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1.
Int J Cancer ; 2020 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-31957002

RESUMO

Triple-negative breast cancer (TNBC) represents 10-20% of all human ductal adenocarcinomas and has a poor prognosis relative to other subtypes, due to the high propensity to develop distant metastases. Hence, new molecular targets for therapeutic intervention are needed for TNBC. We recently conducted a rigorous phenotypic and genomic characterization of four isogenic populations of MDA-MB-231 human triple-negative breast cancer cells that possess a range of intrinsic spontaneous metastatic capacities in vivo, ranging from non-metastatic (MDA-MB-231_ATCC) to highly metastatic to lung, liver, spleen and spine (MDA-MB-231_HM). Gene expression profiling of primary tumours by RNA-Seq identified the fibroblast growth factor homologous factor, FGF13, as highly upregulated in aggressively metastatic MDA-MB-231_HM tumours. Clinically, higher FGF13 mRNA expression was associated with significantly worse relapse free survival in both luminal A and basal-like human breast cancers but was not associated with other clinical variables and was not upregulated in primary tumours relative to normal mammary gland. Stable FGF13 depletion restricted in vitro colony forming ability in MDA-MB-231_HM TNBC cells but not in oestrogen receptor (ER) positive MCF-7 or MDA-MB-361 cells. However, despite augmenting MDA-MB-231_HM cell migration and invasion in vitro, FGF13 suppression almost completely blocked the spontaneous metastasis of MDA-MB-231_HM orthotopic xenografts to both lung and liver while having negligible impact on primary tumour growth. Together, these data indicate that FGF13 may represent a therapeutic target for blocking metastatic outgrowth of certain TNBCs. Further evaluation of the roles of individual FGF13 protein isoforms in progression of the different subtypes of breast cancer is warranted. This article is protected by copyright. All rights reserved.

3.
Platelets ; 31(1): 1-2, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31790625
4.
Mol Psychiatry ; 25(1): 37-47, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31695164

RESUMO

RNA splicing is a key mechanism linking genetic variation with psychiatric disorders. Splicing profiles are particularly diverse in brain and difficult to accurately identify and quantify. We developed a new approach to address this challenge, combining long-range PCR and nanopore sequencing with a novel bioinformatics pipeline. We identify the full-length coding transcripts of CACNA1C in human brain. CACNA1C is a psychiatric risk gene that encodes the voltage-gated calcium channel CaV1.2. We show that CACNA1C's transcript profile is substantially more complex than appreciated, identifying 38 novel exons and 241 novel transcripts. Importantly, many of the novel variants are abundant, and predicted to encode channels with altered function. The splicing profile varies between brain regions, especially in cerebellum. We demonstrate that human transcript diversity (and thereby protein isoform diversity) remains under-characterised, and provide a feasible and cost-effective methodology to address this. A detailed understanding of isoform diversity will be essential for the translation of psychiatric genomic findings into pathophysiological insights and novel psychopharmacological targets.

5.
Mol Psychiatry ; 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801967

RESUMO

Calcium signalling has long been implicated in bipolar disorder, especially by reports of altered intracellular calcium ion concentrations ([Ca2+]). However, the evidence has not been appraised critically. We carried out a systematic review and meta-analysis of studies of cellular calcium indices in bipolar disorder. 2281 records were identified and 117 screened, of which 32 were eligible and 21 were suitable for meta-analyses. The latter each involved up to 642 patients and 404 control subjects. We found that basal free intracellular [Ca2+] is increased in bipolar disorder, both in platelets and in lymphocytes. The effect size is 0.55, with an estimated elevation of 29%. It is observed in medication-free patients. It is present in mania and bipolar depression, but data are equivocal for euthymia. Cells from bipolar disorder individuals also show an enhanced [Ca2+] response to stimulation with 5-HT or thrombin, by an estimated 25%, with an effect size of 0.63. In studies which included other diagnoses, intracellular basal [Ca2+] was higher in bipolar disorder than in unipolar depression, but not significantly different from schizophrenia. Functional parameters of cellular Ca2+ (e.g. calcium transients), and neuronal [Ca2+], have been much less investigated, and no firm conclusions can be drawn. In summary, there is a robust, medium effect size elevation of basal and stimulated free intracellular [Ca2+] in bipolar disorder. The results suggest altered calcium functioning in the disorder, and encourage further investigations into the underlying mechanisms, and the implications for pathophysiology and therapeutics.

6.
J Thromb Haemost ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31833175

RESUMO

BACKGROUND: Platelet P2Y12 antagonist ticagrelor reduces mortality after acute myocardial infarction (AMI) compared to clopidogrel, but the underlying mechanism is unknown. Because activated platelets, leukocytes, and endothelial cells release proinflammatory and prothrombotic extracellular vesicles (EVs), we hypothesized that the release of EVs is more efficiently inhibited by ticagrelor compared to clopidogrel. OBJECTIVES: We compared EV concentrations and EV procoagulant activity in plasma of patients after AMI treated with ticagrelor or clopidogrel. METHODS: After percutaneous coronary intervention, 60 patients with first AMI were randomized to ticagrelor or clopidogrel. Flow cytometry was used to determine concentrations of EVs from activated platelets (CD61+ , CD62p+ ), fibrinogen+ , phosphatidylserine (PS+ ), leukocytes (CD45+ ), endothelial cells (CD31+ , 146+ ), and erythrocytes (CD235a+ ) in plasma at randomization, after 72 hours and 6 months of treatment. A fibrin generation test was used to determine EV procoagulant activity. RESULTS: Concentrations of platelet, fibrinogen+ , PS+ , leukocyte, and erythrocyte EVs increased 6 months after AMI compared to the acute phase of AMI (P ≤ .03). Concentrations of platelet EVs were lower on ticagrelor compared to clopidogrel after 6 months (P = .03). Concentrations of fibrinogen+ , PS+ , and leukocyte EVs were lower on ticagrelor compared to clopidogrel both after 72 hours and 6 months (P ≤ .03). Concentrations of endothelial EVs and EV procoagulant activity did not differ between patient groups and over time (P ≥ .17). CONCLUSIONS: Ticagrelor attenuates the increase of EV concentrations in plasma after acute myocardial infarction compared to clopidogrel. The ongoing release of EVs despite antiplatelet therapy might explain recurrent thrombotic events after AMI and worse clinical outcomes on clopidogrel compared to ticagrelor.

7.
BMJ ; 367: l6132, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748208

RESUMO

OBJECTIVE: To determine whether an injection of platelet rich plasma improves outcomes after acute Achilles tendon rupture. DESIGN: Randomised, placebo controlled, two arm, parallel group, participant and assessor masked, superiority trial. SETTING: Secondary care trauma units across 19 hospitals in the United Kingdom's health service. PARTICIPANTS: Recruitment commenced in July 2015 and follow-up was completed in March 2018. 230 adults aged 18 years and over were included, with acute Achilles tendon rupture presenting within 12 days of injury and managed with non-surgical treatment. Exclusions were injury at the insertion or musculotendinous junction, major leg injury or deformity, diabetes mellitus, platelet or haematological disorder, systemic corticosteroids, anticoagulation treatment, and other contraindicating conditions. INTERVENTIONS: Participants were randomised 1:1 to platelet rich plasma (n=114) or placebo (dry needle; n=116) injection. All participants received standard rehabilitation care (ankle immobilisation followed by physiotherapy). MAIN OUTCOMES AND MEASURES: Primary outcome was muscle tendon function at 24 weeks, measured objectively with the limb symmetry index (injured/uninjured×100) in maximal work done during the heel rise endurance test (an instrumented measure of repeated single leg heel rises until fatigue). Secondary outcomes included patient reported function (Achilles tendon rupture score), quality of life (short form 12 version 2®), pain (visual analogue scale), goal attainment (patient specific functional scale), and adverse events. A central laboratory analysed the quality and content of platelet rich plasma. Analyses were by modified intention to treat. RESULTS: Participants were 46 years old on average, and 57 (25%) of 230 were female. At 24 weeks, 202 (88%) participants completed the heel rise endurance test and 216 (94%) the patient reported outcomes. The platelet rich plasma was of good quality, with expected growth factor content. No difference was detected in muscle tendon function between participants receiving platelet rich plasma injections and those receiving placebo injections (limb symmetry index, mean 34.7% (standard deviation 17.7%) v 38.5% (22.8%); adjusted mean difference -3.9% (95% confidence interval -10.5% to 2.7%)) or in any secondary outcomes or adverse event rates. Complier average causal effect analyses gave similar findings. CONCLUSIONS: There is no evidence to indicate that injections of platelet rich plasma can improve objective muscle tendon function, patient reported function, or quality of life after acute Achilles tendon rupture compared with placebo, or that they offer any patient benefit. TRIAL REGISTRATION: ISRCTN54992179.


Assuntos
Tendão do Calcâneo/lesões , Tratamento Conservador/métodos , Plasma Rico em Plaquetas , Qualidade de Vida , Traumatismos dos Tendões/terapia , Adulto , Feminino , Humanos , Injeções/métodos , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Recuperação de Função Fisiológica , Traumatismos dos Tendões/diagnóstico , Traumatismos dos Tendões/fisiopatologia , Traumatismos dos Tendões/psicologia , Resultado do Tratamento , Reino Unido
8.
Methods Mol Biol ; 2049: 141-164, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31602610

RESUMO

Next-generation sequencing (NGS) and its application to RNA (RNA-seq) has opened up multiple aspects of RNA processing to deep transcriptome-wide analysis at nucleotide resolution. This has been useful in delineating the transcribed areas of the genome, and in quantitation of RNA isoforms. Such isoforms can diversify the regulatory repertoire of mRNAs. For example, the 3'-end of mRNA can vary in two important ways, in the position chosen for cleavage and polyadenylation, and in the length of the poly(A)-tail. Accordingly, the step-up in resolution made possible by NGS has revealed an unexpectedly high level of alternative polyadenylation (APA). Moreover, it has massively simplified the transcriptome-wide detection of poly(A)-tail length changes. Here we present our approach to the study of 3'-end dynamics using a 3'-focused RNA-seq method called PAT-seq (for poly(A)-test sequencing). The approach records gene expression, APA, and poly(A)-tail changes between transcriptomes to reveal complex interplay between transcriptional and posttranscriptional control mechanisms.

9.
Haematologica ; 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467123

RESUMO

Interactions between platelets, leukocytes and the vessel wall provide alternative pathological routes of thrombo-inflammatory leukocyte recruitment. We found that when platelets were activated by a range of agonists in whole blood, they shed platelet-derived extracellular vesicle which rapidly and preferentially bound to blood monocytes compared to other leukocytes. Platelet-derived extracellular vesicle binding to monocytes was initiated by P-selectin-dependent adhesion and was stabilised by binding of phosphatidylserine. These interactions resulted in the progressive transfer of the platelet adhesion receptor GPIbα to the monocytes. GPIbα+-monocytes tethered and rolled on immobilised von Willebrand Factor or were recruited and activated on endothelial cells treated with TGF-ß1 to induce the expression of von Willebrand Factor. In both models monocyte adhesion was ablated by a function-blocking antibody against GPIbα. Monocytes could also bind platelet-derived extracellular vesicle in mouse blood in vitro and in vivo. Intratracheal instillations of diesel nanoparticles, to model chronic pulmonary inflammation, induced accumulation of GPIbα on circulating monocytes. In intravital experiments, GPIbα+-monocytes adhered to the microcirculation of the TGF-ß1-stimulated cremaster muscle, while in the ApoE knockout model of atherosclerosis, GPIbα+-monocytes adhered to the carotid arteries. In trauma patients, monocytes bore platelet markers within 1 hour of injury, the levels of which correlated with severity of trauma and resulted in monocyte clearance from the circulation. Thus, we have defined a novel thrombo-inflammatory pathway in which platelet-derived extracellular vesicle transfer a platelet adhesion receptor to monocytes, allowing their recruitment in large and small blood vessels, and which is likely to be pathogenic.

10.
Proteomics ; 19(15): e1970134, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31368634
12.
Biol Psychiatry ; 86(8): 608-620, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31303260

RESUMO

BACKGROUND: Many polymorphisms in dopamine genes are reported to affect cognitive, imaging, or clinical phenotypes. It is often inferred or assumed that such associations are causal, mediated by a direct effect of the polymorphism on the gene product itself. However, the supporting evidence is not always clear. METHODS: We conducted systematic reviews and meta-analyses to assess the empirical evidence for functional polymorphisms in genes encoding dopaminergic enzymes (COMT, DBH, DDC, MAOA, MAOB, and TH), dopamine receptors (DRD1, DRD2, DRD3, DRD4, and DRD5), the dopamine transporter (DAT), and vesicular transporters (VMAT1 and VMAT2). We defined functionality as an effect of the polymorphism on the expression, abundance, activity, or affinity of the gene product. RESULTS: We screened 22,728 articles and identified 255 eligible studies. We found robust and medium to large effects for polymorphisms in 4 genes. For catechol-O-methyltransferase (COMT), the Val158Met polymorphism (rs4680) markedly affected enzyme activity, protein abundance, and protein stability. Dopamine ß-hydroxylase (DBH) activity was associated with rs1611115, rs2519152, and the DBH-STR polymorphism. Monoamine oxidase A (MAOA) activity was associated with a 5' VNTR polymorphism. Dopamine D2 receptor (DRD2) binding was influenced by the Taq1A (rs1800497) polymorphism, and rs1076560 affected DRD2 splicing. CONCLUSIONS: Some widely studied dopaminergic polymorphisms clearly and substantially affect the abundance or activity of the encoded gene product. However, for other polymorphisms, evidence of such an association is negative, inconclusive, or lacking. These findings are relevant when selecting polymorphisms as "markers" of dopamine function, and for interpreting the biological plausibility of associations between these polymorphisms and aspects of brain function or dysfunction.

13.
J Psychopharmacol ; 33(10): 1264-1273, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31294651

RESUMO

BACKGROUND: Virtual reality (VR) is increasingly used to study and treat psychiatric disorders. Its fidelity depends in part on the extent to which the VR environment provides a convincing simulation, for example whether a putatively stressful VR situation actually produces a stress response. METHODS: We studied the stress response in 28 healthy men exposed either to a stressor VR elevator (which simulated travelling up the outside of a tall building and culminated in the participant being asked to step off the elevator platform), or to a control elevator. We measured psychological and physiological (salivary cortisol and alpha-amylase, blood pressure, pulse, skin conductance) stress indices. We also measured subsequent performance on the N-back task because acute stress has been reported to impact on working memory. RESULTS: Compared to participants in the control elevator, those in the external elevator had increases in skin conductance, pulse and subjective stress and anxiety ratings, altered heart rate variability, and a delayed rise in cortisol. N-back performance was unaffected. CONCLUSIONS: A putatively stressful VR elevator produces a physiological as well as a psychological stress response, supporting its use in the investigation and treatment of stress-related disorders, and its potential value as an experimental laboratory stressor.

14.
Am J Surg ; 218(3): 579-583, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31284948

RESUMO

BACKGROUND: Multi-detector computed tomography imaging is now the reference standard for identifying solid organ injuries, with a high sensitivity and specificity. However, delayed splenic hemorrhage (DSH), defined as no identified injury to the spleen on the index scan but delayed bleeding from a splenic injury, has been reported. We hypothesized that the occurrence of DSH would be minimized by utilization of modern imaging techniques. METHODS: Data was retrospectively collected from 2006 to 2016 in 12 adult Level I and II trauma centers. All patients had an initial CT scan demonstrating no splenic injury but subsequently were diagnosed with splenic bleeding. Demographic, injury characteristics, imaging parameters and results, interventions and outcomes were collected. RESULTS: Of 6867 patients with splenic injuries, 32 cases (0.4%) of blunt splenic hemorrage were identified. Patients were primarily male, had blunt trauma, severely injured (ISS 32 (9-57) and with associated injuries. Injuries of all grades were identified up to 16 days following admission. Overall, half of patients required splenectomy. All index images were obtained using multi-detector CT (16-320 slice). Secondary review of imaging by two trauma radiologists judged 72% (n = 23) of scans as suboptimal. This was due to poor scan quality primary from artifact(23), single phase contrast imaging (16), and/or poor contrast bolus timing or volume (6). Notably, only 28% of scans in patients with DSH were performed with optimal scanning techniques. CONCLUSION: This is the largest reported series of DSH in the era of modern imaging. Although the incidence of DSH is low, it still occurs despite the use of multi-detector imaging and when present, is associated with a high rate of splenectomy. Most cases of DSH can be attributed to missed diagnosis from suboptimal index imaging and ultimately be avoided.


Assuntos
Hemorragia/etiologia , Baço/diagnóstico por imagem , Baço/lesões , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Idoso , Feminino , Hemorragia/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Adulto Jovem
15.
Front Mol Biosci ; 6: 54, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355208

RESUMO

Prions in eukaryotes have been linked to diseases, evolutionary capacitance, large-scale genetic control, and long-term memory formation. Prion formation and propagation have been studied extensively in the budding yeast Saccharomyces cerevisiae. Here, we have analysed the conservation of sequence and of prion-like composition for prion-forming proteins and for other prion-like proteins from S. cerevisiae, across three evolutionary levels. We discover that prion-like status is well-conserved for about half the set of prion-formers at the Saccharomycetes level, and that prion-forming domains evolve more quickly as sequences than other prion-like domains do. Such increased mutation rates may be linked to the acquisition of functional roles for prion-forming domains during the evolutionary epoch of Saccharomycetes. Domain scores for prion-like composition in S. cerevisiae are strongly correlated with scores for such composition weighted evolutionarily over the dozens of fungal species examined, indicating conservation of such prion-like status. Examples of notable prion-like proteins that are highly conserved both in sequence and prion-like composition are discussed.

16.
Mol Psychiatry ; 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31168069

RESUMO

Genome-wide association studies (GWAS) of psychiatric phenotypes have tended to focus on categorical diagnoses, but to understand the biology of mental illness it may be more useful to study traits which cut across traditional boundaries. Here, we report the results of a GWAS of mood instability as a trait in a large population cohort (UK Biobank, n = 363,705). We also assess the clinical and biological relevance of the findings, including whether genetic associations show enrichment for nervous system pathways. Forty six unique loci associated with mood instability were identified with a SNP heritability estimate of 9%. Linkage Disequilibrium Score Regression (LDSR) analyses identified genetic correlations with Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizophrenia, anxiety, and Post Traumatic Stress Disorder (PTSD). Gene-level and gene set analyses identified 244 significant genes and 6 enriched gene sets. Tissue expression analysis of the SNP-level data found enrichment in multiple brain regions, and eQTL analyses highlighted an inversion on chromosome 17 plus two brain-specific eQTLs. In addition, we used a Phenotype Linkage Network (PLN) analysis and community analysis to assess for enrichment of nervous system gene sets using mouse orthologue databases. The PLN analysis found enrichment in nervous system PLNs for a community containing serotonin and melatonin receptors. In summary, this work has identified novel loci, tissues and gene sets contributing to mood instability. These findings may be relevant for the identification of novel trans-diagnostic drug targets and could help to inform future stratified medicine innovations in mental health.

17.
Br J Psychiatry ; : 1-4, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31230606

RESUMO

SummaryWe reappraise the psychiatric potential of calcium channel blockers (CCBs). First, voltage-gated calcium channels are risk genes for several disorders. Second, use of CCBs is associated with altered psychiatric risks and outcomes. Third, research shows there is an opportunity for brain-selective CCBs, which are better suited to psychiatric indications.Declaration of interestE.M.T. and P.J.H. hold an unrestricted educational grant from Johnson & Johnson to work on the molecular neurobiology of calcium channels.

18.
Can J Psychiatry ; 64(10): 686-696, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31129983

RESUMO

OBJECTIVE: Nightmares are relatively common in patients experiencing psychosis but rarely assessed or treated. Nightmares may maintain persecutory delusions by portraying fears in sensory-rich detail. We tested the potential benefits of imagery-focused cognitive behavioural therapy (CBT) for nightmares on nightmare severity and persecutory delusions. METHOD: This assessor-blind parallel-group pilot trial randomized 24 participants with nightmares and persecutory delusions to receive CBT for nightmares delivered over 4 weeks in addition to treatment as usual (TAU) or TAU alone. Assessments were at 0, 4 (end of treatment), and 8 weeks (follow-up). Feasibility outcomes assessed therapy uptake, techniques used, satisfaction, and attrition. The primary efficacy outcome assessed nightmare severity at week 4. Analyses were intention to treat, estimating treatment effect with 95% confidence intervals (CIs). RESULTS: All participants offered CBT completed therapy (mean [SD], 4.8 [0.6] sessions) with high satisfaction, and 20 (83%) participants completed all assessments. Compared with TAU, CBT led to large improvements in nightmares (adjusted mean difference = -7.0; 95% CI, -12.6 to -1.3; d = -1.1) and insomnia (6.3; 95% CI, 2.6 to 10.0; d = 1.4) at week 4. Gains were maintained at follow-up. Suicidal ideation was not exacerbated by CBT but remained stable to follow-up, compared with TAU, which reduced at follow-up (6.8; 95% CI, 0.3 to 3.3; d = 0.7). CBT led to reductions in paranoia (-20.8; 95% CI, -43.2 to 1.7; d = -0.6), although CIs were wide. Three serious adverse events were deemed unrelated to participation (CBT = 2, TAU = 1). CONCLUSIONS: CBT for nightmares is feasible and may be efficacious for treating nightmares and comorbid insomnia for patients with persecutory delusions. It shows promise on paranoia but potentially not on suicidal ideation.

19.
Front Immunol ; 10: 685, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31001279

RESUMO

Major traumatic injury induces significant remodeling of the circulating neutrophil pool and loss of bactericidal function. Although a well-described phenomenon, research to date has only analyzed blood samples acquired post-hospital admission, and the mechanisms that initiate compromised neutrophil function post-injury are therefore poorly understood. Here, we analyzed pre-hospital blood samples acquired from 62 adult trauma patients (mean age 44 years, range 19-95 years) within 1 h of injury (mean time to sample 39 min, range 13-59 min). We found an immediate impairment in neutrophil extracellular trap (NET) generation in response to phorbol 12-myristate 13-acetate (PMA) stimulation, which persisted into the acute post-injury phase (4-72 h). Reduced NET generation was accompanied by reduced reactive oxygen species production, impaired activation of mitogen-activated protein kinases, and a reduction in neutrophil glucose uptake and metabolism to lactate. Pre-treating neutrophils from healthy subjects with mitochondrial-derived damage-associated molecular patterns (mtDAMPs), whose circulating levels were significantly increased in our trauma patients, reduced NET generation. This mtDAMP-induced impairment in NET formation was associated with an N-formyl peptide mediated activation of AMP-activated protein kinase (AMPK), a negative regulator of aerobic glycolysis and NET formation. Indeed, activation of AMPK via treatment with the AMP-mimetic AICAR significantly reduced neutrophil lactate production in response to PMA stimulation, a phenomenon that we also observed for neutrophils pre-treated with mtDAMPs. Furthermore, the impairment in NET generation induced by mtDAMPs was partially ameliorated by pre-treating neutrophils with the AMPK inhibitor compound C. Taken together, our data demonstrate an immediate trauma-induced impairment in neutrophil anti-microbial function and identify mtDAMP release as a potential initiator of acute post-injury neutrophil dysfunction.

20.
Genome Biol ; 20(1): 67, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30922379

RESUMO

Differential gene expression analysis may discover a set of genes too large to easily investigate, so a means of ranking genes by biological interest level is desired. p values are frequently abused for this purpose. As an alternative, we propose a method of ranking by confidence bounds on the log fold change, based on the previously developed TREAT test. These confidence bounds provide guaranteed false discovery rate and false coverage-statement rate control. When applied to a breast cancer dataset, the top-ranked genes by Topconfects emphasize markedly different biological processes compared to the top-ranked genes by p value.


Assuntos
Técnicas Genéticas , Software , Neoplasias da Mama/genética , Humanos
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