Protective Role of Nitric Oxide in Staphylococcus aureus Infection in Mice

This study was carried out to determine the role of nitric oxide (NO) in Staphylococcus aureus infection in mice. NO production in spleen cell cultures was induced by heat-killed S. aureus. Expression of mRNA of the inducible isoform of NO synthase (iNOS) was induced in the spleens and kidneys of S. aureus-infected mice. When mice were treated with monoclonal antibodies (MAbs) against tumor necrosis factor alpha (TNF-α) or gamma interferon (IFN-γ) before S. aureus infection, the induction of iNOS mRNA expression in the kidneys was inhibited. These MAbs also inhibited NO production in spleen cell cultures stimulated with heat-killed S. aureus. NO production in the spleen cell cultures and levels of urinary nitrate plus nitrite were suppressed by treatment with aminoguanidine (AG), a selective inhibitor of iNOS. The survival rates of AG-treated mice were significantly decreased by either lethal or sublethal S. aureus infections. However, an effect of AG administration on bacterial growth was not observed in the spleens and kidneys of mice during either type of infection. Production of TNF-α and IFN-γ was not affected by AG treatment in vitro and in vivo. These results suggest that NO plays an important role in protection from lethality by the infection, but the protective role of NO in host resistance against S. aureus infection was not proved. Moreover, our results show that TNF-α and IFN-γ regulate NO production while NO may not be involved in the regulation of the production of these cytokines during S. aureus infection.     

Extracellular vesicles released from irradiated neonatal mouse cheek tissue increased cell survival after radiation

Alopecia is one of the common symptoms after high-dose radiation exposure. In our experiments, neonatal mice that received 7 Gy X-ray exhibited defects in overall hair growth, except for their cheeks. This phenomenon might suggest that some substances were secreted and prevented hair follicle loss in the infant tissues around their cheeks after radiation damage. In this study, we focused on exosome-like vesicles (ELV) secreted from cheek skin tissues and back skin tissues, as control, and examined their radiation protective effects on mouse fibroblast cell lines. We observed that ELV from irradiated cheek skin showed protective effects from radiation. Our results suggest that ELV from radiation-exposed cheek skin tissue is one of the secreted factors that prevent hair follicle loss after high-dose radiation.     

Microbiome composition comparison in oral and atherosclerotic plaque from patients with and without periodontitis

Odontology - There is no conclusive evidence regarding a causal relationship between periodontitis and atherosclerosis. In this study, we examined the microbiome in the oral cavity and atheromatous...     

Progression in diagnostic pathology; development of virtual microscopy and its applications

Many systems have already been designed and successfully used for clinical laboratory and pathological examination. The evolution of image analysis was enabled when analog images of the original glass slides could be transferred to digital images with the rapid development of virtual microscopy and virtual slides depended upon computer technologies. Today, whole slide can be acquired by virtual microscopes. The applications of virtual microscopy and virtual slides for teaching, diagnosis, telepathology, and research are more widely used than those of real microscope and real glass slides. In traditional cancer diagnosis, pathologists examine biopsies to make diagnostic assessments largely based on two-dimensional cell morphology and tissue distribution. These assessments are subjective and often show considerable variability. However, automated cancer diagnostic system based on three-dimensional image analysis based on nuclear bulging sign enables objective judgments using quantitative measurements. We expect that the shortage of pathologists will be improved when an automated cancer diagnosis system is developed.     

Parallel enlargement of Marinesco bodies and nuclei and progressive deposition of p62 in pigmented neurons of the substantia nigra

Marinesco bodies (MBs) are spherical nuclear inclusions found in pigmented neurons of the substantia nigra. Although MBs are abundant in senescent brains, how they are related to aging processes remains unclear. Here, we performed a morphometric analysis of midbrain pigmented neurons to identify the possible influence of MBs on nuclear size. The transected area of the nucleus (nuclear area) was larger in the presence of MBs and was correlated with the area of MB (MB area) in all tested brains. The MB-associated nuclear enlargement was significant even after MB areas were subtracted from nuclear areas. Moreover, higher MB immunoreactivity of p62 was detected in the nucleoplasm of the enlarged MB-associated nuclei. This study on human brains is the first quantitative approach demonstrating MB-associated nuclear enlargement and progressive accumulation of small nucleoplasmic materials. Although cellular hypertrophy is usually considered to be an indication of the upregulation of cellular function, this might not always be the case. These findings suggest that an age-related decline of ubiquitin-proteasome and autophagy system activity and stagnation of undegradable materials are one of the candidate mechanisms to explain the age-related decline of neural activity in the substantia nigra.     

YES1 activation induces acquired resistance to neratinib in HER2‐amplified breast and lung cancers

Molecular‐targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan‐HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2‐positive breast cancer. However, acquired resistance of various cancers to molecular‐targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib‐resistant cell lines from HER2‐amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib‐resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1‐amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2‐targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.     

An experimental study for tumor detection by indocyanine green with near-infrared topography

We studied tumor detection by indocyanine green (ICG) with near-infrared topography in rat experimental tumors: hepatoma AH109A and osteosarcoma POB 102. Time-intensity curves and topograms after ICG injection were obtained in tumors and surrounding normal tissues. Intensities in tumors were slowly reduced, and intensities in normal tissues were rapidly reduced, resulting in positive tumor image in topogram. It is concluded that near-infrared topography enhanced by ICG is useful for cancer detection.