bluuebunny/crossref_metadata_2025 huggingface dataset:
Painful Cutaneous Electrical Stimulation vs. Heat Pain as Test Stimuli in Conditioned Pain Modulation
Authors: Enax-Krumova Elena , Plaga Ann-Christin , Schmidt Kimberly , Özgül Özüm S. , Eitner Lynn B. , Tegenthoff Martin , Höffken Oliver
Published: September 2020

Different paradigms can assess the effect of conditioned pain modulation (CPM). The aim of the present study was to compare heat pain, as an often used test stimulus (TS), to painful cutaneous electrical stimulation (PCES), having the advantage of the additional recording of PCES-related evoked potentials. In 28 healthy subjects we applied heat and PCES at the dominant hand as test stimulus (TS) to compare the CPM-effect elicited by hand immersion into cold water (10 °C) as conditioning stimulus (CS). Subjects rated the pain intensity of TS at baseline, during and 5 min after CS application and additionally of CS, on a numerical rating scale (NRS) (0–100). The ‘early’ (during CS–before CS) and ‘late’ (after CS–before CS) CPM-effects were analyzed. Parallel to the PCES, the related evoked potentials were recorded via Cz to evaluate any changes in PCES-amplitudes. CS reduced significantly the pain intensity of both PCES and heat pain as TS. On a group level, the CPM-effect did not differ significantly between both paradigms. Both early and late CPM-effect based on PCES correlated significantly with the CS pain intensity (r = −0.630 and −0.503, respectively), whereas using heat pain the correlation was not significant. We found a significant reduction of PCES-amplitudes during CS, but this did not correlate with the PCES-induced pain intensity. Correlation with the CS painfulness (r = −0.464) did not achieve the significance level after Bonferroni correction. The extent of the CPM effects was similar in both testing paradigms at group level, despite intraindividual differences. Future studies should further elicit the exact mechanisms explaining the modality of these specific differences.
The Predictive Role of Executive Functions and Psychological Factors on Chronic Pain after Orthopaedic Surgery: A Longitudinal Cohort Study
Authors: Giusti Emanuele Maria , Manna Chiara , Varallo Giorgia , Cattivelli Roberto , Manzoni Gian Mauro , Gabrielli Samantha , D’Amario Federico , Lacerenza Marco , Castelnuovo Gianluca
Published: September 2020

Prevention and treatment of chronic post-surgical pain should be based on the early identification of patients at risk. The presence of a deficit in executive functions, along with the presence of psychological risk factors, could impair the use of appropriate pain coping strategies and might facilitate the transition to chronic post-surgical pain. A longitudinal cohort study was implemented. Patients listed for orthopaedic surgery were enrolled. Variables measured before surgery were pain intensity, the sensory, affective, cognitive and mixed components of pain, state and trait variables associated with the psychological status of the patient, fear of movement, pain catastrophizing, visual attention and cognitive flexibility. Pain intensity and the components of pain were re-evaluated after surgery and after three months. A linear mixed model was used to assess the predictors of pain intensity, and a multivariate linear mixed model was used to assess the predictors of the pain components. 167 patients were enrolled. Controlling for sex, age, pain duration and surgical procedure, catastrophizing and visual attention were predictors of pain intensity at follow-up. The sensory component of pain was predicted by state anxiety, healthcare-related fears, pain catastrophizing and visual attention. Anxiety and catastrophizing were predictors of the affective and evaluative components of pain. The mixed component of pain was predicted by state anxiety, healthcare-related fears and pain catastrophizing. Executive functions, along with psychological risk factors, shape the course of post-surgical pain. The efficacy of preventive and rehabilitation treatment could be possibly enhanced if these factors are treated.
Targeted-Alpha-Therapy Combining Astatine-211 and anti-CD138 Antibody in a Preclinical Syngeneic Mouse Model of Multiple Myeloma Minimal Residual Disease
Authors: Gouard Sébastien , Maurel Catherine , Marionneau-Lambot Séverine , Dansette Delphine , Bailly Clément , Guérard François , Chouin Nicolas , Haddad Ferid , Alliot Cyril , Gaschet Joëlle , Eychenne Romain , Kraeber-Bodéré Françoise , Chérel Michel
Published: September 2020

Despite therapeutic progress in recent years with the introduction of targeted therapies (daratumumab, elotuzumab), multiple myeloma remains an incurable cancer. The question is therefore to investigate the potential of targeted alpha therapy, combining an anti-CD138 antibody with astatine-211, to destroy the residual cells that cause relapses. A preclinical syngeneic mouse model, consisting of IV injection of 1 million of 5T33 cells in a KaLwRij C57/BL6 mouse, was treated 10 days later with an anti-mCD138 antibody, called 9E7.4, radiolabeled with astatine-211. Four activities of the 211At-9E7.4 radioimmunoconjugate were tested in two independent experiments: 370 kBq (n = 16), 555 kBq (n = 10), 740 kBq (n = 17) and 1100 kBq (n = 6). An isotype control was also tested at 555 kBq (n = 10). Biodistribution, survival rate, hematological parameters, enzymatic hepatic toxicity, histological examination and organ dosimetry were considered. The survival median of untreated mice was 45 days after engraftment. While the activity of 1100 kBq was highly toxic, the activity of 740 kBq offered the best efficacy with 65% of overall survival 150 days after the treatment with no evident sign of toxicity. This work demonstrates the pertinence of treating minimal residual disease of multiple myeloma with an anti-CD138 antibody coupled to astatine-211.
Fusobacterium nucleatum Accelerates the Progression of Colitis-Associated Colorectal Cancer by Promoting EMT
Authors: Yu Mi Ra , Kim Hye Jung , Park Hae Ryoun
Published: September 2020

Recently, it has been reported that Fusobacterium nucleatum, a major pathogen involved in chronic periodontitis, may play an important role in colorectal cancer (CRC) progression. In addition, inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease represent major predisposing conditions for the development of CRC, and this subtype of cancer is called colitis-associated cancer (CAC). Although the importance of F. nucleatum in CRC has attracted attention, its exact role and related mechanism in CAC progression remain unclear. In this study, we investigated the effects of F. nucleatum in experimental colitis induced with dextran sodium sulfate (DSS), which is a well-known colitis-inducing chemical, on the aggressiveness of CAC and its related mechanism in both in vitro and in vivo models. F. nucleatum synergistically increased the aggressiveness and epithelial–mesenchymal transition (EMT) characteristics of CRC cells that were treated with DSS compared to those in non-treated CRC cells. The role of F. nucleatum in CAC progression was further confirmed in mouse models, as F. nucleatum was found to significantly increase the malignancy of azoxymethane (AOM)/DSS-induced colon cancer. This promoting effect of F. nucleatum was based on activation of the EGFR signaling pathways, including protein kinase B (AKT) and extracellular signal-regulated kinase (ERK), and epidermal growth factor receptor (EGFR) inhibition significantly reduced the F. nucleatum-induced EMT alteration. In conclusion, F. nucleatum accelerates the progression of CAC by promoting EMT through the EGFR signaling pathway.
Transcriptomics-Based Drug Repurposing Approach Identifies Novel Drugs against Sorafenib-Resistant Hepatocellular Carcinoma
Authors: Regan-Fendt Kelly , Li Ding , Reyes Ryan , Yu Lianbo , Wani Nissar A. , Hu Peng , Jacob Samson T. , Ghoshal Kalpana , Payne Philip R.O. , Motiwala Tasneem
Published: September 2020

Objective: Hepatocellular carcinoma (HCC) is frequently diagnosed in patients with late-stage disease who are ineligible for curative surgical therapies. The majority of patients become resistant to sorafenib, the only approved first-line therapy for advanced cancer, underscoring the need for newer, more effective drugs. The purpose of this study is to expedite identification of novel drugs against sorafenib resistant (SR)-HCC. Methods: We employed a transcriptomics-based drug repurposing method termed connectivity mapping using gene signatures from in vitro-derived SR Huh7 HCC cells. For proof of concept validation, we focused on drugs that were FDA-approved or under clinical investigation and prioritized two anti-neoplastic agents (dasatinib and fostamatinib) with targets associated with HCC. We also prospectively validated predicted gene expression changes in drug-treated SR Huh7 cells as well as identified and validated the targets of Fostamatinib in HCC. Results: Dasatinib specifically reduced the viability of SR-HCC cells that correlated with up-regulated activity of SRC family kinases, its targets, in our SR-HCC model. However, fostamatinib was able to inhibit both parental and SR HCC cells in vitro and in xenograft models. Ingenuity pathway analysis of fostamatinib gene expression signature from LINCS predicted JAK/STAT, PI3K/AKT, ERK/MAPK pathways as potential targets of fostamatinib that were validated by Western blot analysis. Fostamatinib treatment reversed the expression of genes that were deregulated in SR HCC. Conclusion: We provide proof of concept evidence for the validity of this drug repurposing approach for SR-HCC with implications for personalized medicine.
Transcatheter Arterial Embolization Treatment for Bleeding Visceral Artery Pseudoaneurysms in Patients with Pancreatitis or following Pancreatic Surgery
Authors: Numoto Isao , Tsurusaki Masakatsu , Oda Teruyoshi , Yagyu Yukinobu , Ishii Kazunari , Murakami Takamichi
Published: September 2020

Purpose: To evaluate the efficacy and safety of transcatheter arterial embolization (TAE) for pseudoaneurysms occurring secondary to pancreatitis or because of leakage of pancreatic juice after pancreatectomy. Materials and Methods: This retrospective study included 42 consecutive patients (38 males and 4 females; mean age, 60 years; range, 33–80 years) who underwent TAE for bleeding visceral artery pseudoaneurysms between March 2004 and December 2018. The technical and clinical success rates, incidence of recurrent bleeding and complications, including pancreatitis, were evaluated. Results: Of the 42 enrolled patients, 23 had bleeding due to a complication of pancreatectomy and 19 had bleeding as a complication of pancreatitis. TAE with N-butyl cyanoacrylate (NBCA) or NBCA plus microcoils recurrent bleeding or inability to control bleeding was 15.8% (3 of 19) following TAE with NBCA and 17.4% (4 of 23) following TAE with coils. No clinically significant ischemic events of the pancreas or duodenum were observed in the embolized areas. Serum amylase did not increase compared with the initial levels after any of the procedures. At 30 days after TAE, 32 patients were alive. Conclusion: TAE has a high success rate for the management of hemorrhage, with few complications. The procedure appears to be safe and effective for pseudoaneurysms associated with either pancreatitis or pancreatectomy.
Predicting the Efficacy and Safety of TACTICs (Tumor Angiogenesis-Specific CAR-T Cells Impacting Cancers) Therapy for Soft Tissue Sarcoma Patients
Authors: Fujiwara Kento , Sasawatari Shigemi , Nakai Sho , Imaeda Keisuke , Nagai Seina , Matsuno Yoshihiro , Hatanaka Kanako , Hatanaka Yutaka , Takenaka Satoshi , Okada Naoki
Published: September 2020

Soft tissue sarcomas (STSs) are heterogeneous and aggressive malignancies with few effective therapies available. We have developed T cells expressing a vascular endothelial growth factor receptor 2 (VEGFR2)-specific chimeric antigen receptor (CAR) to establish a tumor angiogenesis-specific CAR-T cells impacting cancers (TACTICs) therapy. In this study, we optimized the manufacturing and transportation of mRNA-transfected anti-VEGFR2 CAR-T cells and collected information that allowed the extrapolation of the efficacy and safety potential of TACTICs therapy for STS patients. Although 5-methoxyuridines versus uridines did not improve CAR-mRNA stability in T cells, the utilization of CleanCap as a 5′ cap-structure extended the CAR expression level, increasing VEGFR2-specific cytotoxicity. Furthermore, 4 °C preservation conditions did not affect the viability/cytotoxicity of CAR-T cells, contrarily to a freeze-thaw approach. Importantly, immunohistochemistry showed that most of the STS patients’ specimens expressed VEGFR2, suggesting a great potential of our TACTICs approach. However, VEGFR2 expression was also detected in normal tissues, stressing the importance of the application of a strict monitoring schedule to detect (and respond to) the occurrence of adverse effects in clinics. Overall, our results support the development of a “first in humans” study to evaluate the potential of our TACTICs therapy as a new treatment option for STSs.
Small-Molecule Inhibitors (SMIs) as an Effective Therapeutic Strategy for Endometrial Cancer
Authors: Megino-Luque Cristina , Moiola Cristian Pablo , Molins-Escuder Clara , López-Gil Carlos , Gil-Moreno Antonio , Matias-Guiu Xavier , Colas Eva , Eritja Núria
Published: September 2020

Endometrial cancer (EC) is the sixth most common cancer in women. A continued number of low-risk EC patients at diagnosis, as well as patients diagnosed with advanced-stage disease, will experience an aggressive disease. Unfortunately, those patients will present recurrence or overt dissemination. Systemic cytotoxic chemotherapy treatment on advanced, recurrent, or metastatic EC patients has shown poor results, with median survival rates of less than one year, and median progression-free survival rates of four months. Therefore, the search for innovative and alternative drugs or the development of combinatorial therapies involving new targeted drugs and standard regimens is imperative. Over the last few decades, some small-molecule inhibitors have been introduced in the clinics for cancer treatment, but only a few have been approved by the Food and Drug Administration (FDA) for EC treatment. In the present review, we present the current state and future prospects of small-molecule inhibitors on EC treatment, both alone and in combination.
Integrated Multiparametric Radiomics and Informatics System for Characterizing Breast Tumor Characteristics with the OncotypeDX Gene Assay
Authors: Jacobs Michael A. , Umbricht Christopher B. , Parekh Vishwa S. , El Khouli Riham H. , Cope Leslie , Macura Katarzyna J. , Harvey Susan , Wolff Antonio C.
Published: September 2020

Optimal use of multiparametric magnetic resonance imaging (mpMRI) can identify key MRI parameters and provide unique tissue signatures defining phenotypes of breast cancer. We have developed and implemented a new machine-learning informatic system, termed Informatics Radiomics Integration System (IRIS) that integrates clinical variables, derived from imaging and electronic medical health records (EHR) with multiparametric radiomics (mpRad) for identifying potential risk of local or systemic recurrence in breast cancer patients. We tested the model in patients (n = 80) who had Estrogen Receptor positive disease and underwent OncotypeDX gene testing, radiomic analysis, and breast mpMRI. The IRIS method was trained using the mpMRI, clinical, pathologic, and radiomic descriptors for prediction of the OncotypeDX risk score. The trained mpRad IRIS model had a 95% and specificity was 83% with an Area Under the Curve (AUC) of 0.89 for classifying low risk patients from the intermediate and high-risk groups. The lesion size was larger for the high-risk group (2.9 ± 1.7 mm) and lower for both low risk (1.9 ± 1.3 mm) and intermediate risk (1.7 ± 1.4 mm) groups. The lesion apparent diffusion coefficient (ADC) map values for high- and intermediate-risk groups were significantly (p < 0.05) lower than the low-risk group (1.14 vs. 1.49 × 10−3 mm2/s). These initial studies provide deeper insight into the clinical, pathological, quantitative imaging, and radiomic features, and provide the foundation to relate these features to the assessment of treatment response for improved personalized medicine.
Cannabidiol and Oxygen-Ozone Combination Induce Cytotoxicity in Human Pancreatic Ductal Adenocarcinoma Cell Lines
Authors: Luongo Margherita , Marinelli Oliviero , Zeppa Laura , Aguzzi Cristina , Morelli Maria , Amantini Consuelo , Frassineti Andrea , di Costanzo Marianne , Fanelli Alessandro , Santoni Giorgio , Nabissi Massimo
Published: September 2020

Pancreatic cancer (PC) is related to lifestyle risks, chronic inflammation, and germline mutations in BRCA1/2, ATM, MLH1, TP53, or CDKN2A. Surgical resection and adjuvant chemotherapy are the main therapeutic strategies but are less effective in patients with high-grade tumors. Oxygen-ozone (O2/O3) therapy is an emerging alternative tool for the treatment of several clinical disorders. O2/O3 therapy has been found to ameliorate mechanisms promoting chronic pain and inflammation, including hypoxia, inflammatory mediators, and infection. The advantages of using cannabinoids have been evaluated in vitro and in vivo models of several human cancers. Regarding PDAC, activation of cannabinoid receptors was found to induce pancreatic cancer cell apoptosis without affecting the normal pancreas cells. In a murine model of PDAC, a combination of cannabidiol (CBD) and gemcitabine increased survival length by nearly three times. Herein, we evaluate the anticancer effect of CBD and O2/O3, alone or in combination, on two human PDAC cell lines, PANC-1 and MiaPaCa-2, examining expression profiles of 92 pancreatic adenocarcinoma associated genes, cytotoxicity, migration properties, and cell death. Finally, we assess the combination effects with gemcitabine and paclitaxel. Summarizing, for the first time the antitumoral effect of combined therapy with CBD and oxygen-ozone therapy in PDAC is evidenced.
Frontiers of Robotic Gastroscopy: A Comprehensive Review of Robotic Gastroscopes and Technologies
Authors: Marlicz Wojciech , Ren Xuyang , Robertson Alexander , Skonieczna-Żydecka Karolina , Łoniewski Igor , Dario Paolo , Wang Shuxin , Plevris John N , Koulaouzidis Anastasios , Ciuti Gastone
Published: September 2020

Upper gastrointestinal (UGI) tract pathology is common worldwide. With recent advancements in robotics, innovative diagnostic and treatment devices have been developed and several translational attempts made. This review paper aims to provide a highly pictorial critical review of robotic gastroscopes, so that clinicians and researchers can obtain a swift and comprehensive overview of key technologies and challenges. Therefore, the paper presents robotic gastroscopes, either commercial or at a progressed technology readiness level. Among them, we show tethered and wireless gastroscopes, as well as devices aimed for UGI surgery. The technological features of these instruments, as well as their clinical adoption and performance, are described and compared. Although the existing endoscopic devices have thus far provided substantial improvements in the effectiveness of diagnosis and treatment, there are certain aspects that represent unwavering predicaments of the current gastroenterology practice. A detailed list includes difficulties and risks, such as transmission of communicable diseases (e.g., COVID-19) due to the doctor–patient proximity, unchanged learning curves, variable detection rates, procedure-related adverse events, endoscopists’ and nurses’ burnouts, limited human and/or material resources, and patients’ preferences to choose non-invasive options that further interfere with the successful implementation and adoption of routine screening. The combination of robotics and artificial intelligence, as well as remote telehealth endoscopy services, are also discussed, as viable solutions to improve existing platforms for diagnosis and treatment are emerging.
Prognostic Role of Serum Cytokeratin-19 Fragment (CYFRA 21-1) in Patients with Hepatocellular Carcinoma
Authors: Caviglia Gian Paolo , Ciruolo Michela , Olivero Antonella , Carucci Patrizia , Rolle Emanuela , Rosso Chiara , Abate Maria Lorena , Risso Alessandra , Ribaldone Davide Giuseppe , Tandoi Francesco , Saracco Giorgio Maria , Bugianesi Elisabetta , Gaia Silvia
Published: September 2020

Keratin 19 (K19) is a cancer stem cell marker expressed by a subpopulation of hepatocellular carcinoma (HCC), associated with tumor aggressiveness. We evaluated the prognostic value of serum K19 fragment (CYFRA 21-1), in comparison or in combination with alpha-fetoprotein (AFP) and protein induced by vitamin-K absence or antagonist-II (PIVKA-II), in patients with HCC. A total of 160 patients (28F/132M; median age 62, range 44–86 years) with a new diagnosis of HCC and available serum samples collected at tumor diagnosis were analyzed retrospectively. Median overall survival (OS) after HCC diagnosis was 35.1, 95% CI 27.1–70.5 months. Multivariate Cox regression analysis showed that CYFRA 21-1 > 2.7 ng/mL (hazard ratio (HR) = 3.39, p < 0.001), AFP > 20 ng/mL (HR = 2.27, p = 0.007), and PIVKA-II > 200 mAU/mL (HR = 2.17, p = 0.020) were independent predictors of OS. The combination of biomarkers positivity allowed us to stratify patients with HCC into four risk categories associated with a progressively lower survival probability (log-rank test, p < 0.001). CYFRA 21-1 resulted an independent prognostic factor of patients with HCC and its combination with AFP and PIVKA-II might be useful to tailor personalized treatment strategies.
The Role of Surgery in Lung Cancer Treatment
Authors: Petrella Francesco
Published: September 2020

[...]
The Metabolic Heterogeneity and Flexibility of Cancer Stem Cells
Authors: Tanabe Atsushi , Sahara Hiroeki
Published: September 2020

Numerous findings have indicated that CSCs, which are present at a low frequency inside primary tumors, are the main cause of therapy resistance and cancer recurrence. Although various therapeutic methods targeting CSCs have been attempted for eliminating cancer cells completely, the complicated characteristics of CSCs have hampered such attempts. In analyzing the biological properties of CSCs, it was revealed that CSCs have a peculiar metabolism that is distinct from non-CSCs to maintain their stemness properties. The CSC metabolism involves not only the catabolic and anabolic pathways, but also intracellular signaling, gene expression, and redox balance. In addition, CSCs can reprogram their metabolism to flexibly respond to environmental changes. In this review, we focus on the flexible metabolic mechanisms of CSCs, and highlight the new therapeutics that target CSC metabolism.
Boosting the Immune Response with the Combination of Electrochemotherapy and Immunotherapy: A New Weapon for Squamous Cell Carcinoma of the Head and Neck?
Authors: Longo Francesco , Perri Francesco , Caponigro Francesco , Della Vittoria Scarpati Giuseppina , Guida Agostino , Pavone Ettore , Aversa Corrado , Muto Paolo , Giuliano Mario , Ionna Franco , Solla Raffaele
Published: September 2020

Head and neck squamous cell carcinomas (SCCHN) are not rare malignancies and account for 7% of all solid tumors. Prognosis of SCCHN patients strongly depends on tumor extension, site of onset, and genetics. Advanced disease (recurrent/metastatic) is associated with poor prognosis, with a median overall survival of 13 months. In these patients, immunotherapy may represent an interesting option of treatment, given the good results reached by check-point inhibitors in clinical practice. Nevertheless, only a minor number of patients with advanced disease respond to immunotherapy, and, disease progressions/hyper-progressions are common. The latter could be a very difficult issue, especially in patients having a wide and highly symptomatic head/neck mass. Given the potentiality to boost the immune response of some local modalities, such as electrochemotherapy, a possible future approach may take into account the combination of electrochemotherapy and immunotherapy to treat patients affected by SCCHN, suffering from symptomatic lesions that need rapid debulking.
In Vitro Studies to Define the Cell-Surface and Intracellular Targets of Polyarginine-Conjugated Sodium Borocaptate as a Potential Delivery Agent for Boron Neutron Capture Therapy
Authors: Fujimura Atsushi , Yasui Seiji , Igawa Kazuyo , Ueda Ai , Watanabe Kaori , Hanafusa Tadashi , Ichikawa Yasuaki , Yoshihashi Sachiko , Tsuchida Kazuki , Kamiya Atsunori , Furuya Shuichi
Published: September 2020

Boron neutron capture therapy (BNCT) requires pharmaceutical innovations and molecular-based evidence of effectiveness to become a standard cancer therapeutic in the future. Recently, in Japan, 4-borono-L-phenylalanine (BPA) was approved as a boron agent for BNCT against head and neck (H&N) cancers. H&N cancer appears to be a suitable target for BPA-BNCT, because the expression levels of L-type amino acid transporter 1 (LAT1), one of the amino acid transporters responsible for BPA uptake, are elevated in most cases of H&N cancer. However, in other types of cancer including malignant brain tumors, LAT1 is not always highly expressed. To expand the possibility of BNCT for these cases, we previously developed poly-arginine peptide (polyR)-conjugated mercaptoundecahydrododecaborate (BSH). PolyR confers the cell membrane permeability and tumor selectivity of BSH. However, the molecular determinants for the properties are not fully understood. In this present study, we have identified the cluster of differentiation 44 (CD44) protein and translational machinery proteins as a major cell surface target and intracellular targets of BSH-polyR, respectively. CD44, also known as a stem cell-associated maker in various types of cancer, is required for the cellular uptake of polyR-conjugated molecules. We showed that BSH-polyR was predominantly delivered to a CD44High cell population of cancer cells. Once delivered, BSH-polyR interacted with the translational machinery components, including the initiation factors, termination factors, and poly(A)-biding protein (PABP). As a proof of principle, we performed BSH-polyR-based BNCT against glioma stem-like cells and revealed that BSH-polyR successfully induced BNCT-dependent cell death specifically in CD44High cells. Bioinformatics analysis indicated that BSH-polyR would be suitable for certain types of malignant tumors. Our results shed light on the biochemical properties of BSH-polyR, which may further contribute to the therapeutic optimization of BSH-BNCT in the future.
Two- and Three-Dimensional Tracking of MFA2 mRNA Molecules in Mating Yeast
Authors: Geva Polina , Komoshvili Konstantin , Liberman-Aronov Stella
Published: September 2020

Intracellular mRNA transport contributes to the spatio-temporal regulation of mRNA function and localized translation. In the budding yeast, Saccharomyces cerevisiae, asymmetric mRNA transport localizes ~30 specific mRNAs including those encoding polarity and secretion factors, to the bud tip. The underlying process involves RNA-binding proteins (RBPs), molecular motors, processing bodies (PBs), and the actin cytoskeleton. Recently, pheromone a-factor expression in mating yeast was discovered to depend on proper localization of its mRNA, MFA2 mRNAs in conjunction with PBs cluster at the shmoo tip to form “mating bodies”, from which a-factor is locally expressed. The mechanism ensuring the correct targeting of mRNA to the shmoo tip is poorly understood. Here we analyzed the kinetics and trajectories of MFA2 mRNA transport in living, alpha-factor treated yeast. Two- (2D) and three-dimensional (3D) analyses allowed us to reconstruct the granule tracks and estimate granule velocities. Tracking analysis of single MFA2 mRNA granules, labeled using a fluorescent aptamer system, demonstrated three types movement: vibrational, oscillatory and translocational. The mRNA granule transport was complex; a granule could change its movement behavior and composition during its journey to the shmoo. Processing body assembly and the actin-based motor, Myo4p, were involved in movement of MFA2 mRNA to the shmoo, but neither was required, indicating that multiple mechanisms for translocation were at play. Our visualization studies present a dynamic view of the localization mechanism in shmoo-bearing cells.
Systemic Inflammatory Markers Are Predictive of the Response to Brachytherapy in the Prostate
Authors: Taussky Daniel , Soulieres Denis , Chagnon Miguel , Delouya Guila , Bahig Houda
Published: September 2020

We analyzed the influence of the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) on the biochemical recurrence (BCR) in low-intermediate risk prostate cancer (PCa). A total of 604 patients treated with exclusive brachytherapy for low- and intermediate-risk cancers were included in this study. No patient received either androgen deprivation or brachytherapy as a boost. BCR was defined according to the Phoenix definition (nadir prostatic specific antigen (PSA) +2). The median follow-up was 60 months (IQR 44–48 months). An NLR > 3 was more frequent in statin users (p = 0.025), but not in diabetics (p = 0.079). In univariate analysis (UVA) and multivariate analysis (MVA), a NLR > 3 (MVA p = 0.03), as well as Cancer of the Prostate Risk Assessment (CAPRA) low- vs. intermediate-risk (MVA p = 0.04), were predictive of BCR. When combining the NLR score with the CAPRA risk group, CAPRA intermediate risk patients with an NLR ≤ 3 (n = 157) had the worst (p = 0.0276) BCR rates, with a 5-year recurrence-free survival (p = 0.004, Bonferroni correction for six comparisons p = 0.024). We were able to identify a subgroup of PCa patients with CAPRA intermediate-risk and an NLR ≤ 3 who had worse BCR. This is in contrast to most other cancers, which have a worse prognosis when the NLR is high.
Tuberculosis-Associated MicroRNAs: From Pathogenesis to Disease Biomarkers
Authors: Sinigaglia Alessandro , Peta Elektra , Riccetti Silvia , Venkateswaran Seshasailam , Manganelli Riccardo , Barzon Luisa
Published: September 2020

Tuberculosis (TB) caused by Mycobacterium tuberculosis is one of the most lethal infectious diseases with estimates of approximately 1.4 million human deaths in 2018. M. tuberculosis has a well-established ability to circumvent the host immune system to ensure its intracellular survival and persistence in the host. Mechanisms include subversion of expression of key microRNAs (miRNAs) involved in the regulation of host innate and adaptive immune response against M. tuberculosis. Several studies have reported differential expression of miRNAs during active TB and latent tuberculosis infection (LTBI), suggesting their potential use as biomarkers of disease progression and response to anti-TB therapy. This review focused on the miRNAs involved in TB pathogenesis and on the mechanism through which miRNAs induced during TB modulate cell antimicrobial responses. An attentive study of the recent literature identifies a group of miRNAs, which are differentially expressed in active TB vs. LTBI or vs. treated TB and can be proposed as candidate biomarkers.
At the Forefront of the Mucosal Barrier: The Role of Macrophages in the Intestine
Authors: Ruder Barbara , Becker Christoph
Published: September 2020

Macrophages are part of the innate immunity and are key players for the maintenance of intestinal homeostasis. They belong to the group of mononuclear phagocytes, which exert bactericidal functions and help to clear apoptotic cells. Moreover, they play essential roles for the maintenance of epithelial integrity and tissue remodeling during wound healing processes and might be implicated in intestinal tumor development. Macrophages are antigen-presenting cells and secrete immune-modulatory factors, like chemokines and cytokines, which are necessary to activate other intestinal immune cells and therefore to shape immune responses in the gut. However, overwhelming activation or increased secretion of pro-inflammatory cytokines might also contribute to the pathogenesis of inflammatory bowel disease. Presently, intestinal macrophages are in the center of intense studies, which might help to develop new therapeutic strategies to counteract the development or treat already existing inflammatory diseases in the gut. In this review, we focus on the origin of intestinal macrophages and, based on current knowledge, discuss their role in the gut during homeostasis and inflammation, as well as during intestinal wound healing and tumor development.
In Situ Gel Incorporating Disulfiram Nanoparticles Rescues the Retinal Dysfunction via ATP Collapse in Otsuka Long–Evans Tokushima Fatty Rats
Authors: Deguchi Saori , Ogata Fumihiko , Yamaguchi Mizuki , Minami Misa , Otake Hiroko , Kanai Kazutaka , Kawasaki Naohito , Nagai Noriaki
Published: September 2020

We attempted to design an ophthalmic in situ gel formulation incorporating disulfiram (DIS) nanoparticles (Dis-NPs/ISG) and demonstrated the therapeutic effect of Dis-NPs/ISG on retinal dysfunction in 15-month-old Otsuka Long–Evans Tokushima Fatty (OLETF) rats, a rat model of diabetes. The DIS particles were crushed using a bead mill to prepare the nanoparticles, and the Dis-NPs/ISG was prepared using a combination of the DIS nanoparticles and an in situ gelling system based on methylcellulose (MC). The particle size of the Dis-NPs/ISG was 80–250 nm, and there was no detectable precipitation or aggregation for 1 month. Moreover, the Dis-NPs/ISG was gelled at 37 °C, and the drug was delivered into the retina by instillation. Only diethyldithiocarbamate (DDC) was detected in the retina (DIS was not detected) when the Dis-NPs/ISG was instilled in the right eye, and the DDC levels in the right retina were significantly higher than those in the left retina. In addition, the retinal residence time of the drug was prolonged by the application of the in situ gelling system, since the DDC levels in the retinas of rats instilled with Dis-NPs/ISG were higher than those in DIS nanoparticles without MC. Furthermore, repetitive instillation of the Dis-NPs/ISG attenuated the deterioration of electroretinograms (ERGs) in 15-month-old OLETF rats by preventing the collapse of ATP production via excessive nitric oxide and recovered the decrease in retinal function. These findings provide important information for the development of novel therapeutic approaches to diabetic retinopathy.
3D Stem Cell Culture
Authors: Ylostalo Joni H.
Published: September 2020

Much interest has been directed towards stem cells, both in basic and translational research, to understand basic stem cell biology and to develop new therapies for many disorders. In general, stem cells can be cultured with relative ease, however, most common culture methods for stem cells employ 2D techniques using plastic. These cultures do not well represent the stem cell niches in the body, which are delicate microenvironments composed of not only stem cells, but also supporting stromal cells, extracellular matrix, and growth factors. Therefore, researchers and clinicians have been seeking optimal stem cell preparations for basic research and clinical applications, and these might be attainable through 3D culture of stem cells. The 3D cultures recapitulate the in vivo cell-to-cell and cell-to-matrix interactions more effectively, and the cells in 3D cultures exhibit many unique and desirable characteristics. The culture of stem cells in 3D may employ various matrices or scaffolds, in addition to the cells, to support the complex structures. The goal of this Special Issue is to bring together recent research on 3D cultures of various stem cells to increase the basic understanding of stem cells and culture techniques, and also highlight stem cell preparations for possible novel therapeutic applications.
The Protective Effect of Exercise in Neurodegenerative Diseases: The Potential Role of Extracellular Vesicles
Authors: Fuller Oliver K , Whitham Martin , Mathivanan Suresh , Febbraio Mark A
Published: September 2020

Physical activity has systemic effects on the body, affecting almost every organ. It is important not only for general health and wellbeing, but also in the prevention of diseases. The mechanisms behind the therapeutic effects of physical activity are not completely understood; however, studies indicate these benefits are not confined to simply managing energy balance and body weight. They also include systemic factors which are released into the circulation during exercise and which appear to underlie the myriad of benefits exercise can elicit. It was shown that along with a number of classical cytokines, active tissues also engage in inter-tissue communication via extracellular vesicles (EVs), specifically exosomes and other small EVs, which are able to deliver biomolecules to cells and alter their metabolism. Thus, EVs may play a role in the acute and systemic adaptations that take place during and after physical activity, and may be therapeutically useful in the treatment of a range of diseases, including metabolic disorders such as type 2 diabetes and obesity; and the focus of this review, neurological disorders such as Alzheimer’s disease.
Aquaporin-4 Expression during Toxic and Autoimmune Demyelination
Authors: Rohr Sven Olaf , Greiner Theresa , Joost Sarah , Amor Sandra , Valk Paul van der , Schmitz Christoph , Kipp Markus
Published: September 2020

The water channel protein aquaporin-4 (AQP4) is required for a normal rate of water exchange across the blood–brain interface. Following the discovery that AQP4 is a possible autoantigen in neuromyelitis optica, the function of AQP4 in health and disease has become a research focus. While several studies have addressed the expression and function of AQP4 during inflammatory demyelination, relatively little is known about its expression during non-autoimmune-mediated myelin damage. In this study, we used the toxin-induced demyelination model cuprizone as well as a combination of metabolic and autoimmune myelin injury (i.e., Cup/EAE) to investigate AQP4 pathology. We show that during toxin-induced demyelination, diffuse AQP4 expression increases, while polarized AQP4 expression at the astrocyte endfeet decreases. The diffuse increased expression of AQP4 was verified in chronic-active multiple sclerosis lesions. Around inflammatory brain lesions, AQP4 expression dramatically decreased, especially at sites where peripheral immune cells penetrate the brain parenchyma. Humoral immune responses appear not to be involved in this process since no anti-AQP4 antibodies were detected in the serum of the experimental mice. We provide strong evidence that the diffuse increase in anti-AQP4 staining intensity is due to a metabolic injury to the brain, whereas the focal, perivascular loss of anti-AQP4 immunoreactivity is mediated by peripheral immune cells.
Electrochemical Hybrid Methods and Sensors for Antioxidant/Oxidant Activity Monitoring and Their Use as a Diagnostic Tool of Oxidative Stress: Future Perspectives and Challenges
Authors: Brainina Khiena Z. , Kazakov Yan E.
Published: September 2020

The terminology used in electrochemical methods which are used to generate the measured signal in antioxidant/oxidant activity (AOA/OA) sensors is briefly considered. The review presents a hybrid version of electrochemical methods for the determination of AOA/OA. Invasive electrochemical methods/sensors for AOA/OA of blood/serum/plasma, and non-invasive ones for semen, sweat, saliva and skin determination are described. AOA/OA sensors application in health estimation, cosmetology, food and nutrients is presented. Attention is paid to widely described approaches and technologies used in chemical/biochemical sensors. It will be considered as base/prototypes for developing sensors of the kind for AOA/OA determination. Prospects for the development of wearable, written sensors and biosensors are considered. Miniature and wireless sensors will allow for the monitoring of the patient’s state, both at the bedside and far beyond the hospital. The development of wearable self-powered written and printed sensors is an important step towards personalized medicine.
Enhancement of Characteristics of Field Asymmetric Ion Mobility Spectrometer with Laser Ionization for Detection of Explosives in Vapor Phase
Authors: Kostarev Vitalii A. , Kotkovskii Gennadii E. , Chistyakov Alexander A. , Akmalov Artem E.
Published: September 2020

Ion mobility spectrometry instrumentation today is widespread in the area of transport security and counterterrorism. This method of detection of explosive substances is highly appreciated for the existence of portable detectors capable of detecting concentrations of 10−13–10−14 g/cm3 at atmospheric pressure using traditional ionization methods including corona discharge and beta radiation. However, low vapor pressure of some explosives imposes requirements on limit of detection (LOD) down to 10–15‒10−16 g/cm3. In this paper we compare a radioactive 63Ni ionization source with a laser ionization source and reveal the parameters of laser ionization of a group of explosives, namely trinitrotoluene (TNT), cyclotrimethylene-trinitramine (RDX), cyclotetramethylene-tetranitramine (HMX) and pentaerythritol tetranitrate (PETN), which can reduce the limit of detection of portable devices. A laser ionization source can provide a higher signal to noise ratio than radioactive 63Ni at optimal intensity of laser radiation for PETN and HMX of 3 × 107 W/cm2 and 2.5 × 107 W/cm2, respectively. Limits of detection were estimated: 3 × 10−15 g/cm3 for RDX, 8 × 10−15 g/cm3 for PETN and less than 3 × 10−15 g/cm3 for HMX. These results are promising to further improve the capabilities of detectors of low volatility explosives without sacrificing portability, light weight and reasonable cost of the laser source.
Use of Ytterbium Trifluoride in the Field of Microinvasive Dentistry—An In Vitro Preliminary Study
Authors: Skucha-Nowak Małgorzata , Nowak-Wachol Anna , Skaba Dariusz , Wachol Kacper , Korytkowska-Wałach Anna
Published: September 2020

Background: The aim of this study was an attempt at determining the quantity of the degree of the addition of ytterbium trifluoride as a marker, aimed at facilitating the observation and assessment of the effectiveness of penetration into the decalcified enamel of human teeth of an experimental preparation with the characteristics of a dental infiltrant and a commercially available commercial preparation called Icon. Methods: The test material was 20 decalcified human teeth. The first half of the batch was soaked in Icon, the second half in an experimental preparation with the characteristics of a dental infiltrant and with a component responsible for bacteriostaticity. Ytterbium trifluoride was added to both preparations to facilitate the microscopic observations: 20 mg/1 g in the first phase of the experiment, 60 mg/1 g in the second phase. Results: YbF3 particles could not be found in the teeth from the first phase of the experiment. Particles rich in ytterbium could be found only in the teeth from the second phase of the experiment, with three times the content of ytterbium. Conclusion: The addition of 6% ytterbium trifluoride (both commercial and laboratory synthesized) facilitates microscopic observation, allowing the conclusion that both Icon and the experimental preparation with the characteristics of a dental infiltrant penetrate the decalcified enamel of a human tooth. The SEM analysis of the preparations in terms of content and particle size of ytterbium trifluoride shows that the distribution is heterogeneous. Large size particles predominate, yet particles with a diameter of less than 1 µm were also found. This may confirm the fact that most of them have probably agglomerated. The method of scattering YbF3 nanoparticles in the infiltrant resin requires further work so that they do not appear as agglomerates.
Powder and High-Solid Coatings as Anticorrosive Solutions for Marine and Offshore Applications? A Review
Authors: Pélissier Krystel , Thierry Dominique
Published: September 2020

The constant change in coating technology and environmental regulations has led to the development of low-solvent to solvent-free organic coatings, such as powder and high-solid coatings. These two technologies are well developed, but are still not the preferred choice when considering anticorrosive coating for marine and offshore applications. This mostly arise from a lack of perspective in their long-term behavior and from the difficulty in their applications. This review’s principal aim is to describe powder and high-solid technologies from their formulation and application to their use in marine and offshore applications while recalling and giving key notions needed when the field of anticorrosive coatings is considered. First, the requirement for coatings to be called anticorrosive will be given alongside with their protection and failure mechanisms. The formulation and application for high-solid and powder coatings will be exposed followed by the description of the type of coating chemistry used in harsh environment. Finally, high-solid and powder coatings behavior in these types of environment will be discussed.
Carbon Nanoparticles and Materials on Their Basis
Authors: Kokorina Alina A. , Ermakov Alexey V. , Abramova Anna M. , Goryacheva Irina Yu. , Sukhorukov Gleb B.
Published: September 2020

Carbon nanoparticles (CNPs) are novel nanostructures with luminescent properties. The development of CNPs involves the elaboration of various synthetic methods, structure characterization, and different applications. However, the problems associated with the CNP structure definition and properties homogeneity are not solved and barely described in depth. In this feature article, we demonstrate the approaches for the effective separation and purification of CNPs by size and size/charge ratio. We propose a promising way for the synthesis of the uniform-size structures by the application of calcium carbonate porous microparticles as reactors with defined size. Additionally, the application of the CNPs agglomerates for controllable release systems triggered by light and in-situ synthesis of fluorescent conductive carbonaceous films on the base of polyelectrolyte multilayers are under consideration.
Stimulated Raman Scattering in Yttrium, Gadolinium, and Calcium Orthovanadate Crystals with Single and Combined Frequency Shifts under Synchronous Picosecond Pumping for Sub-Picosecond or Multi-Wavelength Generation around 1.2 µm
Authors: Frank Milan , Smetanin Sergei N. , Jelínek Michal , Vyhlídal David , Ivleva Lyudmila I. , Dunaeva Elizaveta E. , Voronina Irina S. , Tereshchenko Dmitry P. , Shukshin Vladislav E. , Zverev Petr G. , Kubeček Václav
Published: September 2020

Comparative investigation of stimulated Raman scattering (SRS) characteristics in the YVO4, GdVO4, and Ca3(VO4)2 orthovanadate crystals at both low and high frequency anionic group vibrations is presented. It was found that GdVO4 is the most perspective for SRS generation on both the ν1 stretching and ν2 bending modes of internal anionic group vibrations with the strongest SRS pulse shortening under synchronous picosecond pumping. It is as a result of GdVO4‘s widest linewidth (17cm−1) of the homogeneously broadened scheelite-type component of the bending ν2 Raman line that led to the strongest SRS pulse shortening down to the dephasing time of the widest (scheelite-type) Raman mode at the secondary intracavity short-shifted SRS conversion. It allowed us to achieve SRS pulses with sub-picosecond duration under tens-of-picoseconds pumping due to the strongest 42-fold pulse shortening. Using the Ca3(VO4)2 crystal with essentially wider Raman lines (~50cm−1) did not allow us to generate SRS pulses shorter than 1 ps. It can be explained by inhomogeneous broadening of the Raman lines in Ca3(VO4)2 because of its structural disordering. Using the measured SRS pulse duration, the homogeneous broadening of the inhomogeneously broadened bending Raman line of Ca3(VO4)2 was estimated to be ~9cm−1. Among the orthovanadate crystals, the YVO4 crystal with the highest Raman gain and with homogeneously broadened Raman lines allowed us to realize the most efficient SRS lasing and SRS pulse shortening truly down to inverse half-width of the bending Raman line.