RESUMEN
Enhanced afferent excitability is considered to be an important pathophysiological basis of interstitial cystitis/bladder pain syndrome (IC/BPS). In addition, transient receptor potential vanilloid-1 (TRPV1) receptors are known to be involved in afferent sensitization. Animals with hydrogen peroxide (HP)-induced cystitis have been used as a model exhibiting pathologic characteristics of chronic inflammatory condition of the bladder. This study investigated the effect of gene therapy with replication-defective herpes simplex virus (HSV) vectors encoding poreless TRPV1 (PL) or protein phosphatase 1 α (PP1α), a negative regulator of TRPV1, using a HP-induced rat model of cystitis. HSV vectors encoding green fluorescent protein, PL or PP1α were inoculated into the bladder wall of female rats. After 1 week, 1% HP or normal saline was administered into the bladder, and the evaluations were performed 2 weeks after viral inoculation. In HP-induced cystitis rats, gene delivery of PL or PP1α decreased pain behavior as well as a reduction in the intercontraction interval. Also, both treatments reduced nerve growth factor expression in the bladder mucosa, reduced bladder inflammation characterized by infiltration of inflammatory cells and increased bladder weight. Taken together, HSV-mediated gene therapy targeting TRPV1 receptors could be effective for the treatment of IC/BPS.
Asunto(s)
Cistitis/inducido químicamente , Cistitis/terapia , Terapia Genética/métodos , Vectores Genéticos , Peróxido de Hidrógeno/toxicidad , Proteína Fosfatasa 1/genética , Simplexvirus/genética , Canales Catiónicos TRPV/genética , Animales , Cistitis/enzimología , Cistitis/metabolismo , Virus Defectuosos/genética , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Proteínas Fluorescentes Verdes/genética , Tamaño de los Órganos , Ratas , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Eribulin mesilate (eribulin), a non-taxane microtubule dynamics inhibitor, has shown trends towards greater overall survival (OS) compared with progression-free survival in late-stage metastatic breast cancer patients in the clinic. This finding suggests that eribulin may have additional, previously unrecognised antitumour mechanisms beyond its established antimitotic activity. To investigate this possibility, eribulin's effects on the balance between epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) in human breast cancer cells were investigated. METHODS: Triple negative breast cancer (TNBC) cells, which are oestrogen receptor (ER-)/progesterone receptor (PR-)/human epithelial growth receptor 2 (HER2-) and have a mesenchymal phenotype, were treated with eribulin for 7 days, followed by measurement of EMT-related gene and protein expression changes in the surviving cells by quantitative real-time PCR (qPCR) and immunoblot, respectively. In addition, proliferation, migration, and invasion assays were also conducted in eribulin-treated cells. To investigate the effects of eribulin on TGF-ß/Smad signalling, the phosphorylation status of Smad proteins was analysed. In vivo, the EMT/MET status of TNBC xenografts in mice treated with eribulin was examined by qPCR, immunoblot, and immunohistochemical analysis. Finally, an experimental lung metastasis model was utilised to gauge the metastatic activity of eribulin-treated TNBC in the in vivo setting. RESULTS: Treatment of TNBC cells with eribulin in vitro led to morphological changes consistent with transition from a mesenchymal to an epithelial phenotype. Expression analyses of EMT markers showed that eribulin treatment led to decreased expression of several mesenchymal marker genes, together with increased expression of several epithelial markers. In the TGF-ß induced EMT model, eribulin treatment reversed EMT, coincident with inhibition of Smad2 and Smad3 phosphorylation. Consistent with these changes, TNBC cells treated with eribulin for 7 days showed decreased capacity for in vitro migration and invasiveness. In in vivo xenograft models, eribulin treatment reversed EMT and induced MET as assessed by qPCR, immunoblot, and immunohistochemical analyses of epithelial and mesenchymal marker proteins. Finally, surviving TNBC cells pretreated in vitro with eribulin for 7 days led to decreased numbers of lung metastasis when assessed in an in vivo experimental metastasis model. CONCLUSIONS: Eribulin exerted significant effects on EMT/MET-related pathway components in human breast cancer cells in vitro and in vivo, consistent with a phenotypic switch from mesenchymal to epithelial states, and corresponding to observed decreases in migration and invasiveness in vitro as well as experimental metastasis in vivo. These preclinical findings may provide a plausible scientific basis for clinical observations of prolonged OS by suppression of further spread of metastasis in breast cancer patients treated with eribulin.
Asunto(s)
Transición Epitelial-Mesenquimal/efectos de los fármacos , Furanos/farmacología , Cetonas/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia sin Enfermedad , Femenino , Expresión Génica , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Ratones , Ratones Desnudos , Metástasis de la Neoplasia , Fenotipo , Neoplasias de la Mama Triple Negativas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We investigated the effects of replication-defective herpes simplex virus (HSV) vector expression of interleukin-4 (IL-4) on bladder overactivity and nociception. HSV vector expressing murine interleukin-4 (S4IL4) or the control vector expressing ß-galactosidase (SHZ) were injected to the rat bladder wall. At 1 week after viral injection, in cystometry performed under urethane anesthesia, the S4IL4-treated group did not show the intercontraction intervals reduction during intravesical administration of 10 nM resiniferatoxin (RTx). At 2 weeks after viral injection, behavioral studies were performed on vector-injected animals in an awakened state. Freezing behavior induced by 3 µM RTx, administered for 1 min into the bladder, was significantly suppressed in the S4IL4 group compared with the SHZ group. Murine IL-4 levels examined by ELISA were significantly increased in bladder and bladder afferent dorsal root ganglia at 2 weeks after viral injection. The expression of IL-1ß and IL-2 and bladder inflammatory responses were significantly suppressed in the RTx-irritated bladder of S4IL4-injected rats. These results indicate that HSV vector-mediated interleukin-4 expression in the bladder and bladder afferent pathways reduces the inflammatory response, bladder overactivity and nociceptive behavior induced by bladder irritation in the rat model. Therefore, IL-4 gene therapy could be a new strategy for treating urinary frequency and/or bladder pain.
Asunto(s)
Terapia Genética , Interleucina-4/genética , Nocicepción , Simplexvirus/genética , Vejiga Urinaria Hiperactiva/terapia , Animales , Diterpenos/farmacología , Femenino , Reacción Cataléptica de Congelación , Ganglios Espinales/metabolismo , Expresión Génica , Vectores Genéticos , Inflamación/terapia , Interleucina-4/metabolismo , Ratas , Ratas Sprague-Dawley , Vejiga Urinaria/metabolismo , Vejiga Urinaria/patología , Vejiga Urinaria Hiperactiva/fisiopatologíaRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Renal impairment is unavoidable after laparoscopic radical nephrectomy (LRN) and is an important consideration for drug therapy. It is possible that the renal impairment after LRN causes adverse reactions following reduced elimination of some renally excreted drugs, such as hypoglycaemic drugs. However, there are few studies of renal function in patients with diabetes mellitus (DM) in the first week after LRN. The purpose of this study was to examine whether renal impairment after LRN affected glycaemic control. We assessed pre- and postoperative renal function of DM patients and examined whether re-administration of hypoglycaemic drugs in the first week after LRN causes episodes of hypoglycaemia. METHODS: Renal carcinoma patients undergoing LRN in Nagoya University Hospital from January 2007 to December 2009 were identified in a retrospective cohort study design. Patients were divided into non-DM (n = 60) and DM (n = 14) groups. RESULTS AND DISCUSSION: There were significant differences in postoperative estimated glomerular filtration rate values between the non-DM and DM groups. Four of nine patients (44%) experienced hypoglycaemia induced by re-administration of hypoglycaemic drugs, namely, sulfonylureas. WHAT IS NEW AND CONCLUSION: In the present study, we found the first evidence that renal impairment in the first week after LRN was a risk factor of hypoglycaemia. To prevent hypoglycaemia after LRN, assessment of renal function and the use of insulin therapy are important.
Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Hipoglucemia/etiología , Hipoglucemiantes/farmacología , Nefrectomía/efectos adversos , Anciano , Estudios de Cohortes , Femenino , Tasa de Filtración Glomerular , Hospitales Universitarios , Humanos , Hipoglucemiantes/farmacocinética , Neoplasias Renales/cirugía , Laparoscopía/efectos adversos , Laparoscopía/métodos , Masculino , Persona de Mediana Edad , Nefrectomía/métodos , Insuficiencia Renal/complicaciones , Estudios Retrospectivos , Factores de Riesgo , Compuestos de Sulfonilurea/farmacocinética , Compuestos de Sulfonilurea/farmacologíaRESUMEN
UNLABELLED: Three-dimensional visualization of renal arteries has recently been established by helical contrast-enhanced multiple detector-row computed tomographical angiography (MDCTA) in adults. So far, no information is available on its use in children. We reported two children with renal artery stenosis detected by 64-channel MDCTA. The first patient probably had fibromuscular dysplasia and the other neurofibromatosis type 1. The technique showed a left renal artery stenosis with a small left kidney in the first patient and a right renal artery stenosis in the second. CONCLUSION: MDCTA is an accurate and noninvasive imaging technique, easily performed in children, and can be used as an alternative diagnostic modality in children with suspected renovascular hypertension.
Asunto(s)
Imagenología Tridimensional , Obstrucción de la Arteria Renal/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Niño , Preescolar , Humanos , Hipertensión Renovascular/diagnóstico por imagen , Masculino , Síndromes Mielodisplásicos/complicaciones , Neurofibromatosis 1/complicaciones , Arteria Renal/diagnóstico por imagen , Obstrucción de la Arteria Renal/etiologíaRESUMEN
It is known that administration of mycophenolate mofetile (MMF) is associated with BK virus (BKV) nephropathy in renal transplant recipients. To determine any inhibitory effect of mizoribine for BKV, seven patients with positive BKV in their urine who took MMF as immunosuppressive therapy were evaluated after MMF was changed to mizoribine. Baseline BKV DNA in urine, which ranged from 2.2 x 10(2) to 5.5 x 10(6) copies per milliliter, decreased in all cases (mean = 1.9 x 10(-1) times; median 2.8 x 10(-3) times). Four cases turned negative within 6 months and one within 12 months. No acute rejection or deterioration of graft function occurred during the administration of mizoribine. An inhibitory effect of mizoribine on BKV was suggested.
Asunto(s)
Virus BK , ADN Viral/orina , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Ácido Micofenólico/análogos & derivados , Infecciones por Polyomavirus/diagnóstico , Ribonucleósidos/uso terapéutico , Adulto , Quimioterapia Combinada , Humanos , Trasplante de Riñón/efectos adversos , Persona de Mediana Edad , Ácido Micofenólico/efectos adversosRESUMEN
BACKGROUND: Calcineurin-inhibitor-induced pain syndrome (CIPS) was used as a reference in the literature as reflex sympathetic dystrophy syndrome related to calcineurin inhibitors. Much of the literature describes CIPS that occurred after kidney and bone marrow transplantation. We describe a rare case of CIPS in induction immunosuppression before kidney transplantation, under administration of an anti-rheumatoid drug. METHODS: A 53-year-old woman had pre-status of ABO-incompatible living kidney transplantation. The patient had rheumatoid arthritis, but that was well-controlled with salazosulfapyridine as an anti-rheumatoid drug. Fourteen days before transplantation, she received induction immunosuppressive therapy consisting of tacrolimus (TAC) and mycophenolate mofetil (MMF) and she stopped taking salazosulfapyridine. The third day after that treatment, she had a high fever, fatigue, and joint pains of the knees, elbows, and wrists. RESULTS: When the patient stopped taking TAC and MMF and started taking salazosulfapyridine again, she soon recovered. Next, we challenged same induction immunosuppression therapy with administration of salazosulfapyridine; however, the patient had the same symptom. We considered that the symptom was caused by TAC or MMF, and we did not challenge-test each drug. We found that taking only TAC caused the same symptom for the patient. Also, we challenged cyclosporine (CsA) with MMF and confirmed that she did not have the symptom. CONCLUSIONS: We decided that drugs of the induction immunosuppression therapy were CsA, MMF, prednisolone, and basiliximab. The patient received induction therapy with plasmapheresis and rituximab in addition to the above-mentioned drugs, and we performed ABO-incompatible kidney transplantation for her. The post-surgical course was good, without acute rejection, and she had no pain.
Asunto(s)
Artralgia/inducido químicamente , Inhibidores de la Calcineurina/efectos adversos , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Tacrolimus/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Basiliximab , Incompatibilidad de Grupos Sanguíneos , Ciclosporina/uso terapéutico , Femenino , Supervivencia de Injerto , Humanos , Factores Inmunológicos/uso terapéutico , Fallo Renal Crónico/complicaciones , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Plasmaféresis , Cuidados Preoperatorios , Proteínas Recombinantes de Fusión/uso terapéutico , Rituximab/uso terapéutico , Sulfasalazina/uso terapéuticoRESUMEN
The search for compounds active against solid tumors has led us to the discovery of a novel sulfonamide, E7010 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4- methoxybenzenesulfonamide), which inhibits tubulin polymerization. When administered orally, E7010 showed good antitumor activity against various rodent tumors and human tumor xenografts. In tests on mouse tumor, E7010, administered in doses of 25-100 mg/kg daily for 8 days, inhibited the growth of colon 38 carcinoma inoculated s.c. in mice by 60-99%. E7010 was active against s.c. inoculated M5076 fibrosarcoma (75% tumor growth inhibition), s.c. inoculated Lewis lung carcinoma (84% increase in life span), and i.p. inoculated P388 leukemia (118% increase in life span). In a test on rat tumor, E7010 inhibited the growth of SST-2 mammary carcinoma inoculated s.c. in rats by 84%. In tests on s.c. inoculated human tumor xenografts, E7010, when administered orally, showed a broad spectrum of activity. E7010 inhibited the growth of: four kinds of gastric cancer, H-81, H-111, SC-2, and SC-6 by 60-78%; three kinds of colon cancer, H-143, COLO320DM, and WiDr by 58-83%; three kinds of lung cancer, LC-376, LC-6, and LX-1 by 63-82%; and two kinds of breast cancer, H-31 and MX-1 by 79-87%. In studies on drug-resistant P388 leukemia, E7010 was effective against vincristine-resistant P388, cisplatin-resistant P388, and 5-fluorouracil-resistant P388 sublines in mice. Because of its good activity against rodent tumors and human tumor xenografts, E7010 is currently undergoing Phase I clinical trials.
Asunto(s)
Aminofenoles/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , División Celular/efectos de los fármacos , Línea Celular , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Femenino , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Leucemia P388/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Ratones Desnudos , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Neoplasias/patología , Neoplasias Experimentales/patología , Ratas , Ratas Endogámicas SHR , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
BACKGROUND: Urinary decoy cells develop after renal transplantation and their appearance is attributable primarily to the proliferation of polyomavirus types BK and JC. We measured the levels of these 2 viruses that cause decoy cells to appear in the urine. PATIENTS AND METHODS: BK and JC virus levels were quantified in 1182 urine samples from 335 renal transplant patients using a multiplex Taqman real-time polymerase chain reaction assay. Forty-four samples were excluded from analyses because both viruses were present at ≥10(4) copies/mL. We analyzed the relationship between viral load and the presence of urinary decoy cells. RESULTS: Decoy cells were observed in 237 of 1138 urine samples (21%) and the BK and JC viruses were positive in 205 (18%) and 455 (40%) samples, respectively. Decoy cells were observed in 0%, 21%, 67%, 87%, 100%, and 96% of urine samples when the BK viral load was <10(4), 10(4)-10(5), 10(5)-10(6), 10(6)-10(7), 10(7)-10(8), and ≥10(8) copies/mL, respectively; and in 1%, 13%, 41%, 59%, 87%, and 97% of urine samples when the JC viral load was <10(4), 10(4)-10(5), 10(5)-10(6), 10(6)-10(7), 10(7)-10(8), and ≥10(8) copies/mL, respectively. CONCLUSIONS: BK virus more frequently triggered the appearance of decoy cells than did JC virus at equivalent viral titers.
Asunto(s)
Virus BK/aislamiento & purificación , Virus JC/aislamiento & purificación , Fallo Renal Crónico/patología , Fallo Renal Crónico/virología , Trasplante de Riñón , Infecciones por Polyomavirus/patología , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Fallo Renal Crónico/cirugía , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Urinálisis , Orina/citología , Orina/virología , Carga Viral , Adulto JovenRESUMEN
Proteases of the caspase family, especially caspase-1 (ICE)(-like), caspase-3 (CPP32/Yama/apopain)(-like) and caspase-8 (MACH/FLICE/Mch5) proteases, are implicated in Fas (APO-1/CD95)-mediated apoptosis. Here, we show that the caspase-4 (TX/ICH-2/ICE(rel)II)(-like) protease, another member of the caspase family, is also involved in Fas-mediated apoptosis, based upon the observations: (i) caspase-4 is processed in response to an agonistic anti-Fas antibody treatment, (ii) overexpression of a mutant caspase-4 with active site mutations in both p20 and p10 subunits delays Fas-mediated apoptosis, (iii) microinjected anti-caspase-4 antibodies inhibit Fas-mediated apoptosis. Together with our observations that the mutant caspase-4 inhibits the Fas-mediated activation of caspase-3(-like) proteases and purified caspase-4 cleaves pro-caspase-3 to generate a subunit of active form, these results suggest that Fas-mediated apoptosis is driven by a caspase cascade in which the caspase-4(-like) protease transmits a death signal from caspase-8 to caspase-3(-like) proteases probably through directly cleaving pro-caspase-3(-like) proteases.
Asunto(s)
Apoptosis , Cisteína Endopeptidasas/metabolismo , Receptor fas/fisiología , Anticuerpos/farmacología , Arginina , Caspasa 1 , Cisteína Endopeptidasas/biosíntesis , Cisteína Endopeptidasas/inmunología , Precursores Enzimáticos/metabolismo , Ácido Glutámico , Células HeLa , Humanos , Mutagénesis Sitio-Dirigida , Mutación Puntual , Proteínas Recombinantes/metabolismo , Lugares Marcados de Secuencia , Serina , Transducción de SeñalRESUMEN
Proteases of the caspase family are implicated in mammalian apoptosis and constitute a protease cascade. We characterized caspase-4 (TX/ICH-2/ICErelII) and caspase-5 (ICErelIII/TY), which are most closely related to caspase-1 (ICE) among the caspase family. Although overexpression of caspase-4 and caspase-5 induced apoptosis, confirming previous observations, this apoptosis was not inhibited by a caspase-1-specific tetrapeptide inhibitor (Ac-YVAD-CHO), suggesting that caspase-4 and caspase-5 have different substrate specificities from caspase-1 and also that caspase-4- and caspase-5-induced apoptosis is not mediated by caspase-1. CrmA, a cowpox virus-derived caspase-1 inhibitor that prevents apoptosis induced by various stimuli, was cleaved by caspase-4 and caspase-5, and inhibited their proteolytic activity as assessed by cleavage of pro-caspase-3 (pro-CPP32/Yama/apopain). Thus, caspase-4 and caspase-5 are CrmA-inhibitable proteases like caspase-1 and might be involved in apoptosis.
RESUMEN
CED-3 is a cysteine protease required for programmed cell death in the nematode, Caenorhabditis elegans, and shares a sequence similarity with mammalian ICE (interleukin-1beta converting enzyme) family proteases. Both CED-3 and ICE family proteases can induce programmed cell death in mammalian cells. Structural and functional similarities between CED-3 and ICE family proteases indicate that the mechanism of cell death is evolutionarily conserved, suggesting the presence of a similar mechanism involving CED-3/ICE-like proteases in Drosophila. Here we determined whether CED-3 or ICE functions to induce programmed cell death in Drosophila. We have generated transformant lines in which ced-3 or Ice is ectopically expressed using the GAL4-UAS system. Expression of CED-3 and ICE can elicit cell death in Drosophila and the cell death was blocked by coexpressing the p35 gene which encodes a viral inhibitor of CED-3/ICE proteases. Results support the idea that the mechanism of programmed cell death controlled by CED-3/ICE is conserved among widely divergent animal species including Drosophila, and the system described provides a tool to dissect cell death mechanism downstream of CED-3/ICE proteases.
RESUMEN
Neural cross-sensitization has been postulated as a mechanism underlying overlaps of chronic pelvic pain disorders such as bladder pain syndrome/interstitial cystitis (BPS/IC) and irritable bowel syndrome (IBS). Animals with experimental colitis have been used to study the underlying mechanisms for overlapped pelvic pain symptoms, and shown to exhibit bladder overactivity evidenced by frequent voiding; however, it has not directly been evaluated whether pain sensation derived from the lower urinary tract is enhanced in colitis models. Also, the cross-sensitization between the colon and urethra has not been studied previously. In the present study, we therefore investigated pain behaviors induced by nociceptive stimuli in the lower urinary tract and the involvement of C-fiber afferent pathways using rats with colitis induced by intracolonic application of 2,4,6-trinitrobenzenesulfonic acid (TNBS). In TNBS-induced colitis rats at 10 days, intravesical application of resiniferatoxin (RTx) induced a significantly greater number of episodes of both licking and freezing behaviors, which were reduced by capsaicin-sensitive C-fiber afferent desensitization. Histochemical studies using fluorescent dye tracers injected into the colon, bladder or urethra showed that dichotomized afferent neurons comprised 6.9-14.5% of L1, L6 and S1 dorsal root ganglion (DRG) neurons innervating the colon or the lower urinary tract. Transient receptor potential vanilloid 1 (TRPV1) mRNA expression was significantly increased in, the bladder, urethra and S1 DRG in colitis rats. An increase in myeloperoxidase (MPO) activity was found in the colon, but not in the bladder or urethra after intracolonic TNBS treatment. These results indicate that TNBS-induced colitis increased pain sensitivity in the bladder and urethra via activation of C-fiber afferent pathways due to colon-to-bladder and colon-to-urethral cross-sensitization, suggesting the contribution of pelvic organ cross-sensitization mechanisms to overlapped pain symptoms in BPS/IC and IBS.
Asunto(s)
Colitis/fisiopatología , Dolor/fisiopatología , Uretra/fisiopatología , Vejiga Urinaria/fisiopatología , Animales , Colitis/patología , Colon/inervación , Colon/fisiopatología , Modelos Animales de Enfermedad , Diterpenos , Femenino , Reacción Cataléptica de Congelación/fisiología , Ganglios Espinales/patología , Ganglios Espinales/fisiopatología , Aseo Animal/fisiología , Neuronas Aferentes/patología , Neuronas Aferentes/fisiología , Dolor/patología , Peroxidasa/metabolismo , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Canales Catiónicos TRPV/metabolismo , Ácido Trinitrobencenosulfónico , Uretra/inervación , Vejiga Urinaria/inervaciónRESUMEN
Based on our previously developed scheme to stabilize nonplanar optical resonant cavities utilizing polarization caused by a geometric phase in electromagnetic waves traveling along a twisted path, we report an application of the technique for a cavity installed in the Accelerator Test Facility, a 1.3-GeV electron beam accelerator at KEK, in which photons are generated by laser-Compton scattering. We successfully achieved a power enhancement of 1200 with 1.4% fluctuation, which means that the optical path length of the cavity has been controlled with a precision of 14 pm under an accelerator environment. In addition, polarization switching utilizing a geometric phase of the nonplanar cavity was demonstrated.
RESUMEN
FACS analysis together with PIPLC treatment was applied to PI-anchoring antigens such as DAF (decay-accerelating factor, CD55), 1F5 antigen (CD59), CD14 and CD16 on the cell surfaces of blood cells from a normal adult and a male patient with paroxysmal nocturnal hemoglubinuria (PNH). Through the extensive analysis, this patient proved to be completely defective in 1F5 antigen, a newly found complement-regulatory protein, on all the blood cells tested. In normal blood cells such as lymphocytes, monocytes and granulocytes, 1F5 antigen was expressed as one of PI-anchoring proteins. In contrast to most of PNH patients, this patient reserved DAF, CD14 and CD16 at normal levels in his erythrocytes, monocytes and granulocytes. Also, there were no significant differences between the normal adult and the patient in the activities of erythrocyte acetylcholinesterase and granulocyte alkaline phosphatase which were also known to be PI-anchoring enzymes. Thus, deficiency of 1F5 antigen must be deeply related to the clinical symptoms of PNH in this patient.
Asunto(s)
Antígenos de Diferenciación/deficiencia , Hemoglobinuria Paroxística/inmunología , Fosfatidilinositoles/inmunología , Adulto , Antígenos de Diferenciación/análisis , Antígenos de Diferenciación Mielomonocítica/análisis , Antígenos CD55 , Antígenos CD59 , Proteínas Inactivadoras de Complemento , Eritrocitos/inmunología , Citometría de Flujo , Granulocitos/inmunología , Humanos , Receptores de Lipopolisacáridos , Linfocitos/inmunología , Masculino , Proteínas de la Membrana/análisis , Monocitos/inmunología , Fosfatidilinositol Diacilglicerol-Liasa , Hidrolasas Diéster Fosfóricas/farmacología , Receptores Fc/análisis , Receptores de IgGRESUMEN
PURPOSE: E7010 is an orally active sulfonamide antitumor agent showing good activity against various subcutaneously inoculated rodent tumors and human tumor xenografts. The purpose of this study was to evaluate the effect of E7010 on liver metastasis and life span of mice bearing orthotopically transplanted murine Colon 38 tumor. METHODS: Orthotopic transplantation of murine Colon 38 tumor as intact tissue yielded hepatic metastasis with a high incidence in about 1 month in C57BL/6 mice, and the mice died in about 2 months with cachexia. In this model, the maximum tolerated dose of E7010 (100 mg/kg per day) was administered orally on various schedules, including for 14 days or daily until death, starting at 14 days after transplantation, or for 8 days from 21 days after transplantation. RESULTS: E7010 showed tumor growth inhibition (T/C=40%) at the orthotopic site similar to that at the subcutaneous site (T/C = 32%) when administered from 14 days after transplantation. When E7010 was started from 21 days after transplantation, it significantly decreased the number of hepatic metastases (control 17.1+/-20.8, E7010 2.6+/-5.3), although inhibition of tumor growth at the orthotopic site was only moderate (T/ C=60%). The administration of E7010 until death produced a significant increase in life span (control 49.8+/-8.9 days, E7010 62.5+/-6.1 days). Although the tumor weight of the E7010-treated group on the day of death was similar to that of the untreated group (control 1.166+/-0.507 g, E7010 1.211+/-0.632 g), there were significantly fewer liver metastases in the E7010-treated group (control 41.3+/-31.1, E7010 2.0+/-2.0). CONCLUSION: E7010 suppressed tumor growth at both primary and metastatic sites and increased life span in an orthotopic transplantation model of murine Colon 38 tumor in syngeneic C57BL/6 mice. Hepatic metastasis was inhibited more effectively than the growth of the primary tumor.
Asunto(s)
Aminofenoles/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/prevención & control , Neoplasias Hepáticas Experimentales/secundario , Sulfonamidas/uso terapéutico , Animales , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Femenino , Fluorouracilo/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Trasplante de NeoplasiasRESUMEN
We have developed an improved mouse dorsal air sac model for quantifying in vivo tumor-induced angiogenesis. In our improved model, tumor angiogenesis is determined by measuring the blood volume in an area of skin held in contact with a tumor cell-containing chamber, using 51Cr-labeled red blood cells (RBC). The blood volume induced by murine B16-BL6 melanoma cells increased linearly with the cell number in the range from 2 x 10(5) to 5 x 10(6). Ten of 11 human tumor cell lines examined induced a significant increment in blood volume. For three representative human tumor cell lines (A549, WiDr. and HT1080 cells) that showed different angiogenic potencies, the levels of vascular endothelial growth factor (VEGF) produced by the tumor cells cultured under conditions of hypoxia and high cell density were correlated with the degree of in vivo angiogenesis. Using the improved model, it was confirmed that TNP-470, a well-known inhibitor, and borrelidin, an antibiotic from Streptomyces rochei, significantly inhibited the WiDr cell-induced angiogenesis. Borrelidin also inhibited spontaneous lung metastasis of B16-BL6 melanoma at the same dose that inhibited angiogenesis. Our results suggest that the improved mouse dorsal air sac model can be used for simple and quantitative measurement of tumor-induced angiogenesis and its inhibition.
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Inhibidores de la Angiogénesis/uso terapéutico , Factores de Crecimiento Endotelial/metabolismo , Linfocinas/metabolismo , Melanoma Experimental/irrigación sanguínea , Proteínas de Neoplasias/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Volumen Sanguíneo/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Hidrocortisona/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Melanoma Experimental/metabolismo , Melanoma Experimental/fisiopatología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Neovascularización Patológica/fisiopatología , Células Tumorales Cultivadas , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
We propose an equivalent circuit model of a discrete formulation to describe the interaction between the red cone syncytium and the H1 horizontal cell syncytium in lower vertebrate retinas. Analytical solutions of the model provide intuitive understandings of spatio-temporal properties of light-induced responses in reference to membrane impedance, strength of chemical synapse and coupling resistance connecting neighbouring cells. Physiologically plausible values of these parameters are estimated using the solutions. Quantitative studies are made to elucidate the function of (1) the negative feedback from the H1 horizontal cell to the red cone, and (2) the resistance increase of H1 horizontal cell coupling by dopamine.
Asunto(s)
Modelos Neurológicos , Vías Nerviosas/fisiología , Retina/citología , Células Fotorreceptoras Retinianas Conos/fisiología , Animales , Dopamina/farmacología , Impedancia Eléctrica , Retroalimentación , Matemática , Potenciales de la Membrana/efectos de los fármacos , Estimulación Luminosa , Retina/fisiología , Membranas Sinápticas/fisiología , Transmisión SinápticaRESUMEN
A new family of capillary tube formation inhibitors, designated luminacins, has been discovered in the fermentation broth of a soil bacterium. The strain was identified as Streptomyces sp. Mer-VD1207 from taxonomic studies. By means of a series of chromatographic procedures, fourteen structurally related components, luminacins A1, A2, B1, B2, C1, C2, D, E1, E2, E3, F, G1, G2, and H, were isolated, and their structures were elucidated on the basis of spectroscopic analyses.