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1.
Front Vet Sci ; 11: 1334813, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38655532

RESUMO

A 7-year-old Lhasa Apso presented with a history of left thoracic limb lameness and neck pain. Magnetic resonance imaging revealed a well-defined, extradural lesion that was hyperintense on T1-weighted (T1W) images and isointense on T2-weighted (T2W) images and T2* images located at the left lamina of the C4 vertebra. Computed tomography showed an isoattenuating and contrast-enhancing mass centered on the left C4 vertebral lamina with associated osteolysis. The mass was surgically debulked, and histopathology revealed a malignant melanocytic tumour. The patient recovered completely and received radiotherapy and three doses of the melanoma vaccine as adjunctive treatment. Eighteen months following treatment, the patient presented with neck pain again, but further investigations were declined at this stage, and the patient was euthanised. To the author's knowledge, this is the first case report describing the imaging characteristics of a cervical extradural melanocytic tumour in a dog. This case illustrates the MRI and CT imaging features and treatment of a canine melanocytic tumour of the cervical vertebrae.

2.
J Feline Med Surg ; 26(4): 1098612X241234614, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38647264

RESUMO

OBJECTIVES: The aim of this study was to determine response rates, median progression-free intervals (PFIs) and median survival times (MSTs) for cats with intermediate-large cell lymphoma treated with a vincristine, cyclophosphamide, mitoxantrone and prednisolone (CMOP) protocol. A secondary objective was to determine the tolerability of mitoxantrone used within this multiagent protocol. METHODS: The medical records of 31 cats treated at a single institution between 2009 and 2022 were reviewed to identify suitable cases. Cats were included in the study if they had a confirmed diagnosis of intermediate-large cell lymphoma, had received a CMOP protocol as first-line treatment and had completed at least one 4-week cycle of this protocol. Modifications allowed in the protocol included the use of l-asparaginase, vinblastine substitution for vincristine, chlorambucil substitution for cyclophosphamide and dexamethasone or methylprednisolone substitution for prednisolone. RESULTS: The overall response rate was 74% (n = 23), with 45% (n = 14) achieving complete remission (CR), 29% (n = 9) achieving partial remission (PR) and 26% (n = 8) achieving stable disease (SD). The Kaplan-Meier median PFI and MST were 139 days and 206 days, respectively. Responders (CR or PR) had a significantly longer (P <0.001) median PFI and MST compared with non-responders (SD) (176 days vs 62 days, and 251 days vs 61 days, respectively). Cats that achieved CR had a significantly longer median PFI and MST (P <0.001) at 178 days and 1176 days, respectively. The 6-month and 1- and 2-year survival rates in cats with CR were 64%, 57% and 35%, respectively. Treatment with mitoxantrone was generally well tolerated, with no cats experiencing Veterinary Cooperative Oncology Group adverse effects above grade 2. CONCLUSIONS AND RELEVANCE: The CMOP protocol is an alternative and well-tolerated treatment for cats with intermediate-large cell lymphoma. As demonstrated with previous chemotherapy protocols, cats that respond to treatment, particularly those that achieve CR, are likely to have more durable responses.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Doenças do Gato , Ciclofosfamida , Mitoxantrona , Prednisolona , Vincristina , Animais , Gatos , Mitoxantrona/administração & dosagem , Mitoxantrona/uso terapêutico , Doenças do Gato/tratamento farmacológico , Vincristina/uso terapêutico , Vincristina/administração & dosagem , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico , Masculino , Feminino , Estudos Retrospectivos , Resultado do Tratamento
3.
bioRxiv ; 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38260523

RESUMO

Mammalian DNA replication employs several RecQ DNA helicases to orchestrate the faithful duplication of genetic information. Helicase function is often coupled to the activity of specific nucleases, but how helicase and nuclease activities are co-directed is unclear. Here we identify the inactive ubiquitin-specific protease, USP50, as a ubiquitin-binding and chromatin-associated protein required for ongoing replication, fork restart, telomere maintenance and cellular survival during replicative stress. USP50 supports WRN:FEN1 at stalled replication forks, suppresses MUS81-dependent fork collapse and restricts double-strand DNA breaks at GC-rich sequences. Surprisingly we find that cells depleted for USP50 and recovering from a replication block exhibit increased DNA2 and RECQL4 foci and that the defects in ongoing replication, poor fork restart and increased fork collapse seen in these cells are mediated by DNA2, RECQL4 and RECQL5. These data define a novel ubiquitin-dependent pathway that promotes the balance of helicase: nuclease use at ongoing and stalled replication forks.

4.
Nat Commun ; 14(1): 7834, 2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-38030626

RESUMO

A synthetic lethal relationship exists between disruption of polymerase theta (Polθ), and loss of either 53BP1 or homologous recombination (HR) proteins, including BRCA1; however, the mechanistic basis of these observations are unclear. Here we reveal two distinct mechanisms of Polθ synthetic lethality, identifying dual influences of 1) whether Polθ is lost or inhibited, and 2) the underlying susceptible genotype. Firstly, we find that the sensitivity of BRCA1/2- and 53BP1-deficient cells to Polθ loss, and 53BP1-deficient cells to Polθ inhibition (ART558) requires RAD52, and appropriate reduction of RAD52 can ameliorate these phenotypes. We show that in the absence of Polθ, RAD52 accumulations suppress ssDNA gap-filling in G2/M and encourage MRE11 nuclease accumulation. In contrast, the survival of BRCA1-deficient cells treated with Polθ inhibitor are not restored by RAD52 suppression, and ssDNA gap-filling is prevented by the chemically inhibited polymerase itself. These data define an additional role for Polθ, reveal the mechanism underlying synthetic lethality between 53BP1, BRCA1/2 and Polθ loss, and indicate genotype-dependent Polθ inhibitor mechanisms.


Assuntos
Proteína BRCA1 , Mutações Sintéticas Letais , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Recombinação Homóloga , Reparo do DNA , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , DNA Polimerase teta
5.
J Vet Intern Med ; 37(5): 1738-1749, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37486176

RESUMO

BACKGROUND: Differentiation of gastrointestinal cancer (GIC) from chronic inflammatory enteropathies (CIE) in cats can be challenging and often requires extensive diagnostic testing. MicroRNAs (miRNAs) have promise as non-invasive biomarkers in serum and feces for diagnosis of GIC. HYPOTHESIS/OBJECTIVES: Cats with GIC will have serum and fecal miRNA profiles that differ significantly from healthy cats and cats with CIE. Identify serum and fecal miRNAs with diagnostic potential for differentiation between cats with GIC and CIE as compared to healthy cats. ANIMALS: Ten healthy cats, 9 cats with CIE, and 10 cats with GIC; all client-owned. METHODS: Cats were recruited for an international multicenter observational prospective case-control study. Serum and feces were screened using small RNA sequencing for miRNAs that differed in abundance between cats with GIC and CIE, and healthy cats. Diagnostic biomarker potential of relevant miRNAs from small RNA sequencing and the literature was confirmed using reverse transcription quantitative real-time PCR (RT-qPCR). RESULTS: Serum miR-223-3p was found to distinguish between cats with GIC and CIE with an area under the curve (AUC) of 0.9 (95% confidence interval [CI], 0.760-1.0), sensitivity of 90% (95% CI, 59.6-99.5%), and specificity of 77.8% (95% CI, 45.3-96.1%). Serum miR-223-3p likewise showed promise in differentiating a subgroup of cats with small cell lymphoma (SCL) from those with CIE. No fecal miRNAs could distinguish between cats with GIC and CIE. CONCLUSION AND CLINICAL IMPORTANCE: Serum miR-223-3p potentially may serve as a noninvasive diagnostic biomarker of GIC in cats, in addition to providing a much needed tool for the differentiation of CIE and SCL.


Assuntos
Doenças do Gato , Neoplasias Gastrointestinais , MicroRNAs , Gatos , Animais , Estudos de Casos e Controles , Biomarcadores , Neoplasias Gastrointestinais/veterinária , Fezes , Doenças do Gato/diagnóstico
6.
J Vet Intern Med ; 37(4): 1331-1340, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37218395

RESUMO

BACKGROUND: Radiotherapy (RT) is an effective treatment for dogs presented with neurologic signs caused by pituitary tumors. However, its impact on the outcome of concurrent pituitary-dependent hypercortisolism (PDH) is controversial. OBJECTIVES: Determine whether dogs with PDH have longer survival after pituitary RT compared with dogs with nonhormonally active pituitary masses and to evaluate whether clinical, imaging, and RT variables affect survival. ANIMALS: Ninety-four dogs divided into 2 groups: PDH and non-PDH, based on the presence of hypercortisolism. Forty-seven dogs were allocated to the PDH group and 47 to the non-PDH group. METHODS: Retrospective cohort study in which clinical records of dogs undergoing RT for pituitary macroadenomas between 2008 and 2018 at 5 referral centers were retrospectively evaluated. RESULTS: Survival was not statistically different between PDH and non-PDH groups (median survival time [MST], 590 days; 95% confidence interval [CI], 0-830 days and 738 days; 95% CI, 373-1103 days, respectively; P = .4). A definitive RT protocol was statistically associated with longer survival compared with a palliative protocol (MST 605 vs 262 days, P = .05). The only factor statistically associated with survival from multivariate Cox proportional hazard analysis was total radiation dose (Gy) delivered (P < .01). CONCLUSIONS AND CLINICAL IMPORTANCE: No statistical difference in survival was identified between the PDH and non-PDH groups, and longer survival was associated with higher Gy delivered.


Assuntos
Hiperfunção Adrenocortical , Síndrome de Cushing , Doenças do Cão , Hipersecreção Hipofisária de ACTH , Neoplasias Hipofisárias , Humanos , Cães , Animais , Neoplasias Hipofisárias/radioterapia , Neoplasias Hipofisárias/veterinária , Neoplasias Hipofisárias/complicações , Estudos Retrospectivos , Síndrome de Cushing/veterinária , Hipersecreção Hipofisária de ACTH/radioterapia , Hipersecreção Hipofisária de ACTH/veterinária , Hipersecreção Hipofisária de ACTH/complicações , Hiperfunção Adrenocortical/veterinária , Resultado do Tratamento , Doenças do Cão/tratamento farmacológico
7.
Vet Comp Oncol ; 21(2): 332-338, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36907653

RESUMO

Canine cutaneous mast cell tumours (cMCTs) of the pinna have been associated with an aggressive biological behaviour, although data remain scarce. The knowledge acquired over the past years on histologic gradings, and the value of lymph node (LN) staging, may help in better characterizing this anatomical presentation. The first aim was to describe the frequency, location, and histologic appearance of LN metastases in cMCT of the pinna. A second aim was to evaluate prognosis. Medical records of dogs with cMCT of the pinna, that underwent tumour and sentinel (SLN) or regional LN (RLN) excision, were reviewed. The influence of potential prognostic variables on time to progression (TTP) and tumour-specific survival (TSS) was investigated. Thirty-nine dogs were included: 19 (48.7%) had Kiupel high-grade (K-HG) and 20 (51.3%) had low-grade (K-LG) MCTs. Eighteen (46.1%) dogs underwent SLN mapping: the superficial cervical LN was at least one of SLN in 17 (94.4%) cases. Twenty-two (56.4%) dogs had LN metastases; the superficial cervical LN was always involved. On multivariable analysis, only K-HG was associated with increased risk of progression (p = .043) and tumour-related death (p = .021). Median TTP and TSS were 270 and 370 days in K-HG, respectively; these were not reached in dogs with K-LG tumours (p < .01). cMCTs of the pinna are often K-HG and are also associated with a higher frequency of LN metastasis; however, we confirmed the independent prognostic value of histologic grading. A multimodal treatment may lead to favourable long-term outcome. Moreover, the superficial cervical LN is most often the SLN.


Assuntos
Doenças do Cão , Mastocitoma Cutâneo , Cães , Animais , Estudos Retrospectivos , Doenças do Cão/patologia , Prognóstico , Mastocitoma Cutâneo/veterinária , Metástase Linfática
9.
Sci Rep ; 12(1): 21343, 2022 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-36494414

RESUMO

Monoclonal antibodies (MAb) to members of the Small Ubiquitin-like modifier (SUMO) family are essential tools in the study of cellular SUMOylation. However, many anti-SUMO MAbs are poorly validated, and antibody matching to detection format is without an evidence base. Here we test the specificity and sensitivity of twenty-four anti-SUMO MAbs towards monomeric and polymeric SUMO1-4 in dot-blots, immunoblots, immunofluorescence and immunoprecipitation. We find substantial variability between SUMO MAbs for different conjugation states, for detecting increased SUMOylation in response to thirteen different stress agents, and as enrichment reagents for SUMOylated RanGAP1 or KAP1. All four anti-SUMO4 monoclonal antibodies tested cross-reacted wit SUMO2/3, and several SUMO2/3 monoclonal antibodies cross-reacted with SUMO4. These data characterize the specificity of twenty-four anti-SUMO antibodies across commonly used assays, creating an enabling resource for the SUMO research community.


Assuntos
Anticorpos Monoclonais , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Ubiquitina , Sumoilação , Imunoprecipitação
10.
J Vet Intern Med ; 36(6): 1989-2001, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36120988

RESUMO

BACKGROUND: Reliable biomarkers to differentiate gastrointestinal cancer (GIC) from chronic inflammatory enteropathy (CIE) in dogs are needed. Fecal and serum microRNAs (miRNAs) have been proposed as diagnostic and prognostic markers of GI disease in humans and dogs. HYPOTHESIS/OBJECTIVES: Dogs with GIC have fecal and serum miRNA profiles that differ from those of dogs with CIE. AIMS: (a) identify miRNAs that differentiate GIC from CIE, (b) use high-throughput reverse transcription quantitative real-time PCR (RT-qPCR) to establish fecal and serum miRNA panels to distinguish GIC from CIE in dogs. ANIMALS: Twenty-four dogs with GIC, 10 dogs with CIE, and 10 healthy dogs, all client-owned. METHODS: An international multicenter observational prospective case-control study. Small RNA sequencing was used to identify fecal and serum miRNAs, and RT-qPCR was used to establish fecal and serum miRNA panels with the potential to distinguish GIC from CIE. RESULTS: The best diagnostic performance for distinguishing GIC from CIE was fecal miR-451 (AUC: 0.955, sensitivity: 86.4%, specificity: 100%), miR-223 (AUC: 0.918, sensitivity: 90.9%, specificity: 80%), and miR-27a (AUC: 0.868, sensitivity: 81.8%, specificity: 90%) and serum miR-20b (AUC: 0.905, sensitivity: 90.5%, specificity: 90%), miR-148a-3p (AUC: 0.924, sensitivity: 85.7%, specificity: 90%), and miR-652 (AUC: 0.943, sensitivity: 90.5%, specificity: 90%). Slightly improved diagnostic performance was achieved when combining fecal miR-451 and miR-223 (AUC: 0.973, sensitivity: 95.5%, specificity: 90%). CONCLUSIONS AND CLINICAL IMPORTANCE: When used as part of a diagnostic RT-qPCR panel, the abovementioned miRNAs have the potential to function as noninvasive biomarkers for the differentiation of GIC and CIE in dogs.


Assuntos
Doenças do Cão , Neoplasias Gastrointestinais , MicroRNAs , Animais , Cães , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Doenças do Cão/diagnóstico , Doenças do Cão/genética , Neoplasias Gastrointestinais/veterinária , Perfilação da Expressão Gênica/veterinária , MicroRNAs/genética , Reação em Cadeia da Polimerase em Tempo Real/veterinária
11.
J Cell Sci ; 135(14)2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35748225

RESUMO

Commonly applied super-resolution light microscopies have provided insight into subcellular processes at the nanoscale. However, imaging depth, speed, throughput and cost remain significant challenges, limiting the numbers of three-dimensional (3D) nanoscale processes that can be investigated and the number of laboratories able to undertake such analysis. Expansion microscopy (ExM) solves many of these limitations, but its application to imaging nuclear processes has been constrained by concerns of unequal nuclear expansion. Here, we demonstrate the conditions for isotropic expansion of the nucleus at a resolution equal to or better than 120-130 nm (pre-expansion). Using the DNA damage response proteins BRCA1, 53BP1 (also known as TP53BP1) and RAD51 as exemplars, we quantitatively describe the 3D nanoscale organisation of over 50,000 DNA damage response structures. We demonstrate the ability to assess chromatin-regulated events and show the simultaneous assessment of four elements. This study thus demonstrates how ExM can contribute to the investigation of nanoscale nuclear processes.


Assuntos
Cromatina , Microscopia , Núcleo Celular , Microscopia/métodos
12.
Metallomics ; 14(7)2022 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-35689667

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a disease that remains refractory to existing treatments including the nucleoside analogue gemcitabine. In the current study we demonstrate that an organometallic nucleoside analogue, the ferronucleoside 1-(S,Rp), is cytotoxic in a panel of PDAC cell lines including gemcitabine-resistant MIAPaCa2, with IC50 values comparable to cisplatin. Biochemical studies show that the mechanism of action is inhibition of DNA replication, S-phase cell cycle arrest and stalling of DNA-replication forks, which were directly observed at single molecule resolution by DNA-fibre fluorography. In agreement with this, transcriptional changes following treatment with 1-(S,Rp) include activation of three of the four genes (HUS1, RAD1, RAD17) of the 9-1-1 check point complex clamp and two of the three genes (MRE11, NBN) that form the MRN complex as well as activation of multiple downstream targets. Furthermore, there was evidence of phosphorylation of checkpoint kinases 1 and 2 as well as RPA1 and gamma H2AX, all of which are considered biochemical markers of replication stress. Studies in p53-deficient cell lines showed activation of CDKN1A (p21) and GADD45A by 1-(S,Rp) was at least partially independent of p53. In conclusion, because of its potency and activity in gemcitabine-resistant cells, 1-(S,Rp) is a promising candidate molecule for development of new treatments for PDAC.


Assuntos
Replicação do DNA , Nucleosídeos , Neoplasias Pancreáticas , Proteínas de Ciclo Celular/metabolismo , Dano ao DNA , Proteínas de Ligação a DNA/metabolismo , Humanos , Metalocenos , Nucleosídeos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Fase S , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Pancreáticas
13.
Vet Rec ; 190(7): e946, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34580882

RESUMO

BACKGROUND: Folate deficiency in people can occur in conditions causing increased demand, including haemolytic anaemia. This has not been investigated in dogs with non-associative immune-mediated haemolytic anaemia (IMHA). METHODS: Cohort study of 15 dogs with non-associative IMHA. Haematocrit (HCT) and serum folate concentrations were measured at presentation and each subsequent venipuncture performed for monitoring. The relationship between serum folate concentrations and HCT was investigated using linear and logistic mixed-effects regression models and in paired samples using a one-tailed paired t-test. RESULTS: Low serum folate concentrations occurred in five of 15 dogs. In 126 samples, a significant positive relationship was found between HCT and corresponding serum folate concentrations. A significant relationship was found between dichotomised folate concentrations (below the reference interval or within/above the reference interval) and HCT and between serum folate concentrations and dichotomised HCT (less than or equal/above 0.30 L/L). For paired samples (available in eight dogs), the mean serum folate concentration of samples with the lowest HCT was significantly lower than that of samples in which the HCT first exceeded 0.30 L/L. CONCLUSIONS: Low serum folate concentrations were observed in some dogs with non-associative IMHA. Further studies are needed to determine the cause and investigate whether folate supplementation would be beneficial.


Assuntos
Anemia Hemolítica Autoimune , Anemia Hemolítica , Doenças do Cão , Anemia Hemolítica/veterinária , Anemia Hemolítica Autoimune/veterinária , Animais , Estudos de Coortes , Cães , Ácido Fólico , Humanos
14.
Vet Comp Oncol ; 20(2): 404-415, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34792828

RESUMO

Standardized veterinary neuroimaging response assessment methods for brain tumours are lacking. Consequently, a response assessment in veterinary neuro-oncology (RAVNO) system which uses the sum product of orthogonal lesion diameters on 1-image section with the largest tumour area, has recently been proposed. In this retrospective study, 22 pre-treatment magnetic resonance imaging (MRI) studies from 18 dogs and four cats with suspected intracranial neoplasia were compared by a single observer to 32 post-treatment MRIs using the RAVNO system and two volumetric methods based on tumour margin or area delineation with HOROS and 3D Slicer software, respectively. Intra-observer variability was low, with no statistically significant differences in agreement index between methods (mean AI ± SD, 0.91 ± 0.06 for RAVNO; 0.86 ± 0.08 for HOROS; and 0.91 ± 0.05 for 3D slicer), indicating good reproducibility. Response assessments consisting of complete or partial responses, and stable or progressive disease, agreed in 23 out of 32 (72%) MRI evaluations using the three methods. The RAVNO system failed to identify changes in mass burden detected with volumetric methods in six cases. 3D Slicer differed from the other two methods in three cases involving cysts or necrotic tissue as it allowed for more accurate exclusion of these structures. The volumetric response assessment methods were more precise in determining changes in absolute tumour burden than RAVNO but were more time-consuming to use. Based on observed agreement between methods, low intra-observer variability and decreased time constraint, RAVNO might be a suitable response assessment method for the clinical setting.


Assuntos
Neoplasias Encefálicas , Doenças do Gato/diagnóstico por imagem , Doenças do Cão , Imageamento por Ressonância Magnética , Animais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/veterinária , Gatos , Doenças do Cão/diagnóstico por imagem , Cães , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/veterinária , Neuroimagem/veterinária , Reprodutibilidade dos Testes , Estudos Retrospectivos
15.
J Vet Intern Med ; 35(6): 2853-2864, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34672378

RESUMO

BACKGROUND: Radiation therapy is commonly used as an adjunct to incomplete surgical excision in dogs with mast cell tumors (MCT), but the optimal dose and fractionation regimen have yet to be determined. HYPOTHESIS: We assessed outcomes (time to local recurrence, patient survival and toxicity) of a large population of dogs with MCT that received adjunctive radiation therapy. ANIMALS: Three hundred dogs with 302 MCT treated using adjunctive radiation therapy. METHODS: Retrospective observational study. Clinical records of 4 veterinary radiation centers were reviewed. RESULTS: Local recurrence rates were similar regardless of radiation protocol with 6.6% of patients developing recurrent cutaneous MCT at a median of 526 days. Local recurrence rate was similar between high and low-risk MCT. Mast cell tumor related death was reported in 19% of all dogs, with 13% of dogs with low-risk MCT dying of their disease compared to 29% of dogs with high-risk MCT. No SC MCT (SCMCT) recurred after radiation therapy and only 7% of dogs with SCMCT were reported to have died of their disease. Mild late toxicity was common in both protocols and severe late toxicity occurred in 1.9% of dogs many years after treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Our study supports the use of adjunctive radiation for the long-term control of incompletely or narrowly excised cutaneous and SCMCT in dogs. More moderate dose and fractionation protocols may be appropriate in the adjunctive treatment of low-risk MCT in dogs. Large multicenter prospective studies are required to establish the optimal dose and fractionation for MCT of different risk categories.


Assuntos
Doenças do Cão , Neoplasias , Animais , Doenças do Cão/radioterapia , Cães , Mastócitos , Neoplasias/veterinária , Estudos Retrospectivos
16.
Vet Clin Pathol ; 50(4): 584-588, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34693549

RESUMO

Canine lymphoma represents a heterogeneous group of lymphoid neoplasms, with multicentric nodal lymphoma being the most common presentation. Musculoskeletal involvement is uncommon, and primary muscular lymphoma is a very rare presentation. Only a few cases have been described in dogs, which were of variable classification and immunophenotype. Here, we report the case of a 5-year-old female neutered Beagle that presented with an intramuscular mass on the right shoulder and associated lameness and lethargy. One month after initial presentation, multiple cutaneous nodules appeared on the head, and staging with advanced imaging revealed additional masses affecting other muscles. Cytology, histopathology, immunohistochemistry, and PCR for antigen receptor rearrangements of one of the muscle masses and skin lesions supported a diagnosis of peripheral T-cell lymphoma with large granular lymphocytes at both sites. The dog was euthanized after diagnosis due to the poor prognosis. This is the first report of primary muscular peripheral T-cell lymphoma with large granular lymphocytes and cutaneous involvement in the dog. Despite being a rare presentation, lymphoma must be considered a differential in dogs presenting with a discrete, intramuscular, soft tissue mass.


Assuntos
Doenças do Cão , Linfoma de Células T , Animais , Doenças do Cão/diagnóstico , Cães , Feminino , Imunofenotipagem/veterinária , Linfoma de Células T/veterinária
17.
Breast Cancer Res ; 23(1): 90, 2021 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-34565423

RESUMO

BACKGROUND: During pregnancy, the mouse mammary ductal epithelium branches and grows into the surrounding stroma, requiring extensive extracellular matrix (ECM) and tissue remodelling. It therefore shows parallels to cancer invasion. We hypothesised that similar molecular mechanisms may be utilised in both processes, and that assessment of the stromal changes during pregnancy-associated branching may depict the stromal involvement during human breast cancer progression. METHODS: Immunohistochemistry (IHC) was employed to assess the alterations within the mouse mammary gland extracellular matrix during early pregnancy when lateral branching of the primary ductal epithelium is initiated. Primary mouse mammary fibroblasts from three-day pregnant and age-matched non-pregnant control mice, respectively, were 3D co-cultured with mammary epithelial cells to assess differences in their abilities to induce branching morphogenesis in vitro. Transcriptome analysis was performed to identify the underlying molecular changes. A signature of the human orthologues of the differentially expressed matrisome RNAs was analysed by Kaplan-Meier and multi-variate analysis in two large breast cancer RNA datasets (Gene expression-based Outcome for Breast cancer Online (GOBO) und Kaplan-Meier Plotter), respectively, to test for similarities in expression between early-pregnancy mouse mammary gland development and breast cancer progression. RESULTS: The ECM surrounding the primary ductal network showed significant differences in collagen and basement membrane protein distribution early during pregnancy. Pregnancy-associated fibroblasts (PAFs) significantly enhanced branching initiation compared to age-matched control fibroblast. A combined signature of 64 differentially expressed RNAs, encoding matrisome proteins, was a strong prognostic indicator of distant metastasis-free survival (DMFS) independent of other clinical parameters. The prognostic power could be significantly strengthened by using only a subset of 18 RNAs (LogRank P ≤ 1.00e-13; Hazard ratio (HR) = 2.42 (1.8-3.26); p = 5.61e-09). The prognostic power was confirmed in a second breast cancer dataset, as well as in datasets from ovarian and lung cancer patients. CONCLUSIONS: Our results describe for the first time the early stromal changes that accompany pregnancy-associated branching morphogenesis in mice, specify the early pregnancy-associated molecular alterations in mouse mammary fibroblasts, and identify a matrisome signature as a strong prognostic indicator of human breast cancer progression, with particular strength in oestrogen receptor (ER)-negative breast cancers.


Assuntos
Neoplasias da Mama/genética , Matriz Extracelular/genética , Fibroblastos/metabolismo , Glândulas Mamárias Animais/metabolismo , RNA/genética , Animais , Membrana Basal/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Técnicas de Cocultura , Colágeno/metabolismo , Células Epiteliais/citologia , Matriz Extracelular/metabolismo , Feminino , Fibroblastos/citologia , Perfilação da Expressão Gênica , Humanos , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Camundongos , Morfogênese , Gravidez , Prognóstico , RNA/metabolismo
19.
Semin Cell Dev Biol ; 113: 14-26, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32653304

RESUMO

In response to replication hindrances, DNA replication forks frequently stall and are remodelled into a four-way junction. In such a structure the annealed nascent strand is thought to resemble a DNA double-strand break and remodelled forks are vulnerable to nuclease attack by MRE11 and DNA2. Proteins that promote the recruitment, loading and stabilisation of RAD51 onto single-stranded DNA for homology search and strand exchange in homologous recombination (HR) repair and inter-strand cross-link repair also act to set up RAD51-mediated protection of nascent DNA at stalled replication forks. However, despite the similarities of these pathways, several lines of evidence indicate that fork protection is not simply analogous to the RAD51 loading step of HR. Protection of stalled forks not only requires separate functions of a number of recombination proteins, but also utilises nucleases important for the resection steps of HR in alternative ways. Here we discuss how fork protection arises and how its differences with HR give insights into the differing contexts of these two pathways.


Assuntos
Dano ao DNA/genética , Replicação do DNA/genética , Instabilidade Genômica/genética , Recombinação Homóloga/genética , Humanos
20.
Clin Case Rep ; 8(12): 2498-2503, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33363766

RESUMO

Solitary osseous plasmacytomas affecting the vertebrae, the zygomatic arch, and ribs occur in dogs. In this report, we describe clinical and imaging features of a solitary osseous plasmacytoma affecting the skull with deposition of amyloid forming a mass-like lesion. To the authors' knowledge, no similar cases have been reported before.

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