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BACKGROUND: The definition of partial resuscitative endovascular balloon occlusion of the aorta (pREBOA) is not yet determined and clinical markers of the degree of occlusion, metabolic effects and end-organ injury that are clinically monitored in real time are lacking. The aim of the study was to test the hypothesis that end-tidal carbon dioxide (ETCO2) targeted pREBOA causes less metabolic disturbance compared to proximal systolic blood pressure (SBP) targeted pREBOA in a porcine model of hemorrhagic shock. MATERIALS AND METHODS: Twenty anesthetized pigs (26-35 kg) were randomized to 45 min of either ETCO2 targeted pREBOA (pREBOAETCO2, ETCO2 90-110% of values before start of occlusion, n = 10) or proximal SBP targeted pREBOA (pREBOASBP, SBP 80-100 mmHg, n = 10), during controlled grade IV hemorrhagic shock. Autotransfusion and reperfusion over 3 h followed. Hemodynamic and respiratory parameters, blood samples and jejunal specimens were analyzed. RESULTS: ETCO2 was significantly higher in the pREBOAETCO2 group during the occlusion compared to the pREBOASBP group, whereas SBP, femoral arterial mean pressure and abdominal aortic blood flow were similar. During reperfusion, arterial and mesenteric lactate, plasma creatinine and plasma troponin concentrations were higher in the pREBOASBP group. CONCLUSIONS: In a porcine model of hemorrhagic shock, ETCO2 targeted pREBOA caused less metabolic disturbance and end-organ damage compared to proximal SBP targeted pREBOA, with no disadvantageous hemodynamic impact. End-tidal CO2 should be investigated in clinical studies as a complementary clinical tool for mitigating ischemic-reperfusion injury when using pREBOA.
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In this paper, a micrometre thin film of molybdenum disulfide (MoS2) is characterized for thermoelectric properties. The sample was prepared through mechanical exfoliation of a molybdenite crystal. The Seebeck coefficient measurement was performed by generating a temperature gradient across the sample and recording the induced electrical voltage, and for this purpose a simple measurement setup was developed. In the measurement, platinum was utilized as reference material in the electrodes. The Seebeck value of MoS2 was estimated to be approximately -600 µV/K at a temperature difference of 40 °C. The negative sign indicates that the polarity of the material is n-type. For measurement of the thermal conductivity, the sample was sandwiched between the heat source and the heat sink, and a steady-state power of 1.42 W was provided while monitoring the temperature difference across the sample. Based on Fourier's law of conduction, the thermal conductivity of the sample was estimated to be approximately 0.26 Wm-1 K-. The electrical resistivity was estimated to be 29 Ω cm. The figure of merit of MoS2 was estimated to be 1.99 × 10-4.
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Electrochromic windows and glass facades are able to impart energy efficiency jointly with indoor comfort and convenience. Long-term durability is essential for practical implementation of this technology and has recently attracted broad interest. Here we show that a simple potentiostatic pretreatment of sputter-deposited thin films of amorphous WO3-the most widely studied electrochromic material-can yield unprecedented durability for charge exchange and optical modulation under harsh electrochemical cycling in a Li-ion-conducting electrolyte and effectively evades harmful trapping of Li. The pretreatment consisted of applying a voltage of 6.0 V vs. Li/Li+ for several hours to a film backed by a transparent conducting In2O3:Sn layer. Associated compositional and structural modifications were probed by several techniques, and improved durability was associated with elemental intermixing at the WO3/ITO and ITO/glass boundaries as well as with carbonaceous solid-electrolyte interfacial layers on the WO3 films. Our work provides important new insights into long-term durability of ion-exchange-based devices.
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INTRODUCTION: The management of segmental bone loss poses a significant clinical challenge. The purpose of this study was to conduct a retrospective evaluation of our experience in treating segmental bone loss, using Reamer-Irrigator-Aspirator (RIA)-harvested autologous bone graft. MATERIALS AND METHODS: Between June 2008 and March 2015, 81 patients were treated with the RIA technique for multiple purposes. Inclusion criteria for this study were skeletal mature patients with segmental bone loss, due to acute trauma or non-union, who were treated with RIA-harvested bone graft. Exclusion criteria were skeletal immaturity, pathological fractures and indications for the RIA system other than bone graft harvesting. The primary outcome parameter was clinical and radiographical bone healing. RESULTS: During the study period, 72 patients met the inclusion criteria. In total, 39 patients (54.2%) were classified as having clinical and radiographical bone healing. Although univariate analysis could not reveal any significant influence of specific risk factors to predict the outcome, there was a trend towards statistical significance for defect volume. Further analysis indeed revealed that smaller defect volumes (< 8 cm3) had a lower risk of non-union. CONCLUSIONS: In approximately half of our study population, the use of the RIA technique for autologous bone graft harvesting in cases of segmental bone loss resulted in a successful outcome with bone healing. Defect size seems to be a critical issue regarding the outcome. Although our results are less promising than previously published, the RIA technique has its place in the treatment algorithm of segmental bone defects.
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Trasplante Óseo/instrumentación , Fijación de Fractura/métodos , Fracturas Óseas/cirugía , Recolección de Tejidos y Órganos/instrumentación , Adolescente , Adulto , Anciano , Femenino , Curación de Fractura , Fracturas Óseas/patología , Fracturas no Consolidadas/patología , Fracturas no Consolidadas/cirugía , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Trasplante Autólogo , Resultado del TratamientoRESUMEN
CHK1 is an important regulator of the cell cycle and DNA damage response, and its altered expression has been identified in various tumors. Chk1 inhibitors are currently being evaluated as monotherapy and as potentiators of chemotherapy in clinical settings. However, to our knowledge, no previous study has investigated either the activation status or the therapeutic potential of CHK1 targeting in vulvar cancer. Therefore, we examined the expression status of activated CHK1 forms pCHK1Ser345 , pCHK1Ser317 , pCHK1Ser296 , and pCHK1Ser280 in 294 vulvar squamous cell carcinomas (VSCC) using immunohistochemistry and analyzed their relationships with various clinicopathological variables and clinical outcome. To aid translation of preclinical studies, we also assessed cell sensitivity to the Chk1 inhibition in two vulvar cancer cell lines. Compared to the levels of pCHK1Ser345 , pCHK1Ser317 , pCHK1Ser296 , and pCHK1Ser280 in normal vulvar squamous epithelium, high nuclear pCHK1Ser345 expression was found in 57% of vulvar carcinomas, whereas low nuclear pCHK1Ser317 , pCHK1Ser296 , and pCHK1Ser280 expressions were observed in 58%, 64%, and 40% of the cases, respectively. Low levels of pCHK1Ser317 and pCHK1Ser280 in the nucleus correlated significantly with advanced tumor behaviors and aggressive features. None of pCHK1Ser345 , pCHK1Ser317 , pCHK1Ser296 , and pCHK1Ser280 forms were identified as prognostic factors. In vitro inhibition of CHK1 by small molecular inhibitors or siRNA reduced viability by inducing DNA damage and apoptosis of vulvar cancer cell lines. In summary, we conclude that cellular functions regulated by CHK1 are phosphorylation/localization-dependent and deregulation of CHK1 function occurs in VSCC and might contribute to tumorigenesis. Targeting CHK1 might represent as a useful antitumor strategy for the subgroup of VSCC harboring p53 mutations.
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Carcinoma de Células Escamosas/genética , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/genética , Inhibidores de Proteínas Quinasas/farmacología , Activación Transcripcional , Neoplasias de la Vulva/genética , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis , Biomarcadores de Tumor , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/terapia , Ciclo Celular/genética , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Daño del ADN , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Fosforilación , Pronóstico , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/uso terapéutico , ARN Interferente Pequeño/genética , Estudios Retrospectivos , Neoplasias de la Vulva/tratamiento farmacológico , Neoplasias de la Vulva/metabolismo , Neoplasias de la Vulva/terapiaRESUMEN
Different microRNAs are dysregulated in ovarian cancer where some of them have proved to be valid biomarkers. miRNA profiling analyses have shown that the different histotypes of ovarian carcinoma display differential expression of specific miRNAs. In the present study, we used miRNA-sequencing and Real-Time qPCR to detect the expression levels of miRNAs belonging to the miRNA-192/215 family, namely miR-192, miR-194, and miR-215, in different types of ovarian neoplasia, finding that miR-192, miR-194, and miR-215 were upregulated in ovarian carcinomas of the mucinous subtype, but downregulated in other types of carcinoma and in sex cord-stromal tumors. The expression of the said miRNAs was 6-fold higher in mucinous tumors compared to the other histotypes making them candidates for a possible role as diagnostic biomarkers.
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Adenocarcinoma Mucinoso/genética , MicroARNs/genética , Neoplasias Ováricas/genética , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , HumanosRESUMEN
The aim of this study was to analyze the expression, biological role and clinical relevance of autotaxin (ATX), the enzyme synthetizing lysophosphatidic acid (LPA), and LPA receptors (LPAR) in high-grade serous carcinoma (HGSC). mRNA expression by qRT-PCR of LPAR1-6 was analyzed in 155 HGSC specimens (88 effusions, 67 solid lesions). ATX mRNA expression was analyzed in 97 specimens. ATX, ERK, and AKT protein expression was studied by Western blotting. LPAR2 mRNA was overexpressed in HGSC cells in effusions compared to solid lesions, with opposite findings for LPAR3 and LPAR6 mRNA and ATX protein. Higher LPAR1 levels were significantly related to longer overall survival (OS) in pre-chemotherapy effusions (p = 0.027). Conversely, higher expression of LPAR1, LPAR2, and LPAR5 in post-chemotherapy effusions was significantly associated with shorter OS (p = 0.037, p = 0.025 and p = 0.021, respectively) and progression-free survival (PFS) (p < 0.001, p = 0.007 and p < 0.001, respectively) in univariate survival analysis. LPAR1 mRNA expression was an independent prognosticator of OS in patients with pre-chemotherapy effusions and PFS in patients with post-chemotherapy effusions (p = 0.013 both). In conclusion, LPAR mRNA and ATX protein levels are anatomic site-dependent in HGSC and the former are informative of disease outcome.
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Biomarcadores de Tumor/metabolismo , Carcinoma/enzimología , Lisofosfolípidos/metabolismo , Neoplasias Quísticas, Mucinosas y Serosas/enzimología , Neoplasias Ováricas/enzimología , Hidrolasas Diéster Fosfóricas/metabolismo , Receptores del Ácido Lisofosfatídico/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Carcinoma/genética , Carcinoma/secundario , Carcinoma/terapia , Supervivencia sin Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Análisis Multivariante , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias Quísticas, Mucinosas y Serosas/genética , Neoplasias Quísticas, Mucinosas y Serosas/secundario , Neoplasias Quísticas, Mucinosas y Serosas/terapia , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Hidrolasas Diéster Fosfóricas/genética , Fosforilación , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , Receptores del Ácido Lisofosfatídico/genética , Factores de Riesgo , Transducción de Señal , Factores de Tiempo , Resultado del TratamientoRESUMEN
The objective of this study was to analyze the expression and clinical role of 14-3-3 family proteins in high-grade serous carcinoma (HGSC). Protein expression of 14-3-3 sigma (14-3-3σ) and 14-3-3 eta (14-3-3η) by immunohistochemistry was studied in 298 HGSC specimens (249 peritoneal, 49 pleural) and was analyzed for association with clinicopathologic parameters, chemoresponse and survival. The 14-3-3σ protein was diffusely (>75% of cells) expressed in 100% of carcinomas in analysis of a pilot series and was therefore not further analyzed. The 14-3-3η protein was expressed to a variable extent in 260/298 (87%) effusions. Higher 14-3-3η protein expression was significantly related to higher CA 125 levels at diagnosis (p = 0.004), but was unrelated to other clinicopathologic parameters, chemoresponse or survival. Analysis of the association between 14-3-3η and previously studied proteins regulating mitosis showed positive association with class III ß-tubulin expression (p = 0.025). The present study documents frequent expression of 14-3-3σ and 14-3-3η in HGSC effusions, but does not support a role for these proteins as prognostic markers or predictors of chemotherapy response in metastatic HGSC.
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Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/mortalidad , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígeno Ca-125/metabolismo , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: To profile long non-coding RNA (lncRNA) expression at the various anatomic sites of high-grades serous carcinoma (HGSC) and in effusion-derived exosomes. METHODS: LncRNA profiling was performed on 60 HGSC specimens, including 10 ovarian tumors, 10 solid metastases and 10 malignant effusions, as well as exosomes from 30 effusion supernatants. Anatomic site-related expression of ESRG, Link-A, GAS5, MEG3, GATS, PVT1 H19, Linc-RoR, HOTAIR and MALAT1 was validated by quantitative PCR and assessed for clinical relevance in a series of 77 HGSC effusions, 40 ovarian carcinomas, 21 solid metastases and 42 supernatant exosomes. RESULTS: Significantly different (p<0.05) expression of 241, 406 and 3634 lncRNAs was found in comparative analysis of the ovarian tumors to solid metastases, effusions and exosomes, respectively. Cut-off at two-fold change in lncRNA expression identified 54 lncRNAs present at the 3 anatomic sites and in exosomes. Validation analysis showed significantly different expression of 5 of 10 lncRNAs in the 4 specimen groups (ESRG, Link-A, MEG3, GATS and PVT1, all p<0.001). Higher ESRG levels in HGSC effusions were associated with longer overall survival in the entire effusion cohort (p=0.023) and in patients with pre-chemotherapy effusions tapped at diagnosis (p=0.048). Higher Link-A levels were associated with better overall (p=0.015) and progression-free (p=0.023) survival for patients with post-chemotherapy effusions. Link-A was an independent prognostic marker in Cox multivariate analysis in the latter group (p=0.045). CONCLUSIONS: We present the first evidence of differential LncRNA expression as function of anatomic site in HGSC. LncRNA levels in HGSC effusions are candidate prognostic markers.
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Complejo Multienzimático de Ribonucleasas del Exosoma/genética , Neoplasias Quísticas, Mucinosas y Serosas/genética , Neoplasias Ováricas/genética , Derrame Pleural Maligno/genética , ARN Largo no Codificante/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Expresión Génica , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Neoplasias Quísticas, Mucinosas y Serosas/patología , Neoplasias Quísticas, Mucinosas y Serosas/secundario , Neoplasias Ováricas/patología , Reacción en Cadena de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de SupervivenciaRESUMEN
Nickel oxide thin films are of major importance as anodically coloring components in electrochromic smart windows with applications in energy-efficient buildings. However, the optical performance of these films degrades upon extended electrochemical cycling, which has hampered their implementation. Here, we use a potentiostatic treatment to rejuvenate degraded nickel oxide thin films immersed in electrolytes of LiClO4 in propylene carbonate. Time-of-flight elastic recoil detection analysis provided unambiguous evidence that both Li+ ions and chlorine-based ions participate in the rejuvenation process. Our work provides new perspectives for developing ion-exchange-based devices embodying nickel oxide.
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The purpose of this study was to determine the expression and potential clinical role of epithelial-to-mesenchymal transition (EMT)-related factors in malignant ovarian germ cell tumors (MOGCT). Protein expression of E-cadherin, N-cadherin, P-cadherin, Zeb1, HMGA2, and vimentin by immunohistochemistry was analyzed in 42 MOGCT from patients treated in Norway during the period 1981-2001. Expression was analyzed for association with clinicopathologic parameters. E-cadherin (p = 0.016) and HMGA2 (p = 0.002) expression was significantly higher in immature teratomas and yolk sac tumors compared with dysgerminomas. Vimentin (p < 0.001) and Zeb1 (p = 0.029) staining was significantly higher in immature teratomas compared with yolk sac tumors and dysgerminomas, whereas no significant differences were observed for N-cadherin and P-cadherin. EMT-associated markers were not significantly related to clinicopathologic parameters including age, tumor diameter, and FIGO stage. In conclusion, based on this limited series, EMT-associated markers are not associated with clinical parameters in MOGCT, in contrast to ovarian carcinoma. EMT-related proteins are differentially expressed among various MOGCT subtypes, suggesting differences in biological characteristics associated with invasion and metastasis.
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Cadherinas/metabolismo , Transición Epitelial-Mesenquimal/fisiología , Proteína HMGA2/metabolismo , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias Ováricas/patología , Vimentina/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Adolescente , Adulto , Biomarcadores de Tumor/metabolismo , Niño , Disgerminoma/patología , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Neoplasias de Células Germinales y Embrionarias/terapia , Neoplasias Ováricas/terapia , Teratoma/patología , Adulto JovenRESUMEN
Electrochromic (EC) smart windows are able to decrease our energy footprint while enhancing indoor comfort and convenience. However, the limited durability of these windows, as well as their cost, result in hampered market introduction. Here, we investigate thin films of the most widely studied EC material, WO3. Specifically, we combine optical measurements (using spectrophotometry in conjunction with variable-angle spectroscopic ellipsometry) with time-of-flight secondary ion mass spectrometry and atomic force microscopy. Data were taken on films in their as-deposited state, after immersion in a Li-ion-conducting electrolyte, after severe degradation by harsh voltammetric cycling and after galvanostatic rejuvenation to regain the original EC performance. Unambiguous evidence was found for the trapping and detrapping of Li ions in the films, along with a thickness increase or decrease during degradation and rejuvenation, respectively. It was discovered that (i) the trapped ions exhibited a depth gradient; (ii) following the rejuvenation procedure, a small fraction of the Li ions remained trapped in the film and gave rise to a weak short-wavelength residual absorption; and (iii) the surface roughness of the film was larger in the degraded state than in its virgin and rejuvenated states. These data provide important insights into the degradation mechanisms of EC devices and into means of achieving improved durability.
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The present study analyzed the expression and clinical role of the transforming growth factor-ß (TGFß) pathway in high-grade serous carcinoma (HGSC), with focus on malignant effusions. TGFß1-3 and TGFßRI-III mRNA expression by qRT-PCR was analyzed in 70 HGSC effusions and 55 solid specimens (28 ovarian, 27 abdominal metastases). Protein expression of Smad2 and Smad3 and their phosphorylated forms by Western blotting was analyzed in 73 specimens (42 effusions, 13 ovarian carcinomas, 18 solid metastases). Expression was analyzed for association with anatomic site and clinical parameters, including survival. TGFßRI and TGFßRII mRNA was overexpressed in effusions and solid metastases, particularly the former, compared to that in the ovarian tumors (p < 0.001 to p = 0.05), with anatomic site-dependent expression of splice variants. Conversely, Smad2, p-Smad2, and p-Smad3 were overexpressed in solid specimens (ovarian and peritoneal) compared to those in effusions (p < 0.001 for all). In univariate survival analysis, higher TGFßRI variant 1 and TGFßRIII mRNA levels were associated with a trend for shorter overall survival in patients with post-chemotherapy effusions (p = 0.066 and p = 0.087, respectively), and the latter was an independent prognostic marker in Cox multivariate analysis (p = 0.041). Smad3 protein expression was associated with a trend for shorter overall survival in univariate survival analysis (p = 0.052). TGFß receptor splice variant expression is anatomic site-dependent in HGSC. Elevated levels of TGFß signaling pathway mRNAs are seen in metastatic HGSC, but are not accompanied by increased Smad expression and activation in HGSC effusions, evidence of failure to activate canonical TGFß signaling. Assessment of the prognostic role of this pathway in HGSC effusions merits further research.
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Cistadenocarcinoma Seroso/patología , Neoplasias Ováricas/patología , Factor de Crecimiento Transformador beta/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Empalme Alternativo , Western Blotting , Cistadenocarcinoma Seroso/metabolismo , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Neoplasias Ováricas/metabolismo , Reacción en Cadena de la Polimerasa , Isoformas de Proteínas/metabolismoRESUMEN
The High-mobility group AT-hook 2 protein (HMGA2) is involved in different processes during tumorigenesis. High expression levels of HMGA2 are found in various types of cancer, with recent studies highlighting the important role of miRNAs in the regulation of HMGA2 expression. We report a study of 155 ovarian tumors (30 sex-cord stromal tumors, 22 borderline tumors, and 103 carcinomas) analyzed for HMGA2 expression as well as the expression of two miRNAs targeting this gene, let-7a and miR-30c. We also evaluated the expression of the fragile histidine triad (FHIT) and lin28 homologues (LIN28A/B) genes which are known to be an enhancer of miR-30c expression and a repressor of let-7a, respectively. HMGA2 was found expressed at high levels in most samples analyzed, with clear cell carcinomas as the only exception. let-7a and miR-30c were highly deregulated in all tumor types. LIN28A and FHIT were found overexpressed in all examined tumor types. The chromosomal imbalances that might lead to loss of the genes expressing let-7a and miR-30c could be evaluated on the basis of previously generated karyotypic and high resolution comparative genomic hybridization (CGH) data on 103 tumors. 76% of the samples with an imbalanced genome had at least one chromosomal aberration leading to a deletion of a miRNA cluster for let-7a and miR-30c. FISH using locus specific probes for these clusters validate the aberrations at the gene level. Our study shows that genomic imbalances are involved in miR-30c and let-7a deregulation. One can reasonably assume that dysregulation of these miRNAs is a cause leading to HMGA2 upregulation in ovarian tumors.
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Regulación Neoplásica de la Expresión Génica/genética , Proteína HMGA2/biosíntesis , MicroARNs/genética , Neoplasias Ováricas/genética , Hibridación Genómica Comparativa , Femenino , Perfilación de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Reacción en Cadena en Tiempo Real de la Polimerasa , TranscriptomaRESUMEN
Degradation of electrochromic thin films under extended charge insertion and extraction is a technically important phenomenon for which no in-depth understanding is currently on hand. Here, we report on an explorative study of sputter-deposited WO3 films in a Li-ion-conducting electrolyte by use of cyclic voltammetry, in situ optical transmittance, and impedance spectroscopy. A cycling-dependent decrease of the charge capacity could be accurately modeled by a power-law function, and impedance spectroscopy gave evidence for anomalous diffusion as well as a higher charge-transfer resistance during deintercalation than during intercalation. Thus, a consistent conceptual picture emerged for the degradation dynamics; it includes the growth of an interfacial barrier layer and also embraces anomalous diffusion coupled with dispersive power-law chemical kinetics.
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Juxtaposition of two different genes or gene parts due to chromosomal rearrangement is a well-known neoplasia-associated pathogenetic mechanism. The detection and characterization of such tumorigenic fusions is of great importance both research-wise, diagnostically because they may be specific for distinct tumor entities, and because they may serve as therapeutic targets for antioncogenic drugs that interact directly with the molecular changes responsible for neoplastic transformation.At present, more than 10,000 fusion transcripts have been reported in different types of neoplasia, with one tenth of them being identified in squamous cell carcinomas (SCC) of different locations. No recurrent fusion gene has to date been identified in SCC of the vulva.We performed high-throughput paired-end RNA-sequencing of 12 vulvar SCC and found two recurrent fusions with the STIP1-CREB3L1 and ZDHHC5-GPR137 being present in two tumors each. The transcripts were detected only in the tumor samples, not in normal vulvar tissue from healthy donors used as control. The CREB3L1 and ZDHHC5 genes encode proteins involved in transcription suggesting that the chimeras may alter downstream events in their respective pathways. Expression analysis of the CREB3L1 gene showed the presence of two distinct groups of tumors, one having fusion and downregulation of the gene and the other showing upregulation of CREB3L1.
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Carcinoma de Células Escamosas/genética , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Vulva/genética , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Femenino , Proteínas de Choque Térmico/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Proteínas del Tejido Nervioso/genética , Receptores Acoplados a Proteínas G/genética , Neoplasias de la Vulva/patologíaRESUMEN
The objective of this study was to analyze the expression and clinical role of phospholipase D (PLD) in high-grade serous carcinoma (HGSC). PLD1 and PLD2 isoform expression was studied in 125 HGSC specimens (73 effusions, 28 ovarian tumors, 24 solid metastases) using quantitative real-time reverse-transcription polymerase chain reaction. Expression levels were analyzed for association with clinicopathological parameters, including chemoresponse, and survival. PLD1 and PLD2 isoforms were found in most specimens at all anatomic sites, and their levels were strongly positively related (P<.001 for effusions and solid lesions). PLD2 messenger RNA (mRNA) expression was significantly higher in effusions compared with both carcinomas in the ovary and solid metastases (P<.001). Higher levels of both isoforms were associated with higher CA 125 levels at diagnosis (P<.001), and higher PLD2 mRNA levels in effusions were associated with unfavorable response to chemotherapy (P=.021). Expression levels of the studied isoforms were unrelated to the levels of previously studied mRNAs that form part of the phospholipase A2 pathway or to survival. The present study provides the first evidence of PLD expression in HGSC and suggests a role in mediating progression to effusions and chemoresistance in this cancer.
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Biomarcadores de Tumor/genética , Neoplasias Quísticas, Mucinosas y Serosas/genética , Neoplasias Ováricas/genética , Fosfolipasa D/genética , ARN Mensajero/genética , Adulto , Anciano , Biomarcadores de Tumor/análisis , Biopsia , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Quísticas, Mucinosas y Serosas/enzimología , Neoplasias Quísticas, Mucinosas y Serosas/secundario , Neoplasias Quísticas, Mucinosas y Serosas/terapia , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Valor Predictivo de las Pruebas , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Resultado del TratamientoRESUMEN
The objective of this study was to analyze the expression and clinical role of molecules involved in exosome synthesis and secretion in high-grade serous carcinoma, with focus on malignant effusions. The mRNA expression levels of ARF6, nSMase2, TSAP6, Rab27a and Rab27b by quantitative real-time reverse-transcription polymerase chain reaction were analyzed in 103 HGSC effusions and 65 solid specimens (35 ovarian, 30 abdominal metastases). Protein expression of ARF6, nSMase2, TSAP6 and Rab27a by Western blotting was analyzed in 150 specimens (94 effusions, 29 ovarian carcinomas, 27 solid metastases). Secreted ARF6, nSMase2 and Rab27a protein levels in exosomes were analyzed in supernatants from 75 effusions. Expression levels were analyzed for association with anatomic site and clinical parameters, including survival. nSMase2 and TSAP6 mRNA was overexpressed in effusions compared to solid lesions (P<.001 and P=.003, respectively), whereas ARF6, nSMase2, TSAP6 and Rab27a protein was overexpressed in solid specimens (ovarian and peritoneal) compared to effusions (P<.001 for all). Secreted ARF6, nSMase2 and Rab27a levels were found in all effusion supernatants. In univariate survival analysis, higher TSAP6 protein levels in effusions were associated with shorter overall survival (P=.01), a finding which was reproduced in analysis of specimens from patients with pre-chemotherapy effusions tapped at diagnosis (P=.026). Higher levels of exosomal Rab27a protein were significantly related to longer overall survival (P=.025). Molecules which are part of the exosome secretion machinery are differentially expressed in HGSC effusions and solid lesions and are present in effusion supernatant-derived exosomes. TSAP6 and Rab27a may be novel prognostic markers in metastatic HGSC.