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1.
Genome Res ; 31(2): 337-347, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33361113

RESUMEN

Understanding the changes in diverse molecular pathways underlying the development of breast tumors is critical for improving diagnosis, treatment, and drug development. Here, we used RNA-profiling of canine mammary tumors (CMTs) coupled with a robust analysis framework to model molecular changes in human breast cancer. Our study leveraged a key advantage of the canine model, the frequent presence of multiple naturally occurring tumors at diagnosis, thus providing samples spanning normal tissue and benign and malignant tumors from each patient. We showed human breast cancer signals, at both expression and mutation level, are evident in CMTs. Profiling multiple tumors per patient enabled by the CMT model allowed us to resolve statistically robust transcription patterns and biological pathways specific to malignant tumors versus those arising in benign tumors or shared with normal tissues. We showed that multiple histological samples per patient is necessary to effectively capture these progression-related signatures, and that carcinoma-specific signatures are predictive of survival for human breast cancer patients. To catalyze and support similar analyses and use of the CMT model by other biomedical researchers, we provide FREYA, a robust data processing pipeline and statistical analyses framework.

2.
Vet Ophthalmol ; 2024 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-39072884

RESUMEN

PURPOSE: To describe the clinical features surgical technique, early and long-term outcome with or without surgery, and histopathological findings of melanocytic anterior uveal lesions in young dogs. METHODS: Medical records of dogs at a guide dog facility removed from training due to a pigmented iris lesion were reviewed from 2014 to 2021. Selected dogs had surgical iridectomies performed. RESULTS: Iridal melanocytic lesions were characterized as well-delineated, pigmented, and flat (nevus) or raised (mass) lesions of the iris. Forty dogs (18 Labrador retrievers, 18 German shepherd dogs, 1 Golden retriever, 3 Labrador/Golden mixes) ranging from 0.5 to 3.1 years of age were affected unilaterally (n = 35) or bilaterally (n = 5). Sector iridectomy was performed in 13 dogs with prominent and well-isolated mass lesion and enucleation was carried out in 2 dogs with extensive lesions, while all other cases were monitored without surgical intervention. Postoperative complications included dyscoria (13/13), focal posterior synechia (9/13) and focal nonprogressive cataract (8/13). All eyes remained visual and comfortable up to 6.2 years post-iridectomy with no clinically identifiable local recurrence. Histopathology was consistent with uveal melanocytoma in all samples obtained surgically. All cases that did not undergo surgery remained free of complications up to 4.5 year post diagnosis. CONCLUSION: Melanocytic anterior uveal lesions may be overrepresented in certain lineages of breeds and be present at a young age. While none of the eyes developed complications when monitored without surgery, early surgical excision of the mass by sector iridectomy yields noteworthy functional outcome and retention of a comfortable globe.

3.
Ecol Appl ; 33(6): e2894, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37282355

RESUMEN

Many degraded ecosystems have altered nutrient dynamics due to invaders' possessing a suite of traits that allow them to both outcompete native species and alter the environment. In ecosystems where invasive species have increased nutrient turnover rates, it can be difficult to reduce nutrient availability. This study examined whether a functional trait-based restoration approach involving the planting of species with conservative nutrient-use traits could slow rates of nutrient cycling and consequently reduce rates of invasion. We examined a functional trait restoration initiative in a heavily invaded lowland wet forest site in Hilo, Hawai'i. Native and introduced species were chosen to create four experimental hybrid forest communities, in comparison to the invaded forest, with a factorial design in which communities varied in rates of carbon turnover (slow or moderate [SLOW, MOD]), and in the relationship of species in trait space (redundant or complementary [RED, COMP]). After the first 5 years, we evaluated community-level outcomes related to nutrient cycling: carbon (C), nitrogen (N), and phosphorus (P) via litterfall, litter decomposition, and outplant productivity and rates of invasion. We found that (1) regardless of treatment, the experimental communities had low rates of nutrient cycling through litterfall relative to the invaded reference forest, (2) the MOD communities had greater nutrient release via litterfall than the SLOW communities, (3) introduced species had greater nutrient release than native species in the two MOD experimental communities, and (4) within treatments, there was a positive relationship between nutrient levels and outplant basal area, but outplant basal area was negatively associated with rates of invasion. The negative relationships among basal area and weed invasion, particularly for the two COMP treatments, suggest species existing in different parts of trait space may help confer some degree of invasion resistance. The diversification of trait space was facilitated by the use of introduced species, a new concept in Hawaiian forest management. Although challenges remain in endeavors to restore this heavily degraded ecosystem, this study provides evidence that functional trait-based restoration approaches using carefully crafted hybrid communities can reduce rates of nutrient cycling and invasion in order to reach management goals.


Asunto(s)
Ecosistema , Suelo , Hawaii , Bosques , Especies Introducidas , Nitrógeno/metabolismo , Nutrientes , Carbono , Árboles/metabolismo
4.
Vet Pathol ; 60(2): 162-171, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36541607

RESUMEN

Canine cutaneous epitheliotropic T-cell lymphoma is a neoplasm with heterogeneous clinical and histopathological presentations. Survival times and responses to therapy are variable, and indicators to predict outcomes are lacking. Clinical and histopathological parameters from 176 archival cases from the University of Pennsylvania and University of Bern (2012-2018) were investigated for associations with clinical outcomes. Histopathological evaluation used digitized whole slide images and QuPath software. Cases included 107 female and 69 male dogs from 48 breeds, with a mean age of 10.4 years. Most common clinical signs were erythema (n = 131), crusting (n = 108), and scaling (n = 102). Affected sites were haired skin (n = 159), lip (n = 74), nasal planum (n = 49), and paw pads (n = 48). The median survival time (MST) was 95 days (1-850). Dogs had 4.26-fold and 2.82-fold longer MST when treated with chemotherapy and prednisone, respectively, than when receiving supportive care. Haired skin involvement (hazard ratio [HR]: 2.039, 95% confidence interval [CI]: 1.180-3.523), erosions/ulcers (HR: 1.871, 95% CI: 1.373-2.548), nodules (HR: 1.496, 95% CI: 1.056-2.118), and crusting (HR: 1.454, 95% CI: 1.061-1.994) were clinical parameters predicting poor outcomes, whereas complete posttherapeutic clinical remission (HR: 0.469, 95% CI: 0.324-0.680) and a stable disease (HR: 0.323, 95% CI: 0.229-0.456) were associated with longer survival. Histopathological features associated with the increased risk of death were extensive infiltration of the panniculus (HR: 2.865, 95% CI: 1.565-4.809), mitotic count ≥7/high-power field (HR: 3.027, 95% CI: 2.065-4.439), cell diameter ≥10.0 µm (HR: 2.078, 95% CI: 1.281-3.372), and nuclear diameter ≥8.3 µm (HR: 3.787, 95% CI: 1.647-8.707).


Asunto(s)
Enfermedades de los Perros , Linfoma Cutáneo de Células T , Neoplasias Cutáneas , Masculino , Perros , Animales , Femenino , Pronóstico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/veterinaria , Piel/patología , Linfoma Cutáneo de Células T/diagnóstico , Linfoma Cutáneo de Células T/veterinaria , Enfermedades de los Perros/patología
5.
Cancer Immunol Immunother ; 71(4): 807-818, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-34415404

RESUMEN

Histiocytic sarcoma (HS) is a rare and aggressive tumor in humans with no universally agreed standard of care therapy. Spontaneous canine HS exhibits increased prevalence in specific breeds, shares key genetic and biologic similarities with the human disease, and occurs in an immunocompetent setting. Previous data allude to the immunogenicity of this disease in both species, highlighting the potential for their successful treatment with immunotherapy. Quantification of CD3 tumor-infiltrating lymphocytes (TIL) in five cases of human HS revealed variable intra-tumoral T cell infiltration. Due to the paucity of human cases and lack of current model systems in which to appraise associations between anti-tumor immunity and treatment-outcome in HS, we analyzed clinical data and quantified TIL in 18 dogs that were previously diagnosed with localized HS and treated with curative-intent tumor resection with or without adjuvant chemotherapy. As in humans, assessment of TIL in biopsy tissues taken at diagnosis reveal a spectrum of immunologically "cold" to "hot" tumors. Importantly, we show that increased CD3 and granzyme B TIL are positively associated with favorable outcomes in dogs following surgical resection. NanoString transcriptional analyses revealed increased T cell and antigen presentation transcripts associated with prolonged survival in canine pulmonary HS and a decreased tumor immunogenicity profile associated with shorter survivals in splenic HS. Based on these findings, we propose that spontaneous canine HS is an accessible and powerful novel model to study tumor immunology and will provide a unique platform to preclinically appraise the efficacy and tolerability of anti-cancer immunotherapies for HS.


Asunto(s)
Enfermedades de los Perros , Sarcoma Histiocítico , Animales , Biopsia , Perros , Sarcoma Histiocítico/genética , Sarcoma Histiocítico/patología , Sarcoma Histiocítico/veterinaria , Linfocitos Infiltrantes de Tumor/patología , Bazo/patología
6.
Vet Pathol ; 58(6): 1017-1024, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34190003

RESUMEN

Oral malignant melanoma (OMM) is considered the third most common oral malignant neoplasm in cats, but its variable morphology and frequent lack of melanin pigment make it a diagnostic challenge. Twenty-two cases of cats with malignant oral neoplasms that were diagnosed as OMM or listed OMM as a suspected differential diagnosis on the biopsy report were examined using an immunohistochemistry (IHC) panel for S100, melan-A, PNL2, laminin, CD34, and pan-cytokeratin. Although OMM was suspected (n = 14) or previously diagnosed (n = 8), only 2 cases were immunohistochemically confirmed as OMM. Seven cases were classified as soft tissue sarcoma based on positive expression of CD34 or laminin, and one was classified as carcinoma based on positive expression of pan-cytokeratin. The majority of cases (n = 12) were categorized as unclassified malignant neoplasms because they did not express melan-A, PNL2, laminin, CD34, or pan-cytokeratin; however, a proportion of these did express S100 (n = 7). Long-term prognosis of all 22 cats was poor, with a median survival time of 87 days (range = 2-249 days). Cases with longer survival times (>100 days) were treated with surgery, radiation therapy, or a combination. For feline oral malignant neoplasms thought to be OMM, routine use of IHC is required for an accurate diagnosis.


Asunto(s)
Enfermedades de los Gatos , Melanoma , Sarcoma , Neoplasias Cutáneas , Neoplasias de los Tejidos Blandos , Animales , Enfermedades de los Gatos/diagnóstico , Gatos , Inmunohistoquímica , Melanoma/diagnóstico , Melanoma/veterinaria , Sarcoma/veterinaria , Neoplasias Cutáneas/veterinaria , Neoplasias de los Tejidos Blandos/veterinaria
7.
Proc Natl Acad Sci U S A ; 115(1): 204-209, 2018 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-29203662

RESUMEN

Strongyloides stercoralis hyperinfection causes high mortality rates in humans, and, while hyperinfection can be induced by immunosuppressive glucocorticoids, the pathogenesis remains unknown. Since immunocompetent mice are resistant to infection with S. stercoralis, we hypothesized that NSG mice, which have a reduced innate immune response and lack adaptive immunity, would be susceptible to the infection and develop hyperinfection. Interestingly, despite the presence of large numbers of adult and first-stage larvae in S. stercoralis-infected NSG mice, no hyperinfection was observed even when the mice were treated with a monoclonal antibody to eliminate residual granulocyte activity. NSG mice were then infected with third-stage larvae and treated for 6 wk with methylprednisolone acetate (MPA), a synthetic glucocorticoid. MPA treatment of infected mice resulted in 50% mortality and caused a significant >10-fold increase in the number of parasitic female worms compared with infected untreated mice. In addition, autoinfective third-stage larvae, which initiate hyperinfection, were found in high numbers in MPA-treated, but not untreated, mice. Remarkably, treatment with Δ7-dafachronic acid, an agonist of the parasite nuclear receptor Ss-DAF-12, significantly reduced the worm burden in MPA-treated mice undergoing hyperinfection with S. stercoralis Overall, this study provides a useful mouse model for S. stercoralis autoinfection and suggests a therapeutic strategy for treating lethal hyperinfection.


Asunto(s)
Colestenos/farmacología , Metilprednisolona/análogos & derivados , Strongyloides stercoralis/inmunología , Estrongiloidiasis/tratamiento farmacológico , Estrongiloidiasis/inmunología , Animales , Colestenos/efectos adversos , Femenino , Metilprednisolona/efectos adversos , Metilprednisolona/farmacología , Acetato de Metilprednisolona , Ratones , Estrongiloidiasis/patología
8.
Mol Ther ; 27(5): 974-985, 2019 05 08.
Artículo en Inglés | MEDLINE | ID: mdl-30962164

RESUMEN

Zika virus (ZIKV) infection is endemic to several world regions, and many others are at high risk for seasonal outbreaks. Synthetic DNA-encoded monoclonal antibody (DMAb) is an approach that enables in vivo delivery of highly potent mAbs to control infections. We engineered DMAb-ZK190, encoding the mAb ZK190 neutralizing antibody, which targets the ZIKV E protein DIII domain. In vivo-delivered DMAb-ZK190 achieved expression levels persisting >10 weeks in mice and >3 weeks in non-human primate (NHPs), which is protective against ZIKV infectious challenge. This study is the first demonstration of infectious disease control in NHPs following in vivo delivery of a nucleic acid-encoded antibody, supporting the importance of this new platform.


Asunto(s)
Anticuerpos Neutralizantes/farmacología , ADN/farmacología , Proteínas del Envoltorio Viral/inmunología , Infección por el Virus Zika/genética , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/farmacología , ADN/inmunología , Humanos , Ratones , Primates , Proteínas del Envoltorio Viral/antagonistas & inhibidores , Virus Zika/genética , Virus Zika/inmunología , Virus Zika/patogenicidad , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/terapia , Infección por el Virus Zika/virología
9.
Vet Ophthalmol ; 23(1): 77-89, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31328872

RESUMEN

This retrospective study aimed to describe and classify cats with intraocular lymphoma, determine the proportion of cases with presumed solitary ocular lymphoma (PSOL) compared with ocular manifestations of multicentric disease and assess the clinical outcomes of these patients. One hundred seventy-two cases identified through biopsy submissions were reviewed histologically; 163 of these cases were subtyped according to the WHO classification system. Cases were categorized as having PSOL or ocular lymphoma with suspected systemic involvement (SSI) based on submission forms and follow-up data. The majority of cases exhibited concurrent uveitis (75%) and secondary glaucoma (58%). Diffuse large B-cell lymphoma was the most common subtype (n = 86; 53%), followed by peripheral T-cell lymphoma (n = 44; 27%). Other subtypes included anaplastic large T- (n = 8; 5%) and B-cell (n = 4; 2.5%) lymphomas, and 15 cases (9%) were negative for all immunohistochemical markers. In sixty-nine cases (40%), adequate clinical data and sufficient survival data were obtained to distinguish PSOL from SSI. PSOL comprised the majority of cases (64%), while 36% had SSI. When covarying for age at diagnosis, the median survival time was significantly higher (P = 0.003) for cases of PSOL (154 days) versus those with SSI (69 days); hazards ratio of 0.47 for PSOL (95% CI: 0.241-0.937). The subtype of lymphoma did not affect survival time. Cats with PSOL represent a greater proportion of the disease population, and this subset of cats with intraocular lymphoma has a better clinical outcome.


Asunto(s)
Enfermedades de los Gatos/clasificación , Neoplasias del Ojo/veterinaria , Linfoma/veterinaria , Animales , Enfermedades de los Gatos/patología , Gatos , Neoplasias del Ojo/clasificación , Neoplasias del Ojo/patología , Linfoma/clasificación , Linfoma/patología , Estudios Retrospectivos
10.
J Am Anim Hosp Assoc ; 56(2): 120-126, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31961215

RESUMEN

Canine hemangiosarcoma (HSA), a malignant neoplasm of vascular endothelial or bone marrow progenitor cell origin, most often affects the spleen, heart, and liver and typically has an aggressive biologic behavior. Canine HSA arising from the falciform fat/ligament represents a rare anatomic variant, with only two reports in the veterinary literature. In this study, we describe the clinical presentation, treatment, and outcome of seven dogs with primary HSA of the falciform ligament. Histologic grade and mitotic score were not significantly associated with outcome. All dogs had the primary tumor surgically excised except for one diagnosed at necropsy. Median overall survival for all dogs diagnosed prior to necropsy was 339 days, and the 1 yr survival rate was 50%. Four dogs were treated with adjuvant chemotherapy and had a significantly longer median overall survival (394 versus 83 days) than those that did not (P = .018). Dogs with HSA of the falciform ligament may have improved 1 yr survival rates and longer median survival time compared with dogs with HSA in more common visceral locations.


Asunto(s)
Enfermedades de los Perros/patología , Hemangiosarcoma/veterinaria , Neoplasias Hepáticas/veterinaria , Ligamento Redondo del Hígado/patología , Animales , Antineoplásicos/uso terapéutico , Enfermedades de los Perros/terapia , Perros , Femenino , Hemangiosarcoma/patología , Hemangiosarcoma/terapia , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Masculino , Estudios Retrospectivos
11.
Biologicals ; 59: 12-19, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-31023510

RESUMEN

A sudden, unprecedented failure of USP rabbit pyrogen tests for multiple 10% IGIV-C lots prompted a thorough investigation of the root cause for this phenomenon. All microbe-related testing, including Limulus amebocyte lysate test for endotoxin, proved negative, and no deficiencies were discovered in manufacturing. Plasma pool composition analysis revealed that a single plasma donor ("Donor X″) was common to all pyrogenic IGIV-C lots and that as little as one unit of "Donor X″ plasma (in a pool of ∼4500 units) was sufficient to cause IGIV-C lot failure in the USP rabbit pyrogen test. Whole plasma and Protein A-purified IgG from "Donor X″ caused a temperature increase in rabbits; however, all IgG samples tested pyrogen-negative in two in vitro cell-based pyrogen tests. Flow cytometry showed that "Donor X″ IgG bound strongly to rabbit white blood cells (WBC) but minimally to human WBC. Exclusion of "Donor X″ plasma from manufacturing marked the end of IGIV-C lots registering positive in the USP rabbit pyrogen test. This failure of multiple 10% IGIV-C lots to pass the USP rabbit pyrogen test was demonstrated to be due to the highly unusual anti-rabbit-leukocyte specificity of IgG from a single donor.


Asunto(s)
Donantes de Sangre , Inmunoglobulina G/inmunología , Inmunoglobulinas Intravenosas/inmunología , Leucocitos/inmunología , Pirógenos/inmunología , Animales , Contaminación de Medicamentos/prevención & control , Endotoxinas/análisis , Endotoxinas/inmunología , Humanos , Prueba de Limulus/métodos , Conejos
12.
Vet Pathol ; 56(5): 778-782, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31113291

RESUMEN

Pathologic features of 12 cats with naturally acquired systemic hypertension and concomitant hypertensive encephalopathy were analyzed. All cats demonstrated acute onset of signs localized to the forebrain and/or brainstem, including stupor, coma, and seizures. All cats had systemic hypertension, ranging from 160 to 300 mm Hg. Gross lesions were identified in 4 of 12 cases, including caudal herniation of the cerebrum and cerebellum, sometimes with compression of the rostral colliculus and medulla. Histologically, all cases featured bilaterally symmetrical edema of the cerebral white matter. Associated vascular lesions, especially arteriolar hyalinosis, were also observed. Concurrent lesions were chronic tubulointerstitial nephritis (11/12 cases), adenomatous hyperplasia of the thyroid gland (4 cases), hypertensive choroidal arteriopathy (6 cases), and left ventricular hypertrophy (5 cases). This study demonstrates that the typical histologic manifestation of spontaneous hypertensive encephalopathy in cats is bilaterally symmetrical edema of the subcortical cerebral white matter.


Asunto(s)
Enfermedades de los Gatos/patología , Sistema Nervioso Central/patología , Encefalopatía Hipertensiva/veterinaria , Animales , Gatos , Encefalopatía Hipertensiva/patología
13.
Vet Pathol ; 56(6): 885-888, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31170873

RESUMEN

Nasal polyps in dogs are space-occupying soft-tissue masses that have been encountered concurrently with intranasal neoplasia in surgical biopsy specimens. The proportion of nasal polyp co-occurrence with primary nasal tumors was examined, and follow-up biopsies on dogs initially diagnosed with nasal polyp were reviewed. Histologic sections from 321 cases of intranasal neoplasia and 50 cases of nasal polyp from 2004 to 2017 were reviewed. Of the 321 cases of intranasal neoplasia, 51 (16%) had concurrent nasal polyps, and most of these (47/51) had intranasal carcinoma. Twenty-five of the 50 dogs with a primary diagnosis of nasal polyp were rebiopsied, and the diagnoses in these subsequent biopsies were nasal polyp in 15, malignant neoplasm in 9, and intranasal nematode in 1. Nasal polyps occurred frequently in conjunction with nasal carcinoma. In dogs with a diagnosis of nasal polyp, repeat biopsy to reveal possible neoplasia is warranted.


Asunto(s)
Enfermedades de los Perros/diagnóstico , Pólipos Nasales/veterinaria , Neoplasias Nasales/veterinaria , Animales , Enfermedades de los Perros/patología , Perros , Femenino , Masculino , Cavidad Nasal/patología , Pólipos Nasales/complicaciones , Pólipos Nasales/diagnóstico , Pólipos Nasales/patología , Neoplasias Nasales/complicaciones , Neoplasias Nasales/diagnóstico , Neoplasias Nasales/patología
14.
Vet Surg ; 48(7): 1218-1228, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31287179

RESUMEN

OBJECTIVE: To report outcomes in cats with discrete intermediate- and large-cell gastrointestinal (GI) lymphoma masses after surgical resection. STUDY DESIGN: Retrospective clinical case series. ANIMALS: Forty client-owned cats in which intermediate- or large-cell GI lymphoma was diagnosed. METHODS: Records of 40 cats in which discrete intermediate- or large-cell GI lymphoma masses were diagnosed between 2005 and 2015 were reviewed. Cats were included if they survived curative intent surgery and had a known outcome for at least two weeks. Postoperative death was permitted. Data collected included anatomic site, surgical margins, lymphoma subtype, chemotherapy use, and postoperative and long-term outcome (beyond two weeks). RESULTS: Affected sites consisted of small intestines (n = 23), large intestines (n = 9), and stomach (n = 8). Thirty-six of 40 cats survived to discharge, and 31 cats were alive at suture removal. Median long-term follow-up of 22 cats was 111 days (range, 16-1407). Cats that survived to suture removal had a median survival time (MST) of 185 days (95% confidence interval: 72-465). Cats with large intestinal masses lived longer than those with small intestinal or gastric masses whether all cats (MST, 675, 64, 96 days, respectively; P = .03) or only those surviving to suture removal were considered. Complete surgical resection (n = 20) was positively associated with survival (370 vs 83 days, P = .016). CONCLUSION: Most cats in this population survived the perioperative period, with MST similar to those reported historically with medical management. CLINICAL SIGNIFICANCE: Surgical resection may be a reasonable consideration in cats with solitary lymphoma, particularly those with large intestinal masses.


Asunto(s)
Enfermedades de los Gatos/cirugía , Neoplasias Gastrointestinales/veterinaria , Linfoma/veterinaria , Animales , Gatos , Femenino , Neoplasias Gastrointestinales/cirugía , Humanos , Linfoma/cirugía , Masculino , Periodo Perioperatorio , Estudios Retrospectivos , Resultado del Tratamiento
15.
Vet Pathol ; 55(5): 622-633, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29788797

RESUMEN

The epithelial-mesenchymal transition (EMT) is a dynamic process linked to metastasis in many tumor types, including mammary tumors. In this study, we evaluated E-cadherin and vimentin immunolocalization in primary canine mammary carcinomas (20 cases) and their respective metastases, as well as their relationship with the core regulators SNAIL/SLUG. To assess the number of cells undergoing the process of EMT, we quantitated double-positive (E-cadherin+/vimentin+) cells using immunofluorescence, via cell counting and image analysis. In addition, SNAIL/SLUG expression was evaluated by established immunohistochemical methods. Primary tumors had significantly more E-cadherin+/vimentin+ co-expression than their paired respective lymph node or distant metastasis, respectively. Furthermore, the percentage of E-cadherin+/vimentin+ cells in grade II and III carcinomas was significantly higher than in grade I tumors. Primary tumors had significantly higher SNAIL/SLUG expression when analyzed based on the percentage of positive cells compared with their respective distant metastases in pairwise comparisons. An inverse correlation was noted between SNAIL/SLUG immunoreactivity and percentage of E-cadherin+/vimentin+ immunopositive cells in primary tumor samples when SNAIL/SLUG immunoreactivity was grouped into 2 categories (high versus low) based on percentage-positive staining. These results show a positive correlation between E-cadherin+/vimentin+ cells and higher tumor grade, establish differences between primary tumor and their respective metastases, and provide further support that EMT plays a critical role in the metastasis of canine mammary carcinoma. Furthermore, these data suggest that modulation of this process could provide greater therapeutic control and provide support for further research to determine if E-cadherin+/vimentin+ co-immunoreactivity imparts predictive value in the clinical outcome of patients with canine mammary carcinomas.


Asunto(s)
Carcinoma/veterinaria , Enfermedades de los Perros/patología , Transición Epitelial-Mesenquimal , Neoplasias Mamarias Animales/patología , Animales , Cadherinas/metabolismo , Carcinoma/patología , Perros , Femenino , Técnica del Anticuerpo Fluorescente/veterinaria , Glándulas Mamarias Animales/patología , Vimentina/metabolismo
16.
Vet Ophthalmol ; 21(2): 167-173, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28714087

RESUMEN

The objectives of this retrospective study of 100 dogs with intraocular lymphoma were to describe the histomorphologic and immunohistochemical features of canine intraocular lymphoma, determine the proportion of cases with presumed solitary ocular lymphoma (PSOL) compared to multicentric disease, and assess the clinical outcomes of these patients. Selected cases from Penn Vet Diagnostic Laboratory and Comparative Ocular Pathology Lab of Wisconsin (2004-2015) were evaluated and subtyped using the WHO classification system. Peripheral T-cell lymphoma and diffuse large B-cell lymphoma were the two most common subtypes. Questionnaires were distributed to the referring veterinarians and veterinary ophthalmologists inquiring about clinical signs at time of enucleation, staging, patient outcome, treatment, and disease progression. Cases were categorized as PSOL if only ocular involvement was noted at the time of diagnosis based on the clinical staging criteria. The majority of cases (61%) did not have systemic involvement at the time of diagnosis, and these cases did not progress postoperatively. Median survival time (MST) was significantly higher for the presumed solitary intraocular cases: 769 vs. 103 days, hazard ratio of 0.23 (95% CI: 0.077-0.68). The subtype of lymphoma did not affect survival time. The results of this study suggest two significant points of clinical interest: the majority of dogs (61%) presented without signs of systemic involvement of lymphoma at the time of enucleation, and dogs with only ocular involvement showed no disease progression postenucleation.


Asunto(s)
Enfermedades de los Perros/patología , Neoplasias del Ojo/veterinaria , Linfoma Intraocular/patología , Linfoma Intraocular/veterinaria , Animales , Enfermedades de los Perros/clasificación , Enfermedades de los Perros/inmunología , Perros , Neoplasias del Ojo/clasificación , Neoplasias del Ojo/inmunología , Neoplasias del Ojo/patología , Femenino , Inmunofenotipificación/veterinaria , Linfoma Intraocular/clasificación , Linfoma Intraocular/inmunología , Masculino , Estudios Retrospectivos , Análisis de Supervivencia
17.
Cancer ; 123(6): 1051-1060, 2017 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-28263385

RESUMEN

BACKGROUND: Complete tumor resection is the most important predictor of patient survival with non-small cell lung cancer. Methods for intraoperative margin assessment after lung cancer excision are lacking. This study evaluated near-infrared (NIR) intraoperative imaging with a folate-targeted molecular contrast agent (OTL0038) for the localization of primary lung adenocarcinomas, lymph node sampling, and margin assessment. METHODS: Ten dogs with lung cancer underwent either video-assisted thoracoscopic surgery or open thoracotomy and tumor excision after an intravenous injection of OTL0038. Lungs were imaged with an NIR imaging device both in vivo and ex vivo. The wound bed was re-imaged for retained fluorescence suspicious for positive tumor margins. The tumor signal-to-background ratio (SBR) was measured in all cases. Next, 3 human patients were enrolled in a proof-of-principle study. Tumor fluorescence was measured both in situ and ex vivo. RESULTS: All canine tumors fluoresced in situ (mean Fluoptics SBR, 5.2 [range, 2.7-8.1]; mean Karl Storz SBR 1.9 [range, 1.4-2.6]). In addition, the fluorescence was consistent with tumor margins on pathology. Three positive lymph nodes were discovered with NIR imaging. Also, a positive retained tumor margin was discovered upon NIR imaging of the wound bed. Human pulmonary adenocarcinomas were also fluorescent both in situ and ex vivo (mean SBR, > 2.0). CONCLUSIONS: NIR imaging can identify lung cancer in a large-animal model. In addition, NIR imaging can discriminate lymph nodes harboring cancer cells and also bring attention to a positive tumor margin. In humans, pulmonary adenocarcinomas fluoresce after the injection of the targeted contrast agent. Cancer 2017;123:1051-60. © 2016 American Cancer Society.


Asunto(s)
Receptores de Folato Anclados a GPI/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Imagen Molecular , Imagen Óptica , Espectroscopía Infrarroja Corta , Anciano , Animales , Medios de Contraste , Modelos Animales de Enfermedad , Perros , Femenino , Colorantes Fluorescentes , Humanos , Cuidados Intraoperatorios , Neoplasias Pulmonares/cirugía , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Imagen Molecular/métodos , Estadificación de Neoplasias , Imagen Óptica/métodos , Relación Señal-Ruido , Espectroscopía Infrarroja Corta/métodos , Tomografía Computarizada por Rayos X
18.
Carcinogenesis ; 35(5): 1067-77, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24408928

RESUMEN

Hypoxia-inducible factors (HIFs) accumulate in both neoplastic and inflammatory cells within the tumor microenvironment and impact the progression of a variety of diseases, including colorectal cancer. Pharmacological HIF inhibition represents a novel therapeutic strategy for cancer treatment. We show here that acriflavine (ACF), a naturally occurring compound known to repress HIF transcriptional activity, halts the progression of an autochthonous model of established colitis-associated colon cancer (CAC) in immunocompetent mice. ACF treatment resulted in decreased tumor number, size and advancement (based on histopathological scoring) of CAC. Moreover, ACF treatment corresponded with decreased macrophage infiltration and vascularity in colorectal tumors. Importantly, ACF treatment inhibited the hypoxic induction of M-CSFR, as well as the expression of the angiogenic factor (vascular endothelial growth factor), a canonical HIF target, with little to no impact on the Nuclear factor-kappa B pathway in bone marrow-derived macrophages. These effects probably explain the observed in vivo phenotypes. Finally, an allograft tumor model further confirmed that ACF treatment inhibits tumor growth through HIF-dependent mechanisms. These results suggest pharmacological HIF inhibition in multiple cell types, including epithelial and innate immune cells, significantly limits tumor growth and progression.


Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Acriflavina/administración & dosificación , Acriflavina/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Translocador Nuclear del Receptor de Aril Hidrocarburo/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Transducción de Señal/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética , Ensayos Antitumor por Modelo de Xenoinjerto
19.
J Am Anim Hosp Assoc ; 50(3): 198-202, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24659730

RESUMEN

A 12 yr old castrated male mixed-breed dog presented with a 2 wk history of progressive tetraparesis. Neurologic deficits included a short-strided choppy gait in the thoracic limbs and a long-strided proprioceptive ataxia in the pelvic limbs. Withdrawal reflexes were decreased bilaterally in the thoracic limbs. Signs were consistent with a myelopathy of the caudal cervical/cranial thoracic spinal cord (i.e., the sixth cervical [C] vertebra to the second thoracic [T] vertebra). A mass associated with the C6-C7 articular facet on the left side was identified on MRI of the cervical spinal cord. The lesion was hyperintense to spinal cord parenchyma on T2-weighted images, hypointense on T1-weighted images, and there was strong homogenous contrast enhancement. Significant spinal cord compression was associated with the lesion. The mass was removed through a C6-C7 dorsal laminectomy and facetectomy. Histopathology of the mass was consistent with a synovial myxoma of the articular facet. A postoperative MRI showed complete surgical resection. Albeit rare, synovial myxomas should be included in the list of differential diagnoses for neoplasms affecting the vertebral columns in dogs.


Asunto(s)
Vértebras Cervicales , Enfermedades de los Perros/cirugía , Mixoma/veterinaria , Neoplasias de la Médula Espinal/veterinaria , Animales , Diagnóstico Diferencial , Enfermedades de los Perros/patología , Perros , Laminectomía/veterinaria , Imagen por Resonancia Magnética/veterinaria , Masculino , Mixoma/cirugía , Examen Neurológico/veterinaria , Compresión de la Médula Espinal/cirugía , Compresión de la Médula Espinal/veterinaria , Neoplasias de la Médula Espinal/cirugía
20.
Vet Immunol Immunopathol ; 271: 110741, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38520894

RESUMEN

Tumor-infiltrating lymphocyte (TIL) density plays an important role in anti-tumor immunity and is associated with patient outcome in various human and canine malignancies. As a first assessment of the immune landscape of the tumor microenvironment in canine renal cell carcinoma (RCC), we retrospectively analyzed clinical data and quantified CD3, FoxP3, and granzyme B immunostaining in formalin-fixed paraffin-embedded tumor samples from 16 dogs diagnosed with renal cell carcinoma treated with ureteronephrectomy. Cell density was low for all markers evaluated. Increased numbers of intratumoral FoxP3 labelled (+) cells, as well as decreased granzyme B+: FoxP3+ TIL ratio, were associated with poor patient outcomes. Our initial study of canine RCC reveals that these tumors are immunologically cold and Tregs may play an important role in immune evasion.


Asunto(s)
Complejo CD3 , Carcinoma de Células Renales , Enfermedades de los Perros , Factores de Transcripción Forkhead , Granzimas , Neoplasias Renales , Linfocitos Infiltrantes de Tumor , Animales , Perros , Carcinoma de Células Renales/veterinaria , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/enzimología , Complejo CD3/análisis , Complejo CD3/metabolismo , Enfermedades de los Perros/inmunología , Enfermedades de los Perros/enzimología , Factores de Transcripción Forkhead/análisis , Factores de Transcripción Forkhead/metabolismo , Granzimas/metabolismo , Granzimas/análisis , Inmunohistoquímica/veterinaria , Neoplasias Renales/veterinaria , Neoplasias Renales/inmunología , Neoplasias Renales/enzimología , Linfocitos Infiltrantes de Tumor/inmunología , Estudios Retrospectivos
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