bluuebunny/crossref_metadata_2025 huggingface dataset:
Knowledge, Attitude, and Practices on Water, Sanitation, and Hygiene among Rural Residents in Tigray Region, Northern Ethiopia
Authors: Berhe Abera Aregawi , Aregay Abraham Desta , Abreha Alemnesh Araya , Aregay Asfawosen Berhe , Gebretsadik Ataklti Weldegebrial , Negash Degnesh Zigta , Gebreegziabher Equbay Gebru , Demoz Kiros Ghebremedhin , Fenta Kiros Ajemu , Mamo Nega Bezabih
Published: March 2020

Background. Poor hygienic practices, inadequate water supply, and poor sanitary conditions play a major role in the spread of infectious diseases. Lack of knowledge, attitude, and practices (KAP) on WASH is one of the most imperative causes for transmission of infectious diseases. Therefore, the aim of this study was to assess knowledge, attitude, and practice of rural residents on water, sanitation, and hygiene in Tigray, Ethiopia. Methods. A community-based cross-sectional study was conducted from June to July 2018. Multistage cluster sampling technique was used to collect data from 759 households in Tigray region, Northern Ethiopia. A standardized questionnaire was used to collect data on knowledge, attitude, and practice on water, sanitation, and hygiene (WASH). Descriptive data analysis was done to present the study findings. Results. The response rate was 99.6%, and 574 (75.9%) of the respondents were females. Good knowledge, favorable attitude, and good practice on WASH were observed in 42.2% (95% CI: 38.7%, 45.7%), 48.5% (95% CI: 44.9%, 52.0%), and 49.2% (95% CI: 45.6%, 52.7%) of the respondents, respectively. Conclusions. Poor knowledge, unfavorable attitude, and poor practice on WASH were common amongst the residents in rural Tigray, Northern Ethiopia. Therefore, the health extension programs at primary health care should be revitalized in a way that can enhance the interventional measures to improve knowledge, attitude, and practice on WASH.
Weighted Simultaneous Approximation of the Linear Combinations of Baskakov Operators
Authors: Tang Xiao-jun , Wang Xin-chang , Yi Hua
Published: March 2020

In this paper, the approximation property of the linear combinations of Baskakov operators is investigated by using a Jacobi weight function. Moreover, both the positive and inverse theorems for the weighted simultaneous approximation of the linear combinations of Baskakov operators are proved.
Immunophenotypic Profiles in Polycystic Ovary Syndrome
Authors: Hu Cong , Pang Bo , Ma Zhanchuan , Yi Huanfa
Published: March 2020

Polycystic ovary syndrome (PCOS) a long-known endocrinopathy and one of the most common endocrine-reproductive-metabolic disorders in women, which can lead to infertility. Although the precise etiology remains unclear, PCOS is considered as a complex genetic trait, with a high degree of heterogeneity. Besides, hormones and immune cells, including both innate and adaptive immune cells, are reportedly a cross talk in PCOS. Chronic low-grade inflammation increases autoimmune disease risk. This proinflammatory condition may, in turn, affect vital physiological processes that ultimately cause infertility, such as ovulation failure and embryo implantation. Here, we review the accumulating evidence linking PCOS with inflammatory status providing an overview of the underlying hormone-mediated dysregulation of immune cells. We mainly focus on the correlational evidence of associations between immune status in women and the increased prevalence of PCOS, along with the specific changes in immune responses. Further recognition and exploration of these interactions may help elucidate PCOS pathophysiology and highlight targets for its treatment and prevention.
The Effects of Salt and Glucose Intake on Angiotensin II and Aldosterone in Obese and Nonobese Patients with Essential Hypertension
Authors: Alaagib Nouralsalhin , Sukkar Mohammed , Kardash Mohammed
Published: March 2020

Background. The exact mechanisms for the development of essential hypertension are not known. Activation of the renin-angiotensin-aldosterone system (RAAS) in adipose tissue may represent an important link between obesity and hypertension. This study investigates the effects of oral intake of glucose with and without NaCl on angiotensin II (AngII) and aldosterone in obese and nonobese patients with essential hypertension. Methods. Twenty newly diagnosed untreated essential hypertensive patients and 15 normotensive control subjects matched for age, gender, and BMI were studied. Participants fasted overnight (8–10 hrs), and then each subject took 75 gm glucose alone and with 3 gm NaCl, each dissolved in 250 ml. Subjects were monitored for 2 hours. Half hourly BP, plasma glucose (PG), serum Na+, K+, insulin, AngII, and aldosterone were measured. Subjects were classified into obese (BMI >30 Kg/m2) (11 patients and 8 control) and nonobese (BMI <30 Kg/m2) (9 patients and 7 control). Results. After intake of glucose with NaCl serum, AngII was significantly higher in obese hypertensive patients compared with nonobese patients (P=0.016). Intake of glucose with NaCl resulted in a significantly higher serum Na in obese hypertensive patients compared with nonobese patients Na (P=0.009). Serum aldosterone was significantly higher in obese patients (P=0.03, after glucose; P=0.003, after glucose with NaCl) and in nonobese patients (P=0.000 and P=0.000, respectively) compared with their respective normotensive control subjects. In obese and nonobese patients, intake of glucose and glucose with NaCl showed no significant change in the levels of serum AngII and aldosterone which was associated a significant increase in serum Na in obese patients (P=0.03) and a highly significant reduction in serum K in nonobese patients (P=0.001). Conclusion. Failure of suppression or inappropriate maintenance of secretion of AngII and aldosterone in both hypertensive groups by intake of glucose with NaCl may indicate a possible mechanism of essential hypertension.
Operation Motion Planning and Principle Prototype Design of Four-Wheel-Driven Mobile Robot for High-Voltage Double-Split Transmission Lines
Authors: Li Hong Jun , Jiang Wei , Yan Yu , Zhang An , Zuo Gan
Published: March 2020

In response to the problems of high labor intensity, high risk, and poor reliability of artificial live working, a four-wheel-driven spacer bar replacement mobile operation robot has been designed and developed in this paper, and the corresponding kinematic and dynamics model have been established, based on the established double models, the kinematics and dynamics numerical analysis can be realized through INVENTOR and ADAMS, respectively, based on the established kinematics and dynamics models . The results show that the simulation value of the robot joint displacement, velocity, acceleration, and joint force can be able to meet the requirements of kinematic and dynamic constraints during the robot operation. The robot prototype can meet the requirement of dual-split robot working space and the operation joint force control, which not only extend the robot adaptability to the multisplit lines heterogeneous operation environment but also provide an important theoretical technical support for the exploit of the robot physical prototype. Through the robot kinematics and dynamics analysis, the robot mechanical structure parameters and electrical control parameters have been effectively optimized. The weight and cost of the robot have been reduced by 12% and 15% compared to the existed studies. Finally, the robot principle prototype mobile platform has been developed, and the correctness of robot kinematics and dynamics simulation analysis has been verified through the robot principle prototype mobile platform.
Gearshift Sensorless Control for Direct-Drive-Type AMT Based on Improved GA-BP Neural Network Algorithm
Authors: Li Bo , Ge Wenqing , Li Qiang , Li Yujiao , Tan Cao
Published: March 2020

The automated mechanical transmission (AMT) based on the electromagnetic linear driving device (EMLDD) has good potential for shift performance. However, the direct-drive shifting mechanism based on the displacement sensor is difficult to meet the compactness of the structure and control robustness in complex environment. Through analyzing the working principle of the electromagnetic linear driving device and features of sensorless control strategy, a new displacement prediction method based on the improved GA-BP neural network is proposed to replace the displacement sensor. With current, voltage, and input shaft speed of the electromagnetic linear driving device as input, displacement prediction is obtained by the GA-BP neural network with improved selection factor. Finally, the experiment validated the effectiveness of displacement prediction based on the improved GA-BP neural network of shift control. The results showed that prediction accuracy of the improved GA-BP neural network was greater than 96% under all shift working conditions. The average RMSE was reduced by 21.8%, absolute error of displacement prediction was controlled within ±0.5 mm, and average shift time was less than 0.18 s. In this paper, the BP neural network is applied to complex linear displacement prediction, which has important application and popularization value.
Nontraumatic Spondylolisthesis of the Axis with Cervical Kyphosis
Authors: Mizobuchi Shuhei , Tadokoro Nobuaki , Takaya Shogo , Kiyasu Katsuhito , Takemasa Ryuichi , Ikeuchi Masahiko
Published: March 2020

This study aimed at presenting a rare nontraumatic spondylolisthesis of the axis and considering its possible cause. Traumatic spondylolisthesis of the axis, called hangman’s fracture, frequently occurs as a high-energy trauma. However, nontraumatic spondylolisthesis of the axis is quite rare, and relevant literature on this condition is scarce. We reported a case of a 49-year-old man who had spondylolisthesis of the axis without experiencing a traumatic episode. Plain radiograph and CT image showed 7.0 mm anterolisthesis of the axis. Both C2 and C3 facet joints positioned asymmetrically, and the unilateral side oriented coronally, which was less resistant to rotational motion. These facet joint abnormalities could cause segmental instability and spondylolisthesis of the axis. Due to the resultant myelopathy, the slip with cord compression was surgically corrected by posterior decompression with instrumented fusion.
Comparative Analysis of Bone Tissue Temperature during Implant Preparation with Variable Drilling Parameters: In Vitro Study
Authors: Kosior Piotr , Pelc Anna , Mikulewicz Marcin
Published: March 2020

Purpose. The aim of this work was to compare the temperature fluctuations that occur during the development of the implant bed using three different implant systems and the impact on their value of cooling method and rotational speed of drill. Material and Methods. As a model of the human jaw due to the analogy of bone structure and hardness, pig ribs were used. Drills from three different implant systems were used in the study: Straumann® (Straumann GmbH, Basel, Switzerland), AnyRidge® (Megagen Implant Co., Ltd., Daegu, South Korea), and Osstem (OSSTEM IMPLANT CO., LTD., Seoul, South Korea). The sequence of three successive drills was given—from pilot drill to final drill. For each system, a group with two water cooling methods, without cooling, and three different speed ranges, 800, 1200, and 1500 rpm, and their effect on temperature fluctuations was evaluated. The temperature was measured by thermography. Results. The highest temperature increases were noted during preparation with pilot drills. The maximum temperature (50.8°C) was noted for the AnyRidge pilot drill at 1500 rpm without cooling. When cooling with physiological saline, none of the applied drills exceeded 28°C. Significant differences between lack of cooling and cooling with saline at 20°C and 3°C have been demonstrated. During preparation with cooling, the difference between the times of the maximum temperature achievement was observed between AnyRidge® and Osstem (2.6 vs. 1.6 s, p = 0.004). Conclusion. The experiment showed that the drills of the tested implant systems differed in the amount of heat generated during operation. The temperature of the cooling solution and the rotational speed applied have an influence on its amount.
Aspirin Improves Nonalcoholic Fatty Liver Disease and Atherosclerosis through Regulation of the PPARδ‐AMPK‐PGC‐1α Pathway in Dyslipidemic Conditions
Authors: Han Yoon-Mi , Lee Yong-Jik , Jang Yoo-Na , Kim Hyun-Min , Seo Hong Seog , Jung Tae Woo , Jeong Ji Hoon
Published: March 2020

This study is aimed at elucidating how aspirin could systemically and simultaneously normalize nonalcoholic fatty liver disease (NAFLD) and atherosclerosis through both in vitro and in vivo studies in hyperlipidemic conditions. We evaluated the effects and mechanism of aspirin on the levels of various biomarkers related to NAFLD, atherosclerosis, and oxidative phosphorylation in cells and animals of hyperlipidemic conditions. The protein levels of biomarkers (PPARδ, AMPK, and PGC‐1α) involved in oxidative phosphorylation in both the vascular endothelial and liver cells were elevated by the aspirin in hyperlipidemic condition. Also in the stimulation pathway of oxidative phosphorylation by aspirin, PPARδ was a superior regulator than AMPK and PGC‐1α in HepG2 cells. In the vascular endothelial cells, the phosphorylated endothelial nitric oxide synthase level was increased by the treatment. The protein levels of biomarkers related to lipid synthesis were decreased by the treatment in the liver cells. In rabbits administered with cholesterol diet, the levels of triglyceride, HDL‐cholesterol, and alanine amino transferase in serums were ameliorated by the aspirin treatment, the levels of ATP and TNFα were increased or decreased, respectively, by the aspirin in liver and aorta tissues, and mannose receptor and C‐C chemokine receptor type 2 levels were increased or decreased by the aspirin in spleen, respectively. The elevated levels of macrophage antigen, angiotensin II type1 receptor, and lipid accumulation were decreased in both the liver and aorta tissues in the aspirin‐treated group. In conclusion, aspirin can systemically and simultaneously ameliorate NAFLD and atherosclerosis by inhibiting lipid biosynthesis and inflammation and by elevating catabolic metabolism through the activation of the PPARδ‐AMPK‐PGC‐1α pathway. Furthermore, aspirin may normalize atherosclerosis and NAFLD by modulating the mannose receptor and CCR2 in macrophages.
An Energy Solution for Predicting Buried Pipeline Response Induced by Tunneling Based on a Uniform Ground Movement Model
Authors: Shi Xin , Rong Chuanxin , Cheng Hua , Cui Linzhao , Kong Jie
Published: March 2020

The construction of shield tunnels inevitably causes displacement of the surrounding soil and additional stress and deformation of the buried pipeline. An energy solution for predicting the deformation of buried pipelines caused by tunneling is proposed in this study. First, based on the uniform ground movement model, the interval of the free displacement field of soil around the pipeline induced by tunneling is calculated. Then, we use the Pasternak model to establish the total potential energy equation of the tunnel-soil-pipeline interaction. The final settlement interval of the pipeline is obtained by solving the numerical calculation program with MATLAB. The calculation results of the energy solution are compared with the results of the centrifugal test and the reported theoretical solutions of Winkler and Pasternak, and then the applicability of the solution for predicting the pipeline response under different geotechnical conditions is verified. Combined with an engineering case, the energy method calculation results, numerical simulation results, and measured results are compared to obtain the most unfavorable position of the pipeline caused by tunneling. At the end of this study, the application steps of the proposed method in actual construction are summarized. These steps are used to predict pipeline response in order to take protective measures.
Synergy Effects of the Indian Summer Monsoon and the Tibetan Plateau Heating on Summer Rainfall over North China
Authors: Zhao Siwen , Zhang Jie , Lv Zhihong
Published: March 2020

An analysis based on July-August precipitation reveals that there is a tripole pattern of the precipitation distribution, that is, significantly increased rainfall over North China (NC) is related to the increased rainfall over the Indian subcontinent (IS) and the decreased rainfall over the southeastern Tibetan Plateau (TP) and vice versa, that corresponds to the Indian summer monsoon (ISM) and TP heating pattern, which are interactive. Therefore, it is necessary to investigate the effect of NC rainfall-related atmospheric circulation and the physical linkage with the two thermal forcings together. The linear baroclinic model (LBM) is applied to determine the dynamics of the process. The results show that an enhanced ISM is accompanied by reduced TP heating, favors convection and easterly anomaly over the IS, and produces a Gill-type Rossby wave that affects the vorticity over North Africa. Meanwhile, there is another Rossby wave originating in North Africa and moving eastward to the Pacific Ocean, which interferes with circulation at mid- to high-latitudes, i.e., it strengthens the cyclone over the Baikal region and stretches the western Pacific subtropical high (WPSH) northward to northeastern Asia, and results in abundant water vapor transported to NC. Furthermore, the strong convection over the IS excites the Kelvin waves over the equatorial region, which moves eastward and generates anticyclones over Philippines, consequently leading to the Pacific-Japan (PJ) pattern. The PJ pattern cooperates with the wave train at midlatitudes, resulting in abundant water vapor being transported to NC. The summer rainfall over NC is therefore modulated by synergistic effect of both the ISM and TP heating.
Design and Experimental Verification of Asphalt‐Based Material for Grouting of Prestressed Structure
Authors: Zhu Eryu , Ni Yuancheng , Li Yujie , Zhu Li
Published: March 2020

The quality of the grouting is an important factor affecting the durability of prestressed structures, especially in corrosive environment with stray current. Uncompacted grouting will lead to rapid corrosion and failure of steel strand. In this paper, an asphalt‐based material as grouting material was designed to solve this problem due to the characteristics of asphalt material as impermeability, anticorrosion, and insulation. The viscosity and shear strength were considered as the main performance parameters of the grouting material for prestressed grouting. The composition and proportion of the asphalt‐based material were determined through the tests, including natural asphalt (rock asphalt) being 12.5% and admixture (slaked lime and cement) being 40%. For this grouting material, the shear strength was 697.21 kPa at normal temperature, and the suitable grouting temperature was 115°C. Then, the grouting test of the prestressed concrete beam was carried out to verify the groutability of this material. The grouting slurry can be filled with prestressed duct, and the temperature stress of the concrete near the duct was lower than 1.4 MPa, which met the safety requirement of the concrete. This study provides a new option for guaranteeing the quality of grouting and improving the durability of prestressed structures in corrosive environment.
Quality Indicators of Pharmaceutical Care for Integrative Healthcare: A Scoping Review of Indicators Developed Using the Delphi Technique
Authors: Shawahna Ramzi
Published: March 2020

Background. Recently, measuring and benchmarking provision of healthcare services has drawn a considerable attention. This scoping review was conducted to identify, describe, and summarize studies in which the Delphi technique was used to develop quality indicators of pharmaceutical care. The study also aimed to identify activities and services that could be used to capture the impact of pharmacist in integrative medicine. Methods. Databases were searched from inception to February 2020 using key terms that were combined using Boolean operators. Studies were included if they were relevant to development of quality indicators of pharmaceutical care with regard to medications or complementary and alternative medicine (CAM) modalities. Full text of the selected studies was imported into EndNote. Studies were screened and data were extracted into a standard extraction form. Results. Data were extracted from 31 studies. Of those, 24 (77.4%) were related to provision of pharmaceutical services relevant to medications and 7 (22.6%) were related to provision of care using CAM modalities. Most of the studies (67.7%) were published in 2010 and beyond. Almost half of the studies (48.4%) originated from the United States, United Kingdom, and Canada. A total of 42 different activities and services that could be used as quality indicators were identified from the studies included in this review. Activities and services were related to history taking, performing reconciliations, identifying and resolving therapy problems, providing collaborative care, designing care plans, optimal performance, and continuing education. Conclusions. Although there is an increasing interest in improving healthcare delivery, quality indicators of pharmaceutical services and those relevant to CAM provision in healthcare facilities adopting the integrated healthcare paradigm are still limited. Future studies are needed to develop validated quality indicators that could be successfully used in measuring and benchmarking quality of services in integrated healthcare facilities.
A New Efficient Filtering Model for GPS/SINS Ultratight Integration System
Authors: Wang Chaochen , Bo Yuming , Jiang Changhui
Published: March 2020

Global Positioning System (GPS) and strap-down inertial navigation system (SINS) are recognized as highly complementary and widely employed in the community. The GPS has the advantage of providing precise navigation solutions without divergence, but the GPS signals might be blocked and attenuated. The SINS is a totally self-contained navigation system which is hardly disturbed. The GPS/SINS integration system could utilize the advantages of both the GPS and SINS and provide more reliable navigation solutions. According to the data fusion strategies, the GPS/SINS integrated system could be divided into three different modes: loose, tight, and ultratight integration (LI, TI, and UTC). In the loose integration mode, position and velocity difference from the GPS and SINS are employed to compose measurement vector, in which the vector dimension has nothing to do with the amount of the available satellites. However, in the tight and ultratight modes, difference of pseudoranges and pseudorange rates from the GPS and SINS are employed to compose the measurement vector, in which the measurement vector dimension increases with the amount of available satellites. In addition, compared with the loose integration mode, clock bias and drift are included in the integration state model. The two characteristics magnify the computation load of the tight and ultratight modes. In this paper, a new efficient filter model was proposed and evaluated. Two schemes were included in this design for reducing the computation load. Firstly, a difference between pseudorange measurements was determined, by which clock bias and drift were excluded from the integration state model. This step reduced the dimension of the state vector. Secondly, the integration filter was divided into two subfilters: pseudorange subfilter and pseudorange rate subfilter. A federated filter was utilized to estimate the state errors optimally. In the second step, the two subfilters could run in parallel and the measurement vector was divided into two subvectors with lower dimension. A simulation implemented in MATLAB software was conducted to evaluate the performance of the new efficient integration method in UTC. The simulation results showed that the method could reduce the computation load with the navigation solutions almost unchanged.
Driving Fatigue Prediction Model considering Schedule and Circadian Rhythm
Authors: Zhang Qi , Wu Chaozhong , Zhang Hui
Published: March 2020

Driver fatigue level was considered an accumulated result contributed by circadian rhythms, hours of sleep before driving, driving duration, and break time during driving. This article presents an investigation into the regression model between driver fatigue level and the above four time-related variables. With the cooperation of one commercial transportation company, a Naturalistic Driving Study (NDS) was conducted, and NDS data from thirty-four middle-aged drivers were selected for analysis. With regard to the circadian rhythms, commercial drivers operated the vehicle and started driving at around 09:00, 14:00, and 21:00, respectively. Participants’ time of sleep before driving is also surveyed, and a range from 4 to 7 hours was selected. The commercial driving route was the same for all participants. After getting the fatigue level of all participants using the Karolinska Sleepiness Scale (KSS), the discrete KSS data were converted into consecutive value, and curve fitting methods were adopted for modeling. In addition, a linear regression model was proposed to represent the relationship between accumulated fatigue level and the four time-related variables. Finally, the prediction model was verified by the driving performance measurement: standard deviation of lateral position. The results demonstrated that fatigue prediction results are significantly relevant to driving performance. In conclusion, the fatigue prediction model proposed in this study could be implemented to predict the risk driving period and the maximum consecutive driving time once the driving schedule is determined, and the fatigue driving behavior could be avoided or alleviated by optimizing the driving and break schedule.
The Immune Cell Landscape in Different Anatomical Structures of Knee in Osteoarthritis: A Gene Expression‐Based Study
Authors: Chen Ziming , Ma Yuanchen , Li Xuerui , Deng Zhantao , Zheng Minghao , Zheng Qiujian
Published: March 2020

Background. Immunological mechanisms play a vital role in the pathogenesis of knee osteoarthritis (KOA). Moreover, the immune phenotype is a relevant prognostic factor in various immune‐related diseases. In this study, we used CIBERSORT for deconvolution of global gene expression data to define the immune cell landscape of different structures of knee in osteoarthritis. Methods and Findings. By applying CIBERSORT, we assessed the relative proportions of immune cells in 76 samples of knee cartilage, 146 samples of knee synovial tissue, 40 samples of meniscus, and 50 samples of knee subchondral bone. Enumeration and activation status of 22 immune cell subtypes were provided by the obtained immune cell profiles. In synovial tissues, the differences in proportions of plasma cells, M1 macrophages, M2 macrophages, activated dendritic cells, resting mast cells, and eosinophils between normal tissues and osteoarthritic tissues were statistically significant (P < 0.05). The area under the curve was relatively large in resting mast cells, dendritic cells, and M2 macrophages in receiver operating characteristic analyses. In subchondral bones, the differences in proportions of resting master cells and neutrophils between normal tissues and osteoarthritic tissues were statistically significant (P < 0.05). In subchondral bones, the proportions of immune cells, from the principle component analyses, displayed distinct group‐bias clustering. Resting mast cells and T cell CD8 were the major component of first component. Moreover, we revealed the potential interaction between immune cells. There was almost no infiltration of immune cells in the meniscus and cartilage of the knee joint. Conclusions. The immune cell composition in KOA differed substantially from that of healthy joint tissue, while it also differed in different anatomical structures of the knee. Meanwhile, activated mast cells were mainly associated with high immune cell infiltration in OA. Furthermore, we speculate M2 macrophages in synovium and mast cells in subchondral bone may play an important role in the pathogenesis of OA.
Inactivation of the Prolyl Isomerase Pin1 Sensitizes BRCA1-Proficient Breast Cancer to PARP Inhibition
Authors: Luo Man-Li , Zheng Fang , Chen Wenying , Liang Zhi-Mei , Chandramouly Gurushankar , Tan Jianan , Willis Nicholas A. , Chen Chun-Hau , Taveira Mateus de Oliveira , Zhou Xiao Zhen , Lu Kun Ping , Scully Ralph , Wulf Gerburg M. , Hu Hai
Published: March 2020

PARP inhibitor monotherapies are effective to treat patients with breast, ovary, prostate, and pancreatic cancer with BRCA1 mutations, but not to the much more frequent BRCA wild-type cancers. Searching for strategies that would extend the use of PARP inhibitors to BRCA1-proficient tumors, we found that the stability of BRCA1 protein following ionizing radiation (IR) is maintained by postphosphorylational prolyl-isomerization adjacent to Ser1191 of BRCA1, catalyzed by prolyl-isomerase Pin1. Extinction of Pin1 decreased homologous recombination (HR) to the level of BRCA1-deficient cells. Pin1 stabilizes BRCA1 by preventing ubiquitination of Lys1037 of BRCA1. Loss of Pin1, or introduction of a BRCA1-mutant refractory to Pin1 binding, decreased the ability of BRCA1 to localize to repair foci and augmented IR-induced DNA damage. In vitro growth of HR-proficient breast, prostate, and pancreatic cancer cells were modestly repressed by olaparib or Pin1 inhibition using all-trans retinoic acid (ATRA), while combination treatment resulted in near-complete block of cell proliferation. In MDA-MB-231 xenografts and triple-negative breast cancer patient-derived xenografts, either loss of Pin1 or ATRA treatment reduced BRCA1 expression and sensitized breast tumors to olaparib. Together, our study reveals that Pin1 inhibition, with clinical widely used ATRA, acts as an effective HR disrupter that sensitizes BRCA1-proficient tumors to PARP inhibition.

Significance:

PARP inhibitors have been limited to treat homologous recombination–deficient tumors. All-trans retinoic acid, by inhibiting Pin1 and destabilizing BRCA1, extends benefit of PARP inhibitors to patients with homologous recombination–proficient tumors.

See related commentary by Cai, p. 2977
Drug Sensitivity and Allele Specificity of First-Line Osimertinib Resistance EGFR Mutations
Authors: Starrett Jacqueline H. , Guernet Alexis A. , Cuomo Maria Emanuela , Poels Kamrine E. , van Alderwerelt van Rosenburgh Iris K. , Nagelberg Amy , Farnsworth Dylan , Price Kristin S. , Khan Hina , Ashtekar Kumar Dilip , Gaefele Mmaserame , Ayeni Deborah , Stewart Tyler F. , Kuhlmann Alexandra , Kaech Susan M. , Unni Arun M. , Homer Robert , Lockwood William W. , Michor Franziska , Goldberg Sarah B. , Lemmon Mark A. , Smith Paul D. , Cross Darren A.E. , Politi Katerina
Published: March 2020

Osimertinib, a mutant-specific third-generation EGFR tyrosine kinase inhibitor, is emerging as the preferred first-line therapy for EGFR-mutant lung cancer, yet resistance inevitably develops in patients. We modeled acquired resistance to osimertinib in transgenic mouse models of EGFRL858R-induced lung adenocarcinoma and found that it is mediated largely through secondary mutations in EGFR—either C797S or L718V/Q. Analysis of circulating free DNA data from patients revealed that L718Q/V mutations almost always occur in the context of an L858R driver mutation. Therapeutic testing in mice revealed that both erlotinib and afatinib caused regression of osimertinib-resistant C797S-containing tumors, whereas only afatinib was effective on L718Q mutant tumors. Combination first-line osimertinib plus erlotinib treatment prevented the emergence of secondary mutations in EGFR. These findings highlight how knowledge of the specific characteristics of resistance mutations is important for determining potential subsequent treatment approaches and suggest strategies to overcome or prevent osimertinib resistance in vivo.

Significance:

This study provides insight into the biological and molecular properties of osimertinib resistance EGFR mutations and evaluates therapeutic strategies to overcome resistance.
Heterochronous Suture Line Recurrences in the Jejunal Pouch following Total Gastrectomy for Stage II Gastric Cancer: A Case Report and Literature Review
Authors: Yokoe Takamichi , Sato Michio , Yahagi Masashi , Dogru Murat , Fujisaki Hiroto , Ogura Masaharu , Kawamata Hiroshi , Asahara Fumitaka , Takayama Shin , Harada Hirohisa , Tanaka Yoichi , Miyauchi Jun , Matsui Junichi
Published: March 2020

We report the case of a 65-year-old male who developed heterochronous local recurrences of gastric cancer in the jejunal pouch (J-pouch) four times after total gastrectomy. He underwent total gastrectomy, J-pouch, and Roux-en-Y reconstruction for stage II gastric cancer in 2005. Four local recurrences appeared on the esophago-jejunal anastomosis, the suture line within the pouch, the esophago-jejunal anastomosis, and the anastomosis between the jejunum and Y-loop, which were resected by partial excision or endoscopic submucosal dissection. Suture line recurrence of gastric cancer is rare. The common features for each recurrence included the surgically negative resection margins, observation of the same histopathological subtype, absence of remote metastasis or peritoneal seeding, and the recurrence on the anastomotic suture line, suggesting that the cause of recurrence was the implantation of exfoliated cancer cells probably in the suture line. However, there is no established procedure for preventing implantation recurrence currently, the effectiveness of lumen lavage is suggested.
Tea Consumption Is Associated with Decreased Disease Activity of Rheumatoid Arthritis in a Real-World, Large-Scale Study
Authors: Jin Jiayang , Li Jing , Gan Yuzhou , Liu Jiajia , Zhao Xiaozhen , Chen Jiali , Zhang Ruijun , Zhong Yan , Chen Xiaomei , Wu Lijun , Xiang Xiaohong , Zhou Yunshan , He Jing , Li Ru , Guo Jianping , Li Zhanguo
Published: March 2020

Introduction: The role of tea consumption on rheumatoid arthritis (RA) has been studied in recent years, but no clear conclusion has been drawn as a result of small sample size of the studies or the fact that only in vitro studies have been performed. Objectives: The aim of this study was to explore the possible association of tea consumption with RA through a large-scale, real-world study. Methods: A total of 733 RA patients were investigated from June to December, 2016. The disease activity of RA was assessed according to disease activity score 28-erythrocyte sedimentation rate. The amount and types of tea consumption were recorded by on-site self-administered questionnaires. Logistic regression models were applied to analyze the correlation between tea consumption and disease activity, adjusting for demographics, clinical and laboratory factors. Results: There was an inverse association between tea consumption and disease activity in RA patients (OR 0.66, 95% CI 0.46–0.94). Compared with non-tea drinkers, a higher-intake of tea (>750 mL/day) was associated with lower disease activity of RA (OR 0.39, 95% CI 0.19–0.79), but not low-intake (≤750 mL/day; OR 0.83, 95% CI 0.42–1.63). A significant dose-response association was found between the amount of tea consumption and disease activity (p for trend <0.01). Further hierarchical regression analysis showed that such inverse associations were mainly present in female patients (p = 0.004), non-smokers (p = 0.01) or elders (≥60 years; p = 0.01). Conclusion: Tea consumption is associated with decreased disease activity of RA, suggesting the potential beneficial effect of tea in the disease.
Bullous Pemphigoid and Malignancy in Two Different Hospital Populations: A Retrospective Cohort Review
Authors: Wright Benjamin , Halper Katherine , Worswick Scott
Published: March 2020

Background: Bullous pemphigoid (BP) is a rare autoimmune blistering condition characterized by antibodies to the structural proteins BP1 and BP2 at the dermal-epidermal junction. The link between BP and malignancy remains unclear. Due to the rarity of the disease, there have been few studies with small sample sizes characterizing the association between BP and malignancy. Objectives: There were two main goals of this retrospective cohort study: (1) to look at the associated risk of malignancy in patients with BP compared to controls and (2) to compare the rates of malignancy in two separate hospitals with differing patient populations. Method: We reviewed the medical records of 99 patients diagnosed with BP observed between 2014 and 2019. 66 patients were from Keck Hospital and 33 were from Los Angeles County/University of Southern California (LAC/USC) Hospital. Each patient was age- and sex-matched to a control from the same hospital. Results: Malignancies occurred in 26 BP patients and 29 controls. 7 of the BP patients from LAC/USC Hospital (21.2%) and 19 patients from Keck Hospital (28.8%) had malignancies. Conclusions: Overall, we did not find an increased risk of malignancy in BP patients compared to controls, nor did we find a statistically differing rate of malignancy in BP patients from various socioeconomic and ethnic backgrounds.
Diabetes and Metformin Association with Recurrence Score in a Large Oncotype Database of Breast Cancer Patients
Authors: Tharakan Serena , Zimmerman Brittney , Ru Meng , Blanter Julia , Cascetta Krystal , Tiersten Amy
Published: March 2020

Background: The Oncotype DX® (ODX) is a genomic assay that provides clinicians with a prediction of benefit of chemotherapy in node-negative, tamoxifen-treated breast cancer. However, the relationship between ODX recurrence score (RS) and diabetes, a common comorbidity in breast cancer patients, has been inadequately described in the literature. Specifically, the association of diabetes treatment with metformin and RS is inconclusive, with different studies reporting conflicting results. Because diabetes has been associated with higher RS, it has been suggested that management of diabetes with metformin in breast cancer patients may be associated with a lower RS. Objectives: We studied a large cohort of early-stage, hormone-positive breast cancer patients to determine if there is an association between RS and metformin treatment. Methods: In this study, we retrospectively examined the medical records of 514 early-stage, hormone-positive breast cancer patients who had oncotype testing performed between 2007 and 2017. Number (%) or median were used to describe the patients’ characteristics between groups and were compared by the Kruskal-Wallis test at a significance level of 5%. Results: Of this cohort, 67 (13%) had a diabetes diagnosis at the time of breast cancer diagnosis, including both diabetes mellitus and pre-diabetes. The median RS for non-diabetic patients was 16 and the median RS for diabetic patients was 15. This difference was not significant, nor was there a statistical difference in RS between diabetic patients taking metformin (median RS = 15) and diabetic patients not taking metformin (median RS = 15). These results held true even when controlling for BMI. Conclusions: We conclude that neither diabetes diagnosis nor metformin use is associated with a difference in oncotype RS in this population of diabetic patients.
Targeted Radiotherapy of the Tumor Cavity after Surgical Resection of Aggressive Recurrent Brain Metastasis: A Case Report
Authors: Fadrus Pavel , Kazda Tomas , Dvoracek Petr , Pospisil Petr , Hynkova Ludmila , Zitterbartova Jana , Dymackova Radana , Kolouskova Ivana , Belanova Renata , Prochazka Tomas , Slampa Pavel
Published: March 2020

Postoperative management of patients with brain metastases is controversial. Besides local control, cognitive function and quality of life are the most important outcomes of postoperative radiotherapy. In this case report, we introduce a patient with aggressive recurred solid metastasis treated with repeated surgery and an individual radiotherapy approach in order to highlight that close mutual collaboration leads to a clear benefit for our patients. The local targeted radiotherapy with 35 Gy in 10 fractions was performed with the volumetric modulated arc technique, leading to more than 2.5 years of local control and survival without any of the side effects usually attributed to whole brain radiotherapy.
Nonbacterial Thrombotic Endocarditis and Widespread Skin Necrosis in Newly Diagnosed Lung Adenocarcinoma
Authors: Zakka Katerina , Zakka Patrick , Davarpanah Amir , Koshkelashvili Nikoloz , Bilen Mehmet A. , Owonikoko Taofeek , El-Rayes Bassel , Akce Mehmet
Published: March 2020

Nonbacterial thrombotic endocarditis (NBTE) is a rare entity most commonly diagnosed postmortem with rates in autopsy series ranging from 0.9 to 1.6%. A 63-year-old female with past medical history of hypertension and mitral valve prolapse presented to the hospital with shortness of breath, headache, and necrotic skin lesions on her hands and feet. Computed tomography (CT) scan of her chest demonstrated a pulmonary embolus in the right lower lung segmental artery and right upper lobe lobar to segmental pulmonary artery, a mass-like consolidation in the left upper lung field impeding the hilum. CT scan of the abdomen demonstrated metastatic disease in liver and bone and bilateral femoral deep vein thrombosis. Transesophageal echocardiography revealed severe mitral regurgitation with two small mobile plaques on the mitral valve and two immobile plaques on the descending aorta. Magnetic resonance imaging of the brain was consistent with subacute infarcts and metastatic disease. Bronchoscopy was performed and pathology revealed primary adenocarcinoma of the lung. She was treated with anticoagulation and systemic chemotherapy. The patient and family elected to proceed with hospice due to her clinical decline, poor performance status, and poor prognosis after a prolonged hospital stay. Underlying malignancy is detected in approximately 40–85% of patients with NBTE. Lung cancer is the most frequently associated malignancy followed by pancreatic, stomach, breast, and ovarian cancer. Widespread necrotic skin lesions as presenting symptoms of primary lung adenocarcinoma are rare. In the present case, the diagnosis of necrotic skin lesions and NBTE preceded that of the neoplastic disease. Necrotic skin lesions and NBTE can be the first manifestations of an occult malignancy causing extensive multi-organ infarcts. NBTE can present with such extensive skin lesions as a first presenting sign of malignancy. To the best of our knowledge, this is the first case to present with such extensive skin lesions as the first presenting symptom of lung adenocarcinoma.
Two Novel Variants and One Previously Reported Variant in the Insulin Receptor Gene in Two Cases with Severe Insulin Resistance Syndrome
Authors: Dagdeviren Cakir Aydilek , Saidov Said , Turan Hande , Ceylaner Serdar , Özer Yavuz , Kutlu Tufan , Ercan Oya , Evliyaoglu Olcay
Published: March 2020

Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS) are rare diseases caused by biallelic variants within the insulin receptor gene (INSR). Here, we report 2 cases: one with DS and the other with RMS. The case with DS presented with intrauterine growth retardation, nipple hypertrophy, clitoromegaly, distended abdomen, hypertrichosis, and dysmorphic features. The second case showed severe acanthosis nigricans, hyperkeratosis, and hypertrichosis. In both cases, abnormal glucose homeostasis due to severe insulin resistance was observed. The diagnosis of DS and RMS was established based on clinical characteristics, abnormal glucose homeostasis, high serum insulin levels, and determination of pathogenic variants in the INSR gene. The first case with DS has 2 novel homozygous variants, NM_000208.3, c.3122delA (p.N1041Mfs*16) and c.3419C>G (p.A1140G), and the second case with RMS has a previously reported homozygous variant NM_000208.3, c.3529+5G>A (IVS19+5G>A) in the INSR gene.
Closed vs. Open Oocyte Vitrification Methods Are Equally Effective for Blastocyst Embryo Transfers: Prospective Study from a Sibling Oocyte Donation Program
Authors: Gullo Giuseppe , Petousis Stamatios , Papatheodorou Achilleas , Panagiotidis Yannis , Margioula-Siarkou Chrysoula , Prapas Nikolaos , D’Anna Rosario , Perino Antonio , Cucinella Gaspare , Prapas Yannis
Published: March 2020

Purpose: To assess whether open and closed vitrification protocols are equally effective for sibling-oocyte cycles when performing blastocyst embryo transfers. Materials and Methods: A prospective study was set up comparing the open and the closed vitrification techniques in oocyte recipients sharing sibling oocytes between 2014 and 2016. Sibling oocytes were randomly and equally assigned into the closed group (oocytes vitrified in a closed system) or the open group (oocytes vitrified in an open system). Intracytoplasmic sperm injection was performed on all cases. Embryo transfers were performed on day 5. Power analysis calculation showed that 94 cycles would be needed for each group in the study in order to achieve statistical significance at a 5% level with power 80%. Results: The final number of donors included was 95. A total of 190 recipients matched with their donors were included in the study. There was no difference in the mean number of oocytes vitrified with the closed or the open system (8.26 ± 2.54 vs. 8.31 ± 2.57). No significant difference was observed between the 2 groups regarding survival rate, fertilization rate, cleavage rate, top-quality embryos on day 3, blastocyst rate, and top-quality blastocyst rate. Moreover, no statistically significant difference in the b-human chorionic gonadotropin-positive rate, clinical pregnancy rate per cycle, implantation rate, ongoing pregnancy rate, and live birth rate between closed and open groups. Conclusion: Οpen and closed vitrification protocols are equally effective for sibling-oocyte cycles.
Robot-Assisted Pancreatic Surgery: A Structured Approach to Standardization of a Program and of the Operation
Authors: Müller-Debus Charlotte Friederieke , Thomaschewski Michael , Zimmermann Markus , Wellner Ulrich F. , Bausch Dirk , Keck Tobias
Published: March 2020

Introduction: The use of robots in minimal invasive surgery has become increasingly common in recent years.Robot-assisted pancreatoduodenectomy preponderates against a laparoscopic procedure especially due to the greater flexibility of instruments and therefore a better handling and a better angulation. Furthermore, there are benefits of enlarged 3-D visibility, software-based tremor control, and reduced physical exertion of the surgeon. Methods and Results: This review delivers a point-by-point approach to the setup of a robot-assisted pancreatic program and a detailed approach to robot-assisted pancreatoduodenectomy. Results: In our standardized standard operating procedure approach we use 5 trocars, i.e., 4 robotic trocars and 1 assist trocar. We prefer the position of the robot ports in a straight horizontal line with a distance of 20 cm from the operational field. The operation is dissected into 11 standardized procedural steps as follows: (1) access to the pancreas and visualization, (2) extended Kocher manoeuvre, (3) lower rim and mesentericoportal axis, (4) upper rim and hepatoduodenal ligament, (5) dissection of the pancreatic neck, (6) mesenteric root and pars IV duodeni, (7) mesopancreas, (8) pancreatic anastomosis reconstruction, (9) bilioenteric anastomosis, (10) dudenojejunal anastomosis, and (11) drainage and closure. The setup of the pancreas program and the structured approach to complex pancreatic resections are elucidated. Summary: This review describes the approach to robot-assisted pancreatic surgery in a high-volume pancreas center on a structural and procedural level to support the establishment of such programs at other locations.