RESUMEN
BACKGROUND: Renal transplant recipients have increased risk for developing malignant diseases because of immunosuppression or donor-to-recipient transmission. Malignant rhabdoid tumor (MRT) is a rare, highly aggressive and lethal tumor primarily affecting the kidney of infants and young children. MRT has not been reported in the renal allograft of an adult recipient after kidney transplantation. CASE PRESENTATION: In this report, a 47-year-old woman who received a kidney transplantation from an infant donor and developed a mass in the transplanted kidney is presented. Pathological examinations revealed a malignant tumor with rhabdoid cells morphologically and the loss of INI1 expression immunohistochemically. The diagnosis of malignant rhabdoid tumor in the transplanted kidney was made. We confirmed that donor-to-recipient malignancy transmission was the cause of MRT in the transplanted kidney by fluorescence in situ hybridization (FISH) and short tandem repeat (STR) analysis. CONCLUSION: To our knowledge, this is the first case of MRT in an adult renal allograft recipient. This report highlights the importance of the criteria for selection of donors to screen possible malignant tumors transmission.
Asunto(s)
Aloinjertos/patología , Neoplasias Renales/patología , Trasplante de Riñón , Tumor Rabdoide/patología , Femenino , Humanos , Persona de Mediana Edad , Receptores de TrasplantesRESUMEN
BACKGROUND: Mouse double minute 2 (MDM2) and vascular endothelial growth factor (VEGF) are important molecules involved in tumor progression. We researched potential inhibitors that simultaneously target MDM2 and VEGF. In our recent study involving the performance of high-throughput screening with a fluorescence polarization assay, gossypol was identified as one of the top hits that inhibit protein-RNA binding activity. Because MDM2 is an RNA-binding protein and its targets include VEGF mRNA, we investigated whether gossypol has an inhibitory effect on MDM2-VEGF. METHODS: UV cross-linking and RNA binding assay, isothermal titration calorimetry assay, and ubiquitination assay were performed to determine mechanisms by which gossypol functions as a dual inhibitor of MDM2 and VEGF. The effect of gossypol on MDM2 and VEGF expression, cancer cell apoptosis, tumor growth and VEGF-mediated angiogenesis were studied in vitro and in vivo in different human breast cancer models with a different p53 status. RESULTS: We observed that gossypol inhibited expression of both MDM2 and VEGF in human breast cancer cells with either wild-type or mutant p53. A nechanistic study further demonstrated that, through disrupting the interaction between MDM2 protein and VEGF mRNA, gossypol induced MDM2 self-ubiquitination and decreased VEGF translation simultaneously, which resulted in both apoptosis and anti-angiogenesis effects. In vitro, regardless of p53 status, gossypol induced cancer cell apoptosis. In nude mouse xenograft in vivo models, gossypol suppressed tumor growth and VEGF-mediated angiogenesis. CONCLUSION: Gossypol has anti-cancer effects by dual-targeting MDM2 and VEGF in human breast cancer. Our study reveals a novel mechanism by which gossypol functions as an anticancer agent. We believe that MDM2-VEGF targeting represents a novel strategy for improving cancer outcome.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias de la Mama/metabolismo , Gosipol/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Regiones no Traducidas 3' , Animales , Antineoplásicos Fitogénicos/metabolismo , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Gosipol/metabolismo , Humanos , Ratones , Unión Proteica/efectos de los fármacos , Dominios y Motivos de Interacción de Proteínas , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Estabilidad del ARN/efectos de los fármacos , Ubiquitinación/efectos de los fármacos , Factores de Crecimiento Endotelial Vascular/genética , Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Postoperative pain can cause physiological distress, postoperative complications, and extended lengths of hospitalized stay. In children, management of postoperative pain is still recognized as being inadequate. OBJECTIVE: The aim of this trial was to investigate the effects of intraperitoneal ropivacaine on postoperative pain, and recovery of bowel function and emetic events after laparoscopic herniorrhaphy in toddlers. METHODS: Seventy-six children aged from 9 months to 3 years were recruited between August 2013 and June 2014 at Tongji Hospital and randomly assigned into two groups. One group received intraperitoneal ropivacaine right before surgery and the control group received intraperitoneal saline. A standard combined general anesthesia procedure was performed under regular monitoring. Postoperative pain was assessed by the FLACC scale. Postoperative analgesic consumption, time to flatus, time to first stool, and postoperative emetic events were also recorded. RESULTS: When compared with the control group, children who received intraperitoneal ropivacaine experienced less pain 0-4 h after surgery [P < 0.001, difference in median FLACC (95% CI) for 2 h time point is 2.00 (0.87-3.13), for 4 h time point is 1.00 (0.55-1.45)]. In addition, the number of toddlers who received analgesia 0-24 h after surgery in the ropivacaine group was lower than that in the control group [P < 0.001, difference in proportions (95% CI) is 0.575 (0.3865-0.7638)]. Compared with the control group, time to flatus in ropivacaine group was also much shorter [21.1 h vs 16.7 h, P = 0.04, difference in mean (95% CI) is 4.4 (1.49-7.28)], and the time to first stool after surgery was earlier in the ropivacaine group [30.7 h vs 25.6 h, P = 0.003, difference in mean (95% CI) is 5.1 (1.78-8.45)]. Furthermore, the incidence of emetic events in the ropivacaine group was significantly lower than the control group [32.4% vs 11.1%, P = 0.03, difference in proportions (95% CI) is 0.212 (0.0246-0.4002)]. CONCLUSION: The present results indicate that intraperitoneal ropivacaine reduces early postoperative pain and improves recovery after laparoscopic herniorrhaphy in toddlers. Therefore, IPLA is a good stratagem for postoperative pain management after laparoscopic surgery in toddlers.
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Amidas/uso terapéutico , Anestésicos Locales/uso terapéutico , Herniorrafia , Laparoscopía , Dolor Postoperatorio/tratamiento farmacológico , Amidas/administración & dosificación , Anestésicos Locales/administración & dosificación , Preescolar , Femenino , Humanos , Lactante , Inyecciones Intraperitoneales , Tiempo de Internación/estadística & datos numéricos , Masculino , Manejo del Dolor/métodos , Ropivacaína , Resultado del TratamientoRESUMEN
Triptolide has been shown to exhibit anticancer activity. However, its mechanism of action is not clearly defined. Herein we report a novel signaling pathway, MDM2/Akt, is involved in the anticancer mechanism of triptolide. We observed that triptolide inhibits MDM2 expression in human breast cancer cells with either wild-type or mutant p53. This MDM2 inhibition resulted in decreased Akt activation. More specifically, triptolide interfered with the interaction between MDM2 and the transcription factor REST to increase expression of the regulatory subunit of PI3-kinase p85 and consequently inhibit Akt activation. We further showed that, regardless of p53 status, triptolide inhibited proliferation, induced apoptosis, and caused G1 phase cell cycle arrest. Triptolide also enhanced the cytotoxic effect of doxorubicin. MDM2 inhibition plays a causative role in these effects. The inhibitory effect of triptolide on MDM2-mediated Akt activation was eliminated with MDM2 overexpression. MDM2-overexpressing tumor cells, in turn, were less susceptible to the anticancer and chemosensitization effects of triptolide than control cells. Triptolide also exhibited anticancer and chemosensitization effects in nude mouse xenograft model. When it was administered to tumor-bearing nude mice, triptolide inhibited tumor growth and enhanced the antitumor effects of doxorubicin. In summary, triptolide has anticancer and chemosensitization effects by down-regulating Akt activation through the MDM2/REST pathway in human breast cancer. Our study helps to elucidate the p53-independent regulatory function of MDM2 in Akt signaling, offering a novel view of the mechanism by which triptolide functions as an anticancer agent.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Diterpenos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Fenantrenos/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Represoras/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos Alquilantes/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo , Compuestos Epoxi/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Long-term outcome of high-grade serous epithelial ovarian carcinoma (HGSOC) remains poor as a result of recurrence and the emergence of drug resistance. Almost all the patients were given the same platinum-based chemotherapy after debulking surgery even though some of them are naturally resistant to the first-line chemotherapy. No method could verify this part of patients right after the surgery currently. In this study, we used 156 paraffin-embedded high-grade HGSOC specimens for immunohistochemical analysis with 37 immunology markers, and association between the expression levels of these markers and the chemoresponse were evaluated. A support vector machine (SVM)-based HGSOC prognostic classifier was then established, and was validated by a 95-patient independent cohort. The classifier was strongly predictive of chemotherapy resistance, and divided patients into low- and high-risk groups with significant differences progression-free survival (PFS) and overall survival (OS). This classifier may provide a potential way to predict the chemotherapy resistance of HGSOC right after the surgery, and then allow clinicians to make optimal clinical decision for those potentially chemoresistant patients. The potential clinical application of this classifier will benefit those patients with primary drug resistance.
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Antineoplásicos/uso terapéutico , Técnicas de Apoyo para la Decisión , Resistencia a Antineoplásicos/fisiología , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Criterios de Evaluación de Respuesta en Tumores Sólidos , Máquina de Vectores de Soporte , Carcinoma Epitelial de Ovario , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patologíaRESUMEN
BACKGROUND: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare syndrome that is characterized by congenital aplasia of the uterus and the upper portion (2/3) of the vagina. Previous attempts to identify causal mutations of MRKH syndrome have primarily resulted in negative outcomes. We investigated whether these reported variants are associated with MRKH syndrome (types I and II) in a relatively large sample size of Chinese Han patients, and whether any gene-gene epistatic interactions exist among these variants. METHODS: This study included 182 unrelated Chinese women with MRKH syndrome (155 with type I and 27 with type II) and 228 randomized female controls. Seventeen candidate loci in the AMH, PBX1, WNT4, WNT7A, WNT9B, HOXA10, HOXA11, LHXA1 and GALT genes were genotyped using the Sequenom MassARRAY iPLEX platform. Single-marker association, additive effects and multifactor interactions were investigated. RESULTS: The gene frequency distributions of MRKH type 1 and type 2 were similar. Rs34072914 in WNT9B was found to be associated with MRKH syndrome (P = 0.024, OR = 2.65, 95%CI = 1.14-6.17). The dominant models of rs34072914 and rs2275558 in WNT9B and PBX1, respectively, were significantly associated with MRKH syndrome risk in the Chinese Han patients. Additive gene-gene interaction analyses indicated a significant synergetic interaction between WNT9B and PBX1 (RERI = 1.397, AP = 0.493, SI = 4.204). Multifactor dimensionality reduction (MDR) analysis revealed novel dimensional epistatic four-gene effects (AMH, PBX1, WNT7A and WNT9B) in MRKH syndrome. CONCLUSIONS: This association study successfully identified two susceptibility SNPs (WNT9B and PBX1) associated with MRKH syndrome risk, both separately and interactively. The discovery of a four-gene epistatic effect (AMH, PBX1, WNT7A and WNT9B) in MRKH syndrome provides novel information for the elucidation of the genetic mechanism underlying the etiology of MRKH syndrome.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/genética , Anomalías Congénitas/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Conductos Paramesonéfricos/anomalías , Proteínas Proto-Oncogénicas/genética , Proteínas Wnt/genética , Trastornos del Desarrollo Sexual 46, XX/diagnóstico , Anomalías Múltiples/genética , Adulto , Secuencia de Aminoácidos , Hormona Antimülleriana/genética , Pueblo Asiatico/genética , Secuencia de Bases , China , Anomalías Congénitas/diagnóstico , Femenino , Frecuencia de los Genes/genética , Estudios de Asociación Genética , Humanos , Polimorfismo de Nucleótido Simple/genética , Factor de Transcripción 1 de la Leucemia de Células Pre-B , Alineación de Secuencia , Útero/anomalías , Útero/patología , Vagina/anomalías , Vagina/patologíaRESUMEN
BACKGROUND: Metanephric neoplasms comprised a spectrum of kidney tumors containing renal epithelial or stromal cells or both, including metanephric adenoma, metanephric stromal tumor, and metanephric adenofibroma. The majority of cases were benign; only one case of "metanephric adenosarcoma" had been reported in the English literature. HISTORY: We present the case of a 69-year-old man who developed a neoplasm composed of renal epithelial component identical to metanephric adenoma combined with malignant spindle-cell stroma. The epithelial component was positive for CD57, AE1/AE3, but negative for WT-1, CD56, SYN, and CgA; whereas the sarcomatous component was negative for epithelial markers, SMA, Caldesmon, MyoD1, Myogenin, and S-100; and positive for vimentin, CD10, and WT1 focally. No specific sarcoma differentiation was apparent in the stroma by immunohistochemistry, and no SYT-SS18 rearrangement or BRAF mutation was detected by molecular analysis.A diagnosis of metanephric adenosarcoma was made because of the morphological features and immunohitochemistry and molecular pathology analysis. CLINICAL SIGNIFICANCE: We believe that metanephric adenosarcoma should be in the expanded spectrum of metanephric neoplasia as a malignant stromal variant. CONCLUSIONS: We report a rare case of metanephric adenosarcoma with immunohistochemistry and molecular analysis and emphasize the histopathologic features and differential diagnosis of the rare lesion to promote a better and broader understanding of this less understood subject. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_179.
Asunto(s)
Adenosarcoma/patología , Biomarcadores de Tumor/metabolismo , Neoplasias Renales/patología , Adenosarcoma/metabolismo , Adenosarcoma/cirugía , Anciano , Diagnóstico Diferencial , Resultado Fatal , Humanos , Inmunohistoquímica , Riñón/patología , Neoplasias Renales/metabolismo , Neoplasias Renales/cirugía , Masculino , Células del Estroma/patologíaRESUMEN
MayerRokitanskyKüsterHauser (MRKH) syndrome is a rare congenital female genital anomaly, which is caused by aplasia of the caudalportion of the Müllerian duct. The WNT9B gene encodes a secretory glycoprotein essential for the caudal extension of the Müllerian duct during embryonic development in mice. Coding regions and exon/intron boundaries of the WNT9B gene were amplified and sequenced in 42 Chinese women with MRKH syndrome and 42 controls. Two novel heterozygous mutationswere identified,which were absent in controls. Onewas amissensemutation in exon 1, and the other was located in the 30-untranslated region. Both variants were detected in one out of 42 patients. The two novel mutations may be pathogenic variants in MRKH patients and warrant further functional study.
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Trastornos del Desarrollo Sexual 46, XX/genética , Pueblo Asiatico/genética , Anomalías Congénitas/genética , Conductos Paramesonéfricos/anomalías , Mutación Missense/genética , Proteínas Wnt/genética , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Estudios de Casos y Controles , Cartilla de ADN/genética , Femenino , Humanos , Datos de Secuencia Molecular , Técnicas de Amplificación de Ácido Nucleico , Alineación de Secuencia , Análisis de Secuencia de ADNRESUMEN
OBJECTIVE: Globally, cervical cancer is the second most common cancer among women, and determining potential targets involved in tumor progression is necessary. This study investigated the clinic-pathological significance of twist homolog 2 (TWIST2), a basic helix-loop-helix transcription factor, and correlated TWIST2 and E-cadherin expression in cervical cancer. METHODS: A series of 142 samples, including 14 cases of normal cervical tissues, 58 cases of cervical intraepithelial neoplasia (CIN) and 70 cases of squamous cell carcinoma (SCC), were examined TWIST2 and E-cadherin immunohistochemical staining and statistical analysis. RESULTS: Increased cytoplasmic and nuclear expression levels of TWIST2 were associated with the malignant transformation of cervical epithelium and the histological progression of cervical cancer. A logistic test showed that TWIST2 was a relatively independent predictor of lymph node metastasis of SCC. Further, increased levels of TWIST2 were also associated with aberrant expression of E-cadherin, an important EMT indicator. CONCLUSIONS: The present data suggest that TWIST2 overexpression was significantly linked to cervical cancer progression, which makes it a promising marker for determining the metastatic potential of cervical cancer, and up-regulation of TWIST2, in combination with aberrant E-cadherin expression in primary cervical cancer tissues, may predict the malignant transformation and distal metastasis of carcinomas.
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Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Proteínas Represoras/biosíntesis , Proteína 1 Relacionada con Twist/biosíntesis , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Adolescente , Adulto , Anciano , Cadherinas/biosíntesis , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Núcleo Celular/metabolismo , Transformación Celular Neoplásica/genética , Citoplasma/metabolismo , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Femenino , Humanos , Inmunohistoquímica , Metástasis Linfática , Persona de Mediana Edad , Metástasis de la Neoplasia , Adhesión en Parafina , Pronóstico , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Proteínas Represoras/genética , Proteína 1 Relacionada con Twist/genética , Regulación hacia Arriba , Neoplasias del Cuello Uterino/genética , Adulto Joven , Displasia del Cuello del Útero/genética , Displasia del Cuello del Útero/metabolismo , Displasia del Cuello del Útero/patologíaRESUMEN
Careful normalization is essential for the accurate quantitation of mRNA levels in biopsy-sized tissue samples. Commonly, normalization of the target gene with an endogenous standard, mainly housekeeping genes (HKGs), is applied. However, differences in the expression levels of endogenous reference genes have been reported between different tissues and pathological states. Therefore, we were challenged to identify a set of endogenous reference genes whose mRNA expression levels would not change significantly between normal and cancerous tissues. Quantitative real-time PCR (Q-RT-PCR) analysis was applied to evaluate the variability in gene expression among 21 classical housekeeping genes in colorectal, pancreatic, esophageal and gastric cancer as well as in liver metastases in comparison to the corresponding normal tissue. Our results indicated that some housekeeping genes were candidates with relatively stable gene expression in several of the investigated tissues but for most of the HKGs under investigation our data have revealed distinct differences in the extent of variability in gene expression between the different tissues and pathological states. However, for each of the five tissues investigated we found a group of genes that were expressed at a constant level thus representing a panel of candidates that we can recommend as housekeeping genes in the respective tissue types. In summary, our results can be used as guidance for other scientists studying various carcinomas for tissue-specific selection of the optimal housekeeping gene (HKG) to be used in normalizing target gene expression.