Making Biomarkers Relevant to Healthcare Innovation and Precision Medicine

Translational medicine, the exchange between laboratory (bench) and the clinic (bedside), is decidedly taking on a vital role. Many companies are now focusing on a translational medicinal approach as a therapeutic strategy in decision making upon realizing the expenses of drug attrition in late-stage advancement. In addition, the utility of biomarkers in clinical decision and therapy guidance seeks to improve the patient outcomes and decrease wasteful and harmful treatment. Efficient biomarkers are crucial for the advancement of diagnoses, better molecular targeted therapy, along with therapeutic advantages in a broad spectrum of various diseases. Despite recent advances in the discovery of biomarkers, the advancement route to a clinically validated biomarker remains intensely challenging, and many of the candidate biomarkers do not progress to clinical applications, thereby widening the innovation gap between research and application. The present article will focus on the clinical view of biomarkers in a reverse design, addressing how a biomarker program should appear if it is expected to create an impact on personalized medicine and patient care

Regulative loop between beta-catenin and protein tyrosine phosphatase receptor type gamma (PTPRG) in chronic myeloid leukemia

Introduction. Chronic Myeloid Leukemia (CML) is a myeloproliferative disease characterized by the presence of the oncogene BCR-ABL1, which acts as tyrosine kinase. PTPRG (Protein Tyrosine Phoshatase Receptor type \u3b3) is a tumor suppressor gene down- regulated by hypermethylation of its promoter region in CML. Previous studies demonstrated that a re-expression of PTPRG is correlated with a decreased clonogenic capability of CML cells, as shown by the down-regulation of Ki67, and with an increased cellular differentiation related to a PTPRG-mediated overexpression of GATA-1 and Cyclin D1. In addition, its restored expression was observed in patients with a good response to TKI therapy. In order to understand the regulation between this phosphatase and BCR- ABL1, we searched for PTPRG putative interactors among proteins downstream BCR-ABL1 driven pathways and we focused on b-Catenin, that is at the same time a PTPRG substrate and its transcriptional regulator. Methods. Cells: PTPRG negative cell line K562, with a stable transfection of exogenous PTPRG, and PTPRG positive cell line LAMA-84, treated with a specific siRNA and with a new PTPRG small drug inhibitor. Pull-down assay with purified, recombinant intracellular domain of PTPRG demonstrated a direct interaction between PTPRG and b-Catenin, while Western Blotting or Immunofluorescence were applied to detect a specific dephospho- rylation pattern in presence of PTPRG. Chromatin Immunoprecipitation showed us the binding between DNMT1(b-Catenin transcriptional target) and PTPRG promoter region. Results. We demonstrated that PTPRG binds and dephosphorylates b-Catenin, phosphorylated by BCR-ABL1, causing its cytoplasmic destabilization and the resulting degradation in CML cell lines with an exogenous or endogenous expression of PTPRG (K562 and LAMA-84 cell lines). Consequently, this regulation leads to MYC down-expression and p21/WAF1 increased expression, explaining the slow-down of proliferation in presence of PTPRG. On the contrary, we demonstrated that an increased expression of b-Catenin in PTPRG negative CML cell lines is correlated with an over-expression of the DNA (cytosine-5)-methyltransferase 1 (DNMT1) that is responsible of PTPRG promoter hypermethylation and that an inhibition after a treatment with 5-Azacydine or a down-regulation of this enzyme is closely related to PTPRG re-expression both at mRNA and protein levels. Conclusions. We show for the first time a mechanism that involves b-Catenin degradation control and the consequent down-regulation of genes regulated by the TCF/b-Catenin transcription complex. In return, b-Catenin up-regulation is correlated with an over-expression of DNMT1 that contributes to an hypermethylation of PTPRG promoter region. We hypothesized a regulative loop between PTPRG and b-Catenin and that an imbalance of the system in favor of one or the other could determine a different proliferation fate of CML cells and their clinical aggressiveness

Ptprg and BCR/ABL1 Expression In CML Patients At Diagnosis and Upon TKI Treatment: Preliminary Results

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Cysteamine revisited: repair of arginine to cysteine mutations.

Cysteamine is a small aminothiol endogenously derived from coenzyme A degradation. For some decades, synthetic cysteamine has been employed for the treatment of cystinosis, and new uses of the drug continue to emerge. In this review, we discuss the role of cysteamine in cellular and extracellular homeostasis and focus on the potential use of aminothiols to reconstitute the function of proteins harboring arginine (Arg) to cysteine (Cys) mutations, via repair of the Cys residue into a moiety that introduces an amino group, as seen in basic amino acid residues Lys and Arg. Cysteamine has been utilized in vitro and ex vivo in four different genetic disorders, and thus provides "proof of principle" that aminothiols can modify Cys residues. Other aminothiols such as mercaptoethylguanidine (MEG) with closer structural resemblance to the guanidinium moiety of Arg are under examination for their predicted enhanced capacity to reconstitute loss of function. Although the use of aminothiols holds clinical potential, more studies are required to refine specificity and treatment design. The efficacy of aminothiols to target proteins may vary substantially depending on their specific extracellular and intracellular locations. Redox potential, pH, and specific aminothiol abundance in each physiological compartment are expected to influence the reactivity and turnover of cysteamine and analogous drugs. Upcoming research will require the use of suitable cell and animal models featuring Arg to Cys mutations. Since, in general, Arg to Cys changes comprise about 8% of missense mutations, repair of this specific mutation may provide promising avenues for many genetic diseases.QNR

New horizons for molecular genetics diagnostic and research in autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable, heterogeneous, and complex pervasive neurodevelopmental disorder (PND) characterized by distinctive abnormalities of human cognitive functions, social interaction, and speech development.Nowadays, several genetic changes including chromosome abnormalities, genetic variations, transcriptional epigenetics, and noncoding RNA have been identified in ASD. However, the association between these genetic modifications and ASDs has not been confirmed yet.The aim of this review is to summarize the key findings in ASD from genetic viewpoint that have been identified from the last few decades of genetic and molecular research