[CORRIGENDUM] Corrigendum: Mechanism of Bone Mineralization
(Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - August 3, 2020 Category: Research Authors: Murshed, M. Tags: CORRIGENDUM Source Type: research

[PERSPECTIVES] Influenza Hemagglutinin Structures and Antibody Recognition
Hemagglutinin (HA) is most abundant glycoprotein on the influenza virus surface. Influenza HA promotes viral entry by engaging the receptor and mediating virus–host membrane fusion. At the same time, HA is the major antigen of the influenza virus. HA antigenic shift can result in pandemics, whereas antigenic drift allows human circulating strains to escape herd immunity. Most antibody responses against HA are strain-specific. However, antibodies that have neutralizing activities against multiple strains or even subtypes have now been discovered and characterized. These broadly neutralizing antibodies (bnAbs) target c...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2020 Category: Research Authors: Wu, N. C., Wilson, I. A. Tags: Influenza: The Cutting Edge PERSPECTIVES Source Type: research

[PERSPECTIVES] Quantifying between-Host Transmission in Influenza Virus Infections
The error-prone replication and life cycle of influenza virus generate a diverse set of genetic variants. Transmission between hosts strictly limits both the number of virus particles and the genetic diversity of virus variants that reach a new host and establish an infection. This sharp reduction in the virus population at transmission––the transmission bottleneck––is significant to the evolution of influenza virus and to its epidemic and pandemic potential. This review describes transmission bottlenecks and their effect on the diversity and evolution of influenza virus. It also reviews the methods...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2020 Category: Research Authors: Johnson, K. E. E., Ghedin, E. Tags: Influenza: The Cutting Edge PERSPECTIVES Source Type: research

[TECHNIQUE] Zebrafish In Vivo Models of Cancer and Metastasis
Metastasis, the dispersal of cancer cells from a primary tumor to secondary sites within the body, is the leading cause of cancer-related death. Animal models have been an indispensable tool to investigate the complex interactions between the cancer cells and the tumor microenvironment during the metastatic cascade. The zebrafish (Danio rerio) has emerged as a powerful vertebrate model for studying metastatic events in vivo. The zebrafish has many attributes including ex-utero development, which facilitates embryonic manipulation, as well as optically transparent tissues, which enables in vivo imaging of fluorescently labe...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2020 Category: Research Authors: Astell, K. R., Sieger, D. Tags: Metastasis: Mechanism to Therapy TECHNIQUE Source Type: research

[PERSPECTIVES] New Approaches on Cancer Immunotherapy
Metastasis, which occurs when cancer cells disseminate from the primary tumor site to other parts of the body, is the primary cause of mortality in patients, and the recurrence of multiple metastatic tumors is an obstacle to eliminating cancer. Recent clinical studies demonstrated that patients who respond to immunotherapy have longer survival rates with lower metastatic relapse, suggesting that immunotherapy may be one of the solutions to overcome cancer metastasis. Indeed, various host immune cells not only shape the tumor microenvironment but also participate in multiple stages of metastasis. Therefore, to improve clini...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2020 Category: Research Authors: Cha, J.-H., Chan, L.-C., Song, M. S., Hung, M.-C. Tags: Metastasis: Mechanism to Therapy PERSPECTIVES Source Type: research

[PERSPECTIVES] Tumor-Based Genetic Testing and Familial Cancer Risk
As genetic testing on somatic tumor tissue becomes a more routine part of personalized cancer treatment, a growing opportunity arises to identify hereditary germline variants within those results. These germline results can affect future cancer screening for both patients and their family members. Finding this germline information can be complicated as a result of differences between somatic and germline testing processes, nomenclature, and outcome goals (e.g., treatment impact). The goal of this review is to highlight differences between somatic and germline testing and outline a potential guide to allow for appropriate c...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2020 Category: Research Authors: Forman, A., Sotelo, J. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research

[PERSPECTIVES] Informed Consent in the Genomics Era
Informed consent, the process of gathering autonomous authorization for a medical intervention or medical research participation, is a fundamental component of medical practice. Medical informed consent assumes decision-making capacity, voluntariness, comprehension, and adequate information. The increasing use of genetic testing, particularly genomic sequencing, in clinical and research settings has presented many new challenges for clinicians and researchers when obtaining informed consent. Many of these challenges revolve around the need for patient comprehension of sufficient information. Genomic sequencing is complex&m...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2020 Category: Research Authors: Rego, S., Grove, M. E., Cho, M. K., Ormond, K. E. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research

[PERSPECTIVES] Metabolic Role of PTEN in Insulin Signaling and Resistance
Phosphatase and tensin homolog (PTEN) is most prominently known for its function in tumorigenesis. However, a metabolic role of PTEN is emerging as a result of its altered expression in type 2 diabetes (T2D), which results in impaired insulin signaling and promotion of insulin resistance during the pathogenesis of T2D. PTEN functions in regulating insulin signaling across different organs have been identified. Through the use of a variety of models, such as tissue-specific knockout (KO) mice and in vitro cell cultures, PTEN's role in regulating insulin action has been elucidated across many cell types. Herein, we will revi...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2020 Category: Research Authors: Li, Y. Z., Di Cristofano, A., Woo, M. Tags: The PTEN Family PERSPECTIVES Source Type: research

[RETROSPECTIVE] Discovery of the PTEN Tumor Suppressor and Its Connection to the PI3K and AKT Oncogenes
PTEN (phosphatase and tensin homolog on chromosome 10) was discovered over 20 years ago in 1997 and linked to the phosphatidylinositol 3-kinase (PI3K) and AKT oncogenes the following year. The discovery of PTEN emerged from the linked concepts of oncogenes and tumor suppressor genes that cause and prevent cancer and the fields of tumor viruses and human cancer genetics from which these two concepts arose. While much has been learned since, the initial discovery and characterization, including the discovery that PTEN is a regulator of PI3K and AKT, provide the foundation on which we continue to build our knowledge. To provi...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2020 Category: Research Authors: Parsons, R. Tags: The PTEN Family RETROSPECTIVE Source Type: research

[PERSPECTIVES] The Ecology and Evolution of Influenza Viruses
The patterns and processes of influenza virus evolution are of fundamental importance, underpinning such traits as the propensity to emerge in new host species and the ability to rapidly generate antigenic variation. Herein, we review key aspects of the ecology and evolution of influenza viruses. We begin with an exploration of the origins of influenza viruses within the orthomyxoviruses, showing how our perception of the evolutionary history of these viruses has been transformed with metagenomic sequencing. We then outline the diversity of virus subtypes in different species and the processes by which these viruses have e...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2020 Category: Research Authors: Wille, M., Holmes, E. C. Tags: Influenza: The Cutting Edge PERSPECTIVES Source Type: research

[PERSPECTIVES] Ferreting Out Influenza Virus Pathogenicity and Transmissibility: Past and Future Risk Assessments in the Ferret Model
As influenza A viruses continue to jump species barriers, data generated in the ferret model to assess influenza virus pathogenicity, transmissibility, and tropism of these novel strains continues to inform an increasing scope of public health–based applications. This review presents the suitability of ferrets as a small mammalian model for influenza viruses and describes the breadth of pathogenicity and transmissibility profiles possible in this species following inoculation with a diverse range of viruses. Adaptation of aerobiology-based techniques and analyses have furthered our understanding of data obtained from...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2020 Category: Research Authors: Belser, J. A., Pulit-Penaloza, J. A., Maines, T. R. Tags: Influenza: The Cutting Edge PERSPECTIVES Source Type: research

[PERSPECTIVES] Extracellular Vesicles and Metastasis
Secretion of cell contents through extracellular vesicles (EVs), such as exosomes and microvesicles, is a fundamental cell behavior. Compared with their normal counterparts, cancer cells are different in the amount and composition of EVs they secrete as a result of intrinsic and extrinsic (microenvironmental) alterations. Although EVs were originally recognized as a means to remove undesired cell components, recent studies show their critical role in mediating intercellular interaction through cargo transport. In cancer, EVs can be transferred between different cancer cell subpopulations and between cancer and normal cells...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2020 Category: Research Authors: Wang, S. E. Tags: Metastasis: Mechanism to Therapy PERSPECTIVES Source Type: research

[PERSPECTIVES] Cancer Stem Cells and Epithelial-to-Mesenchymal Transition in Cancer Metastasis
The cancer stem cell (CSC) concept stands for undifferentiated tumor cells with the ability to initiate heterogeneous tumors. It is also relevant in metastasis and can explain how metastatic tumors mirror the heterogeneity of primary tumors. Cellular plasticity, including the epithelial-to-mesenchymal transition (EMT), enables the generation of CSCs at different steps of the metastatic process including metastatic colonization. In this review, we update the concept of CSCs and provide evidence of the existence of metastatic stem cells (MetSCs). In addition, we highlight the nuanced understanding of EMT that has been gained...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2020 Category: Research Authors: Celia-Terrassa, T., Jolly, M. K. Tags: Metastasis: Mechanism to Therapy PERSPECTIVES Source Type: research

[PERSPECTIVES] A Person-Centered Approach to Cardiovascular Genetic Testing
Cardiovascular genetic counselors provide guidance to people facing the reality or prospect of inherited cardiovascular conditions. Key activities in this role include discussing clinical cardiac screening for at-risk family members and offering genetic testing. Psychological factors often influence whether patients choose to have genetic testing and how they understand and communicate the results to at-risk relatives, so psychological counseling increases the impact of genetic education and medical recommendations. This work reviews the literature on the factors that influence patient decisions about cardiovascular geneti...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2020 Category: Research Authors: Platt, J. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research

[PERSPECTIVES] Predictive Genetic Counseling for Neurodegenerative Diseases: Past, Present, and Future
Predictive genetic counseling for neurodegenerative diseases commenced with Huntington's disease (HD). Because the psychological issues and outcomes have been best studied in HD, the HD genetic counseling and testing protocol is still accepted as the gold standard for genetic counseling for these diseases. Yet, advances in genomic technology have produced an abundance of new information about the genetics of diseases such as Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Parkinson's disease. The resulting expansion of genetic tests together with the availability of direct-to-consumer testi...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2020 Category: Research Authors: Goldman, J. S. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research

[PERSPECTIVES] Posttranslational Regulation and Conformational Plasticity of PTEN
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor that is frequently down-modulated in human cancer. PTEN inhibits the phosphatidylinositol 3-phosphate kinase (PI3K)/AKT pathway through its lipid phosphatase activity. Multiple PI3K/AKT-independent actions of PTEN, protein-phosphatase activities and functions within the nucleus have also been described. PTEN, therefore, regulates many cellular processes including cell proliferation, survival, genomic integrity, polarity, migration, and invasion. Even a modest decrease in the functional dose of PTEN may promote cancer development. Understan...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2020 Category: Research Authors: Kotelevets, L., Trifault, B., Chastre, E., Scott, M. G. H. Tags: The PTEN Family PERSPECTIVES Source Type: research

[PERSPECTIVES] The Biology of B-Progenitor Acute Lymphoblastic Leukemia
Genomic analyses have revolutionized our understanding of the biology of B-progenitor acute lymphoblastic leukemia (ALL). Studies of thousands of cases across the age spectrum have revised the taxonomy of B-ALL by identifying multiple new subgroups with diverse sequence and structural initiating events that vary substantially by age at diagnosis and prognostic significance. There is a growing appreciation of the role of inherited genetic variation in predisposition to ALL and drug responsiveness and of the nature of genetic variegation and clonal evolution that may be targeted for improved diagnostic, risk stratification, ...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2020 Category: Research Authors: Roberts, K. G., Mullighan, C. G. Tags: Leukemia and Lymphoma: Molecular and Therapeutic Insights PERSPECTIVES Source Type: research

[ERRATUM] Erratum: Impairment of Synaptic Plasticity by Cannabis, {Delta}9-THC, and Synthetic Cannabinoids
(Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - June 1, 2020 Category: Research Authors: Hoffman, A. F., Hwang, E.-K., Lupica, C. R. Tags: ERRATUM Source Type: research

[CORRIGENDUM] Corrigendum: Glutamatergic Systems and Memory Mechanisms Underlying Opioid Addiction
(Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - June 1, 2020 Category: Research Authors: Heinsbroek, J. A., De Vries, T. J., Peters, J. Tags: CORRIGENDUM Source Type: research

[Early Release Articles] H9 Influenza Viruses: An Emerging Challenge
Influenza A viruses (IAVs) of the H9 subtype are enzootic in Asia, the Middle East, and parts of North and Central Africa, where they cause significant economic losses to the poultry industry. Of note, some strains of H9N2 viruses have been linked to zoonotic episodes of mild respiratory diseases. Because of the threat posed by H9N2 viruses to poultry and human health, these viruses are considered of pandemic concern by the World Health Organization (WHO). H9N2 IAVs continue to diversify into multiple antigenically and phylogenetically distinct lineages that can further promote the emergence of strains with pandemic potent...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2020 Category: Research Authors: Carnaccini, S., Perez, D. R. Tags: Influenza: The Cutting Edge Early Release Articles Source Type: research

[TECHNIQUE] The Different Facets of Liquid Biopsy: A Kaleidoscopic View
The current limitations of cancer diagnosis and molecular profiling based on invasive tissue biopsies or clinical imaging have led to the development of the liquid biopsy field. Liquid biopsy includes the isolation of circulating tumor cells (CTCs), circulating free or tumor DNA (cfDNA or ctDNA), extracellular vesicles (EVs), and tumor-educated platelets (TEPs) from body fluid samples and their molecular characterization to identify biomarkers for early cancer diagnosis, prognosis, therapeutic prediction, and follow-up. These innovative biosources show similar features as the primary tumor from where they originated or int...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2020 Category: Research Authors: Eslami-S, Z., Cortes-Hernandez, L. E., Cayrefourcq, L., Alix-Panabieres, C. Tags: Metastasis: Mechanism to Therapy TECHNIQUE Source Type: research

[PERSPECTIVES] Clinical Perspectives in Brain Metastasis
Brain metastases (BMs) are responsible for decline in neurological function, reduction in overall quality of life, and mortality from recurrent or untreatable lesions. Advances in diagnostics and imaging have led to increased detection of central nervous system (CNS) metastases in patients with progressive cancers. Improved control of extracranial systemic disease, and the limited ability of current therapeutics to cross the blood–brain barrier (BBB) also contribute to the increase in incidence of brain metastases, as tumor cells seek refuge in the brain. Surgery, chemotherapy, and/or radiation (whole-brain radiation...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2020 Category: Research Authors: Deshpande, K., Buchanan, I., Martirosian, V., Neman, J. Tags: Metastasis: Mechanism to Therapy PERSPECTIVES Source Type: research

[PERSPECTIVES] Evidence-Based Genetic Counseling for Psychiatric Disorders: A Road Map
Psychiatric disorders, such as schizophrenia, depression, anxiety, and bipolar disorder, are common conditions that arise as a result of complex and heterogeneous combinations of genetic and environmental factors. In contrast to childhood neurodevelopmental conditions such as autism and intellectual disability, there are no clinical practice guidelines for applying genetic testing in the context of these conditions. But genetic counseling and genetic testing are not synonymous, and people who live with psychiatric disorders and their family members are often interested in what psychiatric genetic counseling can offer. Furt...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2020 Category: Research Authors: Austin, J. C. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research

[PERSPECTIVES] Cancer Genetic Counseling--Current Practice and Future Challenges
Cancer genetic counseling practice is rapidly evolving, with services being provided in increasingly novel ways. Pretest counseling for cancer patients may be abbreviated from traditional models to cover the elements of informed consent in the broadest of strokes. Genetic testing may be ordered by a cancer genetics professional, oncology provider, or primary care provider. Increasingly, direct-to-consumer testing options are available and utilized by consumers anxious to take control of their genetic health. Finally, genetic information is being used to inform oncology care, from surgical decision-making to selection of ch...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2020 Category: Research Authors: Schienda, J., Stopfer, J. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research

[PERSPECTIVES] Supporting Patient Autonomy and Informed Decision-Making in Prenatal Genetic Testing
Genetic counselors have both the burden and the privilege of supporting patients who are faced with making difficult decisions. In the prenatal setting, genetic counselors are responsible for reviewing a growing list of prenatal testing options for patients with the goal of helping people to anticipate the potential consequences of their decision. Prenatal genetic counselors also support patients in making decisions about the next steps after clinical evaluation has indicated a genetic condition, birth defect, or information of uncertain clinical significance in the fetus. The information provided and choices patients face...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2020 Category: Research Authors: Stoll, K., Jackson, J. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research

[PERSPECTIVES] The Complex Landscape of PTEN mRNA Regulation
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a key tumor suppressor in the development and progression of different tumor types. Emerging data indicate that small reductions in PTEN protein levels can promote cancer. PTEN protein levels are tightly controlled by a plethora of mechanisms beginning with epigenetic and transcriptional regulation and ending with control of protein synthesis and stability. PTEN messenger RNA (mRNA) is also subject to exquisite regulation by microRNAs, coding and long noncoding RNAs, and RNA-binding proteins. Additionally, PTEN mRNA is markedly influenced by alternative spli...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2020 Category: Research Authors: Sellars, E., Gabra, M., Salmena, L. Tags: The PTEN Family PERSPECTIVES Source Type: research

[PERSPECTIVES] Epidemiology and Etiology of Leukemia and Lymphoma
Available evidence suggests that the incidence of leukemia and lymphoma tends to be higher in highly developed regions of the world and among Whites in the United States. Temporal trends in incidence are dynamic and multifactorial; for instance, the incidence of non-Hodgkin's lymphoma increased around the turn of the century, in part because of the acquired immune deficiency syndrome (AIDS) epidemic. Most leukemias and lymphomas are sporadic and the specific etiology remains elusive. Still, research shows that these malignancies often develop in the context of genetic abnormalities, immunosuppression, and exposure to risk ...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2020 Category: Research Authors: Bispo, J. A. B., Pinheiro, P. S., Kobetz, E. K. Tags: Leukemia and Lymphoma: Molecular and Therapeutic Insights PERSPECTIVES Source Type: research

[PERSPECTIVES] Myeloid Cells in Metastasis
Metastatic disease is the leading cause of death in patients with solid cancers. The progression to metastasis is a multistep process that involves detachment of tumor cells from their constraining basement membrane at the primary site, migration and intravasation into the circulation, survival in the circulation, extravasation into the secondary organ, and survival and growth at the secondary site. During these steps, tumor and immune cells interact and influence each other both within the tumor microenvironment and systemically. In particular, myeloid cells such as monocytes, macrophages, neutrophils, and myeloid-derived...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2020 Category: Research Authors: Swierczak, A., Pollard, J. W. Tags: Metastasis: Mechanism to Therapy PERSPECTIVES Source Type: research

[PERSPECTIVES] Brain Metastasis Organotropism
Brain metastases are associated with poor prognosis irrespective of the primary tumor they originate from. Current treatments for brain metastases are palliative, and patients with symptomatic brain metastasis have a one-year survival of
Source: Cold Spring Harbor perspectives in medicine - May 1, 2020 Category: Research Authors: Yuzhalin, A. E., Yu, D. Tags: Metastasis: Mechanism to Therapy PERSPECTIVES Source Type: research

[PERSPECTIVES] Toward Systems Pathology for PTEN Diagnostics
Germline alterations of the tumor suppressor PTEN have been extensively characterized in patients with PTEN hamartoma tumor syndromes, encompassing subsets of Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, Proteus and Proteus-like syndromes, as well as autism spectrum disorder. Studies have shown an increase in the risk of developing specific cancer types in the presence of a germline PTEN mutation. Furthermore, outside of the familial setting, somatic variants of PTEN occur in numerous malignancies. Here we introduce and discuss the prospect of moving toward a systems pathology approach for PTEN diagnosti...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2020 Category: Research Authors: Haddadi, N., Travis, G., Nassif, N. T., Simpson, A. M., Marsh, D. J. Tags: The PTEN Family PERSPECTIVES Source Type: research

[TECHNIQUE] Animal Models of Hepatitis C Virus Infection
Hepatitis C virus (HCV) is an important and underreported infectious disease, causing chronic infection in ~71 million people worldwide. The limited host range of HCV, which robustly infects only humans and chimpanzees, has made studying this virus in vivo challenging and hampered the development of a desperately needed vaccine. The restrictions and ethical concerns surrounding biomedical research in chimpanzees has made the search for an animal model all the more important. In this review, we discuss different approaches that are being pursued toward creating small animal models for HCV infection. Although efforts to use ...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2020 Category: Research Authors: Ploss, A., Kapoor, A. Tags: Hepatitis C Virus: The Story of a Scientific and Therapeutic Revolution TECHNIQUE Source Type: research

[PERSPECTIVES] Regulating Preimplantation Genetic Testing across the World: A Comparison of International Policy and Ethical Perspectives
Preimplantation genetic testing (PGT) is a reproductive technology that, in the course of in vitro fertilization (IVF), allows prospective parents to select their future offspring based on genetic characteristics. PGT could be seen as an exercise of reproductive liberty, thus potentially raising significant socioethical and legal controversy. In this review, we examine—from a comparative perspective—variations in policy approaches to the regulation of PGT. We draw on a sample of 19 countries (Australia, Austria, Belgium, Brazil, Canada, China, France, Germany, India, Israel, Italy, Japan, Mexico, Netherlands, S...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2020 Category: Research Authors: Ginoza, M. E. C., Isasi, R. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research

[PERSPECTIVES] Discouraging Elective Genetic Testing of Minors: A Norm under Siege in a New Era of Genomic Medicine
Consistently, the field of genetic counseling has advocated that parents be advised to defer elective genetic testing of minors until adulthood to prevent a range of potential harms, including stigma, discrimination, and the loss of the child's ability to decide for him- or herself as an adult. However, consensus around the policy of "defer-when-possible" obscures the extent to which this norm is currently under siege. Increasingly, routine use of full or partial genome sequencing challenges our ability to control what is discovered in childhood or, when applied in a prenatal context, even before birth. The expan...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2020 Category: Research Authors: Hercher, L. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research

[PERSPECTIVES] PTEN Nuclear Functions
For years, clinical and basic researchers have been aware of the presence of PTEN in the nucleus in cell culture, animal models, and both healthy and diseased human tissues. Despite the early recognition of nuclear PTEN, the understanding of the mechanisms of its nuclear localization, function in the nucleus, and importance in biology and human disease has been lacking. Over the last decade, emerging concepts for the complex involvement of nuclear PTEN in a variety of processes, including genome maintenance and DNA repair, cell-cycle control, gene expression, and DNA replication, are illuminating what could prove to be the...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2020 Category: Research Authors: Ho, J., Cruise, E. S., Dowling, R. J. O., Stambolic, V. Tags: The PTEN Family PERSPECTIVES Source Type: research

[PERSPECTIVES] RNA Regulators in Leukemia and Lymphoma
Posttranscriptional regulation of mRNA is a powerful and tightly controlled process in which cells command the integrity, diversity, and abundance of their protein products. RNA-binding proteins (RBPs) are the principal players that control many intermediary steps of posttranscriptional regulation. Recent advances in this field have discovered the importance of RBPs in hematological diseases. Herein we will review a number of RBPs that have been determined to play critical functions in leukemia and lymphoma. Furthermore, we will discuss the potential therapeutic strategies that are currently being studied to specifically t...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2020 Category: Research Authors: Prieto, C., Kharas, M. G. Tags: Leukemia and Lymphoma: Molecular and Therapeutic Insights PERSPECTIVES Source Type: research

[PERSPECTIVES] Cancer Cell Dormancy in Metastasis
Recurrent metastasis following extended periods of disease-free survival remains a common cause of morbidity and mortality for many cancer patients. Recurrence is thought to be mediated by tumor cells that escaped the primary site early in the disease course and colonize distant organs. In these locations, cells adapt to the local environment, entering a state of long-term dormancy in which they can resist therapy. Then, through mechanisms that are poorly understood, a proportion of these cells are reactivated and become proliferative, forming lethal metastases. Here, we discuss disseminated tumor cell dormancy in recurren...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2020 Category: Research Authors: Summers, M. A., McDonald, M. M., Croucher, P. I. Tags: Metastasis: Mechanism to Therapy PERSPECTIVES Source Type: research

[PERSPECTIVES] The Immune Microenvironment and Cancer Metastasis
The dynamic interplay between neoplastic cells and the immune microenvironment regulates every step of the metastatic process. Immune cells contribute to invasion by secreting a cornucopia of inflammatory factors that promote epithelial-to-mesenchymal transition and remodeling of the stroma. Cancer cells then intravasate to the circulatory system assisted by macrophages and use several pathways to avoid recognition by cytotoxtic lymphocytes and phagocytes. Circulating tumor cells that manage to adhere to the vasculature and encounter premetastic niches are able to use the associated myeloid cells to extravasate into ectopi...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2020 Category: Research Authors: El-Kenawi, A., Hänggi, K., Ruffell, B. Tags: Metastasis: Mechanism to Therapy PERSPECTIVES Source Type: research

[PERSPECTIVES] The Elimination of Hepatitis C as a Public Health Threat
Hepatitis C virus is a global public health threat, affecting 71 million people worldwide. Increasing recognition of the impact of this epidemic and recent advances in biomedical and technical approaches to hepatitis C prevention and cure have provided impetus for the World Health Organization (WHO) to call for global elimination of hepatitis C as a public health threat by 2030. This work reviews the feasibility of hepatitis C elimination and pathways to overcome existing and potential future barriers to elimination. Drawing on cost-effectiveness modeling and providing examples of successful implementation efforts across t...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2020 Category: Research Authors: Hellard, M., Schroeder, S. E., Pedrana, A., Doyle, J., Aitken, C. Tags: Hepatitis C Viruses: The Story of a Scientific and Therapeutic Revolution PERSPECTIVES Source Type: research

[PERSPECTIVES] Natural History of Hepatic and Extrahepatic Hepatitis C Virus Diseases and Impact of Interferon-Free HCV Therapy
The hepatitis C virus (HCV) infects 71.1 million persons and causes 400,000 deaths annually worldwide. HCV mostly infects the liver, causing acute and chronic necroinflammatory damage, which may progress toward cirrhosis and hepatocellular carcinoma. In addition, HCV has been associated with several extrahepatic manifestations. The advent of safe and effective direct-acting antivirals (DAAs) has made the dream of eliminating this public health scourge feasible in the medium term. Prospective studies using DAA-based regimens have shown the benefit of HCV clearance in terms of both liver- and non-liver-related mortality. (So...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2020 Category: Research Authors: Negro, F. Tags: Hepatitis C Viruses: The Story of a Scientific and Therapeutic Revolution PERSPECTIVES Source Type: research

[PERSPECTIVES] Legal Challenges in Genetics, Including Duty to Warn and Genetic Discrimination
This review will explore two legal issues in genetic counseling: genetic discrimination and the duty to warn. It emphasizes the complexity and variability of federal and state genetic nondiscrimination protections in the United States and how the many gaps in such protections may affect people pursuing genetic testing. The limited law addressing legal obligations genetic counselors owe at-risk relatives likely does not require counselors to warn relatives directly about genetic risks. Whether it permits them to make such disclosures, however, is more uncertain and may depend on the jurisdiction. (Source: Cold Spring Harbor...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2020 Category: Research Authors: Suter, S. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research

[PERSPECTIVES] Genetic Counseling in Neurodevelopmental Disorders
Neurodevelopmental disorders (NDDs), including global developmental delay (GDD), intellectual disability (ID), and autism spectrum disorder (ASD), represent a continuum of developmental brain dysfunction. Although the etiology of NDD is heterogeneous, genetic variation represents the largest contribution, strongly supporting the recommendation for genetic evaluation in individuals with GDD/ID and ASD. Technological advances now allow for a specific genetic diagnosis to be identified in a substantial portion of affected individuals. This information has important ramifications for treatment, prognosis, and recurrence risk, ...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2020 Category: Research Authors: Blesson, A., Cohen, J. S. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research

[PERSPECTIVES] PTEN in Hereditary and Sporadic Cancer
Germline pathogenic phosphatase and tensin homolog (PTEN) mutations cause PTEN hamartoma tumor syndrome (PHTS), characterized by various benign and malignant tumors of the thyroid, breast, endometrium, and other organs. Patients with PHTS may present with other clinical features such as macrocephaly, intestinal polyposis, cognitive changes, and pathognomonic skin changes. Clinically, deregulation of PTEN function is implicated in other human diseases in addition to many types of human cancer. PTEN is an important phosphatase that counteracts one of the most critical cancer pathways: the phosphatidylinositol 3-kinase (PI3K)...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2020 Category: Research Authors: Ngeow, J., Eng, C. Tags: The PTEN Family PERSPECTIVES Source Type: research

[PERSPECTIVES] Clonal Hematopoiesis and Premalignant Diseases
Clonal hematopoiesis (CH) arises when mutations in the hematopoietic system confer a fitness advantage to specific clones, thereby favoring their disproportionate growth. The presence of CH increases with age and environmental exposures such as cytotoxic chemotherapy or radiotherapy. The most frequent mutations occur in epigenetic regulators, such as DNMT3A, TET2, and ASXL1, leading to dysregulation of tumor suppressor function, pathogen response, and inflammation. These dysregulated processes elevate risk of overall mortality, cardiovascular disease, and eventual hematologic malignancy (HM). CH is likely acting as an init...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2020 Category: Research Authors: Kaner, J., Desai, P., Mencia-Trinchant, N., Guzman, M. L., Roboz, G. J., Hassane, D. C. Tags: Leukemia and Lymphoma: Molecular and Therapeutic Insights PERSPECTIVES Source Type: research

[PERSPECTIVES] Genetic Counseling and the Central Tenets of Practice
Genetic counseling is a profession growing and evolving at an extraordinary rate. This growth is driven by an explosion in what we know, as a result of progress in science, technology, and bioinformatics, and an explosion in what we do not know, as we strive to understand the impact of genomic information on the lives of our patients and clients. Genetic counselors work in an increasing number of subspecialties and diversity of settings. But although the field has evolved, it has maintained a remarkably unchanged core of shared values and beliefs. The heart of genetic counseling practice is the therapeutic relationship, wi...
Source: Cold Spring Harbor perspectives in medicine - March 2, 2020 Category: Research Authors: Biesecker, B. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research

[PERSPECTIVES] Liver Tropism in Cancer: The Hepatic Metastatic Niche
The liver is the largest organ in the human body and is prone for cancer metastasis. Although the metastatic pattern can differ depending on the cancer type, the liver is the organ to which cancer cells most frequently metastasize for the majority of prevalent malignancies. The liver is unique in several aspects: the vascular structure is highly permeable and has unparalleled dual blood connectivity, and the hepatic tissue microenvironment presents a natural soil for the seeding of disseminated tumor cells. Although 70% of the liver is composed of the parenchymal hepatocytes, the remaining 30% is composed of nonparenchymal...
Source: Cold Spring Harbor perspectives in medicine - March 2, 2020 Category: Research Authors: Mielgo, A., Schmid, M. C. Tags: Metastasis: Mechanism to Therapy PERSPECTIVES Source Type: research

[PERSPECTIVES] Hepatitis C Virus Replication
Replication and amplification of the viral genome is a key process for all viruses. For hepatitis C virus (HCV), a positive-strand RNA virus, amplification of the viral genome requires the synthesis of a negative-sense RNA template, which is in turn used for the production of new genomic RNA. This process is governed by numerous proteins, both host and viral, as well as distinct lipids and specific RNA elements within the positive- and negative-strand RNAs. Moreover, this process requires specific changes to host cell ultrastructure to create microenvironments conducive to viral replication. This review will focus on descr...
Source: Cold Spring Harbor perspectives in medicine - March 2, 2020 Category: Research Authors: Tabata, K., Neufeldt, C. J., Bartenschlager, R. Tags: Hepatitis C Viruses: The Story of a Scientific and Therapeutic Revolution PERSPECTIVES Source Type: research

[PERSPECTIVES] Hepatitis C Virus Epidemiology and the Impact of Interferon-Free Hepatitis C Virus Therapy
The public health impact of hepatitis C virus (HCV) infection has been realized only recently. Globally, 71 million people are living with HCV chronic infection. HCV prevalence is higher in some regions and countries, as well as in some subpopulations such as people who inject drugs, prisoners, or people living with HIV. In 2017, an estimated 580,000 people died from HCV, largely because of long-term complications of the disease. The advent of direct-acting antivirals (DAAs), which are highly effective in treating the infection and are well tolerated, led the World Health Organization (WHO) in 2016 to call for the eliminat...
Source: Cold Spring Harbor perspectives in medicine - March 2, 2020 Category: Research Authors: Lazarus, J. V., Roel, E., Elsharkawy, A. M. Tags: Hepatitis C Viruses: The Story of a Scientific and Therapeutic Revolution PERSPECTIVES Source Type: research

[PERSPECTIVES] Genetic Counseling and Genome Sequencing in Pediatric Rare Disease
Both genome sequencing (GS) and exome sequencing (ES) have proven to be revolutionary in the diagnosis of pediatric rare disease. The diagnostic potential and increasing affordability make GS and ES more accessible as a routine clinical test in some centers. Herein, I review aspects of rare disease in pediatrics associated with the use of genomic technologies with an emphasis on the benefits and limitations of both ES and GS, complexities of variant classification, and the importance of genetic counseling. Indications for testing, the role of genetic counselors in genomic test selection, and the diagnostic potential of ES ...
Source: Cold Spring Harbor perspectives in medicine - March 2, 2020 Category: Research Authors: Elliott, A. M. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research

[PERSPECTIVES] Structural Mechanisms of PTEN Regulation
The tumor suppressor phosphatase and tensin homolog on chromosome 10 (PTEN) is a tightly regulated enzyme responsible for dephosphorylating the progrowth lipid messenger molecule phosphatidylinositol 3,4,5-trisphosphate (PIP3) on the plasma membrane. The carboxy-terminal tail (CTT) of PTEN is key for regulation of the enzyme. When phosphorylated, the unstructured CTT interacts with the phosphatase-C2 superdomain to inactivate the enzyme by preventing membrane association. PTEN mutations associated with cancer also inactivate the enzyme. Alternate translation-initiation sites generate extended isoforms of PTEN, such as PTEN...
Source: Cold Spring Harbor perspectives in medicine - March 2, 2020 Category: Research Authors: Masson, G. R., Williams, R. L. Tags: The PTEN Family PERSPECTIVES Source Type: research

[PERSPECTIVES] The Genetics and Mechanisms of T-Cell Acute Lymphoblastic Leukemia
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from early T-cell progenitors. The recognition of clinical, genetic, transcriptional, and biological heterogeneity in this disease has already translated into new prognostic biomarkers, improved leukemia animal models, and emerging targeted therapies. This work reviews our current understanding of the molecular mechanisms of T-ALL. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - March 2, 2020 Category: Research Authors: Gianni, F., Belver, L., Ferrando, A. Tags: Leukemia and Lymphoma: Molecular and Therapeutic Insights PERSPECTIVES Source Type: research