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1.
Histone deacetylase inhibitors (HDACis) can change the histone acetylation and significantly enhance the developmental competence of the pre‐implantation SCNT embryo. To select a proper histone deacetylase inhibitor to improve the success rate and potentially developmental ability of handmade cloning (HMC) embryos of miniature porcine, we compared the effect of two histone deacetylase inhibitors (SAHA vs. VPA) on HMC embryo development, their histone acetylation level and the expression level of relevant genes. The blastocyst rate and number of blastocyst cells of HMC embryos treated with SAHA (SAHA‐HMC) or VPA (VPA‐HMC) were significantly higher than those of control (Control‐HMC), respectively, but there were no significant difference between SAHA‐HMC and VPA‐HMC groups. In addition, the acetylation level (AcH4K8) of Control‐HMC and VPA‐HMC embryos at the blastocyst stage, respectively, was significantly lower than that of in vitro fertilized (IVF) and SAHA‐HMC embryos. However, the acetylation H4K8 of the blastocysts had no significant difference between SAHA‐HMC and the IVF groups. The SAHA‐HMC blastocysts indicated comparative expression levels of Oct4 and HDAC1 (histone deacetyltransferase gene) with those of IVF blastocysts. In contrast, the expression levels of Oct4 were lower and those of HDAC1 were higher in the VPA‐HMC and Control‐HMC blastocysts, respectively, compared to those of the IVF blastocysts. Our results demonstrated that the HMC embryos treated by SAHA could promote the pre‐implantation development and increase the levels of histone H4K8 acetylation and the expression of the OCT4 gene, yet decrease the expression of the HDAC1 gene to the comparable level of the IVF embryos. Our results proved that SAHA may be a better histone deacetylase inhibitor for porcine HMC compared to VPA, and furthermore, it may indicate that SAHA can effectively correct the abnormal histone acetylation during the HMC embryo development and subsequently improve the full‐term developmental potential of the HMC embryos after embryo transplantation.  相似文献   

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3.
Splenectomy followed by adjuvant chemotherapy is commonly used to treat canine splenic haemangiosarcoma (HSA), although it is unclear if different treatment protocols may have a similar efficacy. The objective of this retrospective study was to assess outcome in dogs with stage I and II splenic HSA treated with either first‐line adjuvant anthracycline (AC) or metronomic (MC)‐based chemotherapy protocols, by comparing median time to progression (TTP) and median survival time (MST). Medical records of nine institutions were searched for dogs diagnosed with stage I and II splenic HSA that underwent adjuvant treatment with AC‐ or MC‐based protocols following splenectomy. Patients treated with MC following AC were included in an additional group (AMC). Ninety‐three dogs were included: 50 in the AC group, 23 in the AMC group and 20 in the MC group. The overall MST was 200 days (range 47‐3352) and the overall median TTP was 185 days (range 37‐1236). The median TTP of stage I dogs was significantly longer compared to stage II dogs (338 vs 151 days, respectively, P = .028). When adjusting for treatment type, the MST was 154 days for the AC group (range 47‐3352 days), 338 days for the AMC group (range 79‐1623 days) and 225 days for the MC group (range 57‐911 days). The difference in MST and median TTP was not found to be statistically significant between treatment groups. This study suggests that adjuvant MC in canine splenic HSA may result in a similar outcome when compared to other treatment protocols. Further studies are warranted to confirm these findings.  相似文献   

4.
A retrospective analysis was done to assess the toxicity and efficacy associated with an alternating chemotherapy protocol of ifosfamide (375 mg m?2) and doxorubicin (30 mg m?2) for adjuvant treatment of 39 dogs with sarcomas. Twelve dogs had various soft‐tissue sarcomas and 27 dogs had hemangiosarcoma (HSA). Complete blood counts were evaluated 7 days after the first dose of ifosfamide and doxorubicin. One dog had grade 4 neutropenia (<500 µL?1) after treatment with ifosfamide and one dog had grade 3 neutropenia (500–1000 µL?1) after treatment with doxorubicin. One dog treated with doxorubicin was hospitalized for 24 h due to vomiting. The median survival time (ST) for the 27 dogs with HSA treated by surgery and with doxorubicin/ifosfamide was 149 days (mean 366 days). Although the protocol of alternating ifosfamide and doxorubicin was well tolerated, it failed to result in a statistically significant improvement in the ST when compared to a historical population of dogs with stage 2 splenic HSA treated by surgery alone.  相似文献   

5.
Haemangiosarcoma (HSA) has an aggressive biological behaviour and carries a poor prognosis, with less than 10% of treated dogs surviving longer than 1 year. In this retrospective study a varied metronomic chemotherapy (MC) regimen preceded by adjuvant doxorubicin‐based maximum‐tolerated dose chemotherapy (MTDC) was compared with MTDC, in terms of efficacy [time to metastasis, (TTM) and survival time (ST)] and safety in dogs with biologically aggressive HSA. Dogs were eligible if they had no metastasis after MTDC and received either no further chemotherapy or MC maintenance. Twelve dogs received MTDC, and 10 received MC thereafter. Median TTM and ST were significantly longer for dogs receiving MTDC‐MC (not reached versus 150 days, P = 0.028; and not reached versus 168 days, P = 0.030, respectively). Treatment was well tolerated. MTDC followed by MC is safe and suggests improved TTM and ST in dogs with surgically removed, biologically aggressive HSA that are treated in the microscopic setting.  相似文献   

6.
Suberoylanilide hydroxamic acid (SAHA), or vorinostat, is a histone deacetylase inhibitor approved for use as chemotherapy for lymphoma in humans. The goal of this study was to establish pharmacological parameters of SAHA in cats. Our interest in treating cats with SAHA is twofold: as an anticancer chemotherapeutic and as antilatency therapy for feline retroviral infections. Relying solely on data from studies in other animals would be inappropriate as SAHA is partially metabolized by glucuronidation, which is absent in feline metabolism. SAHA was administered to cats intravenously (2 mg/kg) or orally (250 mg/m2, ~17 mg/kg) in a cross‐over study design. Clinically, SAHA was well tolerated at these dosages as no abnormalities were noted following administration. The pharmacokinetics of SAHA in cats was found to be similar to that of dogs, but the overall serum drug exposure was much less than that of humans at an equivalent dose. The pharmacodynamic effect of an increase in acetylated histone proteins in blood was detected after both routes of administration. An increased oral dose of 60 mg SAHA/kg administered to one animal resulted in a surprisingly modest increase in peak drug concentration, suggesting possible saturation of absorption kinetics. This study provides a foundation for future studies of the clinical efficacy of SAHA in treating feline disease.  相似文献   

7.
Objective Study aims were to evaluate the safety and efficacy of the Food and Drug Administration‐approved drug Vorinostat [suberoylanilide hydroxamic acid (SAHA)] in the treatment of canine corneal fibrosis using an in vitro model. Methods Healthy donor canine corneas were collected and used to generate primary canine corneal fibroblasts (CCFs) by growing cultures in minimal essential medium supplemented with 10% fetal bovine serum. Canine corneal myofibroblasts, used as a model for corneal fibrosis, were produced by growing CCF cultures in serum‐free medium containing transforming growth factor β1 (1 ng/mL). Trypan blue exclusion assays were used to determine the optimal SAHA dose for this in vitro model. Four hour after culturing with TGFβ1, CCF cultures were treated with 0.06% SAHA for 5 min (group 1) and for 24 h (group 2), representing single and multiple dose treatment regimes, respectively. Cultures were then further incubated in the presence of TGFβ1 (1 ng/μL) under serum‐free conditions until they reached 70% confluence. Trypan blue exclusion, immunocytochemistry, and TUNEL assays were used to evaluate the cytotoxicity of SAHA. Real‐time PCR, western blot analysis, and immunocytochemistry were used to determine the efficacy of SAHA to inhibit canine corneal myofibroblast formation. Results Topical SAHA application in both treatment groups successfully decreased α‐smooth muscle actin expression when compared to the TGFβ1 only treatment group (P < 0.05). Tested SAHA did not affect CCF phenotype or cellular viability and did not cause significant cell death. Conclusions Suberoylanilide hydroxamic acid safely and effectively inhibits TGFβ1‐induced CCFs transformation to myofibroblast in vitro.  相似文献   

8.
OBJECTIVE: To determine whether exposure of canine cancer cells to histone deacetylase (HDAC) inhibitors S(+)-N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)benzamide (OSU-HDAC42) or suberoylanilide hydroxamic acid (SAHA) results in increased histone acetylation and decreased cell viability and whether any changes in viability involve induction of apoptosis or alterations in progression of the cell cycle. Sample POPULATION: 9 canine cancer cell lines. PROCEDURES: Cells from 9 canine cancer cell lines were treated with dimethyl sulfoxide vehicle, OSU-HDAC42, or SAHA, then assays of cell viability were performed. Histone acetylation was assessed by use of western blot analysis. Apoptosis was assessed via ELISA to detect fragmentation of cytoplasmic nucleosomal DNA and western blot analysis to detect cleavage of caspase 3. Cell cycle analysis was performed by use of propidium iodide staining and flow cytometry. RESULTS-Concentrations of OSU-HDAC42 and SAHA required to achieve 50% inhibition of cell viability (IC(50)) were reached in cells of 6 and 4 canine cancer cell lines, respectively, and ranged from approximately 0.4 to 1.3 microM for OSU-HDAC42 and 0.6 to 4.8 microM for SAHA. Cells from T-cell lymphoma, mast cell tumor, osteosarcoma, and histiocytic sarcoma lines were most sensitive to HDAC inhibition, with IC(50)s of < 1 microM for OSU-HDAC42 and < 5 microM for SAHA. Induction of apoptosis was indicated via cleavage of caspase 3 and increases in cytoplasmic nucleosomes and the subG(1) cell population. CONCLUSIONS AND CLINICAL RELEVANCE: Micromolar concentrations of HDAC inhibitors OSU-HDAC42 and SAHA induced histone acetylation, cytotoxicity, and apoptosis in canine cancer cells. In general, OSU-HDAC42 was more potent than SAHA.  相似文献   

9.
Canine hemangiosarcoma (HSA) is a neoplasm of vascular endothelial origin that has an aggressive biological behaviour, with less than 10% of dogs alive at 12‐months postdiagnosis. Treatment of choice consists of surgery followed by adjuvant doxorubicin‐based chemotherapy. We prospectively compared adjuvant doxorubicin and dacarbazine (ADTIC) to a traditional doxorubicin and cyclophosphamide (AC) treatment, aiming at determining safety and assessing whether this regimen prolongs survival and time to metastasis (TTM). Twenty‐seven dogs were enrolled; following staging work‐up, 18 were treated with AC and 9 with ADTIC. Median TTM and survival time were longer for dogs treated with ADTIC compared with those receiving AC (>550 versus 112 days, P = 0.021 and >550 versus 142 days, P = 0.011, respectively). Both protocols were well tolerated, without need for dose reduction or increased interval between treatments. A protocol consisting of combined doxorubicin and dacarbazine is safe in dogs with HSA and prolongs TTM and survival time.  相似文献   

10.
Yunnan Baiyao is a Chinese herbal medicine that has been utilized for its anti‐inflammatory, haemostatic, wound healing and pain relieving properties in people. It has been utilized in the veterinary profession to control bleeding in dogs with hemangiosarcoma (HSA) and has been anecdotally reported to prolong survival times in dogs with this neoplasm. This study evaluated the in vitro activity of Yunnan Baiyao against three canine HSA cell lines after treatment with increasing concentrations of Yunnan Baiyao (50, 100, 200, 400, 600 and 800 µg mL?1) at 24, 48 and 72 h. Mean half maximum inhibitory concentration (IC50) at 72 h for DEN, Fitz, SB was 369.9, 275.9 and 325.3 µg mL?1, respectively. Caspase‐3/7 activity increased in correlation with the IC50 in each cell line which was confirmed by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL, APO‐BRDU Kit; BD Biosciences, San Jose, CA, USA) assay. VEGF in cell supernatant was also quantified. Overall, the study found that Yunnan Baiyao causes dose and time dependent HSA cell death through initiation of caspase‐mediated apoptosis, which supports future studies involving Yunnan Baiyao.  相似文献   

11.
Background – Scleroderma is a rare chronic disease of connective tissues that may affect the skin in humans. Although still unclear, its aetiology may be related to drug reactions. To date, scleroderma has been reported in only a few dogs and one cat. Case report – Localized (morphea‐like) scleroderma was diagnosed in a 3‐year‐old intact male Persian cat that developed a nonpruritic, well‐demarcated alopecic plaque a few days after topical application of a ‘spot‐on’ solution containing praziquantel and emodepside. The lesion occurred at the site of application at the dorsal cervical region, and was characterized histologically by fibrosing dermatitis. There was no response to systemic treatment with pentoxifylline. Following topical therapy with minoxidil 5% for 30 days, hair regrowth occurred, and the lesion had completely disappeared after 60 days. Conclusions and clinical importance – The relationship between the alopecic plaque and the topical application of the spot‐on solution cannot be proved; however, according to the Naranjo scale, which estimates the probability of adverse drug reactions, this case could be classified as a ‘possible’ reaction to one of the components of the product. Sclerodermoid reactions have not been described as a cutaneous drug eruption in veterinary medicine, so this case may possibly represent the first such idiosyncratic reaction to one of the applied substances. Furthermore, to the best of the authors’ knowledge, this is the second report of a morphea‐like lesion in a cat.  相似文献   

12.
旨在探究组蛋白去乙酰化酶抑制剂对小反刍兽疫病毒(peste des petits ruminants virus，PPRV)复制的影响，以确定组蛋白去乙酰化酶(histone deacetylases，HDACs)在PPRV复制过程中的作用。采用RT-qPCR法检测PPRV感染后Vero细胞HDACs(HDAC1~11) mRNA表达水平的变化；用针对不同类型HDACs的抑制剂处理感染PPRV的Vero细胞48 h，Western blot筛选影响PRPV N蛋白表达的抑制剂；应用筛选出的抑制剂处理感染PPRV的Vero细胞，通过RT-qPCR、Western blot和TCID50法进一步分析抑制剂对病毒RNA、蛋白和病毒滴度的影响。结果显示，PPRV感染后，Vero细胞HDAC2 mRNA水平显著升高(P<0.05)；SAHA、TMP269、MGCD0103处理后，PPRV N蛋白的表达量明显降低，且呈剂量负相关；SAHA、TMP269、MGCD0103也显著降低PPRV N RNA表达水平(P<0.05，P<0.05，P<0.01)和病毒滴度(P<0.05,P<0.05,P<0.01)。这表明Ⅱa类HDACs抑制剂和Ⅰ类HDACs抑制剂能抑制PPRV的复制，Ⅰ类HDACs (HDAC1~3)和Ⅱa类HDACs (HDAC4~5、HDAC7、HDAC9)可能参与调控PPRV的感染。  相似文献   

13.
Background – Terbinafine, an allylamine antifungal, is used in pulsatile dose regimens for superficial mycoses in human medicine. Objectives – To compare the clinical efficacy of twice‐weekly versus once‐daily terbinafine administration to determine whether preliminary proof‐of‐concept evidence exists for pulsatile administration of terbinafine in the treatment of canine Malassezia dermatitis and to determine whether twice‐weekly treatment results in fewer clinical and owner‐perceived adverse events. Animals – Twenty client‐owned dogs with Malassezia dermatitis. Methods – In this randomized, single‐blinded clinical trial, dogs were randomly assigned to receive terbinafine (30 mg/kg) either once daily for 21 days (n = 10) or once daily on two consecutive days per week for six doses (n = 10). On day 0 and day 21, a mean yeast count was calculated from eight anatomical locations via adhesive tape‐strip cytology, clinical lesion scores were assigned to the same locations, and owners assessed pruritus using a visual analog scale. Results – There was no significant difference between treatment groups with respect to the reduction in mean yeast count (P = 0.343) and clinical lesion scores (P = 0.887). Pruritus measured by visual analog scale was significantly decreased in the twice‐weekly treatment group compared with the daily treatment group (P = 0.047). Seven of 20 dogs had a clinically measurable or owner‐reported adverse event during treatment that included gastrointestinal disturbances, excessive panting and elevated hepatic enzymes, with no significant difference noted between treatment groups. Conclusions and clinical importance – This pilot study indicates that twice‐weekly terbinafine administration may be an effective alternative treatment for canine Malassezia dermatitis and merits further investigation.  相似文献   

14.
With the exception of solar‐induced dermal hemangiosarcoma (HSA), the biologic behaviour of canine HSA is characterised by rapid tumour growth, a high metastatic rate and short survival times. Outcome of dogs with HSA of the tongue has not been previously reported. The purpose of this study was to assess outcome and prognostic factors in dogs with lingual HSA. Clinical data was collected retrospectively and histopathology was reviewed for 20 dogs. Median progression free survival was 524 days and the median overall survival time was 553 days. All dogs had low or intermediate grade tumours; most tumours were small and located on the ventral surface of the tongue. Prognostic factors significantly associated with increased survival included small tumour size and absence of clinical signs of an oral mass at the time of diagnosis. Dogs with HSA confined to the tongue may have a better prognosis compared with HSA in other organs.  相似文献   

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HistoryA 4‐year old, 500 kg Thoroughbred female horse diagnosed with bilateral forelimb laminitis and cellulitis on the left forelimb became severely painful and refractory to non‐steroidal anti‐inflammatory therapy (flunixin meglumine on days 1, 2, 3 and 4; and phenylbutazone on days 5, 6 and 7) alone or in combination with gabapentin (days 6 and 7).Physical examinationPain scores assessed independently by three individuals with a visual analog scale (VAS; 0 = no pain and 10 = worst possible pain) were 8.5 on day 6, and it increased to 9.5 on day 7. Non‐invasive blood pressure monitoring revealed severe hypertension.ManagementAs euthanasia was being considered for humane reasons, a decision was made to add an experimental new drug, trans‐4‐{4‐[3‐(4‐Trifluoromethoxy‐phenyl)‐ureido]‐cyclohexyloxy}‐benzoic acid (t‐TUCB), which is a soluble epoxide hydrolase (sEH) inhibitor, to the treatment protocol. Dose and frequency of administration were selected based on the drug potency against equine sEH to produce plasma concentrations within the range of 30 nmol L?1 and 2.5 μmol L?1. Pain scores decreased sharply and remarkably following t‐TUCB administration and blood pressure progressively decreased to physiologic normal values. Plasma concentrations of t‐TUCB, measured daily, were within the expected range, whereas phenylbutazone and gabapentin plasma levels were below the suggested efficacious concentrations.Follow upNo adverse effects were detected on clinical and laboratory examinations during and after t‐TUCB administration. No new episodes of laminitis have been noted up to the time of writing (120 days following treatment).ConclusionsInhibition of sEH with t‐TUCB was associated with a significant improvement in pain scores in one horse with laminitis whose pain was refractory to the standard of care therapy. No adverse effects were noticed. Future studies evaluating the analgesic and protective effects of these compounds in painful inflammatory diseases in animals are warranted.  相似文献   

17.
Hemangiosarcoma (HSA) of bone and telangiectatic osteosarcoma (tOSA) can appear similar histologically, but differ in histogenesis (malignant endothelial cells versus osteoblasts), and may warrant different treatments. Immunohistochemistry (IHC) for endothelial cell marker factor VIII‐related antigen/von Willebrand factor (FVIII‐RAg/vWF) is a well‐documented ancillary test to confirm HSA diagnoses in soft tissues, but its use in osseous HSA is rarely described. Archived samples of 54 primary appendicular bone tumours previously diagnosed as HSA or tOSA were evaluated using combination routine histopathology (RHP) and IHC. Approximately 20% of tumours were reclassified on the basis of FVIII‐RAg/vWF immunoreactivity, typically from an original diagnosis of tOSA to a reclassified diagnosis of HSA. No sample with tumour osteoid clearly identified on RHP was immunopositive for FVIII‐RAg/vWF. RHP alone was specific but not sensitive for diagnosis of HSA, compared with combination RHP and IHC. Routine histopathological evaluation in combination with FVIII‐RAg/vWF IHC can help differentiate canine primary appendicular HSA from tOSA.  相似文献   

18.
The ability to use ciclosporin (Atopica®: Novartis Animal Health, Greensboro, NC, USA) prior to intradermal testing (IDT) would help avoid exacerbation of clinical disease that can be associated with drug withdrawal. This study evaluated the effects of 30 days of administration of ciclosporin at a dose of 5 mg/kg once daily on IDT reactivity (immediate phase reactions) in a group of dogs with atopic dermatitis (AD) with initial positive IDT reactions. 16 dogs diagnosed with AD were included in the study. Eight dogs (group A) were treated with ciclosporin orally at 5 mg/kg once daily for 30 days. Eight dogs (group P) were treated with a placebo orally once daily for 30 days. IDT was performed at day 0 and day 30 on all dogs enrolled using a standardized panel of 45 aqueous allergens (Greer Laboratories, Lenoir, NC, USA) appropriate to our geographical region. IDT reactivity was assessed by both subjective and objective methods at 15 min post‐intradermal injection. Serum for allergen‐specific immunoglobulin (IgE) serology was obtained at day 0 and day 30. The study was designed as a double‐blinded, placebo‐controlled, cross‐over study. Data were analysed using a split‐plot analysis of variance with the grouping factor of treatment and the repeat factor of time (SAS System for Windows). At week 4, ciclosporin did not have a statistically significant effect on IDT reactivity or serology results. It therefore appears that, no withdrawal is recommended to evaluate immediate phase reactions.  相似文献   

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20.
Objective – To determine clinical efficacy of the Crotalidae polyvalent immune Fab (ovine) antivenom (OPCA) against progressive crotalid envenomation in the dog as reflected in stabilization or improvement of snakebite severity scores (SSS). Additionally, due to the potential decreased half‐life of the Fab antibodies in dogs we compared SSS between dogs receiving 2 different dosing regimes. Design – Prospective, clinical trial. Setting – Five veterinary emergency and critical care facilities. Animals – One hundred and fifteen client‐owned Crotalid (rattlesnake) snake bitten dogs in whom worsening of the envenomation syndrome was observed before OPCA treatment. Interventions – In a multicenter randomized clinical trial a single dose (1 vial) of OPCA alone was compared with 2 doses (1/2 vial each) administered 6 hours apart. Standard supportive care was provided in all cases. Measurements and Main Results – Data were available for 115 patients, 9 of which were fatalities. All patients' clinical condition was documented with a standardized SSS system accounting for each major body system. Each fatality received maximum severity scores of 20. The mean severity score of the 115 patients decreased from 4.19 to 3.29 points and there was no difference between the 2 treatment groups. The mean severity score of the 107 patients without fatalities decreased from 4.16 to 2.15. Antivenin‐related acute reactions occurred in 6 dogs (6%), and no serum sickness occurred within the 95 cases contacted at the 2‐week posttreatment follow‐up. Conclusions – In the first randomized trial in dogs of antivenin in the United States, OPCA effectively stabilized or terminated venom effects. There were no statistical differences detected between treatment groups within the study time frame.  相似文献   

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