bluuebunny/crossref_metadata_2025 huggingface dataset:
Stopping Power Modulation by Pump Waves of Charged Particles Moving above Two-Dimensional Electron Gases
Authors: Yang Yahong , Zhang Ya , Yi Lin , Jiang Wei
Published: March 2021

The perturbation electron density and stopping power caused by the movement of charged particles above two-dimensional quantum electron gases (2DQEG) have been studied in numerous works using the quantum hydrodynamic (QHD) theory. In this paper, the QHD is modified by introducing the two-dimensional electron exchange-correlation potential at high density Vxc2DH and the pump wave modulations. Based on the modified QHD, the perturbation electron density and stopping power are calculated for pump waves with various parameters. The results show that the stopping power values are more accurate after considering Vxc2DH. Under the modulation of pump waves with the wavelength from 0.1nm to 0.1cm, the perturbation electron density of 2DQEG and the stopping power of charged particles show periodic changes. Under the modulation of pump waves with λ = 1.76 × 10−4 cm and <mml:math xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mnf="http://cambridge.org/core/manifest" xmlns:cup="http://contentservices.cambridge.org" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:m="http://cambridge.org/core/metadata" xmlns:core="http://cambridge.org/core" xmlns:c="http://cambridge.org/core/content" id="M6">Φ0=2×1010e/λf, the average stopping power with respect to the time phase θ becomes negative, which means that the charged particles will gain energy and can be accelerated. This is a new phenomenon in the fields of 2DQEG and of great significance in surface physics and surface modification in nanoelectronic devices with beam matter interactions.
Probiotic-Derived Polyphosphate Accelerates Intestinal Epithelia Wound Healing through Inducing Platelet-Derived Mediators
Authors: Isozaki Shotaro , Konishi Hiroaki , Fujiya Mikihiro , Tanaka Hiroki , Murakami Yuki , Kashima Shin , Ando Katsuyoshi , Ueno Nobuhiro , Moriichi Kentaro , Okumura Toshikatsu
Published: March 2021

Inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn’s disease (CD), is an intractable intestinal inflammation associated with the disruption of the intestinal mucosa. We previously demonstrated that Lactobacillus brevis-derived long-chain polyphosphate (poly P) improved the intestinal barrier function by the upregulation of cell adhesion and relieved intestinal inflammation, thereby exerting a curing effect on colitis in vitro, in vivo, and in an investigator-initiated clinical study of UC. However, how poly P improves mucosal defects induced by intestinal inflammation has not been elucidated. In this study, we detected the accumulation of platelets in inflamed tissues induced by poly P in a dextran sulfate sodium- (DSS-) induced colitis mouse model. A light transmission aggregometry analysis and scanning electron microscopy showed that poly P promoted the platelet aggregation. An SRB assay and ki-67 staining showed that the supernatant of poly P-treated platelet-rich plasma (PRP) increased intestinal epithelial cell growth. A wound healing assay showed that the supernatant of poly P-treated PRP, but not poly P itself, accelerated wound healing. A Western blotting analysis indicated that mitogen-activated protein kinase activation was induced by the supernatant of poly P-treated human PRP in the epithelial cells and its wound healing effect was significantly decreased by the inhibition of ERK signaling. These data suggested that platelet-derived mediators induced by poly P improved intestinal inflammation through the promotion of epithelial cell growth by the activation of the ERK signaling pathway. The mechanism is a novel host-microbe interaction through mammalian platelet-derived mediators induced by bacterial molecules.
Regulatory Effect of Mesenchymal Stem Cells on T Cell Phenotypes in Autoimmune Diseases
Authors: Wei Zhiping , Yuan Jintao , Wang Gaoying , Ocansey Dickson Kofi Wiredu , Xu Zhiwei , Mao Fei
Published: March 2021

Research on mesenchymal stem cells (MSCs) starts from the earliest assumption that cells derived from the bone marrow have the ability to repair tissues. Several scientists have since documented the crucial role of bone marrow-derived MSCs (BM-MSCs) in processes such as embryonic bone and cartilage formation, adult fracture and tissue repair, and immunomodulatory activities in therapeutic applications. In addition to BM-MSCs, several sources of MSCs have been reported to possess tissue repair and immunoregulatory abilities, making them potential treatment options for many diseases. Therefore, the therapeutic potential of MSCs in various diseases including autoimmune conditions has been explored. In addition to an imbalance of T cell subsets in most patients with autoimmune diseases, they also exhibit complex disease manifestations, overlapping symptoms among diseases, and difficult treatment. MSCs can regulate T cell subsets to restore their immune homeostasis toward disease resolution in autoimmune conditions. This review summarizes the role of MSCs in relieving autoimmune diseases via the regulation of T cell phenotypes.
Topological Approaches for Rough Continuous Functions with Applications
Authors: Salama A. S. , Mhemdi A. , Elbarbary O. G. , Al-shami T. M.
Published: March 2021

In this paper, we purposed further study on rough functions and introduced some concepts based on it. We introduced and investigated the concepts of topological lower and upper approximations of near‐open sets and studied their basic properties. We defined and studied new topological neighborhood approach of rough functions. We generalized rough functions to topological rough continuous functions by different topological structures. In addition, topological approximations of a function as a relation were defined and studied. Finally, we applied our approach of rough functions in finding the images of patient classification data using rough continuous functions.
Adaptive Algorithm Recommendation and Application of Learning Resources in English Fragmented Reading
Authors: Cheng Jinyu , Wang Hong
Published: March 2021

This paper firstly designs a five‐dimensional model of learners’ characteristics (learners’ English reading ability, cognitive style, learning goal, learning situation, and learning effect) and a three‐dimensional model of English reading resources’ characteristics (question types, topics, and difficulty of resources) in a fragmented learning environment through literature research. At the same time, to make the learning resources meet the characteristics of fragmented learning time and space, the English Level 4 reading resources are reasonably designed and segmented to adapt to the needs of learners’ mobile fragmented learning. Then, combined with machine learning algorithms, an adaptive recommendation model of learning resources in English fragmented reading is constructed. The algorithm‐based adaptive recommendation algorithm for English fragmented reading resources is designed. Based on the generated decision trees, the expression rules are parsed to achieve adaptive pushing of resources. The results of this study show that adaptive recommendation of learning resources in English fragmented reading can help teachers to develop future resource recommendation strategies through effective data collection to adaptively push resources that are close to learners’ individual needs. The use of mobile by English learners to learn to read in a fragmented learning context enables targeted training in weak areas of English reading, thus enhancing different aspects of learners’ reading skills.
Glutamine Administration Attenuates Kidney Inflammation in Obese Mice Complicated with Polymicrobial Sepsis
Authors: Su Li-Han , Lin Ming-Tsan , Yeh Sung-Ling , Yeh Chiu-Li
Published: March 2021

Obesity is a well-known public health issue around the world. Sepsis is a lethal clinical syndrome that causes multiorgan failure. Obesity may aggravate inflammation in septic patients. Glutamine (GLN) is a nutrient with immune regulatory and anti-inflammatory properties. Since sepsis is a common contributing factor for acute kidney injury (AKI), this study investigated the effects of GLN administration on sepsis-induced inflammation and AKI in obese mice. A high-fat diet which consists of 60% of calories from fat was provided for 10 weeks to induce obesity in the mice. Then, the obese mice were subdivided into sepsis with saline (SS) or GLN (SG) groups. Cecal ligation and puncture (CLP) was performed to produce sepsis. The SS group was intravenously injected with saline while the SG group was administered GLN one or two doses after CLP. Obese mice with sepsis were sacrificed at 12, 24, or 48 h post-CLP. Results revealed that sepsis resulted in upregulated high-mobility group box protein-1 pathway-associated gene expression in obese mice. Also, expressions of macrophage/neutrophil infiltration markers and inflammatory cytokines in kidneys were elevated. Obese mice treated with GLN after sepsis reversed the depletion of plasma GLN, reduced production of lipid peroxides, and downregulated macrophage/neutrophil infiltration and the inflammatory-associated pathway whereas tight junction gene expression increased in the kidneys. These findings suggest that intravenously administered GLN to obese mice after sepsis alleviated inflammation and attenuated AKI. This model may have clinical application to obese patients with a risk for infection in abdominal surgery.
Analysis of Pure Bending Vertical Deflection of Improved Composite Box Girders with Corrugated Steel Webs
Authors: Ma Chi , Liu Shi-zhong , Di Jin , Zhang Rui-jie
Published: March 2021

Steel bottom plates are applied as replacements for the concrete bottom plates in order to reduce the dead weight of the composite box girders with corrugated steel webs and steel bottom plates (CSWSB). Due to the change in the material, the previous analytical calculation methods of vertical deflection of composite box girders with corrugated steel webs (CSWs) cannot be directly applied to the improved composite box girders. The shear lag warpage displacement function was derived based on the shear deformation laws of the upper flange and the bottom plates of the improved composite box girders. The equations for the calculation of the shear deformation and the additional deflection due to the shear lag of continuous and simply supported composite box girders with CSWSB under concentrated and uniformly distribution loads were derived by considering the double effects of the shear lag and the shear deformations of the top and the bottom plates with different elastic moduli. The analytical solutions of the vertical deflection of the improved composite box girders include the theory of the bending deflection of elementary beams, shear deformation of CSWs, and the additional deflection caused by the shear lag. Based on the theoretical derivation, an analytical solution method was established and the obtained vertical deflection analytical solutions were compared with the finite element method (FEM) calculation results and the experimental values. The analytical equations of vertical deflection under the two supporting conditions and the two load cases have verified the analyses and the comparisons. Further, the additional deflections due to the shear lag and the shear deformation are found to be less than 2% and 34% of the total deflection values, respectively. Moreover, under uniform distributed load conditions, the deflection value was found to be higher than that of the under concentrated load condition. It was also found that the ratio of the deflection caused by the shear lag or the shear deformation to the total deflection decreased gradually with the increase in the span width ratio. When the value of the span width ratio of a single box and single chamber composite box girder with CSWSB was equal to or greater than 8, the deflections caused by the shear lag and the shear deformation could be ignored.
Frost Resistance of Desert Sand Concrete
Authors: Liu Haifeng , Ma Yingchang , Ma Jurong , Yang Weiwu , Che Jialing
Published: March 2021

Demand for medium sand has increased greatly with increasing infrastructure construction items. The shortage of construction sand resources has become a serious problem in many districts. It not only increases the engineering cost, and the overexploitation of river sand and mountain as medium sand also brings a series of serious environment problems. There are abundant desert sand (DS) resources in western China. If DS resources can be used to substitute medium sand to produce desert sand concrete (DSC), which was suitable for engineering practice, the environment can be improved and engineering cost can be reduced. Although many researchers had focused on the mechanical performance of DSC, there were few documents on the frost resistance of DSC. Frost resistance experiments of DSC with 50% desert sand replacement ratio (DSRR) and ordinary concrete (OC) were performed in this paper. Influence of freeze‐thaw cycles on the mechanical properties of OC and DSC was analyzed. Experimental results showed that, with increasing freeze‐thaw cycles, the damage, peak strain, and porosity increased, while elastic modulus, Poisson′s ratio, and peak stress declined, the stress‐strain curves tended to be flat. Under the same condition of freeze‐thaw cycles, the frost resistance of DSC with 50% DSRR was higher than that of OC. Constitutive model of DSC after different freeze‐thaw cycles was formulated. The results predicted by constitutive model agreed well with experimental results, which can provide technical support for DSC engineering practice.
Applications of (Neutro/Anti)sophications to Semihypergroups
Authors: Rezaei A. , Smarandache F. , Mirvakili S.
Published: March 2021

In this paper, we extend the notion of semi-hypergroups (resp. hypergroups) to neutro-semihypergroups (resp. neutro-hypergroups). We investigate the property of anti-semihypergroups (resp. anti-hypergroups). We also give a new alternative of neutro-hyperoperations (resp. anti-hyperoperations), neutro-hyperoperation-sophications (resp. anti-hypersophications). Moreover, we show that these new concepts are different from classical concepts by several examples.
Seismic Behavior of Nonductile RC Frame Slotted with Corrugated Steel Plate Shear Walls
Authors: Feng Ningning , Wu Changsheng
Published: March 2021

Two specimens of nonductile reinforced concrete (RC) frame (ND‐1) and nonductile RC frame retrofitted by corrugated steel plate shear walls slotted with columns (ND‐2) are established by finite element. These specimens have same dimensions and steel skeletons. Finite element models had been verified by the existing experimental results. The hysteresis curves, skeleton curves, ductility, and stiffness curves of Specimen ND‐1 and Specimen ND‐2 are compared. The results show that the reinforcement effect is significant. Twenty‐four models are built to study the seismic behavior on different influence parameters. The parameters are slit width, thickness of corrugated steel plate shear walls, concrete strength of nonductile RC frame, and boundary conditions of corrugated steel plate shear walls at slotted parts. The results indicate that the strength is declined with the increase of slit width. With the increase of thickness and concrete strength, the strength and stiffness are enhanced. The strength is larger with the boundary than without. Slit width and thickness have an important impact on the stiffness. Concrete strength and boundary conditions have little impact on stiffness. The strengthened nonductile RC frames have enough ductility.
Reverse Logistics for Solid Waste from the Construction Industry
Authors: Vargas Manuel , Alfaro Miguel , Karstegl Natalia , Fuertes Guillermo , Gracia María D. , Mar-Ortiz Julio , Sabattin Jorge , Duran Claudia , Leal Naudy
Published: March 2021

This article reviews studies on the application of reverse logistics in solid waste from the construction industry. The main objective is to provide a summary of current knowledge and specific areas for future research. In addition, construction, as an economic sector, is in a continuous search for new tools to improve its processes, so this research provides the current situation of the relationship between reverse logistics and solid waste in the industry. The review methodology was content analysis of scientific literature published between 1997 and 2020, and total of 66 articles were used. 73% correspond to research articles, around 13% are case studies, and 12% are literature reviews. Only one of the articles is a survey. In addition, 52% of the works reviewed correspond to solid waste studies and 49% are related to the construction industry; only one publication does not classify in any. The most used keywords for the identification of published works were reverse logistics and supply chain; both terms are frequently related to the process and general management of solid waste and construction. The least used term was the literature review that shows the low number of articles that provide a summary of the proposed topic. Finally, three materials were chosen for the study because they are the most used in construction: metals, bricks, and concrete. 15% of the articles study all three, 18% study only metals, and 63% study other materials or are related to construction and solid waste in general.
Radiation Resistance of a Structural Material Based on Modified Titanium Hydride
Authors: Yastrebinsky R. N. , Pavlenko V. I. , Karnauhov A. A. , Cherkashina N. I. , Yastrebinskaya A. V. , Gorodov A. I.
Published: March 2021

This work investigates the radiation resistance of a structural material based on modified titanium hydride and a Portland cement in a flux of neutron and γ-radiation. An assessment of the geometric and physicomechanical properties is given, along with the surface structure of irradiated cement composites, and the phase composition of the main hydrosilicates of the hydrated cement matrix during its γ-irradiation. It is shown that the use of a shot of titanium hydride increases the radiation resistance of radiation shielding based on a cement matrix, in comparison with the unmodified shot. A composite based on a modified shot of titanium hydride retains its basic properties after γ-irradiation, at an absorbed dose of up to 10 MGy. At an absorbed dose of 2 MGy in the Portland cement matrix of a composite based on a modified shot of titanium hydride, the formation of suolunite hydrosilicates occurs. It was established using X-ray fluorescence that, in the titanium hydride, a redistribution of the electron density occurs at an absorbed dose of γ radiation of 5 MGy, caused by structural phase changes due to the ongoing dehydrogenation processes.
Insights on Crash Injury Severity Control from Novice and Experienced Drivers: A Bivariate Random-Effects Probit Analysis
Authors: Xiao Daiquan , Yuan Quan , Kang Shengyang , Xu Xuecai
Published: March 2021

This study intended to investigate the crash injury severity from the insights of the novice and experienced drivers. To achieve this objective, a bivariate panel data probit model was initially proposed to account for the correlation between both time-specific and individual-specific error terms. The geocrash data of Las Vegas metropolitan area from 2014 to 2017 were collected. In order to estimate two (seemingly unrelated) nonlinear processes and to control for interrelations between the unobservables, the bivariate random-effects probit model was built up, in which injury severity levels of novice and experienced drivers were addressed by bivariate (seemingly unrelated) probit simultaneously, and the interrelations between the unobservables (i.e., heterogeneity issue) were accommodated by bivariate random-effects model. Results revealed that crash types, vehicle types of minor responsibility, pedestrians, and motorcyclists were potentially significant factors of injury severity for novice drivers, while crash types, driver condition of minor responsibility, first harm, and highway factor were significant for experienced drivers. The findings provide useful insights for practitioners to improve traffic safety levels of novice and experienced drivers.
Effect of Helicobacter Pylori Infection on Nutritional Status in Polish Teenagers
Authors: Szaflarska-Popławska Anna , Soroczyńska-Wrzyszcz Anetta
Published: March 2021

Purpose. Data on an association between Helicobacter pylori (H. pylori) and nutritional status in children are conflicting. We designed a large-sampled prospective community-based study to examine the differences in average body indices among Polish teenagers depending on their H. pylori status. Methods. From September 2008 to June 2015, 3067 second junior high school students aged between 13 and 17 years (mean age: 14.5) from 11 randomly selected schools from Grudziadz, Poland, were recruited. For the cohort, 13C urea breath test for current H. pylori infection was performed and data on anthropometric measurements and sociodemographic characteristics were collected.

Z

scores of height for age (HAZ), weight for age (WAZ), and BMI for age (BMIZ) were calculated. Results. The H. pylori colonisation rate was 23.6% with no gender difference. Compared to noninfected, H. pylori infected had significantly lower mean WAZ (0.0085) and BMIZ scores (

p
=
0.0246

). Univariate linear regression models showed that living in the old town district and consumption of tap water were negative predictors of HAZ, living in the old town district, using collective catering facilities, and H. pylori infection were negative predictors of WAZ, and using collective catering facilities and H. pylori infection were negative predictors of BMIZ. In the multiple regression analyses, living in the old town district (

p
=
0.0039

), using collective catering facilities (

p
<
0.0001

), and H. pylori infection (

p
=
0.0269

) were confirmed to be independently associated with lower WAZ, whereas using collective catering facilities (

p
<
0.0001

) and H. pylori infection (

p
=
0.0265

) were confirmed to be independently associated also with lower BMIZ. Conclusion. Our finding confirms the evidence on independent negative influence of H. pylori infection on nutritional status in Polish teenagers.
A New Health Condition Detection Method for Planetary Gears Based on Modified Distributed Compressed Sensing and Multiscale Symbol Dynamic Entropy
Authors: Wu Zhe , Zhang Qiang , Ma Zeyu , Lu Jialong , Qin Zhiying
Published: March 2021

Planetary gear transmission system is an important transmission part of large machinery and is prone to failure. Aiming at the problem of how to extract fault information from vibration signals of nonlinear and nonstationary planetary gearboxes, a performance degradation evaluation index of planetary gearboxes based on improved distributed compressed sensing and modified multiscale symbolic dynamic entropy (DCSMDE) is proposed. DCSMDE combines distributed compression sensing with modified multiscale symbol dynamic entropy and solves the problem of strong nonlinearity and strong vibration signal coupling of the planetary transmission system from the homologous signals of multiple sensors. A distributed compression sensing parameter optimization algorithm based on Rényi entropy is proposed, which uses improved distributed compression sensing technology to simultaneously sample, compress, and denoise the multisource vibration data of rotating machinery. DCSMDE is used to calculate the reconstructed signal, extract the features with higher recognition characteristics, and use the change trend of the DCSMDE value to judge the working status of the planetary gearbox. Experimental results show that DCSMDE can be applied to dynamic evolution and fault identification of mechanical systems and accurately classify actual fault signals. It provides a new idea for the classification of planetary gear faults and the recognition of performance degradation.
A Noninvasive Prediction Model for Hepatitis B Virus Disease in Patients with HIV: Based on the Population of Jiangsu, China
Authors: Yin Yi , Xue Mingyue , Shi Lingen , Qiu Tao , Xia Derun , Fu Gengfeng , Peng Zhihang
Published: March 2021

Objective. To establish a machine learning model for identifying patients coinfected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV) through two sexual transmission routes in Jiangsu, China. Methods. A total of 14197 HIV cases transmitted by homosexual and heterosexual routes were recruited. After data processing, 12469 cases (HIV and HBV, 1033; HIV, 11436) were left for further analysis, including 7849 cases with homosexual transmission and 4620 cases with heterosexual transmission. Univariate logistic regression was used to select variables with significant P value and odds ratio for multivariable analysis. In homosexual transmission and heterosexual transmission groups, 10 and 6 variables were selected, respectively. For identifying HIV individuals coinfected with HBV, a machine learning model was constructed with four algorithms, including Decision Tree, Random Forest, AdaBoost with decision tree (AdaBoost), and extreme gradient boosting decision tree (XGBoost). The detective value of each variable was calculated using the optimal machine learning algorithm. Results. AdaBoost algorithm showed the highest efficiency in both transmission groups (homosexual transmission group: accuracy = 0.928, precision = 0.915, recall = 0.944, F − 1 = 0.930, and AUC = 0.96; heterosexual transmission group: accuracy = 0.892, precision = 0.881, recall = 0.905, F − 1 = 0.893, and AUC = 0.98). Calculated by AdaBoost algorithm, the detective value of PLA was the highest in homosexual transmission group, followed by CR, AST, HB, ALT, TBIL, leucocyte, age, marital status, and treatment condition; in the heterosexual transmission group, the detective value of PLA was the highest (consistent with the condition in the homosexual group), followed by ALT, AST, TBIL, leucocyte, and symptom severity. Conclusions. The univariate logistics regression combined with the AdaBoost algorithm could accurately screen the risk factors of HBV in HIV coinfection without invasive testing. Further studies are needed to evaluate the utility and feasibility of this model in various settings.
Numerical Simulation of Stepped Spillways with Front Step Deformation
Authors: Li Guodong , Zhang Haifeng , Li Xingnan , Guo Lihao , Gao Yanyan , Cai Dandan
Published: March 2021

In order to solve the flood discharge problem of both small- and medium-sized warping dams in the Loess Plateau, a stepped spillway scheme, based on an ecological bag, to achieve full-section water flow and energy dissipation has been proposed in this paper. The hydraulic and energy dissipation characteristics of a stepped spillway layout scheme were studied using 3D numerical simulation. As the height of the dams is low and the spillways are short, the research has shown that the traditional single-step layout scheme leads to a low overall energy dissipation rate due to the small amount of energy dissipated in the initial steps. As a result of this, this paper has put forward two kinds of step layout schemes such as the shunt type and the staggered type for the initial steps. Through analysis of the flow state, the pressure distribution, and the total energy dissipation rate, the results have shown that shunt type and staggered type with front step deformation produced an obvious mixing of the water flow, fewer negative pressure areas, and a higher energy dissipation rate. The optimal energy dissipation rate of the staggered type reached 87.75%, and the maximum energy dissipation rate was increased by 27.97%.
Fulminant Hepatic Failure after Chemosaturation with Percutaneous Hepatic Perfusion and Nivolumab in a Patient with Metastatic Uveal Melanoma
Authors: Teal Lindsey , Yorio Jeffrey
Published: March 2021

Immune checkpoint inhibitors, such as nivolumab, a programmed death receptor-1 (PD-1) inhibitor, have dramatically improved the treatment of advanced melanomas. Chemosaturation with percutaneous hepatic perfusion (PHP) delivers chemotherapy in high doses directly to the liver and is a potentially effective treatment modality in metastatic uveal melanoma with liver metastases. Its safety and effectiveness have not been studied in patients also receiving immunotherapy. A 46-year-old male with a history of uveal melanoma of the right eye was found to have liver metastases. He was treated with PHP using high-dose melphalan for 6 months with a partial response followed by progression. Two months after his last PHP treatment, the patient was started on nivolumab. After two doses of nivolumab, the patient developed severe hepatitis that progressed to fulminant hepatic failure and death despite treatment with high-dose corticosteroids and mycophenolate mofetil. Nivolumab and other immune checkpoint inhibitors have been effective in treating advanced melanoma and extending life. However, there are serious immune adverse events that can occur. While hepatitis after taking nivolumab has been documented, fulminant hepatic failure is rare. We believe that prior PHP treatment contributed to the severity of the hepatitis and, ultimately, fulminant hepatic failure. To our knowledge, this is the only case of fulminant hepatic failure secondary to a checkpoint inhibitor with preceding PHP. Specific precautions should be made in patients who have been exposed to PHP in the past, and further studies should be done to assess the safety of using checkpoint inhibitors after PHP.
Thyroid Dysfunction and Dysmetabolic Syndrome: The Need for Enhanced Thyrovigilance Strategies
Authors: Kalra Sanjay , Aggarwal Sameer , Khandelwal Deepak
Published: March 2021

Thyroid dysfunction (TD) is common in metabolic disorders such as diabetes mellitus (DM), cardiovascular disease (CVD), obesity, dyslipidemia, hyperuricemia, kidney and liver dysfunctions, and polycystic ovary syndrome (PCOS). Subclinical hypothyroidism (SHypo) worsens glycemic control in patients with DM, and these patients, especially those with Type-1DM, have higher prevalence of TD. Both TD and DM increase CVD risk. Even minor alteration in thyroid hormone (TH) levels can alter cardiovascular function. While hyperthyroidism increases systolic blood pressure and leads to high-output heart failure, hypothyroidism increases diastolic blood pressure and leads to low-output heart failure. Chronic subclinical hyperthyroidism (SHyper) and SHypo both increase the risk of hypertension, coronary artery disease (CAD) events, CAD deaths, and total deaths. SHyper alters cardiac morphology and function. SHypo causes dyslipidemia and endothelial dysfunction and increases the risk for weight gain and obesity. Overweight and obese patients often have hyperleptinemia, which increases the secretion of thyroid stimulating hormone (TSH) and induces TD. Dyslipidemia associated with TD can increase serum uric acid levels. Hyperuricemia promotes inflammation and may increase the risk for dyslipidemia, atherosclerosis, and CVD. TD increases the risk for developing chronic kidney disease. In nephrotic syndrome, proteinuria is associated with urinary loss of TH leading to TD. Some correlation between TD and severity of liver disease is also seen. TD and PCOS have common risk factors and pathophysiological abnormalities. Hypothyroidism must be excluded before diagnosing PCOS. Current guidelines do not strongly recommend thyroid screening in the presence of all metabolic disorders. However, pragmatic thyrovigilance is required. Clinicians must stay alert to signs and symptoms of TD, maintain high clinical suspicion, and investigate thoroughly. Drug-induced TD should be considered when TH levels do not match clinical findings or when patients are on medications that can alter thyroid function.
Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas
Authors: Wu Jing , Yuan Ying , Long Priel Debra A. , Fink Danielle , Peer Cody J. , Sissung Tristan M. , Su Yu-Ting , Pang Ying , Yu Guangyang , Butler Madison K. , Mendoza Tito R. , Vera Elizabeth , Ahmad Salman , Bryla Christine , Lindsley Matthew , Grajkowska Ewa , Mentges Kelly , Boris Lisa , Antony Ramya , Garren Nancy , Siegel Christine , Lollo Nicole , Cordova Christine , Aboud Orwa , Theeler Brett J. , Burton Eric M. , Penas-Prado Marta , Leeper Heather , Gonzales Javier , Armstrong Terri S. , Calvo Katherine R. , Figg William D. , Kuhns Douglas B. , Gallin John I. , Gilbert Mark R.
Published: March 2021

Purpose:

To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma.

Patients and Methods:

This two-stage phase I trial determined the MTD of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden.

Results:

Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12–24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value.

Conclusions:

Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.
Enhancing Proteotoxic Stress in Leiomyosarcoma Cells Triggers Mitochondrial Dysfunctions, Cell Death, and Antitumor Activity in vivo
Authors: Iuliano Luca , Drioli Sara , Pignochino Ymera , Cafiero Claudia Maria , Minisini Martina , D'Este Francesca , Picco Raffaella , Dalla Emiliano , Giordano Giorgia , Grignani Giovanni , Di Giorgio Eros , Benedetti Fabio , Felluga Fulvia , Brancolini Claudio
Published: March 2021

Leiomyosarcomas are rare and aggressive tumors characterized by a complex karyotype. Surgical resection with or without radiotherapy and chemotherapy is the standard curative treatment. Unfortunately, a high percentage of leiomyosarcomas recurs and metastasizes. In these cases, doxorubicin and ifosfamide represent the standard treatment but with low response rates. Here, we evaluated the induction of proteotoxic stress as a possible strategy to kill leiomyosarcoma cells in a therapeutic perspective. We show that aggressive leiomyosarcomas coexist with high levels of proteotoxic stress. As a consequence, we hypothesized that leiomyosarcoma cells are vulnerable to further increases of proteotoxic stress. The small compound 2c is a strong inducer of proteotoxic stress. In leiomyosarcoma cells, it triggers cell death coupled to a profound reorganization of the mitochondrial network. By using stimulated emission depletion microscopy, we have unveiled the existence of DIABLO/SMAC clusters that are modulated by 2c. Finally, we have engineered a new version of 2c linked to polyethylene glycol though a short peptide, named 2cPP. This new prodrug is specifically activated by proteases present in the tumor microenvironment. 2cPP shows a strong antitumor activity in vivo against leiomyosarcomas and no toxicity against normal cells.
In Vivo Efficacy of Tesevatinib in EGFR-Amplified Patient-Derived Xenograft Glioblastoma Models May Be Limited by Tissue Binding and Compensatory Signaling
Authors: Kizilbash Sani H. , Gupta Shiv K. , Parrish Karen E. , Laramy Janice K. , Kim Minjee , Gampa Gautham , Carlson Brett L. , Bakken Katrina K. , Mladek Ann C. , Schroeder Mark A. , Decker Paul A. , Elmquist William F. , Sarkaria Jann N.
Published: March 2021

Tesevatinib is a potent oral brain penetrant EGFR inhibitor currently being evaluated for glioblastoma therapy. Tesevatinib distribution was assessed in wild-type (WT) and Mdr1a/b(-/-)Bcrp(-/-) triple knockout (TKO) FVB mice after dosing orally or via osmotic minipump; drug–tissue binding was assessed by rapid equilibrium dialysis. Two hours after tesevatinib dosing, brain concentrations in WT and TKO mice were 0.72 and 10.03 μg/g, respectively. Brain-to-plasma ratios (Kp) were 0.53 and 5.73, respectively. With intraperitoneal infusion, brain concentrations were 1.46 and 30.6 μg/g (Kp 1.16 and 25.10), respectively. The brain-to-plasma unbound drug concentration ratios were substantially lower (WT mice, 0.03–0.08; TKO mice, 0.40–1.75). Unbound drug concentrations in brains of WT mice were 0.78 to 1.59 ng/g. In vitro cytotoxicity and EGFR pathway signaling were evaluated using EGFR-amplified patient-derived glioblastoma xenograft models (GBM12, GBM6). In vivo pharmacodynamics and efficacy were assessed using athymic nude mice bearing either intracranial or flank tumors treated by oral gavage. Tesevatinib potently reduced cell viability [IC50 GBM12 = 11 nmol/L (5.5 ng/mL), GBM6 = 102 nmol/L] and suppressed EGFR signaling in vitro. However, tesevatinib efficacy compared with vehicle in intracranial (GBM12, median survival: 23 vs. 18 days, P = 0.003) and flank models (GBM12, median time to outcome: 41 vs. 33 days, P = 0.007; GBM6, 44 vs. 33 days, P = 0.007) was modest and associated with partial inhibition of EGFR signaling. Overall, tesevatinib efficacy in EGFR-amplified PDX GBM models is robust in vitro but relatively modest in vivo, despite a high brain-to-plasma ratio. This discrepancy may be explained by drug-tissue binding and compensatory signaling.
RNA-Binding Protein Polymorphisms as Novel Biomarkers to Predict Outcomes of Metastatic Colorectal Cancer: A Meta-analysis from TRIBE, FIRE-3, and MAVERICC
Authors: Arai Hiroyuki , Cao Shu , Battaglin Francesca , Wang Jingyuan , Kawanishi Natsuko , Tokunaga Ryuma , Loupakis Fotios , Stintzing Sebastian , Soni Shivani , Zhang Wu , Mancao Christoph , Salhia Bodour , Mumenthaler Shannon M. , Cremolini Chiara , Heinemann Volker , Falcone Alfredo , Millstein Joshua , Lenz Heinz-Josef
Published: March 2021

RNA-binding proteins (RBPs) regulate many posttranscriptional cellular activities. Accumulating evidence suggests associations between RBPs with colonic tumorigenesis and chemosensitivity. We investigated the prognostic and predictive values of SNPs of genes encoding RBPs in metastatic colorectal cancer (mCRC), using clinical and genomic data from three randomized clinical trials of standard first-line chemotherapy for mCRC (TRIBE, FIRE-3, and MAVERICC). Genomic DNA extracted from blood samples was genotyped using an OncoArray. We tested 30 candidate SNPs of 10 major RBP-related genes with additive models. Prognostic values were estimated by meta-analysis approach. Treatment-by-SNP interactions were tested to estimate predictive values for targeted drugs and cytotoxic backbone chemotherapies. This study included 884 patients. The meta-analysis revealed prognostic values of LIN28B rs314277 [HR, 1.26; 95% confidence interval (CI), 1.06–1.49, P = 0.005, FDR-adjusted P = 0.072 for overall survival (OS)] and LIN28B rs314276 (HR, 1.25; 95% CI, 1.08–1.44, P = 0.002, FDR-adjusted P = 0.062 for OS). Although some SNPs showed potentially predictive values, these associations were not confirmed after FDR adjustment. In conclusion, the results of this study are warranting additional studies to provide the evidence that RBP-related SNPs may be associated with the prognosis of patients with mCRC treated with standard first-line chemotherapies. In addition, further studies are warranted to study the predictive value.
Macrophage Activation Status Rather than Repolarization Is Associated with Enhanced Checkpoint Activity in Combination with PI3Kγ Inhibition
Authors: Carnevalli Larissa S. , Taylor Molly A. , King Matthew , Coenen-Stass Anna M.L. , Hughes Adina M. , Bell Sigourney , Proia Theresa A. , Wang Yanjun , Ramos-Montoya Antonio , Wali Neha , Carroll Danielle , Singh Maneesh , Moschetta Michele , Gutierrez Pablo Morentin , Gardelli Cristina , Critchlow Susan E. , Klinowska Teresa , Fawell Stephen E. , Barry Simon T.
Published: March 2021

Suppressive myeloid cells mediate resistance to immune checkpoint blockade. PI3Kγ inhibition can target suppressive macrophages, and enhance efficacy of immune checkpoint inhibitors. However, how PI3Kγ inhibitors function in different tumor microenvironments (TME) to activate specific immune cells is underexplored. The effect of the novel PI3Kγ inhibitor AZD3458 was assessed in preclinical models. AZD3458 enhanced antitumor activity of immune checkpoint inhibitors in 4T1, CT26, and MC38 syngeneic models, increasing CD8+ T-cell activation status. Immune and TME biomarker analysis of MC38 tumors revealed that AZD3458 monotherapy or combination treatment did not repolarize the phenotype of tumor-associated macrophage cells but induced gene signatures associated with LPS and type II INF activation. The activation biomarkers were present across tumor macrophages that appear phenotypically heterogenous. AZD3458 alone or in combination with PD-1–blocking antibodies promoted an increase in antigen-presenting (MHCII+) and cytotoxic (iNOS+)-activated macrophages, as well as dendritic cell activation. AZD3458 reduced IL-10 secretion and signaling in primary human macrophages and murine tumor-associated macrophages, but did not strongly regulate IL-12 as observed in other studies. Therefore, rather than polarizing tumor macrophages, PI3Kγ inhibition with AZD3458 promotes a cytotoxic switch of macrophages into antigen-presenting activated macrophages, resulting in CD8 T-cell–mediated antitumor activity with immune checkpoint inhibitors associated with tumor and peripheral immune activation.
Transplant Glomerulopathy: Importance of Ultrastructural Examination
Authors: Gibson Ian W.
Published: March 2021

Background: Transplant glomerulopathy (TG) is a morphologic alteration in glomeruli of renal allografts, characterized by glomerular basement membrane reduplications. Summary: TG is associated with progressive chronic allograft dysfunction and proteinuria and is a diagnostic feature of chronic antibody-mediated rejection (ABMR) in patients positive for donor-specific antibodies, according to the Banff schema for renal allograft pathology. It is a definitive endpoint in clinical trials and interventional studies for ABMR, but the lesion can also occur in the absence of definitive alloimmune injury, as a consequence of chronic thrombotic microangiopathy, and in some cases in association with hepatitis C infection. This review discusses the pathophysiology and clinical presentation of TG, the diagnostic features by light microscopy, and focuses on the sequential ultrastructural stages of the lesion. The differential diagnosis of TG, and Banff grading of the lesion, are reviewed. Clinicopathological indications for performing routine ultrastructural examination of renal allograft biopsies are discussed. Key Messages: TG can be diagnosed at an early stage by electron microscopy, before histological features are apparent, emphasizing the importance of ultrastructural examination of renal allograft biopsies for an early diagnosis, when therapeutic intervention may be beneficial.
Adjuvant Chemotherapy in High-Risk Prostate Cancer Patients after Primary Local Therapy: Recurrence, Metastasis, and Survival – A Meta-Analysis
Authors: Zhang Qiang , Huang Jing , Xie Chaofan , Wu Tao
Published: March 2021

Context: Several randomized clinical trials (RCTs) have recently tested adjuvant chemotherapy to high-risk prostate cancer patients (PCA) after primary local therapy. Objective: The aim of the study was to perform a systematic review and meta-analysis of RCTs evaluating the adjuvant chemotherapy in high-risk prostate cancer patients after primary local therapy. The primary endpoint was overall survival (OS). The secondary endpoint was disease-free survival (DFS) and biochemical recurrence-free survival (BRFS). Methods: A systematic review of PubMed/Medline, Embase, and Cochrane databases was performed to identify relevant studies published in English up to March 2020. Six trials were selected for inclusion. Results: There were 7 studies included in the present study. The meta-analysis did not show a significant OS benefit from adjuvant chemotherapy in patients with high-risk prostate cancer after primary local therapy (hazard ratio [HR]: 0.87; 95% confidence interval [CI], 0.72–1.05; p = 0.15). But docetaxel in patients with high-risk prostate cancer after primary local therapy was associated with a slightly OS improvement (HR: 0.79; 95% CI, 0.63–0.98; p = 0.03). It also did not show a significant benefit in DFS and BRFS in patients with high-risk prostate cancer (HR: 0.89, 95% CI, 0.75–1.06, p = 0.18; HR: 0.85, 95% CI, 0.69–1.06, p = 0.16). Conclusions: This meta-analysis shows a slightly OS benefit from docetaxel in patients with high-risk prostate cancer after primary local therapy. It did not show a significant benefit in DFS and BRFS from adjuvant chemotherapy in patients with high-risk prostate cancer.
Erythropoietin Resistance Index and the Affecting Factors in Children with Peritoneal Dialysis
Authors: Pınarbaşı Ayşe Seda , Dursun Ismail , Günay Neslihan , Baatar Batsaikhan , Yel Sibel , Dursun Jale , Balaban Aynur Gencer , Poyrazoğlu Muammer Hakan , Düşünsel Ruhan
Published: March 2021

Background: Erythropoiesis-stimulating agents (ESAs) are used to treat anemia in CKD. Erythropoietin resistance index (ERI) is a useful tool used to evaluate the response to ESAs. In this study, we aimed to evaluate the causes of high ERI in children undergoing peritoneal dialysis (PD). Method: Patients who had been on PD for at least 1 year were included in this retrospective study. Demographic characteristics, residual kidney function (RKF), adequacy of dialysis, peritoneal glucose exposure, the number and reason for hospitalization, and medications were recorded. Anemia and laboratory parameters that may affect anemia were noted by taking the average of laboratory values in the last follow-up year (time-averaged). The weekly ESA dose was proportioned to the annual average hemoglobin value and body weight to calculate the ERI in terms of U/kg/week/g/dL. Results: A total of 100 patients were included in the study. The mean ESA dose and ERI value were 119.8 ± 66.22 U/kg/week and 13.01 ± 7.52 U/kg/week/g/dL, respectively. It was determined that the patients <5 years of age have very high ERI value, and these patients need 2 times more ESA than those >10 years of age. Absence of RKF, large number of hospitalization, and ACEI use were also found to affect the ERI value negatively. Conclusion: We demonstrate that the most important factor affecting ERI value is young age. We also reveal that absence of RKF, large number of hospitalization, and ACEI use are also important variables affecting the ERI value.