RESUMEN
CD200 is a widely distributed membrane protein that gives inhibitory signals through its receptor (CD200R) on myeloid cells. CD200 has been acquired by herpesviruses where it has been shown to interact with host CD200R and downmodulate the immune system. It has been hypothesized that poxviruses have acquired CD200; but the potential orthologues show less similarity to their hosts. Myxoma virus M141 protein is a potential CD200 orthologue with a potent immune modulatory function in rabbits. Here, we characterized the rabbit CD200, CD200R and tested the CD200-like sequences for binding CD200R. No binding could be detected using soluble recombinant proteins, full length protein expressed on cells or myxoma virus infected cells. Finally, using knockdown models, we showed that the inhibitory effect of M141 on RAW 264.7 cells upon myxoma virus infection is not due to CD200R. We conclude that the rabbit poxvirus CD200-like proteins cause immunomodulation without utilizing CD200R.
Asunto(s)
Antígenos CD/metabolismo , Myxoma virus/fisiología , Receptores de Superficie Celular/metabolismo , Proteínas Virales/metabolismo , Animales , Línea Celular , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Datos de Secuencia Molecular , Unión Proteica , Conejos , Análisis de Secuencia de ADN , Homología de Secuencia de AminoácidoRESUMEN
INTRODUCTION: Although interstitial cystitis is an inflammatory disease, its etiopathogenesis is not clearly understood. The objective of the present study is to investigate the distribution of TNF-related apoptosis-inducing ligand (TRAIL) and its receptors in bladder biopsy samples of patients diagnosed with interstitial cystitis and the role of TRAIL in the pathogenesis of interstitial cystitis. MATERIALS AND METHODS: TRAIL and its receptors were stained immunohistochemically in bladder biopsy samples of 27 patients diagnosed with interstitial cystitis, and the samples were evaluated independently by two pathologists and were scored in terms of expression intensity and distribution. RESULTS: An evaluation of the results of the statistical analysis showed that the TRAIL-R4 receptor was immunohistochemically stained with a higher score than TRAIL-R1, TRAIL-R2, TRAIL-R3 receptors and TRAIL, with a statistically significant difference (P < 0.05). CONCLUSION: These findings indicate that TRAIL-R4 is the predominant receptor in the interstitial cystitis inflammation.
Asunto(s)
Cistitis Intersticial/etiología , Ligando Inductor de Apoptosis Relacionado con TNF/fisiología , Biopsia , Cistitis Intersticial/patología , Humanos , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/análisis , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/fisiología , Ligando Inductor de Apoptosis Relacionado con TNF/análisis , Vejiga Urinaria/química , Vejiga Urinaria/patologíaRESUMEN
PURPOSE: Expression of the type 1 insulin-like growth factor receptor (IGF1R) confers adverse prognosis in clear cell renal cell cancer (CC-RCC). We recently showed that IGF1R expression is inhibited by the von Hippel-Lindau (VHL) tumor suppressor, and the IGF1R is up-regulated in CC-RCC, in which VHL is frequently inactivated. We tested the hypothesis that IGF1R up-regulation mediates resistance to cancer therapeutics, evaluating the effects of IGF1R depletion on sensitivity to cytotoxic drugs, which are ineffective in RCC, and the mammalian target of rapamycin (mTOR) inhibitor rapamycin, analogues of which have clinical activity in this tumor. EXPERIMENTAL DESIGN: This study used CC-RCC cells harboring mutant VHL, and isogenic cells expressing functional VHL. Cells were transfected with nonsilencing control small interfering RNA (siRNA), or with one of two different IGF1R siRNAs. The more potent siRNA was modified by 2'-O-methyl derivatization for in vivo administration. RESULTS: CC-RCC cells expressing mutant VHL and higher IGF1R were more chemoresistant than cells expressing functional VHL. IGF1R depletion induced apoptosis, blocked cell survival, and sensitized to 5-fluorouracil and etoposide. These effects were significantly greater in CC-RCC cells expressing mutant VHL, supporting the hypothesis that IGF1R up-regulation makes a major contribution to the chemoresistance associated with VHL loss. IGF1R depletion also enhanced sensitivity to mTOR inhibition, at least in part due to suppression of rapamycin-induced Akt activation. Administration of stabilized IGF1R siRNA was shown to sensitize CC-RCC xenografts to rapamycin in vivo. CONCLUSION: These data validate IGF1R as a therapeutic target in CC-RCC, and support the evaluation of IGF1R-inhibitory drugs in patients with renal cancer.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Receptor IGF Tipo 1/metabolismo , Animales , Apoptosis/efectos de los fármacos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Relación Dosis-Respuesta a Droga , Etopósido/farmacología , Femenino , Fluorouracilo/farmacología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Immunoblotting , Neoplasias Renales/genética , Neoplasias Renales/patología , Ratones , Ratones Endogámicos BALB C , Ratones SCID , ARN Interferente Pequeño/genética , Receptor IGF Tipo 1/genética , Sirolimus/farmacología , Transfección , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVES: To investigate whether the urine of interstitial cystitis (IC) patients has a toxic effect on the bladder wall, as determined by mast cell infiltration, and to evaluate the preventive effect of tibial nerve electric stimulation (TNES) on bladder mastocytosis induced by IC urine. MATERIAL AND METHODS: The bladders of female rats were catheterized and instilled with IC urine (Group IC; n=10) and normal urine (Group NU; n=5) obtained from humans, saline (Group S; n=5) and protamine sulphate (Group PS; n=10) for 6 weeks. Additionally, in five rats instilled with IC urine and five instilled with PS, TNES was also performed (Groups IC + TNES and PS + TNES). RESULTS: In the lamina propria of the bladder, the mean number of mast cells per square millimetre was significantly higher in Groups IC (32.5+/-12.3) and PS (39.4+/-11.1) than in Groups S (11.9+/-4.3) and NU (13.7+/-3.5). After TNES, the corresponding values were decreased significantly to 15.3+/-5.4 and 15.3+/-4.1 in Groups IC + TNES and PS + TNES, respectively (p<0.001). A significant reduction in mast cell infiltration in the detrusor was also determined after TNES compared with the value in Group IC (4.6+/-1.6 vs 12.1+/-3.0; p<0.001). CONCLUSIONS: We demonstrated that IC urine may result in increased mast cell infiltration in the bladder wall. TNES may play a therapeutic role by diminishing the mast cell count in the bladder wall, which has a strong relationship with nociceptive neural endings.
Asunto(s)
Cistitis Intersticial/patología , Estimulación Eléctrica , Mastocitos/fisiología , Nervio Tibial , Vejiga Urinaria/patología , Animales , Femenino , Humanos , Ratas , Ratas Wistar , OrinaRESUMEN
PURPOSE: Traditional treatment of dysfunctional voiding in children with urinary retention involves retraining the pelvic floor muscles using biofeedback. Alpha-blockers are reported to also be effective in children with urinary retention and dysfunctional voiding. We compared the efficacy of biofeedback and alpha-blockers for dysfunctional voiding and urinary retention in terms of residual urine volume and urge incontinence episodes, mean flow rates and urinary tract infections. MATERIALS AND METHODS: A total of 28 patients with a mean age of 6.25 years (range 4 to 10) presented with symptoms of urinary incontinence, urgency and urinary tract infections without anatomic and neurogenic causes of urinary retention. All patients had increased post-void residual (PVR) urine volume (mean 59 ml, 32% of age expected capacity [AEC]). The biofeedback group consisted of 16 children (mean age 6.5 years) and the alpha-blocker group consisted of 12 children (mean age 5.9 years). Both groups were also on continued timed voiding, constipation treatment and anticholinergics, which had been used for at least the last 6 months. Biofeedback (median 10, range 6 to 16 sessions) and doxazosin (0.5 to 2 mg) were administered. At 3 and 6 months incontinence episodes, urinary tract infections, mean urinary flow rates, PVR and parental satisfaction grades (1 to 10) were reevaluated. Six refractory cases were started on alpha-blockers and biofeedback, and reevaluated after 1 month and 3 months. RESULTS: Pretreatment mean PVR was 54 ml (30% of AEC), and mean posttreatment PVR was 21 ml (12% of AEC) and 9 ml (5% of AEC) at 3 and 6 months in the biofeedback group (p <0.05). Pretreatment mean PVR was 64 ml (38% of AEC), and posttreatment mean PVR was 17 ml (12% of AEC) and 13 ml (8% of AEC) at 3 and 6 months in the alpha-blocker group (p <0.05). There was no statistical difference in posttreatment PVR between the 2 groups (p >0.05). High PVR persisted in 4 (25%) biofeedback cases and in 2 (16%) alpha-blocker cases. Complete improvement in urge incontinence episodes occurred in 10 (62.5%) and 7 (70%) children in the biofeedback and alpha-blocker groups, respectively. In therapy responsive children parental satisfaction was higher with alpha-blocker than with biofeedback (9.2 vs 7.9, p <0.05). Refractory high PVR decreased significantly after combination treatment with biofeedback and alpha-blocker in 5 of 6 children (mean 80 ml, 35% of AEC vs mean 15 ml, 7% of AEC). No drug related side effect was reported in the alpha-blocker group. CONCLUSIONS: Alpha-blocker therapy seems to be a viable alternative to biofeedback in dysfunctional voiding in children with urinary retention to improve bladder emptying. Combination treatment (biofeedback and alpha-blockers) can be used as additional therapy in refractory cases.
Asunto(s)
Antagonistas Adrenérgicos alfa/uso terapéutico , Biorretroalimentación Psicológica , Doxazosina/uso terapéutico , Retención Urinaria/tratamiento farmacológico , Retención Urinaria/terapia , Trastornos Urinarios/tratamiento farmacológico , Trastornos Urinarios/terapia , Niño , Preescolar , Femenino , Humanos , Masculino , Resultado del TratamientoRESUMEN
OBJECTIVES: To assess the clinical efficacy of tolterodine prescribed to children with non-neurogenic daytime urinary incontinence secondary to overactive bladder who had previously failed to improve with oral oxybutynin treatment and its relation to the side-effect profile and compliance status. METHODS: We evaluated 92 children presenting with daytime wetting, with or without nocturnal enuresis, who were receiving oral oxybutynin treatment. Children with chronic urinary tract infections, a neurologic lesion, an anatomic abnormality of lower urinary tract, voiding abnormality, and less than 1 year of oxybutynin treatment were excluded. Of the remaining 41 children (mean age 7.2 years, range 5 to 14 years), 30 agreed to switch to tolterodine and 11 continued receiving oxybutynin. Anticholinergic side effects, compliance, and clinical efficacy were assessed in the follow-up. RESULTS: Of the 30 patients who switched to tolterodine, a complete response was in 18 patients (60%), partial improvement in 11 (37%), and no improvement in 1 (3%) after a mean of 14.4 months (range 12 to 16 months) of oxybutynin treatment. The anticholinergic side-effect score was 7.2, 9.3, and 11, respectively, for those with a complete response, partial improvement, and no improvement in the compliant group. The noncompliant group had the greatest side-effect score (16.9). The fairly compliant group had a side-effect score of 12.3. After a mean of 7.1 months (range 6 to 9 months) of tolterodine use, a complete response was reported in 24 patients and partial improvement in 5 (17%). In 1 patient, treatment failed completely. However, his side-effect score decreased from 11 to 2. All tolterodine users were compliant with treatment. CONCLUSIONS: The results of this study in children with non-neurogenic daytime urinary incontinence have shown that tolterodine may increase the efficacy of pharmacotherapy, particularly in patients noncompliant to oxybutynin. Additional investigation of the anticholinergic side-effect scores and compliance tables is required to improve the clinical results of pharmacotherapy in incontinence due to overactive bladder in children.