practice. Omics sciences offer tremendous potential in revolutionizing the diagnosis and therapy of UC, enabling more precise diagnostic methods, prognostic evaluations, and personalized treatment selection for UC patients. Future research efforts should focus on overcoming these challenges and translating omics discoveries into meaningful clinical applications to improve outcomes for UC patients