Mucosal melanoma is a rare and poorly characterized subtype of human melanoma. Here we perform a cross-species analysis by sequencing tumor-germline pairs from 46 primary human muscosal, 65 primary canine oral and 28 primary equine melanoma cases from mucosal sites. Analysis of these data reveals recurrently mutated driver genes shared between species such as NRAS, FAT4, PTPRJ, TP53 and PTEN, and pathogenic germline alleles of BRCA1, BRCA2 and TP53. We identify a UV mutation signature in a small number of samples, including human cases from the lip and nasal mucosa. A cross-species comparative analysis of recurrent copy number alterations identifies several candidate drivers including MDM2, B2M, KNSTRN and BUB1B. Comparison of somatic mutations in recurrences and metastases to those in the primary tumor suggests pervasive intra-tumor heterogeneity. Collectively, these studies suggest a convergence of some genetic changes in mucosal melanomas between species but also distinctly different paths to tumorigenesis.
A major challenge in multiple sclerosis research is to understand the cause or causes of remyelination failure and to devise ways of ameliorating its consequences. This requires appropriate experimental models. Although there are many models of acute demyelination, at present there are few suitable models of chronic demyelination. The taiep rat is a myelin mutant that shows progressive myelin loss and, by 1 year of age, its CNS tissue has many features of chronic areas of demyelination in multiple sclerosis: chronically demyelinated axons present in an astrocytic environment in the absence of acute inflammation. Using the taiep rat and a combination of X-irradiation and cell transplantation, it has been possible to address a number of questions concerning remyelination failure in chronic multiple sclerosis lesions, such as whether chronically demyelinated axons have undergone changes that render them refractory to remyelination and why remyelination is absent when oligodendrocyte progenitor cells (OPCs) are present. Our experiments show that (i) transplanted OPCs will not populate OPC-containing areas of chronic demyelination; (ii) myelination competent OPCs can repopulate OPC-depleted chronically demyelinated astrocytosed tissue, but this repopulation does not result in remyelination--closely resembling the situation found in some multiple sclerosis plaques; and (iii) the induction of acute inflammation in this non-remyelinating situation results in remyelination. Thus, we can conclude that axonal changes induced by chronic demyelination are unlikely to contribute to remyelination failure in multiple sclerosis. Rather, remyelination fails either because OPCs fail to repopulate areas of demyelination or because if OPCs are present they are unable to generate remyelinating oligodendrocytes owing to the presence of inhibitory factors and/or a lack of the stimuli required to activate these cells to generate remyelinating oligodendrocytes. This non-remyelinating situation can be transformed to a remyelinating one by the induction of acute inflammation.
Although transformation of melanocytes to melanoma is rare, the rapid growth, systemic spread, as well as the chemoresistance of melanoma present significant challenges for patient care. Here we review animal models of melanoma, including murine, canine, equine, and zebrafish models, and detail the immense contribution these models have made to our knowledge of human melanoma development, and to melanocyte biology. We also highlight the opportunities for cross‐species comparative genomic studies of melanoma to identify the key molecular events that drive this complex disease. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Background Pregnancy loss after Day 70 of gestation manifests as abortion, stillbirth or perinatal death. While previous studies have reported the diagnoses of laboratory submissions, none have quantified the incidence and causes of abortions, stillbirths and perinatal mortality at a population level. Objectives To report the incidence and causes of pregnancy loss after Day 70 of gestation in a cohort of Thoroughbreds. Study design Retrospective cohort study. Methods Outcomes of Day 70 pregnancies were collected from eight Thoroughbred farms over the 2013‐2017 breeding seasons. Stud, veterinary and laboratory records were supplemented with publicly available data. Cause of loss was categorised using custom criteria. Results Data were collected on 3,586 pregnancies from 1,802 mares. The incidence risk of a pregnancy failing to produce a live foal at 24 hours post parturition was 7.3% (95% confidence interval (CI) 6.5‐8.2, equating to 7.3 cases per 100 Day‐70 pregnancies). The incidence of pregnancy loss between Day 70 and 300 of gestation, Day 301‐315 and stillbirth/perinatal death was 4.0% (95% CI 3.4‐4.7), 0.3% (95% CI 0.2‐0.6) and 1.4% (95% CI 1.1‐1.9) respectively. Of the pregnancy losses where tissue was available, 61.1% were submitted for post‐mortem examination. The incidence risk of loss due to umbilical cord‐related pathologies was 1.5% (95% CI 1.1‐1.9), 0.4% (95% CI 0.2‐0.6) for noninfectious placental disease and 0.3% (95% CI 0.2‐0.6) for both infectious placentitis and Equine Herpesvirus infection. No primary diagnosis was made in 11.2% of the cases which underwent full post‐mortem examination. Main limitations It was not possible to differentiate between intra‐partum stillbirth and early post‐partum death. Conclusion Pregnancy loss after Day 70 of gestation is a significant source of loss in the Thoroughbred with umbilical cord‐related pathologies being the most commonly diagnosed cause. Reporting the incidence of pregnancy loss at a population level with clear case definitions will allow for accurate global comparisons.
Equine mammary tumors are uncommon, and relatively sparse histopathologic and molecular data exist. The present study describes the histopathologic features of 7 such tumors, which exhibited infiltrative growth, intermediate to high mitotic rates, and focally extensive necrosis. The tumors exhibited variably strong staining for vimentin and cytokeratin 14, as well as frequently weak cytoplasmic staining for pan-cytokeratin. E-cadherin expression was strong. Interestingly, a subgroup of the tumors exhibited strong nuclear staining for estrogen receptor α. Three of 7 tumors exhibited nuclear expression of the transcription factor STAT3, suggesting that STAT3 was transcriptionally active. Rare to absent nuclear STAT3 expression was observed in carcinomas exhibiting moderate to intense staining for cytokeratin 14. This investigation confirms previous investigators' assertions that equine mammary tumors have a malignant phenotype. A subset of the equine mammary tumors exhibited estrogen receptor α expression, suggesting that these tumors may potentially have similar molecular characteristics to their feline and canine counterparts.
SummarySignificant progress has been made in understanding and monitoring the causes of equine abortion over past decades. However, not all in utero pathology results in abortion. It has long been recognised that some in utero pathology, such as twinning or chronic placentitis, can result in the birth of live but growth-retarded foals and there is historical evidence that birth weight may influence future athletic performance. Clinical experience (e.g. from twins) and experimental studies (pony-Thoroughbred embryo transfer) have highlighted the importance of reduced functional placental area in limiting growth in utero in horses. Many other nonfatal in utero pathologies (e.g. umbilical cord-related circulatory compromise) can potentially affect either placental function or other organ systems. Their influence on the short-and long-term health of the foal and its future athletic performance is in many cases poorly documented or understood. This review summarises the main causes of in utero pathology and reflects on how these may potentially affect the foal if born alive, highlighting the need for long-term studies on this important subject.
Summary This report describes the successful management of a pregnant 14‐year‐old seven‐eighths Thoroughbred mare with an ovarian granulosa cell tumour. The mare initially presented with unilateral ovarian enlargement whilst being managed for artificial insemination, demonstrating normal ovarian function with ovulation from the contralateral ovary leading to conception. The mare subsequently re‐presented with stallion‐like behaviour at 3.5 months gestation and ovarian suppression was evident. The mare maintained her pregnancy and delivered a live colt foal at term. Ovariectomy was performed 3 months post foaling and the mare regained cyclic activity 9 months post surgery. The mare then conceived and became pregnant once more. The diagnostic and therapeutic challenges during pregnancy are discussed.
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