Variant in BCAR4 gene correlated with the breast cancer susceptibility and mRNA expression of lncRNA BCAR4 in Chinese Han population.

BACKGROUND: Long non-coding RNA (LncRNA) Breast cancer anti-estrogen resistance 4 (BCAR4) has been shown to participate in the biological progress of various cancers including breast cancer. Genetic Polymorphisms in BCAR4 may have an influence on the progress of breast cancer, but it is rarely studied. METHODS: In our epidemiology study, three tagging SNPs (rs4561483, rs11649623 and rs13334967) in lncRNA BCAR4 were selected for genotyping among 487 breast cancer cases and 489 healthy controls. And quantitative real-time PCR (qRT-PCR) was performed to evaluate the relative mRNA expression of BCAR4 in different genotypes of the significant locus rs13334967. RESULTS: We found that BCAR4 rs13334967 is associated with lower breast cancer risk both in codominant model (AT vs AA, OR 0.632, 95% CI 0.429-0.931, TT vs AA, OR 0.731, 95% CI 0.511-0.990) and dominant model (AT + TT vs AA, OR 0.798, 95% CI 0.571-0.970). The further results of qRT-PCR displayed that carriers with rs13334967 AT, TT genotype have lower BCAR4 mRNA expression compared with AA genotype. CONCLUSION: The research study implied that BCAR4 rs13334967 was correlated with the susceptibility to breast cancer and may impact the mRNA expression of BCAR4. LncRNA BCAR4 may be a potential biomarker and therapeutic target for breast cancer.

Salidroside improves angiogenesis-osteogenesis coupling by regulating the HIF-1α/VEGF signalling pathway in the bone environment.

Angiogenesis is essential for bone formation during skeletal development. HIF-1α and the HIF-responsive gene VEGF (vascular endothelial growth factor) are reported to be a key mechanism for coupling osteogenesis and angiogenesis. Salidroside (SAL), a major biologically active compound of Rhodiola rosea L., possesses diverse pharmacological effects. However, whether SAL can protect against bone loss via the HIF-1α/VEGF pathway, specifically by inducing angiogenesis-osteogenesis coupling in vivo, remains unknown. Therefore, in the present study, we employed primary human umbilical vein endothelial cells (HUVECs) and the permanent EA.hy926 human endothelial cell line to determine the cellular and molecular effects of SAL on vascular endothelial cells and the HIF-1α-VEGF signalling pathway in the coupling of angiogenesis-osteogenesis. The in vitro study revealed that the HUVECs and EA.hy926 cells treated with conditioned medium from osteoblast cells (MG-63 cells) treated with SAL or treated directly with SAL showed enhanced proliferation, migration and capillary structure formation. However, supplementation with an anti-VEGF antibody during the treatment of endothelial cells (ECs) significantly reversed the pro-angiogenic effect of SAL. Moreover, SAL upregulated HIF-1α expression and increased its transcriptional activity, consequently upregulating VEGF expression at the mRNA and protein levels. In addition, our in vivo analysis demonstrated that SAL can stimulate endothelial sprouting from metatarsal bones. Thus, our mechanistic study demonstrated that the pro-angiogenic effects of SAL involve HIF-1α-VEGF signalling by coordinating the coupling of angiogenesis-osteogenesis in the bone environment. Therefore, we have discovered an ideal molecule that simultaneously enhances angiogenesis and osteogenesis and thereby accelerates bone healing.

Identification of Symptoms Prognostic of COVID-19 Severity: Multivariate Data Analysis of a Case Series in Henan Province.

BACKGROUND: The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease (COVID-19), has been declared a global pandemic. Identifying individuals whose infection can potentially become severe is critical to control the case fatality rate of COVID-19. However, knowledge of symptoms that are prognostic of COVID-19 severity is lacking. OBJECTIVE: The objective of our study was to identify symptoms prognostic of COVID-19 infection severity. METHODS: We analyzed documented symptoms, including fever, cough, fatigue, expectoration, sore throat, chest distress, headache, diarrhea, rhinorrhea, stuffed nose, nausea, vomiting, muscle or joint ache, shortness of breath, and their associations with disease severity using a case series, including 655 confirmed cases from January 23 to February 5, 2020 in Henan Province, China. We also analyzed the influence of individual characteristics, including age, gender, and comorbidities, on symptoms with prognostic value. RESULTS: Fatigue (95% CI 0.141 to 0.334, P<.001), expectoration (95% CI 0.107 to 0.305, P<.001) and stuffed nose (95% CI -0.499 to -0.082, P=.006) were identified as the prognostic symptoms of COVID-19 patients from the multivariate analysis. Fever occurred in 603/655 (92.1%) of the patients but was not associated with disease severity. Fatigue accounted for 184/655 (28.1%) of the patients and was linearly associated with infection severity with statistical significance. Expectoration occurred in 169/655 (25.8%) patients in the cohort and was the sole prognostic factor for patients with cardiovascular complications, including hypertension. Shortness of breath, chest distress, muscle or joint ache, and dry cough, which occurred in 33 (5%), 83 (12.7%), 78 (11.9%), and 276 (42.1%) of the 655 patients, respectively, were significantly enriched among patients classified as severe. Stuffed nose and nausea were associated with favorable disease severity, especially among male patients. More female than male patients were documented as having muscle or joint ache. Headache was most enriched in patents aged 15 to 39 years, followed by those aged 40 to 64 years, with statistical significance. CONCLUSIONS: Fatigue and expectoration are signs of severe COVID-19 infection. Shortness of breath, chest distress, muscle or joint ache, and dry cough are prevalent in severe patients. Expectoration is commonly present in older individuals and patients with cardiovascular disorders, including hypertension. Shortness of breath is prognostic of severe infection in male patients. Stuffed nose and nausea are favorable prognostic factors of severe infection, especially among male patients.

Characterization of lncRNA LINC00520 and functional polymorphisms associated with breast cancer susceptibility in Chinese Han population.

BACKGROUND: The aim was to evaluate the association between the LINC00520 genetic polymorphisms and breast cancer (BC) susceptibility. METHODS: Nine single-nucleotide polymorphisms (SNPs) on LINC00520 genotyping were performed in 504 BC patients and 505 cancer-free controls in Chinese Han population to study the relationship between LINC00520 polymorphism and BC susceptibility. qRT-PCR and luciferase tests were used to explore how rs12880540 affected the expression of LINC00520. RESULTS: The genotype GG (OR:3.58, 95%CI:1.32-9.69) in rs8012083 increased the risk of triple-negative BC. The genotype GG (OR:0.31, 95%CI:0.14-0.69) in rs8012083, the genotype AA (OR:2.74, 95%CI:1.01-7.42) in rs2152275, and genotype TG (OR:1.62, 95%CI:1.04-2.52) in rs12880540 were associated with HER-2 status. The dominant (OR:0.65, 95%CI:0.45-0.95) and overdominant genetic model (OR:0.67, 95%CI:0.46-0.98) consistently showed that rs11622641 T was significantly associated with lower risk of BC. Similarly, the recessive genetic model (OR:1.57, 95%CI:1.07-2.30) of rs12880540 and the dominant (OR:1.62, 95%CI:1.24-2.11) and overdominant (OR:1.56, 95%CI:1.19-2.03) genetic model of rs2152278 may increase the risk of BC. The relative expression of LINC00520 increased linearly with the increase in the number of rs12880540 mutations. rs12880540 alleles were due to the interaction between LINC00520 and miR-3122 at T, but the mutation of rs12880540 G > T had no effect on the binding ability of LINC00520 and miR-3122. CONCLUSION: A genetic variant of rs8012083 in LINC00520 may be used as a biomarker for triple-negative BC after further evaluation of diagnostic tests. The genetic variant of LINC00520 was related to the susceptibility of BC, and rs12880540 might affect the corresponding mRNA expression of lncRNA LINC00520.

Moyamoya disease: A retrospective study of 198 cases / Enfermedad de moyamoya: estudio retrospectivo de 198 casos

Background: Moyamoya disease belongs to rare diseases which are arousing public awareness of its importance in China. In order to investigate the clinical features of inpatients diagnosed Moyamoya disease, the study was conducted to collect clinical information data of subjects on demographic information and clinical characteristics in Henan, China. Methods: The data of 198 cases of Moyamoya disease from 56 tertiary hospitals in Henan province from January 2003 to June 2015 were collected retrospectively. Analysis was performed based on demographic, clinical and radiological characteristics of the patients. Results: The mean onset age was 44.03±14.45 years old. Unilateral limb weakness (36.4%) was the most common physical examination. Primary clinical manifestation was headache and dizziness (50.3%). Cranial CT showed cerebral infarction was mainly located in the frontal lobe (27.4%). MRA and DSA showed lesions mainly located in the middle cerebral artery (30.3% and 18.7%). Conclusions: Clinical manifestations of Moyamoya disease varied. Early diagnosis was necessary to reduce the misdiagnosis rate of this disease. Symptoms, radiological characteristics, and lesion localization characteristics should be fully considered, especially for indicators with a certain onset age, headache and dizziness, lesion located in the frontal lobe of middle cerebral artery

Antecedentes: La enfermedad de moyamoya pertenece al grupo de afecciones raras cuya importancia está despertando la conciencia pública en China. Con el fin de investigar las características clínicas de los pacientes hospitalizados en Henan (China) diagnosticados con la enfermedad de moyamoya, se llevó a cabo este estudio para recopilar información clínica sobre los pacientes junto con información demográfica y características clínicas. Métodos: Se recogieron retrospectivamente datos de 198 casos de la enfermedad de moyamoya en 56 hospitales terciarios de la provincia de Henan entre enero de 2003 y junio de 2015. El análisis se realizó con base en las características demográficas, clínicas y radiológicas de los pacientes. Resultados: La edad media de inicio de la enfermedad era de 44,03±14,45 años. La debilidad unilateral de las extremidades (36,4%) fue el hallazgo más común en las exploraciones físicas y la manifestación clínica primaria fue la combinación de dolor de cabeza y mareos (50,3%). La tomografía craneal mostró que el infarto cerebral afectaba principalmente al lóbulo frontal (27,4%). La angiografía de resonancia magnética y la angiografía por sustracción digital mostraron lesiones ubicadas principalmente en la arteria cerebral media (30,3 y 18,7%, respectivamente). Conclusiones: Las manifestaciones clínicas de la enfermedad de moyamoya fueron muy variadas. El diagnóstico precoz resultó necesario para reducir la tasa de diagnósticos erróneos de esta enfermedad. Se deben considerar los síntomas, las características radiológicas y las características de ubicación en su totalidad, especialmente en el caso de indicadores con una edad específica de inicio, dolor de cabeza y mareos, o una lesión situada en el lóbulo frontal, en la arteria cerebral media

Moyamoya disease: A retrospective study of 198 cases.

BACKGROUND: Moyamoya disease belongs to rare diseases which are arousing public awareness of its importance in China. In order to investigate the clinical features of inpatients diagnosed Moyamoya disease, the study was conducted to collect clinical information data of subjects on demographic information and clinical characteristics in Henan, China. METHODS: The data of 198 cases of Moyamoya disease from 56 tertiary hospitals in Henan province from January 2003 to June 2015 were collected retrospectively. Analysis was performed based on demographic, clinical and radiological characteristics of the patients. RESULTS: The mean onset age was 44.03±14.45 years old. Unilateral limb weakness (36.4%) was the most common physical examination. Primary clinical manifestation was headache and dizziness (50.3%). Cranial CT showed cerebral infarction was mainly located in the frontal lobe (27.4%). MRA and DSA showed lesions mainly located in the middle cerebral artery (30.3% and 18.7%). CONCLUSIONS: Clinical manifestations of Moyamoya disease varied. Early diagnosis was necessary to reduce the misdiagnosis rate of this disease. Symptoms, radiological characteristics, and lesion localization characteristics should be fully considered, especially for indicators with a certain onset age, headache and dizziness, lesion located in the frontal lobe of middle cerebral artery.

A Dose-Response Relationship Between Sleep Duration and Stroke According to Nonhealth Status in Central China: A Population-based Epidemiology Survey.

PURPOSE: The aim was to investigate the relationship between sleep duration and stroke according to nonhealth status among adults in Central China. METHODS: A total of 18,670 participants were selected by stratified multistage random sampling method in Henan province during 2013-2015. Restricted cubic splines and logistic regression were used to calculate the association between sleep duration and stroke. RESULTS: Sleep duration showing a J-shaped dose-response association with risk of stroke among the Chinese adults in the study. The respective percentages of stroke were 6.2%, 5.6%, 3.5%, 4.5%, 5.6%, and 9.2% for those whose sleep duration less than 6 h/day, 6∼7 h/day, 7∼8 h/day, 8∼9 h/day, 9∼10 h/day, and more than or equal to 10 h/day. Compared with sleep duration of 7∼8 h/day, the risk of stroke increased by 37% (95% confidence interval [CI]: 8%, 73%) and 63% (95% CI: 30%, 104%) for those whose sleep duration were 9∼10 h/day and more than or equal to 10 h/day. The correlations between sleep durations and stroke seemed to be stronger in men than women. Stroke was associated with shorter sleep duration in ageing 60-88 years, instead of 18-59 years. The correlation between sleep duration and stroke was statistically significant at lower education level. Furthermore, the risk of stroke was slightly higher in urban residents than rural residents. CONCLUSIONS: In summary, a J-shaped dose-response association between sleep duration and stroke was found among the adults in Central China. Furthermore, people who were male, older, less educated and living in urban areas had a higher risk of stroke.

Functional Variants in Linc-ROR are Associated with mRNA Expression of Linc-ROR and Breast Cancer Susceptibility.

Functional polymorphisms in Linc-ROR may change its ability of regulation by regulating Linc-ROR expression. However, these functional polymorphisms in Linc-ROR and their associations with breast cancer (BC) susceptibility were scarcely reported. In this molecular epidemiological study, four SNPs (rs6420545, rs4801078, rs1942348 and rs9636089) were selected in Linc-ROR by bioinformatics method. Unconditional logistic regression model was performed to analyze the associations between four SNPs and BC susceptibility adjusted for reproductive factors. Quantitative real-time (qRT) PCR was used to evaluate relative expression of Linc-ROR in plasma. The interactions of gene reproductive factors were assessed by Multifactor Dimensionality Reduction (MDR) method. A novel finding showed TT (OR: 1.79; 95%CI: 1.20-2.68) genotype of rs4801078 in Linc-ROR had a significant association with the higher risk of BC and the expression of Linc-ROR mRNA was closely related with the alleles of rs4801078. In addition, we found the interaction of rs4801078, number of pregnancy and menopausal status might increase BC risk (OR: 2.78; 95%CI: 2.74-3.61). Our results suggest that interactions of SNPs in Linc-ROR and reproductive factors might contribute to BC risk, and alleles of rs4801078 might affect Linc-ROR expression level.

Association analyses of genetic variants in long non-coding RNA MALAT1 with breast cancer susceptibility and mRNA expression of MALAT1 in Chinese Han population.

The long non-coding RNA (lncRNA) Metastasis-associated lung adenocarcinoma transcript 1(MALAT1) has been implicated in breast cancer (BC). Polymorphisms in MALAT1 may play a vital role in the progress of breast cancer by its regulation function. However, potential genetic variants in MALAT1 affecting the development of BC is rarely explored. In our current molecular epidemiology study, all three tagging SNPs (rs3200401, rs619586 and rs7927113) in lncRNA MALAT1 were selected for genotyping in 487BCE patients and 489 cancer-free controls in Chinese Han population, and futher experiment of quantitative real-time (qRT) PCR was conducted to examine the relative expression of MALAT1. The results showed that individuals with genotype AG of rs619586 has a decreased risk of BC in codominant model (OR: 0.684, 95%CI: 0.478-0.979), dominant mode (OR: 0.675, 95%CI: 0.479-0.951) and over-dominant model (OR: 0.692, 95%CI: 0484-0.989). Also, qRT-PCR results revealed that the expression for MALAT1 with AG (0.827±0.490), GG (0.511±0.149) and AG+GG genotypes (0.743±0.447) of rs619586 was significantly lower than that with genotype AA (1.511±0.737). In addition, females with genotype CT of rs3200401 had a lower risk of BC in the codominant model (OR: 0.75, 95%CI: 0.559-1.007) and over-dominant model (OR: 0.741, 95%CI: 0.552-0.993). In summary, our results implied that the genetic variants of lncRNA MALAT1 were associated with the susceptibility of BC, and meaningful genetic alteration might affect the corresponding mRNA expression of lncRNA MALAT1.

MiRNA-binding site functional polymorphisms in DNA repair genes RAD51, RAD52, and XRCC2 and breast cancer risk in Chinese population.

RAD51, RAD52, and XRCC2 are all involved in DNA homologous recombinational repair, and there are interactions among those genes. Polymorphisms in 3'-UTR of DNA repair genes may change DNA repair capacity by regulating gene expression. However, potential regulatory variants affecting their expression remain largely unexplored. Five miRNA-binding site SNPs (rs7180135 and rs45549040 in RAD51, rs1051669 and rs7963551 in RAD52 and rs3218550 in XRCC2) selected by bioinformatics method were genotyped in 498 breast cancer (BC) patients and 498 matched controls in Chinese population. Association between SNPs and BC risk was analyzed by adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) in unconditional logistic regression model. Quantitative real-time (qRT) PCR and Western Blot assays were used to calculate the relative expression of RAD52 in recombinant plasmid-pGenesil-1-let-7b group and let-7b-inhibitor group. Gene-reproductive factors interactions were evaluated by multifactor dimensionality reduction (MDR) method. We found that individuals with AC (OR 0.684, 95%CI 0.492-0.951) and CC (OR 0.317, 95%CI 0.200-0.503) genotypes of rs7963551 had a significantly lower risk of breast cancer and qRT-PCR and Western Blot revealed that let-7b might downregulate the expression of RAD52 in MCF-7 and SKBR-3 cells. A significant interaction between the number of pregnancy (≥2) and rs7963551 (Ars7963551) was found to increase breast cancer risk by 2.63-fold (OR 2.63; 95%CI 2.03-3.42). In summary, the miRNA-binding SNPs in DNA repair genes RAD51, RAD52, and XRCC2 and their interaction with reproductive factors might play important roles in the development of BC, and let-7b might downregulate RAD52 expression in MCF-7 and SKBR-3 cells.

Identification of a small molecule that simultaneously suppresses virulence and antibiotic resistance of Pseudomonas aeruginosa.

The rising antibiotic resistance of bacteria imposes a severe threat on human health. Inhibition of bacterial virulence is an alternative approach to develop new antimicrobials. Molecules targeting antibiotic resistant enzymes have been used in combination with cognate antibiotics. It might be ideal that a molecule can simultaneously suppress virulence factors and antibiotic resistance. Here we combined genetic and computer-aided inhibitor screening to search for such molecules against the bacterial pathogen Pseudomonas aeruginosa. To identify target proteins that control both virulence and antibiotic resistance, we screened for mutants with defective cytotoxicity and biofilm formation from 93 transposon insertion mutants previously reported with increased antibiotic susceptibility. A pyrD mutant displayed defects in cytotoxicity, biofilm formation, quorum sensing and virulence in an acute mouse pneumonia model. Next, we employed a computer-aided screening to identify potential inhibitors of the PyrD protein, a dihydroorotate dehydrogenase (DHODase) involved in pyrimidine biosynthesis. One of the predicted inhibitors was able to suppress the enzymatic activity of PyrD as well as bacterial cytotoxicity, biofilm formation and antibiotic resistance. A single administration of the compound reduced the bacterial colonization in the acute mouse pneumonia model. Therefore, we have developed a strategy to identify novel treatment targets and antimicrobial molecules.