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2.
Urol Case Rep ; 38: 101666, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33898264

RESUMO

Immunoglobulin G4-related disease (IgG4-RD) of the ureter is a rarely reported disease, often mimicking urothelial carcinoma. This paper describes a case of an otherwise healthy patient with a lesion involving the ureter revealed on Computed tomography (CT), avid on fludeoxyglucose positron emission tomography (FDG PET), that prior to surgery was suspicious for urothelial carcinoma, until intra-op frozen section revealed otherwise. Diagnosis of ureteral IgG4-RD should be considered as a differential diagnosis, with serum IgG4 levels obtained.

3.
Histopathology ; 77(4): 588-600, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32559341

RESUMO

AIMS: Synovial sarcoma is defined by recurrent t(X;18)(p11;q11) translocations creating SS18-SSX1, SS18-SSX2 or SS18-SSX4 fusions. Recently, a novel rabbit monoclonal antibody designed to identify these fusions (SS18-SSX, clone E9X9V) was proposed to be highly specific (100%), but not completely sensitive (95%) for this diagnosis. Another antibody designed to identify the C-terminal end of SSX (SSX_CT, clone E5A2C) was proposed to be highly sensitive (100%), but not completely specific (96%). We sought to validate these antibodies in an independent cohort. METHODS AND RESULTS: We performed immunohistochemistry for SS18-SSX and SSX_CT on 39 synovial sarcoma samples from 25 patients with confirmed gene rearrangements. Thirty-four (87%) and 36 (92%) were positive for SS18-SSX and SSX_CT, respectively. False-negative staining was associated with suboptimally handled small biopsies and decalcified specimens, even when staining was diffuse and strong in subsequent optimally processed excisions and non-decalcified areas. None of 580 non-synovial sarcoma tumours (76 whole sections, 504 TMA samples) were positive for SS18-SSX (100% specificity), whereas 39 (93% specificity) were positive for SSX_CT. CONCLUSIONS: SS18-SSX fusion-specific IHC is 87-95% sensitive for the diagnosis of synovial sarcoma and highly (perhaps perfectly) specific. Therefore, positive SS18-SSX staining definitively confirms the diagnosis of synovial sarcoma. SSX_CT is less specific (93-96%) but highly sensitive (92%, but approaching 100% when suboptimally processed biopsies and decalcified specimens are excluded). Negative SSX_CT staining may therefore have an ancillary role as a rule-out test for synovial sarcoma. We caution that both antibodies are prone to false-negative staining in decalcified specimens.


Assuntos
Biomarcadores Tumorais/análise , Imuno-Histoquímica/métodos , Proteínas de Fusão Oncogênica/análise , Sarcoma Sinovial/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais , Biomarcadores Tumorais/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Proteínas de Neoplasias/análise , Proteínas Repressoras/análise , Estudos Retrospectivos , Sarcoma Sinovial/genética , Sensibilidade e Especificidade , Neoplasias de Tecidos Moles/genética , Adulto Jovem
5.
Front Neurol ; 8: 617, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29209269

RESUMO

Despite the availability of thrombolytic and endovascular therapy for acute ischemic stroke, many patients are ineligible due to delayed hospital arrival. The identification of factors related to either early or delayed hospital arrival may reveal potential targets of intervention to reduce prehospital delay and improve access to time-critical thrombolysis and clot retrieval therapy. Here, we have reviewed studies reporting on factors associated with either early or delayed hospital arrival after stroke, together with an analysis of stroke onset to hospital arrival times. Much effort in the stroke treatment community has been devoted to reducing door-to-needle times with encouraging improvements. However, this review has revealed that the median onset-to-door times and the percentage of stroke patients arriving before the logistically critical 3 h have shown little improvement in the past two decades. Major factors affecting prehospital time were related to emergency medical pathways, stroke symptomatology, patient and bystander behavior, patient health characteristics, and stroke treatment awareness. Interventions addressing these factors may prove effective in reducing prehospital delay, allowing prompt diagnosis, which in turn may increase the rates and/or efficacy of acute treatments such as thrombolysis and clot retrieval therapy and thereby improve stroke outcomes.

6.
Asia Pac J Clin Oncol ; 13(6): 345-355, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28653815

RESUMO

Oxaliplatin is a platinum-derivative chemotherapeutic agent used for colorectal cancer in the adjuvant and metastatic setting in combination with folinic acid and 5-fluorouracil. Oxaliplatin causes an acute cold-induced neurotoxicity and a chronic cumulative neuropathy, which can require dose modification and impact quality of life. To date, no prevention and treatment strategies have proved effective thus reinforcing the importance of identifying at-risk patients in order to maximize therapeutic benefit while minimizing neurotoxicity. Here we reviewed studies on risk and prognostic factors associated with the development and severity of oxaliplatin-induced peripheral neuropathy. A systematic search was conducted in MEDLINE and Embase, and studies investigating clinical and patient-related factors associated with oxaliplatin-induced peripheral neuropathy as their primary focus were identified, and quantitative data were extracted when available. We identified 15 studies, of which only three were prospective. Notable factors were acute neurotoxicity symptoms predicting chronic neuropathy, baseline laboratory findings, patient demographics such as age and gender, comorbidities, and environmental factors. No factor was consistently identified across multiple studies other than the association with oxaliplatin dose. Further investigation into these factors may yield insight into potential neuropathy prevention and treatment strategies.


Assuntos
Antineoplásicos/efeitos adversos , Compostos Organoplatínicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina , Estudos Prospectivos
7.
Front Cell Neurosci ; 9: 92, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25870538

RESUMO

The development of the mammalian cerebral cortex involves a series of mechanisms: from patterning, progenitor cell proliferation and differentiation, to neuronal migration. Many factors influence the development of the cerebral cortex to its normal size and neuronal composition. Of these, the mechanisms that influence the proliferation and differentiation of neural progenitor cells are of particular interest, as they may have the greatest consequence on brain size, not only during development but also in evolution. In this context, causative genes of human autosomal recessive primary microcephaly, such as ASPM and MCPH1, are attractive candidates, as many of them show positive selection during primate evolution. MCPH1 causes microcephaly in mice and humans and is involved in a diverse array of molecular functions beyond brain development, including DNA repair and chromosome condensation. Positive selection of MCPH1 in the primate lineage has led to much insight and discussion of its role in brain size evolution. In this review, we will present an overview of MCPH1 from these multiple angles, and whilst its specific role in brain size regulation during development and evolution remain elusive, the pieces of the puzzle will be discussed with the aim of putting together the full picture of this fascinating gene.

8.
Nat Commun ; 2: 154, 2011 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-21224845

RESUMO

During mammalian cerebral cortex development, the G1-phase of the cell cycle is known to lengthen, but it has been unclear which neural stem and progenitor cells are affected. In this paper, we develop a novel approach to determine cell-cycle parameters in specific classes of neural stem and progenitor cells, identified by molecular markers rather than location. We found that G1 lengthening was associated with the transition from stem cell-like apical progenitors to fate-restricted basal (intermediate) progenitors. Unexpectedly, expanding apical and basal progenitors exhibit a substantially longer S-phase than apical and basal progenitors committed to neuron production. Comparative genome-wide gene expression analysis of expanding versus committed progenitor cells revealed changes in key factors of cell-cycle regulation, DNA replication and repair and chromatin remodelling. Our findings suggest that expanding neural stem and progenitor cells invest more time during S-phase into quality control of replicated DNA than those committed to neuron production.

9.
Proc Natl Acad Sci U S A ; 107(38): 16595-600, 2010 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-20823249

RESUMO

Mutations in ASPM (abnormal spindle-like microcephaly associated) cause primary microcephaly in humans, a disorder characterized by a major reduction in brain size in the apparent absence of nonneurological anomalies. The function of the Aspm protein in neural progenitor cell expansion, as well as its localization to the mitotic spindle and midbody, suggest that it regulates brain development by a cell division-related mechanism. Furthermore, evidence that positive selection affected ASPM during primate evolution has led to suggestions that such a function changed during primate evolution. Here, we report that in Aspm mutant mice, truncated Aspm proteins similar to those causing microcephaly in humans fail to localize to the midbody during M-phase and cause mild microcephaly. A human ASPM transgene rescues this phenotype but, interestingly, does not cause a gain of function. Strikingly, truncated Aspm proteins also cause a massive loss of germ cells, resulting in a severe reduction in testis and ovary size accompanied by reduced fertility. These germline effects, too, are fully rescued by the human ASPM transgene, indicating that ASPM is functionally similar in mice and humans. Our findings broaden the spectrum of phenotypic effects of ASPM mutations and raise the possibility that positive selection of ASPM during primate evolution reflects its function in the germline.


Assuntos
Microcefalia/genética , Mutação , Proteínas do Tecido Nervoso/genética , Animais , Animais Recém-Nascidos , Sequência de Bases , Encéfalo/anormalidades , Proteínas de Ligação a Calmodulina , Primers do DNA/genética , Modelos Animais de Doenças , Células-Tronco Embrionárias/patologia , Feminino , Mutação em Linhagem Germinativa , Humanos , Infertilidade/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Microcefalia/patologia , Proteínas do Tecido Nervoso/fisiologia , Neurônios/patologia , Oligospermia/genética , Ovário/anormalidades , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/fisiologia , Fenótipo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Deleção de Sequência , Motilidade dos Espermatozoides/genética , Testículo/anormalidades
10.
Development ; 136(11): 1859-68, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19403657

RESUMO

The extent of apoptosis of neural progenitors is known to influence the size of the cerebral cortex. Mouse embryos lacking Brca1, the ortholog of the human breast cancer susceptibility gene BRCA1, show apoptosis in the neural tube, but the consequences of this for brain development have not been studied. Here we investigated the role of Brca1 during mouse embryonic cortical development by deleting floxed Brca1 using Emx1-Cre, which leads to conditional gene ablation specifically in the dorsal telencephalon after embryonic day (E) 9.5. The postnatal Brca1-ablated cerebral cortex was substantially reduced in size with regard to both cortical thickness and surface area. Remarkably, although the thickness of the cortical layers (except for the upper-most layer) was decreased, cortical layering as such was essentially unperturbed. High levels of apoptosis were found at E11.5 and E13.5, but dropped to near-control levels by E16.5. The apoptosis at the early stage of neurogenesis occurred in both BrdU pulse-labeled neural progenitors and the neurons derived therefrom. No changes were observed in the mitotic index of apical (neuroepithelial, radial glial) progenitors and basal (intermediate) progenitors, indicating that Brca1 ablation did not affect cell cycle progression. Brca1 ablation did, however, result in the nuclear translocation of p53 in neural progenitors, suggesting that their apoptosis involved activation of the p53 pathway. Our results show that Brca1 is required for the cerebral cortex to develop to normal size by preventing the apoptosis of early cortical progenitors and their immediate progeny.


Assuntos
Apoptose/fisiologia , Proteína BRCA1/fisiologia , Córtex Cerebral/fisiologia , Neurônios/citologia , Células-Tronco/citologia , Animais , Diferenciação Celular/fisiologia , Córtex Cerebral/anatomia & histologia , Córtex Cerebral/embriologia , Embrião de Mamíferos/fisiologia , Proteínas de Homeodomínio/metabolismo , Camundongos , Tubo Neural/citologia , Tubo Neural/embriologia , Neurônios/fisiologia , Células-Tronco/fisiologia , Telencéfalo/embriologia , Telencéfalo/metabolismo , Fatores de Transcrição/metabolismo
11.
Mamm Genome ; 20(5): 281-95, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19424753

RESUMO

Genetic variation is known to influence the amount of mRNA produced by a gene. Because molecular machines control mRNA levels of multiple genes, we expect genetic variation in components of these machines would influence multiple genes in a similar fashion. We show that this assumption is correct by using correlation of mRNA levels measured from multiple tissues in mouse strain panels to detect shared genetic influences. These correlating groups of genes (CGGs) have collective properties that on average account for 52-79% of the variability of their constituent genes and can contain genes that encode functionally related proteins. We show that the genetic influences are essentially tissue-specific and, consequently, the same genetic variations in one animal may upregulate a CGG in one tissue but downregulate the CGG in a second tissue. We further show similarly paradoxical behaviour of CGGs within the same tissues of different individuals. Thus, this class of genetic variation can result in complex inter- and intraindividual differences. This will create substantial challenges in humans, where multiple tissues are not readily available.


Assuntos
Expressão Gênica , Variação Genética , Camundongos Endogâmicos/genética , Animais , Feminino , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Especificidade de Órgãos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
12.
Development ; 135(23): 3911-21, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18997113

RESUMO

Neurogenesis during the development of the mammalian cerebral cortex involves a switch of neural stem and progenitor cells from proliferation to differentiation. To explore the possible role of microRNAs (miRNAs) in this process, we conditionally ablated Dicer in the developing mouse neocortex using Emx1-Cre, which is specifically expressed in the dorsal telencephalon as early as embryonic day (E) 9.5. Dicer ablation in neuroepithelial cells, which are the primary neural stem and progenitor cells, and in the neurons derived from them, was evident from E10.5 onwards, as ascertained by the depletion of the normally abundant miRNAs miR-9 and miR-124. Dicer ablation resulted in massive hypotrophy of the postnatal cortex and death of the mice shortly after weaning. Analysis of the cytoarchitecture of the Dicer-ablated cortex revealed a marked reduction in radial thickness starting at E13.5, and defective cortical layering postnatally. Whereas the former was due to neuronal apoptosis starting at E12.5, which was the earliest detectable phenotype, the latter reflected dramatic impairment of neuronal differentiation. Remarkably, the primary target cells of Dicer ablation, the neuroepithelial cells, and the neurogenic progenitors derived from them, were unaffected by miRNA depletion with regard to cell cycle progression, cell division, differentiation and viability during the early stage of neurogenesis, and only underwent apoptosis starting at E14.5. Our results support the emerging concept that progenitors are less dependent on miRNAs than their differentiated progeny, and raise interesting perspectives as to the expansion of somatic stem cells.


Assuntos
Diferenciação Celular/genética , MicroRNAs/metabolismo , Neocórtex/citologia , Neocórtex/embriologia , Neurogênese/genética , Neurônios/citologia , Células-Tronco/citologia , Animais , Animais Recém-Nascidos , Apoptose , Contagem de Células , Linhagem da Célula , Proliferação de Células , Sobrevivência Celular , RNA Helicases DEAD-box/metabolismo , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário , Endorribonucleases/metabolismo , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento , Interneurônios/citologia , Interneurônios/metabolismo , Camundongos , Mitose , Neocórtex/metabolismo , Neurônios/enzimologia , Ribonuclease III , Células-Tronco/enzimologia
14.
Dev Growth Differ ; 49(5): 383-94, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17547648

RESUMO

Freshwater planarians have a simple and evolutionarily primitive brain structure. Here, we identified the Djsnap-25 gene encoding a homolog of the evolutionarily conserved synaptic protein SNAP-25 from the planarian Dugesia japonica and assessed its role in brain function. Djsnap-25 was expressed widely in the nervous system. To investigate the specific role of Djsnap-25 in the brain, we developed a unique technique of RNA interference (RNAi), regeneration-dependent conditional gene knockdown (Readyknock), exploiting the high regenerative capacity of planarians, and succeeded in selectively eliminating the DjSNAP-25 activity in the head region while leaving the DjSNAP-25 activity in the trunk region intact. These knockdown animals showed no effect on brain morphology or on undirected movement of the trunk itself. Light-avoidance behavior or negative phototaxis was used to quantitatively analyze brain function in the knockdown animals. The results suggested that the DjSNAP-25 activity within the head region is required for two independent sensory-processing pathways that regulate locomotive activity and directional movement downstream of distinct primary sensory outputs coming from the head margin and the eyes, respectively, during negative phototaxis. Our approach demonstrates that planarians are a powerful model organism to study the molecular basis of the brain as an information-processing center.


Assuntos
Planárias/genética , Planárias/fisiologia , Proteína 25 Associada a Sinaptossoma/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Comportamento Animal , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , Primers do DNA/genética , DNA de Helmintos/genética , Expressão Gênica , Proteínas de Helminto/genética , Dados de Sequência Molecular , Fotobiologia , Planárias/crescimento & desenvolvimento , Interferência de RNA , Regeneração/genética , Homologia de Sequência de Aminoácidos , Proteína 25 Associada a Sinaptossoma/fisiologia
15.
Mamm Genome ; 17(6): 490-5, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16783630

RESUMO

The analysis of the influence of genetic variation on regulation of gene expression at a near-genome-wide level has become the focus of much recent interest. It is widely appreciated that many genes are expressed in a tissue-specific manner and that others are more ubiquitously expressed but relatively little is known about how genetic variation might influence these tissue patterns of gene expression. In this review we discuss what is known about the tissue specificity of the influence of genetic variation and review the challenges that we face in combining hugely parallel, microarray-based gene analysis with equally expensive genetic analysis. We conclude that the available data suggest that genetic variation is essentially tissue specific in its effects upon gene expression and this has important implications for experimental analysis.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica/fisiologia , Especificidade de Órgãos/genética , Animais , Camundongos
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