Long-read sequencing unveils novel somatic variants and methylation patterns in the genetic information system of early lung cancer.

Lung cancer poses a global health challenge, necessitating advanced diagnostics for improved outcomes. Intensive efforts are ongoing to pinpoint early detection biomarkers, such as genomic variations and DNA methylation, to elevate diagnostic precision. We conducted long-read sequencing on cancerous and adjacent non-cancerous tissues from a patient with lung adenocarcinoma. We identified somatic structural variations (SVs) specific to lung cancer by integrating data from various SV calling methods and differentially methylated regions (DMRs) that were distinct between these two tissue samples, revealing a unique methylation pattern associated with lung cancer. This study discovered over 40,000 somatic SVs and over 180,000 DMRs linked to lung cancer. We identified approximately 700 genes of significant relevance through comprehensive analysis, including genes intricately associated with many lung cancers, such as NOTCH1, SMOC2, CSMD2, and others. Furthermore, we observed that somatic SVs and DMRs were substantially enriched in several pathways, such as axon guidance signaling pathways, which suggests a comprehensive multi-omics impact on lung cancer progression across various biological investigation levels. These datasets can potentially serve as biomarkers for early lung cancer detection and may hold significant value in clinical diagnosis and treatment applications.

Association of adenosine triphosphate-related genes to major depression and suicidal behavior: Cognition as a potential mediator.

BACKGROUND: Soluble epoxide hydrolase (sEH, encoded by EPHX2) and P2X2 (a subtype of ATP receptors) may mediate the antidepressant-like effects of ATP. We sought to determine whether polymorphisms and mRNA expression of EPHX2 and P2X2 are associated with depression and suicidal behavior and how cognition may mediate such associations. METHOD: We examined 83 single nucleotide polymorphisms (SNPs) of EPHX2 and P2X2. Subjects were MDD suicide attempters (N = 143), MDD non-suicide attempters (N = 248), and healthy volunteers (HV, N = 110). Data on demographics, depression severity, and suicide attempts were collected. Participants completed a set of cognitive tasks. Polymorphisms were genotyped using MALDI-TOF MS within the MassARRAY system. The expression of mRNA was measured using real-time polymerase chain reaction (RT-PCR). RESULTS: Cognitive function was a significant mediator (p = 0.006) of the genetic effect on depression. Allele C of rs202059124 was associated with depression risk (OR = 11.57, 95%CI: 2.33-209.87, p = 0.0181). A significant relationship was found between P2X2 mRNA expression and depression (OR = 0.68, 95%CI: 0.49-0.94, p = 0.0199). One haploblock (rs9331942 and rs2279590) was associated with suicide attempts: subjects with haplotype GC (frequency = 19.8 %, p = 0.017) and AT (frequency = 35.2 %, p < 0.001) had a lower rate of suicide attempts. CONCLUSIONS: Our results confirmed that cognitive impairment plays a role in the effect of rs9331949 on depression. Moreover, we confirmed a relationship between P2X2, EPHX2, and MDD in humans and presented preliminary haplotype-based evidence that implicates EPHX2 in suicide. LIMITATIONS: The main limitation of this study is the limited sample size. More comprehensive and multi-domain cognition tasks and different assessment measures are required in further study.

Magnetic resonance imaging for evaluation of bowel inflammation and disease activity in Crohn's disease: A systematic review and meta-analysis.

BACKGROUND: The aim of this systematic review and meta-analysis was to determine the performance of magnetic resonance imaging (MRI) in the diagnosis of bowel inflammation and disease activity in Crohn's disease (CD). METHODS: MEDLINE, Embase and Web of Science databases of biomedical literature were systematically searched to identify studies that investigated the diagnostic accuracy of MRI in diagnosing bowel inflammation and disease activity in CD by comparing it with reference standards. Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess study quality. The summary sensitivity and specificity were estimated using the bivariate model, and hierarchical summary receiver operating characteristic (HSROC) parameters were calculated and plotted. RESULTS: Of 5492 citations of interest, 34 articles contained the diagnostic accuracy data. Of these, results for the small bowel and the colorectum were reported separately in 19 studies and jointly by 21 studies. The meta-analytic summary sensitivity and specificity under the bivariate model were 90.9% (95% CI, 85.8%-94.2%) and 90.2% (95% CI, 81.9%-95.0%), respectively. The sensitivities and specificities of individual studies ranged from 55% to 100% and 51% to 100%, respectively. Substantial heterogeneity was observed in both sensitivity (I2=84.9%) and specificity (I2=78.8%). The HSROC curve also showed considerable heterogeneity between studies. CONCLUSION: Although the meta-analytic summary accuracy of MRI was high for the diagnosis of bowel inflammation in CD, the summary estimates might be unreliable due to the presence of high heterogeneity.

Hyperpolarized 3 helium MRI measured apparent diffusion coefficient and its correlations with pulmonary functions tests in patients with chronic obstructive pulmonary disease: A meta-analysis.

BACKGROUND: This study evaluates role of hyperpolarized 3 helium (3 He) MRI measured apparent diffusion coefficient (ADC) in examining pulmonary function of chronic obstructive pulmonary disease (COPD) patients. METHODS: After literature search in electronic databases, studies were selected by following precise eligibility criteria. Meta-analyses were performed to estimate mean difference in ADC between COPD patients and healthy individuals and to seek correlations between lung ADC and pulmonary function. Metaregression analyses were performed to seek relationships between ADC and age, gender, BMI, cigarette pack-years, and pulmonary function tests. RESULTS: Twenty-five studies (622 COPD patients and 469 healthy controls) were included. Lung ADC was 0.402 (95% confidence interval [CI]: 0.374, 0.429) in COPD patients and 0.228 (95% CI: 0.205, 0.252) in healthy individuals (mean difference 0.160 [95% CI: 0.127, 0.193]; p < 0.001). In metaregression, age (coefficient: 0.006; p = 0.004), pack-years (coefficient: 0.005; p = 0.018), forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio (coefficient: -1.815; p = 0.007), percent predicted diffusion capacity of carbon monoxide (DLCO) (coefficient: -0.004; p = 0.008), and percent predicted inspiratory capacity (coefficient: -0.004; p = 0.012) were significantly associated with ADC in COPD patients. In meta-analysis of correlation coefficients, ADC was significantly correlated with FEV1 (r = -0.62; p < 0.00001), FEV1/FVC (r = -0.80; p < 0.00001), DLCO (r = -0.85; p < 0.00001), functional residual capacity (r = 0.71; p < 0.00001), reserve volume (r = 0.53; p = 0.0001), and emphysema index (r = 0.89; p < 0.00001). CONCLUSION: Hyperpolarized 3 He MRI measured ADC was higher in COPD patients than in healthy individuals and was inversely associated with FEV1, FEV1/FVC, DLCO, and inspiratory capacity.

Down-regulated long non-coding RNA RMST ameliorates dopaminergic neuron damage in Parkinson's disease rats via regulation of TLR/NF-κB signaling pathway.

OBJECTIVE: Current treatment and prognosis of Parkinson's disease (PD) are not ideal. This study explored the mechanism of long non-coding RNA (lncRNA) rhabdomyosarcoma 2-associated transcript (RMST) in dopaminergic (DA) neuron damage in PD rats. METHODS: PD rats were modeled and injected with RMST silence or overexpression vectors to figure out its roles in oxidative stress, the apoptosis of DA neurons in brain substantia nigra (SN), and neurobehavioral activities of PD rats. Tyrosine hydroxylase (TH), synaptophysin (SYN), glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule (Iba-1) in SN were detected. RMST and Toll-like receptor (TLR)/nuclear factor kappa B (NF-κB) pathway-related factors were detected. RESULTS: RMST expression in brain SN of rats, TLR2, TLR4 expression in neurons and NF-κB expression in cell nucleus were increased. Silenced RMST improved the neurobehavioral activities, depressed oxidative stress and neuronal apoptosis, increased TH and SYN expression, and reduced the activation degree of glial cells in SN and the inflammatory response via reducing GFAP and Iba-1. Moreover, reduced RMST reduced TLR2 and TLR4 expression in neurons and NF-κB expression in cell nucleus in PD rats. CONCLUSION: Inhibited RMST attenuates DA neuron damage in PD rats, which may be implicated with TLR/NF-κB signaling pathway.

Up-regulated microRNA-218-5p ameliorates the damage of dopaminergic neurons in rats with Parkinson's disease via suppression of LASP1.

OBJECTIVE: Parkinson's disease (PD) is a frequent degenerative disease of the nervous system with undefined pathogenesis. This study explored the protective effect of microRNA (miR)-218-5p on dopaminergic neuron injury in substantia nigra (SN) of rats with PD through the regulation of LIM and SH3 domain protein 1 (LASP1). METHODS: The PD rat model was established by fixed point injection of 6-hydroxydopamine into the rats. The PD rats were injected with miR-218-5p overexpressed recombinant adeno-associated virus (rAAV) or LASP1 silenced rAAV to explore their roles in dopaminergic neurons in SN of rats with PD. The changes in pathological structure of SN were observed and the expression of tyrosine hydroxylase (TH) and deacetylvindoline acetyltransferase (DAT), the dopaminergic neuron apoptosis and oxidative stress factor in the SN were detected. The expression of miR-218-5p, LASP1, Bcl-2 and Bax in SN was detected. The targeting relationship between miR-218-5p and LASP1 was confirmed. RESULTS: Declined miR-218-5p and overexpressed LASP1 existed in the brain SN of PD rats. Up-regulated miR-218-5p or inhibited LASP1 improved the pathological damage of dopaminergic neurons and increased the number of TH and DAT positive cells in brain SN of PD rats. Furthermore, elevated miR-218-5p or depressed LASP1 inhibited the apoptosis, and oxidative stress of dopaminergic neurons in brain SN of PD rats. In addition, increased miR-218-5p repressed the expression of LASP1 in the brain SN of PD rats. LASP1 was proven to be a direct target of miR-218-5p. CONCLUSION: The study highlights that up-regulated miR-218-5p could improve the damage of dopaminergic neurons in PD rats, which was related to the inhibition of LASP1.

miR129-1 regulates protein phosphatase 1D protein expression under hypoxic conditions in non-small cell lung cancer cells harboring a TP53 mutation.

Protein phosphatase 1D (PPM1D), which functions as an oncogene, is a known target of the tumor suppressor p53 and is involved in p53-regulated genomic surveillance mechanisms. PPM1D dephosphorylates both p53 and its ubiquitin ligase mouse double minute 2 homolog, as well as the RNA-binding protein (RBM)38, which turns RBM38 from an inducer to inhibitor of TP53 translation. In addition, RBM38 induces PPM1D translation. Hence, the PPM1D-RBM38-p53 axis is important in maintaining genomic integrity and is often altered during tumorigenesis. TP53, which encodes p53, is deleted or mutated in >50% of cancer types, including lung cancer. Mutant p53 has been revealed to complex with hypoxia-inducible factor 1α (HIF1α) and upregulate transcription of pro-metastatic genes. However, the mechanism underlying the action of the PPM1D-RBM38-p53 axis in the context of mutant p53 under normoxic and hypoxic conditions is yet to be elucidated. In the present study, using non-small cell lung cancer (NSCLC) cell lines harboring wild-type (A549 cells) or hot-spot mutant (NCI-H1770 and R249WΔ-TP53-A549 cells) TP53, it was demonstrated that in cells harboring mutant p53, RBM38 was not the primary regulator of PPM1D translation under hypoxic conditions. Knockdown of RBM38 in TP53 mutant cells did not affect the PPM1D protein expression under hypoxic conditions. Instead, in NCI-H1770 cells maintained under normoxic conditions, PPM1D was revealed as a target of micro RNA (miR)-129-1-3p, a known tumor suppressor in lung cancer. Hypoxia resulted in the downregulation of miR-129-1-3p expression, and thus, in the downregulation of PPM1D messenger RNA (mRNA) translation. In NCI-H1770 cells grown under hypoxic conditions, the transient transfection of miR-129-1-3p mimic, and not control mimic, repressed the expression of a reporter containing wild-type, but not miR-129-1-3p binding mutant, of the PPM1D 3'-untranslated region (UTR). Analysis of NSCLC cell lines from the Broad Institute Cancer Cell Encyclopedia and patients with NSCLC from The Cancer Genome Atlas dataset revealed significant co-occurrence of PPM1D/RBM38 and PPM1D/HIF1A mutations. However, there was no significant difference in the overall survival of patients with NSCLC with or without genomic alterations in TP53, RBM38, PPM1D and HIF1A. In summary, the current study demonstrated hypoxia-dependent miR-129-1-3p-mediated regulation of PPM1D protein expression in NSCLC cell line harboring mutant TP53.

RBM38 induces SIRT1 expression during hypoxia in non-small cell lung cancer cells by suppressing MIR34A expression.

OBJECTIVE: The study is to research how miR-34-SIRT1 is regulated during hypoxia in lung cancer cells. RESULTS: Analysis of publicly available datasets from patients with NSCLC did not reveal significant genomic alterations in RBM38, SIRT1, HIF1A, MIR34A, MIR34B, and MIR34C, but expectedly revealed alterations in TP53. Overall survival in NSCLC patients with or without alterations in these genes was not significantly different. When expanded to include all lung cancer patients, overall survival was significantly lower in patients with genomic alterations in these genes. CONCLUSIONS: Cumulatively, our results reveal a novel mechanism of RBM38-mediated regulation of the HIF1A/miR-34a/SIRT1/p53 axis under hypoxia in NSCLC cells.

MicroRNA-129-5p alleviates nerve injury and inflammatory response of Alzheimer's disease via downregulating SOX6.

There is growing evidence of the position of microRNAs (miRs) in Alzheimer's disease (AD), thus our objective was to discuss the impact of miR-129-5p regulating nerve injury and inflammatory response in AD rats by modulating SOX6 expression. The AD rat model was established by injecting Aß25-35 into the brain. The pathological changes, ultrastructure, number of neurons, cell degeneration and apoptosis of hippocampal tissue were observed in vivo. MiR-129-5p, SOX6, IL-1ß, TNF-α, Bcl-2 and Bax expression in serum and hippocampal tissues were detected by ELISA, RT-qPCR or western blot analysis. The successfully modeled hippocampal neuronal cells of AD were transfected with miR-129-5p mimic, SOX6-siRNA or their controls to figure out their roles in proliferation, apoptosis and inflammatory reaction in vitro. Low expression of SOX6 and high expression of miR-129-5p in vivo of rats would shorten the escape latent period and increase the times of crossing platforms, alleviate the pathological injury, inhibit neuronal apoptosis and reduce the inflammatory reaction. Up-regulation of miR-129-5p and down-regulation of SOX6 promoted proliferation, suppressed apoptosis and degraded the inflammatory reaction of neuronal cells in vitro. Up-regulation of SOX6 reversed the expression of miR-129-5p to reduce the damage and inflammatory response of the cell model of AD. Our study presents that up-regulation of miR-129-5p or down-regulation of SOX6 can reduce nerve injury and inflammatory response in rats with AD. Thus, miR-129-5p may be a potential candidate for the treatment of AD.

MicroRNA-128 knockout inhibits the development of Alzheimer's disease by targeting PPARγ in mouse models.

Alzheimer's disease (AD) is a great threat for the health and life of elderly people. MicroRNA-128 (miR-128) has been reported to be abnormally expressed in the brain of AD patients and associated with the pathogenesis of AD. Our study aimed to have a deep insight into the roles and molecular basis of miR-128 in the development and progression of AD. The cognitive ability and exploratory behaviors were assessed by morris water maze and open-field tests, respectively. The concentrations of amyloid-ß (Aß) 40, Aß 42, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-10 and activity of ß-secretase and α-secretase were determined by corresponding ELISA commercial kits. RT-qPCR assay was performed to detect miR-128 level and the mRNA expression of peroxisome proliferator-activated receptor gamma (PPARγ), ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP). Western blot assay was conducted to determine protein expression of PPARγ, amyloid precursor protein (APP), ß-APP cleaving enzyme (BACE1), sAPPα and sAPPß. The effect of miR-128 and PPARγ on amyloid plaque formation was assessed by immunohistochemistry assay. PPARγ mean optical density was determined by immunofluorescence assay. The interaction between miR-128 and PPARγ were validated by bioinformatics analysis and luciferase reporter assay. We found AD mice showed AD-like performance and an increased cerebral cortex Aß production. MiR-128 expression was upregulated and PPARγ expression was downregulated in cerebral cortex of AD mice. Moreover, PPARγ was a target of miR-128. Additionally, miR-128 knockout or PPARγ upregulation inhibited AD-like performances, amyloid plaque formation, Aß generation, APP amyloidogenic processing and inflammatory responses in AD mice, while these effects of miR-128 knockout were abrogated by PPARγ inhibitor. The results indicated MiR-128 knockout weakened AD-like performances, and reduced Aß production and inflammatory responses by targeting PPARγ in AD mice.

Protective Effect of Curcumin Against Oxidative Stress-Induced Injury in Rats with Parkinson's Disease Through the Wnt/ ß-Catenin Signaling Pathway.

BACKGROUND/AIMS: The study aimed to investigate the protective effect of curcumin against oxidative stress-induced injury of Parkinson's disease (PD) through the Wnt/ß-catenin signaling pathway in rats. METHODS: The successfully established PD rat models and normal healthy rats were randomly assigned into the 6-hydroxydopamine (6-OHDA), the curcumin (Cur) and the control groups. Immunohistochemistry was used to detect the positive expression of tyrosine hydroxylase (TH), dopamine transporter (DAT) and glial fibrillary acidic protein (GFAP). Deutocerebrum primary cells were extracted and classified into the control, 6-OHDA, Cur (5, 10, 15 µmol/L), Dickkopf-1 (DKK-1) and Cur + DKK-1 groups. MTT assays, adhesion tests and TUNEL staining were used to assess cell viability, adhesion and apoptosis, respectively. Western blotting and qRT-PCR were used to examine the protein and mRNA expressions of Wnt3a and ß-catenin and the c-myc and cyclinD1 mRNA expressions. RESULTS: TH and DAT expressions in the Cur group were elevated and GFAP was reduced compared with the 6-OHDA group. Curcumin enhanced viability, survival and adhesion and attenuated apoptosis of deutocerebrum primary cells by activating the Wnt/ß-catenin signaling pathway. Higher Wnt3a and ß-catenin mRNA and protein expressions and c-myc and cyclinD1 mRNA expressions, enhanced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) contents, decreased malondialdehyde (MDA) content and elevated mitochondrial membrane potential (∆ψm) were found in the 10 and 15 µmol/L Cur groups compared with the 6-OHDA group. However, opposite tendencies were found in the Cur + DKK-1 group compared to the 10 µmol/L Cur group. CONCLUSION: This study suggests that curcumin could protect against oxidative stress-induced injury in PD rats via the Wnt/ß-catenin signaling pathway.

Prevalence of comorbidities in chronic obstructive pulmonary disease patients: A meta-analysis.

BACKGROUND: This study compares the prevalence rates of comorbidities between chronic obstructive pulmonary disease (COPD) and non-COPD control patients reported in literature. METHOD: Literature was searched in several electronic databases. After the selection of studies by following précised eligibility criteria, meta-analyses of odds ratios (ORs) were carried out with subgroup and sensitivity analyses under random effects model. RESULTS: Eleven studies (47,695,183 COPD and 47,924,876 non-COPD control patients' data) were used for meta-analysis. Average age of COPD patients was 66.66 ±â€Š8.72 years of whom 55.4 ±â€Š11.9% were males. The prevalence of cardiovascular comorbidities [OR 1.90, 95% confidence interval (95% CI) 1.59-2.28; P < .00001], cerebrovascular comorbidities (OR 1.84, 95% CI 1.47-2.31; P < .00001), hypertension (OR 1.45, 95% CI 1.31-1.61; P < .00001), diabetes mellitus (OR 1.22, 95% CI 1.07-1.38; P = .003), neurological and psychiatric disorders (OR 1.78, 95% CI 1.48-2.14; P < .00001), gut and renal disorders (OR 1.96, 95% CI 1.43-2.68; P < .00001), musculoskeletal disorders (OR 1.51, 95% CI 1.27-1.78; P < .00001), non-COPD respiratory comorbidities (OR 2.81, 95% CI 2.52-3.14; P < .00001), and cancer (OR 1.67, 95% CI 1.25-2.23; P = .0005) were significantly higher in COPD patients than in non-COPD controls. CONCLUSION: COPD is associated with significantly higher comorbidities than in other diseases that should be taken into consideration in COPD control strategies.

PDK1 promotes tumor cell proliferation and migration by enhancing the Warburg effect in non-small cell lung cancer.

Tumor cells prefer glycolysis (Warburg effect) during the proliferation and metastasis. The precise mechanism remains largely unknown. Here, we demonstrated that pyruvate dehydrogenase kinase 1 (PDK1) was a critical enzyme that functioned as an oncogene to promote non-small cell lung cancer (NSCLC) growth and metastasis. We discovered that PDK1 expression was significantly upregulated in NSCLC tissues and correlated with advanced T stage. Moreover, high expression of PDK1 was an independent prognostic factor of NSCLC. Ectopic overexpression of PDK1 promoted cell proliferation and inhibited apoptosis. Also it was shown that PDK1 increased the cell mobility when Transwell assay was performed. Further experiments indicated that PDK1 had a central role in metabolic reprogramming by phosphorylating pyruvate dehydrogenase, leading to enhanced Warburg effect. Collectively, our data reveal a new function for PDK1, which could be used to indicate the prognosis of NSCLC, and provide targeted therapeutic strategy for clinical treatment.

Effects of caffeic acid on learning deficits in a model of Alzheimer's disease.

Caffeic acid is a type of phenolic acid and organic acid. It is found in food (such as tomatoes, carrots, strawberries, blueberries and wheat), beverages (such as wine, tea, coffee and apple juice) as well as Chinese herbal medicines. In the present study, we examined the effects of caffeic acid on learning deficits in a rat model of Alzheimer's disease (AD). The rats were randomly divided into three groups: i) control group, ii) AD model group and iii) caffeic acid group. Caffeic acid significantly rescued learning deficits and increased cognitive function in the rats with AD as demonstrated by the Morris water maze task. Furthermore, caffeic acid administration resulted in a significant decrease in acetylcholinesterase activity and nitrite generation in the rats with AD compared with the AD model group. Furthermore, caffeic acid suppressed oxidative stress, inflammation, nuclear factor­κB­p65 protein expression and caspase­3 activity as well as regulating the protein expression of p53 and phosphorylated (p-)p38 MAPK expression in the rats with AD. These experimental results indicate that the beneficial effects of caffeic acid on learning deficits in a model of AD were due to the suppression of oxidative stress and inflammation through the p38 MAPK signaling pathway.

Effects of curcumin on the apoptosis of cardiomyocytes and the expression of NF-κB, PPAR-γ and Bcl-2 in rats with myocardial infarction injury.

Curcumin is a natural polyphenol with powerful antioxidant and anti-inflammatory properties. The present study evaluated the protective effect of curcumin on myocardial injury in rats as well as the mechanisms underlying these effects, and examined the expression of nuclear factor-κB (NF-κB), peroxisome proliferator-activated receptor-γ (PPAR-γ) and B-cell leukemia/lymphoma-2 (Bcl-2) following myocardial infarction. A rat model of myocardial infarction was successfully established. Hematoxylin and eosin staining showed cellular atrophy and hyperchromatic cytoplasm in the myocardial infarction area. The myocardial cells displayed lysis and breakage of cardiac muscle fibers, karyopyknosis and karyorrhexis associated with infiltration of inflammatory cells and proliferation of fibrous tissue. Curcumin treatment at a dosage of 150 mg/kg/body weight resulted in an increase in surviving cells, fewer apoptotic cells, decreased proliferation of fibrous tissue and reduced infiltration of inflammatory cells, though necrosis was still present compared with the rats without curcumin treatment. The immunohistochemical assay demonstrated that curcumin treatment inhibited the expression of NF-κB, but increased the expression of PPAR-γ. The results of the reverse transcription-polymerase chain reaction indicated that curcumin treatment significantly increased the mRNA expression levels of Bcl-2 (P<0.01). Therefore, curcumin antagonizes cardiomyocyte apoptosis and inhibits inflammatory cell infiltration following myocardial infarction, which may be associated with its inhibitory effects on the expression of NF-κB, and activating effects on the expression of PPAR-γ and Bcl-2 in myocardial cells. Curcumin may be useful in clinical practice for saving more living heart muscle in the area of myocardial infarction and improving cardiac function following the elective opening of obstructed coronary arteries.

[LONG-TERM RESULTS OF DELAYED REPAIR OF MEDIAN NERVE INJURY].

OBJECTIVE: To review and analyze the long-term results of delayed repair of median nerve injury. METHODS: Between January 2004 and December 2008, 228 patients with median nerve injury undergoing delayed repair were followed up for more than 4 years, and the clinical data were retrospectively analyzed. There were 176 males (77.19%) and 52 females (22.81%), aged 2-71 years (median, 29 years). The main injury reason was cutting injury in 159 cases (69.74%); 203 cases had open injury (89.04%). According to the injury level, injury located at area I (upper arm) in 38 cases (16.67%), at area II (elbow and proximal forearm) in 53 cases (23.25%), at area III (anterior interosseous nerve) in 13 cases (5.70%), and at area IV (distal forearm to wrist) in 124 cases (54.39%). The delayed operations included delayed suture (50 cases, 21.93%), nerve release (149 cases, 65.35%), and nerve graft (29 cases, 12.72%). RESULTS: For patients with injury at area I and area II, the results were good in 23 cases (25.27%), fair in 56 cases (61.54%), and poor in 12 cases (13.18%) according to modified Birch and Raji's median nerve grading system; there was significant difference in the results between 3 repair methods for injury at area II (χ2 = 6.228, P = 0.044), but no significant difference was found for injury at area I (χ2 = 2.241, P = 0.326). Twelve patients (13.18%) needed musculus flexor functional reconstruction. Recovery of thenar muscle was poor in all patients, but only 5 cases (5.49%) received reconstruction. Thirteen cases of nerve injury at area III had good results, regardless of the repair methods. For patients with injury at area IV, the results were excellent in 6 cases (4.84%), good in 22 cases (17.74%), fair in 72 cases (58.06%), and poor in 24 cases (19.35%) according to Birch and Raji's grading system; there was significant difference in the results between 3 repair methods (χ2 = 12.646, P = 0.002), and the result of delayed repair was better. CONCLUSION: The results of delayed repair is poor for all median nerve injuries, especially for high level injury. The technique of repair methods vary with injury level. For some delayed median nerve injuries, early nerve transfer may be a better choice for indicative patients.

CRNDE, a long-noncoding RNA, promotes glioma cell growth and invasion through mTOR signaling.

The transcripts of the gene Colorectal Neoplasia Differentially Expressed (CRNDE) are recognized as long-noncoding RNAs (lncRNAs), which are expressed in specific regions within the human brain, and are the most upregulated lncRNA in gliomas. However, the underlying regulation and function of CRNDE in gliomas are largely unknown. In this study, the upregulation of CRNDE was confirmed in both primary specimens from glioma patients and in vitro with cell lines. Overexpression of specific CRNDE transcript promotes cell growth and migration in vitro while knockdown of CRNDE expression manifests a repressive function during these cellular processes. The growth promoting effect of CRNDE was also demonstrated in a xenograft mouse model. Mechanistic studies further revealed that histone acetylation in the promoter region might account for the upregulation of CRNDE, and the level of CRNDE expression could be modulated by mammalian Target of Rapamycin (mTOR) signaling in glioma. Thus, our results shed a light on utilizing CRNDE as a potential novel therapeutic target for the treatment of glioma.

Protective effect of bone marrow mesenchymal stem cells on PC12 cells apoptosis mediated by TAG1.

OBJECTIVE: This study aims to explore the protection effect of bone marrow mesenchymal stem cells (BMSCs) on PC12 cells apoptosis mediated by transient axonal glycoprotein 1 (TAG1). METHODS: PC12 cells were divided into control group, Aß25-35 group and BMSCs + Aß25-35 group. The effects of BMSCs on PC12 cells treated by Aß25-35 were detected using MTT, Hoechst 33258 and Annexin V-FITC/PI staining methods. The expression levels of TAG1, ß-amyloid precursor protein (APP), AICD and p53 were determined by RT-PCR and Western blotting methods. The expression levels of Bax and Bcl-2 were determined by Western blotting method. The activity of Caspase 3 was detected by spectrophotometric method. RESULTS: MTT results showed that cell activity decreased after the treatment of 20 µM Aß25-35 for 48 h (P<0.01) while it increased in BMSCs + Aß25-35 group (P<0.01). Hoechst 33258 and Annexin V-FITC/PI staining results showed that Aß25-35 could induce the apoptosis of PC12 cells while the apoptosis of PC12 cells was inhibited in BMSCs + Aß25-35 group. RT-PCR and Western blotting methods showed that 20 µM Aß25-35 could increase the expression levels of TAG1, APP, AICD and p53 (P<0.01) while they decreased in BMSCs + Aß25-35 group (P<0.01). 20 µM Aß25-35 could increase the expression levels of Bax and decrease the expression levels of Bcl-2 (P<0.01), while the expression levels of Bax decreased and the expression levels of Bcl-2 increase in BMSCs + Aß25-35 group (P<0.01). 20 µM Aß25-35 could enhance Caspase 3 activity while it decreased in BMSCs + Aß25-35 group (P<0.01). Conclusions BMSCs with Aß25-35 could inhibit the apoptosis of PC12 cells, which maybe related with TAG1/APP/AICD signal pathway.

The potential of human umbilical cord-derived mesenchymal stem cells as a novel cellular therapy for multiple sclerosis.

Multiple sclerosis (MS) is a complex disease of neurological disability, affecting more than 300 out of every 1 million people in the world. The purpose of the study was to evaluate the therapeutic effects of human umbilical cord-derived mesenchymal stem cell (hUC-MSC) transplantation in MS patients. Twenty-three patients were enrolled in this study, and 13 of them were given hUC-MSC therapy at the same time as anti-inflammatory treatment, whereas the control patients received the anti-inflammatory treatment only. Treatment schedule included 1,000 mg/kg of methylprednisolone intravenously (IV) daily for 3 days and then 500 mg/kg for 2 days, followed by oral prednisone 1 mg/kg/day for 10 days. The dosage of prednisone was then reduced by 5 mg every 2 weeks until reaching a 5-mg/day maintenance dosage. Intravenous infusion of hUC-MSCs was applied three times in a 6-week period for each patient. The overall symptoms of the hUC-MSC-treated patients improved compared to patients in the control group. Both the EDSS scores and relapse occurrence were significantly lower than those of the control patients. Inflammatory cytokines were assessed, and the data demonstrated a shift from Th1 to Th2 immunity in hUC-MSC-treated patients. Our data demonstrated a high potential for hUC-MSC treatment of MS. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.