bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Direct Comparison of Node and Element-Based Finite Element Modeling Approaches to Study Tissue Growth
Authors: Howe Danielle , Dixit Nikhil N. , Saul Katherine R. , Fisher Matthew B. 
Published: July 2021

Abstract
Finite element analysis is a useful tool to model growth of biological tissues and predict how growth can be impacted by stimuli. Previous work has simulated growth using node-based or element-based approaches, and this implementation choice may influence predicted growth, irrespective of the applied growth model. This study directly compared node-based and element-based approaches to understand the isolated impact of implementation method on growth predictions by simulating growth of a bone rudiment geometry, and determined what conditions produce similar results between the approaches. We used a previously reported node-based approach implemented via thermal expansion and an element-based approach implemented via osmotic swelling, and we derived a mathematical relationship to relate the growth resulting from these approaches. We found that material properties (modulus) affected growth in the element-based approach, with growth completely restricted for high modulus values relative to the growth stimulus, and no restriction for low modulus values. The node-based approach was unaffected by modulus. Node- and element-based approaches matched marginally better when the conversion coefficient to relate the approaches was optimized based on the results of initial simulations, rather than using the theoretically predicted conversion coefficient (median difference in node position 0.042 cm versus 0.052 cm, respectively). In summary, we illustrate here the importance of the choice of implementation approach for modeling growth, provide a framework for converting models between implementation approaches, and highlight important considerations for comparing results in prior work and developing new models of tissue growth.
Assessing Wear Evolutions in Railway Wheelsets Using a Survival Modeling Approach
Authors: Caldeira Guilherme A. C. , Braga Joaquim A. P. , Andrade António R. 
Published: July 2021

Abstract
This paper provides a method to predict maintenance needs for the railway wheelsets by modeling the wear out affecting the wheelsets during its life cycle using survival analysis. Wear variations of wheel profiles are discretized and modeled through a censored survival approach, which is appropriate for modeling wheel profile degradation using real operation data from the condition monitoring systems that currently exist in railway companies. Several parametric distributions for the wear variations are modeled, and the behavior of the selected ones is analyzed and compared with wear trajectories computed by a Monte Carlo simulation procedure. This procedure aims to test the independence of events by adding small fractions of wear to reach larger wear values. The results show that the independence of wear events is not true for all the established events, but it is confirmed for small wear values. Overall, the proposed framework is developed in such a way that the outputs can be used to support predictions in condition-based maintenance models and to optimize the maintenance of wheelsets.
Investigating the Design and Manufacture of PneuNet Actuators as a Prosthetic Tongue for Mimicking Human Deglutition
Authors: Darmont Araya Francis , Radhakrishnan Pradeep 
Published: July 2021

Abstract
The number of total glossectomy cases in the United States is seeing an increasing trend as per the nationwide inpatient sample database. Patients, who have undergone such aggressive surgical procedures, have extensive limitations in performing basic oral functions such as swallowing (deglutition), eating, and speaking. Current rehabilitation prostheses do little in restoring the functionality of the original tongue. This is true especially in deglutition, which is necessary to transfer a bolus to the esophagus. Such patients need advanced prosthetic devices and through this research, investigations into potential solutions for prosthetic tongues to aid in deglutition were carried out. Different designs were considered and based on a decision matrix, pneumatic networks (PneuNets) were adopted as the foundational basis for generating prosthetic tongue designs. Several prototypes were fabricated that used the Fused Filament Deposition process for producing the mold and silicone Eco-flex 00-30 for producing the mechanism. The resulting mechanism with dimensions 2.4 in. × 1.8 in. × 0.24 in. was powered using pneumatic input and kinematic data was collected. The experiments carried out showed potential in the concept but at the same time, there were challenges related to validating the kinematics and in the transfer of the bolus due to uncontrolled silicone expansions. Details from the literature review, design iterations, simulations, validation processes, manufacturing challenges, and conclusions will be discussed in-depth in this paper.
Plume Stability During Direct Contact Condensation of Steam in a Crossflow of Subcooled Water, at High Mass Flux and With a Small Nozzle Diameter
Authors: Alden Zach R. , Maples Gunnar D. , Dressler Kristofer M. , Nellis Gregory F. , Berson Arganthaël 
Published: July 2021

Abstract
The stability of a steam plume during direct-contact condensation into a crossflow of subcooled water is investigated for mass fluxes that are higher (&gt;600 kg/m2s) and a nozzle diameter (2.4 mm) that is smaller than typically seen in the literature. The transition from a stable steam plume to an unstable plume associated with the formation and collapse of steam bubbles is characterized by high-speed imaging and high-frequency pressure measurements. Four regimes are observed: stable, condensation oscillation, transition, and unstable. A regime map and spectral signatures of the different flow regimes are provided. Results are compared with correlations from the literature, which are typically derived for lower mass fluxes, larger nozzles, and injection into stagnant pools of water.
Prediction of Squeal Instabilities of a Finite Element Model Automotive Brake With Uncertain Structural and Environmental Parameters With a Hybrid Surrogate Model
Authors: Denimal Enora , Sinou Jean-Jacques , Nacivet Samuel 
Published: July 2021

Abstract
This study focuses on the prediction of the stability behavior of an industrial automotive brake system under structural and environmental uncertainties. Uncertainties are modeled with a random distribution or an interval and are propagated with a hybrid surrogate model associating polynomial chaos and kriging. The objective is to create a surrogate model of each eigenvalue computed with the complex eigenvalue analysis (CEA). As the modes can be tracked only when unstable, the effective size of the training sets can become extremely small. Despite this limitation, it is shown the hybrid meta-model is still able to predict the stability of the brake system. Moreover, the hybrid meta-model gives a direct access to the mean and variance of the eigenvalues with respect to the design parameters without any additional Monte Carlo simulations (MCS). By considering different probability density function for the friction coefficient, it is shown it has a high influence on the stability and the latter should be accurately estimated.
Brafmutation induces rapid neoplastic transformation in the aged and aberrantly methylated intestinal epithelium
Authors: Fennell Lochlan , Kane Alexandra , Liu Cheng , McKeone Diane , Hartel Gunter , Su Chang , Bond Catherine , Bettington Mark , Leggett Barbara , Whitehall Vicki 
Published: July 2021

ObjectiveSessile serrated lesions (SSLs) are common across the age spectrum, but theBRAFmutant cancers arising occur predominantly in the elderly. Aberrant DNA methylation is uncommon in SSL from young patients. Here, we interrogate the role of ageing and DNA methylation in SSL initiation and progression.DesignWe used an inducible model ofBrafmutation to direct recombination of the oncogenicBraf V637Eallele to the murine intestine.BRAFmutation was activated after periods of ageing, and tissue was assessed for histological, DNA methylation and gene expression changes thereafter. We also investigated DNA methylation alterations in human SSLs.ResultsInducingBrafmutation in aged mice was associated with a 10-fold relative risk of serrated lesions compared with young mice. There were extensive differences in age-associated DNA methylation between animals induced at 9 months versus wean, with relatively little differentialBraf-specific methylation. DNA methylation at WNT pathway genes scales with age andBrafmutation accelerated age-associated DNA methylation. In human SSLs, increased epigenetic age was associated with high-risk serrated colorectal neoplasia.ConclusionsSSLs arising in the aged intestine are at a significantly higher risk of spontaneous neoplastic progression. These findings provide support for a new conceptual model for serrated colorectal carcinogenesis, whereby risk ofBraf-induced neoplastic transformation is dependent on age and may be related to age-associated molecular alterations that accumulate in the ageing intestine, including DNA methylation. This may have implications for surveillance and chemopreventive strategies targeting the epigenome.
Chemoradiation triggers antitumor Th1 and tissue resident memory-polarized immune responses to improve immune checkpoint inhibitors therapy
Authors: Lauret Marie Joseph Elodie , Kirilovsky Amos , Lecoester Benoît , El Sissy Carine , Boullerot Laura , Rangan Laurie , Marguier Amélie , Tochet Florent , Dosset Magalie , Boustani Jihane , Ravel Patrice , Boidot Romain , Spehner Laurie , Haicheur-Adjouri Nacilla , Marliot Florence , Pallandre Jean-René , Bonnefoy Francis , Scripcariu Viorel , Van den Eynde Marc , Cornillot Emmanuel , Mirjolet Céline , Pages Franck , Adotevi Olivier 
Published: July 2021

BackgroundMultiple synergistic combination approaches with cancer drugs are developed to overcome primary resistance to immunotherapy; however, the mechanistic rationale to combine chemoradiotherapy (CRT) with immune checkpoint inhibitors remains elusive.MethodsThis study described the immunological landscape of tumor microenvironment (TME) exposed to CRT. Tumor samples from patients with rectal cancer (n=43) treated with neoadjuvant CRT or radiotherapy were analyzed by nanostring and immunohistochemistry. Studies in mice were performed using three syngeneic tumors (TC1, CT26 and MC38). Tumor-bearing mice were treated either with platinum-based CRT, radiotherapy or chemotherapy. Anti-CTLA-4 and/or anti-Programmed Cell Death Receptor-1 (PD-1) therapy was used in combination with CRT. The therapy-exposed TME was screened by RNA sequencing and flow cytometry and tumor-infiltrating T lymphocyte functionality was evaluated by interferon (IFN)-γ ELIspot and intracellular cytokine staining.ResultsFront-to-front comparison analysis revealed the synergistic effect of CRT to establish a highly inflamed and Th1-polarized immune signature in the TME of patients and mice. In both settings, CRT-exposed TMEs were highly enriched in newly-infiltrated tumor-specific CD8+ T cells as well as tissue resident memory CD103+CD8+ T cells. In mice, CD8 T cells were involved in the antitumor response mediated by CRT and were primed by CRT-activated CD103+ dendritic cells. In the three tumor models, we showed that concurrent combination of CRT with a dual CTLA-4 and PD-1 blockade was required to achieve an optimal antitumor effect and to establish a broad and long-lasting protective antitumor T cell immunity.ConclusionsOur results highlight the ability of CRT to stimulate strong antitumor T-cell-mediated immunity and tissue resident memory T activation in TME, to foster immune checkpoint inhibitors action. These findings have implications in clinic for the design clinical trials combining chemoradiation with immunotherapy.
Novel anti-4-1BB×PD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade
Authors: Jeong Seongju , Park Eunyoung , Kim Hyung-Don , Sung Eunsil , Kim Hyunjoo , Jeon Jaehyoung , Kim Youngkwang , Jung Ui-jung , Son Yong-Gyu , Hong Youngeun , Lee Hanbyul , Lee Shinai , Lim Yangmi , Won Jonghwa , Jeon Minwoo , Hwang Shin , Fang Lei , Jiang Wenqing , Wang Zhengyi , Shin Eui-Cheol , Park Su-Hyung , Jung Jaeho 
Published: July 2021

BackgroundStimulation of 4-1BB with agonistic antibodies is a promising strategy for improving the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or for overcoming resistance to ICIs. However, dose-dependent hepatotoxicity was observed in clinical trials with monoclonal anti-4-1BB agonistic antibodies due to the activation of 4-1BB signaling in liver resident Kupffer cells.MethodsTo avoid this on-target liver toxicity, we developed a novel bispecific antibody (4-1BB×PD-L1 bispecific antibody, termed “ABL503”) uniquely designed to activate 4-1BB signaling only in the context of PD-L1, while also blocking PD-1/PD-L1 signaling.ResultsFunctional evaluation using effector cells expressing both 4-1BB and PD-1 revealed superior biological activity of ABL503 compared with the combination of each monoclonal antibody. ABL503 also augmented T-cell activation in in vitro assays and further enhanced the anti-PD-L1-mediated reinvigoration of tumor-infiltrating CD8+ T cells from patients with cancer. Furthermore, in humanized PD-L1/4-1BB transgenic mice challenged with huPD-L1-expressing tumor cells, ABL503 induced superior anti-tumor activity and maintained an anti-tumor response against tumor rechallenge. ABL503 was well tolerated, with normal liver function in monkeys.ConclusionThe novel anti-4-1BB×PD-L1 bispecific antibody may exert a strong anti-tumor therapeutic efficacy with a low risk of liver toxicity through the restriction of 4-1BB stimulation in tumors.
Escherichia coliadhesin protein-conjugated thermal responsive hybrid nanoparticles for photothermal and immunotherapy against cancer and its metastasis
Authors: Hwang Juyoung , Zhang Wei , Park Hae-Bin , Yadav Dhananjay , Jeon Yong Hyun , Jin Jun-O 
Published: July 2021

BackgroundAdvanced cancer therapy is targeted at primary tumors and also recurrent or metastatic cancers. Combinational cancer treatment has recently shown high efficiency against recurrent and metastatic cancers. In this study, we synthesized a thermal responsive hybrid nanoparticle (TRH) containing FimH, an immune stimulatory recombinant protein, for the induction of a combination of photothermal therapy (PTT) and immunotherapy against cancer and its metastasis.MethodsThe hybrid nanoparticle was incorporated with a near-infrared (NIR) absorbent, indocyanine green, and decorated with FimH on its surface to form F-TRH. F-TRH was evaluated for its anticancer and antimetastatic effects against CT-26 carcinoma in mice by combining PTT and immunotherapy.ResultsNIR laser irradiation elicited an elevation of temperature in F-TRH, which induced apoptosis in CT-26 carcinoma cells in vitro. In addition, F-TRH and NIR laser irradiation promoted photothermal-mediated therapeutic effects against CT-26 and 4T1 tumors in mice. The release of FimH from F-TRH in response to elevated temperature and apoptotic bodies of cancer cells via PTT elicited dendritic cell-mediated cancer antigen-specific T-cell responses, which subsequently inhibited the second challenge of CT-26 and 4T1 cell growth in the lung.ConclusionsThese data demonstrate the potential use of F-TRH for immuno-photothermal therapy against cancer and its recurrence and metastasis.
Metformin generates profound alterations in systemic and tumor immunity with associated antitumor effects
Authors: Veeramachaneni Ratna , Yu Wangjie , Newton Jared M , Kemnade Jan O , Skinner Heath D , Sikora Andrew G , Sandulache Vlad C 
Published: July 2021

BackgroundMetformin is a commonly used antidiabetic medication which has demonstrated promise as an anticancer agent alone and in combination with conventional treatment regimens. There is increasing evidence that metformin can also generate immunomodulatory effects in solid tumors and is currently being investigated as an adjunct to immune checkpoint inhibitors (ICIs). We hypothesized that metformin would generate a shift in immunity unfavorable to tumor growth and tested this hypothesis in a preclinical model of head and neck cancer.MethodsUsing a syngeneic mouse model of human papillomavirus-associated head and neck cancer (mEER/MTEC), we tested the impact of metformin on systemic and local immunity and tumor growth velocity. We compared the effects of acute and chronic treatment regimens on immunocyte presence and activation using a combination of flow cytometry and targeted transcriptomic analysis.ResultsAcute metformin exposure generated measurable shifts in systemic myeloid and T-cell populations in non-tumor-bearing mice and decreased myeloid derived suppressor cell (MDSC) levels in tumor draining lymph nodes of tumor-bearing mice. Although metformin decreased regulatory T-cell (T-reg) and MDSC levels and increased CD8+ levels in murine tumors when combined with ICIs, acute metformin exposure was insufficient to generate substantial antitumor activity. Conversely, long-term metformin treatment significantly reduced tumor growth velocity, increased the CD8+/T-reg ratio, increased tumor infiltrating lymphocyte levels and upregulated component genes of the previously validated T-cell inflamed expression profile.ConclusionsMetformin generates complex systemic and local immune effects which vary as a function of treatment duration. Combinatorial strategies with ICIs must take into account both the complexity and variability of these effects in order to generate maximal antitumor activity in future clinical trials.
Phase 1 study of safety, tolerability and immunogenicity of the human telomerase (hTERT)-encoded DNA plasmids INO-1400 and INO-1401 with or without IL-12 DNA plasmid INO-9012 in adult patients with solid tumors
Authors: Vonderheide Robert H , Kraynyak Kimberly A , Shields Anthony F , McRee Autumn J , Johnson Jennifer M , Sun Weijing , Chintakuntlawar Ashish V , Pawlicki Jan , Sylvester Albert J , McMullan Trevor , Samuels Robert , Kim Joseph J , Weiner David , Boyer Jean D , Morrow Matthew P , Humeau Laurent , Skolnik Jeffrey M 
Published: July 2021

BackgroundHuman telomerase reverse transcriptase (hTERT) is frequently classified as a ‘universal’ tumor associated antigen due to its expression in a vast number of cancers. We evaluated plasmid DNA-encoded hTERT as an immunotherapy across nine cancer types.MethodsA phase 1 clinical trial was conducted in adult patients with no evidence of disease following definitive surgery and standard therapy, who were at high risk of relapse. Plasmid DNA encoding one of two hTERT variants (INO-1400 or INO-1401) with or without plasmid DNA encoding interleukin 12 (IL-12) (INO-9012) was delivered intramuscularly concurrent with the application of the CELLECTRA constant-current electroporation device 4 times across 12 weeks. Safety assessments and immune monitoring against native (germline, non-mutated, non-plasmid matched) hTERT antigen were performed. The largest cohort of patients enrolled had pancreatic cancer, allowing for additional targeted assessments for this tumor type.ResultsOf the 93 enrolled patients who received at least one dose, 88 had at least one adverse event; the majority were grade 1 or 2, related to injection site. At 18 months, 54.8% (51/93) patients were disease-free, with median disease-free survival (DFS) not reached by end of study. For patients with pancreatic cancer, the median DFS was 9 months, with 41.4% of these patients remaining disease-free at 18 months. hTERT immunotherapy induced a de novo cellular immune response or enhanced pre-existing cellular responses to native hTERT in 96% (88/92) of patients with various cancer types. Treatment with INO-1400/INO-1401±INO-9012 drove hTERT-specific IFN-γ production, generated hTERT-specific CD4+ and CD8+ T cells expressing the activation marker CD38, and induced hTERT-specific activated CD8 +CTLs as defined by cells expressing perforin and granzymes. The addition of plasmid IL-12 adjuvant elicited higher magnitudes of cellular responses including IFN-γ production, activated CD4+ and CD8+ T cells, and activated CD8+CTLs. In a subset analysis of pancreatic cancer patients, the presence of immunotherapy-induced activated CD8+ T cells expressing PD-1, granzymes and perforin correlated with survival.ConclusionsPlasmid DNA-encoded hTERT/IL-12 DNA immunotherapy was well-tolerated, immune responses were noted across all tumor types, and a specific CD8+ phenotype increased by the immunotherapy was significantly correlated with survival in patients with pancreatic cancer.
Adaptive servo ventilation for sleep apnoea in heart failure: the FACE study 3-month data
Authors: Tamisier Renaud , Damy Thibaud , Bailly Sebastien , Davy Jean-Marc , Verbraecken Johan , Lavergne Florent , Palot Alain , Goutorbe Frederic , d'Ortho Marie-Pia , Pépin Jean Louis 
Published: July 2021

RationaleAdaptive servo ventilation (ASV) is contraindicated in patients with systolic heart failure (HF) who have a left ventricular ejection fraction (LVEF) below 45% and predominant central sleep apnoea (CSA). However, the effects of ASV in other HF subgroups have not been clearly defined.ObjectiveThe European, multicentre, prospective, observational cohort trial, FACE, evaluated the effects of ASV therapy on morbidity and mortality in patients with HF with sleep-disordered breathing (SDB); 3-month outcomes in patient subgroups defined using latent class analysis (LCA) are presented.MethodsConsecutive patients with HF with predominant CSA (±obstructive sleep apnoea) indicated for ASV were included from 2009 to 2018; the non-ASV group included patients who refused/were noncompliant with ASV. The primary endpoint was time to composite first event (all-cause death, lifesaving cardiovascular intervention or unplanned hospitalisation for worsening of chronic HF).Measurements and main resultsBaseline assessments were performed in 503 patients, and 482 underwent 3-month follow-up. LCA identified six discrete patient clusters characterised by variations in LVEF, SDB type, age, comorbidities and ASV acceptance. The 3- month rate of primary outcome events was significantly higher in cluster 1 patients (predominantly men, low LVEF, severe HF, CSA; 13.9% vs 1.5%–5% in other clusters, p<0.01).ConclusionFor the first time, our data identified homogeneous patient clusters representing clinically relevant subgroups relating to SDB management in patients with HF with different ASV usage, each with a different prognosis. This may improve patient phenotyping in clinical practice and allow individualisation of therapy.