Energy metabolism: a new target for gastric cancer treatment

Gastric cancer is the fifth most common malignancy worldwide having the fourth highest mortality rate. Energy metabolism is key and closely linked to tumour development. Most important in the reprogramming of cancer metabolism is the Warburg effect, which suggests that tumour cells will utilise glycolysis even with normal oxygen levels. Various molecules exert their effects by acting on enzymes in the glycolytic pathway, integral to glycolysis. Second, mitochondrial abnormalities in the reprogramming of energy metabolism, with consequences for glutamine metabolism, the tricarboxylic acid cycle and oxidative phosphorylation, abnormal fatty acid oxidation and plasma lipoprotein metabolism are important components of tumour metabolism. Third, inflammation-induced oxidative stress is a danger signal for cancer. Fourth, patterns of signalling pathways involve all aspects of metabolic transduction, and many clinical drugs exert their anticancer effects through energy metabolic signalling. This review summarises research on energy metabolism genes, enzymes and proteins and transduction pathways associated with gastric cancer, and discusses the mechanisms affecting their effects on postoperative treatment resistance and prognoses of gastric cancer. We believe that an in-depth understanding of energy metabolism reprogramming will aid the diagnosis and subsequent treatment of gastric cancer (AU)

CircRNAs: emerging factors for regulating glucose metabolism in colorectal cancer

Colorectal cancer is a malignant disease with a high incidence and low survival rate, and the effectiveness of traditional treatments, such as surgery and radiotherapy, is very limited. CircRNAs, a kind of stable endogenous circular RNA, generally function by sponging miRNAs and binding or translating proteins. CircRNAs have been identified to play an important role in regulating the proliferation and metabolism of CRC. In recent years, many reports have indicated that by regulating the expression of glycolysis-related proteins, such as GLUT1 and HK2, or directly translating proteins, circRNAs can promote the Warburg effect in cancer cells, thereby driving CRC metabolism. Moreover, the Warburg effect increases lactate production in cancer cells and promotes acidification of the TME, which further drives cancer progression. In this review, we summarized the remarkable role of circRNAs in regulating glucose metabolism in CRC in recent years, which might be useful for finding new targets for the clinical treatment of CRC (AU)

Glycolysis regulator PFKP induces human melanoma cell proliferation and tumor growth

Purpose Cutaneous melanoma is an aggressive and deadly cancer resulting from malignant transformation of cells involved in skin pigmentation. Glycolysis is widely implicated in cancer progression, but its precise role in melanoma has not been extensively studied. Here, we investigated the role of the glycolysis regulator phosphofructokinase 1 platelet isoform (PFKP) in melanoma progression. Methods PFKP expression in human melanoma tissues was analyzed by immunohistochemistry. Knockdown of PFKP by siRNA and overexpression of PFKP were performed to evaluate its functions in vitro. CCK-8 assay was used to assess cell proliferation. Glycolytic activity was determined via measurement of extracellular acidification rate (ECAR), lactic acid level, and ATP content. A tumor xenograft model was used to test the function of PFKP in vivo. Results PFKP upregulation was observed in human melanoma tissues and correlated with poor patient survival. Knockdown of PFKP in human melanoma cells suppressed cell proliferation and reduced ECAR, ATP levels, and lactic acid levels, while overexpression of PFKP displayed the opposite effects. In vivo, knockdown of PFKP in melanoma cells markedly reduced tumorigenesis. Inhibitory effects on cell proliferation, glycolysis, and tumorigenesis due to PFKP knockdown were further augmented upon treatment with the glycolysis inhibitor 2-deoxy-D-glucose (2-DG). Conclusion Collectively, these results indicate that PFKP expression in melanoma cells increases proliferation and glycolytic activity in vitro and promotes tumorigenesis in vivo, suggesting that suppression of PKFP and inhibition of glycolysis may potently suppress melanoma progression (AU)

Essential role of aerobic glycolysis in epithelial-to-mesenchymal transition during carcinogenesis

Epithelial-to-mesenchymal transition (EMT) confers the most lethal characteristics to cancer cells i.e., metastasis and resistance to chemo-and-radio-therapy, and therefore exhibit an appealing target in the field of oncology. Research in the past decade has demonstrated the crucial role of aerobic glycolysis in EMT, which is generally credited as the glucose metabolism for the creation of biomass such as fatty acids, amino acids, and nucleotides thereby providing building blocks for limitless proliferation. In the present review, apart from discussing EMT’s evident role in the metastatic process and cancer stemness, we also talked about the vital role of glycolytic enzymes viz. GLUTs, HKs, PGI, PFK-1, aldolase, enolase, PK, LDHA, etc. in the induction of the EMT process in cancerous cells. (AU)

Circ_03955 promotes pancreatic cancer tumorigenesis and Warburg effect by targeting the miR-3662/HIF-1α axis

Objectives Former studies found that circRNAs play an important part in the occurrence of a variety of malignant biological characteristics that are critical for cancer progression. It has been shown that circ_03955 is highly expressed and implicated with quantities of biological processes in solid tumor. However, whether circ_03955 regulates the tumorigenesis and Warburg effect of pancreatic cancer (PC) remains largely unknown. Materials and methods The level of circ_03955 in PC tissues and cell lines was determined by real-time qPCR (RT-qPCR). Loss-of-function and gain-of-function assays were employed to investigate the biological role of circ_03955 in cell proliferation, apoptosis, and glycolysis. RT-qPCR, western blotting, bioinformatics analysis, luciferase reporter assay, and in vivo tumorigenicity assay were employed to determine the underlying mechanisms. Results In this study, it was investigated that circ_03955 was up-regulated in PC clinical samples as well as PC cell lines and associated with poor clinical outcomes of PC patients. Functional assays revealed that circ_03955 exerts a certain stimulative effect on the growth of PC cells in vitro and in vivo. Circ_03955 also inhibited apoptosis and promotes Warburg effect in PC cells. Mechanistically, bioinformatics analysis indicated that circ_03955 acts as a sponge for microRNA (miR)-3662, and hypoxia-inducible factor 1ɑ (HIF-1ɑ) was one of the transcriptional targets of miR-3662. Importantly, genetic promoting of HIF-1ɑ or downregulation of miR-3662 largely compromised circ_03955 depletion mediated tumor-inhibiting effects. Conclusions Taken together, circ_03955 functions as a tumor promoter through miR-3662/HIF-1α axis, which might provide a novel sight for PC treatment (AU)

UCHL3 promotes aerobic glycolysis of pancreatic cancer through upregulating LDHA expression

Background Aerobic glycolysis has a pivotal role in the carcinogenic process. The current understanding of the functional role and mechanism of UCHL3-related aerobic glycolysis in pancreatic cancer is far from comprehensive, therefore requires an in-depth analysis on this aspect. Methods In the present research, the expressions of ubiquitin carboxyl-terminal hydrolase L3 (UCHL3), lactate dehydrogenase A (LDHA) and Forkhead box protein M1 (FOXM1) were detected by qRT-PCR, Western blot and immunohistochemistry. The effects of UCHL3 knockdown or overexpression on pancreatic cancer cells were examined by determining cell viability and colony formation. Aerobic glycolysis was assessed according to glucose uptake, lactic acid production, and lactate dehydrogenase (LDH) activity. Dual-luciferase reporter assay was performed to detect LDHA promoter activity. Results The results showed that UCHL3 expression was significantly increased in the pancreatic cancer tissues and cells, and that knocking down UCHL3 noticeably inhibited cell viability and aerobic glycolysis. Further investigations revealed that LDHA expression was promoted by UCHL3 and could be reduced by shFOXM1, and that low-expressed LDHA partly reversed the inhibition of aerobic glycolysis induced by overexpressed UCHL3. Conclusions To conclude, this study demonstrates that UCHL3 plays a carcinogenic role by promoting aerobic glycolysis in pancreatic cancer, suggesting that UCHL3 may be a potential diagnostic and therapeutic target for the treatment of cancer (AU)

El papel pronóstico de la PET/TC en el cáncer pulmonar de células pequeñas / The prognostic role of PET/CT in small-cell lung cancer

OBJETIVO: El propósito del presente estudio es determinar el valor pronóstico de los parámetros metabólicos relacionados con los tumores primarios detectados en los exámenes por tomografía por emisión de positrones/tomografía computarizada (PET/TC) del pretratamiento flúor-18 2-fluoro-2-desoxi-D-glucosa (18F FDG) de pacientes a los que se les ha diagnosticado cáncer pulmonar de células pequeñas (SCLC, por sus siglas en inglés). MATERIALES Y MÉTODOS: En este estudio retrospectivo se inscribieron 63 pacientes con un diagnóstico histopatológicamente confirmado de SCLC a los que se les aplicó un escáner PET/TC con 18F FDG en la línea basal. Se registraron la etapa de la enfermedad, la edad en su diagnóstico, el sexo, el nivel de albúmina y el valor máximo de captación estándar (SUVmax), SUVmean, el volumen de tumor metabólico (MTV) y los valores de glucólisis total de la lesión) relacionados con el tumor primario en el escáner PET de línea basal y se evaluó la relación de estos factores con la supervivencia libre de progresión (PFS) y la supervivencia global (OS). RESULTADOS: El estudio incluyó un total de 63 pacientes (10 mujeres, 53 hombres, con una edad media de 64,8 y un rango de edad de 43-82 años), 22 de los cuales tenía enfermedad limitada (LD) y 41 tenía enfermedad extendida (ED). Los OS y PFS fueron significativamente mayores en pacientes con LD que en pacientes con ED (15+/-2,9 ante 10+/-0,9 meses, p = 0,002 para OS; 10+/- 0,7 ante 6+/-0,6 meses, p = 0,014 para PFS). Sin embargo, no se identificó una relación estadísticamente significativa entre el sexo, el nivel de albúmina, la edad y los niveles SUVmax, SUVmean, MTV y TLG relacionados con el tumor primario y PFS u OS. CONCLUSIÓN: El presente estudio descubrió que los parámetros PET del pretratamiento no tenían valor predictivo para el PFS y OS en pacientes con SCLC

OBJECTIVE: The aim in the present study is to determine the prognostic value of metabolic parameters related to the primary tumors detected in pretreatment Fluorine-18 2-fluoro-2-Deoxy-D-glucose (18F FDG) positron emission tomography/computerized tomography (PET/CT) scans of patients diagnosed with small-cell lung cancer (SCLC). MATERIAL AND METHODS: Enrolled in this retrospective study were 63 patients with a histopathologically confirmed diagnosis of SCLC who underwent an 18F FDG PET/CT scan at baseline. Disease stage, age at diagnosis, gender, albumin level and maximum standardized uptake value (SUVmax), SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) values related to the primary tumor at the baseline PET scan were recorded, and the relationship of these factors with progression-free survival (PFS) and overall survival (OS) was evaluated. RESULTS: The study included a total of 63 patients (10 female, 53 male, mean age of 64.8 and age range of 43-82 years), 22 of which had limited disease (LD) and 41 had extensive disease (ED). The OS and PFS were significantly higher in patients with LD than in patients with ED (15+/-2.9 vs. 10+/-0.9 months, p = 0.002 for OS; 10+/- 0.7 vs 6+/-0.6 months, p = 0.014 for PFS). However, no statistically significant relationship was identified between gender, albumin level, age and SUVmax, SUVmean, MTV, TLG values related to the primary tumor and PFS or OS. CONCLUSION: The present study found that pretreatment PET parameters were of not predictive value for PFS and OS in patients with SCLC

Significación pronóstica del volumen metabólico tumoral y de la glucólisis tumoral total en pacientes con cáncer cervical avanzado / Prognostic significance of metabolic tumor volume and total lesion glycolysis in patients with advanced cervical carcinoma

Objetivo: La tomografía por emisión de positrones con 18-flúor-2-desoxi-D-glucosa (18F-FDG PET/TC) es considerada el método de imagen más preciso para la detección de las metástasis ganglionares o a distancia en el cáncer cervical. El volumen metabólico tumoral (VMT) y la glucólisis tumoral total (GTT) de 18F-FDG PET/TC constituyen mediciones volumétricas de las células tumorales, con captación incrementada de 18F-FDG. Se evaluó el valor pronóstico de VMT y GTT en pacientes con cáncer cervical avanzado (CCA). Métodos: A 38 pacientes con CCA de un hospital universitario terciario se les realizó 18F-FDG PET/TC entre junio de 2009 y diciembre de 2015. Se analizaron diversos factores clínico-patológicos y parámetros de PET, para evaluar su relación con la supervivencia libre de progresión (SLP) y la supervivencia global (SG). Dichos parámetros fueron: valor estandarizado de captación máximo (SUVmáx), valor estandarizado de captación medio (SUVmedio), VMT y GTT del tumor primario, los ganglios pélvicos, los ganglios paraaórticos y el volumen metabólico metastásico, de existir. Resultados: Un total de 38 pacientes con CCA cumplieron los criterios de inclusión. A todos ellos se les realizó 18F-FDG PET/TC con anterioridad a la quimiorradioterapia definitiva. En los análisis univariantes el tamaño tumoral mayor, las metástasis de los ganglios pélvicos, el VMT y la GTT reflejaron una asociación significativa con la SLP y la SG (el VMT HR=1,55, p=0,011 y la GTT HR=1,43, p=0,017 para la SLP; y el VMT HR=1,82, p=0,006 y la GTT HR=1,67, p=0,007 para la SG). Conclusión: La suma de GTT y la suma de VMT pretratamiento parecen ser un factor pronóstico independiente para la SG y la SLP en pacientes con CCA tratados mediante quimiorradioterapia definitiva, y reflejan una medición mejor que la clásica de SUVmáx

Aim: 18-Fluoro-2-deoxy-d-glucose positron emission tomography (18F-FDG PET/CT) is considered to be the most accurate image method of detection of node or distant metastases in cervical cancer. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of 18F-FDG PET/CT are volumetric measurements of tumor cells with increased 18F-FDG uptake. The prognostic value of MTV and TLG in patients with advanced cervical cancer (ACC) were evaluated. Methods: 38 patients with ACC from one tertiary university hospital underwent 18F-FDG PET/CT between June 2009 and December 2015. Clinicopathologic factors and various PET parameters were analyzed to evaluate their relationship with recurrence-free survival (RFS) and overall survival (OS). These parameters were: maximum standardized uptake value (SUVmax), mean standardized uptake value (SUV mean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumor, of the pelvic nodes, of the paraaortic nodes and the metabolic volume of the metastases if any. Results: A total of 38 patients with ACC fulfilled the inclusion criteria. All of them underwent a 18F-FDG PET/CT before definitive chemoradiotherapy. In the univariate analyses higher tumor size, pelvic lymph node metastasis and both MTV and TLG showed a significant association with OS and with RFS (MTV HR=1.55, p=0.011 and TLG HR=1.43, p=0.017 for RFS and MTV HR=1.82, p=0.006 and TLG HR=1.67, p=0.007 for OS). Conclusion: Pretreatment TLG sum and MTV sum seem to be independent prognostic factors for OS and RFS in patients with advanced cervical cancer treated with definitive chemoradiotherapy and they are better than the classic measurement of SUVmax

El músculo, paradigma metabólico en la recuperación nutricional / Muscle, metabolic paradigm in nutritional recovery

El músculo esquelético es un tejido que representa la mayor parte de la masa corporal total y de las proteínas corporales y que desempeña diversas funciones vitales. La masa muscular es el resultado del equilibrio entre síntesis y degradación y ambos procesos son sensibles a factores como el estado nutricional, el equilibrio hormonal, la actividad física y el ejercicio, así como a la enfermedad. En diversos estados de desnutrición asociados a varias patologías infecciosas y traumáticas, así como a enfermedades crónicas, la masa muscular es afectada más o menos severamente. Asimismo, la sarcopenia es una alteración progresiva y generalizada del músculo esquelético que aparece con la edad y que se asocia con una mayor probabilidad de eventos adversos, como caídas, fracturas, incapacidad física y mortalidad. Por tanto, la recuperación de la masa y de la funcionalidad muscular es clave para mejorar los estados de desnutrición asociados a numerosas patologías. En el presente artículo se resumen las vías metabólicas y los nutrientes más utilizados por el músculo para la obtención de energía y las vías de señalización celular implicadas en la síntesis y degradación del músculo. Asimismo, se comenta la importancia de algunas mioquinas en la interacción con otros tejidos para el mantenimiento de la homeostasis corporal. Existe un gran número de reguladores positivos de la síntesis de proteína muscular. Especialmente, los aminoácidos de cadena ramificada durante la restricción energética contribuyen a la síntesis de proteína muscular, así como a la atenuación de la excreción de nitrógeno corporal y de la proteólisis muscular

Skeletal muscle is a tissue that represents the majority of total body mass and proteins in healthy humans. Muscle mass is the results of balance between synthesis and proteolysis, both processes being sensitive to a variety of factors including nutritional status, hormonal balance, physical activity and exercise, and disease. Indeed, muscle mass loss is associated with several infectious, traumatic and chronic pathologies. Likewise, sarcopenia is a progressive and generalized skeletal muscle disorder appearing with ageing associated with increased likelihood of adverse outcomes including falls, fractures, physical disability, and mortality. Hence, recovery of muscle mass and functionality is a key factor to improve undernutrition associated with many pathological conditions. The aim of the present article is to summarize the most important substrates, metabolic and cell signaling pathways involved in the synthesis, degradation and turnover in skeletal muscle. Moreover, the importance of some myokines in the interaction between skeletal muscle and other tissues, and in the maintenance of homeostasis is highlighted. A great number of positive regulators for muscle protein synthesis has been reported. Especially, during energy restriction, branched chain amino acids, e.g. leucine, contribute majorly to muscle protein synthesis as well as to attenuate nitrogen body excretion and muscle proteolysis

Monitorización de la actividad glucolítica secundaria a isquemia en cirugía sustitutiva de rodilla / Monitoring of glycolytic activity secondary to ischaemia in knee replacement surgery

Objetivos: Evaluar de forma no invasiva la lesión tisular secundaria a la isquemia aplicada durante la cirugía sustitutiva de rodilla. Objetivos secundarios: evaluar si dicha lesión se correlaciona con el tiempo que se prolonga la isquemia y la influencia de las variables instrumental y sexo. Material y método: Estudio de cohortes prospectivo. Se han determinado los niveles pre- y postoperatorios de lactato sérico, como indicador de actividad glucolítica secundaria a isquemia, en 88 pacientes. Se han empleado tiras reactivas de detección enzimático-amperométrica sobre sangre capilar. Resultados: Niveles preoperatorios de lactato sérico (media y DE): 2,467±1,036 mmol/L. Niveles postoperatorios de lactato sérico: 3,938±2,018 mmol/L. Tiempo de isquemia 102,98±18,25min. Los niveles postoperatorios de lactato sérico han sido significativamente mayores que los preoperatorios. No existen diferencias atendiendo a las variables tiempo que se prolonga la isquemia, sexo o tipo de instrumentación empleada. Conclusiones: En nuestro estudio, los valores de lactato sérico postoperatorios han sido significativamente mayores que los preoperatorios, sin una correlación con el tiempo que se ha prolongado la isquemia durante la cirugía sustitutiva de rodilla

Objectives: To non-invasively assess tissue lesion secondary to ischaemia applied during knee replacement surgery. Secondary objectives: to assess whether this lesion correlates with the duration of ischaemia and whether instrumental and gender variables influence it. Material and methods: Prospective cohort study. Pre and postoperative serum lactate levels have been determined as an indicator of glycolytic activity secondary to ischaemia in 88 patients. Serum lactate determination was performed by reactive strips of enzymatic-amperometric detection on capillary blood. Results: Preoperative serum lactate levels (mean and SD): 2.467±1.036 mmol/L. Postoperative serum lactate levels: 3.938±2.018 mmol/L. Ischaemia time 102.98±18.25minutes. Postoperative serum lactate levels were significantly higher than preoperative lactate levels. There are no statistical differences according to the time that the ischaemia was prolonged, gender or type of instrumentation used. Conclusions: In our study, postoperative serum lactate values were significantly higher than preoperative lactate values, with no correlation to the duration of ischaemia during knee replacement surgery

Parámetros de cuantificación metabólica en la práctica clínica. ¿Es el momento de incluirlos en los informes? / Parameters of metabolic quantification in clinical practice. Is it now time to include them in reports?

Las técnicas de valoración cualitativa han sido el estándar tradicional de valoración diagnóstica en los estudios PET con 18F-FDG. Desde los inicios de la técnica se han buscado parámetros cuantitativos, más exactos y con mejor precisión diagnóstica, que puedan ofrecer información relevante en cuanto al comportamiento, agresividad o pronóstico de los tumores. Cada vez hay más estudios con evidencia de alta calidad sobre la utilidad de diferentes parámetros metabólicos distintos al SUV máximo, cuyo uso es controvertido, a pesar de ser ampliamente utilizado en la práctica clínica, y del que muchos médicos desconocen todavía su significado real. El objetivo de este trabajo ha sido revisar los conceptos clave de estos parámetros metabólicos que pueden ser relevantes en la práctica habitual durante los próximos años. Se ha visto que existe mayor evidencia en la valoración del metabolismo de una lesión de forma completa a través de parámetros volumétricos que reflejan de forma más adecuada la carga tumoral que presenta un paciente. Básicamente, estos parámetros calculan el volumen de tumor que cumple unas características determinadas. Para ello se ha utilizado un software, disponible en la mayor parte de las estaciones de trabajo y procesado de estudios PET, que ha permitido calcular estos volúmenes utilizando criterios más o menos complejos. Los métodos de segmentación más simples, basados en umbrales, están disponibles en la mayor parte de los equipos, son fáciles de calcular y han demostrado en muchos trabajos tener un importante significado pronóstico

Qualitative techniques have traditionally been the standard for the diagnostic assessment with 18F-FDG PET studies. Since the introduction of the technique, quantitative parameters have been sought, more accurate and with better diagnostic precision, that may offer relevant information of the behavior, aggressiveness or prognosis of tumors. Nowadays, more and more studies with high quality evidence show the utility of other metabolic parameters different from the SUV maximum, which despite being widely used in clinical practice is controversial and many physicians still do not know its real meaning. The objective of this paper has been to review the key concepts of these metabolic parameters that could be relevant in normal practice in the future. It has been seen that there is more evidence in the complete evaluation of the metabolism of a lesion, through volumetric parameters that more adequately reflect the patient's tumor burden. Basically, these parameters calculate the volume of tumor that fulfills certain characteristics. A software available in the majority of the workstations has been used for this purpose and it has allowed to calculate these volumes using more or less complex criteria. The simplest threshold-based segmentation methods are available in most equipments, they are easy to calculate and they have been shown in many studies to have an important prognostic significance

Metodología de la PET/TC con 18F-FDG cardíaca para el diagnóstico de la endocarditis protésica y de dispositivos intracardíacos / Cardiac 18F-FDG PET/CT procedure for the diagnosis of prosthetic endocarditis and intracardiac devices

La endocarditis infecciosa (EI) es una patología grave y con mal pronóstico cuya mortalidad no se ha modificado significativamente a pesar de los avances en su diagnóstico y tratamiento en los últimos 30años. La capacidad diagnóstica de los criterios de Duke modificados en la endocarditis protésica y/o de dispositivos no supera el 50%, por lo que se hacen necesarias nuevas herramientas para el diagnóstico de esta entidad en dicho contexto. La 18F-FDG PET/aTC combina una técnica con gran sensibilidad para detectar actividad inflamatoria-infecciosa y una técnica con gran resolución anatómica para valorar las lesiones estructurales asociadas a la endocarditis. Con una sensibilidad diagnóstica entre el 91 y el 97%, esta técnica híbrida se ha convertido en una herramienta de diagnóstico útil en la sospecha de EI de pacientes con válvulas protésicas o dispositivos, convirtiéndose en un criterio mayor en el algoritmo diagnóstico de las guías actuales. Esta excelente capacidad diagnóstica depende de forma directa de la calidad de la exploración obtenida y del conocimiento a la hora de interpretar las imágenes. El objetivo de esta revisión es describir y estandarizar la metodología de la 18F-FDG-PET/aTC cardíaca en el diagnóstico de endocarditis protésica y de dispositivos intracardíacos, haciendo especial énfasis en las particularidades de la preparación del paciente, de la adquisición de los estudios PET y TC, y del posterior posprocesado e interpretación de las imágenes

Infective endocarditis (IE) is a serious condition with a poor prognosis, its mortality unchanged significantly despite diagnostic and therapeutic advances in the last 30years. The diagnostic ability of the modified Duke criteria in prosthetic endocarditis and/or devices does not exceed 50%, so new tools are necessary for the diagnosis of this entity in this context. The 18F-FDG PET/CTA combines a highly sensitive technique to detect inflammatory-infectious activity with a technique with high anatomical resolution to assess the structural lesions associated with endocarditis. With a diagnostic sensitivity between 91-97%, this hybrid technique has become a useful diagnostic tool for patients with prosthetic valves or devices and suspicion of IE, becoming a major criterion in the diagnostic algorithm of current guidelines. This excellent diagnostic ability depends directly on the quality of the obtained exploration and the knowledge at the time of interpreting the images. The aim of this review is to describe and standardize the methodology of cardiac 18F-FDG PET/CTA in the diagnosis of endocarditis in prosthetic valves and intracardiac devices, with special emphasis on the particularities of the patient's preparation, the PET and CT acquisition procedures, and the subsequent imaging postprocessing and interpretation

Correlación de la captación de 18F-FDG de la PET/TC con el Ki67 de la inmunohistoquímica en el cáncer epitelial de ovario pretratamiento / Correlation of 18F-FDG uptake on PET/CT with Ki67 immunohistochemistry in pre-treatment epithelial ovarian cancer

Objetivo. El Standardized uptake value (SUV) y los parámetros volumétricos volumen metabólico tumoral (MTV) y glicolisis total de la lesión (TLG) de la 18F-FDG PET/TC son útiles para determinar el pronóstico preoperatorio y postratamiento del cáncer epitelial de ovario (CEO). El Ki67 es otro marcador pronóstico en el CEO asociado con la agresividad tumoral. El objetivo fue estudiar la asociación entre los parámetros de la 18F-FDG PET/TC y el Ki67 en el CEO pretratamiento para determinar si la PET/TC puede predecir la agresividad tumoral de forma no invasiva. Material y métodos. Se realizó una PET/TC a 18 pacientes con sospecha o recién diagnóstico de CEO. Se obtuvo el SUV máximo (SUVmax), SUV medio (SUVmean) y el MTV y la TLG corporal (wbMTV y wbTLG, respectivamente), con un dintel del 30%-40% del SUVmax. Se estimó el índice de Ki67 (medio y máximo) en muestras del tejido tumoral, y se correlacionó con los parámetros de la PET. Resultados. La edad media fue 57,0 años (desviación estándar 13,6 años). Se observó una moderada correlación entre el Ki67 medio y el SUVmax (r=0.392), SUVmean 30% (r=0.437) y SUVmean 40% (r=0.443), así como entre el Ki67 máximo y el SUVmax (r=0.360), SUVmean 30% (r=0.362) y SUVmean 40% (r=0.319). La correlación fue más débil, e inversamente negativa, entre el Ki67 medio y máximo y los parámetros volumétricos de la PET. No hubo diferencias estadísticamente significativas entre las correlaciones. Conclusiones. SUVmax y SUVmean se correlacionaron moderadamente con el Ki67 mientras que los parámetros volumétricos mostraron una correlación débil. SUVmax y SUVmean podrían utilizarse para predecir la agresividad tumoral en el CEO pretratamiento (AU)

Objective. Standardised uptake value (SUV) and volumetric parameters such as metabolic tumour volume (MTV) and total lesion glycolysis (TLG) from 18F-FDG PET/CT are useful criteria for disease prognosis in pre-operative and post-treatment epithelial ovarian cancer (EOC). Ki67 is another prognostic biomarker in EOC, associated with tumour aggressiveness. The aim of this study is to evaluate the association between 18F-FDG PET/CT measurements and Ki67 in pre-treatment EOC to determine if PET/CT parameters could non-invasively predict tumour aggressiveness. Material and methods. A pre-treatment PET/CT was performed on 18 patients with suspected or newly diagnosed EOC. Maximum SUV (SUVmax), mean SUV (SUVmean), whole-body MTV (wbMTV), and whole-body TLG (wbTLG) with a threshold of 30% and 40% of the SUVmax were obtained. Furthermore, Ki67 index (mean and hotspot) was estimated in tumour tissue specimens. Immunohistochemical findings were correlated with PET parameters. Results. The mean age was 57.0 years old (standard deviation 13.6 years). A moderate correlation was observed between mean Ki67 index and SUVmax (r=0.392), SUVmean 30% (r=0.437), and SUVmean 40% (r=0.443), and also between hotspot Ki67 index and SUVmax (r=0.360), SUVmean 30% (r=0.362) and SUVmean 40% (r=0.319). There was a weaker correlation, which was inversely negative, between mean and hotspot Ki67 and volumetric PET parameters. However, no statistical significant differences were found for any correlations. Conclusions. SUVmax and SUVmean were moderately correlated with Ki67 index, whereas volumetric PET parameters overall, showed a weaker correlation. Thus, SUVmax and SUVmean could be used to assess tumour aggressiveness in pre-treatment EOC (AU)

Sodium butyrate protects against oxidative stress in HepG2 cells through modulating Nrf2 pathway and mitochondrial function

Sodium butyrate (NaBu) is a by-product of microbial fermentation of dietary fiber in the gastrointestinal tract and has been shown to increase the activity of antioxidant enzymes, such as catalase or heme oxidase-1, in vivo. However, the mechanism of this effect is still unclear. This study investigated the antioxidant effect of NaBu on HepG2 cells under H2O2-induced oxidative stress. NaBu (0.3 mM) attenuated cell death and accumulation of reactive oxygen species and improved multiple antioxidant parameters in H2O2-injured HepG2 cells. NaBu inhibited glycogen synthase kinase-3 beta (GSK-3Beta) by increasing the p-GSK-3 Beta (Ser9) level and promoted nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), which increased the expression of downstream antioxidant enzymes. Together with promotion of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and mitochondrial DNA copy number, NaBu modulated energy metabolism and mitochondrial function, decreasing glycolysis, increasing Beta -oxidation, and enhancing the tricarboxylic acid cycle and oxidative phosphorylation. NaBu increased mitochondrial manganese-superoxide dismutase and glutathione peroxidase activity. In conclusion, NaBu protected HepG2 cells against oxidative stress by modulating Nrf2 pathway activity and mitochondrial function

Trichomonas vaginalis: la versatilidad de un parásito tenaz / The versatility of a tenacious parasite

La tricomonosis urogenital humana, causada por el parásito Trichomonas vaginalis, es una de las infecciones de transmisión sexual (I.T.S.) de mayor prevalencia en el mundo, con un total de 276 millones de casos cada año, según la OMS. Algunos autores la han calificado como una enfermedad desatendida u olvidada ligada a la pobreza, a pesar de que más del 50% de las I.T.S. curables se deben a este agente etiológico. La tricomonosis cursa con un rango amplio de manifestaciones clínicas, que van desde casos asintomáticos hasta cuadros más graves e invasivos de los conductos genitourinarios. Se ha relacionado la infección con el riesgo de adquisición y transmisión del VIH y de lesiones preneoplásicas de cérvix y próstata. Este protozoo parásito presenta una gran variabilidad intraespecífica en su comportamiento patogénico, probablemente por el tamaño y complejidad de su genoma, con más de 60.000 genes codificantes. Es capaz de sobrevivir y colonizar un nicho complejo sometido a constantes fluctuaciones, el aparato genitourinario, pasando desapercibido en muchos casos. El tamaño y complejidad de su genoma convierten a T. vaginalis en un parásito de gran interés científico para el estudio de los mecanismos de patogenia y evasión de la respuesta inmune (AU)

Trichomonosis is one of the most prevalent nonviral sexually transmitted infection (S.T.I.) worldwide, with an estimated 276 million cases per year according to WHO overview. Little attention is paid to this disease, although more than 50% of S.T.I. curable are caused by this protozoon. Clinically, Trichomonas vaginalis infection can produce a wide range of pathological manifestations, from asymptomatic presentation to severe inflammatory and invasive lesions in the genitourinary tract of both men and women. The possible role displayed by T. vaginalis as a viral vector might also explain its role as a risk factor in the development of cervical and prostate neoplasia. In addition, trichomonosis is strongly associated with transmission and acquisition of other bacterial and viral pathogens like HIV. T. vaginalis is a very complex organism and has developed diverse mechanisms for the colonization of the genitourinary tract probably due to its extensive genome. This parasite must survive in a hostile environment exposed to continue fluctuations. Surprisingly, T. vaginalis possesses one of the largest and most repetitive genomes, with a core set of 60,000 protein-coding genes. According to all these features, T. vaginalis could be considered an excellent model of parasite to be studied in order to better understand the dynamics and immune evasion mechanisms of such versatile parasite (AU)

Papel pronóstico del volumen metabólico tumoral y de la glucólisis tumoral total en los estudios 18F-FDG PET/TC de estadificación del cáncer localmente avanzado de mama / Prognostic value of metabolic tumour volume and total lesion glycolysis in 18F-FDG PET/CT scans in locally advanced breast cancer staging

Objetivo. Conocer si el volumen metabólico tumoral (VMT) y la glucólisis tumoral total (GTT) pueden predecir el riesgo de recurrencia en cáncer localmente avanzado de mama (CLAM). Material y métodos. Estudio retrospectivo de pacientes con CLAM tratados con tratamiento neoadyuvante, local y adyuvante; en seguimiento. Se realizó una 18F-FDG PET/TC para estadificar la enfermedad, midiéndose diferentes parámetros metabólicos (VMT, GTT, SUVmáx y SUVmed), tanto en el tumor primario (T) como en los ganglios metastásicos (N) y en el cuerpo entero (CE). Resultados. Se incluyeron 40 mujeres entre enero de 2010-2011; seguimiento hasta enero de 2015. Con una mediana de seguimiento de 46 meses el 20% tuvieron recidiva, local (n=2) o a distancia (n=6); fallecieron 3 (38% de aquellas con recidiva y 7,5% del total). EL SUVmáx, VMT y GTT, tanto en T, como N y CE, fue mayor en aquellas que presentaron recidiva. En el T tanto el VMT como la GTT se relacionaron con la recidiva de la enfermedad (p=0,020 y p=0,028, respectivamente), mientras que en la N fue el SUVmáx (p=0,008). Los puntos de corte óptimos para predecir recurrencia fueron: VMT T≥19,3cm3, GTT T≥74,4g y SUVmáx N≥13,8, existiendo 10-12 veces más probabilidad de experimentar progresión tumoral cuando superaban estos umbrales. El grado tumoral fue la única variable clínico-patológica asociada con la recidiva (p=0,035). Conclusiones. En este estudio de CLAM los parámetros metabólicos que más se asocian con la tasa de recidiva son el VMT y la GTT en el tumor primario, el SUVmáx en la enfermedad ganglionar regional y los 3 índices PET en el cuerpo entero. Estos parámetros podrían utilizarse en la práctica asistencial para identificar a las pacientes con mayor riesgo (AU)

Objective. To determine whether metabolic tumour volume (MTV) and total lesion glycolysis (TLG) are able to predict recurrence risk in locally advanced breast cancer (LABC) patients. Material and methods. Retrospective study of LABC patients who undertook neoadjuvant, local and adjuvant treatment and follow up. A 18F-FDG PET/CT study for initial staging was performed analysing in this study different metabolic parameters (MTV, TLG, SUVmax and SUVmed) both in the primary tumour (T) as well as in axillary nodes (N) and whole-body (WB). Results. Forty females were included between January 2010-2011; follow up until January 2015 was completed. The average follow-up was 46 months. Twenty percent presented recurrence: local disease (n=2) and distant metastasis (n=6); 3 patients died (38% of the patients which recurred and 7.5% from the total). SUVmax, MTV and TLG, in T, N and WB, were higher in those patients with recurrence. The MTV and TLG parameters in the tumour (T) were related to the recurrence rate (P=.020 and P=.028, respectively); whereas SUVmax in the lymph nodes (N) was significantly related (P=.008) to the recurrence rate. The best cut-off points to predict recurrence where: MTV T ≥19.3cm3, TLG T≥74.4g and SUVmax N≥13.8, being 10-12 times more likely to recidivate when these thresholds where exceeded. Tumour grade was the only clinical-pathological variable which was related to recurrence probability (p=.035). Conclusions. In this study of LABC patients the metabolic parameters which have a better relationship with recurrence rate are: MTV and TLG in the primary tumour, SUVmax in the regional lymph node disease and whole-body PET data (AU)

Targeting thiamine-dependent enzymes for metabolic therapies in oral squamous cell carcinoma?

Purpose. Thiamine-dependent enzymes (TDEs) linking glycolysis with the tricarboxylic acid cycle (TCA) pyruvate dehydrogenase (PDH), of the pentose phosphate pathway transketolases (TKTs), the TCA alpha-ketoglutarate deydrogenase (KGDH)/2-oxoglutarate dehydrogenase (OGDH) complex, and the amino acid catabolism branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex are crucial factors for tumor metabolism. The expression of these enzymes has not been analyzed for carcinogenesis of oral squamous cell carcinoma (OSCC) with special focus on new targeted metabolic therapies as yet. Methods. TDEs PDH, KGDH (OGDH), and BCKDH were analyzed in normal oral mucosa (n = 14), oral precursor lesions (simple hyperplasia, n = 21; squamous intraepithelial neoplasia, SIN I-III, n = 35), and OSCC specimen (n = 46) by immunohistochemistry and western blot (WB) analysis in OSCC tumor cell lines. Results. Although the total numbers of PDH and KGDH (OGDH) positive samples decreased in OSCC, both enzymes were significantly overexpressed in the carcinogenesis of OSCC compared with normal tissue. BCKDH has been demonstrated to be significantly overexpressed in the carcinogenesis of OSCC. Specificity of the antibodies was confirmed by WB analysis. Conclusions. This is the first study showing increased expression of TDEs in OSCC. Metabolic targeting of TDEs (including TKTs) by antagonistic compounds like oxythiamine or oxybenfothiamine may be a useful strategy to sensitize cancer cells to common OSCC cancer therapies (AU)

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Metodología de determinación de la transición aeróbica-anaeróbica en la evaluación funcional / Methodology to elucidate the aerobic-anaerobic transition in functional Assessment

El consumo de oxígeno máximo (VO2max) es considerado el parámetro más importante en la determinación de la capacidad funcional de una persona. Como consecuencia del gran estres que supone la realizacion de pruebas de esfuerzo con un carácter máximo, se ha buscado la valoración de la capacidad funcional a traves de pruebas con un carácter submaximo, siendo el umbral láctico (UL) el parámetro mas estudiado. Se han propuesto diversas metodologías en la determinación del UL, si bien, aquellas metodologías que asocian el UL a unas determinadas concentraciones fijas de lactato sanguíneo no parecen adecuadas, siendo la metodología mas adecuada la del ajuste algorítmico. El UL indica el comienzo de una participación progresivamente mayor de la glucolisis anaeróbica al metabolismo energético, siendo conocida dicha intensidad de ejercicio como transición aerobica-anaerobica. El inicio de la transición aeróbica anaeróbica, además de caracterizarse por un incremento de las concentraciones de lactato con respecto a los valores de reposo, se acompaña de un incremento desproporcional de la respuesta ventilatoria, electromiografía y de activación del sistema nervioso simpático, en relación a los incrementos de la intensidad de ejercicio, que hasta ese momento habian mantenido una relación proporcional. De este modo, en el inicio de la transición aerobica-anaerobica se puede observar una respuesta de tipo umbral a nivel electromiografico, que se conoce umbral de electromiografía (UE), en los niveles de catecolaminas en plasma, umbral de catecolaminas (UC), y de la ventilacion pulmonar, umbral ventilatorio (VT1). A pesar de que la transición aerobica-anaerobica se ha estudiado ampliamente en ejercicios empleados para el desarrollo de la resistencia cardiorrespiratorio, recientemente se esta estudiando en ejercicios empleados en el entrenamiento contrarresistencias, como la media sentadilla, donde las respuestas son similares a las observadas en cicloergometro (AU)

The maximum oxygen consumption (VO2max) is considered the most important parameter to determine the functional ability of a person. Due to the large stress involved in the maximum effort testing, the submaximal effort test have achieved a relevant role in the capacity functional assessment, being lactic threshold (UL) the parameter most studied. They have proposed different methodologies in determining the UL, although those who associate UL methodologies to certain fixed blood lactate concentrations considered inadequate, the most appropriate methodology of the algorithmic adjustment. The UL marks the beginning of a progressively greater share of the anaerobic glycolysis energy metabolism, being known that as exercise intensity aerobic-anaerobic transition. The onset of transition aerobic anaerobic also characterized by an increase in lactate concentrations over resting values, is accompanied by a disproportionate increase in ventilatory, electromyographic response and activation of the sympathetic nervous system in relation to increases the intensity of exercise, which until then had maintained a proportional relationship. Thus, at the start of the aerobic-anaerobic transition can observe a response threshold type to electromyographic level, the threshold for electromyography (EU) is known, in levels of plasma catecholamines, threshold catecholamines (UC), and pulmonary ventilation, ventilatory threshold (VT1). Although the aerobic-anaerobic transition has been studied extensively in exercises employed for the development of cardiorespiratory endurance, recently it is you studying exercises employed in contrarresistencias training, as the half-squat, where the responses are similar to those observed in I cycle ergometer (AU)

Relación del ciclo clínico con los parámetros metabólicos de la lesión primaria en el cáncer de pulmón / Relationship between primary lesion metabolic parameters and clinical stage in lung cancer

Objetivo: En pacientes con cáncer de pulmón hemos investigado la relación de los parámetros PET como el valor máximo estandarizado de captación (SUVmax), la glucólisis lesional total (TLG) y el volumen tumoral metabólico (MTV) con el estadio clínico y la correlación del SUVmax del tumor primario con el SUVmax de las metástasis. Material y métodos: El estudio incluyó pacientes con cáncer de pulmón enviados para realizar una estadificación con FDG PET/TC. Resultados: Se estudiaron las imágenes PET/TC y los informes anatomopatológicos de 168 pacientes. De los 168 pacientes, 146 (86,9%) tenían cáncer pulmonar de células no peque˜nas (CPCNP) y 22 (13,1%) cáncer pulmonar de células peque˜nas (CPCP). En todos los estadios de los pacientes con CPCP se detectaron diferencias significativas (p < 0,001) en el SUVmax, la TLG y el MTV. Sin embargo, al excluir los tumores de un tama˜no inferior a 25 mm, no se encontró una diferencia significativa en el SUVmax de los diferentes estadios. No se encontraron diferencias significativas entre estos parámetros metabólicos y la enfermedad limitada o extendida del CPCP. El diámetro del tumor se correlacionó con el SUVmax del tumor primario y se obtuvieron diferencias significativas entre el SUVmax del tumor primario y el SUVmax de las metástasis en todo el conjunto de pacientes. Conclusiones: Aunque se encontraron diferencias en los índices metabólicos entre los distintos estadios del CPCNP, las diferencias de SUVmax en los diferentes estadios parecen ser resultado de una infraestimación del SUVmax en las lesiones peque˜nas. Otros índices del metabolismo de la glucosa, como el MTV y la TLG, muestran resultados prometedores de cara a una estratificación pronóstica y se deberían realizar futuros estudios para alcanzar un mejor conocimiento de su contribución clínica (AU)

Objectives. The relation of PET-derived parameters as maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), metabolic tumor volume (MTV) with clinical stage in lung cancer and correlation of SUVmax of primary tumor and that of metastatic lesion was studied in lung cancer patients. Materials and methods. Patients with lung cancer who were referred for FDG PET/CT were included in the study. Results. PET/CT scans and pathology reports of 168 patients were assessed. A total of 146 (86.9%) of these patients had a diagnosis of non-small cell lung cancer (NSCLC) and 22 (13.1%) had small cell lung cancer (SCLC). Metabolic parameters such as SUVmax, TLG and MTV showed significant differences in all the stages in NSCLC patients (p < 0.001). However, after tumors sizes <25 mm were excluded, no significant differences in SUVmax between stages were observed. No significant differences were found between these metabolic parameters and limited or extended disease SCLC. Tumor diameter correlated with primary tumor SUVmax and significant correlations between primary lesion SUVmax and metastatic lesion SUVmax were found. Conclusions. Although differences were found regarding indices between stages of NSCLC cases, SUVmax differences between stages seem to be caused by underestimation of SUVmax in small lesions. Other glucose metabolism indexes such as MTV and TLG show promising results in terms of prognostic stratification. Future studies are needed for better understanding of their contribution to clinical cases (AU)

Expresión de marcadores hipóxicos y glucolíticos CAIX, GLUT-1, HKII y su relación con la respuesta temprana al tratamiento en carcinoma escamocelular de cuello uterino / Expression of the hypoxic and glycolytic markers, CAIX, GLUT-1 and HKII and their association with early treatment response in squamous cell carcinomas of the uterine cervix

Objetivo. Determinar la expresión de CAIX, GLUT-1, HKII y establecer si existe asociación entre la expresión y la respuesta temprana al tratamiento en carcinomas escamocelulares de cuello uterino. Sujetos y métodos. En este estudio de tipo cohorte retrospectiva se incluyó a 66 pacientes en estadios FIGO IIB y IIIB durante el periodo del 2001 al 2007, con una edad promedio de 47 años. De las 66 pacientes, 22 fueron tratadas con radioterapia exclusiva y 44 con quimioterapia concomitante a radioterapia. La expresión de las proteínas CAIX, GLUT-1 y HKII fue determinada mediante inmunohistoquímica en biopsias tomadas antes del tratamiento. Resultados. Se encontró un mayor incremento en la expresión de GLUT-1 (74%), seguido de CAIX (41%) y HKII (18%). La coexpresión de GLUT-1 y CAIX resultó ser significativa (p < 0,002) en comparación con GLUT-1 y HKII. Además, se observó una tendencia de riesgo de no respuesta cuando se expresan simultáneamente las 3 proteínas. Conclusiones. El incremento en la expresión de GLUT-1 respecto de CAIX y HKII reafirma el concepto de que los carcinomas tienen un alto consumo de glucosa y su coexpresión con CAIX y HKII como factores biológicos preexistentes puede contribuir a esclarecer los mecanismos de hipoxia en la invasión tumoral, así como su posible efecto frente a tratamientos como la radioterapia exclusiva y la radioquimioterapia concomitante para el manejo de cáncer de cuello uterino en estadios ii B y iii B (AU)

Objective: To determine the expression of CAIX, GLUT-1 and HKII and whether there is an association between expression of these markers and early treatment response in squamous cell carcinomas of the uterine cervix. Subjects and methods: This retrospective cohort study included 66 patients with squamous cell carcinomas of the uterine cervix in FIGO (International Federation of Gynecology and Obstetrics) stages IIB and IIIB between 2001 and 2007. The mean age was 47 years. Of the 66 patients, 22 were treated with radiotherapy and 44 with concurrent radiochemotherapy. Expression of the proteins CAIX, GLUT-1 and HKII was determined by immunohistochemistry in biopsies taken before treatment. Results: The highest increase was found in expression of GLUT-1 (74%), followed by that of CAIX (41%) and HKII (18%). Coexpression of GLUT-1 and CAIX was significant (p <0.002) compared with that of GLUT-1 and HKII. When all three proteins were expressed simultaneously, we observed a tendency toward lack of treatment response. Conclusions: Increased expression of GLUT-1 compared with that of CAIX and HKII supports the notion that carcinomas have high glucose consumption. Coexpression of GLUT-1 with CAIX and HKII as preexisting biological factors could help to elucidate the mechanisms of hypoxia in tumoral invasion. Coexpression could also help to explain the possible effect of these markers on response to treatments such as exclusive radiotherapy and concurrent radiochemotherapy in the management of stage IIB and IIIB cervical cancer (AU)