TERRA G-quadruplex stabilization behind the anti-multiple myeloma activity: Novel insights about resveratrol pleiotropic effects.

Resveratrol (RSV) is a nutraceutical compound belonging to the nonflavonoid polyphenol family, whose antioxidants, anti-inflammatory, and antitumoral properties have been widely investigated. The ability of RSV to provide beneficial effects for neurological, cardiovascular, and cancer disorders rekindled the interest to explore the molecular mechanisms behind its pleiotropic effects, which are due to the modulation of coding and noncoding genes involved in many key biological pathways. With a computational approach, including docking studies and thermodynamics calculations followed by 200-ns-long molecular dynamics and a clustering analysis, we hypothesized the stabilizing binding between RSV and G4 structures of telomeric repeat-containing RNA (TERRA), which is a tumor-suppressive long noncoding RNAs (lncRNA) involved in the regulation of telomere maintenance.

The Effect of Physical Activity/Exercise on miRNA Expression and Function in Non-Communicable Diseases-A Systematic Review.

Exercise may differently affect the expression of key molecular markers, including skeletal muscle and circulating miRNAs, involved in cellular and metabolic pathways' regulation in healthy individuals and in patients suffering from non-communicable diseases (NCDs). Epigenetic factors are emerging as potential therapeutic biomarkers in the prognosis and treatment of NCDs and important epigenetic factors, miRNAs, play a crucial role in cellular pathways. This systematic review aims to underline the potential link between changes in miRNA expression after different types of physical activity/exercise in some populations affected by NCDs.

Exploring the impact of lipid droplets on the evolution and progress of hepatocarcinoma.

Over the past 10 years, the biological role of lipid droplets (LDs) has gained significant attention in the context of both physiological and pathological conditions. Considerable progress has been made in elucidating key aspects of these organelles, yet much remains to be accomplished to fully comprehend the myriad functions they serve in the progression of hepatic tumors. Our current perception is that LDs are complex and active structures managed by a distinct set of cellular processes.

Identification of ADME genes polymorphic variants linked to trastuzumab-induced cardiotoxicity in breast cancer patients: Case series of mono-institutional experience.

Background: Long-term survival induced by anticancer treatments discloses emerging frailty among breast cancer (BC) survivors. Trastuzumab-induced cardiotoxicity (TIC) is reported in at least 5% of HER2+BC patients. However, TIC mechanism remains unclear and predictive genetic biomarkers are still lacking.

Genetic Biomarkers of Sorafenib Response in Patients with Hepatocellular Carcinoma.

The identification of biomarkers for predicting inter-individual sorafenib response variability could allow hepatocellular carcinoma (HCC) patient stratification. SNPs in angiogenesis- and drug absorption, distribution, metabolism, and excretion (ADME)-related genes were evaluated to identify new potential predictive biomarkers of sorafenib response in HCC patients. Five known SNPs in angiogenesis-related genes, including , , , , and , were investigated in 34 HCC patients (9 sorafenib responders and 25 non-responders).

Downregulation Increases Intracellular Lipids by Reducing Energy Utilization.

Background: ANGPTL3 (angiopoietin-like protein 3) is a circulating protein with a key role in maintaining lipoprotein homeostasis. A monoclonal antibody against ANGPTL3 is an approved and well-tolerated treatment to reduce lipoproteins in familial hypercholesterolemia homozygotes. However, the reduction of hepatic ANGPTL3 synthesis using an antisense oligonucleotide unexpectedly resulted in a dose-dependent increase in liver lipid content and circulating transaminases, resulting in the termination of the clinical trial.

GPER1 Activation Exerts Anti-Tumor Activity in Multiple Myeloma.

G protein-coupled estrogen receptor 1 (GPER1) activation is emerging as a promising therapeutic strategy against several cancer types. While GPER targeting has been widely studied in the context of solid tumors, its effect on hematological malignancies remains to be fully understood. Here, we show that GPER1 mRNA is down-regulated in plasma cells from overt multiple myeloma (MM) and plasma cell leukemia patients as compared to normal donors or pre-malignant conditions (monoclonal gammopathy of undetermined significance and smoldering MM); moreover, lower GPER1 expression associates with worse overall survival of MM patients.

An Uncharacterised lncRNA Coded by the ASAP1 Locus Is Downregulated in Serum of Type 2 Diabetes Mellitus Patients.

Diabetes mellitus (DM) is a complex and multifactorial disease characterised by high blood glucose. Type 2 Diabetes (T2D), the most frequent clinical condition accounting for about 90% of all DM cases worldwide, is a chronic disease with slow development usually affecting middle-aged or elderly individuals. T2D represents a significant problem of public health today because its incidence is constantly growing among both children and adults.

Safety and activity of the first-in-class locked nucleic acid (LNA) miR-221 selective inhibitor in refractory advanced cancer patients: a first-in-human, phase 1, open-label, dose-escalation study.

Background: We developed a 13-mer locked nucleic acid (LNA) inhibitor of miR-221 (LNA-i-miR-221) with a full phosphorothioate (PS)-modified backbone. This agent downregulated miR-221, demonstrated anti-tumor activity against human xenografts in mice, and favorable toxicokinetics in rats and monkeys. Allometric interspecies scaling allowed us to define the first-in-class LNA-i-miR-221 safe starting dose for the clinical translation.

TERRA G-quadruplex stabilization as a new therapeutic strategy for multiple myeloma.

Background: Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability, and telomere dysfunction is an important cause of acquired genomic alterations. Telomeric repeat-containing RNA (TERRA) transcripts are long non-coding RNAs involved in telomere stability through the interaction with shelterin complex. Dysregulation of TERRAs has been reported across several cancer types.

Exploiting DNA Ligase III addiction of multiple myeloma by flavonoid Rhamnetin.

Background: DNA ligases are crucial for DNA repair and cell replication since they catalyze the final steps in which DNA breaks are joined. DNA Ligase III (LIG3) exerts a pivotal role in Alternative-Non-Homologous End Joining Repair (Alt-NHEJ), an error-prone DNA repair pathway often up-regulated in genomically unstable cancer, such as Multiple Myeloma (MM). Based on the three-dimensional (3D) LIG3 structure, we performed a computational screening to identify LIG3-targeting natural compounds as potential candidates to counteract Alt-NHEJ activity in MM.

The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma.

Microtubule-targeting agents (MTAs) are effective drugs for cancer treatment. A novel diaryl [1,2]oxazole class of compounds binding the colchicine site was synthesized as cis-restricted-combretastatin-A-4-analogue and then chemically modified to have improved solubility and a wider therapeutic index as compared to vinca alkaloids and taxanes. On these bases, a new class of tricyclic compounds, containing the [1,2]oxazole ring and an isoindole moiety, has been synthetized, among which SIX2G emerged as improved MTA.

A MIR17HG-derived long noncoding RNA provides an essential chromatin scaffold for protein interaction and myeloma growth.

Long noncoding RNAs (lncRNAs) can drive tumorigenesis and are susceptible to therapeutic intervention. Here, we used a large-scale CRISPR interference viability screen to interrogate cell-growth dependency to lncRNA genes in multiple myeloma (MM) and identified a prominent role for the miR-17-92 cluster host gene (MIR17HG). We show that an MIR17HG-derived lncRNA, named lnc-17-92, is the main mediator of cell-growth dependency acting in a microRNA- and DROSHA-independent manner.

Mitochondrial RNAs as Potential Biomarkers of Functional Impairment in Diabetic Kidney Disease.

Type 2 diabetes and renal damage are strictly linked. The progressive increase in T2D incidence has stimulated the interest in novel biomarkers to improve the diagnostic performance of the commonly utilized markers such as albuminuria and eGFR. Through microarray method, we analyzed the entire transcriptome expressed in 12 serum samples of diabetic patients, six without DKD and six with DKD; the downregulation of the most dysregulated transcripts was validated in a wider cohort of 69 patients by qPCRs.

A Novel Bispecific T-Cell Engager (CD1a x CD3ε) BTCE Is Effective against Cortical-Derived T Cell Acute Lymphoblastic Leukemia (T-ALL) Cells.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy burdened by poor prognosis. While huge progress of immunotherapy has recently improved the outcome of B-cell malignancies, the lack of tumor-restricted T-cell antigens still hampers its progress in T-ALL. Therefore, innovative immunotherapeutic agents are eagerly awaited.

Chromene Derivatives as Selective TERRA G-Quadruplex RNA Binders with Antiproliferative Properties.

In mammalian cells, telomerase transcribes telomeres in large G-rich non-coding RNA, known as telomeric repeat-containing RNA (TERRA), which folds into noncanonical nucleic acid secondary structures called G-quadruplexes (G4s). Since TERRA G4 has been shown to be involved in telomere length and translation regulation, it could provide valuable insight into fundamental biological processes, such as cancer growth, and TERRA G4 binders could represent an innovative strategy for cancer treatment. In this work, the three best candidates identified in our previous virtual screening campaign on bimolecular DNA/RNA G4s were investigated on the monomolecular Tel DNA and TERRA G4s by means of molecular modelling simulations and in vitro and in cell analysis.

A Prognostic and Carboplatin Response Predictive Model in Ovarian Cancer: A Mono-Institutional Retrospective Study Based on Clinics and Pharmacogenomics.

Carboplatin is the cornerstone of ovarian cancer (OC) treatment, while platinum-response, dependent on interindividual variability, is the major prognostic factor for long-term outcomes. This retrospective study was focused on explorative search of genetic polymorphisms in the Absorption, Distribution, Metabolism, Excretion (ADME) genes for the identification of biomarkers prognostic/predictive of platinum-response in OC patients. Ninety-two advanced OC patients treated with carboplatin-based therapy were enrolled at our institution.

miR-221/222 as biomarkers and targets for therapeutic intervention on cancer and other diseases: A systematic review.

Among deregulated microRNAs (miRs) in human malignancies, miR-221 has been widely investigated for its oncogenic role and as a promising biomarker. Moreover, recent evidence suggests miR-221 as a fine-tuner of chronic liver injury and inflammation-related events. Available information also supports the potential of miR-221 silencing as promising therapeutic intervention.

Risk Alleles for Multiple Myeloma Susceptibility in ADME Genes.

The cause of multiple myeloma (MM) remains largely unknown. Several pieces of evidence support the involvement of genetic and multiple environmental factors (i.e.

Integration of DNA Microarray with Clinical and Genomic Data.

DNA microarrays have been widely employed to understand cancer development. This technology is able to measure expression levels of a large numbers of genes or to genotype multiple regions of a genome in a massively parallel experiment. In addition, the detection of methylation patterns and gene copy number variations are also performed.

Tools in Pharmacogenomics Biomarker Identification for Cancer Patients.

The understanding of the biological differences which underlie the inter-individual variability in drug response improved the efficacy of cancer therapy in the era of precision medicine. In fact molecularly targeted drugs and immunotherapy represent a revolution in cancer treatment. The identification of genetic predictive and/or prognostic biomarkers linked to drug pharmacokinetics (PK) and pharmacodynamics (PD) is allowed by the development of high-throughput omics tools for detecting and understanding biological differences among individuals, in order to improve drug efficacy and minimize risk of toxicity.

miR-22 Modulates Lenalidomide Activity by Counteracting MYC Addiction in Multiple Myeloma.

MYC is a master regulator of multiple myeloma (MM) by orchestrating several pro-tumoral pathways, including reprograming of the miRNA transcriptome. MYC is also involved in the acquirement of resistance to anti-MM drugs, including immunomodulatory imide drugs (IMiDs). In silico analysis was performed on MM proprietary and on public MMRF-CoMMpass datasets.

miRNAs and lncRNAs as Novel Therapeutic Targets to Improve Cancer Immunotherapy.

Immunotherapy is presently one of the most promising areas of investigation and development for the treatment of cancer. While immune checkpoint-blocking monoclonal antibodies and chimeric antigen receptor (CAR) T-cell-based therapy have recently provided in some cases valuable therapeutic options, the goal of cure has not yet been achieved for most malignancies and more efforts are urgently needed. Noncoding RNAs (ncRNA), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), regulate several biological processes via selective targeting of crucial molecular signaling pathways.

Therapeutic afucosylated monoclonal antibody and bispecific T-cell engagers for T-cell acute lymphoblastic leukemia.

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a poor cure rate for relapsed/resistant patients. Due to the lack of T-cell restricted targetable antigens, effective immune-therapeutics are not presently available and the treatment of chemo-refractory T-ALL is still an unmet clinical need. To develop novel immune-therapy for T-ALL, we generated an afucosylated monoclonal antibody (mAb) (ahuUMG1) and two different bispecific T-cell engagers (BTCEs) against UMG1, a unique CD43-epitope highly and selectively expressed by T-ALL cells from pediatric and adult patients.

Raman Spectroscopic Stratification of Multiple Myeloma Patients Based on Exosome Profiling.

Multiple myeloma (MM) is a hematological malignancy characterized by abnormal plasma cell proliferation within the bone marrow which leads to progressive bone marrow failure, skeletal osteolytic lesions, and renal insufficiency, thus severely affecting the quality of life. MM is always preceded by monoclonal gammopathy of uncertain significance (MGUS), which progresses to asymptomatic-MM (aMM) or symptomatic-MM (sMM) at a rate of 1% per year. Despite impressive progress in the therapy of the disease, MM remains incurable.