RESUMEN
This study targeted to explore circUQCRC2's role and mechanism in childhood asthma. A mouse model of ovalbumin-induced asthma was established to evaluate the effects of circUQCRC2 on childhood asthma in terms of oxidative stress, inflammation, and collagen deposition. The effects of circUQCRC2 on platelet-derived growth factor-BB (PDGF-BB)-induced smooth muscle cells (SMCs) were evaluated, the downstream mRNA of miRNA and its associated pathways were predicted and validated, and their effects on asthmatic mice were evaluated. circUQCRC2 levels were upregulated in bronchoalveolar lavage fluid of asthmatic mice and PDGF-BB-treated SMCs. Depleting circUQCRC2 alleviated tissue damage in asthmatic mice, improved inflammatory levels and oxidative stress in asthmatic mice and PDGF-BB-treated SMC, inhibited malignant proliferation and migration of SMCs, and improved airway remodeling. Mechanistically, circUQCRC2 regulated VEGFA expression through miR-381-3p and activated the NF-κB cascade. circUQCRC2 knockdown inactivated the NF-κB cascade by modulating the miR-381-3p/VEGFA axis. Promoting circUQCRC2 stimulates asthma development by activating the miR-381-3p/VEGFA/NF-κB cascade. Therefore, knocking down circUQCRC2 or overexpressing miR-381-3p offers a new approach to treating childhood asthma.
Asunto(s)
Asma , MicroARNs , FN-kappa B , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular , Asma/genética , Asma/metabolismo , Asma/patología , MicroARNs/genética , MicroARNs/metabolismo , Animales , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , FN-kappa B/metabolismo , Ratones , Humanos , Niño , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Becaplermina/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , ARN Circular/genética , ARN Circular/metabolismo , Femenino , Masculino , Ratones Endogámicos BALB C , Proliferación Celular , Estrés Oxidativo , Remodelación de las Vías Aéreas (Respiratorias)/genéticaRESUMEN
The relationship between tissue-specific DNA methylation and cancer risk remains inadequately elucidated. Leveraging resources from the Genotype-Tissue Expression consortium, here we develop genetic models to predict DNA methylation at CpG sites across the genome for seven tissues and apply these models to genome-wide association study data of corresponding cancers, namely breast, colorectal, renal cell, lung, ovarian, prostate, and testicular germ cell cancers. At Bonferroni-corrected P < 0.05, we identify 4248 CpGs that are significantly associated with cancer risk, of which 95.4% (4052) are specific to a particular cancer type. Notably, 92 CpGs within 55 putative novel loci retain significant associations with cancer risk after conditioning on proximal signals identified by genome-wide association studies. Integrative multi-omics analyses reveal 854 CpG-gene-cancer trios, suggesting that DNA methylation at 309 distinct CpGs might influence cancer risk through regulating the expression of 205 unique cis-genes. These findings substantially advance our understanding of the interplay between genetics, epigenetics, and gene expression in cancer etiology.
Asunto(s)
Biomarcadores de Tumor , Islas de CpG , Metilación de ADN , Estudio de Asociación del Genoma Completo , Neoplasias , Especificidad de Órganos , Humanos , Islas de CpG/genética , Neoplasias/genética , Masculino , Femenino , Biomarcadores de Tumor/genética , Especificidad de Órganos/genética , Predisposición Genética a la Enfermedad , Regulación Neoplásica de la Expresión Génica , Epigénesis Genética , Neoplasias de Células Germinales y Embrionarias , Neoplasias TesticularesRESUMEN
Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which, two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared with luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates the enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to two-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among patients with breast cancer. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC. Significance: The discovery of subtype-informative genetic risk variants for breast cancer advances our understanding of the etiologic heterogeneity of breast cancer, which could accelerate the identification of targets and personalized strategies for prevention and treatment.
Asunto(s)
Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Estudios de Casos y Controles , Factores de RiesgoRESUMEN
RATIONALE: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare but serious complication in patients with malignancy; its main manifestation includes acute pulmonary hypertension with severe respiratory distress. More than 200 cases have been reported since it was first identified in 1990. PTTM accounts for approximately 0.9% to 3.3% of deaths due to malignancy, but only a minority of patients are diagnosed ante-mortem, with most patients having a definitive diagnosis after autopsy. PATIENT CONCERNS: Two middle-aged women both died within a short period of time due to progressive dyspnea and severe pulmonary hypertension. DIAGNOSES: One patient was definitively confirmed as a gastrointestinal malignant tumor by liver puncture biopsy pathology. Ultimately, the clinical diagnosis was pulmonary tumor thrombotic microangiopathy. INTERVENTIONS: The patient was treated symptomatically with oxygen, diuresis, and anticoagulation, while a liver puncture was perfected to clarify the cause. OUTCOMES: Two cases of middle-aged female patients with rapidly progressive pulmonary hypertension and respiratory failure resulted in death with malignant neoplasm. LESSONS: PTTM has a rapid onset and a high morbidity and mortality rate. Our clinicians need to be more aware of the need for timely diagnosis through a targeted clinical approach, leading to more targeted treatment and a better prognosis.
Asunto(s)
Microangiopatías Trombóticas , Humanos , Femenino , Microangiopatías Trombóticas/etiología , Microangiopatías Trombóticas/diagnóstico , Persona de Mediana Edad , Resultado Fatal , Hipertensión Pulmonar/etiología , Neoplasias Gastrointestinales/complicaciones , Neoplasias Gastrointestinales/patología , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnósticoRESUMEN
Identifying risk protein targets and their therapeutic drugs is crucial for effective cancer prevention. Here, we conduct integrative and fine-mapping analyses of large genome-wide association studies data for breast, colorectal, lung, ovarian, pancreatic, and prostate cancers, and characterize 710 lead variants independently associated with cancer risk. Through mapping protein quantitative trait loci (pQTL) for these variants using plasma proteomics data from over 75,000 participants, we identify 365 proteins associated with cancer risk. Subsequent colocalization analysis identifies 101 proteins, including 74 not reported in previous studies. We further characterize 36 potential druggable proteins for cancers or other disease indications. Analyzing >3.5 million electronic health records, we uncover five drugs (Haloperidol, Trazodone, Tranexamic Acid, Haloperidol, and Captopril) associated with increased cancer risk and two drugs (Caffeine and Acetazolamide) linked to reduced colorectal cancer risk. This study offers novel insights into therapeutic drugs targeting risk proteins for cancer prevention and intervention.
RESUMEN
To clarify the preferences of employees seeking influenza vaccination, a discrete choice experiment aims to understand the essential factors that close the gap between intention and behavior. A total of 866 employees with vaccination willingness willing to participated in a discrete choice experiment (DCE) between October 31st and December 6th, 2022 in China including the following attributes: price, vaccination setting, appointment mode, and service time. The data was analyzed using mixed logit models. Employees from smaller enterprises were more likely to get vaccinated collectively. For employees willing to get the influenza vaccine, 95.08 % of their choice was dominated by price. Employees' behavior varied according to their socioeconomic characteristics. Only female employees strongly favored work-site-based vaccination. Price was the primary factor considered by employees for getting the influenza vaccine. DCE would help to develop influenza vaccination intervention targeted at different groups in future studies.
RESUMEN
Objective: The study established a nomogram based on quantitative parameters of spectral computed tomography (CT) and clinical characteristics, aiming to evaluate its predictive value for preoperative lymphovascular invasion (LVI) in gastric cancer (GC). Methods: From December 2019 to December 2021, 171 patients with pathologically confirmed GC were retrospectively collected with corresponding clinical data and spectral CT quantitative data. Patients were divided into LVI-positive and LVI-negative groups based on their pathological results. The univariate and multivariate logistic regression analyses were used to identify the risk factors and construct a nomogram. The calibration curve and receiver operating characteristic (ROC) curve were adopted to evaluate the predictive accuracy of nomogram. Results: Four clinical characteristics or spectral CT quantitative parameters, including Borrmann classification (P = 0.039), CA724 (P = 0.007), tumor thickness (P = 0.031), and iodine concentration in the venous phase (VIC) (P = 0.004) were identified as independent factors for LVI in GC patients. The nomogram was established based on the four factors, which had a potent predictive accuracy in the training, internal validation and external validation cohorts, with the area under the ROC curve (AUC) of 0.864 (95% CI, 0.798-0.930), 0.964 (95% CI, 0.903-1.000) and 0.877 (95% CI, 0.759-0.996), respectively. Conclusion: This study constructed a comprehensive nomogram consisting spectral CT quantitative parameters and clinical characteristics of GC, which exhibited a robust efficiency in predicting LVI in GC patients.
RESUMEN
The association between metformin use and risk of prostate cancer remains controversial, while data from randomized trials is lacking. We aim to evaluate the association of genetically proxied metformin effects with prostate cancer risk using a drug-target Mendelian randomization (MR) approach. Summary statistics for prostate cancer were obtained from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome Consortium (79,148 cases and 61,106 controls). Cis-expression quantitative trait loci (cis-eQTL) variants in the gene targets of metformin were identified in the GTEx project and eQTLGen consortium. We also obtained male-specific genome-wide association study data for type 2 diabetes, body mass index (BMI), total testosterone, bioavailable testosterone, estradiol, and sex hormone binding globulin for mediation analysis. Inverse-variance weighted (IVW) regression, weighted median, MR-Egger regression, and MR-PRESSO were performed in the main MR analysis. Multivariable MR was used to identify potential mediators and genetic colocalization analysis was performed to assess any shared genetic basis between two traits of interest. We found that genetically proxied metformin effects (1-SD HbA1c reduction, equivalent to 6.75 mmol/mol) were associated with higher risk of prostate cancer (odds ratioIVW [ORIVW]: 1.55, 95% confidence interval, CI: 1.23-1.96, p = 3.0 × 10-3). Two metformin targets, mitochondrial complex I (ORIVW: 1.48, 95% CI: 1.07-2.03, p = 0.016) and gamma-secretase complex (ORIVW: 2.58, 95%CI :1.47-4.55, p = 0.001), showed robust associations with prostate cancer risk, and their effects were partly mediated through BMI (16.4%) and total testosterone levels (34.3%), respectively. These results were further supported by colocalization analysis that expressions of NDUFA13 and BMI, APH1A, and total testosterone may be influenced by shared genetic factors, respectively. In summary, our study indicated that genetically proxied metformin effects may be associated with an increased risk of prostate cancer. Repurposing metformin for prostate cancer prevention in general populations is not supported by our findings.
Asunto(s)
Diabetes Mellitus Tipo 2 , Metformina , Neoplasias de la Próstata , Masculino , Humanos , Metformina/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Testosterona , Polimorfismo de Nucleótido SimpleRESUMEN
Introduction: The purpose of this study is to examine the potential causal relationship between levels of circulating glycine and coronary artery disease (CAD) using a two-step Mendelian randomization (MR) analysis. Methods: We analyzed data from genome-wide association studies (GWAS) conducted on European and East Asian populations. To assess the causal effects of circulating glycine levels on the risk of CAD. We used the inverse-variance weighting (IVW), weighted median (WM), MR-Egger, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) methods. Furthermore, we conducted mediation analysis to investigate the contribution of blood pressure and other cardiovascular disease-related traits. Results: The two-step Mendelian randomization analysis revealed that higher levels of glycine in the blood were associated with a reduced risk of CAD in Europeans [odds ratio ( OR)=0.84, 95% confidence interval ( CI): 0.72, -0.98; P=0.029] and East Asians: ( OR=0.76, 95% CI: 0.66, -0.89; P=3.57×10 -4). Sensitivity analysis confirmed the robustness of these findings. Additionally, our results suggest that about 6.06% of the observed causal effect is mediated through genetically predicted systolic blood pressure (SBP) in the European population. Discussion: Our results contribute to the current knowledge regarding the involvement of glycine in the progression of CAD, and provide valuable methodological insights for the prevention and treatment of this condition.
RESUMEN
Respiratory syncytial virus (RSV) is one of the most important pathogens causing respiratory tract infection in humans, especially in infants and the elderly. The identification and structural resolution of the potent neutralizing epitopes on RSV fusion (F) protein enable an "epitope-focused" vaccine design. However, the display of RSV F epitope II on the surface of the widely-used human hepatitis B virus core antigen (HBcAg) has failed to induce neutralizing antibody response in mice. Here, we used the hepadnavirus core protein (HcAg) from different mammalian hosts as scaffolds to construct chimeric virus-like particles (VLPs) presenting the RSV F epitope II. Mouse immunization showed that different HcAg-based chimeric VLPs elicited significantly different neutralizing antibody responses, among which the HcAg derived from roundleaf bat (RBHcAg) is the most immunogenic. Furthermore, RBHcAg was used as the scaffold platform to present multiple RSV F epitopes, and the immunogenicity was further improved in comparison to that displaying a single epitope II. The designed RBHcAg-based multiple-epitope-presenting VLP formulated with MF59-like adjuvant elicited a potent and balanced Th1/Th2 immune response, and offered substantial protection in mice against the challenge of live RSV A2 virus. The designed chimeric VLPs may serve as the potential starting point for developing epitope-focused vaccines against RSV. Our study also demonstrated that RBHcAg is an effective VLP carrier for presenting foreign epitopes, providing a promising platform for epitope-focused vaccine design.
RESUMEN
Image retrieval performance can be improved by training a convolutional neural network (CNN) model with annotated data to facilitate accurate localization of target regions. However, obtaining sufficiently annotated data is expensive and impractical in real settings. It is challenging to achieve accurate localization of target regions in an unsupervised manner. To address this problem, we propose a new unsupervised image retrieval method named unsupervised target region localization (UTRL) descriptors. It can precisely locate target regions without supervisory information or learning. Our method contains three highlights: 1) we propose a novel zero-label transfer learning method to address the problem of co-localization in target regions. This enhances the potential localization ability of pretrained CNN models through a zero-label data-driven approach; 2) we propose a multiscale attention accumulation method to accurately extract distinguishable target features. It distinguishes the importance of features by using local Gaussian weights; and 3) we propose a simple yet effective method to reduce vector dimensionality, named twice-PCA-whitening (TPW), which reduces the performance degradation caused by feature compression. Notably, TPW is a robust and general method that can be widely applied to image retrieval tasks to improve retrieval performance. This work also facilitates the development of image retrieval based on short vector features. Extensive experiments on six popular benchmark datasets demonstrate that our method achieves about 7% greater mean average precision (mAP) compared to existing state-of-the-art unsupervised methods.
RESUMEN
BACKGROUND: Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common variants, remains incomplete. This study aimed to investigate the genetic basis of CBC to better understand this malignancy. FINDINGS: We performed a genome-wide association analysis in the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age < 55 years including 1161 with CBC who served as cases and 1668 with unilateral breast cancer (UBC) who served as controls. We observed two loci (rs59657211, 9q32, SLC31A2/FAM225A and rs3815096, 6p22.1, TRIM31) with suggestive genome-wide significant associations (P < 1 × 10-6). We also found an increased risk of CBC associated with a breast cancer-specific polygenic risk score (PRS) comprised of 239 known breast cancer susceptibility single nucleotide polymorphisms (SNPs) (rate ratio per 1-SD change: 1.25; 95% confidence interval 1.14-1.36, P < 0.0001). The protective effect of chemotherapy on CBC risk was statistically significant only among patients with an elevated PRS (Pheterogeneity = 0.04). The AUC that included the PRS and known breast cancer risk factors was significantly elevated. CONCLUSIONS: The present GWAS identified two previously unreported loci with suggestive genome-wide significance. We also confirm that an elevated risk of CBC is associated with a comprehensive breast cancer susceptibility PRS that is independent of known breast cancer risk factors. These findings advance our understanding of genetic risk factors involved in CBC etiology.
Asunto(s)
Neoplasias de la Mama , Supervivientes de Cáncer , Humanos , Femenino , Persona de Mediana Edad , Estudio de Asociación del Genoma Completo , Mama , Predisposición Genética a la Enfermedad , Puntuación de Riesgo Genético , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína LigasasRESUMEN
Polysaccharides from Ficus carica L. (FCP) exert multiple biological activities. As a biological macromolecule, the available knowledge about the specific structures and mechanisms of the biological activity of purified 'Brunswick' fig polysaccharides is currently limited. In the present study, chemical purification and characteristics were identified via chemical and instrumental analysis, and then the impact of FCP on immunomodulation activity in vitro and in vivo was examined. Structural characteristics showed that the molecular weight of the FCP sample was determined to be 127.5 kDa; the primary monosaccharides present in the FCP sample were galacturonic acid (GalA), arabinose (Ara), galactose (Gal), rhamnose (Rha), glucose (Glc), and xylose (Xyl) at a ratio of 0.321:0.287:0.269:0.091:0.013:0.011. Based on the investigation of in vitro immunomodulatory activity, FCP was found to stimulate the production of NO, TNF-α, and IL-6, and increased the pinocytic activity of macrophages. Further analysis revealed that FCP activated macrophages by interacting with Toll-like receptor 4 (TLR4). Moreover, the in vivo test results indicate that FCP showed a significant increase in serum pro-inflammatory factors in immunosuppressed mice. Overall, this study suggests that FCP has the potential to be utilized as a novel immunomodulator in the pharmaceutical and functional food industries.
RESUMEN
PURPOSE: Patients with clear cell renal cell carcinoma (ccRCC) might develop metastasis after surgery with curative intent. We aimed to characterize the expression levels of microRNAs in the urine (UmiRNAs) of patients before and after nephrectomy to determine the impact of UmiRNAs expression in the emergence of metastases. METHODS: We prospectively collected pre- and post-nephrectomy urine samples from 117 patients with clinically localized and locally advanced ccRCC. UmiRNAs were extracted, purified, and measured using RT-PCR. Relative quantifications (RQ) of 137 UmiRNAs were calculated through 2-∆∆ method. The post-surgery/pre-surgery RQs ratio represented the magnitude of the expression levels of the UmiRNAs. The association of UmiRNA expression and the development of distant metastases was tested with Cox regression model. RESULTS: Five UmiRNAs (miR-191-5p, miR-324-3p, miR-186-5p, miR-93-5p, miR-30b-5p) levels were upregulated before nephrectomy (p < .05). This conferred a 2- to 4-fold increased risk of metastasis, with miR-191-5p showing the most significant association with this endpoint (HR = 4.16, 95% CI = 1.38-12.58, p = .011). In a multivariate model stratified with stage and Fuhrman grade, we found that miR-191-5p, miR-324-3p, and miR-186-5p exhibited a strong association with metastasis development in patients with pathological T3 (pT3) tumors. Enrichment analysis with the most differentially expressed UmiRNAs showed that these UmiRNAs targeted genes that regulate cell survival and proliferation. CONCLUSION: Our study indicated UmiR-191-5p, UmiR-324-3p, and UmiR-186-5p are potential markers to predict the development of metastasis, particularly in pT3 patients. PATIENT SUMMARY: We compared changes of UmiRNAs expression detected pre- and postnephrectomy of patients with ccRCC. Our findings suggest that UmiRNA expression likely reflects tumor-specific changes that can be promising to predict the metastasis development, particularly in patients with non-metastatic locally advanced ccRCC. If confirmed, these findings may be useful for surveillance protocols for adjuvant therapy protocols.
Asunto(s)
Carcinoma de Células Renales , Carcinoma , Neoplasias Renales , MicroARNs , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/patología , MicroARNs/genética , Neoplasias Renales/genética , Neoplasias Renales/cirugía , Neoplasias Renales/patología , Nefrectomía , Modelos de Riesgos Proporcionales , Carcinoma/genética , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/genéticaRESUMEN
High-purity 1T'-WS2 film has been experimentally synthesized [Nature Materials, 20, 1113-1120 (2021)] and theoretically predicted to be a two-dimensional (2D) superconducting material with Dirac cones [arXiv:2301.11425]. In the present work, we further study the superconducting properties of monolayer 1T'-WS2 by applying biaxial tensile strain. It is shown that the superconducting critical temperature Tc firstly increases and then decreases with respect to tensile strains, with the highest superconducting critical temperature Tc of 7.25 K under the biaxial tensile strain of 3%. In particular, we find that Dirac cones also exist in several tensile strained cases. Our studies show that monolayer 1T'-WS2 may provide a good platform for understanding the superconductivity of 2D Dirac materials.
RESUMEN
Egg white (EW) is a common nutritious food with excellent heat gelation and biocompatibility, but its application in biomaterials is considerably limited. Silk fibroin (SF) is a protein-based fiber with both excellent mechanical properties and biocompatibility, and its application in biomaterials has attracted much attention. Here, the EW/SF composite scaffold was first synthesized with GMA-modified EW/SF composite bioink (G-EW/SF). When homogenized EW and SF were individually grafted with glycidyl methacrylate (GMA), the grafted EW (G-EW) and SF (G-SF) were mixed in different proportions and then added to I2959. The resulting G-EW/SF composite bioink could be bioprinted into various EW/SF composite scaffolds. Among them, the compressive modulus of EW/SF (50%) composite scaffolds incorporating 50% G-SF was significantly improved. It had a three-dimensional (3D) polypore structure with an average pore size of 61 µm and was mainly composed of ß-sheet structures. Compared with the EW scaffold alone, the thermal decomposition temperature of the EW/SF scaffold was 10 °C higher, and the residual rate after 9 days of enzymatic hydrolysis had increased by about 18%. The scaffold prolonged the sustained release of insulin and promoted the adhesion, growth, and proliferation of the L-929 cells. Therefore, the EW/SF composite scaffolds with good cell proliferation ability and certain mechanical properties can be used in different applications including cells, drugs, and tissues. These results provide new prospects for the application of the EW protein to medical tissue engineering materials.
RESUMEN
Transcriptome-wide association studies (TWAS) have been successful in identifying putative disease susceptibility genes by integrating gene expression predictions with genome-wide association studies (GWAS) data. However, current TWAS models only consider cis-located variants to predict gene expression. Here, we introduce transTF-TWAS, which includes transcription factor (TF)-linked trans-located variants for model building. Using data from the Genotype-Tissue Expression project, we predict alternative splicing and gene expression and applied these models to large GWAS datasets for breast, prostate, and lung cancers. Our analysis revealed 887 putative cancer susceptibility genes, including 465 in regions not yet reported by previous GWAS and 137 in known GWAS loci but not yet reported previously, at Bonferroni-corrected P < 0.05. We demonstrate that transTF-TWAS surpasses other approaches in both building gene prediction models and identifying disease-associated genes. These results have shed new light on several genetically driven key regulators and their associated regulatory networks underlying disease susceptibility.
RESUMEN
BACKGROUND: Obesity usually causes diabetes mellitus (DM) and is a serious danger to human health. Type 2 DM (T2DM) mostly occurs along with obesity. Foodborne obesity-induced DM is caused by an excessive long-term diet and surplus energy. Bariatric surgery can improve the symptoms of T2DM in some obese patients. But different types of bariatric surgery may have different effects. AIM: To investigate the effect of bariatric surgery on glucose and lipid metabolism and liver and kidney function in rats. METHODS: Male Sprague-Dawley rats aged 6-8 wk underwent Roux-en-Y gastric bypass surgery (RYGB), sleeve gastrectomy (SG), or gastric banding (GB). Glucose and insulin tolerance tests, analyses of biochemical parameters, histological examination, western blot, and quantitative real-time polymerase chain reaction were conducted. RESULTS: In comparison to the sham operation group, the RYGB, SG, and GB groups had decreased body weight and food intake, reduced glucose intolerance and insulin insensitivity, downregulated biochemical parameters, alleviated morphological changes in the liver and kidneys, and decreased levels of protein kinase C ß/ P66shc. The effect in the RYGB group was better than that in the SG and GB groups. CONCLUSION: These results suggest that RYGB, SG and GB may be helpful for the treatment of foodborne obesity-induced DM.
RESUMEN
Background: Clinically, some patients whose HBsAg becomes negative owing to antiviral therapy or spontaneously still show a low level of HBV DNA persistence in serum. T-lymphocyte subsets, cytokine levels and HBV S gene sequences were analyzed in this study. Methods: A total of 52 HBsAg-negative and HBV DNA-positive patients(HBsAg-/HBV DNA+ patients), 52 persistently HBsAg-positive patients(HBsAg+/HBV DNA+ patients) and 16 healthy people were evaluated. T-lymphocyte subsets of these patients were detected by flow cytometry, serum cytokines and chemokines were detected by the Luminex technique, and the HBV S region was evaluated by Sanger sequencing. T%, T-lymphocyte, CD8+ and CD4+T lymphocyte were lower in the HBsAg-negative group than in the HC group. Compared with the HBsAg-positive group, the HBsAg-negative group had lower levels in T lymphocyte %, CD8+T lymphocyte %, CD8+T lymphocyte and CD4/CD8. These difference were statistically significant (P<0.05). Serum IFN-γ, IFN-α and FLT-3L levels were significantly higher in the HBsAg-negative group than in the HBsAg-positive group (P<0.05). However, levels of many cytokines related to inflammation (i.e., IL-6, IL-8, IL10, IL-12, IL-17A) were lower in the HBsAg-negative group. Fifty-two HBsAg-negative samples were sequenced, revealing high-frequency amino acid substitution sites in the HBV S protein, including immune escape mutations (i.e., Y100C, S114T, C124Y, P127L, G130R, T131N, M133T, C137S, G145A) and TMD region substitutions (i.e., E2K/R/D, G7D/R, G10D, A17R, F20L/S, L21V, L22V). Conclusions: According to the results of T-lymphocyte subsets and serum cytokines, it can be deduced that the cellular immune function of HBsAg-negative patients is superior to that of HBsAg-positive patients, with attenuation of liver inflammation. HBsAg-negative patients may show a variety of mutations and amino acid replacement sites at high frequency in the HBV S region, and these mutations may lead to undetectable HBsAg, HBsAg antigenic changes or secretion inhibition.
Asunto(s)
Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B , Humanos , Antígenos de Superficie de la Hepatitis B/genética , Virus de la Hepatitis B/genética , ADN Viral/genética , Interleucina-12 , CitocinasRESUMEN
OBJECTIVES: Primary biliary cholangitis (PBC) is a rare disease characterized by intrahepatic cholestasis, whereas gallstone disease (GD) is common. In this study, we aimed to investigate the prevalence and impact of GD on the prognosis of PBC in China. METHODS: Medical records of the PBC patients were retrospectively reviewed and their follow-up data were obtained via regular structured, standardized telephone interviews. GD was defined as gallstones on ultrasonography or a history of cholecystectomy for gallstones. Propensity score matching (PSM) and Cox regression analysis were performed. The primary end-point was liver-related death and/or liver transplantation. RESULTS: A total of 985 ursodeoxycholic acid (UDCA)-treated PBC patients were enrolled with a median follow-up duration of 5.3 years (range 1.0-20.9 years). Among them, 258 (26.2%) had GD, including 157 (22.9%) of non-cirrhotic and 101 (33.8%) of cirrhotic patients. Compared with PBC without GD, those with GD were older, more often had type 2 diabetes mellitus, and had a more severe liver disease at baseline. After PSM (1:2), 229 PBC patients with GD were matched with 458 PBC patients without GD based on age, sex, cirrhosis, and total bilirubin level. The transplant-free survival and incidence of hepatic events were similar between the two groups. Furthermore, multivariate Cox regression analysis showed that concomitant GD was not independently associated with a worse prognosis for PBC patients. CONCLUSION: Concomitant GD was common but was not associated with long-term outcomes in patients with UDCA-treated PBC.