Publications by authors named "Iglesias M"

741 Publications

Synthesis, crystal structures and magnetic properties of a P-stereogenic -(4-amino-tempo)phosphinic amide radical and its Cu complex.

Dalton Trans 2021 Feb;50(7):2585-2595

Área de Química Orgánica, Centro de Investigación CIAIMBITAL, Universidad de Almería, Carretera de Sacramento s/n, 04120 Almería, Spain.

The synthesis of phosphinic amides containing one 4-amino-TEMPO substituent at the ortho position has been achieved through copper(i) catalyzed cross-coupling reactions of ortho-iodophosphinic amides with 4-amino-TEMPO. The method has been extended to the preparation of the first example of a P-stereogenic ortho-(4-amino-tempo)phosphinic amide radical 10. The reaction of 10 with Cu(hfac)2 afforded the P-stereogenic CuII complex 19. The crystal structure of both chiral compounds is reported. The molecular structure of 10 consists of a supramolecular zig-zag chain formed by intermolecular hydrogen bonds between the NH group of the phosphinic amide moiety and the nitroxide oxygen atom. In complex 19, the ligand acts as a bridge between two CuII ions coordinated to the oxygen atoms of the P[double bond, length as m-dash]O and N-O· groups leading to the formation of a polymeric helicate chain in which the metal ions exist in a distorted octahedral geometry. The magnetic behavior of ligand 10 is characterized by very weak intermolecular antiferromagnetic interactions, whereas ferro- and anti-ferromagnetic interactions are present in complex 19.
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http://dx.doi.org/10.1039/d0dt04298fDOI Listing
February 2021

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.

Genome Med 2021 02 1;13(1):15. Epub 2021 Feb 1.

CIBERONC, Madrid, Spain.

Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance.

Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants.

Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support.

Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.
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http://dx.doi.org/10.1186/s13073-020-00816-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849104PMC
February 2021

Factors affecting diabetic patient's long-term quality of life after simultaneous pancreas-kidney transplantation: a single-center analysis.

Langenbecks Arch Surg 2021 May 8;406(3):873-882. Epub 2021 Jan 8.

Department of General and Gastrointestinal Surgery, Pancreas Transplant Program, Hospital Universitario de Salamanca, Salamanca, Spain.

Purpose: Pancreas transplantation (PT) is one of the few ways to restore euglycemia within diabetic patients; however, the high morbidity caused by surgical complications and the need for immunosuppressive therapy has raised controversy about PT improving the health-related quality-of-life (HRQoL). The aim of this study is to assess the long-term (≥ 5 years after PT) HRQoL and to identify the factors affecting it.

Methods: A single-center, cross-sectional study of 49 sequential PT was performed. All patients conducted a telephone interview to fulfill the modification of Medical Outcome Health Survey Short Form questionnaire (SF-36v2) and were compared to similar post-PT studies from the literature.

Results: Patients with a history of replacement renal therapy (RRT) or neuropathy undergoing a PT were associated to a worse bodily pain (P = 0.03) and physical function (P = 0.04), respectively, whereas those with retinopathy showed an improved Role Emotional (P = 0.04). Multivariate analysis revealed the presence of RRT as the only independent prognostic factor for a worse bodily pain [relative risk = 3.9; 95% confidence interval (1.1-14.6)], (P = 0.04). Furthermore, nearly all PT recipients (91.8%) claimed an overall better health than prior to PT.

Conclusion: Our study confirms that PT recipients' HRQoL improves after PT, showing similar HRQoL scores across different populations and suggests that patients in predialysis could benefit from an improved HRQoL if transplanted on the early stages of the disease.
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http://dx.doi.org/10.1007/s00423-020-02059-8DOI Listing
May 2021

Status and forecast of leprosy in the still endemic province of Formosa in northern Argentina.

PLoS Negl Trop Dis 2021 01 5;15(1):e0008881. Epub 2021 Jan 5.

Programa de Control de Leishmaniasis y Lepra de Formosa, PCLyL-F. Dirección de Medicina Preventiva y Prestaciones Especiales, Ministerio de Desarrollo Humano, Formosa, Argentina.

Background: The province of Formosa, Argentina, is endemic for leprosy. In the present paper, we assessed the trend (T, 2002-2016 time series) and the forecast for 2022 of new case detection rate (NCDR) and determined the spatial distribution of new cases detected (NCD) of leprosy.

Methodology/principal Findings: This is a descriptive observational study of 713 NCD of leprosy from provincial medical records between January 2002 and December 2016. The whole dataset from the provincial medical record was used to independently estimate the NCDR trends of the general population, age groups, sexes and Departments. This same database was used to estimate the NCDR forecast of the general population for 2022, applying a dynamic linear model with a local linear trend, using the MCMC algorithm. The NCDR was higher in men (p<0.05), increased with age (0.20, 8.17, 21.04, and 29.49 for the 0-14, 15-44, 45-64 and over 65-year-old age groups, respectively; p<0.05) and showed a downward trend (negative values) of estimated slopes for the whole province and each Department. Bermejo Department showed the highest (T:-1.02, 95%CI: [-1.42, -0.66]) and Patiño the lowest decreasing trend (T:-0.45, 95%CI: [-0.74, -0.11]). The NCDR trend for both sexes was similar (T:-0.55, 95%CI: [-0.64, -0.46]), and age groups showed a decreasing trend (S15-44:-103, S45-64:-81, S>65:-61, p<0.05), except for the 0-14 age group (S:-3, p>0.05), which showed no trend. Forecasts predicted that leprosy will not be eliminated by 2022 (3.64, 95%CI: [1.22, 10.25]).

Conclusions/significance: Our results highlight the status of leprosy in Formosa and provide information to the provincial public health authorities on high-risk populations, stressing the importance of timely detection of new cases for further elimination of the disease in the province.
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http://dx.doi.org/10.1371/journal.pntd.0008881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785118PMC
January 2021

Chelation-Assisted Interrupted Copper(I)-Catalyzed Azide-Alkyne-Azide Domino Reactions: Synthesis of Fully Substituted 5-Triazenyl-1,2,3-triazoles.

Org Lett 2021 Jan 24;23(2):334-339. Epub 2020 Dec 24.

Área de Química Orgánica, Centro de Investigación CIAIMBITAL, Universidad de Almería, Carretera de Sacramento s/n, 04120 Almería, Spain.

We describe the synthesis of 1,4-(disubstituted)-5-triazenyl-1,2,3-triazoles through a ligand-free domino copper(I)-catalyzed azide-alkyne-azide process of chelating aryl azides bearing N-P═O, P═O, and SOH groups at the ortho position with a wide variety of acetylenes. DFT calculations reveal that Cu-chelation is a crucial factor in the interception of the CuAAC intermediate by the azide. The crystal structure of the catalytic species has been determined by X-ray diffraction.
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http://dx.doi.org/10.1021/acs.orglett.0c03838DOI Listing
January 2021

A whole-genome sequencing study of an X-family tuberculosis outbreak focus on transmission chain along 25 years.

Tuberculosis (Edinb) 2021 01 28;126:102022. Epub 2020 Nov 28.

Instituto Aragonés de Ciencias de la Salud, Zaragoza, C/de San Juan Bosco, 13, 50009, Zaragoza, Spain; Fundación IIS Aragón, C/de San Juan Bosco, 13, 50009, Zaragoza, Spain; CIBER de Enfermedades Respiratorias, Av. Monforte de Lemos, 3-5. Pabellón 11, Planta 0, 28029, Madrid, Spain. Electronic address:

Lineage 4/X-family of Mycobacterium tuberculosis is not very notorious, except for the CDC1551 strain. One strain of this family, named Ara50, caused one of the largest tuberculosis outbreaks of the Aragon region, Spain, during the 1990s and remained until 2018. These X-strains are characterised by high transmissibility and by carrying a low copy number of IS6110 in their genomes. Epidemiological data of the 61 patients consisted of inmates, HIV seropositives, intravenous drug users and the homeless. The application of whole-genome sequencing (WGS) to 36 out of 61 isolates, selected by IS6110-RFLP, allowed to confirm 32 as recent transmissions. We found 10 SNPs in genes considered as virulence factors, five of them specific of this strain. WGS identified three sub-clusters (CLSs). The largest one, sub-CLS 1, included 10 cases. Seven of them shared a SNP in the mce3C gene, considered a virulence factor gene. Sub-CLS 2 involved familiar cases, and no link was known for sub-CLS 3. Finally, the strain showed efficacy in latency as a confirmed epidemiological link was established between two cases, with 6 years of distance in their diagnosis. This outbreak study combined epidemiological and molecular analyses in order to elucidate tuberculosis transmission.
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http://dx.doi.org/10.1016/j.tube.2020.102022DOI Listing
January 2021

Comparative evaluation of six immunoassays for the detection of antibodies against SARS-CoV-2.

J Virol Methods 2021 03 15;289:114047. Epub 2020 Dec 15.

Servicio de Microbiología Clínica, Hospital Universitario Príncipe de Asturias, Madrid, Spain; Departamento de Biomedicina y Biotecnología, Facultad de Medicina, Universidad de Alcalá de Henares, Spain. Electronic address:

Objectives: Serologic techniques can serve as a complement to diagnose SARS-CoV-2 infection. The objective of our study was to compare the diagnostic performance of six immunoassays to detect antibodies against SARS-CoV-2: three lateral flow immunoassays (LFAs), one ELISA and two chemiluminescence assays (CLIAs).

Methods: We evaluated three LFAs (Alltest, One Step and SeroFlash), one ELISA (Dia.Pro) and two CLIAs (Elecsys and COV2T). To assess the specificity, 60 pre-pandemic sera were used. To evaluate the sensitivity, we used 80 serum samples from patients with positive PCR for SARS-CoV-2. Agreement between techniques was evaluated using the kappa score (k).

Results: All immunoassays showed a specificity of 100 % except for SeroFlash (96.7 %). Overall sensitivity was 61.3 %, 73.8 %, 67.5 %, 85.9 %, 88.0 % and 92.0 % for Alltest, One Step, SeroFlash, Dia.Pro, Elecsys and COV2T, respectively. Sensitivity increased throughout the first two weeks from the onset of symptoms, reaching sensitivities over 85 % from 14 days for all LFAs, being One Step the most sensitive (97.6 %), followed by SeroFlash (95.1 %). Dia.Pro, Elecsys and COV2T showed sensitivities over 97 % from 14 days, being 100 % for COV2T. One Step showed the best agreement results among LFAs, showing excellent agreement with Dia.Pro (agreement = 94.2 %, k = 0.884), COV2T (99.1 %, k = 0.981) and Elecsys (97.3 %, k = 0.943). Dia.Pro, COV2T and Elecsys also showed excellent agreement between them.

Conclusions: One Step, Dia.Pro, Elecsys and COV2T obtained the best diagnostic performance results. All these techniques showed a specificity of 100 % and sensitivities over 97 % from 14 days after the onset of symptoms, as well as excellent levels of agreement.
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http://dx.doi.org/10.1016/j.jviromet.2020.114047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832212PMC
March 2021

A short course of tofacitinib sustains the immunoregulatory effect of CTLA4-Ig in the presence of inflammatory cytokines and promotes long-term survival of murine cardiac allografts.

Am J Transplant 2021 08 18;21(8):2675-2687. Epub 2021 Feb 18.

Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Costimulation blockade-based regimens are a promising strategy for management of transplant recipients. However, maintenance immunosuppression via CTLA4-Ig monotherapy is characterized by high frequency of rejection episodes. Recent evidence suggests that inflammatory cytokines contribute to alloreactive T cell activation in a CD28-independent manner, a reasonable contributor to the limited efficacy of CTLA4-Ig. In this study, we investigated the possible synergism of a combined short-term inhibition of cytokine signaling and CD28 engagement on the modulation of rejection. Our results demonstrate that the JAK/STAT inhibitor tofacitinib restored the immunomodulatory effect of CTLA4-Ig on mouse alloreactive T cells in the presence of inflammatory cytokines. Tofacitinib exposure conferred dendritic cells with a tolerogenic phenotype reducing their cytokine secretion and costimulatory molecules expression. JAK inhibition also directly affected T cell activation. In vivo, the combination of CTLA4-Ig and tofacitinib induced long-term survival of heart allografts and, importantly, it was equally effective when using grafts subjected to prolonged ischemia. Transplant survival correlated with a reduction in effector T cells and intragraft accumulation of regulatory T cells. Collectively, our studies demonstrate a powerful synergism between CTLA4-Ig and tofacitinib and suggest their combined use is a promising strategy for improved management of transplanted patients.
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http://dx.doi.org/10.1111/ajt.16456DOI Listing
August 2021

Preanalytical errors in emergency department samples: Investigating error sources.

J Med Biochem 2020 Oct;39(4):474-480

University of Málaga, Health Sciences School, Nursing and Podiatry Department, Málaga, Spain.

Background: The presence of preanalytical errors is a recurring fact in all areas of healthcare that send samples to laboratories. Increasing the knowledge of possible sources of error in the preanalytical phase has been the objective of this group during the last 10 years.

Methods: In this study, descriptive research has been carried out using professionals' opinions obtained by means of the Strengths, Weaknesses, Opportunities, and Threats method in a focus group.

Results: The opinions expressed within the focus group have emphasised the importance of patients' safety and willingness for the introduction of a computerized analytical module. The most commented weakness in both hospitals was the transport of samples through the pneumatic tube. Improving the duration of workers' contracts, especially in the laboratory, and creating a circuit for professional's localization during the work shift to facilitate potential error solving are some opportunities for the future.

Conclusions: Different approaches have been developed depending on the healthcare scenario. For this, establishing a flow of information between the different professionals allows identifying identical aspects through a priori, different points of view. The line to follow is to improve the safety of the patient and also to give professionals an opportunity to express themselves.
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http://dx.doi.org/10.5937/jomb0-25263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710373PMC
October 2020

Factor Structure and Psychometric Properties of Emotional Eater Questionnaire (EEQ) in Spanish Colleges.

Int J Environ Res Public Health 2020 12 5;17(23). Epub 2020 Dec 5.

Faculty of Health Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain.

Emotional eating (EE) patterns have been shown to play a relevant role in the development of overweight problems. However, there is a gap in research aimed at validating questionnaires to assess EE in specific populations. The aim of the study was to analyze factor structure and psychometric properties of Emotional Eater Questionnaire (EEQ) in Spanish universities. EEQ, state-anxiety subscale of STAI and a questionnaire about health habits were filled out by 295 students. Exploratory Factor Analysis (EFA) by using Unweight Least Squares (ULS) method was carried out. To determine factor numbers we used eigenvalues, parallel analysis, and goodness of fit statistics. Cronbach's alpha and Spearman correlations were used to analyze reliability, convergent, and concurrent validity. The parallel analysis and goodness of fit statistics showed that unifactorial structure of seven items was the most appropriate what accounted for 57% of the variance. Internal consistency was good (α = 0.753), as well as convergent validity (r = 0.317; < 0.001). Concurrent validity was significant for three of the five criteria (r = -0.224; < 0.001 and r = -0.259; < 0.001). The results suggest some differences in the structure of the psychometric assessment of EE in sub-clinical population in comparison with previous studies carried on with an overweight population, what could be relevant to obesity prevention.
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http://dx.doi.org/10.3390/ijerph17239090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730267PMC
December 2020

Can students make a difference in science during a pandemic?

Porto Biomed J 2020 Nov-Dec;5(6):e099. Epub 2020 Nov 24.

Faculty of Medicine of the University of Porto, Porto, Portugal.

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http://dx.doi.org/10.1097/j.pbj.0000000000000099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710167PMC
November 2020

Predictive Value of Carcinoembryonic Antigen in Symptomatic Patients without Colorectal Cancer: A Post-Hoc Analysis within the COLONPREDICT Cohort.

Diagnostics (Basel) 2020 Dec 2;10(12). Epub 2020 Dec 2.

Gastroenterology Department, Complexo Hospitalario Universitario de Ourense, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 32005 Ourense, Spain.

We aimed to assess the risk of cancer in patients with abdominal symptoms after a complete colonoscopy without colorectal cancer (CRC), according to the carcinoembryonic antigen (CEA) concentration, as well as its diagnostic accuracy. For this purpose, we performed a post-hoc analysis within a cohort of 1431 patients from the COLONPREDICT study, prospectively designed to assess the fecal immunochemical test accuracy in detecting CRC. Over 36.5 ± 8.4 months, cancer was detected in 115 (8%) patients. Patients with CEA values higher than 3 ng/mL revealed an increased risk of cancer (HR 2.0, 95% CI 1.3-3.1), CRC (HR 4.4, 95% CI 1.1-17.7) and non-gastrointestinal cancer (HR 1.7, 95% CI 1.0-2.8). A new malignancy was detected in 51 (3.6%) patients during the first year and three variables were independently associated: anemia (OR 2.8, 95% CI 1.3-5.8), rectal bleeding (OR 0.3, 95% CI 0.1-0.7) and CEA level >3 ng/mL (OR 3.4, 95% CI 1.7-7.1). However, CEA was increased only in 31.8% (95% CI, 16.4-52.7%) and 50% (95% CI, 25.4-74.6%) of patients with and without anemia, respectively, who would be diagnosed with cancer during the first year of follow-up. On the basis of this information, CEA should not be used to assist in the triage of patients presenting with lower bowel symptoms who have recently been ruled out a CRC.
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http://dx.doi.org/10.3390/diagnostics10121036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770570PMC
December 2020

The value of the continuous genotyping of multi-drug resistant tuberculosis over 20 years in Spain.

Sci Rep 2020 11 24;10(1):20433. Epub 2020 Nov 24.

CIBER de Enfermedades Respiratorias, Madrid, Spain.

Molecular epidemiology of circulating clinical isolates is crucial to improve prevention strategies. The Spanish Working Group on multidrug resistant tuberculosis (MDR-TB) is a network that monitors the MDR-TB isolates in Spain since 1998. The aim of this study was to present the study of the MDR-TB and extensively drug-resistant tuberculosis (XDR-TB) patterns in Spain using the different recommended genotyping methods over time by a national coordinated system. Based on the proposed genotyping methods in the European Union until 2018, the preservation of one method, MIRU-VNTR, applied to selected clustered strains permitted to maintain our study open for 20 years. The distribution of demographic, clinical and epidemiological characteristics of clustered and non-clustered cases of MDR/XDR tuberculosis with proportion differences as assessed by Pearson's chi-squared or Fisher's exact test was compared. The differences in the quantitative variables using the Student's-t test and the Mann-Whitney U test were evaluated. The results obtained showed a total of 48.4% of the cases grouped in 77 clusters. Younger age groups, having a known TB case contact (10.2% vs 4.7%) and XDR-TB (16.5% vs 1.8%) were significantly associated with clustering. The largest cluster corresponded to a Mycobacterium bovis strain mainly spread during the nineties. A total of 68.4% of the clusters detected were distributed among the different Spanish regions and six clusters involving 104 cases were grouped in 17 and 18 years. Comparison of the genotypes obtained with those European genotypes included in The European Surveillance System (TESSy) showed that 87 cases had become part of 20 European clusters. The continuity of MDR strain genotyping in time has offered a widespread picture of the situation that allows better management of this public health problem. It also shows the advantage of maintaining one genotyping method over time, which allowed the comparison between ancient, present and future samples.
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http://dx.doi.org/10.1038/s41598-020-77249-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686341PMC
November 2020

Human intestinal spirochetosis, a sexually transmissible infection? Review of six cases from two sexually transmitted infection centres in Barcelona.

Int J STD AIDS 2021 01 24;32(1):52-58. Epub 2020 Nov 24.

Infectious Diseases Department, STI Unit Vall d'Hebron Drassanes, Hospital Vall d'Hebron, Barcelona, Spain.

Human intestinal spirochetosis (HIS) is a possible cause of chronic diarrhoea and affects mainly men who have sex with men (MSM) and people living with HIV. Diagnosis is based on colon biopsy, where spirochetes can be observed on the luminal surface, especially with the Warthin-Starry stain or similar silver stains. We conducted a retrospective descriptive study of all HIS cases diagnosed in two sexually transmitted infections (STI) centres in Barcelona from 2009 until 2018. The medical histories were reviewed to gather epidemiological, clinical, and diagnostic variables. Six patients were diagnosed with HIS. All the individuals were MSM, with a median age of 31.5 years (interquartile range [IQR] 29.5;49.25) and half of them were living with HIV. Five patients reported condomless anal intercourse and 4 patients had practised oro-anal sex previously. Concomitantly, two of them had rectal gonorrhoea, one had rectal and none of them had syphilis. The predominant clinical symptom was diarrhoea (5 patients). All cases were diagnosed by a Warthin-Starry stain on a colon biopsy specimen, and mild inflammatory changes were found in 5 cases. Five patients were treated with metronidazole and one with benzathine penicillin G. Treatment was successful in all the patients. HIS should be considered in patients with chronic diarrhoea who report risky sexual practices and/or concomitant STI. HIS may also be sexually transmitted according to the context.
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http://dx.doi.org/10.1177/0956462420958350DOI Listing
January 2021

Pancreatic duct ligation reduces premalignant pancreatic lesions in a Kras model of pancreatic adenocarcinoma in mice.

Sci Rep 2020 10 27;10(1):18344. Epub 2020 Oct 27.

Department of Surgery, Hospital del Mar, Barcelona, Spain.

Pancreatic duct ligation (PDL) in the murine model has been described as an exocrine pancreatic atrophy-inducing procedure. However, its influence has scarcely been described on premalignant lesions. This study describes the histological changes of premalignant lesions and the gene expression in a well-defined model of pancreatic ductal adenocarcinoma by PDL. Selective ligation of the splenic lobe of the pancreas was performed in Ptf1a-Cre; K-ras LSLG12Vgeo mice (PDL-Kras mice). Three experimental groups were evaluated: PDL group, controls and shams. The presence and number of premalignant lesions (PanIN 1-3 and Atypical Flat Lesions-AFL) in proximal (PP) and distal (DP) pancreas were studied for each group over time. Microarray analysis was performed to find differentially expressed genes (DEG) between PP and PD. Clinical human specimens after pancreaticoduodenectomy with ductal occlusion were also evaluated. PDL-Kras mice showed an intense pattern of atrophy in DP which was shrunk to a minimal portion of tissue. Mice in control and sham groups had a 7 and 10-time increase respectively of risk of high-grade PanIN 2 and 3 and AFL in their DP than PDL-Kras mice. Furthermore, PDL-Kras mice had significantly less PanIN 1 and 2 and AFL lesions in DP compared to PP. We identified 38 DEGs comparing PP and PD. Among them, several mapped to protein secretion and digestion while others such as Nupr1 have been previously associated with PanIN and PDAC. PDL in Ptf1a-Cre; K-ras LSLG12Vgeo mice induces a decrease in the presence of premalignant lesions in the ligated DP. This could be a potential line of research of interest in some cancerous risk patients.
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http://dx.doi.org/10.1038/s41598-020-74947-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591874PMC
October 2020

Epithelial Nr5a2 heterozygosity cooperates with mutant Kras in the development of pancreatic cystic lesions.

J Pathol 2021 02 24;253(2):174-185. Epub 2020 Nov 24.

Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre - CNIO, Madrid, Spain.

Cystic neoplasms of the pancreas are an increasingly important public health problem. The majority of these lesions are benign but some progress to invasive pancreatic ductal adenocarcinoma (PDAC). There is a dearth of mouse models of these conditions. The orphan nuclear receptor NR5A2 regulates development, differentiation, and inflammation. Germline Nr5a2 heterozygosity sensitizes mice to the oncogenic effects of mutant Kras in the pancreas. Here, we show that - unlike constitutive Nr5a2 mice - conditional Nr5a2 heterozygosity in pancreatic epithelial cells, combined with mutant Kras (KPN ), leads to a dramatic replacement of the pancreatic parenchyma with cystic structures and an accelerated development of high-grade PanINs and PDAC. Timed histopathological analyses indicated that in KPN mice PanINs precede the formation of cystic lesions and the latter precede PDAC. A single episode of acute caerulein pancreatitis is sufficient to accelerate the development of cystic lesions in KPN mice. Epithelial cells of cystic lesions of KPN mice express MUC1, MUC5AC, and MUC6, but lack expression of MUC2, CDX2, and acinar markers, indicative of a pancreato-biliary/gastric phenotype. In accordance with this, in human samples we found a non-significantly decreased expression of NR5A2 in mucinous tumours, compared with conventional PDAC. These results highlight that the effects of loss of one Nr5a2 allele are time- and cell context-dependent. KPN mice represent a new model to study the formation of cystic pancreatic lesions and their relationship with PanINs and classical PDAC. Our findings suggest that pancreatitis could also contribute to acceleration of cystic tumour progression in patients. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5570DOI Listing
February 2021

Spiny keratoderma.

Dermatol Online J 2020 Sep 15;26(9). Epub 2020 Sep 15.

Department of Dermatology, Hospital Universitari Sagrat Cor, Barcelona.

Spiny keratoderma is a rare entity characterized by filiform keratotic lesions on palms and soles. Although there are some inherited cases the majority are acquired. This last variant can be idiopathic or associated with neoplasms and chronic systemic diseases. We report a new case of spiny keratoderma associated with endometrial carcinoma.
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September 2020

Spiro[1,2]oxaphosphetanes of Nonstabilized and Semistabilized Phosphorus Ylide Derivatives: Synthesis and Kinetic and Computational Study of Their Thermolysis.

J Org Chem 2020 Nov 15;85(22):14570-14591. Epub 2020 Oct 15.

Área de Quı́mica Orgánica, Centro de Investigación CIAIMBITAL, Universidad de Almerı́a, 04120 Almería, Spain.

A series of tri- and tetrasubstituted spiro-oxaphosphetanes stabilized by -benzamide (BA) and -methyl -benzamide (MBA) ligands have been synthesized by the reaction of C,C-dilithiated phosphazenes with aldehydes and ketones. They include enantiopure products and the first example of an isolated oxaphosphetane having a phenyl substituent at C3 of the ring. Kinetic studies of their thermal decomposition showed that the process takes place irreversibly through a polar transition state (ρ = -0.22) under the influence of electronic, [1,2], [1,3] steric, and solvent effects, with C3/P-[1,2] interactions as the largest contribution to Δ of olefination. Inversion of the phosphorus configuration through stereomutation has been observed in a number of cases. DFT calculations showed that BA derivatives olefinated through the isolated (N, O)(Ph, CH, C) oxaphosphetanes (Channel A), whereas MBA compounds decomposed faster via the isomer (CH, O)(C, N, Ph) formed by P-stereomutation involving a M permutational mechanism (Channel B). The energy barrier of P-isomerization is lower than that of olefination. Fragmentation takes place in a concerted asynchronous reaction. The thermal stability of oxaphosphetanes is determined by strong C3/P-[1,2] interactions destabilizing the transition state of olefination. The effect of charge distribution and C3/C4-[1,2] and C4/P-[1,3] steric and solvent interactions on Δ was also evaluated.
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http://dx.doi.org/10.1021/acs.joc.0c01270DOI Listing
November 2020

Conversion of CO into Chloropropene Carbonate Catalyzed by Iron (II) Phthalocyanine Hypercrosslinked Porous Organic Polymer.

Molecules 2020 Oct 9;25(20). Epub 2020 Oct 9.

Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), c/Sor Juana Inés de la Cruz 3, Cantoblanco, 28049 Madrid, Spain.

Commercial iron (II) phthalocyanine (FePc) was knitted with biphenyl using a Friedel-Crafts reaction to yield a micro-meso porous organic polymer (FePc-POP) with a specific surface area of 427 m/g and 5.42% of iron loading. This strategy allowed for the direct synthesis of a heterogeneous catalyst from an iron containing monomer. The catalytic system, formed by the knitted polymer containing FePc and DMAP (4-dimethylamino pyridine) as base, results in an efficient heterogeneous catalyst in the cycloaddition of CO to epichlorohydrin to selectively obtain the corresponding cyclic carbonate. Thus, a TON (mmol substrate converted/mmol catalysts used) value of 2700 was reached in 3 h under mild reaction conditions (solvent free, 90 °C, 3 bar of CO). The catalyst does not exhibit leaching during the reactions, which was attributed to the excellent stability of the metal in the macrocycle.
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http://dx.doi.org/10.3390/molecules25204598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587207PMC
October 2020

Transforming data to information: A parallel hybrid model for real-time state estimation in lignocellulosic ethanol fermentation.

Biotechnol Bioeng 2021 02 15;118(2):579-591. Epub 2020 Oct 15.

Department of Chemical and Biochemical Engineering, Process and Systems Engineering Center (PROSYS), Technical University of Denmark (DTU), Lyngby, Denmark.

Operating lignocellulosic fermentation processes to produce fuels and chemicals is challenging due to the inherent complexity and variability of the fermentation media. Real-time monitoring is necessary to compensate for these challenges, but the traditional process monitoring methods fail to deliver actionable information that can be used to implement advanced control strategies. In this study, a hybrid-modeling approach is presented to monitor cellulose-to-ethanol (EtOH) fermentations in real-time. The hybrid approach uses a continuous-discrete extended Kalman filter to reconciliate the predictions of a data-driven model and a kinetic model and to estimate the concentration of glucose (Glu), xylose (Xyl), and EtOH. The data-driven model is based on partial least squares (PLS) regression and predicts in real-time the concentration of Glu, Xyl, and EtOH from spectra collected with attenuated total reflectance mid-infrared spectroscopy. The estimations made by the hybrid approach, the data-driven models and the internal model were compared in two validation experiments showing that the hybrid model significantly outperformed the PLS and improved the predictions of the internal model. Furthermore, the hybrid model delivered consistent estimates even when disturbances in the measurements occurred, demonstrating the robustness of the method. The consistency of the proposed hybrid model opens the doors towards the implementation of advanced feedback control schemes.
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http://dx.doi.org/10.1002/bit.27586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894558PMC
February 2021

Prospective clinical study of transverse development with orthodontics with self-ligating brackets.

Acta Odontol Latinoam 2020 Sep;33(2):112-116

Universidad de Buenos Aires, Facultad de Odontología, Cátedra de Ortodoncia, Buenos Aires, Argentina.

Orthodontics with low friction, low force, passive self-ligating brackets produces alveolar-dental remodeling, resulting in an increase in the transverse diameter of the dental arches, especially in the premolar sector. The aim of this study was to compare the modifications of the transverse diameter in the pre- and post-dental alignment cast models with orthodontics with passive self-ligating brackets in patients with moderate to severe dental discrepancy. The study included 28 patients of both sexes aged 16 to 48 years with dental discrepancies between -6 and -16 mm, treated with self-ligating Damon brackets and thermally activated Nickel- Titanium-Copper arches. With a digital pachymeter, Mitutoyo brand, five measurements were taken per dental arch: distance between canines (C), first premolars (1PM), second premolars (2 PM), first molars (1M) and second molars (2M), before and after orthodontic alignment. The variations were statistically evaluated by Student T Test for paired samples. Average distance between teeth varied with dental alignment in both jaws. The greatest increases in transverse diameter were recorded in the premolar areas. Minor though statistically significant variations also occurred in the 2M of the maxilla and in the C of the mandible In alignment with passive self-ligating brackets, there is an increase in the transverse diameter due to the development of the dental arches, mainly in the premolar sector of both jaws and also at the level of the canines in the mandible.
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September 2020

Proteomic analysis and optimized production of Alkalihalobacillus patagoniensis PAT 05 extracellular proteases.

Bioprocess Biosyst Eng 2021 Feb 4;44(2):225-234. Epub 2020 Sep 4.

Centro Para el Estudio de Sistemas Marinos (CESIMAR-CCT CONICET-CENPAT), Blvd. Brown 2915, U9120ACD, Puerto Madryn, Chubut, Argentina.

Extracellular proteolytic extracts from the haloalkalitolerant strain Alkalihalobacillus patagoniensis PAT 05 have proved highly efficient to reduce wool felting, as part of an ecofriendly treatment suitable for organic wool. In the present study, we identified the extracellular proteases produced by PAT 05 and we optimized its growth conditions for protease production through statistical methods. A total of 191 proteins were identified in PAT 05 culture supernatants through mass spectrometry analysis. Three of the 6 detected extracellular proteases belonged to the serine-endopeptidase family S8 (EC 3.4.21); two of them showed 86.3 and 67.9% identity with an alkaline protease from Bacillus alcalophilus and another one showed 50.4% identity with Bacillopeptidase F. The other 3 proteases exhibited 55.3, 49.4 and 61.1% identity with D-alanyl-D-alanine carboxypeptidase DacF, D-alanyl-D-alanine carboxypeptidase DacC and endopeptidase LytE, respectively. Using a Fractional Factorial Design followed by a Central Composite Design optimization, a twofold increase in protease production was reached. NaCl concentration was the most influential factor on protease production. The usefulness of PAT 05 extracellular proteolytic extracts to reduce wool felting was possible associated with the activity of the serine-endopeptidases closely related to highly alkaline keratinolytic proteases. The other identified proteases could cooperate, improving protein hydrolysis. This study provided valuable information for the exploitation of PAT 05 proteases which have potential for the valorization of organic wool as well as for other industrial applications.
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http://dx.doi.org/10.1007/s00449-020-02436-zDOI Listing
February 2021

Src-Homology 2 Domain-Containing Phosphatase 2 in Resected Mutation-Positive Lung Adenocarcinoma.

JTO Clin Res Rep 2020 Nov 21;1(4):100084. Epub 2020 Aug 21.

Laboratory of Cellular and Molecular Biology, Institute for Health Science Research Germans Trias i Pujol (IGTP), Badalona, Spain.

Introduction: mutation-positive lung adenocarcinoma (LUAD) displays impaired phosphorylation of ERK and Src-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with wild-type LUADs. We hypothesize that SHP2 expression could be predictive in patients positive with resected mutation versus patients with wild-type LUAD.

Methods: We examined resected LUAD cases from Japan and Spain. mRNA expression levels of , , , , , and were analyzed by quantitative reverse transcriptase polymerase chain reaction. The activity of SHP2 inhibitors plus erlotinib were tested in -mutant cell lines and analyzed by cell viability assay, Western blot, and immunofluorescence.

Results: A total of 50 of 100 mutation-positive LUADs relapsed, among them, patients with higher SHP2 mRNA expression revealed shorter progression-free survival, in comparison with those having low SHP2 mRNA (hazard ratio: 1.83; 95% confidence interval: 1.05-3.23;  = 0.0329). However, SHP2 was not associated with prognosis in the remaining 167 patients with wild-type . In -mutant cell lines, the combination of SHP099 or RMC-4550 (SHP2 inhibitors) with erlotinib revealed synergism via abrogation of phosphorylated AKT (S473) and ERK1/2 (T202/Y204). Although erlotinib translocates phosphorylated SHP2 (Y542) into the nucleus, either RMC-4550 alone, or in combination with erlotinib, relocates SHP2 into the cytoplasm membrane, limiting AKT and ERK1/2 activation.

Conclusions: Elevated mRNA levels are associated with recurrence in resected mutation-positive LUADs, but not in wild-type. EGFR tyrosine kinase inhibitors can enhance SHP2 activation, hindering adjuvant therapy. SHP2 inhibitors could improve the benefit of adjuvant therapy in mutation-positive LUADs.
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http://dx.doi.org/10.1016/j.jtocrr.2020.100084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474259PMC
November 2020

Multiphase Assembly of Small Molecule Microcrystalline Peptide Hydrogel Allows Immunomodulatory Combination Therapy for Long-Term Heart Transplant Survival.

Small 2020 09 18;16(38):e2002791. Epub 2020 Aug 18.

Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Building 376, Boyles St, Frederick, MD, 21702, USA.

Combination therapies that target multiple pathways involved in immune rejection of transplants hold promise for patients in need of restorative surgery. Herein, a noninteracting multiphase molecular assembly approach is developed to crystallize tofacitinib, a potent JAK1/3 inhibitor, within a shear-thinning self-assembled fibrillar peptide hydrogel network. The resulting microcrystalline tofacitinib hydrogel (MTH) can be syringe-injected directly to the grafting site during surgery to locally deliver the small molecule. The rate of drug delivered from MTH is largely controlled by the dissolution of the encapsulated microcrystals. A single application of MTH, in combination with systemically delivered CTLA4-Ig, a co-stimulation inhibitor, affords significant graft survival in mice receiving heterotopic heart transplants. Locoregional studies indicate that the local delivery of tofacitinib at the graft site enabled by MTH is required for the observed enhanced graft survival.
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http://dx.doi.org/10.1002/smll.202002791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686956PMC
September 2020

Influence of KRAS mutations, persistent organic pollutants, and trace elements on survival from pancreatic ductal adenocarcinoma.

Environ Res 2020 11 11;190:109781. Epub 2020 Jun 11.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, USA.

Introduction: Reasons why pancreatic ductal adenocarcinoma (PDAC) continues to have poor survival are only partly known. No previous studies have analyzed the combined influence of KRAS mutations, persistent organic pollutants (POPs), and trace elements upon survival in PDAC or in any other human cancer.

Objective: To analyze the individual and combined influence of KRAS mutations, POPs, and trace elements upon survival from PDAC.

Methods: Incident cases of PDAC (n = 185) were prospectively identified in five hospitals in Eastern Spain in 1992-1995 and interviewed face-to-face during hospital admission. KRAS mutational status was determined from tumour tissue through polymerase chain reaction and artificial restriction fragment length polymorphism. Blood and toenail samples were obtained before treatment. Serum concentrations of POPs were analyzed by high-resolution gas chromatography with electron-capture detection. Concentrations of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. Multivariable Cox proportional hazards regression was used to assess prognostic associations.

Results: Patients with a KRAS mutated tumor had a 70% higher risk of early death than patients with a KRAS wild-type PDAC (hazard ratio [HR] = 1.7, p = 0.026), adjusting for age, sex, and tumor stage. KRAS mutational status was only modestly and not statistically significantly associated with survival when further adjusting by treatment or by treatment intention. The beneficial effects of treatment remained unaltered when KRAS mutational status was taken into account, and treatment did not appear to be less effective in the subgroup of patients with a KRAS mutated tumor. POPs did not materially influence survival: the adjusted HR of the highest POP tertiles was near unity for all POPs. When considering the joint effect on survival of POPs and KRAS, patients with KRAS mutated tumors had modest and nonsignificant HRs (most HRs around 1.3 to 1.4). Higher concentrations of lead, cadmium, arsenic, vanadium, and aluminium were associated with better survival. When KRAS status, POPs, and trace elements were simultaneously considered along with treatment, only the latter was statistically significantly related to survival.

Conclusions: In this study based on molecular, clinical, and environmental epidemiology, KRAS mutational status, POPs, and trace elements were not adversely related to PDAC survival when treatment was simultaneously considered; only treatment was independently related to survival. The lack of adverse prognostic effects of POPs and metals measured at the time of diagnosis provide scientific and clinical reassurance on the effects of such exposures upon survival of patients with PDAC. The weak association with KRAS mutations contributes to the scant knowledge on the clinical implications of a genetic alteration highly frequent in PDAC.
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http://dx.doi.org/10.1016/j.envres.2020.109781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689512PMC
November 2020

Association between aortic stenosis and hereditary transthyretin amyloidosis.

Rev Esp Cardiol (Engl Ed) 2021 02 7;74(2):185-187. Epub 2020 Aug 7.

Instituto de Investigación Sanitaria de Palma (IdISBa), Palma de Mallorca, Balearic Islands, Spain; Servicio de Medicina Interna, Hospital Universitario Son Llàtzer, Palma de Mallorca, Balearic Islands, Spain.

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http://dx.doi.org/10.1016/j.rec.2020.05.037DOI Listing
February 2021

Iron Phthalocyanine-Knitted Polymers as Electrocatalysts for the Oxygen Reduction Reaction.

ACS Appl Mater Interfaces 2020 Jul 7;12(29):32681-32688. Epub 2020 Jul 7.

Knitted iron phthalocyanine-based porous polymer networks (K-FePcs) were prepared in a single step using solvent-knitting strategies with commercial iron phthalocyanine as a building monomer. The incorporation of different aryl comonomers (biphenyl and 1,2,4,5-tetraphenylbenzene) to FePc allowed quantitative yields, high porosities, and excellent ORR activity. The reversible Fe(III)/Fe(II) redox potential of FeN centers of the knitted polymer networks in N-saturated electrolyte solution (i.e., ∼0.8 V vs RHE) were shown as good descriptors of their ORR activity. presented the highest amount of FeN4 active sites and an adequate degree of steric hindrance to maintain the isolation between catalytically active sites. Moreover, it displayed comparable current density limits and superior mass activity and half-wave potential (i.e., 0.88 V vs RHE) than those of 20% benchmark catalyst, while keeping higher stability toward methanol oxidation. can be an interesting alternative to Pt-based ORR electrocatalysts.
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http://dx.doi.org/10.1021/acsami.0c07412DOI Listing
July 2020

Comparison of the touch-screen and traditional versions of the Corsi block-tapping test in patients with psychosis and healthy controls.

BMC Psychiatry 2020 06 23;20(1):329. Epub 2020 Jun 23.

Parc Sanitari Sant Joan de Déu, Fundació Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, SantBoi de Llobregat, Universitat de Barcelona, Dr. Antoni Pujadas, 42, Sant Boi de Llobregat, 08830, Barcelona, Spain.

Background: Working memory (WM) refers to the capacity system for temporary storage and processing of information, which is known to depend on the integrity of the prefrontal cortex. Impairment in working memory is a core cognitive deficit among individuals with psychotic disorders. The Corsi block-tapping test is a widely-used instrument to assess visuospatial working memory. The traditional version is composed of 9 square blocks positioned on a physical board. In recent years, the number of digital instruments has increased significantly; several advantages might derive from the use of a digital version of the Corsi test.

Methods: This study aimed to compare the digital and traditional versions of the Corsi test in 45 patients with psychotic disorders and 45 healthy controls. Both groups completed a neuropsychological assessment involving attention and working memory divided into the two conditions.

Results: Results were consistent between the traditional and digital versions of the Corsi test. The digital version, as well as the traditional version, can discriminate between patients with psychosis and healthy controls. Overall, patients performed worse with respect to the healthy comparison group. The traditional Corsi test was positively related to intelligence and verbal working memory, probably due to a more significant effort to execute the test.

Conclusions: The digital Corsi might be used to enhance clinical practice diagnosis and treatment.The digital version can be administered in a natural environment in real-time. Further, it is easy to administer while ensuring a standard procedure.
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http://dx.doi.org/10.1186/s12888-020-02716-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313222PMC
June 2020

Inferior oblique retro-equatorial myopexy: An alternative weakening.

Arch Soc Esp Oftalmol (Engl Ed) 2020 Aug 16;95(8):367-372. Epub 2020 Jun 16.

Clínica Oftalmológica García de Oteyza, Barcelona, España.

Purpose: To describe an alternative surgical approach to treat inferior oblique overaction, and report the first results of this technique.

Materials And Methods: A total of 6 consecutive eyes of 6patients with primary or secondary inferior oblique overaction underwent inferior oblique retro-equatorial myopexy under general anaesthesia. The primary outcomes measured were the postoperative vertical deviation in the field of action of the inferior oblique muscle, and the intra- and postoperative surgical complications. Final results were evaluated at six-months after surgery.

Results: The patient population consisted of 3girls and 3boys aged between 4 and 7years old. The mean preoperative inferior oblique overaction was 34°±4.6°, equivalent to 3+. Inferior oblique overaction was reduced in all patients with a mean reduction of 28°±1.98°, and the mean postoperative deviation was 6°±2.84°. Total success was achieved in four out of six eyes, and only one case remained under-corrected. No intra- or postoperative complications were reported.

Conclusion: Inferior oblique retro-equatorial myopexy is an alternative surgical approach for inferior oblique overaction. It is an efficient, safe, and reversible technique that could be used in cases of inferior oblique overaction between 2+ to 3+.
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http://dx.doi.org/10.1016/j.oftal.2020.04.024DOI Listing
August 2020

Genetic diversity, antimicrobial resistance, and virulence genes of thermophilic Campylobacter isolated from broiler production chain.

Braz J Microbiol 2020 Dec 9;51(4):2021-2032. Epub 2020 Jun 9.

Departamento de Ciência e Tecnologia Agroindustrial, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil.

The aim of this study was to investigate the prevalence of thermophilic Campylobacter in the broiler production chain of southern Brazil, by evaluating broiler farms and slaughter line samples, and to determine the genetic diversity, antimicrobial resistance, and virulence genes of the isolates. Of the 140 samples investigated in this study, 75 (53.6%) were positive for thermophilic Campylobacter, and all isolates were identified by phenotypic and molecular tests as C. jejuni. The resistance to nalidixic acid was the most common (74%), followed by resistance to enrofloxacin (67.3%) and ciprofloxacin (37.1%). However, there was no resistance to the macrolides tested which are recommended for the treatment of human campylobacteriosis. The PFGE showed that the isolates were grouped in eight macrorestriction patterns (P1 to P8). A representative isolate of each macrorestriction pattern was investigated for the presence of virulence genes and all isolates carried the cadF, ciaB, cdtA, cdtB, cdtC, and flaA genes. The dnaJ gene was detected in 87.5% (7/8) of the isolates. The flhA and racR genes were detected in 75% (6/8), while the pldA gene was present in 62.5% (5/8) and the wlaN gene in 25% (2/8). The presence of C. jejuni in broiler farms and in the slaughterhouse is a hazard to consumer given that this pathogen can be maintained throughout the broiler production chain and contaminates the final product. Moreover, the presence of the major virulence genes in the isolates demonstrates that they have the ability to develop campylobacteriosis in humans.
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http://dx.doi.org/10.1007/s42770-020-00314-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688733PMC
December 2020
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