bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal Control Implementation with Terminal Penalty Using Metaheuristic Algorithms
Authors: Minzu Viorel
Published: October 2020

Optimal control problems can be solved by a metaheuristic based algorithm (MbA) that yields an open-loop solution. The receding horizon control mechanism can integrate an MbA to produce a closed-loop solution. When the performance index includes a term depending on the final state (terminal penalty), the prediction’s time possibly surpasses a sampling period. This paper aims to avoid predicting the terminal penalty. The sequence of the best solution’s state variables becomes a reference trajectory; this one is used by a tracking structure that includes the real process, a process model (PM) and a tracking controller (TC). The reference trajectory must be followed up as much as possible by the real trajectory. The TC makes a one-step-ahead prediction and calculates the control inputs through a minimization procedure. Therefore the terminal penalty’s calculation is avoided. An example of a tracking structure is presented. The TC may also use an MbA for its minimization procedure. The implementation is presented in two versions: using a simulated annealing algorithm and an evolutionary algorithm. The simulations have proved that the proposed approach is realistic. The tracking structure does or does not work well, depending on the PM’s accuracy in reproducing the real process.
Calmodulin Directly Interacts with the Cx43 Carboxyl-Terminus and Cytoplasmic Loop Containing Three ODDD-Linked Mutants (M147T, R148Q, and T154A) that Retain α-Helical Structure, but Exhibit Loss-of-Function and Cellular Trafficking Defects
Authors: Zheng Li , Chenavas Sylvie , Kieken Fabien , Trease Andrew , Brownell Sarah , Anbanandam Asokan , Sorgen Paul L. , Spagnol Gaelle
Published: October 2020

The autosomal-dominant pleiotropic disorder called oculodentodigital dysplasia (ODDD) is caused by mutations in the gap junction protein Cx43. Of the 73 mutations identified to date, over one-third are localized in the cytoplasmic loop (Cx43CL) domain. Here, we determined the mechanism by which three ODDD mutations (M147T, R148Q, and T154A), all of which localize within the predicted 1-5-10 calmodulin-binding motif of the Cx43CL, manifest the disease. Nuclear magnetic resonance (NMR) and circular dichroism revealed that the three ODDD mutations had little-to-no effect on the ability of the Cx43CL to form α-helical structure as well as bind calmodulin. Combination of microscopy and a dye-transfer assay uncovered these mutations increased the intracellular level of Cx43 and those that trafficked to the plasma membrane did not form functional channels. NMR also identify that CaM can directly interact with the Cx43CT domain. The Cx43CT residues involved in the CaM interaction overlap with tyrosines phosphorylated by Pyk2 and Src. In vitro and in cyto data provide evidence that the importance of the CaM interaction with the Cx43CT may lie in restricting Pyk2 and Src phosphorylation, and their subsequent downstream effects.
Allosteric Enzyme-Based Biosensors—Kinetic Behaviours of Immobilised L-Lysine-α-Oxidase from Trichoderma viride: pH Influence and Allosteric Properties
Authors: Guerrieri Antonio , Ciriello Rosanna , Bianco Giuliana , De Gennaro Francesca , Frascaro Silvio
Published: October 2020

The present study describes the kinetics of L-lysine-α-oxidase (LO) from Trichoderma viride immobilised by co-crosslinking onto the surface of a Pt electrode. The resulting amperometric biosensor was able to analyse L-lysine, thus permitting a simple but thorough study of the kinetics of the immobilised enzyme. The kinetic study evidenced that LO behaves in an allosteric fashion and that cooperativity is strongly pH-dependent. Not less important, experimental evidence shows that cooperativity is also dependent on substrate concentration at high pH and behaves as predicted by the Monod-Wyman-Changeux model for allosteric enzymes. According to this model, the existence of two different conformational states of the enzyme was postulated, which differ in Lys species landing on LO to form the enzyme–substrate complex. Considerations about the influence of the peculiar LO kinetics on biosensor operations and extracorporeal reactor devices will be discussed as well. Not less important, the present study also shows the effectiveness of using immobilised enzymes and amperometric biosensors not only for substrate analysis, but also as a convenient tool for enzyme kinetic studies.
Genome, Environment, Microbiome and Metabolome in Autism (GEMMA) Study Design: Biomarkers Identification for Precision Treatment and Primary Prevention of Autism Spectrum Disorders by an Integrated Multi-Omics Systems Biology Approach
Authors: Troisi Jacopo , Autio Reija , Beopoulos Thanos , Bravaccio Carmela , Carraturo Federica , Corrivetti Giulio , Cunningham Stephen , Devane Samantha , Fallin Daniele , Fetissov Serguei , Gea Manuel , Giorgi Antonio , Iris François , Joshi Lokesh , Kadzielski Sarah , Kraneveld Aletta , Kumar Himanshu , Ladd-Acosta Christine , Leader Geraldine , Mannion Arlene , Maximin Elise , Mezzelani Alessandra , Milanesi Luciano , Naudon Laurent , Peralta Marzal Lucia N. , Perez Pardo Paula , Prince Naika Z. , Rabot Sylvie , Roeselers Guus , Roos Christophe , Roussin Lea , Scala Giovanni , Tuccinardi Francesco Paolo , Fasano Alessio
Published: October 2020

Autism Spectrum Disorder (ASD) affects approximately 1 child in 54, with a 35-fold increase since 1960. Selected studies suggest that part of the recent increase in prevalence is likely attributable to an improved awareness and recognition, and changes in clinical practice or service availability. However, this is not sufficient to explain this epidemiological phenomenon. Research points to a possible link between ASD and intestinal microbiota because many children with ASD display gastro-intestinal problems. Current large-scale datasets of ASD are limited in their ability to provide mechanistic insight into ASD because they are predominantly cross-sectional studies that do not allow evaluation of perspective associations between early life microbiota composition/function and later ASD diagnoses. Here we describe GEMMA (Genome, Environment, Microbiome and Metabolome in Autism), a prospective study supported by the European Commission, that follows at-risk infants from birth to identify potential biomarker predictors of ASD development followed by validation on large multi-omics datasets. The project includes clinical (observational and interventional trials) and pre-clinical studies in humanized murine models (fecal transfer from ASD probands) and in vitro colon models. This will support the progress of a microbiome-wide association study (of human participants) to identify prognostic microbiome signatures and metabolic pathways underlying mechanisms for ASD progression and severity and potential treatment response.
Combined Supra- and Sub-Lesional Epidural Electrical Stimulation for Restoration of the Motor Functions after Spinal Cord Injury in Mini Pigs
Authors: Fadeev Filip , Eremeev Anton , Bashirov Farid , Shevchenko Roman , Izmailov Andrei , Markosyan Vage , Sokolov Mikhail , Kalistratova Julia , Khalitova Anastasiia , Garifulin Ravil , Islamov Rustem , Lavrov Igor
Published: October 2020

This study evaluates the effect of combined epidural electrical stimulation (EES) applied above (C5) and below (L2) the spinal cord injury (SCI) at T8–9 combined with motor training on the restoration of sensorimotor function in mini pigs. The motor evoked potentials (MEP) induced by EES applied at C5 and L2 levels were recorded in soleus muscles before and two weeks after SCI. EES treatment started two weeks after SCI and continued for 6 weeks led to improvement in multiple metrics, including behavioral, electrophysiological, and joint kinematics outcomes. In control animals after SCI a multiphasic M-response was observed during M/H-response testing, while animals received EES-enable training demonstrated the restoration of the M-response and H-reflex, although at a lower amplitude. The joint kinematic and assessment with Porcine Thoracic Injury Behavior scale (PTIBS) motor recovery scale demonstrated improvement in animals that received EES-enable training compared to animals with no treatment. The positive effect of two-level (cervical and lumbar) epidural electrical stimulation on functional restoration in mini pigs following spinal cord contusion injury in mini pigs could be related with facilitation of spinal circuitry at both levels and activation of multisegmental coordination. This approach can be taken as a basis for the future development of neuromodulation and neurorehabilitation therapy for patients with spinal cord injury.
The Missing Pieces of the Puzzle: A Review on the Interactive Nature of A-Priori Expectancies and Attention Bias toward Threat
Authors: Abado Elinor , Aue Tatjana , Okon-Singer Hadas
Published: October 2020

The role of attention bias in the etiology and maintenance of anxiety disorders has been studied extensively over decades. Attention bias reflects maladaptation in cognitive processing, as perceived threatening stimuli receive prioritized processing even when they are task-irrelevant or factually unthreatening. Recently, there has been some interest in the role of a-priori expectancies in attention bias toward threat. The current review article will present recent studies as examples that emphasize the need for more comprehensive research about the interactive effects of various factors that affect the relationship between expectancies and attention bias toward threatening stimuli in anxiety. The current review article suggests a holistic view, which advocates for more integrative research, as a dynamic network could underlie changes in attention bias. The study of the interaction between such factors, with a focus on expectancy, can lead to more ecological and clinically important results, and thus to more informed and fine-tuned treatments that are based on manipulation of expectancies. Such methods, in turn, can also help in shedding light on the research of attention bias, in a mutual relationship between research and therapy.
Towards New Diagnostic Approaches in Disorders of Consciousness: A Proof of Concept Study on the Promising Use of Imagery Visuomotor Task
Authors: Naro Antonino , Calabrò Rocco Salvatore
Published: October 2020

Background: advanced paraclinical approaches using functional neuroimaging and electroencephalography (EEG) allow identifying patients who are covertly aware despite being diagnosed as unresponsive wakefulness syndrome (UWS). Bedside detection of covert awareness employing motor imagery tasks (MI), which is a universally accepted clinical indicator of awareness in the absence of overt behavior, may miss some of these patients, as they could still have a certain level of awareness. We aimed at assessing covert awareness in patients with UWS using a visuomotor-guided motor imagery task (VMI) during EEG recording. Methods: nine patients in a minimally conscious state (MCS), 11 patients in a UWS, and 15 healthy individuals (control group—CG) were provided with an VMI (imagine dancing while watching a group dance video to command), a simple-MI (imagine squeezing their right hand to command), and an advanced-MI (imagine dancing without watching a group dance video to command) to detect command-following. We analyzed the command-specific EEG responses (event-related synchronization/desynchronization—ERS/ERD) of each patient, assessing whether these responses were appropriate, consistent, and statistically similar to those elicited in the CG, as reliable markers of motor imagery. Results: All patients in MCS, all healthy individuals and one patient in UWS repeatedly and reliably generated appropriate EEG responses to distinct commands of motor imagery with a classification accuracy of 60–80%. Conclusions: VMI outperformed significantly MI tasks. Therefore, patients in UWS may be still misdiagnosed despite a rigorous clinical assessment and an appropriate MI assessment. It is thus possible to suggest that motor imagery tasks should be delivered to patients with chronic disorders of consciousness in visuomotor-aided modality (also in the rehabilitation setting) to greatly entrain patient’s participation. In this regard, the EEG approach we described has the clear advantage of being cheap, portable, widely available, and objective. It may be thus considered as, at least, a screening tool to identify the patients who deserve further, advanced paraclinical approaches.
Comprehensive Analysis of RNA-Seq Gene Expression Profiling of Brain Transcriptomes Reveals Novel Genes, Regulators, and Pathways in Autism Spectrum Disorder
Authors: Rahman Md Rezanur , Petralia Maria Cristina , Ciurleo Rosella , Bramanti Alessia , Fagone Paolo , Shahjaman Md , Wu Lang , Sun Yanfa , Turanli Beste , Arga Kazim Yalcin , Islam Md Rafiqul , Islam Tania , Nicoletti Ferdinando
Published: October 2020

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with deficits in social communication ability and repetitive behavior. The pathophysiological events involved in the brain of this complex disease are still unclear. Methods: In this study, we aimed to profile the gene expression signatures of brain cortex of ASD patients, by using two publicly available RNA-seq studies, in order to discover new ASD-related genes. Results: We detected 1567 differentially expressed genes (DEGs) by meta-analysis, where 1194 were upregulated and 373 were downregulated genes. Several ASD-related genes previously reported were also identified. Our meta-analysis identified 235 new DEGs that were not detected using the individual RNA-seq studies used. Some of those genes, including seven DEGs (PAK1, DNAH17, DOCK8, DAPP1, PCDHAC2, and ERBIN, SLC7A7), have been confirmed in previous reports to be associated with ASD. Gene Ontology (GO) and pathways analysis showed several molecular pathways enriched by the DEGs, namely, osteoclast differentiation, TNF signaling pathway, complement and coagulation cascade. Topological analysis of protein–protein interaction of the ASD brain cortex revealed proteomics hub gene signatures: MYC, TP53, HDAC1, CDK2, BAG3, CDKN1A, GABARAPL1, EZH2, VIM, and TRAF1. We also identified the transcriptional factors (TFs) regulating DEGs, namely, FOXC1, GATA2, YY1, FOXL1, USF2, NFIC, NFKB1, E2F1, TFAP2A, HINFP. Conclusion: Novel core genes and molecular signatures involved with ASD were identified by our meta-analysis.
Auditory and Somatosensory P3 Are Complementary for the Assessment of Patients with Disorders of Consciousness
Authors: Annen Jitka , Mertel Isabella , Xu Ren , Chatelle Camille , Lesenfants Damien , Ortner Rupert , Bonin Estelle A.C. , Guger Christoph , Laureys Steven , Müller Friedemann
Published: October 2020

The evaluation of the level of consciousness in patients with disorders of consciousness (DOC) is primarily based on behavioural assessments. Patients with unresponsive wakefulness syndrome (UWS) do not show any sign of awareness of their environment, while minimally conscious state (MCS) patients show reproducible but fluctuating signs of awareness. Some patients, although with remaining cognitive abilities, are not able to exhibit overt voluntary responses at the bedside and may be misdiagnosed as UWS. Several studies investigated functional neuroimaging and neurophysiology as an additional tool to evaluate the level of consciousness and to detect covert command following in DOC. Most of these studies are based on auditory stimulation, neglecting patients suffering from decreased or absent hearing abilities. In the present study, we aim to assess the response to a P3-based paradigm in 40 patients with DOC and 12 healthy participants using auditory (AEP) and vibrotactile (VTP) stimulation. To this end, an EEG-based brain-computer interface was used at DOC patient’s bedside. We compared the significance of the P3 performance (i.e., the interpretation of significance of the evoked P3 response) as obtained by ‘direct processing’ (i.e., theoretical-based significance threshold) and ‘offline processing’ (i.e., permutation-based single subject level threshold). We evaluated whether the P3 performances were dependent on clinical variables such as diagnosis (UWS and MCS), aetiology and time since injury. Last we tested the dependency of AEP and VTP performances at the single subject level. Direct processing tends to overestimate P3 performance. We did not find any difference in the presence of a P3 performance according to the level of consciousness (UWS vs. MCS) or the aetiology (traumatic vs. non-traumatic brain injury). The performance achieved at the AEP paradigm was independent from what was achieved at the VTP paradigm, indicating that some patients performed better on the AEP task while others performed better on the VTP task. Our results support the importance of using multimodal approaches in the assessment of DOC patients in order to optimise the evaluation of patient’s abilities.
Suicidal Ideation and Suicidal Attempts in Referred Adolescents with High Functioning Autism Spectrum Disorder and Comorbid Bipolar Disorder: A Pilot Study
Authors: Masi Gabriele , Scullin Silvia , Narzisi Antonio , Muratori Pietro , Paciello Marinella , Fabiani Deborah , Lenzi Francesca , Mucci Maria , D’Acunto Giulia
Published: October 2020

Suicidal ideation and attempts in adolescents are closely associated to bipolar disorders (BD). Growing evidence also suggests that high functioning autism spectrum disorders (HF-ASD) are at increased risk for suicidal ideation and behaviors. Although BD and HF-ASD are frequently comorbid, no studies explored suicidality in these individuals. This exploratory study addressed this issue in a clinical group of inpatient adolescents referred to a psychiatric emergency unit. Seventeen adolescents with BD and HF-ASD and severe suicidal ideation or attempts (BD-ASD-S), were compared to 17 adolescents with BD and HF-ASD without suicidal ideation or attempts (BD-ASD-noS), and to 18 adolescents with BD and suicidal ideation or attempts without ASD (BD-noASD-S), using a structured assessment methodology. Individuals with BD-ASD-S had a higher intelligence quotient, more severe clinical impairment, more lethality in suicide attempts, more internalizing symptoms, less impulsiveness, and lower social competence. Severity of ASD traits in individuals and parents did not correlate with suicidal risk. Some dimensions of resilience were protective in terms of repulsion by life and attraction to death. Main limitations are the small sample size, the lack of a control group of typically developing adolescents. However, a better understanding of the specificities of bipolar HF-ASD individuals with suicidality may improve prevention and treatment strategies.
Management of Cancer-Associated Thrombosis: An Evolving Area
Authors: Frere Corinne , Connors Jean M. , Farge Dominique
Published: October 2020

The management of cancer-associated thrombosis (CAT) is an evolving area. With the use of direct oral anticoagulants as a new option in the management of CAT, clinicians now face several choices for the individual cancer patient with venous thromboembolism. A personalized approach, matching the right drug to the right patient, based on drug properties, efficacy and safety, side effect profile of each drug, and patient values and preference, will probably supplant the one size fits all approach of use of only low-molecular-weight heparin in the near future. We herein present eight translational, clinical research, and review articles on recent advances in the management of CAT published in the Special Issue “Treatment for Cancer-Associated Thrombosis” of Cancers. For now, a multidisciplinary patient-centered approach involving a close cooperation between oncologists and other specialists is warranted to guide clinical decision making and optimize the treatment of VTE in cancer patient.
Perceived Cognitive Impairment in Breast Cancer Survivors and Its Relationships with Psychological Factors
Authors: Boscher Clémence , Joly Florence , Clarisse Bénédicte , Humbert Xavier , Grellard Jean-Michel , Binarelli Giulia , Tron Laure , Licaj Idlir , Lange Marie
Published: October 2020

Cognitive complaints are common adverse effects in cancer patients. Identifying subjects at risk could make it possible to limit their impact. We aimed to explore the relationship between current cognitive complaints and demographic and psychological factors in a group of breast cancer survivors. Through an online survey, cancer survivors reported current cognitive complaints using the FACT-Cog questionnaire (Perceived Cognitive Impairment) and answered questions about their demographics, lifestyle and cancer-related characteristics. Anxiety, depression, fatigue and post-traumatic stress symptoms were also assessed. We used multivariable logistic regression models to explore the relationships between current cognitive complaints and social and psychological factors. Among the 1393 breast cancer survivors, 47.2% (n = 657) reported current cognitive complaints. Chemotherapy (OR = 2.26, 95%CI = 1.67–3.05), age (OR21-44 vs. >65 = 0.14, 95%CI = 0.07–0.27), sleep difficulties (ORnever vs. often = 2.41, 95%CI = 1.47–3.95), frequency of psychotropic treatments (ORnever vs. >1/week = 1.70, 95%CI = 1.23–2.36), post-traumatic stress symptoms (OR = 2.05, 95%CI = 1.57–2.69) and employment status (ORfull-time or part-time vs. sick leave = 1.64, 95%CI = 1.08–2.49) were strongly associated with current cognitive complaints. In this large study, about half of breast cancer survivors reported cognitive complaints, particularly after chemotherapy. Some risk factors should be detected early to reduce persistent cognitive complaints after cancer: mainly sleep difficulties, post-traumatic stress symptoms and psychotropic medications.
Autophagy: New Insights into Its Roles in Cancer Progression and Drug Resistance
Authors: Nawrocki Steffan T. , Wang Wei , Carew Jennifer S.
Published: October 2020

Autophagy is a mechanism of lysosomal proteolysis that is utilized to degrade damaged organelles, proteins, and other cellular components. Although key studies demonstrate that autophagy functions as a mechanism of tumor suppression via the degradation of defective pre-malignant cells, autophagy can also be used as a mechanism to break down cellular components under stress conditions to generate the required metabolic materials for cell survival. Autophagy has emerged as an important mediator of resistance to radiation, chemotherapy, and targeted agents. This series of articles highlight the role of autophagy in cancer progression and drug resistance and underscores the need for new and more effective agents that target this process.
The Mismatch Repair System (MMR) in Head and Neck Carcinogenesis and Its Role in Modulating the Response to Immunotherapy: A Critical Review
Authors: Cilona Maria , Locatello Luca Giovanni , Novelli Luca , Gallo Oreste
Published: October 2020

The mismatch repair (MMR) system has a major role in the detection and correction of DNA replication errors, resulting from DNA polymerase slippage or nucleotides misincorporation. Specific inherited/acquired alterations or epigenetic inactivation of MMR genes are associated with microsatellite instability (MSI): the loss of crucial function in repairing DNA alterations can promote carcinogenesis by favoring the accumulation of thousands of mutations in a broad spectrum of different anatomic sites such as colon, stomach, prostate, esophagus, endometrium, lung and head and neck. Recent extensive data suggest that tumor mutational burden strongly correlates with a clinical response to immunotherapy using checkpoint inhibitors and this response is influenced by MMR deficiency in a wide range of human solid cancers. In this context, few data about this crucial point are available for head and neck cancer (HNC). In this review, we discuss the role of MMR alterations and the resulting MSI in HNC pathogenesis. Furthermore, by summarizing the clinical available data on how they influence the progression of precancerous lesions and the risk of recurrence or second primary tumors, we want to define the current role of MSI in the management of HNC. Finally, we analyze the complex interaction between cancer cells and the immune system addressing the data now available about a potential correlation between microsatellite instability and immunotherapy response in HNC.
Establishment of an Endoscopy-Guided Minimally Invasive Orthotopic Mouse Model of Colorectal Cancer
Authors: Chen Chen , Neumann Jens , Kühn Florian , Lee Serene M. L. , Drefs Moritz , Andrassy Joachim , Werner Jens , Bazhin Alexandr V. , Schiergens Tobias S.
Published: October 2020

Open orthotopic mouse models of colorectal cancer have disadvantages such as the requirement for advanced surgical skills or the trauma caused by laparotomy. To overcome these drawbacks, this study aimed to evaluate the establishment of a minimally invasive model using murine colonoscopy. CT26 and MC38 CRC cells of different concentrations were injected into BALB/C and C57BL/6J mice, respectively. Follow-up endoscopies were performed to assign an endoscopic score to tumor growth. Gross autopsy, histologic and immuno-histochemical evaluation, and immune scoring were performed. To describe the learning curve of the procedures, a performance score was given. Local tumor growth with colorectal wall infiltration, luminal ulceration, the presence of tumor-infiltrating lymphocytes, lympho-vascular invasion, and early spontaneous lymph node, peritoneal, and hepatic metastases were observed. The tumors showed cytoplasmic immuno-staining for CK20. Compared to the MC38/C57BL/6J model, tumorigenicity and immunogenicity of the CT26/BALB/C model were higher. Tumor volume correlated with the endoscopic score. This endoscopy-guided orthotopic mouse model is easy to learn and quick to establish. It features early metastasis and enables the study of interactions with the immune system. When specific cell concentrations and cell lines are applied, controlled local tumor growth and metastasis can be achieved within short observation periods.
Intestinal Microbiota in Colorectal Cancer Surgery
Authors: Koliarakis Ioannis , Athanasakis Elias , Sgantzos Markos , Mariolis-Sapsakos Theodoros , Xynos Evangelos , Chrysos Emmanuel , Souglakos John , Tsiaoussis John
Published: October 2020

The intestinal microbiota consists of numerous microbial species that collectively interact with the host, playing a crucial role in health and disease. Colorectal cancer is well-known to be related to dysbiotic alterations in intestinal microbiota. It is evident that the microbiota is significantly affected by colorectal surgery in combination with the various perioperative interventions, mainly mechanical bowel preparation and antibiotic prophylaxis. The altered postoperative composition of intestinal microbiota could lead to an enhanced virulence, proliferation of pathogens, and diminishment of beneficial microorganisms resulting in severe complications including anastomotic leakage and surgical site infections. Moreover, the intestinal microbiota could be utilized as a possible biomarker in predicting long-term outcomes after surgical CRC treatment. Understanding the underlying mechanisms of these interactions will further support the establishment of genomic mapping of intestinal microbiota in the management of patients undergoing CRC surgery.
Cx43 Present at the Leading Edge Membrane Governs Promigratory Effects of Osteoblast-Conditioned Medium on Human Prostate Cancer Cells in the Context of Bone Metastasis
Authors: Boucher Jonathan , Balandre Annie-Claire , Debant Marjolaine , Vix Justine , Harnois Thomas , Bourmeyster Nicolas , Péraudeau Elodie , Chépied Amandine , Clarhaut Jonathan , Debiais Françoise , Monvoisin Arnaud , Cronier Laurent
Published: October 2020

Among the different interacting molecules implicated in bone metastases, connexin43 (Cx43) may increase sensitivity of prostate cancer (PCa) cells to bone microenvironment, as suggested by our in silico and human tissue samples analyses that revealed increased level of Cx43 expression with PCa progression and a Cx43 specific expression in bone secondary sites. The goal of the present study was to understand how Cx43 influences PCa cells sensitivity and aggressiveness to bone microenvironment. By means of Cx43-overexpressing PCa cell lines, we revealed a Cx43-dependent promigratory effect of osteoblastic conditioned media (ObCM). This effect on directional migration relied on the presence of Cx43 at the plasma membrane and not on gap junctional intercellular communication and hemichannel functions. ObCM stimulation induced Rac1 activation and Cx43 interaction with cortactin in protrusions of migrating PCa cells. Finally, by transfecting two different truncated forms of Cx43 in LNCaP cells, we determined that the carboxy terminal (CT) part of Cx43 is crucial for the responsiveness of PCa cells to ObCM. Our study demonstrates that Cx43 level and its membrane localization modulate the phenotypic response of PCa cells to osteoblastic microenvironment and that its CT domain plays a pivotal role.
Dual Targeting of Cancer Cells with DARPin-Based Toxins for Overcoming Tumor Escape
Authors: Shramova Elena , Proshkina Galina , Shipunova Victoria , Ryabova Anastasia , Kamyshinsky Roman , Konevega Andrey , Schulga Aleksey , Konovalova Elena , Telegin Georgij , Deyev Sergey
Published: October 2020

We report here a combined anti-cancer therapy directed toward HER2 and EpCAM, common tumor-associated antigens of breast cancer cells. The combined therapeutic effect is achieved owing to two highly toxic proteins—a low immunogenic variant of Pseudomonas aeruginosa exotoxin A and ribonuclease Barnase from Bacillus amyloliquefaciens. The delivery of toxins to cancer cells was carried out by targeting designed ankyrin repeat proteins (DARPins). We have shown that both target agents efficiently accumulate in the tumor. Simultaneous treatment of breast carcinoma-bearing mice with anti-EpCAM fusion toxin based on LoPE and HER2-specific liposomes loaded with Barnase leads to concurrent elimination of primary tumor and metastases. Monotherapy with anti-HER2- or anti-EpCAM-toxins did not produce a comparable effect on metastases. The proposed approach can be considered as a promising strategy for significant improvement of cancer therapy.
Genome-Wide Gene Expression Analyses of BRCA1- and BRCA2-Associated Breast and Ovarian Tumours
Authors: Wiggins George A. R. , Walker Logan C. , Pearson John F.
Published: October 2020

Germline pathogenic variants in BRCA1 and BRCA2 increase cumulative lifetime risk up to 75% for breast cancer and 76% for ovarian cancer. Genetic testing for BRCA1 and BRCA2 pathogenic variants has become an important part of clinical practice for cancer risk assessment and for reducing individual risk of developing cancer. Genetic testing can produce three outcomes: positive (a pathogenic variant), uninformative (no pathogenic variant) and uncertain significance (a variant of unknown clinical significance). More than one third of BRCA1 and BRCA2 variants identified have been classified as variants of uncertain significance, presenting a challenge for clinicians. To address this important clinical challenge, a number of studies have been undertaken to establish a gene expression phenotype for pathogenic BRCA1 and BRCA2 variant carriers in several diseased and normal tissues. However, the consistency of gene expression phenotypes described in studies has been poor. To determine if gene expression analysis has been a successful approach for variant classification, we describe the design and comparability of 23 published gene expression studies that have profiled cells from BRCA1 and BRCA2 pathogenic variant carriers. We show the impact of advancements in expression-based technologies, the importance of developing larger study cohorts and the necessity to better understand variables affecting gene expression profiles across different tissue types.
Mitochondria at Center of Exchanges between Cancer Cells and Cancer-Associated Fibroblasts during Tumor Progression
Authors: Nocquet Lisa , Juin Philippe P. , Souazé Frédérique
Published: October 2020

Resistance of solid cancer cells to chemotherapies and targeted therapies is not only due to the mutational status of cancer cells but also to the concurring of stromal cells of the tumor ecosystem, such as immune cells, vasculature and cancer-associated fibroblasts (CAFs). The reciprocal education of cancer cells and CAFs favors tumor growth, survival and invasion. Mitochondrial function control, including the regulation of mitochondrial metabolism, oxidative stress and apoptotic stress are crucial for these different tumor progression steps. In this review, we focus on how CAFs participate in cancer progression by modulating cancer cells metabolic functions and mitochondrial apoptosis. We emphasize that mitochondria from CAFs influence their activation status and pro-tumoral effects. We thus advocate that understanding mitochondria-mediated tumor–stroma interactions provides the possibility to consider cancer therapies that improve current treatments by targeting these interactions or mitochondria directly in tumor and/or stromal cells.
Inhibition of Melanoma Cell Migration and Invasion Targeting the Hypoxic Tumor Associated CAXII
Authors: Giuntini Gaia , Monaci Sara , Cau Ylenia , Mori Mattia , Naldini Antonella , Carraro Fabio
Published: October 2020

Background: Intratumoral hypoxia contributes to cancer progression and poor prognosis. Carbonic anhydrases IX (CAIX) and XII (CAXII) play pivotal roles in tumor cell adaptation and survival, as aberrant Hedgehog (Hh) pathway does. In malignant melanoma both features have been investigated for years, but they have not been correlated before and/or identified as a potential pharmacological target. Here, for the first time, we demonstrated that malignant melanoma cell motility was impaired by targeting CAXII via either CAs inhibitors or through the inhibition of the Hh pathway. Methods: We tested cell motility in three melanoma cell lines (WM-35, SK-MEL28, and A375), with different invasiveness capabilities. To this end we performed a scratch assay in the presence of the smoothened (SMO) antagonist cyclopamine (cyclo) or CAs inhibitors under normoxia or hypoxia. Then, we analyzed the invasiveness potential in the cell lines which were more affected by cyclo and CAs inhibitors (SK-MEL28 and A375). Western blot was employed to assess the expression of the hypoxia inducible factor 1α, CAXII, and FAK phosphorylation. Immunofluorescence staining was performed to verify the blockade of CAXII expression. Results: Hh inhibition reduced melanoma cell migration and CAXII expression under both normoxic and hypoxic conditions. Interestingly, basal CAXII expression was higher in the two more aggressive melanoma cell lines. Finally, a direct CAXII blockade impaired melanoma cell migration and invasion under hypoxia. This was associated with a decrease of FAK phosphorylation and metalloprotease activities. Conclusions: CAXII may be used as a target for melanoma treatment not only through its direct inhibition, but also through Hh blockade.
EVs as Potential New Therapeutic Tool/Target in Gastrointestinal Cancer and HCC
Authors: Słomka Artur , Mocan Tudor , Wang Bingduo , Nenu Iuliana , Urban Sabine , Gonzalez-Carmona Maria , Schmidt-Wolf Ingo , Lukacs-Kornek Veronika , Strassburg Christian , Spârchez Zeno , Kornek Miroslaw
Published: October 2020

For more than a decade, extracellular vesicles (EVs) have been in focus of science. Once thought to be an efficient way to eliminate undesirable cell content, EVs are now well-accepted as being an important alternative to cytokines and chemokines in cell-to-cell communication route. With their cargos, mainly consisting of functional proteins, lipids and nucleic acids, they can activate signalling cascades and thus change the phenotype of recipient cells at local and systemic levels. Their substantial role as modulators of various physiological and pathological processes is acknowledged. Importantly, more and more evidence arises that EVs play a pivotal role in many stages of carcinogenesis. Via EV-mediated communication, tumour cells can manipulate cells from host immune system or from the tumour microenvironment, and, ultimately, they promote tumour progression and modulate host immunity towards tumour’s favour. Additionally, the role of EVs in modulating resistance to pharmacological and radiological therapy of many cancer types has become evident lately. Our understanding of EV biology and their role in cancer promotion and drug resistance has evolved considerably in recent years. In this review, we specifically discuss the current knowledge on the association between EVs and gastrointestinal (GI) and liver cancers, including their potential for diagnosis and treatment.
Tailored Exercise during Hematopoietic Stem Cell Transplantation Hospitalization in Children with Cancer: A Prospective Cohort Study
Authors: Morales Javier S. , González Vicent Marta , Valenzuela Pedro L. , Castillo-García Adrián , Santana-Sosa Elena , Lassaletta Alvaro , Santos-Lozano Alejandro , Fiuza-Luces Carmen , Lucia Alejandro
Published: October 2020

We assessed the clinical effects of a supervised exercise (aerobic + resistance) intervention performed during inpatient hospitalization for pediatric hematopoietic stem cell transplantation (HSCT). Patients were placed in an exercise (n = 65 (47 and 18 with allogeneic (allo-) and autologous (auto-) HSCT, respectively)) or a control (n = 53 (39 and 14)) group. Exercise interventions were performed in isolated hospital patient rooms. Patients were followed-up from the beginning of the conditioning phase up to 6 years. We assessed survival, risk of graft-versus-host disease (GvHD) or graft failure (primary outcomes), and engraftment kinetics, supportive care, toxicity profile, and immune reconstitution for auto-HSCT and allo-HSCT. The exercise intervention was safe and did not affect the risk of mortality, acute/chronic GvHD, or graft failure (all p > 0.05). No between-group differences (p > 0.05) were found for the remainder of clinical endpoints, except for a reduced number of total and viral infections in the exercise group after allo-HSCT (unadjusted p = 0.005 for both total and viral infections, and adjusted p = 0.023 and 0.083, respectively). In conclusion, exercise performed during inpatient hospitalization for pediatric HSCT is safe and well tolerated during both auto and allo-HSCT and tends to decrease the risk of infection after allo-HSCT. These findings provide additional support to the notion that a multidisciplinary approach (i.e., including the work of exercise specialists) is suitable in the management of children undergoing HSCT. Further studies are needed to determine whether applying a different training stimulus (notably, higher exercise intensities) exerts positive effects on HSCT prognosis in these patients.
Mono vs. Difunctional Coumarin as Photoinitiators in Photocomposite Synthesis and 3D Printing
Authors: Rahal Mahmoud , Mokbel Haifaa , Graff Bernadette , Toufaily Joumana , Hamieh Tayssir , Dumur Frédéric , Lalevée Jacques
Published: October 2020

This work is devoted to investigate three coumarin derivatives (Coum1, Coum2, and Coum3), proposed as new photoinitiators of polymerization when combined with an additive, i.e., an iodonium salt, and used for the free radical polymerization (FRP) of acrylate monomers under mild irradiation conditions. The different coumarin derivatives can also be employed in three component photoinitiating systems with a Iod/amine (ethyl 4-dimethylaminobenzoate (EDB) or N-phenylglycine (NPG)) couple for FRP upon irradiation with an LED @ 405 nm. These compounds showed excellent photoinitiating abilities, and high polymerization rates and final conversions (FC) were obtained. The originality of this work relies on the comparison of the photoinitiating abilities of monofunctional (Coum1 and Coum2) vs. difunctional (Coum3) compounds. Coum3 is a combined structure of Coum1 and Coum2, leading to a sterically hindered chemical structure with a relatively high molecular weight. As a general rule, a high molecular weight should reduce the migration of initiating molecules and favor photochemical properties such as photobleaching of the final polymer. As attempted, from the efficiency point of view, Coum3 can initiate the FRP, but a low reactivity was observed compared to the monofunctional compound (Coum1 and Coum2). Indeed, to study the photochemical and photophysical properties of these compounds, different parameters were taken into account, e.g., the light absorption and emission properties, steady state photolysis, and fluorescence quenching. To examine these different points, several techniques were used including UV-visible spectroscopy, real-time Fourier Transform Infrared Spectroscopy (RT-FTIR), fluorescence spectroscopy, and cyclic voltammetry. The photochemical mechanism involved in the polymerization process is also detailed. The best coumarins investigated in this work were used for laser writing (3D printing) experiments and also for photocomposite synthesis containing glass fibers.
GUN1 and Plastid RNA Metabolism: Learning from Genetics
Authors: Tadini Luca , Jeran Nicolaj , Pesaresi Paolo
Published: October 2020

GUN1 (genomes uncoupled 1), a chloroplast-localized pentatricopeptide repeat (PPR) protein with a C-terminal small mutS-related (SMR) domain, plays a central role in the retrograde communication of chloroplasts with the nucleus. This flow of information is required for the coordinated expression of plastid and nuclear genes, and it is essential for the correct development and functioning of chloroplasts. Multiple genetic and biochemical findings indicate that GUN1 is important for protein homeostasis in the chloroplast; however, a clear and unified view of GUN1′s role in the chloroplast is still missing. Recently, GUN1 has been reported to modulate the activity of the nucleus-encoded plastid RNA polymerase (NEP) and modulate editing of plastid RNAs upon activation of retrograde communication, revealing a major role of GUN1 in plastid RNA metabolism. In this opinion article, we discuss the recently identified links between plastid RNA metabolism and retrograde signaling by providing a new and extended concept of GUN1 activity, which integrates the multitude of functional genetic interactions reported over the last decade with its primary role in plastid transcription and transcript editing.
Insulin-Like Growth Factors in Development, Cancers and Aging
Authors: Werner Haim
Published: October 2020

Since their discovery in the late 1950s, insulin-like growth factors (IGFs) have attracted significant interest in multiple areas of biology and medicine, including endocrinology, pediatrics, growth, metabolism, nutrition, aging, and oncology [...]
Is It Meanwhile Biomedical Sciences or Still “Ars Medica”?
Authors: Jost Wolfgang H.
Published: October 2020

Scientific work is usually quite time-intensive and frequently replete with frustrations [...]
The Potential Effects of Short-Chain Fatty Acids on the Epigenetic Regulation of Innate Immune Memory
Authors: Watt Raphael , Parkin Kimberley , Martino David
Published: October 2020

The regulation of innate immunity is substantially more ‘plastic’ than previously appreciated. Innate immune memory (manifested through trained immunity and tolerance) is a recently described epigenetic phenomenon that is a model example, with broad implications for infectious disease, allergy and autoimmunity. Training the innate immune system to combat infections and temper inappropriate responses in non-communicable diseases will likely be an area of intense research. Innate immunity is influenced by short chain fatty acids, which are the natural products of digestion by the intestinal microbiota that possess inherent histone deacetylase inhibitory properties. It therefore stands to reason that a healthy gut microbiome may well influence mucosal and systemic trained immunity via short chain fatty acids. There is a lack of data on this specific topic, and we discuss potential relationships based on available and preliminary evidence. Understanding the link between intestinal microbiome composition, capacity for short chain fatty acid production and downstream effects on innate immune memory in early life will have important implications for host immunobiology. In this review we explore the intersection between the gut microbiota, short chain fatty acids and epigenetic regulation of innate immunity with a focus on early life.
Flexible Carbon Electrodes for Electrochemical Detection of Bisphenol-A, Hydroquinone and Catechol in Water Samples
Authors: Sá Acelino C. de , Barbosa Simone C. , Raymundo-Pereira Paulo A. , Wilson Deivy , Shimizu Flávio M. , Raposo Maria , Oliveira Osvaldo N.
Published: October 2020

The detection of pollutant traces in the public water supply and aquifers is essential for the safety of the population. In this article, we demonstrate that a simple electrochemical procedure in acidic solution can be employed for enhancing the sensitivity of flexible screen-printed carbon electrodes (SPEs) to detect bisphenol-A (BPA), hydroquinone, and catechol, simultaneously. The SPEs were pretreated electrochemically in a H2SO4 solution, which did not affect their morphology, yielding high current signals with well separated oxidation peaks. The sensitivity values were 0.28, 0.230, and 0.056 µA L µmol−1 with detection limits of 0.12, 0.82, and 0.95 µmol L−1 for hydroquinone, catechol, and BPA, respectively. The sensors were reproducible and selective for detecting BPA in plastic cups, and with adequate specificity not to be affected by interferents from water samples. The simple, inexpensive, and flexible SPE may thus be used to detect emerging pollutants and monitor the water quality.
Primary Transverse Closure Compared to Open Wound Treatment for Primary Pilonidal Sinus Disease in Children
Authors: Pfammatter Michèle , Erlanger Tobias E. , Mayr Johannes
Published: October 2020

We aimed to compare the outcome of two different operative methods to correct pilonidal sinus disease (PSD) in children, i.e., excision and open wound care (OW) versus excision and primary transverse closure (PC) of the wound. In this retrospective, observational study, we extracted data from the medical records of 56 patients who underwent surgery for PSD at our institution between 1 January 2006 and 31 December 2016. To test whether the primary variable, i.e., rate of PSD recurrence, differed between the two surgical groups, a logistic regression model was fitted. Secondary explanatory variables were total length of stay (LOS) at the hospital, complications, sex and age of patients, seniority of the surgeon in charge, and volume of excised specimen. Overall, 32 (57%) children and young adults underwent OW, while 24 (43%) patients were treated by PC. Mean age at operation was 15.5 years in either group. PSD recurred in 12 of 32 (37.5%) children in the OW group and in 3 of 24 (12.5%) children in the PC group (ratio: 0.19, 95% confidence interval [95% CI] 0.03–1.07). Thus, treatment of primary PSD by PC proved superior with respect to PSD recurrence. Moreover, our study did not bring to light any high-grade complications in the PC group, and postoperative pain was minimal. Less invasive treatment approaches for chronic PSD are typically performed in an outpatient setting and offer reduced morbidity, low rates of PSD recurrence, and shortened periods of time to return to work or social activities. More radical operations of PSD should be reserved for recurrent PSD where less invasive approaches have failed several times.