bluuebunny/crossref_metadata_2025 huggingface dataset:
Research on the Construction Effect Evaluation System of Smart CBD: A Case Study in Jiangbei New District, Nanjing, China
Authors: Hong Min , Peng Caihong , Niu Mi , Xu Zhao
Published: February 2021

With the update and development of technologies such as IoT, the smart city revolution is boosting construction. Several excellent CBD construction projects designed in smart city construction models have emerged around the world. Exploring the construction model of the CBD through the establishment of an evaluation index system of construction effect is of great significance for CBD’s future development. The main objective of this study is to analyze the factors that affect the effectiveness of the construction of the CBD by using the Delphi method and AHP and to provide a systematic method to establish an index evaluation system for the construction effect of the smart CBD, which reflects the influencing factors of the construction effect in the CBD district from six perspectives: construction, management, service, innovation, strategy, and users. This paper also introduces the construction and development of CBD in the Jiangbei New District in Nanjing, China, and uses the indicator system established in this study to evaluate its construction effect. This paper establishes a four‐level indicator system, from general to specific, and discusses the degree of impact of each indicator on the effectiveness of smart CBD construction. In order to obtain the initial evaluation data more accurately, this study classified the survey subjects into three categories, which are managers, commercial enterprise users, and ordinary residents. Finally, through the analysis of the evaluation results, the effectiveness of the construction of the Jiangbei New District CBD was evaluated, and the focus of the future smart CBD construction was pointed out. The evaluation index system for the construction effect of the smart CBD established is considered to supply a good foundation for the CBD‐related study.
Effects of Bisphosphonates on Osseointegration of Dental Implants in Rabbit Model
Authors: Yu Ru Qing , Wang Jing Yi , Rao Nian Jing , Huo Lei , Zheng Li Wu
Published: February 2021

This study is to investigate the effect of bisphosphonates on the osseointegration of dental implants in a rabbit model. Twenty female New Zealand White rabbits were equally assigned into control and experiment groups which received saline or zoledronic acid treatment 4 weeks prior to surgery. Titanium dental implant was placed on the calvarial bone. Zoledronic acid or saline treatment continued after surgery for 4 weeks (short‐term subgroup) or 8 weeks (long‐term subgroup) until sacrifice. Three different fluorochrome labeling solutions were administrated for assessing bone growth rates. Samples of the calvarial bone and mandible were subjected to microcomputed tomography (micro‐CT), confocal microscope, and histology analysis. Zoledronic acid treatment significantly reduced bone growth rates in the calvarial bone, but had no significant influence in bone mineral density and trabecular microarchitecture. Significantly lower bone‐to‐implant contact ratios were found in zoledronic acid‐treated animals compared to controls at week 4 but not at week 8. Oncologic dose zoledronic acid suppresses the bone growth rates of the calvarial bone; ZA may have an adverse effect on osseointegration of dental implant in short term, but this effect tends to diminish in long term.
Design of a Personal Mobility Device for Elderly Users
Authors: Phannil Natthanon , Jettanasen Chaiyan
Published: February 2021

The ageing society has resulted in imbalances in the population age ratio. The ratio of working-age people was less than that of elderly people resulting in a shortage of elderly caregivers and increased healthcare costs. Although the lifestyle the elderly remains the same, their physical abilities are reduced, requiring them to rely on special equipment when traveling in order to gain more control and safety. Therefore, the Elderly Personal Mobility Device (EPMD) is developed using Internet of Things (IoT) technology to reduce the burden of caregivers, provide freedom and safety for elderly travelers, assess air pollution risks, and alert the occurrence of emergency events. The EPMD is designed in terms of structure, electrical equipment, and sensor systems. First, the shapes, sizes, and thicknesses of the carbon steel used for construction of the EPMD structure are calculated by using SolidWorks software. Next, the electric equipment is carefully selected to meet the requirements of actual use. Finally, the sensor system is designed to monitor the EPMD status and air quality using IoT devices to create a data interface and big data for elderly health service development, as well as an air quality map with distributed measuring stations and a charging station detection system for future use.
The Effect of Aggregate‐Forming Minerals on Thermodynamic Parameters Using Surface Free Energy Concept and Its Relationship with the Moisture Susceptibility of Asphalt Mixtures
Authors: Hamedi Gholam Hossein , Esmaeeli Mohammad Reza , Najafi Moghaddam Gilani Vahid , Hosseinian Seyed Mohsen
Published: February 2021

Moisture damage is known to be a key factor influencing the durability of asphalt pavements. This phenomenon will reduce the mechanical properties of asphalt mixtures due to its destructive effects on the adhesion of the bitumen‐aggregate system and the cohesion of the bitumen membrane. The mineral properties of the aggregates of asphalt mixtures are one of the factors affecting moisture susceptibility. Therefore, the surface free energy (SFE) method, as one of the thermodynamic methods, and indirect tensile strength test (ITST) have been used to determine the failure mechanism and the rate of change of adhesion properties of asphalt mixtures under the influence of mineralogical characteristics. Prior to the above tests, an X‐ray fluorescence spectrometry (XRF) test was performed to identify aggregate‐forming minerals in eight different types of aggregates with various minerals from eight mines, and also the apparent bitumen film thickness was measured. XRF test results showed that most parts of the aggregates in mines 1– 6 were composed of SiO2, which had strong acidic properties, according to the SFE results. ITST results showed that samples constructed with aggregates of mine 7 and 8 (with high CaO mineral content) experienced a higher TSR than other mixtures in all freeze‐thaw (F‐T) cycles. Results of the SFE method showed that aggregates with more calcareous properties had a smaller acidic component and a larger basic component. In mines 7 and 8, where the nonpolar component of their aggregates was larger, the tendency of the aggregates to adherence and wettability by water decreased. The adhesion free energy (AFE) between bitumen and aggregates with higher CaO and less SiO2 amounts was more than AFE between bitumen and aggregates with lower CaO and higher SiO2 amounts, in dry conditions. The presence of higher amounts of CaO in aggregates increased AFE of bitumen‐aggregate in presence of water from a negative value to zero. In linear regression analysis, due to the positive regression coefficient of the CaO mineral, this mineral had a positive impact on TSR; on the other hand, due to the negative regression coefficient of the SiO2 mineral, this mineral had a negative impact on the TSR of asphalt mixtures.
The Prevalence of Temporomandibular Disorders and Dental Attrition Levels in Patients with Posterior Crossbite and/or Deep Bite: A Preliminary Prospective Study
Authors: Khayat Naser , Winocur Efraim , Kedem Ron , Winocur Arias Orit , Zaghal Ayman , Shpack Nir
Published: February 2021

Background. The prevalence of various temporomandibular disorders (TMD) and the severity of attrition in patients with either bilateral or unilateral deep bite and/or posterior crossbite has not been established, nor has the effect of one year of orthodontic treatment on TMD. Methods. Of 310 patients presenting with suspected TMD, 160 were diagnosed with various TMD and 150 were TMD-free. Diagnosis was according to the Axis I of the Diagnostic Criteria for TMD. All participants underwent a dental examination, and 100 patients were reevaluated after one year of orthodontic treatment. Fisher’s exact test and the proportion test with Bonferroni’s correction were used for the categorical univariate analysis. Results. There was a significant association (P<0.001) between deep bite and dental attrition (wear), but not between crossbite and/or deep bite in patients diagnosed with either painful TMD or disc displacement. The risk of sustaining painful TMD when crossbite presented simultaneously on the anterior and the posterior dentition was 2.625-fold greater than when it presented with a normal bite, although this difference was not significant (P=0.286) due to the lack of statistical power. There was no significant sex-related association between the occurrence of either painful TMD or disc displacement. A reduction in TMD findings was demonstrated after one year of treatment, but no statistical power was reached due to the small sample size. Conclusions. Deep bite may be related to dental wear but not to pain from TMD and/or disc displacement. Only crossbite that presents simultaneously on the anterior and the posterior dentition (mixed X-bite) may have some effect on the level of pain in TMD, but not on in the prevalence of disc displacement. Confirmation of these conclusions by well-designed studies on larger patient groups is warranted. There was a clinically significant improvement in TMD findings after one year of treatment.
Analytical Quality by Design Approach of Reverse-Phase High-Performance Liquid Chromatography of Atorvastatin: Method Development, Optimization, Validation, and the Stability-Indicated Method
Authors: Alruwaili Nabil K.
Published: February 2021

The use of analytical quality by design (AQbD) approach in the optimization of the high-performance liquid chromatography (RP-HPLC) method is a novel tool. Three factors and three levels of Box–Behnken statistical design (BBD) were used for method optimization and analysis of atorvastatin. The mobile phase (acetonitrile: water), flow rate (Rt), and UV wavelength were used as independent variables. Their effects were observed in the area of the chromatogram (AU), retention time (Rt, min), and tailing factor (%). The optimized HPLC condition was found as acetonitrile:water (50 : 50), flow rate (0.68 ml/min), and UV wave length (235 nm). It gives the retention time of 2.43 min with the linearity range of 5–30 μg/ml with a high regression value (r2 = 0.999). The method was found to be precise and accurate with low % RSD (<5%). The refrigeration stability indicated that atorvastatin was stable. The force degradation study showed that the atorvastatin was fully unstable in UV light and stable in 0.1 M basic condition. It concluded that this QbD optimized method is suitable for quantification of the atorvastatin from the formulation as well as pharmacokinetic parameters.
Octogenarian Atrial Fibrillation Ablation with New NavX EnSite “Live View” Tool
Authors: Rillo Mariano , Palamà Zefferino , Zonno Francesco , My Giulia , Punzi Raffaele , My Luigi , Sciarra Luigi
Published: February 2021

Background. Atrial Fibrillation ablation in older patients represents a challenge to be addressed to ensure the improvement of the quality of life and survival of these patients. New mapping system tools can help to treat older patients because of its ability to simplify and reduce procedural risks. The new NavX EnSite “Live view” tool allows dynamic “beat to beat” activation and voltage mapping visualization in order to instantly recognize vein disconnection and minimize RF deliveries. Methods. An 81-year old patient with paroxysmal AF and well-documented firing focus trigger underwent pulmonary veins isolation using NavX EnSite Precision, HD Grid multipolar catheter, and the new “Live view” tool. Results. All pulmonary veins were successfully isolated with no procedural complications. “Live view” tool allows to perform shorter and safer procedure (total procedural time: 90 minutes, left atrium dwell time: 60 minutes, total RF delivery number: 78). Conclusion. “Live view tool” allows dynamic activation and voltage mapping in order to perform a safe and tailored approach to ablation, especially in older patients.
Nutritional Knowledge and Dietary Intake Habits among Pregnant Adolescents Attending Antenatal Care Clinics in Urban Community in Ghana
Authors: Appiah Prince Kubi , Naa Korklu Anang Rhoda , Bonchel Duut Abdulai , Fenu Georgina Agartha , Wadga-Mieza Yankey Francis
Published: February 2021

Introduction. Proper nutrition during pregnancy is important for the wellbeing of the mother and foetus and supports health during pregnancy, delivery, and breastfeeding. However, there are little data on nutritional knowledge and dietary intake among adolescents who are pregnant in Ghana. Hence, the study assessed the nutritional knowledge and eating habits of this vulnerable group in the Ledzokuku-Krowor Municipality, Ghana. Methods. The study was cross-sectional and employed a multistage sampling technique to select 423 participants. The study was conducted between October and November 2019. A statistical software was used to analyse data and employed Pearson’s chi-square and logistics regression to assess associations between the outcome and predictor variables. A

p

value <0.05 at a 95% confidence interval was considered statistically significant. Results. Less than half (44.9%) of the pregnant adolescents have high nutritional knowledge. About 19.4% of them have good eating habits, while 23.9%, 18.2%, and 6.4% of them do not take breakfast, lunch, and supper, respectively. However, 15.6%, 13.9%, and 9.2% do take snacks after breakfast, lunch, and supper, respectively. About 55.9%, 59.8%, and 23.0% do not take their breakfast, lunch, and supper on time, respectively. Additionally, only 3.8% of them do take fruits and vegetables daily, while 9.7%, 23.2%, 30.0%, and 26.5% of them do take animal products, energy drinks, carbonated drinks, and legumes/nuts/seeds daily, respectively. The study showed that educational level

p
=
0.014

, occupation

p
=
0.016

, ethnicity

p
=
0.017

, and number of pregnancies

p
=
0.021

were associated with good eating habits. Conclusion. Eating habit of adolescent pregnant women was not encouraging. Therefore, the municipal health authority with the concerned stakeholders should intensify efforts, including nutritional education to improve good eating habits, such as taking snacks in between meals, eating on time, and balance diet among pregnant adolescents, and to reduce adolescent pregnancy in the municipality.
Mid-Epidemic Forecasts of COVID-19 Cases and Deaths: A Bivariate Model Applied to the UK
Authors: Congdon Peter
Published: February 2021

Background. The evolution of the COVID-19 epidemic has been accompanied by efforts to provide comparable international data on new cases and deaths. There is also accumulating evidence on the epidemiological parameters underlying COVID-19. Hence, there is potential for epidemic models providing mid-term forecasts of the epidemic trajectory using such information. The effectiveness of lockdown or lockdown relaxation can also be assessed by modelling later epidemic stages, possibly using a multiphase epidemic model. Methods. Commonly applied methods to analyse epidemic trajectories or make forecasts include phenomenological growth models (e.g., the Richards family of densities) and variants of the susceptible-infected-recovered (SIR) compartment model. Here, we focus on a practical forecasting approach, applied to interim UK COVID data, using a bivariate Reynolds model (for cases and deaths), with implementation based on Bayesian inference. We show the utility of informative priors in developing and estimating the model and compare error densities (Poisson-gamma, Poisson-lognormal, and Poisson-log-Student) for overdispersed data on new cases and deaths. We use cross validation to assess medium-term forecasts. We also consider the longer-term postlockdown epidemic profile to assess epidemic containment, using a two-phase model. Results. Fit to interim mid-epidemic data show better fit to training data and better cross-validation performance for a Poisson-log-Student model. Estimation of longer-term epidemic data after lockdown relaxation, characterised by protracted slow downturn and then upturn in cases, casts doubt on effective containment. Conclusions. Many applications of phenomenological models have been to complete epidemics. However, evaluation of such models based simply on their fit to observed data may give only a partial picture, and cross validation against actual trends is also valuable. Similarly, it may be preferable to model incidence rather than cumulative data, although this raises questions about suitable error densities for modelling often erratic fluctuations. Hence, there may be utility in evaluating alternative error assumptions.
Factors Associated with Anemia among Pregnant Women of Underprivileged Ethnic Groups Attending Antenatal Care at Provincial Level Hospital of Province 2, Nepal
Authors: Yadav Umesh Kumar , Ghimire Prabesh , Amatya Archana , Lamichhane Ashish
Published: February 2021

Background. This study aims at determining the factors associated with anemia among pregnant women of underprivileged ethnic groups attending antenatal care at the provincial level hospital of Province 2. Methods. A hospital-based cross-sectional study was carried out in Janakpur Provincial Hospital of Province 2, Southern Nepal. 287 pregnant women from underprivileged ethnic groups attending antenatal care were selected and interviewed. Face-to-face interviews using a structured questionnaire were undertaken. Anemia status was assessed based on hemoglobin levels determined at the hospital’s laboratory. Bivariate and multiple logistic regression analyses were used to identify the factors associated with anemia. Analyses were performed using IBM SPSS version 23 software. Results. The overall anemia prevalence in the study population was 66.9% (95% CI, 61.1–72.3). The women from most underprivileged ethnic groups (Terai Dalit, Terai Janajati, and Muslims) were twice more likely to be anemic than Madhesi women. Similarly, women having education lower than secondary level were about 3 times more likely to be anemic compared to those with secondary level or higher education. Women who had not completed four antenatal visits were twice more likely to be anemic than those completing all four visits. The odds of anemia were three times higher among pregnant women who had not taken deworming medication compared to their counterparts. Furthermore, women with inadequate dietary diversity were four times more likely to be anemic compared to women having adequate dietary diversity. Conclusions. The prevalence of anemia is a severe public health problem among pregnant women of underprivileged ethnic groups in Province 2. Being Dalit, Janajati, and Muslim, having lower education, less frequent antenatal visits, not receiving deworming medication, and having inadequate dietary diversity are found to be the significant factors. The present study highlights the need of improving the frequency of antenatal visits and coverage of deworming program in ethnic populations. Furthermore, promoting a dietary diversity at the household level would help lower the prevalence of anemia. The study findings also imply that the nutrition interventions to control anemia must target and reach pregnant women from the most-marginalized ethnic groups and those with lower education.
Relevance of the Isoflavone Absorption and Testicular Function: A Systematic Review of Preclinical Evidence
Authors: Lozi Amanda Alves , Pinto da Matta Sérgio Luis , Sarandy Mariáurea Matias , Silveira Alves de Melo Fabiana Cristina , Araujo Diane Costa , Novaes Rômulo Dias , Gonçalves Reggiani Vilela
Published: February 2021

Isoflavone is a phytoestrogen found in different types of food that can act as endocrine disrupters leading to testicular dysfunction. Currently, fragmented data on the action of this compound in the testicles make it difficult to assess its effects to define a safe dose. Thus, we systematically reviewed the preclinical evidence of the impact of isoflavone on testicular function. We also determined which form (aglycones or glycosylated) was the most used, which allowed us to understand the main biological processes involved in testicular function after isoflavone exposure. This systematic review was carried out according to the PRISMA guidelines using a structured search on the biomedical databases MEDLINE (PubMed), Scopus, and Web of Science, recovering and analyzing 22 original studies. The bias analysis and the quality of the studies were assessed by the criteria described in the risk of bias tool developed by SYRCLE (Systematic Review Centre for Laboratory Animal Experimentation). The aglycones and glycosylated isoflavones proved to be harmful to the reproductive health, and the glycosylates at doses of 50, 100, 146, 200, 300, 500, and 600 mg/kg, in addition to 190 and 1000 mg/L, appear to be even more harmful. The main testicular pathologies resulting from the use of isoflavones are associated with Leydig cells resulting from changes in molecular functions and cellular components. The most used isoflavone to evaluate testicular changes was the genistein/daidzein conjugate. The consumption of high doses of isoflavones promotes changes in the functioning of Leydig cells, inducing testicular changes and leading to infertility in murine models.
The Role of Preoperative Computed Tomography on the Quality of Reduction and Outcomes in Intertrochanteric Fracture: A Controlled Trial
Authors: Ma Tao , Hao Lin-Jie , Wen Peng-Fei , Wang Ya-Kang , Wang Hu , Zhang Bin-Fei , Zhang Yu-Min
Published: February 2021

Purpose. The study is aimed at assessing the role of preoperative computerised tomography (CT) examination in the quality of reduction and outcomes in elderly patients with intertrochanteric fracture. Methods. The elderly patients with an intertrochanteric fracture who were treated with proximal femoral nail antirotation were included. The patients were divided into the CT group and the no‐CT group according to the presence of preoperative CT examination. Patients’ baseline characteristics, quality of reduction, and function were recorded at follow‐up. Functional outcomes were evaluated using the Harris hip scores (HHS). Results. Totally, the study included 182 patients with intertrochanteric fractures, with 85 in the CT group and 97 in the no‐CT group, admitted between January 2018 and June 2019. There was no difference in the quality of reduction, HHS, the fracture healing, or postoperative complications between the CT group and the no‐CT group. However, the CT group experienced the shorter mean operative time and blood transfusion, compared to the no‐CT group. Conclusions. The preoperative CT examination seems to be excessive for elderly patients with an intertrochanteric fracture.
Numerical Investigation on Improving the Computational Efficiency of the Material Point Method
Authors: Ma Jingxin , Lu Shengzhuo , Shi Yaqin , Chen Keyi , Chen Weidong
Published: February 2021

Based on the basic theory of the material point method (MPM), the factors affecting the computational efficiency are analyzed and discussed, and the problem of improving calculation efficiency is studied. This paper introduces a mirror reflection boundary condition to the MPM to solve axisymmetric problems; to improve the computational efficiency of solving large deformation problems, the concept of "dynamic background domain (DBD)" is also proposed in this paper. Taking the explosion and/or shock problems as an example, the numerical simulation are calculated, and the typical characteristic parameters and the CPU time are compared. The results show that the processing method introducing mirror reflection boundary condition and MPM with DBD can improve the calculation efficiency of the corresponding problems, which, under the premise of ensuring its calculation accuracy, provide useful reference for further promoting the engineering application of this method.
Occurrence of Tocols in Foods: An Updated Shot of Current Databases
Authors: Durazzo Alessandra , Nazhand Amirhossein , Lucarini Massimo , Delgado Amélia M. , De Wit Maryna , Nyam Kar Lin , Santini Antonello , Fawzy Ramadan Mohamed
Published: February 2021

Tocols are present in various foods, mostly in fruits and in plant seeds. Edible oils are the most important natural dietary sources of tocopherols and tocotrienols, collectively known as tocols. Tocopherols and tocotrienols are considered beneficial for their antioxidant effect which impacts on prevention of different health conditions. This perspective is addressed to give an updated picture of the tocol occurrence in foods. Moreover, the current state of the art of tocols in updated databases is explored and commented outlining their importance and future trends.
A Case Series on Critically Ill Pregnant or Newly Delivered Patients with Covid-19, Treated at Karolinska University Hospital, Stockholm
Authors: Polcer Rasha El-ahmad , Jones Elin , Pettersson Karin
Published: February 2021

In this retrospective report, we present five cases of critically ill pregnant or newly delivered women positive for Covid-19 admitted to our obstetrical departments at Karolinska University Hospital. They compose 6% of eighty-three pregnant women that tested positive for SARS-CoV-2 during the period March 25 to May 4, 2020. Three patients were at the time of admission in gestational week between

21
+
4

and

22
+
5

and treated during their antenatal period; meanwhile, the other two were admitted within 1 week postpartum. All of them were in need of intensive care: one was treated with high flow oxygen therapy, the other four with invasive mechanical ventilation (three with endotracheal intubation and one with extracorporeal membrane oxygenation). Age above thirty, overweight, and gestational diabetes are notable factors in the cases presented. At the time of admission, they all presented with symptoms such as fever, cough, and dyspnea. Chest imaging with computer tomography scan was performed in each case and demonstrated multifocal pneumonic infiltrates in all of them, but no pulmonary embolism was confirmed in any. Neither did the echocardiogram indicate any cardiomyopathy. Four of the patients have been discharged from the hospital, with an average of 20 hospital days. One antenatal pregnant woman needed prolonged ECMO therapy; in gestational week

27
+
3

, she went into cardiac arrest, resulting in an urgent C-section on maternal indication. At the time of writing, she is still hospitalized. In coherence with other published reports, our cases indicate that critically ill pregnant women infected by SARS-Cov-2 may develop severe respiratory distress syndrome requiring prolonged intensive care. The material is limited for conclusions to be made; more detailed information on symptoms, treatment, and outcomes for pregnant and postpartum women managed in intensive care is therefore needed.
Resilience-Based Optimization of Postdisaster Restoration Strategy for Road Networks
Authors: Mao Xinhua , Zhou Jibiao , Yuan Changwei , Liu Dan
Published: February 2021

This work proposes a framework for the optimization of postdisaster road network restoration strategies from a perspective of resilience. The network performance is evaluated by the total system travel time (TSTT). After the implementation of a postdisaster restoration schedule, the network flows in a certain period of days are on a disequilibrium state; thus, a link-based day-to-day traffic assignment model is employed to compute TSTT and simulate the traffic evolution. Two indicators are developed to assess the road network resilience, i.e., the resilience of performance loss and the resilience of recovery rapidity. The former is calculated based on TSTT, and the latter is computed according to the restoration makespan. Then, we formulate the restoration optimization problem as a resilience-based bi-objective mixed integer programming model aiming to maximize the network resilience. Due to the NP-hardness of the model, a genetic algorithm is developed to solve the model. Finally, a case study is conducted to demonstrate the effectiveness of the proposed method. The effects of key parameters including the number of work crews, travelers’ sensitivity to travel time, availability of budget, and decision makers’ preference on the values of the two objectives are investigated as well.
Hydrogen Sulfide Is a Regulator of Hemoglobin Oxygen‐Carrying Capacity via Controlling 2,3‐BPG Production in Erythrocytes
Authors: Wang Gang , Huang Yan , Zhang Ningning , Liu Wenhu , Wang Changnan , Zhu Xiaoyan , Ni Xin
Published: February 2021

Hydrogen sulfide (H2S) is naturally synthesized in a wide range of mammalian tissues. Whether H2S is involved in the regulation of erythrocyte functions remains unknown. Using mice with a genetic deficiency in a H2S natural synthesis enzyme cystathionine‐γ‐lyase (CSE) and high‐throughput metabolomic profiling, we found that levels of erythrocyte 2,3‐bisphosphoglycerate (2,3‐BPG), an erythroid‐specific metabolite negatively regulating hemoglobin‐ (Hb‐) oxygen (O2) binding affinity, were increased in CSE knockout (Cse-/-) mice under normoxia. Consistently, the 50% oxygen saturation (P50) value was increased in erythrocytes of Cse-/- mice. These effects were reversed by treatment with H2S donor GYY4137. In the models of cultured mouse and human erythrocytes, we found that H2S directly acts on erythrocytes to decrease 2,3‐BPG production, thereby enhancing Hb‐O2 binding affinity. Mouse genetic studies showed that H2S produced by peripheral tissues has a tonic inhibitory effect on 2,3‐BPG production and consequently maintains Hb‐O2 binding affinity in erythrocytes. We further revealed that H2S promotes Hb release from the membrane to the cytosol and consequently enhances bisphosphoglycerate mutase (BPGM) anchoring to the membrane. These processes might be associated with S‐sulfhydration of Hb. Moreover, hypoxia decreased the circulatory H2S level and increased the erythrocyte 2,3‐BPG content in mice, which could be reversed by GYY4137 treatment. Altogether, our study revealed a novel signaling pathway that regulates oxygen‐carrying capacity in erythrocytes and highlights a previously unrecognized role of H2S in erythrocyte 2,3‐BPG production.
Research Progress on Stem Cell Therapies for Articular Cartilage Regeneration
Authors: Jiang Shuangpeng , Tian Guangzhao , Li Xu , Yang Zhen , Wang Fuxin , Tian Zhuang , Huang Bo , Wei Fu , Zha Kangkang , Sun Zhiqiang , Sui Xiang , Liu Shuyun , Guo Weimin , Guo Quanyi
Published: February 2021

Injury of articular cartilage can cause osteoarthritis and seriously affect the physical and mental health of patients. Unfortunately, current surgical treatment techniques that are commonly used in the clinic cannot regenerate articular cartilage. Regenerative medicine involving stem cells has entered a new stage and is considered the most promising way to regenerate articular cartilage. In terms of theories on the mechanism, it was thought that stem cell-mediated articular cartilage regeneration was achieved through the directional differentiation of stem cells into chondrocytes. However, recent evidence has shown that the stem cell secretome plays an important role in biological processes such as the immune response, inflammation regulation, and drug delivery. At the same time, the stem cell secretome can effectively mediate the process of tissue regeneration. This new theory has attributed the therapeutic effect of stem cells to their paracrine effects. The application of stem cells is not limited to exogenous stem cell transplantation. Endogenous stem cell homing and in situ regeneration strategies have received extensive attention. The application of stem cell derivatives, such as conditioned media, extracellular vesicles, and extracellular matrix, is an extension of stem cell paracrine theory. On the other hand, stem cell pretreatment strategies have also shown promising therapeutic effects. This article will systematically review the latest developments in these areas, summarize challenges in articular cartilage regeneration strategies involving stem cells, and describe prospects for future development.
Anti‐Inflammatory Effects of Melatonin and 5‐Methoxytryptophol on Lipopolysaccharide‐Induced Acute Pulpitis in Rats
Authors: Kermeoğlu Fatma , Aksoy Umut , Sebai Abdullah , Savtekin Gökçe , Özkayalar Hanife , Sayıner Serkan , Şehirli Ahmet Özer
Published: February 2021

Aim. The aim of this study was to investigate the possible therapeutic impacts of two pineal hormones, melatonin and 5‐methoxytryptophol (5‐MTX), in a rat model of acute pulpitis by analyzing biochemical and histopathological parameters. Methods. This research was done using 32 male and female Wistar albino rats with weight between 200 and 250 g. The rats were randomly divided into four groups: a control group (rats without any treatment), acute pulpitis (AP) group, AP+melatonin group, and AP+5‐MTX group. In the AP‐induced groups, the crowns of the upper left incisors were removed horizontally. Lipopolysaccharide solution was applied to the exposed pulp tissue before the canal orifices were sealed with a temporary filling material. Melatonin (10 mg/kg) and 5‐MTX (5 mg/kg) were administered intraperitoneally. The rats were sacrificed 24 hours after pulp injury, and trunk blood and pulp samples were collected. The concentrations of TNF‐α, IL‐1β, MMP‐1, and MMP‐2 in sera and pulp samples were determined using ELISA assay kits. Results. TNF‐α, IL‐1β, MMP‐1, and MMP‐2 levels in the serum and pulp tissues were considerably higher in the AP group than the control group (p < 0.01‐0.001). In the AP+melatonin and AP+5‐MTX groups, TNF‐α, IL‐1β, MMP‐1, and MMP‐2 levels in the serum and pulp tissues were significantly lower than in the AP group (p < 0.05‐0.001). Conclusions. Both melatonin and 5‐MTX provided protective effects on acute pulpitis, which indicates they may be promising as a therapeutic strategy for oral disease.
Development of Data Integration and Sharing for Geotechnical Engineering Information Modeling Based on IFC
Authors: Wu Jiaming , Chen Jian , Chen Guoliang , Wu Zhe , Zhong Yu , Chen Bin , Ke Wenhui , Huang Juehao
Published: February 2021

With the rapid development of infrastructure construction, geotechnical engineering has always been worthy of attention due to its complexity and diversity. Accelerating the informatization of geotechnical engineering will contribute to the project management, but the information contained in geotechnical engineering cannot be well integrated because of the lack of unified data standards. Building Information Modeling (BIM) has been considered as an effective technology to manage information, and Industry Foundation Classes (IFC) in BIM serves as a neutral and open standard for the exchange of information. However, it was found that BIM cannot express the information of some structure objects and geological objects well during the construction process of geotechnical engineering. Combined with the characteristics of geotechnical engineering, taking advantage of the good extensibility of IFC, this paper proposes a “Built‐In Generation Schema” for geotechnical structure models and a “Plug‐In Extension Schema” for three‐dimensional (3D) geological models, ultimately forming the basic data system of geotechnical engineering information models based on IFC. Applying extended IFC to the modeling process, the BIM‐based modeling method of geotechnical models is proposed. In addition, an IFC‐based platform is developed to integrate geological models and structure models for further displaying and analyzing of geotechnical engineering models. The work in this paper provides a feasible way and technical support for promoting the integration and sharing of geotechnical engineering information and enhancing the multiprofessional collaborative work.
Sensory Disturbance of the Lower Extremity after Sural Artery Flap Elevation
Authors: Tada Kaoru , Suganuma Seigo , Nakada Mika , Matsuta Masashi , Murai Atsuro , Tsuchiya Hiroyuki
Published: February 2021

Purpose. Elevation of the sural artery flap with the sural nerve is associated with donor-site morbidities, such as postoperative sensory disturbance of the lower extremity. We evaluated the sensory disturbance of the lower extremity after elevation of the sural artery flap. Methods. This study included 7 patients who underwent surgery using the sural artery flap. The sensory disturbances immediately after surgery and at present were evaluated on a 10-point scale. The influences of surgery on activities of daily living and patient satisfaction were also evaluated. Results. The sensory disturbance was 4.48 immediately after surgery and 2.24 presently, and the difference between the timepoints was not statistically significant. The influence of surgery on activities of daily living was 2.30, and the patient satisfaction was 7.90. Conclusion. It may be necessary to consider the sural artery flap, which does not include the sural nerve, to avoid unnecessary complications. When it is unavoidable to use the sural artery flap, including the sural nerve, it is important to thoroughly inform patients beforehand about the postsurgery sensory disturbance in the lower extremities.
How Epigenetic Therapy Beats Adverse Genetics in Monosomy Karyotype AML
Authors: O'Hagan Heather M. , Rassool Feyruz V. , Nephew Kenneth P.
Published: February 2021

The study by Greve and colleagues, in this issue of Cancer Research, provides new molecular insights into the intriguing clinical activity of DNA hypomethylating agents (HMA) in patients with acute myeloid leukemia (AML) with monosomal karyotypes. Patients with AML with adverse monosomal karyotypes are known to benefit from HMAs, but not cytarabine, a cytidine analog without HMA activity, but the specific molecular mechanisms remain poorly understood. The authors investigated the mechanistic effects of HMAs on gene reactivation in AML in the context of the most common monosomal karyotypes, genetic deletion of chromosome 7q and 5q. They identified genes with tumor-suppressive properties, an endogenous retrovirus cooperatively repressed by DNA hypermethylation, and increased genetic losses on hemizygous chromosomal regions versus normal biallelic regions in AML cell models. Treatment with HMAs preferentially induced expression of these hemizygous genes to levels similar to those of genes in a biallelic state. In addition to CpG hypomethylation, decitabine treatment resulted in histone acetylation and an open chromatin configuration specifically at hemizygous loci. By using primary blood blasts isolated from patients with AML receiving decitabine and AML patient-derived xenograft models established from patients with either monosomal karyotypes or normal cytogenetics, Greve and colleagues both validated their findings in primary patient samples and demonstrated superior antileukemic activity of decitabine compared with chemotherapy with cytarabine. These mechanistic insights into how epigenetic therapy beats adverse genetics in monosomy karyotype AML will open new therapeutic opportunities for a difficult-to-treat patient group.

See related article by Greve et al., p. 834
Abstract PS16-22: Targeting resistance to current CDK4/6 therapies by RGT-419B, an inhibitor with optimized kinase activity spectrum
Authors: Xie Zhi , Han Jing , Hu Zhilong , He Hu , Sun Xianqiang , Zhang Fei , Lin Jing , Yao Lili , Wang Xinjuan , Mei Liufeng , Liu Yangyang , Zhu Guoyun , Chen Xi , Zhu Xiaotian , Zhong Wenge
Published: February 2021

Cyclin-dependent kinases (CDKs) 4/6 inhibitors are a powerful class of therapeutic drugs for the treatment of advanced metastatic breast cancer. However, the currently approved CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib have dose-limiting toxicities that require treatment holidays or reductions to sub-optimal doses, thus limiting full target inhibition. The residual CDK4/6 activity, together with persistent signaling through CDK2/cyclin E are among key resistant mechanisms that can compromise full clinical benefit. RGT-419B is a 3rd generation CDK inhibitor with an optimized kinase activity spectrum that has been discovered employing a Computer Accelerated Rational Design technology platform. RGT-419B has potent sub-nM CDK4 activity with desired degrees of selectivity against kinases such as CDK6, CDK9 and GSK3β to enable full target engagement with an improved safety profile. Furthermore, single digit nM CDK2 kinase activity has been incorporated into the design of RGT-419B to combat Cyclin E/CDK2-driven resistance. In vitro, RGT-419B showed more robust activity against palbociclib-resistant ER+ breast cancer cells than abemaciclib. In ER+ T47D breast cancer cells with overexpression of Cyclin E1, RGT-419B exhibited better antiproliferation activity than either abemaciclib or palbociclib. RGT-419B also demonstrated more durable in vivo tumor growth inhibition when compared with abemaciclib in an ER+ breast cancer xenograft model. The optimized kinase activity spectrum of RGT-419B provides an opportunity to treat ER+ breast cancer patients refractory to the existing CDK4/6 inhibitors, as either a single agent or in combination with other therapies.

Citation Format: Zhi Xie, Jing Han, Zhilong Hu, Hu He, Xianqiang Sun, Fei Zhang, Jing Lin, Lili Yao, Xinjuan Wang, Liufeng Mei, Yangyang Liu, Guoyun Zhu, Xi Chen, Xiaotian Zhu, Wenge Zhong. Targeting resistance to current CDK4/6 therapies by RGT-419B, an inhibitor with optimized kinase activity spectrum [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-22.
Abstract PS17-31: Investigating the estrogen receptor Y537S mutation in transgenic models of luminal B breast cancer
Authors: Johnson Gabriella , Roccamo Joshua , Lavoie Cynthia , Zuo Dongmei , Sanguin-Gendreau Virginie , Lee Adrian , Li Zheqi , Oesterreich Steffi , Muller William
Published: February 2021

Breast cancer is the most prevalent cancer in women and over two-thirds of cases express the estrogen receptor (ER). Significantly, metastatic ER positive breast cancer is the leading cause of breast cancer mortality. Despite the success of endocrine therapy to treat ER-positive breast cancers, resistance to treatment is a major problem and relapse commonly occurs though patients initially respond well to treatment. The ER Y537S mutant represents one of the most common gain-of-function mutations detected in the metastatic biopsies of patients with ER-positive breast cancer. Previous in-vitro analyses have shown that the ER Y537S mutant exhibits enhanced ER transcriptional activity by adopting a ligand-independent agonist confirmation. In our study, we seek to provide a deeper understanding of the role of this mutant by modeling the human ER Y537S mutant (ER Y541S in mice). Our lab has generated a Cre-inducible knock-in mouse model expressing the activating point mutation driven by the endogenous ER promoter, and it has been shown that when expressed ubiquitously the mutated ER leads to dramatic developmental effects. In order to further our observations in the context of endocrine resistant metastatic breast cancer, we characterize mamary tumour growth of the ER Y541S mutant in combination with luminal B models of mammary tumourigenesis. Consistent with the notion that these ER mutations occur seldom in primary tumours, preliminary data shows that tumour onset and tumour outgrowth is unaffected by the activating point mutation. When analysing tumours from both ER mutant and wildtype ER control animals, it was found that tumours with mutant ER display more basal-like cytokeratins at the RNA level via RNA sequencing and at the protein level via immunohistochemistry. This expression pattern is often associated with poorer prognosis in the clinic. Through ongoing analyses, we also seek to better understand our model through tumour regression studies (doxycycline withdrawal), treatment with tamoxifen and blocking the main source of estrogens via ovariotomies. By studying the ER Y537S mutation in models of luminal B breast cancer, we hope to investigate the factors leading to tumour recurrence and provide a deeper understanding of potential escape pathways to therapy.

Citation Format: Gabriella Johnson, Joshua Roccamo, Cynthia Lavoie, Dongmei Zuo, Virginie Sanguin-Gendreau, Adrian Lee, Zheqi Li, Steffi Oesterreich, William Muller. Investigating the estrogen receptor Y537S mutation in transgenic models of luminal B breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-31.
PTHrP Drives Pancreatic Cancer Growth and Metastasis and Reveals a New Therapeutic Vulnerability
Authors: Pitarresi Jason R. , Norgard Robert J. , Chiarella Anna M. , Suzuki Kensuke , Bakir Basil , Sahu Varun , Li Jinyang , Zhao Jun , Marchand Benoît , Wengyn Maximilian D. , Hsieh Antony , Kim Il-Kyu , Zhang Amy , Sellin Karine , Lee Vivian , Takano Shigetsugu , Miyahara Yoji , Ohtsuka Masayuki , Maitra Anirban , Notta Faiyaz , Kremer Richard , Stanger Ben Z. , Rustgi Anil K.
Published: February 2021

Pancreatic cancer metastasis is a leading cause of cancer-related deaths, yet very little is understood regarding the underlying biology. As a result, targeted therapies to inhibit metastasis are lacking. Here, we report that the parathyroid hormone–related protein (PTHrP encoded by PTHLH) is frequently amplified as part of the KRAS amplicon in patients with pancreatic cancer. PTHrP upregulation drives the growth of both primary and metastatic tumors in mice and is highly enriched in pancreatic ductal adenocarcinoma metastases. Loss of PTHrP—either genetically or pharmacologically—dramatically reduces tumor burden, eliminates metastasis, and enhances overall survival. These effects are mediated in part through a reduction in epithelial-to-mesenchymal transition, which reduces the ability of tumor cells to initiate metastatic cascade. Spp1, which encodes osteopontin, is revealed to be a downstream effector of PTHrP. Our results establish a new paradigm in pancreatic cancer whereby PTHrP is a driver of disease progression and emerges as a novel therapeutic vulnerability.

Significance:

Pancreatic cancer often presents with metastases, yet no strategies exist to pharmacologically inhibit this process. Herein, we establish the oncogenic and prometastatic roles of PTHLH, a novel amplified gene in pancreatic ductal adenocarcinoma. We demonstrate that blocking PTHrP activity reduces primary tumor growth, prevents metastasis, and prolongs survival in mice.

This article is highlighted in the In This Issue feature, p. 1601