scholarly journals The Genomics of Myelodysplastic Syndromes: Origins of Disease Evolution, Biological Pathways, and Prognostic Implications

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2512
Author(s):  
Hassan Awada ◽  
Bicky Thapa ◽  
Valeria Visconte
Keyword(s):  
Experimental Studies ◽  
Gene Mutations ◽  
High Rate ◽  
Murine Models ◽  
Disease Evolution ◽  
Molecular Alterations ◽  
Disease Phenotypes ◽  
Prognostic Implications ◽  
Made In

The molecular pathogenesis of myelodysplastic syndrome (MDS) is complex due to the high rate of genomic heterogeneity. Significant advances have been made in the last decade which elucidated the landscape of molecular alterations (cytogenetic abnormalities, gene mutations) in MDS. Seminal experimental studies have clarified the role of diverse gene mutations in the context of disease phenotypes, but the lack of faithful murine models and/or cell lines spontaneously carrying certain gene mutations have hampered the knowledge on how and why specific pathways are associated with MDS pathogenesis. Here, we summarize the genomics of MDS and provide an overview on the deregulation of pathways and the latest molecular targeted therapeutics.

Effects of perfusate buffer capacity on capillary CO2-HCO3(-)-H+ reactions: theory

1991 ◽  
Vol 71 (4) ◽  
pp. 1460-1468 ◽  
Author(s):  
A. Bidani ◽  
T. A. Heming
Keyword(s):  
Carbonic Anhydrase ◽  
Buffer Capacity ◽  
Experimental Studies ◽  
Nonlinear Effects ◽  
Co2 Exchange ◽  
High Rate ◽  
Pulmonary Capillaries ◽  
Sequential Combination ◽  
Time Courses

The importance of perfusate nonbicarbonate buffer capacity (beta nonHCO3) to intracapillary CO2-HCO3(-)-H+ reactions was assessed by theoretical analysis of CO2 exchange in saline-perfused pulmonary capillaries. Time courses for perfusate PCO2, [HCO3-], and [H+] were computed for capillaries containing different activities of luminal vascular carbonic anhydrase and different amounts of perfusate nonbicarbonate buffers. Mobilization of perfusate HCO3- toward CO2 during capillary transit is determined by the availability of HCO3- and H+. A supply of protons from the nonbicarbonate buffer pool is necessary to maintain a high rate of HCO3- dehydration. The analyses indicate that beta nonHCO3 has marked nonlinear effects on transcapillary CO2 exchange and intravascular pH equilibration. These nonlinear effects differ from those previously computed for CO2 reactions in an open system because the present model system consists of a sequential combination of open (within capillary proper) and closed (within postcapillary vasculature) systems. The role of luminal vascular carbonic anhydrase in capillary CO2 reactions is strongly dependent on beta nonHCO3. Perfusate nonbicarbonate buffer capacity must be considered when the results of experimental studies of transcapillary CO2 exchange and/or intravascular pH equilibration are interpreted.

scholarly journals Hypertension, a Moving Target in COVID-19

2021 ◽  
Vol 128 (7) ◽  
pp. 1062-1079
Author(s):  
Carmine Savoia ◽  
Massimo Volpe ◽  
Reinhold Kreutz
Keyword(s):  
Global Health ◽  
Angiotensin Receptor Blockers ◽  
Experimental Studies ◽  
Renin Angiotensin System ◽  
Host Cells ◽  
High Rate ◽  
Direct Role ◽  
Pressure Lowering ◽  
Ras Blockers

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associates with a considerable high rate of mortality and represents currently the most important concern in global health. The risk of more severe clinical manifestation of COVID-19 is higher in males and steeply raised with age but also increased by the presence of chronic comorbidities. Among the latter, early reports suggested that arterial hypertension associates with higher susceptibility to SARS-CoV-2 infection, more severe course and increased COVID-19–related deaths. Furthermore, experimental studies suggested that key pathophysiological hypertension mechanisms, such as activation of the renin-angiotensin system (RAS), may play a role in COVID-19. In fact, ACE2 (angiotensin-converting-enzyme 2) is the pivotal receptor for SARS-CoV-2 to enter host cells and provides thus a link between COVID-19 and RAS. It was thus anticipated that drugs modulating the RAS including an upregulation of ACE2 may increase the risk for infection with SARS-CoV-2 and poorer outcomes in COVID-19. Since the use of RAS-blockers, ACE inhibitors or angiotensin receptor blockers, represents the backbone of recommended antihypertensive therapy and intense debate about their use in the COVID-19 pandemic has developed. Currently, a direct role of hypertension, independent of age and other comorbidities, as a risk factor for the SARS-COV-2 infection and COVID-19 outcome, particularly death, has not been established. Similarly, both current experimental and clinical studies do not support an unfavorable effect of RAS-blockers or other classes of first line blood pressure lowering drugs in COVID-19. Here, we review available data on the role of hypertension and its management on COVID-19. Conversely, some aspects as to how the COVID-19 affects hypertension management and impacts on future developments are also briefly discussed. COVID-19 has and continues to proof the critical importance of hypertension research to address questions that are important for global health.

scholarly journals The Potential Role of Aldosterone-Producing Cell Clusters in Adrenal Disease

2020 ◽  
Vol 52 (06) ◽  
pp. 427-434
Author(s):  
Jung Soo Lim ◽  
William E. Rainey
Keyword(s):  
Gene Mutations ◽  
Normal Subjects ◽  
Secondary Hypertension ◽  
Cell Clusters ◽  
Somatic Gene ◽  
Aldosterone Production ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Made In

AbstractPrimary aldosteronism (PA) is the most common cause of secondary hypertension. The hallmark of PA is adrenal production of aldosterone under suppressed renin conditions. PA subtypes include adrenal unilateral and bilateral hyperaldosteronism. Considerable progress has been made in defining the role for somatic gene mutations in aldosterone-producing adenomas (APA) as the primary cause of unilateral PA. This includes the use of next-generation sequencing (NGS) to define recurrent somatic mutations in APA that disrupt calcium signaling, increase aldosterone synthase (CYP11B2) expression, and aldosterone production. The use of CYP11B2 immunohistochemistry on adrenal glands from normal subjects, patients with unilateral and bilateral PA has allowed the identification of CYP11B2-positive cell foci, termed aldosterone-producing cell clusters (APCC). APCC lie beneath the adrenal capsule and like APA, many APCC harbor somatic gene mutations known to increase aldosterone production. These findings suggest that APCC may play a role in pathologic progression of PA. Herein, we provide an update on recent research directed at characterizing APCC and also discuss the unanswered questions related to the role of APCC in PA.

scholarly journals Progress in experimental research on SPRED protein family

2020 ◽  
Vol 48 (8) ◽  
pp. 030006052092917
Author(s):  
Jian Gong ◽  
Zhangren Yan ◽  
Qiao Liu
Keyword(s):  
Tumor Metastasis ◽  
Experimental Studies ◽  
Erk Signaling ◽  
Allergic Reactions ◽  
Great Progress ◽  
Ophthalmic Diseases ◽  
Hematopoietic Regulation ◽  
Development Movement ◽  
Made In

The Sprouty-related Ena/vasodilator-stimulated phosphoprotein homology-1 (EVH-1) domain (SPRED) family of proteins was discovered in 2001. These Sprouty-related tyrosine kinase-binding proteins negatively regulate a variety of growth factor-induced Ras/ERK signaling pathways. In recent years, SPRED proteins have been found to regulate vital activities such as cell development, movement, and proliferation, and to participate in pathophysiological processes such as tumor metastasis, hematopoietic regulation, and allergic reactions. The findings of these studies have important implications regarding the involvement of SPRED proteins in disease. Early studies of SPRED proteins focused mainly on various tumors, cardiovascular diseases, and organ development. However, in recent years, great progress has been made in elucidating the role of SPRED proteins in neuropsychiatric, inflammatory, endocrine, and ophthalmic diseases. This article provides a review of the experimental studies performed in recent years on the SPRED proteins and their role in the pathogenesis of certain diseases.

scholarly journals The Diagnostic, Prognostic and Therapeutic Role of miRNAs in Adrenocortical Carcinoma: A Systematic Review

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1501
Author(s):  
Chrysoula Mytareli ◽  
Danae A. Delivanis ◽  
Fani Athanassouli ◽  
Vassiliki Kalotychou ◽  
Marina Mantzourani ◽  
...  
Keyword(s):  
Adrenocortical Carcinoma ◽  
High Rate ◽  
Mirna Regulation ◽  
Therapeutic Role ◽  
Molecular Alterations ◽  
Dismal Prognosis ◽  
Active Research ◽  
New Biomarkers ◽  
Experimental Level

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a dismal prognosis and a high rate of recurrence and mortality. Therapeutic options are limited. In some cases, the distinction of ACCs from benign adrenal neoplasms with the existing widely available pathological and histopathological tools is difficult. Thus, new biomarkers have been tested. We conducted a review of the recent literature on the advances of the diagnostic, prognostic and therapeutic role of miRNAs on ACC patients. More than 10 miRNAs validated by multiple studies were found to present a diagnostic and prognostic role for ACC patients, from which miR-483-5p and miR-195 were the most frequently met biomarkers. In particular, upregulation of miR-483-5p and downregulation of miR-195 were the most commonly validated molecular alterations. Unfortunately, data on the therapeutic role of miRNA are still scarce and limited mainly at the experimental level. Thus, the role of miRNA regulation in ACC remains an area of active research.

scholarly journals Updates on the Role of Molecular Alterations and NOTCH Signalling in the Development of Neuroendocrine Neoplasms

2019 ◽  
Vol 8 (9) ◽  
pp. 1277 ◽  
Author(s):  
Claudia von Arx ◽  
Monica Capozzi ◽  
Elena López-Jiménez ◽  
Alessandro Ottaiano ◽  
Fabiana Tatangelo ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Notch Signalling ◽  
Neuroendocrine Cells ◽  
Neuroendocrine Neoplasms ◽  
Therapeutic Implications ◽  
Molecular Alterations

Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of rare malignancies, mainly originating from hormone-secreting cells, which are widespread in human tissues. The identification of mutations in ATRX/DAXX genes in sporadic NENs, as well as the high burden of mutations scattered throughout the multiple endocrine neoplasia type 1 (MEN-1) gene in both sporadic and inherited syndromes, provided new insights into the molecular biology of tumour development. Other molecular mechanisms, such as the NOTCH signalling pathway, have shown to play an important role in the pathogenesis of NENs. NOTCH receptors are expressed on neuroendocrine cells and generally act as tumour suppressor proteins, but in some contexts can function as oncogenes. The biological heterogeneity of NENs suggests that to fully understand the role and the potential therapeutic implications of gene mutations and NOTCH signalling in NENs, a comprehensive analysis of genetic alterations, NOTCH expression patterns and their potential role across all NEN subtypes is required.

scholarly journals The Development of Mouse APECED Models Provides New Insight into the Role of AIRE in Immune Regulation

2005 ◽  
Vol 12 (3) ◽  
pp. 211-216 ◽  
Author(s):  
Lara E. Pereira ◽  
Pavel Bostik ◽  
Aftab A. Ansari
Keyword(s):  
Single Gene ◽  
Autoimmune Disorder ◽  
Murine Models ◽  
Tissue Destruction ◽  
Autoimmune Polyendocrinopathy ◽  
Transgenic Murine Models ◽  
Variable Combination ◽  
Insight Into ◽  
Made In

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy is a rare recessive autoimmune disorder caused by a defect in a single gene called AIRE (autoimmune regulator). Characteristics of this disease include a variable combination of autoimmune endocrine tissue destruction, mucocutaneous candidiasis and ectodermal dystrophies. The development of Aire-knockout mice has provided an invaluable model for the study of this disease. The aim of this review is to briefly highlight the strides made in APECED research using these transgenic murine models, with a focus on known roles of Aire in autoimmunity. The findings thus far are compelling and prompt additional areas of study which are discussed.

scholarly journals An Update on the Histology of Pheochromocytomas: How Does it Relate to Genetics?

2018 ◽  
Vol 51 (07) ◽  
pp. 403-413 ◽  
Author(s):  
Lindsey Oudijk ◽  
José Gaal ◽  
Karen Koopman ◽  
Ronald R. de Krijger
Keyword(s):  
Succinate Dehydrogenase ◽  
Adrenal Tumor ◽  
Gene Mutations ◽  
High Rate ◽  
Surrogate Markers ◽  
Genetic Syndromes ◽  
Number Of Genes ◽  
Subunit B ◽  
Very High

AbstractPheochromocytomas are rare neuroendocrine tumors of the adrenal gland, whereas any extra-adrenal tumor with similar histology is designated as paraganglioma. These tumors have a very high rate of germline mutations in a large number of genes, up to 35% to 40%, frequently predisposing for other tumors as well. Therefore, they represent a phenomenal challenge for treating physicians. This review focuses on pheochromocytomas only, with special attention to gross and microscopic clues to the diagnosis of genetic syndromes, including the role of succinate dehydrogenase subunit A and subunit B immunohistochemistry as surrogate markers for genetic analysis in the field of succinate dehydrogenase subunit gene mutations.

scholarly journals Molecular Alterations in Thyroid Cancer: From Bench to Clinical Practice

Genes ◽  
2019 ◽  
Vol 10 (9) ◽  
pp. 709 ◽  
Author(s):  
Elena Tirrò ◽  
Federica Martorana ◽  
Chiara Romano ◽  
Silvia Rita Vitale ◽  
Gianmarco Motta ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Tumor Biology ◽  
Cancer Development ◽  
Disease Evolution ◽  
Molecular Alterations ◽  
Genomic Landscape ◽  
Thyroid Malignancies

Thyroid cancer comprises different clinical and histological entities. Whereas differentiated (DTCs) malignancies are sensitive to radioiodine therapy, anaplastic (ATCs) and medullary (MTCs) tumors do not uptake radioactive iodine and display aggressive features associated with a poor prognosis. Moreover, in a majority of DTCs, disease evolution leads to the progressive loss of iodine sensitivity. Hence, iodine-refractory DTCs, along with ATCs and MTCs, require alternative treatments reflective of their different tumor biology. In the last decade, the molecular mechanisms promoting thyroid cancer development and progression have been extensively studied. This has led to a better understanding of the genomic landscape, displayed by thyroid malignancies, and to the identification of novel therapeutic targets. Indeed, several pharmacological compounds have been developed for iodine-refractory tumors, with four multi-target tyrosine kinase inhibitors already available for DTCs (sorafenib and lenvatinib) and MTCs (cabozantib and vandetanib), and a plethora of drugs currently being evaluated in clinical trials. In this review, we will describe the genomic alterations and biological processes intertwined with thyroid cancer development, also providing a thorough overview of targeted drugs already tested or under investigation for these tumors. Furthermore, given the existing preclinical evidence, we will briefly discuss the potential role of immunotherapy as an additional therapeutic strategy for the treatment of thyroid cancer.

scholarly journals Personalized Medicine: Recent Progress in Cancer Therapy

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1009 ◽  
Author(s):  
Valentina Gambardella ◽  
Noelia Tarazona ◽  
Juan Miguel Cejalvo ◽  
Pasquale Lombardi ◽  
Marisol Huerta ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Molecular Alterations ◽  
Metastatic Setting ◽  
Tumor Boards ◽  
History Of ◽  
Personalized Approach ◽  
New Treatments ◽  
Basket Trials ◽  
Generation Sequencing

Translational research has revolutionized how we develop new treatments for cancer patients. The change from an organ-centric concept guiding treatment choice towards deep molecular analysis, driving a personalized approach, is one of the most important advances of modern oncology. Several tools such as next generation sequencing and RNA sequencing have greatly improved the capacity to detect predictive and prognostic molecular alterations. Detection of gene mutations, amplifications, and fusions has therefore altered the history of several diseases in both a localized and metastatic setting. This shift in perspective, in which attention is focused on the specific molecular alterations of the tumor, has opened the door to personalized treatment. This situation is reflected in the increasing number of basket trials selecting specific molecular targets. Nonetheless, some weaknesses need to be addressed. The complexity of cancer cells enriched with concomitant molecular alterations complicates identification of the driver. Moreover, tumor heterogeneity could be responsible for the lack of benefit when targeted agents are used. In light of this, there is growing interest in the role of multidisciplinary committees or molecular tumor boards to try to enhance selection. The aim of this review is to critically analyze the evolution of cancer treatment towards a precision approach, underlining some recent successes and unexpected failures.

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