bluuebunny/crossref_metadata_2025 huggingface dataset:
A Driver Never Works Alone—Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer
Authors: Grzes Maria , Oron Magdalena , Staszczak Zuzanna , Jaiswar Akanksha , Nowak-Niezgoda Magdalena , Walerych Dawid
Published: June 2020

The knowledge accumulating on the occurrence and mechanisms of the activation of oncogenes in human neoplasia necessitates an increasingly detailed understanding of their systemic interactions. None of the known oncogenic drivers work in isolation from the other oncogenic pathways. The cooperation between these pathways is an indispensable element of a multistep carcinogenesis, which apart from inactivation of tumor suppressors, always includes the activation of two or more proto-oncogenes. In this review we focus on representative examples of the interaction of major oncogenic drivers with one another. The drivers are selected according to the following criteria: (1) the highest frequency of known activation in human neoplasia (by mutations or otherwise), (2) activation in a wide range of neoplasia types (universality) and (3) as a part of a distinguishable pathway, (4) being a known cause of phenotypic addiction of neoplastic cells and thus a promising therapeutic target. Each of these universal oncogenic factors—mutant p53, KRAS and CMYC proteins, telomerase ribonucleoprotein, proteasome machinery, HSP molecular chaperones, NF-κB and WNT pathways, AP-1 and YAP/TAZ transcription factors and non-coding RNAs—has a vast network of molecular interrelations and common partners. Understanding this network allows for the hunt for novel therapeutic targets and protocols to counteract drug resistance in a clinical neoplasia treatment.
Modern Radiotherapy for Pediatric Brain Tumors
Authors: DeNunzio Nicholas J. , Yock Torunn I.
Published: June 2020

Cancer is a leading cause of death in children with tumors of the central nervous system, the most commonly encountered solid malignancies in this population. Radiotherapy (RT) is an integral part of managing brain tumors, with excellent long-term survival overall. The tumor histology will dictate the volume of tissue requiring treatment and the dose. However, radiation in developing children can yield functional deficits and/or cosmetic defects and carries a risk of second tumors. In particular, children receiving RT are at risk for neurocognitive effects, neuroendocrine dysfunction, hearing loss, vascular anomalies and events, and psychosocial dysfunction. The risk of these late effects is directly correlated with the volume of tissue irradiated and dose delivered and is inversely correlated with age. To limit the risk of developing these late effects, improved conformity of radiation to the target volume has come from adopting a volumetric planning process. Radiation beam characteristics have also evolved to achieve this end, as exemplified through development of intensity modulated photons and the use of protons. Understanding dose limits of critical at-risk structures for different RT modalities is evolving. In this review, we discuss the physical basis of the most common RT modalities used to treat pediatric brain tumors (intensity modulated radiation therapy and proton therapy), the RT planning process, survival outcomes for several common pediatric malignant brain tumor histologies, RT-associated toxicities, and steps taken to mitigate the risk of acute and late effects from treatment.
TP53 Status, Patient Sex, and the Immune Response as Determinants of Lung Cancer Patient Survival
Authors: Freudenstein Donald , Litchfield Cassandra , Caramia Franco , Wright Gavin , Solomon Benjamin J. , Ball David , Keam Simon P. , Neeson Paul , Haupt Ygal , Haupt Sue
Published: June 2020

Lung cancer poses the greatest cancer-related death risk and males have poorer outcomes than females, for unknown reasons. Patient sex is not a biological variable considered in lung cancer standard of care. Correlating patient genetics with outcomes is predicted to open avenues for improved management. Using a bioinformatics approach across non-small cell lung cancer (NSCLC) subtypes, we identified where patient sex, mutation of the major tumor suppressor gene, Tumour protein P53 (TP53), and immune signatures stratified outcomes in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), among datasets of The Cancer Genome Atlas (TCGA). We exposed sex and TP53 gene mutations as prognostic for LUAD survival. Longest survival in LUAD occurred among females with wild-type (wt) TP53 genes, high levels of immune infiltration and enrichment for pathway signatures of Interferon Gamma (INF-γ), Tumour Necrosis Factor (TNF) and macrophages-monocytes. In contrast, poor survival in men with LUAD and wt TP53 genes corresponded with enrichment of Transforming Growth Factor Beta 1 (TGFB1, hereafter TGF-β) and wound healing signatures. In LUAD with wt TP53 genes, elevated gene expression of immune checkpoint CD274 (hereafter: PD-L1) and also protein 53 (p53) negative-regulators of the Mouse Double Minute (MDM)-family predict novel avenues for combined immunotherapies. LUSC is dominated by male smokers with TP53 gene mutations, while a minor population of TCGA LC patients with wt TP53 genes unexpectedly had the poorest survival, suggestive of a separate etiology. We conclude that advanced approaches to LUAD and LUSC therapy lie in the consideration of patient sex, TP53 gene mutation status and immune signatures.
RAC1B Induces SMAD7 via USP26 to Suppress TGFβ1-Dependent Cell Migration in Mesenchymal-Subtype Carcinoma Cells
Authors: Ungefroren Hendrik , Kumarasinghe Anuradha , Musfeldt Melina , Fiedler Christian , Lehnert Hendrik , Marquardt Jens-Uwe
Published: June 2020

The small GTPase RAC1B has been shown to act as a powerful inhibitor of the transforming growth factor (TGF)β type I receptor ALK5 and TGFβ1/ALK5-induced epithelial–mesenchymal transition and cell motility. However, the precise mechanism has remained elusive. RNAi-mediated knockdown of RAC1B in the pancreatic ductal adenocarcinoma (PDAC)-derived cell line Panc1 failed to alter transcriptional activity from a transfected ALK5 promoter–reporter construct. In contrast, pharmacological inhibition of the proteasome decreased the abundance of ALK5 protein in cell lines of the mesenchymal subtype (Panc1, IMIM-PC-1, and breast cancer MDA-MB-231), but not in a PDAC cell line of the epithelial subtype (Colo357). Here, we focused on the inhibitory Smad protein, SMAD7, as a potential candidate for RAC1B-mediated inhibition of cell migration. In Panc1 cells devoid of RAC1B, SMAD7 protein was dramatically reduced and these cells were refractory to TGFβ1-induced upregulation of SMAD7 protein but not mRNA expression. Intriguingly, RNAi-mediated knockdown or ectopic overexpression of SMAD7 in Panc1 cells up- or downregulated, respectively, ALK5 protein expression and mimicked the suppressive effect of RAC1B on TGFβ/SMAD3-dependent transcriptional activity, target gene expression and cell migration. Transfection of SMAD7 was further able to partially rescue cells from the RAC1B knockdown-mediated increase in migratory properties. Conversely, knockdown of SMAD7 was able to partially rescue Panc1 and MDA-MB-231 cells from the antimigratory effect of ectopically expressed RAC1B. Finally, we demonstrate that RAC1B upregulation of SMAD7 protein requires intermittent transcriptional induction of the deubiquitinating enzyme USP26. Our data suggest that RAC1B induces SMAD7 by promoting its deubiquitination and establishes this Smad as one of RAC1B’s downstream effectors in negative regulation of ALK5 and TGFβ1-induced cell migration in mesenchymal-type carcinoma cells.
What Are Young Women Living Conditions after Breast Cancer? Health-Related Quality of Life, Sexual and Fertility Issues, Professional Reinsertion
Authors: Assogba Emerline L. F. , Mamguem Kamga Ariane , Costaz Helène , Jankowski Clémentine , Dumas Agnès , Roignot Patrick , Jolimoy Geneviève , Coutant Charles , Arveux Patrick , Dabakuyo-Yonli Tienhan Sandrine
Published: June 2020

In recent decades, the living conditions of young breast cancer (BC) survivors have garnered increasing attention. This population-based study aimed to identify the clinical, social and economic determinants of Health-Related Quality of Life (HRQoL), and to describe other living conditions of young long-term BC survivors. Women with non-metastatic BC diagnosed between 2006 and 2015, aged 45 years and younger at the time of diagnosis, were identified through the Breast and Gynecologic Cancer Registry of the Côte d’Or, France. Participants completed self-report questionnaires including standardized measures of HRQoL, anxiety, depression, social deprivation, social support and sexuality. Fertility and professional reintegration issues were also assessed. The determinants of HRQoL were identified using mixed regression model. In total, 218 BC survivors participated in the survey. The main determinants of poor HRQoL were anxiety, depression, comorbidities, social deprivation and menopausal status. Among 72% of women who did not receive information about fertility preservation, 38% of them would have liked to have been informed. Finally, 39% of survivors reported a negative impact of BC on their professional activity. This study showed that BC stage or treatments did not have an impact on HRQOL of young long-term BC survivors. Fertility, sexuality and professional reintegration remained the main concerns for survivors. Specific interventions in these population should focus on these issues.
Bimetallic Cu/Pt Oxygen Reduction Reaction Catalyst for Fuel Cells Cathode Materials
Authors: Alekseeva Elena , Stelmashuk Tatyana , Danilov Stepan , Yang Peixia , Levin Oleg
Published: June 2020

The oxygen reduction reaction (ORR) is a key process for the operation of fuel cells. To accelerate the sluggish kinetics of ORR, a wide range of catalysts have been proposed and tested. In this work, a nano-dispersed copper-impregnated platinum catalyst prepared by electrodeposition of platinum on a poly[Cu(Salen)] template followed by polymer destruction is described. In addition to the high activity of the thus prepared catalyst in the oxygen reduction reaction surpassing that of both polycrystalline platinum catalyst and the commercial carbon-platinum catalyst (“E-TEK”), it showed remarkable tolerance to the presence of methanol in solution.
Tracking of Infused Mesenchymal Stem Cells in Injured Pulmonary Tissue in Atm-Deficient Mice
Authors: Baer Patrick C. , Sann Julia , Duecker Ruth Pia , Ullrich Evelyn , Geiger Helmut , Bader Peter , Zielen Stefan , Schubert Ralf
Published: June 2020

Pulmonary failure is the main cause of morbidity and mortality in the human chromosomal instability syndrome Ataxia-telangiectasia (A-T). Major phenotypes include recurrent respiratory tract infections and bronchiectasis, aspiration, respiratory muscle abnormalities, interstitial lung disease, and pulmonary fibrosis. At present, no effective pulmonary therapy for A-T exists. Cell therapy using adipose-derived mesenchymal stromal/stem cells (ASCs) might be a promising approach for tissue regeneration. The aim of the present project was to investigate whether ASCs migrate into the injured lung parenchyma of Atm-deficient mice as an indication of incipient tissue damage during A-T. Therefore, ASCs isolated from luciferase transgenic mice (mASCs) were intravenously transplanted into Atm-deficient and wild-type mice. Retention kinetics of the cells were monitored using in vivo bioluminescence imaging (BLI) and completed by subsequent verification using quantitative real-time polymerase chain reaction (qRT-PCR). The in vivo imaging and the qPCR results demonstrated migration accompanied by a significantly longer retention time of transplanted mASCs in the lung parenchyma of Atm-deficient mice compared to wild type mice. In conclusion, our study suggests incipient damage in the lung parenchyma of Atm-deficient mice. In addition, our data further demonstrate that a combination of luciferase-based PCR together with BLI is a pivotal tool for tracking mASCs after transplantation in models of inflammatory lung diseases such as A-T.
Lysophosphatidic Acid Receptor 5 Plays a Pathogenic Role in Brain Damage after Focal Cerebral Ischemia by Modulating Neuroinflammatory Responses
Authors: Sapkota Arjun , Lee Chi-Ho , Park Se Jin , Choi Ji Woong
Published: June 2020

Receptor-mediated lysophosphatidic acid (LPA) signaling has come to be considered an important event for various diseases. In cerebral ischemia, LPA1 has recently been identified as a receptor subtype that mediates brain injury, but the roles of other LPA receptor subtypes remain unknown. Here, we investigated the potential role of LPA5 as a novel pathogenic factor for cerebral ischemia using a mouse model of transient middle cerebral artery occlusion (tMCAO). LPA5 was upregulated in the ischemic core region after tMCAO challenge, particularly in activated microglia. When TCLPA5, a selective LPA5 antagonist, was given to tMCAO-challenged mice immediately after reperfusion, brain damage, including brain infarction, functional neurological deficit, and neuronal and non-neuronal apoptosis, was reduced in mice. Similarly, delayed TCLPA5 administration (at three hours after reperfusion) reduced brain infarction and neurological deficit. The histological results demonstrated that TCLPA5 administration attenuated microglial activation, as evidenced by the decreased Iba1 immunoreactivities, the number of amoeboid cells, and proliferation in an injured brain. TCLPA5 administration also attenuated the upregulation of the expression of pro-inflammatory cytokines at mRNA levels in post-ischemic brain, which was also observed in lipopolysaccharide-stimulated BV2 microglia upon LPA5 knockdown. Overall, this study identifies LPA5 as a novel pathogenic factor for cerebral ischemia, further implicating it as a promising target for drug development to treat this disease.
Oxidative Stress Induces a VEGF Autocrine Loop in the Retina: Relevance for Diabetic Retinopathy
Authors: Rossino Maria Grazia , Lulli Matteo , Amato Rosario , Cammalleri Maurizio , Dal Monte Massimo , Casini Giovanni
Published: June 2020

Background: Oxidative stress (OS) plays a central role in diabetic retinopathy (DR), triggering expression and release of vascular endothelial growth factor (VEGF), the increase of which leads to deleterious vascular changes. We tested the hypothesis that OS-stimulated VEGF induces its own expression with an autocrine mechanism. Methods: MIO-M1 cells and ex vivo mouse retinal explants were treated with OS, with exogenous VEGF or with conditioned media (CM) from OS-stressed cultures. Results: Both in MIO-M1 cells and in retinal explants, OS or exogenous VEGF induced a significant increase of VEGF mRNA, which was abolished by VEGF receptor 2 (VEGFR-2) inhibition. OS also caused VEGF release. In MIO-M1 cells, CM induced VEGF expression, which was abolished by a VEGFR-2 inhibitor. Moreover, the OS-induced increase of VEGF mRNA was abolished by a nuclear factor erythroid 2-related factor 2 (Nrf2) blocker, while the effect of exo-VEGF resulted Nrf2-independent. Finally, both the exo-VEGF- and the OS-induced increase of VEGF expression were blocked by a hypoxia-inducible factor-1 inhibitor. Conclusions: These results are consistent with the existence of a retinal VEGF autocrine loop triggered by OS. This mechanism may significantly contribute to the maintenance of elevated VEGF levels and therefore it may be of central importance for the onset and development of DR.
Vitamin D3 Ameliorates DNA Damage Caused by Developmental Exposure to Endocrine Disruptors in the Uterine Myometrial Stem Cells of Eker Rats
Authors: Elkafas Hoda , Ali Mohamed , Elmorsy Engy , Kamel Rehab , Thompson Winston E. , Badary Osama , Al-Hendy Ayman , Yang Qiwei
Published: June 2020

Early-life exposure of the myometrium to endocrine-disrupting chemicals (EDCs) has been shown to increase the risk of uterine fibroid (UF) prevalence in adulthood. Vitamin D3 (VitD3) is an unique, natural compound that may reduce the risk of developing UFs. However, little is known about the role and molecular mechanism of VitD3 on exposed myometrial stem cells (MMSCs). We investigated the role and molecular mechanism underlying VitD3 action on DNA damage response (DDR) defects in rat MMSCs due to developmental exposure to diethylstilbestrol (DES), with the additional goal of understanding how VitD3 decreases the incidence of UFs later in life. Female newborn Eker rats were exposed to DES or a vehicle early in life; they were then sacrificed at 5 months of age (pro-fibroid stage) and subjected to myometrial Stro1+/CD44+ stem cell isolation. Several techniques were performed to determine the effect of VitD3 treatment on the DNA repair pathway in DES-exposed MMSCs (DES-MMSCs). Results showed that there was a significantly reduced expression of RAD50 and MRE11, key DNA repair proteins in DES-exposed myometrial tissues, compared to vehicle (VEH)-exposed tissues (p < 0.01). VitD3 treatment significantly decreased the DNA damage levels in DES-MMSCs. Concomitantly, the levels of key DNA damage repair members, including the MRN complex, increased in DES-MMSCs following treatment with VitD3 (p < 0.01). VitD3 acts on DNA repair via the MRN complex/ATM axis, restores the DNA repair signaling network, and enhances DDR. This study demonstrates, for the first time, that VitD3 treatment attenuated the DNA damage load in MMSCs exposed to DES and classic DNA damage inducers. Moreover, VitD3 targets primed MMSCs, suggesting a novel therapeutic approach for the prevention of UF development.
Women’s Perceptions about Breastfeeding: A Preliminary Study
Authors: Obeng Cecilia , Dickinson Stephanie , Golzarri-Arroyo Lilian
Published: June 2020

Background: Breastfeeding rates are low in many communities in the United States and require attention to come up with ideas that will help increase breastfeeding. This study investigated the effects of income, age, race and education on mothers’ perceptions about breastfeeding and whose needs and views should be considered in a women’s breastfeeding journey. Methods: A survey was distributed via email and Facebook to 525 participants; 453 participants (86.3%) responded to the survey. Results: Younger adults were more likely to agree that fathers should have some say about breastfeeding. Those earning USD 0–USD 50,000 were more likely to agree relative to those with higher incomes on children being entitled to mother’s milk, and children’s needs over-riding those of others. There was a statistically significant difference by education about women's wishes about breastfeeding being considered more important than those of their spouses. However, there was no statistically significant difference for any demographic group for breastfeeding decisions coming from women only. On women’s breasts being primarily for infant's nutrition, people who earned USD 0–USD 50,000 were more likely to agree relative to those who earned more than USD 50,000; younger adults were significantly more likely to agree. Those who earned USD 0–USD 50,000 were more likely to agree relative to those in other income brackets that extended family members should have input regarding babies being breastfed; minority participants were significantly more likely to agree relative to white participants; those with less than 4-year college education were more likely to agree relative to those with a minimum of four-year college education. Younger adults were more likely to agree that employers must provide extended maternity leave to make it easier for mothers to breastfeed. On women having the right to breastfeed in public places, younger adults were significantly more likely to agree compared to older adults. Conclusion: Women have favorable views about breastfeeding and prefer being in charge about decisions to breastfeed.
Synthesis of Molybdenum Blue Dispersions Using Ascorbic Acid as Reducing Agent
Authors: Gavrilova Natalia , Myachina Maria , Harlamova Daria , Nazarov Victor
Published: June 2020

Stable molybdenum blue nanoparticles dispersions were synthesized using ammonium heptamolybdate and ascorbic acid. The effect of molar ratios of reducing agent/Mo and acid/Mo on the speed of formation and stability of the disperse system has been demonstrated. The particles were characterized by UV/vis, infrared (FTIR), nuclear magnetic resonance (NMR) spectroscopy, and dynamic light scattering (DLS) methods. The X-ray photoelectron spectroscopy (XPS) method confirmed the presence of reduced MoV in the structure of molybdenum oxide nanoclusters, the proportion of which was 30%.
Security and Performance of Single Sign-on Based on One-Time Pad Algorithm
Authors: Kihara Maki , Iriyama Satoshi
Published: June 2020

Single sign-on (SSO) techniques allow access control for multiple systems with a single login. The aim of our study is to construct an authentication algorithm that provides the authentication information of a user to a requester without requiring any specific token, thereby achieving domain-free access control. In this study, we propose an authentication algorithm for SSO based on a verifiable encryption (VE)-based authentication algorithm and implementation. VE is a kind of cryptosystem that allows calculation on cyphertexts, generating an encrypted result, which matches the distance between two plaintexts when decrypting. In our approach, we first construct the mathematical SSO algorithm based on the VE-based algorithm, and then implement the algorithm by applying the one-time pad to the algorithm and using sample data. We also consider robustness against theoretical attacks such as man-in-the-middle attack. In addition to that, our algorithm is robust against the well-known classical and theoretical attacks, the man-in-the-middle attack against the proposed algorithm is also impracticable. Furthermore, with security analysis using Proverif, the algorithm has been shown to be secure. The execution speed is less than 1 ms even with a text length of 8192 bits. Based on our results, it is evident that the computational burden of trusted third parties, such as a certificate authority, can be alleviated because the public key agreement is not required in our algorithm. Moreover, since only the authentication information is disclosed to the service provider, big tech such as GAFA cannot obtain personal information of the user without consent. As for the originality of our algorithm, any personal information, such as biometric information and non-contact magnetic IC cards in addition to the pair of ID and password, which is used for common SSO algorithms, is available.
Patterns of Distribution of Phoretic Deutonymphs of Uropodina on Longhorn Beetles in Białowieża Primeval Forest, Central Europe
Authors: Konwerski Szymon , Gutowski Jerzy M. , Błoszyk Jerzy
Published: June 2020

We studied the distributional patterns of phoretic deutonymphs of the genera Oodinychus and Trichouropoda (Uropodina) on the longhorn beetles Monochamus sartor urussovii, Plagionotus detritus, Tetropium castaneum, and Te. fuscum, based on large samples of specimens (992 beetles and 25,587 mites) collected in the Białowieża Primeval Forest in Central Europe in the years 2008 and 2012–2016. All the studied phoretic phoront-host associations are characterized by different patterns of the attachment sites of mites on beetle’s body. In the case of O. ovalis and M. sartor urussovii association, the deutonymphs were found mostly on the pronotum and dorsal surface of the elytra. This is the only instance in which phoronts were absent on the legs. Deutonymphs of T. sociata on P. detritus preferred the abdomnen (both tergites and ventrites) and the hindlegs. Only in this case the phoronts were attached inside the subelytral space. The highest number of deutonymphs of T. shcherbakae on both Tetropium species occured on the legs. In the case of Te. castaneum, similar proportions of mites were recorded on all pairs of legs, while the preferred location of mites phoretic on Te. fuscum were the forelegs. Both the preferences of phoretic deutonymphs for specific parts of the host’s body and the participation of carriers transporting deutonymphs on particular parts of their bodies were very consistent.
How Does the Sexual Reproduction of Marine Life Respond to Ocean Acidification?
Authors: Olischläger Mark , Wild Christian
Published: June 2020

Recent research indicates that synchronicity of sexual reproduction in coral spawning events is breaking down, leading to aging populations and decreased recruitment success. In this perspective, we develop a hypothesis that this phenomenon could be caused by ongoing ocean acidification (OA). We hypothesize, that the underlying physiological machinery could be the carbon concentrating mechanism (CCM). The endosymbiotic zooxanthellae of corals could use this mechanism to sense calm water motion states in a comparable way to that known from macroalgae. In macroalgae, it is well-established that dissolved inorganic carbon (DIC) acts as the trigger for signaling low water motion. Hence, evolutionarily developed signals of low water motion, suited for gamete-release, may be misleading in the future, potentially favoring opportunistic species in a broad range of marine organisms.
Crustacea Decapoda from the Rhodes Island Area (Eastern Mediterranean): New Records and an Updated Checklist
Authors: Kondylatos Gerasimos , Crocetta Fabio , Corsini-Foka Maria , Froglia Carlo
Published: June 2020

Decapod crustaceans are ecologically and commercially important members of marine communities. Faunal surveys constitute essential tools for the understanding of local diversity, especially in areas subjected to significant alterations of community composition due to climate changes, anthropogenic impacts, and biological invasions. Following a literature review and the study of new samples, we hereby update on the Crustacea Decapoda from the Rhodes Island area (Greece), situated in a key position in the eastern Mediterranean Sea. Published data yielded records of 120 species, whereas 28 taxa are recorded here for the first time from the study area. Among them, the collection of Liocarcinus bolivari widens its distribution to the eastern Mediterranean. Details on material examined and distributional/faunal remarks are provided for the species newly recorded and for some other native and alien species rarely reported from Rhodes. The present paper raises the local decapod biodiversity to 148 species, accounting for ~50% of the Hellenic Aegean decapod fauna and provides a useful baseline for analysing the long-term changes in the local fauna and the westward spreading of Lessepsian species. Despite present advances, the lack of records of many common Mediterranean species may be still due to limited fieldwork in some habitats rather than a true absence.
CTLA-4 Expression Plays a Role in PSC and PBC Progression
Authors: Meister Phil , Steinke-Ramming Christian , Beste Mechthild , Lenzen Henrike , Gerken Guido , Canbay Ali , Jochum Christoph
Published: June 2020

Background & Aims: The pathogenesis of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) remains unclear. The aim of this study was to reveal certain single nucleotide polymorphisms (SNP) in genes for regulatory proteins in the immunologic pathway possibly going along with susceptibility of attaining PBC or PSC. Methods: 126 patients with either PBC or PSC with clinical and laboratory data were enrolled in the study. SNPs in three genes (CTLA-4, ICOS, and FOX-P3) which are suspected to play a key role in the autoimmune pathway were analyzed to determine allele variants. Gene expression was measured by RealTime PCR using mRNA. Results: Patients with cirrhosis had a lower number of CTLA-4 copies than patients without cirrhosis (p = 0.04). Accordingly, patients with lower CTLA-4 copies had a poorer recovery of gamma-glutamyltransferase (GGT) in course of their disease (−69.8 U/l vs. −176.1 U/l p = 0.04). Two SNP allele variants (CTLA4 rs733618 and FOXP3 rs2280883) associated with low CTLA-4 expression could be determined. Patients having both variants showed worsening of GGT (−61.7 U/l vs. −132.6 U/l, p = 0.04) and a trend towards a more progressive disease in terms of cirrhosis. (24% vs. 13% p = ns). Conclusions: Low expression of CTLA-4 is associated with a more advanced disease in patients with PBC and PSC. Furthermore, we identified two SNP allele variants (CTLA4-SNP rs733618 and FOXP3-SNP rs2280883) associated with a lower CTLA-4 expression and possibly a more severe course of the diseases. Taken together, these results provide further evidence for the involvement of the immune system in the pathogenesis of these two cholestatic liver diseases. Lay summary: Primary biliary cholangitis and primary sclerosing cholangitis are chronic diseases of the bile ducts. Their cause remains widely unclear, but evidence suggests the immune system plays a central role. This study shows that gene alterations connected to the immune system might play a role in the course of the disease.
Psychosocial and Financial Burden of Therapy in USA Patients with Pulmonary Arterial Hypertension
Authors: Helgeson Scott A. , Menon Divya , Helmi Haytham , Vadlamudi Charitha , Moss John E. , Zeiger Tonya K. , Burger Charles D.
Published: June 2020

Pulmonary arterial hypertension (PAH) is a devastating disease with significant morbidity and mortality. There are many psychosocial and financial implications of this disease; however, little is known how this affects the treatment of PAH patients. A questionnaire-based prospective cohort study was performed on 106 PAH patients from a Pulmonary Hypertension Center and the Pulmonary Hypertension Association national conference in 2018. The demographic, treatment, psychosocial, employment, financial impact on treatment data was obtained. The majority of patients had cardiopulmonary symptoms despite treatment. The symptoms affected their social and work lives, with about one in three applying for disability because of their PAH. The majority of PAH patients had insurance coverage, but still noted a significant financial burden of the disease, with nearly a half who needed financial assistance to pay for their PAH medications. Thirty (28.3%; 95% CI, 20.6–37.5%) patients mentioned they changed their medication regimen, with some skipping doses outright (28 [26.4%; 95% CI, 19–35.6%]) in order to save money. PAH continues to cause significant psychosocial and financial burden on patients despite advances in medications. This impact ranged from dissatisfaction with quality of life, to unemployment, to altering their medication regimen to save money.
Depression and Obesity: Analysis of Common Biomarkers
Authors: Milano Walter , Ambrosio Paola , Carizzone Francesca , De Biasio Valeria , Di Munzio Walter , Foia Maria Gabriella , Capasso Anna
Published: June 2020

Depression and obesity are very common pathologies. Both cause significant problems of both morbidity and mortality and have decisive impacts not only on the health and well-being of patients, but also on socioeconomic and health expenditure aspects. Many epidemiological studies, clinical studies and meta-analyses support the association between mood disorders and obesity in relationships to different conditions such as the severity of depression, the severity of obesity, gender, socioeconomic status, genetic susceptibility, environmental influences and adverse experiences of childhood. Currently, both depression and obesity are considered pathologies with a high-inflammatory impact; it is believed that several overlapping factors, such as the activation of the cortico-adrenal axis, the exaggerated and prolonged response of the innate immune system and proinflammatory cytokines to stress factors and pathogens—as well as alterations of the intestinal microbiota which promote intestinal permeability—can favor the expression of an increasingly proinflammatory phenotype that can be considered a key and common phenomenon between these two widespread pathologies. The purpose of this literature review is to evaluate the common and interacting mechanisms between depression and obesity.
Endoreversible Models for the Thermodynamics of Computing
Authors: De Vos Alexis
Published: June 2020

Landauer’s principle says that, in principle, a computation can be performed without consumption of work, provided no information is erased during the computational process. This principle can be introduced into endoreversible models of thermodynamics.
Stochastic Modeling of the Levelized Cost of Electricity for Solar PV
Authors: Lee Chul-Yong , Ahn Jaekyun
Published: June 2020

With the development of renewable energy, a key measure for reducing greenhouse gas emissions, interest in the levelized cost of electricity (LCOE) is increasing. Although the input variables used in the LCOE calculation, such as capacity factor, capital expenditure, annual power plant operations and maintenance cost, discount and interest rate, and economic life, vary according to region and project, most existing studies estimate the LCOE by using a deterministic methodology. In this study, the stochastic approach was used to estimate the LCOE for solar photovoltaic (PV) in South Korea. In addition, this study contributed to deriving realistic analysis results by securing the actual data generated in the solar PV project compared to the existing studies. The results indicate that the LCOE for commercial solar power ranged from KRW 115 (10 cents)/kWh to KRW 197.4 (18 cents)/kWh at a confidence level of 95%. The median was estimated at KRW 160.03 (15 cents)/kWh. The LCOE for residential solar power ranged from KRW 109.7 (10 cents)/kWh to KRW 194.1 (18 cents)/kWh at a 95% confidence level and a median value of KRW 160.03 (15 cents)/kWh. A sensitivity analysis shows that capital expenditure has the most significant impact on the LCOE for solar power, followed by the discount rate and corporate tax. This study proposes that policymakers implement energy policies to reduce solar PV hardware and soft costs.
Cyclic Performance of RC Columns with Inadequate Lap Splices Strengthened with CFRP Jackets
Authors: Kalogeropoulos George , Tsonos Alexander-Dimitrios
Published: June 2020

The cyclic performance of non-seismically designed reinforced concrete (RC) columns, strengthened with carbon fiber reinforced polymer (CFRP) jackets, was analytically and experimentally investigated herein. Three cantilever column specimens were constructed, incorporating design parameters of the period 1950s–1970s, namely with concrete of a low compressive strength, plain steel bars, widely-spaced ties and inadequate lap splices of reinforcement. The specimens were strengthened using CFRP jackets and were subsequently subjected to cyclic inelastic lateral displacements. The main parameters examined were the length of the lap splices, the acceptable relative bar slipping value and the width of the jackets. The hysteresis behaviors of the enhanced columns were compared, while also being evaluated with respect to those of two original columns and to the seismic performance of a control specimen with continuous reinforcement, tested in a previous work. An analytical formulation was proposed for accurately predicting the seismic responses of the column specimens, comparing the actual shear stress value with the ultimate shear capacity of the concrete in the lap splice region. The test results verified the predictions of the analytical model, regarding the seismic performance of the strengthened columns. Moreover, the influences of the examined parameters in securing the ductile hysteresis performance were evaluated.
Continuous Project-Based Learning in Fluid Mechanics and Hydraulic Engineering Subjects for Different Degrees
Authors: Pérez-Sánchez Modesto , López-Jiménez P. Amparo
Published: June 2020

Subjects related to fluid mechanics for hydraulic engineers ought to be delivered in interesting and active modes. New methods should be introduced to improve the learning students’ abilities in the different courses of the Bachelor’s and Master’s degree. Related to active learning methods, a continuous project-based learning experience is described in this research. This manuscript shows the developed learning methodology, which was included on different levels at Universitat Politècnica de València. The main research goal is to show the active learning methods used to evaluate both skills competences (e.g., “Design and Project”) and specific competences of the students. The research shows a particular developed innovation teaching project, which was developed by lecturers and professors of the Hydraulic Engineering Department, since 2016. This project proposed coordination in different subjects that were taught in different courses of the Bachelor’s and Master’s degrees, in which 2200 students participated. This coordination improved the acquisition of the learning results, as well as the new teaching methods increased the student’s satisfaction index.
Preimplantation Genetic Testing for Polygenic Disease Relative Risk Reduction: Evaluation of Genomic Index Performance in 11,883 Adult Sibling Pairs
Authors: Treff Nathan R. , Eccles Jennifer , Marin Diego , Messick Edward , Lello Louis , Gerber Jessalyn , Xu Jia , Tellier Laurent C.A.M.
Published: June 2020

Preimplantation genetic testing for polygenic disease risk (PGT-P) represents a new tool to aid in embryo selection. Previous studies demonstrated the ability to obtain necessary genotypes in the embryo with accuracy equivalent to in adults. When applied to select adult siblings with known type I diabetes status, a reduction in disease incidence of 45–72% compared to random selection was achieved. This study extends analysis to 11,883 sibling pairs to evaluate clinical utility of embryo selection with PGT-P. Results demonstrate simultaneous relative risk reduction of all diseases tested in parallel, which included diabetes, cancer, and heart disease, and indicate applicability beyond patients with a known family history of disease.
Nucleophosmin 1 Mutations in Acute Myeloid Leukemia
Authors: Zarka Jabra , Short Nicholas J. , Kanagal-Shamanna Rashmi , Issa Ghayas C.
Published: June 2020

Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein involved in ribosome biogenesis, the maintenance of genomic integrity and the regulation of the ARF-p53 tumor-suppressor pathway among multiple other functions. Mutations in the corresponding gene cause a cytoplasmic dislocation of the NPM1 protein. These mutations are unique to acute myeloid leukemia (AML), a disease characterized by clonal expansion, impaired differentiation and the proliferation of myeloid cells in the bone marrow. Despite our improved understanding of NPM1 mutations and their consequences, the underlying leukemia pathogenesis is still unclear. Recent studies that focused on dysregulated gene expression in AML with mutated NPM1 have shed more light into these mechanisms. In this article, we review the current evidence on normal functions of NPM1 and aberrant functioning in AML, and highlight investigational strategies targeting these mutations.
An Overview of International Guidelines Focusing on the Long-Term Management of Coeliac Disease
Authors: Hall Sophie W. , Day Andrew S.
Published: June 2020

Coeliac disease (CD) is an autoimmune disorder characterised by, but not isolated to, intestinal enteropathy in response to exposure to gluten in predisposed individuals. The mainstay of the management of CD is a strict, lifelong gluten free diet (GFD). Although numerous publications have focused on pathways to guide the diagnosis of CD, recommendations for the care of patients after diagnosis are less well established. This manuscript aimed to review the available published guidelines focusing on the ongoing management and follow-up of patients after diagnosis with CD and commencement of a GFD. All available guidelines recommend strict adherence to a GFD with most recommending an annual review by a specialist clinician, focusing on symptoms, adherence and growth. In addition to monitoring micronutrient status, some guidelines suggest monitoring bone mineral density in at-risk groups and screening for other autoimmune disorders. The benefit of multi-disciplinary input was outlined in many guidelines, in particular, the involvement of a specialist dietitian to provide nutritional counselling and support. While the available guidelines provide key messages, they highlight a lack of strong evidence and some inconsistences. Further evidence is required to support high quality, best-practice management strategies that will optimise the outcomes of patients with CD.
Analyzing Near-Surface Regions of Hydrophobic and Long-Term Weathered Natural Stones at Microscopic Scale
Authors: Braun Franziska , Orlowsky Jeanette , Brüggerhoff Stefan
Published: June 2020

The visual appearance of building structures is an important attribute which reflects the character and identity of a region. Due to the influence of weathering, the surfaces of building stones alter, leading to aesthetic changes of the material surface such as discoloration or darkening. In this study, near-surface regions of weathered Baumberger (BST), Schleeriether (SST), and Obernkirchener Sandstones (OKS) have been analyzed at the microscopic scale in order to investigate the intensity and the extent of visual as well as structural changes and how both can be affected due to the presence of surface treatments with hydrophobing agents. It could be detected that aesthetic changes appeared already after 2 years of outdoor exposure, with the slightest variations on BST surfaces, followed by SST and OKS. The use of hydrophobing agents leads to a reduction in surface darkening in the short term. After long-term weathering, no significant changes are visible, as similar values in total color difference (ΔE*) were measured. Biogenic growth and the formation of black weathering crusts are the main reasons for color alterations in the case of the examined stones. The surface damages occur especially on calcareous (BST) followed by clayey (SST) and quartzitic (OKS) stone surfaces.
Complications of Fixed Full-Arch Implant-Supported Metal-Ceramic Prostheses
Authors: Gonzalez-Gonzalez Ignacio , deLlanos-Lanchares Hector , Brizuela-Velasco Aritza , Alvarez-Riesgo Jose-Antonio , Llorente-Pendas Santiago , Herrero-Climent Mariano , Alvarez-Arenal Angel
Published: June 2020

We aimed to assess the biological and mechanical-technical complications and survival rate of implants of full-arch metal-ceramic prostheses, during five years of follow-up. 558 implants (of three different brands) retaining 80 full-arch metal-ceramic prostheses were placed in 65 patients, all of whom were examined annually for biological and mechanical-technical complications during the five years of follow-up. Descriptive statistics and univariate logistic regression were calculated. The cumulative survival rate of the implants was 99.8%, and 98.8% prosthesis-based. Mucositis was the most frequent of the biological complications and peri-implantitis was recorded as 13.8% at restoration-level, 16.9% at patient level and 2.0% at implant level. An implant length greater than 10 mm was shown to be a protective factor against biological complications. The mechanical-technical complications were associated with implant diameter, abutment/implant connection and retention system. Loss of screw access filling was the most frequent prosthetic complication, followed by the fracture of the porcelain. Full-arch metal-ceramic prostheses show a high prevalence of implant and prosthesis survival, with few biological and mechanical-technical complications.
A Flowable Placental Formulation Prevents Bleomycin-Induced Dermal Fibrosis in Aged Mice
Authors: Dhall Sandeep , Lerch Anne , Johnson Nicholas , Jacob Vimal , Jones Brielle , Park Min Sung , Sathyamoorthy Malathi
Published: June 2020

Fibrosis, the thickening and scarring of injured connective tissue, leads to a loss of organ function. Multiple cell types, including T-cells, macrophages, fibrocytes, and fibroblasts/myofibroblasts contribute to scar formation via secretion of inflammatory factors. This event results in an increase in oxidative stress and deposition of excessive extracellular matrix (ECM), characteristic of fibrosis. Further, aging is known to predispose connective tissue to fibrosis due to reduced tissue regeneration. In this study, we investigated the anti-fibrotic activity of a flowable placental formulation (FPF) using a bleomycin-induced dermal fibrosis model in aged mice. FPF consisted of placental amnion/chorion- and umbilical tissue-derived ECM and cells. The mice were injected with either FPF or PBS, followed by multiple doses of bleomycin. Histological assessment of FPF-treated skin samples revealed reduced dermal fibrosis, inflammation, and TGF-β signaling compared to the control group. Quantitative RT-PCR and Next Generation Sequencing analysis of miRNAs further confirmed anti-fibrotic changes in the FPF-treated group at both the gene and transcriptional levels. The observed modulation in miRNAs was associated with inflammation, TGF-β signaling, fibroblast proliferation, epithelial-mesenchymal transition and ECM deposition. These results demonstrate the potential of FPF in preventing fibrosis and may be of therapeutic benefit for those at higher risk of fibrosis due to wounds, aging, exposure to radiation and genetic predisposition.
Generation of Hematopoietic-Like Stem Cells from Adult Human Peripheral Blood Following Treatment with Platelet-Derived Mitochondria
Authors: Yu Haibo , Hu Wei , Song Xiang , Descalzi-Montoya Dante , Yang Zheng , Korngold Robert , Zhao Yong
Published: June 2020

Adult stem cells represent a potential source for cellular therapy to treat serious human diseases. We characterized the insulin-producing cells from adult peripheral blood (designated PB-IPC), which displayed a unique phenotype. Mitochondria are normally located in the cellular cytoplasm, where they generate ATP to power the cell’s functions. Ex vivo and in vivo functional studies established that treatment with platelet-derived mitochondria can reprogram the transformation of adult PB-IPC into functional CD34+ hematopoietic stem cells (HSC)-like cells, leading to the production of blood cells such as T cells, B cells, monocytes/macrophages, granulocytes, red blood cells, and megakaryocytes (MKs)/platelets. These findings revealed a novel function of mitochondria in directly contributing to cellular reprogramming, thus overcoming the limitations and safety concerns of using conventional technologies to reprogram embryonic stem (ES) and induced pluripotent stem (iPS) cells in regenerative medicine.
Considerations for Newborn Screening for Critical Congenital Heart Disease in Low- and Middle-Income Countries
Authors: Zheleva Bistra , Nair Sreehari M. , Dobrzycka Adriana , Saarinen Annamarie
Published: June 2020

We propose several considerations for implementation of critical congenital heart disease (CCHD) screening for low- and middle-income countries to assess health system readiness for countries that may not have all the downstream capacity needed for treatment of CCHD. The recommendations include: (1) assessment of secondary and tertiary level CHD health services, (2) assessment of birth delivery center processes and staff training needs, (3) data collection on implementation and quality surgical outcomes, (4) budgetary consideration, and (5) consideration of the CCHD screening service as part of the overall patient care continuum.