bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma Treatment Limits Human Melanoma Spheroid Growth and Metastasis Independent of the Ambient Gas Composition
Authors: Hasse Sybille , Meder Tita , Freund Eric , von Woedtke Thomas , Bekeschus Sander
Published: September 2020

Melanoma skin cancer is still a deadly disease despite recent advances in therapy. Previous studies have suggested medical plasma technology as a promising modality for melanoma treatment. However, the efficacy of plasmas operated under different ambient air conditions and the comparison of direct and indirect plasma treatments are mostly unexplored for this tumor entity. Moreover, exactly how plasma treatment affects melanoma metastasis has still not been explained. Using 3D tumor spheroid models and high-content imaging technology, we addressed these questions by utilizing one metastatic and one non-metastatic human melanoma cell line targeted with an argon plasma jet. Plasma treatment was toxic in both cell lines. Modulating the oxygen and nitrogen ambient air composition (100/0, 75/25, 50/50, 25/75, and 0/100) gave similar toxicity and reduced the spheroid growth for all conditions. This was the case for both direct and indirect treatments, with the former showing a treatment time-dependent response while the latter resulted in cytotoxicity with the longest treatment time investigated. Live-cell imaging of in-gel cultured spheroids indicated that plasma treatment did not enhance metastasis, and flow cytometry showed a significant modulation of S100A4 but not in any of the five other metastasis-related markers (β-catenin, E-cadherin, LEF1, SLUG, and ZEB1) investigated.
Acute Radiation Colitis after Preoperative Short-Course Radiotherapy for Rectal Cancer: A Morphological, Immunohistochemical and Genetic Study
Authors: Zanelli Magda , Ciarrocchi Alessia , De Petris Giovanni , Zizzo Maurizio , Costantini Massimo , Bisagni Alessandra , Torricelli Federica , Nicoli Davide , Ramundo Dafne , Ricci Stefano , Palicelli Andrea , Sanguedolce Francesca , Ascani Stefano , Castro Ruiz Carolina , Annessi Valerio , Zamponi Raffaella , Bortesi Mara , Martino Veronica , Marchetti Marialisa , De Marco Loredana
Published: September 2020

Preoperative radiotherapy is a widely accepted treatment procedure in rectal cancer. Radiation-induced changes in the tumor are well described, whereas less attention has been given to the non-neoplastic mucosa. Our aim is to provide a detailed analysis of the morphological features present in non-neoplastic mucosa that pathologists need to be familiar with, in order to avoid misdiagnosis, when evaluating rectal cancer specimens of patients preoperatively treated with radiotherapy, especially with short-course regimen. We compared 2 groups of 95 rectal cancer patients treated preoperatively with either short-course (45 patients) or long-course radiotherapy (50 patients). Depending on the type of protocol, different histopathological features, in terms of inflammation, glandular abnormalities and endocrine differentiation were seen in the non-neoplastic mucosa within the irradiated volume. Of note, features mimicking dysplasia, such as crypt distortion, nuclear and cytoplasmic atypia of glandular epithelium, were identified only in the short-course group. DNA mutation analysis, using a panel of 56 genes frequently mutated in cancer, and p53 immunostaining were performed on both tumor and radiation-damaged mucosa in a subset of short course cases. Somatic mutations were identified only in tumors, supporting the concept that tissues with radiation-induced “dysplastic-like” features are not genetically transformed. Pathologists should be aware of the characteristic morphological changes induced by radiation. The presence of features simulating dysplasia in the group treated with short-course radiotherapy may lead to serious diagnostic mistakes, if erroneously interpreted. Next generation sequencing (NGS) analysis further validated the morphological concept that radiation-induced abnormalities do not represent pre-neoplastic lesions.
Amino Acids Regulate Cisplatin Insensitivity in Neuroblastoma
Authors: Gunda Venugopal , Pathania Anup S. , Chava Srinivas , Prathipati Philip , Chaturvedi Nagendra K. , Coulter Don W. , Pandey Manoj K. , Durden Donald L. , Challagundla Kishore B.
Published: September 2020

Neuroblastoma are pediatric, extracranial malignancies showing alarming survival prognosis outcomes due to their resilience to current aggressive treatment regimens, including chemotherapies with cisplatin (CDDP) provided in the first line of therapy regimens. Metabolic deregulation supports tumor cell survival in drug-treated conditions. However, metabolic pathways underlying cisplatin-resistance are least studied in neuroblastoma. Our metabolomics analysis revealed that cisplatin-insensitive cells alter their metabolism; especially, the metabolism of amino acids was upregulated in cisplatin-insensitive cells compared to the cisplatin-sensitive neuroblastoma cell line. A significant increase in amino acid levels in cisplatin-insensitive cells led us to hypothesize that the mechanisms upregulating intracellular amino acid pools facilitate insensitivity in neuroblastoma. We hereby report that amino acid depletion reduces cell survival and cisplatin-insensitivity in neuroblastoma cells. Since cells regulate their amino acids levels through processes, such as autophagy, we evaluated the effects of hydroxychloroquine (HCQ), a terminal autophagy inhibitor, on the survival and amino acid metabolism of cisplatin-insensitive neuroblastoma cells. Our results demonstrate that combining HCQ with CDDP abrogated the amino acid metabolism in cisplatin-insensitive cells and sensitized neuroblastoma cells to sub-lethal doses of cisplatin. Our results suggest that targeting of amino acid replenishing mechanisms could be considered as a potential approach in developing combination therapies for treating neuroblastomas.
A Modern Approach to Endometrial Carcinoma: Will Molecular Classification Improve Precision Medicine in the Future?
Authors: Marnitz Simone , Walter Till , Schömig-Markiefka Birgid , Engler Tobias , Kommoss Stefan , Brucker Sara Yvonne
Published: September 2020

Endometrial cancer has been histologically classified as either an estrogen-dependent cancer with a favorable outcome or an estrogen-independent cancer with a worse prognosis. These parameters, along with the clinical attributions, have been the basis for risk stratification. Recent molecular and histopathological findings have suggested a more complex approach to risk stratification. Findings from the Cancer Genome Atlas Research Network established four distinctive genomic groups: ultramutated, hypermutated, copy-number low and copy-number high prognostic subtypes. Subsequently, more molecular and histopathologic classifiers were evaluated for their prognostic and predictive value. The impact of molecular classification is evident and will be recognized by the upcoming WHO classification. Further research is needed to give rise to a new era of molecular-based endometrial carcinoma patient care.
Influence of Target Location, Size, and Patient Age on Normal Tissue Sparing- Proton and Photon Therapy in Paediatric Brain Tumour Patient-Specific Approach
Authors: Dell’Oro Mikaela , Short Michala , Wilson Puthenparampil , Hua Chia-Ho , Gargone Melissa , Merchant Thomas E. , Bezak Eva
Published: September 2020

Background: Proton radiotherapy produces superior dose distributions compared to photon radiotherapy, reducing side effects. Differences between the two modalities are not fully quantified in paediatric patients for various intracranial tumour sites or age. Understanding these differences may help clinicians estimate the benefit and improve referral across available centres. Our aim was to compare intensity-modulated proton therapy (IMPT) and intensity-modulated photon radiotherapy (IMRT) radiation doses for select paediatric intracranial tumours. Methods: IMPT and IMRT dose distributions for gender-matched paediatric cranial CT-datasets (ages 5, 9 and 13 years) were retrospectively calculated to simulate irradiation of supratentorial (ependymoma) and infratentorial (medulloblastoma) target volumes diameters (1–3 cm) and position (central and 1–2 cm shifts). Results: Clinical dosimetric objectives were achieved for all 216 treatment plans. Whilst infratentorial IMPT plans achieved greater maximum dose sparing to optic structures (4.8–12.6 Gy optic chiasm), brainstem sparing was limited (~0.5 Gy). Mean dose difference for optic chiasm was associated with medulloblastoma target position (p < 0.0197). Supratentorial IMPT plans demonstrated greater dose reduction for the youngest patients (pituitary gland p < 0.001). Conclusions: Normal tissue sparing was achieved regardless of patient age for infratentorial tumours. However, for supratentorial tumours, there was a dosimetric advantage of IMPT across 9 vs. 13-year-old patients.
Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages
Authors: Oelschlaegel Diana , Weiss Sadan Tommy , Salpeter Seth , Krug Sebastian , Blum Galia , Schmitz Werner , Schulze Almut , Michl Patrick
Published: September 2020

Stroma-infiltrating immune cells, such as tumor-associated macrophages (TAM), play an important role in regulating tumor progression and chemoresistance. These effects are mostly conveyed by secreted mediators, among them several cathepsin proteases. In addition, increasing evidence suggests that stroma-infiltrating immune cells are able to induce profound metabolic changes within the tumor microenvironment. In this study, we aimed to characterize the impact of cathepsins in maintaining the TAM phenotype in more detail. For this purpose, we investigated the molecular effects of pharmacological cathepsin inhibition on the viability and polarization of human primary macrophages as well as its metabolic consequences. Pharmacological inhibition of cathepsins B, L, and S using a novel inhibitor, GB111-NH2, led to changes in cellular recycling processes characterized by an increased expression of autophagy- and lysosome-associated marker genes and reduced adenosine triphosphate (ATP) content. Decreased cathepsin activity in primary macrophages further led to distinct changes in fatty acid metabolites associated with increased expression of key modulators of fatty acid metabolism, such as fatty acid synthase (FASN) and acid ceramidase (ASAH1). The altered fatty acid profile was associated with an increased synthesis of the pro-inflammatory prostaglandin PGE2, which correlated with the upregulation of numerous NFkB-dependent pro-inflammatory mediators, including interleukin-1 (IL-1), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor-alpha (TNFα). Our data indicate a novel link between cathepsin activity and metabolic reprogramming in macrophages, demonstrated by a profound impact on autophagy and fatty acid metabolism, which facilitates a pro-inflammatory micromilieu generally associated with enhanced tumor elimination. These results provide a strong rationale for therapeutic cathepsin inhibition to overcome the tumor-promoting effects of the immune-evasive tumor micromilieu.
FUT9-Driven Programming of Colon Cancer Cells towards a Stem Cell-Like State
Authors: Blanas Athanasios , Zaal Anouk , van der Haar Àvila Irene , Kempers Maxime , Kruijssen Laura , de Kok Mike , Popovic Marko A. , van der Horst Joost C. , J. van Vliet Sandra
Published: September 2020

Cancer stem cells (CSCs) are located in dedicated niches, where they remain inert to chemotherapeutic drugs and drive metastasis. Although plasticity in the CSC pool is well appreciated, the molecular mechanisms implicated in the regulation of cancer stemness are still elusive. Here, we define a fucosylation-dependent reprogramming of colon cancer cells towards a stem cell-like phenotype and function. De novo transcriptional activation of Fut9 in the murine colon adenocarcinoma cell line, MC38, followed by RNA seq-based regulon analysis, revealed major gene regulatory networks related to stemness. Lewisx, Sox2, ALDH and CD44 expression, tumorsphere formation, resistance to 5-FU treatment and in vivo tumor growth were increased in FUT9-expressing MC38 cells compared to the control cells. Likewise, human CRC cell lines highly expressing FUT9 displayed phenotypic features of CSCs, which were significantly impaired upon FUT9 knock-out. Finally, in primary CRC FUT9+ tumor cells pathways related to cancer stemness were enriched, providing a clinically meaningful annotation of the complicity of FUT9 in stemness regulation and may open new avenues for therapeutic intervention.
Isolation and Characterization of Two Novel Colorectal Cancer Cell Lines, Containing a Subpopulation with Potential Stem-Like Properties: Treatment Options by MYC/NMYC Inhibition
Authors: Schulte am Esch Jan , Windmöller Beatrice Ariane , Hanewinkel Johannes , Storm Jonathan , Förster Christine , Wilkens Ludwig , Krüger Martin , Kaltschmidt Barbara , Kaltschmidt Christian
Published: September 2020

Cancer stem cells (CSC) are crucial mediators of cancer relapse. Here, we isolated two primary human colorectal cancer cell lines derived from a rectal neuroendocrine carcinoma (BKZ-2) and a colorectal adenocarcinoma (BKZ-3), both containing subpopulations with potential stem-like properties. Protein expression of CSC-markers prominin-1 and CD44 antigen was significantly higher for BKZ-2 and BKZ-3 in comparison to well-established colon carcinoma cell lines. High sphere-formation capacity further confirmed the existence of a subpopulation with potential stem-like phenotype. Epithelial–mesenchymal transition markers as well as immune checkpoint ligands were expressed more pronounced in BKZ-2. Both cell populations demonstrated N-myc proto-oncogene (NMYC) copy number gain. Myc proto-oncogene (MYC)/NMYC activity inhibitor all-trans retinoic acid (ATRA) significantly reduced the number of tumor spheres for both and the volume of BKZ-2 spheres. In contrast, the sphere volume of ATRA-treated BKZ-3 was increased, and only BKZ-2 cell proliferation was reduced in monolayer culture. Treatment with KJ-Pyr-9, a specific inhibitor of MYC/NMYC-myc-associated factor X interaction, decreased survival by the induction of apoptosis of both. In summary, here, we present the novel colorectal cancer cell lines BKZ-2 and BKZ-3 as promising cellular in vitro models for colorectal carcinomas and identify the MYC/NMYC molecular pathway involved in CSC-induced carcinogenesis with relevant therapeutic potential.
Temozolomide-Induced RNA Interactome Uncovers Novel LncRNA Regulatory Loops in Glioblastoma
Authors: Fritah Sabrina , Muller Arnaud , Jiang Wei , Mitra Ramkrishna , Sarmini Mohamad , Dieterle Monika , Golebiewska Anna , Ye Tao , Van Dyck Eric , Herold-Mende Christel , Zhao Zhongming , Azuaje Francisco , Niclou Simone P.
Published: September 2020

Resistance to chemotherapy by temozolomide (TMZ) is a major cause of glioblastoma (GBM) recurrence. So far, attempts to characterize factors that contribute to TMZ sensitivity have largely focused on protein-coding genes, and failed to provide effective therapeutic targets. Long noncoding RNAs (lncRNAs) are essential regulators of epigenetic-driven cell diversification, yet, their contribution to the transcriptional response to drugs is less understood. Here, we performed RNA-seq and small RNA-seq to provide a comprehensive map of transcriptome regulation upon TMZ in patient-derived GBM stem-like cells displaying different drug sensitivity. In a search for regulatory mechanisms, we integrated thousands of molecular associations stored in public databases to generate a background “RNA interactome”. Our systems-level analysis uncovered a coordinated program of TMZ response reflected by regulatory circuits that involve transcription factors, mRNAs, miRNAs, and lncRNAs. We discovered 22 lncRNAs involved in regulatory loops and/or with functional relevance in drug response and prognostic value in gliomas. Thus, the investigation of TMZ-induced gene networks highlights novel RNA-based predictors of chemosensitivity in GBM. The computational modeling used to identify regulatory circuits underlying drug response and prioritizing gene candidates for functional validation is applicable to other datasets.
Adjuvant Chemotherapy for Stage II Colon Cancer
Authors: Rebuzzi Sara Elena , Pesola Guido , Martelli Valentino , Sobrero Alberto Felice
Published: September 2020

In stage II colon cancer management, surgery alone has shown a high cure rate (about 80%), and the role of adjuvant chemotherapy is still a matter of debate. Patients with high-risk features (T4, insufficient nodal sampling, grading, etc.) have a poorer prognosis and, usually, adjuvant chemotherapy is recommended. The purpose of the present study is to highlight and discuss what is still unclear and not completely defined from the previous trials regarding risk stratification and therapeutic benefit of adjuvant chemotherapy. With all the limitations of generalizing, we make the effort of trying to quantify the relative contribution of each prognostic factor and the benefit of adjuvant chemotherapy for stage II colon cancer. Finally, we propose a decision algorithm with the aim of summarizing the current evidence and translating it to clinical practice.
Uncommon Site of Metastasis and Prolonged Survival in Patients with Anaplastic Thyroid Carcinoma: A Systematic Review of the Literature
Authors: Mirabile Aurora , Biafora Matteo , Giordano Leone , Arrigoni Gianluigi , Cangi Maria Giulia , Dell’Oca Italo , Lira Luce Francesca , Di Santo Davide , Galli Andrea , Tulli Michele , Mellone Renata , Valsecchi Davide , Gregorc Vanesa , Bussi Mario
Published: September 2020

Anaplastic thyroid carcinoma (ATC) is a very rare, highly aggressive malignant thyroid tumor with an overall survival from 3 to 5 months in most of the cases. Even the modern and intensive treatments seem not to be enough to provide a cure, also for the resectable ones, and the role of chemotherapy is still unclear but does not seem to prolong survival. Nevertheless, some patients survive longer and have a better outcome, even in the presence of metastasis, than what the literature reports. We present the case of a 64-year-old female affected by ATC, treated on February 2018 with surgery followed by chemoradiation. One year after surgery, the patient developed a subcutaneous recurrence that was radically resected and is still alive 29 months after the diagnosis. We propose a systematic review of the literature to deepen the knowledge of the prognostic factors of ATC with the aim to recognize and select the patients with a better outcome, even if metastatic, and to describe a very uncommon site of metastatization.
RAS Subcellular Localization Inversely Regulates Thyroid Tumor Growth and Dissemination
Authors: García-Ibáñez Yaiza , Riesco-Eizaguirre Garcilaso , Santisteban Pilar , Casar Berta , Crespo Piero
Published: September 2020

RAS mutations are the second most common genetic alteration in thyroid tumors. However, the extent to which they are associated with the most aggressive phenotypes is still controversial. Regarding their malignancy, the majority of RAS mutant tumors are classified as undetermined, which complicates their clinical management and can lead to undesired under- or overtreatment. Using the chick embryo spontaneous metastasis model, we herein demonstrate that the aggressiveness of HRAS-transformed thyroid cells, as determined by the ability to extravasate and metastasize at distant organs, is orchestrated by HRAS subcellular localization. Remarkably, aggressiveness inversely correlates with tumor size. In this respect, we also show that RAS site-specific capacity to regulate tumor growth and dissemination is dependent on VEGF-B secretion. Furthermore, we have identified the acyl protein thioesterase APT-1 as a determinant of thyroid tumor growth versus dissemination. We show that alterations in APT-1 expression levels can dramatically affect the behavior of thyroid tumors, based on its role as a regulator of HRAS sublocalization at distinct plasma membrane microdomains. In agreement, APT-1 emerges in thyroid cancer clinical samples as a prognostic factor. As such, APT-1 levels could serve as a biomarker that could help in the stratification of HRAS mutant thyroid tumors based on their aggressiveness.
How Should We Assign Large Infiltrative Hepatocellular Carcinomas for Staging?
Authors: Lee Yoo Jin , Lee Yoo Ra , Seo Chung Gyo , Goh Hyun Gil , Kim Tae Hyung , Yim Sun Young , Han Na Yeon , Lee Jae Min , Choi Hyuk Soon , Kim Eun Sun , Keum Bora , An Hyonggin , Park Beomjin , Seo Yeon Seok , Yim Hyung Joon , Kim Ji Hoon , Yu Young Dong , Kim Dong Sik , Jeen Yoon Tae , Chun Hoon Jai , Lee Hong Sik , Kim Chang Duck , Um Soon Ho
Published: September 2020

Infiltrative gross morphology of hepatocellular carcinoma (HCC) is known to be associated with poor prognosis, but this is not considered for staging. A total of 774 HCC patients who underwent curative liver resection were retrospectively reviewed and the prognostic significance of infiltrative type HCC was assessed using the American Joint Committee on Cancer (AJCC) and Barcelona Clinic Liver Cancer (BCLC) staging systems. Seventy-four patients (9.6%) had infiltrative HCCs with a higher proportion of multifocal tumors, larger tumors, vessel invasion, increased tumor marker levels, and advanced T-stages than those with nodular HCC (all, p < 0.01). Infiltrative morphology was independently associated with lower overall survival (OS), but its impact was significant when the tumor size was ≥ 4 cm (p < 0.001). Under current AJCC and BCLC staging criteria, these large infiltrative HCCs were associated with significantly worse OS in early AJCC T-stages (T1b/T2, p < 0.001) and BCLC stage A/B (both, p < 0.01) but not in late AJCC (T3/T4) and BCLC C. The reassignment of this subtype to T3 and T4 increased the discriminatory ability of AJCC T-staging with lower AIC values (3090 and 3088 vs. 3109) and higher c-index (0.69 and 0.69 vs. 0.67), respectively (both, p < 0.001). Similarly, the reassignment of large infiltrative HCC to BCLC stages B and C also improved the prognostic performance. Large infiltrative HCCs should be assigned to more advanced stages in current staging systems for their prognostic impact.
A Mathematical Model of Average Dynamics in a Stem Cell Hierarchy Suggests the Combinatorial Targeting of Cancer Stem Cells and Progenitor Cells as a Potential Strategy against Tumor Growth
Authors: Molina-Peña Rodolfo , Tudon-Martinez Juan Carlos , Aquines-Gutiérrez Osvaldo
Published: September 2020

The cancer stem cell hypothesis states that tumors are maintained by a small subpopulation of stem-like cells, often called cancer stem cells (CSCs) or tumor initiating cells. CSCs can self-renew and give rise to more differentiated cells, which comprise the bulk of the tumor. In addition, CSCs are resistant to conventional therapy, which suggests that they are responsible for tumor relapse. This has led researchers to increase efforts to develop directed therapies against CSCs. However, some experiments in mice have shown that the elimination of CSCs might not ensure tumor eradication. This may be due to different events, such as residual CSCs after treatment, the plasticity of cells within the tumor, the presence of different CSCs having their own hierarchy within the same tumor, and the ability of more differentiated cells to maintain the disease, among others. Trying to decipher this complexity may benefit from dissecting the whole in its parts. Here, we hypothesize that tumor relapse after the selective targeting of CSCs may be due to intermediate progenitor (P) cells that can maintain the tumor volume. In order to support the hypothesis, we implemented a mathematical model derived using pseudo-reactions representing the events of each cell subpopulation within the tumor. We aimed to test if a minimal unidirectional hierarchical model consisting of CSCs, P, and terminally differentiated (D) cells could be adjusted to experimental data for selective CSC targeting. We further evaluated therapies ranging from nonselective to specifically directed and combination therapy. We found that selective killing of the CSC compartment has a delaying effect on the overall exponential tumor growth, but was not able to eliminate the disease. We show that therapy that targets both CSCs and intermediate progenitor (P) cells with a sufficient capacity to proliferate and differentiate could represent a more efficient treatment option for tumor depletion. Testing this hypothesis in vivo may allow us to discriminate within the array of possibilities of tumor relapse, and further open the idea of combination therapy against different subpopulations of tumor cells instead of segregating CSCs and bulk tumor cells.
Novel Insights into Beta 2 Adrenergic Receptor Function in the rd10 Model of Retinitis Pigmentosa
Authors: Cammalleri Maurizio , Dal Monte Massimo , Amato Rosario , Lapi Dominga , Bagnoli Paola
Published: September 2020

Background: In retinitis pigmentosa (RP), inherited rod death is followed by cone loss and blindness. Why cones die is still a matter of consideration. Here, we investigate the pathogenic role of the sympathetic transmission in the rd10 mouse model of RP. Methods: Retinal levels of beta adrenergic receptor (BAR) 2 and norepinephrine (NE) were measured. After administration of the BAR1/2 blocker propranolol or the hypoxia-inducible factor (HIF)-1 activator dimethyloxalylglycine (DMOG), retinal levels of HIF-1α, BAR2 or proteins involved in BAR2 desensitization were also measured. In DMOG treated mice, expression and localization of BAR2, inflammatory markers and cone arrestin were determined. Finally, rd10 mice were subjected to electroretinogram (ERG) analysis to assess rod and cone function. Results: In the rd10 retina, BAR2 overexpression and NE accumulation were found, with BAR2 immunoreactivity localized to Müller cells. BAR2 overexpression was likely due to desensitization defects. Upregulated levels of BAR2 were drastically reduced by propranolol that also restored desensitization defects. Due to the low level of HIF-1 consequent to the hyperoxic environment in the rd10 retina, we hypothesized a link between HIF-1 and BAR2. HIF-1α stabilization with DMOG resulted in i. increased HIF-1α accumulation, ii. decreased BAR2 levels, iii. restored desensitization processes, iv. reduced expression of inflammatory markers and v. increased cone survival without improved retinal function. Conclusions: Our results support a pathogenic role of the sympathetic system in RP that might help to understand why rd10 mice show a positive response to BAR blockers.
ER Stress-Induced Secretion of Proteins and Their Extracellular Functions in the Heart
Authors: Meyer Bianca A. , Doroudgar Shirin
Published: September 2020

Endoplasmic reticulum (ER) stress is a result of conditions that imbalance protein homeostasis or proteostasis at the ER, for example ischemia, and is a common event in various human pathologies, including the diseased heart. Cardiac integrity and function depend on the active secretion of mature proteins from a variety of cell types in the heart, a process that requires an intact ER environment for efficient protein folding and trafficking to the secretory pathway. As a consequence of ER stress, most protein secretion by the ER secretory pathway is decreased. Strikingly, there is a select group of proteins that are secreted in greater quantities during ER stress. ER stress resulting from the dysregulation of ER Ca2+ levels, for instance, stimulates the secretion of Ca2+-binding ER chaperones, especially GRP78, GRP94, calreticulin, and mesencephalic astrocyte-derived neurotrophic factor (MANF), which play a multitude of roles outside the cell, strongly depending on the cell type and tissue. Here we review current insights in ER stress-induced secretion of proteins, particularly from the heart, and highlight the extracellular functions of these proteins, ranging from the augmentation of cardiac cell viability to the modulation of pro- and anti-apoptotic, oncogenic, and immune-stimulatory cell signaling, cell invasion, extracellular proteostasis, and more. Many of the roles of ER stress-induced protein secretion remain to be explored in the heart. This article is part of a special issue entitled “The Role of Proteostasis Derailment in Cardiac Diseases.”
Autologous, Non-Invasively Available Mesenchymal Stem Cells from the Outer Root Sheath of Hair Follicle Are Obtainable by Migration from Plucked Hair Follicles and Expandable in Scalable Amounts
Authors: Li Hanluo , Masieri Federica Francesca , Schneider Marie , Kottek Tina , Hahnel Sebastian , Yamauchi Kensuke , Obradović Danilo , Seon Jong-Keun , Yun Sook Jung , Ferrer Rubén A. , Franz Sandra , Simon Jan-Christoph , Lethaus Bernd , Savković Vuk
Published: September 2020

Background: Regenerative therapies based on autologous mesenchymal stem cells (MSC) as well as stem cells in general are still facing an unmet need for non-invasive sampling, availability, and scalability. The only known adult source of autologous MSCs permanently available with no pain, discomfort, or infection risk is the outer root sheath of the hair follicle (ORS). Methods: This study presents a non-invasively-based method for isolating and expanding MSCs from the ORS (MSCORS) by means of cell migration and expansion in air–liquid culture. Results: The method yielded 5 million cells of pure MSCORS cultured in 35 days, thereby superseding prior art methods of culturing MSCs from hair follicles. MSCORS features corresponded to the International Society for Cell Therapy characterization panel for MSCs: adherence to plastic, proliferation, colony forming, expression of MSC-markers, and adipo-, osteo-, and chondro-differentiation capacity. Additionally, MSCORS displayed facilitated random-oriented migration and high proliferation, pronounced marker expression, extended endothelial and smooth muscle differentiation capacity, as well as a paracrine immunomodulatory effect on monocytes. MSCORS matched or even exceeded control adipose-derived MSCs in most of the assessed qualities. Conclusions: MSCORS qualify for a variety of autologous regenerative treatments of chronic disorders and prophylactic cryopreservation for purposes of acute treatments in personalized medicine.
On Neutrophil Extracellular Trap (NET) Removal: What We Know Thus Far and Why So Little
Authors: Santocki Michal , Kolaczkowska Elzbieta
Published: September 2020

Although neutrophil extracellular traps (NETs) were discovered only 16 years ago, they have already taken us from heaven to hell as we learned that apart from beneficial trapping of pathogens, they cause, or contribute to, numerous disorders. The latter is connected to their persistent presence in the blood or tissue, and we hardly know how they are removed in mild pathophysiological conditions and why their removal is impaired in multiple severe pathological conditions. Herein, we bring together all data available up till now on how NETs are cleared—from engaged cells, their phenotypes, to involved enzymes and molecules. Moreover, we hypothesize on why NET removal is challenged in multiple disorders and propose further directions for studies on NET removal as well as possible therapeutic strategies to have them cleared.
Ribosomopathies: New Therapeutic Perspectives
Authors: Orgebin Emilien , Lamoureux François , Isidor Bertrand , Charrier Céline , Ory Benjamin , Lézot Frédéric , Baud’huin Marc
Published: September 2020

Ribosomopathies are a group of rare diseases in which genetic mutations cause defects in either ribosome biogenesis or function, given specific phenotypes. Ribosomal proteins, and multiple other factors that are necessary for ribosome biogenesis (rRNA processing, assembly of subunits, export to cytoplasm), can be affected in ribosomopathies. Despite the need for ribosomes in all cell types, these diseases result mainly in tissue-specific impairments. Depending on the type of ribosomopathy and its pathogenicity, there are many potential therapeutic targets. The present manuscript will review our knowledge of ribosomopathies, discuss current treatments, and introduce the new therapeutic perspectives based on recent research. Diamond–Blackfan anemia, currently treated with blood transfusion prior to steroids, could be managed with a range of new compounds, acting mainly on anemia, such as L-leucine. Treacher Collins syndrome could be managed by various treatments, but it has recently been shown that proteasomal inhibition by MG132 or Bortezomib may improve cranial skeleton malformations. Developmental defects resulting from ribosomopathies could be also treated pharmacologically after birth. It might thus be possible to treat certain ribosomopathies without using multiple treatments such as surgery and transplants. Ribosomopathies remain an open field in the search for new therapeutic approaches based on our recent understanding of the role of ribosomes and progress in gene therapy for curing genetic disorders.
The Use of Geolocation to Manage Passenger Mobility between Airports and Cities
Authors: Sarasa-Cabezuelo Antonio
Published: September 2020

A general problem in large cities is mobility. Every day, there are incidents (accidents, construction, or meteorological events) that increase the duration of the journeys in a city and exert negative effects on the lives of citizens. A particular case of this situation is communications with airports. Shuttles are a type of private transport service that operates in airports. The number of passengers carried by shuttles is small. Moreover, shuttles transport passengers to their final destinations and their prices are more competitive than those other private services. However, shuttle services have a limitation with respect to their routes due to the many different destinations of passengers. For this reason, it is important to be able to calculate the best route to optimize the journey. This work presents an Android application that implements a value-added service to plan the route of a shuttle and manage its service (passengers, journeys, routes, etc.). This application combines information from different sources, such as geolocation information from the shuttle driver’s mobile phone, information on the passengers, and results obtained from the service offered by MapBox to calculate the optimized route between several destinations.
Data on Vietnamese Students’ Acceptance of Using VCTs for Distance Learning during the COVID-19 Pandemic
Authors: Pho Duc-Hoa , Nguyen Xuan-An , Luong Dinh-Hai , Nguyen Hoai-Thu , Vu Thi-Phuong-Thao , Nguyen Thi-Thuong-Thuong
Published: September 2020

The outbreak of COVID-19 at the beginning of 2020 has heavily influenced education all around the world. In Vietnam, educational institutes were suspended, and distance learning was conducted to ensure students’ learning process, with distance learning occurring mainly via video conferencing tools (VTCs). The purpose of this paper is to provide data on Vietnamese students’ acceptance of using VCTs in distance learning during the COVID-19 pandemic through an extended technology acceptance model (TAM) and structural equation modeling (SEM) method. This study used the TAM of Venkatesh and Davis. The questionnaire was designed based on Venkatesh and Davis and Salloum et al.’s scale. An online survey with snowball sampling was selected in April. The final dataset consisted of 277 valid records. This data descriptor presented descriptive statistics (mean, standard deviation), internal consistency (Cronbach’s alpha), reliability and validity measures (composite reliability, average value extracted test), and factor loading of items of eight factors: output quality, computer playfulness, subjective norm, perceived usefulness, perceived ease of use, attitude towards to use, behavioral intention to use, and actual system to use. Results indicated that external factors such as subjective norm and computer playfulness had a significant impact on most TAM constructs. Furthermore, output quality was found to have a positive influence on students’ perceived usefulness and acceptance of VCTs in distance learning.
A Comprehensive Narrative Review on the Evolving Role of Endoscopic Ultrasound in Focal Solid Liver Lesions Diagnosis and Management
Authors: Sbeit Wisam , Kadah Anas , Mari Amir , Mahamid Mahmud , Khoury Tawfik
Published: September 2020

The implications of endoscopic ultrasound (EUS) have expanded considerably in recent years to cover more fields in invasive gastroenterology practice, as both an investigative and therapeutic modality. The utility of EUS in the diagnosis and management of focal liver lesions has gained a special attractiveness recently. The EUS probe proximity to the liver and its excellent spatial resolution enables real-time images coupled with several enhancement techniques, such as contrast-enhanced (CE) EUS. Aside from its notable capability to execute targeted biopsies and therapeutic interventions, EUS has developed into a hopeful therapeutic tool for the management of solid liver lesions. Herein, we provide a comprehensive state-of-the-art review on the efficacy and safety of EUS in the diagnosis and management of focal solid liver lesions. Medline/PubMed and Embase database searches were conducted by two separate authors (T.K. and W.S.), all relevant studies were assessed, and relevant data was extracted and fully reported. EUS-guided diagnosis of focal liver lesions by sonographic morphologic appearance and cytological and histopathological finding of biopsies obtained via fine needle aspiration/biopsy have been shown to significantly improve the diagnosis of solid liver lesions compared with traditional imaging tools. Similarly, EUS-guided treatment has been shown to consistently have excellent technical success, high efficacy, and minor adverse events. The evolving valuable evidences of EUS utility might satisfy the unmet need of optimizing management of focal solid liver lesions.
The Prognostic Significance of Immune-Related Metabolic Enzyme MTHFD2 in Head and Neck Squamous Cell Carcinoma
Authors: Cui Li , Chen Huan , Zhao Xinyuan
Published: September 2020

Metabolic dysregulation has emerged as a crucial determinant of the clinical responses to immunotherapy. The aim of this study was to determine the clinical significance of the candidate immune-related metabolic enzymes (IRMEs) methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2 (MTHFD2) in head and neck squamous cell carcinoma (HNSCC). The gene expression profile of HNSCC cohort and the corresponding clinical information were downloaded from The Cancer Genome Atlas (TCGA). The differentially expressed IRMEs were identified, and then, the prognosis-associated IRMEs were revealed by univariate cox regression analysis. The prognostic significance of MTHFD2 in HNSCC as well as the association between MTHFD2 and immune cell infiltration were further analyzed. A total of 121 significantly altered IRMEs were identified between HNSCC and normal tissues, and 21 IRMEs were found to be strongly associated with overall survival of HNSCC. Upregulation of MTHFD2 was positively correlated with adverse clinicopathological factors in TCGA HNSCC cohort, which was further validated with our own cohort using immunohistochemical analysis. Interestingly, bioinformatic analysis further revealed that increased MTHFD2 expression was negatively associated with NK cells activation, while positively correlated with mast cells activation. In conclusion, MTHFD2 overexpression is closely correlated with unfavorable prognosis of HNSCC, and it might play an important role in modulating the tumor immune microenvironment.
Stepping Out of Equilibrium: The Quest for Understanding the Role of Non-Equilibrium (Thermo-)Dynamics in Electronic and Electrochemical Processes
Authors: Kaiser Waldemar , Gagliardi Alessio
Published: September 2020

This editorial aims to interest researchers and inspire novel research on the topic of non-equilibrium Thermodynamics and Monte Carlo for Electronic and Electrochemical Processes. We present a brief outline on recent progress and challenges in the study of non-equilibrium dynamics and thermodynamics using numerical Monte Carlo simulations. The aim of this special issue is to collect recent advances and novel techniques of Monte Carlo methods to study non-equilibrium electronic and electrochemical processes at the nanoscale.
Spatial Variation of b-Values and Their Relationship with the Fault Blocks in the Western Part of the Tibetan Plateau and Its Surrounding Areas
Authors: Hussain Hamid , Shuangxi Zhang , Usman Muhammad , Abid Muhammad
Published: September 2020

The Tibetan Plateau is considered to be one of the best natural laboratories for seismological research. This study sought to determine the spatial variations of b-values in the western part of the Tibetan Plateau, along with its surrounding areas, and the relation with the region’s fault blocks. The study region lies within 27–36.5° N, 78–89° E, and its fracture structure consists of strike-slip faults, as well as normal and thrust faults. A catalog record from 2009–2019 provided 4431 well-centered earthquakes that varied in magnitude from 0.1 to 8.2 M. The record was obtained from China’s seismological network, which is capable of recording low magnitudes to analyze b-values in the study area. The key findings of this study are as follows: (1) the range of earthquake depth in the region was 0–256 km, with the depth histogram showing a high frequency occurrence of shallow earthquakes in the area; (2) a time histogram showed that the major earthquakes occurred between 2014–2015, including the notable 2015 Gorkha earthquake (M = 8.2); (3) the b-value computed in the study area was 0.5 to 1.6, but in most of the study area, the b-value ranged from 0.6 to 0.9, which was a low to intermediate value, due to the presence of strike-slip faults in the central part of the study area and underthrusting in the region (south of the study area); and (4) a high b-value was found in the northwestern and eastern regions of the area, which proved that the area is prone to small earthquakes in the near future. The study also showed that the central and southern areas of the study region had low to intermediate b-values, meaning that it is prone to destructive and massive earthquakes with high magnitudes, such as the Gorkha earthquake (southern part of the study area). Low b-values revealed the degree of variation in rock properties, including large stress and strain, a fractured medium, a high deformation rate, and large faults. Small b-values were observed when the stress level was high in the investigated region, which might be used to predict a massive high-magnitude earthquake in the near future.
Methodological Aspects of a Comprehensive Analysis of the Fixed Capital of Machine Building Enterprises
Authors: Arsenieva Natalya V. , Putyatina Lyudmila M. , Tarasova Natalia V.
Published: September 2020

The article examines in detail the main areas and methodological features of a comprehensive analysis of movement and use of fixed capital of machine building enterprises. The fixed capital of enterprises is particularly important in the process of economic activity and it requires considerable investment for development and improvement. The purpose of this study is to develop a comprehensive approach to the quantitative assessment of change in the fixed assets of enterprises, their structure, and efficiency of use.
Non-Directional Earth Fault Passage Indication in Isolated Neutral Distribution Networks
Authors: Farughian Amir , Kumpulainen Lauri , Kauhaniemi Kimmo
Published: September 2020

In this paper, two new methods for locating single-phase to ground faults in isolated neutral distribution networks are proposed. The methods are based on the analysis of symmetrical sequence currents. They are solely based on currents, not requiring voltage measurement. The first method employs only the zero sequence current and the second one utilizes the negative sequence current in combination with the zero sequence current. It is revealed why using only zero sequence current with a simple threshold is insufficient and may lead to false results. Using the proposed methods, earth faults with high resistances can be located in isolated neutral distribution networks with overhead lines or cables.
How to Foster the Adoption of Electricity Smart Meters? A Longitudinal Field Study of Residential Consumers
Authors: Kowalska-Pyzalska Anna , Byrka Katarzyna , Serek Jakub
Published: September 2020

The objective of this research was to explore correlates and predictors that play a role in the process of adopting and withdrawing from using a smart metering information platform (SMP). The SMP supports energy monitoring behaviors of the electricity consumers. The literature review shows, however, that not every customer is ready to the same extent to adopt novel solutions. Adoption requires going through stages of readiness to monitor energy consumption in a household. In a longitudinal field experiment on Polish residential consumers, we aimed to see whether messages congruent with the stage of readiness in which participants declared to be at a given moment will be more effective in prompting participants to progress to the next stage than a general message or a passive control condition. We also tested the effect of attitude and knowledge about energy monitoring on phase changes. Our study reveals that what affects the phase change is the participation in the study. The longer the participants were engaged in the usage of SMP, the more willing they were to monitor their energy consumption in the future. This result sheds light on the future educational and marketing efforts of the authorities and energy suppliers.
Development of a Eulerian Multi-Fluid Solver for Dense Spray Applications in OpenFOAM
Authors: Keser Robert , Ceschin Alberto , Battistoni Michele , Im Hong G. , Jasak Hrvoje
Published: September 2020

The new generation of internal combustion engines is facing various research challenges which often include modern fuels and different operating modes. A robust modeling framework is essential for predicting the dynamic behavior of such complex phenomena. In this article, the implementation, verification, and validation of a Eulerian multi-fluid model for spray applications within the OpenFOAM toolbox are presented. Due to its open-source nature and broad-spectrum of available libraries and solvers, OpenFOAM is an ideal platform for academic research. The proposed work utilizes advanced interfacial momentum transfer models to capture the behavior of deforming droplets at a high phase fraction. Furthermore, the WAVE breakup model is employed for the transfer of mass from larger to smaller droplet classes. The work gives detailed instructions regarding the numerical implementation, with a dedicated section dealing with the implementation of the breakup model within the Eulerian multi-fluid formulation. During the verification analysis, the model proved to give stable and consistent results in terms of the selected number of droplet classes and the selected spatial and temporal resolution. In the validation section, the capability of the developed model to predict the dynamic behavior of non-evaporating sprays is presented. It was confirmed that the developed framework could be used as a stable foundation for future fuel spray modeling.