bluuebunny/crossref_metadata_2025 huggingface dataset:
The Prevalence of Burnout and Its Associations with Psychosocial Work Environment among Kaunas Region (Lithuania) Hospitals’ Physicians
Authors: Žutautienė Rasa , Radišauskas Ričardas , Kaliniene Gintare , Ustinaviciene Ruta
Published: May 2020

The primary prevention of occupational burnout should be considered as a public health priority worldwide. The aim of this study was to evaluate the prevalence of burnout and its associations with the work environment among hospital physicians in the Kaunas region, Lithuania. The cross-sectional study was carried out in 2018. The Job Content Questionnaire (JCQ) and the Copenhagen Burnout Inventory (CBI) were administered to examine occupational stress and personal, work-related, and client-related burnout among 647 physicians. Logistic regression analysis was applied to determine the association between dependent variable burnout and psychosocial environment among physicians, adjusting for potential confounders of age and gender. The prevalence rate of client-related, work-related, and personal burnout was 35.1%, 46.7%, and 44.8%, respectively. High job control, lack of supervisor, coworker support, job demands, and job insecurity were significantly associated with all three sub-dimensions of burnout. High job demands increased the probability of all three burnout dimensions, high job control reduced the probability of work-related, and client-related burnout and high job insecurity increased the probability of client-related burnout. The confirmed associations suggest that optimization of job demands and job control and the improvement of job security would be effective preventive measures in reducing occupational burnout among physicians.
Vitamin D in Triple-Negative and BRCA1-Deficient Breast Cancer—Implications for Pathogenesis and Therapy
Authors: Blasiak Janusz , Pawlowska Elzbieta , Chojnacki Jan , Szczepanska Joanna , Fila Michal , Chojnacki Cezary
Published: May 2020

Several studies show that triple-negative breast cancer (TNBC) patients have the lowest vitamin D concentration among all breast cancer types, suggesting that this vitamin may induce a protective effect against TNBC. This effect of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D), can be attributed to its potential to modulate proliferation, differentiation, apoptosis, inflammation, angiogenesis, invasion and metastasis and is supported by many in vitro and animal studies, but its exact mechanism is poorly known. In a fraction of TNBCs that harbor mutations that cause the loss of function of the DNA repair-associated breast cancer type 1 susceptibility (BRCA1) gene, 1,25(OH)2D may induce protective effects by activating its receptor and inactivating cathepsin L-mediated degradation of tumor protein P53 binding protein 1 (TP53BP1), preventing deficiency in DNA double-strand break repair and contributing to genome stability. Similar effects can be induced by the interaction of 1,25(OH)2D with proteins of the growth arrest and DNA damage-inducible 45 (GADD45) family. Further studies on TNBC cell lines with exact molecular characteristics and clinical trials with well-defined cases are needed to determine the mechanism of action of vitamin D in TNBC to assess its preventive and therapeutic potential.
Activity to Breast Cancer Cell Lines of Different Malignancy and Predicted Interaction with Protein Kinase C Isoforms of Royleanones
Authors: Isca Vera , Sencanski Milan , Filipovic Nenad , Dos Santos Daniel , Čipak Gašparović Ana , Saraíva Lucília , Afonso Carlos , Rijo Patrícia , García-Sosa Alfonso
Published: May 2020

Plants have been used for centuries to treat several illnesses. The Plectranthus genus has a vast variety of species that has allowed the isolation of cytotoxic compounds with notable activities. The abietane diterpenes 6,7-dehydroroyleanone (DeRoy, 1), 7α-acetoxy-6β-hydroxyroyleanone (Roy, 2), and Parvifloron D (ParvD, 3) were obtained from Plectranthus spp. and showed promising biological activities, such as cytotoxicity. The inhibitory effects of the different natural abietanes (1-3) were compared in MFC7, SkBr3, and SUM159 cell lines, as well as SUM159 grown in cancer stem cell-inducing conditions. Based on the royleanones’ bioactivity, the derivatives RoyBz (4), RoyBzCl (5), RoyPr2 (6), and DihydroxyRoy (7), previously obtained from 2, were selected for further studies. Protein kinases C (PKCs) are involved in several carcinogenic processes. Thus, PKCs are potential targets for cancer therapy. To date, the portfolio of available PKC modulators remains very limited due to the difficulty of designing isozyme-selective PKC modulators. As such, molecular docking was used to evaluate royleanones 1-6 as predicted isozyme-selective PKC binders. Subtle changes in the binding site of each PKC isoform change the predicted interaction profiles of the ligands. Subtle changes in royleanone substitution patterns, such as a double substitution only with non-substituted phenyls, or hydroxybenzoate at position four that flips the binding mode of ParvD (3), can increase the predicted interactions in certain PKC subtypes.
Sonic Hedgehog and Triiodothyronine Pathway Interact in Mouse Embryonic Neural Stem Cells
Authors: Ostasov Pavel , Tuma Jan , Pitule Pavel , Moravec Jiri , Houdek Zbynek , Vozeh Frantisek , Kralickova Milena , Cendelin Jan , Babuska Vaclav
Published: May 2020

Neural stem cells are fundamental to development of the central nervous system (CNS)—as well as its plasticity and regeneration—and represent a potential tool for neuro transplantation therapy and research. This study is focused on examination of the proliferation dynamic and fate of embryonic neural stem cells (eNSCs) under differentiating conditions. In this work, we analyzed eNSCs differentiating alone and in the presence of sonic hedgehog (SHH) or triiodothyronine (T3) which play an important role in the development of the CNS. We found that inhibition of the SHH pathway and activation of the T3 pathway increased cellular health and survival of differentiating eNSCs. In addition, T3 was able to increase the expression of the gene for the receptor smoothened (Smo), which is part of the SHH signaling cascade, while SHH increased the expression of the T3 receptor beta gene (Thrb). This might be the reason why the combination of SHH and T3 increased the expression of the thyroxine 5-deiodinase type III gene (Dio3), which inhibits T3 activity, which in turn affects cellular health and proliferation activity of eNSCs.
Unravelling the Role of Glycogen Synthase Kinase-3 in Alzheimer’s Disease-Related Epileptic Seizures
Authors: Lin Runxuan , Jones Nigel Charles , Kwan Patrick
Published: May 2020

Alzheimer’s disease (AD) is the most common form of dementia. An increasing body of evidence describes an elevated incidence of epilepsy in patients with AD, and many transgenic animal models of AD also exhibit seizures and susceptibility to epilepsy. However, the biological mechanisms that underlie the occurrence of seizure or increased susceptibility to seizures in AD is unknown. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates various cellular signaling pathways, and plays a crucial role in the pathogenesis of AD. It has been suggested that GSK-3 might be a key factor that drives epileptogenesis in AD by interacting with the pathological hallmarks of AD, amyloid precursor protein (APP) and tau. Furthermore, seizures may also contribute to the progression of AD through GSK-3. In this way, GSK-3 might be involved in initiating a vicious cycle between AD and seizures. This review aims to summarise the possible role of GSK-3 in the link between AD and seizures. Understanding the role of GSK-3 in AD-associated seizures and epilepsy may help researchers develop new therapeutic approach that can manage seizure and epilepsy in AD patients as well as decelerate the progression of AD.
Proprotein Convertase Subtilisin/Kexin Type 9, Angiopoietin-Like Protein 8, Sortilin, and Cholesteryl Ester Transfer Protein—Friends of Foes for Psoriatic Patients at the Risk of Developing Cardiometabolic Syndrome?
Authors: Krahel Julita Anna , Baran Anna , Kamiński Tomasz W. , Flisiak Iwona
Published: May 2020

Psoriasis is a systemic, immune-metabolic disease with strong genetic predispositions and autoimmune pathogenic traits. During psoriasis progression, a wide spectrum of comorbidities comes into play with the leading role of the cardio-metabolic syndrome (CMS) that occurs with the frequency of 30–50% amongst the psoriatic patients. Both conditions—psoriasis and CMS—have numerous common pathways, mainly related to proinflammatory pathways and cytokine profiles. Surprisingly, despite the years of research, the exact pathways linking the occurrence of CMS in the psoriasis population are still not fully understood. Recently published papers, both clinical and based on the basic science, shed new light into this relationship providing an insight into novel key-players proteins with plausible effects on above-mentioned interplay. Taking into account recent advances in this important medical matter, this review aims to discuss comprehensively the role of four proteins: proprotein convertase subtilisin/kexin type-9 (PSCK9), angiopoietin-like protein 8 (ANGPLT8), sortilin (SORT1), and cholesteryl ester transfer proteins (CEPT) as plausible links between psoriasis and CMS.
Gut Microbiota Metabolism and Interaction with Food Components
Authors: Vernocchi Pamela , Del Chierico Federica , Putignani Lorenza
Published: May 2020

The human gut contains trillions of microbes that play a central role in host biology, including the provision of key nutrients from the diet. Food is a major source of precursors for metabolite production; in fact, diet modulates the gut microbiota (GM) as the nutrients, derived from dietary intake, reach the GM, affecting both the ecosystem and microbial metabolic profile. GM metabolic ability has an impact on human nutritional status from childhood. However, there is a wide variability of dietary patterns that exist among individuals. The study of interactions with the host via GM metabolic pathways is an interesting field of research in medicine, as microbiota members produce myriads of molecules with many bioactive properties. Indeed, much evidence has demonstrated the importance of metabolites produced by the bacterial metabolism from foods at the gut level that dynamically participate in various biochemical mechanisms of a cell as a reaction to environmental stimuli. Hence, the GM modulate homeostasis at the gut level, and the alteration in their composition can concur in disease onset or progression, including immunological, inflammatory, and metabolic disorders, as well as cancer. Understanding the gut microbe–nutrient interactions will increase our knowledge of how diet affects host health and disease, thus enabling personalized therapeutics and nutrition.
Butylparaben Is Toxic to Porcine Oocyte Maturation and Subsequent Embryonic Development Following In Vitro Fertilization
Authors: Jeong Pil-Soo , Lee Sanghoon , Park Soo-Hyun , Kim Min Ju , Kang Hyo-Gu , Nanjidsuren Tsevelmaa , Son Hee-Chang , Song Bong-Seok , Koo Deog-Bon , Sim Bo-Woong , Kim Sun-Uk
Published: May 2020

Parabens are widely used in personal care products due to their antimicrobial effects. Although the toxicity of parabens has been reported, little information is available on the toxicity of butylparaben (BP) on oocyte maturation. Therefore, we investigated the effects of various concentrations of BP (0 μM, 100 μM, 200 μM, 300 μM, 400 μM, and 500 μM) on the in vitro maturation of porcine oocytes. BP supplementation at a concentration greater than 300 μM significantly reduced the proportion of complete cumulus cell expansion and metaphase II oocytes compared to the control. The 300 μM BP significantly decreased fertilization, cleavage, and blastocyst formation rates with lower total cell numbers and a higher rate of apoptosis in blastocysts compared to the control. The BP-treated oocytes showed significantly higher reactive oxygen species (ROS) levels, and lower glutathione (GSH) levels than the control. BP significantly increased the aberrant mitochondrial distribution and decreased mitochondrial function compared to the control. BP-treated oocytes exhibited significantly higher percentage of γ-H2AX, annexin V-positive oocytes and expression of LC3 than the control. In conclusion, we demonstrated that BP impaired oocyte maturation and subsequent embryonic development, by inducing ROS generation and reducing GSH levels. Furthermore, BP disrupted mitochondrial function and triggered DNA damage, early apoptosis, and autophagy in oocytes.
Mouthwash-Based Highly Sensitive Pyro-Genotyping for Nine Sexually Transmitted Human Papilloma Virus Genotypes
Authors: Watanabe Yoshiyuki , Seto Yukiko , Oikawa Ritsuko , Nakazawa Takara , Furuya Hanae , Matsui Hidehito , Hosono Sachiko , Noike Mika , Inoue Akiko , Yamamoto Hiroyuki , Itoh Fumio , Wada Kota
Published: May 2020

Human papillomavirus (HPV) is a common sexually transmitted infection worldwide, which spreads via contact with infected genital, anal, and oral/pharyngeal areas (oral sex) owing to diverse manners of sexual intercourse. In this study, we devised an oral HPV detection method using mouthwash waste fluids that causes less psychological resistance to visiting the outpatient otolaryngology departments. We successfully detected only the specific unique reverse sequencing probe (using pyro-genotyping) and identified the nine genotypes of HPV targeted for vaccination by pyrosequencing the mouthwash waste fluids of non-head and neck cancer patient volunteers (n = 52). A relatively large number (11/52) of mouthwash waste fluids tested positive for HPV (21.2%; genotype 6, n = 1; 11, n = 1; 16, n = 1; and 18, n = 8). These results surpassed the sensitivity observed testing the same specimens using the conventional method (1/52, 1.9%). Our method (pyro-genotyping) was developed using nine HPV genotypes targeted for vaccination and the results were highly sensitive compared to those of the conventional method. This less expensive, high-throughput, and simple method can be used for detecting oral HPV infection with fewer socio-psychological barriers.
Cell Density-Dependent Fibroblast Growth Factor-2 Signaling Regulates Syndecan-4 Expression in Cultured Vascular Endothelial Cells
Authors: Hara Takato , Yabushita Shiori , Yamamoto Chika , Kaji Toshiyuki
Published: May 2020

Syndecan-4 is a member of the syndecan family of transmembrane heparan sulfate proteoglycans, and is involved in cell protection, proliferation, and the blood coagulation-fibrinolytic system in vascular endothelial cells. Heparan sulfate chains enable fibroblast growth factor-2 (FGF-2) to form a complex with its receptor and to transduce the cell growth signal. In the present study, bovine aortic endothelial cells were cultured, and the intracellular signal pathways that mediate the regulation of syndecan-4 expression in dense and sparse cultures by FGF-2 were analyzed. We demonstrated the cell density-dependent differential regulation of syndecan-4 expression. Specifically, we found that FGF-2 upregulated the synthesis of syndecan-4 in vascular endothelial cells via the MEK1/2-ERK1/2 pathway in dense cell cultures, with only a transcriptional induction of syndecan-4 at a low cell density via the Akt pathway. This study highlights a critical mechanism underlying the regulation of endothelial cell functions by proteoglycans.
A Phytochemical Constituent, (E)-Methyl-Cinnamate Isolated from Alpinia katsumadai Hayata Suppresses Cell Survival, Migration, and Differentiation in Pre-Osteoblasts
Authors: Park Kyung-Ran , Lee Hanna , Cho MyoungLae , Yun Hyung-Mun
Published: May 2020

Background: (E)-methyl-cinnamate (EMC), a phytochemical constituent isolated from Alpinia katsumadai Hayata, is a natural flavor compound with anti-inflammatory properties, which is widely used in the food and commodity industry. However, the pharmacological effects of methyl-cinnamate on pre-osteoblasts remain unknown. This study aimed to investigate the pharmacological effects and mechanisms of EMC in pre-osteoblast MC3T3-E1 cells (pre-osteoblasts). Methods: Cell viability and apoptosis were evaluated using the MTT assay and TUNEL staining. Cell migration and osteoblast differentiation were examined using migration assays, as well as alkaline phosphatase activity and staining assays. Western blot analysis was used to examine intracellular signaling pathways and apoptotic proteins. Results: EMC decreased cell viability with morphological changes and increased apoptosis in pre-osteoblasts. EMC also induced the cleavage of Poly (ADP-ribose) polymerase (PARP) and caspase-3 and reduced the expression of anti-apoptotic proteins. In addition, EMC increased TUNEL-positive cells in pre-osteoblasts, decreased the activation of mitogen-activated protein kinases, and suppressed cell migration rate in pre-osteoblasts. Subsequently, EMC inhibited the osteoblast differentiation of pre-osteoblasts, as assessed by alkaline phosphatase staining and activity assays. Conclusion: These findings demonstrate that EMC has a pharmacological and biological role in cell survival, migration, and osteoblast differentiation. It suggests that EMC might be a potential phytomedicine for treating abnormalities of osteoblast function in bone diseases.
Neurological Syndromes Associated with Anti-GAD Antibodies
Authors: Dade Maëlle , Berzero Giulia , Izquierdo Cristina , Giry Marine , Benazra Marion , Delattre Jean-Yves , Psimaras Dimitri , Alentorn Agusti
Published: May 2020

Glutamic acid decarboxylase (GAD) is an intracellular enzyme whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter within the central nervous system. GAD antibodies (Ab) have been associated with multiple neurological syndromes, including stiff-person syndrome, cerebellar ataxia, and limbic encephalitis, which are all considered to result from reduced GABAergic transmission. The pathogenic role of GAD Ab is still debated, and some evidence suggests that GAD autoimmunity might primarily be cell-mediated. Diagnosis relies on the detection of high titers of GAD Ab in serum and/or in the detection of GAD Ab in the cerebrospinal fluid. Due to the relative rarity of these syndromes, treatment schemes and predictors of response are poorly defined, highlighting the unmet need for multicentric prospective trials in this population. Here, we reviewed the main clinical characteristics of neurological syndromes associated with GAD Ab, focusing on pathophysiologic mechanisms.
Sperm Differentiation: The Role of Trafficking of Proteins
Authors: Teves Maria , Roldan Eduardo , Krapf Diego , Strauss III Jerome , Bhagat Virali , Sapao Paulene
Published: May 2020

Sperm differentiation encompasses a complex sequence of morphological changes that takes place in the seminiferous epithelium. In this process, haploid round spermatids undergo substantial structural and functional alterations, resulting in highly polarized sperm. Hallmark changes during the differentiation process include the formation of new organelles, chromatin condensation and nuclear shaping, elimination of residual cytoplasm, and assembly of the sperm flagella. To achieve these transformations, spermatids have unique mechanisms for protein trafficking that operate in a coordinated fashion. Microtubules and filaments of actin are the main tracks used to facilitate the transport mechanisms, assisted by motor and non-motor proteins, for delivery of vesicular and non-vesicular cargos to specific sites. This review integrates recent findings regarding the role of protein trafficking in sperm differentiation. Although a complete characterization of the interactome of proteins involved in these temporal and spatial processes is not yet known, we propose a model based on the current literature as a framework for future investigations.
Role of the Ang2–Tie2 Axis in Vascular Damage Driven by High Glucose or Nucleoside Diphosphate Kinase B Deficiency
Authors: Chatterjee Anupriya , Eshwaran Rachana , Huang Hongpeng , Zhao Di , Schmidt Martina , Wieland Thomas , Feng Yuxi
Published: May 2020

Ablation of nucleoside diphosphate kinase B (NDPK-B) in mice causes a breakdown of the neurovascular unit in the retina, mimicking diabetic retinopathy. The NDPK-B deficiency-induced vascular damage is mediated by excessive angiopoietin 2 (Ang2). Herein, the potential involvement of its receptor, Tie2, was investigated. NDPK-B-deficient mouse retinas showed an upregulation of Tie2, specifically in the deep capillary layer. A similar upregulation of Tie2 was observed in cultured endothelial cells (ECs) from different origins upon NDPK-B depletion, whereas high glucose (HG) treatment did not alter Tie2 expression. Immunofluorescence staining and subcellular fractionation showed that the majority of Tie2 upregulation occurred at the plasma membrane. Similar to HG, however, NDPK-B depletion reduced Tie2 tyrosine phosphorylation. Compared to HG, a stronger increase of Ang2 was observed in NDPK-B depleted ECs. Treatment of ECs with soluble Tie2 or siRNA-mediated Tie2 knockdown attenuated NDPK-B depletion- but not HG-induced Ang2 upregulation. Like NDPK-B depletion, overexpression of recombinant Ang2 in ECs enhanced Ang2 secretion and concomitantly promoted the upregulation of Tie2. Thus, we identified a new mechanism showing that after reaching a threshold level of secretion, Ang2 sustains its own expression and secretion by a Tie2-dependent positive feedback loop.
Animal Models to Translate Phage Therapy to Human Medicine
Authors: Brix Alessia , Cafora Marco , Aureli Massimo , Pistocchi Anna
Published: May 2020

Phagotherapy, the use of bacteriophages to fight bacterial infections as an alternative to antibiotic treatments, has become of increasing interest in the last years. This is mainly due to the diffusion of multi-drug resistant (MDR) bacterial infections that constitute a serious issue for public health. Phage therapy is gaining favor due to its success in agriculture and veterinary treatments and its extensive utilization for human therapeutic protocols in the Eastern world. In the last decades, some clinical trials and compassionate treatments have also been performed in the Western world, indicating that phage therapy is getting closer to its introduction in standard therapy protocols. However, several questions concerning the use of phages in human therapeutic treatments are still present and need to be addressed. In this review, we illustrate the state of art of phage therapy and examine the role of animal models to translate these treatments to humans.
Epigallocatechin 3-Gallate Has a Neuroprotective Effect in Retinas of Rabbits with Ischemia/Reperfusion through the Activation of Nrf2/HO-1
Authors: Rivera-Pérez Josué , Martínez-Rosas Martín , Conde-Castañón César A. , Toscano-Garibay Julia D. , Ruiz-Pérez Nancy J. , Flores Pedro L. , Mera Jiménez Elvia , Flores-Estrada Javier
Published: May 2020

Retinal ischemia-reperfusion (rI/R) generates an oxidative condition causing the death of neuronal cells. Epigallocatechin 3-gallate (EGCG) has antioxidant and anti-inflammatory properties. Nonetheless, its correlation with the pathway of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) for the protection of the retina is unknown. We aimed to evaluate the neuroprotective efficacy of single-doses of EGCG in rI/R and its association with Nrf2/Ho-1 expression. In albino rabbits, rI/R was induced and single-doses of EGCG in saline (0–30 mg/kg) were intravenously administered to select an optimal EGCG concentration that protects from retina damage. To reach this goal, retinal structural changes, gliosis by glial fibrillary acidic protein (GFAP) immunostaining, and lipid peroxidation level by TBARS (thiobarbituric acid reactive substance) assay were determined. EGCG in a dose of 15 mg/kg (E15) presented the lowest levels of histological damage, gliosis, and oxidative stress in the studied groups. To determine the neuroprotective efficacy of E15 in a timeline (6, 24, and 48 h after rI/R), and its association with the Nrf2/HO-1 pathway, the following assays were done by immunofluorescence: apoptosis (TUNEL assay), necrosis (high-mobility group box-1; HMGB1), Nrf2, and HO-1. In addition, the Ho-1 mRNA (qPCR) and lipid peroxidation levels were evaluated. E15 showed a protective effect during the first 6 h, compared to 24 and 48 h after rI/R, as revealed by a decrease in the levels of all damage markers. Nuclear translocation Nrf2 and HO-1 staining were increased, including Ho-1 mRNA levels. In conclusion, a single dose of E15 decreases the death of neuronal cells induced by oxidative stress during the first 6 h after rI/R. This protective effect is associated with the nuclear translocation of Nrf2 and with an elevation of Ho-1 expression.
RNAs in Brain and Heart Diseases
Authors: Beis Dimitris , Zerr Inga , Martelli Fabio , Doehner Wolfram , Devaux Yvan
Published: May 2020

In the era of single-cell analysis, one always has to keep in mind the systemic nature of various diseases and how these diseases could be optimally studied. Comorbidities of the heart in neurological diseases as well as of the brain in cardiovascular diseases are prevalent, but how interactions in the brain–heart axis affect disease development and progression has been poorly addressed. Several brain and heart diseases share common risk factors. A better understanding of the brain–heart interactions will provide better insights for future treatment and personalization of healthcare, for heart failure patients’ benefit notably. We review here emerging evidence that studying noncoding RNAs in the brain–heart axis could be pivotal in understanding these interactions. We also introduce the Special Issue of the International Journal of Molecular Sciences RNAs in Brain and Heart Diseases—EU-CardioRNA COST Action.
NTRK Fusions, from the Diagnostic Algorithm to Innovative Treatment in the Era of Precision Medicine
Authors: Zito Marino Federica , Pagliuca Francesca , Ronchi Andrea , Cozzolino Immacolata , Montella Marco , Berretta Massimiliano , Errico Maria Elena , Donofrio Vittoria , Bianco Roberto , Franco Renato
Published: May 2020

In the era of precision medicine, the identification of several predictive biomarkers and the development of innovative therapies have dramatically increased the request of tests to identify specific targets on cytological or histological samples, revolutionizing the management of the tumoral biomaterials. The Food and Drug Administration (FDA) has recently approved a selective neurotrophic tyrosine receptor kinase (NTRK) inhibitor, larotrectinib. Contemporarily, the development of multi-kinase inhibitors with activity in tumors carrying TRK fusions is ongoing. Chromosomal translocations involving the NTRK1, NTRK2, and NTRK3 genes result in constitutive activation and aberrant expression of TRK kinases in numerous cancer types. In this context, the identification of tumors harboring TRK fusions is crucial. Several methods of detection are currently available. We revise the advantages and disadvantages of different techniques used for identifying TRK alterations, including immunohistochemistry, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, and next generation sequencing-based approaches. Finally, we propose a diagnostic algorithm based on histology and the relative frequency of TRK fusions in each specific tumor, considering also the economic feasibility in the clinical practice.
DNA Damage Regulates Senescence-Associated Extracellular Vesicle Release via the Ceramide Pathway to Prevent Excessive Inflammatory Responses
Authors: Hitomi Kazuhiro , Okada Ryo , Loo Tze Mun , Miyata Kenichi , Nakamura Asako J. , Takahashi Akiko
Published: May 2020

DNA damage, caused by various oncogenic stresses, can induce cell death or cellular senescence as an important tumor suppressor mechanism. Senescent cells display the features of a senescence-associated secretory phenotype (SASP), secreting inflammatory proteins into surrounding tissues, and contributing to various age-related pathologies. In addition to this inflammatory protein secretion, the release of extracellular vesicles (EVs) is also upregulated in senescent cells. However, the molecular mechanism underlying this phenomenon remains unclear. Here, we show that DNA damage activates the ceramide synthetic pathway, via the downregulation of sphingomyelin synthase 2 (SMS2) and the upregulation of neutral sphingomyelinase 2 (nSMase2), leading to an increase in senescence-associated EV (SA-EV) biogenesis. The EV biogenesis pathway, together with the autophagy-mediated degradation pathway, functions to block apoptosis by removing cytoplasmic DNA fragments derived from chromosomal DNA or bacterial infections. Our data suggest that this SA-EV pathway may play a prominent role in cellular homeostasis, particularly in senescent cells. In summary, DNA damage provokes SA-EV release by activating the ceramide pathway to protect cells from excessive inflammatory responses.
S-Adenosine Methionine (SAMe) and Valproic Acid (VPA) as Epigenetic Modulators: Special Emphasis on their Interactions Affecting Nervous Tissue during Pregnancy
Authors: Ornoy Asher , Becker Maria , Weinstein-Fudim Liza , Ergaz Zivanit
Published: May 2020

S-adenosylmethionine (SAMe) is involved in many transmethylation reactions in most living organisms and is also required in the synthesis of several substances such as monoamine neurotransmitters and the N-methyl-D-aspartate (NMDA) receptor. Due to its important role as an epigenetic modulator, we discuss in some length the process of DNA methylation and demethylation and the critical periods of epigenetic modifications in the embryo, fetus, and thereafter. We also discuss the effects of SAMe deficiency and the attempts to use SAMe for therapeutic purposes such as the treatment of major depressive disorder, Alzheimer disease, and other neuropsychiatric disorders. SAMe is an approved food additive and as such is also used during pregnancy. Yet, there seems to scanty data on the possible effects of SAMe on the developing embryo and fetus. Valproic acid (VPA) is a well-tolerated and effective antiepileptic drug that is also used as a mood stabilizer. Due to its high teratogenicity, it is contraindicated in pregnancy. A major mechanism of its action is histone deacetylase inhibition, and therefore, it acts as an epigenetic modulator, mainly on the brain. This prompted clinical trials using VPA for additional indications i.e., treating degenerative brain disease such as Alzheimer disease, dementia, HIV, and even cancer. Therefore, we discuss the possible effects of VPA and SAMe on the conceptus and early postnatally, during periods of susceptibility to epigenetic modifications. VPA is also used as an inducer of autistic-like behavior in rodents and was found by us to modify gene expression when administered during the first postnatal week but not when administered to the pregnant dams on day 12 of gestation. In contrast, SAMe modified gene expression when administered on day 12 of pregnancy but not postnatally. If administered together, VPA prevented the changes in gene expression induced by prenatal SAMe administration, and SAMe prevented the gene expression changes and autistic-like behavior induced by early postnatal VPA. It is concluded that both VPA and SAMe are powerful epigenetic modifiers with antagonistic actions on the brain that will probably be used in the future more extensively for the treatment of a variety of epigenetic diseases of the nervous system.
Early Detection of Pancreatic Intraepithelial Neoplasias (PanINs) in Transgenic Mouse Model by Hyperpolarized 13C Metabolic Magnetic Resonance Spectroscopy
Authors: Dutta Prasanta , Castro Pando Susana , Mascaro Marilina , Riquelme Erick , Zoltan Michelle , Zacharias Niki M. , Gammon Seth T. , Piwnica-Worms David , Pagel Mark D. , Sen Subrata , Maitra Anirban , Shams Shayan , McAllister Florencia , Bhattacharya Pratip K.
Published: May 2020

While pancreatic cancer (PC) survival rates have recently shown modest improvement, the disease remains largely incurable. Early detection of pancreatic cancer may result in improved outcomes and therefore, methods for early detection of cancer, even premalignant lesions, may provide more favorable outcomes. Pancreatic intraepithelial neoplasias (PanINs) have been identified as premalignant precursor lesions to pancreatic cancer. However, conventional imaging methods used for screening high-risk populations do not have the sensitivity to detect PanINs. Here, we have employed hyperpolarized metabolic imaging in vivo and nuclear magnetic resonance (1H-NMR) metabolomics ex vivo to identify and understand metabolic changes, towards enabling detection of early PanINs and progression to advanced PanINs lesions that precede pancreatic cancer formation. Progression of disease from tissue containing predominantly low-grade PanINs to tissue with high-grade PanINs showed a decreasing alanine/lactate ratio from high-resolution NMR metabolomics ex vivo. Hyperpolarized magnetic resonance spectroscopy (HP-MRS) allows over 10,000-fold sensitivity enhancement relative to conventional magnetic resonance. Real-time HP-MRS was employed to measure non-invasively changes of alanine and lactate metabolites with disease progression and in control mice in vivo, following injection of hyperpolarized [1-13C] pyruvate. The alanine-to-lactate signal intensity ratio was found to decrease as the disease progressed from low-grade PanINs to high-grade PanINs. The biochemical changes of alanine transaminase (ALT) and lactate dehydrogenase (LDH) enzyme activity were assessed. These results demonstrate that there are significant alterations of ALT and LDH activities during the transformation from early to advanced PanINs lesions. Furthermore, we demonstrate that real-time conversion kinetic rate constants (kPA and kPL) can be used as metabolic imaging biomarkers of pancreatic premalignant lesions. Findings from this emerging HP-MRS technique can be translated to the clinic for detection of pancreatic premalignant lesion in high-risk populations.
Fractalkine/CX3CL1 in Neoplastic Processes
Authors: Korbecki Jan , Simińska Donata , Kojder Klaudyna , Grochans Szymon , Gutowska Izabela , Chlubek Dariusz , Baranowska-Bosiacka Irena
Published: May 2020

Fractalkine/CX3C chemokine ligand 1 (CX3CL1) is a chemokine involved in the anticancer function of lymphocytes—mainly NK cells, T cells and dendritic cells. Its increased levels in tumors improve the prognosis for cancer patients, although it is also associated with a poorer prognosis in some types of cancers, such as pancreatic ductal adenocarcinoma. This work focuses on the ‘hallmarks of cancer’ involving CX3CL1 and its receptor CX3CR1. First, we describe signal transduction from CX3CR1 and the role of epidermal growth factor receptor (EGFR) in this process. Next, we present the role of CX3CL1 in the context of cancer, with the focus on angiogenesis, apoptosis resistance and migration and invasion of cancer cells. In particular, we discuss perineural invasion, spinal metastasis and bone metastasis of cancers such as breast cancer, pancreatic cancer and prostate cancer. We extensively discuss the importance of CX3CL1 in the interaction with different cells in the tumor niche: tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC) and microglia. We present the role of CX3CL1 in the development of active human cytomegalovirus (HCMV) infection in glioblastoma multiforme (GBM) brain tumors. Finally, we discuss the possible use of CX3CL1 in immunotherapy.
Preventative Approach to Microbial Control of Capnodis tenebrionis by Soil Application of Metarhizium brunneum and Beauveria bassiana
Authors: Ment Dana , Kokiçi Hysen , de Lillo Enrico
Published: May 2020

Management of the Mediterranean flat-headed root-borer, Capnodis tenebrionis, is critical due to the larvae’s root localization. Neonate larvae can be exposed to natural enemies before penetrating the roots. Application of Metarhizium brunneum strain Mb7 and Beauveria bassiana strain GHA formulations on rice granules was investigated for their efficacy against C. tenebrionis larvae. Mb7 application, evaluated on apricot twigs, significantly and dose-dependently reduced colonization rates of neonates, with highest mortality at 108 conidia/g soil. Neonate susceptibility to Mb7 and GHA was evaluated on potted rootstocks (GF677 almond × peach, 2729 plum) planted in entomopathogenic fungi (EPF)-premixed soil (1.3–1.6 × 105 conidia/cm3 soil) or in EPF-free soil surface-treated with 5 g Mb7 fungal granules (1.25 × 109 conidia). Larval colonization rates were reduced 7.4-fold in 2729 by both fungi; only Mb7 completely prevented colonization of GF677 by larvae. Larvae inside plant galleries exhibited mycosis with EPF-treated soils and both fungi proliferated on larval frass. Mb7 conidia germinated in the rhizosphere of GF677, and conidia of both fungi remained viable throughout the trial. Galleria baiting technique was used on EPF-treated soil to evaluate EPF infectivity over time; Mb7 and GHA persisted 180 and 90 days post inoculation, respectively. The formulation (fungus-covered rice grains), delivery method (mixing with soil) and persistence (3–6 months) of Mb7 and GHA are feasible for potential field application to control C. tenebrionis.
Population Dynamics of Hyalomma dromedarii on Camels in the United Arab Emirates
Authors: Perveen Nighat , Bin Muzaffar Sabir , Al-Deeb Mohammad Ali
Published: May 2020

Hyalomma dromedarii is the most important tick species infesting camels in the Middle East. So far, there are no studies on the population dynamics of H. dromedarii ticks on camels in the United Arab Emirates (UAE). Thus, the current study was performed: (1) to assess H. dromedarii population dynamics under common camel breeding and management practices in the study area, (2) to evaluate H. dromedarii life stage changes and sex ratio over time, and (3) to measure parasitological indicators of H. dromedarii infestation. We conducted monthly on-site tick visual counts and collection from camels in Al Ain, UAE, over 12 months. Our results show that the infestation prevalence was very high during the whole study period, with a mean of 94.33%. The maximum infestation intensity occurred in June, while the minimum occurred in January. Overall, H. dromedarii ticks were found on camels during the entire year in spite of monthly applications of an acaricide. This study reveals that H. dromedarii has a very high prevalence and continuous presence on camels in the UAE regardless of the weather fluctuations and acaricide applications and showed the need for an effective control strategy.
The Effect of Foraging on Bumble Bees, Bombus terrestris, Reared under Laboratory Conditions
Authors: Dobeš Pavel , Kunc Martin , Hurychová Jana , Votavová Alena , Komzáková Olga , Hyršl Pavel
Published: May 2020

Bumble bees are important pollinators broadly used by farmers in greenhouses and under conditions in which honeybee pollination is limited. As such, bumble bees are increasingly being reared for commercial purposes, which brings into question whether individuals reared under laboratory conditions are fully capable of physiological adaptation to field conditions. To understand the changes in bumble bee organism caused by foraging, we compared the fundamental physiological and immunological parameters of Bombus terrestris workers reared under constant optimal laboratory conditions with workers from sister colonies that were allowed to forage for two weeks in the field. Nutritional status and immune response were further determined in wild foragers of B. terrestris that lived under the constant influence of natural stressors. Both wild and laboratory-reared workers subjected to the field conditions had a lower protein concentration in the hemolymph and increased antimicrobial activity, the detection of which was limited in the non-foragers. However, in most of the tested parameters, specifically the level of carbohydrates, antioxidants, total hemocyte concentration in the hemolymph and melanization response, we did not observe any significant differences between bumble bee workers produced in the laboratory and wild animals, nor between foragers and non-foragers. Our results show that bumble bees reared under laboratory conditions can mount a sufficient immune response to potential pathogens and cope with differential food availability in the field, similarly to the wild bumble bee workers.
Transcriptome Analysis of the Oriental Fruit Fly Bactrocera dorsalis Early Embryos
Authors: Peng Wei , Yu Shuning , Handler Alfred M. , Zhang Hongyu
Published: May 2020

The oriental fruit fly, Bactrocera dorsalis (Hendel), is one of the most devastating and highly invasive agricultural pests world-wide, resulting in severe economic loss. Thus, it is of great interest to understand the transcriptional changes that occur during the activation of its zygotic genome at the early stages of embryonic development, especially the expression of genes involved in sex determination and the cellularization processes. In this study, we applied Illumina sequencing to identify B. dorsalis sex determination genes and early zygotic genes by analyzing transcripts from three early embryonic stages at 0–1, 2–4, and 5–8 h post-oviposition, which include the initiation of sex determination and cellularization. These tests generated 13,489 unigenes with an average length of 2185 bp. In total, 1683, 3201 and 3134 unigenes had significant changes in expression levels at times after oviposition including at 2–4 h versus 0–1 h, 5–8 h versus 0–1 h, and 5–8 h versus 2–4 h, respectively. Clusters of gene orthology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations were performed throughout embryonic development to better understand the functions of differentially expressed unigenes. We observed that the RNA binding and spliceosome pathways were highly enriched and overrepresented during the early stage of embryogenesis. Additionally, transcripts for 21 sex-determination and three cellularization genes were identified, and expression pattern analysis revealed that the majority of these genes were highly expressed during embryogenesis. This study is the first assembly performed for B. dorsalis based on Illumina next-generation sequencing technology during embryogenesis. Our data should contribute significantly to the fundamental understanding of sex determination and early embryogenesis in tephritid fruit flies, and provide gene promoter and effector gene candidates for transgenic pest-management strategies for these economically important species.
Comparison of Chest Compression Quality Using Wing Boards versus Walking Next to a Moving Stretcher: A Randomized Crossover Simulation Study
Authors: Nakashima Yukako , Saitoh Takeji , Yasui Hideki , Ueno Masahide , Hotta Kensuke , Ogawa Takashi , Takahashi Yoshiaki , Maekawa Yuichiro , Yoshino Atsuto
Published: May 2020

Background: When a rescuer walks alongside a stretcher and compresses the patient’s chest, the rescuer produces low-quality chest compressions. We hypothesized that a stretcher equipped with wing boards allows for better chest compressions than the conventional method. Methods: In this prospective, randomized, crossover study, we enrolled 45 medical workers and students. They performed hands-on chest compressions to a mannequin on a moving stretcher, while either walking (the walk method) or riding on wings attached to the stretcher (the wing method). The depths of the chest compressions were recorded. The participants’ vital signs were measured before and after the trials. Results: The average compression depth during the wing method (5.40 ± 0.50 cm) was greater than during the walk method (4.85 ± 0.80 cm; p < 0.01). The average compression rates during the two minutes were 215 ± 8 and 217 ± 5 compressions in the walk and wing methods, respectively (p = ns). Changes in blood pressure (14 ± 11 vs. 22 ± 14 mmHg), heart rate (32 ± 13 vs. 58 ± 20 bpm), and modified Borg scale (4 (interquartile range: 2–4) vs. 6 (5–7)) were significantly lower in the wing method cohort compared to the walking cohort (p < 0.01). The rescuer’s size and physique were positively correlated with the chest compression depth during the walk method; however, we found no significant correlation in the wing method. Conclusions: Chest compressions performed on the stretcher while moving using the wing method can produce high-quality chest compressions, especially for rescuers with a smaller size and physique.
Association between Periodontal Diseases and Polycystic Ovary Syndrome: A Systematic Review
Authors: Márquez-Arrico Cecilia Fabiana , Silvestre-Rangil Javier , Gutiérrez-Castillo Laura , Martinez-Herrera Mayte , Silvestre Francisco Javier , Rocha Milagros
Published: May 2020

Background: A convergent association between polycystic ovary syndrome (PCOS) and periodontal disease, in particular chronic periodontitis (CP), has recently been proposed. The underlying molecular mechanisms of this association are not fully understood, though it is thought that chronic inflammation is responsible. Therefore, the aim of this study was to evaluate the association between periodontal disease—gingivitis and CP—and PCOS. Materials and Methods: The PICO (Participants, Intervention, Control, and Outcomes) question was as follows: “Is there an association between PCOS and CP?” A systematic review of three databases—PubMed, Embase and Scopus—was performed following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Original studies in human cohorts carried out in the last 10 years and including a control group were eligible for inclusion. Letters to the editor, case reports, and reviews were not considered. Results: Ten articles met all the selection criteria and provided a positive answer to the PICO question. Our review of these articles revealed an association between CP and PCOS, since periodontal parameters were altered more frequently in patients with these conditions than in healthy young women. This altered periodontal response in PCOS was associated with a proinflammatory status that seemed to increase susceptibility to periodontal disease. Conclusion: Patients with PCOS appear to be more susceptible to developing periodontal diseases than women without the pathology.
Prevalence of Elbow Joint Arthritis and Enthesitis in Rheumatoid Arthritis
Authors: Schäfer Valentin Sebastian , Recker Florian , Vossen Diana , Geffken Isabelle , Matuschek Eva , Hartung Wolfgang
Published: May 2020

Objectives: The prevalence of elbow joint arthritis in rheumatoid arthritis (RA) assessed by ultrasound has not yet been investigated. Methods: We investigated 102 patients with RA and 50 patients without rheumatological disease. Both elbow joints were examined by ultrasound for effusion, hypervascularization, and enthesitis. A clinical examination was performed, and Disease Activity Score in 28 joints (DAS28), and visual analog scale for pain (VASp) were recorded. Arthritis was defined as joint effusion (≥grade II) and synovial hyperperfusion. Results: The RA cohort versus the control group displayed a joint effusion in 54.9% vs. 6.9%, a hypervascularization in 6.8% vs. 0%. Arthritis was detected in 36 RA patients (35.29%) and no one in the control group. Four (3.8%) RA patients and one (1%) control displayed enthesitis. The RA cohort showed a significant correlation between movement restriction and joint effusion (p-value = 0.001) as well as DAS28 (p-value = 0.02) and between DAS28 and ultrasound detected arthritis (p-value = 0.022). In an overall analysis, a highly significant correlation of VASp with movement restriction (MR) (p-value ≤ 0.001), the presence of joint effusion (p-value ≤ 0.001), and the diagnosis of RA (p-value ≤ 0.001) were observed. Interrater analysis of ultrasound imaging showed good agreement with Cohen’s kappa of 0.896. Conclusion: The prevalence of elbow arthritis in RA seems to be high, with 35.29%. Movement restriction is a good indicator, but not in all RA patients (32 vs. 70 patients without MR) compared to the control group (5 vs. 45 patients without MR). Reported pain correlates with joint effusion and MR (p-value ≤ 0.001).