Linking Disulfide Levels and NAD+ Metabolism with Alzheimer's Disease for Diagnostic Modeling and Target Drug Analysis.

BACKGROUND: Alzheimer's disease (AD) is a condition that affects the nervous system and that requires considerably more in-depth study. Abnormal Nicotinamide Adenine Dinucleotide (NAD+) metabolism and disulfide levels have been demonstrated in AD. This study investigated novel hub genes for disulfide levels and NAD+ metabolism in relation to the diagnosis and therapy of AD. METHODS: Data from the gene expression omnibus (GEO) database were analyzed. Hub genes related to disulfide levels, NAD+ metabolism, and AD were identified from overlapping genes for differentially expressed genes (DEGs), genes in the NAD+ metabolism or disulfide gene sets, and module genes obtained by weighted gene co-expression network analysis (WGCNA). Pathway analysis of these hub genes was performed by Gene Set Enrichment Analysis (GSEA). A diagnostic model for AD was constructed based on the expression level of hub genes in brain samples. CIBERSORT was used to evaluate immune cell infiltration and immune factors correlating with hub gene expression. The DrugBank database was also used to identify drugs that target the hub genes. RESULTS: We identified 3 hub genes related to disulfide levels in AD and 9 related to NAD+ metabolism in AD. Pathway analysis indicated these 12 genes were correlated with AD. Stepwise regression analysis revealed the area under the curve (AUC) for the predictive model based on the expression of these 12 hub genes in brain tissue was 0.935, indicating good diagnostic performance. Additionally, analysis of immune cell infiltration showed the hub genes played an important role in AD immunity. Finally, 33 drugs targeting 10 hub genes were identified using the DrugBank database. Some of these have been clinically approved and may be useful for AD therapy. CONCLUSION: Hub genes related to disulfide levels and NAD+ metabolism are promising biomarkers for the diagnosis of AD. These genes may contribute to a better understanding of the pathogenesis of AD, as well as to improved drug therapy.

miR-148a and miR-551b-5p regulate inflammatory responses via regulating autophagy in acute pancreatitis.

Acute pancreatitis (AP) is a common inflammatory response that occurs in the pancreas with mortality rates as high as 30 %. However, there is still no consistent and effective treatment for AP now. MicroRNA-148 was reported to be involved in AP through IL-6 signaling pathway. Therefore, we aimed to further explore the detailed mechanisms of AP, to develop more therapeutic approach for AP. Exosomes were isolated from peripheral blood mononuclear cells of 20 AP patients and 20 healthy volunteers to evaluate the abnormally expressed miRNA. Then pancreatic acinar cells (PACs) were transfected with retrovirus to overexpress miR-148a/miR-551b-5p to evaluate their function. Both miR-148a and miR-551b-5p were highly expressed in AP patients than these in healthy cases. Then overexpressing miR-551b-5p in PACs could regulate autophagy through directly binding to Baculoviral IAP Repeat Containing 6, leading to the increased secretions of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) through interleukin-1 (IL-1) signaling pathway. Moreover, overexpressing miR-148a in PACs could decrease the secretions of IL-1ß and IL-18 to modulate autophagy. The exosomal miRNA-148a and miRNA-551b-5p derived from peripheral blood mononuclear cells of AP patients may two-way mediate autophagy damage through IL-6/STAT3 signaling pathway, which participated in the AP pathogenesis. Our findings may provide new targets for the diagnosis and treatment of AP.

Expression signature and molecular basis of CDH11 in OSCC detected by a combination of multiple methods.

Oral squamous cell carcinoma (OSCC) is one of the most common malignancy in the oral cancer threatening human health and the survival rate of OSCC has not been effectively improved in recent decades, so more effective biomarkers for the targeted therapy of OSCC are needed. Moreover, the role of CDH11 in OSCC has not been intensively investigated. We here show that the CDH11 protein and mRNA expression levels in the OSCC tissues were all significantly higher than in the non-cancerous tissues using RT-qPCR and western blot. This study also revealed that patients with higher CDH11 levels showed a higher incidence of perineural invasion and lymph node metastasis. By using data available from the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and ArrayExpress databases, overexpressed CDH11 in OSCC that associated with patients'history of alcohol, negative Human Papilloma Virus (HPV) status, perineural invasion, infiltration of multiple immune cells, and Single-cell functional states including quiescence and angiogenesis, possessed an excellent discriminatory capability in the OSCC patients. Moreover, the majority of the biological processes or pathways were significantly clustered by co-expressed genes, including extracellular matrix organization, the epithelial to mesenchymal transition, carbon metabolism, and the PI3K-Akt signaling pathway, and the upstream transcriptional regulation mechanism of CDH11 in OSCC was showed on a transcription factor/miRNA-mRNA network with the online tool NetworkAnalyst. Finally, frequent mutation of CDH11 was observed on a mouse OSCC model through whole-genome sequencing. CDH11 might serve as a valuable biomarker in OSCC, as it was identified to be overexpressed in OSCC and related to its clinical progression.

Identification of a lncRNA/circRNA-miRNA-mRNA ceRNA Network in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) occurs in the elderly and pre-elderly, characterized by decline of memory, cognitive dysfunction, impairment of learning capacity, and motor dysfunction. Recently a competitive endogenous RNA (ceRNA) network has been found to be related to AD progression, but there is still little understanding of the ceRNA regulatory network in AD. This study aims to explore the important regulatory mechanisms of ceRNA regulatory networks containing long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) in AD. METHODS: Data from the gene expression omnibus (GEO) database were used for the analysis. To study enrichment function for the upregulated and downregulated mRNAs, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the Metascape database, respectively. Based on the STRING database and Cytoscape software 3.9.1, a protein-protein interaction (PPI) network was constructed. The hub genes in this network were identified utilizing the CytoHubba plugin in Cytoscape. The TargetScan, miRWalk, and miRDB were selected to calculate the regulatory interaction between miRNAs and the hub genes. LncRNAs were predicted using RNA22. Additionally, circRNA prediction was executed using the circBank database. RESULTS: 711 downregulated and 670 upregulated overlapping mRNAs were identified between AD and control samples. 32 downregulated and 340 upregulated miRNAs were obtained from AD samples compared with control samples. 78 upregulated and 205 downregulated circRNAs were screened. 275 upregulated lncRNAs and 209 downregulated lncRNAs were found between AD samples and control samples. The PPI network constructed consists of 1016 nodes and 13,946 edges. Ten hub genes were selected to identify target miRNAs and ceRNAs. On the basis of the ceRNA hypothesis, a circRNA/lncRNA-miRNA-mRNA network was established. It included five lncRNAs (TRHDE-AS1, SNHG10, OIP5-AS, LINC00926 and LINC00662), 26 circRNAs, five miRNAs (hsa-miR-3158-3p, hsa-miR-4435, hsa-let-7d-3p, hsa-miR-330-5p and hsa-miR-3605-3p), and ten mRNAs (RPL11, RPL34, RPL21, RPL22, RPL6, RPL32, RPL24, RPL35, RPL31, and RPL35A). RPL35 and RPL35A were found to be significantly associated with AD pathology in tau and Aß line AD models by the AlzData database. The study discovered the significance of several lncRNA-miRNA-mRNA axes and circRNA-miRNA-mRNA axes that included RPL35A and RPL35. CONCLUSIONS: ceRNAs were found to be important regulators in the development of AD and provide potential biological therapy targets for AD management.

Temporal and spatial characteristics of tumor evolution in a mouse model of oral squamous cell carcinoma.

OBJECTIVES: We aimed to elucidate the temporal and spatial characteristics of tumor evolution in an oral squamous cell carcinoma (OSCC) mouse model with higher burden of lymphatic metastasis through high-throughput sequencing. METHODS: The OSCC model was established in 9 mice. DNA was extracted from the tumors of primary tongue lesions and disseminated tumor cells (DTCs) of submandibular gland lymph nodes and bone marrow, and then whole genome sequencing was performed. After bioinformatics analysis, somatic single-nucleotide variants (SSNVs) and copy number variations (CNVs) data were obtained. Based on SSNVs, clonal architecture and ancestor-descendant relationships among tumor cell subclones were elucidated. RESULTS: A total of 238 tumor-related SSNVs with 120 high-frequency mutated genes were obtained from 36 samples of 9 mice by whole-genome sequencing. The number of unique SSNVs in the primary lesion, submandibular lymph node and bone marrow was greater than the number of shared SSNVs. Furthermore, the primary lesion-originated subclones, which were identified by SSNVs, were also detected in submandibular lymph nodes in the early stage of oral carcinogenesis. Moreover, at different histopathological stages, unique subclones were also identified in DTCs isolated from lymph nodes. CONCLUSION: Tumor heterogeneity is significant in primary tumor cells and disseminated tumor cells. OSCC cells probably disseminate to lymph nodes in the early stage of oral carcinogenesis. OSCC is characterized by polyclonal dissemination, and the evolutionary trajectory of DTCs is potentially dominated by the tumor microenvironment.

Treatment of status epilepticus in pediatrics: curriculum learning combined with in-situ simulations.

BACKGROUND: Appropriate and timely treatment of status epilepticus (SE) reduces morbidity and mortality. Therefore, skill-based identification and management are critical for emergency physicians. PURPOSE: To assess whether the ability of training physicians, residents, nurses, and others to respond to SE as a team could be improved by using curriculum learning [Strategies and Tools to Enhance Performance and Patient Safety of Team (TeamSTEPPS) course training] combined with in-situ simulations of emergency department (ED) staff. APPROACH: A pre-training-post-training design was used on SE skills and teamwork skills. Emergency training, residents, and N1 and N2 nurses completed the SE skill and teamwork assessments (pre-training) through in-situ simulation. Next, the participating physicians and nurses attended the SE course [Strategies and Tools to Enhance Performance and Patient Safety of Team (TeamSTEPPS) course training], followed by conscious skill practice, including in-situ simulation drills every 20 days (eight times total) and deliberate practice in the simulator. The participants completed the SE skill and teamwork assessments (post-training) again in an in-situ simulation. Pre-training-post-training simulated SE skills and teamwork performance were assessed. The simulation training evaluation showed that the training process was reasonable, and the training medical staff had different degrees of benefit in increasing subject interest, improving operational skills, theoretical knowledge, and work self-confidence. FINDINGS: Sixty doctors and nurses participated in the intervention. When comparing the SE skills of 10 regular training physicians pre-training and post-training, their performance improved from 40% (interquartile range (IQR): 0-1) before training to 100% (IQR: 80.00-100) after training (p < 0.001). The teamwork ability of the 10 teams improved from 2.43 ± 0.09 before training to 3.16 ± 0.08 after training (p < 0.001). CONCLUSION: SE curriculum learning combined with in-situ simulation training provides the learners with SE identification and management knowledge in children and teamwork skills.

Ferritinophagy-Mediated Ferroptosis and Activation of Keap1/Nrf2/HO-1 Pathway Were Conducive to EMT Inhibition of Gastric Cancer Cells in Action of 2,2'-Di-pyridineketone Hydrazone Dithiocarbamate Butyric Acid Ester.

In metastasis of cancer cells, the epithelial-mesenchymal transition (EMT) is prerequired. Ferroptosis is an iron-mediated cellular death process, but whether it involves EMT regulation remains elusive. In addition, how stress responders (Nrf2) respond to the redox alteration and cross-talking between them needs to be determined. Our data revealed that DpdtbA (2,2'-di-pyridineketone hydrazone dithiocarbamate butyric acid ester) resisted TGF-ß1-induced EMT in gastric cancer lines (SGC-7901 and MGC-823) through ferritinophagy-mediated ROS production. Furthermore, the depletion of Gpx4 and xCT as well as enhanced lipid peroxidation indicated that DpdtbA acted as Erastin did in ferroptosis induction, which thus provided chance to explore the causal relationship between ferroptosis and EMT. Our data illustrated that ferritinophagy-mediated ferroptosis promoted the EMT inhibition. In addition, activated Nrf2 involved the regulation on both ferroptosis and EMT in response to the alteration in the cellular redox environment. In brief, ferritinophagy-mediated ferroptosis and activation of the Keap1/Nrf2/HO-1 pathway were conducive to the EMT inhibition.

Circular RNA hsa_circ_0011946 promotes the malignant process of salivary adenoid cystic carcinoma by downregulating miR-1205 expression.

Circular RNA (circRNA/circ) hsa_circ_0011946 has been reported to serve an important role in a number of cancer types; however, to the best of our knowledge, its role in salivary adenoid cystic carcinoma (SACC) has not been reported. In the present study, the primary focus was the effects of hsa_circ_0011946 on the invasion, migration and epithelial-mesenchymal transformation (EMT) of SACC cells, and the specific mechanisms involved. The expression levels of hsa_circ_0011946 and microRNA (miR)-1205 in cancer tissues and paracancerous tissues of patients with SACC were analyzed using reverse transcription-quantitative (RT-q)PCR. The cell proliferation rate was determined using a Cell Counting Kit-8 assay. Wound healing assays were performed to analyze the cell migratory ability, while a transwell assay was used to measure the cell invasion ability. Western blotting was used to analyze the expression levels of EMT-related proteins. Cell transfection was used to knockdown hsa_circ_0011946 and knockdown or overexpress miR-1205. Subcellular localization assays for hsa_circ_0011946 were performed using RT-qPCR. A dual-luciferase reporter gene assay was used to verify the binding between hsa_circ_0011946 and miR-1205. The results of the present study revealed that the expression levels of hsa_circ_0011946 were significantly upregulated in cancer tissues from patients with SACC. The knockdown of hsa_circ_0011946 expression inhibited the proliferation, invasion and migration of SACC cells, thereby inhibiting the EMT process, which was achieved by downregulating miR-1205 expression. In conclusion, circRNA hsa_circ_0011946 was discovered to promote the malignant process of SACC by downregulating miR-1205 expression.

Quercetin Administration Following Hypoxia-Induced Neonatal Brain Damage Attenuates Later-Life Seizure Susceptibility and Anxiety-Related Behavior: Modulating Inflammatory Response.

BACKGROUND: Neonatal seizures commonly caused by hypoxia could lead to brain injury and cognitive deficits. Quercetin could cross the blood brain barrier and exerts neuroprotective effects in many neurological disease settings. In this study, we aim to investigate the role of quercetin in attenuating cognitive impairment following hypoxia-induced neonatal seizure (HINS). METHOD: Sprague-Dawley rats at P7 were exposed to a premixed gas in a hypoxic chamber to induce brain injury, and then continuously administered with quercetin for 21 days. Pentylenetetrazol kindling was used to induce seizures in the evolution. After the hypoxic lesion was stablished, anxiety-related behavior of rats after HINS was assessed using open field test. Memory impairment of rats after HINS was evaluated using novel object-recognition test and elevated plus maze test. The serum and hippocampal concentrations of TNF-a, iNOS, IL-6 MCP-1, and IL-1ß were measured using ELISA. The mRNA expression levels of TNF-a, iNOS, IL-6 in the hippocampus were determined using qRT-PCR. The protein levels of TLR4, NF-κB p65, and p-NF-κB p65 in the hippocampus were determined using Western blot. RESULTS: Quercetin administration significantly reduced later-life seizure susceptibility, anxiety-related behavior, and memory impairments in the rats following the HINS when compared to the HINS group without treatment. Both serum and hippocampal proinflammatory cytokines levels were significantly elevated in the rat after HINS. TLR4 protein expressions were increased in the HINS group when compared to control group, and decreased in the group of quercetin. The protein level of p-NF-κB p65 was significantly lower in the quercetin group compared to the HINS group. CONCLUSION: We demonstrated that Quercetin significantly reduced susceptibility to later-life seizures. Quercetin could downregulate inflammatory response through TLR4/ NF-κB pathway, thereby attenuating HINS-induced anxiety, hippocampal memory impairment, and cognitive impairment in later life following HINS.

Identification of altered exosomal microRNAs and mRNAs in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by decreased memory and cognitive functions. Exosomes carry a variety of important information such as proteins, lipids, DNA and RNA of mother cells. It is reported that exosomes play critical roles in nervous system physiology and neurodegenerative diseases. However, the functions of exosomes in AD progression are not fully elucidated. In this study, we detected the expression pattern of mRNAs and miRNAs in exosomes derived from the AD and health mice. A total of 1320 mRNAs and 29 miRNAs were differentially expressed in exosomes between the two groups. Subsequently, the downregulation of Chi3l1 and upregulation of Rhog in AD mice were verified by qRT-PCR. Meanwhile, the downregulation of miR-148a-5p and upregulation of miR-27a-5p in AD group were also tested by qRT-PCR. The functions of differentially expressed mRNAs and potential target genes of miRNAs were determined by GO and KEGG analysis. According to the ceRNA hypothesis, we established an integrated ceRNA network of circRNA-lncRNA-miRNA-mRNA. In conclusion, exosomal lncRNAs, mRNAs, circRNAs and miRNAs were identified to participate in the progression of AD which might be possible biomarkers and therapeutic targets for AD.

Ferritinophagic Flux Was a Driving Force in Determination of Status of EMT, Ferroptosis, and NDRG1 Activation in Action of Mechanism of 2-Pyridylhydrazone Dithiocarbamate S-Acetic Acid.

Ferritinophagy is a process of ferritin degradation in lysosomes; however, how its effect on other cellular events, such as epithelial-mesenchymal transition (EMT) and ferroptosis remains elusive. In this study, we determined how ferritinophagic flux influence the status of EMT and ferroptosis in HepG2 cell. Our data revealed that 2-pyridylhydrazone dithiocarbamate s-acetic acid (PdtaA) induced EMT inhibition involved ferritinophagy-mediated ROS production, but addition of ferrostatin-1 could attenuate the effect of PdtaA on the regulation of EMT-related proteins, suggesting that ferroptosis might involve in the EMT regulation. Next, downregulation of Gpx4 and xCT as well as enhanced lipid peroxidation further supported that PdtaA was able to induce ferroptosis. Knockdown of NCOA4 significantly attenuated the regulatory effect of PdtaA on related proteins which highlighted that the strength of ferritinophagic flux (NCOA4/ferritin) was a driving force in determination of the status of EMT and ferroptosis. Furthermore, NDRG1 activation was also observed, and knockdown of NDRG1 similarly influenced the expressions of ferroptosis-related proteins, suggesting that NDRG1 also involved ferroptosis induction, which was first reported. Taken together, PdtaA-induced EMT inhibition, ferroptosis, and NDRG1 activation all depended on the strength of ferritinophagic flux.

Effect and safety of topical application of tranexamic acid to reduce perioperative blood loss in elderly patients with intertrochanteric fracture undergoing PFNA.

ABSTRACT: The specific method and dose of tranexamic acid (TXA) topically applied for intertrochanteric fractures have not been well established. The aim of this study is to investigate the efficacy and safety of TXA topically administered via our protocol for perioperative bleeding management in elderly patients with intertrochanteric fractures who underwent proximal femoral nail anti-rotation (PFNA).A retrospective comparative analysis was performed. The TXA group was composed of 82 patients with topical use of TXA, and the control group was composed of 82 patients without TXA use during the PFNA procedure. Intraoperative, total and hidden amounts of blood loss, drainage volumes, postoperative blood transfusion volumes and complications were compared between the 2 groups.The intraoperative, total and hidden amounts of blood loss and the drainage volumes were significantly lower in the TXA group than in the control group (P = .012, P < .01, P < .01, P = .014, respectively). The volume and rate of blood transfusion in the TXA group were significantly lower than those in the control group (P < .01). There were no significant differences in complications between the 2 groups (P > .05).Topical application of TXA offers an effective and safe option for reducing perioperative blood loss and transfusion in elderly patients with intertrochanteric fractures undergoing PFNA.

Diagnostic accuracy of different computer-aided diagnostic systems for prostate cancer based on magnetic resonance imaging: A systematic review with diagnostic meta-analysis.

BACKGROUND: Computer-aided detection (CAD) system for accurate and automated prostate cancer (PCa) diagnosis have been developed, however, the diagnostic test accuracy of different CAD systems is still controversial. This systematic review aimed to assess the diagnostic accuracy of CAD systems based on magnetic resonance imaging for PCa. METHODS: Cochrane library, PubMed, EMBASE and China Biology Medicine disc were systematically searched until March 2019 for original diagnostic studies. Two independent reviewers selected studies on CAD based on magnetic resonance imaging diagnosis of PCa and extracted the requisite data. Pooled sensitivity, specificity, and the area under the summary receiver operating characteristic curve were calculated to estimate the diagnostic accuracy of CAD system. RESULTS: Fifteen studies involving 1945 patients were included in our analysis. The diagnostic meta-analysis showed that overall sensitivity of CAD system ranged from 0.47 to 1.00 and, specificity from 0.47 to 0.89. The pooled sensitivity of CAD system was 0.87 (95% CI: 0.76-0.94), pooled specificity 0.76 (95% CI: 0.62-0.85), and the area under curve (AUC) 0.89 (95% CI: 0.86-0.91). Subgroup analysis showed that the support vector machines produced the best AUC among the CAD classifiers, with sensitivity ranging from 0.87 to 0.92, and specificity from 0.47 to 0.95. Among different zones of prostate, CAD system produced the best AUC in the transitional zone than the peripheral zone and central gland; sensitivity ranged from 0.89 to 1.00, and specificity from 0.38 to 0.85. CONCLUSIONS: CAD system can help improve the diagnostic accuracy of PCa especially using the support vector machines classifier. Whether the performance of the CAD system depends on the specific locations of the prostate needs further investigation.

Childhood Mortality After Fluid Bolus With Septic or Severe Infection Shock: A Systematic Review and Meta-Analysis.

BACKGROUND: A considerable debate on whether fluid bolus could decrease childhood mortality in pediatric patients with septic or severe infection shock is still unresolved. A systematic review and meta-analysis was conducted to investigate the mortality rates after fluid bolus among children with septic or severe infection shock. METHODS: A systematic electronic search of PubMed, MEDLINE, Cochrane Library, and EMBASE databases was conducted to identify relevant published studies till March 30, 2020. RESULTS: A total of 19 studies with 9,321 severe sepsis or septic shock pediatric patients were included and exhibited an acceptable quality. Of the 17 studies that reported mortality at 48 h, no bolus group decreased the mortality rate when compared with bolus group with a risk ratio (RR) of 0.74 [95% confidence interval (CI) = 0.62-0.88, P < 0.01], and showed no heterogeneity (I2 = 0%). Similar results were observed on colloids and crystalloids solution in malaria shock cases with a RR of 0.79 (95% CI = 0.62-1.02). For the subgroup of general shock patients, no significant difference was shown with an RR of 0.79 (95% CI = 0.62-1.02, P = 0.07) and no significant heterogeneity (I2 = 0%). Two studies reported mortality at week 4 and pooled results indicated that no bolus group was protective against mortality when compared with bolus group with RR of 0.71 (95% CI = 0.57-0.88, I2 = 0%). CONCLUSION: For the mortality at 48 h, the no bolus group showed decreased mortality when compared with the bolus group, especially in the malaria group. Similar results were found in the colloids and crystalloids solution in patients with malaria shock. Meta-analysis studies with long-term follow-up period and larger sample size are warranted to address the conclusion in the future.

Induction of mesenchymal stem cell­like transformation in rat primary glial cells using hypoxia, mild hypothermia and growth factors.

The transformation of rat primary glial cells into mesenchymal stem cells (MSCs) is intriguing as more seed cells can be harvested. The present study aimed to evaluate the effects of growth factors, hypoxia and mild hypothermia on the transformation of primary glial cells into MSCs. Rat primary glial cells were induced to differentiate by treatment with hypoxia, mild hypothermia and basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). Immunohistochemistry and western blotting were then used to determine the expression levels of glial fibrillary acidic protein (GFAP), nestin, musashi­1, neuron specific enolase (NSE) and neuronal nuclei (NeuN), in each treatment group. bFGF and EGF increased the proportion of CD44+ and CD105+ cells, while anaerobic mild hypothermia increased the proportion of CD90+ cells. The combination of bFGF and EGF, and anaerobic mild hypothermia increased the proportion of CD29+ cells and significantly decreased the proportions of GFAP+ cells and NSE+ cells. Treatment of primary glial cells with bFGF and EGF increased the expression levels of nestin, Musashi­1, NSE and NeuN. Anaerobic mild hypothermia increased the expression levels of Musashi­1 and decreased the expression levels of NSE and NeuN in glial cells. The results of the present study demonstrated that bFGF, EGF and anaerobic mild hypothermia treatments may promote the transformation of glial cells into MSC­like cells, and that the combination of these two treatments may have the optimal effect.

miR-21 is upregulated, promoting fibrosis and blocking G2/M in irradiated rat cardiac fibroblasts.

BACKGROUND: Radiation exposure of the thorax is associated with a greatly increased risk of cardiac morbidity and mortality even after several decades of advancement in the field. Although many studies have demonstrated the damaging influence of ionizing radiation on cardiac fibroblast (CF) structure and function, myocardial fibrosis, the molecular mechanism behind this damage is not well understood. miR-21, a small microRNA, promotes the activation of CFs, leading to cardiac fibrosis. miR-21 is overexpressed after irradiation; however, the relationship between increased miR-21 and myocardial fibrosis after irradiation is unclear. This study was conducted to investigate gene expression after radiation-induced CF damage and the role of miR-21 in this process in rats. METHODS: We sequenced irradiated rat CFs and performed weighted correlation network analysis (WGCNA) combined with differentially expressed gene (DEG) analysis to observe the effect on the expression profile of CF genes after radiation. RESULTS: DEG analysis showed that the degree of gene changes increased with the radiation dose. WGCNA revealed three module eigengenes (MEs) associated with 8.5-Gy-radiation-the Yellow, Brown, Blue modules. The three module eigengenes were related to apoptosis, G2/M phase, and cell death and S phase, respectively. By blocking with the cardiac fibrosis miRNA miR-21, we found that miR-21 was associated with G2/M blockade in the cell cycle and was mainly involved in regulating extracellular matrix-related genes, including Grem1, Clu, Gdf15, Ccl7, and Cxcl1. Stem-loop quantitative real-time PCR was performed to verify the expression of these genes. Five genes showed higher expression after 8.5 Gy-radiation in CFs. The target genes of miR-21 predicted online were Gdf15 and Rsad2, which showed much higher expression after treatment with antagomir-miR-21 in 8.5-Gy-irradiated CFs. Thus, miR-21 may play the role of fibrosis and G2/M blockade in regulating Grem1, Clu, Gdf15, Ccl7, Cxcl1, and Rsad2 post-irradiation.

Rhinovirus impairs the immune response of alveolar macrophages to facilitate Streptococcus pneumonia infection.

Pneumonia is one important cause of mortality in neonates. However, the mechanism remains still unclear. Viral infection greatly enhances the morbidity of Streptococcus pneumonia. In this study, we tried to understand how human rhinovirus (HRV) would accelerate Streptococcus pneumonia infection. Alveolar macrophages (AMs) were isolated from neonatal mice. Cytokine concentrations were detected using ELISA. The phagocytosis of Streptococcus pneumonia by AMs was indicated by immunofluorescence. Toll-like receptor 3 (TLR3) and CD68 expression in isolated AMs or infected mice were determined by western blot or immunochemistry. The mortality was explored using Kaplan-Meier analysis. HRV infection enhanced cytokine release by AMs, and decreased Streptococcus pneumonia-induced TNF-α, IL-1ß and IL-6 release by AMs, while has no influence on IL-10 release. HRV infection impaired phagocytosis of Streptococcus pneumonia in AMs. Mechanically, HRV infection up-regulated TLR3 expression in AMs. Mortality and pneumococcal burden decreased in TLR3-/- neonatal mice and inflammation and phagocytosis were restored in TLR3-/- AMs. Neonatal rhinovirus impairs the immune response of alveolar macrophages to facilitate Streptococcus pneumonia infection via TLR3 signaling.

Radix Angelica Sinensis and Radix Hedysari Ultrafiltration Extract Protects against X-Irradiation-Induced Cardiac Fibrosis in Rats.

Radiation-induced myocardial fibrosis (RIMF) is the main pathological change associated with radiation-induced heart toxicity after radiation therapy in patients with thoracic tumors. There is an antifibrosis effect of Radix Angelica Sinensis and Radix Hedysari (RAS-RH) ultrafiltration extract from Danggui Buxue decoction (DBD) in X-irradiation-induced rat myocardial fibrosis, and this study aimed to investigate whether that effect correlated with apoptosis and oxidative stress damage in primary rat cardiac fibroblasts; further, the potential mechanisms were also explored. In this study, we first found that the RAS-RH antifibrosis effect was associated with the upregulation of microRNA-200a and the downregulation of TGF-ß1/smad3 and COL1α. In addition, we also found that the antifibrosis effect of RAS-RH was related to the induction of apoptosis in primary rat cardiac fibroblasts and to the prevention of damage caused by reactive oxygen species (ROS). Interestingly, primary rat cardiac fibroblasts exposed to X-ray radiation underwent apoptosis less frequently in the absence of RAS-RH. Therefore, RAS-RH has the ability to protect against fibrosis, which could be occurring through the induction of apoptosis and the resistance to oxidative stress in rats with X-irradiation-induced myocardial fibrosis; thus, in a model of RIMF, RAS-RH acts against X-irradiation-induced cardiac toxicity.

Short Communication: The Association of WNT16 Polymorphisms with the CD4+ T Cell Count in the HIV-Infected Population.

WNT16 is one of the 19 members of the human Wnt gene family, and it plays a positive role in lymphocyte proliferation. We investigated the possible association of WNT16 rs3801385 and rs2707466 with the CD4+ T cell count among the HIV-infected population in Guangxi, China. A total of 93 HIV-1-infected patients aged 20-75 years were separated into a CD4+ T cell count ≥200/mm3 group (60 cases) and a <200/mm3 group (33 cases), and 76 healthy subjects were selected as the control group. All patients have not received any antiretroviral treatment. Direct sequencing was used to detect two functional WNT16 polymorphisms. After adjusting for age and gender, our results showed that rs2707466 A alleles and combined GA+AA genotypes were associated with a CD4+ T cell count maintained ≥200/mm3 in the context of HIV infections compared with the control group (odds ratio [OR] = 2.22, 95% confidence interval [CI]: 1.10-4.48, p = .026, and OR = 2.33, 95% CI: 1.03-5.29, p = .044, respectively). When stratified by viral load, this positive association was significantly strengthened in the viral load group of <20 copies/mL. In contrast, there was no significant difference in any genotype and allele of rs3801385 between the patients and healthy controls. In conclusion, the results suggest that the rs2707466 A allele may have a positive effect on maintaining the CD4+ T cell count in HIV-infected individuals.

Assessment of the quality and content of clinical practice guidelines for post-stroke rehabilitation of aphasia.

OBJECTIVES: The purpose of this study was to evaluate the quality of guidelines for rehabilitation of post-stroke aphasia using the Appraisal of Guidelines for Research and Evaluation (AGREE-II) instrument and identify consistency of different guidelines. METHODS: A systematic search was undertaken from inception to October 2018. Two reviewers independently screened all titles and abstracts, and assessed eligible guidelines using the AGREE-II. Agreement among reviewers was measured by using intra-class correlation coefficient (ICC). RESULTS: From 5008 records screened, 8 guidelines met the inclusion criteria. The quality of guidelines was heterogeneous. Three guidelines were rated high (6.5) across; the highest rated domain was "scope and purpose' (median score 95.8%); the lowest rated domain was "rigor of development' (median score 67.2%). An overall high degree of agreement among reviewers to each domain was observed (ICC ranged from 0.60 to 0.99). The speech language therapy was recommended in 3 guidelines. Four guidelines described group treatment was beneficial for the continuum of care. However, other therapies for aphasia varied in the level of detail across guidelines. CONCLUSIONS: Our study indicated the quality of guidelines for post-stroke aphasia needed to be improved. Moreover, the treatment recommendations of aphasia existed discrepancy among the included guidelines. Therefore, it is suggested to pay more attention on the rigor of methodology and applicability during the process of the formulation of guideline. Future research should focus on the effectiveness, intensity, and duration of treatment measures.