Parallel single-cell metabolic analysis and extracellular vesicle profiling reveal vulnerabilities with prognostic significance in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive disease with a high relapse rate. In this study, we map the metabolic profile of CD34(CD38) AML cells and the extracellular vesicle signatures in circulation from AML patients at diagnosis. CD34 AML cells display high antioxidant glutathione levels and enhanced mitochondrial functionality, both associated with poor clinical outcomes.

Tracking Response and Resistance in Acute Myeloid Leukemia through Single-Cell DNA Sequencing Helps Uncover New Therapeutic Targets.

Acute myeloid leukemia (AML) is an aggressive hematologic neoplasia with a complex polyclonal architecture. Among driver lesions, those involving the gene represent the most frequent mutations identified at diagnosis. The development of tyrosine kinase inhibitors (TKIs) has improved the clinical outcomes of -mutated patients (Pt).

Communicating Adolescent and Young Adult Oncology Treatment Guidelines in Practice: The Importance of Documentation for Ensuring Positive Impacts on Oncology Care.

Improvements in outcomes for adolescent and young adult (AYA) oncology patients have lagged behind those of other age-specific cancer populations. Research has indicated that low availability of clinical trials, biological differences of this age-group, and several psychosocial factors including higher emotional distress impact outcomes. To improve care and survival rates for these patients, hospitals have implemented AYA oncology programs.

Bitter Taste Receptor Agonist Denatonium Inhibits Stemness Characteristics in Hematopoietic Stem/Progenitor Cells.

Bone marrow microenvironmental stimuli profoundly impact hematopoietic stem cell fate and biology. As G protein-coupled receptors, the bitter taste receptors (TAS2Rs) are key in transmitting extracellular stimuli into an intracellular response, within the oral cavity but also in extraoral tissues. Their expression in the bone marrow (BM)-derived cells suggests their involvement in sensing the BM microenvironmental fluctuation.

Expanding the phenotype of Brunner syndrome from childhood to adulthood: Description of the second pediatric patient and his mother.

Brunner syndrome is a recessive X-linked disorder caused by pathogenic variants in the monoamine oxidase A gene (MAOA). It is characterized by distinctive aggressive behavior, mild intellectual disability, sleep disturbances, and typical biochemical alterations deriving from the impaired monoamine metabolism. We herein describe a 5-year-old boy with developmental delay, autistic features, and myoclonic epilepsy, and his mother, who had mild intellectual disability and recurrent episodes of palpitations, headache, abdominal pain, and abdominal bloating.

SETD2 non genomic loss of function in advanced systemic mastocytosis is mediated by an Aurora kinase A/MDM2 axis and can be therapeutically targeted.

Background: The SETD2 tumor suppressor gene encodes a histone methyltransferase that safeguards transcription fidelity and genomic integrity via trimethylation of histone H3 lysine 36 (H3K36Me3). SETD2 loss of function has been observed in solid and hematologic malignancies. We have recently reported that most patients with advanced systemic mastocytosis (AdvSM) and some with indolent or smoldering SM display H3K36Me3 deficiency as a result of a reversible loss of SETD2 due to reduced protein stability.

Lessons Learned from the Development and Roll-Out of the rVSVΔG-ZEBOV-GP Vaccine to Inform Marburg Virus and Vaccines.

This review describes key aspects of the development of the rVSVΔG-ZEBOV-GP Ebola vaccine and key activities which are continuing to further expand our knowledge of the product. Extensive partnerships and innovative approaches were used to address the various challenges encountered during this process. The rVSVΔG-ZEBOV-GP Ebola vaccine was initially approved by the European Medicines Agency and prequalified by the World Health Organization in November 2019.

Droplet digital PCR for the detection of second-generation tyrosine kinase inhibitor-resistant BCR::ABL1 kinase domain mutations in chronic myeloid leukemia.

One of the indications for BCR::ABL1 mutation testing in chronic myeloid leukemia (CML) is when tyrosine kinase inhibitor therapy (TKI) needs to be changed for unsatisfactory response. In this study, we evaluated a droplet digital PCR (ddPCR)-based multiplex strategy for the detection and quantitation of transcripts harbouring mutations conferring resistance to second-generation TKIs (2GTKIs). Parallel quantitation of e13a2, e14a2 and e1a2 BCR::ABL1 fusion transcripts enables to express results as percentage of mutation positive- over total BCR::ABL1 transcripts.

CDC20 in and out of mitosis: a prognostic factor and therapeutic target in hematological malignancies.

Cell division cycle 20 homologue (CDC20) is a well-known regulator of cell cycle, as it controls the correct segregation of chromosomes during mitosis. Many studies have focused on the biological role of CDC20 in cancer development, as alterations of its functionality have been linked to genomic instability and evidence demonstrated that high CDC20 expression levels are associated with poor overall survival in solid cancers. More recently, novel CDC20 functions have been demonstrated or suggested, including the regulation of apoptosis and stemness properties and a correlation with immune cell infiltration.

Combined Inhibition of Polo-Like Kinase-1 and Wee1 as a New Therapeutic Strategy to Induce Apoptotic Cell Death in Neoplastic Mast Cells.

Systemic mastocytosis (SM) is due to the pathologic accumulation of neoplastic mast cells in one or more extracutaneous organ(s). Although midostaurin, a multikinase inhibitor active against both wild-type and D816V-mutated KIT, improves organ damage and symptoms, a proportion of patients relapse or have resistant disease. It is well known that Aurora kinase A (AKA) over-expression promotes tumorigenesis, but its role in the pathogenesis of systemic mastocytosis (SM) has not yet been investigated.

Overcoming Resistance to Kinase Inhibitors: The Paradigm of Chronic Myeloid Leukemia.

Protein kinases (PKs) play crucial roles in cellular proliferation and survival, hence their deregulation is a common event in the pathogenesis of solid and hematologic malignancies. Targeting PKs has been a promising strategy in cancer treatment, and there are now a variety of approved anticancer drugs targeting PKs. However, the phenomenon of resistance remains an obstacle to be addressed and overcoming resistance is a goal to be achieved.

Case Report: A Novel Activating FLT3 Mutation in Acute Myeloid Leukemia.

FMS-like tyrosine kinase 3 (FLT3) is among the most common driver genes recurrently mutated in acute myeloid leukemia (AML), accounting for approximately 30% of cases. Activating mutations of the FLT3 receptor include internal tandem duplications (ITD) that map to the auto-inhibitory juxtamembrane (JM) domain or point mutations within the tyrosine kinase domain (TKD). Several FLT3 tyrosine kinase inhibitors have been developed in the last few years, but midostaurin is currently the only one approved for the treatment of newly diagnosed patients harboring mutations.

Systemic Mastocytosis: Molecular Landscape and Implications for Treatment.

Over the past decade, we have witnessed significant advances in the molecular characterization of systemic mastocytosis (SM). This has provided important information for a better understanding of the pathogenesis of the disease but has also practically impacted the way we diagnose and manage it. Advances in molecular testing have run in parallel with advances in therapeutic targeting of constitutive active KIT, the major driver of the disease.

Targeting Leukemic Stem Cells in Chronic Myeloid Leukemia: Is It Worth the Effort?

Chronic myeloid leukemia (CML) is a classical example of stem cell cancer since it arises in a multipotent hematopoietic stem cell upon the acquisition of the t(9;22) chromosomal translocation, that converts it into a leukemic stem cell (LSC). The resulting fusion gene encodes a deregulated tyrosine kinase that is recognized as the disease driver. Therapy with tyrosine kinase inhibitors (TKIs) eliminates progenitor and more differentiated cells but fails to eradicate quiescent LSCs.

The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities.

Acute myeloid leukemia (AML) is a hematologic malignancy caused by a wide range of alterations responsible for a high grade of heterogeneity among patients. Several studies have demonstrated that the hypoxic bone marrow microenvironment (BMM) plays a crucial role in AML pathogenesis and therapy response. This review article summarizes the current literature regarding the effects of the dynamic crosstalk between leukemic stem cells (LSCs) and hypoxic BMM.

Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations.

Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis.

Corrigendum: Denatonium as a Bitter Taste Receptor Agonist Modifies Transcriptomic Profile and Functions of Acute Myeloid Leukemia Cells.

[This corrects the article DOI: 10.3389/fonc.2020.

Synthesis of Novel Tryptamine Derivatives and Their Biological Activity as Antitumor Agents.

We synthesized five novel tryptamine derivatives characterized by the presence of an azelayl chain or of a 1,1,1-trichloroethyl group, in turn connected to another heterocyclic scaffold. The combination of tryptamin-, 1,1,1-trichloroethyl- and 2-aminopyrimidinyl- moieties produced compound identified as the most active compound in hematological cancer cell lines (IC = 0.57-65.

Distinct profile of CD34 cells and plasma-derived extracellular vesicles from triple-negative patients with Myelofibrosis reveals potential markers of aggressive disease.

Background: Myelofibrosis (MF) is a clonal disorder of hemopoietic stem/progenitor cells (HSPCs) with high prevalence in elderly patients and mutations in three driver genes (JAK2, MPL, or CALR). Around 10-15% of patients are triple-negative (TN) for the three driver mutations and display significantly worse survival. Circulating extracellular vesicles (EVs) play a role in intercellular signaling and are increased in inflammation and cancer.

Denatonium as a Bitter Taste Receptor Agonist Modifies Transcriptomic Profile and Functions of Acute Myeloid Leukemia Cells.

The contribution of cell-extrinsic factors in Acute Myeloid Leukemia (AML) generation and persistence has gained interest. Bitter taste receptors (TAS2Rs) are G protein-coupled receptors known for their primary role as a central warning signal to induce aversion toward noxious or harmful substances. Nevertheless, the increasing amount of evidence about their extra-oral localization has suggested a wider function in sensing microenvironment, also in cancer settings.

Applying lessons from the Ebola vaccine experience for SARS-CoV-2 and other epidemic pathogens.

The world is experiencing an unprecedented global pandemic of coronavirus disease 2019 (COVID-19) caused by a novel coronavirus, Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2). Development of new vaccines and therapeutics are important to achieve long-term prevention and control of the virus. Experience gained in the development of vaccines for Ebola virus disease provide important lessons in the regulatory, clinical, and manufacturing process that can be applied to SARS-CoV-2 and other epidemic pathogens.

Recent Advances in the Molecular Biology of Systemic Mastocytosis: Implications for Diagnosis, Prognosis, and Therapy.

In recent years, molecular characterization and management of patients with systemic mastocytosis (SM) have greatly benefited from the application of advanced technologies. Highly sensitive and accurate assays for D816V mutation detection and quantification have allowed the switch to non-invasive peripheral blood testing for patient screening; allele burden has prognostic implications and may be used to monitor therapeutic efficacy. Progress in genetic profiling of , together with the use of next-generation sequencing panels for the characterization of associated gene mutations, have allowed the stratification of patients into three subgroups differing in terms of pathogenesis and prognosis: i) patients with mast cell-restricted D816V; ii) patients with multilineage D816V-involvement; iii) patients with "multi-mutated disease".

The Case for Revamping New Faculty Orientation: Integrating Case-Based Learning Into Faculty Onboarding.

Introduction: New faculty orientation (NFO) for onboarding faculty members is replete with critical information and resources. Most NFO sessions are facilitated through lecture-based slide presentations. We employed a case-based learning (CBL) format to promote learner engagement through active use of the content being taught.