Publications by authors named "Fernando Campos"

154 Publications

Glucocorticoid exposure predicts survival in female baboons.

Sci Adv 2021 Apr 21;7(17). Epub 2021 Apr 21.

Department of Biology, Duke University, Durham, NC 27708, USA.

Are differences in hypothalamic-pituitary-adrenal (HPA) axis activation across the adult life span linked to differences in survival? This question has been the subject of considerable debate. We analyze the link between survival and fecal glucocorticoid (GC) measures in a wild primate population, leveraging an unusually extensive longitudinal dataset of 14,173 GC measurements from 242 adult female baboons over 1634 female years. We document a powerful link between GCs and survival: Females with relatively high current GCs or high lifelong cumulative GCs face an elevated risk of death. A hypothetical female who maintained GCs in the top 90% for her age across adulthood would be expected to lose 5.4 years of life relative to a female who maintained GCs in the bottom 10% for her age. Hence, differences among individuals in HPA axis activity provide valuable prognostic information about disparities in life span.
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http://dx.doi.org/10.1126/sciadv.abf6759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059933PMC
April 2021

High social status males experience accelerated epigenetic aging in wild baboons.

Elife 2021 Apr 6;10. Epub 2021 Apr 6.

Department of Evolutionary Anthropology, Duke University, Durham, United States.

Aging, for virtually all life, is inescapable. However, within populations, biological aging rates vary. Understanding sources of variation in this process is central to understanding the biodemography of natural populations. We constructed a DNA methylation-based age predictor for an intensively studied wild baboon population in Kenya. Consistent with findings in humans, the resulting 'epigenetic clock' closely tracks chronological age, but individuals are predicted to be somewhat older or younger than their known ages. Surprisingly, these deviations are not explained by the strongest predictors of lifespan in this population, early adversity and social integration. Instead, they are best predicted by male dominance rank: high-ranking males are predicted to be older than their true ages, and epigenetic age tracks changes in rank over time. Our results argue that achieving high rank for male baboons - the best predictor of reproductive success - imposes costs consistent with a 'live fast, die young' life-history strategy.
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http://dx.doi.org/10.7554/eLife.66128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087445PMC
April 2021

Effects of Sodium Chloride-Rich Mineral Water on Intestinal Epithelium. Experimental Study.

Int J Environ Res Public Health 2021 03 22;18(6). Epub 2021 Mar 22.

Professional School of Medical Hydrology, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.

Since knowledge concerning the cellular and tissue substrate that explains the therapeutic action of mineral waters is generally very scarce, we address the different effects that Lanjarón-Capuchina mineral water exerts on the intestinal epithelium in an experimental model as a prototype of the sodium chloride-rich mineral waters used in digestive disorders. In the experimental protocol, two groups of five adult Wistar rats received unrestricted mineral water in their diet or mineral water directly into the gastrointestinal tract through a catheter. A third control group was given a standard diet and water ad libitum. Intestinal samples for scanning electron microscopy were analyzed according to standardized methods. The observations carried out by microscope after the administration of the sodium chloride-rich mineral water clearly indicate that the hypertonic action of this mineral water affects the structure of the intestinal epithelium. It modifies the microvilli absorption in terms of the groups of enterocytes and the secretion of goblet cells, but it particularly affects the epithelial renewal process, accelerating and stimulating cell extrusion. The type of extrusion mechanism observed by microscope allows us to affirm that, although this increased after direct administration, it does not generate an epithelial disruption as it occurs in other circumstances with other extrusion modalities.
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http://dx.doi.org/10.3390/ijerph18063261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004238PMC
March 2021

Ex Vivo Generation and Characterization of Human Hyaline and Elastic Cartilaginous Microtissues for Tissue Engineering Applications.

Biomedicines 2021 Mar 12;9(3). Epub 2021 Mar 12.

Department of Histology, Tissue Engineering Group, Faculty of Medicine, University of Granada, 18016 Granada, Spain.

Considering the high prevalence of cartilage-associated pathologies, low self-repair capacity and limitations of current repair techniques, tissue engineering (TE) strategies have emerged as a promising alternative in this field. Three-dimensional culture techniques have gained attention in recent years, showing their ability to provide the most biomimetic environment for the cells under culture conditions, enabling the cells to fabricate natural, 3D functional microtissues (MTs). In this sense, the aim of this study was to generate, characterize and compare scaffold-free human hyaline and elastic cartilage-derived MTs (HC-MTs and EC-MTs, respectively) under expansion (EM) and chondrogenic media (CM). MTs were generated by using agarose microchips and evaluated ex vivo for 28 days. The MTs generated were subjected to morphometric assessment and cell viability, metabolic activity and histological analyses. Results suggest that the use of CM improves the biomimicry of the MTs obtained in terms of morphology, viability and extracellular matrix (ECM) synthesis with respect to the use of EM. Moreover, the overall results indicate a faster and more sensitive response of the EC-derived cells to the use of CM as compared to HC chondrocytes. Finally, future preclinical in vivo studies are still needed to determine the potential clinical usefulness of these novel advanced therapy products.
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http://dx.doi.org/10.3390/biomedicines9030292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001313PMC
March 2021

Evaluation of the effectiveness of a new cryopreservation system based on a two-compartment vial for the cryopreservation of cell therapy products.

Cytotherapy 2021 Mar 10. Epub 2021 Mar 10.

Unidad de Producción y Reprogramación Celular, Red Andaluza Para el Diseño y Traslación de Terapias Avanzadas, Sevilla, Spain. Electronic address:

Background Aims: Successful cell cryopreservation and banking remain a major challenge for the manufacture of cell therapy products, particularly in relation to providing a hermetic, sterile cryovial that ensures optimal viability and stability post-thaw while minimizing exposure to toxic cryoprotective agents, typically dimethyl sulfoxide (MeSO).

Methods: In the present study, the authors evaluated the effectiveness and functionality of Limbo technology (Cellulis S.L., Santoña, Spain). This system provides a hermetic vial with two compartments (one for adding cells with the cryoprotective agent solution and the other for the diluent solution) and an automated defrosting device. Limbo technology (Cellulis S.L.) allows reduction of the final amount of MeSO, sidestepping washing and dilution steps and favoring standardization. The study was performed in several Good Manufacturing Practice laboratories manufacturing diverse cell therapy products (human mesenchymal stromal cells, hematopoietic progenitor cells, leukapheresis products, fibroblasts and induced pluripotent stem cells). Laboratories compared Limbo technology (Cellulis S.L.) with their standard cryopreservation procedure, analyzing cell recovery, viability, phenotype and functionality.

Results: Limbo technology (Cellulis S.L.) maintained the viability and functionality of most of the cell products and preserved sterility while reducing the final concentration of MeSO.

Conclusions: Results showed that use of Limbo technology (Cellulis S.L.) offers an overall safe alternative for cell banking and direct infusion of cryopreserved cell products into patients.
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http://dx.doi.org/10.1016/j.jcyt.2020.12.004DOI Listing
March 2021

Evaluation of Marine Agarose Biomaterials for Tissue Engineering Applications.

Int J Mol Sci 2021 Feb 15;22(4). Epub 2021 Feb 15.

Tissue Engineering Group, Department of Histology, University of Granada and Instituto de Investigación Biosanitaria ibs.GRANADA, E18016 Granada, Spain.

Five agarose types (D1LE, D2LE, LM, MS8 and D5) were evaluated in tissue engineering and compared for the first time using an array of analysis methods. Acellular and cellular constructs were generated from 0.3-3%, and their biomechanical properties, in vivo biocompatibility (as determined by LIVE/DEAD, WST-1 and DNA release, with = 6 per sample) and in vivo biocompatibility (by hematological and biochemical analyses and histology, with = 4 animals per agarose type) were analyzed. Results revealed that the biomechanical properties of each hydrogel were related to the agarose concentration ( < 0.001). Regarding the agarose type, the highest ( < 0.001) Young modulus, stress at fracture and break load were D1LE, D2LE and D5, whereas the strain at fracture was higher in D5 and MS8 at 3% ( < 0.05). All agaroses showed high biocompatibility on human skin cells, especially in indirect contact, with a correlation with agarose concentration ( = 0.0074 for LIVE/DEAD and = 0.0014 for WST-1) and type, although cell function tended to decrease in direct contact with highly concentrated agaroses. All agaroses were safe in vivo, with no systemic effects as determined by hematological and biochemical analysis and histology of major organs. Locally, implants were partially encapsulated and a pro-regenerative response with abundant M2-type macrophages was found. In summary, we may state that all these agarose types can be safely used in tissue engineering and that the biomechanical properties and biocompatibility were strongly associated to the agarose concentration in the hydrogel and partially associated to the agarose type. These results open the door to the generation of specific agarose-based hydrogels for definite clinical applications such as the human skin, cornea or oral mucosa.
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http://dx.doi.org/10.3390/ijms22041923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919481PMC
February 2021

HIIT Models in Addition to Training Load and Heart Rate Variability Are Related With Physiological and Performance Adaptations After 10-Weeks of Training in Young Futsal Players.

Front Psychol 2021 22;12:636153. Epub 2021 Jan 22.

Physical Effort Laboratory, Federal University of Santa Catarina, Florianópolis, Brazil.

Introduction: The present study aimed to investigate the effects of two high-intensity interval training (HIIT) shuttle-run-based models, over 10 weeks on aerobic, anaerobic, and neuromuscular parameters, and the association of the training load and heart rate variability (HRV) with the change in the measures in young futsal players.

Methods: Eleven young male futsal players (age: 18.5 ± 1.1 years; body mass: 70.5 ± 5.7 kg) participated in this study. This pre-post study design was performed during a typical 10 weeks training period. HIIT sessions were conducted at 86% (HIIT; = 6) and 100% (HIIT; = 5) of peak speed of the FIET. Additionally, friendly and official matches, technical-tactical and strength-power training sessions were performed. Before and after the training period, all players performed the FIET, treadmill incremental, repeated sprint ability (RSA), sprint 15-m, and vertical jump tests (CMJ and SJ), and the HRV was measured. Training load (TL) was monitored using the session rating of perceived effort. Data analysis was carried out using Bayesian inference methods.

Results: The HIIT model showed clear improvements for the peak oxygen uptake (VOpeak), peak speed in the treadmill incremental test, first and second ventilatory thresholds, RSA best and mean times, CMJ, and SJ. The HIIT model presented distinct advances in VOpeak, peak speed in the treadmill incremental test, RSA mean time, and CMJ. Between HIIT models comparisons showed more favorable probabilities of improvement for HIIT than HIIT model in all parameters. TL data and HIIT models strongly explained the changes in the RSA mean and best times ( = 0.71 and 0.87, respectively), as well as HRV changes, and HIIT models explained positively VOpeak changes ( = 0.72). All other changes in the parameters were low to moderately explained.

Conclusion: The HIIT proved to be more effective for improving aerobic, RSA, and neuromuscular parameters than HIIT during a typical 10-week futsal training period. So, strength and conditioning specialists prescribing shuttle-run intermittent exercises at submaximal intensities can manage the individual acceleration load imposed on athlete increasing or decreasing either the set duration or the frequency of change of direction during HIIT programming.
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http://dx.doi.org/10.3389/fpsyg.2021.636153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862135PMC
January 2021

Desmoplastic Small Round Cell Tumor: A Review of Main Molecular Abnormalities and Emerging Therapy.

Cancers (Basel) 2021 Jan 28;13(3). Epub 2021 Jan 28.

Department of Surgery, A.C.Camargo Cancer Center, Sao Paulo 01509-010, Brazil.

Desmoplastic small round cell tumor (DSRCT) is an extremely rare, aggressive sarcoma affecting adolescents and young adults with male predominance. Generally, it originates from the serosal surface of the abdominal cavity. The hallmark characteristic of DSRCT is the EWSR1-WT1 gene fusion. This translocation up-regulates the expression of PDGFRα, VEGF and other proteins related to tumor and vascular cell proliferation. Current management of DSRCT includes a combination of chemotherapy, radiation and aggressive cytoreductive surgery plus intra-peritoneal hyperthermic chemotherapy (HIPEC). Despite advances in multimodal therapy, outcomes remain poor since the majority of patients present disease recurrence and die within three years. The dismal survival makes DSRCT an orphan disease with an urgent need for new drugs. The treatment of advanced and recurrent disease with tyrosine kinase inhibitors, such as pazopanib, sunitinib, and mTOR inhibitors was evaluated by small trials. Recent studies using comprehensive molecular profiling of DSRCT identified potential therapeutic targets. In this review, we aim to describe the current studies conducted to better understand DSRCT biology and to explore the new therapeutic strategies under investigation in preclinical models and in early phase clinical trials.
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http://dx.doi.org/10.3390/cancers13030498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865637PMC
January 2021

Assessing the ability of substrate mapping techniques to guide ventricular tachycardia ablation using computational modelling.

Comput Biol Med 2021 Mar 11;130:104214. Epub 2021 Jan 11.

School of Biomedical Engineering and Imaging Sciences, Rayne Institute, 4th Floor, Lambeth Wing, St. Thomas' Hospital, Westminster Bridge Road, London, SE1 7EH, United Kingdom.

Background: Identification of targets for ablation of post-infarction ventricular tachycardias (VTs) remains challenging, often requiring arrhythmia induction to delineate the reentrant circuit. This carries a risk for the patient and may not be feasible. Substrate mapping has emerged as a safer strategy to uncover arrhythmogenic regions. However, VT recurrence remains common.

Goal: To use computer simulations to assess the ability of different substrate mapping approaches to identify VT exit sites.

Methods: A 3D computational model of the porcine post-infarction heart was constructed to simulate VT and paced rhythm. Electroanatomical maps were constructed based on endocardial electrogram features and the reentry vulnerability index (RVI - a metric combining activation (AT) and repolarization timings to identify tissue susceptibility to reentry). Since scar transmurality in our model was not homogeneous, parameters derived from all signals (including dense scar regions) were used in the analysis. Potential ablation targets obtained from each electroanatomical map during pacing were compared to the exit site detected during VT mapping.

Results: Simulation data showed that voltage cut-offs applied to bipolar electrograms could delineate the scar, but not the VT circuit. Electrogram fractionation had the highest correlation with scar transmurality. The RVI identified regions closest to VT exit site but was outperformed by AT gradients combined with voltage cut-offs. The performance of all metrics was affected by pacing location.

Conclusions: Substrate mapping could provide information about the infarct, but the directional dependency on activation should be considered. Activation-repolarization metrics have utility in safely identifying VT targets, even with non-transmural scars.
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http://dx.doi.org/10.1016/j.compbiomed.2021.104214DOI Listing
March 2021

Histological, Biomechanical, and Biological Properties of Genipin-Crosslinked Decellularized Peripheral Nerves.

Int J Mol Sci 2021 Jan 12;22(2). Epub 2021 Jan 12.

Tissue Engineering Group, Department of Histology, University of Granada, 18016 Granada, Spain.

Acellular nerve allografts (ANGs) represent a promising alternative in nerve repair. Our aim is to improve the structural and biomechanical properties of biocompatible Sondell (SD) and Roosens (RS) based ANGs using genipin (GP) as a crosslinker agent ex vivo. The impact of two concentrations of GP (0.10% and 0.25%) on Wistar rat sciatic nerve-derived ANGs was assessed at the histological, biomechanical, and biocompatibility levels. Histology confirmed the differences between SD and RS procedures, but not remarkable changes were induced by GP, which helped to preserve the nerve histological pattern. Tensile test revealed that GP enhanced the biomechanical properties of SD and RS ANGs, being the crosslinked RS ANGs more comparable to the native nerves used as control. The evaluation of the ANGs biocompatibility conducted with adipose-derived mesenchymal stem cells cultured within the ANGs confirmed a high degree of biocompatibility in all ANGs, especially in RS and RS-GP 0.10% ANGs. Finally, this study demonstrates that the use of GP could be an efficient alternative to improve the biomechanical properties of ANGs with a slight impact on the biocompatibility and histological pattern. For these reasons, we hypothesize that our novel crosslinked ANGs could be a suitable alternative for future in vivo preclinical studies.
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http://dx.doi.org/10.3390/ijms22020674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826762PMC
January 2021

Maternal death and offspring fitness in multiple wild primates.

Proc Natl Acad Sci U S A 2021 01;118(1)

Department of Biology, Duke University, Durham, NC 27708;

Primate offspring often depend on their mothers well beyond the age of weaning, and offspring that experience maternal death in early life can suffer substantial reductions in fitness across the life span. Here, we leverage data from eight wild primate populations (seven species) to examine two underappreciated pathways linking early maternal death and offspring fitness that are distinct from direct effects of orphaning on offspring survival. First, we show that, for five of the seven species, offspring face reduced survival during the years immediately preceding maternal death, while the mother is still alive. Second, we identify an intergenerational effect of early maternal loss in three species (muriquis, baboons, and blue monkeys), such that early maternal death experienced in one generation leads to reduced offspring survival in the next. Our results have important implications for the evolution of slow life histories in primates, as they suggest that maternal condition and survival are more important for offspring fitness than previously realized.
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http://dx.doi.org/10.1073/pnas.2015317118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821045PMC
January 2021

In vivo time-course biocompatibility assessment of biomagnetic nanoparticles-based biomaterials for tissue engineering applications.

Mater Sci Eng C Mater Biol Appl 2021 Jan 3;118:111476. Epub 2020 Sep 3.

Department of Histology, Tissue Engineering Group, Faculty of Medicine, University of Granada, Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain.

Novel artificial tissues with potential usefulness in local-based therapies have been generated by tissue engineering using magnetic-responsive nanoparticles (MNPs). In this study, we performed a comprehensive in vivo characterization of bioengineered magnetic fibrin-agarose tissue-like biomaterials. First, in vitro analyses were performed and the cytocompatibility of MNPs was demonstrated. Then, bioartificial tissues were generated and subcutaneously implanted in Wistar rats and their biodistribution, biocompatibility and functionality were analysed at the morphological, histological, haematological and biochemical levels as compared to injected MNPs. Magnetic Resonance Image (MRI), histology and magnetometry confirmed the presence of MNPs restricted to the grafting area after 12 weeks. Histologically, we found a local initial inflammatory response that decreased with time. Structural, ultrastructural, haematological and biochemical analyses of vital organs showed absence of damage or failure. This study demonstrated that the novel magnetic tissue-like biomaterials with improved biomechanical properties fulfil the biosafety and biocompatibility requirements for future clinical use and support the use of these biomaterials as an alternative delivery route for magnetic nanoparticles.
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http://dx.doi.org/10.1016/j.msec.2020.111476DOI Listing
January 2021

Generation of a novel human dermal substitute functionalized with antibiotic-loaded nanostructured lipid carriers (NLCs) with antimicrobial properties for tissue engineering.

J Nanobiotechnology 2020 Nov 23;18(1):174. Epub 2020 Nov 23.

Tissue Engineering Group, Department of Histology, Faculty of Medicine, University of Granada, Avenida de la Investigación 11, 18016, Granada, Spain.

Background: Treatment of patients affected by severe burns is challenging, especially due to the high risk of Pseudomonas infection. In the present work, we have generated a novel model of bioartificial human dermis substitute by tissue engineering to treat infected wounds using fibrin-agarose biomaterials functionalized with nanostructured lipid carriers (NLCs) loaded with two anti-Pseudomonas antibiotics: sodium colistimethate (SCM) and amikacin (AMK).

Results: Results show that the novel tissue-like substitutes have strong antibacterial effect on Pseudomonas cultures, directly proportional to the NLC concentration. Free DNA quantification, WST-1 and Caspase 7 immunohistochemical assays in the functionalized dermis substitute demonstrated that neither cell viability nor cell proliferation were affected by functionalization in most study groups. Furthermore, immunohistochemistry for PCNA and KI67 and histochemistry for collagen and proteoglycans revealed that cells proliferated and were metabolically active in the functionalized tissue with no differences with controls. When functionalized tissues were biomechanically characterized, we found that NLCs were able to improve some of the major biomechanical properties of these artificial tissues, although this strongly depended on the type and concentration of NLCs.

Conclusions: These results suggest that functionalization of fibrin-agarose human dermal substitutes with antibiotic-loaded NLCs is able to improve the antibacterial and biomechanical properties of these substitutes with no detectable side effects. This opens the door to future clinical use of functionalized tissues.
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http://dx.doi.org/10.1186/s12951-020-00732-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686763PMC
November 2020

Clinical Characteristics, Management, and Outcomes of 19 Nonpediatric Patients with Desmoplastic Small Round Cell Tumor: A Cohort of Brazilian Patients.

Sarcoma 2020 28;2020:8713165. Epub 2020 Oct 28.

Department of Medical Oncology, A. C. Camargo Cancer Center, São Paulo, SP, Brazil.

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive mesenchymal malignancy, usually affecting young males. There is no consensus on the best therapeutic approach. We seek to characterize a cohort of nonpediatric patients with DSRCT treated at a large Brazilian cancer center. We performed a retrospective analysis of patients with histologically confirmed DSRCT referred to our institution (2007-2020). Clinical and imaging data were extracted and summarized with descriptive statistics. Survival analyses were conducted by the Kaplan-Meier method and compared with the log-rank test. We included 19 patients with DSRCT, the median age at diagnosis was 26 years (range: 15-41 years), and 68% were male. Ninety percent presented with abdominopelvic masses, and 32% had extra-abdominal metastasis at diagnosis. Eleven patients (58%) underwent surgery, four patients (21%) received whole abdominal adjuvant radiotherapy, and five patients (26%) had hyperthermic intraperitoneal chemotherapy. Median OS was 27 months (interquartile range: 18-51 m). The five-year OS rate was 12%. Our data confirm the aggressiveness of DSRCT despite intense multimodality treatment. Outcomes of patients treated in a reference cancer center in a developing country are similar to cancer centers in developed nations. Multicenter cooperation is urgent to the development of clinical trials and to improve diagnosis and treatment efficacy.
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http://dx.doi.org/10.1155/2020/8713165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643375PMC
October 2020

Social bonds, social status and survival in wild baboons: a tale of two sexes.

Philos Trans R Soc Lond B Biol Sci 2020 11 21;375(1811):20190621. Epub 2020 Sep 21.

Department of Biology, Duke University, Durham, NC, USA.

People who are more socially integrated or have higher socio-economic status live longer. Recent studies in non-human primates show striking convergences with this human pattern: female primates with more social partners, stronger social bonds or higher dominance rank all lead longer lives. However, it remains unclear whether social environments also predict survival in male non-human primates, as it does in men. This gap persists because, in most primates, males disperse among social groups, resulting in many males who disappear with unknown fate and have unknown dates of birth. We present a Bayesian model to estimate the effects of time-varying social covariates on age-specific adult mortality in both sexes of wild baboons. We compare how the survival trajectories of both sexes are linked to social bonds and social status over the life. We find that, parallel to females, male baboons who are more strongly bonded to females have longer lifespans. However, males with higher dominance rank for their age appear to have shorter lifespans. This finding brings new understanding to the adaptive significance of heterosexual social bonds for male baboons: in addition to protecting the male's offspring from infanticide, these bonds may have direct benefits to males themselves. This article is part of the theme issue 'Evolution of the primate ageing process'.
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http://dx.doi.org/10.1098/rstb.2019.0621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540948PMC
November 2020

A comparison of dominance rank metrics reveals multiple competitive landscapes in an animal society.

Proc Biol Sci 2020 09 9;287(1934):20201013. Epub 2020 Sep 9.

Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.

Across group-living animals, linear dominance hierarchies lead to disparities in access to resources, health outcomes and reproductive performance. Studies of how dominance rank predicts these traits typically employ one of several dominance rank metrics without examining the assumptions each metric makes about its underlying competitive processes. Here, we compare the ability of two dominance rank metrics-simple ordinal rank and proportional or 'standardized' rank-to predict 20 traits in a wild baboon population in Amboseli, Kenya. We propose that simple ordinal rank best predicts traits when competition is density-dependent, whereas proportional rank best predicts traits when competition is density-independent. We found that for 75% of traits (15/20), one rank metric performed better than the other. Strikingly, all male traits were best predicted by simple ordinal rank, whereas female traits were evenly split between proportional and simple ordinal rank. Hence, male and female traits are shaped by different competitive processes: males are largely driven by density-dependent resource access (e.g. access to oestrous females), whereas females are shaped by both density-independent (e.g. distributed food resources) and density-dependent resource access. This method of comparing how different rank metrics predict traits can be used to distinguish between different competitive processes operating in animal societies.
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http://dx.doi.org/10.1098/rspb.2020.1013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542799PMC
September 2020

Social bonds do not mediate the relationship between early adversity and adult glucocorticoids in wild baboons.

Proc Natl Acad Sci U S A 2020 08 3;117(33):20052-20062. Epub 2020 Aug 3.

Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556;

In humans and other animals, harsh conditions in early life can have profound effects on adult physiology, including the stress response. This relationship may be mediated by a lack of supportive relationships in adulthood. That is, early life adversity may inhibit the formation of supportive social ties, and weak social support is itself often linked to dysregulated stress responses. Here, we use prospective, longitudinal data from wild baboons in Kenya to test the links between early adversity, adult social bonds, and adult fecal glucocorticoid hormone concentrations (a measure of hypothalamic-pituitary-adrenal [HPA] axis activation and the stress response). Using a causal inference framework, we found that experiencing one or more sources of early adversity led to a 9 to 14% increase in females' glucocorticoid concentrations across adulthood. However, these effects were not mediated by weak social bonds: The direct effects of early adversity on adult glucocorticoid concentrations were 11 times stronger than the effects mediated by social bonds. This pattern occurred, in part, because the effect of social bonds on glucocorticoids was weak compared to the powerful effects of early adversity on glucocorticoid levels in adulthood. Hence, in female baboons, weak social bonds in adulthood are not enough to explain the effects of early adversity on glucocorticoid concentrations. Together, our results support the well-established notions that early adversity and weak social bonds both predict poor adult health. However, the magnitudes of these two effects differ considerably, and they may act independently of one another.
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http://dx.doi.org/10.1073/pnas.2004524117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443977PMC
August 2020

Improving the regenerative microenvironment during tendon healing by using nanostructured fibrin/agarose-based hydrogels in a rat Achilles tendon injury model.

Bone Joint J 2020 Aug;102-B(8):1095-1106

Department of Histology (Tissue Engineering Group), University of Granada, Granada, Spain.

Aims: Achilles tendon injuries are a frequent problem in orthopaedic surgery due to their limited healing capacity and the controversy surrounding surgical treatment. In recent years, tissue engineering research has focused on the development of biomaterials to improve this healing process. The aim of this study was to analyze the effect of tendon augmentation with a nanostructured fibrin-agarose hydrogel (NFAH) or genipin cross-linked nanostructured fibrin-agarose hydrogel (GP-NFAH), on the healing process of the Achilles tendon in rats.

Methods: NFAH, GP-NFAH, and MatriDerm (control) scaffolds were generated (five in each group). A biomechanical and cell-biomaterial-interaction characterization of these biomaterials was then performed: Live/Dead Cell Viability Assay, water-soluble tetrazolium salt-1 (WST-1) assay, and DNA-released after 48 hours. Additionally, a complete section of the left Achilles tendon was made in 24 Wistar rats. Animals were separated into four treatment groups (six in each group): direct repair (Control), tendon repair with MatriDerm, or NFAH, or GP-NFAH. Animals were euthanized for further histological analyses after four or eight weeks post-surgery. The Achilles tendons were harvested and a histopathological analysis was performed.

Results: Tensile test revealed that NFAH and GP-NFAH had significantly higher overall biomechanical properties compared with MatriDerm. Moreover, biological studies confirmed a high cell viability in all biomaterials, especially in NFAH. In addition, in vivo evaluation of repaired tendons using biomaterials (NFAH, GP-NFAH, and MatriDerm) resulted in better organization of the collagen fibres and cell alignment without clinical complications than direct repair, with a better histological score in GP-NFAH.

Conclusion: In this animal model we demonstrated that NFAH and GP-NFAH had the potential to improve tendon healing following a surgical repair. However, future studies are needed to determine the clinical usefulness of these engineered strategies. Cite this article: 2020;102-B(8):1095-1106.
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http://dx.doi.org/10.1302/0301-620X.102B8.BJJ-2019-1143.R2DOI Listing
August 2020

Experimental determination of pesticide processing factors during extraction of seed oils.

Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2020 Sep 21;37(9):1491-1502. Epub 2020 Jul 21.

EU Vegetable Oil and Proteinmeal Industry Association (FEDIOL) , Brussels, Belgium.

Processing Factors (PFs) reflect the concentration or dilution of pesticide residues resulting from food processing. PFs are key elements to demonstrate the compliance of processed foods with Maximum residue levels (MRLs) as set by Regulation 396/2005. While efforts have been made by the European Food Safety Authority (EFSA) and by national authorities to compile PFs from processing studies, such PFs are not available for all pesticides/processed product combinations. The EU vegetable oil and proteinmeal industry association (FEDIOL) has therefore developed a theoretical approach to approximate MRLs in crude vegetable oils and fats, based on the partition coefficient (log P) of the pesticides and on the oil content of the raw materials. To substantiate this approach, a pilot-scale processing study was initiated with rapeseeds spiked with selected pesticides and the experimental PFs for these pesticides determined. The aims of this study were (i) to study the reliability of pilot-scale conditions for PF determination and (ii) to assess the experimental PFs obtained in comparison to the theoretical PFs proposed by FEDIOL. This study demonstrated that production yields obtained for crude oil and meal in this processing study are similar to those in industrial processes even if differences were observed in the individual production steps (mechanical or solvent extraction steps). The experimental PFs obtained confirmed that the chosen fat-soluble pesticides did concentrate in the oil fraction. For metalaxyl-M having a log P lower than 3, a partitioning between the oil and the meal was observed, as expected. By comparing the experimental PFs and theoretical PFs, it can be concluded that the FEDIOL approach can be recommended as a suitable tool when PFs derived from specific processing studies are missing. Similar studies on pesticides with wider ranges of log P are required in order to complete our conclusions on default PFs for vegetable oils.
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http://dx.doi.org/10.1080/19440049.2020.1778188DOI Listing
September 2020

Evaluation of Fibrin-Agarose Tissue-Like Hydrogels Biocompatibility for Tissue Engineering Applications.

Front Bioeng Biotechnol 2020 16;8:596. Epub 2020 Jun 16.

Department of Histology and Tissue Engineering Group, Faculty of Medicine, University of Granada, Granada, Spain.

Generation of biocompatible and biomimetic tissue-like biomaterials is crucial to ensure the success of engineered substitutes in tissue repair. Natural biomaterials able to mimic the structure and composition of native extracellular matrices typically show better results than synthetic biomaterials. The aim of this study was to perform an time-course biocompatibility analysis of fibrin-agarose tissue-like hydrogels at the histological, imagenological, hematological, and biochemical levels. Tissue-like hydrogels were produced by a controlled biofabrication process allowing the generation of biomechanically and structurally stable hydrogels. The hydrogels were implanted subcutaneously in 25 male Wistar rats and evaluated after 1, 5, 9, and 12 weeks of follow-up. At each period of time, animals were analyzed using magnetic resonance imaging (MRI), hematological analyses, and histology of the local area in which the biomaterials were implanted, along with major vital organs (liver, kidney, spleen, and regional lymph nodes). MRI results showed no local or distal alterations during the whole study period. Hematology and biochemistry showed some fluctuation in blood cells values and in some biochemical markers over the time. However, these parameters were progressively normalized in the framework of the homeostasis process. Histological, histochemical, and ultrastructural analyses showed that implantation of fibrin-agarose scaffolds was followed by a progressive process of cell invasion, synthesis of components of the extracellular matrix (mainly, collagen) and neovascularization. Implanted biomaterials were successfully biodegraded and biointegrated at 12 weeks without any associated histopathological alteration in the implanted zone or distal vital organs. In summary, our study suggests that fibrin-agarose tissue-like hydrogels could have potential clinical usefulness in engineering applications in terms of biosafety and biocompatibility.
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http://dx.doi.org/10.3389/fbioe.2020.00596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308535PMC
June 2020

Argentinian Digital Health Strategy.

Stud Health Technol Inform 2020 Jun;270:818-822

Ministry of Health, Argentina.

Digital Health is one of the three pillars for the effective implementation of Universal Health Coverage in Argentina. The Ministry of Health published the National Digital Health Strategy 2018-2024 in order to establish the conceptual guidelines for the design and development of interoperable health information systems as a state policy. The World Health Organization "National eHealth Strategy Toolkit", "Global Strategy on Digital Health" and other international and local evidence and expert recommendations were taken into account. The path to better healthcare involves adopting systems at the point of care, allowing for the primary recording of information and enabling information exchange through real interoperability. In that way, people, technology and processes will synergize to enhance integrated health service networks. In this paper, we describe the plan and the first two years of implementation of the strategy.
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http://dx.doi.org/10.3233/SHTI200275DOI Listing
June 2020

High mean entropy calculated from cardiac MRI texture analysis is associated with antitachycardia pacing failure.

Pacing Clin Electrophysiol 2020 07 21;43(7):737-745. Epub 2020 Jun 21.

Cardiology Department, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Background: Antitachycardia pacing (ATP), which may avoid unnecessary implantable cardioverter-defibrillator (ICD) shocks, does not always terminate ventricular arrhythmias (VAs). Mean entropy calculated using cardiac magnetic resonance texture analysis (CMR-TA) has been shown to predict appropriate ICD therapy. We examined whether scar heterogeneity, quantified by mean entropy, is associated with ATP failure and explore potential mechanisms using computer modeling.

Methods: A subanalysis of 114 patients undergoing CMR-TA where the primary endpoint was delivery of appropriate ICD therapy (ATP or shock therapy) was performed. Patients receiving appropriate ICD therapy (n = 33) were dichotomized into "successful ATP" versus "shock therapy" groups. In silico computer modeling was used to explore underlying mechanisms.

Results: A total of 16 of 33 (48.5%) patients had successful ATP to terminate VA, and 17 of 33 (51.5%) patients required shock therapy. Mean entropy was significantly higher in the shock versus successful ATP group (6.1 ± 0.5 vs 5.5 ± 0.7, P = .037). Analysis of patients receiving ATP (n = 22) showed significantly higher mean entropy in the six of 22 patients that failed ATP (followed by rescue ICD shock) compared to 16 of 22 that had successful ATP (6.3 ± 0.7 vs 5.5 ± 0.7, P = .048). Computer modeling suggested inability of the paced wavefront in ATP to successfully propagate from the electrode site through patchy fibrosis as a possible mechanism of failed ATP.

Conclusions: Our findings suggest lower scar heterogeneity (mean entropy) is associated with successful ATP, whereas higher scar heterogeneity is associated with more aggressive VAs unresponsive to ATP requiring shock therapy that may be due to inability of the paced wavefront to propagate through scar and terminate the VA circuit.
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http://dx.doi.org/10.1111/pace.13969DOI Listing
July 2020

Social determinants of health and survival in humans and other animals.

Science 2020 05;368(6493)

Social and Biological Determinants of Health Working Group, NC, USA.

The social environment, both in early life and adulthood, is one of the strongest predictors of morbidity and mortality risk in humans. Evidence from long-term studies of other social mammals indicates that this relationship is similar across many species. In addition, experimental studies show that social interactions can causally alter animal physiology, disease risk, and life span itself. These findings highlight the importance of the social environment to health and mortality as well as Darwinian fitness-outcomes of interest to social scientists and biologists alike. They thus emphasize the utility of cross-species analysis for understanding the predictors of, and mechanisms underlying, social gradients in health.
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http://dx.doi.org/10.1126/science.aax9553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398600PMC
May 2020

Differential impact of severe drought on infant mortality in two sympatric neotropical primates.

R Soc Open Sci 2020 Apr 1;7(4):200302. Epub 2020 Apr 1.

Department of Anthropology and Archaeology, University of Calgary, Calgary, AB, Canada.

Extreme climate events can have important consequences for the dynamics of natural populations, and severe droughts are predicted to become more common and intense due to climate change. We analysed infant mortality in relation to drought in two primate species (white-faced capuchins, and Geoffroy's spider monkeys, ) in a tropical dry forest in northwestern Costa Rica. Our survival analyses combine several rare and valuable long-term datasets, including long-term primate life-history, landscape-scale fruit abundance, food-tree mortality, and climate conditions. Infant capuchins showed a threshold mortality response to drought, with exceptionally high mortality during a period of intense drought, but not during periods of moderate water shortage. By contrast, spider monkey females stopped reproducing during severe drought, and the mortality of infant spider monkeys peaked later during a period of low fruit abundance and high food-tree mortality linked to the drought. These divergent patterns implicate differing physiology, behaviour or associated factors in shaping species-specific drought responses. Our findings link predictions about the Earth's changing climate to environmental influences on primate mortality risk and thereby improve our understanding of how the increasing severity and frequency of droughts will affect the dynamics and conservation of wild primates.
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http://dx.doi.org/10.1098/rsos.200302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211846PMC
April 2020

Evaluation of the optical and biomechanical properties of bioengineered human skin generated with fibrin-agarose biomaterials.

J Biomed Opt 2020 05;25(5):1-16

Univ. de Granada, Spain.

Significance: Recent generation of bioengineered human skin allowed the efficient treatment of patients with severe skin defects. However, the optical and biomechanical properties of these models are not known.

Aim: Three models of bioengineered human skin based on fibrin-agarose biomaterials (acellular, dermal skin substitutes, and complete dermoepidermal skin substitutes) were generated and analyzed.

Approach: Optical and biomechanical properties of these artificial human skin substitutes were investigated using the inverse adding-doubling method and tensile tests, respectively.

Results: The analysis of the optical properties revealed that the model that most resembled the optical behavior of the native human skin in terms of absorption and scattering properties was the dermoepidermal human skin substitutes after 7 to 14 days in culture. The time-course evaluation of the biomechanical parameters showed that the dermoepidermal substitutes displayed significant higher values than acellular and dermal skin substitutes for all parameters analyzed and did not differ from the control skin for traction deformation, stress, and strain at fracture break.

Conclusions: We demonstrate the crucial role of the cells from a physical point of view, confirming that a bioengineered dermoepidermal human skin substitute based on fibrin-agarose biomaterials is able to fulfill the minimal requirements for skin transplants for future clinical use at early stages of in vitro development.
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http://dx.doi.org/10.1117/1.JBO.25.5.055002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203517PMC
May 2020

Detergent-based decellularized peripheral nerve allografts: An in vivo preclinical study in the rat sciatic nerve injury model.

J Tissue Eng Regen Med 2020 06 22;14(6):789-806. Epub 2020 Apr 22.

Department of Histology, Tissue Engineering Group, Faculty of Medicine, University of Granada, Granada, Spain.

Nerve autograft is the gold standard technique to repair critical nerve defects, but efficient alternatives are needed. The present study evaluated the suitability of our novel Roosens-based (RSN) decellularized peripheral nerve allografts (DPNAs) in the repair of 10-mm sciatic nerve defect in rats at the functional and histological levels after 12 weeks. These DPNAs were compared with the autograft technique (AUTO) and Sondell (SD) or Hudson (HD) based DPNAs. Clinical and functional assessments demonstrated a partial regeneration in all operated animals. RSN-based DPNAs results were comparable with SD and HD groups and closely comparable with the AUTO group without significant differences (p > .05). Overall hematological studies confirmed the biocompatibility of grafted DPNAs. In addition, biochemistry revealed some signs of muscle affection in all operated animals. These results were confirmed by the loss of weight and volume of the muscle and by muscle histology, especially in DPNAs. Histology of repaired nerves confirmed an active nerve tissue regeneration and partial myelination along with the implanted grafts, being the results obtained with HD and RSN-based DPNAs comparable with the AUTO group. Finally, this in vivo study suggests that our novel RSN-based DPNAs supported a comparable tissue regeneration, along the 10-mm nerve gap, after 12-week follow-up to HD DPNAs, and both were superior to SD group and closely comparable with autograft technique. However, further improvements are needed to overcome the efficacy of the nerve autograft technique.
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http://dx.doi.org/10.1002/term.3043DOI Listing
June 2020

In vitro characterization of a novel magnetic fibrin-agarose hydrogel for cartilage tissue engineering.

J Mech Behav Biomed Mater 2020 04 9;104:103619. Epub 2020 Jan 9.

Instituto de Investigación Biosanitaria Ibs.GRANADA, Granada, Spain; Department of Histology & Tissue Engineering Group, Faculty of Medicine, University of Granada, Spain.

The encapsulation of cells into biopolymer matrices enables the preparation of engineered substitute tissues. Here we report the generation of novel 3D magnetic biomaterials by encapsulation of magnetic nanoparticles and human hyaline chondrocytes within fibrin-agarose hydrogels, with potential use as articular hyaline cartilage-like tissues. By rheological measurements we observed that, (i) the incorporation of magnetic nanoparticles resulted in increased values of the storage and loss moduli for the different times of cell culture; and (ii) the incorporation of human hyaline chondrocytes into nonmagnetic and magnetic fibrin-agarose biomaterials produced a control of their swelling capacity in comparison with acellular nonmagnetic and magnetic fibrin-agarose biomaterials. Interestingly, the in vitro viability and proliferation results showed that the inclusion of magnetic nanoparticles did not affect the cytocompatibility of the biomaterials. What is more, immunohistochemistry showed that the inclusion of magnetic nanoparticles did not negatively affect the expression of type II collagen of the human hyaline chondrocytes. Summarizing, our results suggest that the generation of engineered hyaline cartilage-like tissues by using magnetic fibrin-agarose hydrogels is feasible. The resulting artificial tissues combine a stronger and stable mechanical response, with promising in vitro cytocompatibility. Further research would be required to elucidate if for longer culture times additional features typical of the extracellular matrix of cartilage could be expressed by human hyaline chondrocytes within magnetic fibrin-agarose hydrogels.
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http://dx.doi.org/10.1016/j.jmbbm.2020.103619DOI Listing
April 2020

Expanded Differentiation Capability of Human Wharton's Jelly Stem Cells Toward Pluripotency: A Systematic Review.

Tissue Eng Part B Rev 2020 08 20;26(4):301-312. Epub 2020 Mar 20.

Tissue Engineering Group, Department of Histology, School of Medicine, University of Granada, Granada, Spain.

Human Wharton's jelly stem cells (HWJSC) can be efficiently isolated from the umbilical cord, and numerous reports have demonstrated that these cells can differentiate into several cell lineages. This fact, coupled with the high proliferation potential of HWJSC, makes them a promising source of stem cells for use in tissue engineering and regenerative medicine. However, their real potentiality has not been established to date. In the present study, we carried out a systematic review to determine the multilineage differentiation potential of HWJSC. After a systematic literature search, we selected 32 publications focused on the differentiation potential of these cells. Analysis of these studies showed that HWJSC display expanded differentiation potential toward some cell types corresponding to all three embryonic cell layers (ectodermal, mesodermal, and endodermal), which is consistent with their constitutive expression of key pluripotency markers such as OCT4, SOX2, and NANOG, and the embryonic marker SSEA4. We conclude that HWJSC can be considered cells in an intermediate state between multipotentiality and pluripotentiality, since their proliferation capability is not unlimited and differentiation to all cell types has not been demonstrated thus far. These findings support the clinical use of HWJSC for the treatment of diseases affecting not only mesoderm-type tissues but also other cell lineages. Impact statement Human Wharton's jelly stem cells (HWJSC) are mesenchymal stem cells that are easy to isolate and handle, and that readily proliferate. Their wide range of differentiation capabilities supports the view that these cells can be considered pluripotent. Accordingly, HWJSC are one of the most promising cell sources for clinical applications in advanced therapies.
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http://dx.doi.org/10.1089/ten.TEB.2019.0257DOI Listing
August 2020

Progressive dyspnea and a right atrial mass in an 80-year-old man.

Autops Case Rep 2019 Oct-Dec;9(4):e2019135. Epub 2019 Nov 27.

Universidade de São Paulo (USP), Medical School, Heart Institute, General Outpatient Clinics, Division of Clinical Cardiology. São Paulo, SP, Brazil.

Hepatocellular carcinoma (HCC) is among the five most frequent causes of cancer death worldwide, according to the WHO. The disease is related to alcohol abuse, viral infections, and other causes of cirrhosis, and unfortunately, in some developed countries, the incidence shows an increasing trend. Although the diagnosis of the HCC often relies upon the context of a chronic hepatopathy, some cases may present a silent course, and the initial symptoms ensue when the disease is in an advanced stage with no chance for any therapeutic attempt. The clinical picture of the HCC is varied, and unexpected forms may surprise the clinician. One of the unusual presentations of the HCC is shock by the blockage of the venous return to the right atrium by the inferior vena cava infiltration. Herein we present a case of an old patient who sought medical care complaining of dyspnea. The clinical workup disclosed a right thorax pleural effusion and imaging exams depicted a mass in the right hepatic lobe, invasion of the inferior vena cava (IVC) and the right atrium (RA). During the attempts of clinical investigation, the patient passed away. The autopsy disclosed an HCC involving the right hepatic lobe, with the invasion of the IVC and the RA. The authors highlight the importance of recognizing the bizarre presentation of not so rare diseases.
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http://dx.doi.org/10.4322/acr.2019.135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880769PMC
November 2019