bluuebunny/crossref_metadata_2025 huggingface dataset:
Vision-based Tracking by a Quadrotor on ROS
Authors: Wei Yusheng , Lin Zongli
Published: May 2019

Vision-based tracking of a moving target is achieved in three steps: image processing, coordinate recovery and trajectory following. A testing platform containing two spawned quadrotors as the target and the tracker is developed on ROS, from which sequences of image frames are generated by an on-board camera while the target moves along a given path on the ground. A simple image processing algorithm is developed that achieves visual tracking and is robust to image blur and other background noises. Coordinate recovery recovers the original target trajectory as the desired path of the tracker in the real-world. A target following control law moves the tracker along the desired trajectory point-by-point. An analysis of the robustness of the tracking approach with respect to image blur and measurement noise of the tracker position is carried out to assure the applicability of the approach to real-world scenarios.
Hypoxia-inducible factor hydroxylase inhibition enhances the protective effects of cyclosporine in colitis
Authors: Halligan Doug N. , Khan Mohammed N. , Brown Eric , Rowan Catherine R. , Coulter Ivan S. , Doherty Glen A. , Tambuwala Murtaza M. , Taylor Cormac T.
Published: May 2019

Inflammatory bowel disease (IBD) is characterized by epithelial barrier dysfunction with resultant inflammation as the mucosal immune system becomes exposed to luminal antigens. The hydroxylase inhibitor dimethyloxalylglycine (DMOG) reduces symptoms in experimental colitis through the upregulation of genes promoting barrier function and inhibition of epithelial cell apoptosis. The immunosuppressive drug cyclosporine reduces inflammation associated with IBD via suppression of immune cell activation. Given the distinct barrier protective effect of DMOG and the anti-inflammatory properties of cyclosporine, we hypothesized that combining these drugs may provide an enhanced protective effect by targeting both barrier dysfunction and inflammation simultaneously. We used the dextran sulfate sodium model of colitis in C57BL/6 mice to determine the combinatorial efficacy of cyclosporine and DMOG. While cyclosporine and DMOG ameliorated disease progression, in combination they had an additive protective effect that surpassed the level of protection afforded by either drug alone. The ability of DMOG to augment the anti-inflammatory effects of cyclosporine was largely due to preservation of barrier function and at least in part due to zonula occludens-1 regulation. We propose that combining the barrier protective effects of a hydroxylase inhibitor with the anti-inflammatory effects of cyclosporine provides added therapeutic benefit in colitis.

NEW & NOTEWORTHY Inflammatory bowel disease is the result of decreased intestinal epithelial barrier function leading to exposure of the mucosal immune system to luminal antigens causing inflammation, which in turn further decreases epithelial barrier function. We demonstrate for the first time that strengthening the epithelial barrier with a hydroxylase inhibitor in combination with the administration of the immunosuppressive cyclosporine provides additive therapeutic advantage in a murine model of colitis
Fatigue-independent alterations in muscle activation and effort perception during forearm exercise: role of local oxygen delivery
Authors: Drouin P. J. , Kohoko Z. I. N. , Mew O. K. , Lynn M. J. T. , Fenuta A. M. , Tschakovsky M. E.
Published: May 2019

The oxygen-conforming response (OCR) of skeletal muscle refers to a downregulation of muscle force for a given muscle activation when oxygen delivery (O2D) is reduced, which is rapidly reversed when O2D is restored. We tested the hypothesis that the OCR exists in voluntary human exercise and results in compensatory changes in muscle activation to maintain force output, thereby altering perception of effort. In eight men and eight women, electromyography (EMG), oxyhemoglobin (O2Hb) and deoxyhemoglobin (HHb), forearm blood flow (FBF), and task effort awareness (TEA) were measured. Participants completed two nonfatiguing rhythmic handgrip tests consisting of 5-min steady state (SS) followed by two bouts of 2-min brachial artery compression to reduce FBF by ~50% of SS (C1 and C2), separated by 2 min of no compression (NC1) and ending with 2 min of no compression (NC2). When FBF was compromised during C1, EMG/Force (1.58 ± 0.39) increased compared with SS (1.31 ± 0.33, P = 0.001). However, EMG/Force was not restored upon FBF restoration at NC1 (1.48 ± 0.38, P = 0.479), consistent with C1 evoking skeletal muscle fatigue. When FBF was compromised during C2, EMG/Force increased (1.73 ± 0.50) compared with NC1 (1.48 ± 0.38, P = 0.013). EMG/Force returned to NC1 levels during NC2 (1.50 ± 0.39, P = 0.016), consistent with an OCR in C2. TEA (SS 2.2 ± 2.3, C1 3.9 ± 2.5, NC1 3.4 ± 2.7, C2 4.6 ± 2.7, NC2 3.9 ± 2.8) mirrored changes in EMG. It is noteworthy that during the second compromise and then restoration of muscle oxygenation EMG and TEA were rapidly restored to precompromise levels. We interpreted these findings to support the existence of an OCR and its ability to rapidly modify perception of effort during voluntary exercise.

NEW & NOTEWORTHY In healthy individuals, when force output is maintained during rhythmic handgrip exercise, muscle activation and perception of effort rapidly increase with compromised muscle oxygen delivery (O2D) and then return to precompromised levels when muscle O2D is restored. These findings suggest that an oxygen-conforming response (OCR) exists and is able to modify perception of effort during voluntary exercise. Therefore, similar to fatigue, an OCR may have implications for exercise tolerance.
Passive force enhancement in striated muscle
Authors: Herzog Walter
Published: May 2019

Passive force enhancement is defined as the increase in passive, steady-state, isometric force of an actively stretched muscle compared with the same muscle stretched passively to that same length. Passive force enhancement is long lasting, increases with increasing muscle length and increasing stretch magnitudes, contributes to the residual force enhancement in skeletal and cardiac muscle, and is typically only observed at muscle lengths at which passive forces occur naturally. Passive force enhancement is typically equal to or smaller than the total residual force enhancement, it persists when a muscle is deactivated and reactivated, but can be abolished instantaneously when a muscle is shortened quickly from its stretched length. There is strong evidence that the passive force enhancement is caused by the filamentous sarcomeric protein titin, although the detailed molecular mechanisms underlying passive force enhancement remain unknown. Here I propose a tentative mechanism based on experimental evidence that associates passive force enhancement with the shortening of titin’s free spring length in the I-band region of sarcomeres. I suggest that this shortening is accomplished by titin binding to actin and that the trigger for titin-actin interactions is associated with the formation of strongly bound cross bridges between actin and myosin that exposes actin attachment sites for titin through movement of the regulatory proteins troponin and tropomyosin.
Analysis of the Cavity Formation Mechanism of Wedge Cut Blasting in Hard Rock
Authors: Wang Zhongkang , Gu Xiaowei , Zhang Wenlong , Xie Qiankun , Xu Xiaochuan , Wang Qing
Published: May 2019

The basic process of cut blasting is to break rock, throw fragments, and form a cavity. Based on the characteristics of cut blasting and the combined effect of stress waves and detonation gas, the evolution process of wedge cut blasting is divided into two stages, and a theoretical model is proposed to investigate the cavity formation mechanism by theoretical analysis and field tests. In phase one, rock breaking is caused by stress waves. By considering the dynamic strength of the rock, a computational model is built for the rock failure zone derived from the coupled cylindrical charge explosion. In phase two, the driving force of the detonation gas overcomes the total resistance of the surrounding rock mass, accelerates fragments, and then throws fragments to form a cavity. The criterion of cavity formation is established on the basis of the quasi‐static loading of the detonation gas. The theoretical model provides an overall interpretation of the cavity formation mechanism, in which stress waves break rock and detonation gas throws fragments. A specific case indicates that the range of the failure zone is approximately 18 times the borehole radius in granite and that the hole‐bottom spacing of the wedge cut can be designed as 50 cm; in addition, detonation gas is sufficient to overcome the total resistance, accelerate rock fragments, throw fragments, and form a cavity. Field tests present favourable blasting results, with a high utilization rate of boreholes and uniform fragment sizes. Therefore, the model could provide theoretical support and technical guidance for wedge cut blasting in hard rock.
In-Hospital Diagnosis of Tricuspid Papillary Muscle Rupture in an Asymptomatic Patient after Blunt Chest Trauma
Authors: Nabzdyk C. S. , Tabrizi M. B.
Published: May 2019

Tricuspid papillary muscle rupture after blunt chest trauma is an infrequent injury that often remains undiagnosed until patients become symptomatic months to years after the trauma occurred. It is imperative to diagnose patients early with this condition in order to optimize chances of successful recovery and avoidance of sequelae of long-term tricuspid regurgitation such as atrial fibrillation and right heart failure. Here we describe a case of a 58-year-old man involved in a motocross accident suffering amongst other injuries extensive bilateral rib fractures, hemopneumothoraces, and asymptomatic anterior tricuspid papillary muscle rupture. In addition, a review of the literature and an approach for the workup of trauma patients at risk for blunt cardiac injury are provided.
Successful Use of Octreotide Therapy for Refractory Levofloxacin-Induced Hypoglycemia: A Case Report and Literature Review
Authors: Watson Matthew R. , Ward Ceressa T. , Prabhakar Amit , Fiza Babar , Moll Vanessa
Published: May 2019

Fluoroquinolones are commonly prescribed antimicrobials that have been implicated in alterations of glucose metabolism. We report a case of refractory fluoroquinolone-induced hypoglycemia in a patient with type-2 diabetes mellitus on glipizide that was successfully treated with octreotide. A patient was admitted with hypoglycemia after having been initiated on levofloxacin therapy. Despite treating the hypoglycemia supportively with multiple boluses of 25 g of dextrose, a continuous dextrose infusion, and glucagon, the patient experienced repeated episodes of rebound hypoglycemia. The persistent hypoglycemia was eventually reversed with the administration of subcutaneous octreotide. Clinicians should be cognizant of this adverse effect of fluoroquinolones, as well as predisposing risk factors, and consider octreotide as an adjunctive therapy for refractory hypoglycemia cases.
Bloom Syndrome Protein Activates AKT and PRAS40 in Prostate Cancer Cells
Authors: Chen Kun , Xu Houqiang , Zhao Jiafu
Published: May 2019

Purpose. Prostate cancer (PC) is a common malignant tumor and a leading cause of cancer-related death in men worldwide. In order to design new therapeutic interventions for PC, an understanding of the molecular events underlying PC tumorigenesis is required. Bloom syndrome protein (BLM) is a RecQ-like helicase, which helps maintain genetic stability. BLM dysfunction has been implicated in tumor development, most recently during PC tumorigenesis. However, the molecular basis for BLM-induced PC progression remains poorly characterized. In this study, we investigated whether BLM modulates the phosphorylation of an array of prooncogenic signaling pathways to promote PC progression. Methods. We analyzed differentially expressed proteins (DEPs) using iTRAQ technology. Site-directed knockout of BLM in PC-3 prostate cancer cells was performed using CRISPR/Cas9-mediated homologous recombination gene editing to confirm the effects of BLM on DEPs. PathScan® Antibody Array Kits were used to analyze the phosphorylation of nodal proteins in PC tissue. Immunohistochemistry and automated western blot (WES) analyses were used to validate these findings. Results. We found that silencing BLM in PC-3 cells significantly reduced their proliferative capacity. In addition, BLM downregulation significantly reduced levels of phosphorylated protein kinase B (AKT (Ser473)) and proline-rich AKT substrate of 40 kDa (PRAS40 (Thr246)), and this was accompanied by enhanced ROS (reactive oxygen species) levels. In addition, we found that AKT and PRAS40 inhibition reduced BLM, increased ROS levels, and induced PC cell apoptosis. Conclusions. We demonstrated that BLM activates AKT and PRAS40 to promote PC cell proliferation and survival. We further propose that ROS act in concert with BLM to facilitate PC oncogenesis, potentially via further enhancing AKT signaling and downregulating PTEN expression. Importantly, inhibiting the BLM-AKT-PRAS40 axis induced PC cell apoptosis. Thus, we highlight new avenues for novel anti-PC treatments.
Influences of Different Air-Inhibition Coatings on Monomer Release, Microhardness, and Color Stability of Two Composite Materials
Authors: Marigo Luca , Nocca Giuseppina , Fiorenzano Giulia , Callà Cinzia , Castagnola Raffaella , Cordaro Massimo , Paolone Gaetano , Sauro Salvatore
Published: May 2019

The aim of this study was to evaluate the effect of light-curing protocols on two modern resin composites using different air-inhibition coating strategies. This was accomplished by assessing the amount of monomer elution, surface microhardness, and composite discoloration in different storage conditions. A total of 120 specimens were prepared using Filtek Supreme XTE (3M ESPE, Seefeld, Germany) and CeramX Universal (Dentsply DeTrey, Konstanz, Germany). Specimens were light-cured in air as per manufacturer’s instructions or in the absence of oxygen. This latter condition was achieved using three different approaches: (i) transparent polyester strip; (ii) glycerin; (iii) argon gas. Specimens were assessed for release of monomers, Vickers hardness, and discoloration after storage in different solutions. The results were analyzed with ANOVA one-way test followed by Student-Newman-Keuls test. Moreover, multiple comparisons of means were performed using the Student t-test (p<0.05). The amount of monomers released from the tested specimens was very low in all conditions. The presence of oxygen induced some decrease in microhardness. The highest discoloration values, for both materials, were obtained after ageing in red wine. In case finish and polish procedures are awkward to achieve in posteriors composite restoration, light-curing in the absence of oxygen should be considered, especially when performing composite restoration in esthetic areas.
Bioimpedance Resistance Indices and Cell Membrane Capacitance Used to Assess Disease Status and Cell Membrane Integrity in Children with Nephrotic Syndrome
Authors: Brantlov Steven , Jødal Lars , Frydensbjerg Andersen René , Lange Aksel , Rittig Søren , Ward Leigh C.
Published: May 2019

Background. Accumulation of extracellular water (ECW) is a major clinical manifestation of nephrotic syndrome (NS) in children. Bioimpedance spectroscopy (BIS) is a simple, noninvasive technique that reflects body water volumes. BIS can further measure cell membrane capacitance (CM), which may be altered in NS. The aims of the study were to explore how BIS measurements could reflect disease status in NS, while avoiding prediction equations which are often only validated in adult populations. Methods. The study involved 8 children (2-10 years) with active NS (ANS group), 5 of which were also studied at NS remission (NSR group), as well as 38 healthy children of similar age (HC group). BIS measurements determined resistances RINF, RE, and RI (reflecting total body water, extracellular water, and intracellular water) and CM. Also resistance indices based on height (H) were considered, RI = H2/R. Results. It was found that RE and RINF were significantly lower in the ANS group than in both NSR and HC groups (p < 0.001). Corresponding resistance indices were significantly higher in the ANS group than in the NSR (p < 0.01) and the HC (p < 0.05) groups, in accordance with elevated water volumes in NS patients. Indices of intracellular water were not significantly different between groups. CM was significantly lower in the ANS group than in NSR and HC groups (p < 0.05). Conclusion. BIS could distinguish children with active NS from well-treated and healthy children. Studies with more children are warranted.
Surrogate Modelling for Wing Planform Multidisciplinary Optimisation Using Model-Based Engineering
Authors: Pagliuca G. , Kipouros T. , Savill M. A.
Published: May 2019

Optimisation is aimed at enhancing aircraft design by identifying the most promising wing planforms at the early stage while discarding the least performing ones. Multiple disciplines must be taken into account when assessing new wing planforms, and a model-based framework is proposed as a way to include mass estimation and longitudinal stability alongside aerodynamics. Optimisation is performed with a particle swarm optimiser, statistical methods are exploited for mass estimation, and the vortex lattice method (VLM) with empirical corrections for transonic flow provides aerodynamic performance. Three surrogates of the aerodynamic model are investigated. The first one is based on radial basis function (RBF) interpolation, and it relies on a precomputed database to evaluate the performance of new wing planforms. The second one is based on an artificial neural network, and it needs precomputed data for a training step. The third one is a hybrid model which switches automatically between VLM and RBF, and it does not need any precomputation. Its switching criterion is defined in an objective way to avoid any arbitrariness. The investigation is reported for a test case based on the common research model (CRM). Reference results are produced with the aerodynamic model based on VLM for two- and three-objective optimisations. Results from all surrogate models for the same benchmark optimisation are compared so that their benefits and limitations are both highlighted. A discussion on specific parameters, such as number of samples for example, is given for each surrogate. Overall, a model-based implementation with a hybrid model is proposed as a compromise between versatility and an arbitrary level of accuracy for wing early-stage design.
New Authentication Scheme to Secure against the Phishing Attack in the Mobile Cloud Computing
Authors: E Munivel , A Kannammal
Published: May 2019

A phishing attack is one of the severe threats to the smartphone users. As per the recent lookout report, mobile phishing attack is increasing 85% year to year and going to become a significant threat to the smartphone users. This social engineering attack attempts to get the user’s password by disguising as trusted service provider. Most of the smartphone users are using the Internet services outside of the traditional firewall. Cloud-based documents are one of the primary targets of this phishing attack in mobile cloud computing. Also, most smartphone users are using the cloud storage in their device. To secure against this password attack in a mobile cloud environment, we propose a new authentication scheme to provide novel security to the mobile cloud services. This scheme will verify the user and service provider without transmitting the password using the Zero-knowledge proof based authentication protocol. Moreover, the proposed scheme will provide mutual authentication between the communication entities. The effectiveness of proposed scheme would be verified using protocol verification tool called Scyther.
Positive Selection of Squalene Synthase in Cucurbitaceae Plants
Authors: Qian Jieying , Liu Yong , Ma Chengtong , Chao Naixia , Chen Qicong , Zhang Yangmei , Luo Yu , Cai Danzhao , Wu Yaosheng
Published: May 2019

Triterpenoid saponins are secondary metabolites synthesized through isoprenoid pathways in plants. Cucurbitaceae represent an important plant family in which many species contain cucurbitacins as secondary metabolites synthesized through isoprenoid and triterpenoid pathways. Squalene synthase (SQS) is required for the biosynthesis of isoprenoids, but the forces driving the evolution ofSQSremain undetermined. In this study, 10SQScDNA sequences cloned from 10 species of Cucurbitaceae and 49 sequences ofSQSdownloaded from GenBank and UniProt databases were analyzed in a phylogenetic framework to identify the evolutionary forces for functional divergence. Through phylogenetic construction and positive selection analysis, we found thatSQSsequences are under positive selection. The sites of positive selection map to functional and transmembrane domains. 180L, 189S, 194S, 196S, 265I, 289P, 389P, 390T, 407S, 408A, 410R, and 414N were identified as sites of positive selection that are important during terpenoid synthesis and map to transmembrane domains. 196S and 407S are phosphorylated and influenceSQScatalysis and triterpenoid accumulation. These results reveal that positive selection is an important evolutionary force forSQSin plants. This provides new information into the molecular evolution ofSQSwithin the Cucurbitaceae family.
Balloon-Occluded Trans-Arterial Chemoembolization Technique with Alternate Infusion of Cisplatin and Gelatin Slurry for Small Hepatocellular Carcinoma Nodules Adjacent to the Glisson Sheath
Authors: Irie Toshiyuki , Takahashi Nobuyuki , Kamoshida Toshiro
Published: May 2019

Objective. It is difficult to control small hepatocellular carcinoma (HCC) nodules adjacent to the Glisson sheath (GS) by trans-arterial chemoembolization (TACE) probably due to multiple small tumor feeders directly branching from the trunk artery. The purpose of this study was to conduct a retrospective evaluation of a new TACE technique called the repeated alternate infusion of cisplatin solution and gelatin slurry distal to balloon occlusion (RAIB-TACE), for the treatment of small HCC nodules adjacent to GS. Materials and Methods. Small nodules less than 4 cm attached to proximal portion of the subsegmental to lobar level portal branch were retrospectively selected. Between January 2011 and April 2014, 29 nodules in 29 patients were treated by super-selective lipiodol TACE/balloon-occluded TACE (B-TACE) (Lip-TACE group). Since April 2014, treatment protocols for small nodules adjacent to GS were changed, and 14 nodules in 12 patients were treated by RAIB-TACE (RAIB-TACE group). In RAIB-TACE group, alternate infusion of cisplatin solution and sparse gelatin slurry (mixture of 80 mg of gelatin fragments and 20 mL of contrast medium) were repeated until arterial flow was ceased. In Lip-TACE group, lipiodol was used as drug carrier and dense gelatin slurry (mixture of 80 mg of gelatin fragments and 2 mL of contrast medium) as embolization material. Dynamic CT/MRI was obtained 1-3 months after TACE, and response of each nodule was evaluated basing on modified RECIST criteria. Results. In RAIB-TACE group, all 14 nodules (100%) were diagnosed as CR or PR. In Lip-TACE group, 18 of 29 (62.1%) were diagnosed as CR or PR. There was a statistically significant difference in objective response ratio between the groups (p=0.008, Fisher’s test). Biloma (n=1) and benign stricture of the right hepatic duct (n=1) were seen in RAIB-TACE group. The biloma shrunk without treatment and the patient had no symptom, but the patient with biliary stricture repeated cholangitis and was treated by administration of antibiotics. Conclusion. The study results show that RAIB-TACE is more effective than lipiodol TACE/B-TACE for small hepatocellular carcinoma adjacent to GS. We speculate that one of the reasons to explain why Lip-TACE is inferior to RAIB-TACE is that viscous lipiodol or dense gelatin slurry could not flow into small tumor feeders effectively.
Occurrence and Hydrochemical Characteristics of Saline and Salty Springs in the Sichuan Basin of China
Authors: Guo Juan , Zhou Xun , Zhang Yuqi , Ta Mingming , Wang Yuan
Published: May 2019

Water samples from saline and salty springs (geothermal wells, n=64) with TDS of 2-83 g/L and temperature of 19-95°C were collected in the Sichuan Basin to explore the factors controlling the occurrence of the springs and the differences in hydrochemistry. The saline and salty springs mostly emerge at the margin of the basin where fault zones or anticlines occur, which are clearly controlled by the regional tectonic trend. The springs are mainly of SO4-Na type in the western basin, SO4-Ca·Na and HCO3-Na type in the southwestern basin, Cl-Na and Cl·SO4-Na type in the northeastern basin, and SO4-Ca type in the eastern basin. Good correlation between Na and Cl, Ca and SO4, and Mg and SO4 suggests that the major ions of springs in the Sichuan Basin are from incongruent dissolution of halite, gypsum, dolomite, and magnesium sulfate minerals present in the outcropping Cretaceous and Triassic and Permian strata (sandstone, gypsum, or anhydrite layers or lens) in the western basin. The presence of marine carbonate (limestone and dolomite) interbedded with evaporites (gypsum and halite) in the eastern basin explains the good correlations between SO4 and Ca and between Na and Cl. The groundwater is continuously heated by geothermal heat flow. A conceptual model for the formation of the saline and salty springs is proposed that hypothesizes meteoric water infiltrates in the core of anticlines that occur in the carbonate rocks with fractures or in the fault zones. The water flows into the limbs of the anticlines or deep aquifers along fault planes. During its subsurface transport, incongruent dissolution of carbonates and evaporites (including anhydrite and halite) in the Lower and Middle Triassic strata occurs and the groundwater is heated. The discharge areas are often in the low-lying areas along the limbs of anticlines where carbonate rocks crop out, in the low-lying areas of local river valleys that cut noncarbonate rocks, or in the Yangtze Valley and its tributaries where groundwater flows upward through the Upper Triassic clastic rocks.
Somatostatinoma Presented as Double-Duct Sign
Authors: Zakaria Ali , Hammad Nour , Vakhariya Cynthia , Raphael Michael
Published: May 2019

Somatostatinoma is a rare neuroendocrine tumor with an incidence rate of 1 in 40 million people. It presents mostly as asymptomatic tumor diagnosed incidentally on imaging or surgery when evaluating or treating possible causes of abdominal pain. It also can present with vague symptoms, or as a clinical triad of glucose intolerance, steatorrhea, and achlorhydria. The majority of somatostatinomas are present in the pancreatic head, followed by the duodenum, the pancreatic tail, and rarely the ampulla of Vater. The prognosis is poor as more than 77% of cases present as advanced disease with local invasion or distant metastasis. Surgical resection is the main treatment for early stage disease. Other treatment options include somatostatin analogue, molecular targeted therapy, and cytotoxic chemotherapy. The scarcity of somatostatinoma cases led to the lack of fully formulated treatment options. Herein, we present a 43-year old male patient who was referred by his primary care physician to our gastroenterology clinic due to elevated liver function test and double-duct sign on CT scan. We performed an ERCP, which revealed 2 cm ampullary lesion with upstream obstruction. Biopsies were taken and histopathology was unrevealing. He underwent a laparoscopic pancreaticoduodenectomy with histopathology revealed stage IIb somatostatinoma. Treating physicians should hold a high index of suspicion and maintain a broad differential diagnosis of elevated liver enzymes.
Abstract B03: Sequential liquid biopsies reveal dynamic alterations of EGFR driver mutations and indicate EGFR amplification as a new mechanism of resistance to osimertinib in NSCLC
Authors: Knebel Franciele , Bettoni Fabiana , Shimada Andrea , Cruz Manoel , Alessi João Victor , Negrão Marcelo , Reis Luiz Fernando , Katz Artur , Camargo Anamaria
Published: May 2019

Osimertinib is an EGFR-T790M-specific TKI, which has demonstrated impressive response rates in NSCLC, after failure to first-line anti-EGFR TKIs. However, acquired resistance to osimertinib is also observed and the molecular mechanisms of resistance are not yet fully understood. Monitoring and managing NSCLC patients who progressed on osimertinib is, therefore, emerging as an important clinical challenge. Serial liquid biopsies were used to monitor a patient with EGFR-exon19del positive NSCLC, who received erlotinib and progressed through the acquisition of the EGFR-T790M mutation. Erlotinib was discontinued and she received osimertinib. Blood samples were collected at erlotinib progression and during osimertinib treatment for the detection of the activating (EGFR-exon19del) and resistance mutations (EGFR-T790M, EGFR-C797S, BRAF-V600E, METamp and ERBB2amp) in the plasma DNA using digital droplet PCR. Plasma levels of the activating EGFR-exon19del accurately paralleled the clinical and radiologic progression of the disease and allowed early detection of AR to osimertinib. Resistance to osimertinib coincided with the emergence of a small tumor cell subpopulation carrying the known EGFR-C797S resistance mutation and an additional subpopulation carrying amplified copies of EGFR-exon19del. Given the existence of multiple AR mechanism, quantification of the original EGFR activation mutation, instead of the resistance mutations, can be efficiently used to monitor response to osimertinib, allowing early detection of AR. Absolute quantification of both activation and resistance mutations can provide important information on tumor clonal evolution upon progression to osimertinib. Selective amplification of the EGFR-exon19del allele may represent a novel resistance mechanism to osimertinib.

Citation Format: Franciele Knebel, Fabiana Bettoni, Andrea Shimada, Manoel Cruz, João Victor Alessi, Marcelo Negrão, Luiz Fernando Reis, Artur Katz, Anamaria Camargo. Sequential liquid biopsies reveal dynamic alterations of EGFR driver mutations and indicate EGFR amplification as a new mechanism of resistance to osimertinib in NSCLC [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B03.
Abstract A64: Colon cancer lymph node evaluation among Military Health System beneficiaries: An analysis by race/ethnicity
Authors: Gill Abegail A. , Enewold Lindsey , Zahm Shelia H. , Shriver Craig D. , Stojadinovic Alexander , McGlynn Katherine A. , Zhu Kangmin
Published: May 2019

Introduction: The number of lymph nodes examined during colon cancer surgery falls below nationally recommended guidelines in the general population, with blacks and Hispanics less likely to have adequate nodal evaluation in comparison to whites. The Department of Defense's (DoD's) Military Health System (MHS) provides equal access to medical care for its beneficiaries, regardless of racial/ethnic background. Thus, the MHS provided an excellent opportunity to investigate whether racial/ethnic differences exist in an equal access medical care system.

Methods: Linked data from the DoD cancer registry and administrative claims databases were used and included 2,155 colon cancer cases. Multivariate logistic regression assessed the association between race/ethnicity and the number of lymph nodes examined (<12 and ≥ 12) overall and for stratified analyses.

Results: No overall racial/ethnic difference in the number of lymph nodes examined was identified. Further stratified analyses yielded similar, except potential racial/ethnic differences were found among persons with poorly differentiated tumors, where non-Hispanic blacks (NHBs) tended to be less likely to have ≥12 lymph nodes dissected (OR = 0.31, 95% CI, 0.13-0.74) compared to non-Hispanic whites.

Conclusion: Racial/ethnic disparities in the number of lymph nodes evaluated among patients with colon cancer were not apparent in an equal-access healthcare system. However, among poorly differentiated tumors, there might be racial/ethnic differences in nodal yield, suggesting the possible effects of factors other than access to healthcare.

Citation Format: Abegail A. Gill, Lindsey Enewold, Shelia H. Zahm, Craig D. Shriver, Alexander Stojadinovic, Katherine A. McGlynn, Kangmin Zhu. Colon cancer lymph node evaluation among Military Health System beneficiaries: An analysis by race/ethnicity. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A64.
Abstract B03: Dietary patterns during high school and risk of colorectal adenoma in a cohort of middle-aged women
Authors: Nimptsch Katherina , Malik Vasanti S. , Fung Teresa , Pischon Tobias , Hu Frank B. , Willett Walter C. , Fuchs Charles S. , Ogino Shuji , Chan Andrew T. , Giovannucci Edward L. , Wu Kana
Published: May 2019

Background: Adolescent diet may be etiologically relevant for later risk of colorectal adenoma (CRA), a precursor of colorectal cancer.

Objective: To examine associations between adolescent dietary patterns (derived using factor analysis) and risk of CRA in middle adulthood.

Design: We analyzed data from 17,221 women participating in the Nurses' Health Study II, who had completed a validated high school (HS) food frequency questionnaire in 1998 when they were 34-51 years old, and had subsequently undergone at least one lower bowel endoscopy.

Results: Between 1998 and 2007, 1,299 women were diagnosed with at least one CRA. In multivariable models adjusted for adult dietary patterns, a higher “prudent” pattern during HS, characterized by high consumption of vegetables, fruit, and fish was associated with a statistically significantly lower risk of rectal (odds ratio (OR) highest versus lowest quintile, 0.45, 95% CI 0.27-0.75, p-trend=0.005), but not colon adenomas. A higher “Western” pattern during HS, characterized by high consumption of desserts and sweets, snack foods, and red and processed meat, was significantly associated with rectal (OR 1.78, 95% CI 1.12-2.85, p-trend=0.005) and advanced (OR 1.58, 95% CI 1.07-2.33, p-trend=0.08), but not associated with colon or non-advanced adenomas.

Conclusions: This study suggests that overall eating patterns during high school may influence later risk of rectal and advanced adenoma, independent of adult diet. Our results support the hypothesis that diet during early life may influence colorectal carcinogenesis.

Citation Format: Katherina Nimptsch, Vasanti S. Malik, Teresa Fung, Tobias Pischon, Frank B. Hu, Walter C. Willett, Charles S. Fuchs, Shuji Ogino, Andrew T. Chan, Edward L. Giovannucci, Kana Wu. Dietary patterns during high school and risk of colorectal adenoma in a cohort of middle-aged women. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B03.
Abstract B26: Epigenetic effects of resveratrol on mammary carcinoma
Authors: Qin Wenyi , Zhang Ke , Clarke Kaitlin , Weiland Timothy , Sauter Edward R.
Published: May 2019

Background: We previously reported that resveratrol decreased DNA methyltransferase (DNMT) 1 and 3b expression in vitro and demethylates tumor suppressor RASSF-1a in women at increased breast cancer risk. Herein we document the effects of resveratrol on DNMT and miRNA expression in normal and malignant mammary tissue in a rodent model of estrogen dependent mammary carcinoma.

Methods: 89 female rats received slow release estradiol plus: low dose (lo) resveratrol, high dose (hi) resveratrol, 5-aza-2-deoxycytidine (Aza), a known inhibitor of DNMTs, or control (no additional treatment). After 21 weeks of treatment, animals were sacrificed and mammary glands harvested. Matched tumor and normal tissues were available from 36 rats.

Results: DMNT3b (but not DNMT1) differed in tumor vs. normal tissue after lo (p=.04) and hi p=.007) resveratrol. With hi resveratrol, DNMT3b decreased in tumor but increased normal tissue. Hi resveratrol increased miR21, -129, -204 and -489 from 2.5 to >5 fold in tumor and decreased the same miRs in normal tissue 10-50% compared to control. There was an inverse association between DNMT3b and miR129, 204, and 489 in normal and/or tumor tissue.

Conclusion: Treatment with resveratrol differentially influences malignant vs. normal tissue DNMT3b and miRNA expression. This mechanism of action of resveratrol to influence mammary carcinogenesis warrants further investigation.

Citation Format: Wenyi Qin, Ke Zhang, Kaitlin Clarke, Timothy Weiland, Edward R. Sauter. Epigenetic effects of resveratrol on mammary carcinoma. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B26.
Abstract B37: Urinary melatonin levels and risk of breast cancer in the Nurses' Health Study II
Authors: Brown Susan Boyer , Hankinson Susan E. , Schernhammer Eva S.
Published: May 2019

Shift work has been hypothesized to increase breast cancer risk as two recent meta-analyses suggest a 21- 51% increased risk of breast cancer in women reporting night shift work. Melatonin, a hormone produced by the pineal gland that follows a circadian rhythm with highest levels observed at night, is frequently referenced as the biological mechanism through which shift work may increase breast cancer risk. While decreased urinary melatonin levels are associated with an increased risk of breast cancer in postmenopausal women, only three studies have evaluated the association between melatonin levels and breast cancer in premenopausal women with inconsistent findings. Therefore, we investigated this relationship in predominantly premenopausal women by conducting a nested case-control study in the prospective Nurses' Health Study II cohort. From 1996 to 1999, first morning urine was collected from 29,613 cancer-free participants who were followed through June 2007. Incident breast cancer was confirmed through review of medical records and pathology reports, and potential confounders were reported on biennial questionnaires and a questionnaire administered at urine collection. Concentrations of 6-sulfatoxymelatonin (aMT6s), the major metabolite of melatonin, were available for 603 cases and 798 controls matched for age, menopausal status, ethnicity, fasting status, luteal day of menstrual cycle, and month, year, day, and time of urine collection. We used multivariable conditional logistic regression models to estimate the risk of breast cancer by quartile of urinary aMT6s concentrations, with cutpoints based on values of control participants. We did not observe an association between melatonin levels and risk of breast cancer (odds ratio for highest versus lowest aMT6s quartile: 0.87, 95% confidence interval: 0.57-1.35). Our results were largely unchanged when we examined the relationship between urinary melatonin levels and invasive breast cancer (n=443 cases, odds ratio for highest versus lowest aMT6s quartile: 0.91, 95% CI: 0.54-1.56), in situ breast cancer (n=160 cases, odds ratio for highest versus lowest aMT6s quartile: 1.23, 95% CI: 0.45-3.35), and among women with ER+ tumors (n=398 cases, odds ratio for highest versus lowest aMT6s quartile: 0.77, 95% CI: 0.44-1.34). These prospective data do not provide strong support for a significant association between urinary melatonin levels and breast cancer risk in predominantly premenopausal women.

Citation Format: Susan Boyer Brown, Susan E. Hankinson, Eva S. Schernhammer. Urinary melatonin levels and risk of breast cancer in the Nurses' Health Study II. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B37.
Abstract B52: Time to smoke first cigarette after morning awakening differentiates lung cancer risk beyond standard smoking measures
Authors: Gu Fangyi , Wacholder Sholom , Kovalchik Stephanie , Panagiotou Orestis A. , Reyes-Guzman Carolyn , Freedman Neal D. , Matteis Sara De , Consonni Dario , Bertazzi Pier Alberto , Bergen Andrew W. , Landi Maria Teresa , Caporaso Neil E.
Published: May 2019

Background: Targeting smokers at higher lung cancer risk can improve efficiency and reduce false positive detection in lung cancer screening. We evaluated whether time to first cigarette after waking (TTFC), a single-item measure of nicotine dependency, could improve stratification of lung cancer risk beyond standard smoking metrics (intensity, duration and pack-years).

Methods: In 3249 ever-smokers (1437 cases, 1812 controls) from a population-based case-control study in Italy, we examined the association between TTFC and lung cancer using logistic regression, and estimated lung cancer incidence by levels of TTFC, and smoking intensity, duration, and pack-years using absolute risk regression.

Results: Compared to smokers with TTFC>60 minutes, the lung cancer odds ratios (and 95% confidence intervals) for TTFC 31-60 minutes, 6-30 minutes and ≥5 minutes (i.e. by increasing dependency) were 2.57 (2.03-3.26), 2.27 (1.79-2.88), and 3.50 (2.64-4.64), respectively (p-trend<0.0001). The average lung cancer incidence rates for smokers of 1–10, 11–20, 21–30 and >30 cig/day were consistently and substantially higher among smokers with TTFC≥60 vs. >60 minutes (64.0 vs. 11.7, 125.6 vs. 28.6, 130.1 vs. 40.5, and 260.5 vs. 108.7 per 100,000 person-years, respectively). The slopes of increase in lung cancer rates with smoking duration and pack-years were significantly greater among smokers with higher dependency (p-interaction<0.001).

Conclusion: Lung cancer risk increases with shorter TTFC; this simple nicotine dependency measure substantially improves lung cancer risk stratification beyond standard smoking measures. Assessing TTFC may improve lung cancer risk prediction and could be useful in lung cancer screening and smoking cessation programs.

Citation Format: Fangyi Gu, Sholom Wacholder, Stephanie Kovalchik, Orestis A. Panagiotou, Carolyn Reyes-Guzman, Neal D. Freedman, Sara De Matteis, Dario Consonni, Pier Alberto Bertazzi, Andrew W. Bergen, Maria Teresa Landi, Neil E. Caporaso. Time to smoke first cigarette after morning awakening differentiates lung cancer risk beyond standard smoking measures. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B52.
Abstract C04: Colorectal cancer screening and long-term lifestyle changes: A randomized controlled trial
Authors: Berstad Paula , Løberg Magnus , Larsen Inger Kristin , Kalager Mette , Holme Øyvind , Bretthauer Michael , Hoff Geir
Published: May 2019

Background: There is concern that cancer screening may result in apparent perception of health security and thereby reduce people's incentives for changes towards a favorable lifestyle. The present large-scale population based trial investigates long-term effects of colorectal cancer screening on lifestyle changes.

Methods: The present study evaluated changes in lifestyle after 11-years of follow-up among men and women (aged 50-55 years) randomized to a flexible sigmoidoscopy screening for colorectal cancer or to a no-screening control group in the Norwegian Colorectal Cancer Screening Prevention trial (NORCCAP). The lifestyle factors (including body weight, smoking status, physical exercise and consumption of selected dietary items) were assessed by a questionnaire at inclusion and after three and 11 years, respectively. We tested differences in lifestyle changes over the 11-year follow-up period in single factors and total score (0-4 points, higher score translates to more healthy lifestyle) between individuals randomized to screening and control groups, and between screening participants with positive and negative screening results by logistic regression and ANCOVA analysis, adjusting for covariates including baseline lifestyle differences.

Results: A total of 3,043 (44%) individuals randomized to screening and 2,819 (40%) randomized to the control group completed the questionnaires both at inclusion and after 11 years. We found a small, less favorable change in lifestyle in the screening group (total lifestyle score 1.43 at inclusion; 1.58 after 11 years) compared to the control group (total lifestyle score 1.49 at inclusion; 1.67 after 11 years); adjusted difference -0.05 (95% CI -0.09 to -0.01; p=0.029). 11-year change in total lifestyle score was less favorable in screening participants with positive compared to those with negative screening result (adjusted difference -0.16 (95% CI -0.25 to -0.08; p<0.001)).

Conclusions: Invitation to colorectal cancer screening has no large long-term adverse effect on lifestyle. However, the present study suggests that patients with positive screening results may be inclined to a less favorable lifestyle compared to those who tested negative at screening.

Citation Format: Paula Berstad, Magnus Løberg, Inger Kristin Larsen, Mette Kalager, Øyvind Holme, Michael Bretthauer, Geir Hoff. Colorectal cancer screening and long-term lifestyle changes: A randomized controlled trial. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr C04.