scholarly journals Using genomics to define pediatric blood cancers and inform practice

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 286-300
Author(s):  
Rachel E. Rau ◽  
Mignon L. Loh
Keyword(s):  
Genetic Variants ◽  
Germ Line ◽  
Hematologic Malignancies ◽  
Clinical Implications ◽  
Pediatric Leukemia ◽  
The Past ◽  
Sequencing Technologies ◽  
Sequencing Studies ◽  
Generation Sequencing

Abstract Over the past decade, there has been exponential growth in the number of genome sequencing studies performed across a spectrum of human diseases as sequencing technologies and analytic pipelines improve and costs decline. Pediatric hematologic malignancies have been no exception, with a multitude of next generation sequencing studies conducted on large cohorts of patients in recent years. These efforts have defined the mutational landscape of a number of leukemia subtypes and also identified germ-line genetic variants biologically and clinically relevant to pediatric leukemias. The findings have deepened our understanding of the biology of many childhood leukemias. Additionally, a number of recent discoveries may positively impact the care of pediatric leukemia patients through refinement of risk stratification, identification of targetable genetic lesions, and determination of risk for therapy-related toxicity. Although incredibly promising, many questions remain, including the biologic significance of identified genetic lesions and their clinical implications in the context of contemporary therapy. Importantly, the identification of germ-line mutations and variants with possible implications for members of the patient’s family raises challenging ethical questions. Here, we review emerging genomic data germane to pediatric hematologic malignancies.

scholarly journals Clinical Implications of Polymicrobial Synergism Effects on Antimicrobial Susceptibility

Pathogens ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 144
Author(s):  
William Little ◽  
Caroline Black ◽  
Allie Clinton Smith
Keyword(s):  
Antimicrobial Susceptibility ◽  
Chronic Wounds ◽  
Clinical Laboratory ◽  
Patient Treatment ◽  
Clinical Implications ◽  
Clinical Environment ◽  
Tolerance Mechanisms ◽  
Sequencing Technologies ◽  
Generation Sequencing ◽  
Polymicrobial Infections

With the development of next generation sequencing technologies in recent years, it has been demonstrated that many human infectious processes, including chronic wounds, cystic fibrosis, and otitis media, are associated with a polymicrobial burden. Research has also demonstrated that polymicrobial infections tend to be associated with treatment failure and worse patient prognoses. Despite the importance of the polymicrobial nature of many infection states, the current clinical standard for determining antimicrobial susceptibility in the clinical laboratory is exclusively performed on unimicrobial suspensions. There is a growing body of research demonstrating that microorganisms in a polymicrobial environment can synergize their activities associated with a variety of outcomes, including changes to their antimicrobial susceptibility through both resistance and tolerance mechanisms. This review highlights the current body of work describing polymicrobial synergism, both inter- and intra-kingdom, impacting antimicrobial susceptibility. Given the importance of polymicrobial synergism in the clinical environment, a new system of determining antimicrobial susceptibility from polymicrobial infections may significantly impact patient treatment and outcomes.

scholarly journals Chronic Myelomonocytic Leukemia—Hematopathology Perspective

2021 ◽  
Author(s):  
Siba El Hussein ◽  
Sa A. Wang ◽  
Naveen Pemmaraju ◽  
Joseph D. Khoury ◽  
Sanam Loghavi
Keyword(s):  
Risk Stratification ◽  
Large Scale ◽  
Chronic Myelomonocytic Leukemia ◽  
Clinical Implications ◽  
The Past ◽  
Genomic Landscape ◽  
Sequencing Studies ◽  
Myelomonocytic Leukemia ◽  
Insight Into

ABSTRACT Our understanding of chronic myelomonocytic leukemia (CMML) has evolved tremendously over the past decade. Large-scale sequencing studies have led to increased insight into the genomic landscape of CMML and clinical implications of these changes. This in turn has resulted in refined and improved risk stratification models, which to date remain versatile and subject to remodeling, as new and evolving studies continue to refine our understanding of this disease. In this article, we present an up-to-date review of CMML from a hematopathology perspective, while providing a clinically practical summary that sheds light on the constant evolution of our understanding of this disease.

scholarly journals Genetics of multiple myeloma: another heterogeneity level?

Blood ◽  
2015 ◽  
Vol 125 (12) ◽  
pp. 1870-1876 ◽  
Author(s):  
Jill Corre ◽  
Nikhil Munshi ◽  
Hervé Avet-Loiseau
Keyword(s):  
Molecular Level ◽  
Cell Clone ◽  
Hematologic Malignancies ◽  
Molecular Techniques ◽  
Disease Pathogenesis ◽  
The Past ◽  
Molecular Features ◽  
Malignant Plasma Cell ◽  
Chromosomal Changes ◽  
Generation Sequencing

Abstract Our knowledge of myeloma genetics remained limited and lagged behind many other hematologic malignancies because of the inherent difficulties in generating metaphases within the malignant plasma cell clone. With the development of molecular techniques (microarrays and next-generation sequencing), our understanding has been highly improved in the past 5 years. These studies have not only confirmed the prevalence of wide heterogeneity in myeloma at the molecular level, but has also provided a much clearer picture of the disease pathogenesis and progression. Whether these data will enable improvements in the therapeutic approach is still a matter of debate. The next improvement will come from detailed analyses of these molecular features to try to move from a treatment fitted to every patient to individualized therapies, taking into account the complexity of the chromosomal changes, the mutation spectrum, and subclonality evolution.

scholarly journals Discussing and managing hematologic germ line variants

Blood ◽  
2016 ◽  
Vol 128 (21) ◽  
pp. 2497-2503 ◽  
Author(s):  
Wendy Kohlmann ◽  
Joshua D. Schiffman
Keyword(s):  
Hereditary Cancer ◽  
Genetic Variants ◽  
Germ Line ◽  
Hematologic Malignancies ◽  
Hereditary Cancer Syndromes ◽  
Rare Disorders ◽  
Good Opportunity ◽  
Genomic Technologies ◽  
Clinical Challenge ◽  
Cancer Syndromes

Abstract With the introduction of genomic technologies, more hereditary cancer syndromes with hematologic malignancies are being described. Up to 10% of hematologic malignancies in children and adults may be the result of an underlying inherited genetic risk. Managing these patients with hereditary hematologic malignancies, including familial leukemia, remains a clinical challenge because there is little information about these relatively rare disorders. This article covers some of the issues related to the diagnosis and interpretation of variants associated with hereditary hematologic malignancies, including the importance of an accurate family history in interpreting genetic variants associated with disease. The challenges of screening other family members and offering the most appropriate early malignancy detection is also discussed. We now have a good opportunity to better define hereditary cancer syndromes with associated hematologic malignancies and contribute to clinically effective guidelines.

scholarly journals The genetics and molecular biology of T-ALL

Blood ◽  
2017 ◽  
Vol 129 (9) ◽  
pp. 1113-1123 ◽  
Author(s):  
Tiziana Girardi ◽  
Carmen Vicente ◽  
Jan Cools ◽  
Kim De Keersmaecker
Keyword(s):  
T Cell ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Protein Translation ◽  
Cell Cycle Regulators ◽  
Systematic Screening ◽  
The Past ◽  
Sequencing Technologies ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Generation Sequencing

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy caused by the accumulation of genomic lesions that affect the development of T cells. For many years, it has been established that deregulated expression of transcription factors, impairment of the CDKN2A/2B cell-cycle regulators, and hyperactive NOTCH1 signaling play prominent roles in the pathogenesis of this leukemia. In the past decade, systematic screening of T-ALL genomes by high-resolution copy-number arrays and next-generation sequencing technologies has revealed that T-cell progenitors accumulate additional mutations affecting JAK/STAT signaling, protein translation, and epigenetic control, providing novel attractive targets for therapy. In this review, we provide an update on our knowledge of T-ALL pathogenesis, the opportunities for the introduction of targeted therapy, and the challenges that are still ahead.

scholarly journals Discussing and managing hematologic germ line variants

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 309-315 ◽  
Author(s):  
Wendy Kohlmann ◽  
Joshua D. Schiffman
Keyword(s):  
Hereditary Cancer ◽  
Genetic Variants ◽  
Germ Line ◽  
Hematologic Malignancies ◽  
Hereditary Cancer Syndromes ◽  
Rare Disorders ◽  
Good Opportunity ◽  
Genomic Technologies ◽  
Clinical Challenge ◽  
Cancer Syndromes

Abstract With the introduction of genomic technologies, more hereditary cancer syndromes with hematologic malignancies are being described. Up to 10% of hematologic malignancies in children and adults may be the result of an underlying inherited genetic risk. Managing these patients with hereditary hematologic malignancies, including familial leukemia, remains a clinical challenge because there is little information about these relatively rare disorders. This article covers some of the issues related to the diagnosis and interpretation of variants associated with hereditary hematologic malignancies, including the importance of an accurate family history in interpreting genetic variants associated with disease. The challenges of screening other family members and offering the most appropriate early malignancy detection is also discussed. We now have a good opportunity to better define hereditary cancer syndromes with associated hematologic malignancies and contribute to clinically effective guidelines.

scholarly journals Drug Analyses in Poisoned Patients—The Need to Be Specific

1982 ◽  
Vol 19 (4) ◽  
pp. 254-257 ◽  
Author(s):  
M J Stewart
Keyword(s):  
Clinical Implications ◽  
The Past ◽  
Modern Methods ◽  
The Future ◽  
Drugs In Blood ◽  
Qualitative Determination

Methods for the qualitative determination of drugs in blood and urine which have been used over the past 20 years have on several occasions given rise to incorrect interpretation due to their lack of specificity, which has resulted in falsely high values being reported for commonly requested drugs. Modern methods provide an opportunity to ensure specificity in the future but analysts must continue to be aware of the potential pitfalls. Examples of non-specificity in colorimetric, UV spectrophotometric, and immunological techniques are described and the clinical implications are demonstrated.

Introduction

ESC CardioMed ◽  
2018 ◽  
pp. 661-662
Author(s):  
Heribert Schunkert
Keyword(s):  
Genetic Variants ◽  
Vascular System ◽  
Current Knowledge ◽  
Genetic Diseases ◽  
Clinical Implications ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
System P ◽  
Polygenic Diseases ◽  
Generation Sequencing

The perception of genetic diseases of the heart and vascular system has dramatically changed over the last 10 years. Next-generation sequencing and arrays with millions of single nucleotide polymorphisms allowed significant advances in the understanding of monogenic and polygenic diseases. The chapters in ‘Genetics of cardiovascular diseases’, written by outstanding experts in the field, summarize the current knowledge and provide an overview of the clinical implications of mutations and genetic variants affecting the cardiovascular system.

scholarly journals Perspectives and future directions for epigenetics in hematology

Blood ◽  
2013 ◽  
Vol 121 (26) ◽  
pp. 5131-5137 ◽  
Author(s):  
Margaret A. Goodell ◽  
Lucy A. Godley
Keyword(s):  
Hematologic Malignancies ◽  
Mechanisms Of Action ◽  
Future Research ◽  
Clinical Implications ◽  
Future Directions ◽  
The Past ◽  
Pleiotropic Action ◽  
Epigenetic Regulators ◽  
Underlying Mechanisms

AbstractGenetic analysis of hematologic malignancies over the past 5 years has revealed abundant mutations in epigenetic regulators in all classes of disorders. Here, we summarize the observations made within our review series on the role of epigenetics in hematology. We highlight the clinical implications of mutations in epigenetic regulators and outline what we envision are some of the major areas that merit future research. Recent findings may have immediate prognostic value, but also offer new targets for drug development. However, the pleiotropic action of these regulators indicates caution is warranted and argues for investment in understanding of their underlying mechanisms of action as we proceed to exploit these findings for the benefit of patients.

scholarly journals The Elusive Mitochondrial Genomes of Apicomplexa: Where Are We Now?

2021 ◽  
Vol 12 ◽  
Author(s):  
Luisa Berná ◽  
Natalia Rego ◽  
María E. Francia
Keyword(s):  
Drug Targets ◽  
Genome Structure ◽  
Cellular Respiration ◽  
Mitochondrial Genomes ◽  
Third Generation ◽  
Sequencing Technologies ◽  
Third Generation Sequencing ◽  
Sequencing Studies ◽  
Promising Source ◽  
Generation Sequencing

Mitochondria are vital organelles of eukaryotic cells, participating in key metabolic pathways such as cellular respiration, thermogenesis, maintenance of cellular redox potential, calcium homeostasis, cell signaling, and cell death. The phylum Apicomplexa is entirely composed of obligate intracellular parasites, causing a plethora of severe diseases in humans, wild and domestic animals. These pathogens include the causative agents of malaria, cryptosporidiosis, neosporosis, East Coast fever and toxoplasmosis, among others. The mitochondria in Apicomplexa has been put forward as a promising source of undiscovered drug targets, and it has been validated as the target of atovaquone, a drug currently used in the clinic to counter malaria. Apicomplexans present a single tubular mitochondria that varies widely both in structure and in genomic content across the phylum. The organelle is characterized by massive gene migrations to the nucleus, sequence rearrangements and drastic functional reductions in some species. Recent third generation sequencing studies have reignited an interest for elucidating the extensive diversity displayed by the mitochondrial genomes of apicomplexans and their intriguing genomic features. The underlying mechanisms of gene transcription and translation are also ill-understood. In this review, we present the state of the art on mitochondrial genome structure, composition and organization in the apicomplexan phylum revisiting topological and biochemical information gathered through classical techniques. We contextualize this in light of the genomic insight gained by second and, more recently, third generation sequencing technologies. We discuss the mitochondrial genomic and mechanistic features found in evolutionarily related alveolates, and discuss the common and distinct origins of the apicomplexan mitochondria peculiarities.

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