bluuebunny/crossref_metadata_2025 huggingface dataset:
Objective Assessment of Acute Pain in Foals Using a Facial Expression-Based Pain Scale
Authors: van Loon Johannes , Verhaar Nicole , van den Berg Els , Ross Sarah , de Grauw Janny
Published: September 2020

Pain assessment is very important for monitoring welfare and quality of life in horses. To date, no studies have described pain scales for objective assessment of pain in foals. Studies in other species have shown that facial expression can be used in neonatal animals for objective assessment of acute pain. The aim of the current study was to adapt a facial expression-based pain scale for assessment of acute pain in mature horses for valid pain assessment in foals. The scale was applied to fifty-nine foals (20 patients and 39 healthy controls); animals were assessed from video recordings (30–60 s) by 3 observers, who were blinded for the condition of the animals. Patients were diagnosed with acute health problems by means of clinical examination and additional diagnostic procedures. EQUUS-FAP FOAL (Equine Utrecht University Scale for Facial Assessment of Pain in Foals) showed good inter- and intra-observer reliability (Cronbach’s alpha = 0.95 and 0.98, p < 0.001). Patients had significantly higher pain scores compared to controls (p < 0.001) and the pain scores decreased after treatment with NSAIDs (meloxicam or flunixin meglumine IV) (p < 0.05). Our results indicate that a facial expression-based pain scale could be useful for the assessment of acute pain in foals. Further studies are needed to validate this pain scale.
Beliefs and Attitudes of Residents in Queensland, Australia, about Managing Dog and Cat Impacts on Native Wildlife
Authors: Carter Jennifer , Paterson Mandy B. A. , Morton John M. , Gelves-Gomez Francisco
Published: September 2020

Many humans have created close relationships with wildlife and companion species. Notwithstanding that companion species were at some point themselves wild, some wild (i.e., feral) and domesticated (owned) dogs and cats now have significant impacts on wildlife. Many strategies exist to control the impact of dogs and cats on wildlife, but the successful implementation of management initiatives is tied to public opinions and the degree of acceptability of these measures. This paper reports the findings of a survey assessing the beliefs of residents in Queensland, Australia, about dog and cat impacts on wildlife, and their attitudes towards various strategies and options for controlling wild (i.e., feral) and domesticated (owned) dogs and cats. The responses of 590 participants were analysed. Our respondents collectively grouped strategies into those that directly cause wild dog and cat deaths and those that allow wild dogs and cats to live a ‘natural’ life, which is a variation on past research where respondents grouped strategies into lethal and non-lethal methods. Community acceptability of strategies that directly cause wild dog and cat deaths (each assessed using five-category Likert scores) was lower amongst females and respondents aged 34 years or less. Gender expectations in most places and cultures still predominately suggest that women are more ‘caring’, supportive of animal welfare, and perhaps cognizant that wild dogs and cats are also sentient creatures and appreciate the problematic tension between controlling wild and companion species. Age-related differences may reflect the changing social values of communities at different points in time. There was high support for regulations that enforce responsible pet ownership but not for the importance of pet-free suburbs, which the majority of respondents considered unimportant. These important variations in beliefs and attitudes require careful management within each community for the success of any program to control wild dogs or cats.
Oxidative Stress: Concept and Some Practical Aspects
Authors: Sies Helmut
Published: September 2020

Oxidative stress is defined as “an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage”. This Commentary presents basic features of this global concept which has attracted interest in biology and medicine. The term “antioxidants” in cellular defense against oxidants predominantly includes antioxidant enzymes with their substrates and coenzymes. Exogenous low-molecular-mass compounds also have a role, but this is more limited. Multiple biomarkers of damage due to oxidative stress have been identified for different molecular classes (protein, lipid, carbohydrate, and DNA), and the current state of practical aspects in health and disease is delineated.
Analyzing the Potential Biological Determinants of Autism Spectrum Disorder: From Neuroinflammation to the Kynurenine Pathway
Authors: Savino Rosa , Carotenuto Marco , Polito Anna Nunzia , Di Noia Sofia , Albenzio Marzia , Scarinci Alessia , Ambrosi Antonio , Sessa Francesco , Tartaglia Nicola , Messina Giovanni
Published: September 2020

Autism Spectrum Disorder (ASD) etiopathogenesis is still unclear and no effective preventive and treatment measures have been identified. Research has focused on the potential role of neuroinflammation and the Kynurenine pathway; here we review the nature of these interactions. Pre-natal or neonatal infections would induce microglial activation, with secondary consequences on behavior, cognition and neurotransmitter networks. Peripherally, higher levels of pro-inflammatory cytokines and anti-brain antibodies have been identified. Increased frequency of autoimmune diseases, allergies, and recurring infections have been demonstrated both in autistic patients and in their relatives. Genetic studies have also identified some important polymorphisms in chromosome loci related to the human leukocyte antigen (HLA) system. The persistence of immune-inflammatory deregulation would lead to mitochondrial dysfunction and oxidative stress, creating a self-sustaining cytotoxic loop. Chronic inflammation activates the Kynurenine pathway with an increase in neurotoxic metabolites and excitotoxicity, causing long-term changes in the glutamatergic system, trophic support and synaptic function. Furthermore, overactivation of the Kynurenine branch induces depletion of melatonin and serotonin, worsening ASD symptoms. Thus, in genetically predisposed subjects, aberrant neurodevelopment may derive from a complex interplay between inflammatory processes, mitochondrial dysfunction, oxidative stress and Kynurenine pathway overexpression. To validate this hypothesis a new translational research approach is necessary.
Developing Employment Environments Where Individuals with ASD Thrive: Using Machine Learning to Explore Employer Policies and Practices
Authors: Griffiths Amy Jane , Hanson Amy Hurley , Giannantonio Cristina M. , Mathur Sneha Kohli , Hyde Kayleigh , Linstead Erik
Published: September 2020

An online survey instrument was developed to assess employers’ perspectives on hiring job candidates with Autism Spectrum Disorder (ASD). The investigators used K-means clustering to categorize companies in clusters based on their hiring practices related to individuals with ASD. This methodology allowed the investigators to assess and compare the various factors of businesses that successfully hire employees with ASD versus those that do not. The cluster analysis indicated that company structures, policies and practices, and perceptions, as well as the needs of employers and employees, were important in determining who would successfully hire individuals with ASD. Key areas that require focused policies and practices include recruitment and hiring, training, accessibility and accommodations, and retention and advancement.
Recent Advances and Future Perspectives in the Development of Therapeutic Approaches for Neurodegenerative Diseases
Authors: Bowerman Melissa
Published: September 2020

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD), severely impact the function of neuronal cells in the brain and have devastating consequences on the quality of life of patients and their families [...]
Biomimetic Magnetite Nanoparticles as Targeted Drug Nanocarriers and Mediators of Hyperthermia in an Experimental Cancer Model
Authors: Oltolina Francesca , Peigneux Ana , Colangelo Donato , Clemente Nausicaa , D’Urso Annarita , Valente Guido , Iglesias Guillermo R. , Jiménez-Lopez Concepcion , Prat Maria
Published: September 2020

Biomimetic magnetic nanoparticles mediated by magnetosome proteins (BMNPs) are potential innovative tools for cancer therapy since, besides being multifunctional platforms, they can be manipulated by an external gradient magnetic field (GMF) and/or an alternating magnetic field (AMF), mediating targeting and hyperthermia, respectively. We evaluated the cytocompatibility/cytotoxicity of BMNPs and Doxorubicin (DOXO)-BMNPs in the presence/absence of GMF in 4T1 and MCF-7 cells as well as their cellular uptake. We analyzed the biocompatibility and in vivo distribution of BMNPs as well as the effect of DOXO-BMNPs in BALB/c mice bearing 4T1 induced mammary carcinomas after applying GMF and AMF. Results: GMF enhanced the cell uptake of both BMNPs and DOXO-BMNPs and the cytotoxicity of DOXO-BMNPs. BMNPs were biocompatible when injected intravenously in BALB/c mice. The application of GMF on 4T1 tumors after each of the repeated (6×) iv administrations of DOXO-BMNPs enhanced tumor growth inhibition when compared to any other treatment, including that with soluble DOXO. Moreover, injection of DOXO-BMNPs in the tumor combined with application of an AMF resulted in a significant tumor weight reduction. These promising results show the suitability of BMNPs as magnetic nanocarriers for local targeted chemotherapy and as local agents for hyperthermia.
Exosomes: A Source for New and Old Biomarkers in Cancer
Authors: Logozzi Mariantonia , Mizzoni Davide , Di Raimo Rossella , Fais Stefano
Published: September 2020

Clinical oncology needs reliable tumor biomarkers to allow a follow-up of tumor patients who do not necessarily need invasive approaches. To date, the existing biomarkers are not sufficiently reliable, and many of them have generated more problems than facilitating the commitment of clinical oncologists. Over the last decades, a broad family of extracellular vesicles, with size ranging between micro to nano, has been raised as a new hope for potential sources of new tumor biomarkers. However, while knowledge in the field is increasing, we do not currently have definitive information allowing a clinical use of extracellular vesicles in cancer clinics. Recent evidence provides new perspective in clinical oncology, based on data showing that circulating nanovesicles called exosomes may represent a valuable source of tumor biomarkers. In this review, we discuss the existing clinical data supporting a key role of exosomes as a source of tumor biomarkers, including proteins and miRNAs, but also discuss the importance of the expression of known tumor biomarkers when expressed on exosomes.
Evaluation of Cognitive Function in Trials Testing New-Generation Hormonal Therapy in Patients with Prostate Cancer: A Systematic Review
Authors: Marandino Laura , Vignani Francesca , Buttigliero Consuelo , Gamba Teresa , Necchi Andrea , Tucci Marcello , Di Maio Massimo
Published: September 2020

In patients with prostate cancer, earlier use and longer duration of new-generation hormonal therapy (NGHT), added to androgen deprivation therapy, requires careful evaluation of cognitive function. The aim of this systematic review is to describe the evidence about cognitive function in all the randomized trials (RCTs) testing NGHT (abiraterone, enzalutamide, apalutamide, darolutamide). We assessed the availability of both investigator-assessed cognitive impairment and disorders and patient-reported evaluation of cognitive function. Nineteen RCTs (17,617 patients) were included. The investigator-based evaluation of cognitive impairment was available in seven RCTs (36.8%). In total, 19/19 RCTs (100%) included patient-reported outcomes (PROs) collection, but PRO tools adopted allowed evaluation of cognitive function in two RCTs (10.5%). Among them, PRO-based cognitive function results were presented only in one RCT (5.3%): in ENZAMET, mean changes from baseline were worse with enzalutamide than with placebo, but deterioration-free survival favored enzalutamide. Despite cognitive deterioration could be relevant, clinical development of NGHT has not included a systematic evaluation of cognitive function. Assessment by investigators is at risk of underreporting, and commonly used PROs do not allow proper cognitive function analysis. Furthermore, the methodology of analysis can jeopardize the interpretation of results. Although direct comparisons are scanty, there could be differences between different NGHTs.
Transcriptional Spatial Profiling of Cancer Tissues in the Era of Immunotherapy: The Potential and Promise
Authors: Nerurkar Sanjna Nilesh , Goh Denise , Cheung Chun Chau Lawrence , Nga Pei Qi Yvonne , Lim Jeffrey Chun Tatt , Yeong Joe Poh Sheng
Published: September 2020

Intratumoral heterogeneity poses a major challenge to making an accurate diagnosis and establishing personalized treatment strategies for cancer patients. Moreover, this heterogeneity might underlie treatment resistance, disease progression, and cancer relapse. For example, while immunotherapies can confer a high success rate, selective pressures coupled with dynamic evolution within a tumour can drive the emergence of drug-resistant clones that allow tumours to persist in certain patients. To improve immunotherapy efficacy, researchers have used transcriptional spatial profiling techniques to identify and subsequently block the source of tumour heterogeneity. In this review, we describe and assess the different technologies available for such profiling within a cancer tissue. We first outline two well-known approaches, in situ hybridization and digital spatial profiling. Then, we highlight the features of an emerging technology known as Visium Spatial Gene Expression Solution. Visium generates quantitative gene expression data and maps them to the tissue architecture. By retaining spatial information, we are well positioned to identify novel biomarkers and perform computational analyses that might inform on novel combinatorial immunotherapies.
N-MYC Downstream Regulated Gene 4 (NDRG4), a Frequent Downregulated Gene through DNA Hypermethylation, plays a Tumor Suppressive Role in Esophageal Adenocarcinoma
Authors: Cao Longlong , Hu Tianling , Lu Heng , Peng Dunfa
Published: September 2020

The incidence of esophageal adenocarcinoma (EAC) has been rising dramatically in the past few decades in the United States and Western world. The N-myc downregulated gene 4 (NDRG4) belongs to the human NDRG family. In this study, we aimed to identify the expression levels, regulation, and functions of NDRG4 in EAC. Using an integrative epigenetic approach, we identified genes showing significant downregulation in EAC and displaying upregulation after 5-Aza-deoxycitidine. Among these genes, likely to be regulated by DNA methylation, NDRG4 was among the top 10 candidate genes. Analyses of TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) data sets and EAC tissue samples demonstrated that NDRG4 was significantly downregulated in EAC (p < 0.05). Using Pyrosequencing technology for quantification of DNA methylation, we detected that NDRG4 promoter methylation level was significantly higher in EAC tissue samples, as compared to normal esophagus samples (p < 0.01). A strong inverse correlation between NDRG4 methylation and its gene expression levels (r = −0.4, p < 0.01) was observed. Treatment with 5-Aza restored the NDRG4 expression, confirming that hypermethylation is a driving force for NDRG4 silencing in EAC. Pathway and gene set enrichment analyses of TCGA data suggested that NDRG4 is strongly associated with genes related to cell cycle regulation. Western blotting analysis showed significant downregulation of Cyclin D1, CDK4 and CDK6 in EAC cells after overexpression of NDRG4. Functionally, we found that the reconstitution of NDRG4 resulted in a significant reduction in tumor cell growth in two-dimensional (2D) and three-dimensional (3D) organotypic culture models and inhibited tumor cell proliferation as indicated by the EdU (5-ethynyl-2′-deoxyuridine) proliferation assay.
Mitochondrial Metabolism, Contact Sites and Cellular Calcium Signaling: Implications for Tumorigenesis
Authors: Peruzzo Roberta , Costa Roberto , Bachmann Magdalena , Leanza Luigi , Szabò Ildikò
Published: September 2020

Mitochondria are organelles that are mainly involved in the generation of ATP by cellular respiration. In addition, they modulate several intracellular functions, ranging from cell proliferation and differentiation to cell death. Importantly, mitochondria are social and can interact with other organelles, such as the Endoplasmic Reticulum, lysosomes and peroxisomes. This symbiotic relationship gives advantages to both partners in regulating some of their functions related to several aspects of cell survival, metabolism, sensitivity to cell death and metastasis, which can all finally contribute to tumorigenesis. Moreover, growing evidence indicates that modulation of the length and/or numbers of these contacts, as well as of the distance between the two engaged organelles, impacts both on their function as well as on cellular signaling. In this review, we discuss recent advances in the field of contacts and communication between mitochondria and other intracellular organelles, focusing on how the tuning of mitochondrial function might impact on both the interaction with other organelles as well as on intracellular signaling in cancer development and progression, with a special focus on calcium signaling.
Plasma Nucleosomes in Primary Breast Cancer
Authors: Mego Michal , Kalavska Katarina , Karaba Marian , Minarik Gabriel , Benca Juraj , Sedlackova Tatiana , Gronesova Paulina , Cholujova Dana , Pindak Daniel , Mardiak Jozef , Celec Peter
Published: September 2020

When cells die, nucleosomes composed of DNA and histone proteins enter the extracellular space and end eventually in the circulation. In plasma, they might serve as a nonspecific marker of cell death, potentially useful for noninvasive monitoring of tumor dynamics. The aim of this study was to analyze circulating nucleosomes in relation to patient/tumor characteristics and prognosis in primary breast cancer. This study included 92 patients with breast cancer treated with surgery for whom plasma isolated was available in the biobank. Plasma nucleosomes were detected in samples taken in the morning on the day of surgery using Cell Death Detection ELISA kit with anti-histone and anti-DNA antibodies. Circulating nucleosomes were positively associated with the systemic inflammatory index (SII), but not with other patient/tumor characteristics. Patients with high SII in comparison to low SII had higher circulating nucleosomes (by 59%, p = 0.02). Nucleosomes correlated with plasma plasminogen activator inhibitor-1, IL-15, IL-16, IL-18, and hepatocyte growth factor. Patients with lower nucleosomes had significantly better disease-free survival (HR = 0.46, p = 0.05). In a multivariate analysis, nucleosomes, hormone receptor status, HER2 status, lymph node involvement, and tumor grade were independent predictors of disease-free survival. Our data suggest that plasma nucleosomes in primary breast cancer are associated with systemic inflammation and might have a prognostic value. The underlying mechanisms require further studies.
New Insights into Breast and Endometrial Cancers
Authors: Miki Yasuhiro
Published: September 2020

Cancers of the breast and endometrium are some of the most common cancers affecting women [...]
Multimodality Treatment in Metastatic Gastric Cancer: From Past to Next Future
Authors: Parisi Alessandro , Porzio Giampiero , Ficorella Corrado
Published: September 2020

Gastric cancer (GC) still remains an incurable disease in almost two-thirds of the cases. However, a deeper knowledge of its biology in the last few years has revealed potential biomarkers suitable for tailored treatment with targeted agents. This aspect, together with the improvement in early supportive care and a wiser use of the available cytotoxic drugs across multiple lines of treatment, has resulted in incremental and progressive survival benefits. Furthermore, slowly but surely, targeted therapies and immune checkpoint inhibitors are revising the therapeutic scenario even in metastatic GC and especially in particular subgroups. Moreover, important study results regarding the possible role of an integrated approach combining systemic, surgical, and locoregional treatment in carefully selected oligometastatic GC patients are awaited. This review summarizes the state-of-the-art and the major ongoing trials involving a multimodal treatment of metastatic GC.
Recent Progress in the Systemic Treatment of Advanced/Metastatic Cholangiocarcinoma
Authors: Fostea Raluca Maria , Fontana Elisa , Torga Gonzalo , Arkenau Hendrik-Tobias
Published: September 2020

Cholangiocarcinomas (CCAs) comprise of a heterogeneous group of cancers arising in the biliary tract (intrahepatic or iCCA, perihilar or pCCA and distal or dCCA; the latter are known under the collective term of eCCA), each subtype having its own particularities in carcinogenesis, management and prognosis. The increasing incidence in recent decades, limited treatment options and high mortality rates, even in the early stages, have led to an imperious need for more in-depth understanding and development of tailored treatments for this type of aggressive tumour. The wide use of molecular profiling has increased the understanding of biology and identified key molecular drivers, for example, IDH1 mutations or FGFR2 fusions for iCCA, or BRAF mutations in eCCA. Most recently, the FDA approved pemigatinib, an FGFR inhibitor and ivosidenib, an IDH1 inhibitor, but even though progress has been made to better understand the mechanisms of tumorigenesis, genetic make-up, and tumour resistance to standard chemotherapy and targeted therapies, cholangiocarcinomas still represent an important challenge in the daily clinical practice of oncology. The purpose of this review is to highlight the recent progress in the systemic treatment of advanced/metastatic CCAs with a focus on targeted drugs and their biomarkers currently evaluated in early-phase clinical trials.
Jagged Ligands Enhance the Pro-Angiogenic Activity of Multiple Myeloma Cells
Authors: Palano Maria Teresa , Giannandrea Domenica , Platonova Natalia , Gaudenzi Germano , Falleni Monica , Tosi Delfina , Lesma Elena , Citro Valentina , Colombo Michela , Saltarella Ilaria , Ria Roberto , Amodio Nicola , Taiana Elisa , Neri Antonino , Vitale Giovanni , Chiaramonte Raffaella
Published: September 2020

Multiple myeloma (MM) is an incurable plasma cell malignancy arising primarily within the bone marrow (BM). During MM progression, different modifications occur in the tumor cells and BM microenvironment, including the angiogenic shift characterized by the increased capability of endothelial cells to organize a network, migrate and express angiogenic factors, including vascular endothelial growth factor (VEGF). Here, we studied the functional outcome of the dysregulation of Notch ligands, Jagged1 and Jagged2, occurring during disease progression, on the angiogenic potential of MM cells and BM stromal cells (BMSCs). Jagged1–2 expression was modulated by RNA interference or soluble peptide administration, and the effects on the MM cell lines’ ability to induce human pulmonary artery cells (HPAECs) angiogenesis or to indirectly increase the BMSC angiogenic potential was analyzed in vitro; in vivo validation was performed on a zebrafish model and MM patients’ BM biopsies. Overall, our results indicate that the MM-derived Jagged ligands (1) increase the tumor cell angiogenic potential by directly triggering Notch activation in the HPAECs or stimulating the release of angiogenic factors, i.e., VEGF; and (2) stimulate the BMSCs to promote angiogenesis through VEGF secretion. The observed pro-angiogenic effect of Notch activation in the BM during MM progression provides further evidence of the potential of a therapy targeting the Jagged ligands.
Incidence of Hepatocellular Carcinoma after Treatment with Sofosbuvir-Based or Sofosbuvir-Free Regimens in Patients with Chronic Hepatitis C
Authors: Ogawa Eiichi , Nomura Hideyuki , Nakamuta Makoto , Furusyo Norihiro , Kajiwara Eiji , Dohmen Kazufumi , Kawano Akira , Ooho Aritsune , Azuma Koichi , Takahashi Kazuhiro , Satoh Takeaki , Koyanagi Toshimasa , Ichiki Yasunori , Kuniyoshi Masami , Yanagita Kimihiko , Amagase Hiromasa , Morita Chie , Sugimoto Rie , Kato Masaki , Shimoda Shinji , Hayashi Jun
Published: September 2020

Advanced fibrosis/cirrhosis and related biomarkers have been recognized as useful predictors of the development of hepatocellular carcinoma (HCC) by patients with chronic hepatitis C (CHC) following hepatitis C virus (HCV) cure by direct-acting antivirals (DAAs). However, it remains unclear if DAAs themselves have an influence on or facilitate the development of HCC. This multicenter cohort study included CHC patients without a history of HCC who achieved HCV elimination by DAAs. Cohorts of 835 patients treated with a sofosbuvir (SOF)-based regimen and 835 treated with a SOF-free regimen were matched 1:1 by propensity scoring with nine variables to evaluate differences in HCC incidence. The median observation period was 3.5 years. Sixty-nine cases of HCC were found during 5483.9 person-years (PY) over the entire follow-up period. The annual incidence was similar for both groups (SOF-based 1.25 and SOF-free 1.27 per 100 PY, respectively: adjusted hazard ratio (HR) 1.26, 95% confidence interval (CI) 0.75–2.12, p = 0.39). However, the annual incidence within the first two years was higher for patients treated with SOF than for those without, but did not reach significance (1.50 and 0.97 per 100 PY incidence rates, respectively: adjusted HR 2.05, 95% CI 0.98–4.25, p = 0.06). In summary, DAA treatment with SOF was not associated with an increase in the development of de novo HCC.
Impact of Bone Marrow miR-21 Expression on Acute Myeloid Leukemia T Lymphocyte Fragility and Dysfunction
Authors: Moussa Agha Douâa , Rouas Redouane , Najar Mehdi , Bouhtit Fatima , Fayyad-Kazan Hussein , Lagneaux Laurence , Bron Dominique , Meuleman Nathalie , Lewalle Philippe , Merimi Makram
Published: September 2020

Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy in which antitumor immunity is impaired. The therapeutic management of AML requires understanding the mechanisms involved in the fragility and immune dysfunction of AML T lymphocytes. Methods: In this study, T lymphocytes from healthy donors (HD) and AML patients were used. Extracellular vesicles (EVs) from leukemic cells were screened for their microRNA content and impact on T lymphocytes. Flow cytometry, transcriptomic as well as lentiviral transduction techniques were used to carry out the research. Results: We observed increased cell death of T lymphocytes from AML patients. EVs from leukemia myeloid cell lines harbored several miRNAs, including miR-21, and were able to induce T lymphocyte death. Compared to that in HD, miR-21 was overexpressed in both the bone marrow fluid and infiltrating T lymphocytes of AML patients. MiR-21 induces T lymphocyte cell death by upregulating proapoptotic gene expression. It also increases the immunosuppressive profile of T lymphocytes by upregulating the IL13, IL4, IL10, and FoxP3 genes. Conclusions: Our results demonstrate that miR-21 plays a significant role in AML T lymphocyte dysfunction and apoptosis. Targeting miR-21 may be a novel approach to restore the efficacy of the immune response against AML.
Tsc1 Regulates the Proliferation Capacity of Bone-Marrow Derived Mesenchymal Stem Cells
Authors: Guijarro Maria V. , Danielson Laura S. , Cañamero Marta , Nawab Akbar , Abrahan Carolina , Hernando Eva , Palmer Glyn D.
Published: September 2020

TSC1 is a tumor suppressor that inhibits cell growth via negative regulation of the mammalian target of rapamycin complex (mTORC1). TSC1 mutations are associated with Tuberous Sclerosis Complex (TSC), characterized by multiple benign tumors of mesenchymal and epithelial origin. TSC1 modulates self-renewal and differentiation in hematopoietic stem cells; however, its effects on mesenchymal stem cells (MSCs) are unknown. We investigated the impact of Tsc1 inactivation in murine bone marrow (BM)-MSCs, using tissue-specific, transgelin (Tagln)-mediated cre-recombination, targeting both BM-MSCs and smooth muscle cells. Tsc1 mutants were viable, but homozygous inactivation led to a dwarfed appearance with TSC-like pathologies in multiple organs and reduced survival. In young (28 day old) mice, Tsc1 deficiency-induced significant cell expansion of non-hematopoietic BM in vivo, and MSC colony-forming potential in vitro, that was normalized upon treatment with the mTOR inhibitor, everolimus. The hyperproliferative BM-MSC phenotype was lost in aged (1.5 yr) mice, and Tsc1 inactivation was also accompanied by elevated ROS and increased senescence. ShRNA-mediated knockdown of Tsc1 in BM-MSCs replicated the hyperproliferative BM-MSC phenotype and led to impaired adipogenic and myogenic differentiation. Our data show that Tsc1 is a negative regulator of BM-MSC proliferation and support a pivotal role for the Tsc1-mTOR axis in the maintenance of the mesenchymal progenitor pool.
Alterations in Progesterone Receptor Isoform Balance in Normal and Neoplastic Breast Cells Modulates the Stem Cell Population
Authors: Recouvreux María Sol , Diaz Bessone María Inés , Taruselli Agustina , Todaro Laura , Lago Huvelle María Amparo , Sampayo Rocío G. , Bissell Mina J. , Simian Marina
Published: September 2020

To investigate the role of PR isoforms on the homeostasis of stem cells in the normal and neoplastic mammary gland, we used PRA and PRB transgenic mice and the T47D human breast cancer cell line and its derivatives, T47D YA and YB (manipulated to express only PRA or PRB, respectively). Flow cytometry and mammosphere assays revealed that in murine breast, overexpression of PRB leads to an increase in luminal and basal progenitor/stem cells. Ovariectomy had a negative impact on the luminal compartment and induced an increase in mammosphere-forming capacity in cells derived from WT and PRA mice only. Treatment with ICI 182,780 augmented the mammosphere-forming capacity of cells isolated from WT and PRA mice, whilst those from PRB remained unaltered. T47D YB cells showed an increase in the CD44+/CD24Low/− subpopulation; however, the number of tumorspheres did not vary relative to T47D and YA, even though they were larger, more irregular, and had increased clonogenic capacity. T47D and YA tumorspheres were modulated by estrogen/antiestrogens, whereas YB spheres remained unchanged in size and number. Our results show that alterations in PR isoform balance have an impact on normal and tumorigenic breast progenitor/stem cells and suggest a key role for the B isoform, with implications in response to antiestrogens.
Endocrine Resistance in Breast Cancer: The Role of Estrogen Receptor Stability
Authors: Jeffreys Sarah A. , Powter Branka , Balakrishnar Bavanthi , Mok Kelly , Soon Patsy , Franken André , Neubauer Hans , de Souza Paul , Becker Therese M.
Published: September 2020

Therapy of hormone receptor positive breast cancer (BCa) generally targets estrogen receptor (ER) function and signaling by reducing estrogen production or by blocking its interaction with the ER. Despite good long-term responses, resistance to treatment remains a significant issue, with approximately 40% of BCa patients developing resistance to ET. Mutations in the gene encoding ERα, ESR1, have been identified in BCa patients and are implicated as drivers of resistance and disease recurrence. Understanding the molecular consequences of these mutations on ER protein levels and its activity, which is tightly regulated, is vital. ER activity is in part controlled via its short protein half-life and therefore changes to its stability, either through mutations or alterations in pathways involved in protein stability, may play a role in therapy resistance. Understanding these connections and how ESR1 alterations could affect protein stability may identify novel biomarkers of resistance. This review explores the current reported data regarding posttranslational modifications (PTMs) of the ER and the potential impact of known resistance associated ESR1 mutations on ER regulation by affecting these PTMs in the context of ET resistance.
Intravitreal Co-Administration of GDNF and CNTF Confers Synergistic and Long-Lasting Protection against Injury-Induced Cell Death of Retinal Ganglion Cells in Mice
Authors: Dulz Simon , Bassal Mahmoud , Flachsbarth Kai , Riecken Kristoffer , Fehse Boris , Schlichting Stefanie , Bartsch Susanne , Bartsch Udo
Published: September 2020

We have recently demonstrated that neural stem cell-based intravitreal co-administration of glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) confers profound protection to injured retinal ganglion cells (RGCs) in a mouse optic nerve crush model, resulting in the survival of ~38% RGCs two months after the nerve lesion. Here, we analyzed whether this neuroprotective effect is long-lasting and studied the impact of the pronounced RGC rescue on axonal regeneration. To this aim, we co-injected a GDNF- and a CNTF-overexpressing neural stem cell line into the vitreous cavity of adult mice one day after an optic nerve crush and determined the number of surviving RGCs 4, 6 and 8 months after the lesion. Remarkably, we found no significant decrease in the number of surviving RGCs between the successive analysis time points, indicating that the combined administration of GDNF and CNTF conferred lifelong protection to injured RGCs. While the simultaneous administration of GDNF and CNTF stimulated pronounced intraretinal axon growth when compared to retinas treated with either factor alone, numbers of regenerating axons in the distal optic nerve stumps were similar in animals co-treated with both factors and animals treated with CNTF only.
Changes in Physical and Chemical Properties of Thermally and Oxidatively Degraded Sunflower Oil and Palm Fat
Authors: Wiege Berthold , Fehling Eberhard , Matthäus Bertrand , Schmidt Marcus
Published: September 2020

Deep-fat frying is an important process used worldwide for the preparation of foods. Due to oxidation, hydrolysis, decomposition and oligomerization, numerous polar compounds are formed. These compounds change the physical, nutritional and sensory properties of the oil or fat. The standard methods of the German Society for Fat Science for the assessment of the quality of frying fats are time consuming and cost intensive. Therefore, alternative cost-effective and sensitive rapid methods, which ideally allow the quantitative determination of the quality of frying fats “in-line” in the deep-frying pan are needed. Sunflower oil and palm fat were thermally and oxidatively degraded in a beaker at atmospheric pressure under intensive stirring for 76 h at 175 °C. To evaluate the development of the physical properties during heat treatment, the viscosity and dielectric constant of these oils were measured. The temperature in a deep-frying pan can vary within a wide range (160–190 °C), and the viscosity and dielectric constant show a strong temperature dependence. Therefore, it was necessary to measure the temperature dependence of the viscosity and dielectric constant of the different degraded oils. Additionally, their chemical properties were characterized by high-performance gel permeation chromatography and Fourier-transform infrared spectroscopy (FTIR). The determination of the dielectric constant, which is directly correlated with the concentration of polar compounds, seems to be the best method for the assessment of the quality of used frying oils.
Evaluating Alternatives to Cold Stabilization in Wineries: The Use of Carboxymethyl Cellulose, Potassium Polyaspartate, Electrodialysis and Ion Exchange Resins
Authors: Martínez-Pérez Maria Pilar , Bautista-Ortín Ana Belén , Durant Valerie , Gómez-Plaza Encarna
Published: September 2020

The tartaric stabilization of wines before bottling to avoid the precipitation of tartaric acid salts is an important and common step during wine production. The presence of precipitated salt crystals in bottled wines is detrimental to their quality and can even be a legal issue in some countries. Different methodologies are used in wineries to substitute the classical low-temperature stabilization process, which is an effective but costly process. This study comprises two years of experiments with red wines at an industrial scale. In the first year of the experiment, two subtractive methods (ionic exchange resins and electrodialysis) were tested, whereas two additive methods (potassium polyaspartate and carboxymethyl cellulose, both of them containing gum Arabic) were tested the second year. The tartaric stability of the wines, together with the oenological, chromatic and sensory characteristics, were followed during one year in the bottle. The results indicate that carboxymethyl cellulose and potassium polyaspartate (both combined with gum Arabic) were best at maintaining the sensory and chromatic characteristics during storage, with potassium polyaspartate providing a good tartaric stability to the treated wine and this wine being, in general, preferred in a sensory analysis test.
Application of Liquid Chromatography in Food Analysis
Authors: Núñez Oscar , Lucci Paolo
Published: September 2020

Food products are very complex mixtures consisting of naturally-occurring compounds and other substances, generally originating from technological processes, agrochemical treatments, or packaging materials [...]
Identification of DNMT3B2 as the Predominant Isoform of DNMT3B in Porcine Alveolar Macrophages and Its Involvement in LPS-Stimulated TNF-α Expression
Authors: Zhang Yanbing , Li Hui , Xiang Xiao , Lu Yan , Sharma Mona , Li Zongjie , Liu Ke , Wei Jianchao , Shao Donghua , Li Beibei , Ma Zhiyong , Qiu Yafeng
Published: September 2020

DNA methyltransferase 3B (DNMT3B) as one member of the DNMT family functions as a de novo methyltransferase, characterized as more than 30 splice variants in humans and mice. However, the expression patterns of DNMT3B in pig as well as the biological function of porcine DNMT3B remain to be determined. In this study, we first examined the expression patterns of DNMT3B in porcine alveolar macrophages (PAM). We demonstrated that only DNMT3B2 and DNMT3B3 were the detectable isoforms in PAM. Furthermore, we revealed that DNTM3B2 was the predominant isoform in PAM. Next, in the model of LPS (lipopolysaccharide)-activated PAM, we showed that in comparison to the unstimulated PAM, (1) expression of DNTM3B is reduced; (2) the methylation level of TNF-α gene promoter is decreased. We further establish that DNMT3B2-mediated methylation of TNF-α gene promoter restricts induction of TNF-α in the LPS-stimulated PAM. In summary, these findings reveal that DNMT3B2 is the predominant isoform in PAM and its downregulation contributes to expression of TNF-α via hypomethylation of TNF-α gene promoter in the LPS-stimulated PAM.
Effect of CYP3A4*22 and PPAR-α Genetic Variants on Platelet Reactivity in Patients Treated with Clopidogrel and Lipid-Lowering Drugs Undergoing Elective Percutaneous Coronary Intervention
Authors: Bergmeijer Thomas , Yasmina Alfi , Vos Gerrit , Janssen Paul , Hackeng Christian , Kelder Johannes , Verma Shefali , Ritchie Marylyn , Gong Li , Klein Teri ,   ICPC investigators, de Boer Anthonius , Klungel Olaf , ten Berg Jurriën , Deneer Vera
Published: September 2020

This study aims to determine whether genetic variants that influence CYP3A4 expression are associated with platelet reactivity in clopidogrel-treated patients undergoing elective percutaneous coronary intervention (PCI), and to evaluate the influence of statin/fibrate co-medication on these associations. A study cohort was used containing 1124 consecutive elective PCI patients in whom CYP3A4*22 and PPAR-α (G209A and A208G) SNPs were genotyped and the VerifyNow P2Y12 platelet reactivity test was performed. Minor allele frequencies were 0.4% for CYP3A4*22/*22, 6.8% for PPAR-α G209A AA, and 7.0% for PPAR-α A208G GG. CYP3A4*22 was not associated with platelet reactivity. The PPAR-α genetic variants were significantly associated with platelet reactivity (G209A AA: −24.6 PRU [−44.7, −4.6], p = 0.016; A208G GG: −24.6 PRU [−44.3, −4.8], p = 0.015). Validation of these PPAR-α results in two external cohorts, containing 716 and 882 patients, respectively, showed the same direction of effect, although not statistically significant. Subsequently, meta-analysis of all three cohorts showed statistical significance of both variants in statin/fibrate users (p = 0.04 for PPAR-a G209A and p = 0.03 for A208G), with no difference in statin/fibrate non-users. In conclusion, PPAR-α G209A and A208G were associated with lower platelet reactivity in patients undergoing elective PCI who were treated with clopidogrel and statin/fibrate co-medication. Further research is necessary to confirm these findings.
Underreporting of Obesity in Hospital Inpatients: A Comparison of Body Mass Index and Administrative Documentation in Australian Hospitals
Authors: Di Bella Alexandra L , Comans Tracy , Gane Elise M , Young Adrienne M , Hickling Donna F , Lucas Alisha , Hickman Ingrid J , Banks Merrilyn
Published: September 2020

Despite its high prevalence, there is no systematic approach to documenting and coding obesity in hospitals. This study aimed to determine the prevalence of obesity among inpatients, the proportion of obese patients recognised as obese by hospital administration, and the cost associated with their admission. A cross-sectional study was undertaken in three hospitals in Queensland, Australia. Inpatients present on three audit days were included in this study. Data collected were age, sex, height, and weight. Body mass index (BMI) was calculated in accordance with the World Health Organization’s definition. Administrative data were sourced from hospital records departments to determine the number of patients officially documented as obese. Total actual costing data were sourced from hospital finance departments. From a combined cohort of n = 1327 inpatients (57% male, mean (SD) age: 61 (19) years, BMI: 28 (9) kg/m2), the prevalence of obesity was 32% (n = 421). Only half of obese patients were recognised as obese by hospital administration. A large variation in the cost of admission across BMI categories prohibited any statistical determination of difference. Obesity is highly prevalent among hospital inpatients in Queensland, Australia. Current methods of identifying obesity for administrative/funding purposes are not accurate and would benefit from reforms to measure the true impact of healthcare costs from obesity.
Extension of the Thermographic Signal Reconstruction Technique for an Automated Segmentation and Depth Estimation of Subsurface Defects
Authors: Schager Alexander , Zauner Gerald , Mayr Günther , Burgholzer Peter
Published: September 2020

With increased use of light-weight materials with low factors of safety, non-destructive testing becomes increasingly important. Thanks to the advancement of infrared camera technology, pulse thermography is a cost efficient way to detect subsurface defects non-destructively. However, currently available evaluation algorithms have either a high computational cost or show poor performance if any geometry other than the most simple kind is surveyed. We present an extension of the thermographic signal reconstruction technique which can automatically segment and image defects from sound areas, while also estimating the defect depth, all with low computational cost. We verified our algorithm using real world measurements and compare our results to standard active thermography algorithms with similar computational complexity. We found that our algorithm can detect defects more accurately, especially when more complex geometries are examined.
Sedimentary Facies Analysis, Reservoir Characteristics and Paleogeography Significance of the Early Jurassic to Eocene Carbonates in Epirus (Ionian Zone, Western Greece)
Authors: Kontakiotis George , Moforis Leonidas , Karakitsios Vasileios , Antonarakou Assimina
Published: September 2020

Sedimentological, micropalaeontological, and marine geological results from the Early Jurassic to Eocene carbonate formations of the Ionian zone, from six localities of Epirus, provide new insights into the basin palaeogeographic evolution and better correlation with coeval analogous tectono-stratigraphic successions along the southern margin of the Neo-Tethys Ocean. Facies analysis allowed the recognition of several microfacies types and their depositional characteristics. During the Early Jurassic, autochthonous carbonates (Pantokrator Limestones) were deposited in shallow-water environment. The overlying (hemi)pelagic Siniais or their lateral equivalent Louros Limestones were deposited to the basin borders and mark the general deepening of the Ionian domain. During Toarcian to Tithonian, the Ionian Basin was characterized by an internal differentiation in small sub-basins with half-graben geometry presenting abrupt thickness and facies changes. The deeper parts were characterized by continuous sedimentation, while the elevated parts were marked by unconformities. The Early Cretaceous marks the homogenization of sedimentation by the deposition of the pelagic Vigla Limestones all over the Ionian zone. The transition from the Early to Late Cretaceous records a significant carbonate diversification in terms of biota assemblages, and related mineralogy due to intense tectonic activity in the region. From Late Cretaceous to Paleogene, allochthonous carbonates were transported to the outer shelf by turbidity currents (calciturbidites) and/or debris flows (limestones with breccia) formed by the gravitational collapse of the platform margin. Additional porosity and bulk density measurements showed that petrophysical behavior of these carbonates are controlled by the depositional environment and further influenced by diagenetic processes. The partly dolomitized neritic Jurassic carbonates, but mainly the Senonian calciturbidites and the microbrecciated Paleocene/Eocene limestones display the higher average porosity values, and therefore present enhanced carbonate reservoir quality.
Genome-Scale Metabolic Model of the Human Pathogen Candida albicans: A Promising Platform for Drug Target Prediction
Authors: Viana Romeu , Dias Oscar , Lagoa Davide , Galocha Mónica , Rocha Isabel , Teixeira Miguel Cacho
Published: September 2020

Candida albicans is one of the most impactful fungal pathogens and the most common cause of invasive candidiasis, which is associated with very high mortality rates. With the rise in the frequency of multidrug-resistant clinical isolates, the identification of new drug targets and new drugs is crucial in overcoming the increase in therapeutic failure. In this study, the first validated genome-scale metabolic model for Candida albicans, iRV781, is presented. The model consists of 1221 reactions, 926 metabolites, 781 genes, and four compartments. This model was reconstructed using the open-source software tool merlin 4.0.2. It is provided in the well-established systems biology markup language (SBML) format, thus, being usable in most metabolic engineering platforms, such as OptFlux or COBRA. The model was validated, proving accurate when predicting the capability of utilizing different carbon and nitrogen sources when compared to experimental data. Finally, this genome-scale metabolic reconstruction was tested as a platform for the identification of drug targets, through the comparison between known drug targets and the prediction of gene essentiality in conditions mimicking the human host. Altogether, this model provides a promising platform for global elucidation of the metabolic potential of C. albicans, possibly guiding the identification of new drug targets to tackle human candidiasis.