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1.  The goal of blood pressure in the hypertensive patient with diabetes is defined: now the challenge is go from recommendations to practice 
The recent Latin American and European guidelines published this year has proposed as a goal for blood pressure control in patients with diabetes type 2 a value similar or inferior to 140/90 mmHg. High blood pressure is the leading cause of cardiovascular diseases and deaths globally. Although once hypertension is detected, 80% of individuals are on a pharmacologic therapy only a minority is controlled. Diabetes also is a risk factor for other serious chronic diseases, including cardiovascular disease. Whether specifically targeting lower fasting glucose levels can reduce cardiovascular outcomes remains unknown. Hypertension is present in 20% to 60% of patients with type 2 diabetes, depending on age, ethnicity, obesity, and the presence of micro or macro albuminuria. High blood pressure substantially increases the risk of both macro and micro vascular complications, doubling the risk of all-cause mortality and stroke, tripling the risk of coronary heart disease and significantly hastening the progression of diabetic nephropathy, retinopathy, and neuropathy. Thus, blood pressure lowering is a major priority in preventing cardiovascular and renal events in patients with diabetes and hypertension. During many years the BP goals recommended in patients with diabetes were more aggressive than in patients without diabetes. As reviewed in this article many clinical trials have demonstrated not only the lack of benefits of lowering the BP below 130/80 mmHg, but also the J-shaped relationship in DM patients. Overall we discuss the importance of define the group of patients in whom significant BP reduction could be particularly dangerous and, on the other hand, those with a high risk of stroke who could benefit most from an intensive hypotensive therapy. In any case, the big challenge now is avoid the therapeutic inertia (leaving diabetic patients with BP values of 140/90 mmHg or higher) at all costs, as this would lead to an unacceptable toll in terms of human lives, suffering, and socioeconomic costs.
PMCID: PMC3973894  PMID: 24594121
Hypertension; Diabetes; Guidelines; Blood pressure
2.  Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior 
BMC Cancer  2012;12:260.
Colon cancer patients with the same stage show diverse clinical behavior due to tumor heterogeneity. We aimed to discover distinct classes of tumors based on microarray expression patterns, to analyze whether the molecular classification correlated with the histopathological stages or other clinical parameters and to study differences in the survival.
Hierarchical clustering was performed for class discovery in 88 colon tumors (stages I to IV). Pathways analysis and correlations between clinical parameters and our classification were analyzed. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the main subtype was generated using the 3-Nearest-Neighbor method. Coincidences with other prognostic predictors were assesed.
Hierarchical clustering identified four robust tumor subtypes with biologically and clinically distinct behavior. Stromal components (p < 0.001), nuclear β-catenin (p = 0.021), mucinous histology (p = 0.001), microsatellite-instability (p = 0.039) and BRAF mutations (p < 0.001) were associated to this classification but it was independent of Dukes stages (p = 0.646). Molecular subtypes were established from stage I. High-stroma-subtype showed increased levels of genes and altered pathways distinctive of tumour-associated-stroma and components of the extracellular matrix in contrast to Low-stroma-subtype. Mucinous-subtype was reflected by the increased expression of trefoil factors and mucins as well as by a higher proportion of MSI and BRAF mutations. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the Low-stroma-subtype distinguished low risk patients from high risk patients in the external cohort (Dukes B and C:HR = 8.56(2.53-29.01); Dukes B,C and D:HR = 1.87(1.07-3.25)). Eight different reported survival gene signatures segregated our tumors into two groups the Low-stroma-subtype and the other tumor subtypes.
We have identified novel molecular subtypes in colon cancer with distinct biological and clinical behavior that are established from the initiation of the tumor. Tumor microenvironment is important for the classification and for the malignant power of the tumor. Differential gene sets and biological pathways characterize each tumor subtype reflecting underlying mechanisms of carcinogenesis that may be used for the selection of targeted therapeutic procedures. This classification may contribute to an improvement in the management of the patients with CRC and to a more comprehensive prognosis.
PMCID: PMC3571914  PMID: 22712570
Colon cancer; Microarray gene expression; Molecular classification; Stroma; Survival
3.  Polymorphisms of CD16A and CD32 Fcγ receptors and circulating immune complexes in Ménière's disease: a case-control study 
BMC Medical Genetics  2011;12:2.
Autoimmune diseases with elevated circulating autoantibodies drive tissue damage and the onset of disease. The Fcγ receptors bind IgG subtypes modulating the clearance of circulating immune complexes (CIC). The inner ear damage in Ménière's disease (MD) could be mediated by an immune response driven by CIC. We examined single-nucleotide polymorphism (SNPs) in the CD16A and CD32 genes in patients with MD which may determine a Fcγ receptor with lower binding to CIC.
The functional CD16A (FcγRIIIa*559A > C, rs396991) and CD32A (FcγRIIa*519A > G, rs1801274) SNPs were analyzed using PCR-based TaqMan Genotyping Assay in two cohorts of 156 mediterranean and 112 Galicia patients in a case-control study. Data were analyzed by χ2 with Fisher's exact test and Cochran-Armitage trend test (CATT). CIC were measured by ELISA for C1q-binding CIC.
Elevated CIC were found in 7% of patients with MD during the intercrisis period. No differences were found in the allelic frequency for rs396991 or rs1801274 in controls subjects when they were compared with patients with MD from the same geographic area. However, the frequency of AA and AC genotypes of CD16A (rs396991) differed among mediterranean and Galicia controls (Fisher's test, corrected p = 6.9 × 10-4 for AA; corrected p = 0.02 for AC). Although genotype AC of the CD16A receptor was significantly more frequent in mediterranean controls than in patients, [Fisher's test corrected p = 0.02; OR = 0.63 (0.44-0.91)], a genetic additive effect for the allele C was not observed (CATT, p = 0.23). Moreover, no differences were found in genotype frequencies for rs396991 between patients with MD and controls from Galicia (CATT, p = 0.14). The allelic frequency of CD32 (rs1801274) was not different between patients and controls either in mediterranean (p = 0.51) or Galicia population (p = 0.11).
Elevated CIC are not found in most of patients with MD. Functional polymorphisms of CD16A and CD32 genes are not associated with onset of MD.
PMCID: PMC3022798  PMID: 21208440
4.  CoCl2, a Mimic of Hypoxia, Induces Formation of Polyploid Giant Cells with Stem Characteristics in Colon Cancer 
PLoS ONE  2014;9(6):e99143.
The induction of polyploidy is considered the reproductive end of cells, but there is evidence that polyploid giant cancer cells (PGCCs) contribute to cell repopulation during tumor relapse. However, the role of these cells in the development, progression and response to therapy in colon cancer remains undefined. Therefore, the main objective of this study was to investigate the generation of PGCCs in colon cancer cells and identify mechanisms of formation. Treatment of HCT-116 and Caco-2 colon cancer cells with the hypoxia mimic CoCl2 induced the formation of cells with larger cell and nuclear size (PGCCs), while the cells with normal morphology were selectively eliminated. Cytometric analysis showed that CoCl2 treatment induced G2 cell cycle arrest and the generation of a polyploid cell subpopulation with increased cellular DNA content. Polyploidy of hypoxia-induced PGCCs was confirmed by FISH analysis. Furthermore, CoCl2 treatment effectively induced the stabilization of HIF-1α, the differential expression of a truncated form of p53 (p47) and decreased levels of cyclin D1, indicating molecular mechanisms associated with cell cycle arrest at G2. Generation of PGCCs also contributed to expansion of a cell subpopulation with cancer stem cells (CSCs) characteristics, as indicated by colonosphere formation assays, and enhanced chemoresistance to 5-fluorouracil and oxaliplatin. In conclusion, the pharmacological induction of hypoxia in colon cancer cells causes the formation of PGCCs, the expansion of a cell subpopulation with CSC characteristics and chemoresistance. The molecular mechanisms involved, including the stabilization of HIF-1 α, the involvement of p53/p47 isoform and cell cycle arrest at G2, suggest novel targets to prevent tumor relapse and treatment failure in colon cancer.
PMCID: PMC4059626  PMID: 24932611
5.  CX3CR1 Is a Modifying Gene of Survival and Progression in Amyotrophic Lateral Sclerosis 
PLoS ONE  2014;9(5):e96528.
The objective of this study was to investigate the association of functional variants of the human CX3CR1 gene (Fractalkine receptor) with the risk of Amyotrophic Lateral Sclerosis (ALS), the survival and the progression rate of the disease symptoms in a Spanish ALS cohort. 187 ALS patients (142 sporadic [sALS] and 45 familial) and 378 controls were recruited. We investigated CX3CR1 V249I (rs3732379) and T280M (rs3732378) genotypes and their haplotypes as predictors of survival, the progression rate of the symptoms (as measured by ALSFRS-R and FVC decline) and the risk of suffering ALS disease. The results indicated that sALS patients with CX3CR1 249I/I or 249V/I genotypes presented a shorter survival time (42.27±4.90) than patients with 249V/V genotype (67.65±7.42; diff −25.49 months 95%CI [−42.79,−8.18]; p = 0.004; adj-p = 0.018). The survival time was shorter in sALS patients with spinal topography and CX3CR1 249I alleles (diff = −29.78 months; 95%CI [−49.42,−10.14]; p = 0.003). The same effects were also observed in the spinal sALS patients with 249I–280M haplotype (diff = −27.02 months; 95%CI [−49.57, −4.48]; p = 0.019). In the sALS group, the CX3CR1 249I variant was associated with a faster progression of the disease symptoms (OR = 2.58; 95IC% [1.32, 5.07]; p = 0.006; adj-p = 0.027). There was no evidence for association of these two CX3CR1 variants with ALS disease risk. The association evidenced herein is clinically relevant and indicates that CX3CR1 could be a disease-modifying gene in sALS. The progression rate of the disease's symptoms and the survival time is affected in patients with one or two copies of the CX3CR1 249I allele. The CX3CR1 is the most potent ALS survival genetic factor reported to date. These results reinforce the role of the immune system in ALS pathogenesis.
PMCID: PMC4013026  PMID: 24806473
6.  Candida tropicalis Antifungal Cross-Resistance Is Related to Different Azole Target (Erg11p) Modifications 
Antimicrobial Agents and Chemotherapy  2013;57(10):4769-4781.
Candida tropicalis ranks between third and fourth among Candida species most commonly isolated from clinical specimens. Invasive candidiasis and candidemia are treated with amphotericin B or echinocandins as first-line therapy, with extended-spectrum triazoles as acceptable alternatives. Candida tropicalis is usually susceptible to all antifungal agents, although several azole drug-resistant clinical isolates are being reported. However, C. tropicalis resistant to amphotericin B is uncommon, and only a few strains have reliably demonstrated a high level of resistance to this agent. The resistance mechanisms operating in C. tropicalis strains isolated from clinical samples showing resistance to azole drugs alone or with amphotericin B cross-resistance were elucidated. Antifungal drug resistance was related to mutations of the azole target (Erg11p) with or without alterations of the ergosterol biosynthesis pathway. The antifungal drug resistance shown in vitro correlated very well with the results obtained in vivo using the model host Galleria mellonella. Using this panel of strains, the G. mellonella model system was validated as a simple, nonmammalian minihost model that can be used to study in vitro-in vivo correlation of antifungals in C. tropicalis. The development in C. tropicalis of antifungal drug resistance with different mechanisms during antifungal treatment has potential clinical impact and deserves specific prospective studies.
PMCID: PMC3811422  PMID: 23877676
7.  Deepening our understanding of quality improvement in Europe (DUQuE): overview of a study of hospital quality management in seven countries 
Introduction and Objective
This paper provides an overview of the DUQuE (Deepening our Understanding of Quality Improvement in Europe) project, the first study across multiple countries of the European Union (EU) to assess relationships between quality management and patient outcomes at EU level. The paper describes the conceptual framework and methods applied, highlighting the novel features of this study.
DUQuE was designed as a multi-level cross-sectional study with data collection at hospital, pathway, professional and patient level in eight countries.
Setting and Participants
We aimed to collect data for the assessment of hospital-wide constructs from up to 30 randomly selected hospitals in each country, and additional data at pathway and patient level in 12 of these 30.
Main outcome measures
A comprehensive conceptual framework was developed to account for the multiple levels that influence hospital performance and patient outcomes. We assessed hospital-specific constructs (organizational culture and professional involvement), clinical pathway constructs (the organization of care processes for acute myocardial infarction, stroke, hip fracture and deliveries), patient-specific processes and outcomes (clinical effectiveness, patient safety and patient experience) and external constructs that could modify hospital quality (external assessment and perceived external pressure).
Data was gathered from 188 hospitals in 7 participating countries. The overall participation and response rate were between 75% and 100% for the assessed measures.
This is the first study assessing relation between quality management and patient outcomes at EU level. The study involved a large number of respondents and achieved high response rates. This work will serve to develop guidance in how to assess quality management and makes recommendations on the best ways to improve quality in healthcare for hospital stakeholders, payers, researchers, and policy makers throughout the EU.
PMCID: PMC4001699  PMID: 24671120
quality management systems; clinical indicators; clinical effectiveness; quality of healthcare; hospitals; cross-national research; patient outcomes
8.  The Tumor Necrosis Factor α (-308 A/G) Polymorphism Is Associated with Cystic Fibrosis in Mexican Patients 
PLoS ONE  2014;9(3):e90945.
Environmental and genetic factors may modify or contribute to the phenotypic differences observed in multigenic and monogenic diseases, such as cystic fibrosis (CF). An analysis of modifier genes can be helpful for estimating patient prognosis and directing preventive care. The aim of this study is to determine the association between seven genetic variants of four modifier genes and CF by comparing their corresponding allelic and genotypic frequencies in CF patients (n = 81) and control subjects (n = 104). Genetic variants of MBL2 exon 1 (A, B, C and D), the IL-8 promoter (−251 A/T), the TNFα promoter (TNF1/TNF2), and SERPINA1 (PI*Z and PI*S) were tested in CF patients and control subjects from northeastern Mexico by PCR-RFLP.
The TNF2 allele (P = 0.012, OR 3.43, 95% CI 1.25–9.38) was significantly associated with CF under the dominant and additive models but was not associated with CF under the recessive model. This association remained statistically significant after adjusting for multiple tests using the Bonferroni correction (P = 0.0482). The other tested variants and genotypes did not show any association with the disease.
An analysis of seven genetic variants of four modifier genes showed that one variant, the TNF2 allele, appears to be significantly associated with CF in Mexican patients.
PMCID: PMC3946307  PMID: 24603877
9.  Klebsiella pneumoniae Sequence Type 11 from Companion Animals Bearing ArmA Methyltransferase, DHA-1 β-Lactamase, and QnrB4 
Seven Klebsiella pneumoniae isolates from dogs and cats in Spain were found to be highly resistant to aminoglycosides, and ArmA methyltransferase was responsible for this phenotype. All isolates were typed by multilocus sequence typing (MLST) as ST11, a human epidemic clone reported worldwide and associated with, among others, OXA-48 and NDM carbapenemases. In the seven strains, armA was borne by an IncR plasmid, pB1025, of 50 kb. The isolates were found to coproduce DHA-1 and SHV-11 β-lactamases, as well as the QnrB4 resistance determinant. This first report of the ArmA methyltransferase in pets illustrates their importance as a reservoir for human multidrug-resistant K. pneumoniae.
PMCID: PMC3754351  PMID: 23752506
10.  Executive functioning moderates the relationship between motivation and adolescent depressive symptoms 
We investigated the association between adolescent depressive symptoms and components of executive functioning (EF), including planning (Tower of London), set-shifting (Wisconsin Card Sorting Task), and inhibition (Stop Signal Task) in a community sample of 12–14 year olds. Further, EF was tested as a moderator of motivation (as operationalized by revised Reinforcement Sensitivity Theory) effects on depressive symptoms. Results suggested that planning ability was associated with depressive symptoms. Furthermore, planning ability moderated the relationship between motivation (fight-flight- freeze system; FFFS) and depressive symptoms, such that among adolescents with poor planning ability the FFFS positively predicted depressive symptoms, but among adolescents with strong planning ability the FFFS negatively predicts depressive symptoms. Neither set-shifting nor inhibition was associated with depressive symptoms. Findings highlight the need to consider multiple components of EF and to integrate motivational and executive dysfunction models to the study of depression.
PMCID: PMC3480194  PMID: 23105161
11.  Expression of EhRAD54, EhRAD51, and EhBLM proteins during DNA repair by homologous recombination in Entamoeba histolytica  
Parasite  2014;21:7.
Entamoeba histolytica, the protozoan responsible for human amoebiasis, exhibits a great genome plasticity that is probably related to homologous recombination events. It contains the RAD52 epistasis group genes, including Ehrad51 and Ehrad54, and the Ehblm gene, which are key homologous recombination factors in other organisms. Ehrad51 and Ehrad54 genes are differentially transcribed in trophozoites when DNA double-strand breaks are induced by ultraviolet-C irradiation. Moreover, the EhRAD51 recombinase is overexpressed at 30 min in the nucleus. Here, we extend our analysis of the homologous recombination mechanism in E. histolytica by studying EhRAD51, EhRAD54, and EhBLM expression in response to DNA damage. Bioinformatic analyses show that EhRAD54 has the molecular features of homologous proteins, indicating that it may have similar functions. Western blot assays evidence the differential expression of EhRAD51, EhRAD54, and EhBLM at different times after DNA damage, suggesting their potential roles in the different steps of homologous recombination in this protozoan.
PMCID: PMC3927307  PMID: 24534563
DNA double-strand break repair; Homologous recombination; Amoebiasis
12.  Application of Remote Power-by-Light Switching in a Simplified BOTDA Sensor Network 
Sensors (Basel, Switzerland)  2013;13(12):17434-17444.
We propose and demonstrate the use of spatial multiplexing as a means to reduce the costs of distributed sensing networks. We propose a new scheme in which remote power-by-light switching is deployed to scan multiple branches of a distributed sensing network based on Brillouin Optical Time Domain Analysis (BOTDA) sensors. A proof-of-concept system is assembled with two 5-km sensor fiber branches that are alternatively monitored using a fast remotely controlled and optically powered optical switch. The multiplexed distributed sensor fibers were located 10 km away from the interrogation unit and a Raman pump is used to remotely power the switch. Furthermore, the deployed BOTDA unit uses an alternative configuration that can lead to simplified setups.
PMCID: PMC3892858  PMID: 24351644
BOTDA sensor; remote sensing; optical switch; sensor network
13.  Limitations of Early Serum Creatinine Variations for the Assessment of Kidney Injury in Neonates and Infants with Cardiac Surgery 
PLoS ONE  2013;8(11):e79308.
Changes in kidney function, as assessed by early and even small variations in serum creatinine (ΔsCr), affect survival in adults following cardiac surgery but such associations have not been reported in infants. This raises the question of the adequate assessment of kidney function by early ΔsCr in infants undergoing cardiac surgery.
The ability of ΔsCr within 2 days of surgery to assess the severity of kidney injury, accounted for by the risk of 30-day mortality, was explored retrospectively in 1019 consecutive neonates and infants. Patients aged ≤ 10 days were analyzed separately because of the physiological improvement in glomerular filtration early after birth. The Kml algorithm, an implementation of k-means for longitudinal data, was used to describe creatinine kinetics, and the receiver operating characteristic and the reclassification methodology to assess discrimination and the predictive ability of the risk of death.
Three clusters of ΔsCr were identified: in 50% of all patients creatinine decreased, in 41.4% it increased slightly, and in 8.6% it rose abruptly. Mortality rates were not significantly different between the first and second clusters, 1.6% [0.0–4.1] vs 5.9% [1.9–10.9], respectively, in patients aged ≤ 10 days, and 1.6% [0.5–3.0] vs 3.8% [1.9–6.0] in older ones. Mortality rates were significantly higher when creatinine rose abruptly, 30.3% [15.1–46.2] in patients aged ≤ 10 days, and 15.1% [5.9–25.5] in older ones. However, only 41.3% of all patients who died had an abrupt increase in creatinine. ΔsCr improved prediction in survivors, but not in patients who died, and did not improve discrimination over a clinical mortality model.
The present results suggest that a postoperative decrease in creatinine represents the normal course in neonates and infants with cardiac surgery, and that early creatinine variations lack sensitivity for the assessment of the severity of kidney injury.
PMCID: PMC3823616  PMID: 24244476
14.  Diets Based on Virgin Olive Oil or Fish Oil but Not on Sunflower Oil Prevent Age-Related Alveolar Bone Resorption by Mitochondrial-Related Mechanisms 
PLoS ONE  2013;8(9):e74234.
Aging enhances frequency of chronic diseases like cardiovascular diseases or periodontitis. Here we reproduced an age-dependent model of the periodontium, a fully physiological approach to periodontal conditions, to evaluate the impact of dietary fat type on gingival tissue of young (6 months old) and old (24 months old) rats.
Animals were fed life-long on diets based on monounsaturated fatty acids (MUFA) as virgin olive oil, n-6 polyunsaturated fatty acids (n-6PUFA), as sunflower oil, or n-3PUFA, as fish oil. Age-related alveolar bone loss was higher in n-6PUFA fed rats, probably as a consequence of the ablation of the cell capacity to adapt to aging. Gene expression analysis suggests that MUFA or n-3PUFA allowed mitochondria to maintain an adequate turnover through induction of biogenesis, autophagy and the antioxidant systems, and avoiding mitochondrial electron transport system alterations.
The main finding is that the enhanced alveolar bone loss associated to age may be targeted by an appropriate dietary treatment. The mechanisms involved in this phenomenon are related with an ablation of the cell capacity to adapt to aging. Thus, MUFA or n-3PUFA might allow mitochondrial maintaining turnover through biogenesis or autophagy. They might also be able to induce the corresponding antioxidant systems to counteract age-related oxidative stress, and do not inhibit mitochondrial electron transport chain. From the nutritional and clinical point of view, it is noteworthy that the potential treatments to attenuate alveolar bone loss (a feature of periodontal disease) associated to age could be similar to some of the proposed for the prevention and treatment of cardiovascular diseases, a group of pathologies recently associated with age-related periodontitis.
PMCID: PMC3774624  PMID: 24066124
15.  Safety of intravenous ivabradine in acute ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention: a randomized, placebo-controlled, double-blind, pilot study 
Rapid heart rate lowering may be attractive in acute ST-segment elevation myocardial infarction (STEMI). Accordingly we studied the effect of intravenous ivabradine on heart rate in this setting.
Methods and results:
This was a multicenter randomized double-blind placebo-controlled trial: patients aged 40–80 years were randomized after successful primary percutaneous coronary intervention (PCI) performed within 6 h of STEMI symptom onset. Patients were in sinus rhythm and with heart rate >80 bpm and systolic blood pressure >90 mm Hg. They were randomly assigned (2:1 ratio) to intravenous ivabradine (n=82) (5 mg bolus over 30 s, followed by 5 mg infusion over 8 h) or matching placebo (n=42). The primary outcome measure was heart rate and blood pressure. In both groups, heart rate was reduced over 8 h, with a faster and more marked decrease on ivabradine than placebo (22.2±1.3 vs 8.9±1.8 bpm, p<0.0001). After treatment discontinuation, heart rate was similar in both groups. Throughout the study, there was no difference in blood pressure between groups. There was no difference in cardiac biomarkers (creatine kinase (CK-MB), troponin T and troponin I). On echocardiography performed at baseline and post treatment (median 1.16 days), final left ventricular volumes were lower in the ivabradine group both for left ventricular end-diastolic volume (LVEDV) (87.1±28.2 vs 117.8±21.4 ml, p=0.01) and left ventricular end-systolic volume (LVESV) (42.5±19.0 versus 59.1±11.3 ml, p=0.03) without differences in volume change or left ventricular ejection fraction.
This pilot study shows that intravenous ivabradine may be used safely to slow the heart rate in STEMI. Further studies are needed to characterize its effect on infarct size, left ventricular function and clinical outcomes in this population.
PMCID: PMC3821820  PMID: 24222839
Acute Coronary Syndromes (ACS); heart rate; ivabradine; percutaneous coronary intervention; revascularization; ST-segment elevation myocardial infarction
16.  Src activation by β-adrenoreceptors is a key switch for tumor metastasis 
Nature communications  2013;4:1403.
Norepinephrine (NE) can modulate multiple cellular functions important for cancer progression; however, how this single extracellular signal regulates such a broad array of cellular processes is unknown. Here, we identify Src as a key regulator of phosphoproteomic signaling networks activated in response to beta-adrenergic signaling in cancer cells. These results also identify a new mechanism of Src phosphorylation that mediates beta-adrenergic/PKA regulation of downstream networks, thereby enhancing tumor cell migration, invasion and growth. In human ovarian cancer samples, high tumoral NE levels were correlated with high pSrcY419 levels. Moreover, among cancer patients, the use of beta blockers was significantly associated with reduced cancer-related mortality. Collectively, these data provide a pivotal molecular target for disrupting neural signaling in the tumor microenvironment.
PMCID: PMC3561638  PMID: 23360994
17.  Acute Abdominal Pain Secondary to Chilaiditi Syndrome 
Case Reports in Surgery  2013;2013:756590.
Chilaiditi syndrome is a rare condition occurring in 0.025% to 0.28% of the population. In these patients, the colon is displaced and caught between the liver and the right hemidiaphragm. Patients' symptoms can range from asymptomatic to acute intermittent bowel obstruction. Diagnosis is best achieved with CT imaging. Identification of Chilaiditi syndrome is clinically significant as it can lead to many significant complications such as volvulus, perforation, and bowel obstruction. If the patient is symptomatic, treatment is usually conservative. Surgery is rarely indicated with indications including ischemia and failure of resolution with conservative management.
PMCID: PMC3713330  PMID: 23936720
18.  Gene Deficiency in Activating Fcγ Receptors Influences the Macrophage Phenotypic Balance and Reduces Atherosclerosis in Mice 
PLoS ONE  2013;8(6):e66754.
Immunity contributes to arterial inflammation during atherosclerosis. Oxidized low-density lipoproteins induce an autoimmune response characterized by specific antibodies and immune complexes in atherosclerotic patients. We hypothesize that specific Fcγ receptors for IgG constant region participate in atherogenesis by regulating the inflammatory state of lesional macrophages. In vivo we examined the role of activating Fcγ receptors in atherosclerosis progression using bone marrow transplantation from mice deficient in γ-chain (the common signaling subunit of activating Fcγ receptors) to hyperlipidemic mice. Hematopoietic deficiency of Fcγ receptors significantly reduced atherosclerotic lesion size, which was associated with decreased number of macrophages and T lymphocytes, and increased T regulatory cell function. Lesions of Fcγ receptor deficient mice exhibited increased plaque stability, as evidenced by higher collagen and smooth muscle cell content and decreased apoptosis. These effects were independent of changes in serum lipids and antibody response to oxidized low-density lipoproteins. Activating Fcγ receptor deficiency reduced pro-inflammatory gene expression, nuclear factor-κB activity, and M1 macrophages at the lesion site, while increasing anti-inflammatory genes and M2 macrophages. The decreased inflammation in the lesions was mirrored by a reduced number of classical inflammatory monocytes in blood. In vitro, lack of activating Fcγ receptors attenuated foam cell formation, oxidative stress and pro-inflammatory gene expression, and increased M2-associated genes in murine macrophages. Our study demonstrates that activating Fcγ receptors influence the macrophage phenotypic balance in the artery wall of atherosclerotic mice and suggests that modulation of Fcγ receptor-mediated inflammatory responses could effectively suppress atherosclerosis.
PMCID: PMC3689671  PMID: 23805273
19.  Nanoinformatics: developing new computing applications for nanomedicine 
Nanoinformatics has recently emerged to address the need of computing applications at the nano level. In this regard, the authors have participated in various initiatives to identify its concepts, foundations and challenges. While nanomaterials open up the possibility for developing new devices in many industrial and scientific areas, they also offer breakthrough perspectives for the prevention, diagnosis and treatment of diseases. In this paper, we analyze the different aspects of nanoinformatics and suggest five research topics to help catalyze new research and development in the area, particularly focused on nanomedicine. We also encompass the use of informatics to further the biological and clinical applications of basic research in nanoscience and nanotechnology, and the related concept of an extended “nanotype” to coalesce information related to nanoparticles. We suggest how nanoinformatics could accelerate developments in nanomedicine, similarly to what happened with the Human Genome and other –omics projects, on issues like exchanging modeling and simulation methods and tools, linking toxicity information to clinical and personal databases or developing new approaches for scientific ontologies, among many others.
PMCID: PMC3430140  PMID: 22942787
Nanoinformatics; Computing; Nanotechnology; Bioinformatics; Medical Informatics; Nanomedicine
20.  Tissue-derived mesenchymal stromal cells used as vehicles for anti-tumor therapy exert different in vivo effects on migration capacity and tumor growth 
BMC Medicine  2013;11:139.
Mesenchymal stem cells (MSCs) have been promoted as an attractive option to use as cellular delivery vehicles to carry anti-tumor agents, owing to their ability to home into tumor sites and secrete cytokines. Multiple isolated populations have been described as MSCs, but despite extensive in vitro characterization, little is known about their in vivo behavior.
The aim of this study was to investigate the efficacy and efficiency of different MSC lineages derived from five different sources (bone marrow, adipose tissue, epithelial endometrium, stroma endometrium, and amniotic membrane), in order to assess their adequacy for cell-based anti-tumor therapies. Our study shows the crucial importance of understanding the interaction between MSCs and tumor cells, and provides both information and a methodological approach, which could be used to develop safer and more accurate targeted therapeutic applications.
We first measured the in vivo migration capacity and effect on tumor growth of the different MSCs using two imaging techniques: (i) single-photon emission computed tomography combined with computed tomography (SPECT-CT), using the human sodium iodine symporter gene (hNIS) and (ii) magnetic resonance imaging using superparamagnetic iron oxide. We then sought correlations between these parameters and expression of pluripotency-related or migration-related genes.
Our results show that migration of human bone marrow-derived MSCs was significantly reduced and slower than that obtained with the other MSCs assayed and also with human induced pluripotent stem cells (hiPSCs). The qPCR data clearly show that MSCs and hiPSCs exert a very different pluripotency pattern, which correlates with the differences observed in their engraftment capacity and with their effects on tumor growth.
This study reveals differences in MSC recruitment/migration toward the tumor site and the corresponding effects on tumor growth. Three observations stand out: 1) tracking of the stem cell is essential to check the safety and efficacy of cell therapies; 2) the MSC lineage to be used in the cell therapy needs to be carefully chosen to balance efficacy and safety for a particular tumor type; and 3) different pluripotency and mobility patterns can be linked to the engraftment capacity of the MSCs, and should be checked as part of the clinical characterization of the lineage.
PMCID: PMC3670996  PMID: 23710709
Mesenchymal stromal cells; Migration; In vivo imaging; Tumor growth; Pluripotency
21.  Tailored Internal Communication Strategies for the Life Science Shared Resource 
In the life-science laboratory management setting, there is a constant need to address the question, “what can make us better?” Although there are many variables that can be examined, a review of internal-communication practices can identify areas of opportunity. People in a shared-resource management position have a number of levels of communication responsibilities: communication with the organization's highest-level administration, with individual core facilities, with the users of the shared resource, with peers in academia and industry, and with direct reports. The description and application of internal-communication strategies in the life-science research setting, tailored from the internal strategies originally described by Downs & Adrian in Assessing Organizational Communication (2004), are presented along with ideas for approaches fostering innovation.
PMCID: PMC3635327
22.  Overview of the New Flow Cytometry RG and Proposed Cell Sorting (FACS) Microarray study 
The Flow Cytometry Research Group (FCRG) is the latest addition to the ABRF RG family. The RG is currently in its first year and has 9 members; many of whom are flow cytometrists new to the ABRF. The initial goal of the FCRG is to describe a method for the evaluation of cell stress or other deleterious perturbations caused by cell sorting across a wide range of cell types.
As an example, reports have been published demonstrating the susceptibility of dendritic cells (DCs) to phenotypic and functional changes after manipulation and isolation using techniques such as magnetic bead enrichment. To evaluate the effects of cell sorting on DCs, populations were enriched on both jet-in-air (MoFlo and FACSVantage ) and cuvette-based (FACSAria II) cell sorters, and then assessed in vitro for their ability to function as antigen presenting cells. This study showed that DC populations sorted on a cuvette sorter had decreased numbers of viable cells and decrease ability to induce antigen specific T cell proliferation, while cells sorted on jet-in-air sorters were able to induce proliferation and deemed functional.
The FCRG is expanding upon this work with a 3-year research plan study which will utilize microarray analysis as an aid to identify optimal cell sorting conditions for a wide variety of cell types. This year's pilot study utilized Jurkat cells sorted through a Beckman Coulter MoFlo Legacy flow cytometer with two nozzle sizes at their respective pressures ( 50um nozzle at 70psi compared to 100um nozzle at 20psi), with and without UV laser exposure. Cells were sorted and allowed to incubate for 3 hr in RPMI media in parallel with a matched unsorted cellular control. Total RNA was extracted using Trizol and analyzed using the new Affymetrix Human Gene ST 2.0 microarrays. Results of this pilot study will be presented.
PMCID: PMC3635449
23.  Reconstructing Native American Population History 
Nature  2012;488(7411):370-374.
The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved1–5. One contentious issue is whether the settlement occurred via a single6–8 or multiple streams of migration from Siberia9–15. The pattern of dispersals within the Americas is also poorly understood. To address these questions at higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. We show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call “First American”. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan-speakers on both sides of the Panama Isthmus, who have ancestry from both North and South America.
PMCID: PMC3615710  PMID: 22801491
25.  Baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) 
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S. | Ratkovec, R. | Richardson, R. | Ross, A. | Saleh, N. | Saltzberg, M. | Sarkar, S. | Schmedtje, J. | Schneider, R. | Schuyler, G. | Shanes, J. | Sharma, A. | Siegel, C. | Siegel, R. | Silber, D. | Singh, V. | Singh, N. | Singh, J. | Sklar, J. | Small, R. | Smith, A. | Smith, E. | Smith, E. | Smull, D. | Sotolongo, R. | Staniloae, C. | Stapleton, D. | Steele, P. | Stehlik, J. | Stein, M. | Tang, W. | Thadani, U. | Torre-Amoine, G. | Trichon, B. | Tsai, C. | Tummala, R. | Van Bakel, A. | Vicari, R. | Vijay, N. | Vijayaraghavan, K. | Vittorio, T. | Vossler, M. | Wagoner, L. | Wallis, D. | Ward, N. | Widmer, M. | Wight, J. | Wilkins, C. | Williams, C. | Williams, G. | Winchester, M. | Winkel, E. | Wittmer, B. | Wood, D. | Wormer, D. | Wright, R. | Xu, Z. | Yasin, M. | Zolty, R.
European Journal of Heart Failure  2013;15(3):334-341.
This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes.
Methods and results
Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate <60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106–117) g/L.
The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity.
PMCID: PMC3576902  PMID: 23329651
Heart failure; Anaemia

Results 1-25 (3525)