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1.
Epigenetics ; 18(1): 2196759, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-36994855

RESUMO

Endogenous sex hormones and DNA methylation both play important roles in various diseases. However, their interplay is largely unknown. A deeper understanding of their interrelationships could provide new insights into the pathology of disease development. We, therefore, investigated associations between circulating sex hormones, sex hormone binding globulin (SHBG), and DNA methylation in blood, using samples from 77 men (65 with repeated samples), from the population-based Northern Sweden Health and Disease Study (NSHDS). DNA methylation was measured in buffy coat using the Infinium Methylation EPIC BeadChip (Illumina). Sex hormone (oestradiol, oestrone, testosterone, androstenedione, dehydroepiandrosterone, and progesterone) and SHBG concentrations were measured in plasma using a high-performance liquid chromatography tandem mass spectrometry (LC/MS-MS) method and an enzyme-linked immunoassay, respectively. Associations between sex hormones, SHBG, and DNA methylation were estimated using both linear regression and mixed-effects models. Additionally, we used the comb-p method to identify differentially methylated regions based on nearby P values. We identified one novel CpG site (cg14319657), at which DNA methylation was associated with dehydroepiandrosterone, surpassing a genome-wide significance level. In addition, more than 40 differentially methylated regions were associated with levels of sex hormones and SHBG and several of these mapped to genes involved in hormone-related diseases. Our findings support a relationship between circulating sex hormones and DNA methylation and suggest that further investigation is warranted, both for validation, further exploration and to gain a deeper understanding of the mechanisms and potential consequences for health and disease.


Assuntos
Metilação de DNA , Epigenoma , Masculino , Humanos , Hormônios Esteroides Gonadais/genética , Estradiol , Desidroepiandrosterona
2.
Insect Biochem Mol Biol ; 147: 103775, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35504546

RESUMO

Melanization is a key immune response mediated by serine protease (SP) cascade in insects. Multiple SP pathways exist in different species and it is unclear how conserved these cascades are. The cotton bollworm Helicoverpa armigera is a major worldwide agricultural pest. We reported a conserved melanization pathway in this species, which consists of SP41, cSP1, and cSP6. In this study, we attempted to identify an insect pathogen that elicits the cascade and test whether or not there are other SP cascades in H. armigera. After Micrococcus luteus, Enterobacter cloacae, Beauveria bassiana, or Helicoverpa armigera nucleopolyhedrovirus were injected into larvae, pathogen-induced hemolymph samples were collected for in vitro biochemical assays, which failed to detect proSP41 or procSP1 activation. In contrast, we found that procSP4, a protein proposed to participate in H. armigera melanization, was activated in M. luteus infected hemolymph. We further revealed that cSP8 was a prophenoloxidase (PPO) activating protease downstream of cSP4, and cSP4 was activated by cSP10. The pathway of cSP10-cSP4-cSP8 activated PPO in vitro. Efficiently cleaved procSPH11 and procSPH50 by cSP8 substantially enhanced phenoloxidase activity, suggesting they work together as a cofactor for cSP8 mediated PPO activation. Hemolymph from larvae challenged with M. luteus or its peptidoglycan effectively activated procSP10. Collectively, these results revealed a new PPO activation cascade specifically triggered by the bacterium. In addition, we found that the PPO activation cascades in H. armigera and Manduca sexta are conserved.


Assuntos
Micrococcus luteus , Mariposas , Animais , Catecol Oxidase/metabolismo , Precursores Enzimáticos/metabolismo , Hemolinfa/metabolismo , Proteínas de Insetos/metabolismo , Larva/metabolismo , Micrococcus luteus/metabolismo , Mariposas/metabolismo , Serina Endopeptidases , Serina Proteases/metabolismo
3.
Eur J Neurosci ; 55(5): 1356-1372, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35080077

RESUMO

Amyotrophic lateral sclerosis (ALS) is a lethal and incurable neurodegenerative disease due to the loss of upper and lower motor neurons, which leads to muscle weakness, atrophy, and paralysis. Sigma-1 receptor (σ-1R) is a ligand-operated protein that exhibits pro-survival and anti-apoptotic properties. In addition, mutations in its codifying gene are linked to development of juvenile ALS pointing to an important role in ALS. Here, we investigated the disease-modifying effects of pridopidine, a σ-1R agonist, using a delayed onset SOD1 G93A mouse model of ALS. Mice were administered a continuous release of pridopidine (3.0 mg/kg/day) for 4 weeks starting before the appearance of any sign of muscle weakness. Mice were monitored weekly and several behavioural tests were used to evaluate muscle strength, motor coordination and gait patterns. Pridopidine-treated SOD1 G93A mice showed genotype-specific effects with the prevention of cachexia. In addition, these effects exhibited significant improvement of motor behaviour 5 weeks after treatment ended. However, the survival of the animals was not extended. In summary, these results show that pridopidine can modify the disease phenotype of ALS-associated cachexia and motor deficits in a SOD1 G93A mouse model.


Assuntos
Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Esclerose Lateral Amiotrófica/genética , Animais , Caquexia , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Debilidade Muscular , Fenótipo , Piperidinas , Superóxido Dismutase/genética , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo
4.
Cancer Epidemiol Biomarkers Prev ; 31(4): 793-803, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35086823

RESUMO

BACKGROUND: Endogenous sex hormones may contribute to higher colorectal cancer incidence rates in men compared with women, but despite an increased number of studies, clear evidence is lacking. METHODS: We conducted a comprehensive nested case-control study of circulating concentrations of sex hormones, sex hormone precursors, and sex hormone binding globulin (SHBG) in relation to subsequent colon cancer risk in European men. Concentrations were measured using liquid LC/MS-MS in prospectively collected plasma samples from 690 cases and 690 matched controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Northern Sweden Health and Disease Study (NSHDS) cohorts. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). In addition, we conducted a meta-analysis of previous studies on men. RESULTS: Circulating levels of testosterone (OR, 0.68; 95% CI, 0.51-0.89) and SHBG (OR, 0.77; 95% CI, 0.62-0.96) were inversely associated with colon cancer risk. For free testosterone, there was a nonsignificant inverse association (OR, 0.83; 95% CI, 0.58-1.18). In a dose-response meta-analysis of endogenous sex hormone levels, inverse associations with colorectal/colon cancer risk were found for testosterone [relative risks (RR) per 100 ng/dL = 0.98; 95% CI, 0.96-1.00; I2 = 22%] and free testosterone (RR per 1 ng/dL = 0.98; 95% CI, 0.95-1.00; I2 = 0%). CONCLUSIONS: Our results provide suggestive evidence for the association between testosterone, SHBG, and male colon cancer development. IMPACT: Additional support for the involvement of sex hormones in male colon cancer.


Assuntos
Neoplasias do Colo , Globulina de Ligação a Hormônio Sexual , Estudos de Casos e Controles , Neoplasias do Colo/epidemiologia , Estradiol , Feminino , Hormônios Esteroides Gonadais , Humanos , Modelos Logísticos , Masculino , Estudos Prospectivos , Fatores de Risco , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona
5.
Sci Rep ; 11(1): 5151, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664295

RESUMO

Colorectal cancer prognosis is dependent on stage, and measures to improve early detection are urgently needed. Using prospectively collected plasma samples from the population-based Northern Sweden Health and Disease Study, we evaluated protein biomarkers in relation to colorectal cancer risk. Applying a two-tiered approach, we analyzed 160 proteins in matched sequential samples from 58 incident colorectal cancer case-control pairs. Twenty-one proteins selected from both this discovery phase and the literature were then analyzed in a validation set of 450 case-control pairs. Odds ratios were estimated by conditional logistic regression. LASSO regression and ROC analysis were used for multi-marker analyses. In the main validation analysis, no proteins retained statistical significance. However, exploratory subgroup analyses showed associations between FGF-21 and colon cancer risk (multivariable OR per 1 SD: 1.23 95% CI 1.03-1.47) as well as between PPY and rectal cancer risk (multivariable OR per 1 SD: 1.47 95% CI 1.12-1.92). Adding protein markers to basic risk predictive models increased performance modestly. Our results highlight the challenge of developing biomarkers that are effective in the asymptomatic, prediagnostic window of opportunity for early detection of colorectal cancer. Distinguishing between cancer subtypes may improve prediction accuracy. However, single biomarkers or small panels may not be sufficient for effective precision screening.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Proteínas de Neoplasias/sangue , Proteômica , Adulto , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Detecção Precoce de Câncer , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Suécia
6.
J Transl Med ; 18(1): 435, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33187526

RESUMO

BACKGROUND: Metastasized clear cell renal cell carcinoma (ccRCC) is associated with a poor prognosis. Almost one-third of patients with non-metastatic tumors at diagnosis will later progress with metastatic disease. These patients need to be identified already at diagnosis, to undertake closer follow up and/or adjuvant treatment. Today, clinicopathological variables are used to risk classify patients, but molecular biomarkers are needed to improve risk classification to identify the high-risk patients which will benefit most from modern adjuvant therapies. Interestingly, DNA methylation profiling has emerged as a promising prognostic biomarker in ccRCC. This study aimed to derive a model for prediction of tumor progression after nephrectomy in non-metastatic ccRCC by combining DNA methylation profiling with clinicopathological variables. METHODS: A novel cluster analysis approach (Directed Cluster Analysis) was used to identify molecular biomarkers from genome-wide methylation array data. These novel DNA methylation biomarkers, together with previously identified CpG-site biomarkers and clinicopathological variables, were used to derive predictive classifiers for tumor progression. RESULTS: The "triple classifier" which included both novel and previously identified DNA methylation biomarkers together with clinicopathological variables predicted tumor progression more accurately than the currently used Mayo scoring system, by increasing the specificity from 50% in Mayo to 64% in our triple classifier at 85% fixed sensitivity. The cumulative incidence of progress (pCIP5yr) was 7.5% in low-risk vs 44.7% in high-risk in M0 patients classified by the triple classifier at diagnosis. CONCLUSIONS: The triple classifier panel that combines clinicopathological variables with genome-wide methylation data has the potential to improve specificity in prognosis prediction for patients with non-metastatic ccRCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Metilação de DNA/genética , Epigênese Genética , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Prognóstico
7.
Front Immunol ; 11: 785, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32431706

RESUMO

Melanization is a prominent insect humoral response for encapsulation of and killing invading pathogens. It is mediated by a protease cascade composed of a modular serine protease (SP), and clip domain SPs (cSPs), which converts prophenoloxidase (PPO) into active phenoloxidase (PO). To date, melanization pathway in cotton bollworm Helicoverpa armigera, an important agricultural pest, remains largely unclear. To biochemically reconstitute the pathway in vitro, the putative proteases along with modified proteases containing the factor Xa cleavage site were expressed by Drosophila S2 cell expression system. Purified recombinant proteins were used to examine their role in activating PPO. It is revealed that cascade is initiated by a modular SP-SP41, followed by cSP1 and cSP6. The three-step SP41/cSP1/cSP6 cascade could further activate PPO, and the PO activity was significantly enhanced in the presence of two cSP homologs (cSPHs), cSPH11 and cSPH50, suggesting the latter are cofactors for PPO activation. Moreover, baculovirus infection was efficiently blocked by the reconstituted PPO activation cascade, and the effect was boosted by cSPH11 and cSPH50. Taken together, we unraveled a conserved PPO activation cascade in H. armigera, which is similar to that exists in lepidopteran biochemical model Manduca sexta and highlighted its role in antagonizing viral infection.


Assuntos
Catecol Oxidase/metabolismo , Ativação Enzimática/genética , Precursores Enzimáticos/metabolismo , Proteínas de Insetos/metabolismo , Lepidópteros/enzimologia , Transdução de Sinais/genética , Animais , Linhagem Celular , Infecções por Vírus de DNA/enzimologia , Infecções por Vírus de DNA/virologia , Drosophila/citologia , Fator Xa/metabolismo , Proteínas de Insetos/genética , Lepidópteros/virologia , Manduca/enzimologia , Nucleopoliedrovírus , Proteínas Recombinantes/metabolismo , Transfecção
8.
J Virol ; 93(6)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30602603

RESUMO

Baculovirus entry into insect midgut cells is dependent on a multiprotein complex of per os infectivity factors (PIFs) on the envelopes of occlusion-derived virions (ODVs). The structure and assembly of the PIF complex are largely unknown. To reveal the complete members of the complex, a combination of blue native polyacrylamide gel electrophoresis, liquid chromatography-tandem mass spectrometry, and Western blotting was conducted on three different baculoviruses. The results showed that the PIF complex has a molecular mass of ∼500 kDa and consists of nine PIFs, including a newly discovered member (PIF9). To decipher the assembly process, each pif gene was knocked out from the Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) genome individually by use of synthetic baculovirus technology, and the impact on PIF complex formation was investigated. Deletion of pif8 resulted in the formation of an ∼400-kDa subcomplex. Deletion of pif0, -4, -6, -7, or -9 resulted in a subcomplex of ∼230 kDa, but deletion of pif1, -2, or -3 abolished formation of any complex. Taken together, our data identified a core complex of ∼230 kDa, consisting of PIF1, -2, and -3. This revised the previous knowledge that the core complex was about 170 kDa and contained PIF1 to -4. Analysis of the PIF complex in cellular fractions suggested that it is assembled in the cytoplasm before being transported to the nucleus and subsequently incorporated into the envelopes of ODVs. Only the full complex, not the subcomplex, is resistant to proteolytic attack, indicating the essentiality of correct complex assembly for oral infection.IMPORTANCE Entry of baculovirus into host insects is mediated by a per os infectivity factor (PIF) complex on the envelopes of occlusion-derived viruses (ODVs). Knowledge of the composition and structure of the PIF complex is fundamental to understanding its mode of action. By using multiple approaches, we determined the complete list of proteins (nine) in the PIF complex. In contrast to previous knowledge in the field, the core complex is revised to ∼230 kDa and consists of PIF1 to -3 but not PIF4. Interestingly, our results suggest that the PIF complex is formed in the cytoplasm prior to its transport to the nucleus and subsequent incorporation into ODVs. Only the full complex is resistant to proteolytic degradation in the insect midgut, implying the critical role of the entire complex. These findings provide the baseline for future studies on the ODV entry mechanism mediated by the multiprotein complex.


Assuntos
Baculoviridae/metabolismo , Baculoviridae/patogenicidade , Fatores de Virulência/metabolismo , Animais , Linhagem Celular , Infecções por Vírus de DNA , Insetos/virologia , Nucleopoliedrovírus/patogenicidade , Células Sf9 , Proteínas do Envelope Viral/metabolismo , Vírion/patogenicidade
9.
Breast Cancer Res ; 20(1): 153, 2018 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30558679

RESUMO

BACKGROUND: Overdiagnosis, defined as the detection of a cancer that would not become clinically apparent in a woman's lifetime without screening, has become a growing concern. Similar underlying risk of breast cancer in the screened and control groups is a prerequisite for unbiased estimates of overdiagnosis, but a contemporary control group is usually not available in organized screening programs. METHODS: We estimated the frequency of overdiagnosis of breast cancer due to screening in women 50-69 years old by using individual screening data from the population-based organized screening program in Stockholm County 1989-2014. A hidden Markov model with four latent states and three observed states was constructed to estimate the natural progression of breast cancer and the test sensitivity. Piecewise transition rates were used to consider the time-varying transition rates. The expected number of detected non-progressive breast cancer cases was calculated. RESULTS: During the study period, 2,333,153 invitations were sent out; on average, the participation rate in the screening program was 72.7% and the average recall rate was 2.48%. In total, 14,648 invasive breast cancer cases were diagnosed; among the 8305 screen-detected cases, the expected number of non-progressive breast cancer cases was 35.9, which is equivalent to 0.43% (95% confidence interval (CI) 0.10%-2.2%) overdiagnosis. The corresponding estimates for the prevalent and subsequent rounds were 15.6 (0.87%, 95% CI 0.20%-4.3%) and 20.3 (0.31%, 95% CI 0.07%-1.6%), respectively. The likelihood ratio test showed that the non-homogeneous model fitted the data better than an age-homogeneous model (P <0.001). CONCLUSIONS: Our findings suggest that overdiagnosis in the organized biennial mammographic screening for women 50-69 in Stockholm County is a minor phenomenon. The frequency of overdiagnosis in the prevalent screening round was higher than that in subsequent rounds. The non-homogeneous model performed better than the simpler, traditional homogeneous model.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Detecção Precoce de Câncer/estatística & dados numéricos , Mamografia/estatística & dados numéricos , Programas de Rastreamento/estatística & dados numéricos , Uso Excessivo dos Serviços de Saúde/estatística & dados numéricos , Idoso , Neoplasias da Mama/epidemiologia , Detecção Precoce de Câncer/métodos , Feminino , Seguimentos , Humanos , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Prevalência , Suécia/epidemiologia
10.
Med Phys ; 45(12): 5450-5460, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30242845

RESUMO

PURPOSE: There is increasing interest in computed tomography (CT) image estimations from magnetic resonance (MR) images. The estimated CT images can be utilized for attenuation correction, patient positioning, and dose planning in diagnostic and radiotherapy workflows. This study aims to introduce a novel statistical learning approach for improving CT estimation from MR images and to compare the performance of our method with the existing model-based CT image estimation methods. METHODS: The statistical learning approach proposed here consists of two stages. At the training stage, prior knowledge about tissue types from CT images was used together with a Gaussian mixture model (GMM) to explore CT image estimations from MR images. Since the prior knowledge is not available at the prediction stage, a classifier based on RUSBoost algorithm was trained to estimate the tissue types from MR images. For a new patient, the trained classifier and GMMs were used to predict CT image from MR images. The classifier and GMMs were validated by using voxel-level tenfold cross-validation and patient-level leave-one-out cross-validation, respectively. RESULTS: The proposed approach has outperformance in CT estimation quality in comparison with the existing model-based methods, especially on bone tissues. Our method improved CT image estimation by 5% and 23% on the whole brain and bone tissues, respectively. CONCLUSIONS: Evaluation of our method shows that it is a promising method to generate CT image substitutes for the implementation of fully MR-based radiotherapy and PET/MRI applications.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Aprendizado de Máquina , Tomografia Computadorizada por Raios X , Humanos , Imageamento por Ressonância Magnética
11.
Infect Immun ; 83(8): 3233-42, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26034213

RESUMO

Certain intracellular bacteria use the host cell cytosol as the replicative niche. Although it has been hypothesized that the successful exploitation of this compartment requires a unique metabolic adaptation, supportive evidence is lacking. For Francisella tularensis, many genes of the Francisella pathogenicity island (FPI) are essential for intracellular growth, and therefore, FPI mutants are useful tools for understanding the prerequisites of intracytosolic replication. We compared the growth of bacteria taken up by phagocytic or nonphagocytic cells with that of bacteria microinjected directly into the host cytosol, using the live vaccine strain (LVS) of F. tularensis; five selected FPI mutants thereof, i.e., ΔiglA, ΔiglÇ ΔiglG, ΔiglI, and ΔpdpE strains; and Listeria monocytogenes. After uptake in bone marrow-derived macrophages (BMDM), ASC(-/-) BMDM, MyD88(-/-) BMDM, J774 cells, or HeLa cells, LVS, ΔpdpE and ΔiglG mutants, and L. monocytogenes replicated efficiently in all five cell types, whereas the ΔiglA and ΔiglC mutants showed no replication. After microinjection, all 7 strains showed effective replication in J774 macrophages, ASC(-/-) BMDM, and HeLa cells. In contrast to the rapid replication in other cell types, L. monocytogenes showed no replication in MyD88(-/-) BMDM and LVS showed no replication in either BMDM or MyD88(-/-) BMDM after microinjection. Our data suggest that the mechanisms of bacterial uptake as well as the permissiveness of the cytosolic compartment per se are important factors for the intracytosolic replication. Notably, none of the investigated FPI proteins was found to be essential for intracytosolic replication after microinjection.


Assuntos
Replicação do DNA , Francisella tularensis/crescimento & desenvolvimento , Listeria monocytogenes/crescimento & desenvolvimento , Listeriose/microbiologia , Tularemia/microbiologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Linhagem Celular , Citosol/metabolismo , Citosol/microbiologia , Francisella tularensis/genética , Francisella tularensis/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Listeria monocytogenes/genética , Listeria monocytogenes/metabolismo , Listeriose/genética , Listeriose/metabolismo , Macrófagos/metabolismo , Macrófagos/microbiologia , Microinjeções , Tularemia/genética , Tularemia/metabolismo
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