Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 34
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Nucleic Acids Res ; 49(3): e13, 2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33275158

RESUMO

Recent advances in single-cell open-chromatin and transcriptome profiling have created a challenge of exploring novel applications with a meaningful transformation of read-counts, which often have high variability in noise and drop-out among cells. Here, we introduce UniPath, for representing single-cells using pathway and gene-set enrichment scores by a transformation of their open-chromatin or gene-expression profiles. The robust statistical approach of UniPath provides high accuracy, consistency and scalability in estimating gene-set enrichment scores for every cell. Its framework provides an easy solution for handling variability in drop-out rate, which can sometimes create artefact due to systematic patterns. UniPath provides an alternative approach of dimension reduction of single-cell open-chromatin profiles. UniPath's approach of predicting temporal-order of single-cells using their pathway enrichment scores enables suppression of covariates to achieve correct order of cells. Analysis of mouse cell atlas using our approach yielded surprising, albeit biologically-meaningful co-clustering of cell-types from distant organs. By enabling an unconventional method of exploiting pathway co-occurrence to compare two groups of cells, our approach also proves to be useful in inferring context-specific regulations in cancer cells. Available at https://reggenlab.github.io/UniPathWeb/.


Assuntos
Epigenômica/métodos , RNA-Seq/métodos , Análise de Célula Única/métodos , Animais , Linhagem Celular Tumoral , Cromatina , Análise por Conglomerados , Epigenoma , Genes , Humanos , Camundongos , Neoplasias/genética
2.
Ophthalmology ; 129(4): 406-413, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34763023

RESUMO

PURPOSE: Carriers of functionally deficient mutations in the CYP39A1 gene have been recently reported to have a 2-fold increased risk of exfoliation syndrome (XFS). The aim of this study was to evaluate the risk of blindness and related clinical phenotypes of XFS patients carrying the loss-of-function CYP39A1 G204E mutation in comparison with XFS patients without any CYP39A1 mutation. DESIGN: Retrospective case study. PARTICIPANTS: A total of 35 patients diagnosed with XFS carrying the CYP39A1 G204E mutation and 150 XFS patients without any CYP39A1 mutation who were randomly selected from the Japanese XFS cohort. METHODS: Two-sided Fisher exact test with an alpha level < 0.05 was used to estimate the significance of the calculated odds ratio (OR) for all categorical measures. Comparisons between groups of subjects were performed using linear mixed effect models with group as random effect and taking possible dependence between eyes within a subject into account. MAIN OUTCOME MEASURES: Primary analysis compared the incidence of blindness (defined as visual acuity [VA] < 0.05 decimal), prevalence of exfoliation glaucoma (XFG), history of glaucoma surgery, and indices of glaucoma severity such as visual field (VF) mean deviation (MD), intraocular pressure (IOP), and vertical cup-disc ratio (CDR) between CYP39A1 G204E carriers and those without any CYP39A1 mutation. RESULTS: The overall risk for blindness was significantly higher in XFS patients carrying the CYP39A1 G204E variant (10/35 [28.6%]) compared with XFS patients without any CYP39A1 mutations (8/150 [5.4%]; odds ratio [OR], 7.1; 95% confidence interval [CI], 2.7-20.2]; P < 0.001). A higher proportion of XFS patients with the CYP39A1 G204E mutation (23/35 [65.7%]) had evidence of XFG in at least 1 eye compared with the comparison group (41/150 [27.3%]; OR, 5.1; 95% CI, 2.4-11.4]; P < 0.0001). Significantly higher peak IOP, larger vertical CDR, and worse VF MD were also found in CYP39A1 G204E variant carriers (P < 0.001). Additionally, patients with the CYP39A1 G204E mutation (18/35 [51.4%]) required more laser or glaucoma surgical interventions compared with those without any CYP39A1 mutation (32/150 [21.3%], P < 0.001). CONCLUSIONS: Patients with XFS carrying the CYP39A1 G204E mutation had significantly increased risk of blindness, higher occurrence of XFG, and more severe glaucoma compared with patients with XFS without any CYP39A1 mutation.


Assuntos
Síndrome de Exfoliação , Glaucoma , Esteroide Hidroxilases , Cegueira/genética , Síndrome de Exfoliação/complicações , Síndrome de Exfoliação/genética , Glaucoma/complicações , Glaucoma/genética , Humanos , Estudos Retrospectivos , Esteroide Hidroxilases/genética , Campos Visuais
3.
Osteoporos Int ; 33(12): 2527-2536, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36173415

RESUMO

In this post hoc analysis, we assessed romosozumab efficacy and safety in European patients enrolled in FRAME. Romosozumab treatment through 12 months, followed by denosumab for a further 24 months, resulted in early and sustained risk reduction for major fracture categories, associated with large gains in bone mineral density. INTRODUCTION: In the multinational FRAME phase 3 trial of romosozumab in postmenopausal women with osteoporosis, marked differences between clinical and non-vertebral fracture outcomes were observed among patients from Central and Southern America versus rest of world. This post hoc analysis assessed romosozumab efficacy and safety in European patients enrolled in the FRAME trial and extension study. METHODS: In FRAME (NCT01575834), patients were randomised 1:1 to romosozumab 210 mg or placebo monthly (QM) for 12 months, followed by open-label denosumab 60 mg Q6M to month 36, including a 12-month extension study. We report incidence of major fracture outcomes, bone mineral density (BMD) change from baseline and safety for European patients enrolled in FRAME. RESULTS: In FRAME, 3013/7180 (41.96%) patients were European; 1494 received romosozumab and 1519 received placebo. Through 12 months, romosozumab reduced fracture risk versus placebo for non-vertebral fracture (1.4% versus 3.0%; p = 0.004), clinical fracture (1.4% versus 3.6%; p < 0.001), new vertebral fracture (0.4% versus 2.1%; p < 0.001) and major osteoporotic fracture (0.9% versus 2.8%; p < 0.001), with results sustained through 36 months following transition to denosumab. Hip fractures were numerically reduced with romosozumab at month 12 (0.2% versus 0.6%; p = 0.092). Romosozumab increased BMD versus placebo at month 12; all patients in the romosozumab and placebo groups experienced further increases by month 36 after transition to denosumab. Adverse events were balanced between groups. CONCLUSIONS: Among European patients in FRAME, romosozumab resulted in early and sustained risk reduction for all major fracture categories, associated with large BMD gains that continued after transition to denosumab.


Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Fraturas por Osteoporose , Humanos , Feminino , Denosumab/efeitos adversos , Método Duplo-Cego , Densidade Óssea , Conservadores da Densidade Óssea/efeitos adversos , Fraturas por Osteoporose/induzido quimicamente , Osteoporose Pós-Menopausa/complicações
4.
JAMA ; 325(8): 753-764, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33620406

RESUMO

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. Design, Setting, and Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. Main Outcomes and Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses. Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. Conclusions and Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.


Assuntos
Síndrome de Exfoliação/genética , Variação Genética , Esteroide Hidroxilases/genética , Idoso , Idoso de 80 Anos ou mais , Câmara Anterior/patologia , Estudos de Casos e Controles , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Humanos , Modelos Logísticos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Sequenciamento do Exoma
5.
Stat Med ; 39(22): 2883-2900, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32495349

RESUMO

Bayesian analyses with the arm-based (AB) network meta-analysis (NMA) model require researchers to specify a prior distribution for the covariance matrix of the treatment-specific event rates in a transformed scale, for example, the treatment-specific log-odds when a logit transformation is used. The commonly used conjugate prior for the covariance matrix, the inverse-Wishart (IW) distribution, has several limitations. For example, although the IW distribution is often described as noninformative or weakly informative, it may in fact provide strong information when some variance components are small (eg, when the standard deviation of study-specific log-odds of a treatment is smaller than 1/2), as is common in NMAs with binary outcomes. In addition, the IW prior generally leads to underestimation of correlations between treatment-specific log-odds, which are critical for borrowing strength across treatment arms to estimate treatment effects efficiently and to reduce potential bias. Alternatively, several separation strategies (ie, separate priors on variances and correlations) can be considered. To study the IW prior's impact on NMA results and compare it with separation strategies, we did simulation studies under different missing-treatment mechanisms. A separation strategy with appropriate priors for the correlation matrix and variances performs better than the IW prior, and should be recommended as the default vague prior in the AB NMA approach. Finally, we reanalyzed three case studies and illustrated the importance, when performing AB-NMA, of sensitivity analyses with different prior specifications on variances.


Assuntos
Braço , Teorema de Bayes , Viés , Simulação por Computador , Humanos , Metanálise em Rede
6.
J Am Chem Soc ; 141(37): 14673-14686, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31436967

RESUMO

Tumor initiating cells (TIC) are resistant to conventional anticancer therapy and associated with metastasis and relapse in cancer. Although various TIC markers and their antibodies have been proposed, it is limited to the use of antibodies for in vivo imaging or treatment of TIC. In this study, we discovered heme oxygenase 2 (HMOX2) as a novel biomarker for TIC and developed a selective small molecule probe TiNIR (tumor initiating cell probe with near infrared). TiNIR detects and enriches the functionally active TIC in human lung tumors, and through the photoacoustic property, TiNIR also visualizes lung TIC in the patient-derived xenograft (PDX) model. Furthermore, we demonstrate that TiNIR inhibits tumor growth by blocking the function of HMOX2, resulting in significantly increased survival rates of the cancer model mice. The novel therapeutic target HMOX2 and its fluorescent ligand TiNIR will open a new path for the molecular level of lung TIC diagnosis and treatment.


Assuntos
Corantes Fluorescentes/farmacologia , Heme Oxigenase (Desciclizante)/metabolismo , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Animais , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Camundongos , Células-Tronco Neoplásicas/enzimologia , Taxa de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Angew Chem Int Ed Engl ; 57(11): 2851-2854, 2018 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-29377425

RESUMO

Tumor initiating cells (TICs) have been implicated in clinical relapse and metastasis of a variety of epithelial cancers, including lung cancer. While efforts toward the development of specific probes for TIC detection and targeting are ongoing, a universal TIC probe has yet to be developed. We report the first TIC-specific fluorescent chemical probe, TiY, with identification of the molecular target as vimentin, a marker for epithelial-to-mesenchymal transition (EMT). TiY selectively stains TICs over differentiated tumor cells or normal cells, and facilitates the visualization and enrichment of functionally active TICs from patient tumors. At high concentration, TiY also shows anti-TIC activity with low toxicity to non-TICs. With the unexplored target vimentin, TiY shows potential as a first universal probe for TIC detection in different cancers.


Assuntos
Corantes Fluorescentes/química , Células-Tronco Neoplásicas/patologia , Bibliotecas de Moléculas Pequenas/química , Vimentina/análise , Animais , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Humanos , Neoplasias Pulmonares/patologia , Camundongos
9.
Mol Aspects Med ; 95: 101229, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38039744

RESUMO

Glaucoma, one of the leading causes of irreversible blindness worldwide, is a complex and heterogenous disease. While environmental factors are important, it is well-recognized that the disease has a strong heritable component. With the advent of large-cohort genome wide association studies, a myriad of genetic risk loci has been linked to different forms of glaucoma. Animal models have been an indispensable tool in characterizing these loci, especially if they lie within coding regions in the genome. Not only do these models connect genotype to phenotype, advancing our understanding of glaucoma pathogenesis in the process, they also have valuable utility as a platform for the pre-clinical testing of potential therapies. In this review, we will outline genetic models used for studying the major forms of glaucoma, including primary open angle glaucoma, normal tension glaucoma, primary angle closure glaucoma, pigmentary glaucoma, pseudoexfoliation glaucoma, and early onset glaucoma, including congenital and developmental glaucoma, and how studying these models have helped shed light on human glaucoma.


Assuntos
Glaucoma de Ângulo Aberto , Glaucoma , Animais , Humanos , Glaucoma de Ângulo Aberto/genética , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Glaucoma/genética , Genótipo
10.
ACR Open Rheumatol ; 6(1): 43-51, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37985218

RESUMO

OBJECTIVE: Romosozumab is a bone-forming agent approved for osteoporosis treatment. Here we report results of the protocol-specified, noninferiority osteoarthritis substudy of the fracture study in postmenopausal women with osteoporosis (FRAME), which evaluated the effect of romosozumab versus placebo on knee osteoarthritis in patients with a clinical history of osteoarthritis. METHODS: Women in FRAME with a history of knee osteoarthritis were eligible for enrollment in the osteoarthritis substudy; key inclusion criteria were osteoarthritis-related signal knee pain, morning stiffness lasting less than 30 minutes, knee crepitus, and knee osteoarthritis confirmed by x-ray within 12 months. The protocol-specified outcomes were change from baseline through month 12 in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, incidence of worsening knee osteoarthritis, and treatment-emergent adverse events (TEAEs) with romosozumab versus placebo. In a post hoc analysis, percentage change from baseline to month 12 in bone mineral density (BMD) was assessed. RESULTS: Of 7180 women in FRAME, 347 participated in the osteoarthritis substudy (placebo, 177; romosozumab, 170). At month 12, no significant difference in progression of knee osteoarthritis was observed with romosozumab versus placebo (least squares mean total WOMAC score: -2.2 vs. -1.3; P = 0.71). Incidence of worsening symptoms of knee osteoarthritis was comparable between romosozumab (17.1%) and placebo (20.5%) (odds ratio 0.9 [95% confidence interval: 0.5, 1.7]; P = 0.69). Incidence of TEAEs of osteoarthritis was numerically lower with romosozumab (13 [7.7%]) versus placebo (21 [12.0%]). BMD gains were higher with romosozumab. CONCLUSION: Romosozumab treatment did not impact knee pain or function in postmenopausal women with osteoporosis and knee osteoarthritis and resulted in significant BMD gains in these women.

11.
Adv Sci (Weinh) ; 11(18): e2307630, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38441389

RESUMO

Regulation of excessive inflammation and impaired cell proliferation is crucial for healing diabetic wounds. Although plant-to-mammalian regulation offers effective approaches for chronic wound management, the development of a potent plant-based therapeutic presents challenges. This study aims to validate the efficacy of turmeric-derived nanoparticles (TDNPs) loaded with natural bioactive compounds. TDNPs can alleviate oxidative stress, promote fibroblast proliferation and migration, and reprogram macrophage polarization. Restoration of the fibroblast-macrophage communication network by TDNPs stimulates cellular regeneration, in turn enhancing diabetic wound healing. To address diabetic wound management, TDNPs are loaded in an ultralight-weight, high swelling ratio, breathable aerogel (AG) constructed with cellulose nanofibers and sodium alginate backbones to obtain TDNPs@AG (TAG). TAG features wound shape-customized accessibility, water-adaptable tissue adhesiveness, and capacity for sustained release of TDNPs, exhibiting outstanding performance in facilitating in vivo diabetic wound healing. This study highlights the potential of TDNPs in regenerative medicine and their applicability as a promising solution for wound healing in clinical settings.


Assuntos
Curcuma , Diabetes Mellitus Experimental , Nanopartículas , Cicatrização , Cicatrização/efeitos dos fármacos , Animais , Nanopartículas/química , Curcuma/química , Camundongos , Modelos Animais de Doenças , Proliferação de Células/efeitos dos fármacos , Géis , Ratos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo
12.
J Virol ; 86(15): 8086-96, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22623769

RESUMO

The BZLF1 gene controls the switch between latent and lytic infection by Epstein-Barr virus (EBV). We previously reported that both the ZV and ZIIR elements within the BZLF1 promoter, Zp, are potent transcription silencers within the context of an intact EBV genome. We report here identification of another sequence element, ZV', which synergized with ZV in repressing Zp via binding ZEB1 or ZEB2. We then determined the phenotype of a variant of EBV strain B95.8 in which the ZV, ZV', and ZIIR elements were concurrently mutated. HEK293 cell lines infected with this triple mutant (tmt) virus spontaneously synthesized 6- to 10-fold more viral BZLF1, BRLF1, BMRF1, and BLLF1 RNAs, 3- to 6-fold more viral Zta, Rta, and EAD proteins, 3- to 5-fold more viral DNA, and 7- to 9-fold more infectious virus than did 293 cell lines latently infected with either the ZV ZV' double mutant (dmt) or ZIIR mutant (mt) virus. While ZV ZV' ZIIR tmt EBV efficiently infected human primary blood B cells in vitro, it was highly defective in immortalizing them. Instead of the nearly complete silencing of BZLF1 gene expression that occurs within 4 days after primary infection with wild-type EBV, the ZV ZV' ZIIR tmt-infected cells continued to synthesize BZLF1 RNA, with 90% of them dying within 9 days postinfection. BL41 cells infected with this "superlytic" virus also exhibited increased synthesis of BZLF1 and BMRF1 RNAs. Thus, we conclude that the ZV, ZV', and ZIIR silencing elements act synergistically to repress transcription from Zp, thereby tightly controlling BZLF1 gene expression, which is crucial for establishing and maintaining EBV latency.


Assuntos
Linfócitos B/metabolismo , Transformação Celular Viral , Infecções por Vírus Epstein-Barr/metabolismo , Regulação Viral da Expressão Gênica/fisiologia , Herpesvirus Humano 4/fisiologia , Transativadores/biossíntese , Antígenos Virais/biossíntese , Antígenos Virais/genética , Linfócitos B/patologia , Linfócitos B/virologia , Linhagem Celular Tumoral , Infecções por Vírus Epstein-Barr/genética , Genoma Viral/fisiologia , Células HeLa , Humanos , Mutação , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Viral/biossíntese , RNA Viral/genética , Elementos Silenciadores Transcricionais/fisiologia , Fatores de Tempo , Transativadores/genética , Transcrição Gênica/fisiologia , Latência Viral/fisiologia
13.
Proc Natl Acad Sci U S A ; 107(5): 1894-9, 2010 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-20133837

RESUMO

Cancer cells preferentially metabolize glucose by aerobic glycolysis, characterized by increased lactate production. This distinctive metabolism involves expression of the embryonic M2 isozyme of pyruvate kinase, in contrast to the M1 isozyme normally expressed in differentiated cells, and it confers a proliferative advantage to tumor cells. The M1 and M2 pyruvate-kinase isozymes are expressed from a single gene through alternative splicing of a pair of mutually exclusive exons. We measured the expression of M1 and M2 mRNA and protein isoforms in mouse tissues, tumor cell lines, and during terminal differentiation of muscle cells, and show that alternative splicing regulation is sufficient to account for the levels of expressed protein isoforms. We further show that the M1-specific exon is actively repressed in cancer-cell lines--although some M1 mRNA is expressed in cell lines derived from brain tumors--and demonstrate that the related splicing repressors hnRNP A1 and A2, as well as the polypyrimidine-tract-binding protein PTB, contribute to this control. Downregulation of these splicing repressors in cancer-cell lines using shRNAs rescues M1 isoform expression and decreases the extent of lactate production. These findings extend the links between alternative splicing and cancer, and begin to define some of the factors responsible for the switch to aerobic glycolysis.


Assuntos
Processamento Alternativo , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Piruvato Quinase/genética , Piruvato Quinase/metabolismo , Aerobiose , Animais , Linhagem Celular , Linhagem Celular Tumoral , Éxons , Glioblastoma/genética , Glioblastoma/metabolismo , Glicólise , Células HeLa , Ribonucleoproteína Nuclear Heterogênea A1 , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Ácido Láctico/biossíntese , Camundongos , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Sítios de Splice de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
14.
ACS Nano ; 17(12): 11253-11267, 2023 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-37314783

RESUMO

Developing an effective dressing against bacterial infection and synchronously addressing wound complications, such as bleeding, long-term inflammation, and reinfection, are highly desirable in clinical practice. In this work, a second near-infrared (NIR-II) responsive nanohybrid consisting of imipenem encapsulated liposome with gold-shell and lipopolysaccharide (LPS)-targeting aptamer, namely ILGA, is constructed for bacteria elimination. Benefiting from the delicate structure, ILGA exhibits strong affinity and a reliable photothermal/antibiotic therapeutic effect toward multidrug-resistant Pseudomonas aeruginosa (MDR-PA). Furthermore, by incorporating ILGA with a thermosensitive hydrogel poly(lactic-co-glycolic acid)-polyethylene glycol-poly(lactic-co-glycolic acid) (PLGA-PEG-PLGA), a sprayable dressing ILGA@Gel was prepared, which enables a quick on-demand gelation (10 s) for wound hemostasis and offers excellent photothermal/antibiotic efficacy to sterilize the infected wound. Additionally, ILGA@Gel provides satisfactory wound-healing environments by reeducating wound-associated macrophages for inflammation alleviation and forming a gel layer to block exogenous bacterial reinfection. This biomimetic hydrogel reveals excellent bacteria eradication and wound recovery effectiveness, demonstrating its promising potential for managing complicated infected wounds.


Assuntos
Hidrogéis , Infecção dos Ferimentos , Humanos , Hidrogéis/farmacologia , Hidrogéis/química , Reinfecção , Antibacterianos/farmacologia , Antibacterianos/química , Bandagens , Bactérias , Inflamação , Infecção dos Ferimentos/tratamento farmacológico
15.
J Adolesc Health ; 72(5): 737-745, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36781327

RESUMO

PURPOSE: We examined how antecedent sexual health factors affect lower urinary tract symptoms (LUTS) in adolescent women. METHODS: We analyzed 1,941 adolescent women from the Avon Longitudinal Study of Parents and Children at age 19. At ages 15 and 17, participants reported use of oral contraceptives (OCs), history of sexual intercourse, number of sexual partners, and condom use. At age 19, The Bristol Female Lower Urinary Tract Symptoms questionnaire quantified the frequency over the past month: stress incontinence, any incontinence, urgency, sensation of incomplete emptying, bladder pain, and urinary tract infection. Multivariable regression models examined associations between sexual health behaviors reported at ages 15 and 17 and six LUTS reported at age 19, after controlling for covariates. RESULTS: Commonly reported LUTS at age 19 were past-month stress incontinence (26.8%), bladder pain (26.3%), any urine leakage (22.1%), and urinary tract infection (15.4%). OC use by age 17 was associated with urgency (odds ratio [OR] = 1.62, 95% confidence interval [CI] 1.19-2.20), incomplete emptying (OR = 1.62, 95% CI = 1.17-2.26), bladder pain (OR = 1.45, 95% CI = 1.15-1.83), and urinary tract infections (OR = 1.68, 95% CI = 1.28-2.21) at age 19 after adjustment for covariates. However, associations were attenuated after adjustment for condom use and number of sexual partners. Sexual intercourse by age 17 was associated with 1.53-2.65 increased odds of LUTs categories except incontinence, with lower confidence interval boundaries > 1.0. Associations were stronger among women with ≥ 3 sexual partners (vs. 0) by age 17. DISCUSSION: We found longitudinally assessed associations between OC use, sexual intercourse, and number of sexual partners during adolescence and LUTS at age 19.


Assuntos
Sintomas do Trato Urinário Inferior , Saúde Sexual , Infecções Urinárias , Adolescente , Criança , Feminino , Humanos , Adulto Jovem , Adulto , Estudos Longitudinais , Sintomas do Trato Urinário Inferior/epidemiologia , Sintomas do Trato Urinário Inferior/diagnóstico , Inquéritos e Questionários , Infecções Urinárias/epidemiologia , Comportamentos Relacionados com a Saúde , Dor
16.
Nat Cell Biol ; 25(5): 765-777, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37095322

RESUMO

PBRM1 encodes an accessory subunit of the PBAF SWI/SNF chromatin remodeller, and the inactivation of PBRM1 is a frequent event in kidney cancer. However, the impact of PBRM1 loss on chromatin remodelling is not well examined. Here we show that, in VHL-deficient renal tumours, PBRM1 deficiency results in ectopic PBAF complexes that localize to de novo genomic loci, activating the pro-tumourigenic NF-κB pathway. PBRM1-deficient PBAF complexes retain the association between SMARCA4 and ARID2, but have loosely tethered BRD7. The PBAF complexes redistribute from promoter proximal regions to distal enhancers containing NF-κB motifs, heightening NF-κB activity in PBRM1-deficient models and clinical samples. The ATPase function of SMARCA4 maintains chromatin occupancy of pre-existing and newly acquired RELA specific to PBRM1 loss, activating downstream target gene expression. Proteasome inhibitor bortezomib abrogates RELA occupancy, suppresses NF-κB activation and delays growth of PBRM1-deficient tumours. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumourigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Cromatina/genética , Proteínas Cromossômicas não Histona/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Genômica , Neoplasias Renais/metabolismo , NF-kappa B/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética
17.
Prog Retin Eye Res ; 90: 101066, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35589495

RESUMO

Glaucoma, a diverse group of eye disorders that results in the degeneration of retinal ganglion cells, is the world's leading cause of irreversible blindness. Apart from age and ancestry, the major risk factor for glaucoma is increased intraocular pressure (IOP). In primary open-angle glaucoma (POAG), the anterior chamber angle is open but there is resistance to aqueous outflow. In primary angle-closure glaucoma (PACG), crowding of the anterior chamber angle due to anatomical alterations impede aqueous drainage through the angle. In exfoliation syndrome and exfoliation glaucoma, deposition of white flaky material throughout the anterior chamber directly interfere with aqueous outflow. Observational studies have established that there is a strong hereditable component for glaucoma onset and progression. Indeed, a succession of genome wide association studies (GWAS) that were centered upon single nucleotide polymorphisms (SNP) have yielded more than a hundred genetic markers associated with glaucoma risk. However, a shortcoming of GWAS studies is the difficulty in identifying the actual effector genes responsible for disease pathogenesis. Building on the foundation laid by GWAS studies, research groups have recently begun to perform whole exome-sequencing to evaluate the contribution of protein-changing, coding sequence genetic variants to glaucoma risk. The adoption of this technology in both large population-based studies as well as family studies are revealing the presence of novel, protein-changing genetic variants that could enrich our understanding of the pathogenesis of glaucoma. This review will cover recent advances in the genetics of primary open-angle glaucoma, primary angle-closure glaucoma and exfoliation glaucoma, which collectively make up the vast majority of all glaucoma cases in the world today. We will discuss how recent advances in research methodology have uncovered new risk genes, and how follow up biological investigations could be undertaken in order to define how the risk encoded by a genetic sequence variant comes into play in patients. We will also hypothesise how data arising from characterising these genetic variants could be utilized to predict glaucoma risk and the manner in which new therapeutic strategies might be informed.


Assuntos
Síndrome de Exfoliação , Glaucoma de Ângulo Fechado , Glaucoma de Ângulo Aberto , Glaucoma , Síndrome de Exfoliação/complicações , Síndrome de Exfoliação/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glaucoma/complicações , Glaucoma de Ângulo Fechado/genética , Glaucoma de Ângulo Aberto/genética , Humanos , Pressão Intraocular/genética
18.
Bone ; 154: 116209, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34547521

RESUMO

Vertebral fractures (VFs) are the most common type of osteoporotic fracture, and their prevalence and severity are key risk factors for future fragility fractures. Here, we assess the treatment effect of romosozumab on the incidence of new on-study VFs according to Genant severity grades (mild, moderate, and severe). Data are reported from two phase 3 clinical studies for patients who received romosozumab versus placebo through 12 months, followed by denosumab through 24 months (FRAME: NCT01575834), and for patients who received romosozumab through 12 months, followed by alendronate through 24 months, versus alendronate only through 24 months (ARCH: NCT01631214). The treatment effect of romosozumab is reported for all included patients, and for patients with prevalent and severe baseline VFs. The incidence of new moderate-or-severe VFs was reduced through 12 months for patients treated with romosozumab versus placebo (FRAME; 0.25% versus 1.42%, respectively; p < 0.001) or alendronate (ARCH; 2.78% versus 4.00%, respectively; p = 0.042). Furthermore, the treatment effect of romosozumab on the incidence of new VFs across moderate and severe severity grades was independent of baseline VF prevalence or severity; through 12 months, consistent reductions in new moderate-or-severe VFs were observed regardless of prevalent (FRAME; p = 0.18) or severe (ARCH; p = 0.52) VFs at baseline. Reductions in the incidence of new moderate and severe VFs were sustained through 24 months, after transition from romosozumab to denosumab or alendronate, independent of baseline VF prevalence or severity; no significant interactions were observed between the incidence of new moderate-or-severe VFs and the presence of prevalent (FRAME; p = 0.81) or severe (ARCH; p = 0.99) VFs at baseline. With increasing recommendations for initial treatment with bone-forming agents for postmenopausal women with osteoporosis, these analyses will help to inform treatment decisions for patients at very high risk of VF.


Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Osteoporose , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Anticorpos Monoclonais , Densidade Óssea , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Feminino , Humanos , Incidência , Osteoporose/tratamento farmacológico , Osteoporose Pós-Menopausa/induzido quimicamente , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/tratamento farmacológico , Pós-Menopausa , Fraturas da Coluna Vertebral/induzido quimicamente , Fraturas da Coluna Vertebral/epidemiologia , Fraturas da Coluna Vertebral/prevenção & controle
19.
Quant Imaging Med Surg ; 12(2): 1270-1280, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35111622

RESUMO

BACKGROUND: The molecular subtype of breast cancer is one of the most important factors affecting patient prognosis. The study aimed to analyze the association between quantitative and qualitative features of contrast-enhanced mammography (CEM) images and breast cancer molecular subtypes. METHODS: This retrospective double-center study included women who underwent CEM between November 2017 and April 2020. Each patient had at least 1 malignant lesion confirmed by pathology. The CEM images were evaluated by 2 radiologists to obtain quantitative and qualitative image features. The molecular subtypes were studied as dichotomous outcomes, including luminal versus non-luminal, human epidermal growth factor receptor (HER2)-enriched versus non-HER2-enriched, and triple-negative breast cancer (TNBC) versus non-TNBC subtypes. The association between the image features and molecular subtypes was analyzed by multivariate logistic regression, with odds ratios (ORs) and 95% confidence intervals (CIs) provided. RESULTS: A total of 151 patients with 160 malignant lesions were included in the study. For quantitative features, a higher standard deviation of lesion density was associated with non-luminal (OR =0.88, 95% CI: 0.81 to 0.96, P=0.004) and HER2-enriched breast cancers (OR =1.16, 95% CI: 1.04 to 1.28, P=0.006). The relative degree of enhancement (RDE) and contrast-to-noise ratio (CNR) were not associated with molecular subtypes. However, a higher CNR/lesion size (OR =1.06, 95% CI: 1.01 to 1.12, P=0.012) was associated with luminal subtype cancers, and a higher RDE/lesion size (OR =0.94, 95% CI: 0.88 to 1.00, P=0.035) or a higher CNR/lesion size (OR =0.94, 95% CI: 0.88-1.00, P=0.038) was associated with non-TNBCs. For qualitative features, the presence of calcification was associated with HER2-enriched breast cancers (OR =2.91, 95% CI: 1.10 to 7.67, P=0.031). The presence of architectural distortion was associated with luminal cancer (OR =14.50, 95% CI: 1.91 to 110.14, P=0.010) and non-TNBC (OR =0.05, 95% CI: 0.00 to 0.43, P=0.022). Non-mass enhancement (OR =2.78, 95% CI: 1.08 to 7.14, P=0.033) was associated with HER2-enriched breast cancers. An association remained after adjustments for age, breast thickness, and breast density (all adjusted P<0.050). CONCLUSIONS: The quantitative and qualitative imaging features of CEM could contribute to distinguishing breast cancer molecular subtypes.

20.
J Bone Miner Res ; 37(8): 1437-1445, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35466448

RESUMO

Patients with osteoporosis and chronic kidney disease (CKD) are at increased risk of fracture and associated negative outcomes, including increased mortality. The present post hoc analysis of two randomized, multicenter, phase 3 clinical trials-Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) and Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk (ARCH)-investigated the efficacy and safety of romosozumab in postmenopausal women with osteoporosis and mild-to-moderate CKD. The analysis included data from 7147 patients from FRAME and 4077 from ARCH. Eighty-one percent of patients from FRAME and 85% from ARCH had mild or moderate reduction in estimated glomerular filtration rate (eGFR) at baseline, and part of this reduction is likely age related. During the 1-year double-blind phases of the trials, patients received romosozumab 210 mg sc or placebo monthly in FRAME and romosozumab 210 mg sc monthly or alendronate 70 mg po weekly in ARCH. Bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck and vertebral and nonvertebral fractures were assessed at baseline and month 12. In both trials, the least-square mean percent change from baseline BMD was significantly greater in the romosozumab groups versus controls across all kidney function categories at month 12. Romosozumab reduced the relative risk of new vertebral fractures at month 12 among patients with eGFR of 30-59, 60-89, and ≥90 mL/min by 72% (95% confidence interval [CI] 14-91; p = 0.017), 70% (40-85; p < 0.001), and 84% (30-96; p = 0.005), respectively, in FRAME versus placebo, and by 51% (5-75; p = 0.04), 19% (-28 to 49; p = 0.39), and 57% (1-81, p = 0.04), respectively, in ARCH versus alendronate. Incidences of adverse events, asymptomatic decreases in serum calcium, and evolution of kidney function during the studies were similar across all baseline kidney function groups. Romosozumab is an effective treatment option for postmenopausal women with osteoporosis and mild-to-moderate reduction in kidney function, with a similar safety profile across different levels of kidney function. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Conservadores da Densidade Óssea , Fraturas Ósseas , Osteoporose Pós-Menopausa , Osteoporose , Insuficiência Renal Crônica , Alendronato/farmacologia , Anticorpos Monoclonais , Densidade Óssea , Conservadores da Densidade Óssea/efeitos adversos , Feminino , Colo do Fêmur , Fraturas Ósseas/epidemiologia , Humanos , Osteoporose/tratamento farmacológico , Osteoporose Pós-Menopausa/tratamento farmacológico , Pós-Menopausa , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa