Browsing by Subject "Heterogeneity"
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- PublicationOpen AccessA genetic model for undifferentiated cell tumor formation: similar tumors formed by different cell lines transformed by the EIA oncogene(Murcia : F. Hernández, 1995) Ramón y Cajal, S.; Sánchez-Prieto, R.; Anaya, A.The activation of oncogenes and the mutation/deletion of supressor genes may be involved in tumor heterogeneity. In an attempt to study tumor heterogeneity, we transformed cell lines from epithelial (PAM 212), mesenchymal (NIH-3T3), or melanocytic origin (L-BIOBR) with the wild type Ela oncogene. To make the cell lines tumorigenic, cells were infected with Harvey sarcoma virus carrying the v-H-ras oncogene. The transformed cells were injected into nude mice and the tumors studied by optical and electron microscopy. The tumors formed by v-H-ras-transformed cells consisted of epitheliod melanomas, spindle cells sarcomas and poorly-differentiated carcinomas, depending on the cell of origin. In contrast, the tumors obtained from cells also carrying the Ela oncogene showed a predominant small and undifferentiated cell pattem regardless of the cell of origin. We conclude that the Ela oncogene products induce a negative control of differentiation, independent of the cell type, and that tumors formed by cells carrying the Ela oncogene display an undifferentiated cell pattem.
- PublicationOpen AccessAnálisis de la complejidad y heterogeneidad de los paisajes de México(2018-02-28) Priego Santander, Angel Guadalupe; Esteve Selma, Miguel A.La presente investigación abarca el territorio de México y su objetivo es conocer y evaluar la distribución de la complejidad y heterogeneidad de los paisajes físico-geográficos de este país. Para lograr esto, se aplicaron dos índices de complejidad; uno de riqueza y otro de diversidad al mapa de paisajes naturales de México, a escala 1:500 000. Los resultados indican que México es un mosaico geoecológico donde espacialmente alternan unidades de diversa heterogeneidad y complejidad, de forma continua. Aún los geosistemas más simples y homogéneas, contienen una elevada riqueza de unidades inferiores.
- PublicationEmbargoAnalysis of group performance with categorical data when agents are heterogeneous: the evaluation of scholastic performance in the OECD through PISA(Elsevier, 2014-06) Villar, Antonio; Méndez Martínez, Ildefonso; Economía AplicadaThis paper analyzes the evaluation of the relative performance of a set of groups when their outcomes are defined in terms of categorical data and the groups’ members are heterogeneous. This type of problem has been dealt with in Herrero and Villar (2013) for the case of a homogeneous population. Here we expand their model controlling for heterogeneity by means of inverse probability weighting techniques. We apply this extended model to the analysis of the scholastic performance of fifteen-year-old students in the OECD countries, using the data in the PISA. We evaluate the relative performance of the different countries out of the distribution of the students’ achievements across the different levels of competence, controlling by the students’ characteristics (explanatory variables regarding schooling and family environment). We find that differences in mathematical and reading abilities across OECD countries would lower by between 40% and 50% if the students’ characteristics would be those for the OECD average
- PublicationOpen AccessCharacterization of a monoclonal antibody recognizing mast cells(Murcia : F. Hernández, 1997) Oliveira-Nogueira, T. de; Aubin, J.E.Immunohistochemical screening for monoclonal antibodies prepared by immunization of mice with a rat osteoblastic cell population led to identification of one antibody that reacted against a small population of cells present in the soft connective tissue compartment of 21 days fetal rat calvaria. The morphology of the cells and the immunohistochemical staining characteristics (a distinct intracellular granular pattern) suggested that the antibody might be reacting specifically against mast cells. We used combined histochemistry and immunohistochemistry to further characterize this antibody, designated RCJ102. Cryosections containing calvaria bone, soft connective tissues and skin were prepared from the top of the head of 21 days fetal rats, and from adult rats cryosections of lung, muscle, adipose tissue and small intestine were prepared. Some sections were labelled by indirect immunofluorescence with RCJ102; corresponding sections were labelled histochemically with toluidine blue. There was a direct correspondence between mast cells identified histochemically and cells labelling with RCJ102 in al1 tissues except intestine, in which the mast cell detectable by histochemistry were not labelled by RCJ102. These results suggest that the RCJ102 antibody will be a valuable new reagent for further elucidation of the heterogeneity described between connective tissue and intestinal mucosal mast cells.
- PublicationOpen AccessLa heterogeneidad del yo en Fernando Pessoa, Antonio Machado y Miguel de Unamuno(Universidad de Murcia, Servicio de Publicaciones, 2020) López Ruiz, Patricia TeresaEl presente trabajo tiene como meta abrazar un tema que se venía arrastrando de manera progresiva desde el Romanticismo: la despersonali‐ zación ante la existencia de un ser múl‐ tiple, y que alcanzó cima con el universo creativo de Fernando Pessoa. No obs‐ tante, y debido a la conciencia del fra‐ caso de la razón al intentar aprehender una realidad cambiante, escritores co‐ mo Antonio Machado y Miguel de Unamuno ‒de manera coetánea al lusi‐ tano‒ también emprendieron esa cana‐ lización del ser, como un yo desgarrado, a través de sus obras. La teleología en cada uno de ellos era distinta. No obs‐ tante, en mayor o menor medida, los tres encontraron sustento en la filosofía empirista y el escepticismo, y creyeron en una omnipresente textualidad. Tex‐ tualidad que desdibujó límites antagó‐ nicos y que los adentró en un espacio de falsedad y superchería, de espejis‐ mos irrealizados o de juego tomado en serio.
- PublicationOpen AccessHeterogeneity estimation in meta-analysis of standardized mean differences when the distribution of random effects departs from normal: a Monte Carlo simulation study(BioMed Central, 2023-01-17) Blázquez Rincón, Desirée; Sánchez Meca, Julio; Botella, Juan; Suero, Manuel; Psicología Básica y MetodologíaBackground Advantages of meta-analysis depend on the assumptions underlying the statistical procedures used being met. One of the main assumptions that is usually taken for granted is the normality underlying the population of true effects in a random-effects model, even though the available evidence suggests that this assumption is often not met. This paper examines how 21 frequentist and 24 Bayesian methods, including several novel procedures, for computing a point estimate of the heterogeneity parameter ( ) perform when the distribution of random effects departs from normality compared to normal scenarios in meta-analysis of standardized mean differences. Methods A Monte Carlo simulation was carried out using the R software, generating data for meta-analyses using the standardized mean difference. The simulation factors were the number and average sample size of primary studies, the amount of heterogeneity, as well as the shape of the random-effects distribution. The point estimators were compared in terms of absolute bias and variance, although results regarding mean squared error were also discussed. Results Although not all the estimators were affected to the same extent, there was a general tendency to obtain lower and more variable estimates as the random-effects distribution departed from normality. However, the estimators ranking in terms of their absolute bias and variance did not change: Those estimators that obtained lower bias also showed greater variance. Finally, a large number and sample size of primary studies acted as a bias-protective factor against a lack of normality for several procedures, whereas only a high number of studies was a variance-protective factor for most of the estimators analyzed. Conclusions Although the estimation and inference of the combined effect have proven to be sufficiently robust, our work highlights the role that the deviation from normality may be playing in the meta-analytic conclusions from the simulation results and the numerical examples included in this work. With the aim to exercise caution in the interpretation of the results obtained from random-effects models, the tau2() R function is made available for obtaining the range of values computed from the 45 estimators analyzed in this work, as well as to assess how the pooled effect, its confidence and prediction intervals vary according to the estimator chosen.
- PublicationOpen AccessHeterogeneity of mesenchymal cells in human amniotic membrane at term(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Cortés Sandoval, Salvador; Seco Rovira, Vicente; Beltrán Frutos, Ester; Serrano Sánchez, Mª Isabel; Martínez Hernández, Jesús; Ferrer, Concepción; Delgado, Juan L.; Insausti, Carmen L.; Blanquer, Miguel; Pastor, Luis M.There is increasing interest in understanding the tissue biology of human amniotic membrane (hAM) given its applications in medicine. One cellular component is mesenchymal cells, which can be extracted, cultured and differentiated "in vitro" into various cell types. These studies show that there is heterogeneity among mesenchymal cells. The aim of this work is to study the membrane "in situ" to determine whether this cellular heterogeneity exists. The hAMs were obtained from caesarean deliveries at term and analyzed by histological techniques. Types I-III mesenchymal cells and Hofbauer were distinguished by light microscopy. Histochemically, mesenchymal cell types showed successively increasing positivity to: PAS, vimentin, fibronectin, and Concanavalin-A; VGEF, TGF-β2, PDGF-C, FGF-2. By the semiquantitative point of view, the percentage of Type II cells was 60%, significantly higher than the other types. With transmission electron microscopy, an intermediate cell type between II-III was observed. Strong vesiculation of the rough endoplasmic reticulum (RER) with exocytosis was observed. In addition, an accumulation of a similar material to the extracellular matrix in the RER caused its dilation especially in type IIITEM cells. Some of this material acquired a globular structure. These structures were also found free in the extracellular matrix. In conclusion, the mesenchymal cells of the fibroblastic layer of the hAMs studied are heterogeneous, with some undifferentiated and others with a probably senescent fibroblastic phenotype with accumulation in their RER of fibronectin. These results may be of interest to extract mesenchymal cells from hAMs for use in regenerative medicine and to better understand the mechanisms of fetal membrane rupture
- PublicationOpen AccessInsight into the heterogeneity of prostate cancer through PSA-PSMA prostate clones: mechanisms and consequences(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2014) Jemaa, Awatef Ben; Bouraoui, Yosra; Oueslati, RidhaA major clinical challenge is posed by the current inability to readily distinguish indolent from aggressive tumors in prostate cancer patients. Research efforts are dedicated to overcome this problem by understanding the molecular basis of the transition from normal, benign cells to prostatic intraepithelial neoplasia (PIN), localized carcinoma, and metastatic cancer. Combined with the evidence of the phenotypic heterogeneity of benign prostate hyperplasia, primary tumors and metastases, it is conceivable that several prostate clones emerge progressively during tumor progression. We have identified several PSA-PSMA prostate clones during prostate cancer progression. In this paper we focus on the susceptibilities of these PSAPSMA prostate clones to factors that promote prostate hyperplastic, neoplastic and metastatic development and their consequences in disease outcome.
- PublicationOpen AccessLow-grade gliomas clinical and pathobiological aspects(Murcia : F. Hernández, 2002) Smits, A.The optimal management of patients with low-grade gliomas remains a challenge for the treating physician. The natural history of the disease shows a large variety, and there is a substantial controversy about many of everyday treatment recommendations. H o w e v e r, new developments in clinical and basic research in neuro-oncology have occurred during the last years. In this review some of these new insights into clinical and biological aspects of low-grade gliomas are discussed, with focus on the translation of new knowledge from basic research into clinical practice. For example, molecular genetic profiling of tumour material has started to guide treatment recommendations and clinical management of some patients with oligodendrogliomas. Experimental studies of the different molecular pathways in tumour cells and in their normal counterparts involved in cell-cycle check-point control have elucidated some of the underlying mechanisms of resistance of gliomas to radiotherapy and c h e m o t h e r a p y. Finally, improved classification of the d i fferent subtypes of low-grade gliomas may be achieved in the near future by characterization of the genetic heterogeneity within the tumour and by identification of a putative stem cell as the origin of the tumour cells.
- PublicationOpen AccessPersister state-directed transitioning and vulnerability in melanoma(Springer Nature, 2022-06-01) Chauvistré, Heike; Shannan, Batool; Daignault-Mill, Sheena M.; Ju, Robert J.; Picard, Daniel; Egetemaier, Stefanie; Váraljai, Renáta; Gibhardt, Christine; Sechi, Antonio; Kaschani, Farnusch; Keminer, Oliver; Stehbens, Samantha J.; Liu, Qin; Yin, Xiangfan; Jeyakumar, Kirujan; Vogel, Felix C.E.; Krepler, Clemens; Rebecca, Vito W.; Kubat, Linda; Lueong, Smiths S.; Forster, Jan; Horn, Susanne; Remke, Marc; Ehrmann, Michael; Paschen, Annette; Becker, Jürgen C.; Helfrich, Iris; Rauh, Daniel; Kaiser, Markus; Gul, Sheraz; Herlyn, Meenhard; Bogeski, Ivan; Rodríguez López, José Neptuno; Haass, Nikolas; Schadendorf, Dirk; Roesch, Alexander; Bioquímica y Biología Molecular AMelanoma is a highly plastic tumor characterized by dynamic interconversion of different cell identities depending on the biological context. Melanoma cells with high expression of the H3K4 demethylase KDM5B (JARID1B) rest in a slow-cycling, yet reversible persister state. Over time, KDM5Bhigh cells can promote rapid tumor repopulation with equilibrated KDM5B expression heterogeneity. The cellular identity of KDM5Bhigh persister cells has not been studied so far, missing an important cell state-directed treatment opportunity in melanoma. Here, we have established a doxycycline-titratable system for genetic induction of permanent intratumor expression of KDM5B and screened for chemical agents that phenocopy this effect. Transcriptional profiling and cell functional assays confirmed that the dihydropyridine 2-phenoxyethyl 4-(2-fluorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxylate (termed Cpd1) supports high KDM5B expression and directs melanoma cells towards differentiation along the melanocytic lineage and to cell cycle-arrest. The high KDM5B state additionally prevents cell proliferation through negative regulation of cytokinetic abscission. Moreover, treatment with Cpd1 promoted the expression of the melanocyte-specific tyrosinase gene specifically sensitizing melanoma cells for the tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG). In summary, our study provides proof-of-concept for a dual hit strategy in melanoma, in which persister state-directed transitioning limits tumor plasticity and primes melanoma cells towards lineage-specific elimination
- PublicationOpen AccessSingle-cell spatial proteomics(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Liyanage, Senal; Guo, Jia; Departamento de Biologia Celular e HistiologiaRecent advancements in single-cell spatial proteomics have revolutionized our ability to elucidate cellular signaling networks and their implications in health and disease. This review examines these cutting-edge technologies, focusing on mass spectrometry (MS) imaging and multiplexed immunofluorescence (mIF). Such approaches allow high-resolution protein profiling at the single-cell level, revealing intricate cellular heterogeneity, spatial organization, and protein functions within their native cellular contexts. MS imaging techniques offer unprecedented high-dimensional resolution and provide detailed insights into their subcellular protein localization and abundance. mIF enables rapid and high-throughput protein profiling, enhancing its accessibility for diverse research and clinical applications. This review assesses the current challenges associated with these methodologies and also discusses the potential solutions to overcome these obstacles. The integration of spatial proteomics with other systems biology approaches holds great promise for enhancing our understanding of complex biological systems. It could also lead to significant advancements in molecular diagnostics and personalized treatment strategies.
- PublicationOpen AccessTissue microarray validation in cervical carcinoma studies. A methodological approach(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Lovane, Lucília; Carrilho, Carla; Karlsson, ChristinaTissue microarrays (TMAs) are a cost-effective tool to study biomarkers in clinical research. Cervical cancer (CC) is one of the most prevalent in women worldwide, with the highest prevalence in low-middle-income countries due to a lack of organized screening. CC is associated with persistent high-risk human papillomavirus infection. Several biomarkers have been studied for diagnostic, therapeutic, and prognostic purposes. We aimed to evaluate and validate the effectiveness of TMA in CC compared to whole slide images (WSs). We selected and anonymized twenty cases of CC. P16, cytokeratin 5 (CK5), cytokeratin 7 (CK7), programmed death-ligand 1 (PD-L1), and CD8 expression were immunohistochemically investigated. All WS were scanned and 10 representative virtual TMA cores with 0.6 mm diameter per sample were selected. Ten random combinations of 1-5 cylinders per case were assessed for each biomarker. The agreement of scoring between TMA and WS was evaluated by kappa statistics. We found that three cores of 0.6 mm on TMA can accurately represent WS in our setting. The Kappa value between TMA and WS varied from 1 for p16 to 0.61 for PD-L1. Our study presents an approach to address TMA sampling that could be generalized to TMA-based research, regardless of the tissue and biomarkers of interest.
- PublicationOpen AccessTrade credit and Family control(Springer, 2024-11-08) Díaz Díaz, Nieves Lidia; García Teurel, Pedro J; Martínez-Solano, Pedro; Organización de Empresas y FinanzasThis paper analyses whether trade credit strategies depend on the family identity of the controlling shareholder. We use a sample of 4,022 private Spanish firms for the years 2004 and 2013 and examine family firm heterogeneity by analysing different thresholds of control, involvement in management and firm identification with the family name. The results reveal that family firms have more restrictive trade credit strategies than non-family firms. Moreover, among family-controlled firms, those with the strongest identification between the family shareholders and their firms are the most restrictive. However, family-controlled firms reduced trade credit less after the financial crisis of 2008. These firms supported their customers by limiting the impact of liquidity shocks during the crisis.
- PublicationOpen AccessTumor heterogeneity: morphological, molecular and clinical implications(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2000) Lleonart, M. E.; Martin-Duque, P.; Sanchez-Prieto, R.; Moreno, A.; Ramon y Cajal, S.Malignant tumors are characterized by their great heterogeneity and variability. There are hundreds of different types of malignant tumors that harbour many oncogenic alterations. The tumor heterogeneity has important morphological, molecular and clinical implications. Except for some hematopoietic and lymphoproliferative processes and small cell infant tumors, there are not specific molecular alterations for most human tumors. In this review we summarize the most important aspects of carcinogenesis and chemoradiosensitivity of malignant cells. In this regard, some oncogenes such as neu , ras and bcl-2 have been associated with cellular resistance to treatment with anticancer agents. The knowledge of oncogenic alterations involved in each tumor can be important to correlate the morphological features, the genetic background, the prognosis and the clinical response to treatment with anticancer agents. Based on the molecular background of the tumor there are new cancer gene therapy protocols. For example using adenovirus Ela in tumors with overexpression of neu oncogene, inhibitors of tirosine kinase specific for the PDGF receptor in glioma, inhibitors of farnesil transferase to prevent ras activity in tumors with mutations in the ras gene.
- PublicationOpen AccessValue of the combination of intraepithelial tumor-infiltrating lymphocyte density and the heterogeneity of density as a prognostic marker in stage III colorectal cancers(Universidad de Murcia, Histología e Histopatología, 2025) Lingyan Jin; Hye Yeong Jin; Seung Yeon Yoo; Nam-Yun Cho; Jeong Mo Bae; Jung Ho Kim; Hye Seung Lee; Gyeong Hoon Kang; Sin departamento asociadoTumor-infiltrating lymphocyte (TIL) density is both a prognostic and a predictive factor in colorectal cancer (CRC). Whether the heterogeneity of TIL density across the tumor plays an important role in the clinical outcome of CRC is not well known. Adjuvant chemotherapy-treated patients with stage III CRC were analyzed for survival according to TIL density and density heterogeneity, which were determined on CD8-immunostained slides using a machine learning method and by calculating the Simpson evenness index, respectively. High heterogeneity of the intraepithelial TIL density was found to be an independent prognostic factor, with a hazard ratio of 1.970 (1.207-3.215) in the multivariate analysis of recurrence-free survival. High heterogeneity was closely associated with a high T category, venous invasion, perineural invasion, and KRAS mutation. The combination of both intraepithelial TIL density and density heterogeneity was significantly associated with the prognosis of patients: low TIL density/high TIL heterogeneity showed hazard ratios of 3.284 (1.639- 6.578) and 4.176 (1.713-10.178) in the discovery and validation cohorts, respectively. Our findings suggest that the heterogeneity status of intraepithelial TIL density might help delineate patients with better vs. worse survival when combined with intraepithelial TIL density.