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1.
Acta Oncol ; 52(3): 619-26, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22873767

RESUMEN

BACKGROUND: The objectives of this study were to investigate the predictive value of sequential (18)F-FDG PET scans for pathological tumor response grade (TRG) after preoperative chemoradiotherapy (PCRT) in locally advanced rectal cancer (LARC) and the impact of partial volume effects correction (PVC). METHODS: Twenty-eight LARC patients were included. Responders and non-responders status were determined in histopathology. PET indices [SUV max and mean, volume and total lesion glycolysis (TLG)] at baseline and their evolution after one and two weeks of PCRT were extracted by delineation of the PET images, with or without PVC. Their predictive value was investigated using Mann-Whitney-U tests and ROC analysis. RESULTS: Within baseline parameters, only SUVmean was correlated with response. No evolution after one week was predictive of the response, whereas after two weeks all the parameters except volume were, the best prediction being obtained with TLG (AUC 0.79, sensitivity 63%, specificity 92%). PVC had no significant impact on these results. CONCLUSION: Several PET indices at baseline and their evolution after two weeks of PCRT are good predictors of response in LARC, with or without PVC, whereas results after one week are suboptimal. Best predictor was TLG reduction after two weeks, although baseline SUVmean had smaller but similar predictive power.


Asunto(s)
Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/terapia , Adulto , Anciano , Anciano de 80 o más Años , Quimioradioterapia/métodos , Terapia Combinada , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Periodo Preoperatorio , Pronóstico , Curva ROC , Neoplasias del Recto/patología , Estudios Retrospectivos , Sensibilidad y Especificidad , Factores de Tiempo , Resultado del Tratamiento
2.
Stud Health Technol Inform ; 302: 1007-1008, 2023 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-37203554

RESUMEN

More than 40% of the adult population suffers from functional gastrointestinal disorders, now considered disorders of the "gut-brain axis" (GBA) interactions, a very complex bidirectional neural, endocrine, immune, and humoral communication system modulated by the microbiota. To help discover, understand, and manage GBA disorders, the OnePlanet research center is developing digital twins focused on the GBA, combining novel sensors with artificial intelligence algorithms, providing descriptive, diagnostic, predictive or prescriptive feed-back.


Asunto(s)
Microbioma Gastrointestinal , Microbiota , Encéfalo , Inteligencia Artificial
3.
Cell Oncol (Dordr) ; 46(2): 391-407, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36539575

RESUMEN

PURPOSE: Despite recent advances, approximately 50% of patient with metastatic melanoma eventually succumb to the disease. Patients with melanomas harboring a BRAF mutation (BRAFMut) have a worse prognosis than those with wildtype (BRAFWT) tumors. Unexpectedly, interim AVAST-M Phase III trial data reported benefit from adjuvant anti-VEGF bevacizumab only in the BRAFMut group. We sought to find mechanisms underpinning this sensitivity. METHODS: We investigated this finding in vitro and in vivo using melanoma cell lines and clones generated by BRAFV600E knock-in on a BRAFWT background. RESULTS: Compared with BRAFWT cells, isogenic BRAFV600E clones secreted more VEGF and exhibited accelerated growth rates as spheroids and xenografts, which were more vascular and proliferative. Recapitulating AVAST-M findings, bevacizumab affected only BRAFV600E xenografts, inducing significant tumor growth delay, reduced vascularity and increased necrosis. We identified 814 differentially expressed genes in isogenic BRAFV600E/BRAFWT clones. Of 61 genes concordantly deregulated in clinical melanomas ROR2 was one of the most upregulated by BRAFV600E. ROR2 was shown to be RAF-MEK regulated in BRAFV600E cells and its depletion suppressed VEGF secretion down to BRAFWT levels. The ROR2 ligand WNT5A was also overexpressed in BRAFMut melanomas, and in ROR2-overexpressing BRAFV600E cells MEK inhibition downregulated WNT5A and VEGF secretion. CONCLUSIONS: These data implicate WNT5A-ROR2 in VEGF secretion, vascularity, adverse outcomes and bevacizumab sensitivity of BRAFMut melanomas, suggesting that this axis has potential therapeutic relevance.


Asunto(s)
Melanoma , Proteínas Proto-Oncogénicas B-raf , Receptores Huérfanos Similares al Receptor Tirosina Quinasa , Proteína Wnt-5a , Humanos , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Línea Celular Tumoral , Melanoma/genética , Melanoma/metabolismo , Melanoma/patología , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/genética , Proteína Wnt-5a/genética , Proteína Wnt-5a/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/metabolismo
4.
JMIR Mhealth Uhealth ; 10(2): e28159, 2022 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-35179512

RESUMEN

BACKGROUND: There are 1.1 billion smokers worldwide, and each year, more than 8 million die prematurely because of cigarette smoking. More than half of current smokers make a serious quit every year. Nonetheless, 90% of unaided quitters relapse within the first 4 weeks of quitting due to the lack of limited access to cost-effective and efficient smoking cessation tools in their daily lives. OBJECTIVE: This study aims to enable quantified monitoring of ambulatory smoking behavior 24/7 in real life by using continuous and automatic measurement techniques and identifying and characterizing smoking patterns using longitudinal contextual signals. This work also intends to provide guidance and insights into the design and deployment of technology-enabled smoking cessation applications in naturalistic environments. METHODS: A 4-week observational study consisting of 46 smokers was conducted in both working and personal life environments. An electric lighter and a smartphone with an experimental app were used to track smoking events and acquire concurrent contextual signals. In addition, the app was used to prompt smoking-contingent ecological momentary assessment (EMA) surveys. The smoking rate was assessed based on the timestamps of smoking and linked statistically to demographics, time, and EMA surveys. A Poisson mixed-effects model to predict smoking rate in 1-hour windows was developed to assess the contribution of each predictor. RESULTS: In total, 8639 cigarettes and 1839 EMA surveys were tracked over 902 participant days. Most smokers were found to have an inaccurate and often biased estimate of their daily smoking rate compared with the measured smoking rate. Specifically, 74% (34/46) of the smokers made more than one (mean 4.7, SD 4.2 cigarettes per day) wrong estimate, and 70% (32/46) of the smokers overestimated it. On the basis of the timestamp of the tracked smoking events, smoking rates were visualized at different hours and were found to gradually increase and peak at 6 PM in the day. In addition, a 1- to 2-hour shift in smoking patterns was observed between weekdays and weekends. When moderate and heavy smokers were compared with light smokers, their ages (P<.05), Fagerström Test of Nicotine Dependence (P=.01), craving level (P<.001), enjoyment of cigarettes (P<.001), difficulty resisting smoking (P<.001), emotional valence (P<.001), and arousal (P<.001) were all found to be significantly different. In the Poisson mixed-effects model, the number of cigarettes smoked in a 1-hour time window was highly dependent on the smoking status of an individual (P<.001) and was explained by hour (P=.02) and age (P=.005). CONCLUSIONS: This study reported the high potential and challenges of using an electronic lighter for smoking annotation and smoking-triggered EMAs in an ambulant environment. These results also validate the techniques for smoking behavior monitoring and pave the way for the design and deployment of technology-enabled smoking cessation applications. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2018-028284.


Asunto(s)
Cese del Hábito de Fumar , Tabaquismo , Humanos , Fumadores , Fumar/epidemiología , Cese del Hábito de Fumar/psicología , Encuestas y Cuestionarios
5.
JMIR Form Res ; 6(11): e38562, 2022 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-36265030

RESUMEN

BACKGROUND: The COVID-19 pandemic has greatly boosted working from home as a way of working, which is likely to continue for most companies in the future, either in fully remote or in hybrid form. To manage stress levels in employees working from home, insights into the stressors and destressors in a home office first need to be studied. OBJECTIVE: We present an international remote study with employees working from home by making use of state-of-the-art technology (ie, smartwatches and questionnaires through smartphones) first to determine stressors and destressors in people working from home and second to identify smartwatch measurements that could represent these stressors and destressors. METHODS: Employees working from home from 3 regions of the world (the United States, the United Kingdom, and Hong Kong) were asked to wear a smartwatch continuously for 7 days and fill in 5 questionnaires each day and 2 additional questionnaires before and after the measurement week. The entire study was conducted remotely. Univariate statistical analyses comparing variable distributions between low and high stress levels were followed by multivariate analysis using logistic regression, considering multicollinearity by using variance inflation factor (VIF) filtering. RESULTS: A total of 202 people participated, with 198 (98%) participants finishing the experiment. Stressors found were other people and daily life getting in the way of work (P=.05), job intensity (P=.01), a history of burnout (P=.03), anxiety toward the pandemic (P=.04), and environmental noise (P=.01). Destressors found were access to sunlight (P=.02) and fresh air (P<.001) during the workday and going outdoors (P<.001), taking breaks (P<.001), exercising (P<.001), and having social interactions (P<.001). The smartwatch measurements positively related to stress were the number of active intensity periods (P<.001), the number of highly active intensity periods (P=.04), steps (P<.001), and the SD in the heart rate (HR; P<.001). In a multivariate setting, only a history of burnout (P<.001) and family and daily life getting in the way of work (P<.001) were positively associated with stress, while self-reports of social activities (P<.001) and going outdoors (P=.03) were negatively associated with stress. Stress prediction models based on questionnaire data had a similar performance (F1=0.51) compared to models based on automatic measurable data alone (F1=0.47). CONCLUSIONS: The results show that there are stressors and destressors when working from home that should be considered when managing stress in employees. Some of these stressors and destressors are (in)directly measurable with unobtrusive sensors, and prediction models based on these data show promising results for the future of automatic stress detection and management. TRIAL REGISTRATION: Netherlands Trial Register NL9378; https://trialsearch.who.int/Trial2.aspx?TrialID=NL9378.

6.
Clin Cancer Res ; 27(23): 6500-6513, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34497073

RESUMEN

PURPOSE: Nucleoside analogues form the backbone of many therapeutic regimens in oncology and require the presence of intracellular enzymes for their activation. A ProTide is comprised of a nucleoside fused to a protective phosphoramidate cap. ProTides are easily incorporated into cells whereupon the cap is cleaved and a preactivated nucleoside released. 3'-Deoxyadenosine (3'-dA) is a naturally occurring adenosine analogue with established anticancer activity in vitro but limited bioavailability due to its rapid in vivo deamination by the circulating enzyme adenosine deaminase, poor uptake into cells, and reliance on adenosine kinase for its activation. In order to overcome these limitations, 3'-dA was chemically modified to create the novel ProTide NUC-7738. EXPERIMENTAL DESIGN: We describe the synthesis of NUC-7738. We determine the IC50 of NUC-7738 using pharmacokinetics (PK) and conduct genome-wide analyses to identify its mechanism of action using different cancer model systems. We validate these findings in patients with cancer. RESULTS: We show that NUC-7738 overcomes the cancer resistance mechanisms that limit the activity of 3'-dA and that its activation is dependent on ProTide cleavage by the enzyme histidine triad nucleotide-binding protein 1. PK and tumor samples obtained from the ongoing first-in-human phase I clinical trial of NUC-7738 further validate our in vitro findings and show NUC-7738 is an effective proapoptotic agent in cancer cells with effects on the NF-κB pathway. CONCLUSIONS: Our study provides proof that NUC-7738 overcomes cellular resistance mechanisms and supports its further clinical evaluation as a novel cancer treatment within the growing pantheon of anticancer ProTides.


Asunto(s)
Neoplasias , Nucleósidos , Estudio de Asociación del Genoma Completo , Humanos , Neoplasias/tratamiento farmacológico
7.
Sci Signal ; 13(649)2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32934076

RESUMEN

Forward genetic screens in mammalian cell lines, such as RNAi and CRISPR-Cas9 screens, have made major contributions to the elucidation of diverse signaling pathways. Here, we exploited human haploid cells as a robust comparative screening platform and report a set of quantitative forward genetic screens for identifying regulatory mechanisms of mTORC1 signaling, a key growth control pathway that senses diverse metabolic states. Selected chemical and genetic perturbations in this screening platform, including rapamycin treatment and genetic ablation of the Ragulator subunit LAMTOR4, revealed the known core mTORC1 regulatory signaling complexes and the intimate interplay of the mTORC1 pathway with lysosomal function, validating the approach. In addition, we identified a differential requirement for LAMTOR4 and LAMTOR5 in regulating the mTORC1 pathway under fed and starved conditions. Furthermore, we uncovered a previously unknown "synthetic-sick" interaction between the tumor suppressor folliculin and LAMTOR4, which may have therapeutic implications in cancer treatment. Together, our study demonstrates the use of iterative "perturb and observe" genetic screens to uncover regulatory mechanisms driving complex mammalian signaling networks.


Asunto(s)
Retroalimentación Fisiológica , Pruebas Genéticas/métodos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal , Proteínas Supresoras de Tumor/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/genética , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Células HEK293 , Haploidia , Células HeLa , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Mutación , Proteínas Proto-Oncogénicas/genética , Proteínas Supresoras de Tumor/genética
8.
Med Phys ; 44(9): 4961-4967, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28639302

RESUMEN

PURPOSE: Multiple models have been developed to predict pathologic complete response (pCR) in locally advanced rectal cancer patients. Unfortunately, validation of these models normally omit the implications of cohort differences on prediction model performance. In this work, we will perform a prospective validation of three pCR models, including information whether this validation will target transferability or reproducibility (cohort differences) of the given models. METHODS: We applied a novel methodology, the cohort differences model, to predict whether a patient belongs to the training or to the validation cohort. If the cohort differences model performs well, it would suggest a large difference in cohort characteristics meaning we would validate the transferability of the model rather than reproducibility. We tested our method in a prospective validation of three existing models for pCR prediction in 154 patients. RESULTS: Our results showed a large difference between training and validation cohort for one of the three tested models [Area under the Receiver Operating Curve (AUC) cohort differences model: 0.85], signaling the validation leans towards transferability. Two out of three models had a lower AUC for validation (0.66 and 0.58), one model showed a higher AUC in the validation cohort (0.70). DISCUSSION: We have successfully applied a new methodology in the validation of three prediction models, which allows us to indicate if a validation targeted transferability (large differences between training/validation cohort) or reproducibility (small cohort differences).


Asunto(s)
Modelos Teóricos , Neoplasias del Recto/diagnóstico por imagen , Humanos , Estudios Prospectivos , Neoplasias del Recto/terapia , Reproducibilidad de los Resultados , Resultado del Tratamiento
9.
Comput Biol Med ; 87: 179-186, 2017 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-28601027

RESUMEN

INTRODUCTION: The introduction of omics data and advances in technologies involved in clinical treatment has led to a broad range of approaches to represent clinical information. Within this context, patient stratification across health institutions due to omic profiling presents a complex scenario to carry out multi-center clinical trials. METHODS: This paper presents a standards-based approach to ensure semantic integration required to facilitate the analysis of clinico-genomic clinical trials. To ensure interoperability across different institutions, we have developed a Semantic Interoperability Layer (SIL) to facilitate homogeneous access to clinical and genetic information, based on different well-established biomedical standards and following International Health (IHE) recommendations. RESULTS: The SIL has shown suitability for integrating biomedical knowledge and technologies to match the latest clinical advances in healthcare and the use of genomic information. This genomic data integration in the SIL has been tested with a diagnostic classifier tool that takes advantage of harmonized multi-center clinico-genomic data for training statistical predictive models. CONCLUSIONS: The SIL has been adopted in national and international research initiatives, such as the EURECA-EU research project and the CIMED collaborative Spanish project, where the proposed solution has been applied and evaluated by clinical experts focused on clinico-genomic studies.


Asunto(s)
Neoplasias de la Mama/genética , Expresión Génica , Semántica , Femenino , Humanos
10.
Cancer Res ; 77(21): 5952-5962, 2017 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-28765154

RESUMEN

Gemcitabine constitutes one of the backbones for chemotherapy treatment in pancreatic ductal adenocarcinoma (PDAC), but patients often respond poorly to this agent. Molecular markers downstream of gemcitabine treatment in preclinical models may provide an insight into resistance mechanisms. Using cytokine arrays, we identified potential secretory biomarkers of gemcitabine resistance (response) in the transgenic KRasG12D; Trp53R172H; Pdx-1 Cre (KPC) mouse model of PDAC. We verified the oncogenic role of the cytokine tissue inhibitor of matrix metalloproteinases 1 (TIMP1) in primary pancreatic tumors and metastases using both in vitro techniques and animal models. We identified potential pathways affected downstream of TIMP1 using the Illumina Human H12 array. Our findings were validated in both primary and metastatic models of pancreatic cancer. Gemcitabine increased inflammatory cytokines including TIMP1 in the KPC mouse model. TIMP1 was upregulated in patients with pancreatic intraepithelial neoplasias grade 3 and PDAC lesions relative to matched normal pancreatic tissue. In addition, TIMP1 played a role in tumor clonogenic survival and vascular density, while TIMP1 inhibition resensitized tumors to gemcitabine and radiotherapy. We observed a linear relationship between TIMP-1 expression, liver metastatic burden, and infiltration by CD11b+Gr1+ myeloid cells and CD4+CD25+FOXP3+ Tregs, whereas the presence of tumor cells was required for immune cell infiltration. Overall, our results identify TIMP1 upregulation as a resistance mechanism to gemcitabine and provide a rationale for combining chemo/radiotherapy with TIMP1 inhibitors in PDAC. Cancer Res; 77(21); 5952-62. ©2017 AACR.


Asunto(s)
Desoxicitidina/análogos & derivados , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Inhibidor Tisular de Metaloproteinasa-1/genética , Animales , Antimetabolitos Antineoplásicos/farmacología , Línea Celular Tumoral , Desoxicitidina/farmacología , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Humanos , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/secundario , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Ratones Transgénicos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/radioterapia , Interferencia de ARN , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética , Carga Tumoral/efectos de la radiación , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Gemcitabina
11.
ACS Chem Biol ; 12(10): 2619-2630, 2017 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-28849908

RESUMEN

Histone acetyltransferases of the MYST family are recruited to chromatin by BRPF scaffolding proteins. We explored functional consequences and the therapeutic potential of inhibitors targeting acetyl-lysine dependent protein interaction domains (bromodomains) present in BRPF1-3 in bone maintenance. We report three potent and selective inhibitors: one (PFI-4) with high selectivity for the BRPF1B isoform and two pan-BRPF bromodomain inhibitors (OF-1, NI-57). The developed inhibitors displaced BRPF bromodomains from chromatin and did not inhibit cell growth and proliferation. Intriguingly, the inhibitors impaired RANKL-induced differentiation of primary murine bone marrow cells and human primary monocytes into bone resorbing osteoclasts by specifically repressing transcriptional programs required for osteoclastogenesis. The data suggest a key role of BRPF in regulating gene expression during osteoclastogenesis, and the excellent druggability of these bromodomains may lead to new treatment strategies for patients suffering from bone loss or osteolytic malignant bone lesions.


Asunto(s)
Células de la Médula Ósea/fisiología , Proteínas Portadoras/metabolismo , Diferenciación Celular/fisiología , Osteoclastos/fisiología , Animales , Proteínas Portadoras/genética , Biología Computacional , Humanos , Modelos Moleculares , Familia de Multigenes , Análisis por Matrices de Proteínas , Conformación Proteica , Dominios Proteicos , Células Madre
12.
Int J Mol Med ; 17(6): 1035-43, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16685413

RESUMEN

The main objective of the present study was to determine alterations of calcium handling in the diabetic rat heart during the transition from adaptive to maladaptive phase of cardiomyopathy. By inhibiting the nuclear enzyme poly(ADP-ribose) polymerase (PARP), we also investigated the possible role of this enzyme in the sequence of pathological events. Six weeks after induction of type I diabetes by injection of streptozotocin in rats, the hearts were perfused according to Langendorff. Intracellular-free calcium (Ca(2+)(i)) levels were measured by surface fluorometry using Indo-1 AM. Cyclic changes in Ca(2+)(i) concentrations and hemodynamic parameters were measured simultaneously. The hearts were challenged by infusion of isoproterenol. Six weeks of diabetes resulted in reduced inotropy and lusitropy. The diabetic hearts (DM) expressed a significantly elevated end-diastolic Ca(2+)(i) level (control, 111-/+20 vs DM, 221-/+35 nM). The maximal transport capacity of SERCA2a and conductance of RyR2 were reduced. These changes were not accompanied by major alterations in the tissue content of SERCA2a, RyR2, phospholamban and Na(+)/Ca(2+) exchanger. In response to beta-adrenergic activation, SERCA2a transport capacity and RyR2 conductance were stunted in the DM hearts. Inhibition of PARP induced minor changes in the mechanical function and calcium handling of the DM hearts. In conclusion, the observed changes in contractility and in Ca(2+)(i) handling are most likely attributable to functional disturbances of SERCA2a and RyR2 in this transitional phase of diabetes. At this stage of diabetes, PARP does not appear to play a significant pathogenetic role in the alterations in contractile function and calcium handling.


Asunto(s)
Calcio/metabolismo , Cardiomiopatías/metabolismo , Diabetes Mellitus Experimental/complicaciones , Angiopatías Diabéticas/metabolismo , Miocardio/metabolismo , Animales , Calcio/análisis , ATPasas Transportadoras de Calcio/análisis , ATPasas Transportadoras de Calcio/metabolismo , Cardiomiopatías/etiología , Cardiomiopatías/fisiopatología , Diabetes Mellitus Experimental/fisiopatología , Angiopatías Diabéticas/etiología , Angiopatías Diabéticas/fisiopatología , Hemodinámica , Masculino , Contracción Miocárdica , Miocardio/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Ratas , Ratas Sprague-Dawley , Canal Liberador de Calcio Receptor de Rianodina/análisis , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/química , Retículo Sarcoplasmático/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico
13.
Genome Biol ; 17(1): 140, 2016 06 29.
Artículo en Inglés | MEDLINE | ID: mdl-27358048

RESUMEN

BACKGROUND: Altered metabolism is a hallmark of cancer. However, the role of genomic changes in metabolic genes driving the tumour metabolic shift remains to be elucidated. Here, we have investigated the genomic and transcriptomic changes underlying this shift across ten different cancer types. RESULTS: A systematic pan-cancer analysis of 6538 tumour/normal samples covering ten major cancer types identified a core metabolic signature of 44 genes that exhibit high frequency somatic copy number gains/amplifications (>20 % cases) associated with increased mRNA expression (ρ > 0.3, q < 10(-3)). Prognostic classifiers using these genes were confirmed in independent datasets for breast and kidney cancers. Interestingly, this signature is strongly associated with hypoxia, with nine out of ten cancer types showing increased expression and five out of ten cancer types showing increased gain/amplification of these genes in hypoxic tumours (P ≤ 0.01). Further validation in breast and colorectal cancer cell lines highlighted squalene epoxidase, an oxygen-requiring enzyme in cholesterol biosynthesis, as a driver of dysregulated metabolism and a key player in maintaining cell survival under hypoxia. CONCLUSIONS: This study reveals somatic genomic alterations underlying a pan-cancer metabolic shift and suggests genomic adaptation of these genes as a survival mechanism in hypoxic tumours.


Asunto(s)
Metabolismo Energético/genética , Variación Genética , Neoplasias/genética , Neoplasias/metabolismo , Hipoxia Tumoral/genética , Animales , Biomarcadores de Tumor , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Análisis por Conglomerados , Variaciones en el Número de Copia de ADN , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Estudios de Asociación Genética , Inestabilidad Genómica , Genómica/métodos , Xenoinjertos , Humanos , Ratones , Mutación , Neoplasias/mortalidad , Neoplasias/patología , Pronóstico , Transcriptoma
14.
EBioMedicine ; 10: 109-16, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27474395

RESUMEN

Anti-VEGF antibody bevacizumab has prolonged progression-free survival in several cancer types, however acquired resistance is common. Adaption has been observed pre-clinically, but no human study has shown timing and genes involved, enabling formulation of new clinical paradigms. In a window-of-opportunity study in 35 ductal breast cancer patients for 2weeks prior to neoadjuvant chemotherapy, we monitored bevacizumab response by Dynamic Contrast-Enhanced Magnetic Resonance [DCE-MRI], transcriptomic and pathology. Initial treatment response showed significant overall decrease in DCE-MRI median K(trans), angiogenic factors such ESM1 and FLT1, and proliferation. However, it also revealed great heterogeneity, spanning from downregulation of blood vessel density and central necrosis to continued growth with new vasculature. Crucially, significantly upregulated pathways leading to resistance included glycolysis and pH adaptation, PI3K-Akt and immune checkpoint signaling, for which inhibitors exist, making a strong case to investigate such combinations. These findings support that anti-angiogenesis trials should incorporate initial enrichment of patients with high K(trans), and a range of targeted therapeutic options to meet potential early resistance pathways. Multi-arm adaptive trials are ongoing using molecular markers for targeted agents, but our results suggest this needs to be further modified by much earlier adaptation when using drugs affecting the tumor microenvironment.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/genética , Metabolismo Energético/genética , Inmunomodulación/genética , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Biomarcadores de Tumor , Neoplasias de la Mama/diagnóstico , Proliferación Celular/efectos de los fármacos , Análisis por Conglomerados , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Imagen por Resonancia Magnética/métodos , Neovascularización Patológica/diagnóstico , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Transducción de Señal/efectos de los fármacos , Transcriptoma , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo
15.
Int J Radiat Oncol Biol Phys ; 91(3): 530-9, 2015 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-25680597

RESUMEN

BACKGROUND: Postoperative radiation therapy for stage I endometrial cancer improves locoregional control but is without survival benefit. To facilitate treatment decision support for individual patients, accurate statistical models to predict locoregional relapse (LRR), distant relapse (DR), overall survival (OS), and disease-free survival (DFS) are required. METHODS AND MATERIALS: Clinical trial data from the randomized Post Operative Radiation Therapy for Endometrial Cancer (PORTEC-1; N=714 patients) and PORTEC-2 (N=427 patients) trials and registered group (grade 3 and deep invasion, n=99) were pooled for analysis (N=1240). For most patients (86%) pathology review data were available; otherwise original pathology data were used. Trial variables which were clinically relevant and eligible according to data constraints were age, stage, given treatment (pelvic external beam radiation therapy (EBRT), vaginal brachytherapy (VBT), or no adjuvant treatment, FIGO histological grade, depth of invasion, and lymph-vascular invasion (LVSI). Multivariate analyses were based on Cox proportional hazards regression model. Predictors were selected based on a backward elimination scheme. Model results were expressed by the c-index (0.5-1.0; random to perfect prediction). Two validation sets (n=244 and 291 patients) were used. RESULTS: Accuracy of the developed models was good, with training accuracies between 0.71 and 0.78. The nomograms validated well for DR (0.73), DFS (0.69), and OS (0.70), but validation was only fair for LRR (0.59). Ranking of variables as to their predictive power showed that age, tumor grade, and LVSI were highly predictive for all outcomes, and given treatment for LRR and DFS. The nomograms were able to significantly distinguish low- from high-probability patients for these outcomes. CONCLUSIONS: The nomograms are internally validated and able to accurately predict long-term outcome for endometrial cancer patients with observation, pelvic EBRT, or VBT after surgery. These models facilitate decision support in daily clinical practice and can be used for patient counseling and shared decision making, selecting patients who benefit most from adjuvant treatment, and generating new hypotheses.


Asunto(s)
Neoplasias Endometriales/radioterapia , Nomogramas , Adulto , Anciano , Anciano de 80 o más Años , Braquiterapia , Supervivencia sin Enfermedad , Neoplasias Endometriales/patología , Femenino , Humanos , Histerectomía , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Radioterapia Adyuvante/métodos
16.
Anticancer Res ; 35(6): 3441-6, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26026108

RESUMEN

AIM: To determine the impact of postoperative chemoradiation (POCR) on overall survival (OS) after resection of pancreatic adenocarcinoma (PAC) in elderly (≥75 years) patients. MATERIALS AND METHODS: A multi-center retrospective review of 1248 patients who underwent complete resection with macroscopically negative margins (R0-1) for invasive PAC was performed. Exclusion criteria included age <75 years, metastatic or unresectable disease at surgery, macroscopic residual disease (R2), treatment with intraoperative radiotherapy (IORT) and postoperative death. RESULTS: A total of 98 patients were included in the analysis (males=39.8%, females=60.2%; R1 resections=33.7%; pN1=61.2%); 63 patients received POCR and 26 patients received adjuvant chemotherapy alone. The median follow-up was 25.6 months. The mean age for the entire cohort of patients was 78.1±2.9 (SD) years. No differences were observed between patients receiving or not receiving POCR in terms of age (p=0.081), tumor diameter (p=0.412), rate of R1 resection (p=0.331) and incidence of lymph node-positive disease (p=0.078). The only factor predicting an improved OS was POCR. The median OS was 69.0 months in patients treated by POCR and 23.0 months in patients treated without POCR (p=0.008). Even by Cox multivariate analysis, the only significant predictor of OS was POCR (hazard ratio=0.449; 95% confidence interval=0.212-0.950; p=0.036). CONCLUSION: The study represents the first comparative approach on POCR in elderly patients after resection of PAC. OS was higher in patients who received POCR. Further analyses are warranted to evaluate the toxicity rate/grade and the impact of POCR on patient quality of life.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/radioterapia , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/radioterapia , Adenocarcinoma/epidemiología , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Terapia Combinada , Femenino , Humanos , Masculino , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/patología , Pronóstico , Modelos de Riesgos Proporcionales , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto
17.
Clin Cancer Res ; 21(13): 2984-92, 2015 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-25805800

RESUMEN

PURPOSE: Conventional anticancer treatments are often impaired by the presence of hypoxia. TH-302 selectively targets hypoxic tumor regions, where it is converted into a cytotoxic agent. This study assessed the efficacy of the combination treatment of TH-302 and radiotherapy in two preclinical tumor models. The effect of oxygen modification on the combination treatment was evaluated and the effect of TH-302 on the hypoxic fraction (HF) was monitored using [(18)F]HX4-PET imaging and pimonidazole IHC stainings. EXPERIMENTAL DESIGN: Rhabdomyosarcoma R1 and H460 NSCLC tumor-bearing animals were treated with TH-302 and radiotherapy (8 Gy, single dose). The tumor oxygenation status was altered by exposing animals to carbogen (95% oxygen) and nicotinamide, 21% or 7% oxygen breathing during the course of the treatment. Tumor growth and treatment toxicity were monitored until the tumor reached four times its start volume (T4×SV). RESULTS: Both tumor models showed a growth delay after TH-302 treatment, which further increased when combined with radiotherapy (enhancement ratio rhabdomyosarcoma 1.23; H460 1.49). TH-302 decreases the HF in both models, consistent with its hypoxia-targeting mechanism of action. Treatment efficacy was dependent on tumor oxygenation; increasing the tumor oxygen status abolished the effect of TH-302, whereas enhancing the HF enlarged TH-302's therapeutic effect. An association was observed in rhabdomyosarcoma tumors between the pretreatment HF as measured by [(18)F]HX4-PET imaging and the T4×SV. CONCLUSIONS: The combination of TH-302 and radiotherapy is promising and warrants clinical testing, preferably guided by the companion biomarker [(18)F]HX4 hypoxia PET imaging for patient selection.


Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Nitroimidazoles/farmacología , Mostazas de Fosforamida/farmacología , Animales , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Hipoxia de la Célula , Quimioradioterapia , Imidazoles , Neoplasias Pulmonares/diagnóstico por imagen , Nitroimidazoles/uso terapéutico , Mostazas de Fosforamida/uso terapéutico , Tomografía de Emisión de Positrones , Radiofármacos , Ratas , Resultado del Tratamiento , Triazoles , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Radiother Oncol ; 114(3): 302-9, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25716096

RESUMEN

PURPOSE: Personalized treatments based on predictions for patient outcome require early characterization of a rectal cancer patient's sensitivity to treatment. This study has two aims: (1) identify the main patterns of recurrence and response to the treatments (2) evaluate pathologic complete response (pCR) and two-year disease-free survival (2yDFS) for overall survival (OS) and their potential to be relevant intermediate endpoints to predict. METHODS: Pooled and treatment subgroup analyses were performed on five large European rectal cancer trials (2795 patients), who all received long-course radiotherapy with or without concomitant and/or adjuvant chemotherapy. The ratio of distant metastasis (DM) and local recurrence (LR) rates was used to identify patient characteristics that increase the risk of recurrences. FINDINGS: The DM/LR ratio decreased to a plateau in the first 2 years, revealing it to be a critical follow-up period. According to the patterns of recurrences, three patient groups were identified: 5-15% had pCR and were disease free after 2 years (excellent prognosis), 65-75% had no pCR but were disease free (good prognosis) and 15-30% had neither pCR nor 2yDFS (poor prognosis). INTERPRETATION: Compared with pCR, 2yDFS is a stronger predictor of OS. To adapt treatment most efficiently, accurate prediction models should be developed for pCR to select patients for organ preservation and for 2yDFS to select patients for more intensified treatment strategies.


Asunto(s)
Modelos Biológicos , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Medicina de Precisión/métodos , Neoplasias del Recto/patología , Neoplasias del Recto/terapia , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Terapia Combinada , Supervivencia sin Enfermedad , Determinación de Punto Final , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto Joven
19.
Oncotarget ; 6(4): 1920-41, 2015 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-25605240

RESUMEN

The biochemistry of cancer cells diverges significantly from normal cells as a result of a comprehensive reprogramming of metabolic pathways. A major factor influencing cancer metabolism is hypoxia, which is mediated by HIF1α and HIF2α. HIF1α represents one of the principal regulators of metabolism and energetic balance in cancer cells through its regulation of glycolysis, glycogen synthesis, Krebs cycle and the pentose phosphate shunt. However, less is known about the role of HIF1α in modulating lipid metabolism. Lipids serve cancer cells to provide molecules acting as oncogenic signals, energetic reserve, precursors for new membrane synthesis and to balance redox biological reactions. To study the role of HIF1α in these processes, we used HCT116 colorectal cancer cells expressing endogenous HIF1α and cells in which the hif1α gene was deleted to characterize HIF1α-dependent and independent effects on hypoxia regulated lipid metabolites. Untargeted metabolomics integrated with proteomics revealed that hypoxia induced many changes in lipids metabolites. Enzymatic steps in fatty acid synthesis and the Kennedy pathway were modified in a HIF1α-dependent fashion. Palmitate, stearate, PLD3 and PAFC16 were regulated in a HIF-independent manner. Our results demonstrate the impact of hypoxia on lipid metabolites, of which a distinct subset is regulated by HIF1α.


Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Metabolismo de los Lípidos , Lípidos/biosíntesis , Transducción de Señal , Acetil-CoA C-Aciltransferasa/genética , Acetil-CoA C-Aciltransferasa/metabolismo , Acetil-CoA Carboxilasa/genética , Acetil-CoA Carboxilasa/metabolismo , Anciano , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Western Blotting , Hipoxia de la Célula , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Ácidos Grasos/biosíntesis , Femenino , Genómica/métodos , Células HCT116 , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Masculino , Metabolómica/métodos , Persona de Mediana Edad , Factor de Activación Plaquetaria/genética , Factor de Activación Plaquetaria/metabolismo , Proteómica/métodos , Interferencia de ARN
20.
Radiother Oncol ; 110(2): 370-374, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24309199

RESUMEN

Extensive, multifactorial data sharing is a crucial prerequisite for current and future (radiotherapy) research. However, the cost, time and effort to achieve this are often a roadblock. We present an open-source based data-sharing infrastructure between two radiotherapy departments, allowing seamless exchange of de-identified, automatically translated clinical and biomedical treatment data.


Asunto(s)
Ensayos Clínicos como Asunto/estadística & datos numéricos , Minería de Datos , Difusión de la Información , Neoplasias/radioterapia , Radioterapia/estadística & datos numéricos , Humanos
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