Publications by authors named "Javier Gómez"

126 Publications

Left Ventricular Intramyocardial Dissecting Hematoma: A Multimodality Imaging Diagnostic Approach.

Circ Cardiovasc Imaging 2021 Jun 22:CIRCIMAGING121012410. Epub 2021 Jun 22.

Division of Cardiology, Cook County Health, Chicago, IL. (T.A., S.M., F.I., J.G., J.T., R.D.).

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http://dx.doi.org/10.1161/CIRCIMAGING.121.012410DOI Listing
June 2021

Plitidepsin has a positive therapeutic index in adult patients with COVID-19 requiring hospitalization.

medRxiv 2021 May 25. Epub 2021 May 25.

Plitidepsin is a marine-derived cyclic-peptide that inhibits SARS-CoV-2 replication at low nanomolar concentrations by the targeting of host protein eEF1A (eukaryotic translation-elongation-factor-1A). We evaluated a model of intervention with plitidepsin in hospitalized COVID-19 adult patients where three doses were assessed (1.5, 2 and 2.5 mg/day for 3 days, as a 90-minute intravenous infusion) in 45 patients (15 per dose-cohort). Treatment was well tolerated, with only two Grade 3 treatment-related adverse events observed (hypersensitivity and diarrhea). The discharge rates by Days 8 and 15 were 56.8% and 81.8%, respectively, with data sustaining dose-effect. A mean 4.2 log10 viral load reduction was attained by Day 15. Improvement in inflammation markers was also noted in a seemingly dose-dependent manner. These results suggest that plitidepsin impacts the outcome of patients with COVID-19.

One-sentence Summary: Plitidepsin, an inhibitor of SARS-Cov-2 , is safe and positively influences the outcome of patients hospitalized with COVID-19.
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http://dx.doi.org/10.1101/2021.05.25.21257505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168388PMC
May 2021

Ruptured Sinus of Valsalva Aneurysm: Use of Multimodality Imaging in Delineating Structure and Function.

J Investig Med High Impact Case Rep 2021 Jan-Dec;9:23247096211020684

John H. Stroger Jr Hospital of Cook County, Chicago, IL, USA.

Sinus of Valsalva aneurysm is a rare defect that can present with fatal complications in case of rupture. Heart failure symptoms are common due to high fraction of the resultant shunt. Multimodality imaging and invasive hemodynamic assessment is essential for comprehensive evaluation of the defect and guiding surgical planning. We describe the case of a 40-year-old woman who presented with heart failure symptoms and was found to have ruptured sinus of Valsalva aneurysm on transthoracic echocardiogram. Cardiac computed tomography angiography further characterized the defect and the associated anomalies. Right heart catheterization assessed the hemodynamic significance of the left to right shunt. Intraoperative findings highlighted the associated congenital anomalies including supracristal ventricular septal defect. The use of intraoperative transesophageal echocardiography proved essential in detecting worsening of the right ventricular outflow track infundibular dynamic obstruction post repair thus delineating the importance of maintaining adequate cardiac preload. This case highlights a stepwise approach in the anatomical characterization of sinus of Valsalva aneurysm using multimodality imaging and the use of hemodynamic assessment and intraoperative imaging to guide surgical planning.
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http://dx.doi.org/10.1177/23247096211020684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168023PMC
May 2021

Molecular diagnosis in non-small-cell lung cancer: expert opinion on and testing.

J Clin Pathol 2021 Apr 19. Epub 2021 Apr 19.

Department of Pathology, Hospital Universitario Virgen del Rocío, Sevilla, Spain.

The effectiveness of targeted therapies with tyrosine kinase inhibitors in non-small-cell lung cancer (NSCLC) depends on the accurate determination of the genomic status of the tumour. For this reason, molecular analyses to detect genetic rearrangements in some genes (ie, , , ) have become standard in patients with advanced disease. Since immunohistochemistry is easier to implement and interpret, it is normally used as the screening procedure, while fluorescence in situ hybridisation (FISH) is used to confirm the rearrangement and decide on ambiguous immunostainings. Although FISH is considered the most sensitive method for the detection of and rearrangements, the interpretation of results requires detailed guidelines. In this review, we discuss the various technologies available to evaluate and genomic rearrangements using these techniques. Other techniques such as real-time PCR and next-generation sequencing have been developed recently to evaluate and gene rearrangements, but some limitations prevent their full implementation in the clinical setting. Similarly, liquid biopsies have the potential to change the treatment of patients with advanced lung cancer, but further research is required before this technology can be applied in routine clinical practice. We discuss the technical requirements of laboratories in the light of quality assurance programmes. Finally, we review the recent updates made to the guidelines for the determination of molecular biomarkers in patients with NSCLC.
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http://dx.doi.org/10.1136/jclinpath-2021-207490DOI Listing
April 2021

Experimental Study of the Effect of High Service Temperature on the Flexural Performance of Near-Surface Mounted (NSM) Carbon Fiber-Reinforced Polymer (CFRP)-Strengthened Concrete Beams.

Polymers (Basel) 2021 Mar 17;13(6). Epub 2021 Mar 17.

AMADE, Polytechnic School, University of Girona, 17003 Girona, Spain.

This paper presents a study of the effect of high service temperature (near or beyond glass transition temperature () of structural epoxy adhesive) on the behavior of near-surface mounted (NSM) carbon fiber-reinforced polymer (CFRP)-strengthened reinforced concrete (RC) beams. The study includes experimental work as well as analytical and numerical analysis. To this end, fourteen beams have been tested up to failure in two different series. In series 1, specimens with three different CFRP areas have been tested at two different temperatures (i.e., 20 and 40 °C). In series 2, and with the aim of evaluating the effect of higher temperatures, only one CFRP area was tested under four different temperatures (i.e., 20, 60, 70, and 85 °C). Experimental results are evaluated in terms of load-deflections, failure modes, and bond performance. Furthermore, the experimental load-deflection curves are satisfactorily compared to both analytical predictions and finite element (FE) numerical simulations. In both cases, shrinkage and temperature effects on the short-term response of flexural elements have been accounted for. No significant reduction in stiffness and ultimate load was observed for specimens being tested up to 60 °C (in the range of epoxy ), showing FRP rupture failure in all of them. For specimens under 70 and 85 °C, the failure mode changed from FRP rupture to FRP end debonding and concrete crushing, respectively.
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http://dx.doi.org/10.3390/polym13060920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002408PMC
March 2021

A Practical Guide to Metabolomics Software Development.

Anal Chem 2021 02 19;93(4):1912-1923. Epub 2021 Jan 19.

Department of Chemical and Biomolecular Engineering, Vanderbilt University, PMB 351604, 2301 Vanderbilt Place, Nashville, Tennessee 37235, United States.

A growing number of software tools have been developed for metabolomics data processing and analysis. Many new tools are contributed by metabolomics practitioners who have limited prior experience with software development, and the tools are subsequently implemented by users with expertise that ranges from basic point-and-click data analysis to advanced coding. This Perspective is intended to introduce metabolomics software users and developers to important considerations that determine the overall impact of a publicly available tool within the scientific community. The recommendations reflect the collective experience of an NIH-sponsored Metabolomics Consortium working group that was formed with the goal of researching guidelines and best practices for metabolomics tool development. The recommendations are aimed at metabolomics researchers with little formal background in programming and are organized into three stages: (i) preparation, (ii) tool development, and (iii) distribution and maintenance.
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http://dx.doi.org/10.1021/acs.analchem.0c03581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859930PMC
February 2021

A Slimy Business: the Future of Fish Skin Microbiome Studies.

Microb Ecol 2021 Jan 7. Epub 2021 Jan 7.

Department of Biological Sciences, Sam Houston State University, Huntsville, TX, 77320, USA.

Fish skin contains a mucosal microbiome for the largest and oldest group of vertebrates, a location ideal for microbial community ecology and practical applications in agriculture and veterinary medicine. These selective microbiomes are dominated by Proteobacteria, with compositions different from the surrounding water. Core taxa are a small percentage of those present and are currently functionally uncharacterized. Methods for skin sampling, DNA extraction and amplification, and sequence data processing are highly varied across the field, and reanalysis of recent studies using a consistent pipeline revealed that some conclusions did change in statistical significance. Further, the 16S gene sequencing approaches lack quantitation of microbes and copy number adjustment. Thus, consistency in the field is a serious limitation in comparing across studies. The most significant area for future study, requiring metagenomic and metabolomics data, is the biochemical pathways and functions within the microbiome community, the interactions between members, and the resulting effects on fish host health being linked to specific nutrients and microbial species. Genes linked to skin colonization, such as those for attachment or mucin degradation, need to be uncovered and explored. Skin immunity factors need to be directly linked to microbiome composition and individual taxa. The basic foundation has been laid, and many exciting future discoveries remain.
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http://dx.doi.org/10.1007/s00248-020-01648-wDOI Listing
January 2021

Reactivity and Mechanisms of Photoactivated Heterometallic [Ru Ni ] and [Ru Ni Ru ] Catalysts for Dihydrogen Generation from Water.

Angew Chem Int Ed Engl 2021 Mar 28;60(11):5723-5728. Epub 2021 Jan 28.

Department of Chemistry, Wayne State University, Detroit, MI, 48202, USA.

Two heterometallic photocatalysts were designed and probed for water reduction. Both [(bpy) Ru Ni (L )](ClO ) (1) and [(bpy) Ru Ni (L ) Ru (bpy) ](ClO ) (2) can generate the low-valent precursor involved in hydride formation prior to dihydrogen generation. However, while the bimetallic [Ru Ni ] (1) requires the presence of an external photosensitizer to trigger catalytic activity, the trimetallic [Ru Ni Ru ] (2) displays significant coupling between the catalytic and light-harvesting units to promote intramolecular multielectron transfer and perform photocatalysis at the Ni center. A concerted experimental and theoretical effort proposes mechanisms to explain why 1 is unable to achieve self-supported catalysis, while 2 is fully photocatalytic.
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http://dx.doi.org/10.1002/anie.202013678DOI Listing
March 2021

Flood and Contain: An Optimized Repeal-Based Flooding Algorithm for Wireless Ad Hoc and Sensor Networks.

Sensors (Basel) 2020 Oct 20;20(20). Epub 2020 Oct 20.

Telecommunications Deptartment, Engineering Faculty, National Autonomous University of Mexico, Mexico City 04510, Mexico.

Flooding is a simple yet reliable way of discovering resources in wireless ad hoc networks such as mobile ad hoc networks (MANETs), ad hoc sensors, and recently, IoT networks. However, its operation is resource-intensive, especially in densely populated networks. Several approaches can be found in the literature to reduce the impact of flooding. Many of these approaches follow a repeal-based operation, chasing and stopping further propagation of flooding packets once the target is found. However, repeal-based protocols might end up transmitting even more packets than the original flooding. This work characterizes a maximum repeal-flooding boundary beyond which it is counterproductive to chase the original flooding. We present the Flood and Contain (F&C) algorithm, a method that can quickly establish the maximum repeal-flooding boundary for each node while making no assumptions on the underlying network. F&C's packet overhead increases linearly with the hop count up to the maximum repeal-flooding boundary, in which case there is no attempt to chase the original flooding. In this latter case, F&C generates only as many packets as the original flooding. Simulations show that, on average, F&C reduces the total flooding overhead (compared to traditional flooding) up to 35 percent once considering all possible destinations, with only a slight increase in resource discovery latency, and it outperforms all other repeal-based protocols, particularly for longer routes.
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http://dx.doi.org/10.3390/s20205914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589554PMC
October 2020

Uncertainty in Functional Network Representations of Brain Activity of Alcoholic Patients.

Brain Topogr 2021 01 12;34(1):6-18. Epub 2020 Oct 12.

Department of Computer Science and Statistics, Universidad Rey Juan Carlos, Madrid, Spain.

In spite of the large attention received by brain activity analyses through functional networks, the effects of uncertainty on such representations have mostly been neglected. We here elaborate the hypothesis that such uncertainty is not just a nuisance, but that on the contrary is condition-dependent. We test this hypothesis by analysing a large set of EEG brain recordings corresponding to control subjects and patients suffering from alcoholism, through the reconstruction of the corresponding Maximum Spanning Trees (MSTs), the assessment of their topological differences, and the comparison of two frequentist and Bayesian reconstruction approaches. A machine learning model demonstrates that the Bayesian reconstruction encodes more information than the frequentist one, and that such additional information is related to the uncertainty of the topological structures. We finally show how the Bayesian approach is more effective in the validation of generative models, over and above the frequentist one, by proposing and disproving two models based on additive noise.
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http://dx.doi.org/10.1007/s10548-020-00799-wDOI Listing
January 2021

Identifiers.org - Compact Identifier Services in the Cloud.

Bioinformatics 2020 Oct 8. Epub 2020 Oct 8.

European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Genome Campus, CB10 1SD, Cambridge, UK.

Motivation: Since its launch in 2010, Identifiers.org has become an important tool for the annotation and cross-referencing of Life Science data. In 2016, we established the Compact Identifier (CID) scheme (prefix: accession) to generate globally unique identifiers for data resources using their locally assigned accession identifiers. Since then, we have developed and improved services to support the growing need to create, reference and resolve CIDs, in systems ranging from human readable text to cloud based e-infrastructures, by providing high availability and low latency cloud-based services, backed by a high quality, manually curated resource.

Results: We describe a set of services that can be used to construct and resolve CIDs in Life Sciences and beyond. We have developed a new front end for accessing the Identifiers.org registry data and APIs to simplify integration of Identifiers.org CID services with third party applications. We have also deployed the new Identifiers.org infrastructure in a commercial cloud environment, bringing our services closer to the data.

Availability: https://identifiers.org.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa864DOI Listing
October 2020

Comparison of planar with tomographic pyrophosphate scintigraphy for transthyretin cardiac amyloidosis: Perils and pitfalls.

J Nucl Cardiol 2021 02 8;28(1):104-111. Epub 2020 Sep 8.

Division of Cardiology, Cook County Health, Chicago, USA.

Background: Tc-99m pyrophosphate (PYP) SPECT is recommended for indeterminate findings on planar imaging. We aimed to compare the findings on planar PYP scintigraphy alone to that of routinely performed PYP SPECT.

Methods: PYP scintigraphy data of 133 patients (53% men; mean age 76 years) were evaluated. SPECT was routinely performed following 1-hour planar imaging, in all cases. Semiquantitative visual score and heart-to-contralateral (H/CL) ratio were determined in all patients as recommended.

Results: PYP images from 35 patients (26%) were considered to be positive based on SPECT myocardial uptake. Among them, 20 (57%) had a H/CL ratio ≥1.5 and 34 had a visual score ≥ 2. SPECT identified myocardial uptake in one patient with a visual score < 2 and refuted the presence of myocardial uptake in two patients with a visual score ≥ 2. Visual score correlated well with SPECT (r = 0.94; P < .0001) and had an accuracy of 98% for tomographic myocardial uptake. Addition of H/CL ratio reduced the diagnostic performance of visual score.

Conclusions: Planar-derived visual score has an excellent accuracy for tomographic myocardial uptake, though it misclassifies a small proportion of patients. H/CL ratio decreases the diagnostic certainty of planar imaging. Tomographic imaging prevents misdiagnoses and should always be performed.
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http://dx.doi.org/10.1007/s12350-020-02328-5DOI Listing
February 2021

Coexistent transthyretin amyloid cardiomyopathy and monoclonal gammopathy: Diagnostic challenges and prognostic implications.

J Nucl Cardiol 2020 Jul 27. Epub 2020 Jul 27.

Division of Cardiology, Cook County Health, Chicago, IL, USA.

Establishing an accurate diagnosis of amyloid subtype in patients with coexistent cardiac amyloidosis and monoclonal gammopathy is crucial due to treatment and prognostic implications. Here, we discuss a case of coexistent diagnoses of transthyretin amyloid cardiomyopathy and smoldering multiple myeloma, highlighting the challenges associated with the possibility of several disease combinations and the limitations of diagnostic testing. In addition, the importance of clinical clues such as disease course and progression, patient preference, and multidisciplinary collaboration should not be discounted in the diagnostic and management approach of these patients.
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http://dx.doi.org/10.1007/s12350-020-02281-3DOI Listing
July 2020

Investigation of cobalt(III)-phenylalanine complexes for hypoxia-activated drug delivery.

Dalton Trans 2020 Nov;49(45):16425-16439

Universidade Federal Fluminense, Instituto de Química, Outeiro S. João Batista S/N, 24020-141 Niterói, RJ, Brazil.

Four cobalt(iii)-phenylalanine complexes, [Co(Phe)(py2en)](ClO4)2·H2O (1), [Co(Phe)(TPA)](ClO4)2·H2O (2), [Co(Phe)(py2enMe2)](ClO4)2·H2O (3) and [Co(bipy)2(Phe)](ClO4)2·H2O (4), were investigated as prototype models for hypoxia-activated delivery of melphalan - a phenylalanine derivative anticancer drug of the class of nitrogen mustards. Single crystal X-ray diffraction analysis provided the molecular structures of 1-4, as a single isomer/conformer. According with NMR and theoretical calculations, the solid-state structures of 2 and 4 are maintained in solutions. For complexes 1 and 3, though, a mixture of isomers was found in DMSO solutions: Λ-cisα(exo,exo) and Δ-cisβ1(exo,exo) for 1 (3 : 2 ratio), and Λ-cisα(exo,exo) and Δ-cisα(exo,exo) for 3 (5 : 1 ratio). Theoretical calculations point to a re-equilibration reaction of the solid-state Λ-cisβ1 isomer of 1 in solution. Electrochemical analysis revealed a correlation between the electron-donor capacity of the ancillary ligands and the redox potentials of the complexes. The potentials varied from +0.01 for 1 to +0.31 V vs. SHE for 4 in aqueous media and indicate that reduction should be achieved in biological media. The integrity of the complexes in pH 5.5 and 7.4 buffered solutions was confirmed by UV-Vis monitoring up to 24 h at 25 °C. Reduction by ascorbic acid (AA) shows an O2-dependent dissociation of the l-Phe for complexes 1-3, with higher conversion rates at pH 7.4. For complex 4, a fast dissociation of l-Phe was observed, with conversion rates unaffected by the pH and presence of O2.
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http://dx.doi.org/10.1039/d0dt01389gDOI Listing
November 2020

SPECT-MPI in evaluation of liver transplant candidates: Is the evidence mounting?

Authors:
Javier Gomez

J Nucl Cardiol 2020 Jun 21. Epub 2020 Jun 21.

Division of Cardiology, John H. Stroger Jr, Hospital of Cook County, 1901 W. Harrison St., Suite # 3620, Chicago, IL, 60612, USA.

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http://dx.doi.org/10.1007/s12350-020-02240-yDOI Listing
June 2020

COVID-19: Measures to prevent hospital contagion. What do urologists need to know?

Int Braz J Urol 2020 07;46(suppl.1):113-119

Department of Urology Hospital Central Militar, México DF, México.

A new outbreak of respiratory infection caused by the novel coronavirus in late December 2019 in China caused standards of medical care to change not only for related areas but for the entire healthcare system, and when the WHO declared COVID-19 a pandemic new strategies of patient care had to be defined initially to optimize resources to confront the pandemic and then to protect healthcare personnel. As urologists, we must be involved in these new standards, since without an effective vaccine the risk of contagion is high; thus, the purpose of this review is to have orientation on the measures urologists should take in their everyday clinical practice.
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http://dx.doi.org/10.1590/S1677-5538.IBJU.2020.S117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719994PMC
July 2020

Increased Susceptibility of Mice Lacking Renin-b to Angiotensin II-Induced Organ Damage.

Hypertension 2020 08 8;76(2):468-477. Epub 2020 Jun 8.

From the Department of Physiology, Medical College of Wisconsin, Milwaukee (P.N., J.G., J.W., K.-T.L., J.L.G., C.D.S.).

Several cardiac and renal diseases are attributed to a dysregulation of the renin-angiotensin system. Renin, the rate-limiting enzyme of the renin-angiotensin system, has 2 isoforms. The classical renin isoform (renin-a) encoding preprorenin is mainly confined to the juxtaglomerular cells and released into the circulation upon stimulation. Alternatively, renin-b is predicted to remain intracellular and is expressed in the brain, heart, and adrenal gland. In the brain, ablation of renin-b (Ren-b mice) results in increased brain renin-angiotensin system activity. However, the consequences of renin-b ablation in tissues outside the brain remain unknown. Therefore, we hypothesized that renin-b protects from hypertensive cardiac and renal end-organ damage in mice. Ren-b mice exhibited normal blood pressure at baseline. Thus, we induced hypertension by using a slow pressor dose of Ang II (angiotensin II). Ang II increased blood pressure in both wild type and Ren-b to the same degree. Although the blood pressure between Ren-b and wild-type mice was elevated equally, 4-week infusion of Ang II resulted in exacerbated cardiac remodeling in Ren-b mice compared with wild type. Ren-b mice also exhibited a modest increase in renal glomerular matrix deposition, elevated plasma aldosterone, and a modestly enhanced dipsogenic response to Ang II. Interestingly, ablation of renin-b strongly suppressed plasma renin, but renal cortical renin mRNA was preserved. Altogether, these data indicate that renin-b might play a protective role in the heart, and thus renin-b could be a potential target to treat hypertensive heart disease.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347438PMC
August 2020

Characterization and Simulation of the Bond Response of NSM FRP Reinforcement in Concrete.

Materials (Basel) 2020 Apr 9;13(7). Epub 2020 Apr 9.

AMADE, Polytechnic School, University of Girona, 17003 Girona, Spain.

The near-surface mounted (NSM) technique with fiber reinforced polymer (FRP) reinforcement as strengthening system for concrete structures has been broadly studied during the last years. The efficiency of the NSM FRP-to-concrete joint highly depends on the bond between both materials, which is characterized by a local bond-slip law. This paper studies the effect of the shape of the local bond-slip law and its parameters on the global response of the NSM FRP joint in terms of load capacity, effective bond length, slip, shear stress, and strain distribution along the bonded length, which are essential parameters on the strengthening design. A numerical procedure based on the finite difference method to solve the governing equations of the FRP-to-concrete joint is developed. Pull-out single shear specimens are tested in order to experimentally validate the numerical results. Finally, a parametric study is performed. The effect of the bond-shear strength slip at the bond strength, maximum slip, and friction branch on the parameters previously described is presented and discussed.
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http://dx.doi.org/10.3390/ma13071770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179015PMC
April 2020

Competitive inhibition of protein adsorption to silica surfaces by their coating with high density charge polyelectrolytes.

Colloids Surf B Biointerfaces 2020 Jul 30;191:110993. Epub 2020 Mar 30.

IDiBE, Universidad Miguel Hernández, 03202, Elche, Spain. Electronic address:

The adsorption of proteins to silica surface is a common process mainly governed by the electrostatic attractive interaction between the pH-dependent negatively silica surface and the positive charges of the biomolecule. This process often reduces the conformational stability of the adsorbed protein and may reduce its biological functionality mostly due to multimolecular processes such as aggregation and fibrillation. Here we show that high-density charge cationic polyelectrolytes may successfully compete with the protein for the silica surface containing deprotonated-silanol groups. Therefore, the coating of silica surfaces with these cationic polyelectrolytes precludes the adsorption of the protein to the solid surface. Intensive water washing of the polyelectrolyte-coated silica surfaces had does not result in polyelectrolyte release (even at moderate ionic strength) maintaining the solid surface protected from protein adsorption.
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http://dx.doi.org/10.1016/j.colsurfb.2020.110993DOI Listing
July 2020

Human importin α3 and its N-terminal truncated form, without the importin-β-binding domain, are oligomeric species with a low conformational stability in solution.

Biochim Biophys Acta Gen Subj 2020 Jul 29;1864(7):129609. Epub 2020 Mar 29.

IDIBE, Universidad Miguel Hernández, 03202 Elche, Alicante, Spain; Instituto de Biocomputación y Física de Sistemas Complejos, Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50009 Zaragoza, Spain. Electronic address:

Background: Eukaryotic cells have a continuous transit of macromolecules between the cytoplasm and the nucleus. Several carrier proteins are involved in this transport. One of them is importin α, which must form a complex with importin β to accomplish its function, by domain-swapping its 60-residue-long N terminus. There are several human isoforms of importin α; among them, importin α3 has a particularly high flexibility.

Methods: We studied the conformational stability of intact importin α3 (Impα3) and its truncated form, where the 64-residue-long, N-terminal importin-β-binding domain (IBB) has been removed (ΔImpα3), in a wide pH range, with several spectroscopic, biophysical, biochemical methods and with molecular dynamics (MD).

Results: Both species acquired native-like structure between pH 7 and 10.0, where Impα3 was a dimer (with an apparent self-association constant of ~10 μM) and ΔImpα3 had a higher tendency to self-associate than the intact species. The acquisition of secondary, tertiary and quaternary structure, and the burial of hydrophobic patches, occurred concomitantly. Both proteins unfolded irreversibly at physiological pH, by using either temperature or chemical denaturants, through several partially folded intermediates. The MD simulations support the presence of these intermediates.

Conclusions: The thermal stability of Impα3 at physiological pH was very low, but was higher than that of ΔImpα3. Both proteins were stable in a narrow pH range, and they unfolded at physiological pH populating several intermediate species.

General Significance: The low conformational stability explains the flexibility of Impα3, which is needed to carry out its recognition of complex cargo sequences.
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http://dx.doi.org/10.1016/j.bbagen.2020.129609DOI Listing
July 2020

Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial.

Lancet Oncol 2020 05 27;21(5):645-654. Epub 2020 Mar 27.

Humanitas Clinical and Research Center - IRCCS, Humanitas Cancer Center, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.

Background: Few options exist for treatment of patients with small-cell lung cancer (SCLC) after failure of first-line therapy. Lurbinectedin is a selective inhibitor of oncogenic transcription. In this phase 2 study, we evaluated the acti and safety of lurbinectedin in patients with SCLC after failure of platinum-based chemotherapy.

Methods: In this single-arm, open-label, phase 2 basket trial, we recruited patients from 26 hospitals in six European countries and the USA. Adults (aged ≥18 years) with a pathologically proven diagnosis of SCLC, Eastern Cooperative Oncology Group performance status of 2 or lower, measurable disease as per Response Criteria in Solid Tumors (RECIST) version 1.1, absence of brain metastasis, adequate organ function, and pre-treated with only one previous chemotherapy-containing line of treatment (minimum 3 weeks before study initiation) were eligible. Treatment consisted of 3·2 mg/m lurbinectedin administered as a 1-h intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary outcome was the proportion of patients with an overall response (complete or partial response) as assessed by the investigators according to RECIST 1.1. All treated patients were analysed for activity and safety. This study is ongoing and is registered with ClinicalTrials.gov, NCT02454972.

Findings: Between Oct 16, 2015, and Jan 15, 2019, 105 patients were enrolled and treated with lurbinectedin. Median follow-up was 17·1 months (IQR 6·5-25·3). Overall response by investigator assessment was seen in 37 patients (35·2%; 95% CI 26·2-45·2). The most common grade 3-4 adverse events (irrespective of causality) were haematological abnormalities-namely, anaemia (in nine [9%] patients), leucopenia (30 [29%]), neutropenia (48 [46%]), and thrombocytopenia (seven [7%]). Serious treatment-related adverse events occurred in 11 (10%) patients, of which neutropenia and febrile neutropenia were the most common (five [5%] patients for each). No treatment-related deaths were reported.

Interpretation: Lurbinectedin was active as second-line therapy for SCLC in terms of overall response and had an acceptable and manageable safety profile. Lurbinectedin could represent a potential new treatment for patients with SCLC, who have few options especially in the event of a relapse, and is being investigated in combination with doxorubicin as second-line therapy in a randomised phase 3 trial.

Funding: Pharma Mar.
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http://dx.doi.org/10.1016/S1470-2045(20)30068-1DOI Listing
May 2020

Endovascular Therapy of Arterial Complications Within the First Week After Liver Transplant.

Transplant Proc 2020 Jun 25;52(5):1464-1467. Epub 2020 Mar 25.

Biocruces Bizkaia Health Research Institute. Liver Transplantation Unit, Hospital Universitario Cruces, Bilbao, Spain; University of the Basque Country, Bilbao, Spain.

Background: Recent radiologic advances have made endovascular treatment a very successful option for arterial complications after liver transplant. This article presents our experience of using endovascular treatments during the first week after liver transplant.

Methods: This study is a retrospective, single-center analysis. Liver transplants performed between 2010 and 2018 were analyzed. All patients underwent Doppler ultrasonography on days 1 and 7. Endovascular therapy was indicated in hepatic artery thrombosis diagnosed early after transplant and in stenosis when hepatic narrowing was > 70%. Patients were treated with subcutaneous anticoagulant therapy and with antiplatelet agents after endovascular therapy.

Results: Seven patients (1.1%) were included in the study. Stenosis was the reason in 5 patients while 2 patients had symptoms of thrombosis. The first 2 patients were initially treated with angioplasty; both had restenosis and were treated with angioplasty and stent placement, respectively. The 5 most recent patients received stenting as a primary treatment. Two of these patients developed a new stenosis. No patient developed any hepatic artery complication related to the procedure, and only 1 patient experienced a postprocedure complication (femoral artery pseudoaneurysm), which was managed conservatively. No patient required retransplant. After a median follow-up of 48 months (range, 35-85 months) 1 patient had died, and the rest were alive and asymptomatic.

Conclusions: Although there is scant experience of the use of endovascular therapy very shortly after liver transplant, recent advances in interventional radiology have made the technique feasible and safe, and it achieves a high success rate.
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http://dx.doi.org/10.1016/j.transproceed.2020.02.075DOI Listing
June 2020

Exploration of cardiometabolic and developmental significance of angiotensinogen expression by cells expressing the leptin receptor or agouti-related peptide.

Am J Physiol Regul Integr Comp Physiol 2020 05 18;318(5):R855-R869. Epub 2020 Mar 18.

Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.

Angiotensin II (ANG II) receptor (AT) is expressed in cells of the arcuate nucleus of the hypothalamus that express the leptin receptor () and agouti-related peptide (). expression in these cells is required to stimulate resting energy expenditure in response to leptin and high-fat diets (HFDs), but the mechanism activating AT signaling by leptin remains unclear. To probe the role of local paracrine/autocrine ANG II generation and signaling in this mechanism, we bred mice harboring a conditional allele for angiotensinogen (, encoding AGT) with mice expressing Cre-recombinase via the or promoters to cause cell-specific deletions of ( and mice, respectively). mice were phenotypically normal, arguing against a paracrine/autocrine AGT signaling mechanism for metabolic control. In contrast, mice exhibited reduced preweaning survival, and surviving adults exhibited altered renal structure and steroid flux, paralleling previous reports of animals with whole body deficiency or disruption in albumin ()-expressing cells (thought to cause liver-specific disruption). Surprisingly, adult mice exhibited normal circulating AGT protein and hepatic mRNA expression but reduced mRNA expression in adrenal glands. Reanalysis of RNA-sequencing data sets describing transcriptomes of normal adrenal glands suggests that and are both expressed in this tissue, and fluorescent reporter gene expression confirms Cre activity in adrenal gland of both -Cre and -Cre mice. These findings lead to the iconoclastic conclusion that extrahepatic (i.e., adrenal) expression of is critically required for normal renal development and survival.
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http://dx.doi.org/10.1152/ajpregu.00297.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272763PMC
May 2020

The Renin-Angiotensin System in the Central Nervous System and Its Role in Blood Pressure Regulation.

Curr Hypertens Rep 2020 01 10;22(1). Epub 2020 Jan 10.

Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.

Purpose Of The Review: The main goal of this article is to discuss how the development of state-of-the-art technology has made it possible to address fundamental questions related to how the renin-angiotensin system (RAS) operates within the brain from the neurophysiological and molecular perspective.

Recent Findings: The existence of the brain RAS remains surprisingly controversial. New sensitive in situ hybridization techniques and novel transgenic animals expressing reporter genes have provided pivotal information of the expression of RAS genes within the brain. We discuss studies using genetically engineered animals combined with targeted viral microinjections to study molecular mechanisms implicated in the regulation of the brain RAS. We also discuss novel drugs targeting the brain RAS that have shown promising results in clinical studies and trials. Over the last 50 years, several new physiological roles of the brain RAS have been identified. In the coming years, efforts to incorporate cutting-edge technologies such as optogenetics, chemogenetics, and single-cell RNA sequencing will lead to dramatic advances in our full understanding of how the brain RAS operates at molecular and neurophysiological levels.
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http://dx.doi.org/10.1007/s11906-019-1011-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101821PMC
January 2020

Left ventricular myocardial volume in CZT SPECT: Expanding the horizon?

Authors:
Javier Gomez

J Nucl Cardiol 2019 Dec 19. Epub 2019 Dec 19.

Division of Cardiology, John H. Stroger, Jr. Hospital of Cook County, 1901 W. Harrison St., Suite # 3620, Chicago, IL, 60612, USA.

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http://dx.doi.org/10.1007/s12350-019-01995-3DOI Listing
December 2019

Colombian Andean thermal springs: reservoir of thermophilic anaerobic bacteria producing hydrolytic enzymes.

Extremophiles 2019 Nov 25;23(6):793-808. Epub 2019 Sep 25.

Unidad de Saneamiento y Biotecnología Ambiental, Departamento de Biología, Pontificia Universidad Javeriana, 56710, Bogotá DC, Colombia.

Anaerobic cultivable microbial communities in thermal springs producing hydrolytic enzymes were studied. Thermal water samples from seven thermal springs located in the Andean volcanic belt, in the eastern and central mountain ranges of the Colombian Andes were used as inocula for the growth and isolation of thermophilic microorganisms using substrates such as starch, gelatin, xylan, cellulose, Tween 80, olive oil, peptone and casamino acids. These springs differed in temperature (50-70 °C) and pH (6.5-7.5). The predominant ion in eastern mountain range thermal springs was sulphate, whereas that in central mountain range springs was bicarbonate. A total of 40 anaerobic thermophilic bacterial strains that belonged to the genera Thermoanaerobacter, Caloramator, Anoxybacillus, Caloranaerobacter, Desulfomicrobium, Geotoga, Hydrogenophilus, Desulfacinum and Thermoanaerobacterium were isolated. To investigate the metabolic potential of these isolates, selected strains were analysed for enzymatic activities to identify strains than can produce hydrolytic enzymes. We demonstrated that these thermal springs contained diverse microbial populations of anaerobic thermophilic comprising different metabolic groups of bacteria including strains belonging to the genera Thermoanaerobacter, Caloramator, Anoxybacillus, Caloranaerobacter, Desulfomicrobium, Geotoga, Hydrogenophilus, Desulfacinum and Thermoanaerobacterium with amylases, proteases, lipases, esterases, xylanases and pectinases; therefore, the strains represent a promising source of enzymes with biotechnological potential.
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http://dx.doi.org/10.1007/s00792-019-01132-5DOI Listing
November 2019

A Curious Case of Coronary Vasospasm with Cardiogenic Shock: Type 1 Kounis Syndrome Complicated by Eosinophilic Myocarditis.

Cureus 2019 Apr 22;11(4):e4522. Epub 2019 Apr 22.

Cardiology, John H Stroger Jr. Hospital of Cook County, Chicago, USA.

Kounis syndrome is a rare but life-threatening form of coronary vasospasm, defined by the co-occurrence of acute coronary syndrome and hypersensitivity reaction. We present a case of refractory coronary vasospasm with aborted sudden cardiac arrest secondary to type 1 Kounis syndrome, which was complicated by eosinophilic myocarditis and cardiogenic shock. A 29-year-old Hispanic woman with history of vasospastic angina, presented with recurrent episodes of angina at rest. Initial evaluation revealed hyper-eosinophilia, elevated troponin and diffuse ST segment depression on electrocardiogram (ECG). Suddenly, she developed bradycardia and had a sudden cardiac arrest. An urgent coronary angiogram after resuscitation revealed severe multifocal vasospasm which resolved following high doses of intracoronary vasodilators. Type 1 Kounis syndrome was suspected and she was initiated on intravenous corticosteroids and anti-histamines. Subsequently, she developed cardiogenic shock, and a cardiac magnetic resonance imaging (cMRI) showed diffuse subendocardial late gadolinium enhancement (LGE) suggestive of eosinophilic myocarditis. She was diagnosed with type 1 Kounis syndrome associated with eosinophilic myocarditis. Kounis syndrome should be suspected in patients with refractory vasospastic angina. When indicated, coronary angiography should be performed with administration of intracoronary vasodilators for diagnostic and therapeutic purposes. Although, definite diagnosis of eosinophilic myocarditis requires endomyocardial biopsy, cMRI can be a crucial non-invasive method for establishing the diagnosis.
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http://dx.doi.org/10.7759/cureus.4522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590855PMC
April 2019

Assessment of myocardial viability using single-photon emission computed tomography myocardial perfusion imaging.

Curr Opin Cardiol 2019 09;34(5):473-483

Division of Cardiology, Cook County Health.

Purpose Of Review: The assessment of myocardial viability continues to be a pressing and sometimes challenging clinical question. Among other imaging modalities proven to be useful in the assessment of myocardial viability, single-photon emission computed tomography (SPECT) instrumentation and expertise continue to be the most widely available to the practicing physicians. Understanding the utility of SPECT myocardial perfusion imaging in this domain is an enduring need.

Recent Findings: A wealth of basic science and clinical data established the value of a variety of Tl-201 and Tc-99m SPECT protocols in the assessment of myocardial viability. The diagnostic performance for Tl-201 and Tc-99m imaging protocols for identifying viable myocardium is very good and is comparable for both agents. Quantitative assessment of radiotracer uptake can predict, in an objective manner, the probability of recovery of myocardial function following revascularization.

Summary: SPECT myocardial perfusion imaging with Tl-201 and Tc-99m tracers can provide an objective and quantifiable assessment of myocardial viability, which can help predict the likelihood of myocardial function recovery following coronary revascularization. Effective application of this imaging technique can guide clinical decision-making for coronary revascularization.
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http://dx.doi.org/10.1097/HCO.0000000000000646DOI Listing
September 2019

Prognostic value of regadenoson stress myocardial perfusion imaging in patients with left bundle branch block or ventricular paced rhythm.

J Nucl Cardiol 2019 May 29. Epub 2019 May 29.

Division of Cardiology, Cook County Health, 1901 W. Harrison St, Chicago, IL, 60612, USA.

Background: Vasodilator stress myocardial perfusion imaging (MPI) is the provocative test of choice in patients with left bundle branch block (LBBB) or ventricular paced (V-paced) rhythm. The prognostic value of regadenoson SPECT myocardial perfusion imaging (MPI) in these patients has not been studied.

Methods And Results: We conducted a retrospective cohort study of 562 patients [mean age, 69 ± 11 years; men, 53.3%] with LBBB (50.7%) or V-paced rhythm (49.3%) who underwent regadenoson stress SPECT-MPI. There were 321 (57.1%) subjects with abnormal MPI and 192 (34.2%) with myocardial ischemia. During a mean follow-up of 2.5 ± 1.9 years, 39 (6.9%) patients had a major adverse cardiac event (MACE), defined as cardiac death or myocardial infarction. The annualized MACE rate in patients with normal MPI was 0.9% (LBBB, 0.8%; V-paced, 1.0%). There was a significant stepwise increase in MACE rates with increasing burdens of perfusion abnormality (P < 0.001) and myocardial ischemia (P = 0.001). Increased risk with abnormal MPI [adjusted hazard ratio, 4.26; P = 0.001] and myocardial ischemia [adjusted hazard ratio, 2.70; P = 0.003] was independent of and incremental to important clinical covariates. Abnormal MPI and myocardial ischemia predicted MACE similarly in both LBBB and V-paced subgroups (interaction P values > 0.05).

Conclusion: In patients with LBBB and V-paced rhythm, regadenoson stress SPECT-MPI provides independent and incremental prognostic value in predicting adverse cardiac events.
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http://dx.doi.org/10.1007/s12350-019-01762-4DOI Listing
May 2019

Growth and Characterization of Irradiated Organoids from Mammary Glands.

J Vis Exp 2019 05 3(147). Epub 2019 May 3.

Department of Chemical and Biomolecular Engineering, Vanderbilt University; Department of Biomedical Engineering, Vanderbilt University; Department of Radiation Oncology, Vanderbilt University Medical Center;

Organoids derived from the digested tissue are multicellular three-dimensional (3D) constructs that better recapitulate in vivo conditions than cell monolayers. Although they cannot completely model in vivo complexity, they retain some functionality of the original organ. In cancer models, organoids are commonly used to study tumor cell invasion. This protocol aims to develop and characterize organoids from the normal and irradiated mouse mammary gland tissue to evaluate the radiation response in normal tissues. These organoids can be applied to future in vitro cancer studies to evaluate tumor cell interactions with irradiated organoids. Mammary glands were resected, irradiated to 20 Gy and digested in a collagenase VIII solution. Epithelial organoids were separated via centrifugal differentiation, and 3D organoids were developed in 96-well low-adhesion microplates. Organoids expressed the characteristic epithelial marker cytokeratin 14. Macrophage interaction with the organoids was observed in co-culture experiments. This model may be useful for studying tumor-stromal interactions, infiltration of immune cells, and macrophage polarization within an irradiated microenvironment.
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http://dx.doi.org/10.3791/59293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647833PMC
May 2019