Osteosarcoma (OS) is the most frequent pediatric malignant bone tumor that has a high propensity for metastases. Through osteoblast-specific alteration of p53 status, we developed a genetically ...engineered mouse model of localized and metastatic OS to gain an understanding into the molecular pathogenesis of OS. Microarray analysis of both localized tumors and metastatic tumors identified the downregulation of the naked cuticle homolog 2 (NKD2) gene, a negative regulator of Wnt signaling. Overexpression of NKD2 in metastatic human and mouse OS cells significantly decreases cell proliferation, migration and invasion ability in vitro and drastically diminishes OS tumor growth and metastasis in vivo, whereas downregulation enhances migratory and invasive potential. Evaluation of NKD2-overexpressing tumors revealed upregulation of tumor-suppressor genes and downregulation of molecules involved in blood vessel formation and cell migration. Furthermore, assessment of primary human OS revealed downregulation of NKD2 in metastatic and recurrent OS. Finally, we provide biological evidence that use of small-molecule inhibitors targeting the Wnt pathway can have therapeutic efficacy in decreasing metastatic properties in OS. Our studies provide compelling evidence that downregulation of NKD2 expression and alterations in associated regulated pathways have a significant role in driving OS tumor growth and metastasis.
ABSTRACT
We investigate the contribution of sub-Chandrasekhar mass Type Ia supernovae to the chemical enrichment of the Gaia Sausage galaxy, the progenitor of a significant merger event in the early ...life of the Milky Way. Using a combination of data from Nissen & Schuster, the GALactic Archaeology with HERMES (GALAH) Data Release 3 with 1D non-local thermal equilibrium (NLTE) abundance corrections, and the Apache Point Observatory Galactic Evolution Experiment (APOGEE) Data Release 16, we fit analytic chemical evolution models to a nine-dimensional chemical abundance space (Fe, Mg, Si, Ca, Cr, Mn, Ni, Cu, and Zn) in particular focusing on the iron-peak elements, Mn and Ni. We find that low Mn/Fe $\sim -0.15\, \mathrm{dex}$ and low Ni/Fe $\sim -0.3\, \mathrm{dex}$ Type Ia yields are required to explain the observed trends beyond the α/Fe knee of the Gaia Sausage (approximately at Fe/H $=-1.4\, \mathrm{dex}$). Comparison to theoretical yield calculations indicates a significant contribution from sub-Chandrasekhar mass Type Ia supernovae in this system (from ${\sim} 60\, \mathrm{per\, cent}$ to $100\, \mathrm{per\, cent}$ depending on the theoretical model with an additional ${\pm} 10\, \mathrm{per\, cent}$ systematic from NLTE corrections). We compare to results from other Local Group environments including dwarf spheroidal galaxies, the Magellanic Clouds, and the Milky Way’s bulge, finding the Type Ia Mn/Fe yield must be metallicity dependent. Our results suggest that sub-Chandrasekhar mass channels are a significant, perhaps even dominant, contribution to Type Ia supernovae in metal-poor systems, whilst more metal-rich systems could be explained by metallicity-dependent sub-Chandrasekhar mass yields, possibly with additional progenitor mass variation related to star formation history, or an increased contribution from Chandrasekhar mass channels at higher metallicity.
Most HIV transmissions among men who have sex with men (MSM), the group that accounted for 67% of new US infections in 2014, occur via exposure to the rectal mucosa. However, it is unclear how the ...act of condomless receptive anal intercourse (CRAI) may alter the mucosal immune environment in HIV-negative MSM. Here, we performed a comprehensive characterization of the rectal mucosal immune environment for the phenotype and production of pro-inflammatory cytokines by CD4 and CD8 T cells, global transcriptomic analyses, and the composition of microbiota in HIV-negative MSM. Our results show that compared with men who had never engaged in anal intercourse, the rectal mucosa of MSM engaging in CRAI has a distinct phenotype characterized by higher levels of Th17 cells, greater CD8+ T cell proliferation and production of pro-inflammatory cytokines, molecular signatures associated with mucosal injury and repair likely mediated by innate immune cells, and a microbiota enriched for the Prevotellaceae family. These data provide a high-resolution model of the immunological, molecular, and microbiological perturbations induced by CRAI, will have direct utility in understanding rectal HIV transmission among MSM, and will enhance the design of future biomedical prevention interventions, including candidate HIV vaccines.
Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP's role in ...facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (
mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted
-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-
-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field's progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond
-mutant breast tumors.
In present study, a series of single modified TiO2 nanotubes with varying amounts of Cu was synthesized via two-step chemical solution method and studied as photocatalyst for H2 production under ...sunlight irradiation. The results indicate significant improvement of photocatalytic activity for TiO2 nanotubes modified Cu nanoparticles compared with pristine TiO2 attributed by the formation of the p-n heterojunction between Cu2O and TiO2. This enhanced the photo-generated charge transfer properties, resulting in an improved H2 evolution performance. The modified TiO2 nanotubes with 1.5 wt% Cu (Cu1.5 -TNTs) showed highest photocatalytic activity for H2 generation under sunlight due to structural integrity and uniform distribution of cuprous oxide on the surface of photocatalyst. Additionally, recyclability study for the H2 production of Cu1.5-TNTs material slightly decreased after four times, due to the presence of CuO phase via the oxidation of Cu2O and agglomeration phenomena, rendering them inefficient for H2 evolution performance under sunlight. We believe, addressing these problems would eminently assist in steady-state H2 generation performance under sunlight. Also, expanding the regime of light absorption to visible region for TiO2 1-Dimensional structure decorated Cu2O has higher photocatalytic efficiency for H2 generation in comparison to current 2-Dimensional systems.
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•CuxO-TiO2 nanotubes based composite were synthesized by the simple hydrothermal method for TiO2 followed by impregnation of CuxO.•The highest photocatalytic efficiency was observed to be ∼48 mmol h−1.gcat.−1 for type-II heterojunction photocatalysts.•The factors responsible for decreasing in H2 production after four cycles were examined.
Nanoparticles larger than the reported mesh-pore size range (10-200 nm) in mucus have been thought to be much too large to undergo rapid diffusional transport through mucus barriers. However, large ...nanoparticles are preferred for higher drug encapsulation efficiency and the ability to provide sustained delivery of a wider array of drugs. We used high-speed multiple-particle tracking to quantify transport rates of individual polymeric particles of various sizes and surface chemistries in samples of fresh human cervicovaginal mucus. Both the mucin concentration and viscoelastic properties of these cervicovaginal samples are similar to those in many other human mucus secretions. Unexpectedly, we found that large nanoparticles, 500 and 200 nm in diameter, if coated with polyethylene glycol, diffused through mucus with an effective diffusion coefficient $(D_{\text{eff}})$ only 4- and 6-fold lower than that for the same particles in water (at time scale τ = 1 s). In contrast, for smaller but otherwise identical 100-nm coated particles, $D_{\text{eff}}$ was 200-fold lower in mucus than in water. For uncoated particles 100-500 nm in diameter, $D_{\text{eff}}$ was 2,400- to 40,000-fold lower in mucus than in water. Much larger fractions of the 100-nm particles were immobilized or otherwise hindered by mucus than the large 200- to 500-nm particles. Thus, in contrast to the prevailing belief, these results demonstrate that large nanoparticles, if properly coated, can rapidly penetrate physiological human mucus, and they offer the prospect that large nanoparticles can be used for mucosal drug delivery.
Background
The Internet Gaming Disorder Scale–Short-Form (IGDS9-SF) is among the best with regard to its psychometric properties. Therefore, clinical psychologists are likely guided to use the ...IGDS9-SF if they want to assess or screen the disordered gaming in their practice. However, the information, especially psychometric evidence, concerning the IGDS9-SF has not been fully examined and summarized.
Objective
This systematic review evaluated the psychometric properties of different language versions of the IGDS9-SF and assessed its methodological quality in order to improve the clinicians’ understanding of the IGDS9-SF and facilitate its use.
Methods
Systematic literature searches were carried out using Embase, MEDLINE, PsycINFO, PubMed, ScienceDirect, Scopus, and Web of Science. The review included English-language studies of any research design that have reported at least one psychometric property of the IGDS9-SF, as defined by the COnsensus-based Standards for the selection of health status Measurement INstrument (COSMIN), and have aimed at testing the psychometric properties of the IGDS9-SF.
Results
In total, 21 studies comprising 15 language versions of the IGDS9-SF were included. Overall, the IGDS9-SF showed adequate internal consistency (although some items did not have satisfactory item-total correlation IT), excellent criterion validity, and the ability to distinguish different subgroups with measurement invariance being supported across gender and age. In terms of factor structure, the IGDS9-SF was shown to have a unidimensional factor structure across all 21 studies.
Conclusions
Although there is insufficient evidence regarding the responsiveness and properties of the IGDS9-SF using item response theory, the existing evidence supports its use in assessing disordered gaming among individuals.
Triple-negative breast cancer (TNBC) remains a poor prognostic factor for breast cancer since no effective targeted therapy is readily available. Our previous studies confirmed miR-199a-5p is a ...TNBC-specific circulating biomarker, however, its functional roles in breast cancer is largely unknown. Thus, we investigated the functional implication of miR-199a-5p in TNBC and its potential underlying mechanisms.
MTT assay was performed to investigate the cell proliferation after transient transfection of miR-199a-5p in MDA-MB-231 cell line, followed by cell cycle analysis. Transwell invasion assay and wound healing assay were used to study the invasion and migration ability respectively. To further investigate the stemness-related characteristics of miR-199a-5p in breast cancer cells, single-cell clonogenic assay and aldehyde dehydrogenase (ALDH) assay were performed. 32 normal and 100 breast cancer patients' plasma were recruited to identify the potential circulating markers by qPCR.
Cell proliferation assay revealed significant inhibition after miR-199a-5p ectopic expression (p < 0.0001), as a result of decreased S phase (p = 0.0284), increased G0/G1 phase (p = 0.0260) and apoptosis (p = 0.0374). Invasiveness (p = 0.0005) and wound healing ability were also decreased upon miR-199a-5p overexpression. It significantly altered EMT-related genes expression, namely CDH1, ZEB1 and TWIST. Single-cell clonogenic assay showed decreased colonies in miR-199a-5p (p = 0.0182). Significant downregulation (p = 0.0088) and inhibited activity (p = 0.0390) of ALDH was observed in miR-199a-5p. ALDH1A3, which is the dominant isoform of ALDH, is significantly upregulated in breast cancer plasma especially in TNBC (p = 0.0248). PIK3CD was identified as a potential downstream target of miR-199a-5p.
Taken together, we unraveled, for the first time, the tumor-suppressive role of miR-199a-5p in TNBC, which attributed to EMT and cancer stemness properties, providing a novel therapeutic options towards this aggressive disease.
The relapse rate for children with acute myeloid leukemia is nearly 40% despite aggressive chemotherapy and often stem cell transplant. We sought to understand how environment-induced signaling ...responses are associated with clinical response to treatment. We previously reported that patients whose AML cells showed low G-CSF-induced STAT3 activation had inferior event-free survival compared to patients with stronger STAT3 responses. Here, we expanded the paradigm to evaluate multiple signaling parameters induced by a more physiological stimulus. We measured STAT3, STAT5 and ERK1/2 responses to G-CSF and to stromal cell-conditioned medium for 113 patients enrolled on COG trials AAML03P1 and AAML0531. Low inducible STAT3 activity was independently associated with inferior event-free survival in multivariate analyses. For inducible STAT5 activity, those with the lowest and highest responses had inferior event-free survival, compared to patients with intermediate STAT5 responses. Using existing RNA-sequencing data, we compared gene expression profiles for patients with low inducible STAT3/5 activation with those for patients with higher inducible STAT3/5 signaling. Genes encoding hematopoietic factors and mitochondrial respiratory chain subunits were overexpressed in the low STAT3/5 response groups, implicating inflammatory and metabolic pathways as potential mechanisms of chemotherapy resistance. We validated the prognostic relevance of individual genes from the low STAT3/5 response signature in a large independent cohort of pediatric AML patients. These findings provide novel insights into interactions between AML cells and the microenvironment that are associated with treatment failure and could be targeted for therapeutic interventions.
The use of dopants to regulate ferromagnetism in the rare-earth-free MnBi magnetic materials is one of the fundamental approaches to change the electronic structure and interactions inside the unit ...cell leading to the ability of controlling magnetic properties of materials. This work deals with doping Sb element into the MnBi system. The density functional theory (DFT) calculations revealed the close dependences between the system’s energy, lattice parameters, magnetization, coercivity and the Sb doping amount. The calculated results, supported by the experimental results, show the usefulness of Sb in regulating the magnetic performance of MnBi materials.
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