Transmission of Helicobacter pylori between a human and two dogs: A case report.

BACKGROUND: Whereas non-Helicobacter pylori helicobacters, which are frequently detected in the stomachs of dogs and cats as a source of zoonoses, have attracted considerable attention, the role of pets in H. pylori epidemiology is unclear. In our previous study, an H. pylori infection was detected in the stomach of a dog (Dog 1). Here, we investigated the H. pylori infection status in the female offspring of Dog 1 (Dog 2) and its owner within the same household. MATERIALS AND METHODS: Biopsy specimens were obtained from the dog's owner and tested for H. pylori. DNA from gastric biopsy samples of Dog 1, gastric fluid sediment of Dog 2, and bacteria from the stomach of the owner was obtained, and Helicobacter genus- and species-specific PCRs were performed. Then, sequence analyses of the partial region of the ureAB gene were conducted. RESULTS: Samples from both dogs and the owner reacted positively in the genus-specific PCR and negative in the Helicobacter felis-, Helicobacter bizzozeronii-, and Helicobacter heilmannii sensu stricto-specific PCRs. All three samples also reacted positively in the H. pylori-specific PCR. Sequences of the partial ureAB gene from all subjects were identical. CONCLUSIONS: The results suggested that the two dogs and their owner were infected with an identical H. pylori strain. This report is the first to demonstrate that H. pylori can be transmitted between humans and dogs. Further studies are required to investigate the risk factors for the transmission of H. pylori between humans and dogs from the perspective of preventive epidemiology.

Long-Term Observation of the Progression From Nodal Marginal Zone Lymphoma to Diffuse Large B-Cell Lymphoma in a Dog.

A 4-year and 10-month old female Pembroke Welsh Corgi presented with an enlarged right popliteal lymph node, and a histopathological diagnosis of nodal marginal zone lymphoma (nMZL) was made. After resection of the lymph node, follow-up observation was continued without chemotherapy. At 22 months after initial presentation, the dog developed enlargement of peripheral lymph nodes, and the histopathological diagnosis was late-stage nMZL. Multidrug chemotherapy induced clinical complete remission, but the tumor relapsed with enlargement of peripheral and abdominal lymph nodes 42 months after initial presentation. Second-round multidrug chemotherapy induced complete clinical remission again; however, the tumor relapsed with lymphadenopathy 47 months after initial presentation. The dog died 59 months after initial presentation, and postmortem examination revealed generalized lymphadenopathy; the histopathological diagnosis was diffuse large B-cell lymphoma (DLBCL). Polymerase chain reaction for antigen receptor gene rearrangements revealed that the nMZL and DLBCL samples were derived from the same B-lymphocyte clone.

A histopathological study on spontaneous gastrointestinal epithelial tumors in dogs.

The present study evaluated the histopathological features, biological nature, anatomical location, sex, age and breeds of dogs affected by spontaneous gastrointestinal epithelial tumor. Biopsy samples of gastrointestinal tumors, from 95 dogs were examined and classified according to the WHO histological classification. A total of 131 samples, including 38 gastric, 13 small intestinal, and 80 large intestinal tumors were examined. The study observed that Jack Russell Terriers and Miniature Dachshunds were the breeds with the highest predisposition for gastrointestinal tumors. Gastric tumors included 5 adenomas, 30 adenocarcinomas (12 tubular, 2 papillary, 4 tubulopapillary and 12 signet-ring cell carcinomas) and 3 undifferentiated carcinomas. Intestinal tumors included 35 adenomas, 57 adenocarcinomas (43 acinar, 4 papillary, 7 mucinous and 3 signet-ring cell carcinomas), and 1 undifferentiated carcinoma. The study did not detect any difference among the incidence rates of invasion/metastasis in the tubular (44%), papillary (33%) and tubulopapillary (25%) adenocarcinomas. Additionally, the tubular (acinar), papillary and tubulopapillary adenocarcinomas were further divided into 48 polypoid and 17 non-polypoid types, based on their growth patterns. Invasion/metastasis was detected in 21% of the polypoid type and 100% of the non-polypoid type of adenocarcinomas. A correlation was detected between the occurrence of invasion/metastasis and the type of histopathological growth pattern in adenocarcinomas. The study demonstrated that Jack Russell terriers and Miniature Dachshunds are the most common breeds affected by gastrointestinal tumors and the entire group of the canine adenocarcinomas with non-polypoid growth pattern has greater malignant potentials, compared to the adenocarcinomas with polypoid growth patterns.

Immunohistochemical Profiling of Canine Intestinal T-Cell Lymphomas.

Human enteropathy-associated T-cell lymphoma (EATL) is classified into 2 distinct subgroups based on their phenotypes (type I and type II). Canine intestinal T-cell lymphoma can be morphologically classified into large and small cell lymphomas (LCL and SCL, respectively). Their association with human EATL or immunohistochemical and biological features has not been well characterized. In this study, the immunohistochemical profiles of 17 cases of LCL and 33 cases of SCL were evaluated with markers used for human EATL classification. Morphologically, LCL was characterized by sheet-like proliferation of large to moderately sized neoplastic lymphocytes, with scant clear cytoplasm and pleomorphic, irregularly shaped nuclei containing distinctive nucleoli and scattered chromatin. In contrast, SCL was characterized by the proliferation of monomorphic small neoplastic lymphocytes, accompanied by infiltration of nonneoplastic plasma cells. Interestingly, 8 cases demonstrated mixed LCL and SCL morphologies. Granular cytoplasmic expression of granzyme B was observed in most LCL and SCL cases. Membranous expression of CD56 was demonstrated in only 2 of 17 LCL and 0 of 33 SCL cases. Coexpression of CD20 by neoplastic T cells was observed in more SCL cases (16/33; 48%) than LCL cases (1/17; 6%). The CD56-positive cells in 2 cases were negative for CD20. Although canine LCL shares common features with human EATL type I, canine SCL cells and human EATL type II differ in their immunophenotype. Canine intestinal T-cell lymphoma had a homogeneous immunophenotype regardless of cell morphology. The findings of this study may indicate large cell transformation of SCL rather than 2 distinct entities.

A double-blind, placebo-controlled evaluation of orally administered heat-killed Enterococcus faecalis FK-23 preparation in atopic dogs.

BACKGROUND: Gastrointestinal microbiome modulation is reported to be an effective therapy to reduce the clinical signs of canine atopic dermatitis (cAD). The killed strain of Enterococcus faecalis FK-23 has been shown to reduce allergic responses in mice and people. HYPOTHESIS/OBJECTIVE: The aim of this multicentre, double-blinded, placebo-controlled study was to evaluate the safety and efficacy of an orally administered heat-killed E. faecalis FK-23 preparation (FK-23p) for the control of cAD. ANIMALS: Thirty-nine client-owned dogs with clinical signs of nonseasonal cAD were enrolled by 10 veterinarians at 15 hospitals. METHODS AND MATERIALS: Dogs were randomized to either FK-23p at a dose of ≥100 mg/kg/day or placebo. Owner-assessed pruritus Visual Analog Scale (pVAS), clinician-assessed Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-4) and daily medication scoring (DMS) were evaluated on days 0, 28, 56 and 84. Owners and clinicians were interviewed about the overall response to treatment (RTT), after the study. RESULTS: The CADESI-4 significantly decreased in the FK-23p group compared to the placebo group, by Day 84 (P = 0.035; Wilcoxon-Mann-Whitney U-test). There was no significant difference in pVAS and DMS between the groups. Owners and clinicians reported significantly better RTT in the FK-23p group than the placebo group (P = 0.043 and 0.002, respectively; Wilcoxon-Mann-Whitney U-test). There were no adverse events associated with FK-23p. CONCLUSIONS AND CLINICAL IMPORTANCE: Oral administration of FK-23p provided a small, but measurable benefit when used as an adjunct treatment, in reducing clinical signs of atopic dogs.

Histopathologic Features of Colorectal Adenoma and Adenocarcinoma Developing Within Inflammatory Polyps in Miniature Dachshunds.

Biopsy samples of colorectal polyps were collected and examined from 67 Miniature Dachshund dogs (including 35 cases with an additional biopsy). Histopathologic diagnoses of the initial biopsy samples were "inflammatory polyp" in 52 cases (78%), "adenoma" in 10 cases (15%), and "adenocarcinoma" in 5 cases (8%). Eight of 10 cases (80%) diagnosed as adenoma also had inflammatory polyp lesions in the same specimen. A second biopsy was performed in 25 cases (48%) initially diagnosed with inflammatory polyp. Pathologic diagnoses for the second biopsy were inflammatory polyp in 11 cases (44%), adenoma in 9 cases (36%), and adenocarcinoma in 5 cases (20%). The number of beta-catenin-positive nuclei in epithelial cells was significantly higher in adenoma (46%) and adenocarcinoma (75%) as compared with inflammatory polyp (6%). Normal epithelial cells and hyperplastic goblet cells in inflammatory polyps showed homogeneous positive cytoplasmic immunoreactivity for adenomatous polyposis coli (APC) antigen. However, APC expression was decreased in areas of intense nuclear beta-catenin expression in adenoma and adenocarcinoma lesions. Foci of cytokeratin 5/6-positive squamous cell-like neoplastic cells showed intense beta-catenin nuclear expression that was similar to squamous morules described in human colorectal tumors. The results of the present study suggest that the inflammatory polyp in Miniature Dachshunds is a progressive disease that may develop into adenoma and/or adenocarcinoma. In addition, immunohistochemical findings suggest that aberrations of APC and beta-catenin expression may be involved in tumor development within the inflammatory polyp lesions.

Novel Feline Leukemia Virus Interference Group Based on the env Gene.

Feline leukemia virus (FeLV) subgroups have emerged in infected cats via the mutation or recombination of the env gene of subgroup A FeLV (FeLV-A), the primary virus. We report the isolation and characterization of a novel env gene, TG35-2, and report that the TG35-2 pseudotype can be categorized as a novel FeLV subgroup. The TG35-2 envelope protein displays strong sequence identity to FeLV-A Env, suggesting that selection pressure in cats causes novel FeLV subgroups to emerge.

Intrahepatic cholelithiasis in dogs and cats: A case series.

A retrospective study of intrahepatic cholelithiasis (IC) in 9 dogs and 2 cats was conducted. Only 1 dog showed clinical signs related to hepatobiliary disease before referral and during the follow-up period. Intrahepatic cholelithiasis might be a subclinical finding in both dogs and cats.

Cholélithiase intrahépatique chez les chiens et chats : une série de cas. Nous avons réalisé une étude rétrospective de la cholélithiase intrahépatique (CI) chez 9 chiens et 2 chats. Seulement un chien manifestait des signes cliniques en lien avec la maladie hépatobiliaire avant la recommandation et durant la période de suivi. La cholélithiase intrahépatique pourrait être un résultat subclinique chez les chiens et les chats.(Traduit par Isabelle Vallières).

Adenocarcinoma of Barrett's esophagus in a dog.

An endoscopic examination revealed a mass in the distal esophagus of a 9-year-old intact male bulldog. Histopathologically, the mass was composed of cuboidal to columnar neoplastic epithelial cells and extended from the squamous epithelium of the esophageal mucosa, indicating that the tumor was derived from Barrett's esophagus. Moreover, highly atypical foci that exhibited a cribriform pattern and high mitotic indices were also observed. The epithelial cells on the surface of the lesion often produced mucus that was positive for Alcian blue and immunohistochemically positive for MUC5AC. The neoplastic epithelial cells were diffusely positive for cytokeratin 7 and p53, and occasionally positive for cytokeratin 20. Based on these findings, the tumor was diagnosed as an adenocarcinoma. This report describes the clinical and pathological features of a spontaneous case of adenocarcinoma of Barrett's esophagus in a dog.

Comprehensive genomic characterization of five canine lymphoid tumor cell lines.

BACKGROUND: Leukemia/lymphoma cell lines have been critical in the investigation of the pathogenesis and therapy of hematological malignancies. While human LL cell lines have generally been found to recapitulate the primary tumors from which they were derived, appropriate characterization including cytogenetic and transcriptional assessment is crucial for assessing their clinical predictive value. RESULTS: In the following study, five canine LL cell lines, CLBL-1, Ema, TL-1 (Nody-1), UL-1, and 3132, were characterized using extensive immunophenotyping, karyotypic analysis, oligonucleotide array comparative genomic hybridization (oaCGH), and gene expression profiling. Genome-wide DNA copy number data from the cell lines were also directly compared with 299 primary canine round cell tumors to determine whether the cell lines represent primary tumors, and, if so, what subtype each most closely resembled. CONCLUSIONS: Based on integrated analyses, CLBL-1 was classified as B-cell lymphoma, Ema and TL-1 as T-cell lymphoma, and UL-1 as T-cell acute lymphoblastic leukemia. 3132, originally classified as a B-cell lymphoma, was reclassified as a histiocytic sarcoma based on characteristic cytogenomic properties. In combination, these data begin to elucidate the clinical predictive value of these cell lines which will enhance the appropriate selection of in vitro models for future studies of canine hematological malignancies.

Regulation of p16 gene expression by histone H3 acetylation in canine lymphoid tumor cell lines.

In order to investigate whether suppression of the p16 gene is mediated by histone H3 acetylation in 4 canine lymphoid tumor cell lines, the gene's acetylation status was examined. In 2 canine lymphoid tumor cell lines with low p16 mRNA expression (GL-1 and UL-1), the acetylation level was lower than that in CL-1 cells with high p16 mRNA expression. The expression of the p16 gene in these 2 cell lines was markedly restored after culture in the presence of a histone deacetylase inhibitors trichostatin A, indicating that p16 was inactivated by hypoacetylation. Findings obtained this study will add new insights and lead to the better understanding of the disease pathogenesis and future development of epigenetic therapeutic strategies.

Transcriptomic analysis of bone marrow specimens collected from Miniature Dachshunds diagnosed with non-neoplastic bone marrow disorders.

Non-neoplastic bone marrow disorders are main causes of non-regenerative anemia in dogs. Despite the high incidence of the diseases, their molecular pathophysiology has not been elucidated. We previously reported that Miniature Dachshund (MD) was a predisposed breed to be diagnosed with non-neoplastic bone marrow disorders in Japan, and immunosuppressive treatment-resistant MDs showed higher number of platelets and morphological abnormalities in peripheral blood cells. These data implied that treatment-resistant MDs might possess distinct pathophysiological features from treatment-responsive MDs. Therefore, we conducted transcriptomic analysis of bone marrow specimens to investigate the pathophysiology of treatment-resistant MDs. Transcriptomic analysis comparing treatment-resistant MDs and healthy control dogs identified 179 differentially expressed genes (DEGs). Pathway analysis using these DEGs showed that "Wnt signaling pathway" was a significantly enriched pathway. We further examined the expression levels of DEGs associated with Wnt signaling pathway and confirmed the upregulation of AXIN2 and CCND2 and the downregulation of SFRP2 in treatment-resistant MDs compared with treatment-responsive MDs and healthy control dogs. This alteration implied the activation of Wnt signaling pathway in treatment-resistant MDs. The activation of Wnt signaling pathway has been reported in human patients with myelodysplastic syndrome (MDS), which is characterized by dysplastic features of blood cells. Therefore, the results of this study implied that treatment-resistant MDs have distinct molecular pathological features from treatment-responsive MDs and the pathophysiology of treatment-resistant MDs might be similar to that of human MDS patients.

Use of genome-wide DNA methylation analysis to identify prognostic CpG site markers associated with longer survival time in dogs with multicentric high-grade B-cell lymphoma.

BACKGROUND: DNA methylation analysis might identify prognostic CpG sites in CHOP-treated dogs with multicentric high-grade B-cell lymphoma (MHGL) with heterogenous prognosis. OBJECTIVE: To identify prognostic CpG sites of MHGL through genome-wide DNA methylation analysis with pyrosequencing validation. ANIMALS: Test group: 24 dogs. Validation group: 100 dogs. All client-owned dogs were diagnosed with MHGL and treated with CHOP chemotherapy. METHODS: Cohort study. DNA was extracted from lymph node samples obtained via FNA. Genome-wide DNA methylation analysis using Digital Restriction Enzyme Analysis of Methylation (DREAM) was performed on the test group to identify differentially methylated CpG sites (DMCs). Bisulfite pyrosequencing was used to measure methylation status of candidate DMCs in the validation group. Median survival times (MST) were analyzed using Kaplan-Meier (log-rank) product limit method. RESULTS: DREAM analyzed 101 576 CpG sites. Hierarchical clustering of 16 262 CpG sites in test group identified group with better prognosis (MST = 55-477 days vs 10-301 days, P = .007). Volcano plot identified 1371 differentially methylated CpG sites (DMCs). DMC near the genes of FAM213A (DMC-F) and PHLPP1 (DMC-P) were selected as candidates. Bisulfite-pyrosequencing performed on validation group showed group with methylation level of DMC-F < 40% had favorable prognosis (MST = 11-1072 days vs 8-1792 days, P = .01), whereas group with the methylation level combination of DMC-F < 40% plus DMC-P < 10% had excellent prognosis (MST = 18-1072 days vs 8-1792 days, P = .009). CONCLUSION AND CLINICAL IMPORTANCE: Methylation status of prognostic CpG sites delineate canine MGHL cases with longer MST, providing owners with information on expectations of potential improved treatment outcomes.

Gene expression profiles associated with early relapse during first remission induction in canine multicentric high-grade B-cell lymphoma.

Although chemotherapy using CHOP-based protocol induces remission in most cases of canine multicentric high-grade B-cell lymphoma (mhBCL), some cases develop early relapse during the first induction protocol. In this study, we examined the gene expression profiles of canine mhBCL before chemotherapy and investigated their associations with early relapse during the first whole CHOP-based protocol. Twenty-five cases of mhBCL treated with CHOP-based protocol as first induction chemotherapy were included in this study. Sixteen cases completed the first whole CHOP-based protocol without relapse (S-group), and nine developed relapse during the chemotherapy (R-group). RNA-seq was performed on samples from neoplastic lymph nodes. Differentially expressed genes (DEGs) were extracted by the comparison of gene expression profiles between S- and R-groups, and the differences in the expression levels of these genes were validated by RT-qPCR. Extracted 179 DEGs included the genes related to chemokine CC motif ligand, T-cell receptor signaling pathway, and PD-L1 expression and PD-1 checkpoint pathway. We focused on chemokine CC motif ligand, and CCL4 was confirmed to be significantly downregulated in the R-group (P=0.039). We also focused on the genes related to T-cell signaling pathway, and CD3E (P=0.039), ITK (P=0.023), and LAT (P=0.023) genes were confirmed to be significantly upregulated in the R-group. The current results suggest that both changes in tumor cells and the interactions between tumor cells and immune cells are associated with the efficacy of the chemotherapy for first remission induction.

Clinical characteristics and outcomes of Mott cell lymphoma in nine miniature dachshunds.

BACKGROUND: Lymphoma with Mott cell change, or Mott cell lymphoma (MCL), is an uncommon variant of canine lymphoma. Because of its rare occurrence, there has been no comprehensive study describing the disease so far. Miniature dachshunds, a popular breed in Japan, sometimes experience MCL. OBJECTIVES: To investigate the clinical characteristics and outcomes of MCL in miniature dachshunds. METHODS: Medical records were retrospectively reviewed to identify miniature dachshunds diagnosed with MCL and other types of lymphoma. Data on clinical and laboratory findings, treatments and outcomes were collected. Survival times were compared between miniature dachshunds with MCL and other types of lymphoma. RESULTS: Of the 87 miniature dachshunds diagnosed with lymphoma, 9 (10%) had cytological characteristics of MCL. All 9 miniature dachshunds with MCL were categorised as having alimentary lymphoma (small and/or large intestine, 6 dogs; mesenteric lymph node, 3 dogs). The median age was 3.1 years (range, 2.0-9.4 years). All nine dogs were treated with chemotherapeutic protocols used for large cell lymphoma or alkylating agents such as melphalan or chlorambucil. The overall response rate to initial chemotherapy was 78%, and the median progression-free survival was 105 days. Overall survival in these nine dogs ranged from 6 to >1513 days (median, 240 days), which was significantly longer than in 29 miniature dachshunds with alimentary large cell lymphoma other than MCL (median, 57 days; p = 0.0491). CONCLUSIONS: MCL in miniature dachshunds can be recognised as a peculiar type of B-cell lymphoma occurring in relatively young dogs as an alimentary form and has a longer survival compared with typical alimentary large cell lymphoma.

Analysis of fecal microbial profiles in dogs with intestinal lymphangiectasia.

Intestinal lymphangiectasia (IL) is a common complication in dogs. This study analyzed intestinal microbiota using 16S rRNA amplicon analysis as candidate factors that strongly influence the small intestinal lymphatic vessels in dogs with and without IL. Twelve dogs were included, of which six were diagnosed with lymphoplasmacytic enteritis, four with small-cell lymphoma, and two with large-cell lymphoma. Seven of these dogs had IL, whereas five did not. First, the microbial diversity analyzed by Faith pd index was significantly decreased in dogs with IL compared to dogs without IL. Then, the relative amounts of each bacterial taxa were compared between dogs with and without IL using Linear discriminant analysis effect size analysis. At the genus level, the Ruminococcus gnavus group significantly increased in dogs with IL compared to dogs without IL. A total of four genera, including Ruminococcus torques group and Faecalibacterium, which produce butyrate, significantly decreased in dogs with IL. This study showed decreased intestinal bacterial diversity and several alterations of intestinal microbiota, including a decrease in butyrate-producing bacteria in dogs with IL, compared to dogs without IL.

Retrospective study of feline tracheal mass lesions.

OBJECTIVES: This multicentre, retrospective observational study aimed to describe the clinical presentation, diagnostic methods, treatment and outcomes of cats with tracheal masses. METHODS: Eighteen cats from five academic or secondary/tertiary animal hospitals were included. RESULTS: The median age at diagnosis was 10.7 years (mean 9.5; range 1-17). There were nine castrated males, seven spayed females, one intact male and one intact female. Fourteen (78%) were domestic shorthairs, one (6%) was an Abyssinian, one (6%) was an American Shorthair, one (6%) was a Bengal and one (6%) was a Scottish Fold. The most common presenting complaints included chronic respiratory distress or dyspnoea (n = 14), followed by wheezing/gagging (n = 12), coughing (n = 5) and voice changes (n = 5). There was cervical tracheal involvement in 16/18, and two showed involvement of the intrathoracic trachea. The following methods were used for diagnosis: ultrasound-guided fine-needle biopsy (UG-FNB) and cytology (n = 8), bronchoscopic forceps biopsy and histopathology (n = 5), surgical resection and histopathology (n = 3), forceps biopsy via an endotracheal tube (n = 1) and histology of tissue sputtered from a cough (n = 1). Lymphoma was most often diagnosed (n = 15), followed by adenocarcinoma (n = 2) and squamous cell carcinoma (n = 1). Most lymphoma cases received chemotherapy with or without radiation according to various protocols, and partial (n = 5) or complete responses (n = 8) were noted. Kaplan-Meier survival data for cats with lymphoma revealed a median survival time of 214 days (95% confidence interval >149 days), which was significantly longer than that of other types of tumours (21 days). CONCLUSIONS AND RELEVANCE: Lymphoma was the most prevalent diagnosis, and showed a good response to chemotherapy with or without radiation therapy. Various diagnostic procedures were performed, and UG-FNB and cytology are good diagnostic procedures for cervical tracheal lesions. Owing to the variety of treatment protocols at different centres, it was impossible to compare outcomes.

Serum level of apoptosis inhibitor of macrophage in dogs with histiocytic sarcoma and its association with the disease.

Histiocytic sarcoma (HS) is a rare neoplasm of macrophages or dendritic cells with a poor prognosis in dogs. As the apoptosis inhibitor of macrophage (AIM) is characteristically expressed in canine macrophages, we hypothesised that AIM is involved in the development or progression of HS in dogs. In this study, AIM expression in the tumour region and serum AIM levels in dogs with HS was assessed. Additionally, the effects of AIM overexpression on HS cell viability were investigated using a HS cell line that was selected from five validated HS cell lines. Immunohistochemistry showed that AIM expression was observed in the cytoplasm of the HS cells. CD36, a candidate AIM receptor, was also observed on the cell membrane of HS cells. When the serum AIM level was detected in 36 dogs with HS and 10 healthy dogs via western blot analysis, the AIM levels in the HS dogs were significantly higher than those in the controls. AIM mRNA expression in the 5 HS cell lines varied but was higher than that in the other tumour-derived lines. Among the five HS cell lines, DH82 originally had lower AIM and the highest CD36 expression. When AIM was overexpressed in DH82, therein cell growth speed and invasion, apoptosis inhibition and phagocytic activity were strongly upregulated. These data suggest that elevated intra-tumour expression of AIM could induce the progression of HS cells in dogs. Moreover, elevated serum AIM levels in dogs with HS could serve as a biomarker of HS.

Whole exome and transcriptome analysis revealed the activation of ERK and Akt signaling pathway in canine histiocytic sarcoma.

Histiocytic sarcoma (HS) is an incurable aggressive tumor, and no consensus has been made on the treatment due to its rare occurrence. Since dogs spontaneously develop the disease and several cell lines are available, they have been advocated as translational animal models. In the present study, therefore, we explored gene mutations and aberrant molecular pathways in canine HS by next generation sequencing to identify molecular targets for treatment. Whole exome sequencing and RNA-sequencing revealed gene mutations related to receptor tyrosine kinase pathways and activation of ERK1/2, PI3K-AKT, and STAT3 pathways. Analysis by quantitative PCR and immunohistochemistry revealed that fibroblast growth factor receptor 1 (FGFR1) is over-expressed. Moreover, activation of ERK and Akt signaling were confirmed in all HS cell lines, and FGFR1 inhibitors showed dose-dependent growth inhibitory effects in two of the twelve canine HS cell lines. The findings obtained in the present study indicated that ERK and Akt signaling were activated in canine HS and drugs targeting FGFR1 might be effective in part of the cases. The present study provides translational evidence that leads to establishment of novel therapeutic strategies targeting ERK and Akt signaling in HS patients.

Changes in gene expression profiles and cytokine secretions in peripheral monocytes by treatment with small extracellular vesicles derived from a canine lymphoma cell line.

Interactions between tumor and immune cells within the tumor microenvironment play an important role in tumor progression, and small extracellular vesicles (EVs) derived from these tumor cells have been shown to exert immunomodulatory effects on various immune cells, including macrophages and lymphocytes. Although the immunomodulatory effects of small EVs derived from human cancer cells have been intensively investigated, few studies have investigated the effects of lymphoma-derived small EVs on macrophages in both human and veterinary medicine. Here, we evaluated the effects of canine lymphoma-derived small EVs on canine primary monocytes, which are the major source of macrophages in neoplastic tissues. Comprehensive gene expression analysis of these treated monocytes revealed their distinct activation via the Toll-like receptor (TLR) and NF-κß signaling pathways. In addition, treatment with lymphoma small EVs increased the secretion of MCP-1, which induces the infiltration and migration of monocytes and lymphocytes in neoplastic and cancer tissues. The results of this study indicate that canine lymphoma small EVs activate monocytes, possibly through the activation of TLR and NF-κß signaling pathways, and induce monocytes to secrete of MCP-1, which might contribute to immune cell infiltration within the tumor microenvironment.