bluuebunny/crossref_metadata_2025 huggingface dataset:
The prognostic value of circRNAs for gastric cancer: A systematic review and meta‐analysis
Authors: Chen Hui , Liang Chengtong , Wang Xuechun , Liu Yu , Yang Zhanjun , Shen Ming , Han Chongxu , Ren Chuanli
Published: October 2020

Gastric cancer is the third leading cause of cancer‐related deaths worldwide. Novel biomarkers circRNAs can play an important role in the development of gastric cancer as oncogenes or tumor suppressor genes. The purpose of this study was to clarify the relationship between the abnormal expression of multiple circRNAs and their prognostic value in gastric cancer patients through a meta‐analysis. We researched articles reporting the relationship between circRNAs and the prognosis of gastric cancer published in PubMed, Cochrane, Embase, Web of Science, Wanfang, CNKI, and VIP databases before 31 December 2019. Thirty‐five articles were selected for the meta‐analysis, involving 3135 gastric cancer patients. The total HR values (95% CI) of OS and DFS related to highly expressed circRNAs that indicated worse prognosis were 1.83 (1.64‐2.03; p < 0.001) and 1.66 (1.33‐2.07; p < 0.001), respectively. The total HR (95% CI) of OS and DFS related to highly expressed circRNAs that indicated better prognosis was 0.54 (0.45‐0.66; p < 0.001) and 0.58 (0.43‐0.78; p < 0.001), respectively. Two panels of five circRNAs predicted a more considerable HR value (circ_0009910, hsa_circ_0000467, hsa_circ_0065149, hsa_circ_0081143, and circDLST; and circSMARCA5, circLMTK2, hsa_circ_0001017, hsa_circ_0061276, and circ‐KIAA1244). The results of the meta‐analysis were 2.63 (2.08‐3.33; p < 0.001) and 0.39 (0.27‐0.59; p < 0.001) for OS, respectively. The two panels of dysregulated circRNAs can be considered as more suitable potential prognostic tumor biomarkers in patients with gastric cancer because of their larger HR values.
Small‐Molecule Inhibition of the uPAR ⋅ uPA Interaction by Conformational Selection
Authors: Xu David , Bum‐Erdene Khuchtumur , Leth Julie M. , Ghozayel Mona K. , Ploug Michael , Meroueh Samy O.
Published: October 2020

The urokinase receptor (uPAR) is a cell surface receptor that binds to the serine protease urokinase‐type plasminogen activator (uPA) with high affinity. This interaction is beneficial for extravascular fibrin clearance, but it has also been associated with a broad range of pathological conditions including cancer, atherosclerosis, and kidney disease. Here, starting with a small molecule that we previously discovered by virtual screening and cheminformatics analysis, we design and synthesize several derivatives that were tested for binding and inhibition of the uPAR ⋅ uPA interaction. To confirm the binding site and establish a binding mode of the compounds, we carried out biophysical studies using uPAR mutants, among them uPARH47C−N259C, a mutant previously developed to mimic the structure of uPA‐bound uPAR. Remarkably, a substantial increase in potency is observed for inhibition of uPARH47C−N259C binding to uPA compared to wild‐type uPAR, consistent with our use of the structure of uPAR in its uPA‐bound state to design small‐molecule uPAR ⋅ uPA antagonists. Combined with the biophysical studies, molecular docking followed by extensive explicit‐solvent molecular dynamics simulations and MM‐GBSA free energy calculations yielded the most favorable binding pose of the compound. Collectively, these results suggest that potent inhibition of uPAR binding to uPA with small molecules will likely only be achieved by developing small molecules that exhibit high‐affinity to solution apo structures of uPAR, rather than uPA‐bound structures of the receptor.
Phase 1 study to evaluate Crenigacestat (LY3039478) in combination with dexamethasone in patients with T‐cell acute lymphoblastic leukemia and lymphoma
Authors: Borthakur Gautam , Martinelli Giovanni , Raffoux Emmanuel , Chevallier Patrice , Chromik Jörg , Lithio Andrew , Smith Claire L. , Yuen Eunice , Oakley Gerard Joseph , Benhadji Karim A. , DeAngelo Daniel J.
Published: October 2020

Background

Deregulated Notch signaling is implicated in T‐cell acute lymphoblastic leukemia (T‐ALL)/T‐cell lymphoblastic lymphoma (T‐LBL). Crenigacestat (LY3039478) prevents cleavage of Notch proteins and may benefit patients with relapsed/refractory T‐ALL/T‐LBL.

Methods

JJCB was a multicenter, nonrandomized, open‐label, dose‐escalation, phase 1 study in adult patients with relapsed/refractory T‐ALL/T‐LBL. Eligible patients received Crenigacestat orally 3 times per week plus dexamethasone at 24 mg twice daily on days 1 to 5 every other week in a 28‐day cycle. The starting level of Crenigacestat was 50 mg, and dose escalation was performed with a modified 3+3 scheme for the estimation of dose‐limiting toxicity (DLT) at the recommended dose level.

Results

In total, 36 patients with T‐ALL (n = 31 [86.1%]) or T‐LBL (n = 5 [13.9%]) were treated with Crenigacestat and dexamethasone. Six patients (16.7%) experienced DLTs: 2 of 12 (16.7%) in the 75‐mg cohort (grade 4 gastrointestinal hemorrhage and grade 3 nausea, vomiting, and diarrhea), 1 of 15 (6.7%) in the 100‐mg cohort (grade 3 diarrhea), and 3 of 3 (100%) in the 125‐mg cohort (grade 3 diarrhea, nausea, and vomiting). The maximum tolerated dosewas 75 mg plus 24 mg of dexamethasone daily on days 1 to 5. Twenty‐eight patients (77.8%) experienced 1 or more treatment‐emergent adverse events related to the study treatment. The best overall response was a confirmed response, with 1 patient (2.8%) having a duration of response of 10.51 months. Six patients (16.7%) achieved stable disease, and 12 patients (33.3%) experienced progressive disease. The remaining 17 patients (47.2%) were not evaluable. The median event‐free survival was 1.18 months (95% confidence interval, 0.76‐2.14 months) among all groups. A pharmacodynamic analysis showed decreased plasma amyloid β levels.

Conclusions

Crenigacestat demonstrated limited clinical activity at the recommended dose in adult patients with relapsed/refractory T‐ALL/T‐LBL.
Methods for Expression of Recombinant Proteins Using a Pichia pastoris Cell‐Free System
Authors: Aw Rochelle , Spice Alex J. , Polizzi Karen M.
Published: October 2020

Cell‐free protein synthesis is a powerful tool for engineering biology and has been utilized in many diverse applications, from biosensing and protein prototyping to biomanufacturing and the design of metabolic pathways. By exploiting host cellular machinery decoupled from cellular growth, proteins can be produced in vitro both on demand and rapidly. Eukaryotic cell‐free platforms are often neglected due to perceived complexity and low yields relative to their prokaryotic counterparts, despite providing a number of advantageous properties. The yeast Pichia pastoris (also known as Komagataella phaffii) is a particularly attractive eukaryotic host from which to generate cell‐free extracts, due to its ability to grow to high cell densities with high volumetric productivity, genetic tractability for strain engineering, and ability to perform post‐translational modifications. Here, we describe methods for conducting cell‐free protein synthesis using P. pastoris as the host, from preparing the cell lysates to protocols for both coupled and linked transcription‐translation reactions. By providing these methodologies, we hope to encourage the adoption of the platform by new and experienced users alike. © 2020 The Authors.

Basic Protocol 1: Preparation of Pichia pastoris cell lysate

Basic Protocol 2: Coupled in vitro transcription and translation

Basic Protocol 3: Determining luciferase production from cell‐free protein synthesis reactions

Alternate Protocol 1: Linked in vitro transcription and translation

Alternate Protocol 2: Quantifying HSA protein concentration

Support Protocol 1: Preparation of mRNA by in vitro transcription for linked transcription and translation
Development and evaluation of an interdisciplinary teaching model via 3D printing
Authors: Reymus Marcel , Liebermann Anja , Diegritz Christian , Keßler Andreas
Published: October 2020

The investigation aimed to assess the feasibility of creating an interdisciplinary training model simulating endodontic, restorative as well as implantologic treatment procedures by using 3D printing technology. A CBCT scan of the mandible of a real patient was initially taken. The generated DICOM‐data were converted to a STL‐file, which was further processed to design spaces for exchangeable replica teeth, a bone segment and an adapter to fix the model in a mannequin's head. After the manufacturing process, the model was evaluated by dental students performing a root canal treatment, the insertion of a glass fibre post and the insertion of an implant. The workflow allowed a simple and cost‐effective way of manufacturing a single model, which is suitable for several training scenarios in the fields of endodontics, prosthodontics and implantology. The model was rated as being comparable to the real patient situation and offers repetitive treatment simulations. The present workflow is a feasible way of using DICOM‐data and 3D printing for an interdisciplinary training model. The dental schools can design models according to their own curriculum and put the focus on a patient centered education.
Transition Metal‐Free Synthesis of Carbamates Using CO2 as the Carbon Source
Authors: Schilling Waldemar , Das Shoubhik
Published: October 2020

Utilization of carbon dioxide as a C1 synthon is highly attractive for the synthesis of valuable chemicals. However, activation of CO2 is highly challenging, owing to its thermodynamic stability and kinetic inertness. With this in mind, several strategies have been developed for the generation of carbon–heteroatom bonds. Among these, formation of C−N bonds is highly attractive, especially, when carbamates can be synthesized directly from CO2. This Minireview focuses on transition metal‐free approaches for the fixation of CO2 to generate carbamates for the production of fine chemicals and pharmaceuticals. Within the past decade, transition metal‐free approaches have gained increasing attention, but traditional reviews have rarely focused on these approaches. Direct comparisons between such methods have been even more scarce. This Minireview seeks to address this discrepancy.
Multilevel governance in environmental policy integration: A content analysis of regional and urban nested hierarchies in China
Authors: Sheng Rong
Published: October 2020

This study attempts to identify the different priorities of environmental policy integration under a multilevel governance background in China. The subjects for analysis included the four‐level hierarchies of China's central government, the Yangtze River Delta, Shanghai, and Chongming eco‐island. NVivo 12 Plus software aided the content analysis of regional and urban nested hierarchy planning documents. The results represent environmental policy integration (EPI) priorities in different hierarchical levels and sectors, as well as the sectoral elaboration on prioritized policy instruments. In addition, the implications of the results in the process toward co‐work in multilevel governance of EPI are discussed. Though inconsistencies exist in EPI priorities, it is advised to design the coordinative vertical framework and approach these policy instruments cooperatively across multilevel governance. In the strategic co‐work relations, the four levels follow the same blueprint in their EPI. Regarding the interactions among multilevel ranks, the results show an inclination of being fueled by the central authority. However, how the local governmental levels will embody and enforce higher levels' priorities could depend on the different natural and societal conditions at each level.
Spatial hierarchical modeling of threshold exceedances using rate mixtures
Authors: Yadav Rishikesh , Huser Raphaël , Opitz Thomas
Published: October 2020

We develop new flexible univariate models for light‐tailed and heavy‐tailed data, which extend a hierarchical representation of the generalized Pareto (GP) limit for threshold exceedances. These models can accommodate departure from asymptotic threshold stability in finite samples while keeping the asymptotic GP distribution as a special (or boundary) case and can capture the tails and the bulk jointly without losing much flexibility. Spatial dependence is modeled through a latent process, while the data are assumed to be conditionally independent. Focusing on a gamma–gamma model construction, we design penalized complexity priors for crucial model parameters, shrinking our proposed spatial Bayesian hierarchical model toward a simpler reference whose marginal distributions are GP with moderately heavy tails. Our model can be fitted in fairly high dimensions using Markov chain Monte Carlo by exploiting the Metropolis‐adjusted Langevin algorithm (MALA), which guarantees fast convergence of Markov chains with efficient block proposals for the latent variables. We also develop an adaptive scheme to calibrate the MALA tuning parameters. Moreover, our model avoids the expensive numerical evaluations of multifold integrals in censored likelihood expressions. We demonstrate our new methodology by simulation and application to a dataset of extreme rainfall events that occurred in Germany. Our fitted gamma–gamma model provides a satisfactory performance and can be successfully used to predict rainfall extremes at unobserved locations.
Alteration of lipid profile and value of lipids in the prediction of the length of hospital stay in COVID‐19 pneumonia patients
Authors: Qin Chen , Minghan Huang , Ziwen Zhao , Yukun Luo
Published: October 2020

To observe lipid profiles and their alterations in hospitalized patients with COVID‐19 pneumonia (NCP) and evaluate the value of lipids for the prediction of the length of hospital stay (LOS), a total of 248 patients aged 18 years or older were enrolled in this retrospective study. At admission, the median levels of triglyceride (TG), total cholesterol (TC), high‐density lipoprotein cholesterol (HDL‐C), and low‐density lipoprotein cholesterol (LDL‐C) in all patients were 1.11, 4.00, 0.89, and 2.11 mmol/L, respectively. Compared with common cases (n = 174), severe cases (n = 74) exhibited higher TG and HDL‐C, and lower LDL‐C. Levels of TC and LDL‐C were negatively correlated with LOS. In 68 severe cases, serum lipids were followed up during hospitalization, and the median LOS was 29 days. The average levels of serum lipids were lowest at admission and gradually increased during hospitalization. Compared with the LOS ≤ 29 days group, serum levels of TC, HDL‐C, and LDL‐C were significantly lower in the LOS > 29 days group at admission; this lower trend was found in the subsequent tests for TC and LDL‐C but not for HDL‐C or TG. Multiple‐variant COX regression showed that levels of TC or LDL‐C at admission were independent risk of LOS prolongation. Together, these findings suggest that in patients with NCP, levels of TC and LDL‐C at admission were negatively correlated with LOS. In severe cases, the gradual increase in TC, LDL‐C, and HDL‐C during hospitalization might indicate gradual recovery. TC < 3.75 mmol/L or LDL‐C < 1.7 mmol/L at admission may act as an independent predictor of prolonged LOS.
111 m, 74 m und 37 m lange Probepfähle für den Elbtower in Hamburg
Authors: Kaya‐Sandt Hatice , Borchert Kurt‐Michael , von Quillfeldt Michael , Wedenig Andreas
Published: October 2020

Am östlichen Ende der HafenCity in Hamburg wird der Elbtower mit einer Höhe von rund 245 m geplant. Der Turm mit der angrenzenden Sockelbebauung wird mit zwei bis drei Untergeschossen auf einer Fläche von ca. 15 000 m2 ab voraussichtlich 2020 errichtet. Bei den Baugrunderkundungen stellte sich heraus, dass der Neubau im Bereich eines Kreuzungsbereichs von eiszeitlichen Rinnen zu gründen ist, in dem eine heterogene Baugrundschichtung bis wahrscheinlich rund 200 m unter Gelände vorzufinden ist. Im Bereich des geplanten Turms ist eine für Hamburger Verhältnisse typische Absetztiefe der Pfähle in die bis zu 30 m unter Gelände reichenden Sande, insbesondere mit Blick auf die Setzungen des Bauwerks, nicht realisierbar. Ziel ist es, die Bauwerkslasten aus dem Turm bis in die tiefliegenden Schichten unterhalb der anstehenden, setzungsrelevanten Tone und Schluffe zu leiten und die Setzungen hiermit in einem verträglichen Maß zu halten. Zur Ermittlung der Baugrundverhältnisse und ‐kennwerte wurden umfangreiche Erkundungen im Feld sowie im Labor durchgeführt. Zur Ermittlung von Pfahlsetzungen und ‐tragfähigkeiten erfolgten Probebelastungen mit Bohrpfählen unterschiedlicher Längen. An jedem Pfahl wurden ca. 5 m über dem Pfahlfuß Osterberg‐Zellen angeordnet. Die Probepfähle wurden im August 2019 durch die Bauer Spezialtiefbau GmbH im Kelly‐Bohrverfahren hergestellt. Der Einbau der Belastungs‐ und Messtechnik sowie die Durchführung der Probebelastungen wurden von der Firma Fugro/Loadtest ausgeführt. Die Probebelastungen erfolgten im Oktober 2019. Es konnten für die langen Pfähle Tragfähigkeiten von über 60 MN nachgewiesen werden.
Nodal disease burden and outcome of medullary thyroid carcinoma
Authors: Moses Lindsey E. , Oliver Jamie R. , Rotsides Janine M. , Shao Qianhui , Patel Kepal N. , Morris Luc G. T. , Givi Babak
Published: October 2020

Background

Medullary thyroid carcinoma (MTC) is a rare malignancy with high incidence of cervical lymph node (CLN) metastasis. We investigated the impact of nodal disease burden on survival.

Methods

We searched the National Cancer Database for MTC patients treated surgically. Impact of nodal metastasis on survival was analyzed using Cox univariable and multivariable regression.

Results

We identified 2627 patients from 2004 to 2015. Positive CLNs were identified in 1433 (54.5%), and 542 (20.6%) had >10 CLN+. Overall survival was 94.5% and 89.6% at 3 and 5 years. Patients with 11 to 20 CLN+ had significantly worse survival than patients with 1 to 10 CLN+ in univariable and multivariable analyses (HR = 3.56 (2.31‐5.50) vs 2.26 (1.60‐3.20); P < .0001). The ratio of positive to dissected CLN was associated with overall survival.

Conclusions

Higher burden of nodal disease is associated with worse survival in MTC. The number of positive nodes could be a valuable prognosticator in addition to the current staging system.
A double‐blind randomized trial on subendometrial injection of vasopressin to control bleeding in postpartum hysterectomy due to abnormally invasive placenta
Authors: Ghotbizadeh Vhdani Fahimeh , Nasiri Khormoji Najmeh , Eftekhar Negar , Deldar Pasikhani Maryam , Hantoushzadeh Sedigheh , Ghamari Azin , Panahi Zahra
Published: October 2020

Objective

To investigate the effect of subendometrial vasopressin injection in patients with abnormally invasive placenta (AIP), who underwent cesarean section and hysterectomy.

Methods

This randomized double‐blinded clinical trial was conducted on pregnant women diagnosed with AIP grade 4 and 5 by ultrasonography during cesarean section. Women were randomly divided into two equal groups including group 1 (vasopressin) and group 2 (control) who underwent 20 units of vasopressin and 20 cc normal saline injection, respectively. Vasopressin and placebo were injected subendometrially 1 cm medial to the uterine vessels into the lower uterine segment. The exclusion criteria include presence of myocardial infarction, cardiomyopathy, congestive heart failure, uncontrolled hypertension, chronic obstructive pulmonary disease, pelvic malignancy. The outcome of the study was total quantitative blood loss during the cesarean section. We estimated blood loss by measuring the blood volume in one of the suction bottles with addition for weight changes of mops, pads, and soaked linen savers.

Results

Sixty patients were recruited into the study, 30 as the vasopressin group and 30 as the controls; with no excluded case. The amount of bleeding in the vasopressin group was significantly lower compared with that in the control group (P < 0.001). In the vasopressin group, 83.4% of patients had bleeding of less than 1.5 L, while only 3.3% of the control women had bleeding of less than 1.5 L (relative risk = 5). In addition, the number of injected packed cells was lower in the vasopressin group (P < 0.001).

Conclusion

It was shown that vasopressin injection can help prevent excess hemorrhage and the subsequent risks of anemia or blood transfusions during abdominal hysterectomy in women with AIP.
Male partner involvement and successful completion of the prevention of mother‐to‐child transmission continuum of care in Kenya
Authors: Hampanda Karen , Helova Anna , Odwar Tobias , Odeny Thomas , Onono Maricianah , Bukusi Elizabeth , Turan Janet , Abuogi Lisa
Published: October 2020

Objective

To examine the relationship between male partner involvement (MPI) in prevention of mother‐to‐child transmission (PMTCT) activities and successful completion of the PMTCT continuum of care, which remains sub‐optimal in settings with high prevalence of HIV.

Methods

A cross‐sectional survey was administered in June–August 2017 to a sample of 200 postpartum Kenyan women with HIV enrolled in a parent trial. Composite PMTCT and MPI variables were created. Descriptive, simple and multivariable regression, and mediation analyses were performed.

Results

Of the women, 54% reported successful completion of PMTCT. Depression and internalized HIV stigma were independently associated with lower likelihood of successful completion of PMTCT (adjusted risk ratio [aRR] 0.97; 95% confidence interval [CI] 0.94–0.99; aRR 0.92; 95% CI 0.88–0.98, respectively). Each MPI activity was associated with 10% greater likelihood of successful completion of PMTCT (P < 0.05). The relationship between MPI and the successful completion of PMTCT was partially mediated through women's reduced internalized HIV stigma (β −0.03; 95%CI −0.06 to −0.00).

Conclusion

Greater MPI in PMTCT activities has direct and indirect effects on women's successful completion of all necessary steps across the PMTCT continuum. Reduced internalized HIV stigma is likely a key mechanism in the relationship.
Layered autonomous TSCH scheduler for minimal band occupancy with bounded latency
Authors: Urke Andreas R. , Kure Øivind , Øvsthus Knut
Published: October 2020

Robustness and bounded latency are among the key requirements in wireless industrial networks. A typical traffic patterns is convergecast, where sensors sends data towards a sink, resulting in a funneling effect with increased traffic intensity. This letter proposes the Layered autonomous Time Slotted Channel Hopping (TSCH) scheduler for convergecast traffic, which addresses the funneling effect while reducing the band occupancy. It divides the slotframe into layers where all nodes have one timeslot reserved for forwarding its own traffic. Layers are organized to allow spatially reuse such that traffic belonging to a node may be forwarded at multiple hops simultaneously. This is achieved autonomously by exploiting a node's knowledge of the routing topology. We evaluate the Layered scheduler through theoretical analysis and simulations in Cooja. Results show that Layered attains bounded latency even when nodes are utilizing all their available resources. This is achieved with significantly reduced band occupancy compared to Escalator, an autonomous scheduler for convergecast traffic. The performance is traded‐off by increased maximum latency.
In vitro copper oxide nanoparticle toxicity on intestinal barrier
Authors: Bertero Alessia , Colombo Graziano , Cortinovis Cristina , Bassi Virginia , Moschini Elisa , Bellitto Nicholas , Perego Maria Chiara , Albonico Marco , Astori Emanuela , Dalle‐Donne Isabella , Gedanken Aharon , Perelshtein Ilana , Mantecca Paride , Caloni Francesca
Published: October 2020

The use of CuO nanoparticles (NPs) has increased greatly and their potential effects on human health need to be investigated. Differentiated Caco‐2 cells were treated from the apical (Ap) and the basolateral (Bl) compartment with different concentrations (0, 10, 50 and 100 μg/mL) of commercial or sonochemically synthesized (sono) CuO NPs. Sono NPs were prepared in ethanol (CuOe) or in water (CuOw), obtaining CuO NPs differing in size and shape. The effects on the Caco‐2 cell barrier were assessed via transepithelial electrical resistance (TEER) evaluation just before and after 1, 2 and 24 hours of exposure and through the analysis of cytokine release and biomarkers of oxidative damage to proteins after 24 hours. Sono CuOe and CuOw NPs induced a TEER decrease with a dose‐dependent pattern after Bl exposure. Conversely, TEER values were not affected by the Ap exposure to commercial CuO NPs and, concerning the Bl exposure, only the lowest concentration tested (10 μg/mL) caused a TEER decrease after 24 hours of exposure. An increased release of interleukin‐8 was induced by sono CuO NPs after the Ap exposure to 100 μg/mL and by sono and commercial CuO after the Bl exposure to all the concentrations. No effects of commercial and sono CuO NPs on interleukin‐6 (with the only exception of 100 μg/mL Bl commercial CuO) and tumor necrosis factor‐α release were observed. Ap treatment with commercial and CuOw NPs was able to induce significant alterations on specific biomarkers of protein oxidative damage (protein sulfhydryl group oxidation and protein carbonylation).
Development of tantalum with highly hydrophilic surface and antimicrobial properties obtained by micro‐arc oxidation process
Authors: Sopata Mateusz , Karpiński Tomasz M. , Jakubowicz Jaroslaw , Sopata Maciej
Published: October 2020

Tantalum (Ta) and its application in biomaterials has been attracting more and more attention recently. It can be considered as a material for hard tissue implants. This study focuses on antimicrobial and surface characterization of micro‐arc oxidized (MAO) nanocrystalline Ta compared with its microcrystalline equivalent. For the purposes of the investigation, x‐ray diffractometry (XRD), scanning electron microscopy (SEM), atomic force microscopy (AFM), wetting analysis, optical profilometry, corrosion resistance measurement, and antimicrobial tests were performed. Nanocrystalline Ta was fabricated using high‐energy ball milling (HEBM) and pulse plasma sintering (PPS). The MAO process done at 250 V results in the formation of a porous oxide surface. An XRD analysis confirmed the presence of a Ta2O5 oxide layer. Based on the SEM pictures, the obtained oxide layer was approximately 3–4 μm thick for nanocrystalline Ta substrate. For microcrystalline Ta, the oxide layer was thinner, in the range of 0.3–0.6 μm. The analysis of polarization curves showed a significant improvement of corrosion resistance for MAO nanocrystalline Ta (2.62 × 10−8 A/cm2) versus not oxidized nanocrystalline Ta (1.20 × 10−5 A/cm2). The surface roughness of MAO nanocrystalline Ta proved to be several times higher than that of unoxidized Ta. Wetting analysis showed that the oxide layer on the nanocrystalline substrate is hydrophilic. This research provides detailed information about MAO microcrystalline and MAO nanocrystalline Ta antimicrobial activity against Staphylococcus aureus and Pseudomonas aeruginosa. A significant decrease of S. aureus for MAO nanocrystalline Ta (control 10,435 ± 981 vs. sample 3,453 ± 130) was noticed. No significant difference was noticed for MAO microcrystalline and nanocrystalline Ta tested for P. aeruginosa.
HMGB1 as a therapeutic target in disease
Authors: Xue Jiaming , Suarez Joelle S. , Minaai Michael , Li Shuangjing , Gaudino Giovanni , Pass Harvey I. , Carbone Michele , Yang Haining
Published: October 2020

High‐mobility group box 1 (HMGB1) was initially recognized as a ubiquitous nuclear protein involved in maintaining the nucleosome integrity and facilitating gene transcription. HMGB1 has since been reevaluated to be a prototypical damage‐associated molecular pattern (DAMP) protein, and together with its exogenous counterpart, pathogen‐associated molecular pattern (PAMP), completes the body's alarmin system against disturbances in homeostasis. HMGB1 can be released into the extracellular matrix (ECM) by either granulocytes or necrotic cells to serve as a chemotaxis/cytokine during infection, endotoxemia, hypoxia, ischemia–reperfusion events, and cancer. Different isoforms of HMGB1 present with distinctive physiological functions in ECM—fully‐reduced HMGB1 (all thiol) acts as the initial damage signal to recruit circulating myeloid cells, disulfide HMGB1 behaves as a cytokine to activate macrophages and neutrophils, and both signals are turned off when HMGB1 is terminally oxidized into the final sulfonate form. Targeting HMGB1 constitutes a favorable therapeutic strategy for inflammation and inflammatory diseases. Antagonists such as ethyl pyruvate inhibit HMGB1 by interfering with its cytoplasmic exportation, while others such as glycyrrhizin directly bind to HMGB1 and render it unavailable for its receptors. The fact that a mixture of different HMGB1 isoforms is present in the ECM poses a challenge in pinpointing the exact role of an individual antagonist. A more discriminative probe for HMGB1 may be necessary to advance our knowledge of HMGB1, HMGB1 antagonists, and inflammatory‐related diseases.
Evaluation of length and location of the maxillary sinus intraosseous artery using computerized tomography
Authors: Tran Troy B. , Estrin Nathan E. , Saleh Muhammad H.A. , Yoon Thomas Y.H. , Tattan Mustafa , Wang Hom‐Lay
Published: October 2020

Background

The intraosseous artery is a branch of the posterior superior alveolar artery that supplies the lateral wall of the maxillary sinus. The present study seeks to analyze the location of the intraosseous artery and its site of termination.

Methods

Cone beam computed tomography was used to evaluate 200 patients making up 400 maxillary sinuses. The following criteria were measured: (1) the distance of the lower border of the intraosseous artery to the floor of the sinus, (2) the average length of the artery, (3) the diameter of the artery, (4) the site at which the artery terminates at, and (5) the distance of the artery from the first premolar, second premolar, first molar, second molar, and third molar.

Results

The intraosseous artery was identified in 336 (84.0%) quadrants. The most common site of termination was at the mesial of the second molar (22%), regardless of dental status and right or left quadrant. Its overall mean diameter was 0.91 ± 0.56 mm, with no difference within the dental status. Its overall mean length was 7.40 ± 3.39 mm, with a statistically significant difference between dentate and edentulous quadrants (P < 0.001). Its overall mean distance from the floor was 6.95 ± 6.49 mm, with no difference within the dental status. All parameters showed no difference between right or left quadrants.

Conclusions

The chances of encountering the intraosseous artery at the premolar area is <21% during a lateral window sinus floor elevation. The most common (22%) site of termination of the intraosseous artery is at the mesial of the second molar. Understanding of the course, location, and termination of the artery enhances the precision of a clinician when it comes to pre‐operative treatment planning.
Age of Gimli beach of Lake Agassiz based on new OSL dating
Authors: Teller James T. , Owen Lewis A.
Published: October 2020

Gimli beach in Manitoba is one of the lowest elevation beaches in the southern Lake Agassiz basin, and is a distinct ridge composed of bedded sand and gravel that rises above the lake plain and extends for more than 40 km. Ten new optically stimulated luminescence (OSL) ages from Gimli beach yield ages mostly ranging from 9.7 ± 0.7 to 10.5 ± 0.8 ka (average 10.3 ± 0.5 ka), which is older by 0.6 to >1.0 ka than age estimates of previous researchers. Two of our new OSL ages are notably older than the others, dating to ~11.3 ± 0.8 and 13.9 ± 1.0 ka, which we attribute to poorly bleached sands. We ascribe an age of about 10 ka to Gimli beach, which is several centuries before overflow from Lake Agassiz and its vast drainage basin shifted from the western Great Lakes to glacial Lake Ojibway and the St. Lawrence Valley.
Experimental and computational studies of the mechanism of base‐catalyzed ring opening of 2‐(chloromethyl)oxirane by benzoic acid
Authors: Bespalko Yuliia , Sinel'nikova Marina , Shved Elena , Bakhalova Evgeniia
Published: October 2020

Using methods of chemical kinetics and quantum modeling, we investigated the mechanism by which base catalysts affect the regioselectivity of the ring opening of 2‐(chloromethyl)oxirane by benzoic acid. The model reaction was carried out using 2‐(chloromethyl)oxirane as both reagent and solvent at temperatures of 303‐333 K. Rate constants and activation parameters of the ring opening were determined for the overall reaction and for the formation of the isomeric “normal” and “abnormal” products. Density functional theory B3LYP/6‐31+G** was used to examine possible reaction pathways. A comparison of experimental measurements and theoretical calculations confirm that the rate‐limiting step is the attack of the benzoate anion on the C1 and C2 positions of 2‐(chloromethyl)oxirane. The present results indicate that the regioselectivity of the 2‐(chloromethyl)oxirane ring opening by benzoic acid depends on the ratio of A2 mechanisms, SN2 and “borderline” SN2 type. This suggests that weak nucleophilic base catalysts can increase the reaction regiospecificity by increasing the contribution of the SN2 pathway.
Parenteral Bevacizumab for the Treatment of Severe Respiratory Papillomatosis in an Adult Population
Authors: Tkaczuk Andrew , Trivedi Sumita , Mody Mayur D. , Steuer Conor E. , Shin Dong M. , Klein Adam M. , Saba Nabil F.
Published: October 2020

Objectives/Hypothesis

Recurrent respiratory papillomatosis (RRP) is a rare, potentially life‐threatening, disease that impacts the voice, breathing, and quality of life of patients. Frequent surgical interventions may be needed to control symptoms. We examined the safety and efficacy of utilizing parenteral bevacizumab in the management of severe RRP in adults.

Study Design

This is a retrospective review of clinical management approaches in a group of patients with severe RRP defined as having a high disease burden, frequent need for debridement, and/or tracheobronchial disease. Patients were initially treated with 15 mg/kg of bevacizumab at 3‐week intervals. Bevacizumab dosing and frequency was then individually titrated down.

Results

Fourteen adults received a median of 8.5 (range 2–17) bevacizumab infusions over approximately 24 months. All had a history of laryngeal RRP with 6/14 having additional tracheobronchial lesions. Patients required a median of 4 (range 2–11) procedures in the year prior to treatment. Only 3/10 (30%) patients who continued therapy required any additional procedures. Bevacizumab administration was generally well tolerated, with four patients discontinuing therapy. Medical reasons included severe epistaxis and hypertension and thrombocytopenia in an individual with systemic lupus erythematosus. Common side effects included hypertension (grade 2), headache (grades 1–2), elevated creatinine (grades 1–2), and epistaxis (grade 3).

Conclusions

Intravenous bevacizumab for the primary treatment of severe RRP in adults appears clinically effective and safe. Expected and typically mild side effects related to bevacizumab were observed. Continued investigation of bevacizumab through a prospective clinical trial is warranted.

Level of Evidence

4. Laryngoscope, 131:E921–E928, 2021
Electrochemical Immunosensor for Detection of CCR4 Cancer Biomarker in Human Serum: An Alternative Strategy for Modification of Disposable ITO Electrode
Authors: Aydın Elif Burcu , Aydın Muhammet , Sezgintürk Mustafa Kemal
Published: October 2020

Herein, a new strategy for the fabrication of a sensitive immunosensor capable of determination of CC Chemokine receptor 4 (CCR4) in complex serum samples is developed through the polymer modification on the disposable indium tin oxide electrode. Anti‐CCR4 antibodies, which are utilized as sensing biomolecules, are covalently attached on the succinimide groups of polypyrrole polymer (PPyr‐CSsg). The constructed immunosensor illustrates promising performances for the quantification of CCR4 antigen, with a linear detection range of 0.024–12 pg mL−1 and a low detection limit of 7.3 fg mL−1, calculated at a signal‐to‐noise ratio of 3. In addition, the impedimetric immunosensor displays a very successful analytical performance in terms of sensitivity, selectivity, repeatability, reproducibility, and long‐term stability as well as successful applicability for the accurate quantification of CCR4 in human serum samples. The constructed immunosensor is successfully used for quantification of CCR4 antigen in human serums. In addition, the immunosensor displays only 27.54% loss in its initial signal after nine weeks storage at 4 °C. Moreover, the fabricated immunosensor is economical, highly sensitive, and selective for CCR4 antigen detection, and suitable for potential application in clinical diagnosis.
A Theoretical and Experimental Analysis of the Effect of Nanoclay on Gas Perm‐Selectivity of Biodegradable PLA/EVA Blends in the Presence and Absence of Compatibilizer
Authors: Karimpour‐Motlagh Navid , Moghadam Abolfazl Salehi , Khonakdar Hossein Ali , Jafari Seyed Hassan , Wagenknecht Udo , Kasbi Sina Farahani , Shojaei Shahrokh , Mirzaee Ramin
Published: October 2020

Poly (lactic acid) (PLA)‐based compounds are widely used in thin‐film and food packaging industries. Herein, PLA/ethylene vinyl acetate copolymer (EVA)/nanoclay nanocomposites are prepared in various compositions by melt blending. The gas permeability against N2, CO2, and O2 gases is determined as a function of composition and morphology of the nanocomposites. Inclusion of high aspect ratio of platelet‐like nanoclay to the blend reduces the gas diffusion. The best barrier properties against all gases is observed on introducing 5 wt% poly(ethylene/n‐butyl acrylate glycidyl methacrylate) copolymer as compatibilizer to the PLA/EVA/nanoclay (75/25/5) system. The scanning and transmission electron microscopic analyses and wide‐angle X‐ray scattering studies reveal that inclusion of compatibilizer to the filled‐blends improves the blend morphology, dispersion state, and intercalation level of clay platelets which are preferably localized at the interface of the blend. Analysis of selectivity parameter (α) shows the lowest O2 permeability and the highest αCO2/N2 and αO2/N2 values for the compatibilized filled‐blend (75/25/5/5). In situ aspect ratio of clay and the degree of intercalation are theoretically evaluated based on the permeability data using various empirical models. It is found that the compatibilized filled‐blend has the highest aspect ratio and intercalation level that are responsible for the optimum perm‐selectivity performance.
Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease
Authors: Shadrin Alexey A. , Mucha Sören , Ellinghaus David , Makarious Mary B. , Blauwendraat Cornelis , Sreelatha Ashwin A.K. , Heras‐Garvin Antonio , Ding Jinhui , Hammer Monia , Foubert‐Samier Alexandra , Meissner Wassilios G. , Rascol Olivier , Pavy‐Le Traon Anne , Frei Oleksandr , O'Connell Kevin S. , Bahrami Shahram , Schreiber Stefan , Lieb Wolfgang , Müller‐Nurasyid Martina , Schminke Ulf , Homuth Georg , Schmidt Carsten O. , Nöthen Markus M. , Hoffmann Per , Gieger Christian , Wenning Gregor ,   for the European Multiple System Atrophy Study Group, Gibbs J. Raphael , Franke Andre , Hardy John , Stefanova Nadia , Gasser Thomas , Singleton Andrew , Houlden Henry , Scholz Sonja W. , Andreassen Ole A. , Sharma Manu
Published: October 2020

Background

Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by intracellular accumulations of α‐synuclein and nerve cell loss in striatonigral and olivopontocerebellar structures. Epidemiological and clinical studies have reported potential involvement of autoimmune mechanisms in MSA pathogenesis. However, genetic etiology of this interaction remains unknown. We aimed to investigate genetic overlap between MSA and 7 autoimmune diseases and to identify shared genetic loci.

Methods

Genome‐wide association study summary statistics of MSA and 7 autoimmune diseases were combined in cross‐trait conjunctional false discovery rate analysis to explore overlapping genetic background. Expression of selected candidate genes was compared in transgenic MSA mice and wild‐type mice. Genetic variability of candidate genes was further investigated using independent whole‐exome genotyping data from large cohorts of MSA and autoimmune disease patients and healthy controls.

Results

We observed substantial polygenic overlap between MSA and inflammatory bowel disease and identified 3 shared genetic loci with leading variants upstream of the DENND1B and RSP04 genes, and in intron of the C7 gene. Further, the C7 gene showed significantly dysregulated expression in the degenerating midbrain of transgenic MSA mice compared with wild‐type mice and had elevated burden of protein‐coding variants in independent MSA and inflammatory bowel disease cohorts.

Conclusion

Our study provides evidence of shared genetic etiology between MSA and inflammatory bowel disease with an important role of the C7 gene in both phenotypes, with the implication of immune and gut dysfunction in MSA pathophysiology. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Chemical exchange sensitive MRI of glucose uptake using xylose as a contrast agent
Authors: Wang Jicheng , Fukuda Mitsuhiro , Chung Julius Juhyun , Wang Ping , Jin Tao
Published: October 2020

Purpose

Glucose and its analogs can be detected by CEST and chemical exchange spin‐lock (CESL) MRI techniques, but sensitivity is still a bottleneck for human applications. Here, CESL and CEST sensitivity and the effect of injection on baseline physiology were evaluated for a glucose analog, xylose.

Methods

The CEST and CESL sensitivity were evaluated at 9.4 T in phantoms and by in vivo rat experiments with 0.5 and 1 g/kg xylose injections. Arterial blood glucose level was sampled before and after 1 g/kg xylose injection. The effect of injection on baseline neuronal activity was measured by electrophysiology data during injections of saline, xylose, and 2‐deoxy‐D‐glucose.

Results

In phantoms, xylose shows similar chemical exchange sensitivity and pH‐dependence with that of glucose. In rat experiments with a bolus injection, CESL shows higher sensitivity in the detection of xylose than CEST, and the sensitivity of xylose is much higher than glucose. Injection of xylose does not significantly affect blood glucose level and baseline neural activity for 1‐g/kg and 0.6‐g/kg doses, respectively.

Conclusion

Due to its relatively high sensitivity and safety, xylose is a promising contrast agent for the study of glucose uptake.
The impact of pretransplant opioid exposure on healthcare utilization and costs in kidney transplant
Authors: Wise Bailey , Wilson Lytani Z. , Taber David J. , Pilch Nicole A. , Rohan Vinayak , Fleming James N.
Published: October 2020

Study Objective

Opioid use has been associated with significant morbidity and mortality in the United States. Studies within kidney transplantation have also shown increased risk of mortality, graft loss, and complications in kidney transplant recipients who use opioids prior to transplant. The objective of this analysis was to identify if recent pretransplant opioid exposure would be an effective risk‐stratifier for patients at risk for readmissions and readmission costs. Further, the objective was to see if a brief assessment of recent opioid use could predict chronic opioid use post‐transplant.”

Patients and Design

This study was a single‐center, retrospective cohort analysis of adult renal transplant recipients between January 2010 and December 2016 assessing the impact of pretransplant opioid use on posttransplant readmissions at 1 year postsurgery, as well as it's ability to identify patients at risk of chronic opioid use post‐transplant. Opioid use was identified using medication reconciliation or a national prescription database, and readmissions and normalized costs for hospitalizations were identified via the Vizient clinical database.

Main Results

Pretransplant opioid exposure occurred in 271 (24%) of 1129 patients transplanted during the study time period. There were no differences in index hospitalization length of stay or cost; however, patients with opioid exposure were significantly more likely to have been admitted within 1‐year postsurgery (51 vs. 43%, p = 0.023), had more readmissions per patient (0.93 vs. 0.72, p = 0.010), and had higher normalized readmissions costs ($12,556 vs. $8344, p = 0.009). Patients with opioid exposure were also more likely to be admitted for readmissions, had more admissions per patient, and had higher readmission costs at 30 and 90 days postsurgery. There were no differences in preventability of readmissions between cohorts or in general causes of readmissions. A multivariable logistic regression demonstrated that being opioid experienced and having a history of diabetes mellitus were independently associated with readmissions at 1 year postsurgery. In addition, having opioid exposure at the time of transplant, a history of diabetes mellitus, and younger age were independently associated with chronic opioid use after transplant.

Conclusion

This study demonstrated that recent exposure to opioids prior to kidney transplant was significantly and independently associated with increased readmissions and readmission costs at multiple timepoints up to 1 year posttransplant as well as chronic opioid use after transplant.It also demonstrated that a brief assessment of recent opioid use may be able to identify patients at risk for chronic opioid use. Because opioid use is associated with multiple diseases, it is important to continue to study the association of opioid use, and the potential for disease‐modifying interactions, with various clinical outcomes.
A Physiologically Based Pharmacokinetic Model to Predict Potential Drug–Drug Interactions and Inform Dosing of Acumapimod, an Oral p38 MAPK Inhibitor
Authors: Agyemang Alex , Farrell Colm , Moore William , Parkin Jacqueline
Published: October 2020

Acumapimod, an investigational oral p38 mitogen‐activated protein kinase inhibitor for treatment during severe acute exacerbations of chronic obstructive pulmonary disease, is metabolized primarily by cytochrome P450 3A4 (CYP3A4) and is a P‐glycoprotein (P‐gp) substrate. Concerns about drug–drug interactions (DDIs) have meant patients receiving drugs that inhibit CYP3A4 were ineligible for acumapimod trials. We report on how 2 acumapimod clinical DDI studies and a physiologically‐based pharmacokinetic (PBPK) model assessing how co‐administration of a weak (azithromycin) and strong (itraconazole) CYP3A4 inhibitor affected acumapimod systemic exposure, informed decision making and supported concomitant use of CYP3A4 and P‐gp inhibitors. Studies MBCT102 and MBCT103, respectively, demonstrated that co‐administration of azithromycin or itraconazole had no clinically meaningful impact on acumapimod pharmacokinetics. Findings were consistent with PBPK model results. Safety profiles were similar when acumapimod was co‐administered with azithromycin or itraconazole. These studies highlight the value of PBPK modeling in drug development, and its potential to inform DDI investigations.