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The 2π electron 1,3-dipole boradigermaallyl, valence-isoelectronic to an allyl cation, is synthesized from a bis(germylene). It reacts with benzene at room temperature by insertion of a boron atom into the benzene ring. Computational investigation of the mechanism shows the boradigermaallyl reacting with a benzene molecule in a concerted (4+3) or [π4s+π2s] cycloaddition reaction. Thus, the boradigermaallyl acts as a highly reactive dienophile in this cycloaddition reaction with nonactivated benzene as diene unit. This type of reactivity provides a novel platform for ligand assisted borylene insertion chemistry.
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PURPOSE: Antibiotic resistance may lead to increasing infection rates at transrectal prostate biopsy. Local antimicrobial agents might help to reduce bacterial load. The aim of this study was to test the potency of antimicrobial lubricants to reduce local bacterial loads and specifically fluoroquinolone-resistant strains. PATIENTS AND METHODS: Overall, 384 prostate biopsy (PBx) patients of a larger prospective randomized trial (n = 1000) were included. Patients were randomized for biopsy with pre-interventional instillation of an antimicrobial lubricant (intervention group n = 256) or with the standard lubricant (control group n = 128). Bacteria were recovered on pre- and post-biopsy rectal swab cultures from both patient groups. Bacterial colonization was semi-quantitatively recorded and analyzed for the presence of ciprofloxacin-resistant isolates. RESULTS: Within the intervention group, where antimicrobial lubricant was instilled for PBx, the post-biopsy bacterial count was statistically significantly lower compared to prior biopsy bacterial count (p < 0.001), while in the control group, no statistically significant difference was shown. Moreover, our results demonstrated the tendency for reduction in ciprofloxacin-resistant bacteria growth when instillation of antimicrobial lubricant was used (9.4% versus 5.9%, p = 0.5 prior- and post-biopsy). No reduction in ciprofloxacin-resistant bacterial growth was demonstrated for the control group. Ciprofloxacin-resistance was shown in overall 30 (7.8%) patients. CONCLUSION: Our data demonstrated that the antimicrobial lubricant prior biopsy leads to reduced bacterial load. Moreover, our data show the tendency for reduced ciprofloxacin-resistant bacteria growth when antimicrobial lubricant was instilled prior biopsy. However, the incidence of ciprofloxacin-resistant bacteria is low in our patient population. Rectal swabs should assess fluoroquinolone-resistance rates at prostate biopsy.
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Antibacterianos/farmacología , Profilaxis Antibiótica/métodos , Carga Bacteriana/efectos de los fármacos , Ciprofloxacina/farmacología , Próstata/patología , Recto/microbiología , Biopsia/efectos adversos , Farmacorresistencia Bacteriana , Humanos , Lubricantes , Masculino , Estudios ProspectivosRESUMEN
External controls (eControls) leverage historical data to create non-randomized control arms. The lack of randomization can result in confounding between the experimental and eControl cohorts. To balance potentially confounding variables between the cohorts, one of the proposed methods is to match on prognostic scores. Still, the performance of prognostic scores to construct eControls in oncology has not been analyzed yet. Using an electronic health record-derived de-identified database, we constructed eControls using one of three methods: ROPRO, a state-of-the-art prognostic score, or either a propensity score composed of five (5Vars) or 27 covariates (ROPROvars). We compared the performance of these methods in estimating the overall survival (OS) hazard ratio (HR) of 11 recent advanced non-small cell lung cancer. The ROPRO eControls had a lower OS HR error (median absolute deviation (MAD), 0.072, confidence interval (CI): 0.036-0.185), than the 5Vars (MAD 0.081, CI: 0.025-0.283) and ROPROvars eControls (MAD 0.087, CI: 0.054-0.383). Notably, the OS HR errors for all methods were even lower in the phase III studies. Moreover, the ROPRO eControl cohorts included, on average, more patients than the 5Vars (6.54%) and ROPROvars cohorts (11.7%). The eControls matched with the prognostic score reproduced the controls more reliably than propensity scores composed of the underlying variables. Additionally, prognostic scores could allow eControls to be built on many prognostic variables without a significant increase in the variability of the propensity score, which would decrease the number of matched patients.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Pronóstico , Modelos de Riesgos Proporcionales , Puntaje de PropensiónRESUMEN
BACKGROUND: Growing evidence supports the use of multimedia presentations for informing patients. Therefore, we supported preoperative education by adding a multimedia tool and examined the effects in a randomized controlled trial. METHODS: We randomized German-speaking patients scheduled for radical prostatectomy at our center to receive either a multimedia-supported (MME) or a standard education (SE). Outcomes were measured in a structured interview. Primary outcome was patient satisfaction. In addition, we applied validated instruments to determine anxiety and measures of decision-making. Results were given by mean and standard deviation. For comparison of groups we used t test and chi-square test. For an explorative analysis we applied multivariate logistic regression. RESULTS: We randomized 203 patients to receive MME (n=102) or SE (n=101). Complete satisfaction with preoperative education was more frequent in the MME group (69 vs 52%, p=.016) and patients after MME reported more questions (5.7 vs 4.2, p=.018). There was no difference concerning the duration of talks and the number of recalled risks. However, perceived knowledge was higher after MME (1.3 vs 1.6, p=.037). Anxiety and measures of decision-making were comparable. Patients judged the multimedia tool very positive, and 74% of the MME group thought that their preoperative education had been superior to SE. CONCLUSIONS: Multimedia support should be considered worthwhile for improving the informed consent process before surgery (www.germanctr.de; DRKS00000096).
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Multimedia , Educación del Paciente como Asunto/métodos , Satisfacción del Paciente , Prostatectomía/educación , Anciano , Ansiedad/psicología , Distribución de Chi-Cuadrado , Instrucción por Computador , Toma de Decisiones , Conocimientos, Actitudes y Práctica en Salud , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Periodo Preoperatorio , Prostatectomía/psicología , Prostatectomía/normas , Factores de TiempoRESUMEN
PURPOSE: To evaluate the still controversially discussed prognostic role of preoperative platelet level (PPL) and thrombocytosis (TC) in patients who undergo surgery for renal cell carcinoma (RCC) based on the largest patient series reported to date. METHODS: A total of 3,139 patients, who underwent radical or nephron-sparing nephrectomy at four centres, were subdivided based on a threshold for preoperative platelets of 400 × 10(9) cells/L. Univariate and multivariable Cox regression analyses were applied to determine the prognostic influence of PPL and TC on cancer-specific survival (CSS) for patients with localized and metastatic disease at presentation. RESULTS: Group 1 (PPL ≤ 400/nl) and Group 2 (PPL > 400/nl) included 2,862 (91 %) and 277 patients (9 %), respectively. With a median follow-up (FU) of 69.5 months (IQR: 35-105), CSS of all patients after 5 years was 84.6 % in Group 1 versus 53.4 % in Group 2 (p < 0.001). At multivariable analysis, TC (HR:1.337; p = 0.007) and continuous PPL (HR:1.001; p = 0.002) independently predicted a decreased survival. However, integration of these parameters into multivariable models for the entire study group and for patients with localized tumours did only result in marginal improvement of the model quality (0.66 and 1.04 %, respectively). Interestingly, neither TC (p = 0.257) nor PPL (p = 0.132) significantly influenced survival in M1 patients. CONCLUSIONS: Preoperative TC turned out an independent predictor for decreased CSS in patients undergoing surgery for localized RCC. However, significant improvement of multivariable models comprising standard clinical and pathological parameters by the inclusion of TC is not achieved. In metastatic disease, TC did not reveal an independent influence on CSS.
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Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/cirugía , Neoplasias Renales/diagnóstico , Neoplasias Renales/cirugía , Nefrectomía , Cuidados Preoperatorios , Trombocitosis/diagnóstico , Anciano , Carcinoma de Células Renales/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Análisis Multivariante , Recuento de Plaquetas , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Trombocitosis/sangre , Trombocitosis/epidemiología , Resultado del TratamientoRESUMEN
BACKGROUND: Isolation and characterization of tumourigenic colon cancer initiating cells may help to develop novel diagnostic and therapeutic procedures. METHODS: We characterized a panel of fourteen human colon carcinoma cell lines and their corresponding xenografts for the surface expression of potential stem cell markers CD133, CD24, CD44, CDCP1 and CXCR4. In five cell lines and nine xenografts, mRNA expression of these markers was determined. Tumour growth behaviour of CD133+, CD133- and unsorted SW620 cells was evaluated in vivo. RESULTS: All five putative stem cell markers showed distinct expression patterns in the tumours examined. Two patient-derived cell lines highly expressed CD133 (> 85% of positive cells) and three other cell lines had an expression level of about 50% whereas in long-term culture based models CD133 expression ranged only from 0 to 20%. In 8/14 cell lines, more than 80% of the cells were positive for CD24 and 11/14 were over 70% positive for CD44. 10/14 cell lines expressed CDCP1 on ≥ 83% of cells. CXCR4 expression was determined solely on 94 L and SW480.Analyses of the corresponding xenografts revealed a significant reduction of cell numbers expressing the investigated surface markers and showed single cell fractions expressing up to three markers simultaneously.Statistical analysis revealed that the CXCR4 mRNA level correlates negatively with the protein expression of CD133, CD44, CD24 and CDCP1 in cell lines and xenografts.A lower differentiation grade of donor material correlated with a higher CDCP1 mRNA expression level in the respective tumour model.In vivo growth behaviour studies of SW620 revealed significantly higher take rates and shorter doubling times in the tumour growth of CD133 positive subclones in comparison to the unsorted cell line or CD133 negative subclones. CONCLUSIONS: Our data revealed correlations in the expression of surface markers CD44 and CD24 as well as CD44 and CDCP1 and strongly suggest that CD133 is a stem cell marker within our colon carcinoma panel. Further studies will elucidate its role as a potential therapeutic target.
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Antígenos CD/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma/metabolismo , Neoplasias del Colon/metabolismo , Antígeno AC133 , Adulto , Anciano , Animales , Carcinoma/inmunología , Carcinoma/patología , Línea Celular Tumoral , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Femenino , Citometría de Flujo , Glicoproteínas , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Péptidos , ARN Mensajero/metabolismo , Receptores CXCR4/metabolismoRESUMEN
Background: In early stage clinical trials, changes to levels of tumor infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) are critical biomarkers of the mechanism of action of novel immunotherapies. However, baseline heterogeneity of tumor samples, both between and within patients, and the resultant impact on the validity of clinical trial data is not well defined. Here we identify and quantify the impact of baseline variables on the heterogeneity of FoxP3+ and proliferating CD8+ T-cells levels (MKi67+CD8A+) in the TME both between and within patients for the purpose of informing clinical trial design and analysis. Methods: We compared levels of FoxP3+ and MKi67+CD8+ cell densities (counts/mm2) from >1000 baseline tumor samples from clinical trials and commercially available sources. Using multivariate hierarchical regression techniques, we investigated whether inter-person heterogeneity of activated or regulatory T-cells could be attributed to baseline characteristics including demographics, indication, lesion type, tissue of excision, biopsy method, prior cancer treatment, and tissue type i.e., "fresh" or "archival" status. We also sought to characterize within-patient heterogeneity by lesion type and tissue type. Results: Prior cancer treatment with hormone therapy or chemotherapy that induces immunogenic cell death may alter the TME. Archival tissue is an unreliable substitute for fresh tissue for determining baseline TIL levels. Baseline and on treatment biopsies should be matched by lesion type to avoid bias.
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Linfocitos Infiltrantes de Tumor , Neoplasias , Ensayos Clínicos como Asunto , Factores de Transcripción Forkhead/metabolismo , Humanos , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias/patología , Microambiente TumoralRESUMEN
BACKGROUND: Transrectal prostate biopsy (pbx) is the most frequent outpatient procedure in the urological field. Septic complications are a major health issue. OBJECTIVE: To evaluate complication rates with or without an antimicrobial lubricant. DESIGN, SETTING, AND PARTICIPANTS: A total of 1000 patients received pbx between 2013 and 2015. Information about complications was collected by a 3-wk questionnaire. Return rate was 73.2% (n=732). INTERVENTION: Randomization for pbx with the instillation of an antimicrobial lubricant (intervention group, n=385) or the standard lubricant (control group, n=347) was performed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable analyses assessed the association between infectious complications at biopsy and use of an antimicrobial lubricant, International Prostate Symptom Score (IPSS), history of urogenitourinary infections, and several other confounders. RESULTS AND LIMITATIONS: The use of an antimicrobial lubricant did not reduce infection rate. Overall complication rate was very low. Of all patients, 69.3% described the procedure as pain free. Fever ≥38.5°C was reported in overall 1.9% of patients. Urinary retention with catheterization occurred in 3.1%. Most common complications were hematospermia (47.4%), macrohematuria (23.8%), and rectal bleeding (7.4%). Readmission rate was 1% (n=7). In multivariable analyses, IPSS and previous infectious complications were associated with a higher risk of infectious complications. Our results stem from a large German single center and therefore are limited to this patient group. CONCLUSIONS: No significant reduction was shown in infectious complications in the intervention group with the antimicrobial agent. Low incidence of those complications may be the underlying cause. Severe morbidity at pbx is uncommon. Specifically, the rate of infection was very low. PATIENT SUMMARY: Severe complications at prostate biopsy are rare. Among participants, 69.3% had no pain. Fever was rare (1.9% of patients). Voiding issues with catheterization occurred in 3.1%. Most common complications were blood in the semen (47.4%), urine (23.8%), or stool (7.4%). Men with voiding issues or previous infectious complications had a higher risk of infectious complications.
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Antibacterianos/uso terapéutico , Profilaxis Antibiótica/estadística & datos numéricos , Biopsia Guiada por Imagen/efectos adversos , Lubricantes/administración & dosificación , Próstata/patología , Anciano , Fiebre/epidemiología , Hemorragia Gastrointestinal/epidemiología , Alemania/epidemiología , Hematuria/epidemiología , Hematospermia/epidemiología , Humanos , Biopsia Guiada por Imagen/métodos , Masculino , Readmisión del Paciente/estadística & datos numéricos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/microbiología , Complicaciones Posoperatorias/prevención & control , Estudios Prospectivos , Próstata/microbiología , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/patología , Recto/cirugía , Retención Urinaria/epidemiologíaRESUMEN
INTRODUCTION: Cadherin family proteins are involved in the tumorigenesis of several malignancies. However, their significance in renal cell carcinoma (RCC) has not been extensively investigated. The current study investigates the potential of several cadherins to perform as biomarkers for tumor detection and exert functional RCC activity. METHODS: Pre- and postoperative concentrations of sE-cadherin, cadherin-6, N-cadherin, cadherin-11, cadherin-17, and cadherin-5 were measured in serum of patients undergoing surgery for RCC and correlated to clinical and histopathological parameters. Control serum was obtained from healthy volunteers. A498 and Caki-1 cells were incubated with sE-cadherin and assessed for cell growth, adhesion, and chemotaxis. RESULTS: sE-cadherin was significantly upregulated in RCC patients, as compared to controls, and discriminated them with striking accuracy (area under the curve value 0.83). Serum levels remained stable several days after surgery. Treating A498 and Caki-1 cancer cells with various concentrations of sE-cadherin attenuated cell growth and adhesion, while chemotaxis was augmented. CONCLUSIONS: sE-cadherin is overexpressed in serum of RCC patients and provides a functional cellular switch from sessility to aggressive dissemination. While sE-cadherin is not tumor-specific and thus inappropriate for population-based screening, further studies are warranted to investigate its role in monitoring RCC and employing it as a therapeutic target.
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Biomarcadores de Tumor/sangre , Cadherinas/sangre , Carcinoma de Células Renales/sangre , Neoplasias Renales/sangre , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/patología , Femenino , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estudios Prospectivos , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
Birt-Hogg-Dube (BHD) disease is an autosomal dominant cancer syndrome characterized by benign skin tumors, renal cancer and spontaneous pneumothorax and is caused by mutations in the Folliculin (FLCN) gene. Benign skin tumors and pneumothorax occur in the majority of patients affected by BHD syndrome, but only 30-45% of them develop renal cell carcinoma (RCC) with a median age of diagnosis at 48. The earliest onset of RCC in a BHD patient has been reported at age 20. Here we report a case of a 14 year-old patient with germline FLCN mutation leading to an early-onset bulky RCC that could not be classified strictly according to existing histological types. Germline genetic testing revealed a deletion at FLCN exon 5. The father of the patient was identified as the asymptomatic carrier. We report the youngest patient with BHD-related RCC. This early onset presentation supports genetic testing of at-risk patients and initiation of imaging surveillance for RCC in early adolescence. In addition, future studies are necessary to understand the determinants of reduced penetrance in BHD disease.
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Síndrome de Birt-Hogg-Dubé/genética , Carcinoma de Células Renales/genética , Neoplasias Renales/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Edad de Inicio , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/patología , Exones/genética , Femenino , Mutación de Línea Germinal , Humanos , Riñón/patología , Riñón/ultraestructura , Neoplasias Renales/diagnóstico , Neoplasias Renales/patología , Microscopía Electrónica , Eliminación de Secuencia , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: The purpose of the study was to define clinical factors for successful treatment response and re-exposure to docetaxel in metastatic castration-resistant prostate cancer (mCRPC). METHODS: An mCRPC database of patients receiving first-line docetaxel and rechallenge courses was established. Several clinical factors were evaluated for prediction of treatment response. Multivariate cox-regression analysis was used to define pre-treatment and treatment factors for survival. RESULTS: Between 2005 and 2013, 94 patients with mCRPC were treated with docetaxel. Full data set and follow-up were available for 62 patients. Median follow-up was 84 m [interquartile range (IQR) 64-104 m]. Median biochemical progression-free survival (bPFS) and overall survival under docetaxel were 9 m (IQR 5-16 m) and 20 m (IQR 16-26 m), respectively. Partial PSA-response at first docetaxel-sequence (n = 62), rechallenge (n = 32), and third-sequence (n = 22) docetaxel was 48.4%, 31.6%, and 34.8%, respectively. Time from start of primary androgen deprivation to CRPC > 47 m was the only independent pre-treatment parameter to predict improved overall survival (Hazard Ratio 0.48, p = 0.015). Interestingly, there was a strong trend for improved overall survival in patients with high Gleason Score (Hazard Ratio 0.58; p = 0.08). Partial PSA-response at docetaxel-rechallenge (Hazard Ratio 0.31; p = 0.008) and treatment-free interval > 3 m (Hazard Ratio 3.49; p = 0.014) were the only independent predictive factors under taxane treatment for overall survival. CONCLUSION: Despite novel hormonal drugs, docetaxel still plays an important role in the treatment of mCRPC. Patients with partial-PSA-response at rechallenge or a treatment-free interval > 3 m benefit most from docetaxel re-exposure.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/secundario , Docetaxel/administración & dosificación , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/terapia , Anciano , Androstenos/administración & dosificación , Supervivencia sin Enfermedad , Estudios de Seguimiento , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Clasificación del Tumor , Orquiectomía , Antígeno Prostático Específico/sangre , Prostatectomía , Neoplasias de la Próstata Resistentes a la Castración/sangre , Retratamiento , Estudios Retrospectivos , Tasa de Supervivencia , Taxoides/administración & dosificaciónRESUMEN
Systemic treatment is necessary for one third of patients with renal cell carcinoma. No valid biomarker is currently available to tailor personalized therapy. In this study we established a representative panel of patient derived xenograft (PDX) mouse models from patients with renal cell carcinomas and determined serum levels of high mobility group B1 (HMGB1) protein under treatment with sunitinib, pazopanib, sorafenib, axitinib, temsirolimus and bevacizumab. Serum HMGB1 levels were significantly higher in a subset of the PDX collection, which exhibited slower tumor growth during subsequent passages than tumors with low HMGB1 serum levels. Pre-treatment PDX serum HMGB1 levels also correlated with response to systemic treatment: PDX models with high HMGB1 levels predicted response to bevacizumab. Taken together, we provide for the first time evidence that the damage associated molecular pattern biomarker HMGB1 can predict response to systemic treatment with bevacizumab. Our data support the future evaluation of HMGB1 as a predictive biomarker for bevacizumab sensitivity in patients with renal cell carcinoma.
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Many cancer-associated mutations that deregulate cellular metabolic responses to hypoxia also reprogram carbon metabolism to promote utilization of glutamine. In renal cell carcinoma (RCC), cells deficient in the von Hippel-Lindau (VHL) tumor suppressor gene use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate (αKG). Glutamine can also generate aspartate, the carbon source for pyrimidine biosynthesis, and glutathione for redox balance. Here we have shown that VHL-/- RCC cells rely on RC-derived aspartate to maintain de novo pyrimidine biosynthesis. Glutaminase 1 (GLS1) inhibitors depleted pyrimidines and increased ROS in VHL-/- cells but not in VHL+/+ cells, which utilized glucose oxidation for glutamate and aspartate production. GLS1 inhibitor-induced nucleoside depletion and ROS enhancement led to DNA replication stress and activation of an intra-S phase checkpoint, and suppressed the growth of VHL-/- RCC cells. These effects were rescued by administration of glutamate, αKG, or nucleobases with N-acetylcysteine. Further, we observed that the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib synergizes with GLS1 inhibitors to suppress the growth of VHL-/- cells in vitro and in vivo. This work describes a mechanism that explains the sensitivity of RCC tumor growth to GLS1 inhibitors and supports the development of therapeutic strategies for targeting VHL-deficient RCC.
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Glutaminasa/antagonistas & inhibidores , Neoplasias Renales/tratamiento farmacológico , Ftalazinas/farmacología , Piperazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Animales , Carcinoma de Células Renales , Glutamatos/genética , Glutamatos/metabolismo , Glutaminasa/genética , Glutaminasa/metabolismo , Glutamina/genética , Glutamina/metabolismo , Humanos , Neoplasias Renales/enzimología , Neoplasias Renales/genética , Neoplasias Renales/patología , Ratones , Ratones Desnudos , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Puntos de Control de la Fase S del Ciclo Celular/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The discharging and charging of batteries require ion transfer across phase boundaries. In conventional lithium-ion batteries, Li(+) ions have to cross the liquid electrolyte and only need to pass the electrode interfaces. Future high-energy batteries may need to work as hybrids, and so serially combine a liquid electrolyte and a solid electrolyte to suppress unwanted redox shuttles. This adds new interfaces that might significantly decrease the cycling-rate capability. Here we show that the interface between a typical fast-ion-conducting solid electrolyte and a conventional liquid electrolyte is chemically unstable and forms a resistive solid-liquid electrolyte interphase (SLEI). Insights into the kinetics of this new type of interphase are obtained by impedance studies of a two-chamber cell. The chemistry of the SLEI, its growth with time and the influence of water impurities are examined by state-of-the-art surface analysis and depth profiling.
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BACKGROUND: Novel therapeutic options beyond hormone ablation and chemotherapy are urgently needed for patients with advanced prostate cancer. Tyrosine kinase inhibitors (TKIs) are an attractive option as advanced prostate cancers show a highly altered phosphotyrosine proteome. However, despite favorable initial clinical results, the combination of the TKI dasatinib with docetaxel did not result in improved patient survival for reasons that are not known in detail. METHODS: The National Cancer Institute-Approved Oncology Drug Set II was used in a phenotypic drug screen to identify novel compounds with antineoplastic activity in prostate cancer cells. Validation experiments were carried out in vitro and in vivo. RESULTS: We identified the TKI nilotinib as a novel compound with antineoplastic activity in hormone-refractory prostate cancer cells. However, further analyses revealed that treatment with nilotinib was associated with a significant up-regulation of the phospho-extracellular-signal-regulated kinases (ERK) survival signal. ERK blockade alone led to a significant antitumoral effect and enhanced the cytotoxicity of nilotinib when used in combination. CONCLUSIONS: Our findings underscore that TKIs, such as nilotinib, have antitumoral activity in prostate cancer cells but that survival signals, such as ERK up-regulation, may mitigate their effectiveness. ERK blockade alone or in combination with TKIs may represent a promising therapeutic strategy in advanced prostate cancer.
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Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Animales , Línea Celular Tumoral , Resistencia a Antineoplásicos , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Humanos , Masculino , Ratones , Ratones Mutantes , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/metabolismo , Distribución Aleatoria , Regulación hacia Arriba/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVES: Novel personalized therapeutic approaches are urgently needed for patients with metastatic clear cell renal cell carcinoma (ccRCC). METHODS AND MATERIALS: We combined the development of a primary patient-derived ccRCC cell line with a phenotypic drug screen consisting of 101 approved anticancer compounds. RESULTS: We identified the MNNG HOS transforming gene (MET)-anaplastic lymphoma receptor tyrosine kinase (ALK) inhibitor crizotinib as the top hit of our drug screen, whereas compounds targeting the vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) pathway showed no or only minor in vitro activity. Among the known major crizotinib targets MET, ALK, and ROS-1, only MET was expressed in our ccRCC cell line. Subsequent sequence analysis revealed a heterozygous R988C mutation of the MET gene and a VHL deletion in both the primary tumor and the tumor-derived ccRCC cell line. However, we were unable to show an activation of MET and, further, MET knockdown did not result in increased apoptosis or cytotoxicity. Therefore, our results suggest that MET R988C does not function as a major oncogenic driver mutation but rather represents a sequence variant. However, we provide evidence that the cytotoxic effect of crizotinib in our cell line model correlates with its ability to inhibit P-glycoprotein (ABCB1)-associated transport functions. CONCLUSIONS: Our study shows that a phenotypic screen of a patient-derived tumor cell line can identify compounds with antitumor activity but with an unexpected mode of action. Our results underscore that target validation and phenotype-genotype correlations remain a major experimental challenge. The implications of our findings for a personalized management of patients with cancer are discussed.
Asunto(s)
Antineoplásicos/farmacología , Predisposición Genética a la Enfermedad/genética , Terapia Molecular Dirigida/métodos , Medicina de Precisión/métodos , Apoptosis/efectos de los fármacos , Apoptosis/genética , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Crizotinib , Ensayos de Selección de Medicamentos Antitumorales/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genotipo , Humanos , Immunoblotting , Neoplasias Renales/genética , Neoplasias Renales/patología , Mutación , Fenotipo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirazoles/farmacología , Piridinas/farmacología , Interferencia de ARN , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
OBJECTIVE: To describe a feasible surgical technique for patients with renal cell carcinoma associated with a supradiaphragmatic tumor thrombus that avoids cardiopulmonary bypass procedure. MATERIALS AND METHODS: From 2004 to 2009, 4 patients with a right kidney tumor and tumor thrombus above the diaphragm (pT3c) underwent manual repositioning of the tumor thrombus out of the right atrium into the inferior vena cava on the beating heart. These patients were aged 65.8 years and had a body mass index of 25.5 kg/m(2). Median tumor size was 10.8 cm, and 3 patients had synchronous metastasis. RESULTS: Manual repositioning of the tumor thrombus was safe and feasible in all patients. Mean operating time was 561 minutes (range, 302-613 minutes), and no perioperative death occurred. Auxiliary cardiopulmonary bypass procedure was applied in 1 patient to remove a preoperatively diagnosed pulmonary embolus. Three patients subsequently underwent systemic therapy for metastatic disease. Median survival was 16 months (range, 1.7-26 months). CONCLUSION: Manual repositioning of a vena cava tumor thrombus without cardiopulmonary bypass is a safe and feasible approach. The risk of tumor thrombembolization seems to be low, and cardiopulmonary bypass can be avoided or at least reduced to a minimum time of intervention.