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Multifunctional imaging nanoprobes continue to garner strong interest for their great potential in the detection and monitoring of cancer. In this study, we investigate a series of spatially arranged iron oxide nanocube-based clusters (i.e., chain-like dimer/trimer, centrosymmetric clusters, and enzymatically cleavable two-dimensional clusters) as magnetic particle imaging and magnetic resonance imaging probes. Our findings demonstrate that the short nanocube chain assemblies exhibit remarkable magnetic particle imaging signal enhancement with respect to the individually dispersed or the centrosymmetric cluster analogues. This result can be attributed to the beneficial uniaxial magnetic dipolar coupling occurring in the chain-like nanocube assembly. Moreover, we could effectively synthesize enzymatically cleavable two-dimensional nanocube clusters, which upon exposure to a lytic enzyme, exhibit a progressive increase in magnetic particle imaging signal at well-defined incubation time points. The increase in magnetic particle imaging signal can be used to trace the disassembly of the large planar clusters into smaller nanocube chains by enzymatic polymer degradation. These studies demonstrate that chain-like assemblies of iron oxide nanocubes offer the best spatial arrangement to improve magnetic particle imaging signals. In addition, the nanocube clusters synthesized in this study also show remarkable transverse magnetic resonance imaging relaxation signals. These nanoprobes, previously showcased for their outstanding heat performance in magnetic hyperthermia applications, have great potential as dual imaging probes and could be employed to improve the tumor thermo-therapeutic efficacy, while offering a readable magnetic signal for image mapping of material disassemblies at tumor sites.

Boron nitride nanotubes (BNNTs) represent an extremely interesting class of nanomaterials, and recent findings have suggested a number of applications in the biomedical field. Anyhow, extensive biocompatibility investigations are mandatory before any further advancement toward preclinical testing. Here, we report on the effects of multiwalled BNNTs in freshwater planarians, one of the best-characterized in vivo models for developmental biology and regeneration research. Obtained results indicate that BNNTs are biocompatible in the investigated model, since they do not induce oxidative DNA damage and apoptosis, and do not show adverse effects on planarian stem cell biology and on de novo tissue regeneration. In summary, collected findings represent another important step toward BNNT realistic applications in nanomedicine.

Here, we propose the use of magnetic hyperthermia as a means to trigger the oxidation of Fe 1−x O/Fe 3−δ O 4 core-shell nanocubes to Fe 3−δ O 4 phase. As a first relevant consequence, the specific absorption rate (SAR) of the initial core-shell nanocubes doubles after exposure to 25 cycles of alternating magnetic field stimulation. The improved SAR value was attributed to a gradual transformation of the Fe 1−x O core to Fe 3−δ O 4 , as evidenced by structural analysis including high resolution electron microscopy and Rietveld analysis of X-ray diffraction patterns. The magnetically oxidized nanocubes, having large and coherent Fe 3−δ O 4 domains, reveal high saturation magnetization and behave superparamagnetically at room temperature. In comparison, the treatment of the same starting core-shell nanocubes by commonly used thermal annealing process renders a transformation to γ-Fe 2 O 3 . In contrast to other thermal annealing processes, the method here presented has the advantage of promoting the oxidation at a macroscopic temperature below 37 °C. Using this soft oxidation process, we demonstrate that biotin-functionalized core-shell nanocubes can undergo a mild self-oxidation transformation without losing their functional molecular binding activity.

F/G-actin ratio modulation is known to have an important role in many cell functions and in the regulation of specific cell behaviors. Several attempts have been made in the latest decades to finely control actin production and polymerization, in order to promote certain cell responses. In this paper we demonstrate the possibility of modulating F/G-actin ratio and mechanical properties of normal human dermal fibroblasts by using boron nitride nanotubes dispersed in the culture medium and by stimulating them with ultrasound transducers. Increasing concentrations of nanotubes were tested with the cells, without any evidence of cytotoxicity up to 10 μg/ml concentration of nanoparticles. Cells treated with nanoparticles and ultrasound stimulation showed a significantly higher F/G-actin ratio in comparison with the controls, as well as a higher Young’s modulus. Assessment of Cdc42 activity revealed that actin nucleation/polymerization pathways, involving Rho GTPases, are probably influenced by nanotube-mediated stimulation, but they do not play a primary role in the significant increase of F/G-actin ratio of treated cells, such effect being mainly due to actin overexpression.

Here, we propose the use of magnetic hyperthermia as a means to trigger the oxidation of Fe O/Fe O core-shell nanocubes to Fe O phase. As a first relevant consequence, the specific absorption rate (SAR) of the initial core-shell nanocubes doubles after exposure to 25 cycles of alternating magnetic field stimulation. The improved SAR value was attributed to a gradual transformation of the Fe O core to Fe O , as evidenced by structural analysis including high resolution electron microscopy and Rietveld analysis of X-ray diffraction patterns. The magnetically oxidized nanocubes, having large and coherent Fe O domains, reveal high saturation magnetization and behave superparamagnetically at room temperature. In comparison, the treatment of the same starting core-shell nanocubes by commonly used thermal annealing process renders a transformation to γ-Fe O . In contrast to other thermal annealing processes, the method here presented has the advantage of promoting the oxidation at a macroscopic temperature below 37 °C. Using this soft oxidation process, we demonstrate that biotin-functionalized core-shell nanocubes can undergo a mild self-oxidation transformation without losing their functional molecular binding activity.

Here, we propose the use of magnetic hyperthermia as a means to trigger the oxidation of Fe 1−x O/Fe 3−δ O 4 core-shell nanocubes to Fe 3−δ O 4 phase. As a first relevant consequence, the specific absorption rate (SAR) of the initial core-shell nanocubes doubles after exposure to 25 cycles of alternating magnetic field stimulation. The improved SAR value was attributed to a gradual transformation of the Fe 1−x O core to Fe 3−δ O 4 , as evidenced by structural analysis including high resolution electron microscopy and Rietveld analysis of X-ray diffraction patterns. The magnetically oxidized nanocubes, having large and coherent Fe 3−δ O 4 domains, reveal high saturation magnetization and behave superparamagnetically at room temperature. In comparison, the treatment of the same starting core-shell nanocubes by commonly used thermal annealing process renders a transformation to γ-Fe 2 O 3 . In contrast to other thermal annealing processes, the method here presented has the advantage of promoting the oxidation at a macroscopic temperature below 37 °C. Using this soft oxidation process, we demonstrate that biotin-functionalized core-shell nanocubes can undergo a mild self-oxidation transformation without losing their functional molecular binding activity.

Among the strategies to fight cancer, multi-therapeutic approaches are considered as a wise choice to put in place multiple weapons to suppress tumors. In this work, to combine chemotherapeutic effects to magnetic hyperthermia when using biocompatible scaffolds, we have established an electrospinning method to produce nanofibers of polycaprolactone loaded with magnetic nanoparticles as heat mediators to be selectively activated under alternating magnetic field and doxorubicin as a chemotherapeutic drug. Production of the fibers was investigated with iron oxide nanoparticles of peculiar cubic shape (at 15 and 23 nm in cube edges) as they provide benchmark heat performance under clinical magnetic hyperthermia conditions. With 23 nm nanocubes when included into the fibers, an arrangement in chains was obtained. This linear configuration of magnetic nanoparticles resemble that of the magnetosomes, produced by magnetotactic bacteria, and our magnetic fibers exhibited remarkable heating effects as the magnetosomes. Magnetic fiber scaffolds showed excellent biocompatibility on fibroblast cells when missing the chemotherapeutic agent and when not exposed to magnetic hyperthermia as shown by viability assays. On the contrary, the fibers containing both magnetic nanocubes and doxorubicin showed significant cytotoxic effects on cervical cancer cells following the exposure to magnetic hyperthermia. Notably, these tests were conducted at magnetic hyperthermia field conditions of clinical use. As here shown, on the doxorubicin sensitive cervical cancer cells, the combination of heat damage by magnetic hyperthermia with enhanced diffusion of doxorubicin at therapeutic temperature are responsible for a more effective oncotherapy.

BackgroundData on genetic susceptibility to sporadic gastric carcinoma have been published at a growing pace, but to date no comprehensive overview and quantitative summary has been available.MethodsWe conducted a systematic review and meta-analysis of the evidence on the association between DNA variation and risk of developing stomach cancer. To assess result credibility, summary evidence was graded according to the Venice criteria and false positive report probability (FPRP) was calculated to further validate result noteworthiness. Meta-analysis was also conducted for subgroups, which were defined by ethnicity (Asian vs Caucasian), tumour histology (intestinal vs diffuse), tumour site (cardia vs non-cardia) and Helicobacter pylori infection status (positive vs negative).ResultsLiterature search identified 824 eligible studies comprising 2 530 706 subjects (cases: 261 386 (10.3%)) and investigating 2841 polymorphisms involving 952 distinct genes. Overall, we performed 456 primary and subgroup meta-analyses on 156 variants involving 101 genes. We identified 11 variants significantly associated with disease risk and assessed to have a high level of summary evidence: MUC1 rs2070803 at 1q22 (diffuse carcinoma subgroup), MTX1 rs2075570 at 1q22 (diffuse), PSCA rs2294008 at 8q24.2 (non-cardia), PRKAA1 rs13361707 5p13 (non-cardia), PLCE1 rs2274223 10q23 (cardia), TGFBR2 rs3087465 3p22 (Asian), PKLR rs3762272 1q22 (diffuse), PSCA rs2976392 (intestinal), GSTP1 rs1695 11q13 (Asian), CASP8 rs3834129 2q33 (mixed) and TNF rs1799724 6p21.3 (mixed), with the first nine variants characterised by a low FPRP. We also identified polymorphisms with lower quality significant associations (n=110).ConclusionsWe have identified several high-quality biomarkers of gastric cancer susceptibility. These data will form the backbone of an annually updated online resource that will be integral to the study of gastric carcinoma genetics and may inform future screening programmes.

Background Qualitative alterations or abnormal expression of microRNAs (miRNAs) in colon cancer have mainly been demonstrated in primary tumors. Poorly overlapping sets of oncomiRs, tumor suppressor miRNAs and metastamiRs have been linked with distinct stages in the progression of colorectal cancer. To identify changes in both miRNA and gene expression levels among normal colon mucosa, primary tumor and liver metastasis samples, and to classify miRNAs into functional networks, in this work miRNA and gene expression profiles in 158 samples from 46 patients were analysed. Results Most changes in miRNA and gene expression levels had already manifested in the primary tumors while these levels were almost stably maintained in the subsequent primary tumor-to-metastasis transition. In addition, comparing normal tissue, tumor and metastasis, we did not observe general impairment or any rise in miRNA biogenesis. While only few mRNAs were found to be differentially expressed between primary colorectal carcinoma and liver metastases, miRNA expression profiles can classify primary tumors and metastases well, including differential expression of miR-10b, miR-210 and miR-708. Of 82 miRNAs that were modulated during tumor progression, 22 were involved in EMT. qRT-PCR confirmed the down-regulation of miR-150 and miR-10b in both primary tumor and metastasis compared to normal mucosa and of miR-146a in metastases compared to primary tumor. The upregulation of miR-201 in metastasis compared both with normal and primary tumour was also confirmed. A preliminary survival analysis considering differentially expressed miRNAs suggested a possible link between miR-10b expression in metastasis and patient survival. By integrating miRNA and target gene expression data, we identified a combination of interconnected miRNAs, which are organized into sub-networks, including several regulatory relationships with differentially expressed genes. Key regulatory interactions were validated experimentally. Specific mixed circuits involving miRNAs and transcription factors were identified and deserve further investigation. The suppressor activity of miR-182 on ENTPD5 gene was identified for the first time and confirmed in an independent set of samples. Conclusions Using a large dataset of CRC miRNA and gene expression profiles, we describe the interplay of miRNA groups in regulating gene expression, which in turn affects modulated pathways that are important for tumor development.

Background Although surgery is the gold standard treatment of hepatic metastasis from colorectal cancer (CRC), many patients ultimately die of their disease. We tested the hypothesis that the detection of circulating tumor cells (CTC) might identify patients at high risk of dying of disease recurrence after apparently radical liver surgery. Methods We considered 50 patients undergoing radical surgery for liver-confined hepatic metastasis from CRC. The expression of a panel of cancer-related genes, as assessed by quantitative real-time PCR, was used to detect CTC in the peripheral blood of these patients immediately before surgery. Survival analysis was performed by the Cox regression model. Results Univariate analysis of the expression levels of CD133 (a marker of colon cancer stem cells) and survivin (an antiapoptotic factor) resulted in statistically significant association with patient survival [hazard ratio (HR) 2.7, 95% confidence interval (CI) 1.9–3.7, P  < 0.0001; and hazard ratio 2.1, 95% CI 1.4–3.2, P  < 0.0001, respectively]. Remarkably, multivariate analysis found that only the transcriptional amount of CD133 resulted in statistical significance (HR 2.6, 95% CI 1.9–3.6, P  < 0.0001), indicating that this biomarker can independently predict the survival of these patients. Conclusions CD133-positive CTC may represent a suitable prognostic marker to stratify the risk of patients who undergo liver resection for CRC metastasis, which opens the avenue to identifying and potentially monitoring the patients who are most likely to benefit from adjuvant treatments.