Publications by authors named "Carlos Eduardo Fonseca-Alves"

39 Publications

Biological Performance of Alginate Hydrogel Capsules for Stem Cell Delivery.

Front Bioeng Biotechnol 2021 27;9:674581. Epub 2021 Aug 27.

Department of Veterinary Surgery and Animal Reproduction, School of Veterinary Medicine and Animal Science, São Paulo State University, UNESP, Botucatu, Brazil.

Encapsulation of biological components in hydrogels is a well described method for controlled drug delivery of proteins, tissue engineering and intestinal colonization with beneficial bacteria. Given the potential of tissue engineering in clinical practice, this study aimed to evaluate the feasibility of encapsulation of adipose tissue-derived mesenchymal stem cells (MSCs) of mules in sodium alginate. We evaluated capsule morphology and cell viability, immunophenotype and release after encapsulation. Circular and irregular pores were observed on the hydrogel surface, in which MSCs were present and alive. Capsules demonstrated good capacity of absorption of liquid and cell viability was consistently high through the time points, indicating proper nutrient diffusion. Flow cytometry showed stability of stem cell surface markers, whereas immunohistochemistry revealed the expression of CD44 and absence of MHC-II through 7 days of culture. Stem cell encapsulation in sodium alginate hydrogel is a feasible technique that does not compromise cell viability and preserves their undifferentiated status, becoming a relevant option to further studies of tridimensional culture systems and bioactive agents delivery.
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http://dx.doi.org/10.3389/fbioe.2021.674581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429506PMC
August 2021

Investigation of Prognostic Value of Claudin-5, PSMA, and Ki67 Expression in Canine Splenic Hemangiosarcoma.

Animals (Basel) 2021 Aug 14;11(8). Epub 2021 Aug 14.

Department of Veterinary Surgery and Animal Reproduction, Sao Paulo State University-UNESP, Botucatu 18618-681, Brazil.

Splenic hemangiosarcoma (HSA) is a malignant tumor of endothelial cells that affects middle-aged and elderly dogs and is characterized by the formation of new blood vessels, commonly associated with necrotic and hemorrhagic areas. Despite its importance in veterinary medicine, few studies have identified markers with prognostic value for canine HSA. Thus, this study aimed to associate the clinicopathological findings (prostate-specific membrane antigen [PSMA], Claudin-5, and Ki67 gene and protein expression) with overall survival in HSA-affected patients. Fifty-three formalin-fixed and paraffin-embedded canine splenic HSA samples, previously diagnosed by histopathological examination, were used in this study. Claudin-5, PSMA, and Ki67 protein expression levels were evaluated by immunohistochemistry, and gene expression was evaluated by quantitative polymerase chain reaction. Claudin-5 protein overexpression was observed in patients with metastasis ( = 0.0078) and with stage III tumors compared to those with stage I and II tumors ( = 0.0451). In patients treated with surgery alone, low PSMA gene and protein expression ( = 0.05 and = 0.0355, respectively) were associated with longer survival time. Longer survival time was observed in patients with a low Ki67 index ( = 0.0488). Our results indicate that Claudin-5 protein expression is associated with metastatic status, and PSMA gene and protein expression, and Ki67 index are associated with survival time.
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http://dx.doi.org/10.3390/ani11082406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388721PMC
August 2021

Editorial: Precision Medicine in Veterinary Oncology.

Front Vet Sci 2021 14;8:718891. Epub 2021 Jul 14.

Department of Veterinary Clinic, São Paulo State University-UNESP, Botucatu, Brazil.

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http://dx.doi.org/10.3389/fvets.2021.718891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316583PMC
July 2021

Expression and prognostic significance of vascular endothelial growth factor-A (VEGF-A) and its receptor in canine prostate cancer.

Prostate 2021 Oct 28;81(14):1021-1031. Epub 2021 Jul 28.

Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University-UNESP, Botucatu, Sao Paulo, Brazil.

Background: Vascular endothelial growth factor-A (VEGF-A) and its receptor, VEGF receptor-2 (VEGFR-2), represent a complex family of angiogenic molecules consisting of different ligands and receptors. Due to the importance of VEGF-A/VEGFR-2 signaling in tumor proliferation and angiogenesis, this study aimed to evaluate the protein and gene expression levels of VEGF-A and VEGFR-2 in canine prostate cancer (PC).

Methods: We analyzed VEGF-A and VEGFR-2 expression in 87 PC samples by immunohistochemistry and quantitative-polymerase chain reaction. PC samples were graded according to the Gleason score and the immunohistochemical staining for VEGF-A and VEGFR-2 was quantified using a selected threshold from the ImageJ Software. Microvascular density was assessed by cluster of differentiation 31 staining and counting the number of positive vessels. Additionally, the homology of VEGF-A and VEGFR-2 between humans and dogs was assessed, followed by the construction of a protein structure homology model to compare the tertiary structures of these proteins in both species.

Results: Negative to weakly positive expression levels of VEGF-A and VEGFR-2 were observed in the epithelial cells of the normal prostate (NP) and prostatic hyperplasia samples. In contrast, the canine proliferative atrophy and PC samples exhibited higher VEGF-A (p < .0001) and VEGFR-2 (p < .0001) compared to NP. Moreover, positive correlations between the expression levels of VEGF-A and VEGFR-2 (Spearman's coefficient (r) = .68, p = .013) and the expression levels of VEGF-A and VEGFR-2 proteins (r = .8, p < .0001) were also observed in the NP samples. Additionally, the patients with PC exhibiting higher VEGFR-2 expression levels experienced a shorter survival period (p = .0372). Furthermore, we found an association between the microvascular density and overall survival. Dogs with a higher number of vessels showed a shorter survival time. We further demonstrated that the VEGF-A and VEGFR-2 exhibited high homology between humans and dogs, and identified their protein structures in both species.

Conclusions: In conclusion, VEGFR-2 appears to be an independent prognostic factor in animals with PC. VEGF-A and VEGFR-2 are highly conserved between humans and dogs, which can be investigated further in future cross-species studies to explore their therapeutic applications.
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http://dx.doi.org/10.1002/pros.24199DOI Listing
October 2021

Effects of Lapatinib on HER2-Positive and HER2-Negative Canine Mammary Carcinoma Cells Cultured In Vitro.

Pharmaceutics 2021 Jun 17;13(6). Epub 2021 Jun 17.

Department of Veterinary Clinic, Sao Paulo State University-UNESP, Botucatu 18618-681, Brazil.

HER2 is a prognostic and predictive marker widely used in breast cancer. Lapatinib is a tyrosine kinase inhibitor that works by blocking the phosphorylation of the receptor HER2. Its use is related to relatively good results in the treatment of women with HER2+ breast cancer. Thus, this study aimed to verify the effects of lapatinib on four canine primary mammary gland carcinoma cell cultures and two paired metastatic cell cultures. Cultures were treated with lapatinib at concentrations of 100, 500, 1000 and 3000 nM for 24 h and the 50% inhibitory concentration (IC) for each cell culture was determined. In addition, a transwell assay was performed to assess the ability of lapatinib to inhibit cell migration. Furthermore, we verified expression by RT-qPCR analysis of cell cultures and formalin-fixed paraffin-embedded tissues from samples corresponding to those used in cell culture. Lapatinib was able to inhibit cell proliferation in all cell cultures, but it was not able to inhibit migration in all cell cultures. The higher the expression of in a culture, the more sensitive the culture was to treatment. This relationship may be an indication that the expression of may be a predictive factor and opens a new perspective for the treatment of primary and metastatic mammary gland cancer.
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http://dx.doi.org/10.3390/pharmaceutics13060897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235449PMC
June 2021

Endometrial angiogenesis induced by uterine insufflation with an oxygen-ozone gas mixture in mares.

Reprod Domest Anim 2021 May 22. Epub 2021 May 22.

Department of Animal Reproduction and Veterinary Radiology, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu, Brazil.

Ozone (O ) therapy has been used to improve peripheral tissue oxygenation in humans and domestic animals. The goal of the present study was to characterize histological changes in the endometria of healthy equines following tissue exposure to gas mixtures enriched with different concentrations of O . Cycling mares without endometrial degeneration were divided into three groups according to treatment (n = 9 mares/group). The uteri from the O , ½O and control groups were insufflated for 3 min with gas containing 42, 21 and 0 μg O ml , respectively. Treatments were performed every three days from D0 to D6. Endometrial samples were collected immediately before the first treatment and 24 hr after the last treatment. The following nine histological parameters were evaluated: (i) the number of endometrial blood vessels, (ii) endometrial vascular degree (EVD), (iii) increase rate of blood vessels, (iv) increase rate of EVD, (v) glandular total area, (vi) glandular lumen area, (vii) intraglandular secretion area, (viii) glandular epithelial height and (ix) luminal epithelial height. In the O group, a positive effect from treatment (p < .01) was detected for all vascular parameters (i, ii, iii and iv), glandular total area, intraglandular secretion area and glandular epithelial height. Compared to the control group, the ½O group had greater (p < .01) EVD (84.1 ± 12%) and a higher increase rate of blood vessels (151.9 ± 47.1%). Uterine insufflation with low or intermediate concentrations of the O -O gas mixture induced endometrial angiogenesis. Morphometry, but not morphology, of the endometrial glands was affected by local O therapy. These findings would be of great significance for the development of new therapies for infertility in mares.
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http://dx.doi.org/10.1111/rda.13958DOI Listing
May 2021

Morphological and Molecular Characterization of Proliferative Inflammatory Atrophy in Canine Prostatic Samples.

Cancers (Basel) 2021 Apr 14;13(8). Epub 2021 Apr 14.

School of Veterinary Medicine and Animal Science, São Paulo State University-UNESP, Botucatu 18618-681, Brazil.

Proliferative inflammatory atrophy (PIA) is an atrophic lesion of the prostate gland that occurs in men and dogs and is associated with a chronic inflammatory infiltrate. In this study, we retrospectively reviewed canine prostatic samples from intact dogs, identifying 50 normal prostates, 140 cases of prostatic hyperplasia, 171 cases of PIA, 84 with prostate cancer (PC), 14 with prostatic intraepithelial neoplasia (PIN) and 10 with bacterial prostatitis. PIA samples were then selected and classified according to the human classification. The presence of PIA lesions surrounding neoplastic areas was then evaluated to establish a morphological transition from normal to preneoplastic and neoplastic tissue. In addition, the expression of PTEN, P53, MDM2 and nuclear androgen receptor (AR) were analyzed in 20 normal samples and 20 PIA lesions by immunohistochemistry and qPCR. All PIA lesions showed variable degrees of mononuclear cell infiltration around the glands and simple atrophy was the most common histopathological feature. PIA was identified between normal glands and PC in 51 (61%) out of the 84 PC samples. PIA lesions were diffusely positive for molecular weight cytokeratin (HMWC). Decreased PTEN and AR gene and protein expression was found in PIA compared to normal samples. Overall, our results strongly suggest that PIA is a frequent lesion associated with PC. Additionally, this finding corroborates the hypothesis that in dogs, as is the case in humans, PIA is a pre neoplastic lesion that has the potential to progress into PC, indicating an alternative mechanism of prostate cancer development in dogs.
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http://dx.doi.org/10.3390/cancers13081887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071022PMC
April 2021

Effects of the Latex of Hook F. () on a Preclinical Model of Canine Prostate Cancer.

Front Vet Sci 2021 12;8:605286. Epub 2021 Apr 12.

Animal Pathology Service, Federal University of Goiás- UFG, Goiânia, Brazil.

Prostatic cancer (PC) stands out in terms of its occurrence, pathophysiology, and unfavorable prognostics in humans and dogs. Natural drugs bear an integrative potential for conventional antineoplastic treatments. In this context, the bioproducts of have been empirically used in different parts of Brazil for the integrative treatment of prostate cancer in humans. However, there is no availability of scientific evidence of the antitumor effects of . Therefore, this study aimed to investigate the bioactive compounds in the latex of using the high-resolution mass spectrophotometry (HRMS) and to evaluate its cytotoxic effects on primary canine PC cell cultures. Four fragments of phorbol ester were identified as potential bioactive compounds using the HRMS. With the help of an MTT ([3-(4,5-dimethyldiazol-2-yl)-2,5 diphenyltetrazolium bromide]) assay, two canine prostatic carcinoma cell lines (PC 1 and PC2) showed a decrease in the tumor cell count, with an Inhibitory concentration 50 (IC)of 0.8469 and 0.6068 mg/ml, respectively, for PC1 and PC2. In conclusion, the latex of contains phorbol esters in its composition, and its aqueous solution has a cytotoxic effect on canine metastatic PC cells .
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http://dx.doi.org/10.3389/fvets.2021.605286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071850PMC
April 2021

A Comparative in Silico Analysis of CD24's Prognostic Value in Human and Canine Prostate Cancer.

J Pers Med 2021 Mar 23;11(3). Epub 2021 Mar 23.

Department of Veterinary Surgery and Animal Reproduction, Sao Paulo State University-UNESP, Botucatu 18618-681, Brazil.

CD24 is a cell surface molecule anchored by glycosyl-phosphatidyl-inositol and expressed by different human cancers, including prostate cancer (PC). Some studies have demonstrated that CD24 expression is associated with poor patient outcome; however, few studies have investigated CD24 expression in spontaneous animal models of human PC, such as canine PC. This study aimed to evaluate the expression of CD24 in human PC using the in silico analysis of the data obtained from The Cancer Genome Atlas (TCGA) and comparing it with the previously published prostatic canine transcriptome data. In addition, CD24 expression was confirmed by immunohistochemistry in an independent cohort of canine prostatic samples and its prognostic significance assessed. The systematic review identified 10 publications fitting with the inclusion criteria of this study. Of the 10 manuscripts, 5 demonstrated a direct correlation between CD24 overexpression and patient prognoses. CD24 expression was also associated with PSA relapse (2/5) and tumor progression (1/5). However, the in silico analysis did not validate CD24 as a prognostic factor of human PC. Regarding canine PC, 10 out of 30 normal prostates and 27 out of 40 PC samples were positive for CD24. As in humans, there was no association with overall survival. Overall, our results demonstrated a significant CD24 overexpression in human and canine prostate cancer, although its prognostic value may be questionable. However, tumors overexpressing CD24 may be a reliable model for new target therapies and dogs could be used of a unique preclinical model for these studies.
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http://dx.doi.org/10.3390/jpm11030232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004660PMC
March 2021

Preparation and characterization of leukocyte- and platelet-rich fibrin membrane derived from cats' blood.

Microsc Res Tech 2021 Aug 2;84(8):1802-1808. Epub 2021 Mar 2.

Department of Veterinary Surgery and Animal Reproduction, School of Veterinary Medicine and Animal Science-São Paulo State University (UNESP), Botucatu, Brazil.

Autologous platelet concentrates have been used in regenerative medicine in humans due to the abundance of growth factors, but there are only a few reports in small animals. This study aimed to prepare and characterize a leukocyte and platelet-rich fibrin membrane (L-PRF) produced with blood obtained from cats. Thirteen client-owned healthy adult Maine Coon cats were enrolled. The blood samples were collected and centrifuged at 650g for 12 min using a centrifuge specifically designed for this application. The L-PRF clot was removed from the tube and red blood cell base layer was separated, leaving buffy coat intact. After this, L-PRF clot was compressed by specialized metal plate for 30-60 s, and L-PRF membrane was obtained. Light microscopy examination of the membranes showed three distinct layers: white part, buffy coat, and red part. Immunohistochemical analysis demonstrated expression of vascular endothelial growth factor and platelet derived growth factor. The scanning electron microscopy showed that three-dimensional architecture of fibrin network was more compact in the area near the buffy coat. In conclusion, the method used allowed the characterization of the L-PRF membrane composition, which presented cell types and fibrin network architecture similar to those described in the human species.
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http://dx.doi.org/10.1002/jemt.23737DOI Listing
August 2021

Mechanisms of Resistance to Chemotherapy in Breast Cancer and Possible Targets in Drug Delivery Systems.

Pharmaceutics 2020 Dec 9;12(12). Epub 2020 Dec 9.

Department of Veterinary Surgery and Animal Reproduction, Sao Paulo State University-UNESP, Botucatu-SP 18618-681, Brazil.

Breast cancer (BC) is one of the most important cancers worldwide, and usually, chemotherapy can be used in an integrative approach. Usually, chemotherapy treatment is performed in association with surgery, radiation or hormone therapy, providing an increased outcome to patients. However, tumors can develop resistance to different drugs, progressing for a more aggressive phenotype. In this scenario, the use of nanocarriers could help to defeat tumor cell resistance, providing a new therapeutic perspective for patients. Thus, this systematic review aims to bring the molecular mechanisms involved in BC chemoresistance and extract from the previous literature information regarding the use of nanoparticles as potential treatment for chemoresistant breast cancer.
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http://dx.doi.org/10.3390/pharmaceutics12121193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763855PMC
December 2020

A Comparative Meta-Analysis and Analysis of Differentially Expressed Genes and Proteins in Canine and Human Bladder Cancer.

Front Vet Sci 2020 16;7:558978. Epub 2020 Nov 16.

Department of Veterinary Surgery and Animal Reproduction, School of Veterinary Medicine and Animal Science, São Paulo State University-UNESP, Botucatu, Brazil.

Canine and human bladder cancer present similar anatomical, morphological, and molecular characteristics, and dogs can be considered a model for human bladder cancer. However, the veterinary literature lacks information regarding cross-validation analysis between human and canine large-scale data. Therefore, this research aimed to perform a meta-analysis of the canine literature on bladder cancer, identifying genes and proteins previously evaluated in these studies. In addition, we also performed a cross-validation of the canine transcriptome data and the human data from The Cancer Genome Atlas (TCGA) to identify potential markers for both species. The meta-analysis was performed using the following indexing terms: "bladder" AND "carcinoma" AND "dog" in different international databases, and 385 manuscripts were identified in our initial search. Then, several inclusion criteria were applied, and only 25 studies met these criteria. Among these studies, five presented transcriptome data, and 20 evaluated only isolated genes or proteins. Regarding the studies involving isolated protein analysis, the HER-2 protein was the most studied (3/20), followed by TAG-72 (2/20), COX-2 (2/20), survivin (2/20), and CK7 (2/20), and the remaining nine studies evaluated one isolated protein each. Regarding the cross-validation analysis of human and canine transcriptome data, we identified 35 dysregulated genes, including , and . Our results demonstrate that the canine literature on bladder cancer previously focused on the evaluation of isolated markers with no association with patient survival. This limitation may be related to the lack of a homogenous protocol for treating patients and the lack of follow-up during treatment. In addition, the lack of information regarding tumor muscle invasion can be considered an important limitation when comparing human and canine bladder tumors. Our analysis involving canine and human transcriptome data provided several genes with the potential to be markers for both human and canine bladder tumors, and these genes should be considered for future studies on canine bladder cancer.
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http://dx.doi.org/10.3389/fvets.2020.558978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701042PMC
November 2020

Establishment and Characterization of Canine Mammary Gland Carcinoma Cell Lines With Vasculogenic Mimicry Ability and .

Front Vet Sci 2020 27;7:583874. Epub 2020 Oct 27.

School of Veterinary Medicine and Animal Science, São Paulo State University-UNESP, Botucatu, Brazil.

Mammary tumors affect intact and elderly female dogs, and almost 50% of these cases are malignant. Cell culture offers a promising preclinical model to study this disease and creates the opportunity to deposit cell lines at a cell bank to allow greater assay reproducibility and more reliable validation of the results. Another important aspect is the possibility of establishing models and improving our understanding of tumor characteristics, such as vasculogenic mimicry. Because of the importance of cancer cell lines in preclinical models, the present study established and characterized primary cell lines from canine mammary gland tumors. Cell cultures were evaluated for morphology, phenotype, vasculogenic mimicry (VM), and tumorigenicity abilities. We collected 17 primary mammary carcinoma and three metastases and obtained satisfactory results from 10 samples. The cells were transplanted to a xenograft model. All cell lines exhibited a spindle-shaped or polygonal morphology and expressed concomitant pancytokeratin and cytokeratin 8/18. Four cell lines had vasculogenic mimicry ability , and two cell lines showed tumorigenicity and VM in the xenotransplanted tumor. Cellular characterization will help create a database to increase our knowledge of mammary carcinomas in dogs, including studies of tumor behavior and the identification of new therapeutic targets.
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http://dx.doi.org/10.3389/fvets.2020.583874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655132PMC
October 2020

Preliminary assessment of electrochemotherapy feasibility in dogs with vesical transitional cell carcinoma.

Vet Res Forum 2020 15;11(3):289-293. Epub 2020 Sep 15.

Biopulse Ltd., Naples, Italy.

Electroporation is a technique that increases the uptake of chemotherapeutic drugs by tumors. Electrochemotherapy (ECT) has been successfully used to treat solid tumors. Recently, novel applications have been explored in the treatment of visceral tumors. This report aimed to describe the ECT as an approach to vesical carcinoma in three dogs. The patients received ECT with bleomycin as an intravenous bolus and intra-lesional cisplatin (cases 2 and 3). The ECT was performed by electroporator (Onkodisruptor) using a plate and/or a single pair needle array electrode. Case 1 was a 7-year-old female Pitbull dog with a history of hematuria and stranguria. The ECT was performed during cystotomy using a single pair array electrode. However, the patient developed uroabdomen two days post-ECT and died 5 days later. Case 2 was a 12-year-old female Poodle dog with hematuria, dysuria, and pollakiuria. Cystotomy and ECT were performed using plate array electrodes. Complete remission of the intra-luminal mass was observed 11 days post-ECT. However, 21 days after the procedure, an acute unilateral renal failure occurred possibly due to a neoplastic embolus into the right ureter leading to kidney hydronephrosis, and the patient was euthanized. Case 3 was a 10-year-old female Cocker dog with hematuria and pollakiuria. The patient was fully competent after ECT without clinical signs of pollakiuria and recovered from hematuria 7 days post-ECT. The bladder returned to normal status 28 days post-ECT. The ECT was not able to increase the overall survival of the patients evaluated and should be indicated carefully.
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http://dx.doi.org/10.30466/vrf.2020.113009.2688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597792PMC
September 2020

Response dataset from canine extramedullary plasmacytoma treated with lipophobic drugs enhanced by electroporation.

Data Brief 2020 Oct 29;32:106085. Epub 2020 Jul 29.

Department of Veterinary Surgery and Animal Reproduction, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil.

Over the past 15 years, lipophobic drugs, such as bleomycin and cisplatin, have been used combined with electroporation, which promotes their uptake through the cell membrane. The present data describe general findings following electrochemotherapy and how plasmacytomas can respond to this technique. We will explain and illustrate specific outcomes during the remission process. The data presented here can be useful for researchers, veterinarians, and pet owners. Furthermore, the data could be useful for other cutaneous or oral tumors in which electrochemotherapy may be indicated. Interpretation of the data and outcomes may be found in the research article entitled "Outcome following curative-intent electrochemotherapy for extramedullary plasmocytoma in dogs - case reports ."
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http://dx.doi.org/10.1016/j.dib.2020.106085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417888PMC
October 2020

Outcome Following Curative-Intent Electrochemotherapy for Extramedullary Plasmocytoma in Dogs - Case Reports.

Top Companion Anim Med 2020 Aug 18;40:100441. Epub 2020 May 18.

Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil; Institute of Health Sciences, Universidade Paulista - UNIP, Bauru, São Paulo, Brazil. Electronic address:

Plasma cell tumors can occur as solitary collections referred as extramedullary plasmocytoma (EMP). The present report describes four cases of EMP treated with a local nonthermal ablative approach. Four dogs were diagnosed with extramedullary plasmocytomas (EMP) in different body regions (oral cavity, digits, and lip). Since surgical excision was declined by the owners (maxillectomy; amputation or lip reconstruction), a curative-intent approach was indicated as solely treatment- electrochemotherapy (ECT). All the patients received ECT under general anesthesia using bleomycin intravenously (15,000 UI/m²) or cisplatin intratumorally (1mg/cm³). All dogs developed transitory ulceration and swelling one-week after procedure that completely healed within 30 days post-ECT. Complete remission was achieved in all cases and lasted for 515 (oral case), 695 (one digit), 90 (another digit case) and 240 (lip) days. These results suggested that ECT promoted remission in EMP cases being a possibility for local control in dogs affected by this disease.
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http://dx.doi.org/10.1016/j.tcam.2020.100441DOI Listing
August 2020

Germline Mutation in Resulting in Impaired Protein Stability is Associated with Familial Breast and Thyroid Cancer.

Cancers (Basel) 2020 May 20;12(5). Epub 2020 May 20.

Department of Clinical Genetics, Vejle University Hospital, Institute of Regional Health Research, University of Southern Denmark, 5000 Odense, Denmark.

Multiple primary thyroid cancer (TC) and breast cancer (BC) are commonly diagnosed, and the lifetime risk for these cancers is increased in patients with a positive family history of both TC and BC. Although this phenotype is partially explained by or mutations, a significant number of patients are negative for these alterations. We judiciously recruited patients diagnosed with BC and/or TC having a family history of these tumors and assessed their whole-exome sequencing. After variant prioritization, we selected c.1292G>A (p.R431H) for further investigation. This variant was genotyped in a healthy population and sporadic BC/TC tissues and investigated at the protein level and cellular models. c.1292G>A was the most frequent variant (25%) and the strongest candidate due to its function of double-strand break repair. This variant was confirmed in four relatives from two families. MUS81 p.R431H protein exhibited lower expression levels in tumors from patients positive for the germline variant, compared with wild-type BC, and normal breast and thyroid tissues. Using cell line models, we showed that c.1292G>A induced protein instability and affected DNA damage response. We suggest that is a novel candidate involved in familial BC/TC based on its low frequency in healthy individuals and proven effect in protein stability.
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http://dx.doi.org/10.3390/cancers12051289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281423PMC
May 2020

Investigation of the Prognostic Significance of Vasculogenic Mimicry and Its Inhibition by Sorafenib in Canine Mammary Gland Tumors.

Front Oncol 2019 19;9:1445. Epub 2019 Dec 19.

Department of Veterinary Surgery and Anesthesiology, São Paulo State University-UNESP, Botucatu, Brazil.

Canine mammary gland tumor (CMT) is one of the most important tumors in intact female dogs, and due its similarity to human breast cancer (BC), it is considered a model in comparative oncology. A subset of mammary gland tumors can show aggressive behavior, and a recurrent histological finding is the presence of vasculogenic mimicry (VM). VM is a process in which highly aggressive cancer cells fuse, forming fluid-conducting channels without endothelial cells. Although, VM has been described in canine inflammatory carcinoma, no previous studies have investigated the prognostic and predictive significance of VM in CMT. Thus, this research aimed to investigate the prognostic significance of VM and the capacity of sorafenib to inhibit VM . VM was identified in formalin-fixed paraffin-embedded CMT samples ( = 248) using CD31/PAS double staining. VM was identified in 33% of tumors (82/248). The presence of VM was more strongly related to tumor grade than to histological subtype. Patients with positive VM experienced shorter survival times than dogs without VM ( < 0.0001). Due to the importance of the VEGF-A/VEGFR-2 autocrine feed-forward loop in epithelial tumors, we investigated the association between VEGF-A and VEGFR-2 expression by neoplastic tumor cells and the associations of VEGF-A or VEGFR-2 expression with VM. Among the VM-positive samples, all ( = 82) showed high scores (3 or 4) for VEGF-A and VEGFR-2, indicating that VM was a common finding in tumors overexpressing VEGF-A and VEGFR-2. Thus, we cultured two CMT primary cell lines with VM abilities (CM9 and CM60) and evaluated the anti-tumoral effect of sorafenib. The CM9 cell line showed a half maximal inhibitory concentration (IC) of 2.61 μM, and the CM60 cell line showed an IC of 1.34 μM. We performed a VM assay and treated each cell line with an IC dose of sorafenib, which was able to inhibit VM . Overall, our results indicated that VM was a prognostic factor for dogs bearing CMT and that sorafenib had an inhibitory effect on VM in CMT cancer cells .
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http://dx.doi.org/10.3389/fonc.2019.01445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930929PMC
December 2019

E-Cadherin Downregulation is Mediated by Promoter Methylation in Canine Prostate Cancer.

Front Genet 2019 29;10:1242. Epub 2019 Nov 29.

Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, Sao Paulo State University-UNESP, Botucatu, Brazil.

E-cadherin is a transmembrane glycoprotein responsible for cell-to-cell adhesion, and its loss has been associated with metastasis development. Although E-cadherin downregulation was previously reported in canine prostate cancer (PC), the mechanism involved in this process is unclear. It is well established that dogs, besides humans, spontaneously develop PC with high frequency; therefore, canine PC is an interesting model to study human PC. In human PC, methylation has been associated with E-cadherin downregulation. However, no previous studies have described the methylation pattern of promoter in canine PC. Herein, we evaluated the E-cadherin protein and gene expression in canine PC compared to normal tissues. DNA methylation pattern was investigated as a regulatory mechanism of silencing. Our cohort is composed of 20 normal prostates, 20 proliferative inflammatory atrophy (PIA) lesions, 20 PC, and 11 metastases from 60 dogs. The E-cadherin protein expression was assessed by immunohistochemistry and western blotting and gene expression by qPCR. Bisulfite- pyrosequencing assay was performed to investigate the promoter methylation pattern. Membranous E-cadherin expression was observed in all prostatic tissues. A higher number of E-cadherin negative cells was detected more frequently in PC compared to normal and PIA samples. High-grade PC showed a diffuse membranous positive immunostaining. Furthermore, PC patients with a higher number of E-cadherin negative cells presented shorter survival time and higher Gleason scores. Western blotting and qPCR assays confirmed the immunohistochemical results, showing lower E-cadherin protein and gene expression levels in PC compared to normal samples. We identified promoter hypermethylation in PIA and PC samples. An in vitro assay with two canine prostate cancer cells (PC1 and PC2 cell lines) was performed to confirm the methylation as a regulatory mechanism of E-cadherin expression. PC1 cell line presented hypermethylation and after 5-Aza-dC treatment, a decreased methylation and increased gene expression levels were observed. Positive E-cadherin cells were massively found in metastases (mean of 90.6%). In conclusion, low levels of E-cadherin protein, gene downregulation and hypermethylation was detected in canine PC. However, in metastatic foci occur E-cadherin re-expression confirming its relevance in these processes.
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http://dx.doi.org/10.3389/fgene.2019.01242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895247PMC
November 2019

Tumor-infiltrating CD4 and CD8 lymphocytes and macrophages are associated with prognostic factors in triple-negative canine mammary complex type carcinoma.

Res Vet Sci 2019 Oct 13;126:29-36. Epub 2019 Aug 13.

Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science São Paulo State University - UNESP, Botucatu, SP, Brazil; Universidade Paulista - UNIP, Bauru, SP, Brazil. Electronic address:

This study aimed to evaluate the association of CD3, CD4, and CD8 T cells and tumor-infiltrating macrophages (TIMs) with the clinical parameters of female dogs harboring mammary gland tumors. Thirty female dogs affected with mammary carcinomas were used, and all tumors were histologically classified as complex carcinoma and were triple-negative phenotype determined by immunohistochemistry. Freshly frozen sections were used to determine CD3, CD4 and CD8 T cells by immunohistochemistry, and TIMs were determined by immunofluorescence assays. Ten out of the 30 dogs showed lymph node metastasis at diagnosis. Fifteen dogs had a tumor of grade I (15/30), nine (9/30) had a tumor of grade II and six (6/30) had a tumor of grade III. The mean overall survival was 680.5 days (± 200.4). Dogs with sentinel lymph node positivity (10/30) (P = .0035) and dogs that developed metastasis (P = .0001) showed a shorter survival time. In addition, dogs with a high level of inflammatory infiltrate in tumor tissues presented a shorter survival time (P = .0001) than that of other dogs. Dogs with tumors containing higher numbers of CD3+ T cells (P = .001), CD4+ T cells (P = .001), or TIM cells (P < .0001) showed a shorter survival time than that of other dogs. Our results suggested that characteristics of immune cell infiltrates, including CD3 T cells, CD4 T cells, and TIMs, can be used as potential prognostic indicators for predicting clinical outcomes in dogs with mammary gland tumors, particularly tumors with a complex histological subtype and triple-negative phenotype.
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http://dx.doi.org/10.1016/j.rvsc.2019.08.021DOI Listing
October 2019

Long-Term Survival of a Cat with Primary Leiomyosarcoma of the Urinary Bladder.

Vet Sci 2019 Jun 27;6(3). Epub 2019 Jun 27.

Veterinary Oncology Specialization Course, Instituto Bioethicus, Botucatu SP 18605-545, Brazil.

Primary bladder leiomyosarcoma was diagnosed in a four-year-old, mixed-breed, spayed female cat that presented with lethargy, stranguria, polyuria, hematuria, urinary incontinence and abdominal sensitivity. On abdominal ultrasound, the urinary bladder was observed to have a preserved anatomical position and a hyperechoic mass. The mass measured approximately 1.5 cm, was irregular, and arose from the mucosa of the bladder wall. Due to the evidence of a primary tumor in the urinary bladder, we conducted a partial cystectomy with a 1.0 cm surgical margin and performed histopathology and immunohistochemistry. The histopathology revealed a poorly differentiated malignant neoplasm, characterized by the proliferation of spindle cells with moderate nuclear pleomorphism, suggestive of leiomyosarcoma. Immunohistochemistry confirmed the histopathological diagnosis, showing positive staining for vimentin, desmin and alpha-smooth muscle actin and negative staining for S100, pan-cytokeratin and MyoD1. We also assessed the proliferative index by Ki67 staining and found that 57% of the neoplastic cells were positive for Ki67. We conducted clinical follow-ups every three months in the first year and every six months thereafter. The patient showed no signs of recurrence after 48 months. The surgery was sufficient to treat the leiomyosarcoma, and adjuvant chemotherapy was not necessary in this case.
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http://dx.doi.org/10.3390/vetsci6030060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789653PMC
June 2019

Comprehensive Genomic Profiling of Androgen-Receptor-Negative Canine Prostate Cancer.

Int J Mol Sci 2019 Mar 28;20(7). Epub 2019 Mar 28.

Department of Clinical Genetics, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, 7100 Vejle, Denmark.

Canine carcinomas have been considered natural models for human diseases; however, the genomic profile of canine prostate cancers (PCs) has not been explored. In this study, 14 PC androgen-receptor-negative cases, 4 proliferative inflammatory atrophies (PIA), and 5 normal prostate tissues were investigated by array-based comparative genomic hybridization (aCGH). Copy number alterations (CNAs) were assessed using the Canine Genome CGH Microarray 4 × 44K (Agilent Technologies). Genes covered by recurrent CNAs were submitted to enrichment and cross-validation analysis. In addition, the expression levels of , and were evaluated in an independent set of cases by qPCR. PC cases presented genomic complexity, while PIA samples had a small number of CNAs. Recurrent losses covering well-known tumor suppressor genes, such as , , , and , were found in PC. The in silico functional analysis showed several cancer-related genes associated with canonical pathways and interaction networks previously described in human PC. The , , and copy number alterations were translated into altered expression levels. A cross-validation analysis using The Cancer Genome Atlas (TCGA) database for human PC uncovered similarities between canine and human PCs. Androgen-receptor-negative canine PC is a complex disease characterized by high genomic instability, showing a set of genes with similar alterations to human cancer.
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http://dx.doi.org/10.3390/ijms20071555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480132PMC
March 2019

Characterization of Collagen Fibers (I, III, IV) and Elastin of Normal and Neoplastic Canine Prostatic Tissues.

Vet Sci 2019 Mar 2;6(1). Epub 2019 Mar 2.

Department of Veterinary Clinic, School of Veterinary Medicine and Animal Science, São Paulo State University (Unesp), Botucatu, São Paulo 18618-681, Brazil.

This study aimed to investigate collagen (Coll-I, III, IV) and elastin in canine normal prostate and prostate cancer (PC) using Picrosirius red (PSR) and Immunohistochemical (IHC) analysis. Eight normal prostates and 10 PC from formalin-fixed, paraffin-embedded samples were used. Collagen fibers area was analyzed with ImageJ software. The distribution of Coll-I and Coll-III was approximately 80% around prostatic ducts and acini, 15% among smooth muscle, and 5% surrounding blood vessels, in both normal prostate and PC. There was a higher median area of Coll-III in PC when compared to normal prostatic tissue ( = 0.001 for PSR and = 0.05 for IHC). Immunostaining for Coll-IV was observed in the basal membrane of prostate acini, smooth muscle, blood vessels, and nerve fibers of normal and PC samples. Although there was no difference in Coll-IV area between normal tissue and PC, tumors with Gleason score 10 showed absence of Coll-IV, when compared to scores 6 and 8 ( = 0.0095). Elastic fibers were found in the septa dividing the lobules and around the prostatic acini of normal samples and were statistically higher in PC compared to normal tissue ( = 0.00229). Investigation of ECM components brings new information and should be correlated with prognosis in future studies.
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http://dx.doi.org/10.3390/vetsci6010022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466295PMC
March 2019

Deregulation of VEGFR-2 and PDGFR Expression and Microvascular Density in a Triple-Negative Model of Canine Malignant Mammary Tumors with Lymph Node or Lung Metastasis.

Vet Sci 2019 Jan 9;6(1). Epub 2019 Jan 9.

Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University-UNESP, Botucatu 18618-681, Brazil.

Canine mammary tumors (CMT) represent the most common cancer in noncastrated female dogs. Interestingly, triple-negative tumors are the most common molecular subtype in female dogs. In this study, we proposed to evaluate the expression of vascular endothelial growth factor receptor 2 (VEGFR-2), Platelet-derived growth factor receptor (PDGFR), and microvascular density (MVD) in a group of metastatic and nonmetastatic triple-negative CMT and compare the expression based on clinical parameters. Twenty-six female dogs with triple-negative mammary tumors were divided into three groups: nonmetastatic tumors (NMT) ( = 11), tumors with lymph node metastasis (LNM) ( = 10), and tumors with lung metastasis (LM) ( = 5). We observed increased VEGFR-2 expression in LNM compared with NMT and a positive correlation between tumor grade and VEGFR-2 expression. A positive correlation was noted between VEGFR-2 and PDGFR expression. Regarding microvascular density (MVD), we identified a higher number of vessels in primary tumors with lymph node metastasis and lung metastasis compared with tumors with no metastasis. The primary tumors with lung metastasis exhibited an increased MVD compared with carcinoma with lymph node metastasis. Overall, our results suggest a deregulation of VEGFR-2 and PDGFR and high MVD in metastatic tumors, indicating a role for angiogenesis in tumor progression.
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http://dx.doi.org/10.3390/vetsci6010003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466043PMC
January 2019

Characterization of OCT3/4, Nestin, NANOG, CD44 and CD24 as stem cell markers in canine prostate cancer.

Int J Biochem Cell Biol 2019 03 8;108:21-28. Epub 2019 Jan 8.

São Paulo State University - UNESP, Department of Veterinary Surgery and Anaesthesiology, School of Veterinary Medicine and Animal Science, Botucatu, Sao Paulo, Brazil. Electronic address:

The cancer cell population is heterogeneous, and cancer stem cells (CSCs) are important for tumor growth and maintenance. The CSC population is associated with different neoplastic characteristics, such as cell migration, resistance to apoptosis, radiation therapy and chemotherapy. To increase the knowledge of CSCs in canine prostate cancer (PC), we characterized CSC markers in canine PC tissues and tumorspheres. We performed immunohistochemistry of OCT3/4, Nestin, NANOG, CD44 and CD24 in 10 normal canine prostatic tissue samples, 10 prostatic hyperplastic (PH) tissue samples and 28 PC tissue samples. Then, we established two canine prostate cancer cell cultures and characterized the CSC profile of tumorspheres grown from these cultures. Normal and PH tissues were positive for Nestin, NANOG, CD44 and CD24 only in the basal cell layer. OCT3/4 was expressed in the luminal cells of normal and PH tissues. There was no significant difference in Nestin expression among the prostatic tissues. However, we found higher expression of NANOG and CD44 in canine PC tissues than that in normal and PH tissues. Tumorspheres from canine prostate cancer cells express OCT3/4, Nestin, NANOG and CD44, indicating that these markers may be potential cancer stem cell markers in canine PC. The results obtained can be useful to better characterize the stem cell population in canine prostatic cancer and to guide future studies in comparative oncology.
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http://dx.doi.org/10.1016/j.biocel.2019.01.002DOI Listing
March 2019

An immunohistochemical study of T and B lymphocyte density in prostatic hyperplasia and prostate carcinoma in dogs.

Res Vet Sci 2019 Feb 27;122:189-192. Epub 2018 Nov 27.

School of Veterinary Science, The University of Queensland, Gatton Campus, 4343 Gatton, Queensland, Australia.

The aim of this study was to characterise T and B lymphocyte density in 6 normal prostates, 15 benign prostatic hyperplasia (BPH) and 24 prostate carcinomas (PCs) in dogs by immunohistochemistry. Results revealed a statistically significant increase of T and B cells in PC compared to normal specimens and BPH. Regarding PC histological variants, lower number of CD3 and CD79 lymphocytes were observed in the most undifferentiated (solid) type. CD3 cell density was positively correlated with survival time. These results may help in understanding the immunological mechanisms regulating BPH and PC development and progression, as well as providing background data for future immunotherapeutic trials.
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http://dx.doi.org/10.1016/j.rvsc.2018.11.022DOI Listing
February 2019

Hydroxyurea-induced onychomadesis in a dog with chronic myeloid leukemia: A case report.

Top Companion Anim Med 2018 Sep 12;33(3):73-76. Epub 2018 Jun 12.

School of Veterinary Medicine and Animal Science, Department of Veterinary Clinic, São Paulo State University-UNESP, Botucatu, SP, Brazil. Electronic address:

A 12-year-old Rottweiler dog was presented with a history of prostration, weight loss and hyporexia for six months. Based on complete blood tests (hematological and biochemical analyses), bone marrow examination and imaging analysis, a diagnosis of chronic myeloid leukemia was made. Treatment with hydroxyurea at a dosage of 18 mg/kg twice daily was not effective in controlling the high count of white blood cells. Furthermore, after 35 days of hydroxyurea treatment, the animal developed onycholysis, with sloughing of the claws of the left pelvic and left thoracic limbs and exposure of the distal phalanx. Interruption of the medication was implemented, with clinical healing of the ungual lesions observed three months after initiation of the drug. White blood cells returned to normal after using cyclophosphamide. Currently, the animal is in complete remission, having a disease-free interval of 575 days without chemotherapy. To the authors' knowledge, this is the first report of hydroxyurea-induced onycholysis within a short-term period in a dog diagnosed with chronic myeloid leukemia.
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http://dx.doi.org/10.1053/j.tcam.2018.06.003DOI Listing
September 2018

Immunohistochemical panel to characterize canine prostate carcinomas according to aberrant p63 expression.

PLoS One 2018 12;13(6):e0199173. Epub 2018 Jun 12.

Department of Veterinary Clinic, School of Veterinary Medicine and Animal Science, São Paulo State University-UNESP, Botucatu, SP, Brazil.

An unusual variant of prostate adenocarcinoma (PC) expressing nuclear p63 in secretory cells instead of the typical basal expression has been reported in men. Nevertheless, the biological behavior and clinical significance of this phenomenon is unknown. In dogs, this unusual PC subtype has not been described. In this study, p63 immunoexpression was investigated in 90 canine PCs and 20 normal prostate tissues (NT). The p63 expression pattern in luminal or basal cells was confirmed in a selected group of 26 PCs and 20 NT by immunohistochemistry and/or Western blotting assays. Eleven canine PC samples aberrantly expressing p63 (p63+) in secretory cells were compared with 15 p63 negative (p63-) cases in the context of several molecular markers (high molecular weight cytokeratin-HMWC, CK8/18, CK5, AR, PSA, chromogranin, NKX3.1, PTEN, AKT and C-MYC). P63+ samples were positive for CK5, HMWC and CK8/18 and negative for PSA, NKX3.1, PTEN and chromogranin. Five p63+ PCs were negative for AR, and the remaining six samples had low AR expression. In contrast, p63- PC showed AR and PSA positive expression in all 15 samples. Only five p63- PCs were positive for CK5. Both p63+ and p63- PC samples showed higher cytoplasmic AKT expression and nuclear C-MYC staining in comparison with normal tissues. Metastatic (N = 12) and non-metastatic (N = 14) PCs showed similar immunoexpression for all markers tested. In contrast to human PC, canine PC aberrantly expressing p63 showed higher expression levels of HMWC and CK5 and lower levels of NKX3.1. Canine p63+ PC is a very rare PC group showing a distinct phenotype compared to typical canine PC, including AR and PSA negative expression. Although in a limited number of cases, p63 expression was not associated with metastasis in canine PC, and cytoplasmic p63 expression was observed in animals with shorter survival time, similar to human PC cases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199173PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997330PMC
January 2019

Allogeneic mesenchymal stem cell transplantation in healthy equine superficial digital flexor tendon: A study of the local inflammatory response.

Res Vet Sci 2018 Jun 21;118:423-430. Epub 2018 Mar 21.

Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Distrito de Rubião Júnior s/n, Botucatu, SP 18618-9070, Brazil. Electronic address:

The superficial digital flexor tendon (SDFT) is a structure frequently affected by injuries in high-performance athletic horses, and there are limited therapeutic options. Regenerative medicine has evolved significantly in treating different illnesses. However, understanding the cellular behaviour during mesenchymal stem cell (MSC) transplantation in healthy tissues is not fully known yet. To address the inflammatory response induced by allogeneic MSC transplantation, this study evaluated the local inflammatory response after the application of allogeneic adipose tissue-derived mesenchymal stem cells (AT-MSCs) in the equine tendon compared to an autologous transplant and the control group. Eighteen thoracic limbs (TL) in nine animals were divided into three groups and subjected to the application of AT-MSCs in the healthy tendon. In the allogeneic group (Gallog), the animals received an allogeneic AT-MSC application in the TL. The autologous group (Gauto) received an application of autologous cells in the TL, and in the control group (Gcont), phosphate-buffered saline (PBS) was applied. There were no significant differences among the evaluated groups in the physical, morphological, thermography, and ultrasonography analyses. A higher number of CD3-positive lymphocytes was observed in the Gauto group compared to the control (P < 0.05). Additionally, we did not observe different expressions of CD172 and microvascular density among the groups. The allogeneic transplantation of AT-MSCs did not result in an adverse or inflammatory reaction that compromised the use of these cells in this experiment. Their behaviour was similar to that of autologous transplantation.
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http://dx.doi.org/10.1016/j.rvsc.2018.03.012DOI Listing
June 2018
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