bluuebunny/crossref_metadata_2025 huggingface dataset:
Fatigue Reliability Analysis of Motor Hanger for High‐Speed Train Based on Bayesian Updating and Subset Simulation
Authors: Li Yonghua , Zhi Pengpeng , Zhang Yue , Chen Bingzhi , Wang Yuedong
Published: March 2020

In order to more accurately analyze the fatigue reliability of motor hanger for high‐speed train and reduce the influence of uncertain factors, a Bayesian statistical method is introduced to propose a novel fatigue reliability analysis method based on Bayesian updating and subset simulation. First, considering the influence of various uncertain parameters on the first principal stress (FPS) of motor hanger, the ANSYS parametric design language (APDL) is used to establish the parametric model. The D‐optimal design of experiment is carried out to calculate the FPS of the motor hanger. Second, the experimental data is fitted by the least square method to establish a polynomial response surface function which characterizes the FPS of the motor hanger, and analysis of variance (ANOVA) is carried out. On this basis, the variation trend of the FPS under parameter fluctuation is calculated, and its probability distribution characteristics are obtained. Based on the MATLAB platform, the Bayesian updating method is adopted to correct the probability and statistical characteristics of the FPS to improve the accuracy of prediction. Finally, the subset simulation (SS) method is used to calculate the fatigue failure probability of the motor hanger. The research results show that the proposed method helps to improve the accuracy and efficiency of fatigue reliability analysis.
Omentin-1 Ameliorated Free Fatty Acid-Induced Impairment in Proliferation, Migration, and Inflammatory States of HUVECs
Authors: Chen Yubin , Liu Fen , Han Fei , Lv Lizhi , Tang Can-e , Luo Fanyan
Published: March 2020

Objectives. Endothelial cell injury is a critical pathological change during the development of atherosclerosis. Here, we explored the effect of omentin-1 on free fatty acid- (FFA-) induced endothelial cell injury. Methods. An FFA-induced endothelial cell injury model was established to investigate the role of omentin-1 in this process. Cell proliferation was analyzed with the Cell Counting Kit assay and flow cytometry. Scratch and transwell assays were used to evaluate cell migration. Factors secreted by endothelial cells after injury were detected by western blotting, reverse-transcription quantitative polymerase chain reaction, and cellular fluorescence assay. Results. Omentin-1 rescued the FFA-induced impaired proliferation and migration capabilities of human umbilical vein endothelial cells (HUVECs). It decreased the number of THP-1 cells attached to HUVECs in response to injury and inhibited the FFA-induced proinflammatory state of HUVECs. Conclusion. Omentin-1 could partly ameliorate FFA-induced endothelial cell injury.
Gastrointestinal Bleeding due to Pancreatic Disease-Related Portal Hypertension
Authors: Zheng Kexin , Guo Xiaozhong , Feng Ji , Bai Zhaohui , Shao Xiaodong , Yi Fangfang , Zhang Yongguo , Zhang Rui , Liu Han , Romeiro Fernando Gomes , Qi Xingshun
Published: March 2020

Background and Aims. Left-sided portal hypertension (LSPH) is a rare type of portal hypertension, which occurs due to obstruction, stenosis, or thrombosis within the splenic vein. Pancreatic diseases are the most common etiology of LSPH. This study is aimed at reporting our experiences and discussing the presentation, management, and prognosis of LSPH secondary to pancreatic diseases. Patients and Methods. We retrospectively reviewed five patients who were diagnosed with LSPH secondary to pancreatic diseases at our department. We collected the demographic information, history, comorbidities, clinical presentations, laboratory tests, esophagogastroduodenoscopy (EGD), images, and outcome data. Results. Three elderly patients (>60 years old) were diagnosed with pancreatic cancer, of whom one underwent laparoscopic radical distal pancreatectomy and splenectomy, one received chemotherapy, and another one chose conservative management due to multiple systemic metastases. Two younger patients (<40 years old) were diagnosed with acute recurrent pancreatitis and chronic pancreatitis. Four of these five included patients presented with hematemesis and/or melena at our admission. All patients had gastric varices, and one of them also had esophageal varices. One elderly patient with metastatic pancreatic cancer underwent endoscopic variceal treatment as a rescue therapy but finally died of refractory gastrointestinal (GI) bleeding; another younger patient with chronic pancreatitis died of massive GI bleeding; and the remaining three patients survived at their last follow-up. Conclusions. LSPH should be seriously taken into consideration in patients with pancreatic diseases who develop upper GI bleeding. Clinicians should individualize the treatment strategy of LSPH according to the patients’ clinical conditions and nature of pancreatic diseases.
Proteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress
Authors: Höhn Annika , Tramutola Antonella , Cascella Roberta
Published: March 2020

Protein homeostasis or proteostasis is an essential balance of cellular protein levels mediated through an extensive network of biochemical pathways that regulate different steps of the protein quality control, from the synthesis to the degradation. All proteins in a cell continuously turn over, contributing to development, differentiation, and aging. Due to the multiple interactions and connections of proteostasis pathways, exposure to stress conditions may cause various types of protein damage, altering cellular homeostasis and disrupting the entire network with additional cellular stress. Furthermore, protein misfolding and/or alterations during protein synthesis results in inactive or toxic proteins, which may overload the degradation mechanisms. The maintenance of a balanced proteome, preventing the formation of impaired proteins, is accomplished by two major catabolic routes: the ubiquitin proteasomal system (UPS) and the autophagy-lysosomal system. The proteostasis network is particularly important in nondividing, long-lived cells, such as neurons, as its failure is implicated with the development of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. These neurological disorders share common risk factors such as aging, oxidative stress, environmental stress, and protein dysfunction, all of which alter cellular proteostasis, suggesting that general mechanisms controlling proteostasis may underlay the etiology of these diseases. In this review, we describe the major pathways of cellular proteostasis and discuss how their disruption contributes to the onset and progression of neurodegenerative diseases, focusing on the role of oxidative stress.
Transcriptome Analysis Reveals the Negative Effect of 16 T High Static Magnetic Field on Osteoclastogenesis of RAW264.7 Cells
Authors: Huyan Ting , Peng Hourong , Cai Suna , Li Qi , Dong Dandan , Yang Zhouqi , Shang Peng
Published: March 2020

The magnetic field is the most common element in the universe, and high static magnetic field (HiSMF) has been reported to act as an inhibited factor for osteoclasts differentiation. Although many studies have indicated the negative role of HiSMF on osteoclastogenesis of RANKL‐induced RAW264.7 cells, the molecular mechanism is still elusive. In this study, the HiSMF‐retarded cycle and weakened differentiation of RAW264.7 cells was identified. Through RNA‐seq analysis, RANKL‐induced RAW264.7 cells under HiSMF were analysed, and a total number of 197 differentially expressed genes (DEGs) were discovered. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that regulators of cell cycle and cell division such as Bub1b, Rbl1, Ube2c, Kif11, and Nusap1 were highly expressed, and CtsK, the marker gene of osteoclastogenesis was downregulated in HiSMF group. In addition, pathways related to DNA replication, cell cycle, and metabolic pathways were significantly inhibited in the HiSMF group compared to the Control group. Collectively, this study describes the negative changes occurring throughout osteoclastogenesis under 16 T HiSMF treatment from the morphological and molecular perspectives. Our study provides information that may be utilized in improving magnetotherapy on bone disease.
Posterior Arthroscopic Treatment of a Massive Effusion in the Flexor Hallucis Longus Tendon Sheath Associated with Stenosing Tenosynovitis and Os Trigonum
Authors: Tonogai Ichiro , Sairyo Koichi
Published: March 2020

We report a rare case of massive accumulation of fluid in the flexor hallucis longus tendon sheath with stenosing tenosynovitis and os trigonum. A 34-year-old woman presented to our hospital with pain and swelling in the posteromedial aspect of the left ankle joint after an ankle sprain approximately 8 months earlier. There was tenderness at the posteromedial aspect of the ankle, and the pain worsened on dorsiflexion of the left great toe. Magnetic resonance imaging revealed massive accumulation of fluid around the flexor hallucis longus tendon. We removed the os trigonum, performed tenosynovectomy around the flexor hallucis longus, and released the flexor hallucis longus tendon via posterior arthroscopy using standard posterolateral and posteromedial portals. At 1 week postoperatively, the patient was asymptomatic and able to resume her daily activities. There has been no recurrence of the massive accumulation of fluid around the flexor hallucis longus tendon as of 1 year after the surgery. To our knowledge, this is a rare case report of extreme massive effusion in the flexor hallucis longus tendon sheath with stenosing tenosynovitis and os trigonum treated successfully by removal of the os trigonum, tenosynovectomy around the flexor hallucis longus, and release of the flexor hallucis longus tendon via posterior ankle arthroscopy.
Patient Complications after Interscalene Block: A Retrospective Comparison of Liposomal Bupivacaine to Nonliposomal Bupivacaine
Authors: Hutchins Jacob L. , Habeck Jason , Novaczyk Zac , Campbell Richard , Creedon Christopher , Spartz Ellen , Richter Michael , Wolter Jeremy , Suryawanshi Gaurav , Kaizer Alexander , Berg Aaron A.
Published: March 2020

Background. The purpose of this study was to investigate if the addition of liposome bupivacaine (LB) to an interscalene block (ISB) had an effect on the number of patients with surgical- or block-related complications.Methods. This was a single-center retrospective chart view performed by identifying patients who received an ISB from January 1, 2014, through April 26, 2018, at the University of Minnesota. 1,518 patients were identified who received an ISB (LB = 784, nonliposomal bupivacaine = 734). Patients were divided into two groups those who did receive liposome bupivacaine in their ISB and those who did not receive liposome bupivacaine in their ISB. Medical records were individually reviewed for surgical procedure, block medications, complications related to the block or surgical procedure, phone calls to the healthcare system for issues related to opioids or pain within 3 and within 30 days, readmissions within 30 days, and emergency room visits for complications within 3 and 30 days.Results. There was no significant difference in the number of patients with surgical or anesthetic complications. Only phone calls for pain within 3 days were significantly different. The LB group had 3.2% of patients call compared to 5.6% in the nonliposomal bupivacaine group (aOR = 1.71 (95% CI: 1.04–2.87),p=0.036). We found no significant difference in any of the other secondary outcomes.Conclusions. The use of LB in an ISB demonstrated no significant difference compared to nonliposomal bupivacaine in numbers of complications, emergency room visits, and readmissions.
Measurement of Adhesion of In Situ Electrospun Nanofibers on Different Substrates by a Direct Pulling Method
Authors: Zhang Bin , Yan Xu , Xu Yuan , Zhao Huai-Song , Yu Miao , Long Yun-Ze
Published: March 2020

In some cases, we hope to remove the electrospun nanofibrous mesh from the collector easily. But in some cases such as wound dressing, we observe that the in situ electrospun nanofibers can stick to the collector (e.g., skin). Therefore, the adhesion between the in situ electrospun web and the substrate becomes important in the performance and practical application of the electrospun material. In this paper, we reported a direct pulling method to measure the adhesion and understand the adhesion mechanism. In this method, we used gravity to pull the fiber directly from the substrate and then measured the gravity to calculate the adhesion. This new test method is more convenient and practical than the previously reported methods. In addition, the adhesion of the in situ electrospun web on different substrates (e.g., aluminium foil, wood pulp paper, and silicon paper) was also studied by this method. The adhesion was influenced by spinning voltage, electrical conductivity, and surface roughness of the substrates.
Educational Intervention of Intention Change for Consumption of Junk Food among School Adolescents in Birgunj Metropolitan City, Nepal, Based on Theory of Planned Behaviors
Authors: Singh Upendra Kumar , Gautam Nirmal , Bhandari Tulsi Ram , Sapkota Nirmal
Published: March 2020

Consumption of junk food among adolescents has been recognized as a serious health problem in the world. Therefore, this study aims to assess the effectiveness of an educational intervention program (interactive lecture) based on the theory of planned behavior (TPB) for reducing junk food consumption among school adolescents in Birgunj Metropolitan City, Nepal. A structured questionnaire was deployed for collecting the data from four government schools. Pretest and Posttest group study design and simple random sampling techniques were used. A multiple linear regression model and a paired t-test were used to assess the effectiveness of an educational intervention program. The theory of planned behavior indicates that behavioral intention of junk food consumption was different in pretest and posttest [5.43 ± 1.3 and 7.96 ± 0.3]. Furthermore, the average score of attitude toward junk food consumption was 11.9 ± 1.5 and 16.3 ± 1.6. Meanwhile, perceived behavior control (PBC) toward junk food was also different after intervention [2.42 ± 0.50 and 3.13 ± 0.58]. The interactive lecture method was proved an effective education program for changing the intentions of adolescent students and preventing them from consuming junk food which were statistically significant (<0.05). In addition, behavioral intention of junk food consumption, attitude toward junk food consumption, and perceived behavioral control toward junk food were statistically significant (<0.05). Therefore, study concluded that the intervention program has positive influence on the perceived behavior without control group of school-going adolescents.
Sine Cosine Algorithm with Multigroup and Multistrategy for Solving CVRP
Authors: Yang Qingyong , Chu Shu-Chuan , Pan Jeng-Shyang , Chen Chien-Ming
Published: March 2020

Sine Cosine Algorithm (SCA) has been proved to be superior to some existing traditional optimization algorithms owing to its unique optimization principle. However, there are still disadvantages such as low solution accuracy and poor global search ability. Aiming at the shortcomings of the sine cosine algorithm, a multigroup multistrategy SCA algorithm (MMSCA) is proposed in this paper. The algorithm executes multiple populations in parallel, and each population executes a different optimization strategy. Information is exchanged among populations through intergenerational communication. Using 19 different types of test functions, the optimization performance of the algorithm is tested. Numerical experimental results show that the performance of the MMSCA algorithm is better than that of the original SCA algorithm, and it also has some advantages over other intelligent algorithms. At last, it is applied to solving the capacitated vehicle routing problem (CVRP) in transportation. The algorithm can get better results, and the practicability and feasibility of the algorithm are also proved.
Application of Whale Optimization Algorithm to Inverse Scattering of an Imperfect Conductor with Corners
Authors: Lee Kun-Chou , Lu Pai-Ting
Published: March 2020

In this paper, the whale optimization algorithm (WOA) is applied to the inverse scattering of an imperfect conductor with corners. The WOA is a new metaheuristic optimization algorithm. It mimics the hunting behavior of humpback whales. The inspiration results from the fact that a whale recognizes the location of a prey (i.e., optimal solution) by swimming around the prey within a shrinking circle and along a spiral-shaped path simultaneously. Initially, the inverse scattering is first transformed into a nonlinear optimization problem. The transformation is based on the moment method solution for scattering integral equations. To treat a target with corners and implement the WOA inverse scattering, the cubic spline interpolation is utilized for modelling the target shape function. Numerical simulation shows that the inverse scattering by WOA not only is accurate but also converges fast.
Extensive In Silico Analysis of ATL1 Gene : Discovered Five Mutations That May Cause Hereditary Spastic Paraplegia Type 3A
Authors: Mustafa Mujahed I. , Murshed Naseem S. , Abdelmoneim Abdelrahman H. , Abdelmageed Miyssa I. , Elfadol Nafisa M. , Makhawi Abdelrafie M.
Published: March 2020

Background. Hereditary spastic paraplegia type 3A (SPG3A) is a neurodegenerative disease inherited type of Hereditary spastic paraplegia (HSP). It is the second most frequent type of HSP which is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs. SPG3A gene mutations and the phenotype-genotype correlations have not yet been recognized. The aim of this work was to categorize the most damaging SNPs in ATL1 gene and to predict their impact on the functional and structural levels by several computational analysis tools. Methods. The raw data of ATL1 gene were retrieved from dbSNP database and then run into numerous computational analysis tools. Additionally; we submitted the common six deleterious outcomes from the previous functional analysis tools to I-mutant 3.0 and MUPro, respectively, to investigate their effect on the structural level. The 3D structure of ATL1 was predicted by RaptorX and modeled using UCSF Chimera to compare the differences between the native and the mutant amino acids. Results. Five nsSNPs out of 249 were classified as the most deleterious (rs746927118, rs979765709, rs119476049, rs864622269, and rs1242753115). Conclusions. In this study, the impact of nsSNPs in the ATL1 gene was investigated by various in silico tools that revealed five nsSNPs (V67F, T120I, R217Q, R495W, and G504E) are deleterious SNPs, which have a functional impact on ATL1 protein and, therefore, can be used as genomic biomarkers specifically before 4 years of age; also, it may play a key role in pharmacogenomics by evaluating drug response for this disabling disease.
The Role of Clopidogrel in 2020: A Reappraisal
Authors: Patti Giuseppe , Micieli Giuseppe , Cimminiello Claudio , Bolognese Leonardo
Published: March 2020

Antiplatelet therapy is the mainstay of treatment and secondary prevention of cardiovascular disease (CVD), including acute coronary syndrome (ACS), transient ischemic attack (TIA) or minor stroke, and peripheral artery disease (PAD). The P2Y12 inhibitors, of which clopidogrel was the first, play an integral role in antiplatelet therapy and therefore in the treatment and secondary prevention of CVD. This review discusses the available evidence concerning antiplatelet therapy in patients with CVD, with a focus on the role of clopidogrel. In combination with aspirin, clopidogrel is often used as part of dual antiplatelet therapy (DAPT) for the secondary prevention of ACS. Although newer, more potent P2Y12 inhibitors (prasugrel and ticagrelor) show a greater reduction in ischemic risk compared with clopidogrel in randomized trials of ACS patients, these newer P2Y12 inhibitors are often associated with an increased risk of bleeding. Deescalation of DAPT by switching from prasugrel or ticagrelor to clopidogrel may be required in some patients with ACS. Furthermore, real-world studies of ACS patients have not confirmed the benefits of the newer P2Y12 inhibitors over clopidogrel. In patients with very high-risk TIA or stroke, short-term DAPT with clopidogrel plus aspirin for 21–28 days, followed by clopidogrel monotherapy for up to 90 days, is recommended. Clopidogrel monotherapy may also be used in patients with symptomatic PAD. In conclusion, there is strong evidence supporting the use of clopidogrel antiplatelet therapy in several clinical settings, which emphasizes the importance of this medication in clinical practice.
Advances in Electrospinning of Natural Biomaterials for Wound Dressing
Authors: Wang Fadong , Hu Shui , Jia Qingxiu , Zhang Liqun
Published: March 2020

Electrospinning has been recognized as an efficient technique for the fabrication of polymer nanofibers. Various polymers have been successfully electrospun into ultrafine fibers in recent years. These electrospun biopolymer nanofibers have potential applications for wound dressing based upon their unique properties. In this paper, a comprehensive review is presented on the researches and developments related to electrospun biopolymer nanofibers including processing, structure and property, characterization, and applications. Information of those polymers together with their processing condition for electrospinning of ultrafine fibers has been summarized in the paper. The application of electrospun natural biopolymer fibers in wound dressings was specifically discussed. Other issues regarding the technology limitations, research challenges, and future trends are also discussed.
Genetic Variations in miR‐30 Family Member Regulatory Regions Are Associated with Breast Cancer Risk in a Chinese Population
Authors: Zhou Jing , Wang Lijuan , Liu Sijun , Zhou Wen , Jiang Yue , Du Jiangbo , Dai Juncheng , Jin Guangfu , Ma Hongxia , Hu Zhibin , Chen Jiaping , Shen Hongbing
Published: March 2020

MicroRNAs (miRNAs) of the miR‐30 family are closely linked with tumor metastasis and play key roles in the complex malignant phenotypes of cancers by targeting many tumor‐related genes. Deregulated expression of miR‐30 family members has been commonly observed in breast cancer. However, associations between the genetic variants in the regulatory region of miR‐30 family and the risk of breast cancer are still limited, especially in the Chinese Han population. In the present study, we conducted a case‐control analysis wherein 1064 breast cancer patients and 1073 healthy controls underwent genotyping of 10 SNPs in the regulatory region of miR‐30 family members. Multivariate logistic regression analyses illustrated that the rs763354 variant in the miR‐30a regulatory region was linked with a significant decrease in breast cancer risk in an additive model (adjusted OR = 0.86, 95% CI: 0.75‐0.98, P = 0.022). Further, eQTL analyses also indicated that this SNP was associated with miR‐30a expression levels in breast cancer samples compiled in the TCGA database (P = 0.020). The Kaplan‐Meier plotter showed that breast cancer patients with higher miR‐30a expression have significantly better outcomes than do patients expressing low levels of this miRNA (HR = 0.75, 95% CI: 0.61‐0.91, P = 0.0041). Together, these findings suggest that the miR‐30a rs763354 SNP is an important regulator of breast cancer risk, thus making it a potentially viable prognostic biomarker and one that can be used to guide therapeutic treatment in affected patients.
Therapeutic Effects of BCG Vaccination on Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Chang Yu-Chen , Lin Chien-Ju , Hsiao Yu-Hsuan , Chang Yu-Han , Liu Shu-Jung , Hsu Hsin-Yin
Published: March 2020

Background. Type 1 diabetes mellitus (T1DM) causes the irreversible destruction of pancreatic beta cells. The Bacillus Calmette–Guerin (BCG) vaccine can modulate the immune response and decelerate disease progression. The aim of this study is to investigate the efficacy of the BCG vaccine for the treatment of T1DM. Objective. Six databases were systematically searched from inception to the end of August 2019. The randomized controlled trials (RCTs) that evaluated glycemic control in response to the BCG vaccine for T1DM were enrolled. The primary outcome was glycated hemoglobin (HbA1c) level, and secondary outcomes included fasting and stimulated C-peptide level, daily insulin dosage, and clinical remission. The revised Cochrane risk of bias tool was used for quality assessment, and meta-analyses were conducted to evaluate the efficacy of the BCG vaccine. Results. Four studies with a total of 198 subjects were included. The results of HbA1c and fasting C-peptide levels were extracted for further quantitative assessment. The pooled meta-analysis demonstrated no significant difference in HbA1c levels (mean difference [MD], −0.12; 95% confidence interval [CI], −0.53 to 0.30; I2=56%) or fasting C-peptide levels (MD, −0.15; 95% CI, −0.35 to 0.06; I2=0%) in the BCG intervention group as compared with that in the placebo group. Conclusions. There is no robust evidence to support the use of the BCG vaccine for the treatment of T1DM although the HbA1c levels tended to improve. Additional RCTs to assess the long-term effects of the BCG vaccine on glycemic control are warranted.
Investigation on the Design Method of Shear Strength and Lateral Stiffness of the Cold-Formed Steel Shear Wall
Authors: Nie Shaofeng , Zhou Tianhua , Zhang Yang , Zhang Ben , Wang Shuo
Published: March 2020

The assembled cold-formed steel stud shear walls are the main lateral force resisting members of cold-formed steel residential buildings. In this paper, three cold-formed steel shear walls with different types of sheathings (gypsum board and OSB board) were tested under the monotonic lateral loading. The failure modes, the shear strength, and the load-displacement curves of the shear walls were obtained and analyzed to investigate the relationship between screws and shear walls. The test results showed that the material types of the sheathings influence the shear strength of the CFS shear wall greatly. The sum of shear strengths of CFS shear walls with one-side gypsum board and CFS shear walls with one-side OSB board is close to that of the CFS shear wall with the both-sided board (one side is gypsum board and the other side is OSB board). The shear strength of the screws between the board and the CFS stud plays a decisive role in the shear strength of the CFS shear wall, which is usually governed by the shear strength of the screw connections. The design methods of the shear strength and the lateral stiffness of the CFS shear walls were proposed and evaluated by comparing the calculated results with the test results. The comparison results demonstrated that the modified design method of shear strength is conservative and feasible to predict the shear strength of the CFS shear wall. The design method of the lateral stiffness of the CFS shear wall is available to calculate the lateral displacement of the CFS shear wall under the elastic stage, but it is not useful under the nonelastic stage. The proposed design methods can be served as a reference for engineering practice.
The Essential Thrombocythemia, Thrombotic Risk Stratification, and Cardiovascular Risk Factors
Authors: Mancuso Salvatrice , Accurso Vincenzo , Santoro Marco , Raso Simona , Contrino Angelo Davide , Perez Alessandro , Di Piazza Florinda , Florena Ada Maria , Russo Antonio , Siragusa Sergio
Published: March 2020

Essential thrombocythemia is a rare hematological malignancy with good overall survival, but moderate to high risk of developing arterial or venous thrombosis lifelong. Different thrombotic risk scores for patients with essential thrombocythemia have been proposed, but only one of them (the IPSET-t scoring system) takes into account the classical cardiovascular risk factors as one of the scoring items. Currently, in clinical practice, the presence of cardiovascular risk factors in patients with diagnosis of ET rarely determines the decision to initiate cytoreductive therapies. In our study, we compared different risk models to estimate the thrombotic risk of 233 ET patients and the role of specific driver mutations and evaluated the impact that conventional cardiovascular risk factors (hypertension, cigarette smoking, diabetes, obesity, and dyslipidaemia) have on thrombotic risk in patients with ET. Perspective studies conducted on a polycentric large cohort of patients should be conducted to estimate the impact of cardiovascular risk factors in determining thrombosis in ET patients, evaluating the opportunity of initiating a cytoreductive therapy in patients with cardiovascular risk factors, even if classified into low to moderate risk groups according to other scoring systems.
Sesamin Promotes Neurite Outgrowth under Insufficient Nerve Growth Factor Condition in PC12 Cells through ERK1/2 Pathway and SIRT1 Modulation
Authors: Udomruk Sasimol , Kaewmool Chayanut , Phitak Thanyaluck , Pothacharoen Peraphan , Kongtawelert Prachya
Published: March 2020

The promotion of neurogenesis can be a promising strategy to improve and restore neuronal function in neurodegenerative diseases. Nerve growth factor (NGF) plays a key role in neurite outgrowth and synaptic formation during brain repair stage. Nowadays, there are several studies on the developing methods to enhance the endogenous NGF activity for treatment and restore the neuronal function. In this study, the potentiating effect of sesamin, a major lignan in sesame seeds (Sesamum indicum) and oil, on NGF‐induced neurogenesis and its involved mechanisms were firstly reported. Sesamin effectively enhanced the PC12 neuron‐like cell differentiation and neurite length under insufficient conditions of NGF. The neuronal markers including synaptophysin and growth‐associated protein‐43 along with the synaptic connections were significantly increased in combination treatment between sesamin and NGF. Moreover, sesamin also increased the level of phospho‐ERK1/2 and SIRT1 protein, an important regulatory protein of the neurogenesis process. The neurogenesis was blocked by the specific SIRT1 inhibitor, JGB1741, suggesting that the neuritogenic effect of sesamin was associated with SIRT1 protein modulation. Taken together, the potentiating effect of sesamin on NGF‐induced neurogenesis in this finding could be used for alternative treatment in neurodegenerative diseases, including Alzheimer’s disease.
Pancreatic Adenocarcinoma: Unconventional Approaches for an Unconventional Disease
Authors: Gromisch Christopher , Qadan Motaz , Machado Mariana Albuquerque , Liu Kebin , Colson Yolonda , Grinstaff Mark W.
Published: March 2020

This review highlights current treatments, limitations, and pitfalls in the management of pancreatic cancer and discusses current research in novel targets and drug development to overcome these clinical challenges. We begin with a review of the clinical landscape of pancreatic cancer, including genetic and environmental risk factors, as well as limitations in disease diagnosis and prevention. We next discuss current treatment paradigms for pancreatic cancer and the shortcomings of targeted therapy in this disease. Targeting major driver mutations in pancreatic cancer, such as dysregulation in the KRAS and TGFβ signaling pathways, have failed to improve survival outcomes compared with nontargeted chemotherapy; thus, we describe new advances in therapy such as Ras-binding pocket inhibitors. We then review next-generation approaches in nanomedicine and drug delivery, focusing on preclinical advancements in novel optical probes, antibodies, small-molecule agents, and nucleic acids to improve surgical outcomes in resectable disease, augment current therapies, expand druggable targets, and minimize morbidity. We conclude by summarizing progress in current research, identifying areas for future exploration in drug development and nanotechnology, and discussing future prospects for management of this disease.
Disease Monitoring Using Post-induction Circulating Tumor DNA Analysis Following First-Line Therapy in Patients with Metastatic Colorectal Cancer
Authors: Max Ma Xiaoju , Bendell Johanna C. , Hurwitz Herbert I. , Ju Christine , Lee John J. , Lovejoy Alex , Mancao Christoph , Nicholas Alan , Price Richard , Sommer Nicolas , Tikoo Nalin , Yao Lijing , Yaung Stephanie J. , Palma John F.
Published: March 2020

Purpose:

We assessed plasma circulating tumor DNA (ctDNA) level as a prognostic marker for progression-free survival (PFS) following first-line metastatic colorectal cancer (mCRC) therapy.

Experimental Design:

The Sequencing Triplet With Avastin and Maintenance (STEAM) was a randomized, phase II trial investigating efficacy of bevacizumab (BEV) plus 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) and 5-fluorouracil/leucovorin/irinotecan (FOLFIRI), administered concurrently or sequentially, versus FOLFOX-BEV in first-line mCRC. Evaluation of biomarkers associated with treatment outcomes was an exploratory endpoint. Patients in the biomarker-evaluable population (BEP) had 1 tissue sample, 1 pre-induction plasma sample, and 1 post-induction plasma sample collected ≤60 days of induction from last drug date.

Results:

Among the 280 patients enrolled in STEAM, 183 had sequenced and evaluable tumor tissue, 118 had matched pre-induction plasma, and 54 (BEP) had ctDNA-evaluable sequencing data for pre- and post-induction plasma. The most common somatic variants in tumor tissue and pre-induction plasma were TP53, APC, and KRAS. Patients with lower-than-median versus higher-than-median post-induction mean allele fraction (mAF) levels had longer median PFS (17.7 vs. 7.5 months, HR, 0.33; 95% confidence interval, 0.17–0.63). Higher levels of post-induction mAF and post-induction mean mutant molecules per milliliter (mMMPM), and changes in ctDNA (stratified by a 10-fold or 100-fold reduction in mAF between pre- and post-induction plasma), were associated with shorter PFS. Post-induction mAF and mMMPM generally correlated with each other (ρ = 0.987, P < 0.0001).

Conclusions:

ctDNA quantification in post-induction plasma may serve as a prognostic biomarker for mCRC post-treatment outcomes.
Whole-Exome Sequencing Analysis of the Progression from Non–Low-Grade Ductal CarcinomaIn Situto Invasive Ductal Carcinoma
Authors: Pareja Fresia , Brown David N. , Lee Ju Youn , Da Cruz Paula Arnaud , Selenica Pier , Bi Rui , Geyer Felipe C. , Gazzo Andrea , da Silva Edaise M. , Vahdatinia Mahsa , Stylianou Anthe A. , Ferrando Lorenzo , Wen Hannah Y. , Hicks James B. , Weigelt Britta , Reis-Filho Jorge S.
Published: March 2020

Purpose:

Ductal carcinoma in situ (DCIS) is a nonobligate precursor of invasive breast cancer. Here, we sought to investigate the level of intralesion genetic heterogeneity in DCIS and the patterns of clonal architecture changes in the progression from DCIS to invasive disease.

Experimental Design:

Synchronous DCIS (n = 27) and invasive ductal carcinomas of no special type (IDC-NSTs; n = 26) from 25 patients, and pure DCIS (n = 7) from 7 patients were microdissected separately and subjected to high-depth whole-exome (n = 56) or massively parallel sequencing targeting ≥410 key cancer-related genes (n = 4). Somatic genetic alterations, mutational signatures, clonal composition, and phylogenetic analyses were defined using validated computational methods.

Results:

DCIS revealed genetic alterations similar to those of synchronously diagnosed IDC-NSTs and of non-related IDC-NSTs from The Cancer Genome Atlas (TCGA), whereas pure DCIS lacked PIK3CA mutations. Clonal decomposition and phylogenetic analyses based on somatic mutations and copy number alterations revealed that the mechanisms of progression of DCIS to invasive carcinoma are diverse, and that clonal selection might have constituted the mechanism of progression from DCIS to invasive disease in 28% (7/25) of patients. DCIS displaying a pattern of clonal selection in the progression to invasive cancer harbored higher levels of intralesion genetic heterogeneity than DCIS where no clonal selection was observed.

Conclusions:

Intralesion genetic heterogeneity is a common feature in DCIS synchronously diagnosed with IDC-NST. DCIS is a nonobligate precursor of IDC-NST, whose mechanisms of progression to invasive breast cancer are diverse and vary from case to case.
Comprehensive Genomic Analysis of Translocation Renal Cell Carcinoma Reveals Copy-Number Variations as Drivers of Disease Progression
Authors: Marcon Julian , DiNatale Renzo G. , Sanchez Alejandro , Kotecha Ritesh R. , Gupta Sounak , Kuo Fengshen , Makarov Vladimir , Sandhu Amar , Mano Roy , Silagy Andrew W. , Blum Kyle A. , Nassau Daniel E. , Benfante Nicole E. , Ortiz Michael V. , Carlo Maria I. , Chan Timothy A. , Motzer Robert J. , Voss Martin H. , Coleman Jonathan , Russo Paul , Reuter Victor , Hakimi A. Ari , Reznik Ed
Published: March 2020

Purpose:

Translocation renal cell carcinoma (tRCC) is a rare, aggressive renal cell carcinoma (RCC) subtype. There is currently limited understanding on the role of molecular alterations in the pathogenesis and progression of these tumors. We investigated the association between somatic alterations and clinical outcomes in two independent cohorts profiled using DNA sequencing.

Experimental Design:

Twenty-two tRCCs underwent targeted sequencing [Memorial Sloan Kettering Cancer Center (MSK)-IMPACT]; a subset was profiled using exome-sequencing and combined with exome data from The Cancer Genome Atlas (TCGA) for analysis. The prognostic value of specific somatic aberrations, tumor mutation burden (TMB), and fraction of copy-number–altered genome (FCNAg) was explored. In TCGA cases, neoantigen prediction and immune cell deconvolution were performed using RNA-sequencing and exome data. Overall survival estimates were computed using the Kaplan–Meier method; time-on-treatment was calculated for 14 MSK-IMPACT patients who underwent systemic therapy. Associations between molecular features and outcomes were evaluated using nonparametric testing.

Results:

Copy-number aberrant tRCCs were associated with poor overall survival (P = 0.03). Pediatric patients had tumors with lower FCNAg (P = 0.01). In one adult case with two chronologically distinct tumor samples sequenced, we confirmed that copy-number events occurred early during evolution. TERT promoter mutations were found exclusively in high-stage tumors. We found that tRCCs displayed distinct angiogenesis and PD-L1 gene expression profiles compared with other RCC subtypes.

Conclusions:

Tumors molecularly defined by increased copy-number variations were associated with aggressive disease in tRCC. A higher burden of genomic events in adults compared with pediatric cases likely reflects a more aggressive clinical course. The unique immunophenotypic characteristics of tRCC merit further exploration.
Wee1 Kinase Inhibitor AZD1775 Effectively Sensitizes Esophageal Cancer to Radiotherapy
Authors: Yang Linlin , Shen Changxian , Pettit Cory J. , Li Tianyun , Hu Andrew J. , Miller Eric D. , Zhang Junran , Lin Steven H. , Williams Terence M.
Published: March 2020

Purpose:

Esophageal cancer is a deadly malignancy with a 5-year survival rate of only 5% to 20%, which has remained unchanged for decades. Esophageal cancer possesses a high frequency of TP53 mutations leading to dysfunctional G1 cell-cycle checkpoint, which likely makes esophageal cancer cells highly reliant upon G2–M checkpoint for adaptation to DNA replication stress and DNA damage after radiation. We aim to explore whether targeting Wee1 kinase to abolish G2–M checkpoint sensitizes esophageal cancer cells to radiotherapy.

Experimental Design:

Cell viability was assessed by cytotoxicity and colony-forming assays, cell-cycle distribution was analyzed by flow cytometry, and mitotic catastrophe was assessed by immunofluorescence staining. Human esophageal cancer xenografts were generated to explore the radiosensitizing effect of AZD1775 in vivo.

Results:

The IC50 concentrations of AZD1775 on esophageal cancer cell lines were between 300 and 600 nmol/L. AZD1775 (100 nmol/L) as monotherapy did not alter the viability of esophageal cancer cells, but significantly radiosensitized esophageal cancer cells. AZD1775 significantly abrogated radiation-induced G2–M phase arrest and attenuation of p-CDK1-Y15. Moreover, AZD1775 increased radiation-induced mitotic catastrophe, which was accompanied by increased γH2AX levels, and subsequently reduced survival after radiation. Importantly, AZD1775 in combination with radiotherapy resulted in marked tumor regression of esophageal cancer tumor xenografts.

Conclusions:

Abrogation of G2–M checkpoint by targeting Wee1 kinase with AZD1775 sensitizes esophageal cancer cells to radiotherapy in vitro and in mouse xenografts. Our findings suggest that inhibition of Wee1 by AZD1775 is an effective strategy for radiosensitization in esophageal cancer and warrants clinical testing.
Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia
Authors: Laurent Anouchka P. , Siret Aurélie , Ignacimouttou Cathy , Panchal Kunjal , Diop M'Boyba , Jenni Silvia , Tsai Yi-Chien , Roos-Weil Damien , Aid Zakia , Prade Nais , Lagarde Stephanie , Plassard Damien , Pierron Gaelle , Daudigeos Estelle , Lecluse Yann , Droin Nathalie , Bornhauser Beat C. , Cheung Laurence C. , Crispino John D. , Gaudry Muriel , Bernard Olivier A. , Macintyre Elizabeth , Barin Bonnigal Carole , Kotecha Rishi S. , Geoerger Birgit , Ballerini Paola , Bourquin Jean-Pierre , Delabesse Eric , Mercher Thomas , Malinge Sebastien
Published: March 2020

Purpose:

Children with Down syndrome (constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse, compared with other children with B-cell acute lymphoblastic leukemia (B-ALL). This highlights the lack of suitable treatment for Down syndrome children with B-ALL.

Experimental Design:

To facilitate the translation of new therapeutic agents into clinical trials, we built the first preclinical cohort of patient-derived xenograft (PDX) models of DS-ALL, comprehensively characterized at the genetic and transcriptomic levels, and have proven its suitability for preclinical studies by assessing the efficacy of drug combination between the MEK inhibitor trametinib and conventional chemotherapy agents.

Results:

Whole-exome and RNA-sequencing experiments revealed a high incidence of somatic alterations leading to RAS/MAPK pathway activation in our cohort of DS-ALL, as well as in other pediatric B-ALL presenting somatic gain of the chromosome 21 (B-ALL+21). In murine and human B-cell precursors, activated KRASG12D functionally cooperates with trisomy 21 to deregulate transcriptional networks that promote increased proliferation and self renewal, as well as B-cell differentiation blockade. Moreover, we revealed that inhibition of RAS/MAPK pathway activation using the MEK1/2 inhibitor trametinib decreased leukemia burden in several PDX models of B-ALL+21, and enhanced survival of DS-ALL PDX in combination with conventional chemotherapy agents such as vincristine.

Conclusions:

Altogether, using novel and suitable PDX models, this study indicates that RAS/MAPK pathway inhibition represents a promising strategy to improve the outcome of Down syndrome children with B-cell precursor leukemia.
Oncogenic Genomic Alterations, Clinical Phenotypes, and Outcomes in Metastatic Castration-Sensitive Prostate Cancer
Authors: Stopsack Konrad H. , Nandakumar Subhiksha , Wibmer Andreas G. , Haywood Samuel , Weg Emily S. , Barnett Ethan S. , Kim Chloe J. , Carbone Emily A. , Vasselman Samantha E. , Nguyen Bastien , Hullings Melanie A. , Scher Howard I. , Morris Michael J. , Solit David B. , Schultz Nikolaus , Kantoff Philip W. , Abida Wassim
Published: March 2020

Purpose:

The genomic underpinning of clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer is unclear.

Experimental Design:

In patients with metastatic castration-sensitive prostate cancer at a tertiary referral center, clinical-grade targeted tumor sequencing was performed to quantify tumor DNA copy number alterations and alterations in predefined oncogenic signaling pathways. Disease volume was classified as high volume (≥4 bone metastases or visceral metastases) versus low volume.

Results:

Among 424 patients (88% white), 213 (50%) had high-volume disease and 211 (50%) had low-volume disease, 275 (65%) had de novo metastatic disease, and 149 (35%) had metastatic recurrence of nonmetastatic disease. Rates of castration resistance [adjusted hazard ratio, 1.84; 95% confidence interval (CI), 1.40–2.41] and death (adjusted hazard ratio, 3.71; 95% CI, 2.28–6.02) were higher in high-volume disease. Tumors from high-volume disease had more copy number alterations. The NOTCH, cell cycle, and epigenetic modifier pathways were the highest-ranking pathways enriched in high-volume disease. De novo metastatic disease differed from metastatic recurrences in the prevalence of CDK12 alterations but had similar prognosis. Rates of castration resistance differed 1.5-fold to 5-fold according to alterations in AR, SPOP (inverse), and TP53, and the cell cycle, WNT (inverse), and MYC pathways, adjusting for disease volume and other genomic pathways. Overall survival rates differed 2-fold to 4-fold according to AR, SPOP (inverse), WNT (inverse), and cell-cycle alterations. PI3K pathway alterations were not associated with prognosis once adjusted for other factors.

Conclusions:

This study identified genomic features associated with prognosis in metastatic castration-sensitive disease that may aid in molecular classification and treatment selection.
An Emerging Landscape for Canonical and Actionable Molecular Alterations in Primary and Metastatic Prostate Cancer
Authors: Dawson Nancy A. , Zibelman Matthew , Lindsay Timothy , Feldman Rebecca A. , Saul Michelle , Gatalica Zoran , Korn W. Michael , Heath Elisabeth I.
Published: March 2020

Patients with prostate cancer with tumors harboring defects in DNA-repair genes (DRD) generally do not respond well to AR-directed therapy. Furthermore, canonical pathways evolve during disease progression and may affect treatment with existing therapies. Due to the limited treatment options after failure of hormonal and taxane therapy, and the tumor heterogeneity induced by DRD, we sought to characterize the alterations in primary and metastatic prostate cancer. Tumors from 1,027 patients with advanced prostate cancer that underwent comprehensive genomic profiling for routine clinical care were reviewed to assess DRD mutation rates (27-gene panel) and co-occurring mutations in select canonical prostate cancer pathways. DRD alterations were identified in 20 genes and in 17% of patients (BRCA2 and ATM most common) occurring with slightly higher frequency in specimens from metastatic biopsy sites and men older than 50 years of age. Microsatellite instability-high (MSI-H) and tumor mutational burden-high occurred with 3% frequency in the overall cohort but were not enriched in metastatic disease. Biomarkers previously associated with antitumor immunity are found at high frequencies in MSI-H patients, including JAK1 (68%) and PTEN (32%). Lastly, mutations in TP53, AR, PTEN, APC, CTNNB1, and PIK3CA were all significantly enriched in metastatic samples. We identified clinically significant subgroups of patients demonstrating (1) defects in DNA-repair pathways, (2) intrinsic prostate cancer signaling pathways that may prevent antitumor immunity, and (3) distinct genomic differences between localized and metastatic prostate cancer. These results lend support that genomic profiling for advanced prostate cancer may identify actionable targets not routinely used in the current metastatic paradigm.