[The application of human genetic technology in the medical field urgently needs standardization].

Human gene editing technology is a hot spot and focus in the development of biotechnology, but it has also caused controversies over technical risks, genetic biosecurity, ethical dignity of human society and the legality of application, causing people to worry about the application of this technology. Gene editing for reproductive purposes is generally prohibited internationally, and countries have established legal regulatory systems to regulate the application of gene editing technology according to their own conditions. China shall establish a security risk access system for gene editing technology, ensure national biosecurity, establish and improve the system of ethical norms for scientific research, improve the construction of legislative standardization, and provide legal guarantees for the research and application of gene editing technology.

[Safety and efficacy of the early administration of levosimendan in patients with acute non-ST-segment elevation myocardial infarction and elevated NT-proBNP levels: An Early Management Strategy of Acute Heart Failure (EMS-AHF)].

Objectives: To investigated the safety and efficacy of treating patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) and elevated levels of N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) with levosimendan within 24 hours of first medical contact (FMC). Methods: This multicenter, open-label, block-randomized controlled trial (NCT03189901) investigated the safety and efficacy of levosimendan as an early management strategy of acute heart failure (EMS-AHF) for patients with NSTEMI and high NT-proBNP levels. This study included 255 patients with NSTEMI and elevated NT-proBNP levels, including 142 males and 113 females with a median age of 65 (58-70) years, and were admitted in the emergency or outpatient departments at 14 medical centers in China between October 2017 and October 2021. The patients were randomly divided into a levosimendan group (n=129) and a control group (n=126). The primary outcome measure was NT-proBNP levels on day 3 of treatment and changes in the NT-proBNP levels from baseline on day 5 after randomization. The secondary outcome measures included the proportion of patients with more than 30% reduction in NT-proBNP levels from baseline, major adverse cardiovascular events (MACE) during hospitalization and at 6 months after hospitalization, safety during the treatment, and health economics indices. The measurement data parameters between groups were compared using the t-test or the non-parametric test. The count data parameters were compared between groups using the χ² test. Results: On day 3, the NT-proBNP levels in the levosimendan group were lower than the control group but were statistically insignificant [866 (455, 1 960) vs. 1 118 (459, 2 417) ng/L, Z=-1.25,P=0.21]. However, on day 5, changes in the NT-proBNP levels from baseline in the levosimendan group were significantly higher than the control group [67.6% (33.8%,82.5%)vs.54.8% (7.3%,77.9%), Z=-2.14, P=0.03]. There were no significant differences in the proportion of patients with more than 30% reduction in the NT-proBNP levels on day 5 between the levosimendan and the control groups [77.5% (100/129) vs. 69.0% (87/126), χ²=2.34, P=0.13]. Furthermore, incidences of MACE did not show any significant differences between the two groups during hospitalization [4.7% (6/129) vs. 7.1% (9/126), χ²=0.72, P=0.40] and at 6 months [14.7% (19/129) vs. 12.7% (16/126), χ²=0.22, P=0.64]. Four cardiac deaths were reported in the control group during hospitalization [0 (0/129) vs. 3.2% (4/126), P=0.06]. However, 6-month survival rates were comparable between the two groups (log-rank test, P=0.18). Moreover, adverse events or serious adverse events such as shock, ventricular fibrillation, and ventricular tachycardia were not reported in both the groups during levosimendan treatment (days 0-1). The total cost of hospitalization [34 591.00(15 527.46,59 324.80) vs. 37 144.65(16 066.90,63 919.00)yuan, Z=-0.26, P=0.80] and the total length of hospitalization [9 (8, 12) vs. 10 (7, 13) days, Z=0.72, P=0.72] were lower for patients in the levosimendan group compared to those in the control group, but did not show statistically significant differences. Conclusions: Early administration of levosimendan reduced NT-proBNP levels in NSTEMI patients with elevated NT-proBNP and did not increase the total cost and length of hospitalization, but did not significantly improve MACE during hospitalization or at 6 months.

Cross-cultural adaptation and psychometric evaluation of the Malay version of the Neck Disability Index.

PURPOSE: Translating the Neck Disability Index (NDI) into the Malay language (NDI-M); evaluation of psychometric properties in patients with neck pain. METHODS: The NDI-M was translated according to established guidelines. In the first visit, 120 participants completed the NDI-M, visual analogue scale (VAS) for pain and demographic details. 98 participants returned to complete similar questionnaires and the Global Rating of Change (GRoC) scale. The NDI-M was evaluated for internal consistency, test-retest reliability, content validity, construct validity and responsiveness. RESULTS: The NDI-M demonstrated excellent internal consistency (Cronbach's α = 0.84) and good test-retest reliability (ICC2,1 = 0.79). Content validity was confirmed with no floor or ceiling effects. Construct validity was established revealing three-factor subscales explaining 68% of the total variance. The NDI-M showed a moderate correlation with VAS (Rp = 0.49, p < 0.001). Regarding responsiveness, a moderate correlation between NDI-M change scores and VAS change scores was found (Rp = 0.40, p < 0.001). However, there was no significant correlation between NDI-M with GRoC (Rs = 0.11, p = 0.27). CONCLUSIONS: The NDI-M is a reliable and valid tool to measure functional outcomes in patients with neck pain. It is responsive in detecting changes in pain intensity during a patient's rehabilitation journey.Implications for rehabilitationThe NDI was translated into the Malay language and culturally adapted for Malay-speaking patients with neck pain.The NDI-M demonstrated an excellent level of internal consistency and good test-retest reliability. It demonstrated content and construct validity, with three-factor subscales, and moderate responsiveness for pain intensity.The NDI-M is a reliable, valid and responsive instrument to measure functional limitations in patients with neck pain for rehabilitation.

Quantitative Analysis of DCE-MRI and RESOLVE-DWI for Differentiating Nasopharyngeal Carcinoma from Nasopharyngeal Lymphoid Hyperplasia.

To explore the ability of quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) analysis and readout segmentation of long variable echo-trains diffusion weighted imaging (RESOLVE-DWI) to distinguish nasopharyngeal carcinoma (NPC) from nasopharyngeal lymphoid hyperplasia (NPLH). Twenty-five patients with NPC and 30 patients with NPLH were evaluated. Three quantitative DCE-MRI parameters (Ktrans, Kep and Ve) and the apparent diffusion coeffcient (ADC) of lesions were calculated. The two independent samples t test or Mann-Whitney U test was used to compare the parameters between NPC and NPLH group. Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic ability for distinguishing NPC from NPLH. A P value less than 0.05 was considered statistically significant. The difference in Ktrans value between the NPC group and the NPLH group was statistically significant, and the value of the NPC group was larger than that of the NPLH group. There was no statistical difference in Kep and Ve between the two groups. The ADC value of NPC group was smaller than that of NPLH group, and the difference was statistically significant. ROC curve analysis showed that both Ktrans and ADC were effective in diagnosing NPC and the area under the curve (AUC) was 0.773 and 0.704, respectively. In addition, the combination of Ktrans and ADC demonstrated the obviously improved AUC of 0.884. DCE-MRI and RESOLVE-DWI are effective in differentiating NPC from NPLH, especially the combination of the two models.

High-expression of lncRNA CEBPA-AS1 promotes liver cancer progression.

OBJECTIVE: Long non-coding RNAs (lncRNAs) have been confirmed to play important roles in the progression of different cancers. The aim of this study was to detect the expression level of lncRNA CEBPA-AS1 in liver cancer and to study its influence on cell proliferation, invasion and prognosis. PATIENTS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR), MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, transwell assay, Western blot, Kaplan-Meier survival curve and Cox regression were used to evaluate lncRNA CEBPA-AS1 expression, cell proliferation, invasion, epithelial-mesenchymal transition (EMT)-related molecules expression and prognosis, respectively. RESULTS: The expression of lncRNA CEBPA-AS1 increased significantly in liver cancer tissues (p<0.05). Meanwhile, CEBPA-AS1 expression was associated with tumor size, portal vein tumor thrombus and invasion and metastasis (p<0.05). In vitro experiments indicated that downregulation of lncRNA CEBPA-AS1 could effectively reduce cell proliferation, invasion and EMT process. CONCLUSIONS: LncRNA CEBPA-AS1 acts as an oncogene in liver cancer, which may be a novel biomarker in liver cancer progression.

Neurobiological mechanisms of TENS-induced analgesia.

Pain inhibition by additional somatosensory input is the rationale for the widespread use of Transcutaneous Electrical Nerve Stimulation (TENS) to relieve pain. Two main types of TENS produce analgesia in animal models: high-frequency (∼50-100 Hz) and low-intensity 'conventional' TENS, and low-frequency (∼2-4 Hz) and high-intensity 'acupuncture-like' TENS. However, TENS efficacy in human participants is debated, raising the question of whether the analgesic mechanisms identified in animal models are valid in humans. Here, we used a sham-controlled experimental design to clarify the efficacy and the neurobiological effects of 'conventional' and 'acupuncture-like' TENS in 80 human volunteers. To test the analgesic effect of TENS we recorded the perceptual and brain responses elicited by radiant heat laser pulses that activate selectively Aδ and C cutaneous nociceptors. To test whether TENS has a long-lasting effect on brain state we recorded spontaneous electrocortical oscillations. The analgesic effect of 'conventional' TENS was maximal when nociceptive stimuli were delivered homotopically, to the same hand that received the TENS. In contrast, 'acupuncture-like' TENS produced a spatially-diffuse analgesic effect, coupled with long-lasting changes both in the state of the primary sensorimotor cortex (S1/M1) and in the functional connectivity between S1/M1 and the medial prefrontal cortex, a core region in the descending pain inhibitory system. These results demonstrate that 'conventional' and 'acupuncture-like' TENS have different analgesic effects, which are mediated by different neurobiological mechanisms.

Effect of tannins and cellulase on growth performance, nutrients digestibility, blood profiles, intestinal morphology and carcass characteristics in Hu sheep.

Objective: This study was conducted to evaluate the effects of tannins and cellulase on growth performance, nutrient digestibility, blood profiles, intestinal morphology and carcass characteristics in Hu sheep. Methods: A total of 48 three-month-old meat Hu sheep (25.05 ± 0.9 kg) were blocked based on body weight, and randomly allotted to 4 treatments with 3 replicates of 4 sheep each. The experiment lasted for 80 d, and dietary treatments were as follows: (1) CON, control diet; (2) TAN, CON + 0.1% tannins; (3) CEL, CON + 0.1% cellulase; (4) TAN+ CEL, CON + 0.1% tannins and 0.1% cellulase. Results: Compared with CON, CEL and TAN+CEL had greater (P<0.05) final birth weight (FBW) and average daily gain but lower (P<0.05) F/G, while FBW of TAN+CEL was lower (P<0.05) than that of CEL. The apparent total tract digestibility (ATTD) of DM in TAN, CEL and TAN+CEL groups were higher (P<0.05) than that in CON. CEL and TAN+CEL groups had greater (P<0.05) ATTD of CF compared with TAN and CON, while TAN group had lower (P<0.05) ATTD of CP than other treatments. TAN, CEL and TAN+CEL groups increased (P<0.05) serum globulin and alkaline phosphatase but decreased (P<0.05) A/G. Serum total protein was greatest for TAN+CEL, intermediate for TAN and CEL and least for CON (P<0.05). TAN+CEL group increased (P<0.05) dressing percentage compared with CON, while the backfat thickness of CEL was lower (P<0.05) than that of CON. The villus height of jejunum and ileum in CEL and TAN+CEL groups were greater (P<0.05) than that in CON, and the crypt depth and villus height: crypt depth of jejunum were increased (P<0.05) in TAN, CEL and TAN+CEL groups. Conclusion: The addition of tannins and cellulase together promoted nutrient digestion, liver protein synthesis and intestinal development and thus improved growth performance and carcass characteristics.

Microneedle fractional radiofrequency treatment of facial photoageing as assessed in a split-face model.

BACKGROUND: A new therapeutic device passes radiofrequency energy through microneedles to targeted tissue. Three-dimensional photography may be useful for evaluating the clinical efficacy of microneedle fractional radiofrequency (MFR) used on the appearance of rhytids and to improve facial laxity. AIM: To evaluate the efficacy and safety of MFR in the treatment of facial photoageing. METHODS: In total, participants with facial photoageing were enrolled in the study. All volunteers were randomized to receive split-face treatments with MFR 2 months apart. The participants self-evaluated at baseline, Days 1-7, and Months 1 and 3 after the final treatment. Objective evaluation was provided by a three-dimensional in vivo imaging system. In addition, skin melanin index, erythema index, immediate reactions, healing times and other adverse effects were evaluated. RESULTS: Compared with the untreated side, the treated side of most participants improved, based on clinical assessments at the 1- and 3-month follow-up visits after treatment. Both objective and participative assessments were satisfactory. The participants demonstrated a decrease of roughness parameter (Sa) value at each follow-up visit. Compared with pretreatment value, Sa decreased significantly at Months 1 and 3 on the treated side (P < 0.05). Minimal and reversible adverse effects and rapid healing were recorded. CONCLUSIONS: MFR appears to be an excellent treatment for photodamaged facial skin in Chinese patients.

Metformin enhances inhibitive effects of carboplatin on HeLa cell proliferation and increases sensitivity to carboplatin by activating mitochondrial associated apoptosis signaling pathway.

OBJECTIVE: Cervical cancer has become the fourth most common cancer in developing countries. This study aimed to investigate anti-tumor effects of Metformin combining with carboplatin in cervical cell line, HeLa cell. MATERIALS AND METHODS: Human cervical cancer cell line, HeLa cell, was treated with Metformin (5 mmol/l or 10 mmol/l) or/and carboplatin (25 mg/l or 50 mg/l) at different final concentrations, and divided into 8 groups. 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate cell viability. Acridine orange/ethidium bromide (AO/EB) staining was used to examine nuclear fragments and cell apoptosis. Annexin V/propidium iodide (PI) staining was employed to detect apoptosis of HeLa cells. Mitochondrial membrane potential of the HeLa cells was evaluated by staining with 5,5,6,6-tetrachloro-1,1,3,3-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) reagent. RESULTS: MTT results showed that Metformin combining carboplatin significantly reduced HeLa cell viability compared to that of no-drug treatment group (p<0.05). Metformin combining carboplatin significantly increased the amounts of nuclear fragments compared to that of no-drug treatment group (p<0.05). The flow cytometry assay results indicated that Metformin combining carboplatin significantly enhanced the apoptotic rates compared to that of no-drug treatment group (p<0.05). The JC-1 staining findings illustrated that Metformin combining carboplatin significantly decreased the mitochondrial membrane potential compared to that of no-drug treatment group (p<0.05). CONCLUSIONS: Metformin enhanced the inhibitive effects of carboplatin on HeLa cell proliferation. Metformin increased the sensitivity of HeLa cell to the treatment of Carboplatin by activating mitochondrial-associated apoptosis signaling pathway.

MiR-940 regulates angiogenesis after cerebral infarction through VEGF.

OBJECTIVE: The aim of this study was to investigate whether miR-490 was involved in the regulation of angiogenesis after cerebral infarction by regulating vascular endothelial growth factor (VEGF) expression. MATERIALS AND METHODS: Sprague Dawley (SD) rats were used to establish a middle cerebral artery infarction model. Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was used to detect the expression levels of miR-940 in serum and brain tissues at 1, 3, and 7 days after cerebral infarction. Meanwhile, miR-940 expression in brain microvascular endothelial cells (BMECs) after Oxygen-Glucose Deprivation (OGD) for 2, 4, 6 hours was measured by qRT-PCR, respectively. The cells were transfected with miR-940 mimics/inhibitor to achieve miR-940 overexpression or inhibition. Subsequently, the angiogenesis and proliferation ability of the cells was evaluated by 5-ethynyl-2'-deoxyuridine (EDU) assay. Besides, the mRNA and protein expression levels of VEGF after miR-940 transfection were detected by Western blot and qRT-PCR, respectively. Finally, recovery experiment was used to determine whether miR-940 affected angiogenesis and proliferation of BMECs by regulating VEGF expression. RESULTS: The expression level of miR-940 in serum and brain tissues of rats was markedly decreased at 1, 3, and 7 days after cerebral infarction, which was then recovered on the 7th day. After 2, 4, and 6 hours of glucose and oxygen deprivation in BMECs, the expression level of miR-940 was significantly decreased. However, it was evidently recovered after 6 hours. After miR-940 over-expression in BMECs, the angiogenesis and proliferation of BMECs were remarkably inhibited. Conversely, miR-940 inhibitor transfection could significantly promote the formation of luminal cells and the proliferation of BMECs. QRT-PCR results showed that miR-940 overexpression down-regulated the expression level of VEGF, and the same findings were observed at the protein level. Further studies revealed that VEGF could reverse the inhibitory effect of miR-940 on lumen formation and cell proliferation in BMECs. CONCLUSIONS: The expression of miR-940 was downregulated in cerebral infarction. The low expression of miR-940 could promote the angiogenesis ability of cerebral microvascular endothelial cells after cerebral infarction, which might be resulted from the inhibitory effect of miR-940 on VEGF.

MiR-485-5p promotes the development of osteoarthritis by inhibiting cartilage differentiation in BMSCs.

OBJECTIVE: To investigate whether microRNA-485-5p (miR-485-5p) can participate in osteoarthritis by inhibiting chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and promoting the secretion of inflammatory factors. MATERIALS AND METHODS: BMSCs were obtained from mouse bone marrow samples and identified by flow cytometry. The expression of specific genes and miR-485-5p in the differentiation of BMSCs was detected by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). The influence of miR-485-5p on chondrogenic differentiation was subsequently evaluated by toluidine blue staining, detection of chondrogenic specific gene expression and inflammatory factors. After over-expressing SOX9, it was assessed whether miR-485-5p can affect the chondrogenic differentiation of BMSCs by inhibiting SOX9, so as to promote the secretion of inflammatory factors. RESULTS: The miR-485-5p level was negatively correlated with the degree of differentiation of BMSCs. After overexpression of microRNA-485-5p in BMSCs, the expression of cartilage surface marker genes and toluidine blue staining were reduced, while the expression of cartilage surface inflammation factors, including interleukin and tumor necrosis factor, was significantly enhanced. Meanwhile, opposite results were observed when miR-485-5p was inhibited. In addition, overexpression of SOX9 could restore the secretion of inflammatory cytokines induced by microRNA-485-5p. CONCLUSIONS: MiR-485-5p can decrease the level of SOX9, promote the production of inflammatory factors on the cartilage surface, and block the differentiation of mouse BMSCs into chondrocytes.

Value of texture analysis based on enhanced MRI for predicting an early therapeutic response to transcatheter arterial chemoembolisation combined with high-intensity focused ultrasound treatment in hepatocellular carcinoma.

AIM: To evaluate the potential value of texture analysis (TA) based on contrast-enhanced magnetic resonance imaging (MRI) for predicting an early response of patients with hepatocellular carcinoma (HCC) who were treated with transcatheter arterial chemoembolisation (TACE) combined with high-intensity focused ultrasound (HIFU). MATERIALS AND METHODS: Patients with HCC (n=89) who underwent contrast-enhanced MRI at 1.5 T 1 week before and 1 week, 1 month, and 3 months after TACE/HIFU were included in this retrospective study. Early responses were evaluated by two radiologists according to the Response Evaluation Criteria in Cancer of the Liver (RECICL). An independent Student's t-test and the Mann-Whitney U-test were used to compare the TA parameters between the complete response (CR) group and the non-complete response (NCR) group. Logistic regression and receiver operating characteristic (ROC) curve analyses were performed to assess the predictive value of the NCR lesions. RESULTS: Among the 89 patients, 58 showed CR and 31 showed NCR. Before TACE/HIFU, the CR group showed higher uniformity and energy but lower entropy than the NCR group (p<0.05). After TACE/HIFU, the CR group showed higher uniformity and energy but lower entropy and skewness than the NCR group (p<0.05). The logistic regression and ROC curve analyses showed that the entropy before TACE/HIFU and the skewness and entropy 1 week after TACE/HIFU were predictors of an early response. CONCLUSION: TA parameters based on contrast-enhanced MRI images 1 week before and after TACE/HIFU may act as imaging biomarkers to predict an early response of patients with HCC.

[New thoughts are needed for the study of liver cancer recurrence and metastasis].

In the recent years, our knowledge on cancer and metastasis has been renewed, and therefore new thoughts are needed for the study of cancer metastasis. Based on the fact that cancer is a systemic and dynamic disease which is caused by multiple factors, involves various genes, and has multiple stages, more studies should be conducted in the following aspects: (1) intervention of cancer metastasis; (2) systemic intervention focusing on the nervous system, immune status, endocrine, and metabolism; (3) studies on improving residual cancer and microenvironment; (4) studies on multimodality therapy, especially the combination of eradication and modification; (5) dynamic studies on cancer metastasis, especially the intervention leading to increased metastatic potential after tumor eradication.

Moderate swimming suppressed the growth and metastasis of the transplanted liver cancer in mice model: with reference to nervous system.

Physical activity has been shown to suppress tumor initiation and progression. The neurotransmitter dopamine (DA) is closely related to movement and exhibits antitumor properties. However, whether the suppressive effects of physical activity on tumors was mediated by the nervous system via increased DA level remains unknowns. Here we show that regular moderate swimming (8 min/day, 9 weeks) raised DA levels in the prefrontal cortex, serum and tumor tissue, suppressed growth, reduced lung metastasis of transplanted liver cancer, and prolonged survival in a C57BL/6 mouse model, while overload swimming (16 and 32 min/day, 9 weeks) had the opposite effect. In nude mice that were orthotopically implanted with human liver cancer cell lines, DA treatment significantly suppressed growth and lung metastasis by acting on the D2 receptor (DR2). Furthermore, DR2 blockade attenuated the suppressive effect of moderate swimming on liver cancer. Both moderate swimming and DA treatment suppressed the transforming growth factor-beta (TGF-ß1)-induced epithelial-mesenchymal transition of transplanted liver cancer cells. At the molecular level, DR2 signaling inhibited extracellular signal-regulated kinase phosphorylation and expression of TGF-ß1 in vitro. Together, these findings demonstrated a novel mechanism by which the moderate exercise suppressed liver cancer through boosting DR2 activity, while overload exercise had the opposite effect, highlighting the possible importance of the dopaminergic system in tumor growth and metastasis of liver cancer.

Identifying hub genes and dysregulated pathways in hepatocellular carcinoma.

OBJECTIVE: The aim of this study was to identify the hub genes and dysregulated pathways of hepatocellular carcinoma (HCC) and explore the molecular mechanism of the biological process associated with HCC. MATERIALS AND METHODS: Microarray data were got from NCBI Gene Expression Omnibus (GEO) database. The most significant top 100 up-regulated gene signatures and top 100 down-regulated gene signatures were identified by integrated analysis of the multiple microarray datasets using a novel model genome-wide relative significance (GWRS) and genome-wide global significance (GWGS). Gene Ontology (GO) enrichment analysis and pathway analysis of those genes were performed based on Gene Ontology website and Kyoto Encyclopedia of Genes and Genomes (KEGG). Protein-protein interaction (PPI) network was constructed using Cytoscape 2.1. In addition, we analysed the significantly dysregulated signaling pathways across the PPI network and KEGG pathway analysis. RESULTS: We screened 2920 up-regulated and 2231 down-regulated gene signatures across multiple studies by GWRS and GWGS. The top 100 up-regulated and top 100 down-regulated gene signatures were selected for further research. GO enrichment analysis showed that these genes significantly enriched in terms of mitosis (p = 5.83×10-20), nuclear division (p = 5.83×10-20) and M phase of mitotic cell cycle (p = 9.39×10-20). The most significant terms of KEGG pathway included cell cycle (p = 1.33×10-8), oocyte meiosis (p = 1.41×10-4), drug metabolism (p = 2.15×10-4) and p53 signaling pathway (p = 3.57×10-4). PPI network suggested that BIRC5, CDC20, CCNB1, BUB1B, MAD2L1 and CDK1 were important significant genes which were considered as hub genes. Across the PPI and pathway, cell cycle, oocyte meiosis and p53 signaling pathway were the significantly dysregulated pathways. CONCLUSIONS: Our study displayed robust gene signatures in HCC. It showed that the dysregulations of cell cycle, oocyte meiosis, p53 signaling pathway and progesterone-mediated oocyte maturation pathway were closely associated to the development and progression of HCC. Besides, genes BIRC5, CDC20, CCNB1, BUB1B, MAD2L1 and CDK1 as the hub genes might play important roles for diagnosing and therapy of HCC.

Integrative genomics identifies YY1AP1 as an oncogenic driver in EpCAM(+) AFP(+) hepatocellular carcinoma.

Identification of key drivers and new therapeutic targets is important given the poor prognosis for hepatocellular carcinoma (HCC) patients, particularly those ineligible for surgical resection or liver transplant. However, the approach to identify such driver genes is facing significant challenges due to the genomically heterogenous nature of HCC. Here we tested whether the integrative genomic profiling of a well-defined HCC subset that is classified by an extreme EpCAM(+) AFP(+) gene expression signature and associated with poor prognosis, all attributes of a stem cell-like phenotype, could uncover survival-related driver genes in HCC. Following transcriptomic analysis of the well-defined HCC cases, a Gene Set Enrichment Analysis coupled with genomic copy number alteration assessment revealed that YY1-associated protein 1 (YY1AP1) is a critical oncoprotein specifically activated in EpCAM(+) AFP(+) HCC. YY1AP1 silencing eliminates oncogene addiction by altering the chromatin landscape and triggering massive apoptosis in vitro and tumor suppression in vivo. YY1AP1 expression promotes HCC proliferation and is required for the maintenance of stem cell features. We revealed that YY1AP1 cooperates with YY1 to alter the chromatin landscape and activate transcription of stemness regulators. Thus YY1AP1 may serve as a key molecular target for EpCAM(+) AFP(+) HCC subtype. Our results demonstrate the feasibility and power of a new strategy by utilizing well-defined patient samples and integrative genomics to uncover critical pathways linked to HCC subtypes with prognostic impact.

Protection against ischemia-reperfusion injury in aged liver donor by the induction of exogenous human telomerase reverse transcriptase gene.

BACKGROUND: Liver ischemia-reperfusion (I/R) injury is of great importance in primary graft dysfunction after transplantation, and could be more severe in transplantation using aged donor livers. In order to alleviate the I/R injury in aged donor livers, we transferred exogenous human telomerase reverse transcriptase (hTERT) gene into aged rat's livers before liver transplantation. After transplantation, the effect of the gene for aged rats on cell apoptosis caused by I/R injury was evaluated. METHODS: The experiment was divided into 2 parts: comparative experiment between aged rats and adult rats, and exogenous induction experiment of aged rats. In the first part, Wistar rats were divided into 2 groups; group I was composed of adult rats (5 months) and group II was composed of aged rats (16-18 months). After successful transplantation, chronic oxidative stress and lipid peroxidation-related indicators (contents of vitamin C and vitamin E; activities of superoxide dismutase, catalase, and methane decarboxylic aldehyde) and alanine aminotransferase activity were examined. In the second part, additional aged rats were divided into 3 groups: group A included the donors pretreated with exogenous hTERT gene; group B included the donors pretreated with adenovirus vector; and group C was composed of the donors pretreated with physiological saline. Various indicators were detected to analyze the effect of the gene on I/R injury of the aged rats. RESULTS: The lower vitamin C, vitamin E, SOD, and CAT contents in the aged group than those in the adult group (P < .05), and the higher MDA and ALT contents in the aged group than those in the adult group (P < .05) were observed. The apoptotic index and ALT levels in the hTERT gene-pretreated group were significantly lower than those in the adenovirus vector group and the physiological saline group (P < .05). Meanwhile, mild histological injury and increased telomerase activity were also observed in the hTERT gene-pretreated group. CONCLUSION: Compared with the adult rats, I/R injury in the aged liver donor is more severe. The induction of exogenous hTERT gene offers protection against I/R injury in the aged liver.

Mutations in the HFE gene and sporadic amyotrophic lateral sclerosis risk: a meta-analysis of observational studies.

Iron homeostasis dysregulation has been regarded as an important mechanism in neurodegenerative diseases. The H63D and C282Y polymorphisms in the HFE gene may be involved in the development of sporadic amyotrophic lateral sclerosis (ALS) through the disruption of iron homeostasis. However, studies investigating the relationship between ALS and these two polymorphisms have yielded contradictory outcomes. We performed a meta-analysis to assess the roles of the H63D and C282Y polymorphisms of HFE in ALS susceptibility. PubMed, MEDLINE, EMBASE, and Cochrane Library databases were systematically searched to identify relevant studies. Strict selection criteria and exclusion criteria were applied. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. A fixed- or random-effect model was selected, depending on the results of the heterogeneity test. Fourteen studies were included in the meta-analysis (six studies with 1692 cases and 8359 controls for C282Y; 14 studies with 5849 cases and 13,710 controls for H63D). For the C282Y polymorphism, significant associations were observed in the allele model (Y vs C: OR=0.76, 95%CI=0.62-0.92, P=0.005) and the dominant model (YY+CY vs CC: OR=0.75, 95%CI=0.61-0.92, P=0.006). No associations were found for any genetic model for the H63D polymorphism. The C282Y polymorphism in HFE could be a potential protective factor for ALS in Caucasians. However, the H63D polymorphism does not appear to be associated with ALS.

Mutations in the HFE gene and sporadic amyotrophic lateral sclerosis risk: a meta-analysis of observational studies

Iron homeostasis dysregulation has been regarded as an important mechanism in neurodegenerative diseases. The H63D and C282Y polymorphisms in the HFE gene may be involved in the development of sporadic amyotrophic lateral sclerosis (ALS) through the disruption of iron homeostasis. However, studies investigating the relationship between ALS and these two polymorphisms have yielded contradictory outcomes. We performed a meta-analysis to assess the roles of the H63D and C282Y polymorphisms of HFE in ALS susceptibility. PubMed, MEDLINE, EMBASE, and Cochrane Library databases were systematically searched to identify relevant studies. Strict selection criteria and exclusion criteria were applied. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. A fixed- or random-effect model was selected, depending on the results of the heterogeneity test. Fourteen studies were included in the meta-analysis (six studies with 1692 cases and 8359 controls for C282Y; 14 studies with 5849 cases and 13,710 controls for H63D). For the C282Y polymorphism, significant associations were observed in the allele model (Y vs C: OR=0.76, 95%CI=0.62-0.92, P=0.005) and the dominant model (YY+CY vs CC: OR=0.75, 95%CI=0.61-0.92, P=0.006). No associations were found for any genetic model for the H63D polymorphism. The C282Y polymorphism in HFE could be a potential protective factor for ALS in Caucasians. However, the H63D polymorphism does not appear to be associated with ALS.