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Journal of Cellular and Molecular... Sep 2015Diagnostics and therapies have shown evident advances. Tumour surgery, chemotherapy and radiotherapy are the main techniques in treat cancers. Targeted therapy and drug... (Review)
Review
Diagnostics and therapies have shown evident advances. Tumour surgery, chemotherapy and radiotherapy are the main techniques in treat cancers. Targeted therapy and drug resistance are the main focus in cancer research, but many molecular intracellular mechanisms remain unknown. Src homology region 2-containing protein tyrosine phosphatase 2 (Shp2) is associated with breast cancer, leukaemia, lung cancer, liver cancer, gastric cancer, laryngeal cancer, oral cancer and other cancer types. Signalling pathways involving Shp2 have also been discovered. Shp2 is related to many diseases. Mutations in the ptpn11 gene cause Noonan syndrome, LEOPARD syndrome and childhood leukaemia. Shp2 is also involved in several cancer-related processes, including cancer cell invasion and metastasis, apoptosis, DNA damage, cell proliferation, cell cycle and drug resistance. Based on the structure and function of Shp2, scientists have investigated specific mechanisms involved in cancer. Shp2 may be a potential therapeutic target because this phosphatase is implicated in many aspects. Furthermore, Shp2 inhibitors have been used in experiments to develop treatment strategies. However, conflicting results related to Shp2 functions have been presented in the literature, and such results should be resolved in future studies.
Topics: Animals; Apoptosis; DNA Damage; Drug Resistance, Neoplasm; Humans; Mutation; Neoplasms; Protein Tyrosine Phosphatase, Non-Receptor Type 11
PubMed: 26088100
DOI: 10.1111/jcmm.12618 -
Revista de Neurologia May 2017The term 'RASopathies' covers a series of diseases that present mutations in the genes that code for the proteins of the RAS/MAPK pathway. These diseases include... (Review)
Review
INTRODUCTION
The term 'RASopathies' covers a series of diseases that present mutations in the genes that code for the proteins of the RAS/MAPK pathway. These diseases include neurofibromatosis type 1, Noonan syndrome, Legius syndrome, LEOPARD syndrome, Costello syndrome and cardiofaciocutaneous syndrome. Involvement of the RAS/MAPK pathway not only increases predisposition to develop tumours, but also determines the presence of phenotypic anomalies and alterations in learning processes.
AIM
To review the use of therapeutic strategies with mechanisms that have a selective action on RASopathies.
DEVELOPMENT
The fact that the RAS pathway is involved in a third of all neoplasms has led to the development and study of different drugs at this level. Some of these pharmaceutical agents have been tested in RASopathies, mainly in neurofibromatosis type 1. Here we analyse the use of different antitarget treatments: drugs that act on the membrane receptors, such as tyrosine kinase inhibitors, in the mTOR pathway or MEK inhibitors. These latter have shown potential benefits in recent studies conducted on different RASopathies.
CONCLUSIONS
Today, thanks to the results from the first studies conducted with MEK inhibitor based mainly on animal models, a number of promising clinical trials are being carried out.
Topics: Abnormalities, Multiple; Animals; Clinical Trials as Topic; Drug Evaluation, Preclinical; Genes, ras; Genetic Diseases, Inborn; Humans; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Molecular Targeted Therapy; Neoplastic Syndromes, Hereditary; Neurofibromatosis 1; Noonan Syndrome; Protein Kinase Inhibitors; Syndrome; TOR Serine-Threonine Kinases; ras Proteins
PubMed: 28524213
DOI: No ID Found -
Cells Oct 2022Noonan syndrome (NS) and related Noonan syndrome with multiple lentigines (NSML) contribute to the pathogenesis of human diseases in the RASopathy family. This family of... (Review)
Review
Noonan syndrome (NS) and related Noonan syndrome with multiple lentigines (NSML) contribute to the pathogenesis of human diseases in the RASopathy family. This family of genetic disorders constitute one of the largest groups of developmental disorders with variable penetrance and severity, associated with distinctive congenital disabilities, including facial features, cardiopathies, growth and skeletal abnormalities, developmental delay/mental retardation, and tumor predisposition. NS was first clinically described decades ago, and several genes have since been identified, providing a molecular foundation to understand their physiopathology and identify targets for therapeutic strategies. These genes encode proteins that participate in, or regulate, RAS/MAPK signalling. The RAS pathway regulates cellular metabolism by controlling mitochondrial homeostasis, dynamics, and energy production; however, little is known about the role of mitochondrial metabolism in NS and NSML. This manuscript comprehensively reviews the most frequently mutated genes responsible for NS and NSML, covering their role in the current knowledge of cellular signalling pathways, and focuses on the pathophysiological outcomes on mitochondria and energy metabolism.
Topics: Energy Metabolism; Germ-Line Mutation; Humans; LEOPARD Syndrome; Mitochondria; Noonan Syndrome; ras Proteins
PubMed: 36231062
DOI: 10.3390/cells11193099 -
Anaesthesia Jan 1990'Leopard' syndrome is a rare inherited disorder associated with a high prevalence of cardiac abnormalities. General anaesthesia for dental treatment in a patient who had...
'Leopard' syndrome is a rare inherited disorder associated with a high prevalence of cardiac abnormalities. General anaesthesia for dental treatment in a patient who had cardiomyopathy and bizarre electrocardiographic abnormalities associated with this syndrome is described. A thorough cardiac assessment is advised in a patient with multiple lentigines, although no clinical symptoms or signs may be found. Even if no cardiac abnormality is found before it is better to re-assess the patient, since abnormalities may develop later. The assessment should be repeated if any abnormality was detected before but without clinical significance, since the disease is progressive and may progress more rapidly in some patients than in others.
Topics: Adolescent; Anesthesia, Dental; Anesthesia, General; Arrhythmias, Cardiac; Cardiomyopathies; Electrocardiography; Growth Disorders; Heart Defects, Congenital; Humans; Hypertelorism; Intellectual Disability; Lentigo; Male; Syndrome
PubMed: 2316835
DOI: 10.1111/j.1365-2044.1990.tb14499.x -
The British Journal of Cardiology 2022Various cardiac disorders seen in general and acute medicine have dermatological manifestations that may provide critical clues to the underlying disease. This review...
Various cardiac disorders seen in general and acute medicine have dermatological manifestations that may provide critical clues to the underlying disease. This review will discuss the important dermatological signs seen in cardiac conditions. We believe greater interdisciplinary liaison will improve our understanding of the link between the dermatological and cardiovascular systems and the underlying disease processes.
PubMed: 35747307
DOI: 10.5837/bjc.2022.009 -
Journal of Personalized Medicine Oct 2022Electrocardiogram (ECG) still remains a very useful diagnostic method in modern cardiology. Its broad availability, noninvasiveness and good sensitivity explain why it... (Review)
Review
Electrocardiogram (ECG) still remains a very useful diagnostic method in modern cardiology. Its broad availability, noninvasiveness and good sensitivity explain why it plays a capital role in the very beginning of the process of diagnosis for every patient, with or without cardiac-related complaints. For the practitioner, good training in ECG interpretation is mandatory. Sometimes, the ECG trace reveals particular aspects that may cause confusion and complicate decision-making. In this article, we present several less common situations underlying the general context and ECG features. The syndromes studied have a high pathological significance and may range from acute emergencies that call for a rapid therapeutical response to chronic syndromes that require prolonged observation, monitoring and risk stratification.
PubMed: 36573711
DOI: 10.3390/jpm12111754 -
Saudi Journal of Biological Sciences Jul 2015The BRAF gene encodes for a serine/threonine protein kinase that participates in the MAPK/ERK signalling pathway and plays a vital role in cancers and developmental... (Review)
Review
The BRAF gene encodes for a serine/threonine protein kinase that participates in the MAPK/ERK signalling pathway and plays a vital role in cancers and developmental syndromes (RASopathies). The current review discusses the clinical significance of the BRAF gene and other members of RAS/RAF cascade in human cancers and RAS/MAPK syndromes, and focuses the molecular basis and clinical genetics of BRAF to better understand its parallel involvement in both tumourigenesis and RAS/MAPK syndromes-Noonan syndrome, cardio-facio-cutaneous syndrome and LEOPARD syndrome.
PubMed: 26150740
DOI: 10.1016/j.sjbs.2014.10.002 -
Biochimica Et Biophysica Acta.... Sep 2018The RAS pathway is a highly conserved cascade of protein-protein interactions and phosphorylation that is at the heart of signalling networks that govern proliferation,... (Review)
Review
The RAS pathway is a highly conserved cascade of protein-protein interactions and phosphorylation that is at the heart of signalling networks that govern proliferation, differentiation and cell survival. Recent findings indicate that the RAS pathway plays a role in the regulation of energy metabolism via the control of mitochondrial form and function but little is known on the participation of this effect in RAS-related rare human genetic diseases. Germline mutations that hyperactivate the RAS pathway have been discovered and linked to human developmental disorders that are known as RASopathies. Individuals with RASopathies, which are estimated to affect approximately 1/1000 human birth, share many overlapping characteristics, including cardiac malformations, short stature, neurocognitive impairment, craniofacial dysmorphy, cutaneous, musculoskeletal, and ocular abnormalities, hypotonia and a predisposition to developing cancer. Since the identification of the first RASopathy, type 1 neurofibromatosis (NF1), which is caused by the inactivation of neurofibromin 1, several other syndromes have been associated with mutations in the core components of the RAS-MAPK pathway. These syndromes include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), which was formerly called LEOPARD syndrome, Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Legius syndrome (LS) and capillary malformation-arteriovenous malformation syndrome (CM-AVM). Here, we review current knowledge about the bioenergetics of the RASopathies and discuss the molecular control of energy homeostasis and mitochondrial physiology by the RAS pathway.
Topics: Energy Metabolism; Humans; Rare Diseases; Signal Transduction; ras Proteins
PubMed: 29750912
DOI: 10.1016/j.bbabio.2018.05.003 -
Reviews in Endocrine & Metabolic... Dec 2006Noonan syndrome is a relatively common multiple malformation syndrome with characteristic facies, short stature and congenital heart disease, most commonly pulmonary... (Review)
Review
Noonan syndrome is a relatively common multiple malformation syndrome with characteristic facies, short stature and congenital heart disease, most commonly pulmonary stenosis (Noonan, Clin Pediatr, 33:548-555, 1994). Recently, a mutation in the PTPN11 gene (Tartaglia, Mehler, Goldberg, Zampino, Brunner, Kremer et al., Nat Genet, 29:465-468, 2001) was found to be present in about 50% of individuals with Noonan syndrome. The phenotype noted in Noonan syndrome is also found in a number of other syndromes which include LEOPARD (Gorlin, Anderson, Blaw, Am J Dis Child, 17:652-662, 1969), Cardio-facio-cutaneous syndrome (Reynolds, Neri, Hermann, Blumberg, Coldwell, Miles et al., Am J Med Genet, 28:413-427, 1986) and Costello syndrome (Hennekam, Am J Med Genet, 117C(1):42-48, 2003). All three of these syndromes share similar cardiac defects and all have postnatal short stature. Very recently, HRAS mutations (Aoki, Niihori, Kawame, Kurosawa, Ohashi, Tanaka et al., Nat Genet, 37:1038-1040, 2005) have been found in the Costello syndrome and germline mutations in KRAS and BRAF genes (Rodriguez-Viciana, Tetsu, Tidyman, Estep, Conger, Santa Cruz et al., Nat Genet, 2006; Niihori, Aoki, Narumi, Neri, Cave, Verloes et al., Nat Genet, 38:294-296, 2006) in the Cardio-facio-cutaneous syndrome. Phenotypic overlap between these genetic disorders can now be explained since each is caused by germline mutations that are major components of the RAS-MAPK pathway. This pathway plays an important role in growth factor and cytokine signaling as well as cancer pathogenesis.
Topics: Abnormalities, Multiple; Body Size; Germ-Line Mutation; Humans; LEOPARD Syndrome; Noonan Syndrome; Puberty
PubMed: 17177115
DOI: 10.1007/s11154-006-9021-1 -
Central-European Journal of Immunology 2022Recurrent infections are important problems in syndromic patients. This study aimed to evaluate immunological abnormalities in patients who presented with recurrent...
INTRODUCTION
Recurrent infections are important problems in syndromic patients. This study aimed to evaluate immunological abnormalities in patients who presented with recurrent infections and were diagnosed with rare syndromes.
MATERIAL AND METHODS
This retrospective analysis included 14 patients with complaints of recurrent infections, all of whom were diagnosed with a rare syndrome.
RESULTS
The study group consisted of patients with Aicardi syndrome, Brugada syndrome, Phelan- McDermid syndrome, trichothiodystrophy, LEOPARD syndrome, Prader-Willi syndrome, Seckel syndrome, trisomy 18 (Edwards' syndrome), Wiedemann-Steiner syndrome, West syndrome, Williams syndrome, 47,XYY syndrome, 16p13 deletion syndrome, and 13q1.3 deletion syndrome. Seven patients (50%) were girls and seven (50%) were boys (mean age, 56.7 ±32.9 months; median [range] age: 45.5 [27-153] months). There were high rates of consanguinity (50%), cesarean section delivery (71%), and hospitalization in the intensive care unit (78.5%). No patients had a family history of immunodeficiency. On admission, all patients exhibited humoral and/or cellular immune system abnormalities. During the follow-up period, all T-cell abnormalities were improved after immunoglobulin replacement therapy (IGRT), while B-cell abnormalities persisted. These findings suggested that the patients predominantly had antibody deficiencies associated with mild T-cell abnormalities because of recurrent infections. The rates of infections and hospitalizations were significantly reduced after IGRT (p < 0.001); the rate of intensive care unit admission also significantly decreased (from 78.5% to 21.4%). Two of the three oxygen-dependent patients exhibited improvement therein. IGRT was discontinued in two patients with significant clinical improvement during follow-up.
CONCLUSIONS
An immunological evaluation should be considered in pediatric patients with rare syndromes and recurrent infections. IGRT may help to improve the prognoses of these patients.
PubMed: 36817395
DOI: 10.5114/ceji.2022.124080