The Coiled Coil and C2 Domains Modulate BCR Localization and BCR-ABL1 Compartmentalization, Transforming Activity and TKI Responsiveness.

The BCR-ABL1 chimeric oncoprotein plays a pivotal role in the pathogenesis of Chronic Myeloid Leukemia (CML) as its constitutive kinase activity transforms the hematopoietic stem cell, promoting pro-survival signaling. We and others have previously shown that the manipulation of BCR-ABL1 catalytic activity modulates its intracellular localization, thereby transforming the culprit of CML into a pro-apoptotic protein that selectively kills leukemic cells. Here, we investigated the role of the BCR coiled-coil and C2 domains on BCR-ABL1 intracellular localization and leukemogenic potential.

Bridging the Gap: the role of MDM2 inhibition in overcoming treatment resistance in breast cancer.

Murine double minute 2 (MDM2) is a protein that plays a crucial role in the regulation of the tumor suppressor p53. It is involved in several biological processes and in cancer development, both in a p53-dependent and independent manner. Discordant evidence exists on MDM2 genetic polymorphisms and a possible susceptibility to breast cancer, but more studies are needed to fully understand this relationship.

No Benefit from Hydroxyurea Pre-Treatment in Frontline Chronic Myeloid Leukemia Therapy and Evidence of Quantitative Changes in the Transcript Level.

Hydroxyurea (HU) cytoreduction is usually administered to patients with chronic myeloid leukemia before starting any tyrosine kinase inhibitors (TKIs) therapy. However, up to date, there is no evidence of any benefit of hydroxyurea pre-treatment. Conversely, evidence has been provided on both the prognostic significance of the quantitative assessment of expression at diagnosis and the individual decline of the slope.

An Optimized NGS Workflow Defines Genetically Based Prognostic Categories for Patients with Uveal Melanoma.

Background: Despite advances in uveal melanoma (UM) diagnosis and treatment, about 50% of patients develop distant metastases, thereby displaying poor overall survival. Molecular profiling has identified several genetic alterations that can stratify patients with UM into different risk categories. However, these genetic alterations are currently dispersed over multiple studies and several methodologies, emphasizing the need for a defined workflow that will allow standardized and reproducible molecular analyses.

[Biomarkers and Bone Turnover Markers in Chronic Kidney Disease - Mineral and Bone Disorders (CKD-MBD): Recent Advances].

Chronic Kidney Disease (CKD) provokes biochemical and systemic alterations, causing bone fragility with an increase in bone fracture risk, extraskeletal calcifications, increased morbidity, and cardiovascular mortality. The complex pathophysiological mechanism causes a syndrome called CKD-MBD (Chronic Kidney Disease - Mineral and Bone Disorders), which includes mineral and bone alterations leading to renal osteodystrophy (ROD). An early diagnosis is therefore essential to prevent the onset of more severe complications.

REThinking the role of the RET oncogene in breast cancer.

The REarranged during Transfection (RET) receptor tyrosine kinase plays a crucial role in the development of various anatomical structures during embryogenesis and it is involved in many physiological cellular processes. This protein is also associated with the initiation of various cancer types, such as thyroid cancer, non-small cell lung cancer, and multiple endocrine neoplasms. In breast cancer, and especially in the estrogen receptor-positive (ER+) subtype, the activity of RET is of notable importance.

Prediction of and Variants with Conflicting Clinical Interpretation in a Cohort of Breast Cancer Patients.

Germline alteration has been linked to an increased risk of hereditary breast and ovarian cancer syndromes. As a result, genetic testing, based on NGS, allows us to identify a high number of variants of uncertain significance (VUS) or conflicting interpretation of pathogenicity (CIP) variants. The identification of CIP/VUS is often considered inconclusive and clinically not actionable for the patients' and unaffected carriers' management.

A Multiplex Assay for Fast PIK3CA Hotspot Mutation Characterization in a Single Specimen by 3-Color Digital PCR Analysis.

Background: Activating mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene have been detected often in solid tumors. Targeted therapy for mutant PIK3CA is now available in the clinic, making molecular diagnostics pivotal. Our aim was to design a multiplex digital PCR (dPCR) assay to evaluate the 4 most common PIK3CA hotspot mutations simultaneously to characterize and quantify these in liquid biopsies.

High Expression Defines CD34+ Cells with Significant Alterations in Signal Transduction, Short-Proliferative Potential and Self-Renewal Ability.

Purpose: Chronic Myeloid Leukemia (CML) is a clonal disorder of the hematopoietic stem cell caused by expression of the oncoprotein. High levels have been associated to proliferative advantage of leukemic cells, blast crisis progression and tyrosine kinase inhibitors (TKIs) inefficacy. We have previously shown that high transcripts measured at diagnosis are associated with inferior responses to standard dose Imatinib (IM).

Single-Cell Analysis in the Era: Technologies and Applications in Cancer.

Cancer molecular profiling obtained with conventional bulk sequencing describes average alterations obtained from the entire cellular population analyzed. In the era of precision medicine, this approach is unable to track tumor heterogeneity and cannot be exploited to unravel the biological processes behind clonal evolution. In the last few years, functional single-cell has improved our understanding of cancer heterogeneity.

A case of high-risk AML in a patient with advanced systemic mastocytosis.

Aggressive SM + AML has limited therapeutic options. Even a strong combination of decitabine-venetoclax-midostaurin has a transient effect on AML and a mitigated effect on SM. Larger series are required to identify the best therapeutic strategy.

Glucose-dependent effect of insulin receptor isoforms on tamoxifen antitumor activity in estrogen receptor-positive breast cancer cells.

Introduction: Breast cancer is the most common malignancy in women, and it is linked to several risk factors including genetic alterations, obesity, estrogen signaling, insulin levels, and glucose metabolism deregulation. Insulin and Insulin-like growth factor signaling exert a mitogenic and pro-survival effect. Indeed, epidemiological and pre-clinical studies have shown its involvement in the development, progression, and therapy resistance of several cancer types including breast cancer.

Potential Therapeutic Targets for Luminal Androgen Receptor Breast Cancer: What We Know so Far.

Luminal Androgen Receptor Breast Cancers (LAR BCs) are characterized by a triple negative phenotype and by the expression of Androgen Receptor (AR), coupled with luminal-like genomic features. This unique BC subtype, accounting for about 10% of all triple negative BC, has raised considerable interest given its ill-defined clinical behavior and the chance to exploit AR as a therapeutic target. The complexity of AR activity in BC cells, as revealed by decades of mechanistic studies, holds promise to offer additional therapeutic options beyond mere AR inhibition.

Molecular Analysis of Luminal Androgen Receptor Reveals Activated Pathways and Potential Therapeutic Targets in Breast Cancer.

Background/aim: Triple-negative breast cancers represent 15% of all mammary malignancies and encompass several entities with different genomic characteristics. Among these, luminal androgen receptor (LAR) tumors express the androgen receptor (AR) and are characterized by a genomic profile which resembles luminal breast cancers. Moreover, LAR malignancies are usually enriched in PIK3CA, KMTC, CDH, NF1, and AKT1 alterations.

Impact of Different Cell Counting Methods in Molecular Monitoring of Chronic Myeloid Leukemia Patients.

Background: Detection of transcript level via real-time quantitative-polymerase-chain reaction (Q-PCR) is a clinical routine for disease monitoring, assessing Tyrosine Kinase Inhibitor therapy efficacy and predicting long-term response in chronic myeloid leukemia (CML) patients. For valid Q-PCR results, each stage of the laboratory procedures need be optimized, including the cell-counting method that represents a critical step in obtaining g an appropriate amount of RNA and reliable Q-PCR results. Traditionally, manual or automated methods are used for the detection and enumeration of white blood cells (WBCs).

Mechanistic Translation of Melanoma Genetic Landscape in Enriched Pathways and Oncogenic Protein-Protein Interactions.

Background/aim: Malignant melanoma is a skin cancer originating from the oncogenic transformation of melanocytes located in the epidermal layers. Usually, the patient's prognosis depends on timing of disease detection and molecular and genetic profiling, which may all significantly influence mortality rates. Genetic analyses often detect somatic BRAF, NRAS and cKIT mutations, germline substitutions in CDKN2A, and alterations of the PI3K-AKT-PTEN pathway.

Mutational Analysis of and Genes in Breast Cancer Patients from Eastern Sicily.

Purpose: Germline mutations of and are associated with a defined lifetime risk of breast (BC), ovarian (OC) and other cancers. Testing genes is pivotal to assess individual risk, but also to pursue preventive approaches in healthy carriers and tailored treatments in tumor patients. The prevalence of and alterations varies broadly across different geographic regions and, despite data about pathogenic variants among Sicilian families exist, studies specifically addressing eastern Sicily population are lacking.

A Treatment-free Interval Allowed by Ponatinib as Fourth-line Therapy.

Background: The third-generation tyrosine kinase inhibitor ponatinib has demonstrated high clinical efficacy in the setting of patients with resistant chronic phase chronic myeloid leukemia (CML), also inducing deep molecular responses. However, ponatinib-related cardiovascular toxicities make management challenging, especially of those patients with CML with previous cardiovascular comorbidities.

Case Report: We report on the efficacy of ponatinib treatment used as fourth-line therapy in a 55-year-old woman affected by significant comorbidities (mainly cardiovascular) present before the diagnosis of CML.

Next generation sequencing in a cohort of patients with rare sarcoma histotypes: A single institution experience.

Sarcomas are mesenchymal-derived cancers with overlapping clinical and pathologic features and a remarkable histological heterogeneity. While a precise diagnosis is often challenging to achieve, systemic treatment of sarcomas is still quite uniform. In this scenario, next generation sequencing (NGS) may be exploited to assist diagnosis and to identify specific targetable alterations.

Effective targeting of breast cancer stem cells by combined inhibition of Sam68 and Rad51.

Breast cancer (BC) is the second cause of cancer-related deceases in the worldwide female population. Despite the successful treatment advances, 25% of BC develops resistance to current therapeutic regimens, thereby remaining a major hurdle for patient management. Current therapies, targeting the molecular events underpinning the adaptive resistance, still require effort to improve BC treatment.

Combined Inhibition of Bcl2 and Bcr-Abl1 Exercises Anti-Leukemia Activity but Does Not Eradicate the Primitive Leukemic Cells.

Background: The management of Philadelphia Chromosome-positive (Ph+) hematological malignancies is strictly correlated to the use of BCR-ABL1 tyrosine kinase inhibitors (TKIs). However, these drugs do not induce leukemic stem cells death and their persistence may generate a disease relapse. Published reports indicated that Venetoclax, a selective BCL2 inhibitor, could be effective in Ph+ diseases, as BCL2 anti-apoptotic activity is modulated by BCR-ABL1 kinase.

A Novel System for Semiautomatic Sample Processing in Chronic Myeloid Leukaemia: Increasing Throughput without Impacting on Molecular Monitoring at Time of SARS-CoV-2 Pandemic.

Molecular testing of the transcript via real-time quantitative-polymerase-chain-reaction is the most sensitive approach for monitoring the response to tyrosine-kinase-inhibitors therapy in chronic myeloid leukaemia (CML) patients. Each stage of the molecular procedure has been standardized and optimized, including the total white blood cells (WBCs) and RNA isolation methods. Here, we compare the performance of our current manual protocol to a newly semiautomatic method based on the Biomek i-5 Automated Workstations integrated with the CytoFLEX Flow Cytometer, followed by the automatic QIAsymphony system to facilitate high-throughput processing samples and reduce the hands-on time and the risk associated with SARS-CoV-2.

Opportunities and Challenges of Liquid Biopsy in Thyroid Cancer.

Thyroid cancer is the most common malignancy of the endocrine system, encompassing different entities with distinct histological features and clinical behavior. The diagnostic definition, therapeutic approach, and follow-up of thyroid cancers display some controversial aspects that represent unmet medical needs. Liquid biopsy is a non-invasive approach that detects and analyzes biological samples released from the tumor into the bloodstream.

Impact of the Breakpoint Region on the Leukemogenic Potential and the TKI Responsiveness of Atypical Transcripts.

Chronic Myeloid Leukemia (CML) is a hematological disorder characterized by the clonal expansion of a hematopoietic stem cell carrying the Philadelphia chromosome that juxtaposes the and genes. The ensuing chimeric oncogene is characterized by a breakpoint region that generally involves exons 1, 13 or 14 in and exon 2 in . Additional breakpoint regions, generating uncommon fusion transcripts, have been detected in various CML patients.