bluuebunny/crossref_metadata_2025 huggingface dataset:
Co-Occurrence of Differentiated Thyroid Cancer and Second Primary Malignancy: Correlation with Expression Profiles of Mismatch Repair Protein and Cell Cycle Regulators
Authors: Liu Chih-Yi , Huang Ching-Shui , Huang Chi-Cheng , Ku Wei-Chi , Shih Hsing-Yu , Huang Chi-Jung
Published: November 2021

Some patients with thyroid cancer develop a second primary cancer. Defining the characteristics of patients with double primary cancers (DPCs) is crucial and needs to be followed. In this study, we examine molecular profiles in DPC. We enrolled 71 patients who received thyroid cancer surgery, 26 with single thyroid cancer (STC), and 45 with DPC. A retrograde cohort was used to develop immunohistochemical expressions of mismatch repair (MMR) proteins and cell-cycle-related markers from tissue microarrays to produce an equation for predicting the occurrence of DPC. The multivariate logistic model of 67 randomly selected patients (24 with STC and 43 with DPC) identified that the expression of deficient MMR (dMMR) (odds ratio (OR), 10.34; 95% confidence interval (CI), 2.17–49.21) and pRb (OR, 62.71; 95% CI, 4.83–814.22) were significantly associated with a higher risk of DPC. In contrast, the expression of CDK4 (OR, 0.19; 95% CI, 0.04–0.99) and CDK6 (OR, 0.03; 95% CI, 0.002–0.44) was significantly associated with a lower risk of DPC. Collectively, dMMR, pRb, CDK4, and CDK6 have a sensitivity of 88.9% (95% CI, 75.1–95.8) and a specificity of 69.2% (95% CI, 48.1–84.9) for occurrence of DPC in all 71 patients. This is the first report to demonstrate the molecular differentiation of STC and DPC. Overall, the integral molecular profile performed excellent discrimination and denoted an exponential function to predict the probability of DPC.
In Vivo Reflectance Confocal Microscopy as a Response Monitoring Tool for Actinic Keratoses Undergoing Cryotherapy and Photodynamic Therapy
Authors: Curiel-Lewandrowski Clara , Myrdal Caitlyn N. , Saboda Kathylynn , Hu Chengcheng , Arzberger Edith , Pellacani Giovanni , Legat Franz Josef , Ulrich Martina , Hochfellner Petra , Oliviero Margaret C. , Pasquali Paola , Gill Melissa , Hofmann-Wellenhof Rainer
Published: November 2021

Reflectance confocal microscopy (RCM) presents a non-invasive method to image actinic keratosis (AK) at a cellular level. However, RCM criteria for AK response monitoring vary across studies and a universal, standardized approach is lacking. We aimed to identify reliable AK response criteria and to compare the clinical and RCM evaluation of responses across AK severity grades. Twenty patients were included and randomized to receive either cryotherapy (n = 10) or PDT (n = 10). Clinical assessment and RCM evaluation of 12 criteria were performed in AK lesions and photodamaged skin at baseline, 3 and 6 months. We identified the RCM criteria that reliably characterize AK at baseline and display significant reduction following treatment. Those with the highest baseline odds ratio (OR), good interobserver agreement, and most significant change over time were atypical honeycomb pattern (OR: 12.7, CI: 5.7–28.1), hyperkeratosis (OR: 13.6, CI: 5.3–34.9), stratum corneum disruption (OR: 7.8, CI: 3.5–17.3), and disarranged epidermal pattern (OR: 6.5, CI: 2.9–14.8). Clinical evaluation demonstrated a significant treatment response without relapse. However, in grade 2 AK, 10/12 RCM parameters increased from 3 to 6 months, which suggested early subclinical recurrence detection by RCM. Incorporating standardized RCM protocols for the assessment of AK may enable a more meaningful comparison across clinical trials, while allowing for the early detection of relapses and evaluation of biological responses to therapy over time.
Differential and Common Signatures of miRNA Expression and Methylation in Childhood Central Nervous System Malignancies: An Experimental and Computational Approach
Authors: Lambrou George I. , Poulou Myrto , Giannikou Krinio , Themistocleous Marios , Zaravinos Apostolos , Braoudaki Maria
Published: November 2021

Epigenetic modifications are considered of utmost significance for tumor ontogenesis and progression. Especially, it has been found that miRNA expression, as well as DNA methylation plays a significant role in central nervous system tumors during childhood. A total of 49 resected brain tumors from children were used for further analysis. DNA methylation was identified with methylation-specific MLPA and, in particular, for the tumor suppressor genes CASP8, RASSF1, MGMT, MSH6, GATA5, ATM1, TP53, and CADM1. miRNAs were identified with microarray screening, as well as selected samples, were tested for their mRNA expression levels. CASP8, RASSF1 were the most frequently methylated genes in all tumor samples. Simultaneous methylation of genes manifested significant results with respect to tumor staging, tumor type, and the differentiation of tumor and control samples. There was no significant dependence observed with the methylation of one gene promoter, rather with the simultaneous presence of all detected methylated genes’ promoters. miRNA expression was found to be correlated to gene methylation. Epigenetic regulation appears to be of major importance in tumor progression and pathophysiology, making it an imperative field of study.
High Expression of PPM1D Induces Tumors Phenotypically Similar to TP53 Loss-of-Function Mutations in Mice
Authors: Milosevic Jelena , Fransson Susanne , Gulyas Miklos , Olsen Thale K. , Gallo-Oller Gabriel , Treis Diana , Elfman Lotta H. M. , Wilhelm Margareta , Martinsson Tommy , Baryawno Ninib , Kogner Per , Johnsen John Inge
Published: November 2021

PPM1D is a negative regulator of p53 and genomic aberrations resulting in increased activity of PPM1D have been observed in cancers of different origins, indicating that PPM1D has oncogenic properties. We established a transgenic mouse model overexpressing PPM1D and showed that these mice developed a wide variety of cancers. PPM1D-expressing mice developed tumors phenotypically and genetically similar to tumors in mice with dysfunctional p53. T-cell lymphoblastic lymphoma was the most frequent cancer observed in these mice (55%) followed by adenocarcinomas (24%), leukemia (12%) and other solid tumors including neuroblastoma. Characterization of T-cell lymphomas in mice overexpressing PPM1D demonstrates Pten-deletion and p53-accumulation similar to mice with p53 loss-of-function. Also, Notch1 mutations which are recurrently observed in T-cell acute lymphoblastic lymphoma (T-ALL) were frequently detected in PPM1D-transgenic mice. Hence, PPM1D acts as an oncogenic driver in connection with cellular stress, suggesting that the PPM1D gene status and expression levels should be investigated in TP53 wild-type tumors.
Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma
Authors: Henderson James M. , Xiang Michelle S. W. , Huang Jiali Carrie , Wetzel Stefanie , Jiang Linxuan , Lai Jack H. , Wu Wengen , Kench James G. , Bachovchin William W. , Roediger Ben , McCaughan Geoffrey W. , Zhang Hui Emma , Gorrell Mark D.
Published: November 2021

The mRNA expression of the dipeptidyl peptidase 4 (DPP4) gene family is highly upregulated in human hepatocellular carcinoma (HCC) and is associated with poor survival in HCC patients. Compounds that inhibit the DPP4 enzyme family, such as talabostat and ARI-4175, can mediate tumour regression by immune-mediated mechanisms that are believed to include NLRP1 activation. This study investigated the expression and activity of the DPP4 family during the development of HCC and evaluated the efficacy of ARI-4175 in the treatment of early HCC in mice. This first report on this enzyme family in HCC-bearing mice showed DPP9 upregulation in HCC, whereas intrahepatic DPP8/9 and DPP4 enzyme activity levels decreased with age. We demonstrated that ARI-4175 significantly lowered the total number of macroscopic liver nodules in these mice. In addition, ARI-4175 increased intrahepatic inflammatory cell infiltration, including CD8+ T cell numbers, into the HCC-bearing livers. Furthermore, ARI-4175 activated a critical component of the inflammasome pathway, caspase-1, in these HCC-bearing livers. This is the first evidence of caspase-1 activation by a pan-DPP inhibitor in the liver. Our data suggest that targeting the DPP4 enzyme family may be a novel and effective approach to promote anti-tumour immunity in HCC via caspase-1 activation.
3D-Printed Replica and Porcine Explants for Pre-Clinical Optimization of Endoscopic Tumor Treatment by Magnetic Targeting
Authors: Roeth Anjali A. , Garretson Ian , Beltz Maja , Herbold Till , Schulze-Hagen Maximilian , Quaisser Sebastian , Georgens Alex , Reith Dirk , Slabu Ioana , Klink Christian D. , Neumann Ulf P. , Linke Barbara S.
Published: November 2021

Background: Animal models have limitations in cancer research, especially regarding anatomy-specific questions. An example is the exact endoscopic placement of magnetic field traps for the targeting of therapeutic nanoparticles. Three-dimensional-printed human replicas may be used to overcome these pitfalls. Methods: We developed a transparent method to fabricate a patient-specific replica, allowing for a broad scope of application. As an example, we then additively manufactured the relevant organs of a patient with locally advanced pancreatic ductal adenocarcinoma. We performed experimental design investigations for a magnetic field trap and explored the best fixation methods on an explanted porcine stomach wall. Results: We describe in detail the eight-step development of a 3D replica from CT data. To guide further users in their decisions, a morphologic box was created. Endoscopies were performed on the replica and the resulting magnetic field was investigated. The best fixation method to hold the magnetic field traps stably in place was the fixation of loops at the stomach wall with endoscopic single-use clips. Conclusions: Using only open access software, the developed method may be used for a variety of cancer-related research questions. A detailed description of the workflow allows one to produce a 3D replica for research or training purposes at low costs.
Incorporating Robustness to Imaging Physics into Radiomic Feature Selection for Breast Cancer Risk Estimation
Authors: Acciavatti Raymond J. , Cohen Eric A. , Maghsoudi Omid Haji , Gastounioti Aimilia , Pantalone Lauren , Hsieh Meng-Kang , Conant Emily F. , Scott Christopher G. , Winham Stacey J. , Kerlikowske Karla , Vachon Celine , Maidment Andrew D. A. , Kontos Despina
Published: November 2021

Digital mammography has seen an explosion in the number of radiomic features used for risk-assessment modeling. However, having more features is not necessarily beneficial, as some features may be overly sensitive to imaging physics (contrast, noise, and image sharpness). To measure the effects of imaging physics, we analyzed the feature variation across imaging acquisition settings (kV, mAs) using an anthropomorphic phantom. We also analyzed the intra-woman variation (IWV), a measure of how much a feature varies between breasts with similar parenchymal patterns—a woman’s left and right breasts. From 341 features, we identified “robust” features that minimized the effects of imaging physics and IWV. We also investigated whether robust features offered better case-control classification in an independent data set of 575 images, all with an overall BI-RADS® assessment of 1 (negative) or 2 (benign); 115 images (cases) were of women who developed cancer at least one year after that screening image, matched to 460 controls. We modeled cancer occurrence via logistic regression, using cross-validated area under the receiver-operating-characteristic curve (AUC) to measure model performance. Models using features from the most-robust quartile of features yielded an AUC = 0.59, versus 0.54 for the least-robust, with p < 0.005 for the difference among the quartiles.
ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer
Authors: Putti Sabrina , Giovinazzo Alessandro , Merolle Matilde , Falchetti Maria Laura , Pellegrini Manuela
Published: November 2021

ATM is one of the principal players of the DNA damage response. This protein exerts its role in DNA repair during cell cycle replication, oxidative stress, and DNA damage from endogenous events or exogenous agents. When is activated, ATM phosphorylates multiple substrates that participate in DNA repair, through its phosphoinositide 3-kinase like domain at the 3′end of the protein. The absence of ATM is the cause of a rare autosomal recessive disorder called Ataxia Telangiectasia characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility, and radiation sensitivity. There is a correlation between the severity of the phenotype and the mutations, depending on the residual activity of the protein. The analysis of patient mutations and mouse models revealed that the presence of inactive ATM, named ATM kinase-dead, is more cancer prone and lethal than its absence. ATM mutations fall into the whole gene sequence, and it is very difficult to predict the resulting effects, except for some frequent mutations. In this regard, is necessary to characterize the mutated protein to assess if it is stable and maintains some residual kinase activity. Moreover, the whole-genome sequencing of cancer patients with somatic or germline mutations has highlighted a high percentage of ATM mutations in the phosphoinositide 3-kinase domain, mostly in cancer cells resistant to classical therapy. The relevant differences between the complete absence of ATM and the presence of the inactive form in in vitro and in vivo models need to be explored in more detail to predict cancer predisposition of A-T patients and to discover new therapies for ATM-associated cancer cells. In this review, we summarize the multiple discoveries from humans and mouse models on ATM mutations, focusing into the inactive versus null ATM.
Genetic Landscape and Emerging Therapies in Uveal Melanoma
Authors: Seedor Rino S. , Orloff Marlana , Sato Takami
Published: November 2021

Despite successful treatment of primary uveal melanoma, up to 50% of patients will develop systemic metastasis. Metastatic disease portends a poor outcome, and no adjuvant or metastatic therapy has been FDA approved. The genetic landscape of uveal melanoma is unique, providing prognostic and potentially therapeutic insight. In this review, we discuss our current understanding of the molecular and cytogenetic mutations in uveal melanoma, and the importance of obtaining such information. Most of our knowledge is based on primary uveal melanoma and a better understanding of the mutational landscape in metastatic uveal melanoma is needed. Clinical trials targeting certain mutations such as GNAQ/GNA11, BAP1, and SF3B1 are ongoing and promising. We also discuss the role of liquid biopsies in uveal melanoma in this review.
A Phase Ib Study of Sotrastaurin, a PKC Inhibitor, and Alpelisib, a PI3Kα Inhibitor, in Patients with Metastatic Uveal Melanoma
Authors: Shoushtari Alexander N. , Khan Shaheer , Komatsubara Kimberly , Feun Lynn , Acquavella Nicolas , Singh-Kandah Shahnaz , Negri Tiffany , Nesson Alexandra , Abbate Kelly , Cremers Serge , Musi Elgilda , Ambrosini Grazia , Lee Shing , Schwartz Gary K. , Carvajal Richard D.
Published: November 2021

Uveal melanoma (UM) is a rare subset of melanoma characterized by the presence of early initiating GNAQ/11 mutations, with downstream activation of the PKC, MAPK, and PI3Kα pathways. Activity has been observed with the PKC inhibitors sotrastaurin (AEB071) and darovasertib (IDE196) in patients with UM. Inhibition of the PI3K pathway enhances PKC inhibition in in vivo models. We therefore conducted a phase Ib study of sotrastaurin in combination with the PI3Kα inhibitor alpelisib to identify a tolerable regimen that may enhance the activity of PKC inhibition alone. Patients with metastatic uveal melanoma (n = 24) or GNAQ/11 mutant cutaneous melanoma (n = 1) were enrolled on escalating dose levels of sotrastaurin (100–400 mg BID) and alpelisib (200–350 mg QD). The primary objective was to identify the maximum tolerated dose (MTD) of these agents when administered in combination. Treatment-related adverse events (AE) occurred in 86% (any grade) and 29% (Grade 3). No Grade 4–5-related AEs occurred. Dose Level 4 (sotrastaurin 200 mg BID and alpelisib 350 mg QD) was identified as the maximum tolerated dose. Pharmacokinetic analysis demonstrated increasing concentration levels with increasing doses of sotrastaurin and alpelisib, without evidence of interaction between agents. Pharmacodynamic assessment of pMARCKS and pAKT protein expression with drug exposure suggested modest target inhibition that did not correlate with clinical response. No objective responses were observed, and median progression-free survival was 8 weeks (range, 3–51 weeks). Although a tolerable dose of sotrastaurin and alpelisib was identified with pharmacodynamic evidence of target inhibition and without evidence of a corresponding immunosuppressive effect, limited clinical activity was observed.
Oncogene-Induced Reprogramming in Acute Lymphoblastic Leukemia: Towards Targeted Therapy of Leukemia-Initiating Cells
Authors: Fregona Vincent , Bayet Manon , Gerby Bastien
Published: November 2021

Our understanding of the hierarchical structure of acute leukemia has yet to be fully translated into therapeutic approaches. Indeed, chemotherapy still has to take into account the possibility that leukemia-initiating cells may have a distinct chemosensitivity profile compared to the bulk of the tumor, and therefore are spared by the current treatment, causing the relapse of the disease. Therefore, the identification of the cell-of-origin of leukemia remains a longstanding question and an exciting challenge in cancer research of the last few decades. With a particular focus on acute lymphoblastic leukemia, we present in this review the previous and current concepts exploring the phenotypic, genetic and functional heterogeneity in patients. We also discuss the benefits of using engineered mouse models to explore the early steps of leukemia development and to identify the biological mechanisms driving the emergence of leukemia-initiating cells. Finally, we describe the major prospects for the discovery of new therapeutic strategies that specifically target their aberrant stem cell-like functions.
Targeted Deep Sequencing of Mycosis Fungoides Reveals Intracellular Signaling Pathways Associated with Aggressiveness and Large Cell Transformation
Authors: Wobser Marion , Roth Sabine , Appenzeller Silke , Houben Roland , Schrama David , Goebeler Matthias , Geissinger Eva , Rosenwald Andreas , Maurus Katja
Published: November 2021

Introduction: Large-cell transformation (LCT) of mycosis fungoides (MF) has been associated with a higher risk of relapse and progression and, consequently, restricted prognosis. Its molecular pathogenesis has not been elucidated yet. Materials and Methods: In order to address molecular mechanisms of LCT, we performed hybrid capture panel-based sequencing of skin biopsies from 10 patients suffering from MF with LCT versus 17 patients without LCT including follow-up biopsies during clinical course, respectively (51 samples in total). The analyzed patients were attributed to three different groups based on the presence of LCT and clinical behavior. Results: While indolent MF cases without LCT did not show pathogenic driver mutations, a high rate of oncogenic alterations was detected in patients with LCT and aggressive clinical courses. Various genes of different oncogenic signaling pathways, including the MAPK and JAK-STAT signaling pathways, as well as epigenetic modifiers were affected. A high inter-individual and distinctive intra-individual mutation diversity was observed. Oncogenic RAS mutations were exclusively detected in patients with LCT. Conclusion: Our data demonstrate that LCT transition of MF is associated with increased frequency of somatic mutations in cancer-associated genes. In particular, the activation of RAS signaling—together with epigenetic dysregulation—may crucially contribute to the molecular pathogenesis of the LCT phenotype, thus conveying its adverse clinical behavior.
Computational-Designed Enzyme for β-Tyrosine Production in Lignin Valorization
Authors: Peng Fei , Aliyu Habibu , Delavault André , Engel Ulrike , Rudat Jens
Published: November 2021

Lignin is an underutilized sustainable source of aromatic compounds. To valorize the low-value lignin monomers, we proposed an efficient strategy, involving enzymatic conversion from trans-p-hydroxycinnamic acids to generate valued-added canonical and non-canonical aromatic amino acids. Among them, β-amino acids are recognized as building blocks for bioactive natural products and pharmaceutical ingredients due to their attractive antitumor properties. Using computational enzyme design, the (R)-β-selective phenylalanine aminomutase from Taxus chinensis (TchPAM) was successfully mutated to accept β-tyrosine as the substrate, as well as to generate the (R)-β-tyrosine with excellent enantiopurity (ee > 99%) as the unique product from trans-p-hydroxycinnamic acid. Moreover, the kinetic parameters were determined for the reaction of four Y424 enzyme variants with the synthesis of different phenylalanine and tyrosine enantiomers. In the ammonia elimination reaction of (R)-β-tyrosine, the variants Y424N and Y424C displayed a two-fold increased catalytic efficiency of the wild type. In this work, a binding pocket in the active site, including Y424, K427, I431, and E455, was examined for its influence on the β-enantioselectivity of this enzyme family. Combining the upstream lignin depolymerization and downstream production, a sustainable value chain based on lignin is enabled. In summary, we report a β-tyrosine synthesis process from a monolignol component, offering a new way for lignin valorization by biocatalyst modification.
Dynamics of Reactive Oxygen Species on Cobalt-Containing Spinel Oxides in Cyclic CO Oxidation
Authors: Dreyer Maik , Rabe Anna , Budiyanto Eko , Friedel Ortega Klaus , Najafishirtari Sharif , Tüysüz Harun , Behrens Malte
Published: November 2021

Reactive oxygen species (ROS) are considered to be responsible for the high catalytic activity of transition metal oxides like Co3-xFexO4 in oxidation reactions, but the detailed influences of catalyst composition and morphology on the formation of these reactive oxygen species are not fully understood. In the presented study, Co3O4 spinels of different mesostructures, i.e., particle size, crystallinity, and specific surface area, are characterized by powder X-ray diffraction, scanning electron microscopy, and physisorption. The materials were tested in CO oxidation performed in consecutive runs and compared to a Co3-xFexO4 composition series with a similar mesostructure to study the effects of catalyst morphology and composition on ROS formation. In the first run, the CO conversion was observed to be dominated by the exposed surface area for the pure Co-spinels, while a negative effect of Fe content in the spinels was seen. In the following oxidation run, a U-shaped conversion curve was observed for materials with high surface area, which indicated the in situ formation of ROS on those materials that were responsible for the new activity at low temperature. This activation was not stable at the higher reaction temperature but was confirmed after temperature-programmed oxidation (TPO). However, no activation after the first run was observed for low-surface-area and highly crystalline materials, and the lowest surface-area material was not even activated after TPO. Among the catalyst series studied here, a correlation of small particle size and large surface area with the ability for ROS formation is presented, and the benefit of a nanoscaled catalyst is discussed. Despite the generally negative effect of Fe, the highest relative activation was observed at intermediate Fe contents suggesting that Fe may be involved in ROS formation.
A Model for Correcting the Pressure Drop between Two Monoliths
Authors: Cornejo Ivan
Published: November 2021

This paper is concerned with the modeling of the pressure drop through monolith honeycombs. Monolith substrates are promising for the intensification of catalytic processes, especially because of their low back-pressure. There have been several improvements in the modeling of monolith reactors during the last decade, most of them focused on a single substrate configuration, while research in multiple substrates in a single reactor is still sparse. One example is the so-called "minor losses", such as those because of the flow entering and leaving a substrate. Both phenomena interact when two monoliths are placed close in series, and the extra losses produced by them may become relevant when relatively short monoliths are used. In this paper, a spatially resolved computational model of monolith channels arranged in series is used to compute the extra pressure drop because of the flow leaving one substrate and entering the next one downstream. Several Reynolds numbers and spacing lengths for the channels between substrates are investigated. According to the results, for close-coupled monoliths, the inlet and outlet effects produce a negligible pressure drop compared to that in a single monolith configuration. This phenomenon can be accounted for by introducing a correction factor. The magnitude of the correction factor depends on the channel’s Reynolds number, diameter, and spacing length. A model for such a factor is proposed. The model accurately predicts the trend and magnitude of the correction factor.
Poly(imidazolium) Carbosilane Dendrimers: Synthesis, Catalytic Activity in Redox Esterification of α,β-Unsaturated Aldehydes and Recycling via Organic Solvent Nanofiltration
Authors: Krupková Alena , Kubátová Klára , Červenková Šťastná Lucie , Cuřínová Petra , Müllerová Monika , Karban Jindřich , Čermák Jan , Strašák Tomáš
Published: November 2021

Three series of poly(ionic) carbosilane dendrimers peripherally functionalized with imidazolium groups substituted on N-3 with methyl, isopropyl and 2,6-diisopropylphenyl (Dipp) were prepared up to the 3rd generation together with model monovalent imidazolium iodides and used as N-heterocyclic carbene (NHC) precursors. Catalytic activity of model and dendritic NHCs generated in situ by deprotonation with DBU was tested in redox esterification of α,β-unsaturated aldehydes and the influence of substitution, dendrimer generation, temperature and substrate structure on the reaction outcome was evaluated. Dipp substituted NHCs showed high activity and selectivity in the reaction with primary alcohols. Effectiveness of organic solvent nanofiltration for the recycling of dendritic NHCs was demonstrated on the 1st generation Dipp substituted catalyst in model redox esterification of cinnamaldehyde with benzyl alcohol. A marked increase in both activity and selectivity in the first four reaction runs was observed and this improved performance was preserved in the following catalytic cycles.
The Effect of Cobalt Catalyst Loading at Very High Pressure Plasma-Catalysis in Fischer-Tropsch Synthesis
Authors: Govender Byron Bradley , Iwarere Samuel Ayodele , Ramjugernath Deresh
Published: November 2021

The influence of different catalyst cobalt loadings on the C1–C3 hydrocarbon product yields and energy consumption in plasma-catalytic Fischer-Tropsch synthesis (FTS) was investigated from the standpoint of various reactor operating conditions: pressure (0.5 to 10 MPa), current (250 to 450 mA) and inter-electrode gap (0.5 to 2 mm). This was accomplished by introducing a mullite substrate, coated with 2 wt%-Co/5 wt%-Al2O3, 6 wt%-Co/5 wt%-Al2O3 or 0 wt%-Co/5 wt%-Al2O3 (blank catalyst), into a recently developed high pressure arc discharge reactor. The blank catalyst was ineffective in synthesizing hydrocarbons. Between the blank catalyst, 2 wt%, and the 6 wt% Co catalyst, the 6 wt% improved C1–C3 hydrocarbon production at all conditions, with higher yields and relatively lower energy consumption at (i) 10 MPa at 10 s, and 2 MPa at 60 s, for the pressure variation study; (ii) 250 mA for the current variation study; and (iii) 2 mm for the inter-electrode gap variation study. The inter-electrode gap of 2 mm, using the 6 wt% Co catalyst, led to the overall highest methane, ethane, ethylene, propane and propylene yields of 22 424, 517, 101, 79 and 19 ppm, respectively, compared to 40 ppm of methane and <1 ppm of C1–C3 hydrocarbons for the blank catalyst, while consuming 660 times less energy for the production of a mole of methane. Furthermore, the 6 wt% Co catalyst produced carbon nanotubes (CNTs), detected via transmission electron microscopy (TEM). In addition, scanning electron microscopy (SEM), energy dispersive x-ray spectroscopy (EDX) and x-ray diffraction (XRD) showed that the cobalt catalyst was modified by plasma treatment.
Crystal Imperfections of Industrial Vanadium Phosphorous Oxide Catalysts
Authors: Kappel Isabella , Böcklein Sebastian , Park SoHyun , Wharmby Michael , Mestl Gerhard , Schmahl Wolfgang W.
Published: November 2021

This study presents information about crystal imperfections in the main phase of industrial vanadium phosphorous oxide catalysts that are used to catalyze the oxidation of n-butane to maleic anhydride, being an important intermediate in the chemical industry. The mechanism of this reaction is still debated, and the catalytically active and selective surface centers have not yet been identified. The results presented are based on X-ray diffraction data obtained by both laboratory-scale and synchrotron powder diffraction experiments, as well as laboratory-scale single-crystal diffraction experiments. It has been proven that pronounced Bragg reflection broadening effects found in laboratory-scale powder diffraction patterns of industrial VPO catalysts are real and not due to an insufficient 2-θ resolution of the apparatus. In the framework of this work, a powder diffraction full profile fitting strategy was developed using the TOPAS software, which was applied to analyze the X-ray diffraction data of four differently activated industrial catalyst samples, originating from one batch after they had been catalytically tested. It was found that the reflection broadening is mainly caused by an anisotropic crystal size, which results in platelet-shaped crystallites of vanadyl pyrophosphate. A further contribution to the reflex broadening, especially for (111), was found to be a result of stacking faults perpendicular to the a direction in the crystal structure of vanadyl pyrophosphate. These results were used to elaborate on possible correlations between structural proxies and catalytic performance. A direct correlation between the extension of coherently scattering domains in the z direction and the catalyst’s selectivity could be proven, whereas the activity turned out to be dependent on the crystallite shape. Regarding the phase contents, it could be shown that sample catalysts containing a higher amount of β-VO(PO3)2 showed increased catalytic activity.
The Study of C3H6 Impact on Selective Catalytic Reduction by Ammonia (NH3-SCR) Performance over Cu-SAPO-34 Catalysts
Authors: Duan Yingfeng , Wang Lina , Zhang Yagang , Du Wei , Zhang Yating
Published: November 2021

In present work, the catalytic performance of Cu-SAPO-34 catalysts with or without propylene during the NH3-SCR process was conducted, and it was found that the de-NOx activity decreased during low temperature ranges (<350 °C), but obviously improved within the range of high temperatures (>350 °C) in the presence of propylene. The XRD, BET, TG, NH3-TPD, NOx-TPD, in situ DRIFTS and gas-switch experiments were performed to explore the propylene effect on the structure and performance of Cu-SAPO-34 catalysts. The bulk characterization and TG results revealed that neither coke deposition nor the variation of structure and physical properties of catalysts were observed after C3H6 treatment. Generally speaking, at the low temperatures (<350 °C), active Cu2+ species could be occupied by propylene, which inhibited the adsorption and oxidation of NOx species, confining the SCR reaction rate and causing the deactivation of Cu-SAPO-34 catalysts. However, with the increase of reaction temperatures, the occupied Cu2+ sites would be recovered and sequentially participate into the NH3-SCR reaction. Additionally, C3H6-SCR reaction also showed the synergetic contribution to the improvement of NOx conversion at high temperature (>350 °C).
Effects of Crystallinity on the Photocatalytic Polymerization of 3,4-Ethylenedioxythiophene over CsPbBr3 Inverse Opals
Authors: Zhao Siwei , Jin Shaohua , Liu Huanmin , Li Shengfu , Chen Kun
Published: November 2021

Due to their high absorption coefficient and long carrier lifetime, halide perovskites are promising candidates for photocatalysts. For this study, the antisolvent crystallization protocol and the colloidal crystal templating approach were combined to fabricate the highly crystalline cesium lead bromide perovskite with inverse opal morphology (IO-CsPbBr3). Scanning electron microscopy and transmission electron microscope images demonstrate the three-dimensional well-ordered porous structures of the IO-CsPbBr3 and their single-crystalline features. The presented approach not only provides hierarchical porous structures but also enhances overall crystallinity. When used as catalysts to promote the polymerization of 2,2′,5′,2″-ter-3,4-ethylenedioxythiophene, the highly crystalline IO-CsPbBr3 exhibits a superior photocatalytic performance compared to its polycrystalline counterpart. Furthermore, the morphology and the crystalline structure of the highly crystalline IO-CsPbBr3 are well preserved under photocatalytic conditions. This novel approach enables the preparation of a halide perovskite inverse opal with high crystallinity.
Dynamic Regulation of GH–IGF1 Signaling in Injury and Recovery in Hyperoxia-Induced Neonatal Lung Injury
Authors: Vohlen Christina , Mohr Jasmine , Fomenko Alexey , Kuiper-Makris Celien , Grzembke Tiffany , Aydogmus Rabia , Wilke Rebecca , Hirani Dharmesh , Dötsch Jörg , Alejandre Alcazar Miguel A.
Published: November 2021

Prematurely born infants often require supplemental oxygen that impairs lung growth and results in arrest of alveolarization and bronchopulmonary dysplasia (BPD). The growth hormone (GH)- and insulin-like growth factor (IGF)1 systems regulate cell homeostasis and organ development. Since IGF1 is decreased in preterm infants, we investigated the GH- and IGF1 signaling (1) in newborn mice with acute and prolonged exposure to hyperoxia as well as after recovery in room air; and (2) in cultured murine lung epithelial cells (MLE-12) and primary neonatal lung fibroblasts (pLFs) after treatment with GH, IGF1, and IGF1-receptor (IGF1-R) inhibitor or silencing of GH-receptor (Ghr) and Igf1r using the siRNA technique. We found that (1) early postnatal hyperoxia caused an arrest of alveolarization that persisted until adulthood. Both short-term and prolonged hyperoxia reduced GH-receptor expression and STAT5 signaling, whereas Igf1 mRNA and pAKT signaling were increased. These findings were related to a loss of epithelial cell markers (SFTPC, AQP5) and proliferation of myofibroblasts (αSMA+ cells). After recovery, GH-R-expression and STAT5 signaling were activated, Igf1r mRNA reduced, and SFTPC protein significantly increased. Cell culture studies showed that IGF1 induced expression of mesenchymal (e.g., Col1a1, Col4a4) and alveolar epithelial cell type I (Hopx, Igfbp2) markers, whereas inhibition of IGF1 increased SFTPC and reduced AQP5 in MLE-12. GH increased Il6 mRNA and reduced proliferation of pLFs, whereas IGF1 exhibited the opposite effect. In summary, our data demonstrate an opposite regulation of GH- and IGF1- signaling during short-term/prolonged hyperoxia-induced lung injury and recovery, affecting alveolar epithelial cell differentiation, inflammatory activation of fibroblasts, and a possible uncoupling of the GH-IGF1 axis in lungs after hyperoxia.
Surface Marker Expression in Small and Medium/Large Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Naive or Apoptotic Condition Using Orthogonal Techniques
Authors: Skovronova Renata , Grange Cristina , Dimuccio Veronica , Deregibus Maria Chiara , Camussi Giovanni , Bussolati Benedetta
Published: November 2021

Extracellular vesicles released by mesenchymal stromal cells (MSC-EVs) are a promising resource for regenerative medicine. Small MSC-EVs represent the active EV fraction. A bulk analysis was applied to characterise MSC-EVs’ identity and purity, with the assessment of single EV morphology, size and integrity using electron microscopy. We applied different methods to quantitatively analyse the size and surface marker expression in medium/large and small fractions, namely 10k and 100k fractions, of MSC-EVs obtained using sequential ultracentrifugation. Bone marrow, adipose tissue and umbilical cord MSC-EVs were compared in naive and apoptotic conditions. As detected by electron microscopy, the 100k EV size < 100 nm was confirmed by super-resolution microscopy and ExoView. Single-vesicle imaging using super-resolution microscopy revealed heterogeneous patterns of tetraspanins. ExoView allowed a comparative screening of single MSC-EV tetraspanin and mesenchymal markers. A semiquantitative bead-based cytofluorimetric analysis showed the segregation of immunological and pro-coagulative markers on the 10k MSC-EVs. Apoptotic MSC-EVs were released in higher numbers, without significant differences in the naive fractions in surface marker expression. These results show a consistent profile of MSC-EV fractions among the different sources and a safer profile of the 100k MSC-EV population for clinical application. Our study identified suitable applications for EV analytical techniques.
The Evolutionary Volte-Face of Transposable Elements: From Harmful Jumping Genes to Major Drivers of Genetic Innovation
Authors: Nicolau Melody , Picault Nathalie , Moissiard Guillaume
Published: November 2021

Transposable elements (TEs) are self-replicating DNA elements that constitute major fractions of eukaryote genomes. Their ability to transpose can modify the genome structure with potentially deleterious effects. To repress TE activity, host cells have developed numerous strategies, including epigenetic pathways, such as DNA methylation or histone modifications. Although TE neo-insertions are mostly deleterious or neutral, they can become advantageous for the host under specific circumstances. The phenomenon leading to the appropriation of TE-derived sequences by the host is known as TE exaptation or co-option. TE exaptation can be of different natures, through the production of coding or non-coding DNA sequences with ultimately an adaptive benefit for the host. In this review, we first give new insights into the silencing pathways controlling TE activity. We then discuss a model to explain how, under specific environmental conditions, TEs are unleashed, leading to a TE burst and neo-insertions, with potential benefits for the host. Finally, we review our current knowledge of coding and non-coding TE exaptation by providing several examples in various organisms and describing a method to identify TE co-option events.
Altered Mucus Barrier Integrity and Increased Susceptibility to Colitis in Mice upon Loss of Telocyte Bone Morphogenetic Protein Signalling
Authors: Reyes Nicolás Vilcy , Allaire Joannie M. , Alfonso Alain B. , Pupo Gómez Dianne , Pomerleau Véronique , Giroux Véronique , Boudreau François , Perreault Nathalie
Published: November 2021

FoxL1+-Telocytes (TCFoxL1+) are subepithelial cells that form a network underneath the epithelium. We have shown that without inflammatory stress, mice with loss of function in the BMP signalling pathway in TCFoxL1+ (BmpR1aΔFoxL1+) initiated colonic neoplasia. Although TCFoxL1+ are modulated in IBD patients, their specific role in this pathogenesis remains unclear. Thus, we investigated how the loss of BMP signalling in TCFoxL1+ influences the severity of inflammation and fosters epithelial recovery after inflammatory stress. BmpR1a was genetically ablated in mouse colonic TCFoxL1+. Experimental colitis was performed using a DSS challenge followed by recovery steps to assess wound healing. Physical barrier properties, including mucus composition and glycosylation, were assessed by alcian blue staining, immunofluorescences and RT-qPCR. We found that BmpR1aΔFoxL1+ mice had impaired mucus quality, and upon exposure to inflammatory challenges, they had increased susceptibility to experimental colitis and delayed healing. In addition, defective BMP signalling in TCFoxL1+ altered the functionality of goblet cells, thereby affecting mucosal structure and promoting bacterial invasion. Following inflammatory stress, TCFoxL1+ with impaired BMP signalling lose their homing signal for optimal distribution along the epithelium, which is critical in tissue regeneration after injury. Overall, our findings revealed key roles of BMP signalling in TCFoxL1+ in IBD pathogenesis.
Future Perspectives in Spinal Cord Repair: Brain as Saviour? TSCI with Concurrent TBI: Pathophysiological Interaction and Impact on MSC Treatment
Authors: Köhli Paul , Otto Ellen , Jahn Denise , Reisener Marie-Jacqueline , Appelt Jessika , Rahmani Adibeh , Taheri Nima , Keller Johannes , Pumberger Matthias , Tsitsilonis Serafeim
Published: November 2021

Traumatic spinal cord injury (TSCI), commonly caused by high energy trauma in young active patients, is frequently accompanied by traumatic brain injury (TBI). Although combined trauma results in inferior clinical outcomes and a higher mortality rate, the understanding of the pathophysiological interaction of co-occurring TSCI and TBI remains limited. This review provides a detailed overview of the local and systemic alterations due to TSCI and TBI, which severely affect the autonomic and sensory nervous system, immune response, the blood–brain and spinal cord barrier, local perfusion, endocrine homeostasis, posttraumatic metabolism, and circadian rhythm. Because currently developed mesenchymal stem cell (MSC)-based therapeutic strategies for TSCI provide only mild benefit, this review raises awareness of the impact of TSCI–TBI interaction on TSCI pathophysiology and MSC treatment. Therefore, we propose that unravelling the underlying pathophysiology of TSCI with concomitant TBI will reveal promising pharmacological targets and therapeutic strategies for regenerative therapies, further improving MSC therapy.
Perspectives on miRNAs Targeting DKK1 for Developing Hair Regeneration Therapy
Authors: Papukashvili Dimitri , Rcheulishvili Nino , Liu Cong , Xie Fengfei , Tyagi Deependra , He Yunjiao , Wang Peng George
Published: November 2021

Androgenetic alopecia (AGA) remains an unsolved problem for the well-being of humankind, although multiple important involvements in hair growth have been discovered. Up until now, there is no ideal therapy in clinical practice in terms of efficacy and safety. Ultimately, there is a strong need for developing a feasible remedy for preventing and treating AGA. The Wnt/β-catenin signaling pathway is critical in hair restoration. Thus, AGA treatment via modulating this pathway is rational, although challenging. Dickkopf-related protein 1 (DKK1) is distinctly identified as an inhibitor of canonical Wnt/β-catenin signaling. Thus, in order to stimulate the Wnt/β-catenin signaling pathway, inhibition of DKK1 is greatly demanding. Studying DKK1-targeting microRNAs (miRNAs) involved in the Wnt/β-catenin signaling pathway may lay the groundwork for the promotion of hair growth. Bearing in mind that DKK1 inhibition in the balding scalp of AGA certainly makes sense, this review sheds light on the perspectives of miRNA-mediated hair growth for treating AGA via regulating DKK1 and, eventually, modulating Wnt/β-catenin signaling. Consequently, certain miRNAs regulating the Wnt/β-catenin signaling pathway via DKK1 inhibition might represent attractive candidates for further studies focusing on promoting hair growth and AGA therapy.
Coagulation Factor Xa Induces Proinflammatory Responses in Cardiac Fibroblasts via Activation of Protease-Activated Receptor-1
Authors: D’Alessandro Elisa , Scaf Billy , Munts Chantal , van Hunnik Arne , Trevelyan Christopher J. , Verheule Sander , Spronk Henri M. H. , Turner Neil A. , ten Cate Hugo , Schotten Ulrich , van Nieuwenhoven Frans A.
Published: November 2021

Coagulation factor (F) Xa induces proinflammatory responses through activation of protease-activated receptors (PARs). However, the effect of FXa on cardiac fibroblasts (CFs) and the contribution of PARs in FXa-induced cellular signalling in CF has not been fully characterised. To answer these questions, human and rat CFs were incubated with FXa (or TRAP-14, PAR-1 agonist). Gene expression of pro-fibrotic and proinflammatory markers was determined by qRT-PCR after 4 and 24 h. Gene silencing of F2R (PAR-1) and F2RL1 (PAR-2) was achieved using siRNA. MCP-1 protein levels were measured by ELISA of FXa-conditioned media at 24 h. Cell proliferation was assessed after 24 h of incubation with FXa ± SCH79797 (PAR-1 antagonist). In rat CFs, FXa induced upregulation of Ccl2 (MCP-1; >30-fold at 4 h in atrial and ventricular CF) and Il6 (IL-6; ±7-fold at 4 h in ventricular CF). Increased MCP-1 protein levels were detected in FXa-conditioned media at 24 h. In human CF, FXa upregulated the gene expression of CCL2 (>3-fold) and IL6 (>4-fold) at 4 h. Silencing of F2R (PAR-1 gene), but not F2RL1 (PAR-2 gene), downregulated this effect. Selective activation of PAR-1 by TRAP-14 increased CCL2 and IL6 gene expression; this was prevented by F2R (PAR-1 gene) knockdown. Moreover, SCH79797 decreased FXa-induced proliferation after 24 h. In conclusion, our study shows that FXa induces overexpression of proinflammatory genes in human CFs via PAR-1, which was found to be the most abundant PARs isoform in this cell type.
Dynamic Role of Phospholipases A2 in Health and Diseases in the Central Nervous System
Authors: Sun Grace Y. , Geng Xue , Teng Tao , Yang Bo , Appenteng Michael K. , Greenlief C. Michael , Lee James C.
Published: November 2021

Phospholipids are major components in the lipid bilayer of cell membranes. These molecules are comprised of two acyl or alkyl groups and different phospho-base groups linked to the glycerol backbone. Over the years, substantial interest has focused on metabolism of phospholipids by phospholipases and the role of their metabolic products in mediating cell functions. The high levels of polyunsaturated fatty acids (PUFA) in the central nervous system (CNS) have led to studies centered on phospholipases A2 (PLA2s), enzymes responsible for cleaving the acyl groups at the sn-2 position of the phospholipids and resulting in production of PUFA and lysophospholipids. Among the many subtypes of PLA2s, studies have centered on three major types of PLA2s, namely, the calcium-dependent cytosolic cPLA2, the calcium-independent iPLA2 and the secretory sPLA2. These PLA2s are different in their molecular structures, cellular localization and, thus, production of lipid mediators with diverse functions. In the past, studies on specific role of PLA2 on cells in the CNS are limited, partly because of the complex cellular make-up of the nervous tissue. However, understanding of the molecular actions of these PLA2s have improved with recent advances in techniques for separation and isolation of specific cell types in the brain tissue as well as development of sensitive molecular tools for analyses of proteins and lipids. A major goal here is to summarize recent studies on the characteristics and dynamic roles of the three major types of PLA2s and their oxidative products towards brain health and neurological disorders.