bluuebunny/crossref_metadata_2025 huggingface dataset:
Pull-Out Capability of a 3D Printed Threadless Suture Anchor with Rectangular Cross-Section: A Biomechanical Study
Authors: Hsieh Yueh-Ying , Wu Lien-Chen , Tsuang Fon-Yih , Chen Chia-Hsien , Chiang Chang-Jung
Published: December 2021

Suture anchor fixation is a common method for securing bone and soft tissue in the body, with proven applications in the hip, elbow, hand, knee and foot. A critical limiting factor of suture anchors is the pull-out strength, particularly in suboptimal bone. This study introduces a novel 3D printed threadless suture anchor with a rectangular cross-section. The titanium anchor was designed with surface fenestration and a porous central core to improve bone ingrowth. The aim of this study was to compare the pull-out properties of the novel threadless anchor with a traditional circular threaded suture anchor. The anchors were inserted into a 0.24 g/cm3 synthetic cancellous bone block at angles of 90° and 135° to the surface. The sutures were pulled at 180° (parallel) to the surface under a static pull test (anchor pullout) and cyclic load test using a tensile testing machine. Under the static load, the greatest pullout strength was seen with the novel threadless anchor inserted at 90° (mean, 105.6 N; standard deviation [SD], 3.5 N). The weakest pullout strength was seen with the threaded anchor inserted at 90° (mean, 87.9 N; SD, 4.1 N). In the cyclic load test, all six of the threaded anchors with a 90° insertion angle pulled out after 18 cycles (70 N). All of the threadless anchors inserted at 90° survived the cyclic test (90 N). In conclusion, the novel threadless suture anchor with rectangular cross-section and traditional threaded suture anchor had similar pullout survivorship when inserted at either 90° or 135°. In addition, the 3D printed threadless anchor has the potential for good bone integration to improve long-term stabilization.
A Universal Malicious Documents Static Detection Framework Based on Feature Generalization
Authors: Lu Xiaofeng , Wang Fei , Jiang Cheng , Lio Pietro
Published: December 2021

In this study, Portable Document Format (PDF), Word, Excel, Rich Test format (RTF) and image documents are taken as the research objects to study a static and fast method by which to detect malicious documents. Malicious PDF and Word document features are abstracted and extended, which can be used to detect other types of documents. A universal static detection framework for malicious documents based on feature generalization is then proposed. The generalized features include specification check errors, the structure path, code keywords, and the number of objects. The proposed method is verified on two datasets, and is compared with Kaspersky, NOD32, and McAfee antivirus software. The experimental results demonstrate that the proposed method achieves good performance in terms of the detection accuracy, runtime, and scalability. The average F1-score of all types of documents is found to be 0.99, and the average detection time of a document is 0.5926 s, which is at the same level as the compared antivirus software.
Development and Evaluation of a Child Vaccination Chatbot Real-Time Consultation Messenger Service during the COVID-19 Pandemic
Authors: Hong Yeong-Joo , Piao Meihua , Kim Jeongeun , Lee Jae-Ho
Published: December 2021

The decreased rate of children’s vaccination has resulted in outbreaks of vaccine-preventable diseases, and vaccination hesitancy is being brought about by the uncertainty caused by the continuing COVID-19 pandemic. With this study, we aimed to assess the efficacy of a child vaccination chatbot based on changes in variables such as vaccination information, motivation, self-efficacy, and vaccination behavioral intention. From 30 January to 15 February 2020, 65 parents raising children ≤35 months old who were expected to be vaccinated within three months participated in the trial through online recruitment. Participants were randomly assigned to either the experimental group (n = 34) or the control group (n = 31) and were followed up with over a period of 12 weeks. During this period, both groups of participants were provided with vaccination schedule reminders. The experimental group were additionally provided with vaccination-related information and motivation boosters by a chatbot (real-time consultation messenger service); the control group was provided the same information by brochure. Comparing both groups, the experimental group that used the chatbot scored higher on vaccination information, motivation, self-efficacy, and vaccination behavioral intention than the control group. This suggests that the chatbot provided useful and timely information to parents, increasing vaccination motivation, self-efficacy, and vaccination rates. This study provides evidence that chatbots are useful tools to encourage immunization through the provision of reminders and real-time consultation messenger services during the global health crisis and beyond.
Collaborative Workplace Design: A Knowledge-Based Approach to Promote Human–Robot Collaboration and Multi-Objective Layout Optimization
Authors: Rega Andrea , Di Marino Castrese , Pasquariello Agnese , Vitolo Ferdinando , Patalano Stanislao , Zanella Alessandro , Lanzotti Antonio
Published: December 2021

The innovation-driven Industry 5.0 leads us to consider humanity in a prominent position as the center of the manufacturing field even more than Industry 4.0. This pushes us towards the hybridization of manufacturing plants promoting a full collaboration between humans and robots. However, there are currently very few workplaces where effective Human–Robot Collaboration takes place. Layout designing plays a key role in assuring safe and efficient Human–Robot Collaboration. The layout design, especially in the context of collaborative robotics, is a complex problem to face, since it is related to safety, ergonomics, and productivity aspects. In the current work, a Knowledge-Based Approach (KBA) is adopted to face the complexity of the layout design problem. The framework resulting from the KBA allows for developing a modeling paradigm that enables us to define a streamlined approach for the layout design. The proposed approach allows for placing resource within the workplace according to a defined optimization criterion, and also ensures compliance with various standards. This approach is applied to an industrial case study in order to prove its feasibility. A what-if analysis is performed by applying the proposed approach. Changing three control factors (i.e., minimum distance, robot speed, logistic space configuration) on three levels, in a Design of Experiments, 27 layout configurations of the same workplace are generated. Consequently, the inputs that most affect the layout design are identified by means of an Analysis of Variance (ANOVA). The results show that only one layout is eligible to be the best configuration, and only two out of three control factors are very significant for the designing of the HRC workplace layout. Hence, the proposed approach enables the designing of standard compliant and optimized HRC workplace layouts. Therefore, several alternatives of the layout for the same workplace can be easily generated and investigated in a systematic manner.
Development of an Online Detection Setup for Dissolved Gas in Transformer Insulating Oil
Authors: Chen Yang , Wang Zhentao , Li Zhao , Zheng Hongquan , Dai Jingmin
Published: December 2021

The type and concentration of dissolved gases in transformer insulating oil are used to assess transformer conditions. In this paper, an online detection setup for measuring the concentration of multicomponent gases dissolved in transformer insulating oil is developed, which consists of an oil-gas separation system and an optical system for acquiring the transformer status in real time. The oil-gas separation system uses low pressure, constant temperature, and low-frequency stirring as working conditions for degassing large-volume oil samples based on modified headspace degassing. The optical system uses tunable diode laser absorption spectroscopy (TDLAS) to determine the gas concentration. Six target gases (methane, ethylene, ethane, acetylene, carbon monoxide, and carbon dioxide) were detected by three near-infrared lasers (1569, 1684, and 1532 nm). The stability of the optical system was improved by the common optical path formed by time-division multiplexing (TDM) technology. The calibration experiments show that the second harmonics and the concentrations of the six gases are linear. A comparison experiment with gas chromatography (GC) demonstrates that the error of acetylene reaches the nL/L level, while the other gases reach the μL/L level. The data conforms to the power industry testing standards, and the state of the transformer is analyzed by the detected six characteristic gases. The setup provides an effective basis for the online detection of dissolved gas in transformer insulating oil.
Oscillatory Behavior of Third-Order Quasi-Linear Neutral Differential Equations
Authors: Qaraad Belgees , Moaaz Osama , Santra Shyam Sundar , Noeiaghdam Samad , Sidorov Denis , Elabbasy Elmetwally M.
Published: December 2021

In this paper, we consider a class of quasilinear third-order differential equations with a delay argument. We establish some conditions of such certain third-order quasi-linear neutral differential equation as oscillatory or almost oscillatory. Those criteria improve, complement and simplify a number of existing results in the literature. Some examples are given to illustrate the importance of our results.
Agrobacterium fabrum atu0526-Encoding Protein Is the Only Chemoreceptor That Regulates Chemoattraction toward the Broad Antibacterial Agent Formic Acid
Authors: Wang Hao , Zhang Mengqi , Xu Yujuan , Zong Renjie , Xu Nan , Guo Minliang
Published: December 2021

Soil-born plant pathogens, especially Agrobacterium, generally navigate their way to hosts through recognition of the root exudates by chemoreceptors. However, there is still a lack of appropriate identification of chemoreceptors and their ligands in Agrobacterium. Here, Atu0526, a sCache-type chemoreceptor from Agrobacterium fabrum C58, was confirmed as the receptor of a broad antibacterial agent, formic acid. The binding of formic acid to Atu0526 was screened using a thermo shift assay and verified using isothermal titration calorimetry. Inconsistent with the previously reported antimicrobial properties, formic acid was confirmed to be a chemoattractant to A. fabrum and could promote its growth. The chemotaxis of A. fabrum C58 toward formic acid was completely lost with the knock-out of atu0526, and regained with the complementation of the gene, indicating that Atu0526 is the only chemoreceptor for formic acid in A. fabrum C58. The affinity of formic acid to Atu0526LBD significantly increased after the arginine at position 115 was replaced by alanine. However, in vivo experiments showed that the R115A mutation fully abolished the chemotaxis of A. fabrum toward formic acid. Molecular docking based on a predicted 3D structure of Atu0526 suggested that the arginine may provide “an anchorage” for formic acid to pull the minor loop, thereby forming a conformational change that generates the ligand-binding signal. Collectively, our findings will promote an understanding of sCache-type chemoreceptors and their signal transduction mechanism.
Bioactive Antimicrobial Peptides as Therapeutic Agents for Infected Diabetic Foot Ulcers
Authors: Da Silva Jessica , Leal Ermelindo C. , Carvalho Eugénia
Published: December 2021

Diabetic foot ulcer (DFU) is a devastating complication, affecting around 15% of diabetic patients and representing a leading cause of non-traumatic amputations. Notably, the risk of mixed bacterial–fungal infection is elevated and highly associated with wound necrosis and poor clinical outcomes. However, it is often underestimated in the literature. Therefore, polymicrobial infection control must be considered for effective management of DFU. It is noteworthy that antimicrobial resistance is constantly rising overtime, therefore increasing the need for new alternatives to antibiotics and antifungals. Antimicrobial peptides (AMPs) are endogenous peptides that are naturally abundant in several organisms, such as bacteria, amphibians and mammals, particularly in the skin. These molecules have shown broad-spectrum antimicrobial activity and some of them even have wound-healing activity, establishing themselves as ideal candidates for treating multi-kingdom infected wounds. Furthermore, the role of AMPs with antifungal activity in wound management is poorly described and deserves further investigation in association with antibacterial agents, such as antibiotics and AMPs with antibacterial activity, or alternatively the application of broad-spectrum antimicrobial agents that target both aerobic and anaerobic bacteria, as well as fungi. Accordingly, the aim of this review is to unravel the molecular mechanisms by which AMPs achieve their dual antimicrobial and wound-healing properties, and to discuss how these are currently being applied as promising therapies against polymicrobial-infected chronic wounds such as DFUs.
Keratinases as Versatile Enzymatic Tools for Sustainable Development
Authors: Sypka Marcin , Jodłowska Iga , Białkowska Aneta M.
Published: December 2021

To reduce anthropological pressure on the environment, the implementation of novel technologies in present and future economies is needed for sustainable development. The food industry, with dairy and meat production in particular, has a significant environmental impact. Global poultry production is one of the fastest-growing meat producing sectors and is connected with the generation of burdensome streams of manure, offal and feather waste. In 2020, the EU alone produced around 3.2 million tonnes of poultry feather waste composed primarily of keratin, a protein biopolymer resistant to conventional proteolytic enzymes. If not managed properly, keratin waste can significantly affect ecosystems, contributing to environmental pollution, and pose a serious hazard to human and livestock health. In this article, the application of keratinolytic enzymes and microorganisms for promising novel keratin waste management methods with generation of new value-added products, such as bioactive peptides, vitamins, prion decontamination agents and biomaterials were reviewed.
Liver Regeneration and Cell Transplantation for End-Stage Liver Disease
Authors: Li Yan , Lu Lungen , Cai Xiaobo
Published: December 2021

Liver transplantation is the only curative option for end-stage liver disease; however, the limitations of liver transplantation require further research into other alternatives. Considering that liver regeneration is prevalent in liver injury settings, regenerative medicine is suggested as a promising therapeutic strategy for end-stage liver disease. Upon the source of regenerating hepatocytes, liver regeneration could be divided into two categories: hepatocyte-driven liver regeneration (typical regeneration) and liver progenitor cell-driven liver regeneration (alternative regeneration). Due to the massive loss of hepatocytes, the alternative regeneration plays a vital role in end-stage liver disease. Advances in knowledge of liver regeneration and tissue engineering have accelerated the progress of regenerative medicine strategies for end-stage liver disease. In this article, we generally reviewed the recent findings and current knowledge of liver regeneration, mainly regarding aspects of the histological basis of regeneration, histogenesis and mechanisms of hepatocytes’ regeneration. In addition, this review provides an update on the regenerative medicine strategies for end-stage liver disease. We conclude that regenerative medicine is a promising therapeutic strategy for end-stage liver disease. However, further studies are still required.
Post-COVID-19 Patients Who Develop Lung Fibrotic-like Changes Have Lower Circulating Levels of IFN-β but Higher Levels of IL-1α and TGF-β
Authors: Colarusso Chiara , Maglio Angelantonio , Terlizzi Michela , Vitale Carolina , Molino Antonio , Pinto Aldo , Vatrella Alessandro , Sorrentino Rosalinda
Published: December 2021

Purpose: SARS-CoV-2 infection induces in some patients a condition called long-COVID-19, herein post-COVID-19 (PC), which persists for longer than the negative oral-pharyngeal swab. One of the complications of PC is pulmonary fibrosis. The purpose of this study was to identify blood biomarkers to predict PC patients undergoing pulmonary fibrosis. Patients and Methods: We analyzed blood samples of healthy, anti-SARS-CoV-2 vaccinated (VAX) subjects and PC patients who were stratified according to the severity of the disease and chest computed tomography (CT) scan data. Results: The inflammatory C reactive protein (CRP), complement complex C5b-9, LDH, but not IL-6, were higher in PC patients, independent of the severity of the disease and lung fibrotic areas. Interestingly, PC patients with ground-glass opacities (as revealed by chest CT scan) were characterized by higher plasma levels of IL-1α, CXCL-10, TGF-β, but not of IFN-β, compared to healthy and VAX subjects. In particular, 19 out of 23 (82.6%) severe PC and 8 out of 29 (27.6%) moderate PC patients presented signs of lung fibrosis, associated to lower levels of IFN-β, but higher IL-1α and TGF-β. Conclusions: We found that higher IL-1α and TGF-β and lower plasma levels of IFN-β could predict an increased relative risk (RR = 2.8) of lung fibrosis-like changes in PC patients.
The Immune Regulatory Role of Protein Kinase CK2 and Its Implications for Treatment of Cancer
Authors: Hong Huixian , Benveniste Etty N.
Published: December 2021

Protein Kinase CK2, a constitutively active serine/threonine kinase, fulfills its functions via phosphorylating hundreds of proteins in nearly all cells. It regulates a variety of cellular signaling pathways and contributes to cell survival, proliferation and inflammation. CK2 has been implicated in the pathogenesis of hematologic and solid cancers. Recent data have documented that CK2 has unique functions in both innate and adaptive immune cells. In this article, we review aspects of CK2 biology, functions of the major innate and adaptive immune cells, and how CK2 regulates the function of immune cells. Finally, we provide perspectives on how CK2 effects in immune cells, particularly T-cells, may impact the treatment of cancers via targeting CK2.
Inverse Association between High-Density Lipoprotein Cholesterol and Adverse Outcomes among Acute Ischemic Stroke Patients with Diabetes Mellitus
Authors: Hu Guoliang , Pan Yuesong , Wang Mengxing , Meng Xia , Jiang Yong , Li Zixiao , Li Hao , Wang Yongjun , Wang Yilong
Published: December 2021

A low high-density lipoprotein cholesterol (HDL-C) level is an identified risk factor for cardiovascular diseases. However, results on the association between HDL-C levels and adverse outcomes in diabetic status still remain limited and controversial. Herein, we evaluated the association between HDL-C levels and adverse outcomes among acute ischemic stroke (AIS) patients with diabetes mellitus. The cohort comprised 3824 AIS patients with diabetes mellitus (62.7 ± 10.5 years; 34.2% women) from the Third China National Stroke Registry (n = 15,166). Patients were classified into five groups by quintiles of HDL-C. The outcomes included recurrent stroke and major adverse cardiovascular events (MACEs) within 1 year. The relationship between HDL-C levels and the risk of adverse outcomes was analyzed by Cox proportional hazards models. Patients in the lowest quintile of HDL-C had a higher risk of recurrent stroke (hazard ratio (HR) 1.59, 95% confidence interval (CI), 1.12–2.25) and MACEs (HR 1.53, 95% CI, 1.09–2.15) during 1-year follow-up compared with those in the highest quintile of HDL-C. There were linear associations between HDL-C levels and the risks of both recurrent stroke and MACEs. Low HDL-C levels were associated with higher risks of recurrent stroke and MACEs within 1 year in AIS patients with diabetes mellitus.
Improving Generation of Cardiac Organoids from Human Pluripotent Stem Cells Using the Aurora Kinase Inhibitor ZM447439
Authors: Lee Su-Jin , Kim Hyeon-A , Kim Sung-Joon , Lee Hyang-Ae
Published: December 2021

Drug-induced cardiotoxicity reduces the success rates of drug development. Thus, the limitations of current evaluation methods must be addressed. Human cardiac organoids (hCOs) derived from induced pluripotent stem cells (hiPSCs) are useful as an advanced drug-testing model; they demonstrate similar electrophysiological functionality and drug reactivity as the heart. How-ever, similar to other organoid models, they have immature characteristics compared to adult hearts, and exhibit batch-to-batch variation. As the cell cycle is important for the mesodermal differentiation of stem cells, we examined the effect of ZM447439, an aurora kinase inhibitor that regulates the cell cycle, on cardiogenic differentiation. We determined the optimal concentration and timing of ZM447439 for the differentiation of hCOs from hiPSCs and developed a novel protocol for efficiently and reproducibly generating beating hCOs with improved electrophysiological functionality, contractility, and yield. We validated their maturity through electro-physiological- and image-based functional assays and gene profiling with next-generation sequencing, and then applied these cells to multi-electrode array platforms to monitor the cardio-toxicity of drugs related to cardiac arrhythmia; the results confirmed the drug reactivity of hCOs. These findings may enable determination of the regulatory mechanism of cell cycles underlying the generation of iPSC-derived hCOs, providing a valuable drug testing platform.
Clinicopathological and Molecular Prognostic Classifier for Intermediate/High-Risk Clear Cell Renal Cell Carcinoma
Authors: Roldán Fiorella L. , Lozano Juan J. , Ingelmo-Torres Mercedes , Carrasco Raquel , Díaz Esther , Ramirez-Backhaus Miguel , Rubio José , Reig Oscar , Alcaraz Antonio , Mengual Lourdes , Izquierdo Laura
Published: December 2021

The probability of tumor progression in intermediate/high-risk clear cell renal cell carcinoma (ccRCC) is highly variable, underlining the lack of predictive accuracy of the current clinicopathological factors. To develop an accurate prognostic classifier for these patients, we analyzed global gene expression patterns in 13 tissue samples from progressive and non-progressive ccRCC using Illumina Hi-seq 4000. Expression levels of 22 selected differentially expressed genes (DEG) were assessed by nCounter analysis in an independent series of 71 ccRCCs. A clinicopathological-molecular model for predicting tumor progression was developed and in silico validated in a total of 202 ccRCC patients using the TCGA cohort. A total of 1202 DEGs were found between progressive and non-progressive intermediate/high-risk ccRCC in RNAseq analysis, and seven of the 22 DEGs selected were validated by nCounter. Expression of HS6ST2, pT stage, tumor size, and ISUP grade were found to be independent prognostic factors for tumor progression. A risk score generated using these variables was able to distinguish patients at higher risk of tumor progression (HR 7.27; p < 0.001), consistent with the results obtained from the TCGA cohort (HR 2.74; p < 0.002). In summary, a combined prognostic algorithm was successfully developed and validated. This model may aid physicians to select high-risk patients for adjuvant therapy.
Enhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma
Authors: Lau Peter Kar Han , Cullinane Carleen , Jackson Susan , Walker Rachael , Smith Lorey K. , Slater Alison , Kirby Laura , Patel Riyaben P. , von Scheidt Bianca , Slaney Clare Y. , McArthur Grant A. , Sheppard Karen E.
Published: December 2021

Despite the success of immune checkpoint inhibitors that target cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed-cell-death-1 (PD-1) in the treatment of metastatic melanoma, there is still great need to develop robust options for patients who are refractory to first line immunotherapy. As such there has been a resurgence in interest of adoptive cell transfer (ACT) particularly derived from tumor infiltrating lymphocytes. Moreover, the addition of cyclin dependent kinase 4/6 inhibitors (CDK4/6i) have been shown to greatly extend duration of response in combination with BRAF-MEK inhibitors (BRAF-MEKi) in pre-clinical models of melanoma. We therefore investigated whether combinations of BRAF-MEK-CDK4/6i and ACT were efficacious in murine models of melanoma. Triplet targeted therapy of BRAF-MEK-CDK4/6i with OT-1 ACT led to sustained and robust anti-tumor responses in BRAFi sensitive YOVAL1.1. We also show that BRAF-MEKi but not CDK4/6i enhanced MHC Class I expression in melanoma cell lines in vitro. Paradoxically CDK4/6i in low concentrations of IFN-γ reduced expression of MHC Class I and PD-L1 in YOVAL1.1. Overall, this work provides additional pre-clinical evidence to pursue combination of BRAF-MEK-CDK4/6i and to combine this combination with ACT in the clinic.
SHED-Dependent Oncogenic Signaling of the PEAK3 Pseudo-Kinase
Authors: Ounoughene Youcef , Fourgous Elise , Boublik Yvan , Saland Estelle , Guiraud Nathan , Recher Christian , Urbach Serge , Fort Philippe , Sarry Jean-Emmanuel , Fesquet Didier , Roche Serge
Published: December 2021

The PEAK1 and Pragmin/PEAK2 pseudo-kinases have emerged as important components of the protein tyrosine kinase pathway implicated in cancer progression. They can signal using a scaffolding mechanism that involves a conserved split helical dimerization (SHED) module. We recently identified PEAK3 as a novel member of this family based on structural homology; however, its signaling mechanism remains unclear. In this study, we found that, although it can self-associate, PEAK3 shows higher evolutionary divergence than PEAK1/2. Moreover, the PEAK3 protein is strongly expressed in human hematopoietic cells and is upregulated in acute myeloid leukemia. Functionally, PEAK3 overexpression in U2OS sarcoma cells enhanced their growth and migratory properties, while its silencing in THP1 leukemic cells reduced these effects. Importantly, an intact SHED module was required for these PEAK3 oncogenic activities. Mechanistically, through a phosphokinase survey, we identified PEAK3 as a novel inducer of AKT signaling, independent of growth-factor stimulation. Then, proteomic analyses revealed that PEAK3 interacts with the signaling proteins GRB2 and ASAP1/2 and the protein kinase PYK2, and that these interactions require the SHED domain. Moreover, PEAK3 activated PYK2, which promoted PEAK3 tyrosine phosphorylation, its association with GRB2 and ASAP1, and AKT signaling. Thus, the PEAK1-3 pseudo-kinases may use a conserved SHED-dependent mechanism to activate specific signaling proteins to promote oncogenesis.
Metastatic Colorectal Cancer
Authors: Passardi Alessandro , Marisi Giorgia , Ulivi Paola
Published: December 2021

International experts in the study of metastatic colorectal cancer (mCRC) present this series of 14 articles (eleven original articles and three literature reviews) [...]
Expression of Endogenous Retroviral RNA in Prostate Tumors has Prognostic Value and Shows Differences among Americans of African Versus European/Middle Eastern Ancestry
Authors: Kumar Vinay , McClelland Michael , Nguyen James , De Robles Gabriela , Ittmann Michael , Castro Patricia , Mercola Dan , Jia Zhenyu , Rahmatpanah Farah
Published: December 2021

Endogenous retroviruses (ERVs) are abundant, repetitive elements dispersed across the human genome and are implicated in various diseases. We investigated two potential roles for ERVs in prostate cancer (PCa). First, the PCa of Black Americans (BA) is diagnosed at an earlier median age and at a more advanced stage than the PCa of White Americans (WA). We used publicly available RNA-seq data from tumor-enriched samples of 27 BA and 65 WA PCa patients in order to identify 12 differentially expressed ERVs (padj < 0.1) and used a tissue microarray of the PCa cores from an independent set of BA and WA patients to validate the differential protein expression of one of these ERVs, ERV3-1 (p = 2.829 × 10−7). Second, we used 57 PCa tumors from patients of all ancestries from one hospital as a training set to identify the ERVs associated with time to biochemical relapse. A 29-ERV prognostic panel was then tested and validated on 35 separate PCa tumors from patients obtained in two different hospitals with a dramatic increase in prognostic power relative to clinical parameters alone (p = 7.4 × 10−11). In summary, ERV RNA expression differences in the prostate tumors of patients of different ancestries may be associated with dissimilarities in the mechanism of cancer progression. In addition, the correlation of expression of certain ERVs in prostate tumors with the risk of biochemical relapse indicates a possible role for ERV expression in cancer progression.
Clinically Relevant Oxygraphic Assay to Assess Mitochondrial Energy Metabolism in Acute Myeloid Leukemia Patients
Authors: Fovez Quentin , Laine William , Goursaud Laure , Berthon Celine , Germain Nicolas , Degand Claire , Sarry Jean-Emmanuel , Quesnel Bruno , Marchetti Philippe , Kluza Jerome
Published: December 2021

Resistant acute myeloid leukemia (AML) exhibits mitochondrial energy metabolism changes compared to newly diagnosed AML. This phenotype is often observed by evaluating the mitochondrial oxygen consumption of blasts, but most of the oximetry protocols were established from leukemia cell lines without validation on primary leukemia cells. Moreover, the cultures and storage conditions of blasts freshly extracted from patient blood or bone marrow cause stress, which must be evaluated before determining oxidative phosphorylation (OXPHOS). Herein, we evaluated different conditions to measure the oxygen consumption of blasts using extracellular flow analyzers. We first determined the minimum number of blasts required to measure OXPHOS. Next, we compared the OXPHOS of blasts cultured for 3 h and 18 h after collection and found that to maintain metabolic organization for 18 h, cytokine supplementation is necessary. Cytokines are also needed when measuring OXPHOS in cryopreserved, thawed and recultured blasts. Next, the concentrations of respiratory chain inhibitors and uncoupler FCCP were established. We found that the FCCP concentration required to reach the maximal respiration of blasts varied depending on the patient sample analyzed. These protocols provided can be used in future clinical studies to evaluate OXPHOS as a biomarker and assess the efficacy of treatments targeting mitochondria.
D-Mannose Slows Glioma Growth by Modulating Myeloperoxidase Activity
Authors: Jalali Motlagh Negin , Wang Cuihua , Kuellenberg Enrico Giovanni , Wojtkiewicz Gregory R. , Schmidt Stephan , Chen John W.
Published: December 2021

Host immune response in the tumor microenvironment plays key roles in tumorigenesis. We hypothesized that D-mannose, a simple sugar with anti-inflammatory properties, could decrease oxidative stress and slow glioma progression. Using a glioma stem cell model in immunocompetent mice, we induced gliomas in the brain and tracked MPO activity in vivo with and without D-mannose treatment. As expected, we found that D-mannose treatment decreased the number of MPO+ cells and slowed glioma progression compared to PBS-treated control animals with gliomas. Unexpectedly, instead of decreasing MPO activity, D-mannose increased MPO activity in vivo, revealing that D-mannose boosted the MPO activity per MPO+ cell. On the other hand, D-glucose had no effect on MPO activity. To better understand this effect, we examined the effect of D-mannose on bone marrow-derived myeloid cells. We found that D-mannose modulated MPO activity via two mechanisms: directly via N-glycosylation of MPO, which boosted the MPO activity of each molecule, and indirectly by increasing H2O2 production, the main substrate for MPO. This increased host immune response acted to reduce tumor size, suggesting that increasing MPO activity such as through D-mannose administration may be a potential new therapeutic direction for glioma treatment.
Debating Pros and Cons of Total Neoadjuvant Therapy in Rectal Cancer
Authors: Sclafani Francesco , Corrò Claudia , Koessler Thibaud
Published: December 2021

Recently, two large, randomised phase III clinical trials of total neoadjuvant therapy (TNT) in locally advanced rectal cancer were published (RAPIDO and PRODIGE 23). These two trials compared short-course radiotherapy (SCRT) followed by chemotherapy with standard chemoradiotherapy (CRT) and chemotherapy followed by CRT with standard CRT, respectively. They showed improvement in some of the outcomes such as distant recurrence and pathological complete response (pCR). No improvement, however, was observed in local disease control or the de-escalation of surgical procedures. Although it seems lawful to integrate TNT within the treatment algorithm of localised stage II and III rectal cancer, many questions remain unanswered, including which are the optimal criteria to identify patients who are most likely to benefit from this intensive treatment. Instead of providing a sterile summary of trial results, we put these in perspective in a pros and cons manner. Moreover, we discuss some biological aspects of rectal cancer, which may provide some insights into the current decision-making process, and represent the basis for the future development of alternative, more effective treatment strategies.
Beneficial Prognostic Effects of Aspirin in Patients Receiving Sorafenib for Hepatocellular Carcinoma: A Tale of Multiple Confounders
Authors: Ielasi Luca , Tovoli Francesco , Tonnini Matteo , Tortora Raffaella , Magini Giulia , Sacco Rodolfo , Pressiani Tiziana , Trevisani Franco , Sansone Vito , Marasco Giovanni , Piscaglia Fabio , Granito Alessandro
Published: December 2021

Case–control observational studies suggested that aspirin might prevent hepatocellular carcinoma (HCC) in high-risk patients, even if randomized clinical trials are lacking. Information regarding aspirin in subjects who already developed HCC, especially in its advanced stage, are scarce. While aspirin might be a low-cost option to improve the prognosis, multiple confounders and safety concerns are to be considered. In our retrospective analyses of a prospective dataset (n = 699), after assessing the factors associated with aspirin prescription, we applied an inverse probability treatment weight analysis to address the prescription bias. Analyses of post-sorafenib survival were also performed to reduce the influence of subsequent medications. Among the study population, 133 (19%) patients were receiving aspirin at the time of sorafenib prescription. Aspirin users had a higher platelet count and a lower prevalence of esophageal varices, macrovascular invasion, and Child–Pugh B status. The benefit of aspirin was confirmed in terms of overall survival (HR 0.702, 95% CI 0.543–0.908), progression-free survival, disease control rate (58.6 vs. 49.5%, p < 0.001), and post-sorafenib survival even after weighting. Minor bleeding events were more frequent in the aspirin group. Aspirin use was associated with better outcomes, even after the correction for confounders. While safety concerns arguably remain a problem, prospective trials for patients at low risk of bleeding are warranted.
Identification of Lynch Syndrome Carriers among Patients with Small Bowel Adenocarcinoma
Authors: Sánchez Ariadna , Bujanda Luis , Cuatrecasas Miriam , Bofill Alex , Alvarez-Urturi Cristina , Hernandez Goretti , Aguilera Lara , Carballal Sabela , Llach Joan , Herrera-Pariente Cristina , Iglesias Mar , Rivero-Sánchez Liseth , Jung Gerhard , Moreno Lorena , Ocaña Teresa , Bayarri Carolina , Pellise Maria , Castells Antoni , Castellví-Bel Sergi , Balaguer Francesc , Moreira Leticia
Published: December 2021

Background: Small bowel adenocarcinoma (SBA) is a rare disease which can be associated with Lynch syndrome (LS). LS tumors are characterized by the presence of microsatellite instability (MSI) and/or the loss of mismatch repair (MMR) protein expression. In SBA, the frequency of MMR deficient (MMRd) tumors varies from 5% to 35%. This study aims to describe the prevalence of LS carriers among patients with MMRd small bowel adenocarcinomas. Methods: A multicenter retrospective study with identification and MMR testing of all consecutive SBA between 2004 and 2020 in a multicenter Spanish study. Demographical data, tumor characteristics, follow-up and survival information were collected. Germline testing was driven by identification of MMRd tumors. Results: A total of 94 individuals diagnosed with SBA were recruited. We observed 20 (21.3%) MMRd tumors. In 9/15 (60%) patients with MMRd tumors, a pathogenic variant was identified (three MLH1, four MSH2, one MSH6 and one PMS2). Accordingly, the prevalence of LS among all SBA cases was 10.1%. Conclusions: More than one-fifth of SBA display MMRd and in more than a half is due to LS. Our data supports the implementation of universal MMR tumor testing among SBA for the identification of LS families.
Enhancing Methane Conversion by Modification of Zn States in Co-Reaction of MTA
Authors: Yu Yue , Xi Zhixiang , Zhou Bingjie , Jiang Binbo , Liao Zuwei , Yang Yao , Wang Jingdai , Huang Zhengliang , Sun Jingyuan , Yang Yongrong
Published: December 2021

Limited by harsh reaction conditions, the activation and utilization of methane were regarded as holy grail reaction. Co-reaction with methanol, successfully realizing mild conversion below 450 °C, provides practical strategies for methane conversion on metal-loaded ZSM-5 zeolites, especially for highly efficient Zn loaded ones. However, Zn species, regarded as active acid sites on the zeolite, have not been sufficiently studied. In this paper, Zn-loaded ZSM-5 zeolite was prepared, and Zn was modified by capacity, loading strategy, and treating atmosphere. Apparent methane conversion achieves 15.3% for 1.0Zn/Z-H2 (16.8% as calculated net conversion) with a significantly reduced loading of 1.0 wt.% against deactivation, which is among the best within related zeolite materials. Besides, compared to the MTA reaction, the addition of methane promotes the high-valued aromatic production from 49.4% to 54.8%, and inhibits the C10+ production from 7.8% to 3.6%. Notably, Zn2+ is found to be another active site different from the reported ZnOH+. Medium strong acid sites are proved to be beneficial for methane activation. This work provides suggestions for the modification of the Zn active site, in order to prepare highly efficient catalysts for methane activation and BTX production in co-reaction with methanol.
Kinetics and Mechanism of Aniline and Chloroanilines Degradation Photocatalyzed by Halloysite-TiO2 and Halloysite-Fe2O3 Nanocomposites
Authors: Szczepanik Beata , Słomkiewicz Piotr , Wideł Dariusz , Czaplicka Marianna , Frydel Laura
Published: December 2021

The kinetics of photocatalytic degradation of aniline, 2-chloroaniline, and 2,6-dichloroaniline in the presence of halloysite-TiO2 and halloysite-Fe2O3 nanocomposites, halloysite containing naturally dispersed TiO2, Fe2O3, commercial TiO2, P25, and α-Fe2O3 photocatalysts, were investigated with two approaches: the Langmuir–Hinshelwood and first-order equations. Adsorption equilibrium constants and adsorption enthalpies, photodegradation rate constants, and activation energies for photocatalytic degradation were calculated for all studied amines photodegradation. The photodegradation mechanism was proposed according to organic intermediates identified by mass spectrometry and electrophoresis methods. Based on experimental results, it can be concluded that after 300 min of irradiation, aniline, 2-chloro-, and 2,6-dichloroaniline were completely degraded in the presence of used photocatalysts. Research results allowed us to conclude that higher adsorption capacity and immobilization of TiO2 and Fe2O3 on the halloysite surface in the case of halloysite-TiO2 and halloysite-Fe2O3 nanocomposites significantly increases photocatalytic activity of these materials in comparison to the commercial photocatalyst: TiO2, Fe2O3, and P25.
Dehydration of Xylose to Furfural over Imidazolium-Based Ionic Liquid with Phase Separation
Authors: Hua Derun , Ding Hao , Liu Yunfeng , Li Jian , Han Baojun
Published: December 2021

An environmentally friendly catalyst and task-specific ionic liquid (IL), 1-(4-sulfonic acid) butyl-3-cetyl-2-methyl imidazolium hydrogen sulfate, was applied to the dehydration of xylose to furfural. Its structure was determined by FT-IR, 1H NMR technologies. The solubility of IL in water changed with the temperature, and had the advantages of homogeneous and heterogeneous catalysts. At the given conditions, xylose conversion of 95.3% and furfural yield of 67.5% were achieved over IL.
Shear Stress Alterations Activate BMP4/pSMAD5 Signaling and Induce Endothelial Mesenchymal Transition in Varicose Veins
Authors: Chandran Latha Karthika , Sreekumar Ahalya , Beena Vyshna , S.S. Binil Raj , Lakkappa RaviKumar B. , Kalyani Ravi , Nair Radhakrishnan , Kalpana Saligrama Ramegowda , Kartha Chandrasekharan C. , Surendran Sumi
Published: December 2021

Chronic venous diseases, including varicose veins, are characterized by hemodynamic disturbances due to valve defects, venous insufficiency, and orthostatism. Veins are physiologically low shear stress systems, and how altered hemodynamics drives focal endothelial dysfunction and causes venous remodeling is unknown. Here we demonstrate the occurrence of endothelial to mesenchymal transition (EndMT) in human varicose veins. Moreover, the BMP4-pSMAD5 pathway was robustly upregulated in varicose veins. In vitro flow-based assays using human vein, endothelial cells cultured in microfluidic chambers show that even minimal disturbances in shear stress as may occur in early stages of venous insufficiency induce BMP4-pSMAD5-based phenotype switching. Furthermore, low shear stress at uniform laminar pattern does not induce EndMT in venous endothelial cells. Targeting the BMP4-pSMAD5 pathway with small molecule inhibitor LDN193189 reduced SNAI1/2 expression in venous endothelial cells exposed to disturbed flow. TGFβ inhibitor SB505124 was less efficient in inhibiting EndMT in venous endothelial cells exposed to disturbed flow. We conclude that disturbed shear stress, even in the absence of any oscillatory flow, induces EndMT in varicose veins via activation of BMP4/pSMAD5-SNAI1/2 signaling. The present findings serve as a rationale for the possible use of small molecular mechanotherapeutics in the management of varicose veins.
The Use of Nanomedicine to Target Signaling by the PAK Kinases for Disease Treatment
Authors: Wang Yiling , Minden Audrey
Published: December 2021

P21-activated kinases (PAKs) are serine/threonine kinases involved in the regulation of cell survival, proliferation, inhibition of apoptosis, and the regulation of cell morphology. Some members of the PAK family are highly expressed in several types of cancer, and they have also been implicated in several other medical disorders. They are thus considered to be good targets for treatment of cancer and other diseases. Although there are several inhibitors of the PAKs, the utility of some of these inhibitors is reduced for several reasons, including limited metabolic stability. One way to overcome this problem is the use of nanoparticles, which have the potential to increase drug delivery. The overall goals of this review are to describe the roles for PAK kinases in cell signaling and disease, and to describe how the use of nanomedicine is a promising new method for administering PAK inhibitors for the purpose of disease treatment and research. We discuss some of the basic mechanisms behind nanomedicine technology, and we then describe how these techniques are being used to package and deliver PAK inhibitors.
Neutrophil-Derived Extracellular Vesicles Activate Platelets after Pneumolysin Exposure
Authors: Letsiou Eleftheria , Teixeira Alves Luiz Gustavo , Felten Matthias , Mitchell Timothy J. , Müller-Redetzky Holger C. , Dudek Steven M. , Witzenrath Martin
Published: December 2021

Pneumolysin (PLY) is a pore-forming toxin of Streptococcus pneumoniae that contributes substantially to the inflammatory processes underlying pneumococcal pneumonia and lung injury. Host responses against S. pneumoniae are regulated in part by neutrophils and platelets, both individually and in cooperative interaction. Previous studies have shown that PLY can target both neutrophils and platelets, however, the mechanisms by which PLY directly affects these cells and alters their interactions are not completely understood. In this study, we characterize the effects of PLY on neutrophils and platelets and explore the mechanisms by which PLY may induce neutrophil–platelet interactions. In vitro studies demonstrated that PLY causes the formation of neutrophil extracellular traps (NETs) and the release of extracellular vesicles (EVs) from both human and murine neutrophils. In vivo, neutrophil EV (nEV) levels were increased in mice infected with S. pneumoniae. In platelets, treatment with PLY induced the cell surface expression of P-selectin (CD62P) and binding to annexin V and caused a significant release of platelet EVs (pl-EVs). Moreover, PLY-induced nEVs but not NETs promoted platelet activation. The pretreatment of nEVs with proteinase K inhibited platelet activation, indicating that the surface proteins of nEVs play a role in this process. Our findings demonstrate that PLY activates neutrophils and platelets to release EVs and support an important role for neutrophil EVs in modulating platelet functions in pneumococcal infections.
Unravelling the Impact of the Genetic Variant rs1042058 within the TPL2 Risk Gene Locus on Molecular and Clinical Disease Course Patients with Inflammatory Bowel Disease
Authors: Morsy Yasser , Brillant Nathalie , Franc Yannick , Scharl Michael , Wawrzyniak Marcin ,   on behalf of the Swiss IBD Cohort Study Group
Published: December 2021

Background: The single nucleotide polymorphism (SNP) rs1042058 within the gene locus encoding tumor progression locus 2 (TPL2) has been recently identified as a risk gene for inflammatory bowel disease (IBD). TPL2 has been shown to regulate pro-inflammatory signaling and cytokine secretion, while inhibition of TPL2 decreases intestinal inflammation in vivo. However, the clinical and molecular implications of this disease-associated TPL2 variation in IBD patients have not yet been studied. Methods: We analyzed the impact of the IBD-associated TPL2 variation using clinical data of 2145 genotyped patients from the Swiss IBD Cohort Study (SIBDCS). Furthermore, we assessed the molecular consequences of the TPL2 variation in ulcerative colitis (UC) and Crohn’s disease (CD) patients by real-time PCR and multiplex ELISA of colon biopsies or serum, respectively. Results: We found that presence of the SNP rs1042058 within the TPL2 gene locus results in significantly higher numbers of CD patients suffering from peripheral arthritis. In contrast, UC patients carrying this variant feature a lower risk for intestinal surgery. On a molecular level, the presence of the rs1042058 (GG) IBD-risk polymorphism in TPL2 was associated with decreased mRNA levels of IL-10 in CD patients and decreased levels of IL-18 in the intestine of UC patients. Conclusions: Our data suggest that the presence of the IBD-associated TPL2 variation might indicate a more severe disease course in CD patients. These results reveal a potential therapeutic target and demonstrate the relevance of the IBD-associated TPL2 SNP as a predictive biomarker in IBD.