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1.
Cancer Discov ; 9(10): 1346-1348, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31575564

RESUMO

Identification of cancer-associated mutations in core histone genes has proved challenging due to these genes' highly conserved nature and presence in large arrays. Recent analyses of cancer genomes, including one in this issue of Cancer Discovery, show that mutations in the histone fold can affect nucleosome stability, providing a novel mechanism by which oncohistones contribute to tumorigenesis.See related article by Bennett et al., p. 1438.


Assuntos
Histonas/genética , Nucleossomos , Carcinogênese/genética , Humanos , Mutação , Oncogenes
2.
Cancer Res ; 79(19): 4811-4813, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575628

RESUMO

Analysis of a large group of patients with multifocal premalignant disease by Krysan and colleagues in this issue of Cancer Research provides an informative view of the processes that may underlie progression of these lesions to invasive adenocarcinoma of the lung. The identification of the type and distribution of mutational changes reveals that common processes may be occurring within individuals but that these are generally unique between patients at risk for developing lung cancer. Furthermore, predicted neoantigens are identified and associated with characteristics of immune infiltrates supporting the role of alterations in adaptive immune surveillance in progression of these premalignant lesions. These findings provide critical insights that will help establish a foundation of knowledge for developing personalized prevention strategies with the potential to significantly impact overall mortality in lung cancer.See related article by Krysan et al., p. 5022.


Assuntos
Adenocarcinoma , Neoplasias Pulmonares , Lesões Pré-Cancerosas , Progressão da Doença , Humanos , Mutação
3.
Adv Exp Med Biol ; 1164: 207-224, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576551

RESUMO

Prostate cancers have a justified reputation as one of the most heterogeneous human tumours. Indeed, there are some who consider that advanced and castration-resistant prostate cancers are incurable, as a direct result of this heterogeneity. However, tumour heterogeneity can be defined in different ways. To a clinician, prostate cancer is a number of different diseases, the treatments for which remain equally heterogeneous and uncertain. To the pathologist, the histopathological appearances of the tumours are notoriously heterogeneous. Indeed, the genius of Donald Gleason in the 1960s was to devise a classification system designed to take into account the heterogeneity of the tumours both individually and in the whole prostate context. To the cell biologist, a prostate tumour consists of multiple epithelial cell types, inter-mingled with various fibroblasts, neuroendocrine cells, endothelial cells, macrophages and lymphocytes, all of which interact to influence treatment responses in a patient-specific manner. Finally, genetic analyses of prostate cancers have been compromised by the variable gene rearrangements and paucity of activating mutations observed, even in large numbers of patient tumours with consistent clinical diagnoses and/or outcomes. Research into familial susceptibility has even generated the least tractable outcome of such studies: the genetic loci are of low penetrance and are of course heterogeneous. By fractionating the tumour (and patient-matched non-malignant tissues) heterogeneity can be resolved, revealing homogeneous markers of patient outcomes.


Assuntos
Células Endoteliais , Neoplasias da Próstata , Células Endoteliais/citologia , Heterogeneidade Genética , Humanos , Masculino , Mutação , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia
4.
Medicine (Baltimore) ; 98(39): e17305, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574858

RESUMO

Until now, the recognition of sodium taurocholate cotransporting polypeptide (NTCP) deficiency has been mainly based on sporadic case reports. It was previously believed to be mildly symptomatic and resulting in mild liver dysfunction. However, to our knowledge, there have been no reports about the histopathologic and ultrastructural pathologic characteristics of the disease. The aim of the study was to analyze the clinical, histopathologic and ultrastructural pathologic characteristics of NTCP deficiency in 13 pediatric patients.From August 2012 to October 2018, this retrospective study conducted in the Department of Pediatrics of Tongji Hospital, China analyzed the data of 13 NTCP deficient patients with an SLC10A1 gene mutation. Except for NTCP deficiency, no other liver diseases were present in the patients, which was determined by both a genetic testing panel for jaundice and by reviewing medical records. The laboratory results, imaging, histopathologic, and ultrastructural pathologic information were recorded for analysis.The serum level of total bile acid was high in all 13 patients. All patients had adequate growth and development. Eight of the patients (8/13) presented with visible jaundice and 12 (12/13) were found to have hyperbilirubinemia. A needle liver biopsy was performed in 11 cases, which revealed slightly chronic inflammation in all 11 patients. One of the patients (1/13) was found to be suffering from gallstones.The data showed that although NTCP deficiency was often asymptomatic, some of the patients showed obvious clinical expressions, such as jaundice. Among the 13 pediatric patients with NTCP deficiency, both the biochemical and histopathologic features were similar to those of mild hepatocellular jaundice. In addition, it was determined that the clinical features in the patient with gallstones may have been caused by NTCP deficiency.


Assuntos
Ácidos e Sais Biliares/sangue , Icterícia , Hepatopatias , Fígado , Transportadores de Ânions Orgânicos Dependentes de Sódio , Simportadores , Desenvolvimento Infantil , Pré-Escolar , China/epidemiologia , Testes Genéticos/métodos , Humanos , Biópsia Guiada por Imagem/métodos , Lactente , Icterícia/diagnóstico , Icterícia/etiologia , Fígado/metabolismo , Fígado/patologia , Hepatopatias/diagnóstico , Hepatopatias/genética , Hepatopatias/fisiopatologia , Hepatopatias/terapia , Testes de Função Hepática/métodos , Glicoproteínas de Membrana/metabolismo , Mutação , Transportadores de Ânions Orgânicos Dependentes de Sódio/deficiência , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Pediatria/métodos , Estudos Retrospectivos , Simportadores/deficiência , Simportadores/genética
5.
Medicine (Baltimore) ; 98(39): e17334, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574870

RESUMO

RATIONALE: Subacute combined degeneration (SCD) is a disease caused by decreased vitamin B12 intake or metabolic disorders. It is more common in the elderly and rarely seen in children. Here, we report 2 pediatric cases of SCD in late-onset cobalamin C (CblC) deficiency. PATIENT CONCERNS: The patients complained of unsteady gait. Their physical examination showed sensory ataxia. Magnetic resonance imaging showed classic manifestations of SCD. The serum vitamin B12 level was normal, but urine methylmalonic acid and serum homocysteine levels were high. DIAGNOSIS: The pathogenic gene was confirmed as MMACHC. The 2 patients each had 2 pathogenic mutations C.482 G>A and C.271dupA and C.365A>T and C.609G>A in this gene. They were diagnosed with combined methylmalonic acidemia and homocysteinemia-CblC subtype. INTERVENTIONS: The patients were treated with methylcobalamin 500 µg intravenous injection daily after being admitted. After the diagnosis, levocarnitine, betaine, and vitamin B12 were added to the treatment. OUTCOMES: Twelve days after treatment, the boy could walk normally, and his tendon reflex and sense of position returned to normal. The abnormal gait seemed to have become permanent in the girl and she walked with her legs raised higher than normal. LESSONS: To the best of our knowledge, this is the first report of 2 cases of isolated SCD in children with late-onset CblC disorder. Doctors should consider that SCD could be an isolated symptom of CblC disorder. The earlier the treatment, the lower the likelihood of sequelae.


Assuntos
Proteínas de Transporte/genética , Homocistinúria , Degeneração Combinada Subaguda , Deficiência de Vitamina B 12/congênito , Vitamina B 12/análogos & derivados , Adolescente , Ataxia/diagnóstico , Ataxia/etiologia , Ataxia/terapia , Encéfalo/diagnóstico por imagem , Criança , Feminino , Homocisteína/sangue , Homocistinúria/diagnóstico , Homocistinúria/genética , Humanos , Injeções Intravenosas , Transtornos de Início Tardio , Imagem por Ressonância Magnética/métodos , Masculino , Ácido Metilmalônico/urina , Mutação , Degeneração Combinada Subaguda/diagnóstico , Degeneração Combinada Subaguda/etiologia , Degeneração Combinada Subaguda/fisiopatologia , Degeneração Combinada Subaguda/terapia , Resultado do Tratamento , Vitamina B 12/administração & dosagem , Vitamina B 12/sangue , Deficiência de Vitamina B 12/diagnóstico , Deficiência de Vitamina B 12/genética , Complexo Vitamínico B/administração & dosagem
6.
Medicine (Baltimore) ; 98(39): e17337, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574871

RESUMO

RATIONALE: Diamond-Blackfan anemia (DBA) is a rare inherited marrow disorder, characterized by erythrocyte aplasia and is associated with congenital anomalies and a susceptibility to cancer. Although congenital abnormalities have been observed in ∼50% of DBA patients, the occurrence of an associated congenital diaphragmatic hernia (CDH) has rarely been reported. PATIENT CONCERNS: A 19-month-old male child was referred to our pediatric hematology-oncology outpatient clinic with anemic appearance. He presented to us with recurrent anemia, short stature, and developmental delay. DIAGNOSIS: On bone marrow examination, only erythropoietic cells were markedly decreased in number, whereas other cell lines were unaffected. An abdominal computed tomography scan revealed a Bochdalek type of CDH. A genetic analysis revealed heterozygous mutation of RPS19; therefore, he was diagnosed as having DBA with CDH. INTERVENTIONS: The patient received an initial packed red blood cell transfusion, followed by an administration of oral prednisone. OUTCOMES: The patient is maintained on oral prednisone administered at a dose of 0.3 mg/kg every alternate day and has since a hemoglobin level of >9.0 g/dL without further RBC transfusions. LESSONS: We learned that a Bochdalek type of CDH can manifest in a DBA patient with RPS19 gene mutation. Therefore, patients diagnosed with the latter disorder should also be screened for an early detection of potential CDHs.


Assuntos
Anemia de Diamond-Blackfan , Células da Medula Óssea/patologia , Transfusão de Eritrócitos/métodos , Hérnias Diafragmáticas Congênitas/diagnóstico , Prednisona/administração & dosagem , Proteínas Ribossômicas/genética , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/fisiopatologia , Exame de Medula Óssea/métodos , Glucocorticoides/administração & dosagem , Humanos , Masculino , Mutação , Radioterapia Assistida por Computador/métodos , Resultado do Tratamento , Adulto Jovem
7.
Medicine (Baltimore) ; 98(39): e17372, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574885

RESUMO

INTRODUCTION: Cyclic neutropenia (CyN) is a rare hematological disease, and patients with CyN often experience an early onset of severe periodontitis and are forced to undergo tooth extraction. Here, we report a case of a patient with CyN who showed different periodicity and oscillations of neutrophil count compared with her mother, despite sharing the same novel genetic mutation. PATIENT CONCERNS: A 17-year-old Japanese girl who had been diagnosed with CyN shortly after birth presented to our hospital with a complaint of mobility of her teeth and gingivitis. Upon presentation, an intraoral examination was performed and revealed redness and swelling of the marginal and attached gingiva. Radiographs revealed extreme resorption of the alveolar bone and apical lesions in her mandibular lateral incisors. The patient's hematologic data demonstrated a lack of blood neutrophils (0/µL). The patient had no history of dental extraction, and her mother also had a history of CyN. DIAGNOSES: The patient was diagnosed with severe periodontitis that was associated with CyN. Gene testing showed a novel heterozygous mutation in exon 4 of the ELANE gene (c.538delC, p.Leu180Ser fsX11). INTERVENTIONS: Based on the clinical findings, we planned to extract the patient's mandibular lateral incisors. Although the tooth extraction was scheduled considering the cyclic variation in neutrophil count, the patient's neutrophil count was 0/µL on the day before the planned extraction. Therefore, granulocyte-colony stimulating factor (G-CSF) was administered to increase the patient's neutrophil count. On the day of the patient's admission for the tooth extraction, she presented with fever (body temperature, 38.5°C), tonsillitis, and stomatitis. The extraction was subsequently delayed, and the patient was administered antibiotics and G-CSF for 4 days. At this time, the neutrophil count increased to 750/µL, and the tooth extraction was carried out safely. OUTCOMES: The postoperative course was uneventful, and the healing process at the extraction site was excellent. CONCLUSION: There is a possibility that the periodicity and oscillations of neutrophil count may change with growth in patients with CyN. Therefore, it is important to frequently examine and treat patients with fluctuating neutrophil levels for the management of invasive dental treatment in patients with CyN.


Assuntos
Elastase de Leucócito/genética , Neutropenia/genética , Periodontite/genética , Periodontite/cirurgia , Extração Dentária/efeitos adversos , Adolescente , Éxons , Feminino , Humanos , Contagem de Leucócitos , Mutação , Neutropenia/sangue , Neutropenia/complicações , Neutrófilos , Periodontite/sangue
8.
Exp Suppl ; 111: 3-19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588524

RESUMO

Genetics is the study of heredity. In this introductory chapter of the book Genetics of Endocrine Diseases and Syndromes, we present the basic terms of genetics and basic physiological and pathogenic molecular processes that are implicated in the wide array of genetically determined diseases. Mutations, chromosomes, polymorphisms, and epigenetic terms are also briefly discussed.


Assuntos
Cromossomos Humanos/genética , Doenças do Sistema Endócrino/genética , Hereditariedade , Polimorfismo Genético , Epigênese Genética , Humanos , Mutação
9.
Exp Suppl ; 111: 33-52, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588527

RESUMO

Molecular genetic methods have become an organic part of everyday clinical practice. In the past, molecular diagnostic tests were carried out for genetic diagnosis of a particular monogenic disease. In these situations the tests itself were used for identification of one particular genetic alteration (e.g., point mutation or deletion) of the gene of interest. Later, parallel with the development of the technology, the focus has shifted by allowing investigating at once targeted gene panels and even the whole exome/genome behind a suspected genetic disorder. Historically for these purposes, array-based methods (oligonucleotide arrays) and then next-generation sequencing-based methods have been used. High-throughput methods have been fundamentally transforming the everyday, routine genetic diagnostics, but older molecular techniques still have a role in clinical genetics. Here, we summarize the most important molecular genetic methods and shed light to the advantages and disadvantages of their application in routine diagnostics. We mainly focus on methods used for detection of germline alterations.


Assuntos
Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Técnicas de Diagnóstico Molecular , Reação em Cadeia da Polimerase em Tempo Real , Exoma , Humanos , Mutação
10.
Exp Suppl ; 111: 263-298, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588536

RESUMO

Congenital pituitary hormone deficiency is a disabling condition. It is part of a spectrum of disorders including craniofacial midline developmental defects ranging from holoprosencephaly through septo-optic dysplasia to combined and isolated pituitary hormone deficiency. The first genes discovered in the human disease were based on mouse models of dwarfism due to mutations in transcription factor genes. High-throughput DNA sequencing technologies enabled clinicians and researchers to find novel genetic causes of hypopituitarism for the more than three quarters of patients without a known genetic diagnosis to date. Transcription factor (TF) genes are at the forefront of the functional analysis of novel variants of unknown significance due to the relative ease in in vitro testing in a research lab. Genetic testing in hypopituitarism is of high importance to the individual and their family to predict phenotype composition, disease progression and to avoid life-threatening complications such as secondary adrenal insufficiency.This chapter aims to highlight our current understanding about (1) the contribution of TF genes to pituitary development (2) the diversity of inheritance and phenotype features in combined and select isolated pituitary hormone deficiency and (3) provide an initial assessment on how to approach variants of unknown significance in human hypopituitarism. Our better understanding on how transcription factor gene variants lead to hypopituitarism is a meaningful step to plan advanced therapies to specific genetic changes in the future.


Assuntos
Hipopituitarismo/genética , Hipófise/fisiopatologia , Fatores de Transcrição/genética , Animais , Holoprosencefalia , Humanos , Camundongos , Mutação
11.
Exp Suppl ; 111: 299-315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588537

RESUMO

Neurohypophyseal diabetes insipidus (DI) is most often caused by trauma, including operations, and infiltrating processes in the hypothalamic-pituitary region. Irradiation, ischemia, infections, or autoimmunity can also underlie the disease. Since the middle of the nineteenth century, familial forms of neurohypophyseal DI have been described. Most commonly, the disease is transmitted in an autosomal dominant fashion; very rarely, autosomal recessive inheritance has been observed. Hereditary neurohypophyseal DI is caused by mutations in the gene encoding the antidiuretic hormone vasopressin (AVP) and its carrier protein neurophysin II (NPII). Symptoms result from the lack of hormone, or from the inability of mutant AVP to activate its renal receptor, and respond to treatment with desmopressin (DDAVP). Dominant mutations cause retention of the hormone precursor in the endoplasmic reticulum (ER) of vasopressinergic neurons in the hypothalamus, resulting in cellular dysfunction and eventually neuronal death. This so-called neurotoxicity hypothesis was initially established on the basis of autopsy studies in affected humans and has been supported by heterologous cell culture expression experiments and murine knock-in models. Current data show that retained mutants fail to be eliminated by the cell's quality control system and accumulate in fibrillar aggregations within the ER. Autosomal dominant neurohypophyseal DI may thus be viewed as a neurodegenerative disease confined to vasopressinergic neurons.


Assuntos
Diabetes Insípido Neurogênico/genética , Doenças Neurodegenerativas/genética , Animais , Retículo Endoplasmático/patologia , Humanos , Camundongos , Mutação
12.
Exp Suppl ; 111: 385-416, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588541

RESUMO

In addition to the common types of diabetes mellitus, two major monogenic diabetes forms exist. Maturity-onset diabetes of the young (MODY) represents a heterogenous group of monogenic, autosomal dominant diseases. MODY accounts for 1-2% of all diabetes cases, and it is not just underdiagnosed but often misdiagnosed to type 1 or type 2 diabetes. More than a dozen MODY genes have been identified to date, and their molecular classification is of great importance in the correct treatment decision and in the judgment of the prognosis. The most prevalent subtypes are HNF1A, GCK, and HNF4A. Genetic testing for MODY has changed recently due to the technological advancements, as contrary to the sequential testing performed in the past, nowadays all MODY genes can be tested simultaneously by next-generation sequencing. The other major group of monogenic diabetes is neonatal diabetes mellitus which can be transient or permanent, and often the diabetes is a part of a syndrome. It is a severe monogenic disease appearing in the first 6 months of life. The hyperglycemia usually requires insulin. There are two forms, permanent neonatal diabetes mellitus (PNDM) and transient neonatal diabetes mellitus (TNDM). In TNDM, the diabetes usually reverts within several months but might relapse later in life. The incidence of NDM is 1:100,000-1:400,000 live births, and PNDM accounts for half of the cases. Most commonly, neonatal diabetes is caused by mutations in KCNJ11 and ABCC8 genes encoding the ATP-dependent potassium channel of the ß cell. Neonatal diabetes has experienced a quick and successful transition into the clinical practice since the discovery of the molecular background. In case of both genetic diabetes groups, recent guidelines recommend genetic testing.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus/genética , Doenças do Recém-Nascido/genética , Testes Genéticos , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , Recém-Nascido , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Proteínas Serina-Treonina Quinases/genética , Receptores Sulfonilureia/genética
13.
Adv Exp Med Biol ; 1175: 227-272, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583591

RESUMO

Motor neuron disorders are highly debilitating and mostly fatal conditions for which only limited therapeutic options are available. To overcome this limitation and develop more effective therapeutic strategies, it is critical to discover the pathogenic mechanisms that trigger and sustain motor neuron degeneration with the greatest accuracy and detail. In the case of Amyotrophic Lateral Sclerosis (ALS), several genes have been associated with familial forms of the disease, whilst the vast majority of cases develop sporadically and no defined cause can be held responsible. On the contrary, the huge majority of Spinal Muscular Atrophy (SMA) occurrences are caused by loss-of-function mutations in a single gene, SMN1. Although the typical hallmark of both diseases is the loss of motor neurons, there is increasing awareness that pathological lesions are also present in the neighbouring glia, whose dysfunction clearly contributes to generating a toxic environment in the central nervous system. Here, ALS and SMA are sequentially presented, each disease section having a brief introduction, followed by a focussed discussion on the role of the astrocytes in the disease pathogenesis. Such a dissertation is substantiated by the findings that built awareness on the glial involvement and how the glial-neuronal interplay is perturbed, along with the appraisal of this new cellular site for possible therapeutic intervention.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Astrócitos/citologia , Neurônios Motores/patologia , Atrofia Muscular Espinal/fisiopatologia , Humanos , Mutação
14.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 31(3): 346-348, 2019 Apr 18.
Artigo em Chinês | MEDLINE | ID: mdl-31544425

RESUMO

Malaria is a parasitic disease which threatens human life and health seriously. Sulfadoxine-pyrimethamine (SP) has been recommended for intermittent preventive treatment of malaria in children and pregnant women, and also used as a compound component of artemisinin based therapy. The mechanisms of SP resistance in P. falciparum involve point mutations in the genes encoding dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), and the drug pressure can also lead to the mutations in the two genes of P. vivax. To provide the information for the formulation of anti-malarial strategies, this article reviews the discovery, application, effect of SP, and the resistance mechanism and research progress of the related genes in P. vivax.


Assuntos
Antimaláricos , Resistência a Medicamentos , Plasmodium vivax , Antimaláricos/farmacologia , Di-Hidropteroato Sintase/genética , Combinação de Medicamentos , Resistência a Medicamentos/genética , Humanos , Malária Falciparum/genética , Mutação , Plasmodium vivax/efeitos dos fármacos , Plasmodium vivax/genética , Pirimetamina/farmacologia , Pesquisa/tendências , Sulfadoxina/farmacologia , Tetra-Hidrofolato Desidrogenase/genética
15.
Schmerz ; 33(5): 475-490, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31485751

RESUMO

Erythromelalgia is a rare disease that is associated with hemato-oncological diseases or after taking certain drugs and toxins, but it can also occur as an independent clinical picture, for example, due to mutations in the sodium channel NaV1.7. Clinically, there is a characteristic triad of attack-like burning pain and skin redness in the area of the distal extremities, which can be alleviated by excessive cooling. The attacks are triggered by heat, exertion, and stress. The diagnosis is primarily made clinically and can be confirmed by genetic testing if a sodium channel NaV1.7 mutation is present. Important differential diagnoses are complex regional pain syndrome, the non-freezing cold injury, and small fiber neuropathies. Therapy is multidisciplinary and has to be planned individually and include physical therapy and psychotherapy as well as drug therapy as integral components.


Assuntos
Eritromelalgia , Dor , Eritromelalgia/diagnóstico , Eritromelalgia/genética , Eritromelalgia/patologia , Eritromelalgia/terapia , Humanos , Mutação , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Dor/etiologia , Pele/patologia
16.
J Cancer Res Clin Oncol ; 145(10): 2495-2506, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31494736

RESUMO

PURPOSE: Histology samples are important for the appropriate administration of tumor type-specific cytotoxic and molecular-targeted therapies for the treatment of non-small cell lung cancer (NSCLC). When biopsy samples lack a definite morphology, a diagnosis can be selected from three subtypes based on immunohistochemistry (IHC) results, as follows: favor adenocarcinoma (ADC), favor squamous cell carcinoma (SQC), or not otherwise specified (NOS)-null. In terms of patient outcome, however, the validity of IHC-based classifications remains unknown. METHODS: A large series of 152 patients with advanced NSCLC whose diagnoses had been made based on morphological findings and who had been homogeneously treated were enrolled. We used IHC staining (TTF-1, SP-A, p40, and CK5/6) to examine tumor samples and refined the diagnoses. We then analyzed the pathological subgroups according to the IHC staining results. RESULTS: IHC profiling resulted in 50% of the cases being classified as favor ADC, 31% being classified as favor SQC, and 19% being classified as NOS-null groups. Compared with the favor ADC and favor SQC groups, the NOS-null group had a significantly poorer outcome. Pemetrexed-containing platinum regimens produced a response rate similar to that of other platinum doublet regimens in the favor ADC group (44% vs. 46%), whereas it produced a poorer response in the favor SQC group (0% vs. 52%) and the NOS-null group (0% vs. 24%). The favor ADC group tended to have a higher percentage of EGFR positivity and ALK positivity than the favor SQC group (25% vs. 11% and 7% vs. 0%, respectively). CONCLUSIONS: These findings support the use of immunohistological subtyping of NSCLC biopsy specimens to select patient-appropriate treatments.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Biópsia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Prognóstico , Resultado do Tratamento , Adulto Jovem
17.
Anticancer Res ; 39(9): 4911-4916, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519595

RESUMO

BACKGROUND/AIM: The occurrence of somatic transformation in germ cell tumour (GCT) is rare, with increased incidence in teratomatous tumours. The aim of this study was to understand the clinical outcomes of patients with metastatic GCT with somatic transformation. MATERIALS AND METHODS: A retrospective study was conducted in two tertiary cancer centres in London. Between 1998 and 2016, 30 cases of somatic transformation in GCT treated at the Mount Vernon Cancer Centre and St. Bartholomew's Hospital were identified. The median age at diagnosis was 34 years (range=18-56 years). The histological diagnosis at transformation was rhabdomyosarcoma, sarcomatoid yolk sac, sarcoma (non-specified), clear cell carcinoma, adenocarcinoma and primitive neuro ectodermal tumour (PNET). RESULTS: The 5-year survival rate of all patients was 47%, and that of patients with testicular primary (n=26 patients) was 37%. CONCLUSION: Somatic transformation component in testicular GCTs is generally considered to be an adverse prognostic factor, however, a reasonable 5-year overall survival rate (87.5%) was observed in patients who present with this at first diagnosis.


Assuntos
Transformação Celular Neoplásica/genética , Mutação , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/secundário , Neoplasias Testiculares/genética , Neoplasias Testiculares/secundário , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Suscetibilidade a Doenças , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/terapia , Retratamento , Análise de Sobrevida , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/terapia , Resultado do Tratamento , Adulto Jovem
18.
Hereditas ; 156: 31, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31548836

RESUMO

Background: Cleidocranial dysplasia (CCD) is a rare autosomal dominant disorder mainly characterized by hypoplastic or absent clavicles, delayed closure of the fontanelles, multiple dental abnormalities, and short stature. Runt-related transcription factor 2 (RUNX2) gene variants can cause CCD, but are not identified in all CCD patients. Methods: In this study, we detected genetic variants in seven unrelated children with CCD by targeted high-throughput DNA sequencing or Sanger sequencing. Results: All patients carried a RUNX2 variant, totally including three novel pathogenic variants (c.722_725delTGTT, p.Leu241Serfs*8; c.231_232delTG, Ala78Glyfs*82; c.909C > G, p.Tyr303*), three reported pathogenic variants (c.577C > T, p.Arg193*; c.574G > A, p.Gly192Arg; c.673 C > T, p.Arg225Trp), one likely pathogenic variant (c.668G > T, p.Gly223Val). The analysis of the variant source showed that all variants were de novo except the two variants (c.909C > G, p.Tyr303*; c.668G > T, p.Gly223Val) inherited from the patient's father and mother with CCD respectively. Further bioinformatics analysis indicated that these variants could influence the structure of RUNX2 protein by changing the number of H-bonds or amino acids. The experimental result showed that the Gly223Val mutation made RUNX2 protein unable to quantitatively accumulate in the nucleus. Conclusions: The present study expands the pathogenic variant spectrum of RUNX2 gene, which will contribute to the diagnosis of CCD and better genetic counseling in the future.


Assuntos
Displasia Cleidocraniana/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Núcleo Celular , Criança , Pré-Escolar , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Mutação , Linhagem
19.
N Engl J Med ; 381(10): 933-944, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31483964

RESUMO

BACKGROUND: Pyruvate kinase deficiency is caused by mutations in PKLR and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase in red cells. METHODS: In this uncontrolled, phase 2 study, we evaluated the safety and efficacy of mitapivat in 52 adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. The patients were randomly assigned to receive either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period; eligible patients could continue treatment in an ongoing extension phase. RESULTS: Common adverse events, including headache and insomnia, occurred at the time of drug initiation and were transient; 92% of the episodes of headache and 47% of the episodes of insomnia resolved within 7 days. The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). A total of 26 patients (50%) had an increase of more than 1.0 g per deciliter in the hemoglobin level. Among these patients, the mean maximum increase was 3.4 g per deciliter (range, 1.1 to 5.8), and the median time until the first increase of more than 1.0 g per deciliter was 10 days (range, 7 to 187); 20 patients (77%) had an increase of more than 1.0 g per deciliter in the hemoglobin level at more than 50% of visits during the core study period, with improvement in markers of hemolysis. The response was sustained in all 19 patients remaining in the extension phase, with a median follow-up of 29 months (range, 22 to 35). Hemoglobin responses were observed only in patients who had at least one missense PKLR mutation and were associated with the red-cell pyruvate kinase protein level at baseline. CONCLUSIONS: The administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with pyruvate kinase deficiency, with a sustained response during a median follow-up of 29 months during the extension phase. Adverse effects were mainly low-grade and transient. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02476916.).


Assuntos
Anemia Hemolítica Congênita não Esferocítica/tratamento farmacológico , Hemoglobinas/metabolismo , Piruvato Quinase/deficiência , Erros Inatos do Metabolismo dos Piruvatos/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Anemia Hemolítica Congênita não Esferocítica/sangue , Anemia Hemolítica Congênita não Esferocítica/genética , Catecóis , Esquema de Medicação , Feminino , Seguimentos , Cefaleia/induzido quimicamente , Humanos , Masculino , Mutação , Piruvato Quinase/sangue , Piruvato Quinase/genética , Erros Inatos do Metabolismo dos Piruvatos/sangue , Erros Inatos do Metabolismo dos Piruvatos/genética , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Tirfostinas , Adulto Jovem
20.
Ideggyogy Sz ; 72(7-8): 273-277, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31517460

RESUMO

Cerebral cavernous malformations (CCMs) represent a relatively rare and heterogeneous clinical entity with mutations identified in three genes. Both sporadic and familial forms have been reported. We present a young female patient with episodic paresthesia and headaches, but without acute neurological deficits. Her mother had a hemorrhaged cavernoma surgically removed 21 years ago. Cranial magnetic resonance imaging revealed multiple cavernous malformations in the size of a few millimeters and the ophthalmologic exam detected retinal blood vessel tortuosity in the proband. Targeted exome sequencing analysis identified a nonsense mutation in exon 16 of the KRIT1 gene, which resulted in a premature stop codon and a truncated protein underlying the abnormal development of cerebral and retinal blood vessels. This mutation with pathogenic significance has been reported before. Our case points to the importance of a thorough clinical and molecular work up despite the uncertain neurological complaints, since life style recommendations, imaging monitoring and genetic counseling may have major significance in the long term health of the patient.


Assuntos
Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico , Proteína KRIT1/genética , Vasos Retinianos/diagnóstico por imagem , Feminino , Cefaleia/etiologia , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Humanos , Imagem por Ressonância Magnética , Mutação , Parestesia/etiologia , Linhagem , Deleção de Sequência/genética
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