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1.
Biomedicines ; 10(5)2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35625917

RESUMO

While promising, PD-L1 expression on tumor tissues as assessed by immunohistochemistry has been shown to be an imperfect biomarker that only applies to a limited number of cancers, whereas many patients with PD-L1-negative tumors still respond to anti-PD-(L)1 immunotherapy. Recent studies using patient blood samples to assess immunotherapeutic responsiveness suggests a promising approach to the identification of novel and/or improved biomarkers for anti-PD-(L)1 immunotherapy. In this review, we discuss the advances in our evolving understanding of the regulation and function of PD-L1 expression, which is the foundation for developing blood-based PD-L1 as a biomarker for anti-PD-(L)1 immunotherapy. We further discuss current knowledge and clinical study results for biomarker identification using PD-L1 expression on tumor and immune cells, exosomes, and soluble forms of PD-L1 in the peripheral blood. Finally, we discuss key challenges for the successful development of the potential use of blood-based PD-L1 as a biomarker for anti-PD-(L)1 immunotherapy.

2.
Int J Mol Sci ; 22(21)2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34769278

RESUMO

Immune checkpoint inhibitor (ICI) therapy has revolutionized anti-cancer treatment for many late-stage cancer patients. However, ICI therapy has thus far demonstrated limited efficacy for most patients, and it remains unclear why this is so. Interleukin 10 (IL-10) is a cytokine that has been recognized as a central player in cancer biology with its ability to inhibit anti-tumor T cell responses. Recent studies suggest that IL-10 might also exert some intrinsic anti-tumor T cell responses, and clinical studies using recombinant IL-10 alone or in combination with ICI are underway. This paradoxical effect of IL-10 and its underlying mechanisms impacting ICI-modulated T cell responses remain poorly understood. In this study, using an in vitro mixed lymphocyte reaction assay, we found that treatment with ICIs such as the anti-programmed cell death receptor-1 (PD-1) mAb nivolumab elicits a strong expression of IL-10. While neutralization of IL-10 signaling with an anti-IL-10 specific mAb significantly decreases the production of IFN-γ by T cells in a cohort of donor cells, the opposite effect was observed in other donor cells. Similarly, neutralization of IL-10 signaling significantly decreases the expression of T cell activation markers Ki67 and CD25, as well as the production of Granzyme B in a cohort of donor cells, whereas the opposite effect was observed in others. Furthermore, we found that nivolumab and IL-10 differentially modulate the signal transducer and activator of transcription 3 (STAT3) and AKT serine-threonine kinase pathways. Finally, we found that nivolumab activates the mitogen-activated protein kinase (MAPK) pathway, which in turn is responsible for the observed induction of IL-10 production by nivolumab. These findings provide new insights into the mechanisms underlying anti-PD-1-modulated T cell responses by IL-10, which could lead to the discovery of novel combination treatments that target IL-10 and immune checkpoint molecules.


Assuntos
Interleucina-10/imunologia , Ativação Linfocitária/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Nivolumabe/farmacologia , Linfócitos T/imunologia , Humanos , Interferon gama/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Antígeno Ki-67/imunologia , Sistema de Sinalização das MAP Quinases/imunologia
3.
AAPS J ; 23(5): 99, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34401948

RESUMO

Immune checkpoint inhibitors (ICIs) represent a promising therapy for many types of cancer. However, only a portion of patients respond to this therapy and some patients develop clinically significant immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI), an immune-related adverse event (irAE) that may require the interruption or termination of treatment and administration of systemic corticosteroids or other immunosuppressive agents. Although the incidence of ILICI is lower with monotherapy, the surge in combining ICIs with chemotherapy, targeted therapy, and combination of different ICIs has led to an increase in the incidence and severity of ILICI - a major challenge for development of effective and safe ICI therapy. In this review, we highlight the importance and contribution of the liver microenvironment to ILICI by focusing on the emerging roles of resident liver cells in modulating immune homeostasis and hepatocyte regeneration, two important decisive factors that dictate the initiation, progression, and recovery from ILICI. Based on the proposed contribution of the liver microenvironment on ICILI, we discuss the clinical characteristics of ILICI in patients with preexisting liver diseases, as well as the challenges of identifying prognostic biomarkers to guide the clinical management of severe ILICI. A better understanding of the liver microenvironment may lead to novel strategies and identification of novel biomarkers for effective management of ILICI.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/imunologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Fígado/patologia , Neoplasias/tratamento farmacológico , Animais , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Humanos , Incidência , Fígado/efeitos dos fármacos , Fígado/imunologia , Regeneração Hepática/efeitos dos fármacos , Regeneração Hepática/imunologia , Neoplasias/imunologia , Índice de Gravidade de Doença
4.
Int J Mol Sci ; 21(23)2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33261003

RESUMO

The absence of reliable, robust, and non-invasive biomarkers for anti- Programmed cell death protein 1 (PD-1) immunotherapy is an urgent unmet medical need for the treatment of cancer patients. No predictive biomarkers have been established based on the direct assessment of T cell functions, the primary mechanism of action of anti-PD-1 therapy. In this study, we established a model system to test T cell functions modulated by Nivolumab using anti-CD3 monoclonal antibody (mAb)-stimulated peripheral blood mononuclear cells (PBMCs), and characterized T cell functions primarily based on the knowledge gained from retrospective observations of patients treated with anti-PD-1 immunotherapy. During a comprehensive cytokine profile assessment to identify potential biomarkers, we found that Nivolumab increases expression of T helper type 1 (Th1) associated cytokines such as interferon-γ (IFN-γ) and interleukin-2 (IL-2) in a subset of donors. Furthermore, Nivolumab increases production of Th2, Th9, and Th17 associated cytokines, as well as many proinflammatory cytokines such as IL-6 in a subset of donors. Conversely, Nivolumab treatment has no impact on T cell proliferation, expression of CD25, CD69, or Granzyme B, and only modestly increases in the expansion of regulatory T cells. Our results suggest that assessment of cytokine production using a simple PBMC-based T cell functional assay could be used as a potential predictive marker for anti-PD-1 immunotherapy.


Assuntos
Biomarcadores/metabolismo , Imunoensaio , Imunoterapia , Leucócitos Mononucleares/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Antígenos CD/metabolismo , Proliferação de Células/efeitos dos fármacos , Citocinas/biossíntese , Granzimas/metabolismo , Humanos , Ativação Linfocitária/efeitos dos fármacos , Nivolumabe/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Doadores de Tecidos
5.
Genet Med ; 22(10): 1718-1722, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32555416

RESUMO

PURPOSE: To assess the utilization of genetics on the United States Medical Licensing Examination (USMLE®). METHODS: A team of clinical genetics educators performed an analysis of the representation of genetics content on a robust sample of recent Step 1, Step 2 Clinical Knowledge (CK), and Step 3 examination forms. The content of each question was mapped to curriculum recommendations from the peer reviewed Association of Professors of Human and Medical Genetics white paper, Medical School Core Curriculum in Genetics, and the USMLE Content Outline. RESULTS: The committee identified 13.4%, 10.4%, and 4.4% of Steps 1, 2 and 3 respectively, as having genetics content. The genetics content of the exams became less pertinent to the questions from Step 1 to 3, with decreasing genetics content by exam and increasing percentages of questions identified as having genetics content in the distractors only. CONCLUSION: The current distribution of genetics in USMLE licensing examinations reflects traditional curricular approaches with genetics as a basic science course in the early years of medical school and de-emphasizes clinical relevance of the field. These observations support the notion that further integration is required to move genetics into the clinical curriculum of medical schools and the clinical content of USMLE Step exams.


Assuntos
Educação de Graduação em Medicina , Educação Médica , Competência Clínica , Currículo , Avaliação Educacional , Genômica , Humanos , Licenciamento em Medicina , Estados Unidos
7.
AAPS J ; 22(4): 80, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32462555

RESUMO

Therapeutic proteins can be potent agents for treating serious diseases, but in many patients these proteins provoke antibody responses that blunt therapeutic efficacy. Intravenous administration of high doses of some proteins induces immune tolerance, but the mechanisms underlying this effect are poorly understood. As a model to study tolerance induction in mice, we used rasburicase, a commercial recombinant uricase used for the treatment of hyperuricemia. Intraperitoneal (i.p.) injection of rasburicase without or with alum adjuvants induced a clear anti-rasburicase antibody response, but intravenous (i.v.) injection did not. The lack of response to i.v. rasburicase was apparently due to active immune suppression since i.v.-treated mice showed blunted antibody and reduced T cell responses to subsequent i.p. injections of rasburicase. This blunted response was associated with a decrease in rasburicase-specific B cell and T cell responses and an increase in proportion of CD4+ FoxP3+ regulatory T cells (Treg) in the spleen. We examined the number of lymphocytes in peripheral blood after rasburicase i.v. injection. Rasburicase caused a transient reduction in B and T cells, but a robust and sustained depletion of rasburicase-specific B cells. Further experiments showed that rasburicase i.v. injection decreased the number of lymphocytes and was associated with apoptosis of both B cells and activated T cells and that the enhanced percentage of Treg cells was likely mediated by a macrophage-dependent pathway. Thus, our data suggest that apoptosis and depletion of antigen-specific B lymphocytes and upregulation of Treg cells may play important roles in the immune suppression induced by intravenous administration of a therapeutic protein.


Assuntos
Autoanticorpos/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Urato Oxidase/administração & dosagem , Administração Intravenosa , Animais , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Supressores da Gota/administração & dosagem , Linfócitos/imunologia , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Regulação para Cima/fisiologia
8.
MAbs ; 12(1): 1685814, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31774346

RESUMO

Therapeutic monoclonal antibodies (mAbs) are commonly administered to patients through intravenous (IV) infusion, which involves diluting the medication into an infusion solution (e.g., saline and 5% dextrose). Using the wrong diluent can cause product aggregation, which may compromise patient safety. We and others have shown that Herceptin® (trastuzumab) and Avastin® (bevacizumab) undergo rapid aggregation upon mixing with dextrose and human plasma in vitro. In this study, we evaluated the compatibility of a panel of 11 therapeutic mAbs with dextrose or saline and human serum. These mAbs were randomly selected for their distinct formulations and IgG isotypes (IgG1, IgG2, IgG4, and Fc-fusion protein). All the mAbs appeared to be compatible with saline and human serum. However, mAbs that were formulated at acidic pH (≤ 6.5) exclusively formed insoluble aggregates upon mixing with dextrose and serum. Such aggregation was not detected for the mAbs that are at neutral pH (7.2-7.5) or in buffers containing sodium chloride. Mass spectrometric analysis revealed that the insoluble aggregates were composed of mAb molecules and several serum proteins (e.g., complement proteins, apolipoprotein, fibronectin) that are characterized by an isoelectric point of pH 5.4-6.7. At proximate pH to the isoelectric point values, those abundant serum proteins appeared to undergo isoelectric precipitation with mAb molecules. Our observations highlight a potential risk of protein aggregation at the blood-IV interface if a diluent is incompatible with a specific mAb formulation. This information has implications in guiding the design of product formulations and the selection of the right diluent for intravenous infusion of therapeutic mAbs.Abbreviations: ADC: antibody-drug conjugate; D5W: 5% dextrose in water; IM: intramuscular; IV: intravenous; LC-MS/MS: liquid chromatography-tandem mass spectrometry; mAb: monoclonal antibody; SC: subcutaneous; pI: isoelectric point.


Assuntos
Anticorpos Monoclonais/química , Bevacizumab/química , Isotipos de Imunoglobulinas/química , Solução Salina/química , Trastuzumab/química , Proteínas Sanguíneas/química , Glucose , Humanos , Concentração de Íons de Hidrogênio , Imunoconjugados/química , Infusões Intravenosas , Ponto Isoelétrico , Espectrometria de Massas , Agregados Proteicos
9.
Gynecol Oncol ; 154(3): 467-474, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31248668

RESUMO

BACKGROUND: The current risk stratification systems used to guide management of endometrial cancer are based on irreproducible post surgical pathological information, hence the need for more reliable classification systems. Using microarray and sequencing technologies, TCGA recently identified four prognostically significant endometrial carcinoma subtypes, which subsequently proved reproducible using clinically applicable surrogate tests. Using these tests, we sought to determine the level of concordance between endometrial biopsies and subsequent hysterectomy specimens in assessing the molecular classification of endometrial carcinoma. MATERIALS AND METHODS: Fifty biopsies with corresponding hysterectomy specimens for endometrial carcinomas were collected. Additionally, 10 cases of biopsy proven atypical hyperplasia/EIN who were found to have endometrial carcinoma on resection were included. IHC for mismatch repair (MMR) proteins (MLH1, PMS2, MSH2 and MSH6) and P53 was performed. Microsatellite instability analysis was performed by PCR and Sanger sequencing was performed to detect mutations in exons 9 and 13 of the POLE gene. The level of concordance for tumor grade, histologic subtype, immunohistochemical and molecular profile in both specimens was determined using Cohen's kappa estimates. RESULTS: A high level of concordance was achieved for MMR-loss, MSI-high, P53-wild and abnormal types. In contrast, grade and histologic subtype showed only moderate levels of agreement. POLE gene mutation was detected in two patients. For both cases, mutations were detected only in resection specimens. When comparing atypical hyperplasia/EIN with subsequent hysterectomy tumor, the profile was identical to that of endometrial carcinoma. CONCLUSION: In our cohort of endometrial carcinoma, a high level of concordance was achieved between biopsy and hysterectomy specimens for MMR-loss, MSI-high, P53-wild and abnormal types, superior to that of grade and histologic subtype, providing earlier and more reliable prognostic information to inform management. Similar concordance could not be achieved for POLE mutation, given the low frequency of this mutation in our study.


Assuntos
Neoplasias do Endométrio/classificação , Medicina de Precisão/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Histerectomia , Imuno-Histoquímica , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Gradação de Tumores
10.
Pediatr Clin North Am ; 66(2): 369-386, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30819343

RESUMO

Newborn screening has evolved since its introduction in 1963. The disorders that are being screened for continue to evolve as new treatments and new technologies advance. In this review, the authors discuss the current state of newborn screening in the United States, including the disorders currently being screened for and how newborn screening is performed. They also discuss the special considerations and limitations of newborn screening in sick and premature infants and as well as some ethical issues related to newborn screening. Finally, new disorders being considered for testing and new technologies that may be used in the future of newborn screening are discussed.


Assuntos
Doenças do Recém-Nascido/diagnóstico , Triagem Neonatal/métodos , Humanos , Recém-Nascido , Triagem Neonatal/ética , Estados Unidos
11.
Nature ; 566(7744): 332-333, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30787455
12.
J Matern Fetal Neonatal Med ; 32(7): 1184-1190, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29113516

RESUMO

OBJECTIVE: The primary objective of this study is to evaluate the availability and duration of formal medical genetics and genomics (MGG) education during obstetrics and gynecology (OB/GYN) residency training in the United States compared to other noncore OB/GYN rotations. METHODS: We performed a review of rotation schedules published in all American Council for Graduate Medical Education (ACGME)-accredited OB/GYN residency programs' websites during the month of December 2016. Information regarding availability and duration of MGG rotation and other noncore OB/GYN rotations (ultrasound, breast health, and family planning) were collected. RESULTS: Among 256 ACGME-accredited OB/GYN residency programs, rotation schedule was available for 238 (93%). Only 34 programs (14.3%) had some form of MGG rotations. In the GLM, when compared to other noncore OB/GYN rotations, the mean duration of MGG rotation was significantly less than ultrasound (0.07 versus 0.57 months, p < .05) and family planning (0.07 versus 0.42 months, p < .05). The number of residents was the only variable significantly correlated with the availability of an MGG rotation (OR 1.07, 95%CI 1.02-1.13). CONCLUSIONS: Despite the growing importance of MGG in day-to-day OB/GYN practice, only a limited number of ACGME-accredited OB/GYN residency programs offer an MGG rotation. When compared to other noncore OB/GYN rotations, such as, ultrasound and family planning, any MGG rotation was significantly shorter. With clear evidence that MGG will continue to radically change practice of OB/GYN in the future, it is imperative that steps need to be taken to address this deficiency in training.


Assuntos
Genética Médica/educação , Genômica/educação , Ginecologia/educação , Internato e Residência/tendências , Obstetrícia/educação , Estudos Transversais , Currículo/estatística & dados numéricos , Currículo/tendências , Feminino , Humanos , Internato e Residência/métodos , Internato e Residência/estatística & dados numéricos , Gravidez , Estados Unidos , Universidades
13.
Oncoimmunology ; 8(1): e1512456, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30546949

RESUMO

Immune checkpoint inhibitors (ICIs) such as the anti-PD-1 antibody Nivolumab, achieve remarkable clinical efficacy in patients with late stage cancers. However, only a small subset of patients benefit from this therapy. Numerous clinical trials are underway testing whether combining ICIs with other anti-cancer therapies can increase this response rate. For example, anti-PD-1/PD-L1 therapy combined with MAP kinase inhibition using BRAF inhibitors (BRAFi) and/or MEK inhibitors (MEKi) are in development for treatment of late stage melanomas. However, the benefits and underlying mechanisms of these combinatorial therapies remain unclear. In the current study, we assess the effects of MAPK inhibition on Nivolumab-induced T cell responses. Using an in vitro mixed lymphocyte reaction assay, we demonstrate that Nivolumab-induced T cell activation is highly heterogeneous. While BRAFi inhibits Nivolumab-induced cytokine production, T cell proliferation, activation markers (CD69, CD25), and Granzyme B in a substantial proportion of donor pairs, a small subset of donor pairs shows an additive effect. MEKi alone significantly inhibits Nivolumab-induced T cell activation; the addition of BRAFi significantly enhances this inhibitory effect. Mechanistically, the effects of BRAFi and/or MEKi on Nivolumab-induced T cell activation may be due to alteration of the activation of the AKT and T cell receptor (TCR) signaling pathways. Our results suggest that MAPK inhibition may not provide a clinical benefit for most melanoma patients being treated with anti-PD-1 therapy.

14.
J Clin Nurs ; 27(9-10): 1931-1940, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29495091

RESUMO

AIMS AND OBJECTIVES: To identify preclinical signs of dementia by exploring the experiences of family caregivers and professional care assistants. BACKGROUND: Dementia results in disability, emotional strain and financial loss for people with dementia, family members and nations. Informal identification of social and behavioural risk signifiers could facilitate timely interventions with potential to delay onset of serious disability. DESIGN: A retrospective qualitative approach using a naturalistic interpretive design was used. Focus groups enabled in-depth understanding of the participants' experiences of life or work with people who subsequently developed dementia. METHODS: Purposive sampling was used to recruit family carers and professional carers who had cared for people who later developed dementia. The data from focus groups were fully transcribed and anonymised, and transcripts were analysed by two researchers. These researchers coded and analysed the transcripts independently; subsequently, overlapping and similar themes were identified and consensus reached on final themes. A third researcher was invited to review the analysis and ensure trustworthiness of the study findings. RESULTS: Findings revealed that preclinical signs of dementia were identifiable in retrospect Participants' accounts resulted in four themes, "Lowered Threshold of Frustration", "Insight and Coping Strategies," "Early signs of poor memory" and "Alarming Events." CONCLUSIONS: Earlier recognition of preclinical signs of dementia would allow affected individuals to follow health promotion advice and plan for the future. Identification of social exclusion prior to diagnosis has implications for antistigma campaigns and development of "dementia-friendly communities." RELEVANCE TO CLINICAL PRACTICE: Healthcare professionals could work with those at risk, facilitating lifestyle changes to postpone symptoms and advance planning for improved autonomy. Predementia should be viewed as a disability for which reasonable adjustments can be made at a community level, to enhance and extend emotional well-being and social inclusion.


Assuntos
Atividades Cotidianas , Cuidadores/psicologia , Demência/psicologia , Assistência Domiciliar/psicologia , Adaptação Psicológica , Idoso , Demência/diagnóstico , Família/psicologia , Feminino , Grupos Focais , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Estudos Retrospectivos
15.
J Assist Reprod Genet ; 35(1): 3-16, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28932969

RESUMO

Classic galactosemia is an inborn error of the metabolism with devastating consequences. Newborn screening has been successful in markedly reducing the acute neonatal symptoms from this disorder. The dramatic response to dietary treatment is one of the major success stories of newborn screening. However, as children with galactosemia achieve adulthood, they face long-term complications. A majority of women with classic galactosemia develop primary ovarian insufficiency and resulting morbidity. The underlying pathophysiology of this complication is not clear. This review focuses on the reproductive issues seen in girls and women with classic galactosemia. Literature on the effects of classic galactosemia on the female reproductive system was reviewed by an extensive Pubmed search (publications from January 1975 to January 2017) using the keywords: galactosemia, ovarian function/dysfunction, primary ovarian insufficiency/failure, FSH, oxidative stress, fertility preservation. In addition, articles cited in the search articles and literature known to the authors was also included in the review. Our understanding of the role of galactose metabolism in the ovary is limited and the pathogenic mechanisms involved in causing primary ovarian insufficiency are unclear. The relative rarity of galactosemia makes it difficult to accumulate data to determine factors defining timing of ovarian dysfunction or treatment/fertility preservation options for this group of women. In this review, we present reproductive challenges faced by women with classic galactosemia, highlight the gaps in our understanding of mechanisms leading to primary ovarian insufficiency in this population, discuss new advances in fertility preservation options, and recommend collaboration between reproductive medicine and metabolic specialists to improve fertility in these women.


Assuntos
Galactosemias/complicações , Insuficiência Ovariana Primária/complicações , Adulto , Criança , Feminino , Fertilidade/fisiologia , Preservação da Fertilidade/métodos , Galactosemias/diagnóstico , Galactosemias/fisiopatologia , Galactosemias/terapia , Humanos , Recém-Nascido , Insuficiência Ovariana Primária/diagnóstico , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/terapia
16.
Mol Genet Genomic Med ; 5(6): 795-799, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29178637

RESUMO

BACKGROUND: Elevated plasma and urine formiminoglutamic acid (FIGLU) levels are commonly indicative of formiminoglutamic aciduria (OMIM #229100), a poorly understood autosomal recessive disorder of histidine and folate metabolism, resulting from formiminotransferase-cyclodeaminase (FTCD) deficiency, a bifunctional enzyme encoded by FTCD. METHODS: In order to further understanding about the molecular alterations that contribute to FIGLU-uria, we sequenced FTCD in 20 individuals with putative FTCD deficiency and varying laboratory findings, including increased FIGLU excretion. RESULTS: Individuals tested had biallelic loss-of-function variants in protein-coding regions of FTCD. The FTCD allelic spectrum comprised of 12 distinct variants including 5 missense alterations that replace conserved amino acid residues (c.223A>C, c.266A>G, c.319T>C, c.430G>A, c.514G>T), an in-frame deletion (c.1373_1375delTGG), with the remaining alterations predicted to affect mRNA processing/stability. These included two frameshift variants (c.990dup, c.1366dup) and four nonsense variants (c.337C>T, c.451A>T, c.763C>T, c.1607T>A). CONCLUSION: We observed additional FTCD alleles leading to urinary FIGLU elevations, and thus, providing molecular evidence of FTCD deficiency in cases identified by newborn screening or clinical biochemical genetic laboratory testing.


Assuntos
Amônia-Liases/genética , Glutamato Formimidoiltransferase/deficiência , Erros Inatos do Metabolismo/genética , Alelos , Sequência de Aminoácidos , Códon sem Sentido , Mutação da Fase de Leitura , Deleção de Genes , Genótipo , Glutamato Formimidoiltransferase/genética , Humanos , Erros Inatos do Metabolismo/diagnóstico , Mutação de Sentido Incorreto , Fases de Leitura Aberta/genética , Polimorfismo de Nucleotídeo Único
17.
Clin Case Rep ; 5(8): 1323-1326, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28781851

RESUMO

Maternal cell-free DNA (cfDNA) results that are discordant with the diagnostic fetal karyotype should prompt further investigation. If deeper analysis of the cfDNA results demonstrates a "saw-tooth" pattern characteristic of genome-wide imbalance, maternal malignancy is suggested. Identifying the maternal malignancy can, however, be difficult.

20.
Genet Med ; 18(11): 1075-1084, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27171546

RESUMO

The introduction of diagnostic clinical genome and exome sequencing (CGES) is changing the scope of practice for clinical geneticists. Many large institutions are making a significant investment in infrastructure and technology, allowing clinicians to access CGES, especially as health-care coverage begins to extend to clinically indicated genomic sequencing-based tests. Translating and realizing the comprehensive clinical benefits of genomic medicine remain a key challenge for the current and future care of patients. With the increasing application of CGES, it is necessary for geneticists and other health-care providers to understand its benefits and limitations in order to interpret the clinical relevance of genomic variants identified in the context of health and disease. New, collaborative working relationships with specialists across diverse disciplines (e.g., clinicians, laboratorians, bioinformaticians) will undoubtedly be key attributes of the future practice of clinical genetics and may serve as an example for other specialties in medicine. These new skills and relationships will also inform the development of the future model of clinical genetics training curricula. To address the evolving role of the clinical geneticist in the rapidly changing climate of genomic medicine, two Clinical Genetics Think Tank meetings were held that brought together physicians, laboratorians, scientists, genetic counselors, trainees, and patients with experience in clinical genetics, genetic diagnostics, and genetics education. This article provides recommendations that will guide the integration of genomics into clinical practice.Genet Med 18 11, 1075-1084.


Assuntos
Aconselhamento Genético/tendências , Genética Médica/tendências , Genoma Humano/genética , Genômica , Exoma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
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