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1.
Eur J Cancer ; 162: 194-205, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35026490

RESUMO

BACKGROUND: The aggressive nature of breast cancers detected between planned mammographic screens, so-called interval cancers, remains elusive. Here, we aim to characterise underlying molecular features of interval cancer. METHODS: From 672 patients with invasive breast cancer, we analysed gene expression differences between 90 'true' interval cancer cases (i.e. women with low-dense breasts defined as per cent mammographic density <25%) and 310 screen-detected tumours while accounting for PAM50 subtypes and thus overall tumour aggressiveness. We computed an interval cancer gene expression profile (IC-Gx) in a total of 2270 breast tumours (regardless of interval cancer status) and tested for association with expression-based immune subtypes in breast cancer. In addition, we investigated the contribution of inherited and somatic genetic variants in distinct features of interval cancer. RESULTS: We identified 8331 genes nominally associated with interval cancer (P-value < 0.05, fold-change > 1.5). Gene set enrichment analysis showed immune-related pathways as key processes altered in interval cancer. Our IC-Gx, based on 47 genes with the strongest associations (false discovery rate < 0.05), was found to be associated mainly with immune subtypes involving interferon response. We isolated an interaction network of interval cancer and interferon genes for which a significant load of somatic and germline variants in class I interferon genes was observed. CONCLUSION: We identified novel molecular features of interval breast cancer highlighting interferon pathways as a potential target for prevention or treatment.

2.
J Int Med Res ; 49(11): 3000605211060890, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34851762

RESUMO

OBJECTIVE: This prospective study aimed to evaluate the safety of improved transurethral plasma kinetic enucleation of the prostate (iTUPKEP) in the perioperative period in high-risk patients with benign prostatic hyperplasia (BPH) and coronary artery disease. METHODS: Patients with BPH underwent surgical treatment with transurethral vapour resection of the prostate (TUVP) or iTUPKEP. Serum endothelin-1, cardiac troponin-I, and high-sensitivity C-reactive protein concentrations were evaluated in the short term after surgery. The postvoid residual urine volume, maximum urinary flow rate, international prostate symptom score, and quality of life indicators were evaluated in the long term after surgery. RESULTS: Endothelin-1 concentrations were lower in the iTUPKEP group than in the TUVP group at 1 and 2 days postoperatively. The iTUPKEP group had lower cardiac troponin-I and high-sensitivity C-reactive protein concentrations at all time points postoperatively. The postvoid residual urine volume, international prostate symptom score, and quality of life values were lower, but the maximum urinary flow rate was higher, in the iTUPKEP group than in the TUVP group. CONCLUSIONS: The iTUPKEP procedure has a smaller effect on vascular endothelial function compared with TUVP. Therefore, iTUPKEP may reduce the incidence of postoperative cardiovascular adverse events in high-risk patients with BPH and coronary artery disease.

3.
Genome Med ; 13(1): 185, 2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34857041

RESUMO

BACKGROUND: Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent. METHODS: Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease. RESULTS: PTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35-5.17], moderately vs well-differentiated 2.33 [1.56-3.49]), as well as luminal B [HER-] and triple-negative subtypes (vs luminal A 2.15 [1.58-2.92] and 2.85 [2.17-3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2-] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16-2.28]). CONCLUSIONS: PTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions.

4.
Genet Med ; 2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34906514

RESUMO

PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

5.
Appl Intell (Dordr) ; : 1-15, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-34764591

RESUMO

Knowledge in the source domain can be used in transfer learning to help train and classification tasks within the target domain with fewer available data sets. Therefore, given the situation where the target domain contains only a small number of available unlabeled data sets and multi-source domains contain a large number of labeled data sets, a new Multi-source Fast Transfer Learning algorithm based on support vector machine(MultiFTLSVM) is proposed in this paper. Given the idea of multi-source transfer learning, more source domain knowledge is taken to train the target domain learning task to improve classification effect. At the same time, the representative data set of the source domain is taken to speed up the algorithm training process to improve the efficiency of the algorithm. Experimental results on several real data sets show the effectiveness of MultiFTLSVM, and it also has certain advantages compared with the benchmark algorithm.

6.
Cancer Med ; 10(22): 8182-8191, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34708579

RESUMO

BACKGROUND: Breast cancer incidence is increasing in Asia. However, few women in Singapore attend routine mammography screening. We aim to identify women at high risk of breast cancer who will benefit most from regular screening using the Gail model and information from their first screen (recall status and mammographic density). METHODS: In 24,431 Asian women (50-69 years) who attended screening between 1994 and 1997, 117 developed breast cancer within 5 years of screening. Cox proportional hazard models were used to study the associations between risk classifiers (Gail model 5-year absolute risk, recall status, mammographic density), and breast cancer occurrence. The efficacy of risk stratification was evaluated by considering sensitivity, specificity, and the proportion of cancers identified. RESULTS: Adjusting for information from first screen attenuated the hazard ratios (HR) associated with 5-year absolute risk (continuous, unadjusted HR [95% confidence interval]: 2.3 [1.8-3.1], adjusted HR: 1.9 [1.4-2.6]), but improved the discriminatory ability of the model (unadjusted AUC: 0.615 [0.559-0.670], adjusted AUC: 0.703 [0.653-0.753]). The sensitivity and specificity of the adjusted model were 0.709 and 0.622, respectively. Thirty-eight percent of all breast cancers were detected in 12% of the study population considered high risk (top five percentile of the Gail model 5-year absolute risk [absolute risk ≥1.43%], were recalled, and/or mammographic density ≥50%). CONCLUSION: The Gail model is able to stratify women based on their individual breast cancer risk in this population. Including information from the first screen can improve prediction in the 5 years after screening. Risk stratification has the potential to pick up more cancers.

7.
Mol Pharm ; 18(11): 4029-4045, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34559545

RESUMO

Immunogene therapy provides a new strategy for the treatment of colorectal cancer. Compared to plasmid DNA, mRNA possesses several advantages as a therapeutic nucleic acid material and shows high potential in cancer therapy. Although efforts have been made to conquer the limited efficiency of mRNA delivery, most of the current mRNA vectors possess complex structures or compositions, which introduces additional toxicity and hinders their further clinical application. Hence, it is highly necessary to develop potent mRNA delivery systems with simple structures. Here, we report efficient mRNA delivery using the biodegradable micelle delivery system of DMP (DOTAP-mPEG-PCL). Biodegradable DMP micelles were simply prepared by the self-assembly of cationic lipid DOTAP and the diblock polymer monomethoxy poly(ethylene glycol)-poly(ε-caprolactone). With an average size of only 30 nm, we proved that these single-structured cationic micelles are highly potent in condensing and protecting mRNA molecules, with a delivery efficiency of 60.59% on C26 mouse colon cancer cells. The micelles triggered specific internalization pathways and were fully degraded in vivo. After binding with IL-22BP (interleukin-22 binding protein)-encoding mRNA, a strongly elevated IL-22BP mRNA level was detected in C26 cells. After intraperitoneal and intratumoral injection of the DMP/mIL-22BP complex, strong inhibition effects on C26 colon cancer models were observed, with high therapeutic efficiency and safety when systemically administrated. These data suggest that the DMP micelle is an advanced single-structured mRNA delivery system with high safety.

8.
Int J Nanomedicine ; 16: 5211-5232, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34366664

RESUMO

Background: Gene therapy has emerged as a new strategy for cancer therapy. As an alternative nucleic acid material, messenger ribonucleic acid (mRNA) is being increasingly utilized in cancer gene therapy. However, unfulfilled requirements and a lack of ideal mRNA delivery vectors persist. Methods: We developed an advanced mRNA delivery system, DMP-039, by fusing a cell-penetrating peptide, cRGD-R9, and a cationic nano-sized DMP backbone together. The DMP gene vector backbone was synthesized by the self-assembly of DOTAP lipid and mPEG-PCL polymer. Introduction of the cRGD-R9 peptide onto the DMP backbone was performed to elevate the mRNA delivery capacity, which resulted in a peptide-functionalized hybrid delivery system. Results: The average size of the synthesized DMP-039 was 268.9 ± 12.4 nm (PDI = 0.382), with a potential of 17.4 ± 0.5 mV. The synthesized DMP-039 hybrid nanoparticles exhibited high mRNA delivery efficiency through multiple mechanisms during transmembrane transportation. By loading the encoding mRNA from the suicide gene Bim, a locally administered mBim/DMP-039 complex strongly inhibited growth in two colon cancer models. Moreover, intravenous administration of the mBim/DMP-039 complex efficiently suppressed C26 pulmonary metastatic tumor progression with high safety. The in vivo distribution, degradation, and excretion were also investigated in detail. Conclusion: Our results suggest that the DMP-039 peptide-functionalized hybrid nanoparticle is an advanced candidate for mRNA-based suicide gene therapy.


Assuntos
Neoplasias do Colo , Nanopartículas , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/terapia , Ácidos Graxos Monoinsaturados , Terapia Genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Poliésteres , Polietilenoglicóis , Compostos de Amônio Quaternário , RNA Mensageiro/genética
9.
HGG Adv ; 2(3)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34317694

RESUMO

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

10.
Clin Case Rep ; 9(5): e03852, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34026122

RESUMO

Though typical dysembryoplastic neuroepithelial tumors (DNETs) are located in the cerebral cortex, an atypical DNET could occur in the temporal horn of the lateral ventricle and broadly involve the ependyma. Awareness of this atypical form of DNET is of value for the wright diagnosis and management of atypical DNETs.

11.
J Med Genet ; 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33811135

RESUMO

BACKGROUND: Rare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (PALB2) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in PALB2 in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population. METHODS: Mutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays. RESULTS: PTVs in PALB2 were found in 0.73% of breast cancer patients and 0.14% of healthy individuals (OR=5.44; 95% CI 2.85 to 10.39, p<0.0001). In contrast, rare missense variants in PALB2 were not associated with increased risk of breast cancer. Whereas PTVs were associated with later stage of presentation and higher-grade tumours, no significant association was observed with missense variants in PALB2. However, two novel rare missense variants (p.L1027R and p.G1043V) produced unstable proteins and resulted in a decrease in homologous recombination-mediated repair of DNA double-strand breaks. CONCLUSION: Despite genetic and lifestyle differences between Asian and other populations, the population prevalence of PALB2 PTVs and associated relative risk of breast cancer, are similar to those reported in European populations.

12.
PLoS One ; 16(4): e0250102, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33901219

RESUMO

This article aims to provide a detailed description of the Singapore Breast Cancer Cohort (SGBCC), an ongoing multi-ethnic cohort established with the overarching goal to identify genetic markers for breast cancer risk, prognosis and treatment response, as well as to understand the ethnic differences in disease risk and outcome in an Asian setting. The cohort comprises of breast cancer patients aged 21 years and above from six public hospitals which diagnose and treat nearly 76% breast cancer cases in Singapore. Self-reported data on sociodemographic and lifestyle, reproductive risk factors, medical history and family history of breast or ovarian cancer is collected using a structured questionnaire. Clinical data on tumour characteristics, and treatment modalities are obtained through medical record. Bio-specimens (blood or saliva) is collected at recruitment. Follow-up on survival information is done through routine linkage with the Registry of Births and Deaths. As of 31 December 2016, 7,768 subjects have been recruited to the study with 76% subjects contributed bio-specimens. The SGBCC provides a valuable platform which offers a unique, large and rich resource for new research ideas on breast cancer related phenotypic risk factors and genetic markers.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/patologia , Estudos de Coortes , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Neoplasias Ovarianas , Prognóstico , Fatores de Risco , Singapura/epidemiologia , Inquéritos e Questionários
13.
Signal Transduct Target Ther ; 6(1): 169, 2021 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-33895780

RESUMO

Neurological manifestations are frequently reported in the COVID-19 patients. Neuromechanism of SARS-CoV-2 remains to be elucidated. In this study, we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19. In rhesus monkey, SARS-CoV-2 invades the CNS primarily via the olfactory bulb. Thereafter, viruses rapidly spread to functional areas of the central nervous system, such as hippocampus, thalamus, and medulla oblongata. The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons, microglia, and astrocytes in the CNS. Consistently, SARS-CoV-2 infects neuro-derived SK-N-SH, glial-derived U251, and brain microvascular endothelial cells in vitro. To our knowledge, this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model, which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.


Assuntos
Encefalopatias/metabolismo , Encéfalo/metabolismo , COVID-19/metabolismo , Bulbo Olfatório/metabolismo , SARS-CoV-2/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Astrócitos/virologia , Encéfalo/patologia , Encéfalo/virologia , Encefalopatias/patologia , Encefalopatias/virologia , COVID-19/patologia , Modelos Animais de Doenças , Humanos , Macaca mulatta , Microglia/metabolismo , Microglia/patologia , Microglia/virologia , Neurônios/metabolismo , Neurônios/patologia , Neurônios/virologia , Bulbo Olfatório/patologia , Bulbo Olfatório/virologia
14.
Breast Cancer Res Treat ; 188(3): 713-727, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33768416

RESUMO

BACKGROUND: A breast cancer polygenic risk score (PRS) comprising 313 common variants reliably predicts disease risk. We examined possible relationships between genetic variation, regulation, and expression to clarify the molecular alterations associated with these variants. METHODS: Genome-wide methylomic variation was quantified (MethylationEPIC) in Asian breast cancer patients (1152 buffy coats from peripheral whole blood). DNA methylation (DNAm) quantitative trait loci (mQTL) mapping was performed for 235 of the 313 variants with minor allele frequencies > 5%. Stability of identified mQTLs (p < 5e-8) across lifetime was examined using a public mQTL database. Identified mQTLs were also mapped to expression quantitative trait loci (eQTLs) in the Genotype-Tissue Expression Project and the eQTLGen Consortium. RESULTS: Breast cancer PRS was not associated with DNAm. A higher proportion of significant cis-mQTLs were observed. Of 822 significant cis-mQTLs (179 unique variants) identified in our dataset, 141 (59 unique variants) were significant (p < 5e-8) in a public mQTL database. Eighty-six percent (121/141) of the matched mQTLs were consistent at multiple time points (birth, childhood, adolescence, pregnancy, middle age, post-diagnosis, or treatment). Ninety-three variants associated with DNAm were also cis-eQTLs (35 variants not genome-wide significant). Multiple loci in the breast cancer PRS are associated with DNAm, contributing to the polygenic nature of the disease. These mQTLs are mostly stable over time. CONCLUSIONS: Consistent results from DNAm and expression data may reveal new candidate genes not previously associated with breast cancer.


Assuntos
Neoplasias da Mama , Metilação de DNA , Adolescente , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Criança , Feminino , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
15.
Hum Mutat ; 42(2): 200-212, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33314489

RESUMO

The discovery of high-risk breast cancer susceptibility genes, such as Breast cancer associated gene 1 (BRCA1) and Breast cancer associated gene 2 (BRCA2) has led to accurate identification of individuals for risk management and targeted therapy. The rapid decline in sequencing costs has tremendously increased the number of individuals who are undergoing genetic testing world-wide. However, given the significant differences in population-specific variants, interpreting the results of these tests can be challenging especially for novel genetic variants in understudied populations. Here we report the characterization of novel variants in the Malaysian and Singaporean population that consist of different ethnic groups (Malays, Chinese, Indian, and other indigenous groups). We have evaluated the functional significance of 14 BRCA2 variants of uncertain clinical significance by using multiple in silico prediction tools and examined their frequency in a cohort of 7840 breast cancer cases and 7928 healthy controls. In addition, we have used a mouse embryonic stem cell (mESC)-based functional assay to assess the impact of these variants on BRCA2 function. We found these variants to be functionally indistinguishable from wild-type BRCA2. These variants could fully rescue the lethality of Brca2-null mESCs and exhibited no sensitivity to six different DNA damaging agents including a poly ADP ribose polymerase inhibitor. Our findings strongly suggest that all 14 evaluated variants are functionally neutral. Our findings should be valuable in risk assessment of individuals carrying these variants.

16.
Gastroenterology ; 160(5): 1647-1661, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33307034

RESUMO

BACKGROUND & AIMS: Gastrointestinal (GI) manifestations have been increasingly reported in patients with coronavirus disease 2019 (COVID-19). However, the roles of the GI tract in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not fully understood. We investigated how the GI tract is involved in SARS-CoV-2 infection to elucidate the pathogenesis of COVID-19. METHODS: Our previously established nonhuman primate (NHP) model of COVID-19 was modified in this study to test our hypothesis. Rhesus monkeys were infected with an intragastric or intranasal challenge with SARS-CoV-2. Clinical signs were recorded after infection. Viral genomic RNA was quantified by quantitative reverse transcription polymerase chain reaction. Host responses to SARS-CoV-2 infection were evaluated by examining inflammatory cytokines, macrophages, histopathology, and mucin barrier integrity. RESULTS: Intranasal inoculation with SARS-CoV-2 led to infections and pathologic changes not only in respiratory tissues but also in digestive tissues. Expectedly, intragastric inoculation with SARS-CoV-2 resulted in the productive infection of digestive tissues and inflammation in both the lung and digestive tissues. Inflammatory cytokines were induced by both types of inoculation with SARS-CoV-2, consistent with the increased expression of CD68. Immunohistochemistry and Alcian blue/periodic acid-Schiff staining showed decreased Ki67, increased cleaved caspase 3, and decreased numbers of mucin-containing goblet cells, suggesting that the inflammation induced by these 2 types of inoculation with SARS-CoV-2 impaired the GI barrier and caused severe infections. CONCLUSIONS: Both intranasal and intragastric inoculation with SARS-CoV-2 caused pneumonia and GI dysfunction in our rhesus monkey model. Inflammatory cytokines are possible connections for the pathogenesis of SARS-CoV-2 between the respiratory and digestive systems.


Assuntos
COVID-19/transmissão , Gastroenterite/patologia , Trato Gastrointestinal/patologia , Pulmão/patologia , Animais , Brônquios/metabolismo , Brônquios/patologia , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/patologia , Teste de Ácido Nucleico para COVID-19 , Caspase 3/metabolismo , Citocinas/imunologia , Modelos Animais de Doenças , Mucosa Gástrica , Gastroenterite/metabolismo , Gastroenterite/virologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/metabolismo , Células Caliciformes/patologia , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Antígeno Ki-67/metabolismo , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Pulmão/metabolismo , Macaca mulatta , Mucosa Nasal , RNA Viral/isolamento & purificação , Distribuição Aleatória , Reto/metabolismo , Reto/patologia , SARS-CoV-2 , Traqueia/metabolismo , Traqueia/patologia
17.
Int J Cancer ; 148(4): 884-894, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-32856720

RESUMO

The association between breast cancer risk defined by the Tyrer-Cuzick score (TC) and disease prognosis is not well established. Here, we investigated the relationship between 5-year TC and disease aggressiveness and then characterized underlying molecular processes. In a case-only study (n = 2474), we studied the association of TC with molecular subtypes and tumor characteristics. In a subset of patients (n = 672), we correlated gene expression to TC and computed a low-risk TC gene expression (TC-Gx) profile, that is, a profile expected to be negatively associated with risk, which we used to test for association with disease aggressiveness. We performed enrichment analysis to pinpoint molecular processes likely to be altered in low-risk tumors. A higher TC was found to be inversely associated with more aggressive surrogate molecular subtypes and tumor characteristics (P < .05) including Ki-67 proliferation status (P < 5 × 10-07 ). Our low-risk TC-Gx, based on the weighted sum of 37 expression values of genes strongly correlated with TC, was associated with basal-like (P < 5 × 10-13 ), HER2-enriched subtype (P < 5 × 10-07 ) and worse 10-year breast cancer-specific survival (log-rank P < 5 × 10-04 ). Associations between low-risk TC-Gx and more aggressive molecular subtypes were replicated in an independent cohort from The Cancer Genome Atlas database (n = 975). Gene expression that correlated with low TC was enriched in proliferation and oncogenic signaling pathways (FDR < 0.05). Moreover, higher proliferation was a key factor explaining the association with worse survival. Women who developed breast cancer despite having a low risk were diagnosed with more aggressive tumors and had a worse prognosis, most likely driven by increased proliferation. Our findings imply the need to establish risk factors associated with more aggressive breast cancer subtypes.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Coortes , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Fatores de Risco
18.
Int J Nanomedicine ; 15: 9875-9890, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33324056

RESUMO

Background: Drugs that work based on the mechanism of RNA interference have shown strong potential in cancer gene therapy. Although significant progress has been made in small interfering RNA (siRNA) design and manufacturing, ideal delivery system remains a limitation for the development of siRNA-based drugs. Particularly, it is necessary to focus on parameters including delivery efficiency, stability, and safety when developing siRNA formulations for cancer therapy. Methods: In this work, a novel degradable siRNA delivery system cRGD-R9-PEG-PEI-Cholesterol (rrPPC) was synthesized based on low molecular weight polyethyleneimine (PEI). Functional groups including cholesterol, cell penetrating peptides (CPPs), and poly(ethylene oxide) were introduced to PEI backbone to attain enhanced transfection efficiency and biocompatibility. Results: The synthesized rrPPC was dispersed as nanoparticles in water with an average size of 195 nm and 41.9 mV in potential. rrPPC nanoparticles could efficiently deliver siRNA into C26 clone cancer cells and trigger caveolae-mediated pathway during transmembrane transportation. By loading the signal transducer and activator of transcription 3 (STAT3) targeting siRNA, rrPPC/STAT3 siRNA (rrPPC/siSTAT3) complex demonstrated strong anti-cancer effects in multiple colon cancer models following local delivery. In addition, intravenous (IV) injection of rrPPC/siSTAT3 complex efficiently suppressed lung metastasis tumor progression with ideal in vivo safety. Conclusion: Our results provide evidence that rrPPC nanoparticles constitute a potential candidate vector for siRNA-based colon cancer gene therapy.


Assuntos
Colesterol/química , Neoplasias do Colo/terapia , Peptídeos Cíclicos/química , Polietilenoglicóis/química , Polietilenoimina/análogos & derivados , RNA Interferente Pequeno/genética , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/genética , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Portadores de Fármacos/química , Humanos , Nanopartículas/química , Polietilenoimina/química , Interferência de RNA , RNA Interferente Pequeno/química , Transfecção
19.
J Biomed Nanotechnol ; 16(7): 1018-1044, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33308373

RESUMO

Based on its rapid expression, simple sequence composition, low immunogenicity, and flexible modification possibilities, in vitro synthesized mRNA has demonstrated strong potential as a candidate for gene therapy. Many efforts have been made to enhance its therapeutic efficacy and safety. Profiting from the development in pathogenesis and materials science, much progress has been achieved in mRNA-based therapy studies. Many mRNA-derived therapeutics including vaccines, antibodies, cytokines, and growth factors have emerged for the treatment of diverse diseases that have multiple modes of action. Novel delivery vectors with enhanced capacity, safety, and properties have been developed to meet the demands of mRNA delivery. Advanced strategies like library screening, environment interaction, and bio-inspiration materials have been used in the investigation process and produced valuable results. In this review, we summarize and discuss recent advances in mRNA-based gene therapy studies.


Assuntos
Terapia Genética , Vacinas , RNA Mensageiro
20.
Front Pharmacol ; 11: 566938, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013405

RESUMO

Adult mammalian cardiomyocytes may reenter the cell cycle and cause cardiac hypertrophy. Triptolide (TP) can regulate the expressions of various cell cycle regulators in cancer cells. However, its effects on cell cycle regulators during myocardial hypertrophy and mechanism are unclear. This study was designed to explore the profile of cell cycle of cardiomyocytes and the temporal expression of their regulators during cardiac hypertrophy, as well as the effects of TP. The hypertrophy models employed were neonatal rat ventricular myocytes (NRVMs) stimulated with angiotensin II (Ang II) for scheduled times (from 5 min to 48 h) in vitro and mice treated with isoprenaline (Iso) for from 1 to 21 days, respectively. TP was used in vitro at 1 µg/L and in vivo at 10 µg/kg. NRVMs were analyzed using flow cytometry to detect the cell cycle, and the expression levels of mRNA and protein of various cell cycle regulators were determined using real-time PCR and Western blot. It was found NRVM numbers in phases S and G2 increased, while that in the G1 phase decreased significantly after Ang II stimulation. The mRNA expression levels of p21 and p27 increased soon after stimulation, and thereafter, mRNA expression levels of all cell cycle factors showed a decreasing trend and reached their lowest levels in 1-3 h, except for cyclin-dependent kinase 1 (CDK1) and CDK4 mRNA. The mRNA expression levels of CDK1, p21, and p27 increased markedly after stimulation with Ang II for 24-48 h. In myocardium tissue, CDK and cyclin expression levels peaked in 3-7 days, followed by a decreasing trend, while those of p21 and p27 mRNA remained at a high level on day 21. Expression levels of all protein were consistent with the results of mRNA in NRVMs or mice. The influence of Ang II or Iso on protein expression was more obvious than that on mRNA. TP treatment effectively prevented the imbalance in the expression of cell cycle regulators in the hypertrophy model group. In Conclusion, an imbalance in the expression of cell cycle regulators occurs during cardiac hypertrophy, and triptolide corrects these abnormal expression levels and attenuates cardiac hypertrophy.

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