bluuebunny/crossref_metadata_2025 huggingface dataset:
Adoption of Sustainable Supply Chain Management for Performance Improvement in the Construction Industry: A System Dynamics Approach
Authors: Ghufran Maria , Khan Khurram Iqbal Ahmad , Thaheem Muhammad Jamaluddin , Nasir Abdur Rehman , Ullah Fahim
Published: December 2021

Sustainable supply chain management (SSCM) involves the managing of information, materials, cash flows, and collaboration among enterprises along the supply chain, integrating sustainable development goals. This research paper aims to determine challenges in SSCM adoption and to address related complexity using the system dynamics (SD) approach utilizing modeling and simulation techniques. This research identified challenges from the literature using content analysis. Causality among these identified challenges was determined using interviews and questionnaire surveys that led to the development of a causal loop diagram (CLD), which was used in the development of the SD model. Among the 19 shortlisted variables, CLD had IV reinforcing and II balancing loops. Moreover, CLD was used to build an SD model with two stocks, and a new stock named ‘project performance’ was added to envisage the cumulative impact of all stocks. The model was simulated for five years, and the results predict that the lack of top management commitment and corporate social responsibility adversely affects project performance. This implies that there is a need to improve numerous factors, in particular corporate social responsibility and top management commitment, which would lead to the adoption of SSCM, thus leading to a performance improvement for the construction industry (CI). The model was validated using boundary adequacy, structure, and parametric verification tests, which showed that the developed model is logical and approximately replicates the industry’s actual system. The research findings will help the CI practitioners to adopt sustainability principles in terms of the supply chain and will not only enhance productivity and performance but will also help in the minimization of delays, promote long-term relations, and reduce communication gaps and project complexities.
UNDERGROUND WELBECK: INTAGIBLE SPACES John Cavendish-Scott-Bentinck, 5th Duke of Portland (1800–1879)
Authors: Fernández Naranjo María Isabel , García Tomás García
Published: December 2021

The life of the 5th Duke of Portland is a story about the mental obsession to find a haven of absolute stillness, a worry-free place, and somewhere to feel safe (Pl L1/2/8/3/13: Four letters to Fanny Kemble, 1842–1845. In these letters, the 5th Duke refers to the subsoil as “shelter” and the “only safe place”, found in Manuscripts and Special Collections, Archives Nottingham University). Perhaps it is there, in the space that unfolded away from the visible world, that he found the strength to overcome his difficulties and to understand the scale of space and its intangibility; he was aware of the relationships and interaction between the human body, inhabited space, and the mind, and this information helped him in his hiding process. After his appointment as the heir to his immense estate, a series of investments on an unprecedented scale began almost immediately, which have been considered, both technically and conceptually, to be pioneers of domestic and landscape architecture during the nineteenth century. Welbeck Estate represents the construction of a double city, one that is visible and another that is concealed, but it is also a reflection of how our body and our mind interfere, dialogue, and create an architectural space that is framed in a cognitive process. Space and time were unfolded and folded into themselves in order to build this fascinating scenery, which represents the duke’s life.
Emissions and Air Quality Implications of Upstream and Midstream Oil and Gas Operations in Mexico
Authors: McDonald-Buller Elena , McGaughey Gary , Grant John , Shah Tejas , Kimura Yosuke , Yarwood Greg
Published: December 2021

Mexico approved amendments to its constitution in December 2013 that initiated transformational changes to its energy sector. This study developed a 2016 bottom-up emissions inventory for volatile organic compounds (VOCs), nitrogen oxides (NOx), sulfur dioxide (SO2), carbon monoxide (CO), and fine particulate matter (PM2.5) from upstream and midstream sector sources, including onshore and offshore well sites, gas flaring, natural gas processing facilities, and natural gas compressor stations, throughout Mexican basins. Crude oil storage tanks at onshore oil well sites and venting and fugitive sources at offshore oil production sites were the primary sources of VOC emissions. Key contributions to NOx, CO, and PM2.5 emissions were from internal combustion engines at offshore oil well sites and midstream operations. SO2 emissions were associated with onshore and offshore gas flaring and boilers and process heaters at natural gas processing facilities. Application of the inventory with the Comprehensive Air Quality Model with Extensions (CAMx) indicated that oil and gas production operations could contribute to ozone and PM2.5 concentrations in Mexican and U.S. states under favorable transport patterns. This study provides a foundation for assessing the implications of Mexico’s future energy policies on emissions and domestic and cross-border air quality and public health.
Mechanisms of 1s Double-Core-Hole Excitation and Decay in Neon
Authors: Kiselev Maksim D. , Gryzlova Elena V. , Burkov Sergei M. , Zatsarinny Oleg , Grum-Grzhimailo Alexei N.
Published: December 2021

The formation and decay of double-core-hole (DCH) states of the neon ion irradiated by an intense electromagnetic x-ray field are studied theoretically. In the present research DCH formation is the result of sequential absorption of two photons with the creation of an intermediate ion. Detailed calculations of the partial decays and probabilities of shake-ups at the atomic and ionic ionization stages are presented. The angular distribution of photoelectrons corresponding to various residual ionic states are calculated. Specifically, we predict the lack of any photoelectrons corresponding to the residual ionic state 1s12s22pnmpn′2Sf+1D in the direction of the electric field polarization. Dynamical competition between single-core-hole state decay and excitation is analyzed and pulse parameters corresponding to various dynamical regimes are found.
Comparative Analysis of the Simple WISP and Some Prominent MCDM Methods: A Python Approach
Authors: Stanujkić Dragiša , Karabašević Darjan , Popović Gabrijela , Zavadskas Edmundas Kazimieras , Saračević Muzafer , Stanimirović Predrag S. , Ulutaş Alptekin , Katsikis Vasilios N. , Meidute-Kavaliauskiene Ieva
Published: December 2021

This article presents a comparison of the results obtained using the newly proposed Simple Weighted Sum Product method and some prominent multiple criteria decision-making methods. For comparison, several analyses were performed using the Python programming language and its NumPy library. The comparison was also made on a real decision-making problem taken from the literature. The obtained results confirm the high correlation of the results obtained using the Simple Weighted Sum Product method and selected multiple criteria decision-making methods such as TOPSIS, SAW, ARAS, WASPAS, and CoCoSo, which confirms the usability of the Simple Weighted Sum Product method for solving multiple criteria decision-making problems.
Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice
Authors: Boyd Abigail , Aragon Ileana , Rich Justin , McDonough Will , Oditt Marianna , Irelan Daniel , Fiedler Edward , Abou Saleh Lina , Richter Wito
Published: December 2021

Treatment with PAN-PDE4 inhibitors has been shown to produce hypothermia in multiple species. Given the growing body of evidence that links nausea and emesis to disturbances in thermoregulation in mammals, we explored PDE4 inhibitor-induced hypothermia as a novel correlate of nausea in mice. Using knockout mice for each of the four PDE4 subtypes, we show that selective inactivation of individual PDE4 subtypes per se does not produce hypothermia, which must instead require the concurrent inactivation of multiple (at least two) PDE4 subtypes. These findings contrast with the role of PDE4s in shortening the duration of α2-adrenoceptor-dependent anesthesia, a behavioral surrogate previously used to assess the emetic potential of PDE4 inhibitors, which is exclusively affected by inactivation of PDE4D. These different outcomes are rooted in the distinct molecular mechanisms that drive these two paradigms; acting as a physiologic α2-adrenoceptor antagonist produces the effect of PDE4/PDE4D inactivation on the duration of α2-adrenoceptor-dependent anesthesia, but does not mediate the effect of PDE4 inhibitors on body temperature in mice. Taken together, our findings suggest that selective inhibition of any individual PDE4 subtype, including inhibition of PDE4D, may be free of nausea and emesis.
Mapping the Energetic Costs of Free-Swimming Gilthead Sea Bream (Sparus aurata), a Key Species in European Marine Aquaculture
Authors: Alfonso Sébastien , Zupa Walter , Spedicato Maria Teresa , Lembo Giuseppe , Carbonara Pierluigi
Published: December 2021

Measurement of metabolic rates provides a valuable proxy for the energetic costs of different living activities. However, such measurements are not easy to perform in free-swimming fish. Therefore, mapping acceleration from accelerometer tags with oxygen consumption rates (MO2) is a promising method to counter these limitations and could represent a tool for remotely estimating MO2 in aquaculture environments. In this study, we monitored the swimming performance and MO2 of 79 gilthead sea bream (Sparus aurata; weight range, 219–971 g) during a critical swimming test. Among all the fish challenged, 27 were implanted with electromyography (EMG) electrodes, and 27 were implanted with accelerometer tags to monitor the activation pattern of the red/white muscles during swimming. Additionally, we correlated the acceleration recorded by the tag with the MO2. Overall, we found no significant differences in swimming performance, metabolic traits, and swimming efficiency between the tagged and untagged fish. The acceleration recorded by the tag was successfully correlated with MO2. Additionally, through EMG analyses, we determined the activities of the red and white muscles, which are indicative of the contributions of aerobic and anaerobic metabolisms until reaching critical swimming speed. By obtaining insights into both aerobic and anaerobic metabolisms, sensor mapping with physiological data may be useful for the purposes of aquaculture health/welfare remote monitoring of the gilthead sea bream, a key species in European marine aquaculture.
H2S Donors and Their Use in Medicinal Chemistry
Authors: Magli Elisa , Perissutti Elisa , Santagada Vincenzo , Caliendo Giuseppe , Corvino Angela , Esposito Gianluca , Esposito Giovanna , Fiorino Ferdinando , Migliaccio Marco , Scognamiglio Antonia , Severino Beatrice , Sparaco Rosa , Frecentese Francesco
Published: December 2021

Hydrogen sulfide (H2S) is a ubiquitous gaseous signaling molecule that has an important role in many physiological and pathological processes in mammalian tissues, with the same importance as two others endogenous gasotransmitters such as NO (nitric oxide) and CO (carbon monoxide). Endogenous H2S is involved in a broad gamut of processes in mammalian tissues including inflammation, vascular tone, hypertension, gastric mucosal integrity, neuromodulation, and defense mechanisms against viral infections as well as SARS-CoV-2 infection. These results suggest that the modulation of H2S levels has a potential therapeutic value. Consequently, synthetic H2S-releasing agents represent not only important research tools, but also potent therapeutic agents. This review has been designed in order to summarize the currently available H2S donors; furthermore, herein we discuss their preparation, the H2S-releasing mechanisms, and their -biological applications.
Prebiotics, Probiotics, Synbiotics, Paraprobiotics and Postbiotic Compounds in IBD
Authors: Martyniak Adrian , Medyńska-Przęczek Aleksandra , Wędrychowicz Andrzej , Skoczeń Szymon , Tomasik Przemysław J.
Published: December 2021

The increasing incidence of inflammatory bowel diseases (IBD) and the increasing severity of the course of these diseases create the need for developing new methods of therapy. The gut microbiome is extensively studied as a factor influencing the development and course of IBD. The composition of intestinal microbiota can be relatively easily modified by diet (i.e., prebiotics, mainly dietary fibers) and bacterial supplementation using beneficial bacteria strains called probiotics. Additionally, the effects of the improved microbiome could be enhanced or gained by using paraprobiotics (non-viable, inactivated bacteria or their components) and/or postbiotics (products of bacterial metabolism or equal synthetic products that beneficially modulate immunological response and inflammation). This study summarizes the recent works on prebiotics, probiotics, synbiotics (products merging pre- and probiotics), paraprobiotics and postbiotics in IBD.
A Computational Approach to Investigate TDP-43 RNA-Recognition Motif 2 C-Terminal Fragments Aggregation in Amyotrophic Lateral Sclerosis
Authors: Grassmann Greta , Miotto Mattia , Di Rienzo Lorenzo , Salaris Federico , Silvestri Beatrice , Zacco Elsa , Rosa Alessandro , Tartaglia Gian Gaetano , Ruocco Giancarlo , Milanetti Edoardo
Published: December 2021

Many of the molecular mechanisms underlying the pathological aggregation of proteins observed in neurodegenerative diseases are still not fully understood. Among the aggregate-associated diseases, Amyotrophic Lateral Sclerosis (ALS) is of relevant importance. In fact, although understanding the processes that cause the disease is still an open challenge, its relationship with protein aggregation is widely known. In particular, human TDP-43, an RNA/DNA binding protein, is a major component of the pathological cytoplasmic inclusions observed in ALS patients. Indeed, the deposition of the phosphorylated full-length TDP-43 in spinal cord cells has been widely studied. Moreover, it has also been shown that the brain cortex presents an accumulation of phosphorylated C-terminal fragments (CTFs). Even if it is debated whether the aggregation of CTFs represents a primary cause of ALS, it is a hallmark of TDP-43 related neurodegeneration in the brain. Here, we investigate the CTFs aggregation process, providing a computational model of interaction based on the evaluation of shape complementarity at the molecular interfaces. To this end, extensive Molecular Dynamics (MD) simulations were conducted for different types of protein fragments, with the aim of exploring the equilibrium conformations. Adopting a newly developed approach based on Zernike polynomials, able to find complementary regions in the molecular surface, we sampled a large set of solvent-exposed portions of CTFs structures as obtained from MD simulations. Our analysis proposes and assesses a set of possible association mechanisms between the CTFs, which could drive the aggregation process of the CTFs. To further evaluate the structural details of such associations, we perform molecular docking and additional MD simulations to propose possible complexes and assess their stability, focusing on complexes whose interacting regions are both characterized by a high shape complementarity and involve β3 and β5 strands at their interfaces.
Freeform 3D Bioprinting Involving Ink Gelation by Cascade Reaction of Oxidase and Peroxidase: A Feasibility Study Using Hyaluronic Acid-Based Ink
Authors: Sakai Shinji , Harada Ryohei , Kotani Takashi
Published: December 2021

Freeform bioprinting, realized by extruding ink-containing cells into supporting materials to provide physical support during printing, has fostered significant advances toward the fabrication of cell-laden soft hydrogel constructs with desired spatial control. For further advancement of freeform bioprinting, we aimed to propose a method in which the ink embedded in supporting materials gelate through a cytocompatible and rapid cascade reaction between oxidase and peroxidase. To demonstrate the feasibility of the proposed method, we extruded ink containing choline, horseradish peroxidase (HRP), and a hyaluronic acid derivative, cross-linkable by HRP-catalyzed reaction, into a supporting material containing choline oxidase and successfully obtained three-dimensional hyaluronic acid-based hydrogel constructs with good shape fidelity to blueprints. Cytocompatibility of the bioprinting method was confirmed by the comparable growth of mouse fibroblast cells, released from the printed hydrogels through degradation on cell culture dishes, with those not exposed to the printing process, and considering more than 85% viability of the enclosed cells during 10 days of culture. Owing to the presence of derivatives of the various biocompatible polymers that are cross-linkable through HRP-mediated cross-linking, our results demonstrate that the novel 3D bioprinting method has great potential in tissue engineering applications.
Competitive Endogenous RNA Network Involving miRNA and lncRNA in Non-Hodgkin Lymphoma: Current Advances and Clinical Perspectives
Authors: Fernandes Mara , Marques Herlander , Teixeira Ana Luísa , Medeiros Rui
Published: December 2021

Non-Hodgkin lymphoma (NHL) is a heterogeneous malignancy with variable patient outcomes. There is still a lack of understanding about the different players involved in lymphomagenesis, and the identification of new diagnostic and prognostic biomarkers is urgent. MicroRNAs and long non-coding RNAs emerged as master regulators of B-cell development, and their deregulation has been associated with the initiation and progression of lymphomagenesis. They can function by acting alone or, as recently proposed, by creating competing endogenous RNA (ceRNA) networks. Most studies have focused on individual miRNAs/lncRNAs function in lymphoma, and there is still limited data regarding their interactions in lymphoma progression. The study of miRNAs’ and lncRNAs’ deregulation in NHL, either alone or as ceRNAs networks, offers new insights into the molecular mechanisms underlying lymphoma pathogenesis and opens a window of opportunity to identify potential diagnostic and prognostic biomarkers. In this review, we summarized the current knowledge regarding the role of miRNAs and lncRNAs in B-cell lymphoma, including their interactions and regulatory networks. Finally, we summarized the studies investigating the potential of miRNAs and lncRNAs as clinical biomarkers, with a special focus on the circulating profiles, to be applied as a non-invasive, easy-to-obtain, and reproducible liquid biopsy for dynamic management of NHL patients.
A Gene-Based Machine Learning Classifier Associated to the Colorectal Adenoma—Carcinoma Sequence
Authors: Lacalamita Antonio , Piccinno Emanuele , Scalavino Viviana , Bellotti Roberto , Giannelli Gianluigi , Serino Grazia
Published: December 2021

Colorectal cancer (CRC) carcinogenesis is generally the result of the sequential mutation and deletion of various genes; this is known as the normal mucosa–adenoma–carcinoma sequence. The aim of this study was to develop a predictor-classifier during the “adenoma-carcinoma” sequence using microarray gene expression profiles of primary CRC, adenoma, and normal colon epithelial tissues. Four gene expression profiles from the Gene Expression Omnibus database, containing 465 samples (105 normal, 155 adenoma, and 205 CRC), were preprocessed to identify differentially expressed genes (DEGs) between adenoma tissue and primary CRC. The feature selection procedure, using the sequential Boruta algorithm and Stepwise Regression, determined 56 highly important genes. K-Means methods showed that, using the selected 56 DEGs, the three groups were clearly separate. The classification was performed with machine learning algorithms such as Linear Model (LM), Random Forest (RF), k-Nearest Neighbors (k-NN), and Artificial Neural Network (ANN). The best classification method in terms of accuracy (88.06 ± 0.70) and AUC (92.04 ± 0.47) was k-NN. To confirm the relevance of the predictive models, we applied the four models on a validation cohort: the k-NN model remained the best model in terms of performance, with 91.11% accuracy. Among the 56 DEGs, we identified 17 genes with an ascending or descending trend through the normal mucosa–adenoma–carcinoma sequence. Moreover, using the survival information of the TCGA database, we selected six DEGs related to patient prognosis (SCARA5, PKIB, CWH43, TEX11, METTL7A, and VEGFA). The six-gene-based classifier described in the current study could be used as a potential biomarker for the early diagnosis of CRC.
Discovery, Development, Inventions, and Patent Trends on Mobocertinib Succinate: The First-in-Class Oral Treatment for NSCLC with EGFR Exon 20 Insertions
Authors: Imran Mohd , Khan Shah Alam , Alshammari Mohammed Kanan , Alreshidi Meshal Ayedh , Alreshidi Abeer Abdullah , Alghonaim Rawan Sulaiman , Alanazi Fayez Aboud , Alshehri Sultan , Ghoneim Mohammed M. , Shakeel Faiyaz
Published: December 2021

The majority of lung cancers are non-small-cell lung cancer (NSCLC) having a low survival rate. Recent studies have indicated the involvement of epidermal growth factor receptor (EGFR) oncogene mutations like EGFR exon 20 insertions (EGFRex20ins) mutation among NSCLC patients. The response of patients of NSCLC with the EGFRex20ins mutation to the currently available EGFR inhibitor is negligible. Mobocertinib is the first oral treatment that has been approved by the USFDA, on 15 September 2021, to treat NSCLC with the EGFRex20ins mutation. This patent review discusses the inventions and patent literature of mobocertinib that will help the scientific community to develop additional and improved inventions related to mobocertinib. The structure of mobocertinib was first reported in 2015. Therefore, this article covered the patents/patent applications related to mobocertinib from 2015 to 25 October 2021. The patent search revealed 27 patents/patent applications related to compound, method of treatment, salt, polymorph, process, composition, and drug combinations of mobocertinib. The authors foresee an exciting prospect for developing a treatment for NSCLC with EGFRex20ins mutation, and other cancers employing a combination of mobocertinib with other approved anticancer agents. The inventions related to novel dosage forms, processes, and intermediates used in the synthesis of mobocertinib are also anticipated.
Prediction of Neoadjuvant Chemoradiotherapy Response in Rectal Cancer with Metric Learning Using Pretreatment 18F-Fluorodeoxyglucose Positron Emission Tomography
Authors: Wu Kuo-Chen , Chen Shang-Wen , Hsieh Te-Chun , Yen Kuo-Yang , Law Kin-Man , Kuo Yu-Chieh , Chang Ruey-Feng , Kao Chia-Hung
Published: December 2021

Objectives: Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is the mainstay of treatment for patients with locally advanced rectal cancer. Based on baseline 18F-fluorodeoxyglucose ([18F]-FDG)-positron emission tomography (PET)/computed tomography (CT), a new artificial intelligence model using metric learning (ML) was introduced to predict responses to NCRT. Patients and Methods: This study used the data of 236 patients with newly diagnosed rectal cancer; the data of 202 and 34 patients were for training and validation, respectively. All patients received pretreatment [18F]FDG-PET/CT, NCRT, and surgery. The treatment response was scored by Dworak tumor regression grade (TRG); TRG3 and TRG4 indicated favorable responses. The model employed ML combined with the Uniform Manifold Approximation and Projection for dimensionality reduction. A receiver operating characteristic (ROC) curve analysis was performed to assess the model’s predictive performance. Results: In the training cohort, 115 patients (57%) achieved TRG3 or TRG4 responses. The area under the ROC curve was 0.96 for the prediction of a favorable response. The sensitivity, specificity, and accuracy were 98.3%, 96.5%, and 97.5%, respectively. The sensitivity, specificity, and accuracy for the validation cohort were 95.0%, 100%, and 98.8%, respectively. Conclusions: The new ML model presented herein was used to determined that baseline 18F[FDG]-PET/CT images could predict a favorable response to NCRT in patients with rectal cancer. External validation is required to verify the model’s predictive value.
DNA Methylation of PI3K/AKT Pathway-Related Genes Predicts Outcome in Patients with Pancreatic Cancer: A Comprehensive Bioinformatics-Based Study
Authors: Faleiro Inês , Roberto Vânia Palma , Demirkol Canli Secil , Fraunhoffer Nicolas A. , Iovanna Juan , Gure Ali Osmay , Link Wolfgang , Castelo-Branco Pedro
Published: December 2021

Pancreatic cancer (PCA) is one of the most lethal malignancies worldwide with a 5-year survival rate of 9%. Despite the advances in the field, the need for an earlier detection and effective therapies is paramount. PCA high heterogeneity suggests that epigenetic alterations play a key role in tumour development. However, only few epigenetic biomarkers or therapeutic targets have been identified so far. Here we explored the potential of distinct DNA methylation signatures as biomarkers for early detection and prognosis of PCA. PI3K/AKT-related genes differentially expressed in PCA were identified using the Pancreatic Expression Database (n = 153). Methylation data from PCA patients was obtained from The Cancer Genome Atlas (n = 183), crossed with clinical data to evaluate the biomarker potential of the epigenetic signatures identified and validated in independent cohorts. The majority of selected genes presented higher expression and hypomethylation in tumour tissue. The methylation signatures of specific genes in the PI3K/AKT pathway could distinguish normal from malignant tissue at initial disease stages with AUC > 0.8, revealing their potential as PCA diagnostic tools. ITGA4, SFN, ITGA2, and PIK3R1 methylation levels could be independent prognostic indicators of patients’ survival. Methylation status of SFN and PIK3R1 were also associated with disease recurrence. Our study reveals that the methylation levels of PIK3/AKT genes involved in PCA could be used to diagnose and predict patients’ clinical outcome with high sensitivity and specificity. These results provide new evidence of the potential of epigenetic alterations as biomarkers for disease screening and management and highlight possible therapeutic targets.
Blood Bacterial DNA Load and Profiling Differ in Colorectal Cancer Patients Compared to Tumor-Free Controls
Authors: Mutignani Massimiliano , Penagini Roberto , Gargari Giorgio , Guglielmetti Simone , Cintolo Marcello , Airoldi Aldo , Leone Pierfrancesco , Carnevali Pietro , Ciafardini Clorinda , Petrocelli Giulio , Mascaretti Federica , Oreggia Barbara , Dioscoridi Lorenzo , Cavalcoli Federica , Primignani Massimo , Pugliese Francesco , Bertuccio Paola , Soru Pietro , Magistro Carmelo , Ferrari Giovanni , Speciani Michela C. , Bonato Giulia , Bini Marta , Cantù Paolo , Caprioli Flavio , Vangeli Marcello , Forti Edoardo , Mazza Stefano , Tosetti Giulia , Bonzi Rossella , Vecchi Maurizio , La Vecchia Carlo , Rossi Marta
Published: December 2021

Inflammation and immunity are linked to intestinal adenoma (IA) and colorectal cancer (CRC) development. The gut microbiota is associated with CRC risk. Epithelial barrier dysfunction can occur, possibly leading to increased intestinal permeability in CRC patients. We conducted a case-control study including 100 incident histologically confirmed CRC cases, and 100 IA and 100 healthy subjects, matched to cases by center, sex and age. We performed 16S rRNA gene analysis of blood and applied conditional logistic regression. Further analyses were based on negative binomial distribution normalization and Random Forest algorithm. We found an overrepresentation of blood 16S rRNA gene copies in colon cancer as compared to tumor-free controls. For high levels of gene copies, community diversity was higher in colon cancer cases than controls. Bacterial taxa and operational taxonomic unit abundances were different between groups and were able to predict CRC with an accuracy of 0.70. Our data support the hypothesis of a higher passage of bacteria from gastrointestinal tract to bloodstream in colon cancer. This result can be applied on non-invasive diagnostic tests for colon cancer control.
The Effects of Physical Activity on Cancer Patients Undergoing Treatment with Immune Checkpoint Inhibitors: A Scoping Review
Authors: Shaver Amy L. , Sharma Swapnil , Nikita Nikita , Lefler Daniel S. , Basu-Mallick Atrayee , Johnson Jennifer M. , Butryn Meghan , Lu-Yao Grace
Published: December 2021

Background: Cancer therapies are associated with multiple adverse effects, including (but not limited to) cancer-related fatigue (CRF). Fatigue is one of the most common side effects of immune checkpoint inhibitors (ICIs), occurring in up to 25% of patients. Physical activity has been shown to help reduce CRF through modulating the immune system, and may synergistically aid in the anti-tumor effects of ICIs. This review describes the nature and scope of evidence for the effects associated with concurrent physical activity while undergoing ICI therapy. Method: Scoping review methodology was utilized to identify studies, extract data, and collate and summarize results. Results: In literature published from January 2010 through to August 2021, only one human study and three pre-clinical studies met inclusion criteria. Conclusion: Existing evidence supports that physical activity is associated with decreased treatment-related toxicities such as CRF. However, further investigation is warranted. The dearth of clinical studies illustrates the need for more research to address this question, to guide patients and their providers in the application of appropriate physical activity interventions in those patients undergoing ICI.
Cobaltabis(dicarbollide) ([o-COSAN]−) as Multifunctional Chemotherapeutics: A Prospective Application in Boron Neutron Capture Therapy (BNCT) for Glioblastoma
Authors: Nuez-Martinez Miquel , Pinto Catarina I. G. , Guerreiro Joana F. , Mendes Filipa , Marques Fernanda , Muñoz-Juan Amanda , Xavier Jewel Ann Maria , Laromaine Anna , Bitonto Valeria , Protti Nicoletta , Crich Simonetta Geninatti , Teixidor Francesc , Viñas Clara
Published: December 2021

Purpose: The aim of our study was to assess if the sodium salt of cobaltabis(dicarbollide) and its di-iodinated derivative (Na[o-COSAN] and Na[8,8′-I2-o-COSAN]) could be promising agents for dual anti-cancer treatment (chemotherapy + BNCT) for GBM. Methods: The biological activities of the small molecules were evaluated in vitro with glioblastoma cells lines U87 and T98G in 2D and 3D cell models and in vivo in the small model animal Caenorhabditis elegans (C. elegans) at the L4-stage and using the eggs. Results: Our studies indicated that only spheroids from the U87 cell line have impaired growth after treatment with both compounds, suggesting an increased resistance from T98G spheroids, contrary to what was observed in the monolayer culture, which highlights the need to employ 3D models for future GBM studies. In vitro tests in U87 and T98G cells conclude that the amount of 10B inside the cells is enough for BNCT irradiation. BNCT becomes more effective on T98G after their incubation with Na[8,8′-I2-o-COSAN], whereas no apparent cell-killing effect was observed for untreated cells. Conclusions: These small molecules, particularly [8,8′-I2-o-COSAN]−, are serious candidates for BNCT now that the facilities of accelerator-based neutron sources are more accessible, providing an alternative treatment for resistant glioblastoma.
CNA Profiling of Single CTCs in Locally Advanced Esophageal Cancer Patients during Therapy Highlights Unexplored Molecular Pathways
Authors: Gallerani Giulia , Rossi Tania , Valgiusti Martina , Angeli Davide , Fici Pietro , De Fanti Sara , Bandini Erika , Cocchi Claudia , Frassineti Giovanni Luca , Bonafè Massimiliano , Fabbri Francesco
Published: December 2021

Background: Here, we monitored the evolution of CTCs spread in 11 patients affected by locally advanced EC who were undergoing therapy. Methods: In this perspective study, we designed multiple blood biopsies from individual patients: before and after neoadjuvant chemo-radio therapy and after surgery. We developed a multi-target array, named Grab-all assay, to estimate CTCs for their epithelial (EpCAM/E-Cadherin/Cytokeratins) and mesenchymal/stem (N-Cadherin/CD44v6/ABCG2) phenotypes. Identified CTCs were isolated as single cells by DEPArray, subjected to whole genome amplification, and copy number aberration (CNA) profiles were determined. Through bioinformatic analysis, we assessed the genomic imbalance of single CTCs, investigated specific focal copy number changes previously reported in EC and aberrant pathways using enrichment analysis. Results: Longitudinal monitoring allowed the identification of CTCs in at least one time-point per patient. Through single cell CNA analysis, we revealed that CTCs showed significantly dynamic genomic imbalance during treatment. Individual CTCs from relapsed patients displayed a higher degree of genomic imbalance relative to disease-free patients’ groups. Genomic aberrations previously reported in EC occurred mostly in post-neoadjuvant therapy CTCs. In-depth analysis showed that networks enrichment in all time-point CTCs were inherent to innate immune system. Transcription/gene regulation, post-transcriptional and epigenetic modifications were uniquely affected in CTCs of relapsed patients. Conclusions: Our data add clues to the comprehension of the role of CTCs in EC aggressiveness: chromosomal aberrations on genes related to innate immune system behave as relevant to the onset of CTC-status, whilst pathways of transcription/gene regulation, post-transcriptional and epigenetic modifications seem linked to patients’ outcome.
Transcriptome Analysis in Vulvar Squamous Cell Cancer
Authors: Prieske Katharina , Alawi Malik , Jaeger Anna , Wankner Maximilian Christian , Eylmann Kathrin , Reuter Susanne , Lebok Patrick , Burandt Eike , Blessin Niclas C. , Schmalfeldt Barbara , Oliveira-Ferrer Leticia , Joosse Simon A. , Woelber Linn
Published: December 2021

To date, therapeutic strategies in vulvar squamous cell carcinoma (VSCC) are lacking molecular pathological information and targeted therapy hasn’t been approved in the treatment of VSCC, yet. Two etiological pathways are widely accepted: HPV induced vs. HPV independent, associated with chronic skin disease, often harboring TP53 mutations (mut). The aim of this analysis was to analyze the RNA expression patterns for subtype stratification on VSCC samples that can be integrated into the previously performed whole exome sequencing data for the detection of prognostic markers and potential therapeutic targets. We performed multiplex gene expression analysis (NanoString) with 770 genes in 24 prior next generation sequenced samples. An integrative data analysis was performed. Here, 98 genes were differentially expressed in TP53mut vs. HPV+ VSCC, in the TP53mut cohort, where 56 genes were upregulated and 42 were downregulated in comparison to the HPV+ tumors. Aberrant expression was primarily observed in cell cycle regulation, especially in HPV+ disease. Within the TP53mut group, a distinct cluster was identified that was correlated to a significantly worse overall survival (p = 0.017). The RNA expression profiles showed distinct patterns with regard to the known VSCC subtypes and could potentially enable further subclassification in the TP53mut groups
Patient Selection for Local Aggressive Treatment in Oligometastatic Non-Small Cell Lung Cancer
Authors: Werner Raphael S. , Opitz Isabelle
Published: December 2021

One-fourth of all patients with metastatic non-small cell lung cancer presents with a limited number of metastases and relatively low systemic tumor burden. This oligometastatic state with limited systemic tumor burden may be associated with remarkably improved overall and progression-free survival if both primary tumor and metastases are treated radically combined with systemic therapy. This local aggressive therapy (LAT) requires a multidisciplinary approach including medical oncologists, radiation therapists, and thoracic surgeons. A surgical resection of the often advanced primary tumor should be part of the radical treatment whenever feasible. However, patient selection, timing, and a correct treatment allocation for LAT appear to be essential. In this review, we aimed to summarize and discuss the current evidence on patient selection criteria such as characteristics of the primary tumor and metastases, response to neoadjuvant or first-line treatment, molecular characteristics, mediastinal lymph node involvement, and other factors for LAT in oligometastatic NSCLC.
Influence of Estrogen Treatment on ESR1+ and ESR1− Cells in ER+ Breast Cancer: Insights from Single-Cell Analysis of Patient-Derived Xenograft Models
Authors: Mori Hitomi , Saeki Kohei , Chang Gregory , Wang Jinhui , Wu Xiwei , Hsu Pei-Yin , Kanaya Noriko , Wang Xiaoqiang , Somlo George , Nakamura Masafumi , Bild Andrea , Chen Shiuan
Published: December 2021

A 100% ER positivity is not required for an endocrine therapy response. Furthermore, while estrogen typically promotes the progression of hormone-dependent breast cancer via the activation of estrogen receptor (ER)-α, estrogen-induced tumor suppression in ER+ breast cancer has been clinically observed. With the success in establishing estrogen-stimulated (SC31) and estrogen-suppressed (GS3) patient-derived xenograft (PDX) models, single-cell RNA sequencing analysis was performed to determine the impact of estrogen on ESR1+ and ESR1– tumor cells. We found that 17β-estradiol (E2)-induced suppression of GS3 transpired through wild-type and unamplified ERα. E2 upregulated the expression of estrogen-dependent genes in both SC31 and GS3; however, E2 induced cell cycle advance in SC31, while it resulted in cell cycle arrest in GS3. Importantly, these gene expression changes occurred in both ESR1+ and ESR1– cells within the same breast tumors, demonstrating for the first time a differential effect of estrogen on ESR1– cells. E2 also upregulated a tumor-suppressor gene, IL-24, in GS3. The apoptosis gene set was upregulated and the G2M checkpoint gene set was downregulated in most IL-24+ cells after E2 treatment. In summary, estrogen affected pathologically defined ER+ tumors differently, influencing both ESR1+ and ESR1– cells. Our results also suggest IL-24 to be a potential marker of estrogen-suppressed tumors.
Anticancer Activity of Ω-6 Fatty Acids through Increased 4-HNE in Breast Cancer Cells
Authors: Bose Chhanda , Hindle Ashly , Lee Jihyun , Kopel Jonathan , Tonk Sahil , Palade Philip T. , Singhal Sharad S. , Awasthi Sanjay , Singh Sharda P.
Published: December 2021

Her2-amplified breast cancers resistant to available Her2-targeted therapeutics continue to be a challenge in breast cancer therapy. Dox is the mainstay of chemotherapy of all types of breast cancer, but its usefulness is limited by cumulative cardiotoxicity. Because oxidative stress caused by dox generates the pro-apoptotic Ω-6 PUFA metabolite 4-hydroxynonenal (4-HNE), we surmised that Ω-6 PUFAs would increase the effectiveness of dox chemotherapy. Since the mercapturic acid pathway enzyme RALBP1 (also known as RLIP76 or Rlip) that limits cellular accumulation of 4-HNE also mediates dox resistance, the combination of Ω-6 PUFAs and Rlip depletion could synergistically improve the efficacy of dox. Thus, we studied the effects of the Ω-6 PUFA arachidonic acid (AA) and Rlip knockdown on the antineoplastic activity of dox towards Her2-amplified breast cancer cell lines SK-BR-3, which is sensitive to Her2 inhibitors, and AU565, which is resistant. AA increased lipid peroxidation, 4-HNE generation, apoptosis, cellular dox concentration and dox cytotoxicity in both cell lines while sparing cultured immortalized cardiomyocyte cells. The known functions of Rlip including clathrin-dependent endocytosis and dox efflux were inhibited by AA. Our results support a model in which 4-HNE generated by AA overwhelms the capacity of Rlip to defend against apoptosis caused by dox or 4-HNE. We propose that Ω-6 PUFA supplementation could improve the efficacy of dox or Rlip inhibitors for treating Her2-amplified breast cancer.
Identification of Genetic Variants Associated with Sex-Specific Lung-Cancer Risk
Authors: Shi Xiaoshun , Young Sylvia , Morahan Grant
Published: December 2021

Background: The incidence of lung cancer differs between men and women, suggesting the potential role of sex-specific influences in susceptibility to this cancer. While behavioural differences may account for some of the risk, another possibility is that X chromosome susceptibility genes may have an effect. Little is known about genetic variants on the X chromosome that contribute to sex-specific lung-cancer risk, so we investigated this in a previously characterized cohort. Methods: We conducted a genetic association reanalysis of 518 lung cancer patients and 844 controls to test for lung cancer susceptibility variants on the X chromosome. Annotated gene expression, co-expression analysis, pathway, and immune infiltration analyses were also performed. Results: 24 SNPs were identified as significantly associated with male, but not female, lung cancer cases. These resided in blocks near the annotated genes DMD, PTCHD1-AS, and AL008633.1. Of these, DMD was differentially expressed in lung cancer cases curated in The Cancer Genome Atlas. A functional enrichment and a KEGG pathway analysis of co-expressed genes revealed that differences in immune function could play a role in sex-specific susceptibility. Conclusions: Our analyses identified potential genetic variants associated with sex-specific lung cancer risk. Integrating GWAS and RNA-sequencing data revealed potential targets for lung cancer prevention.
Insights of RKIP-Derived Suppression of Prostate Cancer
Authors: Dong Ying , Lin Xiaozeng , Kapoor Anil , Gu Yan , Xu Hui , Major Pierre , Tang Damu
Published: December 2021

Prostate cancer (PC) is a major cause of cancer death in men. The disease has a great disparity in prognosis. Although low grade PCs with Gleason scores ≤ 6 are indolent, high-risk PCs are likely to relapse and metastasize. The standard of care for metastatic PC (mPC) remains androgen deprivation therapy (ADT). Resistance commonly occurs in the form of castration resistant PC (CRPC). Despite decades of research efforts, CRPC remains lethal. Understanding of mechanisms underpinning metastatic progression represents the overarching challenge in PC research. This progression is regulated by complex mechanisms, including those regulating PC cell proliferation, epithelial–mesenchymal transition (EMT), and androgen receptor (AR) signaling. Among this PC metastatic network lies an intriguing suppressor of PC metastasis: the Raf kinase inhibitory protein (RKIP). Clinically, the RKIP protein is downregulated in PC, and showed further reduction in mPC. In xenograft mouse models for PC, RKIP inhibits metastasis. In vitro, RKIP reduces PC cell invasion and sensitizes PC cells to therapeutic treatments. Mechanistically, RKIP suppresses Raf-MEK-ERK activation and EMT, and modulates extracellular matrix. In return, Snail, NFκB, and the polycomb protein EZH2 contribute to inhibition of RKIP expression. In this review, we will thoroughly analyze RKIP’s tumor suppression actions in PC.
Differences in Cell-Intrinsic Inflammatory Programs of Yolk Sac and Bone Marrow Macrophages
Authors: Elhag Sara , Stremmel Christopher , Zehrer Annette , Plocke Josefine , Hennel Roman , Keuper Michaela , Knabe Clarissa , Winterhalter Julia , Gölling Vanessa , Tomas Lukas , Weinberger Tobias , Fischer Maximilian , Liu Lulu , Wagner Franziska , Lorenz Michael , Stark Konstantin , Häcker Hans , Schmidt-Supprian Marc , Völker Uwe , Jastroch Martin , Lauber Kirsten , Straub Tobias , Walzog Barbara , Hammer Elke , Schulz Christian
Published: December 2021

Background: Tissue-resident macrophages have mixed developmental origins. They derive in variable extent from yolk sac (YS) hematopoiesis during embryonic development. Bone marrow (BM) hematopoietic progenitors give rise to tissue macrophages in postnatal life, and their contribution increases upon organ injury. Since the phenotype and functions of macrophages are modulated by the tissue of residence, the impact of their origin and developmental paths has remained incompletely understood. Methods: In order to decipher cell-intrinsic macrophage programs, we immortalized hematopoietic progenitors from YS and BM using conditional HoxB8, and carried out an in-depth functional and molecular analysis of differentiated macrophages. Results: While YS and BM macrophages demonstrate close similarities in terms of cellular growth, differentiation, cell death susceptibility and phagocytic properties, they display differences in cell metabolism, expression of inflammatory markers and inflammasome activation. Reduced abundance of PYCARD (ASC) and CASPASE-1 proteins in YS macrophages abrogated interleukin-1β production in response to canonical and non-canonical inflammasome activation. Conclusions: Macrophage ontogeny is associated with distinct cellular programs and immune response. Our findings contribute to the understanding of the regulation and programming of macrophage functions.
Sperm Selection for ICSI: Do We Have a Winner?
Authors: Baldini Domenico , Ferri Daniele , Baldini Giorgio Maria , Lot Dario , Catino Assunta , Vizziello Damiano , Vizziello Giovanni
Published: December 2021

In assisted reproductive technology (ART), the aim of sperm cells’ preparation is to select competent spermatozoa with the highest fertilization potential and in this context, the intracytoplasmic sperm injection (ICSI) represents the most applied technique for fertilization. This makes the process of identifying the perfect spermatozoa extremely important. A number of methods have now been developed to mimic some of the natural selection processes that exist in the female reproductive tract. Although many studies have been conducted to identify the election technique, many doubts and disagreements still remain. In this review, we will discuss all the sperm cell selection techniques currently available for ICSI, starting from the most basic methodologies and continuing with those techniques suitable for sperm cells with reduced motility. Furthermore, different techniques that exploit some sperm membrane characteristics and the most advanced strategy for sperm selection based on microfluidics, will be examined. Finally, a new sperm selection method based on a micro swim-up directly on the ICSI dish will be analyzed. Eventually, advantages and disadvantages of each technique will be debated, trying to draw reasonable conclusions on their efficacy in order to establish the gold standard method.
Sulfated Hydrogels in Intervertebral Disc and Cartilage Research
Authors: Lazarus Emily , Bermudez-Lekerika Paola , Farchione Daniel , Schofield Taylor , Howard Sloan , Mambetkadyrov Iskender , Lamoca Mikkael , Rivero Iris V. , Gantenbein Benjamin , Lewis Christopher L. , Wuertz-Kozak Karin
Published: December 2021

Hydrogels are commonly used for the 3D culture of musculoskeletal cells. Sulfated hydrogels, which have seen a growing interest over the past years, provide a microenvironment that help maintain the phenotype of chondrocytes and chondrocyte-like cells and can be used for sustained delivery of growth factors and other drugs. Sulfated hydrogels are hence valuable tools to improve cartilage and intervertebral disc tissue engineering. To further advance the utilization of these hydrogels, we identify and summarize the current knowledge about different sulfated hydrogels, highlight their beneficial effects in cartilage and disc research, and review the biofabrication processes most suitable to secure best quality assurance through deposition fidelity, repeatability, and attainment of biocompatible morphologies.