Francisco Valladares

Universidad de La Laguna

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Jesús Villar

St. Michael's Hospital

Carlos Flores

Instituto Tecnológico y de Energías Renovables

Arthur S. Slutsky

University of Toronto

Robert M. Kacmarek

Massachusetts General Hospital

Mercedes Muros

Hospital Universitario Nuestra Señora de Candelaria

Lucio Díaz‐Flores

Universidad de La Laguna

Delia Báez

Universidad de La Laguna

Aixa R. Bello

Hospital de Santa Cruz

Nuria E. Cabrera-Benítez

Instituto de Salud Carlos III

Teresa Almeida

Universidad de La Laguna

Cooperative Institutions

Universidad de La Laguna

Universidade de Brasília

Instituto de Salud Carlos III

Hospital Universitario de Canarias

Hospital Universitario de Gran Canaria Doctor Negrín

Hospital Universitario Nuestra Señora de Candelaria

Centro de Investigación Biomédica en Red

Canary Institute of Cancer Research

Centro de Investigación Biomédica en Red de Enfermedades Respiratorias

St. Michael's Hospital

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Soluble platelet-endothelial cell adhesion molecule-1, a biomarker of ventilator-induced lung injury

Critical Care (2014)

Jesús Villar Mercedes Muros Nuria E. Cabrera-Benítez Francisco Valladares Milagros López-Hernández

Endothelial cell injury is an important component of acute lung injury. Platelet-endothelial cell adhesion molecule-1 (PECAM1) is a transmembrane protein that connects endothelial cells to one another and can be detected as a soluble, truncated protein (sPECAM1) in serum. We hypothesized that injurious mechanical ventilation (MV) leads to shedding of PECAM1 from lung endothelial cells resulting in increasing sPECAM1 levels in the systemic circulation.We studied 36 Sprague-Dawley rats in two prospective, randomized, controlled studies (healthy and septic) using established animal models of ventilator-induced lung injury. Animals (n = 6 in each group) were randomized to spontaneous breathing or two MV strategies: low tidal volume (VT) (6 ml/kg) and high-VT (20 ml/kg) on 2 cmH2O of positive end-expiratory pressure (PEEP). In low-VT septic animals, 10 cmH2O of PEEP was applied. We performed pulmonary histological and physiological evaluation and measured lung PECAM1 protein content and serum sPECAM1 levels after four hours ventilation period.High-VT MV caused severe lung injury in healthy and septic animals, and decreased lung PECAM1 protein content (P < 0.001). Animals on high-VT had a four- to six-fold increase of mean sPECAM1 serum levels than the unventilated counterpart (35.4 ± 10.4 versus 5.6 ± 1.7 ng/ml in healthy rats; 156.8 ± 47.6 versus 35.6 ± 12.6 ng/ml in septic rats) (P < 0.0001). Low-VT MV prevented these changes. Levels of sPECAM1 in healthy animals on high-VT MV paralleled the sPECAM1 levels of non-ventilated septic animals.Our findings suggest that circulating sPECAM1 may represent a promising biomarker for the detection and monitoring of ventilator-induced lung injury.

10.1186/cc13754

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Citations (18)

Experimental Ventilator-induced Lung Injury

Anesthesiology (2009)

Jesús Villar Maria Teresa Herrera-Abreu Francisco Valladares Mercedes Muros Lina Pérez‐Méndez

Background Previous experimental studies of ventilator-induced lung injury have shown that positive end-expiratory pressure (PEEP) is protective. The authors hypothesized that the application of PEEP during volume-controlled ventilation with a moderately high tidal volume (VT) in previously healthy in vivo rats does not attenuate ventilator-induced lung injury if the peak airway pressure markedly increases during the application of PEEP. Methods Sixty healthy, male Sprague-Dawley rats were anesthetized and randomized to be mechanically ventilated for 4 h at (1) VT of 6 ml/kg, (2) VT of 20 ml/kg, or (3) VT of 20 ml/kg plus 10 cm H2O of PEEP. Peak airway pressures, gas exchange, histologic evaluation, mortality, total lung tissue cytokine gene expression, and serum cytokine concentrations were analyzed. Results Peak airway pressures exceeded 30 cm H2O with high VT plus PEEP. All lungs ventilated with high VT had perivascular edema and inflammatory infiltrates. In addition, those ventilated with PEEP had small hemorrhages foci. Five animals from the high VT plus PEEP group died (P = 0.020). Animals ventilated with high VT (with or without PEEP) had a substantial increase in serum interleukin-6 (P = 0.0002), and those ventilated with high VT plus PEEP had a 5.5-fold increase in systemic levels of tumor necrosis factor-alpha (P = 0.007). Conclusions In contrast to previous reports, PEEP exacerbated lung damage and contributed to fatal outcome in an in vivo, mild overdistension model of ventilator-induced lung injury in previously healthy rats. That is, the addition of high PEEP to a constant large VT causes injury in previously healthy animals.

Positive End-Expiratory Pressure

Mean airway pressure

10.1097/aln.0b013e31819fcba9

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Analysis of the Expression of Tachykinins and Tachykinin Receptors in the Rat Uterus During Early Pregnancy1

Biology of Reproduction (2015)

Francisco M. Pinto Aixa R. Bello Manuel Gallardo-Castro Francisco Valladares Teresa Almeida

The peptides of the tachykinin family participate in the regulation of reproductive function acting at both central and peripheral levels. Our previous data showed that treatment of rats with a tachykinin NK3R antagonist caused a reduction of litter size. In the present study, we analyzed the expression of tachykinins and tachykinin receptors in the rat uterus during early pregnancy. Uterine samples were obtained from early pregnant rats (Days 1-9 of pregnancy) and from nonpregnant rats during the proestrus stage of the ovarian cycle, and real-time quantitative RT-PCR, immunohistochemistry, and Western blot studies were used to investigate the pattern of expression of tachykinins and tachykinin receptors. We found that all tachykinins and tachykinin receptors were locally synthesized in the uterus of early pregnant rats. The expression of substance P, neurokinin B, and the tachykinin receptors NK1R and NK3R mRNAs and proteins underwent major changes during the days around implantation and they were widely distributed in implantation sites, being particularly abundant in decidual cells. These findings support the involvement of the tachykinin system in the series of uterine events that occur around embryo implantation in the rat.

Tachykinin receptor

Neurokinin B

Neurokinin A

10.1095/biolreprod.115.130617

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Citations (4)

Alterations in IQGAP1 expression and localization in colorectal carcinoma and liver metastases following oxaliplatin-based chemotherapy

Oncology Letters (2017)

Deborah Rotoli Manuel Morales‐Ruiz María Del Carmen Maeso Maria del Pino García Ricardo Gutiérrez

IQGAP1 is a scaffolding protein that serves a key role in cell dynamics by integrating internal and external stimuli to distinct signal outputs. Previous studies have identified several genes that are significantly up- or downregulated in the peripheral white cells (PWCs) of patients with colorectal adenocarcinoma (CRC), who underwent oxaliplatin-based chemotherapy (CT). In addition, screening studies have reported that IQ-motif containing GTPase activating protein 1 (IQGAP1) transcriptional expression levels varied from 'off' to 'on' following oxaliplatin CT. In order to determine if variations previously described in PWCs are able to be observed at the protein level in tumors and in metastases following CT, the present study performed an immunohistochemical analysis of IQGAP1 in CRC and primary metastases. IQGAP1 expression was observed in the nuclear envelope and in lateral cell membranes and cytoplasm in normal colon tissue. However, in tumor tissue, cells exhibited a diffuse pattern, with variable expression levels of staining in the nuclear membrane and cytoplasm, with the highest expression intensity observed at the invasive front. In healthy and metastasized liver tissue and in the metastases themselves, expression levels varied from cell to cell from no expression to a high level. In the majority of cells, IQGAP1 co-localized with microtubules at the cytoplasmic face of the nuclear envelope. Strong positive expression was observed in areas of the lesion where cells were detaching from the lesion into the lumen. Despite the homogeneous IQGAP1 staining pattern observed in healthy colon tissue sections, CRC demonstrated heterogeneity in staining, which was more marked in metastasized liver tissue resected following CT. However, the most notable findings were the observed effects on the cellular and subcellular distribution and its implications for cancer biology. These results suggest that IQGAP1 may be a putative biomarker, a candidate for clinical diagnostics and a potential novel target for anti-cancer therapeutics.

IQGAP1

10.3892/ol.2017.6525

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Citations (14)

Neurotensin and Neurotensin Receptor 1 Expression in Human Myometrium and Uterine Leiomyomas1

Biology of Reproduction (2010)

Yurena Rodríguez Rodríguez Teresa Almeida Francisco Valladares Delia Báez Francisco Montes de

Leiomyomas or fibroids are the most frequently diagnosed tumors of the female genital tract, and their growth seems to be steroid-hormone dependent by a yet undetermined cellular and molecular mechanism. Sexual hormones induce the secretion of growth factor peptides and the expression of their receptors, stimulating cell proliferation. One of these factors is neurotensin, and increasing evidence suggests that it can promote growth of different cancer cells. Since there are no data on neurotensin expression in normal and tumoral uterine tissue, we have analyzed the expression of NTS and NTSR1 receptor using immunohistochemistry for protein detection, in situ hybridization to detect cells expressing NTS mRNA, and RT-PCR to detect NTSR1 transcript as well as any of the alternative splice variants recently described for this receptor. We found that NTS and NTSR1 are expressed in connective cells of normal myometrium. In leiomyomas, immunoreactivity for NTS and NTSR1 receptor is colocalized in the smooth muscle cells that are also transcribing NTS. Women receiving high doses of steroids for in vitro fertilization showed tumor growth and increased immunoreactivity for neurotensin and NTSR1 receptor. Interestingly, alternative splice variants of NTSR1 receptor were detected only in tumoral tissue. These findings suggest a role of steroid hormones inducing neurotensin expression in leiomyoma smooth muscle cells. In these cells, NTS could act autocrinally through NTSR1 receptor, promoting their proliferation.

Myometrium

Progesterone receptor

Relaxin

Receptor expression

10.1095/biolreprod.110.084962

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Citations (11)

Metastatic uveal melanoma: Is there a role for conventional chemotherapy? A single experience based on 58 patients.

Journal of Clinical Oncology (2010)

Nieves Plana Francisco Valladares J. Maria Caminal Mitjana J. Pera Isabel Fernandes

e19006 Background: Uveal melanoma is a rare disease. Metastases develop in 6.5%-35% of the patients, most commonly in the liver. Metastatic uveal melanoma (MUM) survival is poor, with 5 to 7 months median survival. The aim of this study is to assess clinical characteristics and survival in patients with MUM. Methods: We reviewed retrospectively all patients with MUM diagnosed between 1990 and end 2008 at our institution. Results: We analyzed a total of 58 patients with a median age of 61 years (31-84). Median time for the development of metastases was 25,63 months (0.17-102.43). 56 patients had hepatic involvement, 63.8% bilobar and ≥ 7 hepatic lesions on 51.7%. Sixteen patients (27.6%) had two or more organs involved. Six patients (10.71%) were treated with surgery, 25 patients (44.67%) received systemic chemotherapy, and 23 (41.07%) had best supportive care (BSC). The median overall survival (OS) for the total of the patients was 10,83 months (6.92-14.74; 95%CI). Patients with local metastatic treatment were not assessable for individual OS. Patients who did chemotherapy presented 10,83 months (5.35-16.308; CI 95%) median OS survival and the patients without treatment had an OS of 8,033 months (2.46-13.61; 95%CI). There were more patients with poor survival characteristics such as worst ECOG in the BSC group. Only ≥ 7 hepatic lesions was significative in the univariate analysis. ECOG and ≥ 7 hepatic lesions were significative in the multivariate test. Treatment with chemotherapy was not statistically significant in the univariate neither in the multivariate analysis. Conclusions: Overall survival was poor in treated and BSC patients. Differences on survival are more likely related to patient characteristics, such as ECOG, rather than chemotherapy effect. Patients with MUM should be included in clinical trials evaluating other options with newer agents. No significant financial relationships to disclose.

Univariate analysis

10.1200/jco.2010.28.15_suppl.e19006

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Citations (0)

Sequential Targeted Therapy Following Pazopanib (PZ) in Patients (PTS) with Metastatic Renal Cell Cancer (MRCC): Efficacy and Toxicity

Annals of Oncology (2012)

Francisco Valladares Toni K. Choueiri Thomas E. Hutson T.B. Powles Camillo Porta

Pazopanib

10.1016/s0923-7534(20)33411-6

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WNT/β-catenin signaling is modulated by mechanical ventilation in an experimental model of acute lung injury

Intensive Care Medicine (2011)

Jesús Villar Nuria E. Cabrera Milena Casula Francisco Valladares Carlos Flores

Perforation

10.1007/s00134-011-2234-0

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Citations (49)

Tryptophan ingestion by pregnant rats induces pituitary and mammary tumours in the adult female offspring

Human Reproduction (1999)

Cristo Santana L. Martin Francisco Valladares Lucio Díaz‐Flores Celsa Santana-Herrera

The present study was designed to evaluate the long-term consequences of tryptophan treatment on the central serotonergic activity in the female offspring of rats, and particularly on serotonin-controlled hormone release. During the second half of gestation, tryptophan (200 mg/kg/day) was given daily by stomach intubation to pregnant rats and the brain concentrations of serotonin and 5-hydroxyindole acetic acid and the plasma concentrations of prolactin, progesterone, oestradiol and luteinizing hormone were quantified in the adult female offspring. The offspring showed an increase in hypothalamic serotonin and serum progesterone and prolactin. In addition, maternal ingestion of tryptophan induced a marked rise in 665-day-old offspring in the incidence of both pituitary prolactinomas (62%) and mammary adenomas (49%). Present data suggest that tryptophan regulates serotonergic differentiation during early development. A transitory modification of the tryptophan concentration in the fetal brain induces a permanent increase in hypothalamic serotonin level and, in addition to modifying the release of prolactin, increases the incidence of tumours in the hypophysis and mammary gland.

Tryptophan hydroxylase

10.1093/humrep/14.8.2155

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Citations (1)

Continuous Contraceptive Use Combined with Overweight or Obesity Triggers the Risk of Surgery Due to Leiomyomas

Archives of Epidemiology (2017)

Delia Báez Francisco Valladares Armando Aguirre-Jaíme

Background: Uterine leiomyomas or fibroids are the most common bening tumours of the myometrium and the most common neoplasia of the female genital tract and being the most common indication for hysterectomy as the predominant treatment option.We have conducted a study in order to identify the hormonal factors associated with risk of uterine leiomyomas requiring surgery in premenopausal women. Methods:Case-control study in a Caucasian spanish population conducted with women attending the gynecology departments of two hospitals in Canary Islands.A total of 577 women who underwent hysterectomy or myomectomy for uterine leiomiomas in a four years period at both hospitals were included as cases and 644 women with intact uteri and free of uterine leiomyoma as confirmed by ultrasound diagnosis served as control subjects.Age, menarche, number of term pregnancies, height, weight, history of oral contraceptive and in vitro fecundation treatment was recorded at baseline.For cases, gynaecological data include number of leiomyomas, location, size and diagnosis of polymyomatosis.Logistic regression equation was applied to estimate the chance of suffer surgery due to leiomyoma. Results:In vitro fecundation increase 14 (95%CI: 8-21) times the risk of surgery due to uterine leiomyomas.Overweight and obesity increased the risk of surgery over 7 (95%CI: 4-11) and 11 (95%CI: 5-19) times respectively.Every month of contraceptive intake increases in 29% (95%CI: 5%-219%) the risk of surgery.Finally, the risk associated with ovarian activity was near 7 (95%CI:2-14) times and each additional year of age increases the risk or leiomioma surgery by 8% (95%CI:4%-9%).Discussion: Based on our results, at age 50 the probability of surgery because leiomyomas for women with normal weight increases four times more than at 20 years old.Fixing the age, the probability of needing surgery increased from 50 to 60 percent for overweight to obese women.Fixing age and weight, after a year of contraception use the probability of surgery because leiomyoma raise to two-thirds, and is nearly 100% in case she is 50 years old and overweight or obese. Conclusion:Age increase, prolonged contraceptive use, in vitro fecundation, overweight and obesity, lead to a higher and more prolonged exposure of the uterus to steroid hormones, cumulative effect leading to increased risk of growth of already existing fibroid or the formation of new ones in those uteri at risk of developing leiomyomas, that contributes to increase the risk of surgery for fibroids.

10.29011/2577-2252.000003

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Citations (1)