bluuebunny/crossref_metadata_2025 huggingface dataset:
The Use of Microfabrication Techniques for the Design and Manufacture of Artificial Stem Cell Microenvironments for Tissue Regeneration
Authors: Ramos-Rodriguez David H. , MacNeil Sheila , Claeyssens Frederik , Asencio Ilida Ortega
Published: April 2021

The recapitulation of the stem cell microenvironment is an emerging area of research that has grown significantly in the last 10 to 15 years. Being able to understand the underlying mechanisms that relate stem cell behavior to the physical environment in which stem cells reside is currently a challenge that many groups are trying to unravel. Several approaches have attempted to mimic the biological components that constitute the native stem cell niche, however, this is a very intricate environment and, although promising advances have been made recently, it becomes clear that new strategies need to be explored to ensure a better understanding of the stem cell niche behavior. The second strand in stem cell niche research focuses on the use of manufacturing techniques to build simple but functional models; these models aim to mimic the physical features of the niche environment which have also been demonstrated to play a big role in directing cell responses. This second strand has involved a more engineering approach in which a wide set of microfabrication techniques have been explored in detail. This review aims to summarize the use of these microfabrication techniques and how they have approached the challenge of mimicking the native stem cell niche.
Assessment of the Tissue Response to Modification of the Surface of Dental Implants with Carboxyethylphosphonic Acid and Basic Fibroblastic Growth Factor Immobilization (Fgf-2): An Experimental Study on Minipigs
Authors: Aragoneses Javier , Suárez Ana , López-Valverde Nansi , Martínez-Martínez Francisco , Aragoneses Juan Manuel
Published: April 2021

The aim of this study was to evaluate the effect of implant surface treatment with carboxyethylphosphonic acid and fibroblast growth factor 2 on the bone–implant interface during the osseointegration period in vivo using an animal model. The present research was carried out in six minipigs, in whose left tibia implants were inserted as follows: eight implants with a standard surface treatment, for the control group, and eight implants with a surface treatment of carboxyethylphosphonic acid and immobilization of FGF-2, for the test group. At 4 weeks after the insertion of the implants, the animals were sacrificed for the histomorphometric analysis of the samples. The means of the results for the implant–bone contact variable (BIC) were 46.39 ± 17.49% for the test group and 34.00 ± 9.92% for the control group; the difference was not statistically significant. For the corrected implant–bone contact variable (BICc), the mean value of the test group was 60.48 ± 18.11%, and that for the control group, 43.08 ± 10.77%; the difference was statistically significant (p-value = 0.035). The new bone formation (BV/TV) showed average results of 27.28 ± 3.88% for the test group and 26.63 ± 7.90% for the control group, meaning that the differences were not statistically significant (p-value = 0.839). Regarding the bone density at the interthread level (BAI/TA), the mean value of the test group was 32.27 ± 6.70%, and that of the control group was 32.91 ± 7.76%, with a p-value of 0.863, while for the peri-implant density (BAP/TA), the mean value of the test group was 44.96 ± 7.55%, and that for the control group was 44.80 ± 8.68%, without a significant difference between the groups. The current research only found a significant difference for the bone–implant contact at the cortical level; therefore, it could be considered that FGF-2 acts on the mineralization of bone tissue. The application of carboxyethylphosphonic acid on the surface of implants can be considered a promising alternative as a biomimetic coating for the immobilization of FGF-2. Despite no differences in the new bone formation around the implants or in the interthread or peri-implant bone density being detected, the biofunctionalization of the implant surface with FGF-2 accelerates the mineralization of the bone–implant interface at the cortical level, thereby reducing the osseointegration period.
RNA–Binding Protein HuD as a Versatile Factor in Neuronal and Non–Neuronal Systems
Authors: Jung Myeongwoo , Lee Eun Kyung
Published: April 2021

HuD (also known as ELAVL4) is an RNA–binding protein belonging to the human antigen (Hu) family that regulates stability, translation, splicing, and adenylation of target mRNAs. Unlike ubiquitously distributed HuR, HuD is only expressed in certain types of tissues, mainly in neuronal systems. Numerous studies have shown that HuD plays essential roles in neuronal development, differentiation, neurogenesis, dendritic maturation, neural plasticity, and synaptic transmission by regulating the metabolism of target mRNAs. However, growing evidence suggests that HuD also functions as a pivotal regulator of gene expression in non–neuronal systems and its malfunction is implicated in disease pathogenesis. Comprehensive knowledge of HuD expression, abundance, molecular targets, and regulatory mechanisms will broaden our understanding of its role as a versatile regulator of gene expression, thus enabling novel treatments for diseases with aberrant HuD expression. This review focuses on recent advances investigating the emerging role of HuD, its molecular mechanisms of target gene regulation, and its disease relevance in both neuronal and non–neuronal systems.
Glycine-Conjugated Bile Acids Protect RPE Tight Junctions against Oxidative Stress and Inhibit Choroidal Endothelial Cell Angiogenesis In Vitro
Authors: Warden Cassandra , Brantley Milam A.
Published: April 2021

We previously demonstrated that the bile acid taurocholic acid (TCA) inhibits features of age-related macular degeneration (AMD) in vitro. The purpose of this study was to determine if the glycine-conjugated bile acids glycocholic acid (GCA), glycodeoxycholic acid (GDCA), and glycoursodeoxycholic acid (GUDCA) can protect retinal pigment epithelial (RPE) cells against oxidative damage and inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis in choroidal endothelial cells (CECs). Paraquat was used to induce oxidative stress and disrupt tight junctions in HRPEpiC primary human RPE cells. Tight junctions were assessed via transepithelial electrical resistance and ZO-1 immunofluorescence. GCA and GUDCA protected RPE tight junctions against oxidative damage at concentrations of 100–500 µM, and GDCA protected tight junctions at 10–500 µM. Angiogenesis was induced with VEGF in RF/6A macaque CECs and evaluated with cell proliferation, cell migration, and tube formation assays. GCA inhibited VEGF-induced CEC migration at 50–500 µM and tube formation at 10–500 µM. GUDCA inhibited VEGF-induced CEC migration at 100–500 µM and tube formation at 50–500 µM. GDCA had no effect on VEGF-induced angiogenesis. None of the three bile acids significantly inhibited VEGF-induced CEC proliferation. These results suggest glycine-conjugated bile acids may be protective against both atrophic and neovascular AMD.
Apolipoprotein Mimetic Peptides: An Emerging Therapy against Diabetic Inflammation and Dyslipidemia
Authors: Wolkowicz Paul , White C. Roger , Anantharamaiah G. M.
Published: April 2021

Obesity has achieved epidemic status in the United States, resulting in an increase in type 2 diabetes mellitus, dyslipidemia, and cardiovascular disease. Numerous studies have shown that inflammation plays a key role in the development of insulin resistance and diabetic complications. HDL cholesterol levels are inversely associated with coronary heart disease in humans. The beneficial effect of HDL is due, in part, to apolipoproteins A-I and E, which possess anti-inflammatory properties. The functional quality of HDL, however, may be reduced in the context of diabetes. Thus, raising levels of functional HDL is an important target for reducing inflammation and diabetic complications. Apo A-I possesses eight alpha-helical sequences, most of which form class A amphipathic helical structures. Peptides belonging to this class inhibit atherogenesis in several mouse models. Additional peptides based on structural components of apoE have been shown to mediate a rapid clearance of atherogenic lipoproteins in dyslipidemic mice. In this review, we discuss the efficacy of apolipoprotein mimetic peptides in improving lipoprotein function, reducing inflammation, and reversing insulin resistance and cardiometabolic disease processes in diabetic animals.
Centrosome Dynamics and Its Role in Inflammatory Response and Metastatic Process
Authors: Pancione Massimo , Cerulo Luigi , Remo Andrea , Giordano Guido , Gutierrez-Uzquiza Álvaro , Bragado Paloma , Porras Almudena
Published: April 2021

Metastasis is a process by which cancer cells escape from the location of the primary tumor invading normal tissues at distant organs. Chromosomal instability (CIN) is a hallmark of human cancer, associated with metastasis and therapeutic resistance. The centrosome plays a major role in organizing the microtubule cytoskeleton in animal cells regulating cellular architecture and cell division. Loss of centrosome integrity activates the p38-p53-p21 pathway, which results in cell-cycle arrest or senescence and acts as a cell-cycle checkpoint pathway. Structural and numerical centrosome abnormalities can lead to aneuploidy and CIN. New findings derived from studies on cancer and rare genetic disorders suggest that centrosome dysfunction alters the cellular microenvironment through Rho GTPases, p38, and JNK (c-Jun N-terminal Kinase)-dependent signaling in a way that is favorable for pro-invasive secretory phenotypes and aneuploidy tolerance. We here review recent data on how centrosomes act as complex molecular platforms for Rho GTPases and p38 MAPK (Mitogen activated kinase) signaling at the crossroads of CIN, cytoskeleton remodeling, and immune evasion via both cell-autonomous and non-autonomous mechanisms.
Macrophages in Health and Non-Infectious Disease
Authors: Bezsonov Evgeny E. , Gratchev Alexei , Orekhov Alexander N.
Published: April 2021

In this Special Issue of Biomedicines, we have many insightful reviews and research papers on the subject “Macrophages in Health and Non-infectious Disease”, but first; we should discuss briefly the current situation in the field [...]
The Prognostic Value of Brain Dysfunction in Critically Ill Patients with and without Sepsis: A Post Hoc Analysis of the ICON Audit
Authors: Crippa Ilaria , Taccone Fabio , Wittebole Xavier , Martin-Loeches Ignacio , Schroeder Mary , François Bruno , Kotfis Katarzyna , Ñamendys-Silva Silvio , Forceville Xavier , Solé-Violán Jordi , Fontes Luis , Vincent Jean-Louis ,   on behalf of the ICON Investigators
Published: April 2021

Brain dysfunction is associated with poor outcome in critically ill patients. In a post hoc analysis of the Intensive Care over Nations (ICON) database, we investigated the effect of brain dysfunction on hospital mortality in critically ill patients. Brain failure was defined as a neurological sequential organ failure assessment (nSOFA) score of 3–4, based on the assumed Glasgow Coma Scale (GCS) score. Multivariable analyses were performed to assess the independent roles of nSOFA and change in nSOFA from admission to day 3 (ΔnSOFA) for predicting hospital mortality. Data from 7192 (2096 septic and 5096 non-septic) patients were analyzed. Septic patients were more likely than non-septic patients to have brain failure on admission (434/2095 (21%) vs. 617/4665 (13%), p < 0.001) and during the ICU stay (625/2063 (30%) vs. 736/4665 (16%), p < 0.001). The presence of sepsis (RR 1.66 (1.31–2.09)), brain failure (RR 4.85 (3.33–7.07)), and both together (RR 5.61 (3.93–8.00)) were associated with an increased risk of in-hospital death, but nSOFA was not. In the 3280 (46%) patients in whom ΔnSOFA was available, sepsis (RR 2.42 (1.62–3.60)), brain function deterioration (RR 6.97 (3.71–13.08)), and the two together (RR 10.24 (5.93–17.67)) were associated with an increased risk of in-hospital death, whereas improvement in brain function was not.
Synaptic Vesicle Protein 2A Expression in Glutamatergic Terminals Is Associated with the Response to Levetiracetam Treatment
Authors: Contreras-García Itzel Jatziri , Gómez-Lira Gisela , Phillips-Farfán Bryan Víctor , Pichardo-Macías Luz Adriana , García-Cruz Mercedes Edna , Chávez-Pacheco Juan Luis , Mendoza-Torreblanca Julieta G.
Published: April 2021

Synaptic vesicle protein 2A (SV2A), the target of the antiepileptic drug levetiracetam (LEV), is expressed ubiquitously in all synaptic terminals. Its levels decrease in patients and animal models of epilepsy. Thus, changes in SV2A expression could be a critical factor in the response to LEV. Epilepsy is characterized by an imbalance between excitation and inhibition, hence SV2A levels in particular terminals could also influence the LEV response. SV2A expression was analyzed in the epileptic hippocampus of rats which responded or not to LEV, to clarify if changes in SV2A alone or together with glutamatergic or GABAergic markers may predict LEV resistance. Wistar rats were administered saline (control) or pilocarpine to induce epilepsy. These groups were subdivided into untreated or LEV-treated groups. All epileptic rats were video-monitored to assess their number of seizures. Epileptic rats with an important seizure reduction (>50%) were classified as responders. SV2A, vesicular γ-aminobutyric acid transporter and vesicular glutamate transporter (VGLUT) expression were assessed by immunostaining. SV2A expression was not modified during epilepsy. However, responders showed ≈55% SV2A-VGLUT co-expression in comparison with the non-responder group (≈40%). Thus, SV2A expression in glutamatergic terminals may be important for the response to LEV treatment.
Cannabis Use among Older Persons with Arthritis, Cancer and Multiple Sclerosis: Are We Comparing Apples and Oranges?
Authors: Kaskie Brian , Kang Hyojung , Bhagianadh Divya , Bobitt Julie
Published: April 2021

Although researchers have identified medications that relieve symptoms of multiple sclerosis (MS), none are entirely effective and some persons with multiple sclerosis (PwMS) use alternatives. Our study compared cannabis use among PwMS (N = 135) and persons diagnosed with arthritis (N = 582) or cancer (N = 622) who were age 60 and older, enrolled in the State of Illinois Medical Cannabis Program, and invited to complete a survey fielded between June and September, 2019. We used logistic regression to identify significant differences in self-reported effects of cannabis on psychological wellbeing, quality of life, and three behavioral outcomes, and we also considered effects of past year opioid use relative to these outcomes. We found that the majority of individuals from all groups used cannabis to address pain and improve quality of sleep. While PwMS reported lower baseline levels across all five outcomes, we found that the reported effects of cannabis were largely comparable across the groups. We also found that cannabis benefitted persons with sleep and digestive issues regardless of condition, whereas persons who used opioids in addition to cannabis were less likely to experience an improvement in any of the outcomes. This comparative evaluation suggests that cannabis’ effects are not specific to MS, arthritis, or cancer as much as they impact processes common among these distinct conditions. We also found evidence that cannabis may be a viable alternative to opioids for those with these conditions and experiencing pain.
Daily Lifestyle Modifications to Improve Quality of Life and Survival in Glioblastoma: A Review
Authors: Travers Sarah , Litofsky N. Scott
Published: April 2021

Survival in glioblastoma remains poor despite advancements in standard-of-care treatment. Some patients wish to take a more active role in their cancer treatment by adopting daily lifestyle changes to improve their quality of life or overall survival. We review the available literature through PubMed and Google Scholar to identify laboratory animal studies, human studies, and ongoing clinical trials. We discuss which health habits patients adopt and which have the most promise in glioblastoma. While results of clinical trials available on these topics are limited, dietary restrictions, exercise, use of supplements and cannabis, and smoking cessation all show some benefit in the comprehensive treatment of glioblastoma. Marital status also has an impact on survival. Further clinical trials combining standard treatments with lifestyle modifications are necessary to quantify their survival advantages.
Assessing the Impact of COVID-19 on Work-Related Quality of Life through the Lens of Sexual Orientation
Authors: Mendes Cindy , Pereira Henrique
Published: April 2021

In the face of the COVID-19 pandemic and the exceptional situation that has been experienced on a global scale since 2020, it is essential to assess the impact of COVID-19 in several areas and domains. Therefore, this research seeks to evaluate the impact of COVID-19 on work-related quality of life (WRQoL) in a Portuguese-speaking sample, through the lens of sexual orientation. One thousand, five hundred and seventy-seven individuals participated in this study, of which 1396 (88.5%) self-identified as heterosexual, 95 (6.0%) as gay or lesbian, and 87 (5.5%) as bisexual. Participants responded to the “Work-Related Quality of Life” scale, the “Fear of COVID-19” scale, and the “Negative Impact of COVID-19” scale. Bisexuals scored higher on “Fear of COVID-19” and “Negative Impact of COVID-19” than heterosexual, and gay, or lesbian participants. Differences between sexual orientations for all dimensions of WRQoL were found: heterosexual participants scored higher on general well-being, home–work interface, career satisfaction, working conditions, and lower on stress at work, compared to bisexual, and gay, or lesbian participants. Gay or lesbian participants scored lower than heterosexual and bisexual participants on career satisfaction and working conditions. Sexual orientation, the fear of COVID-19, and the negative impact of COVID-19 were significant predictors of overall WRQoL (explaining 13% of variance). Moderation analysis also showed that sexual orientation is a significant moderator of the association between the fear of COVID-19, the negative impact of COVID-19, and WRQoL. LGB people (especially bisexuals) suffer more severe impacts of COVID-19 and have lower WRQoL than heterosexual people. Inevitably, this has consequences in terms of mental health and overall quality of life for sexual minorities, thus reinforcing the need to adopt inclusive policies in organizations and companies to improve their WRQoL.
Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context
Authors: Moreno Eva , Pandit Shusil K. , Toussaint Mathilda J. M. , Bongiovanni Laura , Harkema Liesbeth , van Essen Saskia C. , van Liere Elsbeth A. , Westendorp Bart , de Bruin Alain
Published: April 2021

E2F-transcription factors activate many genes involved in cell cycle progression, DNA repair, and apoptosis. Hence, E2F-dependent transcription must be tightly regulated to prevent tumorigenesis, and therefore metazoan cells possess multiple E2F regulation mechanisms. The best-known is the Retinoblastoma protein (RB), which is mutated in many cancers. Atypical E2Fs (E2F7 and −8) can repress E2F-target gene expression independently of RB and are rarely mutated in cancer. Therefore, they may act as emergency brakes in RB-mutated cells to suppress tumor growth. Currently, it is unknown if and how RB and atypical E2Fs functionally interact in vivo. Here, we demonstrate that mice with liver-specific combinatorial deletion of Rb and E2f7/8 have reduced life-spans compared to E2f7/8 or Rb deletion alone. This was associated with increased proliferation and enhanced malignant progression of liver tumors. Hence, atypical repressor E2Fs and RB cooperatively act as tumor suppressors in hepatocytes. In contrast, loss of either E2f7 or E2f8 largely prevented the formation of pituitary tumors in Rb+/− mice. To test whether atypical E2Fs can also function as oncogenes independent of RB loss, we induced long-term overexpression of E2f7 or E2f8 in mice. E2F7 and −8 overexpression increased the incidence of tumors in the lungs, but not in other tissues. Collectively, these data show that atypical E2Fs can promote but also inhibit tumorigenesis depending on tissue type and RB status. We propose that the complex interactions between atypical E2Fs and RB on maintenance of genetic stability underlie this context-dependency.
On the Equivalence of the Biological Effect Induced by Irradiation of Clusters of Heavy Atom Nanoparticles and Homogeneous Heavy Atom-Water Mixtures
Authors: Villagomez-Bernabe Balder , Ramos-Méndez José , Currell Frederick J.
Published: April 2021

A multiscale local effect model (LEM)-based framework was implemented to study the cell damage caused by the irradiation of clusters of gold nanoparticles (GNPs) under clinically relevant conditions. The results were compared with those obtained by a homogeneous mixture of water and gold (MixNP) irradiated under similar conditions. To that end, Monte Carlo simulations were performed for the irradiation of GNP clusters of different sizes and MixNPs with a 6 MV Linac spectrum to calculate the dose enhancement factor in water. The capabilities of our framework for the prediction of cell damage trends are examined and discussed. We found that the difference of the main parameter driving the cell damage between a cluster of GNPs and the MixNP was less than 1.6% for all cluster sizes. Our results demonstrate for the first time a simple route to intuit the radiobiological effects of clusters of nanoparticles through the consideration of an equivalent homogenous gold/water mixture. Furthermore, the negligible difference on cell damage between a cluster of GNPs and MixNP simplifies the modelling for the complex geometries of nanoparticle aggregations and saves computational resources.
Dietary Modulation of Bacteriophages as an Additional Player in Inflammation and Cancer
Authors: Marongiu Luigi , Burkard Markus , Venturelli Sascha , Allgayer Heike
Published: April 2021

Natural compounds such as essential oils and tea have been used successfully in naturopathy and folk medicine for hundreds of years. Current research is unveiling the molecular role of their antibacterial, anti-inflammatory, and anticancer properties. Nevertheless, the effect of these compounds on bacteriophages is still poorly understood. The application of bacteriophages against bacteria has gained a particular interest in recent years due to, e.g., the constant rise of antimicrobial resistance to antibiotics, or an increasing awareness of different types of microbiota and their potential contribution to gastrointestinal diseases, including inflammatory and malignant conditions. Thus, a better knowledge of how dietary products can affect bacteriophages and, in turn, the whole gut microbiome can help maintain healthy homeostasis, reducing the risk of developing diseases such as diverse types of gastroenteritis, inflammatory bowel disease, or even cancer. The present review summarizes the effect of dietary compounds on the physiology of bacteriophages. In a majority of works, the substance class of polyphenols showed a particular activity against bacteriophages, and the primary mechanism of action involved structural damage of the capsid, inhibiting bacteriophage activity and infectivity. Some further dietary compounds such as caffeine, salt or oregano have been shown to induce or suppress prophages, whereas others, such as the natural sweeter stevia, promoted species-specific phage responses. A better understanding of how dietary compounds could selectively, and specifically, modulate the activity of individual phages opens the possibility to reorganize the microbial network as an additional strategy to support in the combat, or in prevention, of gastrointestinal diseases, including inflammation and cancer.
ADAM17 Inhibition Increases the Impact of Cisplatin Treatment in Ovarian Cancer Spheroids
Authors: Hedemann Nina , Herz Andreas , Schiepanski Jan Hendrik , Dittrich Jan , Sebens Susanne , Dempfle Astrid , Feuerborn Julia , Rogmans Christoph , Tribian Nils , Flörkemeier Inken , Weimer Jörg , Krüger Sandra , Maass Nicolai , Bauerschlag Dirk O.
Published: April 2021

Chemotherapy resistance is a major challenge in ovarian cancer (OvCa). Thus, novel treatment combinations are highly warranted. However, many promising drug candidates tested in two-dimensional (2D) cell culture have not proved successful in the clinic. For this reason, we analyzed our drug combination not only in monolayers but also in three-dimensional (3D) tumor spheroids. One potential therapeutic target for OvCa is A disintegrin and metalloprotease 17 (ADAM17). ADAM17 can be activated by chemotherapeutics, which leads to enhanced tumor growth due to concomitant substrate cleavage. Therefore, blocking ADAM17 during chemotherapy may overcome resistance. Here, we tested the effect of the ADAM17 inhibitor GW280264X in combination with cisplatin on ovarian cancer cells in 2D and 3D. In 2D, the effect on five cell lines was analyzed with two readouts. Three of these cell lines formed dense aggregates or spheroids (HEY, SKOV-3, and OVCAR-8) in 3D and the treatment effect was analyzed with a multicontent readout (cytotoxicity, viability, and caspase3/7 activation). We tested the combined therapy on tumor spheroids derived from primary patient cells. In 2D, we found a significant reduction in the half minimal (50%) inhibitory concentration (IC50) value of the combined treatment (GW280264X plus cisplatin) in comparison with cisplatin monotherapy in all five cell lines with both 2D readout assays (viability and caspase activation). In contrast, the combined treatment only showed an IC50 reduction in HEY and OVCAR-8 3D tumor spheroid models using caspase3/7 activity or CelltoxTM Green as the readout. Finally, we found an improved effect of GW280264X with cisplatin in tumor spheroids derived from patient samples. In summary, we demonstrate that ADAM17 inhibition is a promising treatment strategy in ovarian cancer.
Small Extracellular Vesicles in Pre-Therapy Plasma Predict Clinical Outcome in Non-Small-Cell Lung Cancer Patients
Authors: Vetsika Eleni-Kyriaki , Sharma Priyanka , Samaras Ioannis , Markou Alexandra , Georgoulias Vassilis , Whiteside Theresa L. , Kotsakis Athanasios
Published: April 2021

The potential use of plasma-derived small extracellular vesicles (sEV) as predictors of response to therapy and clinical outcome in chemotherapy-naïve patients with non-small-cell lung cancer (NSCLC) was explored. sEV were isolated by size-exclusion chromatography from the plasma of 79 chemotherapy-naïve NSCLC patients and 12 healthy donors (HD). sEV were characterized with regard to protein content, particle size, counts by qNano, morphology by transmission electron microscopy, and molecular profiles by Western blots. PD-1 and PD-L1 expression on circulating immune cells was analysed by flow cytometry. Pre-treatment levels of total sEV protein (TEP) were correlated with overall (OS) and progression-free survival (PFS). The sEV numbers and protein levels were significantly elevated in the plasma of NSCLC patients compared to HD (p = 0.009 and 0.0001, respectively). Baseline TEP levels were higher in patients who developed progressive disease compared to patients with stable disease (p = 0.007 and 0.001, stage III and IV, respectively). Patient-derived sEV were enriched in immunosuppressive proteins as compared to proteins carried by sEV from HD. TEP levels were positively correlated with CD8+PD-1+ and CD8+PD-L1+ circulating T cell percentages and were independently associated with poorer PFS (p < 0.00001) and OS (p < 0.00001). Pre-therapy sEV could be useful as non-invasive biomarkers of response to therapy and clinical outcome in NSCLC.
How to Make Immunotherapy an Effective Therapeutic Choice for Uveal Melanoma
Authors: Marseglia Mariarosaria , Amaro Adriana , Solari Nicola , Gangemi Rosaria , Croce Elena , Tanda Enrica Teresa , Spagnolo Francesco , Filaci Gilberto , Pfeffer Ulrich , Croce Michela
Published: April 2021

Uveal melanoma (UM), though a rare form of melanoma, is the most common intraocular tumor in adults. Conventional therapies of primary tumors lead to an excellent local control, but 50% of patients develop metastases, in most cases with lethal outcome. Somatic driver mutations that act on the MAP-kinase pathway have been identified, yet targeted therapies show little efficacy in the clinics. No drugs are currently available for the G protein alpha subunitsGNAQ and GNA11, which are the most frequent driver mutations in UM. Drugs targeting the YAP–TAZ pathway that is also activated in UM, the tumor-suppressor gene BRCA1 Associated Protein 1 (BAP1) and the Splicing Factor 3b Subunit 1 gene (SF3B1) whose mutations are associated with metastatic risk, have not been developed yet. Immunotherapy is highly effective in cutaneous melanoma but yields only poor results in the treatment of UM: anti-PD-1 and anti-CTLA-4 blocking antibodies did not meet the expectations except for isolated cases. Here, we discuss how the improved knowledge of the tumor microenvironment and of the cross-talk between tumor and immune cells could help to reshape anti-tumor immune responses to overcome the intrinsic resistance to immune checkpoint blockers of UM. We critically review the dogma of low mutational load, the induction of immune-suppressive cells, and the expression of alternative immune checkpoint molecules. We argue that immunotherapy might still be an option for the treatment of UM.
Genetic Determinants for Prediction of Outcome of Patients with Papillary Thyroid Carcinoma
Authors: Póvoa Antónia Afonso , Teixeira Elisabete , Bella-Cueto Maria Rosa , Batista Rui , Pestana Ana , Melo Miguel , Alves Thalita , Pinto Mafalda , Sobrinho-Simões Manuel , Maciel Jorge , Soares Paula
Published: April 2021

Papillary thyroid carcinoma (PTC) usually presents an excellent prognosis, but some patients present with aggressive metastatic disease. BRAF, RAS, and TERT promoter (TERTp) genes are altered in PTC, and their impact on patient outcomes remains controversial. We aimed to determine the role of genetic alterations in PTC patient outcomes (recurrent/persistent disease, structural disease, and disease-specific mortality (DSM)). The series included 241 PTC patients submitted to surgery, between 2002–2015, in a single hospital. DNA was extracted from tissue samples of 287 lesions (primary tumors and metastases). Molecular alterations were detected by Sanger sequencing. Primary tumors presented 143 BRAF, 16 TERTp, and 13 RAS mutations. Isolated TERTpmut showed increased risk of structural disease (HR = 7.0, p < 0.001) and DSM (HR = 10.1, p = 0.001). Combined genotypes, BRAFwt/TERTpmut (HR = 6.8, p = 0.003), BRAFmut/TERTpmut (HR = 3.2, p = 0.056) and BRAFmut/TERTpwt (HR = 2.2, p = 0.023) showed increased risk of recurrent/persistent disease. Patients with tumors BRAFwt/TERTpmut (HR = 24.2, p < 0.001) and BRAFmut/TERTpmut (HR = 11.5, p = 0.002) showed increased risk of structural disease. DSM was significantly increased in patients with TERTpmut regardless of BRAF status (BRAFmut/TERTpmut, log-rank p < 0.001; BRAFwt/TERTpmut, log-rank p < 0.001). Our results indicate that molecular markers may have a role in predicting PTC patients’ outcome. BRAFmut/TERTpwt tumors were prone to associate with local aggressiveness (recurrent/persistent disease), whereas TERTpmut tumors were predisposed to recurrent structural disease and DSM.
Next-Generation Sequencing with Liquid Biopsies from Treatment-Naïve Non-Small Cell Lung Carcinoma Patients
Authors: Hofman Paul
Published: April 2021

Recently, the liquid biopsy (LB), a non-invasive and easy to repeat approach, has started to compete with the tissue biopsy (TB) for detection of targets for administration of therapeutic strategies for patients with advanced stages of lung cancer at tumor progression. A LB at diagnosis of late stage non-small cell lung carcinoma (NSCLC) is also being performed. It may be asked if a LB can be complementary (according to the clinical presentation or systematics) or even an alternative to a TB for treatment-naïve advanced NSCLC patients. Nucleic acid analysis with a TB by next-generation sequencing (NGS) is gradually replacing targeted sequencing methods for assessment of genomic alterations in lung cancer patients with tumor progression, but also at baseline. However, LB is still not often used in daily practice for NGS. This review addresses different aspects relating to the use of LB for NGS at diagnosis in advanced NSCLC, including its advantages and limitations.
Influencers of the Decision to Undergo Contralateral Prophylactic Mastectomy among Women with Unilateral Breast Cancer
Authors: Singareeka Raghavendra Akshara , Alameddine Hala F. , Andersen Clark R. , Selber Jesse C. , Brewster Abenaa M. , Barcenas Carlos H. , Caudle Abigail S. , Arun Banu K. , Tripathy Debu , Ibrahim Nuhad K.
Published: April 2021

(1) Background: The relatively high rate of contralateral prophylactic mastectomy (CPM) among women with early stage unilateral breast cancer (BC) has raised concerns. We sought to assess the influence of partners, physicians, and the media on the decision of women with unilateral BC to undergo CPM and identify clinicopathological variables associated with the decision to undergo CPM. (2) Patients and Methods: Women with stage 0 to III unilateral BC who underwent CPM between January 2010 and December 2017. Patients were surveyed regarding factors influencing their self-determined decision to undergo CPM. Partner, physician, and media influence factors were modeled by logistic regressions with adjustments for a family history of breast cancer and pathological stage. (3) Results: 397 (29.6%) patients completed the survey and were included in the study. Partners, physicians, and the media significantly influenced patients’ decision to undergo CPM. The logistic regression models showed that, compared to self-determination alone, overall influence on the CPM decision was significantly higher for physicians (p = 0.0006) and significantly lower for partners and the media (p < 0.0001 for both). Fifty-nine percent of patients’ decisions were influenced by physicians, 28% were influenced by partners, and only 17% were influenced by the media. The model also showed that patients with a family history of BC had significantly higher odds of being influenced by a partner than did those without a family history of BC (p = 0.015). (4) Conclusions: Compared to self-determination, physicians had a greater influence and partners and the media had a lower influence on the decision of women with unilateral BC to undergo CPM. Strong family history was significantly associated with a patient’s decision to undergo CPM.
Evaluation of Survival, Recurrence Patterns and Adjuvant Therapy in Surgically Staged High-Grade Endometrial Cancer with Retroperitoneal Metastases
Authors: McEachron Jennifer , Marshall Lila , Zhou Nancy , Tran Van , Kanis Margaux J. , Gorelick Constantine , Lee Yi-Chun
Published: April 2021

Background: We seek to evaluate the difference in recurrence patterns and survival among stage IIIC high-grade endometrial cancer treated with surgery followed by adjuvant chemotherapy alone, radiation therapy alone, or both (chemoradiation). Methods: A multicenter retrospective analysis of surgically staged IIIC HGEC receiving adjuvant therapy was conducted. HGEC was defined as grade 3 endometrioid adenocarcinoma, serous, clear cell and carcinosarcoma. Differences in the frequency of recurrence sites and treatment delays were identified using Pearson’s χ2 test. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan–Meier estimates. Results: A total of 155 patients were evaluable: 41.9% carcinosarcoma, 36.8% serous, 17.4% grade 3 and 3.9% clear cell. Of these, 67.1% received chemoradiation, 25.8% received chemotherapy and 7.1% received radiation therapy. There was no difference in the frequency of treatment delays between regimens (p = 0.571). There was a trend towards greater retroperitoneal recurrence with chemotherapy (25.9%) versus chemoradiation (8.4%) and radiation therapy (7.7%) (p = 0.252). Grade 3 tumors had improved progression-free and overall survival (26 and 42 months, respectively) versus serous (17 and 30 months, respectively), carcinosarcoma (14 and 24 months, respectively) and clear cell (24 and 30 months respectively) (p = 0.002, p < 0.001). Overall, chemoradiation was superior to chemotherapy and radiation therapy in PFS (p < 0.001) and OS (p < 0.001). Upon multivariate analysis, only histology and receipt of chemoradiation were independent predictors of survival. Conclusion: The majority of stage IIIC high-grade endometrial carcinomas recurred. Chemoradiation was associated with improved survival and less retroperitoneal recurrence. Grade 3 tumors demonstrated improved survival versus other histologies regardless of adjuvant treatment modality.
Membrane-Less Ethanol Electrooxidation over Pd-M (M: Sn, Mo and Re) Bimetallic Catalysts
Authors: Ruiz-López Estela , Diaz-Perez Manuel Antonio , de Lucas-Consuegra Antonio , Dorado Fernando , Serrano-Ruiz Juan Carlos
Published: April 2021

The effect of the addition of three oxophilic co-metals (Sn, Mo and Re) on the electrochemical performance of Pd in the ethanol oxidation reaction (EOR) was investigated by performing half-cell and membrane-less electrolysis cell experiments. While the additions of Sn and Re were found to improve significantly the EOR performance of Pd, Mo produced no significant promotional effect. When added in significant amounts (50:50 ratio), Sn and Re produced a 3–4 fold increase in the mass-normalized oxidation peak current as compared to the monometallic Pd/C material. Both the electrochemical surface area and the onset potential also improved upon addition of Sn and Re, although this effect was more evident for Sn. Cyclic voltammetry (CV) measurements revealed a higher ability of Sn for accommodating OH- species as compared to Re, which could explain these results. Additional tests were carried out in a membrane-less electrolysis system. Pd50Re50/C and Pd50Sn50/C both showed higher activity than Pd/C in this system. Chronopotentiometric measurements at constant current were carried out to test the stability of both catalysts in the absence of a membrane. Pd50Sn50/C was significantly more stable than Pd50Re50/C, which showed a rapid increase in the potential with time. Despite operating in the absence of a membrane, both catalysts generated a high-purity (e.g., 99.99%) hydrogen stream at high intensities and low voltages. These conditions could lead to significant energy consumption savings compared to commercial water electrolyzers.
Channelling the Force to Reprogram the Matrix: Mechanosensitive Ion Channels in Cardiac Fibroblasts
Authors: Stewart Leander , Turner Neil A.
Published: April 2021

Cardiac fibroblasts (CF) play a pivotal role in preserving myocardial function and integrity of the heart tissue after injury, but also contribute to future susceptibility to heart failure. CF sense changes to the cardiac environment through chemical and mechanical cues that trigger changes in cellular function. In recent years, mechanosensitive ion channels have been implicated as key modulators of a range of CF functions that are important to fibrotic cardiac remodelling, including cell proliferation, myofibroblast differentiation, extracellular matrix turnover and paracrine signalling. To date, seven mechanosensitive ion channels are known to be functional in CF: the cation non-selective channels TRPC6, TRPM7, TRPV1, TRPV4 and Piezo1, and the potassium-selective channels TREK-1 and KATP. This review will outline current knowledge of these mechanosensitive ion channels in CF, discuss evidence of the mechanosensitivity of each channel, and detail the role that each channel plays in cardiac remodelling. By better understanding the role of mechanosensitive ion channels in CF, it is hoped that therapies may be developed for reducing pathological cardiac remodelling.
Mechanosensitive Regulation of Fibrosis
Authors: Yang Shuying , Plotnikov Sergey V.
Published: April 2021

Cells in the human body experience and integrate a wide variety of environmental cues. A growing interest in tissue mechanics in the past four decades has shown that the mechanical properties of tissue drive key biological processes and facilitate disease development. However, tissue stiffness is not only a potent behavioral cue, but also a product of cellular signaling activity. This review explores both roles of tissue stiffness in the context of inflammation and fibrosis, and the important molecular players driving such processes. During inflammation, proinflammatory cytokines upregulate tissue stiffness by increasing hydrostatic pressure, ECM deposition, and ECM remodeling. As the ECM stiffens, cells involved in the immune response employ intricate molecular sensors to probe and alter their mechanical environment, thereby facilitating immune cell recruitment and potentiating the fibrotic phenotype. This powerful feedforward loop raises numerous possibilities for drug development and warrants further investigation into the mechanisms specific to different fibrotic diseases.
Effect of Air Pollution on Obesity in Children: A Systematic Review and Meta-Analysis
Authors: Parasin Nichapa , Amnuaylojaroen Teerachai , Saokaew Surasak
Published: April 2021

Air pollution exposure has been identified as being associated with childhood obesity. Nevertheless, strong evidence of such an association is still lacking. To analyze whether air pollution exposure affects childhood obesity, we conducted a systematic review and meta-analysis utilizing the PRISMA guidelines. Of 7343 studies identified, eight studies that investigated the effects of air pollutant characteristics, including PM2.5, PM10, PMcoarse, PMabsorbance, NOx, and NO2, on childhood obesity were included. The polled effects showed that air pollution is correlated with a substantially increased risk of childhood obesity. PM2.5 was found to be associated with a significantly increased risk (6%) of childhood obesity (OR 1.06, 95% CI 1.02–1.10, p = 0.003). In addition, PM10, PM2.5absorbance, and NO2 appeared to significantly increase the risk of obesity in children (OR 1.07, 95% CI 1.04–1.10, p < 0.00; OR 1.23, 95% CI 1.06–1.43, p = 0.07; and OR 1.10, 95% CI 1.04–1.16, p < 0.001, respectively). PMcoarse and NOx also showed trends towards being associated with an increased risk of childhood obesity (OR 1.07, 95% CI 0.95–1.20, p = 0.291, and OR 1.00, 95% CI 0.99–1.02, p = 0.571, respectively). Strong evidence was found to support the theory that air pollution exposure is one of the factors that increases the risk of childhood obesity.
Magnetic Resonance Imaging as the Primary Imaging Modality in Children Presenting with Inflammatory Nontraumatic Atlantoaxial Rotatory Subluxation
Authors: Wenger Katharina J. , Hattingen Elke , Porto Luciana
Published: April 2021

Inflammatory nontraumatic atlantoaxial rotatory subluxation (AAS) in children is an often-missed diagnosis, especially in the early stages of disease. Abscess formation and spinal cord compression are serious risks that call for immediate surgical attention. Neither radiographs nor non-enhanced computed tomography (CT) images sufficiently indicate inflammatory processes. Magnetic resonance imaging (MRI) allows a thorough evaluation of paraspinal soft tissues, joints, and ligaments. In addition, it can show evidence of vertebral distraction and spinal cord compression. After conducting a scoping review of the literature, along with scientific and practical considerations, we outlined a standardized pediatric MRI protocol for suspected inflammatory nontraumatic AAS. We recommend contrast-enhanced MRI as the primary diagnostic imaging modality in children with signs of torticollis in combination with nasopharyngeal inflammatory or ear nose and throat (ENT) surgical history.
High-Temperature Tribological Performance of Al2O3/a-C:H:Si Coating in Ambient Air
Authors: Podgursky Vitali , Alamgir Asad , Yashin Maxim , Jõgiaas Taivo , Viljus Mart , Raadik Taavi , Danilson Mati , Sergejev Fjodor , Lümkemann Andreas , Kluson Jan , Sondor Jozef , Bogatov Andrei
Published: April 2021

The study investigates thermal stability and high temperature tribological performance of a-C:H:Si diamond-like carbon (DLC) coating. A thin alumina layer was deposited on top of the a-C:H:Si coating to improve the tribological performance at high temperatures. The a-C:H:Si coating and alumina layer were prepared using plasma-activated chemical vapour deposition and atomic layer deposition, respectively. Raman and X-ray photoelectron spectroscopy were used to investigate the structures and chemical compositions of the specimens. The D and G Raman peaks due to sp2 bonding and the peaks corresponding to the trans-polyacetylene (t-Pa) and sp bonded chains were identified in the Raman spectra of the a-C:H:Si coating. Ball-on-disc sliding tests were carried out at room temperature and 400 °C using Si3N4 balls as counter bodies. The a-C:H:Si coating failed catastrophically in sliding tests at 400 °C; however, a repeatable and reproducible regime of sliding with a low coefficient of friction was observed for the Al2O3/a-C:H:Si coating at the same temperature. The presence of the alumina layer and high stress and temperature caused structural changes in the bulk a-C:H:Si and top layers located near the contact area, leading to the modification of the contact conditions, delivering of extra oxygen into the contact area, reduction of hydrogen effusion, and suppression of the atmospheric oxidation.
Synthesis of Cubic Aluminum Nitride (AlN) Coatings through Suspension Plasma Spray (SPS) Technology
Authors: Barandehfard Faranak , Aluha James , Gitzhofer François
Published: April 2021

Thermal spraying of aluminum nitride (AlN) is a challenging issue because it decomposes at a high temperature. In this work, the use of suspension plasma spray (SPS) technology is proposed for the in situ synthesis and deposition of cubic-structured AlN coatings on metallic substrates. The effects of the nitriding agent, the suspension liquid carrier, the substrate materials and the standoff distance during deposition by SPS were investigated. The plasma-synthesized coatings were analyzed by X-ray diffraction (XRD), optical microscopy (OM) and scanning electron microscopy (SEM). The results show higher AlN content in the coatings deposited on a carbon steel substrate (~82%) when compared to titanium substrate (~30%) or molybdenum (~15%). Melamine mixed with pure aluminum powder produced AlN-richer coatings of up to 82% when compared to urea mixed with the Al (~25% AlN). Hexadecane was a relatively better liquid carrier than the oxygen-rich liquid carriers such as ethanol or ethylene glycol. When the materials were exposed to a molten aluminum–magnesium alloy at 850 °C for 2 h, the corrosion resistance of the AlN-coated carbon steel substrate showed improved performance in comparison to the uncoated substrate.
First, Do No Harm: Critical Appraisal of Protein Restriction for Diabetic Kidney Disease
Authors: Yamada Satoru
Published: April 2021

Low-protein diets have been recommended as diet therapy for the management of chronic kidney disease; however, its effect on chronic kidney disease has not been scientifically proven. Although several studies have reported significantly more favorable results with low-protein diet than with normal-protein diet, the renal protective effects of low-protein diets are still unclear in diabetic patients with chronic kidney disease. Moreover, some studies have reported that extremely low-protein diets may increase the risk of mortality. Thus, this paper describes the effectiveness and safety of low-protein diets for patients with diabetic kidney disease by reviewing the historical background of different low-protein diets that were critically examined in several studies.