Altered spontaneous brain activities in maintenance hemodialysis patients with cognitive impairment and the construction of cognitive function prediction models.

OBJECTIVE: The brain neuromechanism in maintenance hemodialysis patients (MHD) with cognitive impairment (CI) remains unclear. The study aimed to probe the relationship between spontaneous brain activity and CI by using resting-state functional magnetic resonance imaging (rs-fMRI) data. METHODS: Here, 55 MHD patients with CI and 28 healthy controls were recruited. For baseline data, qualitative data were compared between groups using the χ2 test; quantitative data were compared between groups using the independent samples t-test, ANOVA test, Mann-Whitney U-test, or Kruskal-Wallis test. Comparisons of ALFF/fALFF/ReHo values among the three groups were calculated by using the DPABI toolbox, and then analyzing the correlation with clinical variables. p < .05 was considered a statistically significant difference. Furthermore, back propagation neural network (BPNN) was utilized to predict cognitive function. RESULTS: Compared with the MHD-NCI group, the patients with MHD-CI had more severe anemia and higher urea nitrogen levels, lower mALFF values in the left postcentral gyrus, lower mfALFF values in the left inferior temporal gyrus, and greater mALFF values in the right caudate nucleus (p < .05). The above-altered indicators were correlated with MOCA scores. BPNN prediction models indicated that the diagnostic efficacy of the model which inputs were hemoglobin, urea nitrogen, and mALFF value in the left central posterior gyrus was optimal (R2 = 0.8054), validation cohort (R2 = 0.7328). CONCLUSION: The rs-fMRI can reveal the neurophysiological mechanism of cognitive impairment in MHD patients. In addition, it can serve as a neuroimaging marker for diagnosing and evaluating cognitive impairment in MHD patients.

Identification of a miRNA biomarker for the large artery atherosclerosis subtype of acute ischemic stroke.

AIM OF THE STUDY: To identify miRNA biomarkers of arterial atherosclerosis subtypes in acute ischemic stroke. MATERIAL AND METHODS: 40 participants recruited in our hospital from October 2017 to January 2018. There were 12 patients with acute ischemic stroke (AIS), 13 patients with atherosclerosis (AS) and 15 healthy subjects. They were divided into the AIS group, AS group and healthy control (HC) group. The miRNA expression levels of the AIS group, AS group and HC group were measured by DNA microarray. Bioinformatics analysis was performed using the miRNA target prediction database. RESULTS: The expression of 3 miRNAs, miR-129-1-3p, miR-4312, miR-5196-3p, was significantly different between the AIS and AS/HC groups. Genes targeted by miR-129-1-3p were involved in 12 pathways, of which axon guidance, retrograde endocannabinoid signalling and sphingolipid signalling pathways were associated with axonal and synaptic function. miR-129-1-3p mimics significantly decreased cortical neurite length and Runx2 levels, while miR-129-1-3p inhibitors promoted neurite growth and increased Runx2 expression. CONCLUSIONS: miR-129-1-3p may be a relevant biomarker for the diagnosis of stroke caused by large artery atherosclerosis and could represent a novel therapeutic target for stroke treatment.

Prognostic Role of Serum Lactate Dehydrogenase in Patients With Urothelial Carcinoma: A Systematic Review and Meta-Analysis.

Background: To investigate the potential prognostic role of serum lactate dehydrogenase (LDH) in patients with urothelial carcinoma (UC) using the method of systematic review and meta-analysis. Materials and Methods: We searched PubMed, Embase, Cochrane Library, and Web of Science for eligible studies up to February 2020. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were used to estimate the relationship. Results: A total of 14 studies including 4,009 patients with UC were incorporated. The results showed that a high pretreatment serum LDH was associated with an inferior overall survival (OS, HR 1.61, 95% CI 1.39-1.87, p < 0.001), cancer-specific survival (CSS, HR 1.41, 95% CI 1.05-1.90, p = 0.022), and disease-free survival (DFS, HR 1.64, 95% CI 1.04-2.59, p = 0.034) in UC. Subgroup analyses identified that a high pretreatment serum LDH was associated with a poor OS (HR 1.97, 95% CI 1.02-3.81, p = 0.042) and DFS (HR 1.64, 95% CI 1.04-2.59, p = 0.034) in upper tract urothelial carcinoma, a short OS (HR 1.71, 95% CI 1.37-2.15, p < 0.001) in urothelial carcinoma of bladder. Conclusion: Our findings indicated that a high level of pretreatment serum LDH was associated with inferior OS, CSS, and DFS in patients with UC. This biomarker can be an important factor incorporated into the prognostic models for UC.

DL-Propargylglycine protects against myocardial injury induced by chronic intermittent hypoxia through inhibition of endoplasmic reticulum stress.

BACKGROUND: Chronic intermittent hypoxia (CIH), an important basis of the pathogenesis of organ damage induced by obstructive sleep apnea syndrome (OSAS), is associated with myocardial injury, such as left ventricular dysfunction, apoptosis, and oxidative stress. Endogenous hydrogen sulfide (H2S) plays an important role in maintaining cardiovascular functions. Many studies have demonstrated that exogenous H2S has protective effects against myocardial injury induced by various cardiovascular diseases, and inhibiting the generation of endogenous H2S has opposite effects. However, the effect of DL-propargylglycine (PAG), an effective inhibitor of cystathionine γ-lyase (CSE)-synthesized H2S, on the regulation myocardial injury remains controversial. PURPOSE: The present study was aimed to explore the influence of PAG on myocardial injury induced in rats by CIH. METHODS: Sprague-Dawley rats were randomly divided into a normal control (NC) group, a CIH group, a NC + PAG group, and a CIH + PAG group. After establishing the CIH model in rats, blood pressure, left ventricular function, oxidative stress, apoptosis, and the level of endoplasmic reticulum (ER) stress were detected. RESULTS: In NC rats, PAG had no effect on blood pressure, but induced myocardial dysfunction and up-regulated oxidative stress and apoptosis of the myocardium. In the CIH + PAG group, pretreatment with PAG significantly reduced blood pressure and improved the left ventricular ejection fraction (LVEF) and the left ventricular fractional shortening (LVFS) compared to the CIH group. Significantly lower levels of oxidative stress, apoptosis, and the ER stress were detected in the CIH + PAG group than in the CIH group. CONCLUSION: These results suggest that PAG can protect the myocardium against CIH-induced injury through inhibition of endoplasmic reticulum stress.

Establishment of a Rabbit Model of Chronic Obstructive Sleep Apnea and Application in Cardiovascular Consequences.

BACKGROUND: Although obstructive sleep apnea (OSA) has been recognized as a major risk factor for cardiovascular complications and its clinical features are well characterized, it is difficult to replicate the OSA hypoxic model in humans. We aimed to establish an experimental rabbit model for chronic OSA and to explore its application to measure blood pressure (BP), myocardial systolic function, and oxidative stress. METHODS: The rabbit model for OSA was established by repeatedly closing the airway and then reopening it. A tube specially designed with a bag that could be alternately inflated and deflated according to a predetermined time schedule, resulting in recurrent airway occlusions and chronic intermittent hypoxia (CIH) imitating OSA patterns in humans, was used. Twenty-four rabbits were randomly divided into obstruction, sham, and control groups, and their upper airways were alternately closed for 15 s and then reopened for 105 s in a 120-s-long cycle, for 8 h each day over 12 consecutive weeks. Before and after the experiment, the BP of each rabbit was monitored. Levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the serum, superoxide dismutase (SOD) activity, malondialdehyde (MDA) and reactive oxygen species (ROS) contents, as well as Na+-K+-ATPase/Ca2+-ATPase activities in cardiac muscle were examined. In addition, cardiac functional parameters were measured using echocardiography. RESULTS: After 3 months, all rabbits in the obstruction group manifested sleepiness performance similar to that observed in OSA patients. Traces of airflow and SpO2showed that this model mimicked the respiratory events involved in OSA, including increased respiratory effort and decreased oxygen saturation. Gradually, the BP rose each month. CIH led to obvious oxidative stress and injured myocardial systolic performance. The serum levels of IL-6 and TNF-α increased significantly (64.75 ± 9.05 pg/ml vs. 147.00 ± 19.24 pg/ml and 59.38 ± 8.21 pg/ml vs. 264.75 ± 25.54 pg/ml, respectively, both P < 0.001). Compared with the sham and the control groups, myocardial activities of Na+-K+-ATPase/Ca2+-ATPase and SOD in the obstruction group decreased markedly, while ROS and MDA content increased. CONCLUSIONS: These results show that the rabbit model for OSA simulates the pathophysiological characteristics of OSA in humans, which implies that this animal model is feasible and useful to study the mechanisms involved in the cardiovascular consequences of OSA.

The role of the Nox4-derived ROS-mediated RhoA/Rho kinase pathway in rat hypertension induced by chronic intermittent hypoxia.

BACKGROUND: Obstructive sleep apnea syndrome, which is a risk factor for resistant hypertension, is characterized by chronic intermittent hypoxia (CIH) and is associated with many cardiovascular diseases. CIH elicits systemic oxidative stress and sympathetic hyperactivity, which lead to hypertension. Rho kinases (ROCKs) are considered to be major effectors of the small GTPase RhoA and have been extensively studied in the cardiovascular field. Upregulation of the RhoA/ROCK signaling cascade is observed in various cardiovascular disorders, such as atherosclerosis, pulmonary hypertension, and stroke. However, the exact molecular function of RhoA/ROCK in CIH remains unclear and requires further study. OBJECTIVE: This study aimed to investigate the role of the NADPH oxidase 4 (Nox4)-induced ROS/RhoA/ROCK pathway in CIH-induced hypertension in rats. METHODS: Male Sprague-Dawley rats were exposed to CIH for 21 days (intermittent hypoxia of 21% O2 for 60 s and 5% O2 for 30 s, cyclically repeated for 8 h/day). We randomly assigned 56 male rats to groups of normoxia (RA) or vertically implemented CIH together with vehicle (CIH-V), GKT137831 (CIH-G), N-acetyl cysteine (NAC) (CIH-N), or Y27632 (CIH-Y). The rats in the RA group were continuously exposed to room air, whereas the rats in the other groups were exposed to CIH. Systolic blood pressure (BP) was monitored at the beginning of each week. After the experiment, renal sympathetic nerve activity (RSNA) was recorded, and serum and renal tissues were subjected to molecular biological and biochemical analyses. RESULTS: Compared with the BP of RA rats, the BP of CIH-V rats started to increase 2 weeks after the beginning of the experiment, subsequently stabilizing at a high level at the end of the third week. CIH increased both RSNA and oxidative stress. This response was attenuated by treatment of the rats with GKT137831 or NAC. Inhibiting Nox4 activity or ROS production reduced RhoA/ROCK expression. Treatment with Y27632 reduced both BP and RSNA in rats exposed to CIH. CONCLUSION: Hypertension can be induced by CIH in SD rats. The CIH-induced elevation of BP is at least partially mediated via the Nox4-induced ROS/RhoA/ROCK pathway.

Adenotonsillectomy can decrease enuresis and sympathetic nervous activity in children with obstructive sleep apnea syndrome.

BACKGROUND: The nocturnal intermittent hypoxia caused by obstructive sleep apnea syndrome (OSAS) can provoke the sympathetic nervous activity (SNA). Salivary alpha-amylase (sAA) is a sensitive, non-invasive biomarker for reflecting the SNA, and a useful marker for pediatric OSAS subjects. Adenotonsillar hypertrophy (ATH) is the most commonly identified risk factor in OSAS childhood, therefore, several studies showed that the adenotonsillectomy (T&A) may alleviate nocturnal enuresis (NE) in children with OSAS. OBJECTIVE: The present study was to investigate the effect of T&A on NE, the change of sAA value in ATH and OSAS children, with/without NE, and with/without the operation. STUDY DESIGN: 37 children (Group A) were admitted for ATH and NE. The saliva samples were taken before and after polysomnography for the measure of sAA. After the T&A, the children were followed-up for 1 year. 35 OSAS children with NE but no T&A were as a NE watchful-waiting group (Group B), 32 subjects without OSAS or NE were as non-OSAS control (Group C), 42 cases who underwent T&A but did not have NE were admitted to evaluate the SNA (Group D). Follow-up included evaluations for NE, sAA and urinary catecholamine after the T&A or at the equivalent time points. RESULTS: The observational results in the present study showed a significant rate of the disappearance of NE 1 month after the T&A and had an almost complete resolution 1 year later. OSAS may irritate oxidative stress and increase SNA in pediatric subjects, which reflected by increased levels of sAA and urinary catecholamine, while the T&A can decrease enuresis and the SNA in children with OSAS (Figure). DISCUSSION: Little research has previously focused on the relationship between childhood OSAS and the SNA. No data are currently available regarding comparisons of sAA levels before and after the T&A in children with OSAS and enuresis. Our findings in this present study showed that there was a resolution or decrease in enuresis events and drops in sAA levels following T&A, which were consistent with earlier study. However, there was no significant difference in the urinary catecholamine levels was found between OSAS groups with or without NE. Furthermore, there was no correlation between the urinary catecholamine and polysomnography parameters. CONCLUSIONS: T&A has a favorable therapeutic effect on NE and may decrease SNA in children with OSAS. sAA might be associated with instability of ANS by OSAS and have a consistent relationship with the apnea-hypopnea index. Our studying aims had been met.

Anti-tumor activity of tanshinone IIA in combined with cyclophosphamide against Lewis mice with lung cancer.

OBJECTIVE: To explore the anti-tumor activity of tanshinone IIA in combined with cyclophosphamide against Lewis mice with lung cancer and the effect on cellular immune function. METHODS: Lewis tumor cells were inoculated subcutaneously into the right armpit of mice in each group (n = 20) to establish Lewis lung cancer mice model. After model establishment, mice in the model group were given normal saline by lavage, qd. Mice in treatment I group were given intraperitoneal injection of Tan IIA, 15 mg/kg, qd. Mice in treatment II group were given intraperitoneal injection of CTX, 25 mg/kg, qd. Mice in treatment III group were given intraperitoneal injections of Tan IIA and CTX, in which the administration method of Tan IIA was the same as in treatment I group, continuously for 2 weeks, and the dosage of CTX was the same as in treatment II group, 24 h after model establishment, every other day. Mice were sacrificed 2 weeks after establishment. The tumor tissues were collected to calculate the anti-tumor rate. Immunohistochemistry was used to detect the expressions of Bcl-2, Bax, VEGF, Angiostatin, and Endostatin. FCM was used to detect T lymphocyte subsets in spleen and liver of mice. RESULTS: The tumor weight in treatment I, II, and III groups was significantly lower than that in the model group (P < 0.05). The tumor weight in treatment III group was significantly lower than that in treatment I and II groups (P < 0.05). The anti-tumor rate in treatment II and III groups was significantly higher than that in treatment I group (P < 0.05). Bcl-2 expression in the tumor tissues of treatment I, II, and III groups was significantly lower than that in the model group (P < 0.05), while Bax expression was significantly higher than that in the model group (P < 0.05). Bcl-2 expression in the tumor tissues of treatment I and II groups was significantly higher than that in treatment III group (P < 0.05), while Bax expression was significantly lower than that in treatment III group (P < 0.05). CD4+ and CD4+/CD8+ in treatment I, II, and III groups were significantly higher than those in the model group (P < 0.05). CD4+ in treatment III group was significantly higher than that in treatment I and II groups (P < 0.05), while CD4+/CD8+ was significantly higher than that in treatment II group (P < 0.05). The comparison of CD8+ among each group was not statistically significant (P > 0.05). NK cell activity in treatment I, II, and III groups was significantly higher than that in the model group (P < 0.05). NK cell activity in treatment III group was significantly higher than that in treatment I and II groups (P < 0.05). CONCLUSIONS: Tan IIA in combined with CTX can down regulate Bcl-2 expression in lung cancer tissues, up regulate Bax expression, inhibit the neovascularization of tumor tissues, and enhance the immunological function, with a significant anti-tumor activity.

Dissociation Dynamics of XPC-RAD23B from Damaged DNA Is a Determining Factor of NER Efficiency.

XPC-RAD23B (XPC) plays a critical role in human nucleotide excision repair (hNER) as this complex recognizes DNA adducts to initiate NER. To determine the mutagenic potential of structurally different bulky DNA damages, various studies have been conducted to define the correlation of XPC-DNA damage equilibrium binding affinity with NER efficiency. However, little is known about the effects of XPC-DNA damage recognition kinetics on hNER. Although association of XPC is important, our current work shows that the XPC-DNA dissociation rate also plays a pivotal role in achieving NER efficiency. We characterized for the first time the binding of XPC to mono- versus di-AAF-modified sequences by using the real time monitoring surface plasmon resonance technique. Strikingly, the half-life (t1/2 or the retention time of XPC in association with damaged DNA) shares an inverse relationship with NER efficiency. This is particularly true when XPC remained bound to clustered adducts for a much longer period of time as compared to mono-adducts. Our results suggest that XPC dissociation from the damage site could become a rate-limiting step in NER of certain types of DNA adducts, leading to repression of NER.

Antagonism effects of cypermethrin on interleukin-6-induced androgen receptor activation.

To identify whether androgen receptor (AR) antagonism by cypermethrin involves interleukin-6 (IL-6)-induced ligand-independent AR signaling, we have developed the AR reporter gene assay. The reporter gene plasmid pMMTV-chloramphenicol transferase (CAT) was transfected into LNCaP cells. IL-6 increased expression of MMTV-CAT significantly (P<0.05). Cypermethrin decreased CAT reporter expression induced by IL-6 (50 ng/ml), and the significant inhibition was detected at 10(-5)M (P<0.05). IL-6 induces ligand-independent activation of AR. Cypermethrin exhibits inhibitory effects on IL-6-induced ligand-independent AR signaling. We provide a novel insight into cypermethrin-mediated antagonism of the IL-6-mediated ligand-independent activation of the AR.

Downregulation of MLL3 in esophageal squamous cell carcinoma is required for the growth and metastasis of cancer cells.

The mixed lineage leukemia 3 (MLL3), a member of the mixed lineage leukemia (MLL) family, has been reported to be mutated in multiple cancer types. However, its function in esophageal squamous cell carcinoma (ESCC) remains poorly understood. Here, we found that the expression of MLL3 was downregulated in ESCC tissues. Moreover, over-expression of MLL3 in ESCC cells inhibited cell proliferation and migration, while the knockdown expression of MLL3 promoted the tumorigenicity of ESCC cells. Mechanistically, MLL3 regulated the expression of multiple growth-related and migration-related genes. Taken together, our study suggested that downregulation of MLL3 was very important in the progression of ESCC.

Identification of a novel gene fusion (BMX-ARHGAP) in gastric cardia adenocarcinoma.

BACKGROUND: Gastric cardia adenocarcinoma (GCA) is one of the major causes of cancer related mortality worldwide. We aim to provide new understanding in the pathogenesis of GCA through investigations on gene expression alterations. METHODS: We preformed RNA-Seq for one pair of GCA and matched non-tumor tissues. Differentially expressed genes (DEGs) and fusion genes were acquired. PCR and gel analysis in additional 14 pairs of samples were performed to validate the chimeric transcripts. RESULTS: 1590 up-regulated and 709 down-regulated genes were detected. Functional analysis revealed that these DEGs were significantly overrepresented in gene ontology items of cell cycle, tumor invasion and proliferation. Moreover, we firstly discovered 3 fusion genes in GCA, including BMX-ARHGAP, LRP5- LITAF and CBX3-C15orf57. The chimeric transcript BMX-ARHGAP was validated and recurrently occurred in 4/15 independent tumor tissues. CONCLUSIONS: Our results may provide new understanding of GCA and biomarkers for further therapeutic studies. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_218.

Synthesis, characterization, and self-assembly of linear poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ε-caprolactone) (PEO-PPO-PCL) copolymers.

Amphiphilic triblock copolymers of PEO-PPO-PCL with various block compositions have been synthesized by ring-opening polymerization (ROP) of ε-caprolactone (ε-CL) initiated by the OH group of methoxy-poly(ethylene oxide)-poly(propylene oxide) (Me-PEO-PPO). Their structures were confirmed by Fourier transform infrared (FT-IR) measurements, and their self-assembly in aqueous solution was studied using fluorescence spectroscopy, transmission electron microscopy (TEM), UV-vis spectra, differential scanning calorimetry (DSC), and surface tension. For the copolymers studied in this paper, the critical aggregation concentrations (CAC) ranged from 5×10(3) to 2 mg/L. The critical micelle concentrations (CMC) decreased with increasing PCL block length, and the downtrend was more significant in the short PCL block length. All of the three copolymers were capable of solubilizing hydrophobic molecules (pyrene) in aqueous solution and copolymers with a longer PCL block exhibited a stronger solubilizing ability. The TEM images showed that the size and morphology of the aggregations could be tuned by varying the compositions or the concentration.

Binary and ternary binding affinities between exonuclease-deficient Klenow fragment (Kf-exo(-)) and various arylamine DNA lesions characterized by surface plasmon resonance.

We used surface plasmon resonance (SPR) to characterize the binding interactions between the exonulease-free Klenow fragment (Kf-exo(-)) and unmodified and modified dG adducts derived from arylamine carcinogens: fluorinated 2-aminofluorene (FAF), 2-acetylaminofluorene (FAAF), and 4-aminobiphenyl (FABP). Tight polymerase binding was detected with unmodified dG and the correct dCTP. The discrimination of correct versus incorrect nucleotides was pronounced with K(D) values in the order of dCTP ≪ dTTP < dATP < dGTP. In contrast, minimal selectivity was observed for the modified templates with Kf-exo(-) binding tighter to the FAAF (k(off): 0.02 s(-1)) and FABP (k(off): 0.01 s(-1)) lesions than to FAF (k(off): 0.04 s(-1)).