Despite substantial research, uncertainty remains about the clinical and etiological heterogeneity of major depression (MD). Can meaningful and valid subtypes be identified and would they be stable cross-culturally?
Symptoms at their lifetime worst depressive episode were assessed at structured psychiatric interview in 6008 women of Han Chinese descent, age ≥30 years, with recurrent DSM-IV MD. Latent class analysis (LCA) was performed in Mplus.
Using the nine DSM-IV MD symptomatic A criteria, the 14 disaggregated DSM-IV criteria and all independently assessed depressive symptoms (n=27), the best LCA model identified respectively three, four and six classes. A severe and non-suicidal class was seen in all solutions, as was a mild/moderate subtype. An atypical class emerged once bidirectional neurovegetative symptoms were included. The non-suicidal class demonstrated low levels of worthlessness/guilt and hopelessness. Patterns of co-morbidity, family history, personality, environmental precipitants, recurrence and body mass index (BMI) differed meaningfully across subtypes, with the atypical class standing out as particularly distinct.
MD is a clinically complex syndrome with several detectable subtypes with distinct clinical and demographic correlates. Three subtypes were most consistently identified in our analyses: severe, atypical and non-suicidal. Severe and atypical MD have been identified in multiple prior studies in samples of European ethnicity. Our non-suicidal subtype, with low levels of guilt and hopelessness, may represent a pathoplastic variant reflecting Chinese cultural influences.
Atypical depression; China; depression; latent class analysis; melancholia; suicidal ideation
Previous studies support Beck's cognitive model of vulnerability to depression. However, the relationship between his cognitive triad and other clinical features and risk factors among those with major depression (MD) has rarely been systematically studied.
The three key cognitive symptoms of worthlessness, hopelessness and helplessness were assessed during their lifetime worst episode in 1970 Han Chinese women with recurrent MD. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression.
Compared to patients who did not endorse the cognitive trio, those who did had a greater number of DSM-IV A criteria, more individual depressive symptoms, an earlier age at onset, a greater number of episodes, and were more likely to meet diagnostic criteria for melancholia, postnatal depression, dysthymia and anxiety disorders. Hopelessness was highly related to all the suicidal symptomatology, with ORs ranging from 5.92 to 6.51. Neuroticism, stressful life events (SLEs) and a protective parental rearing style were associated with these cognitive symptoms.
During the worst episode of MD in Han Chinese women, the endorsement of the cognitive trio was associated with a worse course of depression and an increased risk of suicide. Individuals with high levels of neuroticism, many SLEs and high parental protectiveness were at increased risk for these cognitive depressive symptoms. As in Western populations, symptoms of the cognitive trio appear to play a central role in the psychopathology of MD in Chinese women.
Cognitive trio; Han Chinese women; major depression; suicide; symptoms
The symptoms of major depression (MD) are clinically diverse. Do they form coherent factors that might clarify the underlying nature of this important psychiatric syndrome?
Symptoms at lifetime worst depressive episode were assessed at structured psychiatric interview in 6008 women of Han Chinese descent, age ⩾30 years with recurrent DSM-IV MD. Exploratory factor analysis (EFA) and confirmatoryfactor analysis (CFA) were performed in Mplus in random split-half samples.
The preliminary EFA results were consistently supported by the findings from CFA. Analyses of the nine DSM-IV MD symptomatic A criteria revealed two factors loading on: (i) general depressive symptoms; and (ii) guilt/suicidal ideation. Examining 14 disaggregated DSM-IV criteria revealed three factors reflecting: (i) weight/appetite disturbance; (ii) general depressive symptoms; and (iii) sleep disturbance. Using all symptoms (n = 27), we identified five factors that reflected: (i) weight/appetite symptoms; (ii) general retarded depressive symptoms; (iii) atypical vegetative symptoms; (iv) suicidality/hopelessness; and (v) symptoms of agitation and anxiety.
MD is a clinically complex syndrome with several underlying correlated symptom dimensions. In addition to a general depressive symptom factor, a complete picture must include factors reflecting typical/atypical vegetative symptoms, cognitive symptoms (hopelessness/suicidal ideation), and an agitated symptom factor characterized by anxiety, guilt, helplessness and irritability. Prior cross-cultural studies, factor analyses of MD in Western populations and empirical findings in this sample showing risk factor profiles similar to those seen in Western populations suggest that our results are likely to be broadly representative of the human depressive syndrome.
Atypical symptoms; China; cognitive symptoms; depression; factor analysis
Syndecan-1 (Sdc-1) shedding induced by matrix metalloproteinase-7 (MMP-7) and additional proteases has an important role in cancer development. However, the impact of Sdc-1 shedding on chemotherapeutic resistance has not been reported.
We examined Sdc-1 shedding in colorectal cancer by enzyme-linked immunosorbent assay (ELISA), Dot blot, reverse transcription-PCR (RT-PCR), immunohistochemistry and so on, its impact on chemotherapeutic sensitivity by collagen gel droplet embedded culture-drug sensitivity test (CD-DST) and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide), and potential mechanisms of action by Dot blot, western blot and immunofluorescence.
Sdc-1 shedding was increased in colorectal cancer patients, Sdc-1 serum levels in postoperative patients were lower than in preoperative patients, but still higher than those observed in healthy adults. Patients with high preoperative Sdc-1 serum levels were less responsive to 5-Fluorouracil, Oxaliplatin, Irintecan, Cisplatin or Paclitaxel chemotherapy. Moreover, the disease-free survival of patients with high preoperative Sdc-1 serum levels was significantly poorer. The possible mechanism of chemotherapy resistance in colorectal cancer can be attributed to Sdc-1 shedding, which enhances EGFR phosphorylation and downstream signalling.
Shed Sdc-1 is involved in chemotherapy resistance via the EGFR pathway in colorectal cancer, and Sdc-1 serum levels could be a new prognostic marker in colorectal cancer.
syndecan-1; HB-EGF; colorectal cancer; chemotherapy
Horizontal gene transfer (HGT) is viewed as very common in the plant mitochondrial (mt) genome, but, to date, only one case of HGT has been found in gymnosperms. Here we report a new case of HGT, in which a mt nad5-1 fragment was transferred from an angiosperm to Pinus canariensis. Quantitative assay and sequence analyses showed that the foreign nad5-1 is located in the mt genome of P. canariensis and is nonfunctional. An extensive survey in the genus Pinus revealed that the angiosperm-derived nad5-1 is restricted to P. canariensis and present across the species' range. Molecular dating based on chloroplast DNA suggested that the HGT event occurred in the late Miocene after P. canariensis split from its closest relatives, and that the foreign copy became fixed in P. canariensis owing to drift during its colonization of the Canary Islands. The mechanism of this HGT is unclear but it was probably achieved through either direct cell–cell contact or external vectors. Our discovery provides evidence for an important role of HGT in plant mt genome evolution.
Sunitinib is approved worldwide for treatment of advanced pancreatic neuroendocrine tumours (pNET), but no validated markers exist to predict response. This analysis explored biomarkers associated with sunitinib activity and clinical benefit in patients with pNET and carcinoid tumours in a phase II study.
Plasma was assessed for vascular endothelial growth factor (VEGF)-A, soluble VEGF receptor (sVEGFR)-2, sVEGFR-3, interleukin (IL)-8 (n=105), and stromal cell-derived factor (SDF)-1α (n=28). Pre-treatment levels were compared between tumour types and correlated with response, progression-free (PFS), and overall survival (OS). Changes in circulating myelomonocytic and endothelial cells were also analysed.
Stromal cell-derived factor-1α and sVEGFR-2 levels were higher in pNET than in carcinoid (P=0.003 and 0.041, respectively). High (above-median) baseline SDF-1α was associated with worse PFS, OS, and response in pNET, and high sVEGFR-2 with longer OS (P⩽0.05). For carcinoid, high IL-8, sVEGFR-3, and SDF-1α were associated with shorter PFS and OS, and high IL-8 and SDF-1α with worse response (P⩽0.05). Among circulating cell types, monocytes showed the largest on-treatment decrease, particularly CD14+ monocytes co-expressing VEGFR-1 or CXCR4.
Interleukin-8, sVEGFR-3, and SDF-1α were identified as predictors of sunitinib clinical outcome. Putative pro-tumorigenic CXCR4+ and VEGFR-1+ monocytes represent novel candidate markers and biologically relevant targets explaining the activity of sunitinib.
carcinoid; pancreatic neuroendocrine tumours; circulating biomarkers; cellular responses to anticancer drugs; pro-tumorigenic myeloid cells
Magnetic interactions in solids are normally mediated by short-range exchange or weak dipole fields. Here we report a magnetic interaction that can propagate over long distances (∼10 nm) across a polar insulating oxide spacer. Evidence includes oscillations of magnetization, coercivity and field-cooled loop shift with the thickness of LaAlO3 in La0.67Sr0.33MnO3/LaAlO3/SrTiO3 heterostructures. Similar modifications of the hysteresis loop appear when two coupled films of La0.67Sr0.33MnO3 are separated by LaAlO3, or another polar insulator, but they are absent when the oxide spacer layer is nonpolar. The loop shift is attributed to strong spin–orbit coupling and Dzyaloshinskii–Moriya interaction at the interfaces. There is evidence from inelastic light scattering that the polar spacer mediates long-range transmission of orbital magnetization. This coupling mechanism is expected to apply for any conducting ferromagnetic oxide with mixed valence; in view of electron hopping frequency involved, it raises the prospect of terahertz tunability of magnetic coupling.
Magnetic interactions in solids are usually short-range or else they involve itinerant electrons. Here, the authors evidence a long-range magnetic coupling mediated by orbital moments in a polar spacer layer of nonmagnetic insulating oxide, with a sign which oscillates with spacer thickness.
Mer is a receptor tyrosine kinase implicated in acute lymphoblastic leukemia (ALL), the most common malignancy in children. The currently available data provide a rationale for development of Mer kinase inhibitors as cancer therapeutics that can target both cell autologous and immune-modulatory anti-tumor effects. We have previously reported several series of potent Mer inhibitors and the objective of the current report is to identify a chemically dissimilar back-up series that might circumvent potential, but currently unknown, flaws inherent to the lead series. To this end, we virtually screened a database of ∼3.8 million commercially available compounds using high-throughput docking followed by a filter involving Structural Protein-Ligand Interaction Fingerprints (SPLIF). SPLIF permits a quantitative assessment of whether a docking pose interacts with the protein target similarly to an endogenous or known synthetic ligand, and therefore helps to improve both sensitivity and specificity with respect to the docking score alone. Of the total of 62 experimentally tested compounds, 15 demonstrated reliable dose-dependent responses in the Mer in vitro kinase activity assay with inhibitory potencies ranging from 0.46 μM to 9.9 μM.
Dapper homolog (DACT) 2 is one of the Dact gene family members, which are important modulators of Wnt signaling pathway. We aim to clarify its epigenetic inactivation, biological function and clinical implication in colon cancer. DACT2 was silenced in five out of eight colon cancer cell lines, but robustly expressed in normal colon tissues. The loss of DACT2 expression was regulated by promoter hypermethylation. Restoring DACT2 expression in colon cancer cell lines suppressed tumor cell growth by inducing cell apoptosis and inhibiting cell proliferation both in vitro and in vivo. Moreover, DACT2 overexpression effectively reduced lung metastasis of colon cancer cells in nude mice. These effects by DACT2 were attributed to inhibition of Wnt/β-catenin signaling. Reexpression of DACT2 significantly suppressed the transcriptional activity of both wild-type β-catenin and degradation-resistant form mutant β-catenin (S33Y). DACT2 could actively shuttle into and out of nuclei, with its predominant steady-state localization in the cytoplasm dependent on its nuclear export signal. Co-immunoprecipitation results indicated that DACT2 strongly associated β-catenin as well as lymphoid enhancer-binding factor 1 (LEF1) and directly disrupted the formation of the β-catenin–LEF1 complex in the nucleus. Whereas in the cytoplasm, DACT2 restored junctional localization of E-cadherin–β-catenin complexes and prevented β-catenin nuclear translocation through direct interaction with β-catenin. DACT2 methylation was detected in 43.3% (29/67) of colon cancer tissues, but none in normal controls. Multivariate analysis revealed that patients with DACT2 methylation had a significant decrease in overall survival (P=0.006). Kaplan–Meier survival curves showed that DACT2 methylation was significantly associated with shortened survival in stage I–III colon cancer patients. In conclusion, DACT2 acts as a functional tumor suppressor in colon cancer through inhibiting Wnt/β-catenin signaling. Its methylation at early stages of colon carcinogenesis is an independent prognostic factor.
Callosobruchus chinensis (Linnaeus) is one of the most destructive pests of leguminous seeds. Genetic differentiation and diversity analysis of 345 C. chinensis individuals from 23 geographic populations using 20 polymorphic simple sequence repeats revealed a total of 149 alleles with an average of 7.45 alleles per locus. The average Shannon's information index was 1.015. The gene flow and genetic differentiation rate values at the 20 loci ranged from 0.201 to 1.841 and 11.0–47.2%, with averages of 0.849 and 24.4%, respectively. In the 23 geographic populations, the effective number of alleles and observed heterozygosity ranged from 1.441 to 2.218 and 0.191–0.410, respectively. Shannon's information index ranged from 0.357 to 0.949, with the highest value in Hohhot and the lowest in Rudong. In all comparisons, the fixation index (FST) values ranged from 0.049 to 0.441 with a total FST value of 0.254 among the 23 C. chinensis populations, indicating a moderate level of genetic differentiation and gene flow among these populations. Analysis of molecular variance revealed that the genetic variation within populations accounted for 76.7% of the total genetic variation. The genetic similarity values between populations varied from 0.617 to 0.969, whereas genetic distances varied from 0.032 to 0.483. Using unweighted pair-group method using arithmetical averages cluster analysis, the 23 geographic collections were classified into four distinct genetic groups but most of them were clustered into a single group. The pattern of the three concentrated groups from polymerase chain reactions analysis showed a somewhat different result with cluster.
Callosobruchus chinensis; simple sequence repeat; geographic populations; genetic differentiation; genetic diversity
Recent theoretical and experimental findings suggest the long-known but not well understood low temperature resistance plateau of SmB6 may originate from protected surface states arising from a topologically non-trivial bulk band structure having strong Kondo hybridization. Yet others have ascribed this feature to impurities, vacancies, and surface reconstructions. Given the typical methods used to prepare SmB6 single crystals, flux and floating-zone procedures, such ascriptions should not be taken lightly. We demonstrate how compositional variations and/or observable amounts of impurities in SmB6 crystals grown using both procedures affect the physical properties. From X-ray diffraction, neutron diffraction, and X-ray computed tomography experiments we observe that natural isotope containing (SmB6) and doubly isotope enriched (154Sm11B6) crystals prepared using aluminum flux contain co-crystallized, epitaxial aluminum. Further, a large, nearly stoichiometric crystal of SmB6 was successfully grown using the float-zone technique; upon continuing the zone melting, samarium vacancies were introduced. These samarium vacancies drastically alter the resistance and plateauing magnitude of the low temperature resistance compared to stoichiometric SmB6. These results highlight that impurities and compositional variations, even at low concentrations, must be considered when collecting/analyzing physical property data of SmB6. Finally, a more accurate samarium-154 coherent neutron scattering length, 8.9(1) fm, is reported.
Vascular endothelial growth factor (VEGF) has been reported to mediate both osteogenesis and angiogenesis in bone regeneration. We previously found an up regulation of VEGF in adipose-derived stem cells (ASC) when obvious mineralization occurred on a novel fluorapatite (FA) coated surfaces. This study investigated the effect of FA and VEGF on the growth, differentiation and mineralization of (ASC) grown on ordered FA surfaces. Cells grown on FA and treated with VEGF demonstrated osteogenic differentiation as measured with ALP staining, and obvious mineralization as measured by Alizarin Red staining. A combined stimulating effect of FA and VEGF was seen using both indicators. VEGF signaling pathway perturbation using a specific VEGF receptor inhibitor showed the lowest levels of ALP and Alizarin Red staining, which was partially rescued when the cells were grown on FA and/or treated with the addition of VEGF. The osteogenic differentiation of ASCs stimulated by these FA surfaces as well as VEGF has been shown to be mediated through, but probably not only, the VEGF signaling pathway. The enhancement of osteogenic differentiation and mineralization supports the potential use of therapeutic VEGF and FA coatings in bone regeneration.
Fluorapatite; vascular endothelial growth factor; differentiation; mineralization; signaling pathway
FAM20C is an evolutionarily reserved molecule highly expressed in mineralized tissues. Previously we demonstrated that Sox2-Cre;Fam20Cfl/fl mice, in which Fam20C was ubiquitously inactivated, had dentin and enamel defects as well as hypophosphatemic rickets. We also showed that K14-Cre;Fam20Cfl/fl mice, in which Fam20C was specifically inactivated in the epithelium, had enamel defects but lacked hypophosphatemia and defects in the bone and dentin. These results indicated that the enamel defects in the Sox2-Cre;Fam20Cfl/fl mice were independent of dentin defects and hypophosphatemia. To determine if the dentin defects in the Sox2-Cre;Fam20Cfl/fl mice were associated with the enamel defects and hypophosphatemia, we crossed Fam20Cfl/fl mice with Wnt1-Cre and Osr2-Cre transgenic mice to inactivate Fam20C in the craniofacial mesenchymal cells that form dentin and alveolar bone. The resulting Wnt1-Cre;Fam20Cfl/fl and Osr2-Cre;Fam20Cfl/fl mice showed remarkable dentin and alveolar bone defects, while their enamel did not show apparent defects. The serum FGF23 levels in these mice were higher than normal but lower than those in the Sox2-Cre;Fam20Cfl/fl mice; they developed a mild type of hypophosphatemia that did not cause major defects in long bones. These results indicate that the dentin defects in the Sox2-Cre;Fam20Cfl/fl mice were independent of the enamel defects.
FGF23; hypophosphatemia; neural crest cells; dentin; enamel; bone
InN-based metal-insulator-semiconductor (MIS) structures were prepared with Al2O3 as the gate oxides. Surface morphologies of InN films are improved with increasing Mg doping concentrations. At high frequencies, the measured capacitance densities deviate from the real ones with turning frequencies inversely proportional to series resistances. An ultralow leakage current density of 1.35 × 10−9 A/cm2 at 1 V is obtained. Fowler-Nordheim tunneling is the main mechanism of the leakage current at high fields, while Schottky emission dominates at low fields. Capacitance densities shift with different biases, indicating that the InN-based MIS structures can serve as potential candidates for MIS field-effect transistors.
InN; Al2O3; MIS
We study transverse electron momentum distribution in strong field atomic ionization driven by laser pulses with varying ellipticity. We show, both experimentally and theoretically, that the transverse electron momentum distribution in the tunneling and over the barrier ionization regimes evolves in a qualitatively different way when the ellipticity parameter describing polarization state of the driving laser pulse increases.
This review aims to assess the efficacy and safety of epithelial removal (ER) and transepithelial (TE) corneal collagen crosslinking (CXL) for the treatment of keratoconus. We used MEDLINE to identify all ER and TE CXL studies on keratoconic eyes (n≥20, follow-up ≥12 months). Ex vivo and studies for non-keratoconus indications or in conjunction with other procedures were excluded. Data on uncorrected (UDVA) and corrected (CDVA) distance visual acuity, refractive cylinder, maximum keratometry (Kmax), and adverse events were collected at the latest follow-up and 1 year. Only one randomised controlled trial (RCT) qualified inclusion. Forty-four ER and five TE studies were included. For logMAR UDVA, CDVA, mean spherical equivalent, refractive cylinder and Kmax, at latest follow-up 81, 85, 93, 62, and 93% ER studies vs 66.7, 80, 75, 33, and 40% TE studies reported improvement, respectively. Whereas at 1 year, 90, 59, and 91% ER studies vs 80, 50, and 25% TE studies reported improvement, respectively. The majority of studies showed reduced pachymetry in both groups. Treatment failure, retreatment rates, and conversion to transplantation were reported to be up to 33, 8.6, and 6.25%, respectively, in ER studies only. Stromal oedema, haze, keratitis, and scarring were only reported in ER studies, whereas endothelial cell counts remained variable in both groups. Both ER and TE studies showed improvement in visual acuity, refractive cylinder but Kmax worsened in most TE studies. Adverse events were reported more with ER studies. This review calls for more high quality ER and TE studies with comparable parameters for further assessment of safety and efficacy.
We show here a new phenomenon in La0.5Sr0.5TiO3/SrTiO3 (LSTO/STO) heterostructures; that is a coexistence of three-dimensional electron liquid (3DEL) and 2D electron gas (2DEG), separated by an intervening insulating LSTO layer. The two types of carriers were revealed through multi-channel analysis of the evolution of nonlinear Hall effect as a function of film thickness, temperature and back gate voltage. We demonstrate that the 3D electron originates from La doping in LSTO film and the 2D electron at the surface of STO is due to the polar field in the intervening insulating layer. As the film thickness is reduced below a critical thickness of 6 unit cells (uc), an abrupt metal-to-insulator transition (MIT) occurs without an intermediate semiconducting state. The properties of the LSTO layer grown on different substrates suggest that the insulating phase of the intervening layer is a result of interface strain induced by the lattice mismatch between the film and substrate. Further, by fitting the magnetoresistance (MR) curves, the 6 unit cell thick LSTO is shown to exhibit spin-orbital coupling. These observations point to new functionalities, in addition to magnetism and superconductivity in STO-based systems, which could be exploited in a multifunctional context.
Viral infections such as influenza have been shown to predispose hosts to increased colonization of the respiratory tract by pathogenic bacteria and secondary bacterial pneumonia. To examine how viral infections and host antiviral immune responses alter the upper respiratory microbiota, we analyzed nasal bacterial composition by 16S ribosomal RNA (rRNA) gene sequencing in healthy adults at baseline and at 1 to 2 weeks and 4 to 6 weeks following instillation of live attenuated influenza vaccine or intranasal sterile saline. A subset of these samples was submitted for microarray host gene expression profiling.
We found that live attenuated influenza vaccination led to significant changes in microbial community structure, diversity, and core taxonomic membership as well as increases in the relative abundances of Staphylococcus and Bacteroides genera (both p < 0.05). Hypergeometric testing for the enrichment of gene ontology terms in the vaccinated group reflected a robust up-regulation of type I and type II interferon-stimulated genes in the vaccinated group relative to controls. Translational murine studies showed that poly I:C administration did in fact permit greater nasal Staphylococcus aureus persistence, a response absent in interferon alpha/beta receptor deficient mice.
Collectively, our findings demonstrate that although the human nasal bacterial community is heterogeneous and typically individually robust, activation of a type I interferon (IFN)-mediated antiviral response may foster the disproportionate emergence of potentially pathogenic species such as S. aureus.
This study was registered with Clinicaltrials.gov on 11/3/15, NCT02597647.
Electronic supplementary material
The online version of this article (doi:10.1186/s40168-015-0133-2) contains supplementary material, which is available to authorized users.
Human microbiome; Nasal colonization; Influenza; Interferons; Antiviral immune response
Lung cancer is a leading cause of cancer-related mortality worldwide and non-small-cell lung carcinoma (NSCLC) is responsible for almost 80% of lung cancer-related deaths. Identifying novel molecules that can repress the invasiveness and metastasis of lung cancer will facilitate the development of new antilung cancer strategies. The aim of this study is to determine the roles of NUAK1 (a downstream of Akt) and miR-204 in the invasiveness and metastasis of NSCLC and to reveal the correlation between NUAK1 and miR-204.
The expression of NUAK1 in primary human NSCLC tissues was evaluated by immunohistochemistry. Real-time PCR was employed to measure the expression level of miR-204. The effect of NUAK1 and miR204 on the prognosis of NSCLC patients was evaluated by log-rank test. The siRNA transfection was used to manipulate the expression levels of NUAK1 and miR204 in cancer cells. Chemotaxis assay, Scratch assay, and Matrigel invasion assay were performed to evaluate the migration and invasion of cells. Cellular F-actin measurement was used to measure F-actin polymerisation in lung cancer cells. Western blot was used to detect the expression levels of corresponding proteins. The Luciferase assay and RNA immunoprecipitation were used to confirm the actual binding site of miR-204 to 3′UTR of NUAK1.
Increased expression of NUAK1 is correlated with the invasiveness and metastasis of human NSCLC. Knockdown of NUAK1 inhibited cell migration and invasion. In addition, this study showed that NUAK1 influenced mTOR phosphorylation and induced the phosphorylation of p70S6K1 and eukaryotic initiation factor 4E-binding protein1 (4E-BP1), two downstream targets of mTOR in NSCLC cells. At the same time, decreased expression of miR-204 promoted NSCLC progression and, contrarily, manipulated upregulation of miR-204-inhibited cell migration and invasion. There is clinical relevance between miR-204 downregulation and NUAK1 upregulation in human NSCLC. Furthermore, we found that miR-204 inhibited NSCLC tumour invasion by directly targeting and downregulating NUAK1 expression. Finally, our data suggested that the downregulation of miR-204 was due to hypermethylation of its promoter region.
Our results indicate that NUAK1 is excessively expressed in NSCLC and plays important roles in NSCLC invasion. The miR-204 acts as a tumour suppressor by inhibiting NUAK1 expression in NSCLC. Both NUAK1 and miR-204 may serve as potential targets of NSCLC therapy.
miR-204; NUAK1; mTOR; invasion
Reactivation of tumor-suppressor p53 for targeted cancer therapy is an attractive strategy for cancers bearing wild-type (WT) p53. Targeting the Mdm2–p53 interface or MdmX ((MDM4), mouse double minute 4)–p53 interface or both has been a focus in the field. However, targeting the E3 ligase activity of Mdm2–MdmX really interesting new gene (RING)–RING interaction as a novel anticancer strategy has never been explored. In this report, we describe the identification and characterization of small molecule inhibitors targeting Mdm2–MdmX RING–RING interaction as a new class of E3 ligase inhibitors. With a fluorescence resonance energy transfer-based E3 activity assay in high-throughput screening of a chemical library, we identified inhibitors (designated as MMRis (Mdm2–MdmX RING domain inhibitors)) that specifically inhibit Mdm2–MdmX E3 ligase activity toward Mdm2 and p53 substrates. MMRi6 and its analog MMRi64 are capable of disrupting Mdm2–MdmX interactions in vitro and activating p53 in cells. In leukemia cells, MMRi64 potently induces downregulation of Mdm2 and MdmX. In contrast to Nutlin3a, MMRi64 only induces the expression of pro-apoptotic gene PUMA (p53 upregulated modulator of apoptosis) with minimal induction of growth-arresting gene p21. Consequently, MMRi64 selectively induces the apoptotic arm of the p53 pathway in leukemia/lymphoma cells. Owing to the distinct mechanisms of action of MMRi64 and Nutlin3a, their combination synergistically induces p53 and apoptosis. Taken together, this study reveals that Mdm2–MdmX has a critical role in apoptotic response of the p53 pathway and MMRi64 may serve as a new pharmacological tool for p53 studies and a platform for cancer drug development.
The refractory tungsten alloys with high ductility/strength/plasticity are highly desirable for a wide range of critical applications. Here we report an interface design strategy that achieves 8.5 mm thick W-0.5 wt. %ZrC alloy plates with a flexural strength of 2.5 GPa and a strain of 3% at room temperature (RT) and ductile-to-brittle transition temperature of about 100 °C. The tensile strength is about 991 MPa at RT and 582 MPa at 500 °C, as well as total elongation is about 1.1% at RT and as large as 41% at 500 °C, respectively. In addition, the W-ZrC alloy plate can sustain 3.3 MJ/m2 thermal load without any cracks. This processing route offers the special coherent interfaces of grain/phase boundaries (GB/PBs) and the diminishing O impurity at GBs, which significantly strengthens GB/PBs and thereby enhances the ductility/strength/plasticity of W alloy. The design thought can be used in the future to prepare new alloys with higher ductility/strength.
Tumor suppressor p53 has a key role in maintaining genomic stability and preventing tumorigenesis through its regulation of cellular stress responses, including apoptosis, cell cycle arrest and senescence. To ensure its proper levels and functions in cells, p53 is tightly regulated mainly through post-translational modifications, such as ubiquitination. Here, we identified E3 ubiquitin ligase TRIM32 as a novel p53 target gene and negative regulator to regulate p53-mediated stress responses. In response to stress, such as DNA damage, p53 binds to the p53 responsive element in the promoter of the TRIM32 gene and transcriptionally induces the expression of TRIM32 in cells. In turn, TRIM32 interacts with p53 and promotes p53 degradation through ubiquitination. Thus, TRIM32 negatively regulates p53-mediated apoptosis, cell cycle arrest and senescence in response to stress. TRIM32 is frequently overexpressed in different types of human tumors. TRIM32 overexpression promotes cell oncogenic transformation and tumorigenesis in mice in a largely p53-dependent manner. Taken together, our results demonstrated that as a novel p53 target and a novel negative regulator for p53, TRIM32 has an important role in regulation of p53 and p53-mediated cellular stress responses. Furthermore, our results also revealed that impairing p53 function is a novel mechanism for TRIM32 in tumorigenesis.
Necroptosis is mediated by a signaling complex called necrosome, containing receptor-interacting protein (RIP)1, RIP3, and mixed-lineage kinase domain-like (MLKL). It is known that RIP1 and RIP3 form heterodimeric filamentous scaffold in necrosomes through their RIP homotypic interaction motif (RHIM) domain-mediated oligomerization, but the signaling events based on this scaffold has not been fully addressed. By using inducible dimer systems we found that RIP1–RIP1 interaction is dispensable for necroptosis; RIP1–RIP3 interaction is required for necroptosis signaling, but there is no necroptosis if no additional RIP3 protein is recruited to the RIP1–RIP3 heterodimer, and the interaction with RIP1 promotes the RIP3 to recruit other RIP3; RIP3–RIP3 interaction is required for necroptosis and RIP3–RIP3 dimerization is sufficient to induce necroptosis; and RIP3 dimer-induced necroptosis requires MLKL. We further show that RIP3 oligomer is not more potent than RIP3 dimer in triggering necroptosis, suggesting that RIP3 homo-interaction in the complex, rather than whether RIP3 has formed homo polymer, is important for necroptosis. RIP3 dimerization leads to RIP3 intramolecule autophosphorylation, which is required for the recruitment of MLKL. Interestingly, phosphorylation of one of RIP3 in the dimer is sufficient to induce necroptosis. As RIP1–RIP3 heterodimer itself cannot induce necroptosis, the RIP1–RIP3 heterodimeric amyloid fibril is unlikely to directly propagate necroptosis. We propose that the signaling events after the RIP1–RIP3 amyloid complex assembly are the recruitment of free RIP3 by the RIP3 in the amyloid scaffold followed by autophosphorylation of RIP3 and subsequent recruitment of MLKL by RIP3 to execute necroptosis.