José Mariano Ruiz Almodóvar | University of Granada (original) (raw)

Papers by José Mariano Ruiz Almodóvar

[EN] The invention relates to a method for producing a biomaterial comprising a support of activa... more [EN] The invention relates to a method for producing a biomaterial comprising a support of activated carbon fibres and cells of osteochondral lineage, wherein stem cells are brought into contact with said support and are cultivated in the presence of serum and in the absence of additional osteogenic and/or chondrogenic differentiation factors. The invention also relates to biomaterial thus produced and to the different medical applications of said biomaterial.[FR] La présente invention concerne un procédé d'obtention d'un biomatériau comprenant un support de fibres de charbon actif et des cellules de la lignée ostéochondrale, les cellules souches étant placées en contact direct avec ledit support et cultivées en présence de sérum et en l'absence de facteurs de différenciation ostéogénique et/ou chondrogénique additionnels. L'invention concerne également le biomatériau ainsi obtenu et les différentes applications médicales dudit biomatériau.[Es] La presente invención está dirigida a un método de obtención de un biomaterial que comprende un soporte de fibras de carbón activado y células de linaje osteocondral, en el que células madre se ponen en contacto con dicho soporte y se cultivan en presencia de suero y ausencia de factores de diferenciación osteogénica y/o condrogénica adicionales. La invención se dirige asimismo al biomaterial así obtenido y a las diferentes aplicaciones médicas de dicho biomaterial.Peer reviewedUniversidad de Granada, Consejo Superior de Investigaciones CientíficasA1 Solicitud de patente con informe sobre el estado de la técnic

Biochemical Journal, 2005

p53 deficiency confers resistance to doxo (doxorubicin), a clinically active and widely used anti... more p53 deficiency confers resistance to doxo (doxorubicin), a clinically active and widely used antitumour anthracycline antibiotic. The purpose of the present study was to investigate the reversal mechanism of doxo resistance by the potent PARP [poly(ADP-ribose) polymerase] inhibitor ANI (4-amino-1,8-naphthalimide) in the p53-deficient breast cancer cell lines EVSA-T and MDA-MB-231. The effects of ANI, in comparison with doxo alone, on doxo-induced apoptosis, were investigated in matched pairs of EVSA-T or MDA-MB-231 with or without ANI co-treatment. Doxo elicited PARP activation as determined by Western blotting and immunofluorescence of poly(ADP-ribose), and ANI enhanced the cytotoxic activity of doxo 2.3 times and in a caspase-dependent manner. The long-term cytotoxic effect was studied by a colony-forming assay. Using this assay, ANI also significantly potentiates the long-term cytotoxic effect with respect to treatment with doxo alone. Decrease in mitochondrial potential together...

European Urology, 2002

Objective: This study was undertaken to investigate whether hypermethylation in p16 INK4a gene pr... more Objective: This study was undertaken to investigate whether hypermethylation in p16 INK4a gene promoter could serve as plasma biomarker of bladder cancer. Methods and Patients: We examined the p16 INK4a status using methylation-specific PCR in 86 cancer patients and 49 controls (31 healthy people and 18 patients with benign urological diseases). Results: The p16 INK4a methylation was found in 22% of the serum samples and in 26% of the bladder cancer biopsies; one of them with carcinoma in situ. The presence of hypermethylated p16 INK4a in serum seems to be a product from tumour cells because a strong statistical association was found between both matched DNA signals (p < 0:0001). Using the control group, the presence of methylated p16 INK4a in the serum of individuals with suspicion of bladder cancer was found to be associated with the tumour presence (p ¼ 0:0009). Aberrant p16 INK4a methylation was also observed in one non-cancer patient, which is undergoing further assessment. Conclusions: According with our results, methylation of p16 INK4a promoter may be involved in the bladder cancer genesis and the presence of p16 INK4a methylated in serum of these patients could be useful in the cancer diagnosis with values of sensitivity, specificity and positive predictive value of 0.226, 0.950 and 0.98, respectively. These figures support the use of methylated p16 INK4a as a new class of tumour marker in bladder cancer.

$Research paper thumbnail of Radiation-Induced DNA Damage as a Predictor of Long-Term Toxicity in Locally Advanced Breast Cancer Patients Treated with High-Dose Hyperfractionated Radical Radiotherapy$

Radiation Research, 2007

This 14-year-long study makes a novel contribution to the debate on the relationship between the ... more This 14-year-long study makes a novel contribution to the debate on the relationship between the in vitro radiosensitivity of peripheral blood lymphocytes and normal tissue reactions after radiation therapy. The aims were (1) to prospectively assess the degree and time of onset of skin side effects in 40 prospectively recruited consecutive patients with locally advanced breast cancer treated with a hyperfractionated dose-escalation radiotherapy schedule and (2) to assess whether initial radiation-induced DNA damage in peripheral blood lymphocytes of these patients could be used to determine their likelihood of suffering severe late damage to normal tissue. Initial radiation-induced DNA double-strand breaks (DSBs) were assessed in peripheral blood lymphocytes of these patients by pulsed-field electrophoresis. Acute and late cutaneous and subcutaneous toxicity was evaluated using the Radiation Therapy Oncology Group morbidity score. A wide interindividual variation was observed in toxicity grades and in radiation-induced DNA DSBs in peripheral blood lymphocytes (mean 1.61 +/- 0.76 DSBs/Gy per 200 MBp, range 0.63- 4.08), which were not correlated. Multivariate analysis showed a correlation (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.008) between late toxicity and higher prescribed protocol dose (81.6 Gy). Analysis of the 29 patients referred to 81.6 Gy revealed significantly (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.031) more frequent late subcutaneous toxicity in those with intrinsic sensitivity to radiation-induced DNA DSBs of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1.69 DSBs/Gy per DNA unit. Our demonstration of a relationship between the sensitivity of in vitro-irradiated peripheral blood lymphocytes and the risk of developing late toxic effects opens up the possibility of predicting normal tissue response to radiation in individual patients, at least in high-dose non-conventional radiation therapy regimens.

Oncotarget, Jan 11, 2014

Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults and one of the mo... more Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults and one of the most aggressive cancers. PARP-1 is a nuclear protein involved in multiple facets of DNA repair and transcriptional regulation. In this study we dissected the action of PARP inhibition in different GBM cell lines with either functional or mutated PTEN that confers resistance to diverse therapies. In PTEN mutant cells, PARP inhibition induced a severe genomic instability, exacerbated homologous recombination repair (HR) deficiency and down-regulated the Spindle Assembly Checkpoint (SAC) factor BUBR1, leading to mitotic catastrophe (MC). EGFR gene amplification also represents a signature of genetic abnormality in GBM. To more effectively target GBM cells, co-treatment with a PARP inhibitor and an EGFR blocker, erlotinib, resulted in a strong suppression of ERK1/2 activation and in vivo the combined effect elicited a robust reduction in tumour development. In conclusion, PARP inhibition targe...

[ES] Las fibras de carbón activo son materiales biocompatibles sobre los que las células pueden a... more [ES] Las fibras de carbón activo son materiales biocompatibles sobre los que las células pueden adherirse y proliferar. La adhesión de las células vivas sobre el carbón activo incluye, en primera aproximación, un fenómeno de adsorción que tiene lugar entre la superficie del carbón y las macromoléculas que conforman la estructura de la membrana celular (entre ellas los antígenos de membrana)Peer reviewe

Conference poster presented on the I International Symposium on Cell and Gene-Based Therapies at ... more Conference poster presented on the I International Symposium on Cell and Gene-Based Therapies at Granada (Spain) on June of 2014.

Activated-carbon cloth supports umbilical-cord stromal stem cells growth and differentiation. Ora... more Activated-carbon cloth supports umbilical-cord stromal stem cells growth and differentiation. Oral communication presented on the World conference on Carbon in Rio de Janeiro on July 17th of 2013.

Conference poster presented at I Congreso Ibérico de Ciencias del Animal de Laboratorio from the ... more Conference poster presented at I Congreso Ibérico de Ciencias del Animal de Laboratorio from the Spanish Society for the Laboratory Animal Sciences (SECAL).

Copyright information:Taken from "Early and late skin reactions to radiot... more Copyright information:Taken from "Early and late skin reactions to radiotherapy for breast cancer and their correlation with radiation-induced DNA damage in lymphocytes"Breast Cancer Research 2005;7(5):R690-R698.Published online 1 Jul 2005PMCID:PMC1242135.Copyright © 2005 López et al.; licensee BioMed Central Ltd. Irradiation volumes were estimated from the women's bra size, and the severity of the early effects were scored in the same women (n = 50). Dotted line shows the corresponding regression line (< 0.001).

Copyright information:Taken from "Early and late skin reactions to radiot... more Copyright information:Taken from "Early and late skin reactions to radiotherapy for breast cancer and their correlation with radiation-induced DNA damage in lymphocytes"Breast Cancer Research 2005;7(5):R690-R698.Published online 1 Jul 2005PMCID:PMC1242135.Copyright © 2005 López et al.; licensee BioMed Central Ltd. Horizontal solid lines are the mean values for each group of patients with breast cancer. Moderate (= 38), women with reactions scored as highly or moderately radioresistant or as having an average response; severe (= 12), patients with reactions scored as highly radiosensitive.

Copyright information:Taken from "Early and late skin reactions to radiot... more Copyright information:Taken from "Early and late skin reactions to radiotherapy for breast cancer and their correlation with radiation-induced DNA damage in lymphocytes"Breast Cancer Research 2005;7(5):R690-R698.Published online 1 Jul 2005PMCID:PMC1242135.Copyright © 2005 López et al.; licensee BioMed Central Ltd. Skin morbidity in 60 women was assessed on the treated skin using the scoring system summarized in Table 1. Lymphocyte molecular radiosensitivity was measured as DNA double-strand breaks (dsb) by dose unit (Gy) and DNA unit (200 Mbp). bp, base pairs.

Radiotherapy and Oncology, 2002

Purpose: The purpose of this study was to determine whether the distribution of sensitivities in ... more Purpose: The purpose of this study was to determine whether the distribution of sensitivities in breast cancer patients, measured using a DNA damage assay on lymphocytes, is likely to provide sufficient discrimination to enable the reliable identification of patients with abnormal sensitivities. Material and methods: Radiosensitivity (x) was assessed in 226 samples of lymphocytes from unselected women with breast cancer and was quantified as the initial number of DNA double-strand breaks (dsb) induced per Gy and per DNA unit (200 Mbp). Results: The existence of an inter-individual variation in the parameter (x) is described through the range (0.40-4.72 dsb/Gy/DNA unit) of values found, which have been fitted to the mathematical model defined by the log-normal distribution (m ¼ 0:42^0:03; s ¼ 0:52^0:03; R 2 ¼ 0:9475). A total of 189 patients received radiotherapy after surgical treatment. Among them, we have detected 15 patients who developed severe skin reactions and we have compared their radiosensitivity values with the rest of patients treated. Conclusions: Our results suggest that DNA initial damage measured on lymphocytes offers an approach to predict the acute response of human normal tissues prior to radiotherapy. Values of x higher than 3.20 dsb/Gy/DNA unit theoretically should correspond to the highly radio-sensitive patients. Using the experimental results, we have calculated the strength of the test by means of the area under the receiver operator characteristic curves (A Z) to determine whether the radiosensitivity assay can discriminate between patients according to their radiation response. The value found ðA Z ¼ 0:675^0:072Þ is indicative of a fair-poor discriminating capacity of the test to identify the patients with higher risk of developing a severe acute reaction during the radiotherapy treatment.

Breast Cancer Research and Treatment, 2002

Reporting of the outcome of radiotherapy is not satisfactory without a description of the treatme... more Reporting of the outcome of radiotherapy is not satisfactory without a description of the treatment-related side effects. The purposes of this paper were: (1) to evaluate the frequency and the severity of collateral skin reactions in a group of breast cancer patients; (2) to report the acute reactions using some current scoring systems and to compare the application of them, and (3) to investigate the variation between intra-and interobservers using these different scales. We studied 108 breast cancer patients who, after surgical treatment, received adjuvant radiotherapy. Clinical skin evaluation was always performed by the same radiotherapist the last day of treatment, and the collateral radiation effects were photographed at that moment to facilitate later evaluations by another two expert doctors. Normal tissue damage was scored according to the Radiation Therapy Oncology Group/The European Organisation for Research, and Treatment of Cancer/ (RTOG/EORTC), the Danish, the European, and the Biomed2 side-effect scales. The most frequent acute complications found were erythema (91.7%), dry desquamation (29.6%) and moist desquamation (35.2%). The reactions were classified as severe in 13.9, 23, 18.5 and 13% of the patients with each of the different systems used, respectively. The concordance between the scoring of radiation-induced side effects on the skin assessed by direct observation of the patients or by examination of the photographic document was sufficient. This is a warrant of accuracy in the evaluation of acute normal tissue lesions. Our results allow us to state the advantage of the RTOG system over the others in terms of evaluating the acute effects produced by radiotherapy of women with breast cancer.

Breast cancer research : BCR, 2005

Radiotherapy outcomes might be further improved by a greater understanding of the individual vari... more Radiotherapy outcomes might be further improved by a greater understanding of the individual variations in normal tissue reactions that determine tolerance. Most published studies on radiation toxicity have been performed retrospectively. Our prospective study was launched in 1996 to measure the in vitro radiosensitivity of peripheral blood lymphocytes before treatment with radical radiotherapy in patients with breast cancer, and to assess the early and the late radiation skin side effects in the same group of patients. We prospectively recruited consecutive breast cancer patients receiving radiation therapy after breast surgery. To evaluate whether early and late side effects of radiotherapy can be predicted by the assay, a study was conducted of the association between the results of in vitro radiosensitivity tests and acute and late adverse radiation effects. Intrinsic molecular radiosensitivity was measured by using an initial radiation-induced DNA damage assay on lymphocytes ob...

Copyright information:Taken from "Early and late skin reactions to radiot... more Copyright information:Taken from "Early and late skin reactions to radiotherapy for breast cancer and their correlation with radiation-induced DNA damage in lymphocytes"Breast Cancer Research 2005;7(5):R690-R698.Published online 1 Jul 2005PMCID:PMC1242135.Copyright © 2005 López et al.; licensee BioMed Central Ltd. Skin morbidity in 108 women was assessed on the treated skin using the scoring system summarized in Table 1. Lymphocyte molecular radiosensitivity was measured as DNA double-strand breaks (dsb) by dose unit (Gy) and DNA unit (200 Mbp). bp, base pairs.

Cells, 2020

We have previously shown that the combination of radiotherapy with human umbilical-cord-derived m... more We have previously shown that the combination of radiotherapy with human umbilical-cord-derived mesenchymal stromal/stem cells (MSCs) cell therapy significantly reduces the size of the xenotumors in mice, both in the directly irradiated tumor and in the distant nonirradiated tumor or its metastasis. We have also shown that exosomes secreted from MSCs preirradiated with 2 Gy are quantitatively, functionally and qualitatively different from the exosomes secreted from nonirradiated mesenchymal cells, and also that proteins, exosomes and microvesicles secreted by MSCs suffer a significant change when the cells are activated or nonactivated, with the amount of protein present in the exosomes of the preirradiated cells being 1.5 times greater compared to those from nonirradiated cells. This finding correlates with a dramatic increase in the antitumor activity of the radiotherapy when is combined with MSCs or with preirradiated mesenchymal stromal/stem cells (MSCs*). After the proteomic an...

Previously we have shown that the combination of radiotherapy with human-umbilical-cord-derived m... more Previously we have shown that the combination of radiotherapy with human-umbilical-cord-derived mesenchymal stem-cell therapy significantly reduces the size of the xenotumours in mice, both in the directly irradiated tumour and in the distant non-irradiated tumour or in its metastasis. We have also shown that exosomes secreted from mesenchymal stem-cells pre-irradiated with 2 Gy are quantitatively, functionally and qualitatively different from the exosomes secreted from non-irradiated mesenchymal cells and also that proteins, exosomes and microvesicles secreted by mesenchymal cells suffer a dramatic change when cells are activated or non-activated, with the amount of protein present in the exosomes of the pre-irradiated cells being 1.5-fold times greater compared to those from non-irradiated cells. This finding correlates with a dramatic increase in the anti-tumour activity of the exosomes secreted by pre-irradiated mesenchymal-cells. After the proteomic analysis of the load of the ...

Biochemical Journal, 2005

European Urology, 2002

Radiation Research, 2007

Oncotarget, Jan 11, 2014

Copyright information:Taken from "Early and late skin reactions to radiot... more Copyright information:Taken from "Early and late skin reactions to radiotherapy for breast cancer and their correlation with radiation-induced DNA damage in lymphocytes"Breast Cancer Research 2005;7(5):R690-R698.Published online 1 Jul 2005PMCID:PMC1242135.Copyright © 2005 López et al.; licensee BioMed Central Ltd. Horizontal solid lines are the mean values for each group of patients with breast cancer. Moderate (= 38), women with reactions scored as highly or moderately radioresistant or as having an average response; severe (= 12), patients with reactions scored as highly radiosensitive.

Copyright information:Taken from "Early and late skin reactions to radiot... more Copyright information:Taken from "Early and late skin reactions to radiotherapy for breast cancer and their correlation with radiation-induced DNA damage in lymphocytes"Breast Cancer Research 2005;7(5):R690-R698.Published online 1 Jul 2005PMCID:PMC1242135.Copyright © 2005 López et al.; licensee BioMed Central Ltd. Skin morbidity in 60 women was assessed on the treated skin using the scoring system summarized in Table 1. Lymphocyte molecular radiosensitivity was measured as DNA double-strand breaks (dsb) by dose unit (Gy) and DNA unit (200 Mbp). bp, base pairs.

Radiotherapy and Oncology, 2002

Breast Cancer Research and Treatment, 2002

Breast cancer research : BCR, 2005

Copyright information:Taken from "Early and late skin reactions to radiot... more Copyright information:Taken from "Early and late skin reactions to radiotherapy for breast cancer and their correlation with radiation-induced DNA damage in lymphocytes"Breast Cancer Research 2005;7(5):R690-R698.Published online 1 Jul 2005PMCID:PMC1242135.Copyright © 2005 López et al.; licensee BioMed Central Ltd. Skin morbidity in 108 women was assessed on the treated skin using the scoring system summarized in Table 1. Lymphocyte molecular radiosensitivity was measured as DNA double-strand breaks (dsb) by dose unit (Gy) and DNA unit (200 Mbp). bp, base pairs.

Cells, 2020