Predicting the BRAF mutation with pretreatment MRI radiomics features for melanoma brain metastases receiving Gamma Knife radiosurgery.

AIM: To develop a model using radiomics features extracted from magnetic resonance imaging (MRI) images of Gamma Knife radiosurgery (GKRS) to predict the BRAF mutation in patients with melanoma brain metastases (MBM). MATERIALS AND METHODS: Data of 220 tumours were classified into two groups. One was a group whose BRAF mutation was identified, and the other group whose BRAF mutation was not identified. We extracted 1,962 radiomics features from gadolinium contrast-enhanced T1-weighted MRI treatment-planning images. Synthetic Minority Over-sampling TEchnique (SMOTE) was performed to address the unbalanced data-related issues. A single-layer neural network (NN) was used to build predictive models with radiomics features. The sensitivity, specificity, accuracy, and the area under the curve (AUC) were evaluated to assess the model performance. RESULTS: The prediction performance for the final evaluation without the SMOTE had an accuracy of 77.14%, a specificity of 82.44%, a sensitivity of 81.85%, and an AUC of 0.79. The application of SMOTE improved the prediction model to an accuracy of 83.1%, a specificity of 87.07%, a sensitivity of 78.82%, and an AUC of 0.82. CONCLUSION: The current study showed the feasibility of generating a highly accurate NN model for the BRAF mutation prediction. The prediction performance improved with SMOTE. The model assists physicians to obtain more accurate expectations of the treatment outcome without a genetic test.

Prognostic significance of preoperative inflammatory response biomarkers in patients undergoing curative thoracoscopic esophagectomy for esophageal squamous cell carcinoma.

BACKGROUND: Recent studies have revealed significant relationships between the lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) and survival in various cancers. The purpose of this study was to confirm whether the LMR, NLR, and PLR have prognostic values, independent of clinicopathological criteria, in patients undergoing curative resection for esophageal cancer. METHODS: The LMR, NLR and PLR were calculated in 147 consecutive patients who underwent curative esophagectomy between January 2006 and December 2014. Receiver operating characteristics (ROC) curve analysis was conducted to identify the optimal cutoff values of each biomarkers. RESULTS: In multivariate analysis for cancer-specific survival (CSS), pTNM stage (p < 0.0001) and low LMR (p = 0.0081) were selected as independent prognostic factor. Similarly, pTNM stage(p < 0.0001) and low LMR (p = 0.0225) were found to be independent prognostic factor for overall survival (OS). There was no significant relationship between LMR, NLR and PLR and survival in patients with stage I or II, however, significant relationships between LMR and CSS or OS were observed in patients with stage III esophageal cancer. CONCLUSIONS: LMR can be used as a novel predictor of postoperative CSS and OS in patients with esophageal cancer and that it may be useful in identifying patients with a poor prognosis even after radical esophagectomy.

Electron microscopic investigation on the osteogenesis at titanium implant/bone marrow interface under masticatory loading.

Electron microscopic investigation on osteogenetic process at the implant surface of threadless rod-type titanium implants with different surface roughness of Ra 0.4 +/- 0.01 microm, Sm 2.6 +/- 0.3 microm and Ra 2.0 +/- 0.12 microm, Sm 36 +/- 9.1 microm was performed at the early stage of 21 and 42 days post implantation into the jawbones of four beagles under the load bearing condition of functional mastication. The implant surfaces were covered with a blood clot and haematopoietic stem cells (HSC) including phagocytic monocytes immediately after the implantation. Successively, osteogenic stem cells (OSC) migrated from cortical and/or trabecular endosteum to the HSC-layer on the implant surface. The new bone formation at the implant/bone marrow interface was developed by collaboration of osteomediator cells (OMC) differentiated from monocytes of HSC and osteoblast phenotype cells of OSC derived from endosteum of cortical bone and/or trabecular. The new bone layer at the implant surface consisted of two layers, solution-mediated calcification layer of pseudo bone and cell (osteoblast) -mediated calcification layer of true bone. The pseudo bone was produced by solution-mediated calcification of OMC- and HSC-remnants near by the implant surface. The bone healing process at the implant/bone marrow interface depended upon two factors; the migration of OSC from cortical and/or trabecular endosteum to the implant surface and the healing potentiality. Topographic dependency upon the bone healing potential at implant/bone marrow interface was not confirmed in this experiment under the load bearing condition of functional mastication.

No evidence to indicate topographic dependency on bone formation around cp titanium implants under masticatory loading.

In vitro studies have proved the topographic dependency upon osteogenesis on titanium plate by investigating the cell-adhesion, -shape, -proliferation, -differentiation, ALP activity and osteocalcin production of osteogenic stem cells, MG36, MC3T3-E1 and wild strains of bone formative cells from animal and human. However, this in vivo study on bone growth around cp titanium dental implants under masticatory loading did not demonstrate significant difference among the different surface roughness in the range of Ra 0.4-1.9 microm, Rz 2.8-11.2 microm, Rmax 3.6-28.1 microm and Sm 2.9-41.0 microm, which was estimated by measuring the bone contacts, bone occupancies and bone bonding strengths at the implant/bone marrow interface. It is revealed that the topographic dependency on the osteogenetic activity is apt to be covered with wide variation in bone healing potential under the clinical condition with functional biting load.

In vitro study on bone formation and surface topography from the standpoint of biomechanics.

Effect of surface topography upon cell-adhesion, -orientation and -differentiation was investigated by in vitro study on cellular responses to titanium substratum with different surface roughness. Cell-shape, -function and -differentiation depending upon the surface topography were clarified by use of bone formative group cells (BFGCs) derived from bone marrow of beagle's femur. BFGCs consisted of hematopoietic stem cells (HSC) and osteogenetic stem cells (OSC). Cell differentiation of BFGCs was expressed and promoted by structural changes of cytoskeleton, and cell-organella, which was caused by mechanical stress with cytoplasmic stretching of cell adhesions to the substratum. Phagocytic monocytes of HSC differentiated to osteomediator cells (OMC) by cytoplasmic stretching with cell adhesion to the substratum. The OMC mediated and promoted cell differentiation from OSC to osteoblast through osteoblastic phenotype cell (OBC) by cell-aggregation of nodules with "pile up" phenomenon of OBC onto OMC. The osteogenesis might be performed by coupling work of both cells, OMC originated from monocyte of HSC and OBC originated from OSC, which were explained by SEM, TEM and fluorescent probe investigation on BFGCs on the test plate of cp titanium plates with different topographies. This osteogenetic process was proved by investigating cell proliferation, DNA contents, cell-adhesion, alkaline phosphatase activity and osteocalcine productivity for cells on the titanium plates with different topographies. The study showed increased osteogenic effects for cells cultured on Ti with increased surface roughness. Possible mechanisms were discussed from a biomechanical perspective.

Morphologic studies on the biologic seal of titanium dental implants. Report II. In vivo study on the defending mechanism of epithelial adhesions/attachment against invasive factors.

Clinical measurements on gingival indices and morphologic observations were performed in this study to verify the defending mechanism of gingival soft tissue against foreign invasions from the perspective of epithelial adhesion/attachment to implant surfaces in the monkey mandible. The following zones were observed using scanning electron microscopy: (1) plaque zone, suggesting susceptibility of the gingival tissue to bacterial invasion; (2) nude zone, demonstrating indirect adhesion of epithelial cells to the implant surface through the mucous layer and preventing bacterial invasion; and (3) epithelial cell attached zone, having greater bond strength of epithelial cells at the cell-implant interface as compared to cell-cell bonding within the epithelial cell layer. This study suggested that epithelial cell attachment/adhesion may play a dominant role in retaining the successful condition of a dental implant.

Morphologic studies on the biologic seal of titanium dental implants. Report I. In vitro study on the epithelialization mechanism around the dental implant.

To propose a mechanism for apical epithelialization at the implant-tissue interface, cell contact to titanium surfaces and adhesive strength of epithelial-like (HGE) and fibroblastic (HGF) cells derived from human gingiva were investigated under three different media conditions containing plaque extracts: nonfiltered, 5-micron pore filtered, and 0.22-micron pore filtered. The plaque extracts had a greater effect in decreasing the growth rate of the HGF than of the HGE. Similarly, the HGE exhibited greater adhesive strength than the HGF. These differences in the cells' resistance to plaque extracts were also observed using light and electron microscopy. Evidence from this study suggests that the difference in growth, contact, and adhesive strength of the HGE and HGF cells to titanium surfaces may promote apical epithelialization under the pathologic condition.

Surface characterization of radio-frequency glow discharged and autoclaved titanium surfaces.

To characterize titanium surfaces treated with radio-frequency glow discharge (RFGD) after media exposure, surface chemical analyses were performed using x-ray photoelectron spectroscopy. Auger electron spectroscopy, and Fourier transform infrared-reflection absorption spectroscopy (FTIR-RAS). The RFGD treatments resulted in a cleaner surface as compared to as-sputtered or as-autoclaved titanium specimens. The oxide thickness of RFGD-treated titanium specimens was not statistically different from the as-autoclaved and as-sputter cleaned titanium specimens. Exposure to a phosphate-buffered saline solution revealed a greater deposition of calcium and phosphorous on the RFGD-treated surfaces. Auger electron spectroscopy depth profiles showed that calcium and phosphorous ions diffused into the titanium oxide layer. The calcium and phosphorous deposits were identified as amorphous calcium phosphate compounds using FTIR-RAS. These results suggest that RFGD treatments of titanium enhance calcium and/or phosphate affinity because of an increase in elemental interactions at the surface, thereby resulting in the formation of amorphous calcium phosphate compounds.

A naturally occurring 6-9-kilodalton interleukin-1 (IL-1) inhibitor prevents IL-1-mediated islet cytotoxicity but not IL-1-mediated suppression of insulin secretion.

Earlier studies have shown direct effects of interleukin-1 (IL-1) on isolated pancreatic islets. Coculture of isolated rat pancreatic islets with human rIL-1 beta for 6 days resulted in dose-dependent cytotoxicity (up to 100%) and suppression of insulin secretion (up to 88.5%). The cytotoxic effects of rIL-1 beta beta were blocked by the simultaneous presence of a naturally occurring 6-9-kilodalton (kDa) inhibitor of IL-1-induced T-cell proliferation. However, the ability of rIL-1 beta to suppress insulin secretion was not blocked by the 6-9-kDa inhibitor of IL-1 activity. This IL-1 inhibitor is produced by mononuclear cells and is resistant to pH 2, sensitive to heating at 56 degrees C for 30 min, has a pI of 4.5-5.6, and appears to be different from other recognized IL-1 inhibitors in both composition and mechanism of action. Unlike this IL-1 inhibitor, a monoclonal antibody specific for rIL-1 beta was able to neutralize both the islet cytotoxic and insulin modulatory effects of rIL-1 beta. These results demonstrate the use of an IL-1 inhibitor to prevent at least one mechanism of islet destruction, and suggest separate pathways for IL-1 mediated islet cytotoxicity and suppression of insulin secretion.

Species differences in human and rat islet sensitivity to human cytokines. Monoclonal anti-interleukin-1 (IL-1) influences on direct and indirect IL-1-mediated islet effects.

Species differences in sensitivity to human recombinant cytokines were observed when human or rat islets were co-cultured with human recombinant cytokines for 6 days. Suppression of both human and rat islet insulin secretion resulted from co-culture with recombinant interleukin-1 alpha (rIL-1 alpha) or interleukin-1 beta (rIL-1 beta); however, direct rIL-1 alpha and rIL-1 beta cytotoxicity was seen with rat islets but not with human islets. Human islet insulin secretion was also suppressed during co-culture with recombinant tumor necrosis factor (rTNF) or interferon (rIFN), but not with lymphotoxin (rLT) or rIL-6; rat islet insulin secretion was not suppressed by any of these cytokines. No direct cytotoxic effects resulted from co-culture of human islets with rLT, rTNF, rIFN, or rIL-6; rLT was slightly cytotoxic for rat islets. Human islet cytotoxic synergy occurred between rLT and rIL-1 alpha, rIL-1 beta, or rIFN; synergy in suppression of human islet insulin secretion occurred between rLT and rIL-1 beta, and between rIFN and rTNF. Pretreatment of rIL-1 with monoclonal antibody (mAb) specific for non-crossreactive epitopes on rIL-1 alpha (H43 and H12) or rIL-1 beta (H34 and H21) prevented islet cytotoxic synergy between rIL-1 alpha or rIL-1 beta, respectively, and rLT. Although all four mAb's neutralize the thymocyte and fibroblast stimulatory activities of rIL-1 alpha or rIL-1 beta, mAb H21 does not neutralize rIL-1 beta activity against rat islets. Implications for cytokine-mediated islet cytotoxicity and suppression of insulin secretion are discussed.

Heterogeneity in the specificity of the islet cell cytoplasmic antibody response in insulin-dependent diabetes mellitus.

We assessed the heterogeneity in the islet cell cytoplasmic antibody (ICA) response of insulin-dependent diabetes mellitus (IDDM) patients via indirect immunofluorescence on frozen sections of human, bovine, and porcine pancreas. The three substrates detected comparable frequencies of ICA positives among the IDDM sera tested, whereas control sera were ICA negative on all three substrates. However, individual IDDM serum samples showed heterogeneity in ICA binding on the three pancreata. Of 28 sera tested on all three substrates, 22 were ICA positive on human pancreas, three were ICA positive on bovine pancreas, and two were ICA positive on porcine pancreas. Sensitivity of ICA epitopes to neuraminidase treatment and periodate oxidation suggests that glycoconjugates are recognized by serum ICA. Cholera toxin blocked ICA binding. However, the functional cholera toxin receptor ganglioside Gm1 is resistant to neuraminidase treatment and periodate oxidation. Therefore, it is unlikely that Gm1 is the ICA determinant. These data suggest that not all ICA antigens are equivalently expressed on islets from different pancreata and/or that each individual responds to a hierarchy of islet antigens such that restricted patterns of specific ICA binding are found.

[Usefulness of collagen gel matrix culture for biological evaluation of dental materials (in vitro)].

Cytotoxicity of zinc oxide-eugenol cement was investigated using collagen gel matrix culture. Diffusibility of the main components into the collagen gel was measured by either atomic absorption or ultraviolet spectroscopy. The agar overlay culture method was also carried out for comparison. Results from solution cultures containing diluted collagen were similar to those with diluted agar. Longer culture with either cement liquid, eugenol, or zinc chloride solution, resulted in more depressed cell growth. The lower the powder/liquid ratio for mixing, the higher the cytotoxicity for all the materials tested in gelled collagen. Also, cytotoxicity levels were always lower in cultures with collagen than in those with agar. Diffusibility of the materials into collagen gel was similar to that into agar, but the of diffused components in collagen gel was less. Thus, the usefulness of collagen gel matrix culture for biological evaluation of dental materials was equivalent to that of agar overlay culture. However, it is suggested that collagen as a tissue matrix might provide a favorable environment for cell culture, and hence allow biocompatibility testing of biomaterials under simulated conditions.

The induction of helper and suppressor cells with secondary anti-hen egg-white lysozyme B hybridoma cells in the absence of antigen.

The results presented in this report define a dominant T cell-recognized public idiotype (SRId) expressed on monoclonal anti-chicken egg-white lysozyme (HEL) antibodies produced by hybridomas derived from secondary response lymphocytes. This Id mediates interactions between SRId+ B cells and SRId-recognizing T cells. In the absence of exogenous antigen, irradiated secondary anti-HEL B hybridoma cells (B-Hyb) of nonoverlapping specificity can be used to induce a helper T cell population capable of specifically stimulating an in vitro anti-HEL plaque-forming cell (PFC) response. Importantly, similar immunizations using carbodiimide-treated secondary anti-HEL B-Hyb cross-primed for a suppressor T cell population capable of suppressing this in vitro anti-HEL PFC response. That is, suppression was seen not only to the response induced by the homologous B-Hyb but to other B-Hyb which express anti-HEL monoclonal antibody of nonoverlapping specificity. This evidence is consistent with the presence of a pre-existent regulatory Id network involving SRId in antigennaive animals. After immunization with HEL, regulatory cells exert a strong selective pressure which leads to a secondary anti-HEL B population, of varying fine specificity, but uniformly positive for SRId.

H-2-linked Ir gene control of VH determinant(s)-specific helper T cells.

The fact that helper T cells (Th) recognize antigen in the context of class II MHC antigens is well documented. T cells specific for immunoglobulin (Ig) determinants have been demonstrated as have Th cells that interact with B cells in an idiotype (Id)-restricted manner. It is still controversial whether or not such T cells recognize idiotype in an MHC-restricted fashion. In tackling this problem it is important to have a T cell population selected by the introduction of the Ig bearing the determinant(s) in question and to have both the T cell and B cell populations unbiased by prior intentional exposure to specific exogenous antigen. Thus, the likelihood of such specific antigen-induced interactions is reduced and a clearer view of the Ig-induced interaction can be obtained. With this in mind, we found that T cells from B10.D2 mice immunized with normal BALB/c serum Ig were able to stimulate the response of BALB/c B cells to sheep red blood cells (SRBC) in vitro. H-2-linked Ir gene control was revealed by the ability of these Th cells to recognize BALB/c Ig in association with H-2d (BALB/c) but not H-2b (BALB.B). Through the use of Igh congenic mice, BAB/14 and C.B20, we found the Th cells to be specific for VH (idiotypic) rather than CH (allotypic) determinants; the determinant(s) in question was apparently expressed on some BALB/c anti-SRBC antibodies since these Th cells could help anti-SRBC responses but not anti-horse or anti-burro RBC responses. This conclusion of idiotypic specificity was supported by the fact that these Th cells could be primed with either IgM or IgG from BALB/c serum, one BALB/c anti-SRBC hybridoma protein but not two others or a BALB/c IgM myeloma protein, and by the fact that absorption of the serum on SRBC prior to separation of the Ig for immunization removed the priming ability of that Ig preparation. From the use of B cell mixing experiments, it was determined that the restriction elements of H-2 complex and the appropriate Ig determinants had to be borne on the responding B cells, suggesting that direct T-B collaboration was involved in the Th cell action. Therefore, by priming with normal serum Ig we have generated Th cells which act through direct interaction with responding B cells via a VH determinant(s). In addition, unlike the findings of others using different methods of priming Id-specific Th cells, these Th cells are under H-2-linked Ir gene control.(ABSTRACT TRUNCATED AT 400 WORDS)

Antigen-specific T helper clones in a nonresponder strain require augmentation for expression of helper activity. Evidence for a possible antigen presentation defect in B cells.

Hen egg-white lysozyme (HEL)-specific Thy-1+, Lyt-1+2- T cell lines and clones were derived from the nonresponder C57BL/6 strain. Although the antigen-specific proliferative response of these T cells in the presence of syngeneic irradiated spleen cells as a source of antigen-presenting cells (APC) was normal, the same cells were incapable of stimulating B cells to secrete antibody in vitro. This deficiency could, however, be corrected by the addition of an excess of normal T cells or a supernatant from concanavalin A-stimulated rat spleen cells. Alternatively, the use of highly cross-reactive ring-necked pheasant lysozyme in the cultures allowed expression of efficient help, ruling out any inherent deficiency in the T cells. The antibody response was specific and required MHC compatibility between the T lines and responding B cells. By using (H-2b X H-2d)F1 B cells and another H-2d-restricted HEL-specific T line, it was shown that only the H-2b-restricted T-B collaboration required exogenous factors, and the H-2d-restricted collaboration did not. Because both proliferative and helper responses are dependent upon MHC-restricted antigen presentation by macrophage-APC and B cells, respectively, these results suggest that the defect in the nonresponder H-2b-restricted T-B collaborative pathway may relate to the inability of B cells to adequately process and present HEL to clonal T cells.

Ice cream in the diet of insulin-dependent diabetic patients.

We investigated the effect of ice cream ingestion on blood glucose control in conventionally treated and intensively treated insulin-dependent (type I) diabetic patients. After the ingestion of 100 g of ice cream, plasma glucose excursions as measured by the peak increment (90 +/- 30 mg/dL) and area under the curve (166 +/- 59 mg/dL X hour) were modest and not significantly different between the subgroups of intensively treated and conventionally treated diabetics. A small dose (3 to 5 units) of rapid-acting insulin given 30 minutes before ingestion of ice cream reduced the modest plasma glucose excursion. A modest amount of ice cream may be included in weight-maintaining diets of insulin-dependent diabetics. Small doses of rapid-acting insulin prevent any adverse effect of the ice cream on blood glucose control.