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1.
Psychiatry Res ; 306: 114217, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34644661

RESUMO

The COVID-19 pandemic has heightened social isolation and loneliness. There is a lack of consensus on rating scales to measure these constructs. Our objectives were to identify commonly used loneliness and social isolation scales over the last two decades and test their user characteristics. 7928 articles were searched in PubMed/MEDLINE, CINAHL, Web of Science, and APA PsychINFO databases. 41 articles were included based on study criteria. Among fourteen scales reported, UCLA 3-item loneliness scale was found to be most commonly used. The scale is specifically developed for telephone use and is the fastest taking less than a minute for self-administration.

2.
Nat Commun ; 12(1): 4919, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389725

RESUMO

BRCA1 or BRCA2 germline mutations predispose to breast, ovarian and other cancers. High-throughput sequencing of tumour genomes revealed that oncogene amplification and BRCA1/2 mutations are mutually exclusive in cancer, however the molecular mechanism underlying this incompatibility remains unknown. Here, we report that activation of ß-catenin, an oncogene of the WNT signalling pathway, inhibits proliferation of BRCA1/2-deficient cells. RNA-seq analyses revealed ß-catenin-induced discrete transcriptome alterations in BRCA2-deficient cells, including suppression of CDKN1A gene encoding the CDK inhibitor p21. This accelerates G1/S transition, triggering illegitimate origin firing and DNA damage. In addition, ß-catenin activation accelerates replication fork progression in BRCA2-deficient cells, which is critically dependent on p21 downregulation. Importantly, we find that upregulated p21 expression is essential for the survival of BRCA2-deficient cells and tumours. Thus, our work demonstrates that ß-catenin toxicity in cancer cells with compromised BRCA1/2 function is driven by transcriptional alterations that cause aberrant replication and inflict DNA damage.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Oncogenes/genética , Transcrição Genética/genética , beta Catenina/genética , Proteína BRCA1/deficiência , Proteína BRCA2/deficiência , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Dano ao DNA , Feminino , Perfilação da Expressão Gênica/métodos , Células HeLa , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , RNA-Seq/métodos , beta Catenina/metabolismo
3.
Pediatr Dev Pathol ; : 10935266211024552, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34176359

RESUMO

BACKGROUND: Diagnosis of non-esophageal eosinophilic gastrointestinal disorders requires quantification of tissue eosinophils. Our objective was to evaluate eosinophil peroxidase (EPX) immunohistochemistry (IHC) as a method for histologic diagnosis of eosinophilic gastritis (EG) and eosinophilic duodenitis (EoD). METHODS: We performed a retrospective analysis of biopsies from pediatric EG/EoD cases and controls. Subjects with EG or EoD had ≥30 eosinophils per high power field (eos/hpf) in ≥5 hpf in the stomach and/or ≥3 hpf in the duodenum, respectively. Controls had no histopathologic diagnosis recorded. Tissue eosinophil counts were assessed by hematoxylin & eosin stains. EPX stains were assessed using a unique histopathologic scoring system. Slides were digitized and EPX+ staining area/mm2 was quantified by image analysis. RESULTS: Twenty-six EG/EoD cases and 40 controls were analyzed. EPX scores and EPX/mm2 levels were markedly elevated in EG/EoD (p ≤ 0.0001). Eosinophil density (eos/mm2) correlated strongly with EPX scores and EPX/mm2 levels in the stomach (r ≥ 0.77) and moderately with EPX scores and EPX/mm2 levels in the duodenum (r ≥ 0.52); (p < 0.0001). EPX quantification identified EG/EoD subjects with high diagnostic accuracy (EPX score: AUC = 1 for EG and EoD; EPX/mm2: AUC = 0.98 (95%CI 0.96-1) for EG, AUC = 0.91 (95%CI 0.81-1) for EoD). CONCLUSION: EPX-based assessment of eosinophilic inflammation may facilitate automated histologic diagnosis.

4.
J R Coll Physicians Edinb ; 51(2): 143-145, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34131670

RESUMO

Sinusitis is a common condition, but only very rarely accompanied by isolated cranial nerve palsies. We describe a case of a 64-year-old male with a two-day history of left-sided ptosis associated with one week of nasal congestion and frontal sinus pain. Examination revealed ptosis with left pupil mydriasis. Uncontrasted computed tomography and angiography of the head demonstrated neither intracranial vascular abnormalities nor acute lesions; however, it did show mucosal thickening in the left frontal sinus, ethmoid air cells and left maxillary sinus, indicating potential obstruction of the left ostiomeatal complex. The sinusitis was treated with intranasal steroids, xylomethazoline and nasal douching. The patient reported resolution of all symptoms, including left ptosis, within one week of therapy. This rare case of sinusitis causing ptosis is presented due to its infrequent nature, such that awareness of the differential diagnosis of cranial nerve palsy and complications of sinusitis may be improved.


Assuntos
Doenças do Nervo Oculomotor , Sinusite , Doença Aguda , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Nervo Oculomotor/diagnóstico , Doenças do Nervo Oculomotor/etiologia , Sinusite/complicações , Tomografia Computadorizada por Raios X
5.
J Med Genet ; 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006618

RESUMO

BACKGROUND: Wolfram syndrome (WFS) is a rare disorder characterised by childhood-onset diabetes mellitus and progressive optic atrophy. Most patients have variants in the WFS1 gene. We undertook functional studies of WFS1 variants and correlated these with WFS1 protein expression and phenotype. METHODS: 9 patients with a clinical diagnosis of WFS were studied with quantitative PCR for markers of endoplasmic reticulum (ER) stress and immunoblotting of fibroblast protein extracts for WFS1 protein expression. Luciferase reporter assay was used to assess ATF-6 dependent unfolded protein response (UPR) activation. RESULTS: 6 patients with compound heterozygous nonsense mutations in WFS1 had no detectable WFS1 protein expression; 3 patients with missense variants had 4%, 45% and 48% WFS1 protein expression. One of these also had an OPA1 mutation and was reclassified as autosomal dominant optic atrophy-plus syndrome. There were no correlations between ER stress marker mRNA and WFS1 protein expression. ERSE-luciferase reporter indicated activation of the ATF6 branch of UPR in two patients tested. Patients with partial WFS1 expression showed milder visual acuity impairment (asymptomatic or colour blind only), compared with those with absent expression (registered severe vision impaired) (p=0.04). These differences remained after adjusting for duration of optic atrophy. CONCLUSIONS: Patients with WFS who have partial WFS1 protein expression present with milder visual impairment. This suggests a protective effect of partial WFS1 protein expression on the severity and perhaps progression of vision impairment and that therapies to increase residual WFS1 protein expression may be beneficial.

7.
Front Immunol ; 12: 636225, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33833757

RESUMO

Gain-of-function mutations in STING1 cause the monogenic interferonopathy, SAVI, which presents with early-onset systemic inflammation, cold-induced vasculopathy and/or interstitial lung disease. We identified 5 patients (3 kindreds) with predominantly peripheral vascular disease who harbor 3 novel STING1 variants, p.H72N, p.F153V, and p.G158A. The latter two were predicted by a previous cryo-EM structure model to cause STING autoactivation. The p.H72N variant in exon 3, however, is the first SAVI-causing variant in the transmembrane linker region. Mutations of p.H72 into either charged residues or hydrophobic residues all led to dramatic loss of cGAMP response, while amino acid changes to residues with polar side chains were able to maintain the wild type status. Structural modeling of these novel mutations suggests a reconciled model of STING activation, which indicates that STING dimers can oligomerize in both open and closed states which would obliviate a high-energy 180° rotation of the ligand-binding head for STING activation, thus refining existing models of STING activation. Quantitative comparison showed that an overall lower autoactivating potential of the disease-causing mutations was associated with less severe lung disease, more severe peripheral vascular disease and the absence of a robust interferon signature in whole blood. Our findings are important in understanding genotype-phenotype correlation, designing targeted STING inhibitors and in dissecting differentially activated pathways downstream of different STING mutations.


Assuntos
Inflamação/genética , Doenças Pulmonares Intersticiais/genética , Proteínas de Membrana/genética , Mutação , Doenças Vasculares Periféricas/genética , Adulto , Criança , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Células HEK293 , Humanos , Inflamação/diagnóstico , Inflamação/metabolismo , Inflamação/terapia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/metabolismo , Doenças Pulmonares Intersticiais/terapia , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Modelos Moleculares , Doenças Vasculares Periféricas/diagnóstico , Doenças Vasculares Periféricas/metabolismo , Doenças Vasculares Periféricas/terapia , Fenótipo , Conformação Proteica , Multimerização Proteica , Índice de Gravidade de Doença , Relação Estrutura-Atividade , Sequenciamento Completo do Exoma , Adulto Jovem
8.
Front Immunol ; 12: 640837, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746983

RESUMO

Inflammatory cardiomyopathy covers a group of diseases characterized by inflammation and dysfunction of the heart muscle. The immunosuppressive agents such as prednisolone, azathioprine and cyclosporine are modestly effective treatments, but a molecular rationale underpinning such therapy or the development of new therapeutic strategies is lacking. We aimed to develop a network-based approach to identify therapeutic targets for inflammatory cardiomyopathy from the evolving myocardial transcriptome in a mouse model of the disease. We performed bulk RNA sequencing of hearts at early, mid and late time points from mice with experimental autoimmune myocarditis. We identified a cascade of pathway-level events involving early activation of cytokine and chemokine-signaling pathways that precede leucocyte infiltration and are followed by innate immune, antigen-presentation, complement and cell-adhesion pathway activation. We integrated these pathway events into a network-like representation from which we further identified a 50-gene subnetwork that is predominantly induced during the course of autoimmune myocardial inflammation. We developed a combinatorial attack strategy where we quantify network tolerance to combinatorial node removal to determine target-specific therapeutic potential. We find that combinatorial attack of Traf2, Nfkb1, Rac1, and Vav1 disconnects 80% of nodes from the largest network component. Two of these nodes, Nfkb1 and Rac1, are directly targeted by prednisolone and azathioprine respectively, supporting the idea that the methodology developed here can identify valid therapeutic targets. Whereas Nfkb1 and Rac1 removal disconnects 56% of nodes, we show that additional removal of Btk and Pik3cd causes 72% node disconnection. In conclusion, transcriptome profiling, pathway integration, and network identification of autoimmune myocardial inflammation provide a molecular signature applicable to the diagnosis of inflammatory cardiomyopathy. Combinatorial attack provides a rationale for immunosuppressive therapy of inflammatory cardiomyopathy and provides an in silico prediction that the approved therapeutics, ibrutinib and idelalisib targeting Btk and Pik3cd respectively, could potentially be re-purposed as adjuncts to immunosuppression.


Assuntos
Doenças Autoimunes , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Miocardite , Animais , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Endogâmicos BALB C , Miocárdio/imunologia , Miocárdio/metabolismo , Miocárdio/patologia , Transcriptoma
9.
Animals (Basel) ; 11(2)2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33672178

RESUMO

The inoculation of one-day-old broiler chicks with the cecal contents from a mature broiler breeder resulted in a highly diverse and uniform cecal bacterial community. CM did not affect feed consumption, weight gain, nor the richness, evenness, or diversity of the cecal bacterial community. However, the structure of the bacterial community was altered in birds fed the CM diet. Although the CM diet was formulated to contain equivalent metabolizable energy to the control diet, it contained more dietary fiber. The abundance of bacterial families, including those that are known to contain species able to metabolize fiber was altered (e.g., bacteria within the families, Methanobacteriaceae, Atopobiaceae, Prevotellaceae, Clostridiales Family XIII, Peptostreptococcaceae, and Succinivibrionaceae), and concentrations of SCFAs were higher in the ceca of birds fed the CM diet. Moreover, concentrations of isoleucine, isobutyrate, glutamate, and 2-oxoglutarate were higher, whereas concentrations of phenyllactic acid, indole, glucose, 3-phenylpropionate, and 2-oxobutyrate were lower in the digesta of chickens that were fed CM. The metabolic profiles of pancreas, liver, and breast muscle tissues of birds fed the CM diet differed from control birds. Metabolites that were associated with energy production, protection against oxidative stress, and pathways of amino acid and glycerophospholipid metabolism had altered concentrations in these tissues. Some of the observed changes in metabolite levels may indicate an increased disease risk in birds fed the CM diet (e.g., pancreatitis), and others suggested that birds mounted metabolic response to offset the adverse impacts of CM (e.g., oxidative stress in the liver).

10.
J Clin Rheumatol ; 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33492030

RESUMO

BACKGROUND: PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) syndrome is diagnosed clinically. Adult-onset PFAPA syndrome is rare and often has a more diverse clinical presentation that its childhood counterpart. This is the first reported case of adult-onset PFAPA syndrome with complete response to lingual tonsillectomy. CASE SUMMARY: A 41-year-old man was evaluated for periodic fevers associated with uvulitis, cervical lymphadenitis, pharyngitis, and lower extremity rash. He had a variable response to steroids and was intolerant of colchicine. Laboratory workup revealed intermittent elevation of erythrocyte sedimentation rate and C-reactive protein level. Computed tomography neck and laryngoscopy confirmed adenoidal and lingual tonsillar hypertrophy. He underwent adenoidectomy and lingual tonsillectomy with resolution of symptoms. CONCLUSIONS: Hypertrophy of the remaining lymphoid structures within Waldeyer's ring may be associated with remote recurrence of PFAPA syndrome after tonsillectomy. Lingual tonsillectomy may be an alternative treatment strategy in select patients with PFAPA, prominent lingual hypertrophy, and incomplete response to steroids.

11.
Dis Esophagus ; 34(1)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33016307

RESUMO

As the awareness among gastroenterologists regarding endoscopic features suggesting eosinophilic esophagitis is increasing, individuals without symptoms of esophageal dysfunction are increasingly being found to have esophageal eosinophilia on biopsies performed during upper gastrointestinal endoscopies. However, the course of disease and the management of these asymptomatic individuals with esophageal eosinophilia remain elusive. In this review, we propose a definition of asymptomatic individuals with esophageal eosinophilia and discuss the prevalence, risk factors, and course of disease of this specific patient group. Furthermore, we have established a diagnostic and therapeutic pathway based on the most recent available data.

12.
Clin Gastroenterol Hepatol ; 19(6): 1151-1159.e14, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32434067

RESUMO

BACKGROUND & AIMS: Gastrointestinal side effects are common during oral immunotherapy (OIT) and eosinophilic esophagitis (EoE) is a potential complication. We aimed to characterize eosinophilic gastrointestinal responses to peanut OIT, in which peanut protein is given orally, with incremental increases in dose over time. METHODS: Twenty adults with IgE-mediated peanut allergy were randomly assigned to groups given peanut OIT (n = 15) or placebo (n = 5); 1 additional subject withdrew before randomization. Serial gastrointestinal biopsies were collected at baseline (n = 21, 0 weeks), following dose escalation (n = 10, 52 weeks), and during the maintenance phase (n = 11, 104 weeks). Endoscopic findings were characterized using the EoE endoscopic reference score. Biopsies were assessed for eosinophils per high-power field (eos/hpf) and other pathology features using EoE histologic scoring system scores. We performed immunohistochemical analyses of eosinophil peroxidase deposition, quantified using automated image analysis. RESULTS: At baseline, no subjects reported current gastrointestinal symptoms. However, 3 of the 21 subjects (14%) had esophageal peak eosinophil counts ≥15 eos/hpf and all subjects had dilated intercellular spaces (DIS). OIT induced or exacerbated esophageal eosinophilia (EE) at 52 weeks in most subjects (peak eosinophil counts >5 eos/hpf in 6 of 7 patients [86%]; peak eosinophil counts ≥15 eos/hpf in 4 of 7 patients [57%]). One subject met clinicopathologic criteria for EoE and withdrew; no significant changes in esophageal peak eosinophil counts were observed in the placebo group. EE in the OIT group corresponded with significant increases in EoE histologic scoring system scores and deposition of eosinophil peroxidase. In 4 of 6 participants (67%), OIT-induced EE and gastrointestinal eosinophilia resolved by the end of the maintenance phase. Gastrointestinal symptoms were not clearly associated with EE or gastrointestinal eosinophilia. CONCLUSIONS: In this pilot study, we found that peanut OIT-induced EE and gastrointestinal eosinophilia are usually transient and are not always associated with gastrointestinal symptoms. Clinicaltrials.gov no: NCT02103270.

13.
Dig Dis Sci ; 66(3): 775-783, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32248390

RESUMO

BACKGROUND: Diagnosis of eosinophilic esophagitis (EoE) requires manual quantification of tissue eosinophils. Eosinophil peroxidase (EPX) is an eosinophil-specific, cytoplasmic granule protein released during degranulation. AIMS: The objective of this study was to evaluate image analysis of EPX immunohistochemistry as an automated method for histologic diagnosis of EoE. METHODS: We performed a secondary analysis of prospectively collected esophageal biopsies obtained from adult subjects with EoE and controls. Tissue sections were stained with hematoxylin and eosin (H&E) and evaluated for peak eosinophils per high power field (eos/hpf). The same slides were de-stained and re-stained to detect EPX for direct comparison. Slides were digitized, and EPX staining area/mm2 was quantified using image analysis. Paired samples were compared for changes in EPX staining in treatment responders and non-responders. RESULTS: Thirty-eight EoE cases and 49 controls were analyzed. Among EoE subjects, matched post-treatment biopsies were available for 21 responders and 10 non-responders. Baseline EPX/mm2 was significantly increased in EoE subjects and decreased in treatment responders. EPX quantification correlated strongly with eos/hpf (r = 0.84, p < 0.0001) and identified EoE subjects with high diagnostic accuracy (AUC 0.95, p < 0.0001). The optimal diagnostic EPX-positive pixel/area threshold was 17,379 EPX/mm2. Several controls (5/49) with < 15 eos/hpf on H&E staining exceeded this cutoff. CONCLUSIONS: EPX/mm2 correlates strongly with eos/hpf, accurately identifies subjects with EoE, and decreases in treatment responders. Automated quantification of intact eosinophils and their degranulation products may enhance pathologic assessment. Future studies are needed to correlate EPX/mm2 with symptoms, endoscopic findings, and esophageal distensibility.

15.
Front Immunol ; 11: 603295, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33335531

RESUMO

Eosinophilic esophagitis (EoE) is an antigen-driven disease associated with epithelial barrier dysfunction and chronic type 2 inflammation. Eosinophils are the defining feature of EoE histopathology but relatively little is known about their role in disease onset and progression. Classically defined as destructive, end-stage effector cells, eosinophils (a resident leukocyte in most of the GI tract) are increasingly understood to play roles in local immunity, tissue homeostasis, remodeling, and repair. Indeed, asymptomatic esophageal eosinophilia is observed in IgE-mediated food allergy. Interestingly, EoE is a potential complication of oral immunotherapy (OIT) for food allergy. However, we recently found that patients with peanut allergy may have asymptomatic esophageal eosinophilia at baseline and that peanut OIT induces transient esophageal eosinophilia in most subjects. This is seemingly at odds with multiple studies which have shown that EoE disease severity correlates with tissue eosinophilia. Herein, we review the potential role of eosinophils in EoE at different stages of disease pathogenesis. Based on current literature we suggest the following: (1) eosinophils are recruited to the esophagus as a homeostatic response to epithelial barrier disruption; (2) eosinophils mediate barrier-protective activities including local antibody production, mucus production and epithelial turnover; and (3) when type 2 inflammation persists, eosinophils promote fibrosis.


Assuntos
Alérgenos/efeitos adversos , Antígenos/imunologia , Dessensibilização Imunológica/efeitos adversos , Esofagite Eosinofílica/imunologia , Eosinófilos/imunologia , Estenose Esofágica/imunologia , Esôfago/imunologia , Hipersensibilidade Alimentar/terapia , Administração Oral , Alérgenos/administração & dosagem , Animais , Progressão da Doença , Esofagite Eosinofílica/metabolismo , Esofagite Eosinofílica/patologia , Esofagite Eosinofílica/terapia , Eosinófilos/metabolismo , Estenose Esofágica/metabolismo , Estenose Esofágica/patologia , Estenose Esofágica/terapia , Esôfago/metabolismo , Esôfago/patologia , Fibrose , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/metabolismo , Humanos , Fatores de Risco , Transdução de Sinais
17.
Oncology ; 98(5): 318-320, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32182611

RESUMO

BACKGROUND: Bullous pemphigoid (BP) is a rare autoimmune blistering condition characterized by antibodies to the structural proteins BP1 and BP2 at the dermal-epidermal junction. The link between BP and malignancy remains unclear. Due to the rarity of the disease, there have been few studies with small sample sizes characterizing the association between BP and malignancy. OBJECTIVES: There were two main goals of this retrospective cohort study: (1) to look at the associated risk of malignancy in patients with BP compared to controls and (2) to compare the rates of malignancy in two separate hospitals with differing patient populations. METHOD: We reviewed the medical records of 99 patients diagnosed with BP observed between 2014 and 2019. 66 patients were from Keck Hospital and 33 were from Los Angeles County/University of Southern California (LAC/USC) Hospital. Each patient was age- and sex-matched to a control from the same hospital. RESULTS: Malignancies occurred in 26 BP patients and 29 controls. 7 of the BP patients from LAC/USC Hospital (21.2%) and 19 patients from Keck Hospital (28.8%) had malignancies. CONCLUSIONS: Overall, we did not find an increased risk of malignancy in BP patients compared to controls, nor did we find a statistically differing rate of malignancy in BP patients from various socioeconomic and ethnic backgrounds.


Assuntos
Neoplasias/epidemiologia , Penfigoide Bolhoso/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Estudos Retrospectivos
19.
Clin Transl Gastroenterol ; 10(12): e00099, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31789931

RESUMO

OBJECTIVES: Dietary elimination for treatment of eosinophilic esophagitis (EoE) is limited by lack of accuracy in current allergy tests. We aimed to develop an immunologic approach to identify dietary triggers and prospectively test allergen-specific immune signature-guided dietary elimination therapy. METHODS: In the first phase, we developed and assessed 2 methods for determining selected food triggers using samples from 24 adults with EoE: a CD4+ T-cell proliferation assay in peripheral blood and food-specific tissue IgG4 levels in esophageal biopsies. In the second phase, we clinically tested elimination diets created from these methods in a prospective cohort treated for 6 weeks (NCT02722148). Outcomes included peak eosinophil counts (eos/hpf), endoscopic findings (measured by the EoE Endoscopic Reference Score), and symptoms (measured by the EoE Symptom Activity Index). RESULTS: Parameters were optimized with a positive test on either assay, yielding agreements of 60%, 75%, 53%, 58%, and 53% between predicted and known triggers of peanut, egg, soy, wheat, and milk, respectively. In clinical testing, the mean number of foods eliminated based on the assays was 3.4, and 19 of 22 subjects were compliant with treatment. After treatment, median peak eosinophil counts decreased from 75 to 35 (P = 0.007); there were 4 histologic responders (21%). The EoE Endoscopic Reference Score and EoE Symptom Activity Index score also decreased after treatment (4.6 vs 3.0; P = 0.002; and 32.5 vs 25.0; P = 0.06, respectively). DISCUSSION: We successfully developed a new testing approach using CD4 T-cell proliferation and esophageal food-specific IgG4 levels, with promising accuracy rates. In clinical testing, this led to improvement in eosinophil counts, endoscopic severity, and symptoms of dysphagia, but a smaller than expected number of patients achieved histologic remission.


Assuntos
Alérgenos/análise , Esofagite Eosinofílica/dietoterapia , Eosinófilos/imunologia , Hipersensibilidade Alimentar/diagnóstico , Adulto , Alérgenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Esofagite Eosinofílica/sangue , Esofagite Eosinofílica/diagnóstico , Esofagite Eosinofílica/imunologia , Esofagoscopia , Esôfago/diagnóstico por imagem , Esôfago/imunologia , Feminino , Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/dietoterapia , Hipersensibilidade Alimentar/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
20.
Nat Commun ; 10(1): 3143, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31316060

RESUMO

Heterozygous germline mutations in BRCA2 predispose to breast and ovarian cancer. Contrary to non-cancerous cells, where BRCA2 deletion causes cell cycle arrest or cell death, tumors carrying BRCA2 inactivation continue to proliferate. Here we set out to investigate adaptation to loss of BRCA2 focusing on genome-wide transcriptome alterations. Human cells in which BRCA2 expression is inhibited for 4 or 28 days are subjected to RNA-seq analyses revealing a biphasic response to BRCA2 abrogation. The early, acute response consists of downregulation of genes involved in cell cycle progression, DNA replication and repair and is associated with cell cycle arrest in G1. Surprisingly, the late, chronic response consists predominantly of upregulation of interferon-stimulated genes (ISGs). Activation of the cGAS-STING-STAT pathway detected in these cells further substantiates the concept that BRCA2 abrogation triggers cell-intrinsic immune signaling. Importantly, we find that treatment with PARP inhibitors stimulates the interferon response in cells and tumors lacking BRCA2.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Animais , Neoplasias da Mama/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Dano ao DNA , Reparo do DNA , Feminino , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade Inata , Camundongos SCID , Ftalazinas/farmacologia , Piperazinas/farmacologia
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