RESUMO
Radiation and bacillus Calmette-Guérin (BCG) instillations are used clinically for treatment of urothelial carcinoma, but the precise mechanisms by which they activate an immune response remain elusive. The role of the cGAS-STING pathway has been implicated in both BCG and radiation-induced immune response; however, comparison of STING pathway molecules and the immune landscape following treatment in urothelial carcinoma has not been performed. We therefore comprehensively analyzed the local immune response in the bladder tumor microenvironment following radiotherapy and BCG instillations in a well-established spontaneous murine model of urothelial carcinoma to provide insight into activation of STING-mediated immune response. Mice were exposed to the oral carcinogen, BBN, for 12 weeks prior to treatment with a single 15 Gy dose of radiation or three intravesical instillations of BCG (1 × 108 CFU). At sacrifice, tumors were staged by a urologic pathologist and effects of therapy on the immune microenvironment were measured using the NanoString Myeloid Innate Immunity Panel and immunohistochemistry. Clinical relevance was established by measuring immune biomarker expression of cGAS and STING on a human tissue microarray consisting of BCG-treated non-muscle-invasive urothelial carcinomas. BCG instillations in the murine model elevated STING and downstream STING-induced interferon and pro-inflammatory molecules, intratumoral M1 macrophage and T-cell accumulation, and complete tumor eradication. In contrast, radiotherapy caused no changes in STING pathway or innate immune gene expression; rather, it induced M2 macrophage accumulation and elevated FoxP3 expression characteristic of immunosuppression. In human non-muscle-invasive bladder cancer, STING protein expression was elevated at baseline in patients who responded to BCG therapy and increased further after BCG therapy. Overall, these results show that STING pathway activation plays a key role in effective BCG-induced immune response and strongly indicate that the effects of BCG on the bladder cancer immune microenvironment are more beneficial than those induced by radiation. © 2021 The Pathological Society of Great Britain and Ireland.
Assuntos
Antineoplásicos/administração & dosagem , Vacina BCG/administração & dosagem , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/efeitos da radiação , Imunoterapia , Proteínas de Membrana/imunologia , Doses de Radiação , Neoplasias da Bexiga Urinária/terapia , Urotélio/efeitos dos fármacos , Urotélio/efeitos da radiação , Administração Intravesical , Animais , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/efeitos da radiação , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/efeitos da radiação , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/efeitos da radiação , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Urotélio/imunologia , Urotélio/metabolismoRESUMO
Long term-side effects from cancer therapies are a growing health care concern as life expectancy among cancer survivors increases. Damage to the bladder is common in patients treated with radiation therapy for pelvic cancers and can result in radiation (hemorrhagic) cystitis (RC). The disease progression of RC consists of an acute and chronic phase, separated by a symptom-free period. Gaining insight in tissue changes associated with these phases is necessary to develop appropriate interventions. Using a mouse preclinical model, we have previously shown that fibrosis and vascular damage are the predominant pathological features of chronic RC. The goal of this study was to determine the pathological changes during acute RC. We identified that radiation treatment results in a temporary increase in micturition frequency and decrease in void volume 4-8 weeks after irradiation. Histologically, the micturition defect is associated with thinning of the urothelium, loss of urothelial cell-cell adhesion and tight junction proteins and decrease in uroplakin III expression. By 12 weeks, the urothelium had regenerated and micturition patterns were similar to littermate controls. No inflammation or fibrosis were detected in bladder tissues after irradiation. We conclude that functional bladder defects during acute RC are driven primarily by a urothelial defect.
Assuntos
Cistite/fisiopatologia , Lesões Experimentais por Radiação/fisiopatologia , Bexiga Urinária/patologia , Micção/efeitos da radiação , Animais , Caderinas/análise , Caderinas/metabolismo , Cistite/etiologia , Cistite/patologia , Feminino , Humanos , Camundongos , Neoplasias Pélvicas/radioterapia , Lesões Experimentais por Radiação/etiologia , Lesões Experimentais por Radiação/patologia , Bexiga Urinária/fisiopatologia , Bexiga Urinária/efeitos da radiação , Micção/fisiologia , Uroplaquina III/análise , Uroplaquina III/metabolismo , Urotélio/patologia , Urotélio/efeitos da radiação , Proteína da Zônula de Oclusão-1/análise , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
PURPOSE: In a previous study we have shown in a mouse model that administration of nuclear factor-kappa B (NF-κB) inhibitor thalidomide has promising therapeutic effects on early radiation cystitis (ERC) and late radiation sequelae (LRS) of the urinary bladder. The aim of this study was to evaluate in the same mice the effect of thalidomide on adherens junction (AJ) proteins in ERC and LRS. METHODS: Urothelial expressions of Ecadherin and ßcatenin were assessed by immunohistochemistry in formalin-fixed paraffin-embedded (FFPE) bladder specimens over 360 days post single-dose irradiation on day 0. First, the effect of irradiation on AJ expression and then effects of thalidomide on irradiation-induced AJ alterations were assessed using three different treatment times. RESULTS: Irradiation provoked a biphasic upregulation of Ecadherin and ßcatenin in the early phase. After a mild decrease of Ecadherin and a pronounced decrease of ßcatenin at the end of the early phase, both increased again in the late phase. Early administration of thalidomide (day 1-15) resulted in a steeper rise in the first days, an extended and increased expression at the end of the early phase and a higher expression of ßcatenin alone at the beginning of the late phase. CONCLUSION: Upregulation of AJ proteins is an attempt to compensate irradiation-induced impairment of urothelial barrier function. Early administration of thalidomide improves these compensatory mechanisms by inhibiting NF-κB signaling and its interfering effects.
Assuntos
Caderinas/biossíntese , Regulação da Expressão Gênica/efeitos da radiação , NF-kappa B/antagonistas & inibidores , Lesões Experimentais por Radiação/metabolismo , Talidomida/farmacologia , Bexiga Urinária/efeitos da radiação , beta Catenina/biossíntese , Junções Aderentes/efeitos da radiação , Animais , Caderinas/genética , Cistite/etiologia , Cistite/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C3H , Lesões Experimentais por Radiação/etiologia , Fatores de Tempo , Bexiga Urinária/metabolismo , Urotélio/metabolismo , Urotélio/efeitos da radiação , beta Catenina/genéticaRESUMO
The therapeutic benefit of immune checkpoint inhibitor monotherapy is limited to a subset of patients in urothelial carcinoma (UC). Previous studies showed the immunogenicity of cisplatin and irradiation. Here, we investigated whether chemoradiotherapy (CRT), a combination of cisplatin and irradiation, could improve the efficacy of postirradiation anti-programmed cell death 1 (PD-1) treatment in UC. In our advanced UC patient cohort, patients with CRT showed a significantly better objective response rate (75%/22%) and overall survival (88%/30% at 12 months) following later pembrolizumab therapy compared to those without. Then, we created syngeneic UC mouse models by inoculating MB49 cells s.c. in C57BL/6J mice to examine the potential of CRT to enhance antitumor immunity in conjunction with postirradiation anti-PD-1 treatment. Nonirradiated tumors of the mice treated with CRT/postirradiation anti-PD-1 treatment had a significantly slower growth rate and a significantly higher expression of cytotoxic T cells compared to those of the mice treated with anti-PD-1 treatment alone. The mice treated with CRT/postirradiation anti-PD-1 treatment showed the best survival. Mechanistically, CRT provoked strong direct cytotoxicity and increased expressions of immunogenic cell death markers in MB49 cells. Therefore, the combination of cisplatin and irradiation induces immunogenic cell death and potentiates postirradiation anti-PD-1 treatment efficacy in UC.
Assuntos
Carcinoma/tratamento farmacológico , Carcinoma/radioterapia , Cisplatino/farmacologia , Morte Celular Imunogênica/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/farmacologia , Carcinoma/genética , Carcinoma/patologia , Quimiorradioterapia , Terapia Combinada , Xenoenxertos , Humanos , Camundongos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Urotélio/efeitos dos fármacos , Urotélio/patologia , Urotélio/efeitos da radiaçãoRESUMO
Laser technology has long been a standard treatment for many diseases. In particular, laser treatment is considered the standard of care in various urological diseases. While originally primarily restricted to stone treatment, lasers have since evolved to play an important role even in the treatment of malignant diseases. In this review, we take a closer look at the history of lasers in urology and some implications for treatments today.
Assuntos
Terapia a Laser/métodos , Urologia/métodos , Humanos , Litotripsia , Masculino , Doenças Prostáticas/terapia , Doenças Urológicas/terapia , Urotélio/efeitos da radiaçãoRESUMO
OBJECTIVE: To determine the role of cyclooxygenase (COX) expression in the urothelium of the urinary bladder during radiation injury caused by pelvic radiotherapy for cancer therapy. STUDY DESIGN: Twenty-four male Swiss Albino mice were separated into 4 groups. The first group was the control group (Group 1) and the second, third, and fourth groups were euthanized after 24 hours (Group 2), 48 hours (Group 3), and 7 days (Group 4), respectively. A single-fractioned 10 Gy of ionizing radiation was applied to all mice's pelvic zone with Co-60. Bladders were removed completely from the pelvic region. Histochemical analysis using hematoxylin and eosin and immunohistochemical analysis using anti-COX-1 and COX-2 antibodies were performed on tissue samples. The immunoreactivities of the urinary bladder were quantified using H-score measurement, and statistical comparison was performed. RESULTS: In the immunohistochemical examination the COX-1 immunoreactivities were found to be higher in the urothelium of the bladder in the radiation exposed groups than in the normal control group (group 1) (p < 0.005). Additionally, high immunoreactivity of COX-2 molecule was established in groups 2, 3, and 4 of radiation groups as compared to group 1 (p < 0.005) in examination of the urothelium. COX-1 and COX-2 immunoreactivities in the submucosa were detected higher in group 4 than in the other groups (p < 0.005). CONCLUSION: COX-1 and COX-2 expressions in the urothelium and subepithelium of the urinary bladder were investigated in mice during the acute radiation response. The expression of COX-1 and COX-2 in the urothelium seems to prevent bladder damage from radiation, supplying differentiation and restoration of the urothelium.
Assuntos
Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Proteínas de Membrana/metabolismo , Bexiga Urinária/efeitos da radiação , Urotélio/efeitos da radiação , Animais , Masculino , Camundongos , Bexiga Urinária/enzimologia , Bexiga Urinária/patologia , Urotélio/enzimologia , Urotélio/patologiaRESUMO
BACKGROUND: While radical nephroureterectomy is the treatment of choice for localized or regional urothelial carcinoma of the upper urinary tract (UTUC), the role of adjuvant radiotherapy is unclear, with conflicting data from various small studies. PATIENTS AND METHODS: We sought to study the impact of adjuvant radiotherapy on UTUC by utilizing the Survelliance, Epidemiolgy, and End Results (SEER) 9 database from 1998-2011. RESULTS: Of 2,572 identified cases, 113 patients (4.4%) received adjuvant radiotherapy, with a median age of 74 years (range=22-100 years). In univariate analysis, patients treated with adjuvant radiation therapy seemed to have a lower survival time than those without radiation therapy (19 months versus 31 months, p<0.05). However, after adjusting for covariates, including age at diagnosis, gender, race, year of diagnosis, stage, histological grade and surgery, radiation therapy did not seem to influence survival (hazard ratio=0.68; 95% confidence interval=0.68-1.06, p=0.85). CONCLUSION: This hypothesis-generating, population-based analysis shows that adjuvant radiotherapy may not influence survival among patients with locoregional UTUC.
Assuntos
Recidiva Local de Neoplasia/radioterapia , Radioterapia Adjuvante/métodos , Neoplasias da Bexiga Urinária/radioterapia , Urotélio/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Radioterapia Adjuvante/efeitos adversos , Neoplasias da Bexiga Urinária/epidemiologia , Neoplasias da Bexiga Urinária/patologia , Urotélio/efeitos da radiaçãoRESUMO
Urothelial defects may manifest as various types of signs of symptoms such as frequency and urgency, haematuria and pain. Both prevention and treatment of urothelial damage is fundamental. Many currently adopted treatments lack robust clinical data and are associated with variability in management strategies. Glycosoaminoglycan (GAG) therapy is one of the most promising therapies in treatment of chemotherapy and radiotherapy-induced urothelium defects, and has been investigated in both animal models and clinical studies.
Assuntos
Antineoplásicos/efeitos adversos , Cistite/tratamento farmacológico , Cistite/etiologia , Glicosaminoglicanos/uso terapêutico , Lesões por Radiação/tratamento farmacológico , Lesões por Radiação/etiologia , Humanos , Radioterapia/efeitos adversos , Urotélio/efeitos dos fármacos , Urotélio/efeitos da radiaçãoRESUMO
PURPOSE: We primarily determined whether the small animal radiation research platform could create a rat radiation cystitis model via targeted bladder irradiation (phase I). The response to treating early phase radiation cystitis in rats with transurethral catheter instillation of liposomal tacrolimus was also examined (phase II). MATERIALS AND METHODS: In phase I 16 adult female Sprague Dawley® rats were used. Metabolic urination patterns were analyzed before and after exposure to 20, 30 or 40 Gy radiation. In phase II irradiated rats were randomly assigned to receive a single instillation of saline or liposomal tacrolimus. RESULTS: The 40 Gy radiation dose induced statistically significant reductions in the intermicturition interval compared to the lower radiation doses. By approximately 20 minutes 40 Gy radiation caused a significant decrease in the mean intermicturition interval (p < 0.0001). Histological analysis revealed degenerative epithelial changes and urothelial swelling with evidence of pseudocarcinomatous epithelial hyperplasia. Therefore, 40 Gy were chosen for the phase II efficacy study. There was no measurable change in total voided urine volume after irradiation, or after liposomal tacrolimus or saline instillation. Liposomal tacrolimus significantly increased the post-irradiation intermicturition interval by approximately 30 minutes back to baseline (p < 0.001). CONCLUSIONS: The radiation cystitis rat model showed a dose dependent decrease in the intermicturition interval without inducing short-term skin or gastrointestinal damage. This study demonstrates that liposomal tacrolimus may be a promising new intravesical therapy for the rare, serious condition of radiation cystitis.
Assuntos
Cistite/prevenção & controle , Lesões Experimentais por Radiação/prevenção & controle , Tacrolimo/administração & dosagem , Bexiga Urinária/efeitos da radiação , Administração Intravesical , Animais , Cistite/etiologia , Cistite/patologia , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Feminino , Imunossupressores/administração & dosagem , Instilação de Medicamentos , Neoplasias Experimentais/radioterapia , Neoplasias Pélvicas/radioterapia , Substâncias Protetoras , Lesões Experimentais por Radiação/complicações , Lesões Experimentais por Radiação/patologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Bexiga Urinária/patologia , Urotélio/patologia , Urotélio/efeitos da radiaçãoRESUMO
The management of patients with cystitis-related symptoms due to urinary tract infection, bladder pain syndrome (BPS) or radio/chemo-induced cystitis remains challenging. A component in the pathophysiology of these symptoms relates to the fact that the urothelium is a highly metabolically active structure and that alterations in this structure can give rise to a variety of symptoms.
Assuntos
Cistite/etiologia , Cistite/terapia , Antineoplásicos/efeitos adversos , Humanos , Lesões por Radiação/etiologia , Lesões por Radiação/terapia , Radioterapia/efeitos adversos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/efeitos da radiação , Urotélio/efeitos dos fármacos , Urotélio/efeitos da radiaçãoRESUMO
The differentiation of urothelial cells results in normal terminally differentiated cells or by alternative pathways in low-grade or high-grade urothelial carcinomas. Treatments with traditional surgical and chemotherapeutical approaches are still inadequate and expensive, as bladder tumours are generally highly recurrent. In such situations, alternative approaches, using irradiation of the cells and nanoparticles, are promising. The ways in which urothelial cells, at different differentiation levels, respond to UV-irradiation (photolytic treatment) or to the combination of UV-irradiation and nanoparticles (photocatalytic treatment), are unknown. Here we tested cytotoxicity of UV-irradiation on (i) normal porcine urothelial cells (NPU), (ii) human low-grade urothelial cancer cells (RT4), and (iii) human high-grade urothelial cancer cells (T24). The results have shown that 1 minute of UV-irradiation is enough to kill 90% of the cells in NPU and RT4 cultures, as determined by the live/dead viability assay. On the other hand, the majority of T24 cells survived 1 minute of UV-irradiation. Moreover, even a prolonged UV-irradiation for 30 minutes killed <50% of T24 cells. When T24 cells were pre-supplemented with mesoporous TiO2 microbeads and then UV-irradiated, the viability of these high-grade urothelial cancer cells was reduced to <10%, which points to the highly efficient cytotoxic effects of TiO2 photocatalysis. Using electron microscopy, we confirmed that the mesoporous TiO2 microbeads were internalized into T24 cells, and that the cell's ultrastructure was heavily compromised after UV-irradiation. In conclusion, our results show major differences in the sensitivity to UV-irradiation among the urothelial cells with respect to cell differentiation. To achieve an increased cytotoxicity of urothelial cancer cells, the photocatalytic approach is recommended.
Assuntos
Microesferas , Titânio/química , Titânio/farmacologia , Raios Ultravioleta , Neoplasias Urológicas/patologia , Urotélio/efeitos dos fármacos , Urotélio/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Humanos , Gradação de Tumores , Urotélio/patologiaRESUMO
INTRODUCTION: The incidence, treatment, and outcome of urethral recurrence (UR) after radical cystectomy (RC) for muscle-invasive bladder cancer with orthotopic neobladder in women have rarely been addressed in the literature. PATIENTS AND METHODS: A total of 12 patients (median age at recurrence: 60 years) who experienced UR after RC with an orthotopic neobladder were selected for this study from a cohort of 456 women from participating institutions. The primary clinical and pathological characteristics at RC, including the manifestation of the UR and its treatment and outcome, were reviewed. RESULTS: The primary bladder tumors in the 12 patients were urothelial carcinoma in 8 patients, squamous cell carcinoma and adenocarcinoma in 1 patient each, and mixed histology in 2 patients. Three patients (25%) had lymph node-positive disease at RC. The median time from RC to the detection of UR was 8 months (range 4-55). Eight recurrences manifested with clinical symptoms and 4 were detected during follow-up or during a diagnostic work-up for clinical symptoms caused by distant metastases. Treatment modalities were surgery, chemotherapy, radiotherapy, and bacillus Calmette-Guérin urethral instillations. Nine patients died of cancer. The median survival after the diagnosis of UR was 6 months. CONCLUSIONS: UR after RC with an orthotopic neobladder in females is rare. Solitary, noninvasive recurrences have a favorable prognosis when detected early. Invasive recurrences are often associated with local and distant metastases and have a poor prognosis.
Assuntos
Adenocarcinoma/cirurgia , Carcinoma de Células Escamosas/cirurgia , Cistectomia/métodos , Recidiva Local de Neoplasia , Estruturas Criadas Cirurgicamente , Neoplasias da Bexiga Urinária/cirurgia , Bexiga Urinária/cirurgia , Urotélio/patologia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Europa (Continente) , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Invasividade Neoplásica , Reoperação , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , Urotélio/efeitos dos fármacos , Urotélio/efeitos da radiação , Urotélio/cirurgiaRESUMO
We review the morphology and differential diagnoses of pseudocarcinomatous hyperplasia of the bladder, using a study case to illustrate the discussion. Pseudocarcinomatous hyperplasia is a rare, reactive response to an ischemic insult, classically to radiation therapy, and consists of proliferative, pseudoinfiltrative urothelial nests within the stroma. The presence of background radiation therapy-related changes, such as numerous dilated thrombosed vessels, reactive-appearing endothelial and stromal cells, edema, and hemorrhage, can provide clues to the diagnosis. The main differential diagnoses include invasive urothelial carcinoma and the nested variant of urothelial carcinoma; morphologic features, such as the presence or absence of background therapy-related changes and the architecture and the cytologic atypia of the nests, can help distinguish between pseudocarcinomatous hyperplasia and urothelial carcinoma.
Assuntos
Cistite/diagnóstico , Lesões por Radiação/diagnóstico , Bexiga Urinária/patologia , Adenocarcinoma/complicações , Adenocarcinoma/radioterapia , Carcinoma/diagnóstico , Carcinoma/patologia , Carcinoma/fisiopatologia , Cistite/etiologia , Cistite/imunologia , Cistite/fisiopatologia , Diagnóstico Diferencial , Hematúria/etiologia , Humanos , Hiperplasia , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/complicações , Neoplasias da Próstata/radioterapia , Lesões por Radiação/etiologia , Lesões por Radiação/fisiopatologia , Bexiga Urinária/imunologia , Bexiga Urinária/efeitos da radiação , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/fisiopatologia , Urotélio/imunologia , Urotélio/patologia , Urotélio/efeitos da radiaçãoRESUMO
PURPOSE: Technological developments provide a lot of conveniences to our lives. This issue is one of the risks that arise along with these conveniences. In our study we tried to understand the impact of electromagnetic waves from mobile phones on bladder tissue. MATERIALS AND METHODS: Twenty-one adult male albino rats were divided into three equal groups. Group 1 was exposed to electromagnetic wave for 8 hours per day for 20 days and then their bladders were taken off immediately. Group 2 was firstly exposed to electromagnetic wave for 8 hours per day for 20 days then secondly another for 20 days without exposition to electromagnetic wave and then their bladders were taken off. Group 3 was the control group and they were not exposed to electromagnetic wave. RESULTS: Under microscopic examination of bladder tissue, in the first group severe inflammatory cell infiltration was seen in lamina propria and muscle layer in contrast to intact urothelium. In the second group mild inflammatory cell infiltration was seen in lamina propria and muscle layer. The mean scores for the three groups were 5.5 ± 2.5, 0.8 ± 1.3 and 1.2 ± 1.5 respectively. Mean score of group 1 was statistically higher than others (p = 0.001). CONCLUSION: Intensive use of mobile phones has negative impact on bladder tissue as well as the other organs. Keeping a minimum level of mobile phone use makes it easy to be kept under control of diseases in which inflammation is an etiologic factor.
Assuntos
Telefone Celular , Cistite/etiologia , Radiação Eletromagnética , Doenças da Bexiga Urinária/etiologia , Animais , Masculino , Microscopia Eletrônica de Transmissão , Lesões Experimentais por Radiação/etiologia , Ratos Wistar , Fatores de Tempo , Bexiga Urinária/efeitos da radiação , Urotélio/efeitos da radiaçãoRESUMO
Purpose Technological developments provide a lot of conveniences to our lives. This issue is one of the risks that arise along with these conveniences. In our study we tried to understand the impact of electromagnetic waves from mobile phones on bladder tissue. Materials and Methods Twenty-one adult male albino rats were divided into three equal groups. Group 1 was exposed to electromagnetic wave for 8 hours per day for 20 days and then their bladders were taken off immediately. Group 2 was firstly exposed to electromagnetic wave for 8 hours per day for 20 days then secondly another for 20 days without exposition to electromagnetic wave and then their bladders were taken off. Group 3 was the control group and they were not exposed to electromagnetic wave. Results Under microscopic examination of bladder tissue, in the first group severe inflammatory cell infiltration was seen in lamina propria and muscle layer in contrast to intact urothelium. In the second group mild inflammatory cell infiltration was seen in lamina propria and muscle layer. The mean scores for the three groups were 5.5 ± 2.5, 0.8 ± 1.3 and 1.2 ± 1.5 respectively. Mean score of group 1 was statistically higher than others (p = 0.001). Conclusion Intensive use of mobile phones has negative impact on bladder tissue as well as the other organs. Keeping a minimum level of mobile phone use makes it easy to be kept under control of diseases in which inflammation is an etiologic factor. .
Assuntos
Animais , Masculino , Telefone Celular , Cistite/etiologia , Radiação Eletromagnética , Doenças da Bexiga Urinária/etiologia , Microscopia Eletrônica de Transmissão , Ratos Wistar , Lesões Experimentais por Radiação/etiologia , Fatores de Tempo , Bexiga Urinária/efeitos da radiação , Urotélio/efeitos da radiaçãoRESUMO
Irradiation of rats with γ-quanta at relatively low doses induces a sustainable dose-independent increase in the occurrence of lethal cytoplasmic disorders in the renal tubules epithelium together with sustainable and as well dose-independent subcelluar compensation and restorative processes. Over the period of research (6 months) these processes led to no population recovery. The detected alterations are referred to the category of non-targeted non-mutagenic effects and they are of interest because they address the issue of the sensitivity of low renewable tissues to radiation.
Assuntos
Estruturas Citoplasmáticas/efeitos da radiação , Raios gama/efeitos adversos , Túbulos Renais Proximais/efeitos da radiação , Regeneração/efeitos da radiação , Urotélio/efeitos da radiação , Adaptação Fisiológica/efeitos da radiação , Animais , Relação Dose-Resposta à Radiação , Túbulos Renais Proximais/fisiologia , Túbulos Renais Proximais/ultraestrutura , Doses de Radiação , Ratos , Fatores de Tempo , Urotélio/fisiologia , Urotélio/ultraestruturaRESUMO
INTRODUCTION: Advanced urothelial carcinoma is associated with a poor prognosis. In the metastatic setting, the response rate to first-line, cisplatin-containing chemotherapy is high, but survival is poor. Second-line treatment options are limited. Advanced age at diagnosis and the presence of comorbidities often preclude treatment with cisplatin-containing regimens. AREAS COVERED: This review addresses the current therapy of urothelial carcinoma, the unmet needs in treatment and the status of drug development in this disease. The molecular targets identified and efforts to incorporate targeted agents into therapy will be addressed. EXPERT OPINION: There have been no major advances in the treatment of urothelial carcinoma in three decades. Despite high response rates in the first-line setting, survival is limited. Major impediments to improved outcomes include poor durability of response to first-line chemotherapy and lack of second-line treatments. Better understanding in tumor biology has identified multiple targets in urothelial carcinoma; however, such discoveries have yet to lead to the incorporation of targeted agents into the routine treatment of urothelial carcinoma. Multiple ongoing clinical trials are investigating the use of targeted agents in urothelial carcinoma. Continued efforts are underway to better understand the molecular drivers of disease and such efforts are likely to identify additional therapeutic targets.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Urotélio/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Carcinoma/patologia , Carcinoma/radioterapia , Carcinoma/cirurgia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Descoberta de Drogas , Humanos , Terapia de Alvo Molecular , Terapia Neoadjuvante , Invasividade Neoplásica , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/radioterapia , Neoplasias da Bexiga Urinária/cirurgia , Urotélio/patologia , Urotélio/efeitos da radiação , Urotélio/cirurgiaRESUMO
Human DNA polymerase iota (pol ι) possesses high error-prone DNA replication features and performs translesion DNA synthesis. It may be specialized and strictly regulated in normal mammalian cells. Dysregulation of pol ι may contribute to the acquisition of a mutator phenotype. However, there are few reports describing the transcription regulatory mechanism of pol ι, and there is controversy regarding its role in carcinogenesis. In this study, we performed the deletion and point-mutation experiment, EMSA, ChIP, RNA interference and western blot assay to prove that c-Jun activated by c-Jun N-terminal kinase (JNK) regulates the transcription of pol ι in normal and cancer cells. Xeroderma pigmentosum group C protein (XPC) and ataxia-telangiectasia mutated related protein (ATR) promote early JNK activation in response to DNA damage and consequently enhance the expression of pol ι, indicating that the novel role of JNK signal pathway is involved in DNA damage response. Furthermore, associated with elevated c-Jun activity, the overexpression of pol ι is positively correlated with the clinical tumor grade in 97 bladder cancer samples and may contribute to the hypermutagenesis. The overexpressed pol ι-involved mutagenesis is dependent on JNK/c-Jun pathway in bladder cancer cells identifying by the special mutation spectra. Our results support the conclusion that dysregulation of pol ι by JNK/c-Jun is involved in carcinogenesis and offer a novel understanding of the role of pol ι or c-Jun in mutagenesis.
Assuntos
DNA Polimerase Dirigida por DNA/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Mutagênese/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Neoplasias da Bexiga Urinária/enzimologia , Neoplasias da Bexiga Urinária/genética , Proteínas Mutadas de Ataxia Telangiectasia , Sequência de Bases , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , DNA Polimerase Dirigida por DNA/genética , Ativação Enzimática , Células HEK293 , Humanos , Dados de Sequência Molecular , Taxa de Mutação , Regiões Promotoras Genéticas/genética , Raios Ultravioleta , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia , Urotélio/efeitos da radiação , DNA Polimerase iotaRESUMO
Radiotherapy is often used to treat prostate tumors, but the normal bladder is usually adversely affected. Using an animal model of pelvic radiation, we investigated whether glutamine nutritional supplementation can prevent radiation-induced damage to the bladder, especially in its more superficial layers. Male rats aged 3-4 months were divided into groups of 8 animals each: controls, which consisted intact animals; radiated-only rats, which were sacrificed 7 (R7) or 15 (R15) days after a radiation session (10Gy aimed at the pelvico-abdominal region); and radiated rats receiving l-glutamine supplementation (0.65g/kg body weight/day), which were sacrificed 7 (RG7) or 15 (RG15) days after the radiation session. Cells and blood vessels in the vesical lamina propria, as well as the urothelium, were then measured using histological methods. The effects of radiation were evaluated by comparing controls vs. either R7 or R15, while a protective effect of glutamine was assessed by comparing R7 vs. RG7 and R15 vs. RG15. The results showed that, in R7, epithelial thickness, epithelial cell density, and cell density in the lamina propria were not significantly affected. However, density of blood vessels in R7 was reduced by 48% (p<0.05) and this alteration was mostly prevented by glutamine (p<0.02). In R15, density of blood vessels in the lamina propria was not significantly modified. However, epithelial thickness was reduced by 25% (p<0.05) in R15, and this effect was prevented by glutamine (p<0.01). In R15, epithelial cell density was increased by 35% (p<0.02), but glutamine did not protect against this radiation-induced increase. Cell density in the lamina propria was likewise unaffected in R15. Density of mast cells in the lamina propria was markedly reduced in R7 and R15. The density was still reduced in RG7, but a higher density in RG15 suggested a glutamine-mediated recovery. Alpha-actin positive cells in the lamina propria formed a suburothelial layer and were identified as myofibroblasts. Thickness of this layer was increased in R7, but was similar to controls in RG7, while changes in R15 and RG15 were less evident. In conclusion, pelvic radiation leads to significant acute and post-acute alterations in the composition and structural features of the vesical lamina propria and epithelium. Most of these changes, however, can be prevented by glutamine nutritional supplementation. These results emphasize, therefore, the potential use of this aminoacid as a radioprotective drug.