Publications by authors named "Juan Medina"

97 Publications

Role of eprinomectin as inhibitor of the ruminant ABCG2 transporter: Effects on plasma distribution of danofloxacin and meloxicam in sheep.

Res Vet Sci 2021 Apr 1;136:478-483. Epub 2021 Apr 1.

Departmento de Ciencias Biomédicas, Fisiología, Facultad de Veterinaria, Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), Universidad de León, Campus de Vegazana, León, Spain. Electronic address:

Therapeutic outcome results of the coadministration of several drugs in veterinary medicine is affected by, among others, the relationship between drugs and ATP-binding cassette (ABC) transporters, such as ABCG2. ABCG2 is an efflux protein involved in the bioavailability and milk secretion of drugs. The aim of this work was to determine the role of eprinomectin, a macrocyclic lactone (ML) member of avermectin class, as inhibitor of ABCG2. The experiments were carried out through in vitro inhibition assays based on mitoxantrone accumulation and transport assays in ovine ABCG2 transduced cells using the antimicrobial drug danofloxacin and the anti-inflammatory drug meloxicam, both widely used in veterinary medicine and well known ABCG2 substrates. The inhibition results obtained showed that eprinomectin was an efficient in vitro ABCG2 inhibitor, tested in mitoxantrone accumulation assays. In addition, this ML decreased ovine ABCG2-mediated transport of danofloxacin and meloxicam. To evaluate the role of eprinomectin in systemic exposure of drugs, pharmacokinetic assays based on subcutaneous coadministration of eprinomectin with danofloxacin (1.25 mg/kg) or meloxicam (0.5 mg/kg) in sheep were performed obtaining a significant increase of systemic exposure of these drugs. Especially relevant was the increase of the systemic concentration of meloxicam, since coadministration with eprinomectin increased significantly the plasma concentration of meloxicam, obtaining an increase of AUC (0-72 h) value of more than 40%.
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http://dx.doi.org/10.1016/j.rvsc.2021.03.026DOI Listing
April 2021

Unusual presentations of cardiac rupture during COVID-19 pandemic.

Echocardiography 2021 03 18;38(3):469-472. Epub 2021 Feb 18.

Sanatorio Profesor Itoiz, Avellaneda, Argentina.

The Covid-19 pandemia has many other undesirable consequences apart of virus infection. Less people is hospitalized due to acute coronary syndrome and the delay to seek medical attention has increased. Patients with ST segment elevation myocardial infarction arrive at the hospital too late to be timely treated and we have recently seen mechanical complications that were more frequent in the past decades before the use of reperfusion strategies. In this report we describe the presentation, evolution and detailed imaging evaluation of two patients with unusual presentations of cardiac rupture: left ventricular pseudoaneurysm and left ventricular intramyocardial dissecting hematoma.
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http://dx.doi.org/10.1111/echo.15006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014092PMC
March 2021

[Convalescent plasma as a therapy for severe COVID-19 pneumonia].

Medicina (B Aires) 2020 ;80 Suppl 6:9-17

Sección Hematología, CEMIC, Buenos Aires, Argentina.

The COVID-19 pandemic presented high mortality from its beginning, without effective treatment for seriously ill patients. Build on the experience in Argentine hemorrhagic fever with convalescent plasma, we incorporated 90 patients with COVID-19, of which 87 were evaluable, into a multicenter study. We collected 397 plasma donations from 278 convalescent donors. Patients received plasma with an IgG concentration of 0.7-0.8 (measured by Abbott chemiluminescence) for every 10 kg of body weight. Survival during the first 28 days was the primary objective; 77% were male, age 54 ± 15.6 y/o (range 27-85), body mass index 29.7 ± 4.4; hypertension 39% and diabetes 20.7%; 19.5% had an immunosuppressive condition, 23% were health workers. Plasma was administered to 55 (63%) on spontaneous breathing with oxygen supplementation (mainly oxygen mask with reservoir bag in 80%), and to 32 patients (37%) on mechanical ventilation. The 28-day survival rate was 80%; 91% in patients infused on spontaneous breathing and 63% in those on mechanical ventilation (p = 0.0002). There was a significant improvement in the WHO pneumonia clinical scale at 7 and 14 days, and in PaO2 / FiO2, ferritin and LDH, in the week post-infusion. We observed an episode of circulatory volume overload and a febrile reaction, both mild. Convalescent plasma infusions are feasible, safe, and potentially effective, especially before requiring mechanical ventilation. They are an attractive clinical option for treating severe forms of COVID-19 until other effective therapies become available.
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January 2021

Primary biliary cholangitis: pathogenic mechanisms.

Curr Opin Gastroenterol 2021 Mar;37(2):91-98

Unit of Medical Training, School of Medicine, University of Navarra, Pamplona, Spain.

Purpose Of Review: Primary biliary cholangitis (PBC) is characterized by autoimmune damage of intrahepatic bile ducts associated with a loss of tolerance to mitochondrial antigens. PBC etiopathogenesis is intriguing because of different perplexing features, namely: a) although mitochondria are present in all cell types and tissues, the damage is mainly restricted to biliary epithelial cells (BECs); b) despite being an autoimmune disorder, it does not respond to immunosuppressive drugs but rather to ursodeoxycholic acid, a bile salt that induces HCO3- rich choleresis; c) the overwhelming female preponderance of the disease remains unexplained. Here we present an etiopathogenic view of PBC which sheds light on these puzzling facts of the disease.

Recent Findings: PBC develops in patients with genetic predisposition to autoimmunity in whom epigenetic mechanisms silence the Cl-/HCO3- exchanger AE2 in both cholangiocytes and lymphoid cells. Defective AE2 function can produce BECs damage as a result of decreased biliary HCO3- secretion with disruption of the protective alkaline umbrella that normally prevents the penetration of toxic apolar bile salts into cholangiocytes. AE2 dysfunction also causes increased intracellular pH (pHi) in cholangiocytes, leading to the activation of soluble adenylyl cyclase, which sensitizes BECs to bile salt-induced apoptosis. Recently, mitophagy was found to be inhibited by cytosolic alkalization and stimulated by acidification. Accordingly, we propose that AE2 deficiency may disturb mitophagy in BECs, thus, promoting the accumulation of defective mitochondria, oxidative stress and presentation of mitochondrial antigens to the immune cells. As women possess a more acidic endolysosomal milieu than men, mitophagy might be more affected in women in an AE2-defective background. Apart from affecting BECs function, AE2 downregulation in lymphocytes may also contribute to alter immunoregulation facilitating autoreactive T-cell responses.

Summary: PBC can be considered as a disorder of Cl-/HCO3- exchange in individuals with genetic predisposition to autoimmunity.
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http://dx.doi.org/10.1097/MOG.0000000000000703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879833PMC
March 2021

The urban contrast: A nationwide assessment of avian diversity in Mexican cities.

Sci Total Environ 2021 Jan 22;753:141915. Epub 2020 Aug 22.

Instituto de Biología, UNAM, Mexico.

In this study we focused on urban bird diversity across Mexico, a megadiverse country, with a special focus on the relative role of urban greenspaces and heavily-built sites. We considered a country-wide approach, including 24 different sized Mexican cities. Our aims were to describe the urban bird diversity in focal cities and further assess the relationships between it and the biogeographic region where cities are located, their size, elevation, and annual rainfall. Additionally, we evaluated differences in the functional composition of bird communities in both studied urban scenarios (i.e., urban greenspaces, heavily-built sites). Our results confirm that urban greenspaces are home to a large proportion of species when contrasted with heavily-built sites. While total species richness and species richness of greenspaces were related with the cities' biogeographic region -with higher species richness in the Neotropical region and Transition Zone-, the relationship did not hold true in heavily-built sites. We found that annual rainfall was negatively related to bird richness in heavily-built sites, suggesting that species from arid systems can be more tolerant to urbanization. Regarding the bird functional group assessment, results show a clear differentiation between the functional groups of greenspaces and those of heavily-built sites, with granivores and omnivores associated with the latter and a highly diverse array of functional groups associated with urban greenspaces.
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http://dx.doi.org/10.1016/j.scitotenv.2020.141915DOI Listing
January 2021

Study of the Diagnostic Delay of Tuberculosis in Spain.

Arch Bronconeumol 2020 Sep 22. Epub 2020 Sep 22.

Fundación Respira. Programa Integrado de Investigación en Tuberculosis (PII-TB) de la Sociedad Española de Neumología y Cirugía Torácica (SEPAR), Barcelona, España; Fundación Unidad de Investigación en Tuberculosis (fuiTB), Barcelona, España; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, España. Electronic address:

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http://dx.doi.org/10.1016/j.arbres.2020.09.003DOI Listing
September 2020

Toll-like receptor 2-modulating pectin-polymers in alginate-based microcapsules attenuate immune responses and support islet-xenograft survival.

Biomaterials 2021 Jan 19;266:120460. Epub 2020 Oct 19.

Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, EA 11, 9713 GZ, Groningen, the Netherlands.

Encapsulation of pancreatic islets in alginate-microcapsules is used to reduce or avoid the application of life-long immunosuppression in preventing rejection. Long-term graft function, however, is limited due to varying degrees of host tissue responses against the capsules. Major graft-longevity limiting responses include inflammatory responses provoked by biomaterials and islet-derived danger-associated molecular patterns (DAMPs). This paper reports on a novel strategy for engineering alginate microcapsules presenting immunomodulatory polymer pectin with varying degrees of methyl-esterification (DM) to reduce these host tissue responses. DM18-pectin/alginate microcapsules show a significant decrease of DAMP-induced Toll-Like Receptor-2 mediated immune activation in vitro, and reduce peri-capsular fibrosis in vivo in mice compared to higher DM-pectin/alginate microcapsules and conventional alginate microcapsules. By testing efficacy of DM18-pectin/alginate microcapsules in vivo, we demonstrate that low-DM pectin support long-term survival of xenotransplanted rat islets in diabetic mice. This study provides a novel strategy to attenuate host responses by creating immunomodulatory capsule surfaces that attenuate activation of specific pro-inflammatory immune receptors locally at the transplantation site.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120460DOI Listing
January 2021

Purinergic System Signaling in Metainflammation-Associated Osteoarthritis.

Front Med (Lausanne) 2020 28;7:506. Epub 2020 Aug 28.

Bone and Joint Research Unit, IIS-Fundación Jiménez Díaz UAM, Madrid, Spain.

Inflammation triggered by metabolic imbalance, also called metainflammation, is low-grade inflammation caused by the components involved in metabolic syndrome (MetS), including central obesity and impaired glucose tolerance. This phenomenon is mainly due to excess nutrients and energy, and it contributes to the pathogenesis of osteoarthritis (OA). OA is characterized by the progressive degeneration of articular cartilage, which suffers erosion and progressively becomes thinner. Purinergic signaling is involved in several physiological and pathological processes, such as cell proliferation in development and tissue regeneration, neurotransmission and inflammation. Adenosine and ATP receptors, and other members of the signaling pathway, such as AMP-activated protein kinase (AMPK), are involved in obesity, type 2 diabetes (T2D) and OA progression. In this review, we focus on purinergic regulation in osteoarthritic cartilage and how different components of MetS, such as obesity and T2D, modulate the purinergic system in OA. In that regard, we describe the critical role in this disease of receptors, such as adenosine A2A receptor (A2AR) and ATP P2X7 receptor. Finally, we also assess how nucleotides regulate the inflammasome in OA.
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http://dx.doi.org/10.3389/fmed.2020.00506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485330PMC
August 2020

Immunotherapy via PD-L1-presenting biomaterials leads to long-term islet graft survival.

Sci Adv 2020 Aug 28;6(35):eaba5573. Epub 2020 Aug 28.

Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.

Antibody-mediated immune checkpoint blockade is a transformative immunotherapy for cancer. These same mechanisms can be repurposed for the control of destructive alloreactive immune responses in the transplantation setting. Here, we implement a synthetic biomaterial platform for the local delivery of a chimeric streptavidin/programmed cell death-1 (SA-PD-L1) protein to direct "reprogramming" of local immune responses to transplanted pancreatic islets. Controlled presentation of SA-PD-L1 on the surface of poly(ethylene glycol) microgels improves local retention of the immunomodulatory agent over 3 weeks in vivo. Furthermore, local induction of allograft acceptance is achieved in a murine model of diabetes only when receiving the SA-PD-L1-presenting biomaterial in combination with a brief rapamycin treatment. Immune characterization revealed an increase in T regulatory and anergic cells after SA-PD-L1-microgel delivery, which was distinct from naïve and biomaterial alone microenvironments. Engineering the local microenvironment via biomaterial delivery of checkpoint proteins has the potential to advance cell-based therapies, avoiding the need for systemic chronic immunosuppression.
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http://dx.doi.org/10.1126/sciadv.aba5573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455180PMC
August 2020

Association of ERAP2 polymorphisms in Colombian HLA-B27+ or HLA-B15+ patients with SpA and its relationship with clinical presentation: axial or peripheral predominance.

RMD Open 2020 09;6(2)

Clinical Training Unit, School of Medicine, Universidad de Navarra, Pamplona, Spain.

Objective: To determine the association between endoplasmic reticulum aminopeptidase (ERAP)1 and ERAP2 single-nucleotide polymorphisms (SNPs) and human leukocyte antigens (HLA)-B27+ or HLA-B15+ patients with spondyloarthritis (SpA).

Methods: 104 patients with SpA according to Assessment of Spondyloarthritis International Society criteria were included in the study. HLA typing was performed by PCR. The polymorphisms were determined by real-time PCR on genomic DNA using customised probes for SNPs rs27044, rs17482078, rs10050860 and rs30187 in , and rs2910686, rs2248374 and rs2549782 in .

Results: 70 of the104 patients with SpA were HLA-B27+ and 34 were HLA-B15+. The distribution of ERAP1 and ERAP2 SNPs between the HLA-B15+ and HLA-B27+ patients with SpA did not reveal differences. Likewise, no differences in the frequencies of ERAP1 SNP haplotypes and alleles HLA-B15 or HLA-B27 were found. Interestingly, however, the frequencies of three particular haplotypes formed by ERAP2 SNPs rs2549782/rs2248374/rs2910686 varied between HLA-B15+ and HLA-B27+ patients: the ERAP2 SNPs haplotype TGT was more common in HLA-B15+ patients with SpA (OR 2.943, 95% CI 1.264 to 6.585; P=0.009), whereas the ERAP2 SNP haplotypes TGC and CAT were more associated with HLA-B27+ patients with SpA: (OR 4.483, 95% CI 1.524 to 13.187; p=0.003) and (OR 9.014, 95% CI 1.181 to 68.807; p=0.009), respectively.

Conclusion: An association was found between HLA-B15+ patients with SpA and haplotype TGT of ERAP2 SNPs. On the other hand, HLA-B27+ patients with SpA were associated with ERAP2 haplotypes TGC and CAT. These associations could be related to the clinical presentation of the disease, specifically with a peripheral or axial predominance, respectively.
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http://dx.doi.org/10.1136/rmdopen-2020-001250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525252PMC
September 2020

A Role for Gut Microbiome Fermentative Pathways in Fatty Liver Disease Progression.

J Clin Med 2020 May 7;9(5). Epub 2020 May 7.

Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Universidad de Cantabria, 39011 Santander, Spain.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease in which environmental and genetic factors are involved. Although the molecular mechanisms involved in NAFLD onset and progression are not completely understood, the gut microbiome (GM) is thought to play a key role in the process, influencing multiple physiological functions. GM alterations in diversity and composition directly impact disease states with an inflammatory course, such as non-alcoholic steatohepatitis (NASH). However, how the GM influences liver disease susceptibility is largely unknown. Similarly, the impact of strategies targeting the GM for the treatment of NASH remains to be evaluated. This review provides a broad insight into the role of gut microbiota in NASH pathogenesis, as a diagnostic tool, and as a therapeutic target in this liver disease. We highlight the idea that the balance in metabolic fermentations can be key in maintaining liver homeostasis. We propose that an overabundance of alcohol-fermentation pathways in the GM may outcompete healthier, acid-producing members of the microbiota. In this way, GM ecology may precipitate a self-sustaining vicious cycle, boosting liver disease progression.
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http://dx.doi.org/10.3390/jcm9051369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291163PMC
May 2020

Functionalization of Alginate with Extracellular Matrix Peptides Enhances Viability and Function of Encapsulated Porcine Islets.

Adv Healthc Mater 2020 05 7;9(9):e2000102. Epub 2020 Apr 7.

Mechanical Engineering, Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA, 30332, USA.

Translation of transplanted alginate-encapsulated pancreatic islets to treat type 1 diabetes has been hindered by inconsistent long-term efficacy. This loss of graft function can be partially attributed to islet dysfunction associated with the destruction of extracellular matrix (ECM) interactions during the islet isolation process as well as immunosuppression-associated side effects. This study aims at recapitulating islet-ECM interactions by the direct functionalization of alginate with the ECM-derived peptides RGD, LRE, YIGSR, PDGEA, and PDSGR. Peptide functionalization is controlled in a concentration-dependent manner and its presentation is found to be homogeneous across the microcapsule environment. Preweaned porcine islets are encapsulated in peptide-functionalized alginate microcapsules, and those encapsulated in RGD-functionalized alginate displays enhanced viability and glucose-stimulated insulin release. Effects are RGD-specific and not observed with its scrambled control RDG nor with LRE, YIGSR, PDGEA, and PDSGR. This study supports the sustained presentation of ECM-derived peptides in helping to maintain health of encapsulated pancreatic islets and may aid in prolonging longevity of encapsulated islet grafts.
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http://dx.doi.org/10.1002/adhm.202000102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598935PMC
May 2020

Diagnostic and Prognostic Value of Coronary Computed Tomography Angiography in Patients with Severe Calcification.

J Cardiovasc Transl Res 2021 Feb 1;14(1):131-139. Epub 2020 Apr 1.

Unidad de Imagen Cardiaca, Departamento de Cardiología, HM Hospitales-Centro Integral de Enfermedades Cardiovasculares HM CIEC, Madrid, Spain.

Our aim was to analyze its diagnostic and prognostic value in patients with high coronary calcium score (CCS). A total of 113 patients with CCS > 400 were included. Significant coronary artery disease (CAD) was defined as stenosis ≥ 50%. Invasive coronary angiography and major cardiovascular events were recorded. The CCS and heart rate during the acquisition were significantly lower in the diagnostic coronary computed tomography angiography (CCTA) group. The cut-off value of CCS to establish the diagnostic utility of CCTA was 878. The rate of cardiovascular events was 9.3%. The positive predictive value of CCTA to detect significant CAD was 73.5% and the negative predictive value for predicting cardiovascular events was 96%. In patients with high CCS, CCTA is useful to evaluate CAD, especially when the CCS is lower or equal to 878; moreover, the prognostic value of CCTA is better in patients where significant CAD has been ruled out.
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http://dx.doi.org/10.1007/s12265-020-09977-4DOI Listing
February 2021

Promoter hypermethylation of the gene in PBC.

JHEP Rep 2019 Sep 7;1(3):145-153. Epub 2019 Jun 7.

Division of Gene Therapy and Hepatology, CIMA, School of Medicine and Clinic University of Navarra, and Ciberehd, Pamplona.

Background & Aims: Patients with primary biliary cholangitis (PBC) exhibit reduced gene expression in the liver and peripheral blood mononuclear cells (PBMCs). encodes a Cl/HCO exchanger involved in biliary bicarbonate secretion and intracellular pH regulation. Reduced expression in PBC may be pathogenic, as -knockout mice reproduce characteristic PBC features. Herein, we aimed to identify CpG-methylation abnormalities in promoter regions that might contribute to the reduced gene transcription in PBC livers and PBMCs.

Methods: CpG-cytosine methylation rates were interrogated at 1-base pair resolution in upstream and alternate promoter regions through pyrosequencing of bisulphite-modified genomic DNA from liver specimens and PBMCs. and alternative and mRNA levels were measured by real-time PCR. Human lymphoblastoid-T2 cells were treated with 5-aza-2´-deoxycytidine for demethylation assays.

Results: promoters were found to be hypermethylated in PBC livers compared to normal and diseased liver specimens. Receiver operating characteristic (ROC) curve analysis showed that minimal CpG-hypermethylation clusters of 3 -CpG sites and 4 alternate--CpG sites specifically differentiated PBC from normal and diseased controls, with mean methylation rates inversely correlating with respective transcript levels. Additionally, in PBMCs a minimal cluster of 3 hypermethylated -CpG sites distinguished PBC from controls, and mean methylation rates correlated negatively with mRNA levels in these immune cells. Alternate promoters in PBMCs were constitutively hypermethylated, in line with absent alternative mRNA expression in diseased and healthy PBMCs. Demethylation assays treating lymphoblastoid-T2 cells with 5-aza-2´-deoxycytidine triggered expression and upregulated -promoter expression.

Conclusions: Disease-specific hypermethylation of promoter regions and subsequent downregulation of -gene expression in the liver and PBMCs of patients with PBC might be critically involved in the pathogenesis of this complex disease.

Lay Summary: Primary biliary cholangitis (PBC) is a chronic immune-associated cholestatic liver disease with unclear complex/multifactorial etiopathogenesis affecting mostly middle-aged women. Patients with PBC exhibit reduced expression of the gene. Herein, we found that promoter regions are hypermethylated in the liver and peripheral blood mononuclear cells of patients with PBC. This increased methylation is associated with downregulated -gene expression, which might contribute to the pathogenesis of PBC. Therefore, novel epigenetic targets may improve treatment in patients with PBC who respond poorly to current pharmacological therapies.
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http://dx.doi.org/10.1016/j.jhepr.2019.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001545PMC
September 2019

Determination of four bisphenols in water and urine samples by magnetic dispersive solid-phase extraction using a modified zeolite/iron oxide composite prior to liquid chromatography diode array detection.

J Sep Sci 2020 May 1;43(9-10):1808-1816. Epub 2020 Jan 1.

Departamento de Química Analítica, Nutrición y Bromatología e Instituto Universitario de Materiales, Universidad de Alicante, Alicante, Spain.

A novel approach is presented to determine four bisphenols in water and urine samples, employing magnetic dispersive solid-phase extraction combined with liquid chromatography and diode array detection. A modified zeolite-based magnetic composite was used as an efficient sorbent, combining the advantages of magnetic materials with the remarkable properties of zeolites. A multivariate optimization design was employed to optimize some experimental factors affecting magnetic dispersive solid-phase extraction. The method was evaluated under optimized conditions (i.e., amount of sorbent, 50 mg; sample pH, unadjusted; NaCl concentration, 1.25%; extraction and elution time, 2 min; eluent solvent, ethanol; eluent solvent volume, 400 µL), obtaining good linearity with correlation coefficients ranging between 0.995 and 0.999 (N = 5) (from 2 to 250 µg/L for bisphenol A, bisphenol AP, and bisphenol P and from 5 to 250 µg/L for bisphenol AF). Method repeatability was assessed obtaining coefficients of variation between 3 and 11% (n = 6). Finally, the method was applied to spiked real samples, obtaining for water samples relative recoveries between 83 and 105%, and for urine samples between 81 and 108% for bisphenol A, bisphenol AP, and bisphenol AF, and between 47 and 59% for bisphenol P.
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http://dx.doi.org/10.1002/jssc.201901022DOI Listing
May 2020

Classroom-comfort-data: A method to collect comprehensive information on thermal comfort in school classrooms.

MethodsX 2019 7;6:2698-2719. Epub 2019 Nov 7.

University of Los Andes, Bogotá, Colombia.

Data from post-occupancy studies in real constructions have been instrumental in the development of mainstream thermal comfort standards for the built environment. However, there is growing evidence of the need to advance these standards, through more robust and comprehensive fieldwork records from a broader spectrum of geographies, climates, architectural characteristics and occupancies. It has been shown that the standards have limited suitability in environments such as educational buildings, as they were developed based mainly on adult subjects working in offices. The lack of guidance in data collection methodologies is also thought to require particular attention, as the accuracy of the assessment models relies significantly on the quality of the information gathered. This manuscript proposes a method to systematically acquire an extensive range of data specifically from school classrooms. The method seeks to improve current techniques as follows: •The post-occupancy surveys suggested in mainstream standards focus mainly on the collection of physical and environmental parameters related to adult subjects. Classroom-comfort-data can be used to collect information not only on physical and environmental parameters but also on physiological and psychological aspects. It also includes tools tailored for occupants from different ages (7 years old and above).•The assessment models suggested in mainstream standards employ between 2-5 parameters to predict thermal comfort ranges. The Classroom-comfort-data method is designed to gather up to 49 different thermal comfort parameters, which allow a more comprehensive evaluation of perception and preference, as well as adaptive strategies, social context, and cognitive and emotional appraisals.•The existing surveys in the standards were formulated primarily for office environments in subtropical and temperate climates. The Classroom-comfort-data method can be adapted to fieldwork within different conditions of climate, building design, occupancy levels, and cultural contexts.
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http://dx.doi.org/10.1016/j.mex.2019.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881643PMC
November 2019

Evaluation of the Integrated Tuberculosis Research Program Sponsored by the Spanish Society of Pulmonology and Thoracic Surgery: 11 Years on.

Arch Bronconeumol 2020 08 25;56(8):483-492. Epub 2019 Nov 25.

Fundación Unidad de Investigación en Tuberculosis (fuiTB), Barcelona, España; Fundación Respira, Programa Integrado de Investigación en Tuberculosis (PII-TB), Sociedad Española de Neumología y Cirugía Torácica (SEPAR), Barcelona, España.

Objective: The objective of the study was to determine the trend of variables related to tuberculosis (TB) from the Integrated Tuberculosis Research Program (PII-TB) registry of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), and to evaluate the PII-TB according to indicators related to its scientific objectives.

Method: Cross-sectional, population-based, multicenter study of new TB cases prospectively registered in the PII-TB between 2006 and 2016. The time trend of quantitative variables was calculated using a lineal regression model, and qualitative variables using the χy test for lineal trend.

Results: A total of 6,892 cases with an annual median of 531 were analyzed. Overall, a significant downward trend was observed in women, immigrants, prisoners, and patients initially treated with 3 drugs. Significant upward trends were observed in patients aged 40-50 and > 50 years, first visit conducted by a specialist, hospitalization, diagnostic delay, disseminated disease and single extrapulmonary location, culture(+), sensitivity testing performed, drug resistance, directly observed treatment, prolonged treatment, and death from another cause. The scientific objectives of the PII-TB that showed a significant upward trend were publications, which reached a maximum of 8 in 2016 with a total impact factor of 49,664, numbers of projects initiated annually, presentations at conferences, and theses.

Conclusions: PII-TB provides relevant information on TB and its associated factors in Spain. A large team of researchers has been created; some scientific aspects of the registry were positive, while others could have been improved.
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http://dx.doi.org/10.1016/j.arbres.2019.10.006DOI Listing
August 2020

Isospora toxostomai n. sp. (Apicomplexa: Eimeriidae) from the curved-billed thrasher Toxostoma curvirostre (Swainson) (Passeriformes: Mimidae) at the Central highlands of Mexico.

Syst Parasitol 2019 12 14;96(9):789-793. Epub 2019 Oct 14.

Centro de Investigación y Estudios Avanzados en Salud Animal, Facultad de Medicina Veterinaria y Zootecnia, Universidad Autónoma del Estado de México, Carretera Toluca-Atlacomulco km 15.5, 50200, Toluca, Mexico, Mexico.

Isospora toxostomai n. sp. (Apicomplexa: Eimeriidae) is described based on material from the curved-billed thrasher Toxostoma curvirostre (Swainson) in the Central Highlands of Mexico. The new species possesses subspherical oöcysts, with a smooth, bi-layered wall. Sporulated oöcysts measure 22-25 × 21-24 (23.4 × 22.3) µm; length/width (L/W) ratio of 1.0-1.1 (1.1). Sporocysts are ellipsoidal, 15-17 × 10-11 (15.8 × 10.5); L/W ratio of 1.3-1.6 (1.5). Micropyle and oöcyst residuum are both absent, and a polar granule present (many fibrils). Mean dimensions of both sporulated oöcysts and sporocysts of I. toxostomai n. sp. appear to be considerably larger than those of Isospora mimusi Coelho, Berto, Neves, Oliveira Flausino & Lopes, 2011 from the tropical mockingbird Mimus gilvus (Vieilot) in Brazil. This is the second species of Isospora Schneider, 1881 infecting a host of the Mimidae in the Americas.
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http://dx.doi.org/10.1007/s11230-019-09884-6DOI Listing
December 2019

Cognitive rigidity in patients with depression and fibromyalgia.

Int J Clin Health Psychol 2019 May 11;19(2):160-164. Epub 2019 Mar 11.

Department of Clinical Psychology and Psychobiology, Universitat de Barcelona, Spain.

Background/objective: The comorbidity of depression and fibromyalgia chronic syndrome has been well documented in the literature; however, the cognitive structure of these patients has not been assessed. Previous results reported variability in cognitive rigidity in depressive patients, the key for this might be the presence of chronic physical pain such as fibromyalgia. The present study explores and compares the cognitive rigidity and differentiation, between patients with depression with and without fibromyalgia syndrome.

Method: Thirty one patients with depression and fibromyalgia were matched, considering age, sex and number of depressive episodes, with 31 patients with depression but without fibromyalgia diagnosis. Cognitive rigidity and differentiation were measured with the repertory grid technique.

Results: The results indicated that depressed patients with fibromyalgia presented higher levels of depressive symptoms, greater cognitive rigidity and lower cognitive differentiation than those without fibromyalgia.

Conclusions: The results might inform future treatments to address the cognitive structure of these patients.
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http://dx.doi.org/10.1016/j.ijchp.2019.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517680PMC
May 2019

Linkage Groups within Thiol-Ene Photoclickable PEG Hydrogels Control In Vivo Stability.

Adv Healthc Mater 2019 07 21;8(14):e1900371. Epub 2019 May 21.

Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr. NW, Atlanta, GA, 30332, USA.

Thiol-norbornene (thiol-ene) photoclickable poly(ethylene glycol) (PEG) hydrogels are a versatile biomaterial for cell encapsulation, drug delivery, and regenerative medicine. Numerous in vitro studies with these 4-arm ester-linked PEG-norbornene (PEG-4eNB) hydrogels demonstrate robust cytocompatibility and ability to retain long-term integrity with nondegradable crosslinkers. However, when transplanted in vivo into the subcutaneous or intraperitoneal space, these PEG-4eNB hydrogels with nondegradable crosslinkers rapidly degrade within 24 h. This characteristic limits the usefulness of PEG-4eNB hydrogels in biomedical applications. Replacing the ester linkage with an amide linkage (PEG-4aNB) mitigates this rapid in vivo degradation, and the PEG-4aNB hydrogels maintain long-term in vivo stability for months. Furthermore, when compared to PEG-4eNB, the PEG-4aNB hydrogels demonstrate equivalent mechanical properties, crosslinking kinetics, and high cytocompatibility with rat islets and human mesenchymal stem cells. Thus, the PEG-4aNB hydrogels may be a suitable replacement platform without necessitating critical design changes or sacrificing key properties relevant to the well-established PEG-4eNB hydrogels.
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http://dx.doi.org/10.1002/adhm.201900371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658339PMC
July 2019

Eimeria aegoliusia n. sp. (Sporozoa: Eimeriidae) from the northern saw-whet owl Aegolius acadicus (Gmelin) (Strigiformes: Strigidae) in Mexico.

Syst Parasitol 2019 07 14;96(6):521-526. Epub 2019 May 14.

Centro de Investigación y Estudios Avanzados en Salud Animal, Facultad de Medicina Veterinaria y Zootecnia, Universidad Autónoma del Estado de México, Carretera Toluca-Atlacomulco km 15.5, Toluca, 50200, Mexico, Mexico.

A new coccidian species (Chromista: Sporozoa: Eimeriidae) collected from the northern saw-whet owl Aegolius acadicus (Gmelin) is reported from Mexico. Eimeria aegoliusia n. sp. has subspherical oöcysts, with smooth, bi-layered wall. Micropyle and oöcyst residuum are both absent and a polar granule is present. To date, eight species of Eimeria Schneider, 1875 have been described from strigiform birds. Mean dimensions of sporulated oöcysts (23.7 × 22.4 µm) and sporocysts (12.8 × 8.3 µm) appear to be considerably smaller than those from other Eimeria spp. with owl definitive hosts: E. atheni Chauhan & Jain, 1979; E. megabubonis Upton, Campbell, Weigel & McKown, 1990; E. spenotytoi Carini, 1939; E. strigis Kutzer, 1963; and E. varia Upton, Campbell, Weigel & McKown. Dimensions of these sporulated oöcysts appear to be larger than those in E. bemricki Averbeck, Cooney, Guarnera, Redig & Stromberg, 1998. The presence of polar granules and their number allowed differentiation from E. bubonis Cawthorn & Stockdale, 1981 and E. nycteae Volf, Koudela & Modry, 1999. This is the first description of an eimeriid coccidian infecting A. acadicus.
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http://dx.doi.org/10.1007/s11230-019-09863-xDOI Listing
July 2019

Adaptive downregulation of Cl-/HCO3- exchange activity in rat hepatocytes under experimental obstructive cholestasis.

PLoS One 2019 21;14(2):e0212215. Epub 2019 Feb 21.

Instituto de Fisiología Experimental (IFISE)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas-Universidad Nacional de Rosario, Rosario, Argentina.

In obstructive cholestasis, there is an integral adaptive response aimed to diminish the bile flow and minimize the injury of bile ducts caused by increased intraluminal pressure and harmful levels of bile salts and bilirrubin. Canalicular bicarbonate secretion, driven by the anion exchanger 2 (AE2), is an influential determinant of the canalicular bile salt-independent bile flow. In this work, we ascertained whether AE2 expression and/or activity is reduced in hepatocytes from rats with common bile duct ligation (BDL), as part of the adaptive response to cholestasis. After 4 days of BDL, we found that neither AE2 mRNA expression (measured by quantitative real-time PCR) nor total levels of AE2 protein (assessed by western blot) were modified in freshly isolated hepatocytes. However, BDL led to a decrease in the expression of AE2 protein in plasma membrane fraction as compared with SHAM control. Additionally, AE2 activity (JOH-, mmol/L/min), measured in primary cultured hepatocytes from BDL and SHAM rats, was decreased in the BDL group versus the control group (1.9 ± 0.3 vs. 3.1 ± 0.2, p<0.005). cAMP-stimulated AE2 activity, however, was not different between SHAM and BDL groups (3.7 ± 0.3 vs. 3.5 ± 0.3), suggesting that cAMP stimulated insertion into the canalicular membrane of AE2-containing intracellular vesicles, that had remained abnormally internalized after BDL. In conclusion, our results point to the existence of a novel adaptive mechanism in cholestasis aimed to reduce biliary pressure, in which AE2 internalization in hepatocytes might result in decreased canalicular HCO3- output and decreased bile flow.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212215PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383990PMC
November 2019

Left Bundle Branch Block after Transcatheter Aortic Valve Implantation with Edwards Sapien 3 Valve: Influence of the Valve Depth Implantation.

Cardiovasc Revasc Med 2019 Nov 9;20(11):949-955. Epub 2019 Jan 9.

Clinical Cardiology, Hospital Universitario HM Montepríncipe, Spain.

Objectives: The aim of this study is to determine the relation between the valve depth implantation and the new-onset left bundle branch block (LBBB) in patients treated with transcatheter aortic valve implantation (TAVI) using Edwards Sapien 3 (S3) prosthesis.

Background: LBBB is the most common conduction disturbance after TAVI. The S3 has been associated with a higher incidence of LBBB. A deep valve implant could be related to new-onset LBBB with S3.

Methods: Seventy-six consecutive patients treated with transfemoral TAVI with S3 were included. Electrocardiogram (ECG) registries were recorded at baseline, after the procedure, and before discharge. Valve depth implantation was determined in 40 patients by off-line analysis of the two/three-dimensional transeophageal echocardiogram (TEE) images, with measure of the valve stent percentage under the aortic annulus. Previous and new conduction anomalies were documented; and patient, anatomic and procedural characteristics were retrospectively analyzed.

Results: Complete atrioventricular block (AVB) incidence was 2.9%. LBBB after TAVI appeared in 39% of patients, being transient in almost half of the cases (permanent LBBB rate 20%). Patients with new-onset LBBB after TAVI were older, with a higher STS Score and a wider basal QRS. A deep valve position was associated with new-onset LBBB, with a ROC curve establishing a cut-off point of 34% of depth implant as risk factor for new-onset LBBB (sensitivity and specificity 0.8).

Conclusions: In transfemoral TAVI with S3 prosthesis, a higher valve implantation (<34% of valve stent introduced into the ventricle) may minimize the new-onset LBBB, especially in old and high-risk patients with a wide basal QRS.
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http://dx.doi.org/10.1016/j.carrev.2019.01.006DOI Listing
November 2019

Impact of High-Molecular-Risk Mutations on Transplantation Outcomes in Patients with Myelofibrosis.

Biol Blood Marrow Transplant 2019 06 6;25(6):1142-1151. Epub 2019 Jan 6.

Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Mutational profiling has demonstrated utility in predicting the likelihood of disease progression in patients with myelofibrosis (MF). However, there is limited data regarding the prognostic utility of genetic profiling in MF patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). We performed high-throughput sequencing of 585 genes on pre-transplant samples from 101 patients with MF who underwent allo-HCT and evaluated the association of mutations and clinical variables with transplantation outcomes. Overall survival (OS) at 5 years post-transplantation was 52%, and relapse-free survival (RFS) was 51.1 % for this cohort. Nonrelapse mortality (NRM) accounted for most deaths. Patient's age, donor's age, donor type, and Dynamic International Prognostic Scoring System score at diagnosis did not predict for outcomes. Mutations known to be associated with increased risk of disease progression, such as ASXL1, SRSF2, IDH1/2, EZH2, and TP53, did not impact OS or RFS. The presence of U2AF1 (P = .007) or DNMT3A (P = .034) mutations was associated with worse OS. A Mutation-Enhanced International Prognostic Scoring System 70 score was available for 80 patients (79%), and there were no differences in outcomes between patients with high risk scores and those with intermediate and low risk scores. Collectively, these data identify mutational predictors of outcome in MF patients undergoing allo-HCT. These genetic biomarkers in conjunction with clinical variables may have important utility in guiding transplantation decision making.
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http://dx.doi.org/10.1016/j.bbmt.2019.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918823PMC
June 2019

and mutations are enriched in distinct subgroups of mixed phenotype acute leukemia with T-lineage differentiation.

Blood Adv 2018 12;2(23):3526-3539

Hematopathology Diagnostic Service, Department of Pathology.

The genetic aberrations that drive mixed phenotype acute leukemia (MPAL) remain largely unknown, with the exception of a small subset of MPALs harboring and translocations. We performed clinicopathologic and genetic evaluation of 52 presumptive MPAL cases at Memorial Sloan Kettering Cancer Center. Only 29 out of 52 (56%) cases were confirmed to be bona fide MPAL according to the 2016 World Heath Organization classification. We identified and mutations as the most common recurrent mutations in MPAL, each occurring in 6 out of 26 (23%) cases. These mutations are mutually exclusive of each other and / translocations. - and -mutated MPAL showed marked predilection for T-lineage differentiation (5/6 mutated, 6/6 mutated). -mutated MPAL occurred in a younger patient cohort compared with -mutated cases (median age, 27 years vs 61 years, < .01). All 3 MPAL cases with both T- and B-lineage differentiation harbored mutations. MPAL with T-lineage differentiation was associated with nodal or extramedullary involvement (9/15 [60%] vs 0, = .001) and a higher relapse incidence (78% vs 22%, = .017) compared with those without T-lineage differentiation. Sequencing studies on flow-cytometry-sorted populations demonstrated that mutations are present in all blast compartments regardless of lineage differentiation with high variant allele frequency, implicating as an early mutation in MPAL pathogenesis. In conclusion, and mutations are the most common somatic alterations identified in MPAL and appear to define 2 distinct subgroups of MPAL with T-lineage differentiation with inferior outcomes.
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http://dx.doi.org/10.1182/bloodadvances.2018023531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290101PMC
December 2018

Validation of Musculoskeletal Ultrasound in the Assessment of Experimental Gout Synovitis.

Ultrasound Med Biol 2018 07 24;44(7):1516-1524. Epub 2018 Apr 24.

Bone and Joint Research Unit, Department of Rheumatology, Hospital Universitario Fundación Jiménez Díaz, IIS-Fundación Jiménez Díaz UAM, Madrid, Spain.

The objective of this study was to validate musculoskeletal ultrasound (US) in a rabbit model of acute gout. Acute gout was induced by intra-articular injection of monosodium urate (MSU) crystals in 10 rabbits; the 3 controls received vehicle. Rabbit knees were assessed by B-mode and power Doppler (PD) US 24 and 72 h after injections. After 72 h, all rabbits were euthanized. US discriminated between the MSU-injected and control groups with respect to the different inflammatory findings at both at 24 and 72 h and for MSU crystal-related findings after 24 h of injection. US synovial thickening, intra-synovial power Doppler signal and global joint distension significantly correlated with the synovial global histopathological score (r = 0.47, p = 0.0188), tissue vascularization measured by CD31 immunohistochemical-positive staining (r = 0.46, p = 0.0172) and tissue levels of interleukin-1β (r = 0.53, p = 0.0078), respectively. US is a valid method for assessment of synovial inflammation in experimental gouty arthritis in rabbits.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2018.03.018DOI Listing
July 2018

Electrocardiographic changes and conduction disturbances after transfemoral aortic valve implantation with Edwards Sapien 3 prosthesis.

J Electrocardiol 2018 May - Jun;51(3):416-421. Epub 2018 Feb 20.

Clinical Cardiology Department, Hospital Universitario HM Montepríncipe, Madrid, Spain.

Objectives: The aim of this study is to describe electrocardiographic changes and conduction abnormalities in patients undergoing transcatheter aortic valve implantation (TAVI).

Methods: 76 patients who underwent TAVI using Edwards Sapien 3 prosthesis were included, comparing electrocardiographic registries at admission, post-procedure and before discharge.

Results: Patients after TAVI presented a longer PR interval, a wider QRS, and a longer corrected QT, with a left deviation of QRS axis and T waves; reversible changes that tended to correct in the following days after TAVI. Complete atrioventricular block incidence was 2.9%. New-onset left bundle branch block (LBBB) incidence was 39%, although solved in almost half of patients before discharge.

Conclusions: TAVI was associated with different reversible electrocardiographic changes that suggest a transient impact on the conduction system. One of every five patients presented permanent LBBB after valve implant.
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http://dx.doi.org/10.1016/j.jelectrocard.2018.02.009DOI Listing
March 2019

Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms.

Cancer Cell 2018 01 14;33(1):29-43.e7. Epub 2017 Dec 14.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Genetic and functional studies underscore the central role of JAK/STAT signaling in myeloproliferative neoplasms (MPNs). However, the mechanisms that mediate transformation in MPNs are not fully delineated, and clinically utilized JAK inhibitors have limited ability to reduce disease burden or reverse myelofibrosis. Here we show that MPN progenitor cells are characterized by marked alterations in gene regulation through differential enhancer utilization, and identify nuclear factor κB (NF-κB) signaling as a key pathway activated in malignant and non-malignant cells in MPN. Inhibition of BET bromodomain proteins attenuated NF-κB signaling and reduced cytokine production in vivo. Most importantly, combined JAK/BET inhibition resulted in a marked reduction in the serum levels of inflammatory cytokines, reduced disease burden, and reversed bone marrow fibrosis in vivo.
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http://dx.doi.org/10.1016/j.ccell.2017.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760343PMC
January 2018

Targeting the anion exchanger 2 with specific peptides as a new therapeutic approach in B lymphoid neoplasms.

Haematologica 2018 06 30;103(6):1065-1072. Epub 2017 Nov 30.

Division of Hematological-Oncology, Center for Applied Medical Research (CIMA), University of Navarra, CIBERONC, IDISNA, Pamplona, Spain

Regulatory T (Treg) cells can weaken antitumor immune responses, and inhibition of their function appears to be a promising therapeutic approach in cancer patients. Mice with targeted deletion of the gene encoding the Cl/HCO anion exchanger AE2 (also termed SLC4A2), a membrane-bound carrier involved in intracellular pH regulation, showed a progressive decrease in the number of Treg cells. We therefore challenged AE2 as a potential target for tumor therapy, and generated linear peptides designed to bind the third extracellular loop of AE2, which is crucial for its exchange activity. Peptide p17AE2 exhibited optimal interaction ability and indeed promoted apoptosis in mouse and human Treg cells, while activating effector T-cell function. Interestingly, this linear peptide also induced apoptosis in different types of human leukemia, lymphoma and multiple myeloma cell lines and primary malignant samples, while it showed only moderate effects on normal B lymphocytes. Finally, a macrocyclic AE2 targeting peptide exhibiting increased stability was effective in mice xenografted with B-cell lymphoma. These data suggest that targeting the anion exchanger AE2 with specific peptides may represent an effective therapeutic approach in B-cell malignancies.
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http://dx.doi.org/10.3324/haematol.2017.175687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058773PMC
June 2018