Integrin Inhibitor Suppresses Bevacizumab-Induced Glioma Invasion

Glioblastoma is known to secrete high levels of vascular endothelial growth factor (VEGF), and clinical studies with bevacizumab, a monoclonal antibody to VEGF, have demonstrated convincing therapeutic benefits in glioblastoma patients. However, its induction of invasive proliferation has also been reported. We examined the effects of treatment with cilengitide, an integrin inhibitor, on bevacizumab-induced invasive changes in glioma. U87 Delta EGFR cells were stereotactically injected into the brain of nude mice or rats. Five days after tumor implantation, cilengitide and bevacizumab were administered intraperitoneally three times a week. At 18 days after tumor implantation, the brains were removed and observed histopathologically. Next, the bevacizumab and cilengitide combination group was compared to the bevacizumab monotherapy group using microarray analysis. Bevacizumab treatment led to increased cell invasion in spite of decreased angiogenesis. When the rats were treated with a combination of bevacizumab and cilengitide, the depth of tumor invasion was significantly less than with only bevacizumab. Pathway analysis demonstrated the inhibition of invasion-associated genes such as the integrin-mediated cell adhesion pathway in the combination group. This study showed that the combination of bevacizumab with cilengitide exerted its anti-invasive effect. The elucidation of this mechanism might contribute to the treatment of bevacizumab-refractory glioma

Gene expression profiling of the anti-glioma effect of Cilengitide

Cilengitide (EMD121974), an inhibitor of the adhesive function of integrins, demonstrated preclinical efficacy against malignant glioma. It is speculated that cilengitide can inhibit tumor growth, invasion, and angiogenesis. However, the effects of cilengitide on these processes have not been sufficiently examined. In this study, we investigated the anti-glioma effect of cilengitide using DNA microarray analysis. U87ΔEGFR cells (human malignant glioma cell line) were used for this experiment. The cells were harvested after 16 h of cilengitide treatment, and mRNA was extracted. Gene expression and pathway analyses were performed using a DNA microarray (CodeLink™Human Whole Genome Bioarray). The expression of 265 genes was changed with cilengitide treatment. The expression of 214 genes was up-regulated by more than 4-fold and the expression of 51 genes was down-regulated by more than 4-fold compared to the controls. In pathway analysis, "apoptotic cleavage of cellular proteins" and "TNF receptor signaling pathway" were over-represented. Apoptotic-associated genes such as caspase 8 were up-regulated. Gene expression profiling revealed more detailed mechanism of the anti-glioma effect of cilengitide. Genes associated with apoptosis were over-represented following cilengitide treatment

Genomic Profiling of a Case of Glioneuronal Tumor with Neuropil-like Islands

Glioneuronal tumor with neuropil-like islands (GNTNI) is a very rare subtype of glioneuronal tumor. We present a case of a 62-year-old man with GNTNI. Two adjacent lesions in the left parietal lobe were removed by left parietal craniotomy. The histological findings were glial cell proliferation and scattered rosettes consisting of synaptophysin-positive and NeuN-positive cells, leading to the diagnosis of GNTNI. Target sequencing revealed a genetic alteration similar to glioblastoma, IDH-wild type, which suggested adjuvant therapies. There are few previous reports on the treatment of this disease, and the patient should be followed carefully

Utility of Comprehensive Genomic Profiling for Precise Diagnosis of Pediatric-Type Diffuse High-Grade Glioma

In the current World Health Organization classification of central nervous system tumors, comprehensive genetic and epigenetic analyses are considered essential for precise diagnosis. A 14-year-old male patient who presented with a cerebellar tumor was initially diagnosed with glioblastoma and treated with radiation and concomitant temozolomide chemotherapy after resection. During maintenance temozolomide therapy, a new contrast-enhanced lesion developed in the bottom of the cavity formed by the resection. A second surgery was performed, but the histological findings in specimens from the second surgery were different from those of the first surgery. Although genome-wide DNA methylation profiling was conducted using frozen tissue for a precise diagnosis, the proportion of tumor cells was insufficient and only normal cerebellum was observed. We then performed comprehensive genetic analysis using formalin-fixed paraffin-embedded sections, which revealed MYCN amplification without alteration of IDH1, IDH2, or Histone H3. Finally, the patient was diagnosed with pediatric-type diffuse high-grade glioma, H3-wildtype and IDH-wildtype. In conclusion, comprehensive genetic and epigenetic analysis should be considered in pediatric brain tumor cases

Two cases of mandibular and masticatory reconstruction with vascularized fibra bone flaps and implants

　Defects of the jawbone have conventionally been repaired using free bone grafts and metallic plates, but patients undergoing reconstruction using these materials experience difficulty using dentures and restoring masticatory function. The use of vascularized bone grafts, which has recently been enabled, has improved bone graft survival rates, and its combination with dental implants has enabled both morphological and functional reconstruction, leading to a higher quality of life. 　We experienced two patients with tumors of the jaw that were treated by resecting and reconstructing it using a vascularized bone graft with the cooperation of the Department of Plastic Surgery in the School of Medicine. We subsequently inserted dental implants, and the superstructure was created by the Department of Prosthetics. We report the course of these patients, who achieved sufficient jaw morphology as well as masticatory function and who are presently satisfied overall three years to three years and nine months postoperatively

Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration

Glioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells

Examination of the PONV after general anesthesia for orthognathic surgery

The purpose of this study is to evaluate the rate of incidence and risk factor of postoperative nausea and vomiting (PONV) in patients who underwent orthognathic surgery. The subjects were 84 patients aged 1₅–₅2 years old (3₇ males and 4₇ females) who underwent orthognathic surgery under general anesthesia in Matsumoto Dental University Hospital from January 2011 to October 2016. The operation methods were sagittal split ramus osteotomy （SSRO) 44 cases, SSRO and Le Fort I osteotomy（Le Fort I）28 cases, SSRO, Le Fort I and genioplasty 6 cases, SSRO and genioplasty 4 cases, Le Fort I and anterior maxillary alveolar osteotomy 1 case, and SSRO, Le Fort I and genioplasty with upper and lower alveolar bone osteotomy 1case. Anesthesia was maintained with nitrous oxide or air in oxygen, sevoflurane or desflurane, remifentanil and fentanyl. The factors investigated were age, gender, minimum alveolar concentration hours (MAC hours), use of nitrous oxide, remifentanil dose, anesthesia time and the type of surgery. Statistical investigation was preformed using logistic regression analysis to confirm the significance between the incidence of PONV and follows; age, gender, MAC hours, use of nitrous oxide, remifentanil dose, anesthesia time and the type of surgery. The rate of incidence in nausea was ₇₇％, and that in vomiting was 3₅%. The incidence of nausea was 4.4 times higher in females than males. The incidence of vomiting was 4.6 times higher in cases with nitrous oxide than those without nitrous oxide

Addressing ecological effects of radiation on populations and ecosystems to improve protection of the environment against radiation: Agreed statements from a Consensus Symposium

This paper reports the output of a consensus symposium organized by the International Union of Radioecology in November 2015. The symposium gathered an academically diverse group of 30 scientists to consider the still debated ecological impact of radiation on populations and ecosystems. Stimulated by the Chernobyl and Fukushima disasters' accidental contamination of the environment, there is increasing interest in developing environmental radiation protection frameworks. Scientific research conducted in a variety of laboratory and field settings has improved our knowledge of the effects of ionizing radiation on the environment. However, the results from such studies sometimes appear contradictory and there is disagreement about the implications for risk assessment. The Symposium discussions therefore focused on issues that might lead to different interpretations of the results, such as laboratory versus field approaches, organism versus population and ecosystemic inference strategies, dose estimation approaches and their significance under chronic exposure conditions. The participating scientists, from across the spectrum of disciplines and research areas, extending also beyond the traditional radioecology community, successfully developed a constructive spirit directed at understanding discrepancies. From the discussions, the group has derived seven consensus statements related to environmental protection against radiation, which are supplemented with some recommendations. Each of these statements is contextualized and discussed in view of contributing to the orientation and integration of future research, the results of which should yield better consensus on the ecological impact of radiation and consolidate suitable approaches for efficient radiological protection of the environment.Keywords: Consensus development, Environmental protection, Populations, Radiation effects, Ecosystems, Ecological risk assessmen

Community and trophic structures of pelagic copepods down to greater depths in the western subarctic Pacific (WEST-COSMIC)

As part of the research program “WEST-COSMIC (Western Pacific Environment Study on CO2 Ocean Sequestration for Mitigation of Climate Change)”, vertical distribution and community structure of copepods were studied at Station Knot (44˚N, 155˚E) down to 4000 m depth in the western subarctic Pacific. Vertical carbon flux mediated by copepod communities was also estimated. Both abundance and biomass of copepods were greatest in the near surface layer and decreased with increasing depth. Decrease of abundance with depth was best fitted to power regression model, while that of biomass was best described by an exponential regression model. Copepod carcasses occurred throughout the layer, and carcasses/living specimens ratios were greatest in the deepest layer (the ratio was 9.3 at 3000-4000 m depth). A total of 98 calanoid copepod species belonging to 38 genera and 15 families occurred in the 0-4000 m water column (Cyclopoida, Harpacticoida and Poecilostomatoida were not identified to species). The number of genera and species showed bimodal vertical distributions with peaks at 500-1000, and at 2000-3000 m both during day and night. Based on the species similarity indices, copepod community could be classified into epipelagic, mesopelagic and bathypelagic communities. Based on the feeding pattern, copepods were divided into four types: suspension feeders, suspension feeders in diapause, detritivores and carnivores. In terms of abundance, the most dominant group was suspension feeders (mainly the cyclopoid genus Oithona) in the epipelagic zone, while detritivores (mainly Poecilostomatoida genus Oncaea) were dominant in the meso- and bathypelagic zones. In terms of biomass, suspension feeders in diapause (calanoid genera Neocalanus and Eucalanus) were the major component (ca. 70%), especially at 200-2000 m depth. Comparison of vertical flux of particulate carbon with estimated copepod ingestion/egestion rates suggests that the suspension feeding copepods receive sufficient food. For detritivorous copepods, copepod carcasses, a possible food source, are not abundant enough, so other food sources need to be considered. As a food source for carnivorous copepods, the abundance of suspension feeding and detritivorous copepods appears to be high enough to meet their demand. Our calculation showed that an average of 32% of the particulate carbon flux is consumed by copepods in the 0-4000 m water column