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1.
Arch Gynecol Obstet ; 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34889994

RESUMO

PURPOSE: Ovarian cancer is the seventh most frequent form of malignant diseases in women worldwide and over 150,000 women die from it every year. More than 70 percent of all ovarian cancer patients are diagnosed at a late-stage disease with poor prognosis necessitating the development of sufficient screening biomarkers. MicroRNAs displayed promising potential as early diagnostics in various malignant diseases including ovarian cancer. The presented study aimed at identifying single microRNAs and microRNA combinations detecting ovarian cancer in vitro and in vivo. METHODS: Intracellular, extracellular and urinary microRNA expression levels of twelve microRNAs (let-7a, let-7d, miR-10a, miR-15a, miR-15b, miR-19b, miR-20a, miR-21, miR-100, miR-125b, miR-155, miR-222) were quantified performing quantitative real-time-PCR. Therefore, the three ovarian cancer cell lines SK-OV-3, OAW-42, EFO-27 as well as urine samples of ovarian cancer patients and healthy controls were analyzed. RESULTS: MiR-15a, miR-20a and miR-222 showed expression level alterations extracellularly, whereas miR-125b did intracellularly across the analyzed cell lines. MicroRNA expression alterations in single cell lines suggest subtype specificity in both compartments. Hypoxia and acidosis showed scarce effects on single miRNA expression levels only. Furthermore, we were able to demonstrate the feasibility to clearly detect the 12 miRNAs in urine samples. In urine, miR-15a was upregulated whereas let-7a was down-regulated in ovarian cancer patients. CONCLUSION: Intracellular, extracellular and urinary microRNA expression alterations emphasize their great potential as biomarkers in liquid biopsies. Especially, miR-15a and let-7a qualify for possible circulating biomarkers in liquid biopsies of ovarian cancer patients.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34916844

RESUMO

PURPOSE: In 2020, breast cancer still represents the most common type of cancer in women worldwide. Depending on the specific molecular subtype, clinical breast cancer management comprises surgery, radiotherapy, chemotherapy and targeted therapy. Furthermore, there are some therapeutic approaches from the field of complementary and alternative medicine. Current research focuses on the elucidation of new therapeutic targets for treatment development. Odorant substances affect apoptosis, proliferation and cell cycle in healthy and cancerous cells. Exact signalling pathways involved are not entirely clear. The present study aims to analyse their therapeutic potential in breast cancer. METHODS: This study focuses on the effect of commonly used odorant substances (citral, citrathal R, cyclovertal, para-cymol, hexylacetat, herbavert, dihydromyrcerol and limonen) on the breast cancer cell lines MDA-MB-231, T47-D and BT474. Methodologically, this study applied cell culturing, MTT assay for detection of IC50 of the odorant substance, RNA purification followed by qRT-PCR, protein isolation and Western Blot, as well as immunocytochemistry. Further, this study investigates the role of transient receptor potential channel V1 (TRPV1), involved in the mechanisms of action for some odorant substances. Therefore, capsazepine, a TRPV1 antagonist, was used. RESULTS: The odorant substances citral, citrathal R and cyclovertal have significant pro-apoptotic (p < 0.001), anti-proliferative (p < 0.001) and cell cycle-arresting effects measurable in RNA expression as well as in protein levels and immunocytochemical staining. The combination of citral and capsazepine no longer showed significant pro-apoptotic, antiproliferative, and cell cycle inhibitory effects compared to the compounds alone. This indicates that TRPV1 is necessary for the signal transduction of citral. CONCLUSION: This present study reveals three odorant substances with effects on cell viability, indicating their potential use in breast cancer therapy.

3.
Acta Derm Venereol ; 101(9): adv00560, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34427313

RESUMO

The globally increasing prevalence of chronic inflammatory skin diseases has substantial costs. Biologicals have become available as therapeutic options, but are encumbered with barriers to prescription. The aim of this study was to evaluate the barriers to prescription of biologicals in the treatment of chronic dermatological diseases. Dermatologists working in private practices in the German federal states of Bavaria and Lower Saxony participated in a cross-sectional study. Economic and legal aspects, including "high therapy costs", "low reimbursements", and "fear of regress claims", were identified as the most prevalent barriers. Significant differences between dermatologists from Bavaria and Lower Saxony were found only regarding the treatment of atopic dermatitis. This study demonstrates the prevalence of barriers to the prescription of biologicals in the treatment of chronic dermatological diseases. Overcoming these barriers could improve the usage of modern therapies and thereby expand patient-centred care for chronic skin diseases.


Assuntos
Produtos Biológicos , Dermatite Atópica , Dermatopatias , Produtos Biológicos/efeitos adversos , Estudos Transversais , Dermatite Atópica/diagnóstico , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/epidemiologia , Humanos , Prescrições , Dermatopatias/diagnóstico , Dermatopatias/tratamento farmacológico , Dermatopatias/epidemiologia
4.
Int J Gynecol Cancer ; 31(6): 868-874, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33911004

RESUMO

OBJECTIVE: To find dysregulated urinary microRNAs associated with endometrial cancer as a first step in finding a non-invasive new diagnostic biomarker. The second objective is to determine the correlation of urinary microRNAs with clinicopathological characteristics. METHODS: A prospective cohort study of patients presenting with abnormal bleeding between March and November 2019 was performed at the Royal Cornwall Hospital Trust Truro. Urine samples were obtained from women diagnosed with endometrial cancer and benign endometrial sampling. MicroRNA was isolated and quantitative real time PCR was used to detect expression levels of microRNAs. RESULTS: A total of 61 women were included in this study: 24 endometrial cancer patients, and 37 controls. Median age was 64 years (range 45-94) and median body mass index was 29 kg/m2 (range 17-54). MiR-223 was significantly up-regulated in urine of endometrial cancers patients (p=0.003). Furthermore, let7-i, miR-34a, and miR-200c were significantly down-regulated and miR-424 was up-regulated in obese women. In addition, miR-148a and miR-222 were significantly down-regulated in elderly women, and miR-16, miR-26b, and miR-200c were significantly deregulated in women with multiple comorbidities. CONCLUSION: MicroRNA expression levels in urine can potentially be used as a non-invasive diagnostic test for endometrial cancer. Furthermore, aberrant microRNA expression in urine is associated with patient characteristics. Further research in larger trials is needed to validate the potential utility of urinary microRNAs.


Assuntos
Neoplasias do Endométrio/diagnóstico , MicroRNAs/urina , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Estudos de Viabilidade , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos
5.
Acta Obstet Gynecol Scand ; 100(6): 1148-1154, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33705566

RESUMO

INTRODUCTION: MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression and contribute to the development of cancer. They have been shown to be stable in tissue samples and may be promising diagnostic biomarkers for endometrial cancer. MATERIAL AND METHODS: A retrospective cohort study of women diagnosed with endometrial cancer between January 2017 and December 2017 was performed at the Royal Cornwall Hospital. Archived formalin-fixed paraffin-embedded samples were obtained from patients with endometrial cancer and healthy women. MicroRNA was isolated and quantitative real-time polymerase chain reaction was used to detect expression levels of miRNAs. RESULTS: A total of 76 women were included: 36 endometrial cancer patients, 40 healthy controls. A distinct panel of miR-200a, miR-200b, miR-200c, miR-205, and miR-182 showed an area under the curve of 0.958, sensitivity 92%, specificity 89%, positive predictive value of 89% (95% CI 82%-94%) and negative predictive value of 91% (95% CI 85%-96%) in diagnosing endometrial cancer. High miR-182 expression levels were significantly related to high-grade endometrioid tumors compared with low-grade tumors. CONCLUSIONS: We demonstrated high diagnostic accuracy of miRNA for detecting endometrial cancer. In addition, miRNA contributed to an improvement in distinguishing between high-grade and low-grade endometrioid tumors.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Endometrioide/diagnóstico , Transformação Celular Neoplásica/genética , Neoplasias do Endométrio/diagnóstico , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , Adulto , Biomarcadores Tumorais/metabolismo , Carcinoma Endometrioide/genética , Estudos de Casos e Controles , Transformação Celular Neoplásica/metabolismo , Neoplasias do Endométrio/genética , Feminino , Perfilação da Expressão Gênica/métodos , Alemanha , Humanos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Inclusão em Parafina , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem
6.
Mol Med Rep ; 22(5): 4048-4060, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33000259

RESUMO

Early diagnosis and therapy in the first stages of a malignant disease is the most crucial factor for successful cancer treatment and recovery. Currently, there is a high demand for novel diagnostic tools that indicate neoplasms in the first or pre­malignant stages. MicroRNAs (miRNA or miR) are small non­coding RNAs that may act as oncogenes and downregulate tumor­suppressor genes. The detection and mutual discrimination of the three common female malignant neoplasia types breast (BC), ovarian (OC) and endometrial cancer (EC) could be enabled by identification of tumor entity­specific miRNA expression differences. In the present study, the relative expression levels of 25 BC, EC and OC­related miRNAs were assessed by reverse transcription­quantitative PCR and determined using the 2­ΔΔCq method for normalization against the mean of four housekeeping genes. Expression levels of all miRNAs were analyzed by regression against cell line as a factor. An expression level­based discrimination between BC and OC cell types was obtained for a subgroup of ten different miRNA types. miR­30 family genes, as well as three other miRNAs, were found to be uniformly upregulated in OC cells compared with BC cells. BC and EC cells could be distinguished by the expression profiles of six specific miRNAs. In addition, four miRNAs were differentially expressed between EC and OC cells. In conclusion, miRNAs were identified as a potential novel tool to detect and mutually discriminate between BC, OC and EC. Based on a subset of 25 clinically relevant human miRNA types, the present study could significantly discriminate between these three female cancer types by means of their expression levels. For further verification and validation of miRNA­based biomarker expression signatures that enable valuable tumor detection and characterization in routine screening or potential therapy monitoring, additional and extended in vitro analyses, followed by translational studies utilizing patients' tissue and liquid biopsy materials, are required.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias do Endométrio/diagnóstico , Perfilação da Expressão Gênica/métodos , MicroRNAs/genética , Neoplasias Ovarianas/diagnóstico , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Diagnóstico Diferencial , Detecção Precoce de Câncer , Neoplasias do Endométrio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Ovarianas/genética
7.
Mol Diagn Ther ; 24(2): 215-232, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32112368

RESUMO

INTRODUCTION: Breast cancer (BC) is the most frequent malignant disease in women worldwide and is therefore challenging for the healthcare system. Early BC detection remains a leading factor that improves overall outcome and disease management. Aside from established screening procedures, there is a constant demand for additional BC detection methods. Routine BC screening via non-invasive liquid biopsy biomarkers is one auspicious approach to either complete or even replace the current state-of-the-art diagnostics. The study explores the diagnostic potential of urinary exosomal microRNAs with specific BC biomarker characteristics to initiate the potential prospective application of non-invasive BC screening as routine practice. METHODS: Based on a case-control study (69 BC vs. 40 healthy controls), expression level quantification and subsequent biostatistical computation of 13 urine-derived microRNAs were performed to evaluate their diagnostic relevance in BC. RESULTS: Multilateral statistical assessment determined and repeatedly confirmed a specific panel of four urinary microRNA types (miR-424, miR-423, miR-660, and let7-i) as a highly specific combinatory biomarker tool discriminating BC patients from healthy controls, with 98.6% sensitivity and 100% specificity. DISCUSSION: Urine-based BC diagnosis may be achieved through the analysis of distinct microRNA panels with proven biomarker abilities. Subject to further validation, the implementation of urinary BC detection in routine screening offers a promising non-invasive alternative in women's healthcare.


Assuntos
Biomarcadores Tumorais/urina , Neoplasias da Mama/diagnóstico , Exossomos/genética , MicroRNAs/urina , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/urina , Estudos de Casos e Controles , Detecção Precoce de Câncer , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Biópsia Líquida , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade
8.
Cancer Biomark ; 27(2): 225-242, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32083575

RESUMO

BACKGROUND: Deregulated microRNAs (miRNAs) in breast and gynecological cancer might contribute to improve early detection of female malignancies. OBJECTIVE: Specification of miRNA types in serum and urine as minimally-invasive biomarkers for breast (BC), endometrial (EC) and ovarian cancer (OC). METHODS: In a discovery phase, serum and urine samples from 17 BC, five EC and five OC patients vs. ten healthy controls (CTRL) were analyzed with Agilent human miRNA microarray chip. Selected miRNA types were further investigated by RT-qPCR in serum (31 BC, 13 EC, 15 OC patients, 32 CTRL) and urine (25 BC, 10 EC, 10 OC patients, 30 CTRL) applying two-sample t-tests. RESULTS: Several miRNA biomarker candidates exhibited diagnostic features due to distinctive expression levels (serum: 26; urine: 22). Among these, miR-518b, -4719 and -6757-3p were found specifically deregulated in BC serum. Four, non-entity-specific, novel biomarker candidates with unknown functional roles were identified in urine (miR-3973; -4426; -5089-5p and -6841). RT-qPCR identified miR-484/-23a (all p⩽ 0.001) in serum as potential diagnostic markers for EC and OC while miR-23a may also serve as an endogenous control in BC diagnosis. CONCLUSIONS: Promising miRNAs as liquid biopsy-based tools in the detection of BC, EC and OC qualified for external validation in larger cohorts.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias do Endométrio/genética , Neoplasias Ovarianas/genética , Idoso , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/urina , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Neoplasias da Mama/urina , Estudos de Casos e Controles , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/urina , Feminino , Humanos , Biópsia Líquida/métodos , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/urina , Prognóstico
9.
Int J Oncol ; 56(1): 47-68, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31789396

RESUMO

Due to the positive association between neoadjuvant chemotherapy (NACT) and the promising early response rates of patients with triple negative breast cancer (TNBC), including probabilities of pathological complete response, NACT is increasingly used in TNBC management. Liquid biopsy­based biomarkers with the power to diagnose the early response to NACT may support established monitoring tools, which are to a certain extent imprecise and costly. Simple serum­ or urine­based analyses of non­coding RNA (ncRNA) expression may allow for fast, minimally­invasive testing and timely adjustment of the therapy regimen. The present study investigated breast cancer­related ncRNAs [microRNA (miR)­7, ­9, ­15a, ­17, ­18a, ­19b, ­21, ­30b, ­222 and ­320c, PIWI­interacting RNA­36743 and GlyCCC2] in triple positive BT­474 cells and three TNBC cell lines (BT­20, HS­578T and MDA­MB­231) treated with various chemotherapeutic agents using reverse transcription­quantitative PCR. Intracellular and secreted microvesicular ncRNA expression levels were analysed using a multivariable statistical regression analysis. Chemotherapy­driven effects were investigated by analysing cell cycle determinants at the mRNA and protein levels. Serum and urine specimens from 8 patients with TNBC were compared with 10 healthy females using two­sample t­tests. Samples from the patients with TNBC were compared at two time points. Chemotherapeutic treatments induced distinct changes in ncRNA expression in TNBC cell lines and the BT­474 cell line in intra­ and extracellular compartments. Serum and urine­based ncRNA expression analysis was able to discriminate between patients with TNBC and controls. Time point comparisons in the urine samples of patients with TNBC revealed a general rise in the level of ncRNA. Serum data suggested a potential association between piR­36743, miR­17, ­19b and ­30b expression levels and an NACT­driven complete clinical response. The present study highlighted the potential of ncRNAs as liquid biopsy­based biomarkers in TNBC chemotherapy treatment. The ncRNAs tested in the present study have been previously investigated for their involvement in BC or TNBC chemotherapy responses; however, these previous studies were restricted to patient tissue or in vitro models. The data from the present study offer novel insight into ncRNA expression in liquid samples from patients with TNBC, and the study serves as an initial step in the evaluation of ncRNAs as diagnostic biomarkers in the monitoring of TNBC therapy.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Terapia Neoadjuvante/métodos , RNA não Traduzido/sangue , RNA não Traduzido/genética , Neoplasias de Mama Triplo Negativas/sangue , Apoptose , Proliferação de Células , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Prognóstico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas
10.
Oncol Rep ; 38(2): 993-1004, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28627686

RESUMO

Due to their post-transcriptional regulatory impact on gene expression, microRNAs (miRNA, miRs) influence decisively cellular processes of differentiation, proliferation and apoptosis. In oncogenic pathways various miRNAs exert either oncogenic or tumor suppressor activities in a stage-specific manner. Dysregulation of miRNA expression pattern has been associated with several human cancers including endometrial cancer (EC). In the present study, expression profile alterations of EC associated secreted miRNAs were determined under the microenvironmental stress situations hypoxia and acidosis occurring in tumor progression and metastasis. The potential influence of hypoxia and acidosis vs. control conditions on the expression levels of 24 EC-relevant miRNA types was quantitatively accessed via real-time PCR in three established EC in vitro models. Expression data were analyzed statistically. In vitro application of hypoxia resulted in downregulation of miR-15a, miR-20a, miR-20b and miR-128-1 in Ishikawa cells (type I EC) and upregulation of miR-21 in EFE-184 cells (type I EC). Acidosis triggered upregulation of tumor promoting miR-125b in AN3-CA cell (type II EC), whereas in Ishikawa cells (type I EC) miRNAs with tumor suppressive function were found altered in divergent directions, both up- (let-7a) and down- (miR-22) regulated. Our current findings emphasize the functional importance of secreted miRNAs in the immediate response of EC cells to exogenic stress situations such as the typical tumor epiphenomena hypoxia and acidosis. Focusing on the specific potential of secreted, thus circulating miRNA molecules, alterations in expression levels not only influence intracellular gene expression and signaling cascades, but also transfer the induction of (tumor)biological cellular changes to adjacent cells.


Assuntos
Carcinogênese/genética , Hipóxia Celular/genética , Neoplasias do Endométrio/genética , MicroRNAs/genética , Acidose/complicações , Acidose/genética , Acidose/patologia , Apoptose/genética , Linhagem Celular Tumoral , Neoplasias do Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos
11.
Plast Reconstr Surg ; 132(6): 1542-1549, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24281582

RESUMO

BACKGROUND: Pathologic fractures of the mandible can be devastating to cancer patients and are due in large part to the pernicious effects of irradiation on bone vascularity. The authors' aim was to ascertain whether amifostine, a radioprotective drug, will preserve vascularity and improve bone healing in a murine model of irradiated mandibular fracture repair. METHODS: Rats were randomized into three groups: nonirradiated fracture (n = 9), irradiation/fracture (n = 5), and amifostine/irradiation/fracture (n = 7). Animals in the irradiation groups underwent a human equivalent dose of radiation directed at the left hemimandible. Animals treated in the amifostine group received amifostine concomitantly with radiation. All animals underwent unilateral left mandibular osteotomy with external fixation set to a 2.1-mm fracture gap. Fracture healing was allowed for 40 days before perfusion with Microfil. Vascular radiomorphometrics were quantified with micro-computed tomography. RESULTS: When compared with the irradiated/fractured group, amifostine treatment more than doubled the rate of fracture unions to 57 percent. Amifostine treatment also resulted in an increase in vessel number (123 percent; p < 0.05) and a corresponding decrease in vessel separation (55.5 percent; p < 0.05) there was no statistical difference in the vascularity metrics between the amifostine/irradiation/fracture group and the nonirradiated/fracture group. CONCLUSIONS: Amifostine prophylaxis during radiation maintains mandibular vascularity at levels observed in nonirradiated fracture specimens, corresponding to improved unions. These results set the stage for clinical exploration of this targeted therapy alone and in combination with other treatments, to mitigate the effects of irradiation on bone healing and fracture repair.


Assuntos
Amifostina/farmacologia , Consolidação da Fratura/efeitos dos fármacos , Consolidação da Fratura/efeitos da radiação , Fraturas Mandibulares/cirurgia , Lesões Experimentais por Radiação/tratamento farmacológico , Protetores contra Radiação/farmacologia , Animais , Modelos Animais de Doenças , Humanos , Mandíbula/irrigação sanguínea , Mandíbula/efeitos da radiação , Mandíbula/cirurgia , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/efeitos da radiação , Osteonecrose/tratamento farmacológico , Osteotomia , Distribuição Aleatória , Ratos
12.
Bone ; 57(1): 56-61, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23860272

RESUMO

BACKGROUND: Pathologic fractures (Fx) of the mandibles are severely debilitating consequences of radiation (XRT) in the treatment of craniofacial malignancy. We have previously demonstrated Amifostine's effect (AMF) in the remediation of radiation-induced cellular damage. We posit that AMF prophylaxis will preserve bone strength and drastically reverse radiotherapy-induced non-union in a murine mandibular model of pathologic fracture repair. MATERIALS AND METHODS: Twenty-nine rats were randomized into 3 groups: Fx, XRT/Fx, and AMF/XRT/Fx. A fractionated human equivalent dose of radiation was delivered to the left hemimandibles of XRT/Fx and AMF/XRT/Fx. AMF/XRT/Fx was pre-treated with AMF. All groups underwent left mandibular osteotomy with external fixation and setting of a 2.1mm fracture gap post-operatively. Utilizing micro-computed tomography and biomechanical testing, the healed fracture was evaluated for strength. RESULTS: All radiomorphometrics and biomechanical properties were significantly diminished in XRT/Fx compared to both Fx and AMF/XRT/Fx. No difference was demonstrated between Fx and AMF/XRT/Fx in both outcomes. CONCLUSION: Our investigation establishes the significant and substantial capability of AMF prophylaxis to preserve and enhance bone union, quality and strength in the setting of human equivalent radiotherapy. Such novel discoveries establish the true potential to utilize pharmacotherapy to prevent and improve the treatment outcomes of radiation-induced late pathologic fractures.


Assuntos
Amifostina/uso terapêutico , Fraturas Espontâneas/tratamento farmacológico , Fraturas Espontâneas/prevenção & controle , Mandíbula/efeitos dos fármacos , Mandíbula/efeitos da radiação , Protetores contra Radiação/uso terapêutico , Animais , Densitometria , Masculino , Ratos , Ratos Sprague-Dawley
13.
J Craniofac Surg ; 24(2): 540-4, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23524737

RESUMO

The advent of stem cell-based therapies makes current models of mandibular distraction osteogenesis unwieldy. We thereby designed an isogenic model of distraction osteogenesis whose purpose was to allow for the free transfer of cells and components between rats. As immune response plays a significant role in healing and prevention of infection, an immune-competent mode is desirable rather than an athymic rat/xenograft model. The purposes of this study were as follows: (1) to replicate established models of distraction osteogenesis in a rodent model using an isogenic rat strain, and (2) to characterize the differences between inbred, isogenic rats and outbred rats in mandibular distraction osteogenesis via radiomorphometry and biomechanical response analysis. We demonstrated successful distraction osteogenesis to 5.1 mm in all Lewis (isogenic) rat mandibles as well as all Sprague-Dawley (outbred) rat mandibles, with no significant difference in volume-normalized radiomorphometrics, trending difference in non-volume-normalized radiomorphometrics and significant differences in biomechanical response parameters. We attribute the differences demonstrated to the decreased size of the Lewis rat mandible in comparison to Sprague-Dawley mandibles. We also provide information with caring with the additional needs of the Lewis rat. Given these differences, we find that Lewis rats function as an excellent model for isogenic mandibular distraction osteogenesis, but data procured may not be comparable between isogenic and nonisogenic models.


Assuntos
Modelos Animais de Doenças , Mandíbula/cirurgia , Osteogênese por Distração , Animais , Densidade Óssea , Masculino , Mandíbula/diagnóstico por imagem , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Estresse Mecânico , Microtomografia por Raio-X
14.
Bone ; 52(1): 318-25, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23085084

RESUMO

BACKGROUND: Medically based efforts and alternative treatment strategies to prevent or remediate the corrosive effects of radiotherapy on pathologic fracture healing have failed to produce clear and convincing evidence of success. Establishing an effective pharmacologic option to prevent or treat the development of non-unions in this setting could have immense therapeutic potential. Experimental studies have shown that deferoxamine (DFO), an iron-chelating agent, bolsters vascularity and subsequently enhances normal fracture healing when injected locally into a fracture callus in long bone animal models. Since radiotherapy is known to impede angiogenesis, we hypothesized that the pharmacologic addition of DFO would serve to mitigate the effects of radiotherapy on new vessel formation in vitro and in vivo. MATERIALS AND METHODS: In vitro investigation of angiogenesis was conducted utilizing HUVEC cells in Matrigel. Endothelial tubule formation assays were divided into four groups: Control, Radiated, Radiated+Low-Dose DFO and Radiated+High-Dose DFO. Tubule formation was quantified microscopically and video recorded for the four groups simultaneously during the experiment. In vivo, three groups of Sprague-Dawley rats underwent external fixator placement and fracture osteotomy of the left mandible. Two groups received pre-operative fractionated radiotherapy, and one of these groups was treated with DFO after fracture repair. After 40 days, the animals were perfused and imaged with micro-CT to calculate vascular radiomorphometrics. RESULTS: In vitro, endothelial tubule formation assays demonstrated that DFO mitigated the deleterious effects of radiation on angiogenesis. Further, high-dose DFO cultures appeared to organize within 2h of incubation and achieved a robust network that was visibly superior to all other experimental groups in an accelerated fashion. In vivo, animals subjected to a human equivalent dose of radiotherapy (HEDR) and left mandibular fracture demonstrated quantifiably diminished µCT metrics of vascular density, as well as a 75% incidence of associated non-unions. The addition of DFO in this setting markedly improved vascularity as demonstrated with 3D angiographic modeling. In addition, we observed an increased incidence of bony unions in the DFO treated group when compared to radiated fractures without treatment (67% vs. 25% respectively). CONCLUSION: Our data suggest that selectively targeting angiogenesis with localized DFO injections is sufficient to remediate the associated severe vascular diminution resulting from a HEDR. Perhaps the most consequential and clinically relevant finding was the ability to reduce the incidence of non-unions in a model where fracture healing was not routinely observed.


Assuntos
Desferroxamina/administração & dosagem , Consolidação da Fratura , Radioterapia , Animais , Células Cultivadas , Humanos , Neovascularização Patológica , Ratos , Ratos Sprague-Dawley
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