bluuebunny/crossref_metadata_2025 huggingface dataset:
Vibrotactile Stimulation of Nail of Hallux during Walking: Effect on Center-of-Mass Movement in Healthy Young Adults
Authors: Toda Haruki , Hashimoto Yuki , Tada Mitsunori
Published: June 2020

Previous studies have reported that vibrotactile stimulation of the nail of the hallux decreases the variability of the center-of-mass (CoM) movement in the lateral direction in subjects performing unsteady walking on the spot. This study investigated the effect of vibrotactile stimulation of the nail of the hallux on the CoM movement during walking. Healthy young males were asked to walk with and without stimulation, and their CoM was measured. The intrasubject mean and coefficient of variation (CV) of their walking speed, stance time, and CoM movement were evaluated. The differences between the variables with and without stimulation were determined, and the baseline-dependent effects of the stimulation on these variables were analyzed. It was observed that stimulation had a negative baseline-dependent effect on the CVs of the walking speed, stance time, and the CoM movement in the lateral direction. In particular, stimulation decreased the CV of the CoM movement in the lateral direction for subjects with a greater variability. Vibrotactile stimulation of the nail of the hallux can reduce the variability of the lateral displacement of the CoM movement in healthy young subjects who otherwise show a large variability of the CoM movement during walking without stimulation.
Influence of Chloride Ions on Electrochemical Corrosion Behavior of Dual-Phase Steel over Conventional Rebar in Pore Solution
Authors: Abdo Hany S. , Seikh Asiful H. , Mohammed Jabair A. , Luqman Monis , Ragab Sameh A. , Almotairy Saud M.
Published: June 2020

Reinforced steel bars (rebar) are extensively used in construction, and the main challenge is in minimizing corrosion due to oxide or passive layer breakdown. In contrast, dual-phase (DP) steel has good corrosion resistance. This study investigated the effect of Cl− ions on the electrochemical corrosion behavior of DP rebar and conventional rebar. Corrosion behavior studies and electrochemical measurements were conducted on DP rebar and conventional rebar in simulated concrete pore solution with different concentrations of Cl− ions. Microstructure analysis, surface morphology analysis, and corroded surface characterization were performed using optical microscopy, field emission scanning electron microscopy, and Raman spectroscopy, respectively. Potentiodynamic polarization and electrochemical impedance spectroscopy measurements revealed that DP rebar has good passivity, leading to better corrosion resistance and greater strength compared to ordinary rebar. In addition, DP rebar showed better passivity behavior compared to conventional rebar in alkaline solution. Therefore, the presence of a dual phase (ferrite and martensite) in reinforced concrete structured steel induces good corrosion resistance.
Impact of the Emission Control of Diesel Vehicles on Black Carbon (BC) Concentrations over China
Authors: Zhou Jiamao , Tie Xuexi , Yu Yunbo , Zhao Shuyu , Li Guohui , Liu Suixin , Zhang Ting , Dai Wenting
Published: June 2020

In order to reduce black carbon (BC) emissions from diesel vehicles, a regional atmospheric chemistry model (WRF-Chem) was used to investigate the effects of installing a high-efficiency device for vehicle exhaust control, a diesel particulate filter (DPF), on diesel vehicles in China. To reduce the uncertainty of estimation, three sensitivity experiments were designed and conducted for different emission scenarios. The first experiment uses the standard black carbon emissions of diesel vehicles without engaging in any emission control actions (referred to as CTRL), and the other two experiments were conducted using different DPF devices to reduce BC emissions by 65% (CASE1) and 39% (CASE2), respectively. The results show that the model simulation reasonably represents the measured BC concentrations. The highest BC concentrations occurred in large cities of the North China Plain (NCP) and present important seasonal variations. The results suggest that the reduction in diesel vehicle emissions has great benefits for reducing BC pollution not only in winter but also in other seasons. Sensitivity studies show that in CASE1, the average BC concentrations decreased about ~6% in January and by more than 10% in the other seasons. The greatest reduction exceeded 50%. In CASE2, the average BC concentrations decreased by about ~3.5% in January and by more than 7% in the other seasons. This study suggests that adding DPF to a diesel vehicle can have a significant influence on reducing BC concentrations in China. Thus, this study provides a practical basis by which diesel vehicle emissions can be reduced.
Regulation of the Ocular Cell/Tissue Response by Implantable Biomaterials and Drug Delivery Systems
Authors: Baino Francesco , Kargozar Saeid
Published: June 2020

Therapeutic advancements in the treatment of various ocular diseases is often linked to the development of efficient drug delivery systems (DDSs), which would allow a sustained release while maintaining therapeutic drug levels in the target tissues. In this way, ocular tissue/cell response can be properly modulated and designed in order to produce a therapeutic effect. An ideal ocular DDS should encapsulate and release the appropriate drug concentration to the target tissue (therapeutic but non-toxic level) while preserving drug functionality. Furthermore, a constant release is usually preferred, keeping the initial burst to a minimum. Different materials are used, modified, and combined in order to achieve a sustained drug release in both the anterior and posterior segments of the eye. After giving a picture of the different strategies adopted for ocular drug release, this review article provides an overview of the biomaterials that are used as drug carriers in the eye, including micro- and nanospheres, liposomes, hydrogels, and multi-material implants; the advantages and limitations of these DDSs are discussed in reference to the major ocular applications.
Concise Polygenic Models for Cancer-Specific Identification of Drug-Sensitive Tumors from Their Multi-Omics Profiles
Authors: Naulaerts Stefan , Menden Michael P. , Ballester Pedro J.
Published: June 2020

In silico models to predict which tumors will respond to a given drug are necessary for Precision Oncology. However, predictive models are only available for a handful of cases (each case being a given drug acting on tumors of a specific cancer type). A way to generate predictive models for the remaining cases is with suitable machine learning algorithms that are yet to be applied to existing in vitro pharmacogenomics datasets. Here, we apply XGBoost integrated with a stringent feature selection approach, which is an algorithm that is advantageous for these high-dimensional problems. Thus, we identified and validated 118 predictive models for 62 drugs across five cancer types by exploiting four molecular profiles (sequence mutations, copy-number alterations, gene expression, and DNA methylation). Predictive models were found in each cancer type and with every molecular profile. On average, no omics profile or cancer type obtained models with higher predictive accuracy than the rest. However, within a given cancer type, some molecular profiles were overrepresented among predictive models. For instance, CNA profiles were predictive in breast invasive carcinoma (BRCA) cell lines, but not in small cell lung cancer (SCLC) cell lines where gene expression (GEX) and DNA methylation profiles were the most predictive. Lastly, we identified the best XGBoost model per cancer type and analyzed their selected features. For each model, some of the genes in the selected list had already been found to be individually linked to the response to that drug, providing additional evidence of the usefulness of these models and the merits of the feature selection scheme.
Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation
Authors: Jossin Yves
Published: June 2020

During embryonic development and adulthood, Reelin exerts several important functions in the brain including the regulation of neuronal migration, dendritic growth and branching, dendritic spine formation, synaptogenesis and synaptic plasticity. As a consequence, the Reelin signaling pathway has been associated with several human brain disorders such as lissencephaly, autism, schizophrenia, bipolar disorder, depression, mental retardation, Alzheimer’s disease and epilepsy. Several elements of the signaling pathway are known. Core components, such as the Reelin receptors very low-density lipoprotein receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2), Src family kinases Src and Fyn, and the intracellular adaptor Disabled-1 (Dab1), are common to most but not all Reelin functions. Other downstream effectors are, on the other hand, more specific to defined tasks. Reelin is a large extracellular protein, and some aspects of the signal are regulated by its processing into smaller fragments. Rather than being inhibitory, the processing at two major sites seems to be fulfilling important physiological functions. In this review, I describe the various cellular events regulated by Reelin and attempt to explain the current knowledge on the mechanisms of action. After discussing the shared and distinct elements of the Reelin signaling pathway involved in neuronal migration, dendritic growth, spine development and synaptic plasticity, I briefly outline the data revealing the importance of Reelin in human brain disorders.
Vibrational Spectroscopy of Peritoneal Dialysis Effluent for Rapid Assessment of Patient Characteristics
Authors: Grunert Tom , Herzog Rebecca , Wiesenhofer Florian M. , Vychytil Andreas , Ehling-Schulz Monika , Kratochwill Klaus
Published: June 2020

Peritoneal dialysis (PD) offers specific advantages over hemodialysis, enabling increased autonomy of patients with end-stage renal disease, but PD-related complications need to be detected in a timely manner. Fourier transform infrared (FTIR) spectroscopy could provide rapid and essential insights into the patients’ risk profiles via molecular fingerprinting of PD effluent, an abundant waste material that is rich in biological information. In this study, we measured FTIR spectroscopic profiles in PD effluent from patients taking part in a randomized controlled trial of alanyl-glutamine addition to the PD-fluid. Principal component analysis of FTIR spectra enabled us to differentiate between effluent samples from patients immediately after completion of instillation of the PD-fluid into the patients’ cavity and 4 h later as well as between patients receiving PD-fluid supplemented with 8 mM alanyl-glutamine compared with control. Moreover, feasibility of FTIR spectroscopy coupled to supervised classification algorithms to predict patient-, PD-, as well as immune-associated parameters were investigated. PD modality (manual continuous ambulatory PD (CAPD) vs. cycler-assisted automated PD (APD)), residual urine output, ultrafiltration, transport parameters, and cytokine concentrations showed high predictive potential. This study provides proof-of-principle that molecular signatures determined by FTIR spectroscopy of PD effluent, combined with machine learning, are suitable for cost-effective, high-throughput diagnostic purposes in PD.
Validation of a Novel Zebrafish Model of Dengue Virus (DENV-3) Pathology Using the Pentaherbal Medicine Denguenil Vati
Authors: Balkrishna Acharya , Solleti Siva Kumar , Verma Sudeep , Varshney Anurag
Published: June 2020

Dengue is a devastating viral fever of humans, caused by dengue virus. Using a novel zebrafish model of dengue pathology, we validated the potential anti-dengue therapeutic properties of pentaherbal medicine, Denguenil Vati. At two different time points (at 7 and 14 days post infection with dengue virus), we tested three translational doses (5.8 μg/kg, 28 μg/kg, and 140 μg/kg). Dose- and time-dependent inhibition of the viral copy numbers was identified upon Denguenil Vati treatment. Hepatocyte necrosis, liver inflammation, and red blood cell (RBC) infiltration into the liver were significantly inhibited upon Denguenil treatment. Treatment with Denguenil Vati significantly recovered the virus-induced decreases in total platelet numbers and total RBC count, and concomitantly increasing hematocrit percentage, in a dose- and time-dependent manner. Conversely, virus-induced white blood cell (WBC) counts were significantly normalized. Virus-induced hemorrhage was completely abrogated by Denguenil after 14 days, at all the doses tested. Gene expression analysis identified a significant decrease in disease-induced endothelial apoptotic marker Angiopoetin2 (Ang-2) and pro-inflammatory chemokine marker CCL3 upon Denguenil treatment. Presence of gallic acid, ellagic acid, palmetin, and berberine molecules in the Denguenil formulation was detected by HPLC. Taken together, our results exhibit the potential therapeutic properties of Denguenil Vati in ameliorating pathological features of dengue.
Prediction Value of Serum NGAL in the Diagnosis and Prognosis of Experimental Acute and Chronic Kidney Injuries
Authors: Wang Weida , Li Zhaojun , Chen Yuanyuan , Wu Haijie , Zhang Sen , Chen Xiaoguang
Published: June 2020

Sensitive and accurate serum biomarkers for monitoring acute and chronic kidney disease progression are more convenient and can better evaluate drug efficiency in pharmacological research. Neutrophil Gelatinase-associated Lipocalin (NGAL) is considered a hopeful early biomarker of acute kidney injury (AKI), but its utility in early prediction and prognosis of diabetic nephropathy (DN) and immune-mediated glomerulonephritis is still not clear. Moreover, detailed prognosis studies of NGAL in AKI are lacking, and most studies use a urine source. In the current study, through two experimental AKI and two chronic kidney injury animal models, serum NGAL (sNGAL) prediction values on diagnosis and prognosis of kidney injuries in animal disease models have been investigated thoroughly. Four experimental kidney disease models include cisplatin-induced and lipopolysaccharide (LPS)-induced AKI, streptozocin-induced diabetic nephropathy (DN), and cationized-bovine serum albumin (c-BSA)-induced membranous nephropathy (MN), respectively. The sNGAL concentration was measured at different stages of kidney injury (KI) in each experimental model, and receiver operating characteristic (ROC) analyses were performed to investigate the diagnosis efficiency of sNGAL for KI. Western blot and immunohistochemistry were used to measure the protein levels in the kidneys, and pathological analysis was used as the gold standard to confirm KI. Results suggest that sNGAL can predict early diagnosis of cisplatin-induced AKI accurately but is less powerful in later stages compared to blood urea nitrogen (BUN) and serum creatinine (Scr). sNGAL is sensitive but lacks specificity to evaluate early kidney injury for LPS-induced AKI under low-dosage LPS challenge. sNGAL is not an efficient biomarker for early diagnosis of STZ-induced DN, but sNGAL is an efficient predictor for the early diagnosis and prognosis of immune-mediated MN. In conclusion, application of sNGAL as a kidney injury biomarker to determine the diagnosis and prognosis in pharmacological studies is dependent on experimental animal models.
The Fabp4-Cre-Model is Insufficient to Study Hoxc9 Function in Adipose Tissue
Authors: Dommel Sebastian , Berger Claudia , Kunath Anne , Kern Matthias , Gericke Martin , Kovacs Peter , Guiu-Jurado Esther , Klöting Nora , Blüher Matthias
Published: June 2020

Developmental genes are important regulators of fat distribution and adipose tissue (AT) function. In humans, the expression of homeobox c9 (HOXC9) is significantly higher in subcutaneous compared to omental AT and correlates with body fat mass. To gain more mechanistic insights into the role of Hoxc9 in AT, we generated Fabp4-Cre-mediated Hoxc9 knockout mice (ATHoxc9-/-). Male and female ATHoxc9-/- mice were studied together with littermate controls both under chow diet (CD) and high-fat diet (HFD) conditions. Under HFD, only male ATHoxc9-/- mice gained less body weight and exhibited improved glucose tolerance. In both male and female mice, body weight, as well as the parameters of glucose metabolism and AT function were not significantly different between ATHoxc9-/- and littermate control CD fed mice. We found that crossing Hoxc9 floxed mice with Fabp4-Cre mice did not produce a biologically relevant ablation of Hoxc9 in AT. However, we hypothesized that even subtle reductions of the generally low AT Hoxc9 expression may cause the leaner and metabolically healthier phenotype of male HFD-challenged ATHoxc9-/- mice. Different models of in vitro adipogenesis revealed that Hoxc9 expression precedes the expression of Fabp4, suggesting that ablation of Hoxc9 expression in AT needs to be achieved by targeting earlier stages of AT development.
The Role of Cutibacterium acnes in Intervertebral Disc Inflammation
Authors: Schmid Bettina , Hausmann Oliver , Hitzl Wolfgang , Achermann Yvonne , Wuertz-Kozak Karin
Published: June 2020

Recently, the role of infection of the intervertebral disc (IVD) with Cutibacterium acnes (C. acnes) as a contributor to disc-related low back pain (LBP) has been discussed. The aim of this study was to investigate whether and how C. acnes contributes to the inflammatory processes during IVD disease. The prevalence of C. acnes infection in human IVD tissue was determined by aerobic and anaerobic culture. Thereafter, primary human IVD cells were infected with a reference and a clinical C. acnes strain and analyzed for pro-inflammatory markers (gene/protein level). In a subsequent experiment, the involvement of the Toll-like receptor (TLR) pathway was investigated by co-treatment with sparstolonin B, a TLR2/4 inhibitor. We detected C. acnes in 10% of IVD biopsies (with either herniation or degeneration). Stimulating IVD cells with both C. acnes strains strongly and significantly upregulated expression of Interleukin (IL)-1β, IL-6, IL-8, and inducible nitric oxide synthase (iNOS). IL-6, cyclooxygenase (COX)-2, and iNOS expression was reduced upon TLR2/4 inhibition in 3 out of 5 donors, whereby responders and non-responders could not be differentiated by their basal TLR2 or TLR4 expression levels. We demonstrate that exposure of IVD cells to C. acnes induces an inflammatory response that may contribute to the development of discogenic LBP by involving TLR2/4 activation, yet only in a subgroup of patients. Whether the same response will be observed in vivo and where lower inoculums are present remains to be proven in future studies.
Regulatory Effects of Skate Skin-Derived Collagen Peptides with Different Molecular Weights on Lipid Metabolism in the Liver and Adipose Tissue
Authors: Woo Minji , Noh Jeong Sook
Published: June 2020

This study investigated the effects of skate skin collagen peptide (SSCP) with different molecular weights (MWs) on the lipid metabolism in the liver and adipose tissue. Male db/db mice were orally administered with water (control group) or low SSCP (LCP group) or high SSCP (HCP group) MW for 8 weeks whereas male m/m mice were used for comparison (normal group) (n = 10 each group). Compared to the control group, the LCP and HCP groups had lower adipose tissue mass, plasma and hepatic lipid concentrations, and plasma leptin levels (p < 0.05). Protein expression levels of lipogenesis-related protein were reduced in both liver and adipose tissues of SSCP-fed groups whereas those for lipolysis were elevated (p < 0.05). In particular, the LCP had the higher effects relative to the HCP. The above results were supported by histological analysis, revealing that SSCP administration decreased the size of adipose droplets and suppressed hepatic lipid accumulation. Our results showed that SSCP has potential antiobesity properties through the improvement of lipid metabolism in the liver and adipose tissue; in particular, the lower MW of collagen peptide had the greater effects.
Domesticity ‘Behind Bars’: Project by Rem Koolhaas/OMA for the Renovation of a Panopticon Prison in Arnhem
Authors: Martinez-Millana Elena , Cánovas Alcaraz Andrés
Published: June 2020

This article focuses on the project for the renovation of a Panopticon prison in Arnhem, the Netherlands (1979–1980), designed by Rem Koolhaas/OMA. The analysis of its reception shows that, despite being well known, it has been little studied and discussed, and although it was not built, it had an impact on prison architecture. It seems appropriate to tackle it now because the Koepelgevangenis (dome prison) of Arnhem has gained current relevance due to plans for it to be turned into a hotel. The renovation project for the Koepelgevangenis explicitly shows the presence of Foucault’s ideas on power and how these ideas exerted significant influence on the works carried out by Koolhaas. For Foucault, the Panopticon prison, such as the Koepelgevangenis, was the paradigmatic example of what he called the “disciplinary society”. Domesticity “behind bars” suggests that prisons can also be understood as domestic spaces. Moreover, it could be said that for Koolhaas, this Panopticon prison was a social condenser or a hotel for voluntary or involuntary prisoners. As a prison or as a hotel, it can also be interpreted as Foucault’s heterotopia, the intervention thus acquiring a new meaning which anticipated the future of this unique building.
Graphene Oxide/Fe-Based Composite Pre-Polymerized Coagulants: Synthesis, Characterization, and Potential Application in Water Treatment
Authors: Tolkou Athanasia K. , Zouboulis Anastasios I.
Published: June 2020

This study presents for the first time the synthesis and characterization of GO (graphene oxide), PFSiC (polyferric silicate chloride), and hybrid GO-PFSiC derivatives, aiming to enhance synergistically the performance of coagulation, when applied for the treatment of water. The structure and the morphology of composite GO-PFSiC coagulants were studied in detail by the application of FTIR, XRD, and SEM characterization techniques. Furthermore, the proposed coagulants were applied for the treatment of simulated turbid surface water. The effects of the reagent’s dosage, pH value, and experimental/operational conditions on the coagulation efficiency, applied mainly for the removal of turbidity, were examined. The results, obtained from the FTIR and XRD measurements, showed the presence of a bond between the PFSiC and the GO surface, indicating that the PFSiC particles are distributed uniformly on the surface of graphene, which was also confirmed by the SEM images. Especially, the composite compound GO-PFSiC1.5-15-0.5 presents the most uniform distribution of iron on the surface of graphene oxide and exhibits the optimum coagulation efficiency, while it significantly reduces the turbidity for doses above 3–5 mg/L, i.e., achieving the respective legislation limit as proposed by WHO. Specifically, at the alkaline pH values (>7.9), the removal of turbidity reaches 96%. Consequently, the results of this study render these materials as potential coagulant agents for further research and applications, aiming to also achieve the co-removal of other water components.
Optimizing Oncolytic Viral Design to Enhance Antitumor Efficacy: Progress and Challenges
Authors: Chaurasiya Shyambabu , Fong Yuman , Warner Susanne G.
Published: June 2020

The field of oncolytic virotherapy has seen remarkable advancements in last two decades, leading to approval of the first oncolytic immuno-virotherapy, Talimogene Laherparepvec, for the treatment of melanoma. A plethora of preclinical and clinical studies have demonstrated excellent safety profiles of other oncolytic viruses. While oncolytic viruses show clinical promise in already immunogenic malignancies, response rates are inconsistent. Response rates are even less consistent in immunosuppressed tumor microenvironments like those found in liver, pancreas, and MSI-stable colon cancers. Therefore, the efficacy of oncolytic viruses needs to be improved for more oncolytic viruses to enter mainstream cancer therapy. One approach to increase the therapeutic efficacy of oncolytic viruses is to use them as primers for other immunotherapeutics. The amenability of oncolytic viruses to transgene-arming provides an immense opportunity for investigators to explore different ways of improving the outcome of oncolytic therapy. In this regard, genes encoding immunomodulatory proteins are the most commonly studied genes for arming oncolytic viruses. Other transgenes used to arm oncolytic viruses include those with the potential to favorably modulate tumor stroma, making it possible to image the virus distribution and increase its suitability for combination with other therapeutics. This review will detail the progress made in arming oncolytic viruses with a focus on immune-modulatory transgenes, and will discuss the challenges that need to be addressed for more armed oncolytic viruses to find widespread clinical use.
Dysregulation of MITF Leads to Transformation in MC1R-Defective Melanocytes
Authors: Lavelle Timothy J. , Alver Tine Norman , Heintz Karen-Marie , Wernhoff Patrik , Nygaard Vegard , Nakken Sigve , Øy Geir Frode , Bøe Sigurd Leinæs , Urbanucci Alfonso , Hovig Eivind
Published: June 2020

The MC1R/cAMP/MITF pathway is a key determinant for growth, differentiation, and survival of melanocytes and melanoma. MITF-M is the melanocyte-specific isoform of Microphthalmia-associated Transcription Factor (MITF) in human melanoma. Here we use two melanocyte cell lines to show that forced expression of hemagglutinin (HA) -tagged MITF-M through lentiviral transduction represents an oncogenic insult leading to consistent cell transformation of the immortalized melanocyte cell line Hermes 4C, being a melanocortin-1 receptor (MC1R) compound heterozygote, while not causing transformation of the MC1R wild type cell line Hermes 3C. The transformed HA-tagged MITF-M transduced Hermes 4C cells form colonies in soft agar and tumors in mice. Further, Hermes 4C cells display increased MITF chromatin binding, and transcriptional reprogramming consistent with an invasive melanoma phenotype. Mechanistically, forced expression of MITF-M drives the upregulation of the AXL tyrosine receptor kinase (AXL), with concomitant downregulation of phosphatase and tensin homolog (PTEN), leading to increased activation of the PI3K/AKT pathway. Treatment with AXL inhibitors reduces growth of the transformed cells by reverting AKT activation. In conclusion, we present a model system of melanoma development, driven by MITF-M in the context of MC1R loss of function, and independent of UV exposure. This model provides a basis for further studies of critical changes in the melanocyte transformation process.
Dendrogenin A Synergizes with Cytarabine to Kill Acute Myeloid Leukemia Cells In Vitro and In Vivo
Authors: Serhan Nizar , Mouchel Pierre-Luc , de Medina Philippe , Segala Gregory , Mougel Aurélie , Saland Estelle , Rives Arnaud , Lamaziere Antonin , Despres Gaëtan , Sarry Jean-Emmanuel , Larrue Clément , Vergez François , Largeaud Laetitia , Record Michel , Récher Christian , Silvente-Poirot Sandrine , Poirot Marc
Published: June 2020

Dendrogenin A (DDA) is a mammalian cholesterol metabolite that displays potent antitumor properties on acute myeloid leukemia (AML). DDA triggers lethal autophagy in cancer cells through a biased activation of the oxysterol receptor LXRβ, and the inhibition of a sterol isomerase. We hypothesize that DDA could potentiate the activity of an anticancer drug acting through a different molecular mechanism, and conducted in vitro and in vivo combination tests on AML cell lines and patient primary tumors. We report here results from tests combining DDA with antimetabolite cytarabine (Ara-C), one of the main drugs used for AML treatment worldwide. We demonstrated that DDA potentiated and sensitized AML cells, including primary patient samples, to Ara-C in vitro and in vivo. Mechanistic studies revealed that this sensitization was LXRβ-dependent and was due to the activation of lethal autophagy. This study demonstrates a positive in vitro and in vivo interaction between DDA and Ara-C, and supports the clinical evaluation of DDA in combination with Ara-C for the treatment of AML.
Pimasertib Versus Dacarbazine in Patients With Unresectable NRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover
Authors: Lebbé Celeste , Dutriaux Caroline , Lesimple Thierry , Kruit Willem , Kerger Joseph , Thomas Luc , Guillot Bernard , de Braud Filippo , Garbe Claus , Grob Jean-Jacques , Loquai Carmen , Ferraresi Virginia , Robert Caroline , Vasey Paul , Conry Robert , Isaacs Richard , Espinosa Enrique , Schueler Armin , Massimini Giorgio , Dréno Brigitte
Published: June 2020

This study investigated the efficacy and safety of pimasertib (MEK1/MEK2 inhibitor) versus dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma. Phase II, multicenter, open-label trial. Patients with unresectable, stage IIIc/IVM1 NRAS-mutated cutaneous melanoma were randomized 2:1 to pimasertib (60 mg; oral twice-daily) or DTIC (1000 mg/m2; intravenously) on Day 1 of each 21-day cycle. Patients progressing on DTIC could crossover to pimasertib. Primary endpoint: investigator-assessed progression-free survival (PFS); secondary endpoints: overall survival (OS), objective response rate (ORR), quality of life (QoL), and safety. Overall, 194 patients were randomized (pimasertib n = 130, DTIC n = 64), and 191 received treatment (pimasertib n = 130, DTIC n = 61). PFS was significantly improved with pimasertib versus DTIC (median 13 versus 7 weeks, respectively; hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42–0.83; p = 0.0022). ORR was improved with pimasertib (odds ratio 2.24, 95% CI 1.00–4.98; p = 0.0453). OS was similar between treatments (median 9 versus 11 months, respectively; HR 0.89, 95% CI 0.61–1.30); 64% of patients receiving DTIC crossed over to pimasertib. Serious adverse events (AEs) were more frequent for pimasertib (57%) than DTIC (20%). The most common treatment-emergent AEs were diarrhea (82%) and blood creatine phosphokinase (CPK) increase (68%) for pimasertib, and nausea (41%) and fatigue (38%) for DTIC. Most frequent grade ≥3 AEs were CPK increase (34%) for pimasertib and neutropenia (15%) for DTIC. Mean QoL scores (baseline and last assessment) were similar between treatments. Pimasertib has activity in NRAS-mutated cutaneous melanoma and a safety profile consistent with known toxicities of MEK inhibitors. Trial registration: ClinicalTrials.gov, NCT01693068.
Expression Patterns of Immune Genes Reveal Heterogeneous Subtypes of High-Risk Neuroblastoma
Authors: Liu Zhenqiu , Grant Christa N. , Sun Lidan , Miller Barbara A. , Spiegelman Vladimir S. , Wang Hong-Gang
Published: June 2020

High risk neuroblastoma (HR-NB) remains difficult to treat, and its overall survival (OS) is still below 50%. Although HR-NB is a heterogeneous disease, HR-NB patients are currently treated in a similar fashion. Through unsupervised biclustering, we further stratified HR-NB patients into two reproducible and clinically distinct subtypes, including an ultra-high risk neuroblastoma (UHR-NB) and high risk neuroblastoma (HR-NB). The UHR-NB subtype consistently had the worst OS in multiple independent cohorts ( p < 0.008 ). Out of 283 neuroblastoma-specific immune genes that were used for stratification, 39 of them were differentiated in UHR-NB, including four upregulated and 35 downregulated, as compared to HR-NB. The four UHR-NB upregulated genes (ADAM22, GAL, KLHL13 and TWIST1) were all upregulated in MYCN amplified neuroblastoma in 5 additional cohorts. TWIST1 and ADAM22 were also positively correlated with cancer stage, while GAL was an independent OS predictor in addition to MYCN and age. Furthermore, we identified 26 commonly upregulated and 311 downregulated genes in UHR-NB from all 4723 immune-related genes. While 43 KEGG pathways with molecular functions were enriched in the downregulated immune-related genes, only the P53 signaling pathway was enriched in the upregulated ones, which suggested that UHR-NB was a TP53 related subtype with reduced immune activities.
Monoclonal Gammopathies of Renal Significance: Renal Biopsy and Beyond
Authors: Menè Paolo , De Alexandris Lorenzo , Moioli Alessandra , Raffa Salvatore , Stoppacciaro Antonella
Published: June 2020

Monoclonal Gammopathies of Renal Significance (MGRS) are a rather heterogeneous group of renal disorders caused by a circulating monoclonal (MC) immunoglobulin (Ig) component, often in the absence of multiple myeloma (MM) or another clinically relevant lymphoproliferative disorder. Nevertheless, substantial kidney damage could occur, despite the “benign” features of the bone-marrow biopsy. One example is renal amyloidosis, often linked to a small clone of plasma cells, without the invasive features of MM. However, patients with amyloidosis may present with a nephrotic syndrome and renal failure, eventually leading to end-stage kidney disease. At the same time, other organs, such as the heart and the liver, may be severely damaged by Ig light chains or amyloid deposits, occasionally resulting in fatal arrhythmias and/or organ failure. Acute kidney injury (AKI) may as well result from massive excretion of MC proteins, with deposition disease in glomeruli or renal tubules, not rarely obstructed by luminal aggregates, or “casts”. Proliferative glomerulonephritis with monoclonal Ig deposits is another, less frequent clinical presentation of an MGRS. The present review deals with the implications of MGRS for renal function and prognosis, and the potential of tools, such as the renal biopsy, for assessing clinical risk and guiding therapy of the underlying condition.
Essential Thrombocythemia and Acquired von Willebrand Syndrome: The Shadowlands between Thrombosis and Bleeding
Authors: Awada Hassan , Voso Maria , Guglielmelli Paola , Gurnari Carmelo
Published: June 2020

Over the past decade, new insights have emerged on the pathophysiology of essential thrombocythemia (ET), its clinical management, and associated thrombohemostatic disturbances. Here, we review the latest diagnostic and risk stratification modalities of ET and its therapeutics. Moreover, we discuss the clinical evidence-based benefits, deriving from major clinical trials, of using cytoreductive therapy and antiplatelet agents to lower the risk of fatal vascular events. Also, we focus on the condition of extreme thrombocytosis (>1000 × 109/L) and bleeding risk, the development and pathogenesis of acquired von Willebrand syndrome, and the clinical approach to this paradoxical scenario in ET.
Amyloid Proteins and Peripheral Neuropathy
Authors: Albariqi Mohammed , Engelsman Sjoukje , Eijkelkamp Niels , Höppener Jo
Published: June 2020

Painful peripheral neuropathy affects millions of people worldwide. Peripheral neuropathy develops in patients with various diseases, including rare familial or acquired amyloid polyneuropathies, as well as some common diseases, including type 2 diabetes mellitus and several chronic inflammatory diseases. Intriguingly, these diseases share a histopathological feature—deposits of amyloid-forming proteins in tissues. Amyloid-forming proteins may cause tissue dysregulation and damage, including damage to nerves, and may be a common cause of neuropathy in these, and potentially other, diseases. Here, we will discuss how amyloid proteins contribute to peripheral neuropathy by reviewing the current understanding of pathogenic mechanisms in known inherited and acquired (usually rare) amyloid neuropathies. In addition, we will discuss the potential role of amyloid proteins in peripheral neuropathy in some common diseases, which are not (yet) considered as amyloid neuropathies. We conclude that there are many similarities in the molecular and cell biological defects caused by aggregation of the various amyloid proteins in these different diseases and propose a common pathogenic pathway for “peripheral amyloid neuropathies”.
Redox Regulation of NOX Isoforms on FAK(Y397)/SRC(Y416) Phosphorylation Driven Epithelial-to-Mesenchymal Transition in Malignant Cervical Epithelial Cells
Authors: Kim Young Mee , Muthuramalingam Karthika , Cho Moonjae
Published: June 2020

Epithelial-to-mesenchymal transition (EMT) promulgates epithelial cell associated disease-defining characteristics in tumorigenesis and organ fibrosis. Growth factors such as epidermal growth factor and fibroblast growth factor in addition to cytokines such as transforming growth factor-β1 (TGF-β1) is said to play a prominent role in remodeling related pathological events of cancer progression such as invasion, metastasis, apoptosis, EMT, etc. through redox related cellular secondary messengers, in particular the reactive oxygen species (ROS). However, the signaling cascade underlying the redox mechanism and thereby the progression of EMT remains largely unknown. In this study, upon TGF-β1 treatment, we observed an induction in NOX isoforms—NOX2 and NOX4—that have time (early and late) and cellular localization (nucleus and autophagosome co-localized) dependent effects in mediating EMT associated cell proliferation and migration through activation of the focal adhesion kinase (FAK)/SRC pathway in HeLa, human cervical cancer cells. Upon silencing NOX2/4 gene expression and using the SRC inhibitor (AZD0530), progression of TGF-β1 induced EMT related cellular remodeling, extra cellular matrix (ECM) production, cell migration and invasion, got significantly reverted. Together, these results indicate that NOX2 and NOX4 play important, albeit distinct, roles in the activation of cytokine mediated EMT and its associated processes via tyrosine phosphorylation of the FAK/SRC pathway.
Circulating microRNA Signature Associated to Interstitial Lung Abnormalities in Respiratory Asymptomatic Subjects
Authors: Ortiz-Quintero Blanca , Buendía-Roldán Ivette , Ramírez-Salazar Eric Gustavo , Balderas-Martínez Yalbi I , Ramírez-Rodríguez Sandra Lizbeth , Martínez-Espinosa Karen , Selman Moisés
Published: June 2020

Interstitial lung abnormalities (ILA) are observed in around 9% of older respiratory asymptomatic subjects, mainly smokers. Evidence suggests that ILA may precede the development of interstitial lung diseases and may evolve to progressive fibrosis. Identifying biomarkers of this subclinical status is relevant for early diagnosis and to predict outcome. We aimed to identify circulating microRNAs (miRNAs) associated to ILA in a cohort of respiratory asymptomatic subjects older than 60 years. We identified 81 subjects with ILA from our Lung-Aging Program in Mexico City (n = 826). We randomly selected 112 subjects without ILA (Ctrl) from the same cohort. Using polymerase chain reaction PCR-Array technology (24 ILA and 24 Ctrl, screening cohort) and reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) (57 ILA and 88 Ctr, independent validation cohort) we identified seven up-regulated miRNAs in serum of ILA compared to Ctrl (miR-193a-5p, p < 0.0001; miR-502-3p, p < 0.0001; miR-200c-3p, p = 0.003; miR-16-5p, p = 0.003; miR-21-5p, p = 0.002; miR-126-3p, p = 0.004 and miR-34a-5p, p < 0.005). Pathways regulated by these miRNAs include transforming growth factor beta (TGF-β), Wnt, mammalian target of rapamycin (mTOR), Insulin, mitogen-activated protein kinase (MAPK) signaling, and senescence. Receiver operator characteristic (ROC) curve analysis indicated that miR-193a-5p (area under the curve AUC: 0.75) and miR-502-3p (AUC 0.71) have acceptable diagnostic value. This is the first identification of circulating miRNAs associated to ILA in respiratory asymptomatic subjects, providing potential non-invasive biomarkers and molecular targets to better understand the pathogenic mechanisms associated to ILA.
Substantially Altered Expression Profile of Diabetes/Cardiovascular/Cerebrovascular Disease Associated microRNAs in Children Descending from Pregnancy Complicated by Gestational Diabetes Mellitus—One of Several Possible Reasons for an Increased Cardiovascular Risk
Authors: Hromadnikova Ilona , Kotlabova Katerina , Dvorakova Lenka , Krofta Ladislav , Sirc Jan
Published: June 2020

Gestational diabetes mellitus (GDM), one of the major pregnancy-related complications, characterized as a transitory form of diabetes induced by insulin resistance accompanied by a low/absent pancreatic beta-cell compensatory adaptation to the increased insulin demand, causes the acute, long-term, and transgenerational health complications. The aim of the study was to assess if alterations in gene expression of microRNAs associated with diabetes/cardiovascular/cerebrovascular diseases are present in whole peripheral blood of children aged 3–11 years descending from GDM complicated pregnancies. A substantially altered microRNA expression profile was found in children descending from GDM complicated pregnancies. Almost all microRNAs with the exception of miR-92a-3p, miR-155-5p, and miR-210-3p were upregulated. The microRNA expression profile also differed between children after normal and GDM complicated pregnancies in relation to the presence of overweight/obesity, prehypertension/hypertension, and/or valve problems and heart defects. Always, screening based on the combination of microRNAs was superior over using individual microRNAs, since at 10.0% false positive rate it was able to identify a large proportion of children with an aberrant microRNA expression profile (88.14% regardless of clinical findings, 75.41% with normal clinical findings, and 96.49% with abnormal clinical findings). In addition, the higher incidence of valve problems and heart defects was found in children with a prior exposure to GDM. The extensive file of predicted targets of all microRNAs aberrantly expressed in children descending from GDM complicated pregnancies indicates that a large group of these genes is involved in ontologies of diabetes/cardiovascular/cerebrovascular diseases. In general, children with a prior exposure to GDM are at higher risk of later development of diabetes mellitus and cardiovascular/cerebrovascular diseases, and would benefit from dispensarisation as well as implementation of primary prevention strategies.
Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease
Authors: Cianflone Eleonora , Torella Michele , Biamonte Flavia , De Angelis Antonella , Urbanek Konrad , Costanzo Francesco S. , Rota Marcello , Ellison-Hughes Georgina M. , Torella Daniele
Published: June 2020

Adult stem/progenitor are a small population of cells that reside in tissue-specific niches and possess the potential to differentiate in all cell types of the organ in which they operate. Adult stem cells are implicated with the homeostasis, regeneration, and aging of all tissues. Tissue-specific adult stem cell senescence has emerged as an attractive theory for the decline in mammalian tissue and organ function during aging. Cardiac aging, in particular, manifests as functional tissue degeneration that leads to heart failure. Adult cardiac stem/progenitor cell (CSC) senescence has been accordingly associated with physiological and pathological processes encompassing both non-age and age-related decline in cardiac tissue repair and organ dysfunction and disease. Senescence is a highly active and dynamic cell process with a first classical hallmark represented by its replicative limit, which is the establishment of a stable growth arrest over time that is mainly secondary to DNA damage and reactive oxygen species (ROS) accumulation elicited by different intrinsic stimuli (like metabolism), as well as external stimuli and age. Replicative senescence is mainly executed by telomere shortening, the activation of the p53/p16INK4/Rb molecular pathways, and chromatin remodeling. In addition, senescent cells produce and secrete a complex mixture of molecules, commonly known as the senescence-associated secretory phenotype (SASP), that regulate most of their non-cell-autonomous effects. In this review, we discuss the molecular and cellular mechanisms regulating different characteristics of the senescence phenotype and their consequences for adult CSCs in particular. Because senescent cells contribute to the outcome of a variety of cardiac diseases, including age-related and unrelated cardiac diseases like diabetic cardiomyopathy and anthracycline cardiotoxicity, therapies that target senescent cell clearance are actively being explored. Moreover, the further understanding of the reversibility of the senescence phenotype will help to develop novel rational therapeutic strategies.
Mitochondrial Dysfunction and Inflammaging in Heart Failure: Novel Roles of CYP-Derived Epoxylipids
Authors: Keshavarz-Bahaghighat Hedieh , Darwesh Ahmed M. , Sosnowski Deanna K. , Seubert John M.
Published: June 2020

Age-associated changes leading to a decline in cardiac structure and function contribute to the increased susceptibility and incidence of cardiovascular diseases (CVD) in elderly individuals. Indeed, age is considered a risk factor for heart failure and serves as an important predictor for poor prognosis in elderly individuals. Effects stemming from chronic, low-grade inflammation, inflammaging, are considered important determinants in cardiac health; however, our understanding of the mechanisms involved remains unresolved. A steady decline in mitochondrial function is recognized as an important biological consequence found in the aging heart which contributes to the development of heart failure. Dysfunctional mitochondria contribute to increased cellular stress and an innate immune response by activating the NLRP-3 inflammasomes, which have a role in inflammaging and age-related CVD pathogenesis. Emerging evidence suggests a protective role for CYP450 epoxygenase metabolites of N-3 and N-6 polyunsaturated fatty acids (PUFA), epoxylipids, which modulate various aspects of the immune system and protect mitochondria. In this article, we provide insight into the potential roles N-3 and N-6 PUFA have modulating mitochondria, inflammaging and heart failure.
The RNA Replication Site of Tula Orthohantavirus Resides within a Remodelled Golgi Network
Authors: Davies Katherine A. , Chadwick Benjamin , Hewson Roger , Fontana Juan , Mankouri Jamel , Barr John N.
Published: June 2020

The family Hantaviridae within the Bunyavirales order comprises tri-segmented negative sense RNA viruses, many of which are rodent-borne emerging pathogens associated with fatal human disease. In contrast, hantavirus infection of corresponding rodent hosts results in inapparent or latent infections, which can be recapitulated in cultured cells that become persistently infected. In this study, we used Tula virus (TULV) to investigate the location of hantavirus replication during early, peak and persistent phases of infection, over a 30-day time course. Using immunofluorescent (IF) microscopy, we showed that the TULV nucleocapsid protein (NP) is distributed within both punctate and filamentous structures, with the latter increasing in size as the infection progresses. Transmission electron microscopy of TULV-infected cell sections revealed these filamentous structures comprised aligned clusters of filament bundles. The filamentous NP-associated structures increasingly co-localized with the Golgi and with the stress granule marker TIA-1 over the infection time course, suggesting a redistribution of these cellular organelles. The analysis of the intracellular distribution of TULV RNAs using fluorescent in-situ hybridization revealed that both genomic and mRNAs co-localized with Golgi-associated filamentous compartments that were positive for TIA. These results show that TULV induces a dramatic reorganization of the intracellular environment, including the establishment of TULV RNA synthesis factories in re-modelled Golgi compartments.