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1.
Res Pract Thromb Haemost ; 6(6): e12792, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36186101

RESUMO

Background: In Australia, prescribing restrictions limit access to internationally recommended second-line therapies such as rituximab and thrombopoietin agonists (TPO-A) (eltrombopag and romiplostim). Subsequent lines of therapy include an array of immunosuppressive and immune-modulating agents directed by drug availability and physician and patient preference. Objectives: The objective of the study was to describe the use of first and subsequent lines of treatment for adult immune thrombocytopenia (ITP) in Australia and to assess their effectiveness and tolerability. Patients/Methods: A retrospective review of medical records was conducted of 322 patients treated for ITP at eight participating centers in Australia between 2013 and 2020. Data were analyzed by descriptive statistics and frequency distribution using pivot tables, and comparisons between centers were assessed using paired t tests. Results: Mean age at diagnosis of ITP was 48.8 years (standard deviation [SD], 22.6) and 58.3% were women. Primary ITP was observed in 72% and secondary ITP in 28% of the patients; 95% of patients received first-line treatment with prednisolone (76%), dexamethasone (15%), or intravenous immunoglobulin (48%) alone or in combination. Individuals with secondary ITP were less steroid dependent (72% vs. 76%) and required less treatment with a second-line agent (47% vs. 58%) in the study sample. Over half (56%) of the cohort received treatment with one or more second-line agents. The mean number of second-line agents used for each patient was 1.9 (SD, 1.2). The most used second-line therapy was rituximab, followed by etrombopag and splenectomy. These also generated the highest rates of complete response (60.3%, 72.1%, and 71.8% respectively). The most unfavorable side effect profiles were seen in long-term corticosteroids and splenectomy. Conclusion: A wide range of "second-line" agents were used across centers with variable response rates and side effect profiles. Findings suggest greater effectiveness of rituximab and TPO-A, supporting their use earlier in the treatment course of patients with ITP across Australia.

2.
Nat Commun ; 12(1): 491, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479218

RESUMO

Mass releases of sterilized male insects, in the frame of sterile insect technique programs, have helped suppress insect pest populations since the 1950s. In the major horticultural pests Bactrocera dorsalis, Ceratitis capitata, and Zeugodacus cucurbitae, a key phenotype white pupae (wp) has been used for decades to selectively remove females before releases, yet the gene responsible remained unknown. Here, we use classical and modern genetic approaches to identify and functionally characterize causal wp- mutations in these distantly related fruit fly species. We find that the wp phenotype is produced by parallel mutations in a single, conserved gene. CRISPR/Cas9-mediated knockout of the wp gene leads to the rapid generation of white pupae strains in C. capitata and B. tryoni. The conserved phenotype and independent nature of wp- mutations suggest this technique can provide a generic approach to produce sexing strains in other major medical and agricultural insect pests.


Assuntos
Proteínas de Insetos/genética , Mutação , Controle Biológico de Vetores/métodos , Pupa/genética , Tephritidae/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Sistemas CRISPR-Cas , Ceratitis capitata/genética , Feminino , Fertilidade/genética , Genoma de Inseto/genética , Masculino , Fenótipo , Reprodução/genética , Tephritidae/classificação
3.
Platelets ; 32(8): 998-1008, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33284715

RESUMO

Ionotropic glutamate receptors include α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), kainate receptors (KAR), and N-methyl-D-aspartate receptors (NMDAR). All function as cation channels; AMPAR and KAR are more permeable to sodium and NMDAR to calcium ions. Compared to the brain, receptor assemblies in platelets are unusual, suggesting distinctive functionalities.There is convincing evidence that AMPAR and KAR amplify platelet function and thrombus formation in vitro and in vivo. Transgenic mice lacking GluA1 and GluK2 (AMPAR and KAR subunits, respectively) have longer bleeding times and prolonged time to thrombosis in an arterial model. In humans, rs465566 KAR gene polymorphism associates with altered in vitro platelet responses suggesting enhanced aspirin effect. The NMDAR contribution to platelet function is less well defined. NMDA at low concentrations (≤10 µM) inhibits platelet aggregation and high concentrations (≥100 µM) have no effect. However, open NMDAR channel blockers interfere with platelet activation and aggregation induced by other agonists in vitro; anti-GluN1 antibodies interfere with thrombus formation under high shear rates ex vivo; and rats vaccinated with GluN1 develop iron deficiency anemia suggestive of mild chronic bleeding. In this review, we summarize data on glutamate receptors in platelets and propose a unifying model that reconciles some of the opposing effects observed.


Assuntos
Plaquetas/metabolismo , Receptores Ionotrópicos de Glutamato/metabolismo , Animais , Humanos , Masculino , Ratos
4.
Int J Mol Sci ; 21(21)2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33182365

RESUMO

Ischaemic brain damage induces autoimmune responses, including the production of autoantibodies with potential neuroprotective effects. Platelets share unexplained similarities with neurons, and the formation of anti-platelet antibodies has been documented in neurological disorders. The aim of this study was to investigate the presence of anti-platelet antibodies in the peripheral blood of patients after ischaemic stroke and determine any clinical correlations. Using a flow cytometry-based platelet immunofluorescence method, we detected platelet-reactive antibodies in 15 of 48 (31%) stroke patients and two of 50 (4%) controls (p < 0.001). Western blotting revealed heterogeneous reactivities with platelet proteins, some of which overlapped with brain proteins. Stroke patients who carried anti-platelet antibodies presented with larger infarcts and more severe neurological dysfunction, which manifested as higher scores on the National Institutes of Health Stroke Scale (NIHSS; p = 0.009), but they had a greater recovery in the NIHSS by the time of hospital discharge (day 7 ± 2) compared with antibody-negative patients (p = 0.043). Antibodies from stroke sera reacted more strongly with activated platelets (p = 0.031) and inhibited platelet aggregation by up to 30.1 ± 2.8% (p < 0.001), suggesting the potential to interfere with thrombus formation. In conclusion, platelet-reactive antibodies can be found in patients soon after ischaemic stroke and correlate with better short-term outcomes, suggesting a potential novel mechanism limiting thrombosis.


Assuntos
Autoanticorpos/imunologia , Plaquetas/imunologia , Isquemia Encefálica/imunologia , AVC Isquêmico/imunologia , Idoso , Autoimunidade/imunologia , Coagulação Sanguínea/imunologia , Feminino , Humanos , Masculino , Agregação Plaquetária/imunologia , Contagem de Plaquetas/métodos , Trombose/imunologia
5.
Nat Commun ; 11(1): 2321, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385305

RESUMO

The diamondback moth, Plutella xylostella is a cosmopolitan pest that has evolved resistance to all classes of insecticide, and costs the world economy an estimated US $4-5 billion annually. We analyse patterns of variation among 532 P. xylostella genomes, representing a worldwide sample of 114 populations. We find evidence that suggests South America is the geographical area of origin of this species, challenging earlier hypotheses of an Old-World origin. Our analysis indicates that Plutella xylostella has experienced three major expansions across the world, mainly facilitated by European colonization and global trade. We identify genomic signatures of selection in genes related to metabolic and signaling pathways that could be evidence of environmental adaptation. This evolutionary history of P. xylostella provides insights into transoceanic movements that have enabled it to become a worldwide pest.


Assuntos
Genoma de Inseto/genética , Herbivoria/genética , Animais , Evolução Biológica , Entomologia/métodos , Genética Populacional/métodos , Filogenia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
6.
Res Pract Thromb Haemost ; 4(1): 106-110, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31989091

RESUMO

Germline mutations of runt-related transcription factor-1 (RUNX1) cause familial platelet disorder with predisposition to myeloid malignancy (FPDMM), most commonly associated with thrombocytopenia and propensity to develop myeloid neoplasms. A key clinical question is which patients with a family history of thrombocytopenia should undergo genetic testing for RUNX1 mutations. Typically, molecular diagnosis by genetic sequencing is performed when the clinical phenotype is suggestive of this diagnosis; however, our understanding of the spectrum of associated features suggestive of this diagnosis continues to evolve. Herein, we report a case series of 3 unrelated families with RUNX1-associated FPDMM and clinical phenotypes not typically reported with this condition. These cases expand our understanding of FPDMM and highlight the complexity of transcriptional regulation of hematopoiesis and its potentially diverse phenotypes. We describe our approach to diagnosis and management of these individuals and the importance of long-term surveillance in these cases.

7.
Thromb Res ; 196: 561-568, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-31229273

RESUMO

The possibility of an acquired platelet function disorder should be considered in patients who present with recent onset muco-cutaneous bleeding. Despite the availability of newer and faster platelet function assays, light transmission aggregometry (LTA) remains the preferred diagnostic test. This review examines and discusses the causes of acquired platelet dysfunction; most commonly drugs, dietary factors, medical disorders and procedures. In addition to well-known antiplatelet therapies, clinicians should be alert for newer drugs which can affect platelets, such as ibrutinib. There is little clinical trial evidence to guide the management of acquired platelet function defects, but we summarise commonly employed strategies, which include addressing the underlying cause, antifibrinolytic agents, desmopressin infusions, and in selected patients, platelet transfusions.


Assuntos
Transtornos Plaquetários , Agregação Plaquetária , Transtornos Plaquetários/diagnóstico , Plaquetas , Humanos , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Testes de Função Plaquetária , Transfusão de Plaquetas
8.
Bioinformatics ; 36(8): 2587-2588, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31841127

RESUMO

MOTIVATION: High throughput next generation sequencing (NGS) has become exceedingly cheap, facilitating studies to be undertaken containing large sample numbers. Quality control (QC) is an essential stage during analytic pipelines and the outputs of popular bioinformatics tools such as FastQC and Picard can provide information on individual samples. Although these tools provide considerable power when carrying out QC, large sample numbers can make inspection of all samples and identification of systemic bias a challenge. RESULTS: We present ngsReports, an R package designed for the management and visualization of NGS reports from within an R environment. The available methods allow direct import into R of FastQC reports along with outputs from other tools. Visualization can be carried out across many samples using default, highly customizable plots with options to perform hierarchical clustering to quickly identify outlier libraries. Moreover, these can be displayed in an interactive shiny app or HTML report for ease of analysis. AVAILABILITY AND IMPLEMENTATION: The ngsReports package is available on Bioconductor and the GUI shiny app is available at https://github.com/UofABioinformaticsHub/shinyNgsreports. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Software , Viés , Controle de Qualidade
9.
Res Pract Thromb Haemost ; 3(3): 429-430, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31294332
10.
Res Pract Thromb Haemost ; 3(3): 431-497, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31294333

RESUMO

The 27th Congress of the International Society of Thrombosis and Haemostasis (ISTH) is an international conference held July 6-10, 2019, in Melbourne, the capital of the state of Victoria, Australia. The ISTH congress has previously been held every other year, with the Scientific and Standardization Committee (SSC) meeting held annually, until 2019 when it became one combined annual meeting of the ISTH and SSC. The conference covers clinical and basic aspects of hemostasis and thrombosis, and this year includes 5 Plenary lectures and >50 State of Art (SOA) lectures, presented by internationally recognized speakers, as well as numerous oral session and poster presentations selected from submitted abstracts, including many early career and reach the world support recipients. This SOA review article in RPTH contains concise Illustrated Review Articles or 'Capsules' consisting of short text, three references and a figure, with topics including stroke, cancer-associated thrombosis, hemophilia, coagulation, the interface between infection and inflammation, and in the experimental and discovery areas, megakaryocyte biology and platelet production, structure-function of key receptors and coagulation factors, and emerging new roles for thrombotic/hemostatic factors. Together, these articles highlight novel findings which will advance knowledge and with the potential to change clinical practice and improve outcomes. It is hoped that conference attendees and followers will enjoy utilizing the images for ongoing education and during the conference for live tweeting during sessions, to assist in the broadcasting and promotion of the science to those unable to attend, or who have chosen to attend a concurrent session. Use #IllustratedReview and #ISTH2019 on social media.

11.
Insect Mol Biol ; 28(6): 873-886, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31150140

RESUMO

Bactrocera tryoni (Queensland fruit fly) are polyphagous horticultural pests of eastern Australia. Heterogametic males contain a sex-determining Y-chromosome thought to be gene poor and repetitive. Here, we report 39 Y-chromosome scaffolds (~700 kb) from B. tryoni identified using genotype-by-sequencing data and whole-genome resequencing. Male diagnostic PCR assays validated eight Y-scaffolds, and one (Btry4096) contained a novel gene with five exons that encode a predicted 575 amino acid protein. The Y-gene, referred to as typo-gyf, is a truncated Y-chromosome paralogue of X-chromosome gene gyf (1773 aa). The Y-chromosome contained ~41 copies of typo-gyf, and expression occurred in male flies and embryos. Analysis of 13 tephritid transcriptomes confirmed typo-gyf expression in six additional Bactrocera species, including Bactrocera latifrons, Bactrocera dorsalis and Bactrocera zonata. Molecular dating estimated typo-gyf evolved within the past 8.02 million years (95% highest posterior density 10.56-5.52 million years), after the split with Bactrocera oleae. Phylogenetic analysis also highlighted complex evolutionary histories among several Bactrocera species, as discordant nuclear (116 genes) and mitochondrial (13 genes) topologies were observed. B. tryoni Y-sequences may provide useful sites for future transgene insertions, and typo-gyf could act as a Y-chromosome diagnostic marker for many Bactrocera species, although its function is unknown.


Assuntos
Cromossomos de Insetos/genética , Proteínas de Insetos/genética , Tephritidae/genética , Sequência de Aminoácidos , Animais , Feminino , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Masculino , Filogenia , Alinhamento de Sequência
12.
Med J Aust ; 210(11): 509-516, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31155728

RESUMO

INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder that occurs following the administration of heparin and is caused by antibodies to platelet factor 4 and heparin. Diagnosis of HIT is essential to guide treatment strategies using non-heparin anticoagulants and to avoid unwanted and potential fatal thromboembolic complications. This consensus statement, formulated by members of the Thrombosis and Haemostasis Society of Australia and New Zealand, provides an update on HIT pathogenesis and guidance on the diagnosis and management of patients with suspected or confirmed HIT. MAIN RECOMMENDATIONS: A 4Ts score is recommended for all patients with suspected HIT prior to laboratory testing. Further laboratory testing with a screening immunoassay or confirmatory functional assay is not recommended in individuals with a low 4Ts score. However, if there are missing or unreliable clinical data, then laboratory testing should be performed. A positive functional assay result confirms the diagnosis of HIT and should be performed to confirm a positive immunoassay result. Heparin exposure must be ceased in patients with suspected or confirmed HIT and initial treatment with a non-heparin alternative instituted. Non-heparin anticoagulants (danaparoid, argatroban, fondaparinux and bivalirudin) used to treat HIT should be given in therapeutic rather than prophylactic doses. Direct oral anticoagulants may be used in place of warfarin after patients with HIT have responded to alternative parenteral anticoagulants with platelet count recovery. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: These are the first Australasian recommendations for diagnosis and management of HIT, with a focus on locally available diagnostic assays and therapeutic options. The importance of examining both clinical and laboratory data in considering a diagnosis of HIT cannot be overstated.


Assuntos
Anticoagulantes/efeitos adversos , Heparina/efeitos adversos , Trombocitopenia/diagnóstico , Trombocitopenia/tratamento farmacológico , Anticoagulantes/uso terapêutico , Austrália , Consenso , Hemorragia/induzido quimicamente , Heparina/imunologia , Humanos , Nova Zelândia , Fator Plaquetário 4/imunologia , Receptores de IgG/imunologia , Trombocitopenia/induzido quimicamente , Trombose/etiologia
13.
Genome Biol Evol ; 10(11): 2973-2985, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30321345

RESUMO

Cryptic species are genetically distinct taxa without obvious variation in morphology and are occasionally discovered using molecular or sequence data sets of populations previously thought to be a single species. The world-wide Brassica pest, Plutella xylostella (diamondback moth), has been a problematic insect in Australia since 1882, yet a morphologically cryptic species with apparent endemism (P. australiana) was only recognized in 2013. Plutella xylostella and P. australiana are able to hybridize under laboratory conditions, and it was unknown whether introgression of adaptive traits could occur in the field to improve fitness and potentially increase pressure on agriculture. Phylogenetic reconstruction of 29 nuclear genomes confirmed P. xylostella and P. australiana are divergent, and molecular dating with 13 mitochondrial genes estimated a common Plutella ancestor 1.96 ± 0.175 Ma. Sympatric Australian populations and allopatric Hawaiian P. xylostella populations were used to test whether neutral or adaptive introgression had occurred between the two Australian species. We used three approaches to test for genomic admixture in empirical and simulated data sets including 1) the f3 statistic at the level of the population, 2) pairwise comparisons of Nei's absolute genetic divergence (dXY) between populations, and 3) changes in phylogenetic branch lengths between individuals across 50-kb genomic windows. These complementary approaches all supported reproductive isolation of the Plutella species in Australia, despite their ability to hybridize. Finally, we highlight the most divergent genomic regions between the two cryptic Plutella species and find they contain genes involved with processes including digestion, detoxification, and DNA binding.


Assuntos
Mariposas/genética , Isolamento Reprodutivo , Animais , Genoma de Inseto , Genoma Mitocondrial , Hibridização Genética , Filogenia , Comportamento Sexual Animal
14.
Res Pract Thromb Haemost ; 2(1): 125-138, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30046713

RESUMO

BACKGROUND: N-methyl-d-aspartate receptors (NMDARs) contribute calcium influx in megakaryocytic cells but their roles remain unclear; both pro- and anti-differentiating effects have been shown in different contexts. OBJECTIVES: The aim of this study was to clarify NMDAR contribution to megakaryocytic differentiation in both normal and leukemic cells. METHODS: Meg-01, Set-2, and K-562 leukemic cell lines were differentiated using phorbol-12-myristate-13-acetate (PMA, 10 nmol L-1) or valproic acid (VPA, 500 µmol L-1). Normal megakaryocytes were grown from mouse marrow-derived hematopoietic progenitors (lineage-negative and CD41a-enriched) in the presence of thrombopoietin (30-40 nmol L-1). Marrow explants were used to monitor proplatelet formation in the native bone marrow milieu. In all culture systems, NMDARs were inhibited using memantine and MK-801 (100 µmol L-1); their effects compared against appropriate controls. RESULTS: The most striking observation from our studies was that NMDAR antagonists markedly inhibited proplatelet formation in all primary cultures employed. Proplatelets were either absent (in the presence of memantine) or short, broad and intertwined (with MK-801). Earlier steps of megakaryocytic differentiation (acquisition of CD41a and nuclear ploidy) were maintained, albeit reduced. In contrast, in leukemic Meg-01 cells, NMDAR antagonists inhibited differentiation in the presence of PMA and VPA but induced differentiation when applied by themselves. CONCLUSIONS: NMDAR-mediated calcium influx is required for normal megakaryocytic differentiation, in particular proplatelet formation. However, in leukemic cells, the main NMDAR role is to inhibit differentiation, suggesting diversion of NMDAR activity to support leukemia growth. Further elucidation of the NMDAR and calcium pathways in megakaryocytic cells may suggest novel ways to modulate abnormal megakaryopoiesis.

15.
BMC Evol Biol ; 18(1): 77, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29843598

RESUMO

BACKGROUND: Understanding genomic and phenotypic diversity among cryptic pest taxa has important implications for the management of pests and diseases. The diamondback moth, Plutella xylostella L., has been intensively studied due to its ability to evolve insecticide resistance and status as the world's most destructive pest of brassicaceous crops. The surprise discovery of a cryptic species endemic to Australia, Plutella australiana Landry & Hebert, raised questions regarding the distribution, ecological traits and pest status of the two species, the capacity for gene flow and whether specific management was required. Here, we collected Plutella from wild and cultivated brassicaceous plants from 75 locations throughout Australia and screened 1447 individuals to identify mtDNA lineages and Wolbachia infections. We genotyped genome-wide SNP markers using RADseq in coexisting populations of each species. In addition, we assessed reproductive compatibility in crossing experiments and insecticide susceptibility phenotypes using bioassays. RESULTS: The two Plutella species coexisted on wild brassicas and canola crops, but only 10% of Plutella individuals were P. australiana. This species was not found on commercial Brassica vegetable crops, which are routinely sprayed with insecticides. Bioassays found that P. australiana was 19-306 fold more susceptible to four commonly-used insecticides than P. xylostella. Laboratory crosses revealed that reproductive isolation was incomplete but directionally asymmetric between the species. However, genome-wide nuclear SNPs revealed striking differences in genetic diversity and strong population structure between coexisting wild populations of each species. Nuclear diversity was 1.5-fold higher in P. australiana, yet both species showed limited variation in mtDNA. Infection with a single Wolbachia subgroup B strain was fixed in P. australiana, suggesting that a selective sweep contributed to low mtDNA diversity, while a subgroup A strain infected just 1.5% of P. xylostella. CONCLUSIONS: Despite sympatric distributions and the capacity to hybridize, strong genomic and phenotypic divergence exists between these Plutella species that is consistent with contrasting colonization histories and reproductive isolation after secondary contact. Although P. australiana is a potential pest of brassicaceous crops, it is of secondary importance to P. xylostella.


Assuntos
Variação Genética , Hibridização Genética , Mariposas/genética , Animais , Austrália , Bioensaio , Cruzamentos Genéticos , DNA Mitocondrial/genética , Feminino , Fertilidade , Genética Populacional , Geografia , Haplótipos/genética , Heterozigoto , Hibridização Genética/efeitos dos fármacos , Resistência a Inseticidas/efeitos dos fármacos , Resistência a Inseticidas/genética , Inseticidas/toxicidade , Funções Verossimilhança , Masculino , Mitocôndrias/genética , Mariposas/microbiologia , Filogenia , Especificidade da Espécie , Simpatria , Wolbachia/efeitos dos fármacos , Wolbachia/fisiologia
16.
J Invest Dermatol ; 138(3): 511-519, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29106928

RESUMO

Epithelial-to-mesenchymal transition (EMT) is critical for embryonic development and wound healing, and occurs in fibrotic disease and carcinoma. Here, we show that EMT also occurs within the bulge, the epithelial stem cell (eSC) niche of human scalp hair follicles, during the inflammatory permanent alopecia, lichen planopilaris. We show that a molecular EMT signature can be experimentally induced in healthy human eSCs in situ by antagonizing E-cadherin, combined with transforming growth factor-ß1, epidermal growth factor, and IFN-γ administration, which to our knowledge has not been reported previously. Moreover, induction of EMT within primary human eSCs can be prevented and even partially reversed ex vivo by peroxisome proliferator-activated receptor-γ agonists, likely through suppression of the transforming growth factor-ß signaling pathway. Furthermore, we show that peroxisome proliferator-activated receptor-γ agonists also attenuates the EMT signature even in lesional lichen planopilaris hair follicles ex vivo. We introduce lichen planopilaris as a model disease for pathological EMT in human adult eSCs, report a preclinical assay for therapeutically manipulating eSC EMT within a healthy human (mini-)organ, and show that peroxisome proliferator-activated receptor-γ agonists are promising agents for suppressing and partially reversing EMT in human hair follicles eSCs ex vivo, including in lichen planopilaris.


Assuntos
Transição Epitelial-Mesenquimal , Líquen Plano/patologia , Células-Tronco Mesenquimais/patologia , Adulto , Idoso , Células Cultivadas , Feminino , Humanos , Queratina-15/análise , PPAR gama/fisiologia , Peroxissomos/efeitos dos fármacos , Pioglitazona/farmacologia , Nicho de Células-Tronco
17.
Platelets ; 29(8): 793-800, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29090586

RESUMO

MYH9-related disorders (MYH9-RDs) caused by mutation of the MYH9 gene which encodes non-muscle myosin heavy-chain-IIA (NMMHC-IIA), an important motor protein in hemopoietic cells, are the most commonly encountered cause of inherited macrothrombocytopenia. Despite distinguishing features including an autosomal dominant mode of inheritance, giant platelets on the peripheral blood film accompanied by leucocytes with cytoplasmic inclusion bodies (döhle-like bodies), these disorders remain generally under-recognized and often misdiagnosed as immune thrombocytopenia (ITP). This may result in inappropriate treatment with corticosteroids, immunosupressants and in some cases, splenectomy. We explored the efficacy of next generation sequencing (NGS) with a candidate gene panel to establish the aetiology of thrombocytopenia for individuals who had been referred to our center from hematologists in the Australasian region in whom the cause of thrombocytopenia was suspected to be secondary to an inherited condition but which remained uncharacterized despite phenotypic investigations. Pathogenic MYH9 variants were detected in 15 (15/121, 12.4%) individuals and the pathogenecity of a novel variant of uncertain significance was confirmed in a further two related individuals following immunofluorescence (IF) staining performed in our laboratory. Concerningly, only one (1/17) individual diagnosed with MYH9-RD had been referred with this as a presumptive diagnosis, in all other cases (16/17, 94.1%), a diagnosis was not suspected by referring clinicians, indicating a lack of awareness or a failing of our diagnostic approach to these conditions. We examined the mean platelet diameter (MPD) measurements as a means to better identify and quantify platelet size. MPDs in cases with MYH9-RDs were significantly larger than controls (p < 0.001) and in 91% were greater than a previously suggested threshold for platelets in cases of ITP. In addition, we undertook IF staining in a proportion of cases and confirm that this test and/or NGS are satisfactory diagnostic tests. We propose that fewer cases of MYH9-RDs would be missed if diagnostic algorithms prioritized IF and/or NGS in cases of thrombocytopenia associated with giant platelets, even if döhle-like bodies are not appreciated on the peripheral blood film. Finally, our report describes the long-term use of a thrombopoietin agonist in a case of MYH9-RD that had previously been diagnosed as ITP, and demonstrates that treatment with these agents may be possible, and is well tolerated, in this group of patients.


Assuntos
Plaquetas/metabolismo , Perda Auditiva Neurossensorial/genética , Mutação , Cadeias Pesadas de Miosina/genética , Púrpura Trombocitopênica Idiopática/genética , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombocitopenia/congênito , Trombopoetina/uso terapêutico , Adulto , Australásia , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Tamanho Celular , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Genes Dominantes , Perda Auditiva Neurossensorial/sangue , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Corpos de Inclusão/efeitos dos fármacos , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Masculino , Volume Plaquetário Médio , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/sangue , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Trombocitopenia/tratamento farmacológico , Trombocitopenia/genética
18.
PLoS One ; 12(12): e0187449, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29216196

RESUMO

Oral squamous cell carcinoma (OSCC) is a highly aggressive cancer that is associated with poor 5-year patient survival. Disease treatment is further compounded by the difficulty in predicting pre-cancerous tissues that will progress to OSCC and the high recurrence rates following surgical resection. Here we have assessed expression of the oral epithelial markers E-cadherin, EMP1 and 5T4 and the pro-invasive N-cadherin proteins using fully characterised antibodies and quantitative immunofluorescence microscopy in normal tissue (NT), fibroepithelial polyp (FEP), low-grade dysplasia (LGD), high-grade dysplasia (HGD), T1 OSCC and T4 OSCC biopsies. Decreased E-cadherin expression was associated with FEP, LGD and HGD biopsies, demonstrating that loss of E-cadherin is an early event within abnormal epithelium and occurs in the absence of an E- to N-cadherin switch, the latter of which was only observed in T4 OSCC. Furthermore, loss of E-cadherin and EMP1 is an indicator of LGD (p = 0.0006) and loss of E-cadherin, EMP1 and 5T4 an indicator of HGD (p = 0.0006). Expression patterns of E-cadherin, EMP1 and N-cadherin could predict abnormal epithelium in LGD, HGD, T1 and T4 OSCC biopsies (z-value = 0 for all disease grades) and allowed classification of LGD (z = 1.47), HGD (z = 2.138), T1 (z = 1.05) and T4 OSCC (z = 1.49) biopsies. Therefore, these markers provide a useful means to predict abnormal epithelium in patient biopsies. Linear regression and coefficient of determination analysis revealed positive correlation with a NT>LGD>HGD disease transition but low correlation with a putative HGD>T1 OSCC>T4 OSCC disease transition. Furthermore, expression of E-cadherin, EMP1, 5T4 and N-cadherin in pathologically normal surgical safety margins of LGD, HGD and T1 OSCC patient biopsies revealed significant differences to NT and the use of safety margins or FEP as 'normal tissue' controls introduced Type II errors in all patient cohorts. This work forms the basis for further investigation of the role of E-cadherin loss in abnormal epithelium and in the development of automated analyses for use in cancer diagnostics.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Mucosa Bucal/metabolismo , Neoplasias Bucais/metabolismo , Lesões Pré-Cancerosas/metabolismo , Biópsia , Carcinoma de Células Escamosas/patologia , Humanos , Neoplasias Bucais/patologia
19.
Genome Announc ; 5(43)2017 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-29074653

RESUMO

Wolbachia spp. are endosymbiotic bacteria that infect around 50% of arthropods and cause a broad range of effects, including manipulating host reproduction. Here, we present the annotated draft genome assembly of Wolbachia strain wAus, which infects Plutella australiana, a cryptic ally of the major Brassica pest Plutella xylostella (diamondback moth).

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