Peptide RL-QN15 promotes regeneration of epidermal nerve fibers and recovery of sensory function in diabetic skin wounds.

Epidermal nerve fiber regeneration and sensory function are severely impaired in skin wounds of diabetic patients. To date, however, research on post-traumatic nerve regeneration and sensory reconstruction remains scarce, and effective clinical therapeutics are lacking. In the current study, localized treatment with RL-QN15, considered as a drug candidate for intervention in skin wounds in our previous research, accelerated the healing of full-thickness dorsal skin wounds in diabetic mice and footpad skin wounds in diabetic rats. Interestingly, nerve density and axonal plasticity in the skin wounds of diabetic rats and mice, as well as plantar sensitivity in diabetic rats, were markedly enhanced by RL-QN15 treatment. Furthermore, RL-QN15 promoted the proliferation, migration, and axonal length of neuron-like PC12 cells, which was likely associated with activation of the phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt) signaling pathway. The therapeutic effects of RL-QN15 were partially reduced by blocking the PI3K/Akt signaling pathway with the inhibitor LY294002. Thus, RL-QN15 showed positive therapeutic effects on the distribution of epidermal nerve fibers and stimulated the recovery of sensory function after cutaneous injury. This study lays a solid foundation for the development of RL-QN15 peptide-based therapeutics against diabetic skin wounds.

Effect of MR-guided perfusion imaging mismatch profiles within 6 h on endovascular thrombectomy outcomes.

BACKGROUND: The treatment of acute ischemic stroke (AIS) aims to achieve early vascular recanalization and reperfusion of the penumbra. However, the effect of early penumbral imaging within 6 h on clinical outcomes remains unclear. The objective of this study was to determine the effect of magnetic resonance-guided (MR-guided) perfusion imaging within 6 h after symptom onset on endovascular thrombectomy outcomes in AIS patients. METHODS: We prospectively collected the clinical information of consecutive AIS patients undergoing endovascular thrombectomy based on MR-guided perfusion imaging within 6 h after symptom onset from AISRNA and EVTRNA studies. The primary outcome was defined as the poor outcome (mRS > 2 within 90 days). The perfusion-weighted imaging/diffusion-weighted imaging (PWI/DWI) mismatch was assessed by an automated software. RESULTS: We enrolled 84 patients (25 in the mismatch ≤ 1.8 group and 59 in the mismatch > 1.8 group). Significant difference was found between the mismatch > 1.8 group and the mismatch ≤ 1.8 group for the incidence of disabling stroke (mRS > 2) within 90 days (40.7% vs. 68.0%, OR: 3.099, 95% CI: 1.154-8.323, P = 0.025). Intracranial hemorrhage occurred in 8 patients (13.6%) in the mismatch > 1.8 group and 10 patients in the mismatch ≤ 1.8 group (40.0%) (P = 0.010). The risk of severe cerebral edema was 2/59 (3.4%) vs. 7/25 (28.0%) (P = 0.004). These findings remained stable after adjustment. CONCLUSIONS: MR-guided perfusion imaging mismatch profiles within 6 h after symptom onset may be feasible to predictclinical outcomes and reduce clinically ineffective reperfusion after endovascular thrombectomy.

Circular RNA circ0104103 inhibits colorectal cancer progression through interactions with HuR and miR-373-5p.

Emerging evidence has suggested that circular RNAs (circRNAs) have vital functions during the initiation and progression of various diseases. However, circRNA potential mechanisms in colorectal cancer (CRC) are largely unknown. Here, we sought to investigate the role and underlying regulatory mechanism of circ0104103 in CRC. circ0104103 was validated by quantitative RT-PCR (qRT-PCR) and Sanger sequencing. Gain- and loss-of-function assays in cell lines and mouse xenograft models were utilized to investigate the effects of circ0104103 in CRC. RNA pull-down assays, RNA immunoprecipitation assays, bioinformatics analyses, RNA FISH, and luciferase reporter assays were used to elucidate the potential mechanism of circ0104103 in CRC. We identified circ0104103, which is strongly downregulated in CRC tissues and cell lines. Functional studies revealed that circ0104103 inhibited CRC cell growth, migration, and invasion both in vitro and in vivo. Mechanistically, circ0104103 binds to HuR, a functional RNA-binding protein commonly expressed in CRC. HuR binds to the 3'UTR of LACTB mRNA to facilitate stabilization and increase its expression. Moreover, circ0104103 was verified as a competing endogenous RNA (ceRNA) via negative regulation of miR-373-5p to increase LACTB expression, resulting in inhibiting the occurrence and progression of CRC. Taken together, our study revealed that circ0104103 acts as a tumor suppressor and may be a novel biomarker and therapeutic target in CRC.

miR-186-5p targets TGFßR2 to inhibit RAW264.7 cell migration and proliferation during mouse skin wound healing.

BACKGROUND: Active peptides play a vital role in the development of new drugs and the identification and discovery of drug targets. As the first reported native peptide homodimer with pro-regenerative potency, OA-GP11d could potentially be used as a novel molecular probe to help elucidate the molecular mechanism of skin wound repair and provide new drug targets. METHODS: Bioinformatics analysis and luciferase assay were adopted to determine microRNAs (miRNAs) and its target. The prohealing potency of the miRNA was determined by MTS and a Transwell experiment against mouse macrophages. Enzyme-linked immunosorbent assay, realtime polymerase chain reaction, and western blotting were performed to explore the molecular mechanisms. RESULTS: In this study, OA-GP11d was shown to induce Mus musculus microRNA-186-5p (mmu-miR-186-5p) down-regulation. Results showed that miR-186-5p had a negative effect on macrophage migration and proliferation as well as a targeted and negative effect on TGF-ß type II receptor (TGFßR2) expression and an inhibitory effect on activation of the downstream SMAD family member 2 (Smad2) and protein-p38 kinase signaling pathways. Importantly, delivery of a miR-186-5p mimic delayed skin wound healing in mice. CONCLUSION: miR-186-5p regulated macrophage migration and proliferation to delay wound healing through the TGFßR2/Smad2/p38 molecular axes, thus providing a promising new pro-repair drug target.

SNHG15 is a negative regulator of inflammation by mediating TRAF2 ubiquitination in stroke-induced immunosuppression.

BACKGROUND: Abnormal expression of long noncoding RNAs (lncRNAs) has been reported in the acute stage of acute ischemic stroke (AIS). This study aimed to explore differential lncRNA expression in the subpopulations of peripheral blood mononuclear cells (PBMCs) from AIS patients and further evaluate its underlying mechanisms in stroke-induced immunosuppression. METHODS: We reanalyzed lncRNA microarray data and investigated abnormally expressed lncRNAs in the subpopulations of PBMCs by magnetic cell sorting and real-time quantitative PCR. The potential mechanism of small nucleolar RNA host gene 15 (SNHG15) was explored through in vitro and in vivo approaches. RESULTS: The stroke-induced SNHG15 acted as a checkpoint to inhibit peripheral inflammatory responses. Functional studies showed that SNHG15 promoted M2 macrophage polarization. Mechanistically, SNHG15 expression was dysregulated through the Janus kinase (JAK)-signal transducer and activator of transcription 6 (STAT6) signaling pathway. SNHG15, localized in the cytoplasm, interfered with K63-linked ubiquitination of tumor necrosis factor receptor-associated factor 2 and thereby repressed the activation of mitogen-activated protein kinase and nuclear factor kappa-B signaling pathways and prevented the production of proinflammatory cytokines. Administration of an adenovirus targeting SNHG15 improved stroke-induced immunosuppression in mice. CONCLUSIONS: This study identified SNHG15 as a negative regulator of inflammation in stroke-induced immunosuppression, suggesting it as a novel biomarker and therapeutic target in stroke-associated infection. Trial registration ClinicalTrials.gov NCT04175691. Registered November 25, 2019, https://www.clinicaltrials.gov/ct2/show/NCT04175691 .

Lactobacillus rhamnosus GG combined with inosine ameliorates alcohol-induced liver injury through regulation of intestinal barrier and Treg/Th1 cells.

BACKGROUND: Intestinal epithelial barrier disruption and bacterial translocation exacerbates the progression of alcoholic liver disease. Lactobacillus rhamnosus GG (LGG), a probiotic, has been shown benefits in chronic liver disease and in regulating gut dysbiosis. Previous studies showed the protective roles of LGG in ethanol-disrupted gut barrier functions and liver injury. Inosine, a metabolite produced by intestinal bacteria, has the anti-inflammatory and immunregulatory functions. In this study, the synergistic effect of LGG and inosine was investigated in a mouse model of alcohol-induced liver disease (ALD). METHODS: Male C57BL/6 mice were fed with a Lieber-DeCarli diet containing 5% alcohol for four weeks to establish a model of alcohol-induced liver injury. LGG or a combination of LGG and inosine were administrated orally to explore a new therapeutic method for alcohol-induced liver disease and to investigate the underlying mechanisms. Liver damage was evaluated by transaminases and pathological changes. Tight junction proteins, composition of the gut microbiome, cytokines, lipopolysaccharides (LPS), glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), F4/80+ macrophages, as well as p38, Jun N-terminal kinase (JNK), were determined by qRT-PCR, RNAseq, ELISA, IHC and western blot. Regulatory T (Treg) cells were characterized by positive staining of CD4, CD25 and Foxp3 using flow cytometry. IFN-γ-producing CD4+ T (Th1) cells were examined by intracellular cytokine staining. RESULTS: Alcohol consumption induced elevated liver enzymes, steatosis and inflammation, while LGG combined with inosine treatment was more significant to ameliorate these symptoms compared with LGG alone. When LGG combined with inosine were administered to ALD mice, intestinal microecology significantly improved reflected by intestinal villi and tight junction proteins recovery and the restoration of intestinal flora. Combined therapy inhibited phosphorylation of p38 and JNK to alleviate hepatic inflammation. Moreover, flow cytometry analysis showed that long-term excessive alcohol consumption reduced Tregs population while increased Th1 population, which was restored by a combination of LGG and inosine treatment. CONCLUSIONS: The findings from the study indicate that the combined LGG and inosine treatment ameliorates ALD by improving the gut ecosystem, intestinal barrier function, immune homeostasis and liver injury.

Decreased taste sensitivity to sucrose in dopamine D3 receptor mutant mice.

Dopamine plays a key role in food rewards and sweet-taste stimulation. We examined the basis for behavioral responses to sweet taste in dopamine D3 receptor-deficient (D3-/-) mice by determining whether the absence of D3 receptors affects the sensitivity to dilute sucrose solutions. In experiment 1, we measured the intensity generalization threshold of conditioned taste aversion (CTA) to a 0.2 M sucrose solution. Results showed that the generalization thresholds were 0.025-0.05 M in D3-/- mice and 0.0025-0.005 M in wild-type (WT) mice. In experiment 2, we found that D3-/- and WT mice had similar capabilities to form and extinguish CTAs. Since the intensity generalization threshold is mainly due to a combination of sweet-taste sensitivity and the robust nature of CTA formation, the results showed that taste sensitivity to sucrose in D3-/- mice was lower than that in WT mice. In experiment 3, to test whether the peripheral sensory signaling may also be affected by the disruption of the dopamine D3 receptors, the mRNA expression levels of sweet-taste-related proteins in taste buds of D3-/- mice were determined. The T1R1 and BDNF mRNA expression levels in D3-/- mice were higher than the controls, whereas T1R2, T1R3, α-gustducin, and TRPM5 mRNA were similar. These findings suggest that disruption of dopamine D3 receptor-mediated signaling decreases the sweet-taste sensitivity and alters the mRNA expression levels of some taste-related molecules.

The Impacts of Iron Overload and Ferroptosis on Intestinal Mucosal Homeostasis and Inflammation.

Intestinal homeostasis is maintained through the interplay of the intestinal mucosa, local and systemic immune factors, and the microbial content of the gut. Iron is a trace mineral in most organisms, including humans, which is essential for growth, systemic metabolism and immune response. Paradoxically, excessive iron intake and/or high iron status can be detrimental to iron metabolism in the intestine and lead to iron overload and ferroptosis-programmed cell death mediated by iron-dependent lipid peroxidation within cell membranes, which contributes to several intestinal diseases. In this review, we comprehensively review recent findings on the impacts of iron overload and ferroptosis on intestinal mucosal homeostasis and inflammation and then present the progress of iron overload and ferroptosis-targeting therapy in intestinal diseases. Understanding the involved mechanisms can provide a new understanding of intestinal disease pathogenesis and facilitate advanced preventive and therapeutic strategies for intestinal dysfunction and diseases.

Novel scorpion venom peptide HsTx2 ameliorates cerebral ischemic brain injury in rats via the MAPK signaling pathway.

Ischemic stroke is a severe threat to human health due to its high recurrence, mortality, and disability rates. As such, how to prevent and treat ischemic stroke effectively has become a research hotspot in recent years. Here, we identified a novel peptide, named HsTx2 (AGKKERAGSRRTKIVMLKCIREHGH, 2 861.855 Da), derived from the scorpion Heterometrus spinifer, which showed obvious anti-apoplectic effects in rats with ischemic stroke. Results further demonstrated that HsTx2 significantly reduced formation of infarct area and improved behavioral abnormalities in ischemic stroke rats. These protective effects were likely exerted via activation of the mitogen-activated protein kinase (MAPK) signaling pathway, i.e., up-regulation of phosphorylated ERK1/2 in both rat cerebral cortex and activated microglia (AM); up-regulation of phosphorylated p38 (p-p38) in the cerebral cortex; and inhibition of phosphorylated JNK and p-p38 levels in the AM. In conclusion, this study highlights HsTx2 as a potential neuroprotective agent for stroke.

Mesoporous polydopamine nanoparticles carrying peptide RL-QN15 show potential for skin wound therapy.

BACKGROUND: Skin wound healing remains a considerable clinical challenge, thus stressing the urgent need for the development of new interventions to promote repair. Recent researches indicate that both peptides and nanoparticles may be potential therapies for the treatment of skin wounds. METHODS: In the current study, the mesoporous polydopamine (MPDA) nanoparticles were prepared and the peptide RL-QN15 that was previously identified from amphibian skin secretions and exhibited significant potential as a novel prohealing agent was successfully loaded onto the MPDA nanoparticles, which was confirmed by results of analysis of scanning electron microscopy and fourier transform infrared spectroscopy. The encapsulation efficiency and sustained release rate of RL-QN15 from the nanocomposites were determined. The prohealing potency of nanocomposites were evaluated by full-thickness injured wounds in both mice and swine and burn wounds in mice. RESULTS: Our results indicated that, compared with RL-QN15 alone, the prohealing potency of nanocomposites of MPDA and RL-QN15 in the full-thickness injured wounds and burn wounds in mice was increased by up to 50 times through the slow release of RL-QN15. Moreover, the load on the MPDA obviously increased the prohealing activities of RL-QN15 in full-thickness injured wounds in swine. In addition, the obvious increase in the prohealing potency of nanocomposites of MPDA and RL-QN15 was also proved by the results from histological analysis. CONCLUSIONS: Based on our knowledge, this is the first research to report that the load of MPDA nanoparticles could significantly increase the prohealing potency of peptide and hence highlighted the promising potential of MPDA nanoparticles-carrying peptide RL-QN15 for skin wound therapy.

Hollow polydopamine nanoparticles loading with peptide RL-QN15: a new pro-regenerative therapeutic agent for skin wounds.

BACKGROUND: Although the treatments of skin wounds have greatly improved with the increase in therapeutic methods and agents, available interventions still cannot meet the current clinical needs. Therefore, the development of new pro-regenerative therapies remains urgent. Owing to their unique characteristics, both nanomaterials and peptides have provided novel clues for the development of pro-regenerative agents, however, more efforts were still be awaited and anticipated. RESULTS: In the current research, Hollow polydopamine (HPDA) nanoparticles were synthesized and HPDA nanoparticles loading with RL-QN15 (HPDAlR) that was an amphibian-derived peptide with obvious prohealing activities were prepared successfully. The characterization, biodistribution and clearance of both HPDA nanoparticles and HPDAlR were evaluated, the loading efficiency of HPDA against RL-QN15 and the slow-releasing rate of RL-QN15 from HPDAlR were also determined. Our results showed that both HPDA nanoparticles and HPDAlR exerted no obvious toxicity against keratinocyte, macrophage and mice, and HPDA nanoparticles showed no prohealing potency in vivo and in vitro. Interestingly, HPDAlR significantly enhanced the ability of RL-QN15 to accelerate the healing of scratch of keratinocytes and selectively modulate the release of healing-involved cytokines from macrophages. More importantly, in comparison with RL-QN15, by evaluating on animal models of full-thickness injured skin wounds in mice and oral ulcers in rats, HPDAlR showed significant increasing in the pro-regenerative potency of 50 and 10 times, respectively. Moreover, HPDAlR also enhanced the prohealing efficiency of peptide RL-QN15 against skin scald in mice and full-thickness injured wounds in swine. CONCLUSIONS: HPDA obviously enhanced the pro-regenerative potency of RL-QN15 in vitro and in vivo, hence HPDAlR exhibited great potential in the development of therapeutics for skin wound healing.

Admission blood cell counts are predictive of stroke-associated infection in acute ischemic stroke patients treated with endovascular therapy.

Stroke-associated infection (SAI) is a major medical complication in acute ischemic stroke patients (AIS) treated with endovascular therapy (EVT). Three hundred thirty-three consecutive patients with AIS caused by a large vessel occlusion in the anterior circulation who received EVT (142 (42.6%) of them were given IV tPA as bridging therapy) and 337 AIS patients who received IV tPA only (non-EVT) were enrolled in the study and evaluated to determine the association of inflammatory factors on admission with SAI. Among the 333 AIS patients undergoing EVT, SAI occurred in 219 (65.8%) patients. Patients with SAI had higher baseline National Institutes of Health Stroke Scale (NIHSS) total scores, white blood cell (WBC) and neutrophil counts, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) than those without SAI (P < 0.05). The multivariable logistic regression analyses showed that older age in addition to higher diastolic blood pressure (DBP), NIHSS score, fasting blood glucose, WBC and neutrophil counts, NLR, and PLR were significantly associated with SAI (P < 0.05). However, these associations were not revealed in 337 non-EVT AIS patients. Furthermore, based on the inflammatory markers, we developed a nomogram that provided the opportunity for more accurate predictions (compared with conventional factors) and appeared a better prognostic tool for SAI according to the decision curve analysis. In summary, if proven externally valid, our nomogram that included WBC count, NLR, and PLR may be a useful tool for SAI prediction in clinical practice.

MiR-142-3p functions as a tumor suppressor by targeting RAC1/PAK1 pathway in breast cancer.

MicroRNA-142-3p (miR-142-3p) was previously investigated in various cancers, whereas, it's role in breast cancer (BC) remains far from understood. In this study, we found that miR-142-3p was markedly decreased both in cell lines and BC tumor tissues. Elevated miR-142-3p expression suppressed growth and metastasis of BC cell lines via gain-of-function assay in vitro and in vivo. Mechanistically, miR-142-3p could regulate the ras-related C3 botulinum toxin substrate 1 (RAC1) expression in protein level, which simultaneously suppressed the epithelial-to-mesenchymal transition related protein levels and the activity of PAK1 phosphorylation, respectively. In addition, rescue experiments revealed RAC1 overexpression could reverse tumor-suppressive role of miR-142-3p. Our results showed miR-142-3p could function as a tumor suppressor via targeting RAC1/PAK1 pathway in BC, suggesting a potent therapeutic target for BC treatment.

LncRNA SATB2-AS1 inhibits tumor metastasis and affects the tumor immune cell microenvironment in colorectal cancer by regulating SATB2.

BACKGROUND: Emerging studies suggest that long non-coding RNAs (lncRNAs) play crucial roles in colorectal cancer (CRC). Here, we report a lncRNA, SATB2-AS1, which is specifically expressed in colorectal tissue and is significantly reduced in CRC. We systematically elucidated its functions and possible molecular mechanisms in CRC. METHODS: LncRNA expression in CRC was analyzed by RNA-sequencing and RNA microarrays. The expression level of SATB2-AS1 in tissues was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH). The functional role of SATB2-AS1 in CRC was investigated by a series of in vivo and in vitro assays. RNA pull-down, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), chromatin isolation by RNA purification (ChIRP), Bisulfite Sequencing PCR (BSP) and bioinformatics analysis were utilized to explore the potential mechanisms of SATB2-AS1. RESULTS: SATB2-AS1 is specifically expressed in colorectal tissues and downregulated in CRC. Survival analysis indicates that decreased SATB2-AS1 expression is associated with poor survival. Functional experiments and bioinformatics analysis revealed that SATB2-AS1 inhibits CRC cell metastasis and regulates TH1-type chemokines expression and immune cell density in CRC. Mechanistically, SATB2-AS1 directly binds to WDR5 and GADD45A, cis-activating SATB2 (Special AT-rich binding protein 2) transcription via mediating histone H3 lysine 4 tri-methylation (H3K4me3) deposition and DNA demethylation of the promoter region of SATB2. CONCLUSIONS: This study reveals the functions of SATB2-AS1 in CRC tumorigenesis and progression, suggesting new biomarkers and therapeutic targets in CRC.

Polymorphisms of IL-23R predict survival of gastric cancer patients in a Chinese population.

IL-17/IL-23 pathway has been hypothesized to play a role in occurrence and progression of gastric cancer. To investigate the susceptibility and prognostic value of polymorphisms in genes in the IL-17/IL-23 pathway to gastric cancer, we performed a case-control study combined a retrospective study in a Chinese population. The Sequenom's MassARRAY® genotyping platform was used to genotype the polymorphisms, and infection of Helicobacter pylori (H. pylori) was determined by using a commercial H. pylori immunogold testing kit. The results showed that IL-17A rs3748067 T allele carriers have a higher gastric cancer risk than non-carriers in the subgroup of individuals with age >64 years old (CT/TT vs. CC: adjusted OR = 1.55, 95% CI = 1.04-2.29). The result of prognosis shown that IL-23R rs1884444 GG and rs6682925 CC genotype were associated with unfavorable survival (rs1884444 GG vs. GT/TT: adjusted HR = 1.40, 95%CI:1.02-1.93; rs6682925 CC vs. CT/TT: HR = 1.43, 95%CI:1.06-1.92), respectively. The stratified analysis revealed that the significant association of rs1884444 was maintained in the subgroup of older than 64 years old, and that rs6682925 was associated with unfavorable survival in the subgroup of female and patients received chemotherapy. In short, we concluded two polymorphisms (rs1884444 and rs6682925) in IL-23R were associated with prognosis of gastric cancer patients.

From one to all: self-assembled theranostic nanoparticles for tumor-targeted imaging and programmed photoactive therapy.

BACKGROUND: In recent years, multifunctional theranostic nanoparticles have been fabricated by integrating imaging and therapeutic moieties into one single nano-formulations. However, Complexity of production and safety issues limits their further application. RESULTS: Herein, we demonstrated self-assembled nanoparticles with single structure as a "from one to all" theranostic platform for tumor-targeted dual-modal imaging and programmed photoactive therapy (PPAT). The nanoparticles were successfully developed through self-assembling of hyaluronic acid (HA)-cystamine-cholesterol (HSC) conjugate, in which IR780 was simultaneously incorporated (HSCI NPs). Due to the proper hydrodynamic size and intrinsic targeting ability of HA, the HSCI NPs could accumulate at the tumor site effectively after systemic administration. In the presence of incorporated IR780, in vivo biodistribution and accumulation behaviors of HSCI NPs could be monitored by photoacoustic imaging. After cellular uptake, the HSCI NPs would disintegrate resulting from cystamine reacting with over-expressed GSH. The released IR780 would induce fluorescence "turn-on" conversion, which could be used to image tumor sites effectively. Upon treatment with 808 nm laser irradiation, PPAT could be achieved in which generated reactive oxygen species (ROS) would produce photodynamic therapy (PDT), and subsequently the raised temperature would be beneficial to tumor photothermal therapy (PTT). CONCLUSION: The self-assembled HSCI NPs could act as "from one to all" theranostic platform for high treatment efficiency via PPAT pattern, which could also real-time monitor NPs accumulation by targeted and dual-modal imaging in a non-invasive way.

Establishment and evaluation of a model for predicting 3-month mortality in Chinese patients with hepatic encephalopathy.

Hepatic encephalopathy (HE) is a serious complication of liver disease. To establish a model for predicting 3-month mortality in patients with HE in China. This retrospective study included 609 patients with HE admitted to the Peoples' Hospital, Liaocheng City, China (August 2006 to January 2016). Patients were allocated to a modeling (n = 409) or validation (n = 200) group. Demographic/clinical characteristics, laboratory test results, Model for End Stage Liver Disease (MELD) score and Child-Turcotte-Pugh (CTP) score were extracted from medical records. A model for predicting death within 3 months after admission was established using logistic regression analysis (modeling group). Model validity (validation group) was assessed using receiver operating characteristic (ROC) curve analysis. 270/409(66.0%) patients died in the modeling group and 142/203(70.0%) died in the validation group. Compared with survivors, patients who died had more severe HE, and higher MELD score, CTP score, incidence of complications including hepatorenal syndrome (HRS) and upper gastrointestinal bleeding, and values for laboratory parameters including red blood cell count(RBC) and total bilirubin(TBIL)(P < 0.05). Regression analysis revealed RBC, TBIL, HE stage, HRS and upper gastrointestinal bleeding as independent factors associated with death (P < 0.05). The area under the ROC curve (AUC) for the model was 0.931.The model had a higher Youden index than MELD or CTP scores and predicted death in the validation group with a sensitivity of 83.1% and specificity of 93.4%. The established model has superior performance to MELD and CTP scores for predicting mortality in patients with HE.

Leachability of heavy metals in loess-amended dredged sediment from Northwest of China.

Considerable studies have been done on heavy metal removing from aqueous solutions using loess. However, application of loess to heavy metal contaminated sediment is limited. The present study was to determine the effectiveness of loess to immobilize Cu, Zn, Cd and Pb in sediment. The loess was incubated with 10 kg wet sediment in doses of 0, 0.5, 1, 2, 5, 10 and 20 kg for 70 d and then subjected to the toxicity characteristic leaching procedure (TCLP). The possible mechanisms for heavy metal immobilization were illustrated using X-ray diffraction and scanning electron microscope. Results from TCLP confirmed loess reduced leaching rate of Cu and Zn achieving up to 42.4% and 17.6% reductions, respectively, when compared with untreated sediment. The loess could significantly immobilize Cu and Zn in sediment, and the optimum dose of loess in 10 kg wet sediment was 5 kg. However, loess was inefficient for Cd and Pb immobilization. Correlation analysis showed that TCLP extraction method could be used to predict the toxicity of Cu, Zn, Cd and Pb in the loess-amended sediment. The pH, EC, OM and CaCO3 of the loess-amended sediment played predominant roles in the TCLP leaching test.

The long noncoding RNA SNHG1 regulates colorectal cancer cell growth through interactions with EZH2 and miR-154-5p.

BACKGROUND: Mounting evidence demonstrates that long noncoding RNAs (lncRNAs) have critical roles during the initiation and progression of cancers. In this study, we report that the small nucleolar RNA host gene 1 (SNHG1) is involved in colorectal cancer progression. METHODS: We analyzed RNA sequencing data to explore abnormally expressed lncRNAs in colorectal cancer. The effects of SNHG1 on colorectal cancer were investigated through in vitro and in vivo assays (i.e., CCK-8 assay, colony formation assay, flow cytometry assay, EdU assay, xenograft model, immunohistochemistry, and western blot). The mechanism of SNHG1 action was explored through bioinformatics, RNA fluorescence in situ hybridization, luciferase reporter assay, RNA pull-down assay, chromatin immunoprecipitation assay and RNA immunoprecipitation assay. RESULTS: Our analysis revealed that SNHG1 was upregulated in human colorectal cancer tissues, and high SNHG1 expression was associated with reduced patient survival. We also found that high SNHG1 expression was partly induced by SP1. Moreover, SNHG1 knockdown significantly repressed colorectal cancer cells growth both in vitro and in vivo. Mechanistic investigations demonstrated that SNHG1 could directly interact with Polycomb Repressive Complex 2 (PRC2) and modulate the histone methylation of promoter of Kruppel like factor 2 (KLF2) and Cyclin dependent kinase inhibitor 2B (CDKN2B) in the nucleus. In the cytoplasm, SNHG1 acted as a sponge for miR-154-5p, reducing its ability to repress Cyclin D2 (CCND2) expression. CONCLUSIONS: Taken together, the results of our studies illuminate how SNHG1 formed a regulatory network to confer an oncogenic function in colorectal cancer and suggest that SNHG1 may serve as a potential target for colorectal cancer diagnosis and treatment.

The pro-metastasis effect of circANKS1B in breast cancer.

BACKGROUND: Recent studies indicate that circular RNA (circRNA) plays a pivotal role in cancer progression. Here, we sought to investigate its role in breast cancer. METHODS: CircANKS1B (a circRNA originated from exons 5 to 8 of the ANKS1B gene, hsa_circ_0007294) was identified by RNA-sequencing and validated by qRT-PCR and Sanger sequencing. Clinical breast cancer samples were used to evaluate the expression of circANKS1B and its associations with clinicopathological features and prognosis. Gain- and loss-of-function experiments in cell lines and mouse xenograft models were performed to support clinical findings and elucidate the function and underlying mechanisms of circANKS1B in breast cancer. RESULTS: CircANKS1B was significantly up-regulated in triple-negative breast cancer (TNBC) compared with non-TNBC tissues and cell lines. Increased circANKS1B expression was closely associated with lymph node metastasis and advanced clinical stage and served as an independent risk factor for overall survival of breast cancer patients. Functional studies revealed that circANKS1B promoted breast cancer invasion and metastasis both in vitro and in vivo by inducing epithelial-to-mesenchymal transition (EMT), while had no effect on breast cancer growth. Mechanistically, circANKS1B abundantly sponged miR-148a-3p and miR-152-3p to increase the expression of transcription factor USF1, which could transcriptionally up-regulate TGF-ß1 expression, resulting in activating TGF-ß1/Smad signaling to promote EMT. Moreover, we found that circANKS1B biogenesis in breast cancer was promoted by splicing factor ESRP1, whose expression was also regulated by USF1. CONCLUSIONS: Our data uncover an essential role of the novel circular RNA circANKS1B in the metastasis of breast cancer, which demonstrate that therapeutic targeting of circANKS1B may better prevent breast cancer metastasis.