YAP1-CPNE3 positive feedback pathway promotes gastric cancer cell progression.

Hippo-Yes-associated protein 1 (YAP1) plays an important role in gastric cancer (GC) progression; however, its regulatory network remains unclear. In this study, we identified Copine III (CPNE3) was identified as a novel direct target gene regulated by the YAP1/TEADs transcription factor complex. The downregulation of CPNE3 inhibited proliferation and invasion, and increased the chemosensitivity of GC cells, whereas the overexpression of CPNE3 had the opposite biological effects. Mechanistically, CPNE3 binds to the YAP1 protein in the cytoplasm, inhibiting YAP1 ubiquitination and degradation mediated by the E3 ubiquitination ligase ß-transducin repeat-containing protein (ß-TRCP). Thereby activating the transcription of YAP1 downstream target genes, which creates a positive feedback cycle to facilitate GC progression. Immunohistochemical analysis demonstrated significant upregulation of CPNE3 in GC tissues. Survival and Cox regression analyses indicated that high CPNE3 expression was an independent prognostic marker for GC. This study elucidated the pivotal involvement of an aberrantly activated CPNE3/YAP1 positive feedback loop in the malignant progression of GC, thereby uncovering novel prognostic factors and therapeutic targets in GC.

TMEM160 promotes tumor immune evasion and radiotherapy resistance via PD-L1 binding in colorectal cancer.

BACKGROUND: The effectiveness of anti-programmed cell death protein 1(PD-1)/programmed cell death 1 ligand 1(PD-L1) therapy in treating certain types of cancer is associated with the level of PD-L1. However, this relationship has not been observed in colorectal cancer (CRC), and the underlying regulatory mechanism of PD-L1 in CRC remains unclear. METHODS: Binding of TMEM160 to PD-L1 was determined by co-immunoprecipitation (Co-IP) and GST pull-down assay.The ubiquitination levels of PD-L1 were verified using the ubiquitination assay. Phenotypic experiments were conducted to assess the role of TMEM160 in CRC cells. Animal models were employed to investigate how TMEM160 contributes to tumor growth.The expression and clinical significance of TMEM160 and PD-L1 in CRC tissues were evaluated by immunohistochemistry(IHC). RESULTS: In our study, we made a discovery that TMEM160 interacts with PD-L1 and plays a role in stabilizing its expression within a CRC model. Furthermore, we demonstrated that TMEM160 hinders the ubiquitination-dependent degradation of PD-L1 by competing with SPOP for binding to PD-L1 in CRC cells. Regarding functionality, the absence of TMEM160 significantly inhibited the proliferation, invasion, metastasis, clonogenicity, and radioresistance of CRC cells, while simultaneously enhancing the cytotoxic effect of CD8 + T cells on tumor cells. Conversely, the upregulation of TMEM160 substantially increased these capabilities. In severely immunodeficient mice, tumor growth derived from lentiviral vector shTMEM160 cells was lower compared with that derived from shNC control cells. Furthermore, the downregulation of TMEM160 significantly restricted tumor growth in immune-competent BALB/c mice. In clinical samples from patients with CRC, we observed a strong positive correlation between TMEM160 expression and PD-L1 expression, as well as a negative correlation with CD8A expression. Importantly, patients with high TMEM160 expression exhibited a worse prognosis compared with those with low or no TMEM160 expression. CONCLUSIONS: Our study reveals that TMEM160 inhibits the ubiquitination-dependent degradation of PD-L1 that is mediated by SPOP, thereby stabilizing PD-L1 expression to foster the malignant progress, radioresistance, and immune evasion of CRC cells. These findings suggest that TMEM160 holds potential as a target for the treatment of patients with CRC.

Application of postmortem computed tomography angiography to settle a medical dispute after aortic dissection surgery: a forensic case report.

BACKGROUND: In the present case, we applied postmortem computed tomography angiography (PMCTA) in a medical dispute involving sudden death after cardiovascular surgery. CASE PRESENTATION: A 39-year-old man underwent aortic arch replacement combined with stented elephant trunk implantation surgery under extracorporeal circulation. All vital signs were stable and he was arranged for discharge seven days after surgery. Several days later, the patient was sent back to the hospital for chest pain and poor appetite. Unfortunately, his condition worsened and he ultimately died. PMCT scanning detect pericardial effusion. Family members suspected that the surgical sutures were not dense enough, causing the patient's postoperative bleeding and resulting in cardiac tamponade and death. PMCTA was performed before autopsy, which showed pericardial effusion. However, postmortem angiography with simulated blood pressure showed no leakage of contrast agent, which guided the subsequent autopsy and histological examinations. CONCLUSIONS: While many previous postmortem imaging case reports have shown positive results that provided evidence of medical malpractice, the current case excludes the possibility of physician negligence and reasonably settles the medical dispute from another perspective. In short, the PMCTA approach we describe here was an effective tool that can be applied to certain medical-related forensic cases.

Unleashing the potential of combining FGFR inhibitor and immune checkpoint blockade for FGF/FGFR signaling in tumor microenvironment.

BACKGROUND: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play a crucial role in cell fate and angiogenesis, with dysregulation of the signaling axis driving tumorigenesis. Therefore, many studies have targeted FGF/FGFR signaling for cancer therapy and several FGFR inhibitors have promising results in different tumors but treatment efficiency may still be improved. The clinical use of immune checkpoint blockade (ICB) has resulted in sustained remission for patients. MAIN: Although there is limited data linking FGFR inhibitors and immunotherapy, preclinical research suggest that FGF/FGFR signaling is involved in regulating the tumor microenvironment (TME) including immune cells, vasculogenesis, and epithelial-mesenchymal transition (EMT). This raises the possibility that ICB in combination with FGFR-tyrosine kinase inhibitors (FGFR-TKIs) may be feasible for treatment option for patients with dysregulated FGF/FGFR signaling. CONCLUSION: Here, we review the role of FGF/FGFR signaling in TME regulation and the potential mechanisms of FGFR-TKI in combination with ICB. In addition, we review clinical data surrounding ICB alone or in combination with FGFR-TKI for the treatment of FGFR-dysregulated tumors, highlighting that FGFR inhibitors may sensitize the response to ICB by impacting various stages of the "cancer-immune cycle".

Pan-cancer analysis reveals potential of FAM110A as a prognostic and immunological biomarker in human cancer.

Background: Despite great success, immunotherapy still faces many challenges in practical applications. It was previously found that family with sequence similarity 110 member A (FAM110A) participate in the regulation of the cell cycle and plays an oncogenic role in pancreatic cancer. However, the prognostic value of FAM110A in pan-cancer and its involvement in immune response remain unclear. Methods: The Human Protein Atlas (HPA) database was used to detect the expression of FAM110A in human normal tissues, the Tumor Immune Estimation Resource (TIMER) and TIMER 2.0 databases were used to explore the association of FAM110A expression with immune checkpoint genes and immune infiltration, and the Gene Set Cancer Analysis (GSCA) database was used to explore the correlation between FAM110A expression and copy number variations (CNV) and methylation. The LinkedOmics database was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Statistical analysis and visualization of data from the The Cancer Genome Atlas (TCGA) or the Genotype-Tissue Expression (GTEx) databases were performed using the R software (version 3.6.3). Clinical samples were validated using immunohistochemistry. Results: FAM110A expression was elevated in most tumor tissues compared with that in normal tissues. CNV and methylation were associated with abnormal FAM110A mRNA expression in tumor tissues. FAM110A affected prognosis and was associated with the expression of multiple immune checkpoint genes and abundance of tumor-infiltrating immune cells across multiple types of cancer, especially in liver hepatocellular carcinoma (LIHC). FAM110A-related genes were involved in multiple immune-related processes in LIHC. Conclusion: FAM110A participates in regulating the immune infiltration and affecting the prognosis of patients in multiple cancers, especially in LIHC. FAM110A may serve as a prognostic and immunological biomarker for human cancer.

Diversified access to di- and trisubstituted allenes via nickel-catalysed reactions of 1,3-enynes with alkyl N-hydroxyphthalimide esters.

Herein, a new nickel-catalysed protocol for the preparation of di- and trisubstituted allenes has been successfully developed via the reactions of 1,3-enynes with alkyl N-hydroxyphthalimide esters. The new method based on a reductive radical-polar crossover (RPC) process features broad substrate scope, wide functional group tolerance, and a simple catalyst system. The late-stage allenylation of drugs has also been illustrated.

Electrically Copolymerized Polydopamine Melanin/Poly(3,4-ethylenedioxythiophene) Applied for Bioactive Multimodal Neural Interfaces with Induced Pluripotent Stem Cell-Derived Neurons.

Multimodal neural interfaces include combined functions of electrical neuromodulation and synchronic monitoring of neurochemical and physiological signals in one device. The remarkable biocompatibility and electrochemical performance of polystyrene sulfonate-doped poly(3,4-ethylenedioxythiophene) (PEDOT:PSS) have made it the most recommended conductive polymer neural electrode material. However, PEDOT:PSS formed by electrochemical deposition, called PEDOT/PSS, often need multiple doping to improve structural instability in moisture, resolve the difficulties of functionalization, and overcome the poor cellular affinity. In this work, inspired by the catechol-derived adhesion and semiconductive properties of polydopamine melanin (PDAM), we used electrochemical oxidation polymerization to develop PDAM-doped PEDOT (PEDOT/PDAM) as a bioactive multimodal neural interface that permits robust electrochemical performance, structural stability, analyte-trapping capacity, and neural stem cell affinity. The use of potentiodynamic scans resolved the problem of copolymerizing 3,4-ethylenedioxythiophene (EDOT) and dopamine (DA), enabling the formation of PEDOT/PDAM self-assembled nanodomains with an ideal doping state associated with remarkable current storage and charge transfer capacity. Owing to the richness of hydrogen bond donors/acceptors provided by the hydroxyl groups of PDAM, PEDOT/PDAM presented better electrochemical and mechanical stability than PEDOT/PSS. It has also enabled high sensitivity and selectivity in the electrochemical detection of DA. Different from PEDOT/PSS, which inhibited the survival of human induced pluripotent stem cell-derived neural progenitor cells, PEDOT/PDAM maintained cell proliferation and even promoted cell differentiation into neuronal networks. Finally, PEDOT/PDAM was modified on a commercialized microelectrode array system, which resulted in the reduction of impedance by more than one order of magnitude; this significantly improved the resolution and reduced the noise of neuronal signal recording. With these advantages, PEDOT/PDAM is anticipated to be an efficient bioactive multimodal neural electrode material with potential application to brain-machine interfaces.

USP49 mediates tumor progression and poor prognosis through a YAP1-dependent feedback loop in gastric cancer.

The importance of the Hippo-Yes-associated protein 1 (YAP1) pathway in gastric carcinogenesis and metastasis has attracted considerable research attention; however, the regulatory network of YAP1 in gastric cancer (GC) is not completely understood. In this study, ubiquitin-specific peptidase 49 (USP49) was identified as a novel deubiquitinase of YAP1, knockdown of USP49 inhibited the proliferation, metastasis, chemoresistance, and peritoneal metastasis of GC cells. Overexpression of USP49 showed opposing biological effects. Moreover, USP49 was transcriptionally activated by the YAP1/TEAD4 complex, which formed a positive feedback loop with YAP1 to promote the malignant progression of GC cells. Finally, we collected tissue samples and clinical follow-up information from 482 GC patients. The results showed that USP49 expression was high in GC cells and positively correlated with the expression of YAP1 and its target genes, connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61). Survival and Cox regression analysis showed that high USP49 expression was associated with poor prognosis and was an independent prognostic factor. Moreover, patients with high USP49 and YAP1 expression had extremely short overall survival. The findings of this study reveal that the aberrant activation of the USP49/YAP1 positive feedback loop plays a critical role in the malignant progression of GC, thus providing potential novel prognostic factors and therapeutic targets for GC.

Modular access to 1,2-allenyl ketones based on a photoredox-catalysed radical-polar crossover process.

Herein, a new protocol dealing with the preparation of 1,2-allenyl ketones has been successfully developed via the reactions of enynes with radicals enabled by dual photoredox/copper catalysis. Based on the results of a deuteration experiment and the competition reaction between cyclopropanation and allenation, the mechanism based on a photoredox-neutral-catalysed radical-polar crossover process has been proposed. Synthetic applications of allenes have also been demonstrated.

Protective effect of Phaeoporus obliquus polysaccharide against acute liver injury induced by carbon tetrachloride and alcohol in mice.

Studied the optimum extraction process of polysaccharide from Phaeoporus obliquus and the effect of Phaeoporus obliquus polysaccharide on carbon tetrachloride (CCl4)- or alcohol-induced acute liver injury in mice. The main factor in influencing the extraction rate of Phaeoporus obliquus polysaccharide were extraction power and time, which was a kind of pyran glucose by infrared spectroscopy. CCl4 and alcohol were employed respectively to establish CCl4 and alcohol-induced acute liver injury mouse models. Compared with model groups mice, Phaeoporus obliquus polysaccharide treatment at the doses of 100mg/kg and 200mg/kg exhibited an obvious reduction liver index, ALP, ALT, AST levels, MDA content and TNF-α level (p<0.01) and SOD activity was increased, which was in a dose-dependent manner. Compared with the model group, the necrosis degree of hepatocytes was obviously reduced and the small fat droplets were formed in some cytoplasm, especially in high dose group, which the liver cells recovered to the level of normal group. Rt-PCR results showed that the expression of CYP2E1 mRNA in liver tissues of Phaeoporus obliquus polysaccharide groups were significantly reduced, and the difference were statistically significant compared with the model group (p<0.05). These results demonstrated that Phaeoporus obliquus polysaccharide has significantly hepatoprotective effect on CCl4 and alcohol-induced acute liver injury in mice.

Synovial and pulmonary dysfunctions are induced by crosstalk of Smad and Erk pathways in an arthritis model.

In the current experiment, the effects of transforming growth factor (TGF)-ß1/Smad and ERK pathway crosstalk on synovial and pulmonary systems during rheumatoid arthritis have been investigated. For this purpose, rats were divided into normal control (NC) and model control (MC) groups. In the MC group, 0.1 ml Freund's complete adjuvant was injected intradermally into the right hind paw, and the resulting inflammation represented a rheumatoid arthritis model. Joint swelling and changes in lung functions were observed in arthritic rats. Synovial and lung were observed by light and electron microscopies. Enzyme-linked immunosorbent assays were used to detect TGF-ß1, interleukin (IL)-1ß, IL-4, IL-10, interferon-γ (IFN-γ), connective tissue growth factor (CTGF), and fibroblast growth factor (FGF). PCR, immunohistochemistry, and immunoblotting were used to detect changes in Smad and ERK pathways of synovial and lung tissues. Compared with the NC group, toe swelling was elevated in the MC group. Pulmonary functions FEV1, FEF50, FEF75, MMF, and PEF were decreased (P< 0.01). Serum cytokines IL-1ß, IL-4, TGF-ß1, and CTGF were increased, while IFN-γ, IL-10, Th1/Th2 cell ratio, and FGF were decreased (P< 0.01 or P< 0.05). Expression of TGF-ß1 and Smad2/3/4 mRNAs and TGF-ß1, TßRI, TßRII, Smad2/3, p-Smad2/3, and Smad4 proteins in the synovial membrane and lung tissue were increased, and expression of Smad7 mRNA and protein was decreased (P<0.01) or P<0.05). Expression of ERK2 mRNA and p-ERK1/2 protein was increased in the synovial membrane and lung tissue, and expression of ERK1/2 mRNAs and ERK1/2 and p-ERK1/2 proteins was increased in lung tissue (P< 0.01 or P< 0.05). Correlation analysis showed that FEV1 was negatively correlated with TGF-ß1 mRNA and protein in arthritic rats, FEF25 was negatively correlated with Smad4 protein, and FEF50 was negatively correlated with the TßRII protein, and FEF75, TGF-ß1 and Smad3 mRNAs. There was a negative correlation between Smad2/3 protein and a negative correlation between PEF and TGF-ß1 protein (P< 0.05). FEF50 and MMF were positively correlated with Smad7 mRNA (P< 0.05). FEV1 was negatively correlated with ERK2 mRNA, and FEF25 was negatively correlated with p-ERK1/2 protein. FEF75 and MMF were negatively correlated with ERK1/2 and p-ERK1/2, respectively (P< 0.05). ERK1 mRNA was positively correlated with Smad3 mRNA and TßRII protein, ERK2 mRNA was positively correlated with p-Smad2/3, and ERK1/2 protein was positively correlated with Smad2 mRNA, Smad4 protein, p-ERK1/2 protein, Smad4 mRNA, and p-Smad2/3 protein (P< 0.05). p-ERK1/2 protein was negatively correlated with Smad7 protein (P< 0.05). It is concluded that arthritic rats have synovial and systemic pulmonary damage. Smad and ERK pathway crosstalk leads to systemic lesions. Smad and ERK pathways are gradually activated by phosphorylation under the induction of the TGF-ß1 promoter, and then participate in transcriptional activities, leading to the increase in synovial inflammation of arthritis, pulmonary lesions, and decreases in lung functions.

Characteristic response of striatal astrocytes to dopamine depletion.

Astrocytes and astrocyte-related proteins play important roles in maintaining normal brain function, and also regulate pathological processes in brain diseases and injury. However, the role of astrocytes in the dopamine-depleted striatum remains unclear. A rat model of Parkinson's disease was therefore established by injecting 10 µL 6-hydroxydopamine (2.5 µg/µL) into the right medial forebrain bundle. Immunohistochemical staining was used to detect the immunoreactivity of glial fibrillary acidic protein (GFAP), calcium-binding protein B (S100B), and signal transducer and activator of transcription 3 (STAT3) in the striatum, and to investigate the co-expression of GFAP with S100B and STAT3. Western blot assay was used to measure the protein expression of GFAP, S100B, and STAT3 in the striatum. Results demonstrated that striatal GFAP-immunoreactive cells had an astrocytic appearance under normal conditions, but that dopamine depletion induced a reactive phenotype with obvious morphological changes. The normal striatum also contained S100B and STAT3 expression. S100B-immunoreactive cells were uniform in the striatum, with round bodies and sparse, thin processes. STAT3-immunoreactive cells presented round cell bodies with sparse processes, or were darkly stained with a large cell body. Dopamine deprivation induced by 6-hydroxydopamine significantly enhanced the immunohistochemical positive reaction of S100B and STAT3. Normal striatal astrocytes expressed both S100B and STAT3. Striatal dopamine deprivation increased the number of GFAP/S100B and GFAP/STAT3 double-labeled cells, and increased the protein levels of GFAP, S100B, and STAT3. The present results suggest that morphological changes in astrocytes and changes in expression levels of astrocyte-related proteins are involved in the pathological process of striatal dopamine depletion. The study was approved by Animal Care and Use Committee of Sun Yat-sen University, China (Zhongshan Medical Ethics 2014 No. 23) on September 22, 2014.

Genomic profiling in amyloid light-chain amyloidosis reveals mutation profiles associated with overall survival.

Background: Amyloid light chain (AL) amyloidosis is characterized by tissue deposition of amyloid fibres derived from immunoglobulin that can lead to irreversible organ damage. Information about genomic profiles of AL amyloidosis is lacking.Methods: In this study, we adopted a two-step strategy to investigate the mutational profile of AL amyloidosis bone marrow plasma cells (PCs) and their clinical implications. In step one, whole-exome sequencing was performed in bone marrow PCs and paired with normal tissue from 10 AL amyloidosis patients, by which we identified 10 significantly mutated genes (SMGs). In step two, we constituted a targeted gene sequencing (TGS) panel covering the frequently mutated genes identified in step one, genes reported in prior AL amyloidosis studies, and known cancer driver mutations. Then, we analysed an expanded cohort of AL amyloidosis patients (N = 48) with this panel comprising 98 genes.Results: Four recurrent mutations were identified by TGS and verified by Sanger sequencing: ASB15 (c. 844 C > T), ASCC3 (c. 1595 A > G), HIST1H1E (c. 311 C > T) and KRAS (c. 35 G > A), among which the first three mutations were associated with inferior overall survival (OS). Additionally, we found that the number of mutations identified by the TGS panel of 98 genes could be a prognostic predictor for OS.Conclusions: In summary, we revealed genomic profiling in AL amyloidosis and found mutation profiles associated with OS.

The efficacy of computerized cognitive drill and practice training for patients with a schizophrenia-spectrum disorder: A meta-analysis.

BACKGROUND: Computerized methods for improving cognitive functioning in schizophrenia have gained popularity during the past decades. Therefore, this study evaluates the available evidence for the efficacy of computerized cognitive drill and practice training for patients with schizophrenia-spectrum disorders. METHODS: A systematic search was carried out using PubMed, Embase, Cochrane Database of Systematic Reviews, and PsycINFO. A meta-analysis was performed to compare cognitive drill and practice training in patients with a schizophrenia-spectrum disorder with non-cognitively oriented control conditions. The primary outcome was cognitive functioning. Secondary outcome measures included psychotic symptoms, depressive symptoms, and functional outcomes. Effect sizes (ES) for all included studies were calculated as Hedges' g. RESULTS: 24 studies were included with 1262 patients in total. Compared to a control condition, patients receiving computerized cognitive drill and practice training showed significantly more improvement on attention (ES = 0.31, p = 0.001), working memory (ES = 0.38, p < 0.001), positive symptoms (ES = 0.31, p = 0.003), and depressive symptoms (ES = 0.37, p = 0.002). Small, marginally significant effect sizes were found for processing speed, verbal and visual learning and memory, and verbal fluency. However, significant effects on functional outcomes and social cognition were absent. DISCUSSION: The current study showed evidence for the efficacy of computerized cognitive drill and practice training in patients with schizophrenia-spectrum disorders. However, the absence of effects on social cognition and functional outcomes questions the generalization of treatment effects. Together, these results stimulate further development of computerized training programs for schizophrenia that not only improve cognitive functioning, but also generalize cognitive improvement to functional outcomes.

LINC00662 promotes gastric cancer cell growth by modulating the Hippo-YAP1 pathway.

Long non-coding RNAs (lncRNAs) function as vital regulators of the progression of various diseases, particularly cancers. In the present study, utilizing the Cancer Genome Atlas (TCGA) data set and a series of cell experiments and clinical tissue samples assays, we found that LINC00662 expression was significantly up-regulated in gastric cancer (GC) tissues and cell lines. High expression of LINC00662 predicted poor prognosis compared to in patients showing low expression. Knockdown of LINC00662 expression decreased GC cell proliferation and increased the chemo-sensitivity of GC cells. Further, we demonstrated that knockdown of LINC00662 suppressed the Hippo-YAP1 signaling pathway in GC cells. Mechanistically, LINC00662 regulated YAP1-mediated GC cell proliferation by sponging miR-497-5p. Overall, our results revealed a critical role for the LINC00662-miR-497-5p-YAP1 axis in GC cell growth, providing a new target for GC.

Efficacy of different types of cognitive enhancers for patients with schizophrenia: a meta-analysis.

Cognitive impairment is a core feature of schizophrenia, which is predictive for functional outcomes and is, therefore, a treatment target in itself. Yet, literature on efficacy of different pharmaco-therapeutic options is inconsistent. This quantitative review provides an overview of studies that investigated potential cognitive enhancers in schizophrenia. We included pharmacological agents, which target different neurotransmitter systems and evaluated their efficacy on overall cognitive functioning and seven separate cognitive domains. In total, 93 studies with 5630 patients were included. Cognitive enhancers, when combined across all different neurotransmitter systems, which act on a large number of different mechanisms, showed a significant (yet small) positive effect size of 0.10 (k = 51, p = 0.023; 95% CI = 0.01 to 0.18) on overall cognition. Cognitive enhancers were not superior to placebo for separate cognitive domains. When analyzing each neurotransmitter system separately, agents acting predominantly on the glutamatergic system showed a small significant effect on overall cognition (k = 29, Hedges' g = 0.19, p = 0.01), as well as on working memory (k = 20, Hedges' g = 0.13, p = 0.04). A sub-analysis of cholinesterase inhibitors (ChEI) showed a small effect on working memory (k = 6, Hedges' g = 0.26, p = 0.03). Other sub-analyses were positively nonsignificant, which may partly be due to the low number of studies we could include per neurotransmitter system. Overall, this meta-analysis showed few favorable effects of cognitive enhancers for patients with schizophrenia, partly due to lack of power. There is a lack of studies involving agents acting on other than glutamatergic and cholinergic systems, especially of those targeting the dopaminergic system.

The effect of raloxifene augmentation in men and women with a schizophrenia spectrum disorder: a systematic review and meta-analysis.

Recognizing the robust sex differences in schizophrenia prevalence, the selective estrogen receptor modulator (SERM) raloxifene is a likely candidate for augmentation therapy in this disorder. Therefore, a systematic search was performed using PubMed (Medline), Embase, PsychInfo, and Cochrane Database of Systematic Reviews. Randomized controlled trials investigating the effect of raloxifene in schizophrenia spectrum disorders were included in the quantitative analyses. Outcome measures were psychotic symptom severity, depression, and cognition. Meta-analyses were performed using Comprehensive Meta-Analysis software. A random-effects model was used to compute overall weighted effect sizes in Hedges' g. Nine studies were included, investigating 561 patients with a schizophrenia spectrum disorder. Raloxifene was superior to placebo in improving total symptom severity (N = 482; Hedge's g = .57, p = 0.009), as well as positive (N = 561; Hedge's g = 0.32, p = 0.02), negative (N = 561; Hedge's g = 0.40, p = 0.02), and general (N = 526; Hedge's g = 0.46, p = 0.01) subscales, as measured by the Positive and Negative Syndrome Scale. No significant effects were found for comorbid depression and cognitive functioning. Altogether, these results confirm the potential of raloxifene augmentation in the treatment of schizophrenia.

Enhanced efficacy of curcumin with phosphatidylserine-decorated nanoparticles in the treatment of hepatic fibrosis.

Hepatic macrophages have been considered as a therapeutic target for liver fibrosis treatment, and phosphatidylserine (PS)-containing nanoparticles are commonly used to mimic apoptotic cells that can specifically regulate macrophage functions, resulting in anti-inflammatory effects. This study was designed to test the efficacy of PS-modified nanostructured lipid carriers (mNLCs) containing curcumin (Cur) (Cur-mNLCs) in the treatment of liver fibrosis in a rat model. Carbon tetrachloride-induced liver fibrosis in rats was used as an experimental model, and the severity of the disease was examined by both biochemical and histological methods. Here, we showed that mNLCs were spherical nanoparticles with decreased negative zeta potentials due to PS decoration, and significantly increased both mean residence time and area under the curve of Cur. In the rats with liver fibrosis, PS-modification of NLCs enhanced the nanoparticles targeting to the diseased liver, which was evidenced by their highest accumulation in the liver. As compared to all the controls, Cur-mNLCs were significantly more effective at reducing the liver damage and fibrosis, which were indicated by in Cur-mNLCs-treated rats the least increase in liver enzymes and pro-inflammatory cytokines in the circulation, along with the least increase in collagen fibers and alpha smooth muscle actin and the most increased hepatocyte growth factors (HGF) and matrix metalloprotease (MMP) two in the livers. In conclusion, PS-modified NLCs nanoparticles prolonged the retention time of Cur, and enhanced its bioavailability and delivery efficiency to the livers, resulting in reduced liver fibrosis and up-regulating hepatic expression of HGF and MMP-2.

A high-sensitivity electrochemical aptasensor of carcinoembryonic antigen based on graphene quantum dots-ionic liquid-nafion nanomatrix and DNAzyme-assisted signal amplification strategy.

In this work, we have developed an electrochemical aptasensor for high-sensitivity determination of carcinoembryonic antigen (CEA) based on lead ion (Pb2+)-dependent DNAzyme-assisted signal amplification and graphene quantum dot-ionic liquid-nafion (GQDs-IL-NF) composite film. We designed hairpin DNA containing CEA-specific aptamers and DNAzyme chains. In the presence of CEA, hairpin DNA recognized the target and performed a DNAzyme-assisted signal amplification reaction to yield a large number of single-stranded DNA. The GQDs-IL-NF composite film was immobilized on the glassy carbon electrode for the interaction with single-stranded DNA through noncovalent π-π stacking interaction. Therefore, the methylene blue-labeled substrate DNA (MB-substrate) was fixed on the electrode and exhibited an initial electrochemical signal. Under optimal conditions, the response current change was proportional to the concentration of CEA, demonstrating a wide linear range from 0.5fgmL-1 to 0.5ngmL-1, with a low detection limit of 0.34fgmL-1. Furthermore, the proposed aptasensor was successfully applied in determining CEA in serum samples, showing its superior prospects in clinical diagnosis.

Activation of RAGE/STAT3 pathway by methylglyoxal contributes to spinal central sensitization and persistent pain induced by bortezomib.

Bortezomib is a first-line chemotherapeutic drug widely used for multiple myeloma and other nonsolid malignancies. Although bortezomib-induced persistent pain is easily diagnosed in clinic, the pathogenic mechanism remains unclear. Here, we studied this issue with use of a rat model of systemic intraperitoneal administration of bortezomib for consecutive 5days. Consisted with our previous study, we found that bortezomib treatment markedly induced mechanical allodynia in rats. Furthermore, we first found that bortezomib treatment significantly induced the upregulation of methylglyoxal in spinal dorsal horn of rats. Spinal local application of methylglyoxal also induced mechanical allodynia and central sensitization in normal rats. Moreover, administration of bortezomib upregulated the expression of receptors for advanced glycation end products (RAGE) and phosphorylated STAT3 (p-STAT3) in dorsal horn. Importantly, intrathecal injection of metformin, a known scavenger of methylglyoxal, significantly attenuated the upregulation of methylglyoxal and RAGE in dorsal horn, central sensitization and mechanical allodynia induced by bortezomib treatment, and blockage of RAGE also prevented the upregulation of p-STAT3, central sensitization and mechanical allodynia induced by bortezomib treatment. In addition, inhibition of STAT3 activity by S3I-201 attenuated bortezomib-induced mechanical allodynia and central sensitization. Local knockdown of STAT3 also ameliorated the mechanical allodynia induced by bortezomib administration. Our results suggest that accumulation of methylglyoxal may activate the RAGE/STAT3 signaling pathway in dorsal horn, and contributes to the spinal central sensitization and persistent pain induced by bortezomib treatment.