The NEDD8-activating enzyme inhibitor MLN4924 reduces ischemic brain injury in mice.

Blood-brain barrier (BBB) breakdown and inflammation occurring at the BBB have a key, mainly a deleterious role in the pathophysiology of ischemic stroke. Neddylation is a ubiquitylation-like pathway that is critical in various cellular functions by conjugating neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) to target proteins. However, the roles of neddylation pathway in ischemic stroke remain elusive. Here, we report that NEDD8 conjugation increased during acute phase after ischemic stroke and was present in intravascular and intraparenchymal neutrophils. Inhibition of neddylation by MLN4924, also known as pevonedistat, inactivated cullin-RING E3 ligase (CRL), and reduced brain infarction and improved functional outcomes. MLN4924 treatment induced the accumulation of the CRL substrate neurofibromatosis 1 (NF1). By using virus-mediated NF1 silencing, we show that NF1 knockdown abolished MLN4924-dependent inhibition of neutrophil trafficking. These effects were mediated through activation of endothelial P-selectin and intercellular adhesion molecule-1 (ICAM-1), and blocking antibodies against P-selectin or anti-ICAM-1 antibodies reversed NF1 silencing-induced increase in neutrophil infiltration in MLN4924-treated mice. Furthermore, we found that NF1 silencing blocked MLN4924-afforded BBB protection and neuroprotection through activation of protein kinase C δ (PKCδ), myristoylated alanine-rich C-kinase substrate (MARCKS), and myosin light chain (MLC) in cerebral microvessels after ischemic stroke, and treatment of mice with the PKCδ inhibitor rottlerin reduced this increased BBB permeability. Our study demonstrated that increased neddylation promoted neutrophil trafficking and thus exacerbated injury of the BBB and stroke outcomes. We suggest that the neddylation inhibition may be beneficial in ischemic stroke.

Inhibition of Anaplastic Lymphoma Kinase Protects From Ischemic Stroke.

BACKGROUND: Ischemic stroke is often accompanied by oxidative stress and inflammatory response, both of which work synergistically to exacerbate the disruption of the blood-brain barrier and ischemic brain injury. ALK (anaplastic lymphoma kinase), a cancer-associated receptor tyrosine kinase, was found to play a role in oxidative stress and inflammation. In this study, we investigated the role of ALK inhibition in a murine model of ischemic stroke. METHODS: Focal cerebral ischemia was induced by temporary occlusion of the right middle cerebral artery in mice with a filament. The ALK inhibitor alectinib was administered following the stroke. ALOX15 (arachidonic acid 15-lipoxygenase) was overexpressed by adenovirus injection. The immunohistochemistry, Western blot, oxidative stress, inflammation, blood-brain barrier leakage, infarct volume, and functional outcomes were determined. RESULTS: We found that the expression of ALK was markedly increased in the neurovascular unit after cerebral ischemia. Treatment with the ALK inhibitor alectinib reduced the accumulation of reactive oxygen species, lipid peroxidation, and oxidative DNA, increased the vascular levels of antioxidant enzymes, inactivated the vascular NLRP3 (nucleotide-binding oligomerization domain-like receptor protein 3) inflammasome pathway, and reduced vascular inflammation (ICAM-1 [intercellular adhesion molecule-1] and MCP-1 [monocyte chemoattractant protein-1]) after ischemia. Moreover, alectinib reduced the loss of cerebrovascular integrity and blood-brain barrier damage, consequently decreasing brain infarction and neurological deficits. Furthermore, alectinib reduced stroke-evoked ALOX15 expression, whereas virus-mediated overexpression of ALOX15 abolished alectinib-dependent inhibition of oxidative stress and vascular inflammation, blood-brain barrier protection, and neuroprotection, suggesting the protective effects of alectinib for stroke may involve ALOX15. CONCLUSIONS: Our findings demonstrated that alectinib protects from stroke by regulating ischemic signaling cascades and suggest that ALK may be a novel therapeutic target for ischemic stroke.

Effects of mild hyperbaric oxygen therapy on timing sequence recovery of muscle fatigue in chinese university male athletes.

Objectives: This study aimed to investigate the timing sequence recovery effects of single and repeated Mild Hyperbaric Oxygen Therapy (MHOT) on muscle fatigue induced by cycling exercise through a comprehensive set of parameters. Methods: This study employed a controlled crossover design involving 12 Chinese secondary national-level male athletes. Each participant completed two identical trials over six days. Each trial consisted of a 90-min cycling exercise followed by either a Control (CON) intervention (1 atm absolute (ATA), 20.9 % oxygen, 60 min) or MHOT intervention (1.25 ATA, 26%-28 % oxygen, 60 min). Various physiological parameters including Rating of Perceived Exertion (RPE), Heart Rate (HR), Peripheral Oxygen Saturation (SpO2), Perfusion Index (PI%), Creatine Kinase (CK), Lactate Dehydrogenase (LDH), Lactic Acid (LA), Blood Urea Nitrogen (BUN), Superoxide Dismutase (SOD), Malondialdehyde (MDA), and Standing Long Jump Distance (SLJ) were measured at six different time points throughout the trials. Results: RPE revealed that the MHOT group experienced reduced subjective fatigue in comparison to the CON group (P < 0.05). Additionally, MHOT demonstrated quicker recovery in HR and PI% compared to the CON group (P < 0.05). Regarding CK, LA, BUN, SOD, and MDA levels, the MHOT group exhibited accelerated recovery post-6 intervention and at the 24-h mark after six interventions, showing significant improvement over the CON group (P < 0.05). However, no notable disparity was observed between groups concerning SpO2, LDH, and SLJ. Conclusions: Both single and repeated sessions of MHOT demonstrated efficacy in alleviating subjective fatigue and promoting recovery of heart rate and blood perfusion following muscle fatigue, ensuring parallel structure and consistency in their effects. Repeated MHOT sessions (six times) exhibit a significant reduction in levels of blood markers associated with muscle damage, metabolites, and oxidative stress. However, the impact of a single MHOT intervention was less pronounced.

Systematic review and meta-analysis: Prognostic impact of time from diagnosis to treatment in patients with acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) has been considered an oncologic emergency that requires initiation of chemotherapy immediately after diagnosis. With the introduction of novel targeted therapies, there is a potential benefit associated with delaying definitive treatment for identification of actionable therapeutic targets. Unfortunately, cytogenetic/molecular testing can take >7 days to return, and there is not a consensus regarding the prognostic impact of time from diagnosis to treatment (TDT) in AML. METHODS: A literature review and meta-analysis of studies done to date that evaluate TDT was conducted. Studies that reported baseline characteristics, TDT, and outcomes for patients with AML were selected. Outcomes included overall survival (OS), complete remission (CR), and mortality. Studies that measured CR rates within each TDT range and data to calculate odds ratios were included in the meta-analysis. The remaining outcomes were synthesized descriptively for literature review. RESULTS: Thirteen studies were identified, which comprised a total of 14,946 patients. Median TDT values were between 1 and 8 days. Several studies found a significant association between prolonged TDT and older age and lower proliferation burden. Four of 11 studies did not detect a significant relationship between TDT and OS. No studies found a significant association between TDT and early death. Six of eight studies did not find a significant association between TDT and CR rate. The meta-analysis found a significant association between prolonged TDT and decreased achievement of CR (p < .05). CONCLUSIONS: Results were highly variable but suggest it may be feasible to pursue cytogenetic/molecular testing in patients who are clinically stable, particularly in those aged 60 years and older.

Different hydration methods for the prevention of contrast-induced nephropathy in patients with elective percutaneous coronary intervention: a retrospective study.

BACKGROUND: Hydration is currently the main measure to prevent contrast-induced nephropathy (CIN). We aimed to compare the preventive effect of preprocedure and postprocedure hydration on CIN in patients with coronary heart disease undergoing elective percutaneous coronary intervention (PCI). METHODS: A retrospective study included 198 cases of postprocedure hydration and 396 cases of preprocedure hydration using propensity score matching. The incidence of CIN 48 h after PCI and adverse events within 30 days after contrast media exposure were compared between the two groups. Logistic regression analysis was used to analyse the risk factors for CIN. RESULTS: The incidence of CIN in the postprocedure hydration group was 3.54%, while that in the preprocedure hydration group was 4.8%. There was no significant difference between the two groups (p = 0.478). Multivariate logistic regression analysis showed that diabetes mellitus, baseline BNP and cystatin C levels, and contrast agent dosage were independent risk factors for CIN. There was no significant difference in the incidence of major adverse events between the two groups (3.03% vs. 2.02%, p = 0.830). CONCLUSIONS: Postprocedure hydration is equally effective compared to preoperative hydration in the prevention of CIN in patients with coronary heart disease undergoing elective PCI.

Risk Factors for Stroke Development After Thoracic Aortic Surgery.

OBJECTIVES: Stroke after thoracic aortic surgery is a complication that is associated with poor outcomes. The aim is to characterize the intraoperative risk factors for stroke development. DESIGN: A retrospective analysis. SETTING: Tertiary, high-volume cardiac surgery center. PARTICIPANTS: Patients who had surgical repair of thoracic aortic diseases from January 1, 2017, through December 31, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 704 patients were included, of whom 533 had ascending aortic aneurysms, and 171 had type A aortic dissection. The incidence of postoperative stroke was 4.5% (95% CI 2.9%-6.6%) for ascending aortic aneurysms compared with 12.3% (95% CI 7.8%-18.16%) in type-A aortic dissections. Patients who developed postoperative strokes had significantly lower intraoperative hemoglobin median (7.5 gm/dL [IQR 6.8-8.6] v 8.55 gm/dL [IQR 7.3-10.0]; p < 0.001). The median cardiopulmonary bypass time was 185 minutes (IQR 136-328) in the stroke group versus 156 minutes (IQR 113-206) in the nonstroke group (p = 0.014). Circulatory arrest was used in 57.8% versus 38.5% of the nonstroke patients (p = 0.017). The initial temperature after leaving the operating room was lower, with a median of 35.0°C (IQR 34-35.92) in the stroke group versus 35.5°C (IQR 35-36) in the nonstroke cohort (p = 0.021). CONCLUSIONS: This single-center study highlighted the potential importance of intra-operative factors in preventing stroke. Lower hemoglobin, longer duration of cardiopulmonary bypass, deep hypothermic circulatory arrest, and postoperative hypothermia are potential risk factors for postoperative stroke. Further studies are needed to prevent this significant complication in patients with thoracic aortic diseases.

Impact of Left Atrial Appendage Closure Combined with Catheter Ablation on Endocrine and Mechanical Cardiac Function in Patients with Atrial Fibrillation.

Background: The combined procedure of left atrial appendage closure (LAAC) and catheter ablation (CA) is a safe and feasible therapy to treat patients with atrial fibrillation (AF). However, the effect of the combined procedure on cardiac function remains unclear. This study aimed to investigate the changes in endocrine and mechanical function of the heart following the combined procedure. Methods: This retrospective study included 62 consecutive patients who underwent the combined procedure of AF ablation and WATCHMAN LAAC and 62 sex and age-matched patients who only received AF ablation. During follow-up, patients were examined for brain natriuretic peptide (BNP) levels to represent endocrine cardiac function. Mechanical cardiac function was assessed during echocardiographic examination by means of the LA ejection fraction, LA strain (Ƹ), and LA strain rate (SR). Results: (1) The BNP levels decreased acutely after the procedure, rose at day 3 postoperation, but trended downwards at 3 months postoperation in both groups. No significant difference was observed between the two groups. (2) LA ejection fraction, LA Ƹ, and SR exhibited a continuous upward trend over a 3-month follow-up in both groups. There was no significant difference in LA ejection fractions, SRe (the parameter of LA conduit function), and SRa (the parameter of LA booster pump function) between the two groups. However, the Ƹ and SRs (the parameters of LA reservoir function) improved in patients treated with CA alone. Conclusions: The combined procedure of LAAC and CA significantly improved the endocrine and mechanical function of the heart. Compared to simple CA, based on CA with LAAC intervention, it does not significantly change LA endocrine function but may lead to a decline in the LA reservoir function.

The overestimated prevalence of hypertension in a population survey: a cross-sectional study from Hebei province, China.

OBJECTIVE: Currently, the prevalence of hypertension is mainly ascertained using a one-visit population survey, which may lead to overestimation. The purpose of this study was to assess the accuracy of hypertension prevalence determined by a one-visit population survey. METHODS: For this cross-sectional study, we continuously enrolled 1116 volunteers without a hypertension history in Hebei province from January 2018 to December 2019. The study population included 511 (45.80%) males and 605 (54.20%) females with a mean age of 48 years. The hypertension prevalence was assessed using two methods: one-visit screening and daytime ambulatory blood pressure (BP) monitoring. We directly compared the performances of daytime ambulatory BP monitoring and one-visit screening in the same group of subjects. In addition, we explored possible thresholds to improve the detection of hypertension. RESULTS: During the one-visit survey, the mean BP value was about 8 mmHg higher than that determined by daytime ambulatory BP monitoring. The prevalence of hypertension was 29.84% and 14.07% during the one-visit and daytime multiple visit surveys, respectively. The risk factors for overestimated hypertension were female sex, body mass index < 24.00 kg/m2, and diastolic BP of 100 mmHg. The positive predictive value of the one-visit population survey for diagnosing hypertension was 36.34%. Furthermore, receiver operating characteristic analysis showed that in males, the best diagnostic threshold for hypertension diagnosis was 148/96 mmHg. CONCLUSION: The hypertension prevalence was likely overestimated by 2-fold in the one-visit survey group compared to the daytime ambulatory BP monitoring group. Thus, the threshold for one-visit BP screening should be raised to 148/96 mmHg to improve the accuracy of hypertension diagnosis.

Validation and derivation of short-term prognostic risk score in acute decompensated heart failure in China.

BACKGROUND: Few prognostic risk scores (PRSs) have been routinely used in acute decompensated heart failure (ADHF). We, therefore, externally validated three published PRSs (3A3B, AHEAD, and OPTIME-CHF) and derived a new PRS to predict the short-term prognosis in ADHF. METHODS: A total of 4550 patients from the Heb-ADHF registry in China were randomly divided into the derivation and validation cohorts (3:2). Discrimination of each PRS was assessed by the area under the receiver operating characteristic curve (AUROC). Logistic regression was exploited to select the predictors and create the new PRS. The Hosmer-Lemeshow goodness-of-fit test was used to assess the calibration of the new PRS. RESULTS: The AUROCs of the 3A3B, AHEAD, and OPTIME-CHF score in the derivation cohort were 0.55 (95% CI 0.53-0.57), 0.54 (95% CI 0.53-0.56), and 0.56 (95% CI 0.54-0.57), respectively. After logistic regression analysis, the new PRS computed as 1 × (diastolic blood pressure < 80 mmHg) + 2 × (lymphocyte > 1.11 × 109/L) + 1 × (creatinine > 80 µmol/L) + 2 × (blood urea nitrogen > 21 mg/dL) + 1 × [BNP 500 to < 1500 pg/mL (NT-proBNP 2500 to < 7500 pg/mL)] or 3 × [BNP ≥ 1500 (NT-proBNP ≥ 7500) pg/mL] + 3 × (QRS fraction of electrocardiogram < 55%) + 4 × (ACEI/ARB not used) + 1 × (rhBNP used), with a better AUROC of 0.67 (95% CI 0.64-0.70) and a good calibration (Hosmer-Lemeshow χ2 = 3.366, P = 0.186). The results in validation cohort verified these findings. CONCLUSIONS: The short-term prognostic values of 3A3B, AHEAD, and OPTIME-CHF score in ADHF patients were all poor, while the new PRS exhibited potential predictive ability. We demonstrated the QRS fraction of electrocardiogram as a novel predictor for the short-term outcomes of ADHF for the first time. Our findings might help to recognize high-risk ADHF patients.

Safety assessment of phytase transgenic maize 11TPY050 in Sprague-Dawley rats by 90-day feeding study.

The present study aimed to evaluate the subchronic toxicity of feeding with phytase-transgenic maize line 11TPY050 in Sprague-Dawley (SD) rats. Rats (n = 10/sex/group) were fed with 12.5%, 25% or 50% (w/w) transgenic maize diet, 12.5%, 25% or 50% (w/w) non-transgenic isoline OSL940 maize diet, or 50% (w/w) commercially available Zhengdan958 maize diet for 90 days. Daily clinical observations and weekly measurements of body weights and food consumption were conducted. Blood samples were collected on day 46 and day 91 for hematology and clinical chemistry evaluations. At the end of the study, macroscopic and microscopic examinations were performed. No effects on body weight and food consumption were observed. The results of hematology, clinical chemistry, and absolute and relative organ weights in the transgenic maize group were comparable to those in the parental maize group. Several statistical differences were not dose-related and were not considered to be biologically significant. Furthermore, the terminal necropsy and histopathological examination showed no treatment-related changes among the groups. The results from the present 90-day feeding study of phytase-transgenic maize 11TPY050 indicated no unexpected adverse effects in SD rats. The phytase transgenic maize 11TPY050 has substantial equivalence with non-transgenic maize.

An investigation into gender bias in the evaluation of orthopedic trainee arthroscopic skills.

BACKGROUND: Women surgeons receive lower compensation, hold fewer academic positions, and hold fewer leadership positions than men, particularly in orthopedic surgery. Gender bias at the trainee level has been demonstrated in various surgical subspecialties, but there is a lack of information on gender bias within the orthopedic training environment. This study investigated whether implicit gender bias is present in the subjective evaluation of orthopedic trainee arthroscopic skills. METHODS: After institutional review board approval, a web-based survey was sent to American Shoulder and Elbow Surgeons (ASES) members via the society's email listserve. Study participants were informed that the study was being done to develop a systematic evaluation method for trainees. The survey randomized participants to view and evaluate a prefellowship and a postfellowship video of "Rachel" (she/her) or "Charles" (he/him) performing a 15-point diagnostic shoulder arthroscopy. The videos for Rachel and Charles were identical except for the pronouns used in the video. Participants evaluated the trainee's skill level using questions from the Arthroscopic Surgical Skill Evaluation Tool (ASSET). Blinded and deidentified additional comments regarding the trainee's skill were classified as positive, negative, or neutral. Statistical analyses were used to compare scores and comments between Rachel and Charles. RESULTS: Of 1115 active ASES members, 181 ASES members started the survey and 106 watched both videos and were included in the analysis. Of the 106 participants completing the survey, 96 (91%) were men and 10 (9%) were women with a median (interquartile range) age of 44 (38-51). A teaching role was reported by 84 of 106 participants (79%). There was no significant difference between prefellowship scores (P = .87) or between postfellowship scores (P = .84) for the woman and man fellow. The numbers of comments classified as positive, negative, or neutral were not significantly different between the man and woman fellow (P = .19). Participants in teaching roles gave significantly lower scores to both fellows at both time points (P = .04), and participants who had fellow trainees were more likely to give negative comments to both fellows (P = .02). DISCUSSION: Trainee gender did not influence the ratings and comments participants gave for trainee arthroscopic skills, suggesting that gender bias may not play a major role in the evaluation of arthroscopic skill during orthopedic training.

Protective Effects of Liquiritigenin against Cisplatin-Induced Nephrotoxicity via NRF2/SIRT3-Mediated Improvement of Mitochondrial Function.

Acute kidney injury (AKI) induced by cisplatin (CP), a first-line anticancer drug for chemotherapy, is common. To date, there is an urgent need to find effective treatments to reduce the nephrotoxicity caused by CP. Meanwhile, the restoration of mitochondrial dysfunction shows potential to be used as an adjunct to conventional therapeutic strategies. This study found that liquiritigenin can ameliorate mitochondrial dysfunction and acute kidney injury induced by CP in mice. The intraperitoneal injection of 15 mg/kg body weight liquiritigenin for 2 days markedly protected against CP-induced mitochondrial dysfunction, restored renal tubule and mitochondrial morphology, decreased blood Scr and BUN levels, and decreased cell apoptosis. Furthermore, the elevated expression of SIRT3 induced by liquiritigenin, which can be upregulated by NRF2, was confirmed in vivo and in vitro. The underlying protective mechanisms of liquiritigenin in CP-induced nephrotoxicity were then investigated. Molecular docking results showed that liquiritigenin has potent binding activities to KEAP1, GSK-3ß and HRD1. Further results showed that liquiritigenin induced the nuclear translocation of NRF2 and increased the levels of mitochondrial bioenergetics-related protein such as PGC-1α, and TFAM, which are related to NRF2 activity and mitochondrial biogenesis. In addition, liquiritigenin was found to possibly reverse the decrease in BCL2/BAX ratio induced by CP in live cultured renal tubule epithelial cells. Collectively, these results indicated that liquiritigenin could be used as a potential nephroprotective agent to protect against cisplatin-induced acute kidney injury in a NRF2-dependent manner by improving mitochondria function.

Antioxidant Effects of Roasted Licorice in a Zebrafish Model and Its Mechanisms.

Licorice (Gan-Cao, licorice) is a natural antioxidant and roasted licorice is the most common processing specification used in traditional Chinese medicine prescriptions. Traditional Chinese medicine theory deems that the honey-roasting process can promote the efficacy of licorice, including tonifying the spleen and augmenting "Qi" (energy). The antioxidant activity and mechanisms underlying roasted licorice have not yet been reported. In this study, we found that roasted licorice could relieve the oxidative stress injury induced by metronidazole (MTZ) and could restrain the production of excessive reactive oxygen species (ROS) induced by 2,2'-azobis (2-methylpropionamidine) dihydrochloride (AAPH) in a zebrafish model. It was further found that roasted licorice could exert its oxidative activity by upregulating the expression of key genes such as heme oxygenase 1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), glutamate-cysteine ligase modifier subunit (GCLM), and glutamate-cysteine ligase catalytic subunit (GCLC) in the nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway both in vivo and in vitro. Furthermore, consistent results were obtained showing that rat serum containing roasted licorice was estimated to reduce cell apoptosis induced by H2O2. Then, the UHPLC-Q-Exactive Orbitrap MS analysis results elucidated the chemical composition of rat plasma containing roasted licorice extracts, including ten prototype chemical components and five metabolic components. Among them, six compounds were found to have binding activity with Kelch-like ECH-associated protein 1 (KEAP1), which plays a crucial role in the transcriptional activity of NRF2, using a molecular docking simulation. The results also showed that liquiritigenin had the strongest binding ability with KEAP1. Immunofluorescence further confirmed that liquiritigenin could induce the nuclear translocation of NRF2. In summary, this study provides a better understanding of the antioxidant effect and mechanisms of roasted licorice, and lays a theoretical foundation for the development of a potential antioxidant for use in clinical practice.

Long-term follow-up assessment of cardiac safety in SAFE-HEaRt, a clinical trial evaluating the use of HER2-targeted therapies in patients with breast cancer and compromised heart function.

PURPOSE: HER2-targeted therapies are associated with cardiotoxicity which is usually asymptomatic and reversible. We report the updated cardiac safety assessment of patients with compromised heart function receiving HER2-targeted therapy for breast cancer, enrolled in the SAFE-HEaRt trial, at a median follow-up of 3.5 years. METHODS: Thirty patients with stage I-IV HER2-positive breast cancer receiving trastuzumab with or without pertuzumab, or ado-trastuzumab emtansine (T-DM1), with asymptomatic LVEF (left ventricular ejection fraction) 40-49%, were started on cardioprotective medications, with the primary endpoint being completion of HER2-targeted therapy without cardiac events (CE) or protocol-defined asymptomatic worsening of LVEF. IRB-approved follow-up assessment included 23 patients. RESULTS: Median follow-up as of June 2020 is 42 months. The study met its primary endpoint with 27 patients (90%) completing their HER2-targeted therapies without cardiac issues. Of the 23 evaluable patients at long-term f/u, 14 had early stage breast cancer, and 9 had metastatic disease, 8 of whom remained on HER2-targeted therapies. One patient developed symptomatic heart failure with no change in LVEF. There were no cardiac deaths. The mean LVEF improved to 52.1% from 44.9% at study baseline, including patients who remained on HER2-targeted therapy, and those who received prior anthracyclines. CONCLUSIONS: Long-term follow-up of the SAFE-HEaRt study continues to provide safety data of HER2-targeted therapy use in patients with compromised heart function. The late development of cardiac dysfunction is uncommon and continued multi-disciplinary oncologic and cardiac care of patients is vital for improved patient outcomes.

Relationship among atrial fibrillation, the CHA2DS2-VASc score and ischaemic stroke in patients with coronary artery disease: a propensity score matching study in Hebei, China.

BACKGROUND: Recent evidence has shown that the pathogenesis of ischaemic stroke associated with atrial fibrillation (AF) is complex and involves other factors in addition to arrhythmias. The purpose of this study was to investigate the relationship among AF, CHA2DS2-VASc score and ischaemic stroke in patients with coronary artery disease (CAD) in Hebei, China. METHODS: A total of 2,335 patients with CAD from September 2016 to May 2019 at the Second Hospital of Hebei Medical University were included (mean age 62.73 ± 10.35 years, range 26-92 years; 41.58% female). This was a cross-sectional study, and participants were divided into non-stroke (n = 1997) and ischaemic stroke groups (n = 338). Propensity score matching (PSM) was performed to match ischaemic stroke patients with non-stroke patients in a 1:4 ratio. The relationship among AF, the CHA2DS2-VASc score and ischaemic stroke was evaluated using univariable generalized linear models for different sex, age, body mass index (BMI), CAD and CHA2DS2-VASc score subgroups. Univariable and multivariable generalized linear models were used to evaluate the relationship between AF and ischaemic stroke in the different models. RESULTS: Compared with that in the non-stroke group, the prevalence of AF (8.81% vs. 14.20%, P = 0.002) in the ischaemic stroke group was higher. The proportion of patients with ischaemic stroke was significantly different between the AF group and the non-AF group (28.74% vs. 19.04%, P = 0.003). An increasing CHA2DS2-VASc score was associated with a gradual increase in the prevalence of AF (P for trend < 0.001). Subgroup analysis showed that the trend towards increased stroke risk in the AF group was consistent across the various subgroups. The multivariable analysis demonstrated that AF was not associated with ischaemic stroke compared with the absence of AF (OR = 1.55, 95% CI 0.94-2.56, P = 0.087). CONCLUSION: In our cross-sectional study, after adjustment for confounding factors, there was no association between AF and ischaemic stroke. The increased risk of ischaemic stroke associated with AF was attenuated by atherosclerotic factors. Our study supports the current view that enhanced control of modifiable cardiovascular risk factors in patients with AF is essential.

lncRNA RNCR2 facilitates cell proliferation and epithelial-mesenchymal transition in melanoma through HK2-mediated Warburg effect via targeting miR-495-3p.

Melanoma is a potentially lethal skin cancer with a high death rate. LncRNAs were reported to be implicated in melanoma progression. However, the function and mechanisms of lncRNA RNCR2 in melanoma are little known. In this study, RNCR2, miR-495-3p, and HK2 expression levels were measured in melanoma tissue specimens and cell lines by qPCR. EdU and CCK-8 assays were performed to assess cell proliferation. Enolase activity, ATP level, lactate production, and glucose consumption measurement kits were used to evaluate the glycolysis of tumor cells. Immunofluorescence and western blot were used to detect the expression of epithelial-mesenchymal transition (EMT) and glycolysis-related proteins. Luciferase reporter assay was applied to confirm the target relationships. The role of RNCR2 in tumorigenesis was examined using murine xenograft models. LncRNA RNCR2 was upregulated in melanoma tissues and cell lines. Cell function detection showed that RNCR2 knockdown remarkably inhibited cell proliferation and EMT via glycolysis, as well as reduced the growth of a tumor. Mechanically, RNCR2 was confirmed to bind to miR-495-3p and positively regulated HK2 expression level, and the miR-495-3p level was negatively correlated with RNCR2 or HK2 in melanoma tissues. Further, miR-495-3p downregulation or HK2 upregulation partially reversed RNCR2 knockdown-induced inhibition of melanoma cell growth, EMT, and glycolysis. Collectively, RNCR2 might be an oncogenic lncRNA to promote tumor cell glycolysis and accelerate tumor growth via the miR-495-3p/HK2 axis, providing a promising treatment target for melanoma.

Ambient air pollutants and hospital visits for pneumonia: a case-crossover study in Qingdao, China.

BACKGROUND: Pneumonia is one of the principal reasons for incidence and death in the world. The former research mainly concentrated on specific sources of patients. Besides, due to the heterogeneity among regions, there are inconsistencies in the outcome of these surveys. To explore the relationship between atmospheric pollution and hospital visits for pneumonia under the climate and pollution conditions in Qingdao, we carried out this study. METHODS: The medical records of pneumonia patients were gathered from the affiliated hospital of Qingdao University during Jan 1st, 2014, and Dec 31st,2018. Daily concentrations of PM2.5, PM10, SO2, NO2, as well as CO, were collected from the national air quality monitoring stations in Qingdao. Case-crossover study design and conditional logistic regression model were used to estimate the associations. Daily temperature, relative humidity, and atmospheric pressure were adjusted as the covariates in all models. A principal component analysis was used to solve the multicollinearity between atmospheric pollutants and investigate the relationship between various air pollutants and pneumonia occurs. RESULTS: In the single pollutant model, with interquartile range increment of the density of PM2.5, PM10, NO2 and SO2 at the lag2 days, the odds ratio of hospital visits for pneumonia patients increased by 6.4% (95%CI, 2.3-10.7%), 7.7% (95%CI, 3.2-12.4%), 6.7% (95%CI, 1.0-12.7%), and 7.2% (95%CI, 1.1-13.5%). Stratified analysis showed that pollutants were more significant in the cold period. Besides, the impact of atmospheric particulates on different ages mainly occurs in the young child (0 to 3-year-old). The odds ratio was 1.042 (95%CI, 1.012-1.072) when the principal components of atmospheric pollutants were included in the conditional logistic model. CONCLUSIONS: Our study found a significant relationship between short-term uncovering to PM2.5, PM10, NO2, SO2, and hospital visits for pneumonia in Qingdao. The effect of atmospheric pollutants mainly arose in a cold period. The particulate matter might be the principal reason in inducing hospital visits for pneumonia.

Safety evaluation of BPL9K-4 rice in a subchronic rodent feeding study.

In the present study, a new genetically modified rice producing phytase-lactoferricin fusion protein, BPL9K-4, was evaluated for safety in a 90-day rat feeding study. Rats were fed rodent diets formulated with BPL9K-4 rice, and were compared with rats fed diets formulated with its corresponding non-transgenic parental rice 9 K, commercially available non-transgenic rice Weiyou64, and a basal diet. BPL9K-4 and 9 K rice were formulated into diets at concentrations of 15%, 30% and 60%, and Weiyou64 common rice was added to diets at concentration of 60%. AIN93G diet was set as a basal-diet control. Diets of all groups were fed to rats (10/sex/group) for 90 days. Compared with rats in the 9 K, Weiyou64 and the basal-diet group, rats fed the BPL9K-4 diet did not show any treatment-related adverse effects on mortality, body weights, feed consumption, clinical chemistry, hematology, organ weights and gross and microscopic pathology. Under the conditions of this study, the genetically modified BPL9K-4 diets did not cause any toxicologically significant effects in rats following 90 days of dietary administration as compared with rats fed diets with the corresponding non-transgenic control diet and the basal-diet group. The results indicated that BPL9K-4 rice is as safe as its conventional comparators.

Enzymatic characterization and validation of gene expression of phosphoglucomutase from Cordyceps militaris.

The purification and characterization of PGM (Phosphoglucomutase) from Cordyceps militaris (C. militaris) was investigated. PGM was purified using a combination of ultrafiltration, salting-out and ion exchange chromatography resulting in 4.23-fold enhancement of activity with a recovery of 20.01%. Molecular mass was 50.01 kDa by SDS-PAGE. The optimal activity was achieved at pH 7.5 and 30 °C with NADPH as substrate. The results showed that SDS, DTT Li+, Cu2+, Na+, Mn2+ and Al3+ were effective PGM inhibitors; whereas glycerol, Zn2+, Mg2+, Ca2+, Fe2+ and Fe3+ could enhance the activity of PGM, and the Km and Vmax values were 11.62 mmol/L and 416.67 U/mL, respectively. At the same time, qRT-PCR was used to test the changes of mRNA transcription level of PGM gene encoding under two fermentation conditions: basic medium and optimized medium. The relative quantitative results of PGM target genes resulting in 2.60-fold enhancement than the control group.

BRCA1/2 mutations and risk-reducing bilateral salpingo-oophorectomy among Latinas: The UPTAKE study.

Bilateral salpingo-oophorectomy (BSO) is a risk management approach with strong evidence of mortality reduction for women with germline mutations in the tumor suppressor genes BRCA1 and BRCA2 (BRCA1/2). Few studies to date have evaluated uptake of BSO in women from diverse racial and ethnic backgrounds who carry BRCA1/2 mutations. The objective of the UPTAKE study was to explore rates and predictors of risk-reducing BSO among Latinas affected and unaffected with breast cancer who had a deleterious BRCA1/2 mutation. We recruited 100 Latina women with deleterious BRCA1/2 mutations from community hospitals, academic health systems, community, and advocacy organizations. Women completed interviews in Spanish or English. We obtained copies of genetic test reports for participants who provided signed medical release. After performing threefold cross-validation LASSO for variable selection, we used multiple logistic regression to identify demographic and clinical predictors of BSO. Among 100 participants, 68 had undergone BSO at the time of interview. Of these 68, 35 were US-born (61% of all US-born participants) and 33 were not (77% of the non-US-born participants). Among Latinas with BRCA1/2 mutations, older age (p = 0.004), personal history of breast cancer (p = 0.003), higher income (p = 0.002), and not having a full-time job (p = 0.027) were identified as variables significantly associated with uptake of BSO. Results suggest a high rate of uptake of risk-reducing BSO among a sample of Latinas with BRCA1/2 mutations living in the US. We document factors associated with BSO uptake in a diverse sample of women. Relevant to genetic counseling, our findings identify possible targets for supporting Latinas' decision-making about BSO following receipt of a positive BRCA1/2 test.