bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of Damage Level of Slab-Column Joints under Blast Load
Authors: Lim Kwang Mo , Yoo Do Guen , Lee Bo Yeon , Lee Joo Ha
Published: August 2020

The behavior of a slab-column joint subjected to blast loads was studied by numerical analysis using a general-purpose finite element analysis program, LS-DYNA. Under the explosive load, the joint region known as the stress disturbed zone was defined as a region with a scaled distance of 0.1 m/kg1/3 or less through comparison with ConWep’s empirical formula. Displacement and support rotation according to Trinitrotoluene (TNT) weight and scaled distance were investigated by dividing in and out of the joint region. In addition, fracture volume was newly proposed as an evaluation factor for blast-resistant performance, and it was confirmed that the degree of damage to a member due to blast loads was well represented by the fracture volume. Finally, a prediction equation for the blast-resistant performance of the slab-column joint was proposed, and the reliability and accuracy of the equation were verified through additional numerical analysis.
The Effects of Wild Ginseng Extract on Psychomotor and Neuromuscular Performance Recovery Following Acute Eccentric Exercise: A Preliminary Study
Authors: Jung Hyun Chul , Lee Nan Hee , Kim Young Chan , Lee Sukho
Published: August 2020

To examine the efficacy of wild ginseng extract (WGE) on psychomotor and neuromuscular performance recovery following acute eccentric exercise. This study was a double-blind, crossover, and placebo-controlled design with a 14-day washout period. Ten male adults, aged 27.1 ± 4.33 years old, voluntarily participated in the study. Subjects were assigned to one of two parallel conditions (WGE or placebo) in a counterbalanced manner. Subjects consumed two packs of WGE (350 mg/package) or placebo drink immediately after acute eccentric exercise and the following four days. The eccentric exercise consisted of 20 min of downhill running at 60% of VO2peak and five sets (of 20) of drop jump exercise. Computer-based cognitive function test and neuromuscular performance tests, including straight leg raise, vertical jump, isometric leg strength, and anaerobic power test were administered four times, at baseline, 2 h, 48 h, and 96 h after acute exercise. The interleukin-6 (IL-6), myoglobin, cortisol, total antioxidant capacity (TAC), and perceived muscle soreness were also assessed at each time point. A significance level was set at 0.05. No significant differences between the WGE and the placebo groups were observed in psychomotor and neuromuscular performance variables. Blood markers, including IL-6 (p = 0.013), myoglobin (p < 0.001), and cortisol level (p = 0.047) were changed significantly across the time. A post-hoc test revealed that a significant increase in IL-6 was observed only in the placebo group (p = 0.014), while no significant changes found in the WGE condition. The perceived muscle soreness was not different between the WGE and the placebo conditions. The administration of WGE immediately after acute eccentric exercise and the following four days have no benefits on psychomotor and neuromuscular performance recovery in healthy adults. However, the acute WGE supplementation may attenuate the eccentric exercise-induced inflammatory process, such as IL-6, but future study with a large sample size is required to clarify the anti-inflammation process in response to acute eccentric exercise.
Reliability Model Based Dynamic Multi-Level Trust Analysis
Authors: Zhang Li , Zhang Bin , Liu Anqing , Xing Liudong
Published: August 2020

Trust assessment is of great significance to related issues such as privacy protection and rumor transmission in online social networks. At present, there are mainly two types of trust models: discrete type and continuous, type. Little work has been done on considering distrust and trust at the same time, especially on the propagation mechanism of distrust. To this end, this paper proposes a multilevel trust model and a corresponding trust evaluation method based on a reliability model called multivalued decision diagrams (MDDs). The proposed trust model combines characteristics of both discrete and continuous trust and considers the dynamic changing mechanism of the multilevel trust. The propagation of distrust and conflicts of opinions are also handled. Experimental results show that the proposed method outperforms other existing methods.
Modified Recurrence Plot for Robust Condition Monitoring of Electrode Tips in a Resistance Spot Welding System
Authors: Jung Wonho , Oh Hyunseok , Yun Dong Ho , Kim Young Gon , Youn Jong Pil , Park Jae Hong
Published: August 2020

Degraded electrodes in a resistance spot welding system should be replaced to ensure that weld quality is maintained. Welding electrodes are subjected to different environmental and operational loading conditions during use. When they are replaced with a fixed interval, replacement may occur too early (raising maintenance costs) or too late (leading to quality issues). This motivates condition monitoring strategies for resistance spot welding electrode tips. Thus, this paper proposes a modified recurrence plot (RP) for robust condition monitoring of welding electrode tips in resistance spot welding systems. The overall procedure for the proposed condition monitoring approach consists of three steps: (1) transformation of a one-dimensional signal to a two-dimensional image, (2) unsupervised feature extraction with LeNet architecture-based convolutional neural networks, and (3) health indicator calculation. RP methods convert dynamic resistance waveforms to RPs. The original RP method provides an image with binary-colored pixels (i.e., black or white) that makes this method insensitive to the change of the waveform signal. The proposed RP method is devised to be sensitive to the change of the waveform signal, while enhancing robustness to external noise. The performance of the proposed RP method is evaluated by examining simulated aperiodic waveform signals with and without external noise. A case study is presented to examine the proposed method’s ability to monitor the condition of resistance spot welding electrodes. The results show that the proposed method outperforms handcrafted, feature-based condition monitoring methods. This study can be used to accurately determine the lifetime of welding electrodes in real time during the spot welding process.
The Other Side of Hospitality: Migratory Aesthetics in Yael Bartana’s True Finn
Authors: Anzi Achia
Published: August 2020

My paper examines Mieke Bal’s concept of migratory aesthetics through the prism of hospitality. Critical of academic and institutional tendencies that either deny particularism or pin agents and artefacts to their alleged context, Bal develops her concept as a way of accommodating contemporary mobility without undermining cultural specificity. While arguing that “there is no such thing as site-unspecific art”, Bal is also critical of new historicism’s and traditional art history’s overemphasis on “provenance”, and underscores the political ramifications of this approach. Her critique can be read through the framework of hospitality. The notion of “provenance” frames the guest as the other and limits her ability to participate in the host’s culture. Hospitality, however, as Jacques Derrida maintains, is an ambivalent concept. While extending a friendly welcome, it also preserves hierarchy between the host and the guest. In my paper, I examine this other side of hospitality in Yael Bartana’s film True Finn (2014) and in Lost in Space (2005) of Mieke Bal and Shahram Entekhabi. I explore how these films organise the host/guest relation and how they deal with the political entanglement of hospitality.
Distribution of Viable Bacteria in the Dust-Generating Natural Source Area of the Gobi Region, Mongolia
Authors: Hagiwara Katsuro , Matsumoto Tamaki , Tsedendamba Purevsuren , Baba Kenji , Hoshino Buho
Published: August 2020

The Gobi Desert is a major source of dust events, whose frequency of occurrence and damage caused have recently significantly increased. In the present study, we investigated the types of live bacteria present in the surface soil of the Gobi Desert in Mongolia, and determined their genetic identification as well as their geographical distribution. During the survey, four different topographies (dry lake bed, wadi, well, and desert steppe) were selected, and land characteristics were monitored for moisture and temperature. The surface soil was aerobically cultured to isolate bacterial colonies, and their 16s rDNA regions were sequenced. The sequence data were identified through NCBI-BLAST analysis and generated phylogenetic trees. The results revealed two phyla and seven families of isolates from the sample points. Each isolate was characterized by their corresponding sample site. The characteristics of land use and soil surface bacteria were compared. Most of the bacteria originated from the soil, however, animal-derived bacteria were also confirmed in areas used by animals. Our findings confirmed the existence of live bacteria in the dust-generating area, suggesting that their presence could affect animal and human health. Therefore, it is necessary to further investigate dust microbes based on the One Health concept.
Rainfall Symmetry Related to Moisture, Storm Intensity, and Vertical Wind Shear for Tropical Cyclones Landfalling over the U.S. Gulf Coastline
Authors: Kim Sanghoon , Matyas Corene J. , Yan Guoqian
Published: August 2020

There continues to be a need to relate rainfall produced by tropical cyclones (TCs) to moisture in the near-storm environment. This research measured the distribution of volumetric rainfall around 43 TCs at the time of landfall over the U.S. Gulf Coast. The spatial patterns of rainfall were related to atmospheric moisture, storm intensity, vertical wind shear, and storm motion. We employed a geographic information system (GIS) to perform the spatial analysis of satellite-derived rain rates and total precipitable water (TPW), which was measured on the day before landfall. Mann–Whitney U tests revealed statistically significant differences in conditions when TCs were grouped by location. TCs moving over Texas entrained dry air from the continent to produce less rainfall to the left of their moving direction. As moisture was plentiful, rainfall symmetry during landfall over the central Gulf Coast was mainly determined by the vector of vertical wind shear and storm intensity. For landfalls over the Florida peninsula, interaction with a cooler and drier air mass left of center created an uplift boundary that corresponded with more rainfall on the TC’s left side when the moisture boundary represented by the 40 mm contour of TPW existed 275–350 km from the storm center.
Solvent-Free Mechanochemical Approach towards Thiospinel MgCr2S4 as a Potential Electrode for Post-Lithium Ion Batteries
Authors: Caggiu Laura , Enzo Stefano , Stievano Lorenzo , Berthelot Romain , Gerbaldi Claudio , Falco Marisa , Garroni Sebastiano , Mulas Gabriele
Published: August 2020

Several new compounds, with desirable properties of ion mobility and working voltage, have been recently proposed using a density functional theory (DFT) computational approach as potential electrode materials for beyond-lithium battery systems. After evaluation of the ‘energy above hull’, thiospinel MgCr2S4 has been suggested as interesting multivalent battery cathode candidate, even though the synthesis of its exact stoichiometry poses serious challenges. In this work, MgCr2S4 is prepared using an innovative mechanochemical route starting from magnesium or magnesium hydride, chromium, and sulfur powders. The progress of such mechanically induced reaction as a function of processing time is carefully monitored by XRD with Rietveld refinement, evidencing the occurrence of a mechanically induced self-propagating reaction (MSR). The effect of parameters associated with the milling apparatus (impact energy) on the products composition are also investigated. To our knowledge, this work represents the first report of the scalable and simple mechanical alloying synthesis of thiospinel MgCr2S4 (space group Fd-3 m, a = 10.09 Å) and opens up interesting possibilities for the exploitation of such material in next-generation post-lithium batteries.
Immune Dysfunction and Multiple Treatment Modalities for the SARS-CoV-2 Pandemic: Races of Uncontrolled Running Sweat?
Authors: Kothari Ashish , Singh Vanya , Nath Uttam Kumar , Kumar Sandeep , Rai Vineeta , Kaushal Karanvir , Omar Balram Ji , Pandey Atul , Jain Neeraj
Published: August 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic threat with more than 11.8 million confirmed cases and more than 0.5 million deaths as of 3 July 2020. Given the lack of definitive pharmaceutical interventions against SARS-CoV-2, multiple therapeutic strategies and personal protective applications are being used to reduce the risk of high mortality and community spread of this infection. Currently, more than a hundred vaccines and/or alternative therapeutic regimens are in clinical trials, and some of them have shown promising results in improving the immune cell environment and controlling the infection. In this review, we discussed high-performance multi-directory strategies describing the uncontrolled deregulation of the host immune landscape associated with coronavirus disease (COVID-19) and treatment strategies using an anti-neoplastic regimen. We also followed selected current treatment plans and the most important on-going clinical trials and their respective outcomes for blocking SARS-CoV-2 pathogenesis through regenerative medicine, such as stem cell therapy, chimeric antigen receptors, natural killer (NK) cells, extracellular vesicular-based therapy, and others including immunomodulatory regimens, anti-neoplastic therapy, and current clinical vaccine therapy.
PMEPA1 Gene Isoforms: A Potential Biomarker and Therapeutic Target in Prostate Cancer
Authors: Sharad Shashwat , Dobi Albert , Srivastava Shiv , Srinivasan Alagarsamy , Li Hua
Published: August 2020

The identification of prostate transmembrane protein androgen induced 1 (PMEPA1), an androgen responsive gene, came initially from the studies of androgen regulatory gene networks in prostate cancer. It was soon followed by the documentation of the expression and functional analysis of transmembrane prostate androgen-induced protein (TMEPAI)/PMEPA1 in other solid tumors including renal, colon, breast, lung, and ovarian cancers. Further elucidation of PMEPA1 gene expression and sequence analysis revealed the presence of five isoforms with distinct extracellular domains (isoforms a, b, c, d, and e). Notably, the predicted amino acid sequences of PMEPA1 isoforms show differences at the N-termini, a conserved membrane spanning and cytoplasmic domains. PMEPA1 serves as an essential regulator of multiple signaling pathways including androgen and TGF-β signaling in solid tumors. Structure-function studies indicate that specific motifs present in the cytoplasmic domain (PY, SIM, SH3, and WW binding domains) are utilized to mediate isoform-specific functions through interactions with other proteins. The understanding of the “division of labor” paradigm exhibited by PMEPA1 isoforms further expands our knowledge of gene’s multiple functions in tumorigenesis. In this review, we aim to summarize the most recent advances in understanding of PMEPA1 isoform-specific functions and their associations with prostate cancer progression, highlighting the potentials as biomarker and therapeutic target in prostate cancer.
Characterization of In Vivo Function(s) of Members of the Plant Mitochondrial Carrier Family
Authors: Nunes-Nesi Adriano , Cavalcanti João , Fernie Alisdair
Published: August 2020

Although structurally related, mitochondrial carrier family (MCF) proteins catalyze the specific transport of a range of diverse substrates including nucleotides, amino acids, dicarboxylates, tricarboxylates, cofactors, vitamins, phosphate and H+. Despite their name, they do not, however, always localize to the mitochondria, with plasma membrane, peroxisomal, chloroplast and thylakoid and endoplasmic reticulum localizations also being reported. The existence of plastid-specific MCF proteins is suggestive that the evolution of these proteins occurred after the separation of the green lineage. That said, plant-specific MCF proteins are not all plastid-localized, with members also situated at the endoplasmic reticulum and plasma membrane. While by no means yet comprehensive, the in vivo function of a wide range of these transporters is carried out here, and we discuss the employment of genetic variants of the MCF as a means to provide insight into their in vivo function complementary to that obtained from studies following their reconstitution into liposomes.
Biosensors and Sensing Systems for Rapid Analysis of Phenolic Compounds from Plants: A Comprehensive Review
Authors: Forzato Cristina , Vida Veronica , Berti Federico
Published: August 2020

Phenolic compounds are secondary metabolites frequently found in plants that exhibit many different effects on human health. Because of the relevant bioactivity, their identification and quantification in agro-food matrices as well as in biological samples are a fundamental issue in the field of quality control of food and food supplements, and clinical analysis. In this review, a critical selection of sensors and biosensors for rapid and selective detection of phenolic compounds is discussed. Sensors based on electrochemistry, photoelectrochemistry, fluorescence, and colorimetry are discussed including devices with or without specific recognition elements, such as biomolecules, enzymes and molecularly imprinted materials. Systems that have been tested on real matrices are prevalently considered but also techniques that show potential development in the field.
Biosensing Cytokine IL-6: A Comparative Analysis of Natural and Synthetic Receptors
Authors: Alfinito Eleonora , Beccaria Matteo , Ciccarese Mariangela
Published: August 2020

Cytokines are a family of proteins which play a major role in the regulation of the immune system and the development of several diseases, from rheumatoid arthritis to cancer and, more recently, COVID-19. Therefore, many efforts are currently being developed to improve therapy and diagnosis, as well as to produce inhibitory drugs and biosensors for a rapid, minimally invasive, and effective detection. In this regard, even more efficient cytokine receptors are under investigation. In this paper we analyze a set of IL-6 cytokine receptors, investigating their topological features by means of a theoretical approach. Our results suggest a topological indicator that may help in the identification of those receptors having the highest complementarity with the protein, a feature expected to ensure a stable binding. Furthermore, we propose and discuss the use of these receptors in an idealized experimental setup.
Age-Dependency of Neurite Outgrowth in Postnatal Mouse Cochlear Spiral Ganglion Explants
Authors: Frick Claudia , Fink Stefan , Schmidbauer Dominik , Rousset Francis , Eickhoff Holger , Tropitzsch Anke , Kramer Benedikt , Senn Pascal , Glueckert Rudolf , Rask-Andersen Helge , Wiesmüller Karl-Heinz , Löwenheim Hubert , Müller Marcus
Published: August 2020

Background: The spatial gap between cochlear implants (CIs) and the auditory nerve limits frequency selectivity as large populations of spiral ganglion neurons (SGNs) are electrically stimulated synchronously. To improve CI performance, a possible strategy is to promote neurite outgrowth toward the CI, thereby allowing a discrete stimulation of small SGN subpopulations. Brain-derived neurotrophic factor (BDNF) is effective to stimulate neurite outgrowth from SGNs. Method: TrkB (tropomyosin receptor kinase B) agonists, BDNF, and five known small-molecule BDNF mimetics were tested for their efficacy in stimulating neurite outgrowth in postnatal SGN explants. To modulate Trk receptor-mediated effects, TrkB and TrkC ligands were scavenged by an excess of recombinant receptor proteins. The pan-Trk inhibitor K252a was used to block Trk receptor actions. Results: THF (7,8,3′-trihydroxyflavone) partly reproduced the BDNF effect in postnatal day 7 (P7) mouse cochlear spiral ganglion explants (SGEs), but failed to show effectiveness in P4 SGEs. During the same postnatal period, spontaneous and BDNF-stimulated neurite outgrowth increased. The increased neurite outgrowth in P7 SGEs was not caused by the TrkB/TrkC ligands, BDNF and neurotrophin-3 (NT-3). Conclusions: The age-dependency of induction of neurite outgrowth in SGEs was very likely dependent on presently unidentified factors and/or molecular mechanisms which may also be decisive for the age-dependent efficacy of the small-molecule TrkB receptor agonist THF.
Proximal Upper Limb Sensorimotor Integration in Response to Novel Motor Skill Acquisition
Authors: O’Brien Sinead , Andrew Danielle , Zabihhosseinian Mahboobeh , Yielder Paul , Murphy Bernadette
Published: August 2020

Previous studies have shown significant changes in cortical and subcortical evoked potential activity levels in response to motor training with the distal upper-limb muscles. However, no studies to date have assessed the neurological processing changes in somatosensory evoked potentials (SEPs) associated with motor training whole-arm movements utilizing proximal upper-limb muscles. The proximal upper-limb muscles are a common source of work-related injuries, due to repetitive glenohumeral movements. Measuring neurophysiological changes following performance of a proximal motor task provide insight into potential neurophysiological changes associated with occupational postures and movements involving proximal upper limb muscles. This study sought to assess the impact of a novel motor skill acquisition task on neural processing of the proximal upper-limb muscle groups, through the measurement of short-latency median nerve SEPs. One group of 12 participants completed a novel motor training task, consisting of tracing a sinusoidal waveform varying in amplitude and frequency. Baseline SEP measurements were recorded from each participant, followed by a mental recitation control task. Pre-test SEP measurements were then recorded, followed by the motor training task, and post-test SEP recordings. The participants completed the tracing with their right thumb, using glenohumeral rotation only to move their hand. Significant improvements in task accuracy were demonstrated, indicating that motor acquisition had occurred. Significant changes were also seen in the N11, N13, N20, N24, P25, and the N30 SEP peaks were seen following the motor training task. Conclusion: Early SEPs appear to be a sensitive measure of changes in sensorimotor integration in response to novel motor skill acquisition within the proximal upper-limb muscles.
Dynamic Advances in Emotion Processing: Differential Attention towards the Critical Features of Dynamic Emotional Expressions in 7-Month-Old Infants
Authors: Segal Shira C. , Moulson Margaret C.
Published: August 2020

Infants’ visual processing of emotion undergoes significant development across the first year of life, yet our knowledge regarding the mechanisms underlying these advances is limited. Additionally, infant emotion processing is commonly examined using static faces, which do not accurately depict real-world emotional displays. The goal of this study was to characterize 7-month-olds’ visual scanning strategies when passively viewing dynamic emotional expressions to examine whether infants modify their scanning patterns depending on the emotion. Eye-tracking measures revealed differential attention towards the critical features (eyes, mouth) of expressions. The eyes captured the greatest attention for angry and neutral faces, and the mouth captured the greatest attention for happy faces. A time-course analysis further elucidated at what point during the trial differential scanning patterns emerged. The current results suggest that 7-month-olds are sensitive to the critical features of emotional expressions and scan them differently depending on the emotion. The scanning patterns presented in this study may serve as a link to understanding how infants begin to differentiate between expressions in the context of emotion recognition.
Skipping Exon-v6 from CD44v6-Containing Isoforms Influences Chemotherapy Response and Self-Renewal Capacity of Gastric Cancer Cells
Authors: Lobo Silvana , Pereira Carla , Oliveira Carla , Almeida Gabriela M.
Published: August 2020

De novo expressed CD44 isoforms containing exon-v6 are frequently associated with gastric cancer (GC) aggressiveness, and may predict chemotherapy response in vitro. Whether exon-v6 itself is responsible for conferring these properties to CD44v6-containing isoforms remains to be elucidated. CRISPR/Cas9 and Phosphorodiamidate Morpholino oligomers (PMOs) were used to induce specific exon-v6 skipping, maintaining the CD44 reading frame, in two GC cell lines endogenously expressing CD44v6. Cisplatin and 5-fluorouracil treatment response, and self-renewal ability was compared between CRISPR/Cas9-edited, CD44v6 knockdown and mock cells. We obtained homozygous genome-edited cell lines with exon-v6 deletion. Edited cells transcribed CD44v isoforms presenting in frame v5–v7 splicing, mimicking exon-v6 skipping. Results showed that removing specifically exon-v6 sensitizes cells to cisplatin and impairs cells’ self-renewal ability, similarly to CD44v6 knockdown. In parallel, we also tested a clinically feasible approach for transient exon-v6 skipping with a PMO-based strategy. We demonstrate that exon-v6 specific removal from CD44v isoforms increases cell sensitivity to cisplatin and impairs GC cells self-renewal. We trust that a PMO approach designed towards CD44v6 overexpressing GC cells may be a suitable approach to sensitize tumor cells for conventional therapy.
Thrombocytosis as a Biomarker in Type II, Non-Endometrioid Endometrial Cancer
Authors: Bussies Parker , Eta Ayi , Pinto Andre , George Sophia , Schlumbrecht Matthew
Published: August 2020

Thrombocytosis (platelets ≥ 400K) is a common hematologic finding in gynecologic malignancies and associated with worse outcomes. Limited data exist on the prognostic capability of thrombocytosis in women with high-grade endometrial cancer (EC). Our objective was to describe the associations between elevated platelets at diagnosis, clinicopathologic features, and survival outcomes among women with high-grade, non-endometrioid EC. A review of the institutional cancer registry was performed to identify these women treated between 2005 and 2017. Sociodemographic, clinical, and outcomes data were collected. Analyses were performed using chi-square tests, Cox proportional hazards models, and the Kaplan–Meier method. A total of 271 women were included in the analysis. A total of 19.3% of women had thrombocytosis at diagnosis. Thrombocytosis was associated with reduced median overall survival (OS) compared with those not displaying thrombocytosis (29.4 months vs. 60 months, p < 0.01). This finding was most pronounced in uterine serous carcinoma (16.4 months with thrombocytosis vs. 34.4 months without, p < 0.01). While non-White women had shorter median OS for the whole cohort in the setting of thrombocytosis (29.4 months vs. 39.6 months, p < 0.01), among those with uterine serous carcinoma (USC), this finding was reversed, with decreased median OS in White women (22.1 vs. 16.4 months, p = 0.01). Thrombocytosis is concluded to have negative associations with OS and patient race.
An Integrative Omics Approach Reveals Involvement of BRCA1 in Hepatic Metastatic Progression of Colorectal Cancer
Authors: Gerovska Daniela , Larrinaga Gorka , Solano-Iturri Jon Danel , Márquez Joana , García Gallastegi Patricia , Khatib Abdel-Majid , Poschmann Gereon , Stühler Kai , Armesto María , Lawrie Charles H. , Badiola Iker , Araúzo-Bravo Marcos J.
Published: August 2020

(1) Background & Aims: The roles of different cells in the tumor microenvironment (TME) are critical to the metastatic process. The phenotypic transformation of the liver cells is one of the most important stages of the hepatic metastasis progression of colorectal cancer (CRC). Our aim was to identify the major molecules (i.e., genes, miRNAs and proteins) involved in this process. (2) Methods: We isolated and performed whole-genome analysis of gene, miRNA, and protein expression in three types of liver cells (Ito cells, Kupffer cells, and liver sinusoidal endothelial cells) from the TME of a murine model of CRC liver metastasis. We selected the statistically significant differentially expressed molecules using the Student’s t-test with Benjamini-Hochberg correction and performed functional statistically-significant enrichment analysis of differentially expressed molecules with hypergeometric distribution using the curated collection of molecular signatures, MSigDB. To build a gene-miRNA-protein network centered in Brca1, we developed a software package (miRDiana) that collects miRNA targets from the union of the TargetScan, MicroCosm, mirTarBase, and miRWalk databases. This was used to search for miRNAs targeting Brca1. We validated the most relevant miRNAs with real-time quantitative PCR. To investigate BRCA1 protein expression, we built tissue microarrays (TMAs) from hepatic metastases of 34 CRC patients. (3) Results: Using integrated omics analyses, we observed that the Brca1 gene is among the twenty transcripts simultaneously up-regulated in all three types of TME liver cells during metastasis. Further analysis revealed that Brca1 is the last BRCA1-associated genome surveillance complex (BASC) gene activated in the TME. We confirmed this finding in human reanalyzing transcriptomics datasets from 184 patients from non-tumor colorectal tissue, primary colorectal tumor and colorectal liver metastasis of the GEO database. We found that the most probable sequence of cell activation during metastasis is Endothelial→Ito→Kupffer. Immunohistochemical analysis of human liver metastases showed the BRCA1 protein was co-localized in Ito, Kupffer, and endothelial cells in 81.8% of early or synchronous metastases. However, in the greater part of the metachronous liver metastases, this protein was not expressed in any of these TME cells. (4) Conclusions: These results suggest a possible role of the co-expression of BRCA1 in Ito, Kupffer, and sinusoidal endothelial cells in the early occurrence of CRC liver metastases, and point to BRCA1 as a potential TME biomarker.
Proteotoxic Stress and Cell Death in Cancer Cells
Authors: Brancolini Claudio , Iuliano Luca
Published: August 2020

To maintain proteostasis, cells must integrate information and activities that supervise protein synthesis, protein folding, conformational stability, and also protein degradation. Extrinsic and intrinsic conditions can both impact normal proteostasis, causing the appearance of proteotoxic stress. Initially, proteotoxic stress elicits adaptive responses aimed at restoring proteostasis, allowing cells to survive the stress condition. However, if the proteostasis restoration fails, a permanent and sustained proteotoxic stress can be deleterious, and cell death ensues. Many cancer cells convive with high levels of proteotoxic stress, and this condition could be exploited from a therapeutic perspective. Understanding the cell death pathways engaged by proteotoxic stress is instrumental to better hijack the proliferative fate of cancer cells.
Genetic Counseling for Hereditary Gastric and Pancreatic Cancer in High-Risk Gastrointestinal Cancer Clinics: An Effective Strategy
Authors: Llach Joan , Moreno Lorena , Sánchez Ariadna , Herrera-Pariente Cristina , Ocaña Teresa , Cuatrecasas Miriam , Rivero-Sánchez Liseth , Moreira Rebeca , Díaz Mireia , Jung Gerhard , Pellisé Maria , Castells Antoni , Balaguer Francesc , Carballal Sabela , Moreira Leticia
Published: August 2020

The identification of high-risk groups of gastric (GC) and pancreatic adenocarcinoma (PC) due to a hereditary basis could imply a benefit in the affected families by establishing personalized preventive strategies. We aimed at assessing the diagnostic yield of GC/PC hereditary syndromes in individuals evaluated based on specific clinical criteria. In total, 77 unrelated individuals (45 from GC group/32 from PC group) were recruited: 51 (66.2%) cancer diagnosis ≤60 years, 3 (4%) with personal history of GC/PC and other cancer and 23 (29.8%) due to family history. Immunohistochemical analysis of DNA mismatch repair proteins was performed in 38 (49.3%) available tumors, being pathological in one (2%) GC. A genetic analysis was performed if clinical criteria of hereditary syndrome were fulfilled, identifying a mutation in 10/22 (45.5%) families [7/16 (43.7%) with GC and 3/6 (50%) with PC] and 19 (24.7%) fulfilled criteria of familial cancer. Diagnosis of cancer <40 years and personal history of other cancers were independent risk factors of a hereditary syndrome [OR:11.3 (95%IC 1.9–67); p = 0.007 and OR:17.4 (95% IC 2.5–119.9); p = 0.004; respectively]. The selection of patients based on clinical criteria leads to high diagnostic yield, detecting a causative germline mutation in almost half of the cases; therefore, both meticulous genetic counseling and use of multi-gen panels is crucial.
HPV-Induced Oropharyngeal Cancer and the Role of the E7 Oncoprotein Detection via Brush Test
Authors: Borena Wegene , Schartinger Volker H. , Dudas Jozsef , Ingruber Julia , Greier Maria C. , Steinbichler Teresa B. , Laimer Johannes , Stoiber Heribert , Riechelmann Herbert , Kofler Barbara
Published: August 2020

Background: High risk human papillomavirus (hr-HPV)-associated oropharyngeal cancers (OPCs) are characterized by significantly better therapy responses. In order to implement a de-escalated treatment strategy for this tumor entity, it is highly crucial to accurately distinguish HPV-associated OPCs from non-HPV-associated ones. Methods: In this prospective study, 56 patients with histologically confirmed OPC were evaluated. A commercially available sandwich ELISA test system was used for the detection of hr-HPV E7 oncoprotein targeting the genotypes 16, 18 and 45. Results were presented as optical density. Positivity for HPV DNA and p16 immunohistochemistry (IHC) was taken as the reference method. Results: E7 positivity was significantly associated with the reference method (p = 0.048). The sensitivity, specificity, positive predictive value and negative predictive value for the E7 oncoptotein was 60.9% (95% CI 38.5 to 80.3%), 66.7% (95% CI 46% to 83.5%), 64.2% (95% CI 49.4 to 77.4%) and 63.01% (95% CI 48.9–75.2%), respectively, for the cutoff provided by the manufacturer. Conclusions: We found a significant association between E7 oncoprotein detection and the currently used combination. We believe that the use of the ELISA based E7 antigen test could be a valuable addition in cases of ambiguous findings and may be used in combination with other techniques to distinguish between HPV-driven and non-HPV-driven OPCs. However, the low sensitivity of the assay coupled with the small sample size in our study may represent a limitation. We recommend that future larger studies elucidate the diagnostic value of the E7 brush test.
Loss of Two-Pore Channel 2 (TPC2) Expression Increases the Metastatic Traits of Melanoma Cells by a Mechanism Involving the Hippo Signalling Pathway and Store-Operated Calcium Entry
Authors: D’Amore Antonella , Hanbashi Ali Ahmed , Di Agostino Silvia , Palombi Fioretta , Sacconi Andrea , Voruganti Aniruddha , Taggi Marilena , Canipari Rita , Blandino Giovanni , Parrington John , Filippini Antonio
Published: August 2020

Melanoma is one of the most aggressive and treatment-resistant human cancers. The two-pore channel 2 (TPC2) is located on late endosomes, lysosomes and melanosomes. Here, we characterized how TPC2 knockout (KO) affected human melanoma cells derived from a metastatic site. TPC2 KO increased these cells’ ability to invade the extracelullar matrix and was associated with the increased expression of mesenchymal markers ZEB-1, Vimentin and N-Cadherin, and the enhanced secretion of MMP9. TPC2 KO also activated genes regulated by YAP/TAZ, which are key regulators of tumourigenesis and metastasis. Expression levels of ORAI1, a component of store-operated Ca2+ entry (SOCE), and PKC-βII, part of the HIPPO pathway that negatively regulates YAP/TAZ activity, were reduced by TPC2 KO and RNA interference knockdown. We propose a cellular mechanism mediated by ORAI1/Ca2+/PKC-βII to explain these findings. Highlighting their potential clinical significance, patients with metastatic tumours showed a reduction in TPC2 expression. Our research indicates a novel role of TPC2 in melanoma. While TPC2 loss may not activate YAP/TAZ target genes in primary melanoma, in metastatic melanoma it could activate such genes and increase cancer aggressiveness. These findings aid the understanding of tumourigenesis mechanisms and could provide new diagnostic and treatment strategies for skin cancer and other metastatic cancers.
Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies
Authors: Gupta Gagan K. , Collier Amber L. , Lee Dasom , Hoefer Richard A. , Zheleva Vasilena , Siewertsz van Reesema Lauren L. , Tang-Tan Angela M. , Guye Mary L. , Chang David Z. , Winston Janet S. , Samli Billur , Jansen Rick J. , Petricoin Emanuel F. , Goetz Matthew P. , Bear Harry D. , Tang Amy H.
Published: August 2020

Triple-negative breast cancer (TNBC), characterized by the absence or low expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), is the most aggressive subtype of breast cancer. TNBC accounts for about 15% of breast cancer cases in the U.S., and is known for high relapse rates and poor overall survival (OS). Chemo-resistant TNBC is a genetically diverse, highly heterogeneous, and rapidly evolving disease that challenges our ability to individualize treatment for incomplete responders and relapsed patients. Currently, the frontline standard chemotherapy, composed of anthracyclines, alkylating agents, and taxanes, is commonly used to treat high-risk and locally advanced TNBC. Several FDA-approved drugs that target programmed cell death protein-1 (Keytruda) and programmed death ligand-1 (Tecentriq), poly ADP-ribose polymerase (PARP), and/or antibody drug conjugates (Trodelvy) have shown promise in improving clinical outcomes for a subset of TNBC. These inhibitors that target key genetic mutations and specific molecular signaling pathways that drive malignant tumor growth have been used as single agents and/or in combination with standard chemotherapy regimens. Here, we review the current TNBC treatment options, unmet clinical needs, and actionable drug targets, including epidermal growth factor (EGFR), vascular endothelial growth factor (VEGF), androgen receptor (AR), estrogen receptor beta (ERβ), phosphoinositide-3 kinase (PI3K), mammalian target of rapamycin (mTOR), and protein kinase B (PKB or AKT) activation in TNBC. Supported by strong evidence in developmental, evolutionary, and cancer biology, we propose that the K-RAS/SIAH pathway activation is a major tumor driver, and SIAH is a new drug target, a therapy-responsive prognostic biomarker, and a major tumor vulnerability in TNBC. Since persistent K-RAS/SIAH/EGFR pathway activation endows TNBC tumor cells with chemo-resistance, aggressive dissemination, and early relapse, we hope to design an anti-SIAH-centered anti-K-RAS/EGFR targeted therapy as a novel therapeutic strategy to control and eradicate incurable TNBC in the future.
Do Biliary Complications after Proton Beam Therapy for Perihilar Hepatocellular Carcinoma Matter?
Authors: Yoo Gyu Sang , Yu Jeong Il , Park Hee Chul , Hyun Dongho , Jeong Woo Kyoung , Lim Ho Yeong , Choi Moon Seok , Ha Sang Yun
Published: August 2020

We aimed to evaluate the biliary complications and efficacy of proton beam therapy (PBT) for hepatocellular carcinoma (HCC). We retrospectively analyzed 167 patients who received PBT with ≥ 75 GyRBE of biological effective dose with ?/β = 10 for primary HCC. The perihilar region was defined as a 1-cm area extending from the right, left, and common hepatic ducts, including the gallbladder and cystic duct. PBT-related biliary complications were defined as follows: significant elevation in bilirubin level to > 3.0 mg/dL; elevation to more than twice of the baseline level after the completion of PBT; or newly developed radiological biliary abnormalities, which were not caused by HCC progression, comorbidities, or other treatments. Eighty (47.9%) had perihilar HCC. PBT-related events occurred in seven (4.2%), three of whom had perihilar HCC. Radiologic biliary abnormalities developed in 12 patients (7.2%); however, no events were PBT-related. All patients who experienced PBT-related biliary complications had underlying liver cirrhosis. The albumin-bilirubin grade was identified as an independent factor associated with PBT-related biliary complications. PBT at the current dose showed a low rate of PBT-related biliary complications even for patients with perihilar HCC. PBT for HCC patients with risk factors requires attention to reduce PBT-related biliary complications.
Combined Targeting of Estrogen Receptor Alpha and Exportin 1 in Metastatic Breast Cancers
Authors: Cotul Eylem Kulkoyluoglu , Zuo Qianying , Santaliz-Casiano Ashlie , Imir Ozan Berk , Mogol Ayca Nazli , Tunc Elif , Duong Kevin , Lee Jenna Kathryn , Ramesh Rithva , Odukoya Elijah , Kesavadas Mrinali P. , Ziogaite Monika , Smith Brandi Patrice , Mao Chengjian , Shapiro David J. , Park Ben Ho , Katzenellenbogen Benita S. , Daly Drew , Aranda Evelyn , O’Neill John D. , Walker Christopher , Landesman Yosef , Madak-Erdogan Zeynep
Published: August 2020

The majority of breast cancer specific deaths in women with estrogen receptor positive (ER+) tumors occur due to metastases that are resistant to therapy. There is a critical need for novel therapeutic approaches to achieve tumor regression and/or maintain therapy responsiveness in metastatic ER+ tumors. The objective of this study was to elucidate the role of metabolic pathways that undermine therapy efficacy in ER+ breast cancers. Our previous studies identified Exportin 1 (XPO1), a nuclear export protein, as an important player in endocrine resistance progression and showed that combining selinexor (SEL), an FDA-approved XPO1 antagonist, synergized with endocrine agents and provided sustained tumor regression. In the current study, using a combination of transcriptomics, metabolomics and metabolic flux experiments, we identified certain mitochondrial pathways to be upregulated during endocrine resistance. When endocrine resistant cells were treated with single agents in media conditions that mimic a nutrient deprived tumor microenvironment, their glutamine dependence for continuation of mitochondrial respiration increased. The effect of glutamine was dependent on conversion of the glutamine to glutamate, and generation of NAD+. PGC1α, a key regulator of metabolism, was the main driver of the rewired metabolic phenotype. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and our findings reveal a critical role that ERα-XPO1 crosstalk plays in reducing cancer recurrences. Combining SEL with current therapies used in clinical management of ER+ metastatic breast cancer shows promise for treating and keeping these cancers responsive to therapies in already metastasized patients.
Impact of ERCC1, XPF and DNA Polymerase β Expression on Platinum Response in Patient-Derived Ovarian Cancer Xenografts
Authors: Guffanti Federica , Alvisi Maria Francesca , Caiola Elisa , Ricci Francesca , De Maglie Marcella , Soldati Sabina , Ganzinelli Monica , Decio Alessandra , Giavazzi Raffaella , Rulli Eliana , Damia Giovanna
Published: August 2020

Platinum resistance is an unmet medical need in ovarian carcinoma. Molecular biomarkers to predict the response to platinum-based therapy could allow patient stratification and alternative therapeutic strategies early in clinical management. Sensitivity and resistance to platinum therapy are partially determined by the tumor’s intrinsic DNA repair activities, including nucleotide excision repair (NER) and base excision repair (BER). We investigated the role of the NER proteins—ERCC1, XPF, ERCC1/XPF complex—and of the BER protein DNA polymerase β, as possible biomarkers of cisplatin (DDP) response in a platform of recently established patient-derived ovarian carcinoma xenografts (OC-PDXs). ERCC1 and DNA polymerase β protein expressions were measured by immunohistochemistry, the ERCC1/XPF foci number was detected by proximity ligation assay (PLA) and their mRNA levels by real-time PCR. We then correlated the proteins, gene expression and ERCC1/XPF complexes with OC-PDXs’ response to platinum. To the best of our knowledge, this is the first investigation of the role of the ERCC1/XPF complex, detected by PLA, in relation to the response to DDP in ovarian carcinoma. None of the proteins in the BER and NER pathways studied predicted platinum activity in this panel of OC-PDXs, nor did the ERCC1/XPF foci number. These results were partially explained by the experimental evidence that the ERCC1/XPF complex increases after DDP treatment and this possibly better associates with the cancer cells’ abilities to activate the NER pathway to repair platinum-induced damage than its basal level. Our findings highlight the need for DNA functional assays to predict the response to platinum-based therapy.
Proteoglycans in the Pathogenesis of Hormone-Dependent Cancers: Mediators and Effectors
Authors: Tzanakakis George , Giatagana Eirini-Maria , Kuskov Andrey , Berdiaki Aikaterini , Tsatsakis Aristidis , Neagu Monica , Nikitovic Dragana
Published: August 2020

Hormone-dependent cancers exhibit high morbidity and mortality. In spite of advances in therapy, the treatment of hormone-dependent cancers remains an unmet health need. The tumor microenvironment (TME) exhibits unique characteristics that differ among various tumor types. It is composed of cancerous, non-cancerous, stromal, and immune cells that are surrounded and supported by components of the extracellular matrix (ECM). Therefore, the interactions among cancer cells, stromal cells, and components of the ECM determine cancer progression and response to therapy. Proteoglycans (PGs), hybrid molecules consisting of a protein core to which sulfated glycosaminoglycan chains are bound, are significant components of the ECM that are implicated in all phases of tumorigenesis. These molecules, secreted by both the stroma and cancer cells, are crucial signaling mediators that modulate the vital cellular pathways implicated in gene expression, phenotypic versatility, and response to therapy in specific tumor types. A plethora of deregulated signaling pathways contributes to the growth, dissemination, and angiogenesis of hormone-dependent cancers. Specific inputs from the endocrine and immune systems are some of the characteristics of hormone-dependent cancer pathogenesis. Importantly, the mechanisms involved in various aspects of cancer progression are executed in the ECM niche of the TME, and the PG components crucially mediate these processes. Here, we comprehensively discuss the mechanisms through which PGs affect the multifaceted aspects of hormone-dependent cancer development and progression, including cancer metastasis, angiogenesis, immunobiology, autophagy, and response to therapy.