Current understanding of comparative pathology and prospective research approaches for canine hemangiosarcoma.

Hemangiosarcoma (HSA) is a malignant tumor originating from endothelial cells. HSA typically develops in dogs, but is rare in other animals, including humans. Although surgery and chemotherapy are conventional treatments for HSA, neither treatment can significantly improve patient prognosis. To develop novel and effective therapeutics, a deeper understanding of HSA pathogenesis must be acquired. However, the limited research tools for HSA have been unable to make a breakthrough; therefore, it is crucial to widely utilize or establish novel research tools such as patient-derived xenograft models, organoids, and chicken embryo xenograft models. The pathogenesis of the human counterpart of HSA, angiosarcoma (AS), also remains incompletely understood, preventing the extrapolation of findings from humans to dogs, unlike other diseases. In this review, we summarize the clinicopathological and morphological features of HSA, and then we discuss the current understanding of the molecular pathology of HSA. Finally, we highlight promising research tools that may accelerate HSA basic research toward developing novel therapeutics. We also briefly summarize AS to help researchers comprehend HSA from the perspective of comparative pathology.

Diverse genome-wide DNA methylation alterations in canine hepatocellular tumours.

BACKGROUND: Canine hepatocellular tumours (HCTs) are common primary liver tumours. However, the exact mechanisms of tumourigenesis remain unclear. Although some genetic mutations have been reported, DNA methylation alterations in canine HCT have not been well studied. OBJECTIVES: In this study, we aimed to analyse the DNA methylation status of canine HCT. METHODS: Tissues from 33 hepatocellular carcinomas, 3 hepatocellular adenomas, 1 nodular hyperplasia, 21 non-tumour livers from the patients and normal livers from 5 healthy dogs were used. We analysed the DNA methylation levels of 72,367 cytosine-guanine dinucleotides (CpG sites) in all 63 samples. RESULTS AND CONCLUSIONS: Although a large fraction of CpG sites that were highly methylated in the normal liver became hypomethylated in tumours from most patients, we also found some patients with less remarkable change or no change in DNA methylation. Hierarchical clustering analysis revealed that 32 of 37 tumour samples differed from normal livers, although the remaining 5 tumour livers fell into the same cluster as normal livers. In addition, the number of hypermethylated genes in tumour livers varied among tumour cases, suggesting various DNA methylation patterns in different tumour groups. However, patient and clinical parameters, such as age, were not associated with DNA methylation status. In conclusion, we found that HCTs undergo aberrant and diverse patterns of genome-wide DNA methylation compared with normal liver tissue, suggesting a complex epigenetic mechanism in canine HCT.

Virological, pathological, and glycovirological investigations of an Ezo red fox and a tanuki naturally infected with H5N1 high pathogenicity avian influenza viruses in Hokkaido, Japan.

In winter/spring 2021-2022, high pathogenicity avian influenza viruses (HPAIVs) that are genetically closely related to each other were detected worldwide. In a public garden in Sapporo, Hokkaido, Japan, a crow die-off by HPAIV infection occurred from March 29 to May 18, 2022. During the event, H5N1 HPAIVs were isolated from an Ezo red fox (Vulpes vulpes schrencki) and a tanuki (Nyctereutes procyonoides albus) found in the same garden. The fox showed viral meningoencephalitis and moderate virus replication in the upper respiratory tract, whereas the tanuki showed viral conjunctivitis and secondary bacterial infection in the eyes accompanied with visceral larva migrans. Viruses isolated from the fox and the tanuki were genetically closely related to those isolated from crows in the same garden. Various α2-3 sialosides were found in the respiratory tracts of these canid mammals, consistent with HPAIV infections in these animals. This study highlighted the importance of monitoring HPAIV infections in wild carnivore mammals to detect the potential virus spreading in nature.

Retrospective evaluation of clinical signs, clinical course, and prognosis between dogs with left atrial rupture secondary to myxomatous mitral valve disease and those with neoplastic cardiac tamponade (2015-2019): 70 cases.

OBJECTIVE: To describe the clinical signs, clinical course, and prognosis of suspected left atrial rupture (LAR) secondary to myxomatous mitral valve disease (MMVD) in dogs and to compare them with dogs with suspected neoplastic cardiac tamponade (NCT). DESIGN: Retrospective study from November 2015 to October 2019 SETTING: An out-of-hours Emergency Animal Hospital. ANIMALS: Twenty-three dogs with LAR secondary to MMVD (LAR group) and 47 dogs with NCT (NCT group). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The following were the characteristics of the study population (LAR group vs NCT groups) with P < 0.05 as the significance threshold: male sex, 83% vs 66%; median age, 11.9 vs 12.5 years; and median weight, 3.8 vs 6.4 kg (P < 0.001). Chihuahuas and Miniature Dachshunds were overrepresented in the LAR and NCT groups, respectively. Statistically different clinical findings between the 2 groups were as follows (LAR vs NCT): pulmonary edema, 43% vs 0%; pericardial thrombus, 70% vs 6% (P < 0.001); ineffectiveness of pericardiocentesis (whether aspiration of pericardial fluid was successful or not), 58% vs 2% (P < 0.001); mortality rate within 48 hours of visiting hospital, 35% vs 9% (P < 0.01). No significant difference was observed in survival time after discharge between the 2 groups. CONCLUSIONS: The proportion of dogs with a diagnosis of LAR secondary to MMVD in dogs with cardiac tamponade was higher than the previously reported rate. Furthermore, the frequency of pulmonary edema, ineffectiveness of pericardiocentesis, and short-term mortality rate was higher in the LAR group than in the NCT group.

Manipulating histone acetylation leads to antitumor effects in hemangiosarcoma cells.

Canine hemangiosarcoma (HSA) is a malignant tumour derived from endothelial cells. No effective treatment has yet been developed because of the lack of understanding of its pathogenesis. Histone acetylation, an epigenetic modification, is highly associated with cancer pathogenesis. Manipulating histone acetylation by histone deacetylase inhibitors (HDACi) or bromodomain and extraterminal domain inhibitors (BETi) is one approach to treat various cancers. However, the role of histone acetylation in HSA remains unknown. This study aimed to investigate how histone acetylation functions in HSA pathogenesis using two HDACi, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), and one BETi, JQ1, in vitro and in vivo. Histone acetylation levels were high in cell lines and heterogeneous in clinical cases. SAHA and JQ1 induced apoptosis in HSA cell lines. HSA cell lines treated with SAHA and VPA upregulated inflammatory-related genes and attracted macrophage cell line RAW264 cells, which suggests that SAHA and VPA can affect immune responses. JQ1 stimulated autophagy and inhibited the cell cycle in HSA cell lines. Finally, we demonstrated that JQ1 suppressed HSA tumour cell proliferation in vivo although SAHA and VPA did not affect tumour growth. These results suggest that BETi can be alternative drugs for HSA treatment. Although further research is required, our study indicated that dysregulation of histone acetylation is likely to be involved in HSA malignancy.

Hemangiosarcoma cells induce M2 polarization and PD-L1 expression in macrophages.

Hemangiosarcoma (HSA) is a malignant tumor derived from endothelial cells. Tumor-associated macrophages are one of the major components of tumor microenvironment and crucial for cancer development. The presence and function of macrophages in HSA have not been studied because there is no syngeneic model for HSA. In this study, we evaluated two mouse HSA cell lines and one immortalized mouse endothelial cell line for their usefulness as syngeneic models for canine HSA. Our results showed that the ISOS-1 cell line developed tumors with similar morphology to canine HSA. ISOS-1 cells highly expressed KDM2B and had similar KDM2B target expression patterns with canine HSA. Moreover, we determined that in both ISOS-1 and canine HSA tumors, macrophages were present as a major constituent of the tumor microenvironment. These macrophages were positive for CD204, an M2 macrophage marker, and express PD-L1, an immune checkpoint molecule. Canine HSA with macrophages expressing PD-L1 had a smaller number of T-cells in tumor tissues than tumors with PD-L1 negative macrophages. ISOS-1-conditioned medium could induce M2 polarization and PD-L1 expression in RAW264.7 mouse macrophage cell line and mouse peritoneal macrophages. These results show that ISOS-1 can be used as a syngenic model for canine HSA and suggest that macrophages play an important role in immune evasion in HSA. Using the syngeneic mouse model for canine HSA, we can further study the role of immune cells in the pathology of HSA.

Selenoneine, a novel selenium-containing compound, mediates detoxification mechanisms against methylmercury accumulation and toxicity in zebrafish embryo.

The selenium (Se)-containing antioxidant selenoneine (2-selenyl-N α,N α,N α-trimethyl-L-histidine) has recently been discovered to be the predominant form of organic Se in tuna blood. Although dietary intake of fish Se has been suggested to reduce methylmercury (MeHg) toxicity, the molecular mechanism of MeHg detoxification by Se has not yet been determined. Here, we report evidence that selenoneine accelerates the excretion and demethylation of MeHg, mediated by a selenoneine-specific transporter, organic cations/carnitine transporter-1 (OCTN1). Selenoneine was incorporated into human embryonic kidney HEK293 cells transiently overexpressing OCTN1 and zebrafish blood cells by OCTN1. The K m for selenoneine uptake was 13.0 µM in OCTN1-overexpressing HEK293 cells and 9.5 µM in zebrafish blood cells, indicating high affinity of OCTN1 for selenoneine in human and zebrafish cells. When such OCTN1-expressing cells and embryos were exposed to MeHg-cysteine (MeHgCys), MeHg accumulation was decreased and the excretion and demethylation of MeHg were enhanced by selenoneine. In addition, exosomal secretion vesicles were detected in the culture water of embryos that had been microinjected with MeHgCys, suggesting that these may be responsible for MeHg excretion and demethylation. In contrast, OCTN1-deficient embryos accumulated MeHg, and MeHg excretion and demethylation were decreased. Furthermore, Hg accumulation was decreased in OCTN1-overexpressing HEK293 cells, but not in mock vector-transfected cells, indicating that selenoneine and OCTN1 can regulate MeHg detoxification in human cells. Thus, the selenoneine-mediated OCTN1 system regulates secretory lysosomal vesicle formation and MeHg demethylation.

Stress coping ability in nursing students: studies on the influence factor of Sense of Coherence (SOC).

The researchers conducted an investigation on factors influencing stress coping ability, referred to as a Sense of Coherence (SOC). 278 students in the 2nd to 4th year of "A" University nursing program were subjected to this survey, and the response rate was 75.5%. The average SOC value was 39.5 +/- 6.6 for males, and 37.4 +/- 7.0 for females. The value for age group 20 to 24 years old was 37.1 +/- 6.8. The average SOC value obtained through this survey was higher than the survey results of the Kanto region and lower than the national results. When a comparison was made between "the group with higher average SOC" and "the group with lower average SOC" among the entire survey average SOC, especially significant differences were discovered in the following items. "Prospects for the future is bright", "Difficult experiences have meaning", "I have good relationship with friends", "I feel stressed", and "I was seriously ill" (P < 0.001). "I am always interested in other people", and "I have a friend to rely on in difficult circumstances" (P<0.01). "I can do most anything if I put my mind to it", "We can encourage each other", "I am satisfied with my current situation", "I was satisfied with my role in my club", and "I was able to enter my desired university" (P<0.05). The researchers categorized these items into 1) Positive meaning from a difficult experience, 2) Cognition to prevent stressor from becoming negative stress, 3) Experience of success, 4) Satisfaction and self-confidence, 5) Sociability, and 6) Presence of a reliable other. It was discovered that offering environment where people can work hard together by learning from others is an important issue to improve SOC.

Consideration of grand design for the care environment in hospitals--smell, lighting and sound.

We investigated grand designs for the care environment in hospitals, focusing on smell, lighting and sound, based on a database of observed domestic general hospitals (12 institutions), consisting of 1235 photographs and descriptive data. As a result, we identified four areas that should be incorporated into grand designs for this type of care environment: [1] The smell environment with (1) the exclusion of "odors", and (2) regulation of "fragrances"; [2] the lighting environment with lighting that successfully incorporates nature; [3] the sound environment that incorporates (1) pleasant sounds, and (2) the exclusion of excess noise; and [4] a natural environment and a healing space where individuals can feel at ease. The most important challenges in reform of the care environment are an emphasis on an approach that employs the senses, and the necessity of raising the awareness of healthcare providers in relation to this type of environment. Although current hospital care environments are being improved through the independent efforts of hospitals themselves, we anticipate that the future will bring about a care environment in which more attention is paid to air quality, lighting and sound, when assessing, hospital function.