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TNF signalling was reported to mediate resistance to EGFR inhibition in non-small cell lung cancer (NSCLC). Here, the authors examine the efficacy of a broad versus focused targeting of this resistance, and they show that a broad inhibitor of inflammation, prednisone is the most effective.

Tumor necrosis factor (TNF) and its receptors are widely expressed in non-small cell lung cancer (NSCLC). TNF has an established role in inflammation and also plays a key role in inflammation-induced cancer. TNF can induce cell death in cancer cells and has been used as a treatment in certain types of cancer. However, TNF is likely to play an oncogenic role in multiple types of cancer, including NSCLC. TNF is a key activator of the transcription factor NF-κB. NF-κB, in turn, is a key effector of TNF in inflammation-induced cancer. Data from The Cancer Genome Atlas database suggest that TNF could be a biomarker in NSCLC and indicate a complex role for TNF and its receptors in NSCLC. Recent studies have reported that TNF is rapidly upregulated in NSCLC in response to targeted treatment with epidermal growth factor receptor (EGFR) inhibition, and this upregulation leads to NF-κB activation. The TNF upregulation and consequent NF-κB activation play a key role in mediating both primary and secondary resistance to EGFR inhibition in NSCLC, and a combined inhibition of EGFR and TNF can overcome therapeutic resistance in experimental models. TNF may mediate the toxic side effects of immunotherapy and may also modulate resistance to immune checkpoint inhibitors. Drugs inhibiting TNF are widely used for the treatment of various inflammatory and rheumatologic diseases and could be quite useful in combination with targeted therapy of NSCLC and other cancers.

The aim of this study is to discover research status and hotspots of economic evaluation (EE) in nursing area using co-word cluster analysis.

【Abstract】 Objective: To evaluate all the possible therapeutic measures concerning the acute management of traumatic brain injury (TBI) mentioned in Cochrane System-atic Reviews published in the Cochrane Database of Sys-tematic Reviews (CDSR). Methods: An exhausted literature search for all pub-lished Cochrane Systematic Reviews discussing therapeu-tic rather than prevention or rehabilitative interventions of TBI was conducted. We retrieved such databases as CDSR and Cochrane Injury Group, excluded the duplications, and eventually obtained 20 results, which stand for critical ap-praisal for as many as 20 different measures for TBI patients. The important data of each systematic review, including total population, intervention, outcome, etc, were collected and presented in a designed table. Besides, we also tried to find out the possible weakness of these clinical trials in-cluded in each review. Results: Analysis of these reviews yielded meanfuling observations: (1) The effectiveness of most ordinary treat-ments in TBI is inconclusive except that corticosteroids are likely to be ineffective or harmful, and tranexamic acid, nimodipine and progesterone show a promising effect in bleeding trauma, traumatic subarachnoid hemorrhage, TBI or severe TBI. (2) A majority of the systematic reviews in-clude a small number of clinical trials and the modest num-bers of patients, largely due to the uncertainty of the effectiveness. (3) The quality of most trials reported in the systematic reviews is more or less questionable. (4) In addition, lots of other complex factors together may lead to the inconclusive results demonstrated in the Cochrane Sys-tematic Reviews. Conclusions: For clinical physicians, to translate these conclusions into practice with caution is essential. Basic medication and nursing care deserve additional attention as well and can be beneficial. For researchers, high quality trials with perfect design and comprehensive consideration of various factors are urgently required. Key words: Brain injuries; Meta-analysis; Review; Acute management

Elastin production is characteristically turned off during the maturation of elastin-rich organs such as the aorta. MicroRNAs (miRNAs) are small regulatory RNAs that down-regulate target mRNAs by binding to miRNA regulatory elements (MREs) typically located in the 3' UTR. Here we show a striking up-regulation of miR-29 and miR-15 family miRNAs during murine aortic development with commensurate down-regulation of targets including elastin and other extracellular matrix (ECM) genes. There were a total of 14 MREs for miR-29 in the coding sequences (CDS) and 3' UTR of elastin, which was highly significant, and up to 22 miR-29 MREs were found in the CDS of multiple ECM genes including several collagens. This overrepresentation was conserved throughout mammalian evolution. Luciferase reporter assays showed synergistic effects of miR-29 and miR-15 family miRNAs on 3' UTR and coding-sequence elastin constructs. Our results demonstrate that multiple miR-29 and miR-15 family MREs are characteristic for some ECM genes and suggest that miR-29 and miR-15 family miRNAs are involved in the down-regulation of elastin in the adult aorta.

Marfan syndrome is an autosomal dominantly inherited disorder of connective tissue with prominent skeletal, ocular, and cardiovascular manifestations. Aortic aneurysm and dissection are the major determinants of premature death in untreated patients. In previous work, we showed that extracts of aortic tissues from the mgR mouse model of Marfan syndrome showed increased chemotactic stimulatory activity related to the elastin-binding protein. Aortic samples were collected from 6 patients with Marfan syndrome and 8 with isolated aneurysms of the ascending aorta. Control samples were obtained from 11 organ donors without known vascular or connective tissue diseases. Soluble proteins extracted from the aortic samples of the two patient groups were compared against buffer controls and against the aortic samples from controls with respect to the ability to induce macrophage chemotaxis as measured using a modified Boyden chamber, as well as the reactivity to a monoclonal antibody BA4 against bioactive elastin peptides using ELISA. Samples from Marfan patients displayed a statistically significant increase in chemotactic inductive activity compared to control samples. Additionally, reactivity to BA4 was significantly increased. Similar statistically significant increases were identified for the samples from patients with idiopathic thoracic aortic aneurysm. There was a significant correlation between the chemotactic index and BA4 reactivity, and the increases in chemotactic activity of extracts from Marfan patients could be inhibited by pretreatment with lactose, VGVAPG peptides, or BA4, which indicates the involvement of EBP in mediating the effects. Our results demonstrate that aortic extracts of patients with Marfan syndrome can elicit macrophage chemotaxis, similar to our previous study on aortic extracts of the mgR mouse model of Marfan syndrome (Guo et al., Circulation 2006; 114:1855-62).

We describe a consanguineous Iraqi family in which affected siblings had mild mental retardation and congenital ataxia characterized by quadrupedal gait. Genome-wide linkage analysis identified a 5.8 Mb interval on chromosome 8q with shared homozygosity among the affected persons. Sequencing of genes contained in the interval revealed a homozygous mutation, S100P, in carbonic anhydrase related protein 8 (CA8), which is highly expressed in cerebellar Purkinje cells and influences inositol triphosphate (ITP) binding to its receptor ITPR1 on the endoplasmatic reticulum and thereby modulates calcium signaling. We demonstrate that the mutation S100P is associated with proteasome-mediated degradation, and thus presumably represents a null mutation comparable to the Ca8 mutation underlying the previously described waddles mouse, which exhibits ataxia and appendicular dystonia. CA8 thus represents the third locus that has been associated with quadrupedal gait in humans, in addition to the VLDLR locus and a locus at chromosome 17p. Our findings underline the importance of ITP-mediated signaling in cerebellar function and provide suggestive evidence that congenital ataxia paired with cerebral dysfunction may, together with unknown contextual factors during development, predispose to quadrupedal gait in humans.

Abstract Background Fragile X syndrome (FXS) is caused by the absence of the mRNA-binding protein Fragile X mental retardation protein (FMRP), encoded by the Fmr1 gene. Overactive signaling by group 1 metabotropic glutamate receptor (Grp1 mGluR) could contribute to slowed synaptic development and other symptoms of FXS. Our previous study has identified that facilitation of synaptic long-term potentiation (LTP) by D1 receptor is impaired in Fmr1 knockout (KO) mice. However, the contribution of Grp1 mGluR to the facilitation of synaptic plasticity by D1 receptor stimulation in the prefrontal cortex has been less extensively studied. Results Here we demonstrated that DL-AP3, a Grp1 mGluR antagonist, rescued LTP facilitation by D1 receptor agonist SKF81297 in Fmr1KO mice. Grp1 mGluR inhibition restored the GluR1-subtype AMPA receptors surface insertion by D1 activation in the cultured Fmr1KO neurons. Simultaneous treatment of Grp1 mGluR antagonist with D1 agonist recovered the D1 receptor signaling by reversing the subcellular redistribution of G protein-coupled receptor kinase 2 (GRK2) in the Fmr1KO neurons. Treatment of SKF81297 alone failed to increase the phosphorylation of NR2B-containing N-methyl D-aspartate receptors (NMDARs) at Tyr-1472 (p-NR2B-Tyr1472) in the cultures from KO mice. However, simultaneous treatment of DL-AP3 could rescue the level of p-NR2B-Tyr1472 by SKF81297 in the cultures from KO mice. Furthermore, behavioral tests indicated that simultaneous treatment of Grp1 mGluR antagonist with D1 agonist inhibited hyperactivity and improved the learning ability in the Fmr1KO mice. Conclusion The findings demonstrate that mGluR1 inhibition is a useful strategy to recover D1 receptor signaling in the Fmr1KO mice, and combination of Grp1 mGluR antagonist and D1 agonist is a potential drug therapy for the FXS.

Abstract Background Liver dominates the production and secretion of apolipoprotein B (apoB) and evidence shows that liver malfunction induced by hepatitis B virus (HBV) infection could lead to apolipoprotein metabolism disorders. The present study was undertaken to assess the effects of HBV on apoB expression. Methods Clinical examination: serum apoB levels in patients with chronic HBV infection and in healthy individuals were measured by immunoturbidimetry using biochemical analyzer Olympus 5400. Cell study: mRNA and protein expression levels of apoB in HepG2 and HepG2.2.15 cells were measured by RT-PCR and Western blot. Alternatively, HBV infectious clone pHBV1.3 or control plasmid pBlue-ks were tranfected into HepG2 cells, and mRNA and protein expression levels of apoB, as well as the microsomal triglyceride transfer protein (MTP) in tranfected HepG2 cells were also measured by RT-PCR and western blot. Results Serum apoB level was much lower in chronic HBV patients as compared to healthy individuals (P < 0.05). Expression of apoB mRNA and protein was lower in HepG2.2.15 cells than in HepG2 cells. Similarly, expression of apoB mRNA and protein was lower in pHBV1.3 transfected HepG2 cells than in pBlue-ks transfected HepG2 cells. Expression of MTP mRNA and protein in pHBV1.3 transfected HepG2 cells was reduced in a dose-dependent fashion. Conclusion HBV infection plays an inhibitory effect on apoB expression.

Abstract Background To examine the expression of SMAD4 at gene and protein levels in glioma samples with different WHO grades and its association with survival. Methods Two hundreds fifty-two glioma specimens and 42 normal control tissues were collected. Immunochemistry assay, quantitative real-time PCR and Western blot analysis were carried out to investigate the expression of SMAD4. Kaplan-Meier method and Cox's proportional hazards model were used in survival analysis. Results Immunohistochemistry showed that SMAD4 expression was decreased in glioma. SMAD4 mRNA and protein levels were both lower in glioma compared to control on real-time PCR and Western blot analysis (both P < 0.001). In addition, its expression levels decrease from grade I to grade IV glioma according to the results of real-time PCR, immunohistochemistry analysis and Western blot. Moreover, the survival rate of SMAD4-positive patients was higher than that of SMAD4-negative patients. We further confirmed that the loss of SMAD4 was a significant and independent prognostic indicator in glioma by multivariate analysis. Conclusions Our data provides convincing evidence for the first time that the reduced expression of SMAD4 at gene and protein levels is correlated with poor outcome in patients with glioma. SMAD4 may play an inhibitive role during the development of glioma and may be a potential prognosis predictor of glioma.

Abstract In this article, PtAg alloy nanoislands/graphene hybrid composites were prepared based on the self-organization of Au@PtAg nanorods on graphene sheets. Graphite oxides (GO) were prepared and separated to individual sheets using Hummer's method. Graphene nano-sheets were prepared by chemical reduction with hydrazine. The prepared PtAg alloy nanomaterial and the hybrid composites with graphene were characterized by SEM, TEM, and zeta potential measurements. It is confirmed that the prepared Au@PtAg alloy nanorods/graphene hybrid composites own good catalytic function for methanol electro-oxidation by cyclic voltammograms measurements, and exhibited higher catalytic activity and more stability than pure Au@Pt nanorods and Au@AgPt alloy nanorods. In conclusion, the prepared PtAg alloy nanoislands/graphene hybrid composites own high stability and catalytic activity in methanol electro-oxidation, so that it is one kind of high-performance catalyst, and has great potential in applications such as methanol fuel cells in near future.