Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication

Background: Homeobox B9 (HOXB9), a transcriptional factor, regulates developmental processes and tumor progression and has recently been recognized as one of important transcriptional factors related to angiogenesis. This study aimed to investigate the role of HOXB9 in tumorigenesis and angiogenesis. Methods: We examined the expression of HOXB9 in colorectal cancer using qPCR and in situ hybridization. We also examined the effect of HOXB9 overexpression in colorectal cancer using a proliferation assay, ELISA, a multiplex assay, and xenograft models. The clinical significance of HOXB9 was statistically evaluated in resected specimens. Results: HOXB9 was expressed in colorectal cancer specimens. HOXB9 induced angiogenesis and tumor proliferation in vitro, which resulted in high tumorigenicity in vivo and poor overall survival. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, remarkably suppressed tumor proliferation by inhibiting angiogenesis in HOXB9-overexpressing xenografts, and it improved overall survival and provided prolonged progression-free survival in HOXB9-overexpressing patients. A comprehensive multiplex assay of the supernatant of cancer cells co-cultured with human vascular endothelial cells and fibroblasts indicated significantly higher interleukin-6 (IL6) levels than those in the supernatant of monocultured cells. HOXB9 overexpression in clinical specimens was significantly correlated with increased IL6 expression. An IL6-neutralizing antibody inhibited VEGF secretion and tumor proliferation in the co-culture system. Conclusions: HOXB9 promotes the secretion of angiogenic factors, including VEGF, to induce tumor proliferation through microenvironmental production of cytokines including IL6 signaling. Moreover, silencing of VEGF or IL6 terminates cytokine release in tumor microenvironment. Thus, HOXB9 and IL6 may be potential biomarkers for bevacizumab treatment

Open Access

Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communicatio

Five doses of the mRNA vaccination potentially suppress ancestral-strain stimulated SARS-CoV2-specific cellular immunity: a cohort study from the Fukushima vaccination community survey, Japan

The bivalent mRNA vaccine is recommended to address coronavirus disease variants, with additional doses suggested for high-risk groups. However, the effectiveness, optimal frequency, and number of doses remain uncertain. In this study, we examined the long-term cellular and humoral immune responses following the fifth administration of the mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in patients undergoing hemodialysis. To our knowledge, this is the first study to monitor long-term data on humoral and cellular immunity dynamics in high-risk populations after five doses of mRNA vaccination, including the bivalent mRNA vaccine. Whereas most patients maintained humoral immunity throughout the observation period, we observed reduced cellular immune reactivity as measured by the ancestral-strain-stimulated ELISpot assay in a subset of patients. Half of the individuals (50%; 14/28) maintained cellular immunity three months after the fifth dose, despite acquiring humoral immunity. The absence of a relationship between positive controls and T-Spot reactivity suggests that these immune alterations were specific to SARS-CoV-2. In multivariable analysis, participants aged ≥70 years showed a marginally significant lower likelihood of having reactive results. Notably, among the 14 individuals who received heterologous vaccines, 13 successfully acquired cellular immunity, supporting the effectiveness of this administration strategy. These findings provide valuable insights for future vaccination strategies in vulnerable populations. However, further research is needed to evaluate the involvement of immune tolerance and exhaustion through repeated vaccination to optimize immunization strategies

Semi-quantitative analyses of metabolic systems of human colon cancer metastatic xenografts in livers of superimmunodeficient NOG mice

Analyses of energy metabolism in human cancer have been difficult because of rapid turnover of the metabolites and difficulties in reducing time for collecting clinical samples under surgical procedures. Utilization of xenograft transplantation of human-derived colon cancer HCT116 cells in spleens of superimmunodeficient NOD/SCID/IL-2Rγnull (NOG) mice led us to establish an experimental model of hepatic micrometastasis of the solid tumor, whereby analyses of the tissue sections collected by snap-frozen procedures through newly developed microscopic imaging mass spectrometry (MIMS) revealed distinct spatial distribution of a variety of metabolites. To perform intergroup comparison of the signal intensities of metabolites among different tissue sections collected from mice in fed states, we combined matrix-assisted laser desorption/ionization time-of-flight imaging mass spectrometry (MALDI–TOF-IMS) and capillary electrophoresis–mass spectrometry (CE–MS), to determine the apparent contents of individual metabolites in serial tissue sections. The results indicated significant elevation of ATP and energy charge in both metastases and the parenchyma of the tumor-bearing livers. To note were significant increases in UDP-N-acetyl hexosamines, and reduced and oxidized forms of glutathione in the metastatic foci versus the liver parenchyma. These findings thus provided a potentially important method for characterizing the properties of metabolic systems of human-derived cancer and the host tissues in vivo

Adjuvants that Enhance Th2 or Tr Responses

It is well-known that many isoforms of toll-like receptors (TLRs) function as Th1 adjuvant receptors. Thus, the ligands induce Th1 differentiation in an antigen non-specific manner. During the past few years, not only Th1, but also Th2 adjuvants have been reported. Allergy-inducing materials, such as parasites, first stimulate dendritic cells (DCs) to change their character as professional antigen-presenting cells. Such a DC population (DC2) can stimulate naive CD4T cells to induce differentiation into Th2. In some instances, DCs that can stimulate regulatory T cells are also induced. Interestingly, many of such substances are glycolipids or phospholipids that mammalian species do not usually carry. In this paper, we show a cellular and molecular basis for Th2 adjuvants

Effects of Grain Size on Ultrasonic Attenuation in Type 316L Stainless Steel

A lead bismuth eutectic (LBE) spallation target will be installed in the Target Test Facility (TEF-T) in the Japan Proton Accelerator Research Complex (J-PARC). The spallation target vessel filled with LBE is made of type 316L stainless steel. However, various damages, such as erosion/corrosion damage and liquid metal embrittlement caused by contact with flowing LBE at high temperature, and irradiation hardening caused by protons and neutrons, may be inflicted on the target vessel, which will deteriorate the steel and might break the vessel. To monitor the target vessel for prevention of an accident, an ultrasonic technique has been proposed to establish off-line evaluation for estimating vessel material status during the target maintenance period. Basic R&D must be carried out to clarify the dependency of ultrasonic wave propagation behavior on material microstructures and obtain fundamental knowledge. As a first step, ultrasonic waves scattered by the grains of type 316L stainless steel are investigated using new experimental and numerical approaches in the present study. The results show that the grain size can be evaluated exactly and quantitatively by calculating the attenuation coefficient of the ultrasonic waves scattered by the grains. The results also show that the scattering regimes of ultrasonic waves depend heavily on the ratio of wavelength to average grain size, and are dominated by grains of extraordinarily large size along the wave propagation path