bluuebunny/crossref_metadata_2025 huggingface dataset:
An Approach for Quantifying a Regional Haze Stress: Case Study in Three Cities of Taiwan
Authors: Liang Chen-Jui , Liang Jeng-Jong , Lin Feng-Cheng , Jheng Chiao-Wun
Published: November 2020

This study proposes an approach of evaluating the haze stress index (HSI) and quantifying people’s feelings for haze stress. The three special municipalities in Taiwan were selected as representative cities of slightly, moderately, and heavily contaminated with fine particulate matter (PM2.5) to evaluate the adaptability of the proposed approach. Equations with weightings of parameters to evaluate four temporal HSIs—hourly, daily, monthly, and yearly HSIs—were established. The parameters were measured PM2.5, relative humidity, and secondary organic aerosol (represented by the sum of measured O3 and NO2). The results of evaluating the HSIs in the three cities demonstrated that the inverse-variance weighting method is the best because the haze stress sensitivities in the four temporal periods were higher than those obtained using the unit and variance weighting methods to respond to the real situation of air quality. Variation in the four temporal HSIs for the three cities demonstrates that the variation increases with an increasing level of air pollution. When comparing between 2015 and 2018, the fractional reductions in HSIs in the slightly, moderately, and heavily contaminated cities were ≤18.4%, ≤10.8%, and ≤11.3%, respectively. It is recommended that the HSIs are categorized into five haze stress groups based on the haze stress level. The people’s feelings in the three cities on the haze stresses were represented using the established quantifying descriptors in detail. The results show that the proposed approach can provide quantification indices of haze stress and people’s feelings in a regional haze, thereby firmly establishing the governmental improvement policy.
Efficiency of Melatonin as a Sedative for Auditory Brainstem Response in Children
Authors: Chaouki Anass , El Krimi Zineb , Mkhatri Amine , Youssef Oukessou , Rouadi Sami , Abada Reda , Roubal Mohamed , Mahtar Mohamed
Published: November 2020

Introduction—Although auditory brainstem response (ABR) testing is among the most frequently used investigations in pediatric audiology and it often requires sedation or general anesthesia. In recent years, melatonin has been successfully used as an alternative way of inducing sleep, particularly in children undergoing magnetic resonance imaging (MRI) or electroencephalography (EEG). Purpose—To assess the effectiveness of orally administered melatonin as an alternative to sedation or general anesthesia during ABR testing. Method—In total, 33 children with suspected hearing loss underwent ABR tests in melatonin-induced sleep. Each patient received an initial dose of 5 mg, which was re-administered in case of failure to obtain sleep. Click-induced ABR tests were performed on both ears. Results—ABR tests were successfully performed in 72.7% of the patients. The average total length of time needed to obtain sleep and complete the ABR testing was 45 min. There was no significant difference between the patients who completed the examination and those who did not in terms of age or psychomotor development. There was a statistically significant association between receiving a maintenance dose and successful completion of the test (p < 0.001). There was also a significant connection between the degree of hearing loss and the success rate of the ABR tests (p < 0.001). Conclusions—Melatonin-induced sleep is a good and safer alternative to anesthesia to perform ABR testing in young children. It is easily administered, tolerated by the patients, and accepted by parents.
Treatment of Diabetic Neuropathy with A Novel PAR1-Targeting Molecule
Authors: Shavit-Stein Efrat , Gofrit Shany Guly , Gayster Alexandra , Teldan Yotam , Ron Ariel , Abu Bandora Eiman , Golderman Valery , Gera Orna , Harnof Sagi , Chapman Joab , Dori Amir
Published: November 2020

Diabetic peripheral neuropathy (DPN) is a disabling common complication of diabetes mellitus (DM). Thrombin, a coagulation factor, is increased in DM and affects nerve function via its G-protein coupled protease activated receptor 1 (PAR1). Methods: A novel PAR1 modulator (PARIN5) was designed based on the thrombin PAR1 recognition site. Coagulation, motor and sensory function and small fiber loss were evaluated by employing the murine streptozotocin diabetes model. Results: PARIN5 showed a safe coagulation profile and showed no significant effect on weight or glucose levels. Diabetic mice spent shorter time on the rotarod (p < 0.001), and had hypoalgesia (p < 0.05), slow conduction velocity (p < 0.0001) and reduced skin innervation (p < 0.0001). Treatment with PARIN5 significantly improved rotarod performance (p < 0.05), normalized hypoalgesia (p < 0.05), attenuated slowing of nerve conduction velocity (p < 0.05) and improved skin innervation (p <0.0001). Conclusion: PARIN5 is a novel pharmacological approach for prevention of DPN development, via PAR1 pathway modulation.
Potential Nutraceutical Properties of Leaves from Several Commonly Cultivated Plants
Authors: Amat-ur-Rasool Hafsa , Symes Fenella , Tooth David , Schaffert Larissa-Nele , Elmorsy Ekramy , Ahmed Mehboob , Hasnain Shahida , Carter Wayne G.
Published: November 2020

Chronic dietary ingestion of suitable phytochemicals may assist with limiting or negating neurodegenerative decline. Current therapeutics used to treat Alzheimer disease elicit broad adverse drug reactions, and alternative sources of cholinesterase inhibitors (ChEIs) are required. Herein, we screened methanolic extracts from seven commonly cultivated plants for their nutraceutical potential; ability to inhibit acetylcholinesterase (AChE) and butyryl-cholinesterase (BuChE), and provision of antioxidant activity through their 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) free radical scavenging capabilities. Potential neurotoxicity of plant extracts was examined via application to SHSY-5Y neuroblastoma cells and quantitation of cell viability. Methanolic extracts of Citrus limon (Lemon), Bombax ceiba (Red silk-cotton), Lawsonia inermis (Henna), Eucalyptus globulus (Eucalyptus), Ocimum basilicum (Basil), Citrus reticulata (Mandarin orange), and Mentha spicata (Spearmint) all displayed concentration-dependent inhibition of AChE and BuChE. The majority of extracts inhibited AChE and BuChE to near equipotency, with Henna and Eucalyptus extracts the two most potent ChEIs. All plant extracts were able to scavenge free radicals in a concentration-dependent manner, with Eucalyptus the most potent antioxidant. Toxicity of plant extracts to neuronal cells was concentration dependent, with Eucalyptus also the most toxic extract. Fractionation of plant extracts and analysis by mass spectrometry identified a number of plant polyphenols that might have contributed to the cholinesterase inhibition: 3-caffeoylquinic acid, methyl 4-caffeoylquinate, kaempferol-acetyl-glycoside, quercetin 3-rutinoside, quercetin-acetyl-glycoside, kaempferol 3-O-glucoside, and quercetin 3-O-glucoside. In silico molecular modeling of these polyphenols demonstrated their improved AChE and BuChE binding affinities compared to the current FDA-approved dual ChEI, galantamine. Collectively, all the plant extracts contained nutraceutical agents as antioxidants and ChEIs and, therefore, their chronic consumption may prove beneficial to combat the pathological deficits that accrue in Alzheimer disease.
More than Meets the ISG15: Emerging Roles in the DNA Damage Response and Beyond
Authors: Sandy Zac , da Costa Isabelle Cristine , Schmidt Christine K.
Published: November 2020

Maintenance of genome stability is a crucial priority for any organism. To meet this priority, robust signalling networks exist to facilitate error-free DNA replication and repair. These signalling cascades are subject to various regulatory post-translational modifications that range from simple additions of chemical moieties to the conjugation of ubiquitin-like proteins (UBLs). Interferon Stimulated Gene 15 (ISG15) is one such UBL. While classically thought of as a component of antiviral immunity, ISG15 has recently emerged as a regulator of genome stability, with key roles in the DNA damage response (DDR) to modulate p53 signalling and error-free DNA replication. Additional proteomic analyses and cancer-focused studies hint at wider-reaching, uncharacterised functions for ISG15 in genome stability. We review these recent discoveries and highlight future perspectives to increase our understanding of this multifaceted UBL in health and disease.
Emerging Concepts of Hybrid Epithelial-to-Mesenchymal Transition in Cancer Progression
Authors: Sinha Dona , Saha Priyanka , Samanta Anurima , Bishayee Anupam
Published: November 2020

Epithelial mesenchymal transition (EMT) is a complex process through which epithelial (E) cells lose their adherens junctions, transform into mesenchymal (M) cells and attain motility, leading to metastasis at distant organs. Nowadays, the concept of EMT has shifted from a binary phase of interconversion of pure E to M cells and vice versa to a spectrum of E/M transition states preferably coined as hybrid/partial/intermediate EMT. Hybrid EMT, being a plastic transient state, harbours cells which co-express both E and M markers and exhibit high tumourigenic properties, leading to stemness, metastasis, and therapy resistance. Several preclinical and clinical studies provided the evidence of co-existence of E/M phenotypes. Regulators including transcription factors, epigenetic regulators and phenotypic stability factors (PSFs) help in maintaining the hybrid state. Computational and bioinformatics approaches may be excellent for identifying new factors or combinations of regulatory elements that govern the different EMT transition states. Therapeutic intervention against hybrid E/M cells, though few, may evolve as a rational strategy against metastasis and drug resistance. This review has attempted to present the recent advancements on the concept and regulation of the process of hybrid EMT which generates hybrid E/M phenotypes, evidence of intermediate EMT in both preclinical and clinical setup, impact of partial EMT on promoting tumourigenesis, and future strategies which might be adapted to tackle this phenomenon.
Behavioral and Oxidative Stress Changes in Mice Subjected to Combinations of Multiple Stressors Relevant to Irritable Bowel Syndrome
Authors: Cojocariu Roxana Oana , Balmus Ioana Miruna , Lefter Radu , Ababei Daniela Carmen , Ciobica Alin , Hritcu Luminita , Kamal Fatimazahra , Doroftei Bogdan
Published: November 2020

Background and Objectives: Irritable bowel syndrome (IBS) is a well-known functional gastrointestinal (GI) disorder exhibiting a wide range of symptoms due to individual variability and multifactorial etiology. Stress exposure is a major risk factor for the development of IBS. Here, we investigate the differential effects of psychological stress exposures on behavior and oxidative status in mice by using increasingly complex combinations of etiologic IBS-relevant stressors (maternal separation and chronic unpredictable mild stress combinations). Materials and Methods: Mice were subjected to three different combinations of psychological stress factors and subsequent behavioral cognitive and affective parameters and oxidative status markers (superoxide dismutase and glutathione peroxidase antioxidant activity and malondialdehyde level) in the brain and bowel tissues of the animals were analyzed. Results: GI transit modifications reflected by decreased fecal output, cognitive and affective behavioral deficits were observed in all stress exposed groups, but were more evident for the more complex combinations of stressors. Behavioral deficits were accompanied by mild oxidative stress occurring in the bowel and to a greater extent in brain tissue. Conclusions: The presented data depict the effect of various associations in mimicking IBS symptoms and comorbidities and suggest that an all-inclusive combination of early and adult-life psychological stressors is more effective in IBS symptoms modulation. Oxidative stress in both brain and bowel, suggestive for brain-gut molecular connectivity, may play an important role in IBS mechanistic.
Promising Therapy in Lung Cancer: Spotlight on Aurora Kinases
Authors: Galetta Domenico , Cortes-Dericks Lourdes
Published: November 2020

Despite tremendous efforts to improve the treatment of lung cancer, prognosis still remains poor; hence, the search for efficacious therapeutic option remains a prime concern in lung cancer research. Cell cycle regulation including mitosis has emerged as an important target for cancer management. Novel pharmacological agents blocking the activities of regulatory molecules that control the functional aspects of mitosis such as Aurora kinases are now being investigated. The Aurora kinases, Aurora-A (AURKA), and Aurora B (AURKB) are overexpressed in many tumor entities such as lung cancer that correlate with poor survival, whereby their inhibition, in most cases, enhances the efficacy of chemo-and radiotherapies, indicating their implication in cancer therapy. The current knowledge on Aurora kinase inhibitors has increasingly shown high potential in ensuing targeted therapies in lung malignancies. In this review, we will briefly describe the biology of Aurora kinases, highlight their oncogenic roles in the pre-clinical and clinical studies in lung cancer and, finally, address the challenges and potentials of Aurora kinases to improve the therapy of this malignancy.
Tumor Microenvironment and Immunotherapy Response in Head and Neck Cancer
Authors: Economopoulou Panagiota , Kotsantis Ioannis , Psyrri Amanda
Published: November 2020

The tumor microenvironment (TME) encompasses cellular and non-cellular components which play an important role in tumor evolution, invasion, and metastasis. A complicated interplay between tumor cells and adjacent TME cells, such as stromal cells, immune cells, inflammatory cells, and cytokines, leads to severe immunosuppression and the proliferation of cancer cells in several solid tumors. An immunosuppressive TME has a significant impact on treatment resistance and may guide response to immunotherapy. In head and neck cancer (HNC), immunotherapeutic drugs have been incorporated in everyday clinical practice. However, despite an exceptional rate of durable responses, only a low percentage of patients respond. In this review, we will focus on the complex interactions occurring in this dynamic system, the TME, which orchestrate key events that lead to tumor progression, immune escape, and resistance. Furthermore, we will summarize current clinical trials that depict the TME as a potential therapeutic target for improved patient selection.
Osteopontin: A Key Regulator of Tumor Progression and Immunomodulation
Authors: Moorman Hannah R. , Poschel Dakota , Klement John D. , Lu Chunwan , Redd Priscilla S. , Liu Kebin
Published: November 2020

OPN is a multifunctional phosphoglycoprotein expressed in a wide range of cells, including osteoclasts, osteoblasts, neurons, epithelial cells, T, B, NK, NK T, myeloid, and innate lymphoid cells. OPN plays an important role in diverse biological processes and is implicated in multiple diseases such as cardiovascular, diabetes, kidney, proinflammatory, fibrosis, nephrolithiasis, wound healing, and cancer. In cancer patients, overexpressed OPN is often detected in the tumor microenvironment and elevated serum OPN level is correlated with poor prognosis. Initially identified in activated T cells and termed as early T cell activation gene, OPN links innate cells to adaptive cells in immune response to infection and cancer. Recent single cell RNA sequencing revealed that OPN is primarily expressed in tumor cells and tumor-infiltrating myeloid cells in human cancer patients. Emerging experimental data reveal a key role of OPN is tumor immune evasion through regulating macrophage polarization, recruitment, and inhibition of T cell activation in the tumor microenvironment. Therefore, in addition to its well-established direct tumor cell promotion function, OPN also acts as an immune checkpoint to negatively regulate T cell activation. The OPN protein level is highly elevated in peripheral blood of human cancer patients. OPN blockade immunotherapy with OPN neutralization monoclonal antibodies (mAbs) thus represents an attractive approach in human cancer immunotherapy.
Induction of Lysosomal Membrane Permeabilization Is a Major Event of FTY720-Mediated Non-Apoptotic Cell Death in Human Glioma Cells
Authors: Min Kyoung-jin , Kwon Taeg Kyu
Published: November 2020

FTY720, a sphingosine-1-phosphate (S1P) receptor modulator, is a synthetic compound produced by the modification of a metabolite from I. sinclairii. Here, we found that FTY720 induced non-apoptotic cell death in human glioma cells (U251MG, U87MG, and U118MG). FTY720 (10 µM) dramatically induced cytoplasmic vacuolation in glioma cells. However, FTY720-mediated vacuolation and cell death are not associated with autophagy. Genetic or pharmacological inhibition of autophagy did not inhibit FTY720-induced cell death. Herein, we detected that FTY720-induced cytoplasmic vacuoles were stained with lysotracker red, and FTY720 induced lysosomal membrane permeabilization (LMP). Interestingly, cathepsin inhibitors (E64D and pepstatin A) and ectopic expression of heat shock protein 70 (HSP70), which is an endogenous inhibitor of LMP, markedly inhibited FTY720-induced cell death. Our results demonstrated that FTY720 induced non-apoptotic cell death via the induction of LMP in human glioma cells.
Beyond DNA Repair: DNA-PKcs in Tumor Metastasis, Metabolism and Immunity
Authors: Yang Haitang , Yao Feng , Marti Thomas M. , Schmid Ralph A. , Peng Ren-Wang
Published: November 2020

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key component of the DNA-PK complex that has a well-characterized function in the non-homologous end-joining repair of DNA double-strand breaks. Since its identification, a large body of evidence has demonstrated that DNA-PKcs is frequently overexpressed in cancer, plays a critical role in tumor development and progression, and is associated with poor prognosis of cancer patients. Intriguingly, recent studies have suggested novel functions beyond the canonical role of DNA-PKcs, which has transformed the paradigm of DNA-PKcs in tumorigenesis and has reinvigorated the interest to target DNA-PKcs for cancer treatment. In this review, we update recent advances in DNA-PKcs, in particular the emerging roles in tumor metastasis, metabolic dysregulation, and immune escape. We further discuss the possible molecular basis that underpins the pleiotropism of DNA-PKcs in cancer. Finally, we outline the biomarkers that may predict the therapeutic response to DNA-PKcs inhibitor therapy. Understanding the functional repertoire of DNA-PKcs will provide mechanistic insights of DNA-PKcs in malignancy and, more importantly, may revolutionize the design and utility of DNA-PKcs-based precision cancer therapy.
Altered Tissue and Plasma Levels of Fibroblast Activation Protein-α (FAP) in Renal Tumours
Authors: Solano-Iturri Jon Danel , Errarte Peio , Etxezarraga María C. , Echevarria Enrique , Angulo Javier , López José I. , Larrinaga Gorka
Published: November 2020

(1) Background: Renal cell carcinoma (RCC) is a heterogeneous and complex disease with only partial response to therapy, high incidence of metastasis and recurrences, and scarce reliable biomarkers indicative of progression and survival. Cancer-associated fibroblasts (CAFs) play an important role supporting and promoting renal cancer progression. (2) Methods: In this study, we analysed fibroblast activation protein-α (FAP) immunohistochemical expression and its soluble isoform (sFAP) in tumour tissues and plasma from 128 patients with renal tumours. (3) Results: FAP is expressed in the cell surface of CAFs of the tumour centre and infiltrating front from clear cell renal cell carcinomas (CCRCC, n = 89), papillary renal cell carcinomas (PRCC, n = 21), and chromophobe renal cell carcinomas (ChRCC, n = 8), but not in the benign tumour renal oncocytoma (RO, n = 10). A high expression of FAP and low levels sFAP are significantly associated with high tumour diameter, high grade, and high pT stage, lymph node invasion, development of early metastases, and worse 5-year cancer specific survival of CCRCC patients. (4) Conclusions: These findings corroborate the potential usefulness of FAP immunohistochemistry and plasma sFAP as a biomarker of CCRCC progression and point to CAF-related proteins as promising immunohistochemical biomarkers for the differential diagnosis of ChRCC and RO.
A “Lymphocyte MicroRNA Signature” as Predictive Biomarker of Immunotherapy Response and Plasma PD-1/PD-L1 Expression Levels in Patients with Metastatic Renal Cell Carcinoma: Pointing towards Epigenetic Reprogramming
Authors: Incorvaia Lorena , Fanale Daniele , Badalamenti Giuseppe , Brando Chiara , Bono Marco , De Luca Ida , Algeri Laura , Bonasera Annalisa , Corsini Lidia Rita , Scurria Salvatore , Iovanna Juan Lucio , Russo Antonio , Bazan Viviana
Published: November 2020

Introduction of checkpoint inhibitors resulted in durable responses and improvements in overall survival in advanced RCC patients, but the treatment efficacy is widely variable, and a considerable number of patients are resistant to PD-1/PD-L1 inhibition. This variability of clinical response makes necessary the discovery of predictive biomarkers for patient selection. Previous findings showed that the epigenetic modifications, including an extensive microRNA-mediated regulation of tumor suppressor genes, are key features of RCC. Based on this biological background, we hypothesized that a miRNA expression profile directly identified in the peripheral lymphocytes of the patients before and after the nivolumab administration could represent a step toward a real-time monitoring of the dynamic changes during cancer evolution and treatment. Interestingly, we found a specific subset of miRNAs, called “lymphocyte miRNA signature”, specifically induced in long-responder patients (CR, PR, or SD to nivolumab >18 months). Focusing on the clinical translational potential of miRNAs in controlling the expression of immune checkpoints, we identified the association between the plasma levels of soluble PD-1/PD-L1 and expression of some lymphocyte miRNAs. These findings could help the development of novel dynamic predictive biomarkers urgently needed to predict the potential response to immunotherapy and to guide clinical decision-making in RCC patients.
Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses against Hepatocellular Carcinoma
Authors: Silva Leyre , Egea Josune , Villanueva Lorea , Ruiz Marta , Llopiz Diana , Repáraz David , Aparicio Belén , Lasarte-Cia Aritz , Lasarte Juan José , Ruiz de Galarreta Marina , Lujambio Amaia , Sangro Bruno , Sarobe Pablo
Published: November 2020

Therapies based on immune checkpoint inhibitors (ICPI) have yielded promising albeit limited results in patients with hepatocellular carcinoma (HCC). Vaccines have been proposed as combination partners to enhance response rates to ICPI. Thus, we analyzed the combined effect of a vaccine based on the TLR4 ligand cold-inducible RNA binding protein (CIRP) plus ICPI. Mice were immunized with vaccines containing ovalbumin linked to CIRP (OVA-CIRP), with or without ICPI, and antigen-specific responses and therapeutic efficacy were tested in subcutaneous and orthotopic mouse models of liver cancer. OVA-CIRP elicited polyepitopic T-cell responses, which were further enhanced when combined with ICPI (anti-PD-1 and anti-CTLA-4). Combination of OVA-CIRP with ICPI enhanced ICPI-induced therapeutic responses when tested in subcutaneous and intrahepatic B16-OVA tumors, as well as in the orthotopic PM299L HCC model. This effect was associated with higher OVA-specific T-cell responses in the periphery, although many tumor-infiltrating lymphocytes still displayed an exhausted phenotype. Finally, a new vaccine containing human glypican-3 linked to CIRP (GPC3-CIRP) induced clear responses in humanized HLA-A2.01 transgenic mice, which increased upon combination with ICPI. Therefore, CIRP-based vaccines may generate anti-tumor immunity to enhance ICPI efficacy in HCC, although blockade of additional checkpoint molecules and immunosuppressive targets should be also considered.
Impact of the First Wave of COVID-19 on Pediatric Oncology and Hematology: A Report from the French Society of Pediatric Oncology
Authors: Rouger-Gaudichon Jérémie , Thébault Eric , Félix Arthur , Phulpin Aurélie , Paillard Catherine , Alimi Aurélia , Brethon Benoît , Gouache Elodie , Raimbault Sandra , de Berranger Eva , Poirée Marilyne , Bouttefroy Séverine , André Nicolas , Gandemer Virginie ,   on behalf of Société Française de lutte contre les Cancers et leucémies de l’Enfant et de l’adolescent (SFCE)
Published: November 2020

Data regarding coronavirus disease 2019 (COVID-19) description are still limited in pediatric oncology. The French society of pediatric oncology (SFCE) initiated a study to better describe COVID-19 in patients followed in French pediatric oncology and hematology wards. All patients diagnosed with COVID-19 and followed in a SFCE center were enrolled. Data from medical records were analyzed for all patients enrolled up to the end of May 2020. Data were available for 37 patients. Thirty-one were children under 18 years of age. Nineteen patients were female. Seventeen patients had a solid tumor, 16 had a hematological malignancy and four recently underwent hematopoietic stem cell transplantation (HSCT) for non-oncological conditions. Twenty-eight patients presented symptoms, most often with fever, cough, rhinorrhea and asthenia. Ground-glass opacities were the most frequent radiological finding with abnormalities mostly bilateral and peripherally distributed. Twenty-four patients received chemotherapy a month prior to COVID-19 diagnosis. Most patients did not require hospitalization. Three patients required oxygen at the time of diagnosis. In total, five patients were admitted in an intensive care unit because of COVID-19 and one died from the disease. Children and young adults treated for a cancer and/or with a HSCT may be at risk for severe COVID-19 and should be closely monitored.
Targeting Tumor-Associated Macrophages to Increase the Efficacy of Immune Checkpoint Inhibitors: A Glimpse into Novel Therapeutic Approaches for Metastatic Melanoma
Authors: Ceci Claudia , Atzori Maria Grazia , Lacal Pedro Miguel , Graziani Grazia
Published: November 2020

Immune checkpoint inhibitors (ICIs) represent a promising therapeutic intervention for a variety of advanced/metastatic solid tumors, including melanoma, but in a large number of cases, patients fail to establish a sustained anti-tumor immunity and to achieve a long-lasting clinical benefit. Cells of the tumor micro-environment such as tumor-associated M2 macrophages (M2-TAMs) have been reported to limit the efficacy of immunotherapy, promoting tumor immune evasion and progression. Thus, strategies targeting M2-TAMs have been suggested to synergize with immune checkpoint blockade. This review recapitulates the molecular mechanisms by which M2-TAMs promote cancer immune evasion, with focus on the potential cross-talk between pharmacological interventions targeting M2-TAMs and ICIs for melanoma treatment.
Integrity of the Antiviral STING-mediated DNA Sensing in Tumor Cells Is Required to Sustain the Immunotherapeutic Efficacy of Herpes Simplex Oncolytic Virus
Authors: Froechlich Guendalina , Caiazza Carmen , Gentile Chiara , D’Alise Anna Morena , De Lucia Maria , Langone Francesca , Leoni Guido , Cotugno Gabriella , Scisciola Vittorio , Nicosia Alfredo , Scarselli Elisa , Mallardo Massimo , Sasso Emanuele , Zambrano Nicola
Published: November 2020

The dichotomic contribution of cancer cell lysis and tumor immunogenicity is considered essential for effective oncovirotherapy, suggesting that the innate antiviral immune response is a hurdle for efficacy of oncolytic viruses. However, emerging evidence is resizing this view. By sensing cytosolic DNA, the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) axis can both counteract viral spread and contribute to the elicitation of adaptive immunity via type I interferon responses. In this paper, we analyzed the tumor-resident function of Sting-mediated DNA sensing in a combined approach of oncovirotherapy and PD-1 immune checkpoint blockade, in an immunocompetent murine model. While supporting increased lytic potential by oncolytic HER2-retargeted HSV-1 in vitro and in vivo, Sting-knockout tumors showed molecular signatures of an immunosuppressive tumor microenvironment. These signatures were correspondingly associated with ineffectiveness of the combination therapy in a model of established tumors. Results suggest that the impairment in antiviral response of Sting-knockout tumors, while favoring viral replication, is not able to elicit an adequate immunotherapeutic effect, due to lack of immunogenic cell death and the inability of Sting-knockout cancer cells to promote anti-tumor adaptive immune responses. Accordingly, we propose that antiviral, tumor-resident Sting provides fundamental contributions to immunotherapeutic efficacy of oncolytic viruses.
In Situ Preparation of Copper-Loaded Carbon-Based Catalyst with Chelate Resin and Its Application on Persulfate Activation for X-3B Degradation
Authors: Cui Yan , Ran Xuemei , Zeng Zequan , Huang Zhanggen , Yang Jieyang
Published: November 2020

Under the guidance of the idea of “treating waste with waste”, copper-loaded carbon-based catalysts were prepared in situ using waste chelating resin with adsorbed copper. The effect of the catalyst activation temperature on dye brilliant red (X-3B) degradation was investigated and the characterization of the catalysts was analyzed. The results show that a catalyst activated at 800 °C (Cu-AC-800) has the largest specific surface area and abundant pore structure and the highest proportion of Cu under low valence states, which leads to the best performance in adsorbing and degrading X-3B. The influences of operation conditions and inorganic salt anions on persulfate (PS) activation were also investigated. Moreover, the degradation mechanism was preliminarily explored by quenching reactions. The main active free radicals in the system were determined as sulfate radicals (•SO4−). Given its use in solid waste recycling, copper-loaded carbon-based catalyst may provide some new insights for the remediation of wastewater.
Preparation and Characterization of Ni/ZrTiAlOx Catalyst via Sol-Gel and Impregnation Methods for Low Temperature Dry Reforming of Methane
Authors: Shin Seol A , Alizadeh Eslami Ali , Noh Young Su , Song Hyun-tae , Kim Hyun Dong , Ghaffari Saeidabad Nasim , Moon Dong Ju
Published: November 2020

Recently, the dry reforming of methane (DRM) has received much attention as a conversion technology of greenhouse gases. Ni-based catalysts supported on ternary metal oxide composite (ZrTiAlOx) were prepared to improve the coke resistance properties in the DRM (CH4:CO2 = 1) at low temperature. The ZrTiAlOx supports with different ratios of Zr/Ti were prepared through the modified Pechini sol-gel method, and then the Ni was impregnated on the synthesized support via the incipient wetness impregnation method. Considering the Zr/Ti ratios, different catalytic activity and durability in the DRM were identified. The Ni/ZrTiAlOx catalyst with Zr/Ti of 2 exhibited enhanced coke inhibition property compared to the others at low temperature DRM for 50 h. The catalysts with a high Zr/Ti ratio under the same condition were rapidly deactivated, while the catalyst with a low Zr/Ti ratio showed deficient activity. It was found from temperature-programmed surface reactions (TPSR) and DRIFTS (Diffuse Reflectance Infrared Fourier Transform Spectroscopy) analysis that the addition of Ti has led in to higher catalytic stability at Zr/Ti = 2, which could be as a result of oxygen vacancies generated by the ternary metal oxides. Ni/ZrTiAlOx catalyst with ratio of Zr/Ti = 2 showed high stability and good catalytic activity towards DRM for the production of syngas.
Special Issue “Recent Developments in Annexin Biology”
Authors: Rescher Ursula , Gerke Volker , Lim Lina Hsiu Kim , Jaiswal Jyoti K.
Published: November 2020

Discovered over 40 years ago, the annexin proteins were found to be a structurally conserved subgroup of Ca2+-binding proteins. While the initial research on annexins focused on their signature feature of Ca2+-dependent binding to membranes, over the years the biennial Annexin conference series has highlighted additional diversity in the functions attributed to the annexin family of proteins. The roles of these proteins now extend from basic science to biomedical research, and are being translated into the clinic. The research on annexins involves a global network of researchers, and the 10th biennial Annexin conference brought together over 80 researchers from ten European countries, USA, Brazil, Singapore, Japan and Australia for 3 days in September 2019. In this conference, the discussions focused on two distinct themes—the role of annexins in cellular organization and in health and disease. The articles published in this Special Issue cover these two main themes discussed at this conference, offering a glimpse into some of the notable findings in the field of annexin biology.
Drug Crystal-Related Gastrointestinal Complications Involve Crystal-Induced Release of Neutrophil and Monocyte Extracellular Traps
Authors: Kim Tehyung , de Oliveira Silva Lautenschlager Sueli , Ma Qiuyue , Eller Kathrin , Pollheimer Marion Julia , Lazarin-Bidóia Danielle , Nakamura Celso Vataru , Anders Hans-Joachim , Steiger Stefanie
Published: November 2020

Ion-exchange resins are commonly used to manage complications of chronic kidney disease, such as hyperphosphatemia, hyperkalemia, and hypercholesterolemia. Occasionally, these drugs can irritate the gastrointestinal lining and cause life-threatening intestinal necrosis. Currently, the pathophysiology of drug crystal-induced intestinal necrosis is not well understood. We hypothesized that crystals of ion-exchange resins like sevelamer, polystyrene sulfonate, and cholestyramine can trigger the formation of neutrophil and monocyte extracellular traps by contributing to intestinal barrier dysfunction. Light and fluorescence microscopy of the colonic resection specimen from a patient with chronic kidney disease revealed severe intestinal necrosis, ulceration, sevelamer crystals, and inflammation upon oral intake of sevelamer, as well as the formation of neutrophil extracellular traps in proximity to small sevelamer crystals. Indeed, drug crystals reduced metabolic activity and induced barrier dysfunction and cell death in human intestinal epithelial cells in vitro. In addition, drug crystals triggered the release of neutrophil and monocyte extracellular traps. Taken together, these data raise the possibility that besides other factors including chronic kidney disease, diabetes mellitus, and hypertension, drug crystals may further amplify a pre-existing barrier dysfunction and necroinflammation in a crescendo of local intestinal necrosis and systemic inflammation/infection, as occasionally observed in patients on ion-exchange resin therapy.
Methionine Supplementation Affects Metabolism and Reduces Tumor Aggressiveness in Liver Cancer Cells
Authors: Tripodi Farida , Badone Beatrice , Vescovi Marta , Milanesi Riccardo , Nonnis Simona , Maffioli Elisa , Bonanomi Marcella , Gaglio Daniela , Tedeschi Gabriella , Coccetti Paola
Published: November 2020

Liver cancer is one of the most common cancer worldwide with a high mortality. Methionine is an essential amino acid required for normal development and cell growth, is mainly metabolized in the liver, and its role as an anti-cancer supplement is still controversial. Here, we evaluate the effects of methionine supplementation in liver cancer cells. An integrative proteomic and metabolomic analysis indicates a rewiring of the central carbon metabolism, with an upregulation of the tricarboxylic acid (TCA) cycle and mitochondrial adenosine triphosphate (ATP) production in the presence of high methionine and AMP-activated protein kinase (AMPK) inhibition. Methionine supplementation also reduces growth rate in liver cancer cells and induces the activation of both the AMPK and mTOR pathways. Interestingly, in high methionine concentration, inhibition of AMPK strongly impairs cell growth, cell migration, and colony formation, indicating the main role of AMPK in the control of liver cancer phenotypes. Therefore, regulation of methionine in the diet combined with AMPK inhibition could reduce liver cancer progression.
Extracellular ATP: A Feasible Target for Cancer Therapy
Authors: Vultaggio-Poma Valentina , Sarti Alba Clara , Di Virgilio Francesco
Published: November 2020

Adenosine triphosphate (ATP) is one of the main biochemical components of the tumor microenvironment (TME), where it can promote tumor progression or tumor suppression depending on its concentration and on the specific ecto-nucleotidases and receptors expressed by immune and cancer cells. ATP can be released from cells via both specific and nonspecific pathways. A non-regulated release occurs from dying and damaged cells, whereas active release involves exocytotic granules, plasma membrane-derived microvesicles, specific ATP-binding cassette (ABC) transporters and membrane channels (connexin hemichannels, pannexin 1 (PANX1), calcium homeostasis modulator 1 (CALHM1), volume-regulated anion channels (VRACs) and maxi-anion channels (MACs)). Extracellular ATP acts at P2 purinergic receptors, among which P2X7R is a key mediator of the final ATP-dependent biological effects. Over the years, P2 receptor- or ecto-nucleotidase-targeting for cancer therapy has been proposed and actively investigated, while comparatively fewer studies have explored the suitability of TME ATP as a target. In this review, we briefly summarize the available evidence suggesting that TME ATP has a central role in determining tumor fate and is, therefore, a suitable target for cancer therapy.
The Role of Histone Variants in the Epithelial-To-Mesenchymal Transition
Authors: Lone Imtiaz Nisar , Sengez Burcu , Hamiche Ali , Dimitrov Stefan , Alotaibi Hani
Published: November 2020

The epithelial-to-mesenchymal transition (EMT) is a physiological process activated during early embryogenesis, which continues to shape tissues and organs later on. It is also hijacked by tumor cells during metastasis. The regulation of EMT has been the focus of many research groups culminating in the last few years and resulting in an elaborate transcriptional network buildup. However, the implication of epigenetic factors in the control of EMT is still in its infancy. Recent discoveries pointed out that histone variants, which are key epigenetic players, appear to be involved in EMT control. This review summarizes the available data on histone variants’ function in EMT that would contribute to a better understanding of EMT itself and EMT-related diseases.
Adhesive Properties of Silicone-Coated Release Liner Paper Enhanced by Atmospheric Pressure Plasma Pre- and Post-Treatment
Authors: Kelar Tučeková Zlata , Galmiz Oleksandr , Kelar Jakub , Kováčik Dušan , Stupavská Monika , Šrámková Petra , Zemánek Miroslav , Vallade Julien , Černák Mirko
Published: November 2020

For release-liner preparation, coating stabilization of the silicone layer on base paper often requires pre- and post-treatment. In this study, we used atmospheric pressure diffuse coplanar surface barrier discharge in roll-to-roll configuration. The results of prepared coating showed that the A4 size clay-coated paper sprayed with silicone oil (0.25–0.50 mL) gradually decreased the tape peeling force (180°) with prolonged and repeated air plasma post-treatment. Best results showing increased hydrophobicity and significantly enhanced release factor of the coating were obtained after the plasma treatment in a nitrogen atmosphere. The silicone coating on the clay-coated paper reduced the reference release force from 5.5 N/cm to less than 1.5 N/cm after the repeated silicone spraying and short nitrogen plasma post-treatment. The results of X-ray photoelectron spectroscopy and scanning electron microscopy indicate silicone curing by plasma post-treatment and pore-closing of base paper without changes of the bulk material. The aging test lasting 3 months revealed the stability of the prepared coating.
Crack Propagation Behavior of a Ni-Based Single-Crystal Superalloy during In Situ SEM Tensile Test at 1000 °C
Authors: Jiang Wenxiang , Ren Xiaoyi , Zhao Jinghao , Zhou Jianli , Ma Jinyao , Zhang Wenjing , Zhang Yuefei , Zhang Ze
Published: November 2020

An in situ scanning electron microscope (SEM) tensile test for Ni-based single-crystal superalloy was carried out at 1000 °C. The stress displacement was obtained, and the yield strength and tensile strength of the superalloy were 699 MPa and 826 MPa, respectively. The crack propagation process, consisting of Model I crack and crystallographic shearing crack, was determined. More interestingly, the crack propagation path and rate affected by eutectics was directly observed and counted. Results show that the coalescence of the primary crack and second microcrack at the interface of a γ/γ′ matrix and eutectics would make the crack propagation rate increase from 0.3 μm/s to 0.4 μm/s. On the other hand, crack deflection decreased the rate to 0.05 μm/s. Moreover, movement of dislocations in front of the crack was also analyzed to explain the different crack propagation behavior in the superalloy.
Is Computed Tomography Necessary for Diagnostic Workup in Displaced Pediatric Medial Epicondyle Fractures?
Authors: Kim Sungmin , Kim Hyun Woo , Park Kun-Bo , Hong Kee-Bum , Park Hoon
Published: November 2020

This study aimed to compare the treatment outcomes and complications between operatively and nonoperatively treated medial epicondyle fractures with displacement of >5 mm as accurately measured on three-dimensional computed tomography (3D CT). We retrospectively reviewed 77 patients who had isolated medial epicondylar fractures with displacement of >5 mm. The mean age at injury was 11.4 years. Patients were assigned to one of two groups: 21 patients treated nonoperatively and 56 patients treated surgically. Additionally, patients treated operatively were divided into two subgroups according to fixation method; 31 patients underwent internal fixation with K-wires and 25 patients underwent internal fixation with a screw. Radiological and functional outcomes were compared among the three groups. Although the bony union rate was significantly higher in patients treated operatively compared to patients treated non-operatively (96.4% vs. 23.8%, p < 0.001), there were no significant differences in functional outcomes between the two groups. In the nonoperative group, three patients underwent osteosynthesis for symptomatic nonunion. There were no significant differences in radiological and functional outcomes between the two subgroups divided by fixation method. In a pediatric medial epicondylar fracture with a displacement of >5 mm as accurately measured on 3D CT, despite the difference in union rate, there was no difference in functional outcomes between operative and nonoperative treatment. Performing CT only to measure the fracture displacement in obviously displaced medial epicondylar fracture is not considered as a part of the “necessary” diagnostic workups.
Chronic Pain Diagnosis Using Machine Learning, Questionnaires, and QST: A Sensitivity Experiment
Authors: Santana Alex Novaes , de Santana Charles Novaes , Montoya Pedro
Published: November 2020

In the last decade, machine learning has been widely used in different fields, especially because of its capacity to work with complex data. With the support of machine learning techniques, different studies have been using data-driven approaches to better understand some syndromes like mild cognitive impairment, Alzheimer’s disease, schizophrenia, and chronic pain. Chronic pain is a complex disease that can recurrently be misdiagnosed due to its comorbidities with other syndromes with which it shares symptoms. Within that context, several studies have been suggesting different machine learning algorithms to classify or predict chronic pain conditions. Those algorithms were fed with a diversity of data types, from self-report data based on questionnaires to the most advanced brain imaging techniques. In this study, we assessed the sensitivity of different algorithms and datasets classifying chronic pain syndromes. Together with this assessment, we highlighted important methodological steps that should be taken into account when an experiment using machine learning is conducted. The best results were obtained by ensemble-based algorithms and the dataset containing the greatest diversity of information, resulting in area under the receiver operating curve (AUC) values of around 0.85. In addition, the performance of the algorithms is strongly related to the hyper-parameters. Thus, a good strategy for hyper-parameter optimization should be used to extract the most from the algorithm. These findings support the notion that machine learning can be a powerful tool to better understand chronic pain conditions.
Brick Assembly Networks: An Effective Network for Incremental Learning Problems
Authors: Ho Jiacang , Kang Dae-Ki
Published: November 2020

Deep neural networks have achieved high performance in image classification, image generation, voice recognition, natural language processing, etc.; however, they still have confronted several open challenges that need to be solved such as incremental learning problem, overfitting in neural networks, hyperparameter optimization, lack of flexibility and multitasking, etc. In this paper, we focus on the incremental learning problem which is related with machine learning methodologies that continuously train an existing model with additional knowledge. To the best of our knowledge, a simple and direct solution to solve this challenge is to retrain the entire neural network after adding the new labels in the output layer. Besides that, transfer learning can be applied only if the domain of the new labels is related to the domain of the labels that have already been trained in the neural network. In this paper, we propose a novel network architecture, namely Brick Assembly Network (BAN), which allows a trained network to assemble (or dismantle) a new label to (or from) a trained neural network without retraining the entire network. In BAN, we train labels with a sub-network (i.e., a simple neural network) individually and then we assemble the converged sub-networks that have trained for a single label together to form a full neural network. For each label to be trained in a sub-network of BAN, we introduce a new loss function that minimizes the loss of the network with only one class data. Applying one loss function for each class label is unique and different from standard neural network architectures (e.g., AlexNet, ResNet, InceptionV3, etc.) which use the values of a loss function from multiple labels to minimize the error of the network. The difference of between the loss functions of previous approaches and the one we have introduced is that we compute a loss values from node values of penultimate layer (we named it as a characteristic layer) instead of the output layer where the computation of the loss values occurs between true labels and predicted labels. From the experiment results on several benchmark datasets, we evaluate that BAN shows a strong capability of adding (and removing) a new label to a trained network compared with a standard neural network and other previous work.