Association between coffee and caffeine intake and risk of COPD: Findings based on NHANES 2007-2012.

BACKGROUND: The association between coffee and caffeine intake and the risk of COPD and lung function has not been thoroughly discussed in Americans, with subgroup and threshold effects remaining unclear. OBJECTIVES: This study investigated the association between coffee and caffeine consumption and the risk of chronic obstructive pulmonary disease (COPD) as well as lung function utilizing data from the NHANES 2007-2012. METHODS: We assessed the associations of coffee and caffeine consumption with the risk of COPD and lung function parameters, including FEV1 and FVC, adjusting for common demographic and disease characteristics in a cross-sectional analysis of NHANES data. RESULTS: A total of 9763 participants were included in the study, and 592 were diagnosed with COPD. Multivariate regression models revealed positive associations between coffee and caffeine consumption and the risk of COPD and lung function. Subgroup analyses stratified by sex, DM, hypertension status, and smoking habits identified potential effect modifiers as well as inflection points from threshold effect examinations. CONCLUSIONS: The results of this cross-sectional study indicated significant positive correlations between coffee and caffeine consumption and the risk of COPD. Additionally, positive correlations between exposure variables and FEV1 and FVC were detected. Among the stratification factors, smoking status exhibited the most potential for modifying effects. Future practices and research are needed to validate the results and explore the underlying mechanisms.

Safety and efficacy of magnesium-rich artificial cerebrospinal fluid for subarachnoid hemorrhage.

Objectives: This study aimed to investigate the efficacy of using a newly formulated magnesium-rich artificial cerebrospinal fluid (MACSF) as an alternative to normal saline (NS) for intraoperative irrigation during aneurysm clipping in improving the prognosis of patients with Aneurysmal subarachnoid hemorrhage (aSAH). Methods: Patients with aSAH who underwent intraoperative irrigation with MACSF or NS during the clipping in the First Affiliated Hospital of Xi 'an Jiaotong University from March 2019 to March 2022 were selected as MACSF group and NS group, respectively. The primary prognostic indicators were the incidence of favorable outcomes (mRS 0-2). The secondary outcome measures included cerebral vasospasm (CVS), mortality, total hospital stay, and intensive care unit (ICU) stay. Safety was evaluated based on the occurrence rates of hypermagnesemia, meningitis, and hydrocephalus. Results: Overall, 34 and 37 patients were enrolled in the MACSF and NS groups, respectively. At 90 days after aSAH onset, the proportion of favorable prognosis in the MACSF group was significantly higher than that in the NS group (p = 0.035). The incidence of CVS within 14 days after surgery was significantly lower in the MACSF group than that in the NS group (p = 0.026). The mortality rate in the MACSF group was significantly lower than in the NS group (p = 0.048). The median lengths of hospital stay (p = 0.008) and ICU stay (p = 0.018) were significantly shorter in the MACSF group than in the NS group. No significant differences were observed in safety measures. Conclusion: Using MACSF as an irrigation fluid for aneurysm clipping can significantly improve the 90-day prognosis of patients with aSAH, which may be related to the reduced incidence of CVS. Clinical trial registration: https://www.clinicaltrials.gov, identifier NCT04358445.

The dynamic equilibrium between the protective and toxic effects of matrine in the development of liver injury: a systematic review and meta-analysis.

Background: Matrine, an alkaloid derived from the dried roots of Sophora flavescens Aiton, has been utilized for the treatment of liver diseases, but its potential hepatotoxicity raises concerns. However, the precise condition and mechanism of action of matrine on the liver remain inconclusive. Therefore, the objective of this systematic review and meta-analysis is to comprehensively evaluate both the hepatoprotective and hepatotoxic effects of matrine and provide therapeutic guidance based on the findings. Methods: The meta-analysis systematically searched relevant preclinical literature up to May 2023 from eight databases, including PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure, WanFang Med Online, China Science and Technology Journal Database, and China Biomedical Literature Service System. The CAMARADES system assessed the quality and bias of the evidence. Statistical analysis was conducted using STATA, which included the use of 3D maps and radar charts to display the effects of matrine dosage and frequency on hepatoprotection and hepatotoxicity. Results: After a thorough screening, 24 studies involving 657 rodents were selected for inclusion. The results demonstrate that matrine has bidirectional effects on ALT and AST levels, and it also regulates SOD, MDA, serum TG, serum TC, IL-6, TNF-α, and CAT levels. Based on our comprehensive three-dimensional analysis, the optimal bidirectional effective dosage of matrine ranges from 10 to 69.1 mg/kg. However, at a dose of 20-30 mg/kg/d for 0.02-0.86 weeks, it demonstrated high liver protection and low toxicity. The molecular docking analysis revealed the interaction between MT and SERCA as well as SREBP-SCAP complexes. Matrine could alter Ca2+ homeostasis in liver injury via multiple pathways, including the SREBP1c/SCAP, Notch/RBP-J/HES1, IκK/NF-κB, and Cul3/Rbx1/Keap1/Nrf2. Conclusion: Matrine has bidirectional effects on the liver at doses ranging from 10 to 69.1 mg/kg by influencing Ca2+ homeostasis in the cytoplasm, endoplasmic reticulum, Golgi apparatus, and mitochondria. Systematic review registration: https://inplasy.com/, identifier INPLASY202340114.

Dose-dependent bidirectional pharmacological effects of vinorelbine-based metronomic combination chemotherapy on tumor growth and metastasis and mechanisms in melanoma mouse model.

BACKGROUND: There is evidence that the empirical setting of doses and schedules of antineoplastic agents in metronomic chemotherapy (MC) might lead to undesirable outcomes, such as promoting tumor growth or metastasis at certain low doses. However, details about the dose effect of antineoplastic agents in MC have not been fully known yet. OBJECTIVES: Vinorelbine combined with cisplatin or fluorouracil (VNR/CDDP or VNR/FU) was selected to investigate its effects on tumor growth or metastasis as well as mechanisms. METHODS: Experimental techniques, including immunohistochemistry, western blot, immunofluorescence, and flow cytometry, were used to explore the mechanisms, along with cell proliferation, apoptosis, migration, and invasion. RESULTS: The results showed that VNR/CDDP or VNR/FU promoted tumor growth and metastasis at low doses and inhibited them at high ones. Except that expressions of apoptotic proteins were elevated at both low and high doses, low-dose treatments enhanced angiogenesis and promoted the mobilization and recruitment of myeloid-derived suppressor cells (MDSCs), while high-dose treatments reversed these effects. Additionally, low concentrations of VNR/CDDP or VNR/FU stimulated tumor cell functions such as anti-apoptosis, migration, and invasion, but high concentrations only suppressed cell proliferation and increased apoptosis. CONCLUSION: This study elucidated a bidirectional action mode regulated by multiple mechanisms at different doses in MC and also highlighted the risks of low-dose metronomic administration of antineoplastic agents in the clinic. More preclinical and clinical studies focusing on the dose-effect of metronomic regimens are urgently needed because an effective therapeutic regimen should be an optimal setting of drugs, doses, schedules, or combinations.

Dual­directional effect of vinorelbine combined with cisplatin or fluorouracil on tumor growth and metastasis in metronomic chemotherapy in breast cancer.

Metronomic chemotherapy (MCT) regimens may be associated with risks to the patient due to the ambiguity surrounding low dosages and schedules. In the present study, metronomic regimens of vinorelbine (NVB) combined with cisplatin (CDDP) or fluorouracil (5­FU) were chosen to study the dose­response associations with tumor growth and metastasis, along with the underlying mechanisms in angiogenesis, apoptosis and tumor immunity, using experimental techniques such as immunofluorescence, immunohistochemistry, western blotting and flow cytometry. The results demonstrated a dual­directional pharmacological action of promoting and suppressing tumor growth or metastasis in BALB/c mice bearing a 4T1 tumor at certain low and high doses of the drugs. Low doses of NVB combined with CDDP or 5­FU accelerated tumor growth by enhancing angiogenesis, increasing the expression of angiogenic proteins, NF­κB and osteopontin in tumor tissues, and inducing the accumulation of myeloid­derived suppressor cells and macrophages. By contrast, higher doses inhibited tumor growth by suppressing these effects. Notably, the upregulation of apoptotic proteins was observed after low­ and high­dose treatments. Furthermore, at low concentrations, NVB combined with CDDP or 5­FU stimulated certain functions of endothelial and tumor cells, including migration and invasion, whereas at higher concentrations they suppressed proliferation and induced apoptosis. Therefore, the results of the present study suggested the potential risks of metronomic combination chemotherapy by demonstrating that, at certain low doses, tumor growth or metastasis was promoted, and emphasized the existence of an effective dose interval that changes with different drug combinations. However, further studies are needed before a specific metronomic combination regimen can be administered clinically for cancer treatment.

Low-dose Cisplatin Induces Tumor Growth via Mobilization of Proangiogenic Bone Marrow-derived Cells in Mouse Models.

BACKGROUND/AIM: It is generally accepted that low-dose metronomic (LDM) chemotherapy mostly exerts its antitumor effects by inhibiting tumor angiogenesis. However, there is some evidence that LDM chemotherapy subsequently promotes tumor angiogenesis under certain regimens in animal models. The mechanisms responsible for these contradictory results are unclear. MATERIALS AND METHODS: Cisplatin (CDDP) was intraperitoneally administered to tumor-bearing mice at doses of 0.05-3 mg/kg every other day. The effects of LDM chemotherapy with CDDP on tumor growth and angiogenesis were observed. To determine the involved mechanisms, we analyzed the expression of vascular basement membrane proteins, transcription of angiogenesis-related genes in tumor tissues, and mobilization of proangiogenic bone marrow-derived cells (BMDCs) in circulating blood. RESULTS: The mean tumor weight with the 3 mg/kg q.o.d. regimen CDDP was significantly lower (by 57.3%) in the CDDP than in the control group. However, the tumor weight was 52.1% higher for the 0.19 mg/kg q.o.d. regimen in the CDDP group, which could be antagonized using 30 mg/kg all-trans retinoic acid. For the 0.19 mg/kg q.o.d., more tumor vascular structures were observed in the CDDP than in the control group (47.9±5.0 vs. 22.3±0.8, p<0.001). The mobilization of VEGFR2+ BMDCs and the mRNA expression of the proangiogenic genes MMP9, VEGFR1, VEGFR2 and VE-cadherin were increased in the 0.19 mg/kg regimen. CONCLUSION: These results indicate that metronomic CDDP promoted tumor angiogenesis and tumor growth via increased mobilization of proangiogenic BMDCs at certain low doses. This implies a potential therapeutic risk from an inappropriate LDM chemotherapy dosage and suggests that optimizing the LDM chemotherapy regimen is urgently needed.

Association of prothrombin complexe concentrate with venous thrombosis after cardiac surgery: a case-control study.

Background: Prothrombin complex concentrate (PCC) enhances coagulation and controls bleeding. We aimed to assess whether perioperative infusion of PCC is associated with venous thrombosis after cardiac surgery. Methods: We conducted a case-control study of patients undergoing cardiac surgery at our hospital in 2021. Multivariate logistic regression was used to assess the correlation between perioperative PCC infusion and postoperative venous thrombosis in cardiac surgery. Stratified analysis was also performed by age, hospitalization days, and whether warfarin, warfarin combined with heparin, warfarin combined with antiplatelet drugs were used postoperatively. Results: Data from 161 patients undergoing cardiac surgery were included in the analysis. Of these, 37 (23.0%) patients in the case group developed venous thrombosis, and 124 (77.0%) patients in the control group did not develop venous thrombosis. In the analysis without adjustment for confounders (model 1), perioperative PCC infusion significantly increased the risk of postoperative venous thrombosis (OR: 3.10, 95% CI: 1.26-7.59, P = 0.0135). In the model analysis adjusted for sex, age, and hospitalization days (model 2), perioperative PCC infusion was no longer significantly associated with the risk of postoperative venous thrombosis (OR: 1.76, 95% CI: 0.56-7.59, P = 0.3317). In the fully adjusted model (model 3), there was a marginally significant association between perioperative infusion of PCC and the risk of postoperative venous thrombosis (OR: 0.03, 95% CI: 0.00-1.23, P = 0.0637). Conclusions: Our findings show no significant association between perioperative PCC infusion in cardiac surgery and the development of postoperative venous thrombosis. Randomized controlled trials are needed to determine the causal relationship between perioperative PCC infusion and venous thrombosis in cardiac surgery.

Associations of MTHFR gene polymorphism with lipid metabolism and risk of cerebral infarction in the Northwest Han Chinese population.

Objective: Genetic variation in the methylenetetrahydrofolate reductase (MTHFR) gene may contribute to the development of cerebral infarction (CI); however, results have been inconsistent across studies with different populations, including studies of the Chinese population. The aim of this study was to analyze the effect of MTHFR gene polymorphism on serum lipid and homocysteine levels among patients with CI in the Northwest Chinese Han population. Patients and methods: A total of 521 CI patients and 524 non-CI controls were enrolled in the study. Polymerase chain reaction and hybridization were utilized to identify MTHFR gene polymorphisms. Multivariate logistic regression analysis was used to assess the associations of MTHFR gene polymorphism with risk of CI. Results: Frequencies of the TT genotype and the T allele were markedly higher among CI patients than among controls. After stratifying our data by sex and age, we determined that these differences in frequency of the TT genotype and the T allele were statistically significant among participants of two different age brackets and among men, but not among women (i.e., there were no statistically significant differences between female patients and female controls). CI patients and control participants with the CT or TT genotype had significantly higher homocysteine (Hcy) levels than those with the CC genotype. Among CI patients, CT/TT carriers showed significantly lower high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (ApoA-I) levels as compared with CC carriers, but there was no significant difference for control participants. Multivariable logistic regression analysis showed that drinking; smoking; diabetes mellitus; levels of Hcy, direct bilirubin (DB), indirect bilirubin (IB), ApoA-I, and total protein (TP); and TT genotype were significant independent risk factors for CI. Conclusions: The results suggested that the TT genotype of the MTHFR C677T gene polymorphism, which is associated with hyperhomocysteinemia (HHcy), might be of great clinical significance in the identification of new biomarkers for CI and in the development of individualized preventive and therapeutic strategies.

Protective role of baicalin in the dynamic progression of lung injury to idiopathic pulmonary fibrosis: A meta-analysis.

BACKGROUND AND PURPOSE: The pathological progression of lung injury (LI) to idiopathic pulmonary fibrosis (IPF) is a common feature of the development of lung disease. At present, effective strategies for preventing this progression are unavailable. Baicalin has been reported to specifically inhibit the progression of LI to IPF. Therefore, this meta-analysis aimed to assess its clinical application and its potential as a therapeutic drug for lung disease based on integrative analysis. METHODS: We systematically searched preclinical articles in eight databases and reviewed them subjectively. The CAMARADES scoring system was used to assess the degree of bias and quality of evidence, whereas the STATA software (version 16.0 software) was used for statistical analysis, including a 3D analysis of the effects of dosage frequency of baicalin in LI and IPF. The protocol of this meta-analysis is documented in the PROSPERO database (CRD42022356152). RESULTS: A total of 23 studies and 412 rodents were included after several rounds of screening. Baicalin was found to reduce the levels of TNF-α, IL-1ß, IL-6, HYP, TGF-ß and MDA and the W/D ratio and increase the levels of SOD. Histopathological analysis of lung tissue validated the regulatory effects of baicalin, and the 3D analysis of dosage frequency revealed that the effective dose of baicalin is 10-200 mg/kg. Mechanistically, baicalin can prevent the progression of LI to IPF by modulating p-Akt, p-NF-κB-p65 and Bcl-2-Bax-caspase-3 signalling. Additionally, baicalin is involved in signalling pathways closely related to anti-apoptotic activity and regulation of lung tissue and immune cells. CONCLUSION: Baicalin at the dose of 10-200 mg/kg exerts protective effects against the progression of LI to IPF through anti-inflammatory and anti-apoptotic pathways.

Evolutionary route of nasopharyngeal carcinoma metastasis and its clinical significance.

It is critical to understand factors associated with nasopharyngeal carcinoma (NPC) metastasis. To track the evolutionary route of metastasis, here we perform an integrative genomic analysis of 163 matched blood and primary, regional lymph node metastasis and distant metastasis tumour samples, combined with single-cell RNA-seq on 11 samples from two patients. The mutation burden, gene mutation frequency, mutation signature, and copy number frequency are similar between metastatic tumours and primary and regional lymph node tumours. There are two distinct evolutionary routes of metastasis, including metastases evolved from regional lymph nodes (lymphatic route, 61.5%, 8/13) and from primary tumours (hematogenous route, 38.5%, 5/13). The hematogenous route is characterised by higher IFN-γ response gene expression and a higher fraction of exhausted CD8+ T cells. Based on a radiomics model, we find that the hematogenous group has significantly better progression-free survival and PD-1 immunotherapy response, while the lymphatic group has a better response to locoregional radiotherapy.

NLRC3 is a potential prognostic biomarker that is correlated with immune cell infiltration in lung adenocarcinoma.

The NLR family CARD domain containing 3 (NLRC3) gene has been reported to have a crucial effect on immunity, inflammation, and tumorigenesis. However, the clinical relevance of NLRC3 in lung adenocarcinoma (LUAD) remains unclear. This study analyzed both RNA sequencing data and corresponding clinical outcomes obtained from public databases to identify (i) NLRC3 as a tumor suppressor in LUAD and (ii) its predictive value for the likelihood of patient responsiveness to immunotherapy. The results showed that NLRC3 expression was reduced in LUAD and was lower in advanced-stage tumors. Additionally, reduced NLRC3 expression was correlated with worse patient prognosis. The protein level of NLRC3 was also observed to have prognostic significance. Moreover, downregulation of NLRC3 was found to suppress the chemotaxis and infiltration of antitumor lymphocyte subpopulations as well as natural killer cells. Mechanistic analysis indicated that NLRC3 may be involved in immune infiltration by regulating chemokines and their receptors in LUAD. Furthermore, NLRC3 functions as a molecular switch in macrophages, whereby it mediates the polarization of M1 macrophages. Patients with high NLRC3 expression were also found to exhibit a more promising response to immunotherapy. In conclusion, NLRC3 could serve as a potential prognostic biomarker for LUAD, help predict the immunotherapeutic response of patients, and guide personalized strategies for the treatment of LUAD.

Collective memory and social imaginaries of the epidemic situation in COVID-19-based on the qualitative research of college students in Wuhan, China.

This study conducted in-depth interviews with 20 students from a university in Wuhan so as to obtain data regarding their collective memory at the early stage of the COVID-19 outbreak and their social imaginaries in the longitudinal dimension of time. Compared with those in other regions, interviewees from Wuhan show more fear and dissatisfaction and think that others find it difficult to empathize with their first-hand experiences. Interviewees from Wuhan are more dependent on the media. However, media use can cause problems related to redundant information and emotional impact. While one is confined to home, he/she is forced to participate in communication with family members and the topic of the body is discussed again from a new angle. Trauma leads to self-reconciliation, as facilitated by the re-examination of and reflection on one' nomination of and reflection on n family members and the months in the wake of the COVID-19 outbreak. However, having received a collectivist education since childhood and having been guided by the discourse system created by the state media, they have since been able to shape their sense of identity and strengthen their sense of national honor.

Antineoplastic agents in chemotherapy facilitating tumor growth and angiogenesis in the interval administrations.

AIMS: There is emerging evidence that antineoplastic agents and the cytotoxic effects on tumor tissues attenuate the benefits of chemotherapy due to tumor microenvironment changes. Nevertheless, the actual relationship between chemotherapy and recurrent tumors in which the genotypes differ from the original tumor after chemotherapy is unclear. MATERIALS AND METHODS: Bone marrow transplantation, flow cytometer, immune inhibition and immunofluorescence will be utilized to investigate the effect of antineoplastic agents on bone-marrow-derived cells (BMDCs) release and recruitment, and to explore the pathways and mechanisms of antineoplastic agents in promoting tumor growth. KEY FINDINGS: Tumor growth and angiogenesis were significantly enhanced in the mouse model after treatment with antineoplastic agents such as cyclophosphamide, 5-fluorouracil, or cisplatin, along with large increases in proangiogenic vascular endothelial growth factor receptor-2 (VEGFR2+), ß3+, CD11b+Gr-1+, and VEGFR2+ß3+ BMDCs in circulating blood. BMDC recruitment and VEGFR2 and ß3 mRNA transcription in tumor tissues were also enhanced by antineoplastic agents. Antineoplastic-agent-treated BMDCs markedly augmented tumor and endothelial cell proliferation, and ß3 mRNA transcription in endothelial cells (ECs). SIGNIFICANCE: The results suggested that antineoplastic-agent treatment augmented the tumor microenvironment by mobilizing proangiogenic BMDCs, enhancing BMDC recruitment and angiogenesis, and increasing BMDC-mediated tumor and EC functions. These results led to tumor growth and angiogenesis aggravation. It is paramount to elucidate the potential mechanism by which the cellular and molecular effects triggered by the antineoplastic agents attenuate the effects of cancer therapy, and thereafter to explore possible methods for improving tumor treatment efficacy.

Quantitative evaluation and pharmacokinetic characteristics of the irreversible BTK inhibitor zanubrutinib in mouse plasma using LC-MS/MS.

Zanubrutinib (BGB-3111) belongs to the class of irreversible inhibitors of Bruton's tyrosine kinase (BTK) for treating B-cell malignancies. A validated assay with excellent sensitivity, selectivity, and simplicity is required to measure plasma concentration and investigate its pharmacokinetics. The plasma of mice containing zanubrutinib and roxithromycin (internal standard) was processed with acetonitrile for protein precipitation. Then the supernatant was analyzed by high-performance liquid chromatography coupled with a triple quadrupole mass spectrometer using electrospray ionization in the positive mode. Zanubrutinib was given to mice intragastrically at 30 mg/kg to determine its pharmacokinetic parameters. The method was verified and showed good linearity in the range of 0.1-100 ng/mL. The method's sensitivity, accuracy, and precision were all within acceptable bounds. By this method, the pharmacokinetic profile of zanubrutinib in mouse plasma was measured.

Promotion of tumor progression induced by continuous low-dose administration of antineoplastic agent gemcitabine or gemcitabine combined with cisplatin.

MAJOR FINDING: This study observes a previously neglected pharmacological phenomenon and investigates its mechanism of that the continuous low-dose administration of some antineoplastic agents in certain dose ranges can promote tumorigenesis and tumor progression in vitro and in vivo, through stimulation of tumor cell functions directly as well as enhancement of tumor angiogenesis by BMDCs recruitment indirectly. The results alert to a potential risk in current empirically based continuous low-dose chemotherapy regimens such as metronomic chemotherapy. BACKGROUND AND OBJECTIVES: There are indications that certain antineoplastic agents at low dosages may exhibit abnormal pharmacological actions, such as promoting tumor growth. However, the phenomenon still needs to be further confirmed, and its underlying mechanisms have not yet been fully elucidated. METHODS: Gemcitabine (GEM) and cisplatin (CDDP) were employed as representative antineoplastic agents to observe effects of continuous low-dose chemotherapy with GEM or GEM combined with CDDP (GEM+CDDP) on tumor formation and growthin xenograft tumor models in vivo. Tumor and endothelial cell functions, apoptosis, cell cycle analysis, as well as bone marrow derived cells (BMDCs) mobilization, were evaluated with transwell, MTT or flow cytometry analysis in vitro, respectively. Histological methods were employed to assess angiogenesis in tumor tissues. RESULTS: The results showed that tumor formation and growth were both significantly promoted by GEM or GEM+CDDP at as low as half of the metronomic dosages, which were accompanied by enhancements of angiogenesis in tumor tissues and the release of proangiogenic BMDCs in the circulating blood. Additionally, GEM or GEM+CDDP at low concentrations dramatically facilitated the proliferation, migration, and invasion of tumor cells in vitro. Cell-cycle arrest, activation of associated apoptotic proteins, and inhibition of apoptosis were also observed in tumor cells. CONCLUSIONS: These findings indicate that, the continuous low-dose administration of GEM and GEM+CDDP can promote tumorigenesis and tumor progression in vivo by inhibiting apoptosis, mobilizing BMDCs, and promoting angiogenesis in certain dose ranges. These findings urge further investigations to avoid the potential risks in current empiric continuous low-dose chemotherapy regimens with antineoplastic agents.

Effect of Apolipoprotein E ε4 Allele on the Progression of Carotid Atherosclerosis Through Apolipoprotein Levels.

Background: The apolipoprotein E (ApoE) genetic variation may be involved in the development of Carotid Atherosclerosis (CAS) disease. So far, few data are available on the role of ApoE isoforms in CAS. The association between this ApoE genotype and CAS remains controversial. The aim of this study was to investigate ApoE gene polymorphism in relation to CAS and the relationships between ApoE gene polymorphism and plasma lipid levels in the ShaanXi Han populations. Patients and methods: The study group enrolled 399 CAS participants and 399 non-CAS controls. ApoE gene polymorphisms were determined by Polymerase chain reaction and hybridization. Results: The ε3/ε4 genotype and ε4 allele in patients with CAS were significantly higher than control participants. In stratified analyses by age and sex, the elevated risk conferred by ɛ4 allele was evident in adults under 60 years old, but not in adults over 60 years old, females and males. ε4 carriers had significantly elevated ApoB and ApoB/ApoA and decreased ApoE levels than ε2 carriers in CAS patients. After adjusting for confounding factors, hypertension, ApoA-I, low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and ε4 allele were significant independent risk factor for CAS. ApoE-ε4 allele was associated with a nearly 1.5-fold increased risk of CAS. Conclusion: This study provides convincing evidence that ε4 allele, hypertension, ApoA-I, LDL-C and TG levels are independent risk factor for CAS in the ShaanXi Han populations. ApoE polymorphism was associated with CAS and this association was partly mediated through blood lipids. Also, the clinical use of genomic data may become useful in optimizing individual preventative and therapeutic strategies.

Doxorubicin Loaded Dextran-coated Superparamagnetic Iron Oxide Na-noparticles with Sustained Release Property: Intracellular Uptake, Phar-macokinetics and Biodistribution Study.

BACKGROUND: Due to the short biological half-life and serious side effects (especially for heart and kidney), the application of Doxorubicin (Dox) in clinical therapy is strictly limited. To overcome these shortcomings, a novel sustained release formulation of doxorubicin-loaded dextran-coated superparamagnetic iron oxide nanoparticles (Dox-DSPIONs) was prepared. OBJECTIVE: The purpose of this study was to evaluate the intracellular uptake behavior of Dox-DSPIONs and to investigate their pharmacokinetics and biodistribution properties. METHOD: Confocal laser scanning microscopy was employed to study the intracellular uptake and release properties of Dox from Dox-DSPIONs in SMMC-7721 cells. Simple high-performance liquid chromatography with fluorescence detection (HPLC-FLD) method was established to study the pharmacokinetics and biodistribution properties of Dox-DSPIONs in vivo after intravenous administration and compared with free Dox. RESULTS: Intracellular uptake experiment indicated that Dox could be released sustainedly from Dox-DSPIONs over time. The pharmacokinetics parameters displayed that the T1/2and AUC0-24h of Dox-DSPIONs were higher than those of free Dox, while the Cmax of Dox-DSPIONs was significantly lower than that of free drug. The biodistribution behaviors of the drug were altered by Dox-DSPIONs in mice, which showed obvious liver targeting, and significantly reduced the distribution of the drug in the heart and kidney. CONCLUSION: Dox-DSPIONs have the sustained-release property in vitro and in vivo, which could significantly prolong blood circulation time, improve bioavailability, and reduce the side effects of Dox. Therefore, the novel formulation of the Dox-DSPIONs has the potential as a promising drug delivery system in cancer therapy.

Current understanding of autoantibody against angiotensin II type 1 receptor in preeclampsia.

Preeclampsia (PE) remains a leading cause of fetal and maternal mortality. Angiotensin II type 1 receptor autoantibody (AT1-AA) is implicated in the dysregulation of the renin-angiotensin-aldosterone system. A strong relationship between AT1-AA and the occurrence and severity of PE has been confirmed in previous literature. Recent evidences suggested that AT1-AA was responsible for blood pressure elevation, reactive oxygen species synthesis, and inflammatory factors release and engaged in multiple signaling cascades. The inhibition of AT1-AA might be a potential therapeutic target in future days. Here we reviewed the current understanding of AT1-AA, aiming to provide clarity surrounding the role of AT1-AA in PE.

Apolipoprotein E Gene Polymorphism and Coronary Artery Disease Risk Among Patients in Northwest China.

PURPOSE: The association between apolipoprotein E (ApoE) gene polymorphisms and the risk of coronary artery disease (CAD) among different populations has been assessed in numerous previous studies, but the results remain inconclusive. The present study aimed to determine the role of ApoE genotypes in CAD risk and the interrelationships between lipid profiles and ApoE alleles and genotypes among the population of northwest China. PATIENTS AND METHODS: This study was performed on 308 patients with CAD and 308 control participants. ApoE gene polymorphism was analysed using the polymerase chain reaction and hybridization. RESULTS: The findings indicated that the frequencies of ε3/ε4 genotype and ε4 allele frequency were significantly higher in patients with CAD than in the control participants. ε2 carriers had significantly lower total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) levels than did ε3 or ε4 carriers among the control participants. However, our study found no significant differences in plasma lipoprotein levels between ɛ2, ɛ3 and ɛ4 carriers in patients with CAD. Moreover, ε4 carriers had significantly higher ApoB, ApoB/ApoA-I levels and significantly lower ApoE levels in both patients with CAD and control participants. ε4 allele presence was associated with a nearly two-fold higher CAD risk. After adjusting for other established risk factors, ε4 allele was an independent risk factor for CAD. After stratified by age (≤ 60 years and >60 years), ε4 allele was indicated to increase the CAD risk 3.3-fold in elderly patients with CAD, but not in young patients with CAD. After stratified by sex, ε4 allele was not a risk factor in females and males patients with CAD. CONCLUSION: This study provides evidence that the ε4 allele, drinking, smoking, hypertension, and TG and ApoE levels are independent risk factor for CAD among patients in northwest China.

Genome-wide identification and characterization of circular RNA m6A modification in pancreatic cancer.

BACKGROUND: N6-methyladenosine (m6A) is the most abundant modification of RNA in eukaryotic cells and play critical roles in cancer. While most related studies focus on m6A modifications in linear RNA, transcriptome-wide profiling and exploration of m6A modification in circular RNAs in cancer is still lacking. METHODS: For the detection of m6A modification in circRNAs, we developed a new bioinformatics tools called Circm6A and applied it to the m6A-seq data of 77 tissue samples from 58 individuals with pancreatic ductal adenocarcinoma (PDAC). RESULTS: Circm6A performs better than the existing circRNA identification tools, which achieved highest F1 score among these tools in the detection of circRNAs with m6A modifications. By using Circm6A, we identified a total of 8807 m6A-circRNAs from our m6A-seq data. The m6A-circRNAs tend to be hypermethylated in PDAC tumor tissues compared with normal tissues. The hypermethylated m6A-circRNAs were associated with a significant gain of circRNA-mRNA coexpression network, leading to the dysregulation of many important cancer-related pathways. Moreover, we found the cues that hypermethylated m6A-circRNAs may promote the circularization and translation of circRNAs. CONCLUSIONS: These comprehensive findings further bridged the knowledge gaps between m6A modification and circRNAs fields by depicting the m6A-circRNAs genomic landscape of PDAC patients and revealed the emerging roles played by m6A-circRNAs in pancreatic cancer. Circm6A is available at https://github.com/canceromics/circm6a .