Search

Abstract This in vitro study evaluated comprehensively the performances of zirconia brackets with varying yttria proportions in manufacturing advanced orthodontic brackets. Three experimental groups of zirconia brackets were fabricated using yttria-stabilized zirconia (YSZ) materials with different yttria proportions—3 mol% yttria (3Y-YSZ), 4 mol% yttria (4Y-YSZ), and 5 mol% yttria (5Y-YSZ) (Tosoh Ceramic, Japan). A polycrystalline alumina ceramic bracket (3M™ Clarity™ Advanced, MBT 0.022-in. slot) was employed as the control group. Morphological properties, including slot surface structure and dimensions, were examined using scanning electron microscopy and surface profiler analysis. Manufacturing accuracy was assessed with root mean square calculations of trueness and precision. Mechanical properties were tested, encompassing static and kinetic frictional resistance (FR) and fracture strength. Optical stability was evaluated through 20,000 cycles of thermocycling and a 7-day immersion in various coloring agents. Within the limitations of this study, zirconia brackets containing 3 to 5 mol% YSZ presented enhanced reliability in terms of dimensional accuracy and demonstrated favorable optical stability. Notably, owing to its advantageous mechanical properties, the 3Y-YSZ variant showed remarkable potential as an advanced material for fabricating orthodontic brackets.

Abstract SAR439459, a ‘second‐generation’ human anti‐transforming growth factor‐beta (TGFβ) monoclonal antibody, inhibits all TGFβ isoforms and improves the antitumor activity of anti‐programmed cell death protein‐1 therapeutics. This study reports the pharmacodynamics (PD) and biomarker results from phase I/Ib first‐in‐human study of SAR439459 ± cemiplimab in patients with advanced solid tumors (NCT03192345). In dose‐escalation phase (Part 1), SAR439459 was administered intravenously at increasing doses either every 2 weeks (Q2W) or every 3 weeks (Q3W) with cemiplimab IV at 3 mg/kg Q2W or 350 mg Q3W, respectively, in patients with advanced solid tumors. In dose‐expansion phase (Part 2), patients with melanoma received SAR439459 IV Q3W at preliminary recommended phase II dose (pRP2D) of 22.5/7.5 mg/kg or at 22.5 mg/kg with cemiplimab 350 mg IV Q3W. Tumor biopsy and peripheral blood samples were collected for exploratory biomarker analyses to assess target engagement and PD, and results were correlated with patients' clinical parameters. SAR439459 ± cemiplimab showed decreased plasma and tissue TGFβ, downregulation of TGFβ‐pathway activation signature, modulation of peripheral natural killer (NK) and T cell expansion, proliferation, and increased secretion of CXCL10. Conversion of tumor tissue samples from ‘immune‐excluded’ to ‘immune‐infiltrated’ phenotype in a representative patient with melanoma SAR439459 22.5 mg/kg with cemiplimab was observed. In paired tumor and plasma, active and total TGFβ1 was more consistently elevated followed by TGFβ2, whereas TGFβ3 was only measurable (lower limit of quantitation ≥2.68 pg/mg) in tumors. SAR439459 ± cemiplimab showed expected peripheral PD effects and TGFβ alteration. However, further studies are needed to identify biomarkers of response.

In non-aqueous Li–air batteries, the liquid electrolytes penetrate the porous media such as carbon nanotube (CNT) paper structure, transport dissolved substances such as oxygen, and play a role in generating reactants on the surface of the porous media. Although the trapped air generated during the electrolyte penetration process could affect the oxygen transport and performance of the battery, this issue has not been sufficiently investigated. Therefore, in this study, the patterns of electrolyte penetration and air entrapment in porous media were investigated through numerical analysis. A multi-relaxation time color-gradient lattice Boltzmann method was employed for modeling. Based on a two-phase flow simulation in porous media, electrolyte penetration and trapped-air saturation were analyzed in terms of porosity, wettability, and viscosity ratio. The porosity and viscosity ratio did not considerably affect the trapped-air saturation, whereas wettability had a significant effect on the aforementioned parameter. In addition, for each variable, an increase in the effective diffusive coefficient corresponded to increased porosity and hydrophilicity, as well as an improved viscosity ratio.

A procedure for the treatment of tricuspid regurgitation through membrane insertion has been developed recently. However, membrane optimization is required to balance treatment effectiveness with valve damage. This optimization must be performed based on hemodynamic analyses, using the computational fluid dynamics method. The objectives of this study were to analyze hemodynamic features and provide guidelines for the patient-specific optimization of membranes. We used the lattice Boltzmann method for the base blood flow solver and the immersed boundary method to analyze the interactions among the membrane, leaflet, and blood flow. Optimization was performed by the membrane’s volume and insertion angle, and the effects of the shape and surface contact angle of the membrane were observed. Among various patient-specific features, the annulus ratio, hematocrit, and age were selected as control variables. Hemodynamic features were classified as features related to treatment effectiveness, including the regurgitant volume, jet area, and pressure gradient, and those related to the valve leaflet thickening risk, including the Reynolds shear stress, turbulent kinetic energy, and vorticity magnitude. Our analysis results revealed that treatment effectiveness and leaflet damage have a tradeoff relationship; nevertheless, optimizing certain features such as the membrane shape or surface treatment can reduce damage.

There is a need for potent and non-toxic estrogen receptor (ER) antagonists to overcome the limitations of existing endocrine therapies. Here the authors report the results from Arm 1 of the Phase 1/2 study (AMEERA-1) among postmenopausal women with ER+/HER2− advanced breast cancer, which evaluates the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of amcenestrant administered as monotherapy.

Abstract Lithium metal is considered one of the most promising anode materials for application in next-generation batteries. However, despite decades of research, practical application of lithium metal batteries has not yet been achieved because the fundamental interfacial mechanism of lithium dendrite growth is not yet fully understood. In this study, a series of reactive molecular dynamics (MD) simulations was performed to investigate the electrochemical dynamic reactions at the electrode/electrolyte interface. It allows quantitative characterization of morphological phenomena and real-time interfacial visualization of the dynamic growth of dead lithium and dendrites during repeated charging. This computational protocol was utilized to investigate the dendrite mitigation mechanism when an electrolyte additive (hydrogen fluoride) is dissolved in an organic ethylene carbonate (EC) electrolyte solvent. It was confirmed that beneficial decomposition reactions between electrolyte components form a protective film on the anode surface, suppressing large interphase volume changes and unnecessary degradation reactions.

Abstract Metallic surface finishes have been used in the anti-biofouling, but it is very difficult to produce surfaces with hierarchically ordered structures. In the present study, anti-biofouling metallic surfaces with nanostructures superimposed on curved micro-riblets were produced via top-down fabrication. According to the attachment theory, these surfaces feature few attachment points for organisms, the nanostructures prevent the attachment of bacteria and algal zoospores, while the micro-riblets prohibit the settlement of macrofoulers. Anodic oxidation was performed to induce superhydrophilicity. It forms a hydration layer on the surface, which physically blocks foulant adsorption along with the anti-biofouling topography. We characterized the surfaces via scanning electron and atomic force microscopy, contact-angle measurement, and wear-resistance testing. The contact angle of the hierarchical structures was less than 1°. Laboratory settlement assays verified that bacterial attachment was dramatically reduced by the nanostructures and/or the hydration layer, attributable to superhydrophilicity. The micro-riblets prohibited the settlement of macrofoulers. Over 77 days of static immersion in the sea during summer, the metallic surface showed significantly less biofouling compared to a surface painted with an anticorrosive coating.

BackgroundCoronary computed tomography angiography (CTA) and optical coherence tomography (OCT) provide additional functional information beyond the anatomy by applying computational fluid dynamics (CFD). This study sought to evaluate a novel approach for estimating computational fractional flow reserve (FFR) from coronary CTA-OCT fusion images.MethodsAmong patients who underwent coronary CTA, 148 patients who underwent both pressure wire-based FFR measurement and OCT during angiography to evaluate intermediate stenosis in the left anterior descending artery were included from the prospective registry. Coronary CTA-OCT fusion images were created, and CFD was applied to estimate computational FFR. Based on pressure wire-based FFR as a reference, the diagnostic performance of Fusion-FFR was compared with that of CT-FFR and OCT-FFR.ResultsFusion-FFR was strongly correlated with FFR (r = 0.836, P < 0.001). Correlation between FFR and Fusion-FFR was stronger than that between FFR and CT-FFR (r = 0.682, P < 0.001; z statistic, 5.42, P < 0.001) and between FFR and OCT-FFR (r = 0.705, P < 0.001; z statistic, 4.38, P < 0.001). Area under the receiver operating characteristics curve to assess functionally significant stenosis was higher for Fusion-FFR than for CT-FFR (0.90 vs. 0.83, P = 0.024) and OCT-FFR (0.90 vs. 0.83, P = 0.043). Fusion-FFR exhibited 84.5% accuracy, 84.6% sensitivity, 84.3% specificity, 80.9% positive predictive value, and 87.5% negative predictive value. Especially accuracy, specificity, and positive predictive value were superior for Fusion-FFR than for CT-FFR (73.0%, P = 0.007; 61.4%, P < 0.001; 64.0%, P < 0.001) and OCT-FFR (75.7%, P = 0.021; 73.5%, P = 0.020; 69.9%, P = 0.012).ConclusionCFD-based computational FFR from coronary CTA-OCT fusion images provided more accurate functional information than coronary CTA or OCT alone.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT03298282].

Controlling ion transport in nanofluidics is fundamental to numerous material applications but designing a material for ion selection is challenging. Here the authors report a confined van der Waals graphene oxide membrane as cation selective channel for energy generation inspired by neuron electromotive force.

In the wide array of physiological processes, protein–protein interactions and their binding are the most basal activities for achieving adequate biological metabolism. Among the studies on binding proteins, the examination of interactions between immunoglobulin G (IgG) and natural immunoglobulin-binding ligands, such as staphylococcal protein A (spA) and streptococcal protein G (spG), is essential in the development of pharmaceutical science, biotechnology, and affinity chromatography. The widespread utilization of IgG-spA/spG binding characteristics has allowed researchers to investigate these molecular interactions. However, the detailed binding strength of each ligand and the corresponding binding mechanisms have yet to be fully investigated. In this study, the authors analyzed the binding strengths of IgG–spA and IgG–spG complexes and identified the mechanisms enabling these bindings using molecular dynamics simulation, steered molecular dynamics, and advanced Poisson–Boltzmann Solver simulations. Based on the presented data, the binding strength of the spA ligand was found to significantly exceed that of the spG ligand. To find out which non-covalent interactions or amino acid sites have a dominant role in the tight binding of these ligands, further detailed analyses of electrostatic interactions, hydrophobic bonding, and binding free energies have been performed. In investigating their binding affinity, a relatively independent and different unbinding mechanism was found in each ligand. These distinctly different mechanisms were observed to be highly correlated to the protein secondary and tertiary structures of spA and spG ligands, as explicated from the perspective of hydrogen bonding.

Abstract Background Laparoscopic surgery for T4 colon cancer may be safe in selected patients. We hypothesized that small tumor size might preoperatively predict a good laparoscopic surgery outcome. Herein, we compared the clinicopathologic and oncologic outcomes of laparoscopic and open surgery in small T4 colon cancer. Methods In a retrospective multicenter study, we reviewed the data of 449 patients, including 117 patients with tumors ≤ 4.0 cm who underwent surgery for T4 colon cancer between January 2014 and December 2017. We compared the clinicopathologic and 3-year oncologic outcomes between the laparoscopic and open groups. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards model. A p < 0.05 was considered statistically significant. Results Blood loss, length of hospital stay, and postoperative morbidity were lower in the laparoscopic group than in the open group (median [range], 50 [0–700] vs. 100 [0–4000] mL, p < 0.001; 8 vs. 10 days, p < 0.001; and 18.0 vs. 29.5%, p = 0.005, respectively). There were no intergroup differences in 3-year overall survival or disease-free survival (86.6 vs. 83.2%, p = 0.180, and 71.7 vs. 75.1%, p = 0.720, respectively). Among patients with tumor size ≤ 4.0 cm, blood loss was significantly lower in the laparoscopic group than in the open group (median [range], 50 [0–530] vs. 50 [0–1000] mL, p = 0.003). Despite no statistical difference observed in the 3-year overall survival rate (83.3 vs. 78.7%, p = 0.538), the laparoscopic group had a significantly higher 3-year disease-free survival rate (79.2 vs. 53.2%, p = 0.012). Conclusions Laparoscopic surgery showed similar outcomes to open surgery in T4 colon cancer patients and may have favorable short-term oncologic outcomes in patients with tumors ≤ 4.0 cm.

Spinal cord lesions could mimic Guillain-Barré syndrome (GBS). Misdiagnosis as GBS can incur severe neurologic sequelae. We report the case of a previously healthy, 14-year-old boy with traumatic spinal epidural hematoma masquerading as GBS. He presented with sudden onset of tingling sensation on both hands and feet, which progressed into motor weakness of both legs. No abnormalities were found in brain magnetic resonance imaging and cerebrospinal fluid study. Despite intravenous immunoglobulin therapy for presumed GBS, the weakness progressed rapidly over 8 hours, resulting in complete loss of sensorimotor function below T4 level and loss of deep tendon reflexes. Whole spine magnetic resonance imaging showed a large epidural hematoma over the C5-T5 level. We found that he had experienced whiplash injury on an amusement ride about 3 weeks before. He underwent emergency decompressive laminectomy and hematoma removal, followed by vigorous rehabilitation treatment. On the fifth week of follow-up, he recovered from the complete loss of sensorimotor function. Thorough review of detailed history in emergency departments is required for children presenting with ascending paralysis. Also, rapid diagnostic and therapeutic interventions are crucial for maximum recovery of neurologic symptoms.

Purpose This study aimed to assess the evaluation of clinical outcomes and consequences of complications after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for the peritoneal carcinomatosis (PC) from colorectal cancer. Methods A total 26 patients underwent CRS and HIPEC for PC from colorectal cancer between March 2009 and April 2018. All the patients underwent CRS with the purpose of complete or near-complete cytoreduction. Intraoperative HIPEC was performed simultaneously after the CRS. Mitomycin C was used as chemotherapeutic agent for HIPEC. Results Median disease-free survival was 27.8 months (range, 13.4–42.2 months). Median overall survival was 56.0 months (range, 28.6–83.5 months). The mean peritoneal cancer index (PCI) was 8.73 ± 5.54. The distributions thereof were as follows: PCI

Immune checkpoint blockade elicits durable anti-cancer responses in the clinic, however a large proportion of patients do not benefit from treatment. Several mechanisms of innate and acquired resistance to checkpoint blockade have been defined and include mutations of MHC I and IFNγ signaling pathways. However, such mutations occur in a low frequency of patients and additional mechanisms have yet to be elucidated. In an effort to better understand acquired resistance to checkpoint blockade, we generated a mouse tumor model exhibiting in vivo resistance to anti-PD-1 antibody treatment. MC38 tumors acquired resistance to PD-1 blockade following serial in vivo passaging. Lack of sensitivity to PD-1 blockade was not attributed to dysregulation of PD-L1 or β2M expression, as both were expressed at similar levels in parental and resistant cells. Similarly, IFNγ signaling and antigen processing and presentation pathways were functional in both parental and resistant cell lines. Unbiased gene expression analysis was used to further characterize potential resistance mechanisms. RNA-sequencing revealed substantial differences in global gene expression, with tumors resistant to anti-PD-1 displaying a marked reduction in expression of immune-related genes relative to parental MC38 tumors. Indeed, resistant tumors exhibited reduced immune infiltration across multiple cell types, including T and NK cells. Pathway analysis revealed activation of TGFβ and Notch signaling in anti-PD-1 resistant tumors, and activation of these pathways was associated with poorer survival in human cancer patients. While pharmacological inhibition of TGFβ and Notch in combination with PD-1 blockade decelerated tumor growth, a local mRNA-based immunotherapy potently induced regression of resistant tumors, resulting in complete tumor remission, and resensitized tumors to treatment with anti-PD-1. Overall, this study describes a novel anti-PD-1 resistant mouse tumor model and underscores the role of two well-defined signaling pathways in response to immune checkpoint blockade. Furthermore, our data highlights the potential of intratumoral mRNA therapy in overcoming acquired resistance to PD-1 blockade.

Pre-clinical studies have shown that TP53 mutations can account for acquired resistance to HDM2 antagonists. This study provides clinical evidence for the emergence of TP53mutations in circulating cell-free DNA, seen in 5 out of 20 de-differentiated liposarcoma patients treated with an HDM2 antagonist.

Despite recent development of computational fluid dynamics (CFD) research, analysis of computational fluid dynamics of cerebral vessels has several limitations. Although blood is a non-Newtonian fluid, velocity and pressure fields were computed under the assumptions of incompressible, laminar, steady-state flows and Newtonian fluid dynamics. The pulsatile nature of blood flow is not properly applied in inlet and outlet boundaries. Therefore, we present these technical limitations and discuss the possible solution by comparing the theoretical and computational studies.

A 2-year-old girl, previously healthy, was brought to the emergency department because of significant cramping abdominal pain with recurrent hematochezia after an accidental hydrogen peroxide enema (35%, 5 mL) by her caregiver. She was hospitalized to the pediatric department and treated with nothing per mouth, intravenous fluid and parenteral antibiotic therapy. Laboratory, radiologic and endoscopic evaluation was performed during the admission period. She was discharged in a fully recovered state on the tenth hospital day, and this is the first case report of acute chemical colitis by accidental hydrogen peroxide enema in children.