Publications by authors named "Ana Ferrer"

68 Publications

Lack of expression of LMO2 clone SP51 identifies MYC rearrangements in aggressive large B-cell lymphomas.

Virchows Arch 2021 Apr 3. Epub 2021 Apr 3.

Department of Pathology, Hospital del Mar, Institut Hospital del Mar d'Investigacions Mediques (IMIM), Barcelona, Spain.

MYC rearrangements (MYC-R) confer unfavorable prognosis to large B-cell lymphomas (LBCL). Because of the low incidence of such genetic alteration, surrogates to screen MYC-R may be useful in daily practice. Previous studies suggested that clone 1A9-1 of LMO2 loss may be a good predictor for the presence of MYC-R in LBCL. The present study examines the utility of LMO2 clone SP51. For this purpose, we have analyzed 20 Burkitt lymphomas and 325 LBCL. Among them, 245 cases were studied prospectively using whole tissue sections, and 100 retrospectively by tissue microarrays. The cohort of CD10-positive prospective cases achieved the best results. Lack of LMO2 SP51 expression predicted the presence of MYC-R with high specificity, accuracy, positive and negative predictive value (PPV/NPV), and positive and negative likelihood ratios (PLR/NLR). Compared with MYC protein expression, LMO2 SP51 obtained significantly higher specificity, accuracy, PPV, and PLR (94%, 91%, 85%, and 14.33 vs 73%, 77%, 56%, and 3.26, respectively), and similar NPV and NLR (92% and 0.22 vs 95% and 0.12). Compared with LMO2 clone 1A9-1, the sensitivity of LMO2 SP51 was lower (79% vs 89%). We conclude that LMO2 SP51 may be a useful marker to screen MYC-R in CD10-positive LBCL.
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http://dx.doi.org/10.1007/s00428-021-03091-9DOI Listing
April 2021

Circulating Tumor DNA Detection by Digital-Droplet PCR in Pancreatic Ductal Adenocarcinoma: A Systematic Review.

Cancers (Basel) 2021 Feb 27;13(5). Epub 2021 Feb 27.

Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain.

Pancreatic cancer (PC) is one of the most devastating malignant tumors, being the seventh leading cause of cancer-related death worldwide. Researchers and clinicians are endeavoring to develop strategies for the early detection of the disease and the improvement of treatment results. Adequate biopsy is still challenging because of the pancreas's poor anatomic location. Recently, circulating tumor DNA (ctDNA) could be identified as a liquid biopsy tool with huge potential as a non-invasive biomarker in early diagnosis, prognosis and management of PC. ctDNA is released from apoptotic and necrotic cancer cells, as well as from living tumor cells and even circulating tumor cells, and it can reveal genetic and epigenetic alterations with tumor-specific and individual mutation and methylation profiles. However, ctDNA sensibility remains a limitation and the accuracy of ctDNA as a biomarker for PC is relatively low and cannot be currently used as a screening or diagnostic tool. Increasing evidence suggests that ctDNA is an interesting biomarker for predictive or prognosis studies, evaluating minimal residual disease, longitudinal follow-up and treatment management. Promising results have been published and therefore the objective of our review is to understand the current role and the future perspectives of ctDNA in PC.
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http://dx.doi.org/10.3390/cancers13050994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956845PMC
February 2021

Reduced expansion of CD94/NKG2C NK cells in chronic lymphocytic leukemia and CLL-like monoclonal B-cell lymphocytosis is not related to increased human cytomegalovirus seronegativity or NKG2C deletions.

Int J Lab Hematol 2021 Feb 22. Epub 2021 Feb 22.

Molecular Cytogenetics Laboratory, Hematological Cytology Laboratory, Pathology Department, Hospital del Mar, Barcelona, Spain.

Introduction: Dysregulated NK cell-mediated immune responses contribute to tumor evasion in chronic lymphocytic leukemia (CLL), although the NK cell compartment in CLL-like monoclonal B-cell lymphocytosis (MBL) is poorly understood. In healthy individuals, human cytomegalovirus (HCMV) induces the expansion of NK cells expressing high levels of CD94/NKG2C NK cell receptor (NKR) specific for HLA-E.

Methods: We analyzed the expression of NKG2A, NKG2C, ILT2, KIR, CD161, and CD57 in 24 MBL and 37 CLL. NKG2C was genotyped in these patients and in 81 additional MBL/CLL, while NKG2C gene expression was assessed in 26 cases. In 8 CLL patients with increased lymphocytosis (≥20 × 10 /L), tumor HLA-E and HLA-G expression was evaluated.

Results: NKR distribution did not significantly differ between MBL and CLL patients, although they exhibited reduced NKG2C NK cells compared with a non-CLL group (4.6% vs 12.2%, P = .012). HCMV patients showed increased percentages of NKG2C NK cells compared with HCMV (7.3% vs 2.9%, P = .176). Frequencies of NKG2C deletions in MBL/CLL were similar to those of the general population. Low/undetectable NKG2C expression was found among NKG2C (45%) and NKG2C (12%) patients. CLL cases with increased lymphocytosis displayed especially reduced NKG2C expression (1.8% vs 8.1%, P = .029) and tumor cells with high HLA-E (>98%) and variable HLA-G expression (12.4%, range: 0.5-56.4). CLL patients with low NKG2C expression (<7%) showed shorter time to first treatment (P = .037).

Conclusion: Reduced percentages of CD94/NKG2C NK cells were observed in CLL and MBL patients independently of HCMV serostatus and NKG2C zygosity, particularly in CLL patients with increased lymphocytosis, which could potentially be related to the exposure to tumor cells.
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http://dx.doi.org/10.1111/ijlh.13494DOI Listing
February 2021

Chronic lymphocytic leukemia-like monoclonal B-cell lymphocytosis exhibits an increased inflammatory signature that is reduced in early-stage chronic lymphocytic leukemia.

Exp Hematol 2021 Mar 7;95:68-80. Epub 2021 Jan 7.

Laboratori de Citogenètica Molecular, Laboratori de Citologia Hematològica, Servei de Patologia, Hospital del Mar, Barcelona, Spain; Grup de Recerca Translacional en Neoplàsies Hematològiques, Cancer Research Program, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain. Electronic address:

Several studies in chronic lymphocytic leukemia (CLL) patients have reported impaired immune cell functions, which contribute to tumor evasion and disease progression. However, studies on CLL-like monoclonal B-cell lymphocytosis (MBL) are scarce. In the study described here, we characterized the immune environment in 62 individuals with clinical MBL, 56 patients with early-stage CLL, and 31 healthy controls. Gene expression arrays and quantitative reverse transcription polymerase chain reaction were performed on RNA from CD4 peripheral blood cells; serum cytokines were measured with immunoassays; and HLA-DR expression on circulating monocytes, as well as the percentages of Th1, cytotoxic, exhausted, and effector CD4 T cells, were evaluated by flow cytometry. In addition, cell cultures of clonal B cells and CD14-enriched or -depleted cell fractions were performed. Strikingly, MBL and early-stage CLL differed in pro-inflammatory signatures. An increased inflammatory drive orchestrated mainly by monocytes was identified in MBL, which exhibited enhanced phagocytosis, pattern recognition receptors, interleukin-8 (IL8), HMGB1, and acute response signaling pathways and increased pro-inflammatory cytokines (in particular IL8, interferon γ [IFNγ], and tumor necrosis factor α). This inflammatory signature was diminished in early-stage CLL (reduced IL8 and IFNγ levels, IL8 signaling pathway, and monocytic HLA-DR expression compared with MBL), especially in those patients with mutations in IGHV genes. Additionally, CD4 T cells of MBL and early-stage CLL exhibited a similar upregulation of Th1 and cytotoxic genes and expanded CXCR3 and perforin CD4 T cells, as well as PD1 CD4 T cells, compared with controls. Cell culture assays disclosed tumor-supporting effects of monocytes similarly observed in MBL and early-stage CLL. These novel findings reveal differences in the inflammatory environment between MBL and CLL, highlighting an active role for antigen stimulation in the very early stages of the disease, potentially related to malignant B-cell transformation.
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http://dx.doi.org/10.1016/j.exphem.2020.12.007DOI Listing
March 2021

Inactivated trivalent influenza vaccination is associated with lower mortality among patients with COVID-19 in Brazil.

BMJ Evid Based Med 2020 Dec 11. Epub 2020 Dec 11.

Department of Pediatrics, University of São Paulo Medical School, São Paulo, Brazil.

Objective: To estimate associations between trivalent influenza vaccination and COVID-19 mortality as well as severe clinical outcomes among hospitalised patients.

Design: Retrospective observational study.

Setting: This study was conducted among hospitalised patients with COVID-19 in Brazil.

Participants: We analysed all hospitalised patients with COVID-19 with available vaccination information captured in Brazil's national electronic respiratory infection data system between 1 January 2020 and 23 June 2020.

Main Outcome Measures: The primary outcomes were age-specific mortality rates of hospitalised patients with COVID-19 with and without recent inactivated trivalent influenza vaccination.

Results: A total of 53 752 clinically confirmed COVID-19 cases were analysed. Controlling for health facility of treatment, comorbidities as well as an extensive range of sociodemographic factors, patients who received a recent influenza vaccine experienced on average 7% lower odds of needing intensive care treatment (95% CI 0.87 to 0.98), 17% lower odds of requiring invasive respiratory support (95% CI 0.77 to 0.88) and 16% lower odds of death (95% CI 0.78 to 0.90). Protective effects were larger when the vaccine was administered after onset of symptoms as well as among younger patients.

Conclusion: Patients with COVID-19 with recent inactivated influenza vaccination experience significantly better health outcomes than non-vaccinated patients in Brazil. Beneficial off-target effects of influenza vaccination through trained innate immune responses seem plausible and need to be further explored. Large-scale promotion of influenza vaccines seems advisable, especially in populations at high risk for severe COVID-19 disease progression.
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http://dx.doi.org/10.1136/bmjebm-2020-111549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735072PMC
December 2020

Inactivated trivalent influenza vaccination is associated with lower mortality among patients with COVID-19 in Brazil.

BMJ Evid Based Med 2020 Dec 11. Epub 2020 Dec 11.

Department of Pediatrics, University of São Paulo Medical School, São Paulo, Brazil.

Objective: To estimate associations between trivalent influenza vaccination and COVID-19 mortality as well as severe clinical outcomes among hospitalised patients.

Design: Retrospective observational study.

Setting: This study was conducted among hospitalised patients with COVID-19 in Brazil.

Participants: We analysed all hospitalised patients with COVID-19 with available vaccination information captured in Brazil's national electronic respiratory infection data system between 1 January 2020 and 23 June 2020.

Main Outcome Measures: The primary outcomes were age-specific mortality rates of hospitalised patients with COVID-19 with and without recent inactivated trivalent influenza vaccination.

Results: A total of 53 752 clinically confirmed COVID-19 cases were analysed. Controlling for health facility of treatment, comorbidities as well as an extensive range of sociodemographic factors, patients who received a recent influenza vaccine experienced on average 7% lower odds of needing intensive care treatment (95% CI 0.87 to 0.98), 17% lower odds of requiring invasive respiratory support (95% CI 0.77 to 0.88) and 16% lower odds of death (95% CI 0.78 to 0.90). Protective effects were larger when the vaccine was administered after onset of symptoms as well as among younger patients.

Conclusion: Patients with COVID-19 with recent inactivated influenza vaccination experience significantly better health outcomes than non-vaccinated patients in Brazil. Beneficial off-target effects of influenza vaccination through trained innate immune responses seem plausible and need to be further explored. Large-scale promotion of influenza vaccines seems advisable, especially in populations at high risk for severe COVID-19 disease progression.
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http://dx.doi.org/10.1136/bmjebm-2020-111549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735072PMC
December 2020

Oligomonocytic and overt chronic myelomonocytic leukemia show similar clinical, genomic, and immunophenotypic features.

Blood Adv 2020 10;4(20):5285-5296

Laboratori de Citologia Hematològica, Servei de Patologia, Grup de Recerca Translacional en Neoplàsies Hematològiques (GRETNHE), and.

Oligomonocytic chronic myelomonocytic leukemia (OM-CMML) is defined as those myelodysplastic syndromes (MDSs) or myelodysplastic/myeloproliferative neoplasms, unclassifiable with relative monocytosis (≥10% monocytes) and a monocyte count of 0.5 to <1 × 109/L. These patients show clinical and genomic features similar to those of overt chronic myelomonocytic leukemia (CMML), although most of them are currently categorized as MDS, according to the World Health Organization 2017 classification. We analyzed the clinicopathologic features of 40 patients with OM-CMML with well-annotated immunophenotypic and molecular data and compared them to those of 56 patients with overt CMML. We found similar clinical, morphological, and cytogenetic features. In addition, OM-CMML mirrored the well-known complex molecular profile of CMML, except for the presence of a lower percentage of RAS pathway mutations. In this regard, of the different genes assessed, only CBL was found to be mutated at a significantly lower frequency. Likewise, the OM-CMML immunophenotypic profile, assessed by the presence of >94% classical monocytes (MO1s) and CD56 and/or CD2 positivity in peripheral blood monocytes, was similar to overt CMML. The MO1 percentage >94% method showed high accuracy for predicting CMML diagnosis (sensitivity, 90.7%; specificity, 92.2%), even when considering OM-CMML as a subtype of CMML (sensitivity, 84.9%; specificity, 92.1%) in our series of 233 patients (39 OM-CMML, 54 CMML, 23 MDS, and 15 myeloproliferative neoplasms with monocytosis and 102 reactive monocytosis). These results support the consideration of OM-CMML as a distinctive subtype of CMML.
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http://dx.doi.org/10.1182/bloodadvances.2020002206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594385PMC
October 2020

PEDIATRICIANS AFTER RESIDENCY: A SURVEY OF PERSONAL/PROFESSIONAL DATA AND ISSUES.

Rev Paul Pediatr 2021 3;39:e2019190. Epub 2020 Aug 3.

Universidade de São Paulo, São Paulo, SP, Brazil.

Objective: To assess personal, professional, medical, and scientific educational characteristics and issues reported by pediatricians.

Methods: Cross-sectional study based on an online survey including 614 pediatricians who graduated in the last 15 years at a University Pediatric Department in Brazil.

Results: The response rate was 331/614(54%). The majority were females (82%), the median age was 33 years (27-40) and median years of pediatric practice was 5 (1-13). High workload (>60 hours/week) occurred in 25% and 47% earned ≥15 minimum wages/month. The most work-related issues reported were long working hours, poor social life and a sedentary lifestyle (>50%). Pediatricians were further divided into two groups, according to years of pediatric clinical practice: group 1 (≤5 years) and group 2 (>5 years). The median of overall satisfaction with pediatric residency [8(0-10) vs. 9 (4-10); p=0.002] was significantly reduced in group 1. The frequencies of workload >60 hours, work on pediatric ward and pediatric intensive care were significantly higher in the first group (p<0.05). Regarding main issues related to clinical practice in the last year, long working hours (73 vs. 53%; p<0.001), poor social life (75 vs. 62%; p=0.018) and harassment (23 vs. 4%; p=0.003) were significantly higher in the first group.

Conclusions: Very early career pediatricians (≤5 years) reported higher workload, lower income, work-related issues and different location of pediatric practice compared to early career pediatricians (>5 years). The overall satisfaction with pediatric residency was good, however, reduced in very early career pediatricians.
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http://dx.doi.org/10.1590/1984-0462/2021/39/2019190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401498PMC
May 2021

Impact of Acute Hemoglobin Falls in Heart Failure Patients: A Population Study.

J Clin Med 2020 Jun 15;9(6). Epub 2020 Jun 15.

Cardiovascular and Renal Research Group INCLIVA Research Institute University of Valencia, 46010 Valencia, Spain.

This study assessed the impact of acute hemoglobin (Hb) falls in heart failure (HF) patients. HF patients with repeated Hb values over time were included. Falls in Hb greater than 30% were considered to represent an acute episode of anemia and the risk of hospitalization and all-cause mortality after the first episode was assessed. In total, 45,437 HF patients (54.9% female, mean age 74.3 years) during a follow-up average of 2.9 years were analyzed. A total of 2892 (6.4%) patients had one episode of Hb falls, 139 (0.3%) had more than one episode, and 342 (0.8%) had concomitant acute kidney injury (AKI). Acute heart failure occurred in 4673 (10.3%) patients, representing 3.6/100 HF patients/year. The risk of hospitalization increased with one episode (Hazard Ratio = 1.30, 95% confidence interval (CI) 1.19-1.43), two or more episodes (HR = 1.59, 95% CI 1.14-2.23, and concurrent AKI (HR = 1.61, 95% CI 1.27-2.03). A total of 10,490 patients have died, representing 8.1/100 HF patients/year. The risk of mortality was HR = 2.20 (95% CI 2.06-2.35) for one episode, HR = 3.14 (95% CI 2.48-3.97) for two or more episodes, and HR = 3.20 (95% CI 2.73-3.75) with AKI. In the two or more episodes and AKI groups, Hb levels at the baseline were significantly lower (10.2-11.4 g/dL) than in the no episodes group (12.8 g/dL), and a higher and significant mortality in these subgroups was observed. Hb falls in heart failure patients identified those with a worse prognosis requiring a more careful evaluation and follow-up.
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http://dx.doi.org/10.3390/jcm9061869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355985PMC
June 2020

Survive and Thrive in Brazil: The Boa Vista Early Childhood Program: study protocol of a stepped-wedge, randomized controlled trial.

Trials 2020 May 7;21(1):390. Epub 2020 May 7.

Department of Epidemiology and Public Health, Swiss TPH and University of Basel, Socintrasse 57, 4002, Basel, Switzerland.

Background: A growing body of evidence suggests that early life health and developmental outcomes can be improved through parental support programs. The objective of this project was to test the feasibility, impact, and relative cost-effectiveness of an adapted "Reach Up and Learn" program delivered through home-visiting programs as well as through center-based parenting groups on child health and development in the municipality of Boa Vista, Brazil.

Methods: A randomized, stepped-wedge design was used to roll out and evaluate the two parenting platforms in Boa Vista municipality. A total of 39 neighborhoods with a high Neighborhood Vulnerability Index were selected for the study. For the first phase of the program, nine neighborhoods were randomly selected for home visits, and two were randomly selected for the center-based parenting groups. In the second phase of the program, 10 neighborhoods were added to the home-visiting program, and eight were added to the center-based program. In the final phase of the program, the remaining 10 control areas will also be assigned to treatment. Study eligibility will be assessed through a baseline survey completed by all pregnant women in the 39 study areas. Pregnant women will be eligible to participate in the study if they are either classified as poor, were under age 20 years when they became pregnant, or if they indicate to have been exposed to domestic or sexual violence. To assess program impact, an endline survey will be conducted when children reach age 2 years. The primary study outcome is child development at age 2 years as measured by the PRIDI instrument. Secondary outcome will be infant mortality, which will be assessed linking municipal vital registration systems to the program rollout.

Discussion: This trial will assess the feasibility and impact of parenting programs rolled out at medium scale. The results from the trial should create evidence urgently needed for guiding Brazil's national Criança Feliz program as well as similar efforts in other countries.

Trial Registration: ClinicalTrials.gov, ID: NCT03386747. Registered on 13 December 2017. All items of the World Health Organization Trial Registration Data Set are available in this record.
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http://dx.doi.org/10.1186/s13063-020-4217-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206708PMC
May 2020

HDAC5 Inhibitors as a Potential Treatment in Breast Cancer Affecting Very Young Women.

Cancers (Basel) 2020 Feb 10;12(2). Epub 2020 Feb 10.

INCLIVA Biomedical Research Institute, Hospital Clínico Universitario Valencia, University of Valencia, 46010 Valencia, Spain.

Background: Breast cancer in very young women (BCVY) defined as <35 years old, presents with different molecular biology than in older patients. High expression has been associated with poor prognosis in breast cancer (BC) tissue. We aimed to analyze expression in BCVY and older patients and their correlation with clinical features, also studying the potential of HDAC5 inhibition in BC cell lines.

Methods: expression in 60 BCVY and 47 older cases were analyzed by qRT-PCR and correlated with clinical data. The effect of the HDAC5 inhibitor, LMK-235, was analyzed in BC cell lines from older and young patients. We performed time and dose dependence viability, migration, proliferation, and apoptosis assays.

Results: Our results correlate higher expression with worse prognosis in BCVY. However, we observed no differences between expression and pathological features. Our results showed greatly reduced progression in BCVY cell lines and also in all triple negative subtypes when cell lines were treated with LMK-235.

Conclusions: In BCVY, we found higher expression of HDAC5. Overexpression of in BCVY correlates with lower survival rates. LMK-235 could be a potential treatment in BCVY.
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http://dx.doi.org/10.3390/cancers12020412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072585PMC
February 2020

The importance of adequate recognition of normal and dysplastic myelopoiesis for the diagnosis of myelodysplastic syndromes.

Histol Histopathol 2019 Aug 19;34(8):857-873. Epub 2019 Feb 19.

Escola de Citologia Hematològica Soledad Woessner-Parc de Salut Mar, Laboratorio de Citología Hematológica, Patología, GRETNHE, IMIM Hospital del Mar Research Institute, Barcelona, Spain.

The diagnosis of myelodysplastic syndromes is based on the presence of cytopenias, dysplastic morphological features on peripheral blood (PB) and bone marrow (BM), cytogenetic abnormalities and requires to rule out other diseases resembling these conditions. Optical cytomorphology is the cornerstone of diagnosis of MDS. The recognition of cytological myelodysplasia has a crucial value in diagnosis and prognosis of MDS. Assessment of cytological morphology requires, like other diagnostic techniques (flow cytometry, cytogenetics, histological morphology), experienced observers and the availability of high quality and properly stained samples. The morphological analysis has shown moderate reproducibility among hematopathologists. The better characterization and standardization of morphological features has improved the reliability and reproducibility of MDS diagnosis. Maintaining the competence in morphology assessment requires experience and continuous training. For the correct assessment of cytologic myelodysplasia it is essential to keep in mind the morphology of normal myelopoiesis. To the extent of our knowledge there are no studies describing together morphological data on normal and dysplastic myelopoiesis in the framework of MDS. Therefore, by combining these data, this manuscript could serve as a useful tool for quotidian process of diagnosis.
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http://dx.doi.org/10.14670/HH-18-093DOI Listing
August 2019

Disease-biased and shared characteristics of the immunoglobulin gene repertoires in marginal zone B cell lymphoproliferations.

J Pathol 2019 04 30;247(4):416-421. Epub 2019 Jan 30.

IMGT®, the international ImMunoGeneTics Information System®, Université de Montpellier, LIGM, Institut de Génétique Humaine IGH, UMR CNRS UM, Montpellier, France.

The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ-related or not; n = 65 837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non-malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5209DOI Listing
April 2019

Restricted T cell receptor repertoire in CLL-like monoclonal B cell lymphocytosis and early stage CLL.

Oncoimmunology 2018;7(6):e1432328. Epub 2018 Feb 20.

Laboratori de Citogenètica Molecular, Laboratori de Citologia Hematològica, Servei de Patologia, Hospital del Mar, Barcelona, Spain.

Analysis of the T cell receptor (TR) repertoire of chronic lymphocytic leukemia-like monoclonal B cell lymphocytosis (CLL-like MBL) and early stage CLL is relevant for understanding the dynamic interaction of expanded B cell clones with bystander T cells. Here we profiled the T cell receptor β chain (TRB) repertoire of the CD4 and CD8 T cell fractions from 16 CLL-like MBL and 13 untreated, Binet stage A/Rai stage 0 CLL patients using subcloning analysis followed by Sanger sequencing. The T cell subpopulations of both MBL and early stage CLL harbored restricted TRB gene repertoire, with CD4 T cell clonal expansions whose frequency followed the numerical increase of clonal B cells. Longitudinal analysis in MBL cases revealed clonal persistence, alluding to persistent antigen stimulation. In addition, the identification of shared clonotypes among different MBL/early stage CLL cases pointed towards selection of the T cell clones by common antigenic elements. T cell clonotypes previously described in viral infections and immune disorders were also detected. Altogether, our findings evidence that antigen-mediated TR restriction occurs early in clonal evolution leading to CLL and may further increase together with B cell clonal expansion, possibly suggesting that the T cell selecting antigens are tumor-related.
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http://dx.doi.org/10.1080/2162402X.2018.1432328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980379PMC
February 2018

A gene signature that distinguishes conventional and leukemic nonnodal mantle cell lymphoma helps predict outcome.

Blood 2018 07 16;132(4):413-422. Epub 2018 May 16.

Institute for Biomedical Research August Pi i Sunyer, Barcelona, Spain.

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy, but some patients have a very indolent evolution. This heterogeneous course is related, in part, to the different biological characteristics of conventional MCL (cMCL) and the distinct subgroup of leukemic nonnodal MCL (nnMCL). Robust criteria to distinguish these MCL subtypes and additional biological parameters that influence their evolution are not well defined. We describe a novel molecular assay that reliably distinguishes cMCL and nnMCL using blood samples. We trained a 16-gene assay (L-MCL16 assay) on the NanoString platform using 19 purified leukemic samples. The locked assay was applied to an independent cohort of 70 MCL patients with leukemic presentation. The assay assigned 37% of cases to nnMCL and 56% to cMCL. nnMCL and cMCL differed in nodal presentation, lactate dehydrogenase, immunoglobulin heavy chain gene mutational status, management options, genomic complexity, and / deletions, but the proportion with 17p/ aberrations was similar in both subgroups. Sequential samples showed that assay prediction was stable over time. nnMCL had a better overall survival (OS) than cMCL (3-year OS 92% vs 69%; = .006) from the time of diagnosis and longer time to first treatment. Genomic complexity and / aberrations predicted for shorter OS in the entire series and cMCL, whereas only genomic complexity was associated with shorter time to first treatment and OS in nnMCL. In conclusion, the newly developed assay robustly recognizes the 2 molecular subtypes of MCL in leukemic samples. Its combination with genetic alterations improves the prognostic evaluation and may provide useful biological information for management decisions.
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http://dx.doi.org/10.1182/blood-2018-03-838136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071558PMC
July 2018

Patients with chronic lymphocytic leukemia and complex karyotype show an adverse outcome even in absence of deletions.

Oncotarget 2017 Aug 21;8(33):54297-54303. Epub 2017 Apr 21.

Laboratorio de Citogenética y Servicio de Hematología, Hospital Vall d'Hebron, Barcelona, Spain.

Genomic complexity identified by chromosome banding analysis (CBA) predicts a worse clinical outcome in CLL patients treated either with standard or new treatments. Herein, we analyzed the clinical impact of complex karyotypes (CK) with or without high-risk FISH deletions ( and/or , HR-FISH) in a cohort of 1045 untreated MBL/CLL patients. In all, 99/1045 (9.5%) patients displayed a CK. Despite and deletions were more common in CK (25% vs 7%; < 0.001; 40% vs 5%; < 0.001, respectively), only 44% (40/90) patients with deletions showed a CK. CK group showed a significant higher two-year cumulative incidence of treatment (48% vs 20%; < 0.001), as well as a shorter overall survival (OS) (79 mo vs not reached; < 0.001). When patients were categorized regarding CK and HR-FISH, those with both characteristics showed the worst median OS (52 mo) being clearly distinct from those non-CK and non-HR-FISH (median not reached), but no significant differences were detected between cases with only CK or HR-FISH. Both CK and deletion remained statistically significant in the multivariate analysis for OS. In conclusion, CK group is globally associated with advanced disease and poor prognostic markers. Further investigation in larger cohorts with CK lacking HR-FISH is needed to elucidate which mechanisms underlie the poor outcome of this subgroup.
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http://dx.doi.org/10.18632/oncotarget.17350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589581PMC
August 2017

Enumerating bone marrow blasts from nonerythroid cellularity improves outcome prediction in myelodysplastic syndromes and permits a better definition of the intermediate risk category of the Revised International Prognostic Scoring System (IPSS-R).

Am J Hematol 2017 Jul 9;92(7):614-621. Epub 2017 May 9.

Laboratorio Citología Hematológica. Servicio Patología, GRETNHE, IMIM Hospital del Mar Research Institute, Barcelona, Spain.

The Revised International Prognostic Scoring System (IPSS-R) has been recognized as the score with the best outcome prediction capability in MDS, but this brought new concerns about the accurate prognostication of patients classified into the intermediate risk category. The correct enumeration of blasts is essential in prognostication of MDS. Recent data evidenced that considering blasts from nonerythroid cellularity (NECs) improves outcome prediction in the context of IPSS and WHO classification. We assessed the percentage of blasts from total nucleated cells (TNCs) and NECs in 3924 MDS patients from the GESMD, 498 of whom were MDS with erythroid predominance (MDS-E). We assessed if calculating IPSS-R by enumerating blasts from NECs improves prognostication of MDS. Twenty-four percent of patients classified into the intermediate category were reclassified into higher-risk categories and showed shorter overall survival (OS) and time to AML evolution than those who remained into the intermediate one. Likewise, a better distribution of patients was observed, since lower-risk patients showed longer survivals than previously whereas higher-risk ones maintained the outcome expected in this poor prognostic group (median OS < 20 months). Furthermore, our approach was particularly useful for detecting patients at risk of dying with AML. Regarding MDS-E, 51% patients classified into the intermediate category were reclassified into higher-risk ones and showed shorter OS and time to AML. In this subgroup of MDS, IPSS-R was capable of splitting our series in five groups with significant differences in OS only when blasts were assessed from NECs. In conclusion, our easy-applicable approach improves prognostic assessment of MDS patients.
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http://dx.doi.org/10.1002/ajh.24732DOI Listing
July 2017

Lignin Films from Spruce, Eucalyptus, and Wheat Straw Studied with Electroacoustic and Optical Sensors: Effect of Composition and Electrostatic Screening on Enzyme Binding.

Biomacromolecules 2017 04 23;18(4):1322-1332. Epub 2017 Mar 23.

Departments of Forest Biomaterials and Chemical and Biomolecular Engineering, North Carolina State University , Raleigh, North Carolina 27695, United States.

Lignins were isolated from spruce, wheat straw, and eucalyptus by using the milled wood lignin (MWL) method. Functional groups and compositional analyses were assessed via 2D NMR and P NMR to realize their effect on enzyme binding. Films of the lignins were fabricated and ellipsometry, atomic force microscopy, and water contact angle measurements were used for their characterization and to reveal the changes upon enzyme adsorption. Moreover, lignin thin films were deposited on quartz crystal microgravimetry (QCM) and surface plasmon (SPR) resonance sensors and used to gain further insights into the lignin-cellulase interactions. For this purpose, a commercial multicomponent enzyme system and a monocomponent Trichoderma reesei exoglucanase (CBH-I) were considered. Strong enzyme adsorption was observed on the various lignins but compared to the multicomponent cellulases, CBH-I displayed lower surface affinity and higher binding reversibility. This resolved prevalent questions related to the affinity of this enzyme with lignin. Remarkably, a strong correlation between enzyme binding and the syringyl/guaiacyl (S/G) ratio was found for the lignins, which presented a similar hydroxyl group content (P NMR): higher protein affinity was determined on isolated spruce lignin (99% G units), while the lowest adsorption occurred on isolated eucalyptus lignin (70% S units). The effect of electrostatic interactions in enzyme adsorption was investigated by SPR, which clearly indicated that the screening of charges allowed more extensive protein adsorption. Overall, this work furthers our understanding of lignin-cellulase interactions relevant to biomass that has been subjected to no or little pretreatment and highlights the widely contrasting effects of the nature of lignin, which gives guidance to improve lignocellulosic saccharification and related processes.
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http://dx.doi.org/10.1021/acs.biomac.7b00071DOI Listing
April 2017

Assessment of access to primary health care among children and adolescents hospitalized due to avoidable conditions.

Rev Assoc Med Bras (1992) 2016 Sep;62(6):513-523

Full Professor, Department of Pediatrics, FMUSP, São Paulo, SP, Brazil.

Introduction:: Hospitalizations for ambulatory care-sensitive conditions (HACSC) are considered an indicator of the effectiveness of primary health care (PHC). High rates of HACSC represent problems in the access or the quality of health care. In Brazil, HACSC rates are high and there are few studies on the factors associated with it.

Objective:: To evaluate the access to PHC offered to children and adolescents hospitalized due to ACSC and analyze the conditioning factors.

Method:: Cross-sectional study with a quantitative and qualitative approach. Five hundred and one (501) users (guardians/caregivers) and 42 professionals of PHC units were interviewed over one year. Quantitative data were obtained using Primary Care Assessment Tool validated in Brazil (PCATool-Brazil), while qualitative data were collected by semi-structured interview. The independent variables were: age, maternal education, family income, type of diagnosis, and model of care offered, and the dependent variables were access and its components (accessibility and use of services).

Results:: Sixty-five percent (65.2%) of hospitalizations were ACSC. From the perspective of both users and professionals, access and its components presented low scores. Age, type of diagnosis, and model of care affected the results.

Conclusion:: The proportion of HACSC was high in this population. Access to services is inappropriate due to: barriers to access, appreciation of the emergency services, and attitude towards health needs. Professional attitudes and opinions reinforce inadequate ideas of users reflecting on the pattern of service use.
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http://dx.doi.org/10.1590/1806-9282.62.06.513DOI Listing
September 2016

Karyotypic complexity rather than chromosome 8 abnormalities aggravates the outcome of chronic lymphocytic leukemia patients with TP53 aberrations.

Oncotarget 2016 Dec;7(49):80916-80924

Laboratori de Citogenètica Molecular, Laboratori de Citologia Hematològica, Servei de Patologia, Hospital del Mar, Barcelona, Spain.

Patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations (TP53abs; chromosome 17p deletion and/or TP53 mutation) exhibit an unfavorable clinical outcome. Chromosome 8 abnormalities, namely losses of 8p (8p-) and gains of 8q (8q+) have been suggested to aggravate the outcome of patients with TP53abs. However, the reported series were small, thus hindering definitive conclusions. To gain insight into this issue, we assessed a series of 101 CLL patients harboring TP53 disruption. The frequency of 8p- and 8q+ was 14.7% and 17.8% respectively. Both were associated with a significantly (P < 0.05) higher incidence of a complex karyotype (CK, ≥3 abnormalities) detected by chromosome banding analysis (CBA) compared to cases with normal 8p (N-8p) and 8q (N-8q), respectively. In univariate analysis for 10-year overall survival (OS), 8p- (P = 0.002), 8q+ (P = 0.012) and CK (P = 0.009) were associated with shorter OS. However, in multivariate analysis only CK (HR = 2.47, P = 0.027) maintained independent significance, being associated with a dismal outcome regardless of chromosome 8 abnormalities. In conclusion, our results highlight the association of chromosome 8 abnormalities with CK amongst CLL patients with TP53abs, while also revealing that CK can further aggravate the prognosis of this aggressive subgroup.
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http://dx.doi.org/10.18632/oncotarget.13106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348364PMC
December 2016

Erythroleukemia shares biological features and outcome with myelodysplastic syndromes with excess blasts: a rationale for its inclusion into future classifications of myelodysplastic syndromes.

Mod Pathol 2016 12 26;29(12):1541-1551. Epub 2016 Aug 26.

Laboratorio Citología Hematológica. Servicio Patología, GRETNHE, IMIM Hospital del Mar Research Institute, Hospital del Mar, Barcelona, Spain.

Erythroleukemia was considered an acute myeloid leukemia in the 2008 World Health Organization (WHO) classification and is defined by the presence of ≥50% bone marrow erythroblasts, having <20% bone marrow blasts from total nucleated cells but ≥20% bone marrow myeloblasts from nonerythroid cells. Erythroleukemia shares clinicopathologic features with myelodysplastic syndromes, especially with erythroid-predominant myelodysplastic syndromes (≥50% bone marrow erythroblasts). The upcoming WHO revision proposes to eliminate the nonerythroid blast cell count rule and to move erythroleukemia patients into the appropriate myelodysplastic syndrome category on the basis of the absolute blast cell count. We conducted a retrospective study of patients with de novo erythroleukemia and compared their clinico-biological features and outcome with those of de novo myelodysplastic syndromes, focusing on erythroid-predominant myelodysplastic syndromes. Median overall survival of 405 erythroid-predominant myelodysplastic syndromes without excess blasts was significantly longer than that observed in 57 erythroid-predominant refractory anemias with excess blasts-1 and in 59 erythroleukemias, but no significant difference was observed between erythroid-predominant refractory anemias with excess blasts-1 and erythroleukemias. In this subset of patients with ≥50% bone marrow erythroblasts and excess blasts, the presence of a high-risk karyotype defined by the International Prognostic Scoring System or by the Revised International Prognostic Scoring System was the main prognostic factor. In the same way, the survival of 459 refractory anemias with excess blasts-2, independently of having ≥20% bone marrow blasts from nonerythroid cells or not, was almost identical to the observed in 59 erythroleukemias. Interestingly, 11 low-blast count erythroleukemias with 5 to <10% bone marrow blasts from total nucleated cells showed similar survival than the rest of erythroleukemias. Our data suggest that de novo erythroleukemia is in the spectrum of myelodysplastic syndromes with excess blasts and support its inclusion into future classifications of myelodysplastic syndromes.
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http://dx.doi.org/10.1038/modpathol.2016.146DOI Listing
December 2016

Considering Bone Marrow Blasts From Nonerythroid Cellularity Improves the Prognostic Evaluation of Myelodysplastic Syndromes.

J Clin Oncol 2016 09 5;34(27):3284-92. Epub 2016 Jul 5.

Leonor Arenillas, Xavier Calvo, Carme Pedro, Ana Ferrer, and Lourdes Florensa, Hospital del Mar Research Institute; Esther Alonso, Hospital Universitario Bellvitge Hospitalet de Llobregat; Julia Montoro, Hospital Universitario Vall d' Hebron; Salut Brunet, Hospital Santa Creu i Sant Pau; Benet Nomdedeu, Hospital Clínic, Barcelona; Elisa Luño, Hospital Universitario Central Asturias, Oviedo; Leonor Senent and Guillermo F. Sanz, Hospital Universitario La Fe; Mar Tormo, Hospital Clínico Universitario de Valencia; Rafael Andreu, Hospital Universitario Doctor Peset, Valencia; Fernando Ramos, Hospital Universitario de León, León; María Teresa Ardanaz, Hospital Universitario Txagorritxu, Vitoria; Víctor Marco, Hospital Arnau Vilanova, Lleida; María Díez-Campelo, Hospital Universitario de Salamanca, Salamanca; Beatriz Arrizabalaga, Hospital Universitario Cruces, Baracaldo; Blanca Xicoy, ICO-Badalona, Badalona; Santiago Bonanad, Hospital La Ribera, Alzira; and Andrés Jerez, Hospital Morales Meseguer, IMIB-Arrixaca, Murcia, Spain.

Purpose: WHO classification of myeloid malignancies is based mainly on the percentage of bone marrow (BM) blasts. This is considered from total nucleated cells (TNCs), unless there is erythroid-hyperplasia (erythroblasts ≥ 50%), calculated from nonerythroid cells (NECs). In these instances, when BM blasts are ≥ 20%, the disorder is classified as erythroleukemia, and when BM blasts are < 20%, as myelodysplastic syndrome (MDS). In the latter, the percentage of blasts is considered from TNCs.

Patients And Methods: We assessed the percentage of BM blasts from TNCs and NECs in 3,692 patients with MDS from the Grupo Español de Síndromes Mielodisplásicos, 465 patients with erythroid hyperplasia (MDS-E) and 3,227 patients without erythroid hyperplasia. We evaluated the relevance of both quantifications on classification and prognostication.

Results: By enumerating blasts systematically from NECs, 22% of patients with MDS-E and 12% with MDS from the whole series diagnosed within WHO categories with < 5% BM blasts, were reclassified into higher-risk categories and showed a poorer overall survival than did those who remained in initial categories (P = .006 and P = .001, respectively). Following WHO recommendations, refractory anemia with excess blasts (RAEB)-2 diagnosis is not possible in MDS-E, as patients with 10% to < 20% BM blasts from TNCs fulfill erythroleukemia criteria; however, by considering blasts from NECs, 72 patients were recoded as RAEB-2 and showed an inferior overall survival than did patients with RAEB-1 without erythroid hyperplasia. Recalculating the International Prognostic Scoring System by enumerating blasts from NECs in MDS-E and in the overall MDS population reclassified approximately 9% of lower-risk patients into higher-risk categories, which indicated the survival expected for higher-risk patients.

Conclusion: Regardless of the presence of erythroid hyperplasia, calculating the percentage of BM blasts from NECs improves prognostic assessment of MDS. This fact should be considered in future WHO classification reviews.
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http://dx.doi.org/10.1200/JCO.2016.66.9705DOI Listing
September 2016

Occupational Skills and Labour Market Progression of Married Immigrant Women in Canada.

Labour Econ 2016 Apr 2;39:88-98. Epub 2016 Mar 2.

Department of Economics, University of Waterloo, 200 University Avenue, Waterloo, ON, Canada N2L 3G1,

We use the confidential files of the 1991-2006 Canadian Census, combined with information from O*NET on the skill requirements of jobs, to explore whether immigrant women behave as secondary workers, remaining marginally attached to the labour market and experiencing little career progression over time. Our results show that the current labour market patterns of female immigrants to Canada do not fit this profile, as previous studies found, but rather conform to patterns recently exhibited by married native women elsewhere, with rising participation and wage progression. At best, only relatively uneducated immigrant women in unskilled occupations may fit the profile of secondary workers, with slow skill mobility and low-status job-traps. Educated immigrant women, on the other hand, experience skill assimilation over time: a reduction in physical strength and an increase in analytical skills required in their jobs relative to those of natives.
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http://dx.doi.org/10.1016/j.labeco.2016.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874528PMC
April 2016

Comparison between Hodgkin-Huxley and Markov formulations of cardiac ion channels.

J Theor Biol 2016 06 5;399:92-102. Epub 2016 Apr 5.

Ci2B - Universitat Politecnica de Valencia, Valencia, Spain. Electronic address:

When simulating the macroscopic current flowing through cardiac ion channels, two mathematical formalisms can be adopted: the Hodgkin-Huxley model (HHM) formulation, which describes openings and closings of channel 'gates', or the Markov model (MM) formulation, based on channel 'state' transitions. The latter was first used in 1995 to simulate the effects of mutations in ionic currents and, since then, its use has been extended to wild-type channels also. While the MMs better describe the actual behavior of ion channels, they are mathematically more complex than HHMs in terms of parameter estimation and identifiability and are computationally much more demanding, which can dramatically increase computational time in large-scale (e.g. whole heart) simulations. We hypothesize that a HHM formulation obtained from classical patch-clamp protocols in wild-type and mutant ion channels can be used to correctly simulate cardiac action potentials and their static and dynamic properties. To validate our hypothesis, we selected two pivotal cardiac ionic currents (the rapid delayed rectifier K(+) current, IKr, and the inward Na(+) current, INa) and formulated HHMs for both wild-type and mutant channels (LQT2-linked T474I mutation for IKr and LQT3-linked ΔKPQ mutation for INa). Action potentials were then simulated using the MM and HHM versions of the currents, and the action potential waveforms, biomarkers and action potential duration rate dependence properties were compared in control conditions and in the presence of physiological variability. While small differences between ionic currents were found between the two models (correlation coefficient ρ>0.92), the simulations yielded almost identical action potentials (ρ>0.99), suggesting that HHMs may also be valid to simulate the effects of mutations affecting IKr and INa on the action potential.
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http://dx.doi.org/10.1016/j.jtbi.2016.03.039DOI Listing
June 2016

Rollout of community-based family health strategy (programa de saude de familia) is associated with large reductions in neonatal mortality in São Paulo, Brazil.

SSM Popul Health 2016 Dec 21;2:55-61. Epub 2016 Feb 21.

Department of International Health Economics, Harvard School of Public Health, Cambridge, MA, USA.

Rationale: Several recent studies suggest that Brazil's Estratégia Saude de Familia (Family Health Strategy-FHS) has contributed to declines in mortality at the national and regional level. Comparatively little is known whether this approach is effective in urban populations with relatively easy access to health services.

Objectives: To use detailed medical data collected as part of São Paulo's Western Region project to examine whether the FHS program had an impact on child health in São Paulo, Brazil.

Results: No associations were found between FHS and birth weight (OR 1.03, 95% CI 0.93-1.29), gestational length (OR 0.98, 95% CI 0.83-1.15) or stillbirth (OR 1.51, 95% CI 0.75-3.03). FHS eligibility was associated with a 42% reduction in the odds of child mortality (OR 0.58, 95% CI 0.34, 0.91), with largest effect sizes for the early neonatal period (OR 0.18, 95% CI 0.04-0.79).

Conclusions: Community based health delivery platforms may be a highly effective way to reduce neonatal mortality in urban areas of low and middle income countries, even when access to general health services is almost universal.
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http://dx.doi.org/10.1016/j.ssmph.2016.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757818PMC
December 2016

Interactions between Cellulolytic Enzymes with Native, Autohydrolysis, and Technical Lignins and the Effect of a Polysorbate Amphiphile in Reducing Nonproductive Binding.

Biomacromolecules 2015 Dec 25;16(12):3878-88. Epub 2015 Nov 25.

Department of Forest Biomaterials, North Carolina State University , Raleigh, North Carolina 27695-8005, United States.

Understanding enzyme-substrate interactions is critical in designing strategies for bioconversion of lignocellulosic biomass. In this study we monitored molecular events, in situ and in real time, including the adsorption and desorption of cellulolytic enzymes on lignins and cellulose, by using quartz crystal microgravimetry and surface plasmon resonance. The effect of a nonionic surface active molecule was also elucidated. Three lignin substrates relevant to the sugar platform in biorefinery efforts were considered, namely, hardwood autohydrolysis cellulolytic (HWAH), hardwood native cellulolytic (MPCEL), and nonwood native cellulolytic (WSCEL) lignin. In addition, Kraft lignins derived from softwoods (SWK) and hardwoods (HWK) were used as references. The results indicated a high affinity between the lignins with both, monocomponent and multicomponent enzymes. More importantly, the addition of nonionic surfactants at concentrations above their critical micelle concentration reduced remarkably (by over 90%) the nonproductive interactions between the cellulolytic enzymes and the lignins. This effect was hypothesized to be a consequence of the balance of hydrophobic and hydrogen bonding interactions. Moreover, the reduction of surface roughness and increased wettability of lignin surfaces upon surfactant treatment contributed to a lower affinity with the enzymes. Conformational changes of cellulases were observed upon their adsorption on lignin carrying preadsorbed surfactant. Weak electrostatic interactions were determined in aqueous media at pH between 4.8 and 5.5 for the native cellulolytic lignins (MPCEL and WSCEL), whereby a ∼20% reduction in the enzyme affinity was observed. This was mainly explained by electrostatic interactions (osmotic pressure effects) between charged lignins and cellulases. Noteworthy, adsorption of nonionic surfactants onto cellulose, in the form cellulose nanofibrils, did not affect its hydrolytic conversion. Overall, our results highlight the benefit of nonionic surfactant pretreatment to reduce nonproductive enzyme binding while maintaining the reactivity of the cellulosic substrate.
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http://dx.doi.org/10.1021/acs.biomac.5b01203DOI Listing
December 2015

Detailed Anatomical and Electrophysiological Models of Human Atria and Torso for the Simulation of Atrial Activation.

PLoS One 2015 2;10(11):e0141573. Epub 2015 Nov 2.

Centro de Investigación e Innovación en Bioingeniería (Ci2B), Universitat Politècnica de València, Valencia, Spain.

Atrial arrhythmias, and specifically atrial fibrillation (AF), induce rapid and irregular activation patterns that appear on the torso surface as abnormal P-waves in electrocardiograms and body surface potential maps (BSPM). In recent years both P-waves and the BSPM have been used to identify the mechanisms underlying AF, such as localizing ectopic foci or high-frequency rotors. However, the relationship between the activation of the different areas of the atria and the characteristics of the BSPM and P-wave signals are still far from being completely understood. In this work we developed a multi-scale framework, which combines a highly-detailed 3D atrial model and a torso model to study the relationship between atrial activation and surface signals in sinus rhythm. Using this multi scale model, it was revealed that the best places for recording P-waves are the frontal upper right and the frontal and rear left quadrants of the torso. Our results also suggest that only nine regions (of the twenty-one structures in which the atrial surface was divided) make a significant contribution to the BSPM and determine the main P-wave characteristics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141573PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629897PMC
June 2016

Ventricular Tachycardia and Early Fibrillation in Patients With Brugada Syndrome and Ischemic Cardiomyopathy Show Predictable Frequency-Phase Properties on the Precordial ECG Consistent With the Respective Arrhythmogenic Substrate.

Circ Arrhythm Electrophysiol 2015 Oct 7;8(5):1133-43. Epub 2015 Aug 7.

From the Arrhythmia Unit, Hospital Universitario Central de Asturias, Oviedo, Spain (D.C., J.R.); Center for Arrhythmia Research, University of Michigan, Ann Arbor (J.J., O.B.); Arrhythmia Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain (F.A., P.Á., Á.A.); Centro de Investigación e Innovación en Bioingeniería, Ci2B, Universitat Politècnica de Valencia, Valencia, Spain (J.S., L.M., A.F.); Arrhythmia Unit, Hospital Río Hortega de Valladolid and Universitario de Burgos, Valladolid-Burgos, Spain (B.H., J.G.-F.); Universitat de Valencia, Valencia, Spain (R.S.); and Department of Statistics, Hospital Universitario Central de Asturias, Oviedo, Spain (P.M.-C.).

Background: Ventricular fibrillation (VF) has been proposed to be maintained by localized high-frequency sources. We tested whether spectral-phase analysis of the precordial ECG enabled identification of periodic activation patterns generated by such sources.

Methods And Results: Precordial ECGs were recorded from 15 ischemic cardiomyopathy and 15 Brugada syndrome (type 1 ECG) patients during induced VF and analyzed in the frequency-phase domain. Despite temporal variability, induced VF episodes lasting 19.6±7.9 s displayed distinctly high power at a common frequency (shared frequency, 5.7±1.1 Hz) in all leads about half of the time. In patients with Brugada syndrome, phase analysis of shared frequency showed a V1-V6 sequence as would be expected from patients displaying a type 1 ECG pattern (P<0.001). Hilbert-based phases confirmed that the most stable sequence over the whole VF duration was V1-V6. Analysis of shared frequency in ischemic cardiomyopathy patients with anteroseptal (n=4), apical (n=3), and inferolateral (n=4) myocardial infarction displayed a sequence starting at V1-V2, V3-V4, and V5-V6, respectively, consistent with an activation origin at the scar location (P=0.005). Sequences correlated with the Hilbert-based phase analysis (P<0.001). Posterior infarction (n=4) displayed no specific sequence. On paired comparison, phase sequences during monomorphic ventricular tachycardia correlated moderately with VF (P<0.001). Moreover, there was a dominant frequency gradient from precordial leads facing the scar region to the contralateral leads (5.8±0.8 versus 5.4±1.1 Hz; P=0.004).

Conclusions: Noninvasive analysis of ventricular tachycardia and early VF in patients with Brugada syndrome and ischemic cardiomyopathy shows a predictable sequence in the frequency-phase domain, consistent with anatomic location of the arrhythmogenic substrate.
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http://dx.doi.org/10.1161/CIRCEP.114.002717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608487PMC
October 2015

Classification and clinical behavior of blastic plasmacytoid dendritic cell neoplasms according to their maturation-associated immunophenotypic profile.

Oncotarget 2015 Aug;6(22):19204-16

Cancer Research Centre (IBMCC, USAL-CSIC), Institute for Biomedical Research of Salamanca (IBSAL), and Department of Medicine and Cytometry Service, University of Salamanca (USAL), Salamanca, Spain.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of leukemia/lymphoma, whose diagnosis can be difficult to achieve due to its clinical and biological heterogeneity, as well as its overlapping features with other hematologic malignancies. In this study we investigated whether the association between the maturational stage of tumor cells and the clinico-biological and prognostic features of the disease, based on the analysis of 46 BPDCN cases classified into three maturation-associated subgroups on immunophenotypic grounds. Our results show that blasts from cases with an immature plasmacytoid dendritic cell (pDC) phenotype exhibit an uncommon CD56- phenotype, coexisting with CD34+ non-pDC tumor cells, typically in the absence of extramedullary (e.g. skin) disease at presentation. Conversely, patients with a more mature blast cell phenotype more frequently displayed skin/extramedullary involvement and spread into secondary lymphoid tissues. Despite the dismal outcome, acute lymphoblastic leukemia-type therapy (with central nervous system prophylaxis) and/or allogeneic stem cell transplantation appeared to be the only effective therapies. Overall, our findings indicate that the maturational profile of pDC blasts in BPDCN is highly heterogeneous and translates into a wide clinical spectrum -from acute leukemia to mature lymphoma-like behavior-, which may also lead to variable diagnosis and treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662485PMC
http://dx.doi.org/10.18632/oncotarget.4146DOI Listing
August 2015

Neoadjuvant and conversion treatment of patients with colorectal liver metastasis: the potential role of bevacizumab and other antiangiogenic agents.

Target Oncol 2015 Dec 11;10(4):453-65. Epub 2015 Mar 11.

Medical Oncology Service, Hospital Obispo Polanco, Teruel, Spain.

More than 50 % of patients with colorectal cancer develop liver metastases. Surgical resection is the only available treatment that improves survival in patients with colorectal liver metastases (CRLM). New antiangiogenic targeted therapies, such as bevacizumab, aflibercept, and regorafenib, in combination with neoadjuvant and conversion chemotherapy may lead to improved response rates in this population of patients and increase the proportion of patients eligible for surgical resection. The present review discusses the available data for antiangiogenic targeted agents in this setting. One of these therapies, bevacizumab, which targets the vascular endothelial growth factor (VEGF) has demonstrated good results in this setting. In patients with initially unresectable CRLM, the combination of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus bevacizumab has led to high response and resection rates. This combination is also effective for patients with unresectable CRLM. Moreover, the addition of bevacizumab to chemotherapy in the neoadjuvant setting of liver metastasis has a higher impact on pathological response rate. This drug also has a manageable safety profile, and according to recent data, bevacizumab may protect against the sinusoidal dilation provoked in the liver by certain cytotoxic agents. In phase II trials, antiangiogenic therapy has demonstrated benefits in the presurgical treatment of CRLM and may represent a new treatment pathway for these patients.
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http://dx.doi.org/10.1007/s11523-015-0362-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668275PMC
December 2015
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