bluuebunny/crossref_metadata_2025 huggingface dataset:
Coexpression Network Analysis Identifies a Novel Nine‐RNA Signature to Improve Prognostic Prediction for Prostate Cancer Patients
Authors: Cai Jiarong , Chen Zheng , Chen Xuelian , Huang He , Lin Xia , Miao Bin
Published: September 2020

Background. Prostate cancer (PCa) is the most common malignancy and the leading cause of cancer death in men. Recent studies suggest the molecular signature was more effective than the clinical indicators for the prognostic prediction, but all of the known studies focused on a single RNA type. The present study was to develop a new prognostic signature by integrating long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) and evaluate its prognostic performance. Methods. The RNA expression data of PCa patients were downloaded from The Cancer Genome Atlas (TCGA) or Gene Expression Omnibus database (GSE17951, GSE7076, and GSE16560). The PCa‐driven modules were identified by constructing a weighted gene coexpression network, the corresponding genes of which were overlapped with differentially expressed RNAs (DERs) screened by the MetaDE package. The optimal prognostic signature was screened using the least absolute shrinkage and selection operator analysis. The prognostic performance and functions of the combined prognostic signature was then assessed. Results. Twelve PCa‐driven modules were identified using TCGA dataset and validated in the GSE17951 and GSE7076 datasets, and six of them were considered to be preserved. A total of 217 genes in these 6 modules were overlapped with 699 DERs, from which a nine‐gene prognostic signature was identified (including 3 lncRNAs and 6 mRNAs), and the risk score of each patient was calculated. The overall survival was significantly shortened in patients having the risk score higher than the cut‐off, which was demonstrated in TCGA (p = 5.063E − 03) dataset and validated in the GSE16560 (p = 3.268E − 02) dataset. The prediction accuracy of this risk score was higher than that of clinical indicators (the Gleason score and prostate‐specific antigen) or the single RNA type, with the area under the receiver operator characteristic curve of 0.945. Besides, some new therapeutic targets and mechanisms (MAGI2‐AS3‐SPARC/GJA1/CYSLTR1, DLG5‐AS1‐DEFB1, and RHPN1‐AS1‐CDC45/ORC) were also revealed. Conclusion. The risk score system established in this study may provide a novel reliable method to identify PCa patients at a high risk of death.
Double Burden of Malnutrition: Evidence from a Selected Nigerian Population
Authors: Alamu Emmanuel O. , Eyinla Toluwalope E. , Sanusi Rasaki A. , Maziya-Dixon Busie
Published: September 2020

Indices reflecting the double burden of malnutrition in sub-Saharan Africa are increasing. Evidence to support this claim in households of Africa’s most populous country—Nigeria—is scant. This study, therefore, presents results from a study of mother-child pairs sampled from Akwa Ibom State in the southern region of Nigeria. Anthropometric measures for 660 mother-child pairs were collected according to standard procedures. Indices were expressed as the standard deviation of units from the median for the reference group. Chi-square analysis was used to test significant differences in proportion, and p<0.05 was taken as significant. A total of 37.4% of the children were stunted out of which 19.8% were moderately stunted, and 17.6% were severely stunted. Prevalence of wasting was 13.1%, 6.2% were moderately wasted, and 6.9% were severely wasted. Mean maternal body mass index was (23.54 ± 4.60) kgm2. 9.0% were underweight mothers, 23.2% were overweight, and 9.3% were obese. The co-existence of undernutrition among children and overnutrition in women of child-bearing age is prevalent in this population. We recommend that more effort be placed on active nutrition surveillance to ascertain malnutrition prevalence and periodically reassess priority challenges.
Association between Chronic Urticaria and Helicobacter pylori Infection among Patients Attending a Tertiary Hospital in Tanzania
Authors: Dennis Magdalena F. , Mavura Daudi R. , Kini Luryritha , Philemon Rune , Masenga Elisante J.
Published: September 2020

Background. Chronic urticaria (CU) is a common skin disease; however, its etiology is rarely recognized. Infection due to Helicobacter pylori (H. pylori) has been shown in some studies to play a significant role in the pathogenesis of CU. Objective. This study was conducted to determine the association between CU and H. pylori infection among patients attending the Regional Dermatology Training Center, Northern Tanzania, from October 2018 to April 2019. Methodology. A matched case-control study that included 55 cases and 55 controls matched by age and sex was conducted. Data were collected through direct interviews, and the results of laboratory investigations were recorded in the extraction sheet. An enzyme-linked immunosorbent assay test was used to detect H. pylori antigen in the stool samples. Conditional logistic regression was used to measure the association between CU and H. pylori. Results. The total number of participants in this study was 110 patients (55 cases and 55 controls), whereby the median age was 31 (IQR 27–45) among controls versus 34 (IQR: 22–46) years among the cases. Both cases and controls had the same number of females and males. There was no significant association between CU and baseline characteristics of the participants. There was an association between CU and H. pylori infection, such that subjects with CU had a higher number of positive H. pylori test (15/55 = 27%) versus controls (6/55 = 10.1%) (p=0.0225). The adjusted odds of CU among patients who were positive for H. pylori were sixfolds higher (OR = 6.9; CI: 1.3–36.2; p=0.021) than those of patients who were negative for H. pylori.Conclusion. There was a strong and significant association between CU and H. pylori infection. We recommend investigating for H. pylori in all cases of CU and conducting further trials on H. pylori eradication.
On Some Problems of Strongly Ozaki Close-to-Convex Functions
Authors: Maleki Zahra , Shams Saeid , Ebadian Ali , Analouei Adegani Ebrahim
Published: September 2020

The purpose of the current paper is to investigate some geometric properties of the class FOν,γ, called strongly Ozaki close-to-convex functions, such as strongly starlikeness and close-to-convexity. Further, we find sharp bounds on Fekete-Szegö functionals and logarithmic coefficients for functions belonging to the class FOν,γ, which incorporates some known outcomes as the specific cases.
Epidemiology of Soft Tissue Sarcoma and Bone Sarcoma inItaly: Analysis of Data from 15 Population-Based Cancer Registries
Authors: Fabiano Sabrina , Contiero Paolo , Barigelletti Giulio , D’Agostino Anna , Tittarelli Andrea , Mangone Lucia , Bisceglia Isabella , Bongiorno Salvatore , De Lorenzis Lucia Elena , Mazzoleni Guido , Castaing Marine , Intrieri Teresa , Puppo Antonella , Carrozzi Giuliano , Sini Giovanna Maria , Fontanili llaria , Boschetti Lorenza , Tumino Rosario , Bella Francesca , Fanetti AnnaClara , Castelli Maurizio , Ardizzone Antonio , Vittadello Fabio , Sciacca Salvatore , Manneschi Gianfranco , Casella Claudia , Cirilli Claudia , Pala Filomena , Michiara Maria , Migliazza Simona , Ferrari Francesca , Spata Eugenia , Dinaro Ylenia , Cometti Ivan , Maghini Anna , Tagliabue Giovanna
Published: September 2020

Sarcomas are a heterogeneous group of rare cancers of mesenchymal origin. In this study, we provide updated, world age-standardised incidence rate (ASR) and European age-standardised incidence rate for malignant soft tissue sarcoma (ICD-O-3 topographic code C47–C49) and bone sarcoma (C40, C41) in Italy, by area (north, centre, and south) and by cancer registry. We also assess morphology in relation to site and area and assess metastases at diagnosis. We analysed 1,112 cases, with incidence 2009–2012, provided by 15 cancer registries (CRs) affiliated to the Association of Italian Cancer Registries (AIRTUM). Overall, ASR was 1.7/100,000/year for soft tissue sarcoma and 0.7 for bone sarcoma. Central Italy had the highest (2.4) ASR and south Italy had the lowest (1.6) ASR for soft tissue sarcoma. Central Italy had the highest (1.1) ASR and north Italy had the lowest (0.7) ASR for bone sarcoma. By CR, ASRs ranged from 1.1 to 2.6 for soft tissue sarcoma and from 0 to 1.4 for bone sarcoma. The most frequent soft tissue sarcomas were sarcoma not otherwise specified (NOS) (29.4%) and liposarcoma (22.2%); the most common bone sarcoma was chondrosarcoma (37.6%). Soft tissue sarcomas occurred most frequently (35.6%) in lower limb connective tissue; bone sarcomas arose mainly (68.8%) in long bones. The frequencies of morphologies arising at different sites varied considerably by Italian area; for example, 20% of hemangiosarcomas occurred in the head and neck in south Italy with 17% at this site in the centre and 6% in the north. For soft tissue sarcoma, the highest ASRs of 2.6 and 2.4 contrast with the lowest ASRs 1.1 and 1.3, suggesting high-risk hot spots that deserve further investigation. The marked variations in morphology distribution with site and geography suggest geographic variation in risk factors that may also repay further investigation particularly since sarcoma etiology is poorly understood.
Theoretical Investigation of Design Methodology, Optimized Molecular Geometries, and Electronic Properties of Benzene-Based Single Molecular Switch with Metal Nanoelectrodes
Authors: Tharammal Rafsa Koyadeen , Kumar Anand , Rajak A. R. Abdul , Gaidhane Vilas Haridas
Published: September 2020

Understanding the electronic properties at the single molecular level is the first step in designing functional electronic devices using individual molecules. This paper proposes a simulation methodology for the design of a single molecular switch. A single molecular switch has two stable states that possess different chemical configurations. The methodology is implemented for 1,4-benzene dithiol (BDT) molecule with gold, silver, platinum, and palladium metal nanoelectrodes. The electronic properties of the designed metal-molecule-metal sandwich structure have been investigated using density functional theory (DFT) and Hartree-Fock (HF) method. It has been perceived that the DFT and HF values are slightly different as HF calculation does not include an electron-electron interaction term. Computation of the switching ratio gives the insight that BDT with gold has a high switching ratio of 0.88 compared with other three metal nanoelectrodes. Further, calculations of quantum chemical descriptors, analysis of the density of states (DOS) spectrum, and frontier molecular orbitals for both the stable states (i.e., ON and OFF state geometries) have been carried out. Exploring the band gap, ionization potential, and potential energy of two stable states reveals that the ON state molecule shows slightly higher conductivity and better stability than the OFF state molecule for every chosen electrode in this work. The proposed methodology for the single molecular switch design suggests an eclectic promise for the application of these new materials in novel single molecular nanodevices.
Learning and Development of Diagnostic Reasoning in Occupational Therapy Undergraduate Students
Authors: Moruno-Miralles Pedro , Reyes-Torres Adriana , Talavera-Valverde Miguel-Ángel , Souto-Gómez Ana-Isabel , Márquez-Álvarez Luis-Javier
Published: September 2020

Background/Aim. One way to facilitate occupational therapy undergraduate students transferring their academic skills of data gathering and analysis to professional settings is to ensure they can competently use diagnostic reasoning. Nevertheless, there are several obvious gaps in empirical evidence related to the learning and development of this style of reasoning in occupational therapy undergraduates. The most important are related to promoting higher-order thinking and the use of information to solve problems in the context of professional practice. This study analyses undergraduates’ diagnostic reasoning and its changes during their education. Materials and Methods. This multicentre study was conducted with a descriptive observational design. The study took place at the University of Coruña (Spain), University of Castilla-La Mancha (Spain), and University of el Valle (Colombia). The sample was n=247. For data collection, a clinical case was specifically designed. IBM SPSS Statistics (v19) and EPIDAT 3.1 were used for the data analysis. Results. Participants identified and categorized occupational performance problems. However, they had difficulties when identifying and categorizing the occupational performance components (specifically, the symptoms and signs of the disease presented in the study case). They presented limitations to analyse and synthesize the information collected to develop an explanation of the occupational problems and their causes. Conclusions. Undergraduate students’ ability to analyse and synthesize information during data collection is poorly organized, so it makes the problem formulation difficult. This study contributes to the knowledge of undergraduates’ diagnostic reasoning features, specifically the undergraduate students’ capacities and limits to process information during the occupational assessment.
Wave Fronts in a Causality-Violating Gödel-Type Metric
Authors: Kling Thomas P. , Ahmed Faizuddin , Lalumiere Megan
Published: September 2020

The light rays and wave fronts in a linear class of the Gödel-type metric are examined to reveal the causality-violating features of the space-time. Noncausal features demonstrated by the development of unusual wave front singularities are shown to be related to the nonmonotonic advance of time along the light rays, as measured by a system of observers at rest with respect to one another with synchronized clocks.
Neural Network-Based Study about Correlation Model between TCM Constitution and Physical Examination Indexes Based on 950 Physical Examinees
Authors: Luo Yue , Lin Bing , Zhao Shuting , He Li , Wen Chuanbiao
Published: September 2020

Purpose. To establish the correlation model between Traditional Chinese Medicine (TCM) constitution and physical examination indexes by backpropagation neural network (BPNN) technology. A new method for the identification of TCM constitution in clinics is proposed, which is trying to solve the problem like shortage of TCM doctor, complicated process, low efficiency, and unfavorable application in the current TCM constitution identification methods. Methods. The corresponding effective samples were formed by sorting out and classifying the original data which were collected from physical examination indexes and TCM constitution types of 950 physical examinees, who were examined at the affiliated hospital of Chengdu University of TCM. The BPNN algorithm was implemented using the C# programming language and Google’s AI library. Then, the training group and the test (validation) group of the effective samples were, respectively, input into the algorithm, to complete the construction and validation of the target model. Results. For all the correlation models built in this paper, the accuracy of the training group and the test group of entire physical examination indexes-constitutional-type network model, respectively, was 88% and 53%, and the error was 0.001. For the other network models, the accuracy of the learning group and the test group and error, respectively, was as follows: liver function (31%, 42%, and 11.7), renal function (41%, 38%, and 6.7), blood routine (56%, 42%, and 2.4), and urine routine (60%, 40%, and 2.6). Conclusions. The more the physical examination indexes are used in training, the more accurate the network model is established to predict TCM constitution. The sample data used in this paper showed that there was a relatively strong correlation between TCM constitution and physical examination indexes. Construction of the correlation model between physical examination indexes and TCM constitution is a kind of study for the integration of Chinese and Western medicine, which provides a new approach for the identification of TCM constitution, and it may be expected to avoid the existing problem of TCM constitution identification at present.
A Robust Indoor Mobile Localization Algorithm for Wireless Sensor Network in Mixed LOS/NLOS Environments
Authors: Yong Kang Ou , Long Cheng
Published: September 2020

Wireless sensor network (WSN) is a self-organizing network which is composed of a large number of cheap microsensor nodes deployed in the monitoring area and formed by wireless communication. Since it has the characteristics of rapid deployment and strong resistance to destruction, the WSN positioning technology has a wide application prospect. In WSN positioning, the nonline of sight (NLOS) is a very common phenomenon affecting accuracy. In this paper, we propose a NLOS correction method algorithm base on the time of arrival (TOA) to solve the NLOS problem. We firstly propose a tendency amendment algorithm in order to correct the NLOS error in geometry. Secondly, this paper propose a particle selection strategy to select the standard deviation of the particle swarm as the basis of evolution and combine the genetic evolution algorithm, the particle filter algorithm, and the unscented Kalman filter (UKF) algorithm. At the same time, we apply orthogon theory to the UKF to make it have the ability to deal with the target trajectory mutation. Finally we use maximum likelihood localization (ML) to determine the position of the mobile node (MN). The simulation and experimental results show that the proposed algorithm can perform better than the extend Kalman filter (EKF), Kalman filter (KF), and robust interactive multiple model (RIMM).
The Robustness and Sustainability of Port Logistics Systems for Emergency Supplies from Overseas
Authors: Chen Yanyu , Zheng Wenzhe , Li Wenbo , Huang Yimiao
Published: September 2020

When the epidemic comes, in addition to eliminating people’s panic, quickly enacting corresponding laws and implementing corresponding policies, and isolating infected people, providing emergency supplies are of course essential. The purpose of this article is to study the robustness and sustainability of the port logistics system for outbreak emergency supplies from overseas. This paper analyzes the sustainable development capability of the port logistics system for outbreak emergency supplies from overseas and formulates response strategies and robust collaborative optimization methods. The optimized and robust system is obtained through formula derivation and analysis, which realizes the coordinated optimization of emergency logistics infrastructure positioning and emergency rescue vehicle path positioning and minimizes the economic loss caused by the outbreak. Research data show that the shortest path can be planned between each material supply location. The research results show that the proportion of demand fluctuations during the outbreak is 6.5%, the time window needs to be controlled between 0 and 600, and the robustness and sustainability of the port logistics system have saved the time of the entire process by about 45%, greatly optimizing the delivery route and delivery time. The robustness of the logistics system can be widely used in emergency events.
Model and Hybrid Algorithm of Collaborative Distribution System with Multiple Drones and a Truck
Authors: Lin Min , Lyu Jun-Yan , Gao Jia-Jing , Li Ling-Yu
Published: September 2020

This paper studies a coordinated system for multidrone single-truck distribution, where a truck delivers goods to a group of customers along a closed ground path with the help of a number of drones. For each delivery, the truck departs from the distribution centre with drones and all goods needed and returns back to the centre after fulfilling the delivery tasks. That is, the truck assigns these delivery tasks to several of its drones, each of which is responsible for sending goods to a different subgroup of customers in the empty air space. This study provides a new mixed-integer programming model of the routing problem with this distribution system based on urban road network. Meanwhile, a hybrid genetic algorithm and a hybrid particle swarm algorithm are designed. Experimental results show that the performance of the hybrid algorithms is better than that of the corresponding basic algorithms.
Applications of Artificial Intelligence and Big Data Analytics in m-Health: A Healthcare System Perspective
Authors: khan Z. Faizal , Alotaibi Sultan Refa
Published: September 2020

Mobile health (m-health) is the term of monitoring the health using mobile phones and patient monitoring devices etc. It has been often deemed as the substantial breakthrough in technology in this modern era. Recently, artificial intelligence (AI) and big data analytics have been applied within the m-health for providing an effective healthcare system. Various types of data such as electronic health records (EHRs), medical images, and complicated text which are diversified, poorly interpreted, and extensively unorganized have been used in the modern medical research. This is an important reason for the cause of various unorganized and unstructured datasets due to emergence of mobile applications along with the healthcare systems. In this paper, a systematic review is carried out on application of AI and the big data analytics to improve the m-health system. Various AI-based algorithms and frameworks of big data with respect to the source of data, techniques used, and the area of application are also discussed. This paper explores the applications of AI and big data analytics for providing insights to the users and enabling them to plan, using the resources especially for the specific challenges in m-health, and proposes a model based on the AI and big data analytics for m-health. Findings of this paper will guide the development of techniques using the combination of AI and the big data as source for handling m-health data more effectively.
Targeting the Nrf2/ARE Signalling Pathway to Mitigate Isoproterenol-Induced Cardiac Hypertrophy: Plausible Role of Hesperetin in Redox Homeostasis
Authors: Velusamy Prema , Mohan Thangarajeswari , Ravi Divya Bhavani , Kishore Kumar S. N. , Srinivasan Ashokkumar , Chakrapani Lakshmi Narasimhan , Singh Abhilasha , Varadharaj Saradhadevi , Kalaiselvi Periandavan
Published: September 2020

Cardiac hypertrophy is the underlying cause of heart failure and is characterized by excessive oxidative stress leading to collagen deposition. Therefore, understanding the signalling mechanisms involved in excessive extracellular matrix deposition is necessary to prevent cardiac remodelling and heart failure. In this study, we hypothesized that hesperetin, a flavanone that elicits the activation of Nrf2 signalling and thereby suppresses oxidative stress, mediated pathological cardiac hypertrophy progression. A cardiac hypertrophy model was established with subcutaneous injection of isoproterenol in male Wistar rats. Oxidative stress markers, antioxidant defense status, and its upstream signalling molecules were evaluated to discover the impacts of hesperetin in ameliorating cardiac hypertrophy. Our results implicate that hesperetin pretreatment resulted in the mitigation of oxidative stress by upregulating antioxidant capacity of the heart. This curative effect might be owing to the activation of the master regulator of antioxidant defense system, known as Nrf2. Further, analysis of Nrf2 revealed that hesperetin enhances its nuclear translocation as well as the expression of its downstream targets (GCLC, NQO1, and HO-1) to boost the antioxidative status of the cells. To support this notion, in vitro studies were carried out in isoproterenol-treated H9c2 cells. Immunocytochemical analysis showed augmented nuclear localization of Nrf2 implicating the action of hesperetin at the molecular level to maintain the cellular redox homeostasis. Thus, it is conceivable that hesperetin could be a potential therapeutic candidate that enhances Nrf2 signalling and thereby ameliorates pathological cardiac remodelling.
Hypoxia Induces Resistance to EGFR Inhibitors in Lung Cancer Cells via Upregulation of FGFR1 and the MAPK Pathway
Authors: Lu Yuhong , Liu Yanfeng , Oeck Sebastian , Zhang Gary J. , Schramm Alexander , Glazer Peter M.
Published: September 2020

Development of resistance remains the key obstacle to the clinical efficacy of EGFR tyrosine kinase inhibitors (TKI). Hypoxia is a key microenvironmental stress in solid tumors associated with acquired resistance to conventional therapy. Consistent with our previous studies, we show here that long-term, moderate hypoxia promotes resistance to the EGFR TKI osimertinib (AZD9291) in the non–small cell lung cancer (NSCLC) cell line H1975, which harbors two EGFR mutations including T790M. Hypoxia-induced resistance was associated with development of epithelial–mesenchymal transition (EMT) coordinated by increased expression of ZEB-1, an EMT activator. Hypoxia induced increased fibroblast growth factor receptor 1 (FGFR1) expression in NSCLC cell lines H1975, HCC827, and YLR086, and knockdown of FGFR1 attenuated hypoxia-induced EGFR TKI resistance in each line. Upregulated expression of FGFR1 by hypoxia was mediated through the MAPK pathway and attenuated induction of the proapoptotic factor BIM. Consistent with this, inhibition of FGFR1 function by the selective small-molecule inhibitor BGJ398 enhanced EGFR TKI sensitivity and promoted upregulation of BIM levels. Furthermore, inhibition of MEK activity by trametinib showed similar effects. In tumor xenografts in mice, treatment with either BGJ398 or trametinib enhanced response to AZD9291 and improved survival. These results suggest that hypoxia is a driving force for acquired resistance to EGFR TKIs through increased expression of FGFR1. The combination of EGFR TKI and FGFR1 or MEK inhibitors may offer an attractive therapeutic strategy for NSCLC.

Significance:

Hypoxia-induced resistance to EGFR TKI is driven by overexpression of FGFR1 to sustain ERK signaling, where a subsequent combination of EGFR TKI with FGFR1 inhibitors or MEK inhibitors reverses this resistance.
Phosphorylation Control of p53 DNA-Binding Cooperativity Balances Tumorigenesis and Aging
Authors: Timofeev Oleg , Koch Lukas , Niederau Constantin , Tscherne Alina , Schneikert Jean , Klimovich Maria , Elmshäuser Sabrina , Zeitlinger Marie , Mernberger Marco , Nist Andrea , Osterburg Christian , Dötsch Volker , Hrabé de Angelis Martin , Stiewe Thorsten
Published: September 2020

Posttranslational modifications are essential for regulating the transcription factor p53, which binds DNA in a highly cooperative manner to control expression of a plethora of tumor-suppressive programs. Here we show at the biochemical, cellular, and organismal level that the cooperative nature of DNA binding is reduced by phosphorylation of highly conserved serine residues (human S183/S185, mouse S180) in the DNA-binding domain. To explore the role of this inhibitory phosphorylation in vivo, new phosphorylation-deficient p53-S180A knock-in mice were generated. Chromatin immunoprecipitation sequencing and RNA sequencing studies of S180A knock-in cells demonstrated enhanced DNA binding and increased target gene expression. In vivo, this translated into a tissue-specific vulnerability of the bone marrow that caused depletion of hematopoietic stem cells and impaired proper regeneration of hematopoiesis after DNA damage. Median lifespan was significantly reduced by 20% from 709 days in wild type to only 568 days in S180A littermates. Importantly, lifespan was reduced by a loss of general fitness and increased susceptibility to age-related diseases, not by increased cancer incidence as often seen in other p53-mutant mouse models. For example, S180A knock-in mice showed markedly reduced spontaneous tumorigenesis and increased resistance to Myc-driven lymphoma and Eml4–Alk-driven lung cancer. Preventing phosphorylation of S183/S185 in human cells boosted p53 activity and allowed tumor cells to be killed more efficiently. Together, our data identify p53 DNA-binding domain phosphorylation as a druggable mechanism that balances tumorigenesis and aging.

Significance:

These findings demonstrate that p53 tumor suppressor activity is reduced by DNA-binding domain phosphorylation to prevent aging and identify this phosphorylation as a potential target for cancer therapy.

See related commentary by Horikawa, p. 5164
Copy-Number Alteration Burden Differentially Impacts Immune Profiles and Molecular Features of Hepatocellular Carcinoma
Authors: Bassaganyas Laia , Pinyol Roser , Esteban-Fabró Roger , Torrens Laura , Torrecilla Sara , Willoughby Catherine E. , Franch-Expósito Sebastià , Vila-Casadesús Maria , Salaverria Itziar , Montal Robert , Mazzaferro Vincenzo , Camps Jordi , Sia Daniela , Llovet Josep M.
Published: September 2020

Purpose:

Chromosomal instability is a hallmark of cancer that results in broad and focal copy-number alterations (CNAs), two events associated with distinct molecular, immunologic, and clinical features. In hepatocellular carcinoma (HCC), the role of CNAs has not been thoroughly assessed. Thus, we dissected the impact of CNA burdens on HCC molecular and immune features.

Experimental Design:

We analyzed SNP array data from 452 paired tumor/adjacent resected HCCs and 25 dysplastic nodules. For each sample, broad and focal CNA burdens were quantified using CNApp, and the resulting broad scores (BS) and focal scores (FS) were correlated with transcriptomic, mutational, and methylation profiles, tumor immune composition, and clinicopathologic data.

Results:

HCCs with low broad CNA burdens (defined as BS ≤ 4; 17%) presented high inflammation, active infiltrate signaling, high cytolytic activity, and enrichment of the “HCC immune class” and gene signatures related to antigen presentation. Conversely, tumors with chromosomal instability (high broad CNA loads, BS ≥ 11; 40%), displayed immune-excluded traits and were linked to proliferation, TP53 dysfunction, and DNA repair. Candidate determinants of the low cytotoxicity and immune exclusion features of high-BS tumors included alterations in antigen-presenting machinery (i.e., HLA), widespread hypomethylation, and decreased rates of observed/expected neoantigenic mutations. High FSs were independent of tumor immune features, but were related to proliferation, TP53 dysfunction, and progenitor cell traits.

Conclusions:

HCCs with high chromosomal instability exhibit features of immune exclusion, whereas tumors displaying low burdens of broad CNAs present an immune active profile. These CNA scores can be tested to predict response to immunotherapies.
Long-term Outcomes of Oral Vinorelbine in Advanced, Progressive Desmoid Fibromatosis and Influence of CTNNB1 Mutational Status
Authors: Mir Olivier , Honoré Charles , Chamseddine Ali N. , Dômont Julien , Dumont Sarah N. , Cavalcanti Andrea , Faron Matthieu , Rimareix Françoise , Haddag-Miliani Leila , Le Péchoux Cécile , Levy Antonin , Court Charles , Briand Sylvain , Fadel Elie , Mercier Olaf , Bayle Arnaud , Brunet Anaïs , Ngo Carine , Rouleau Etienne , Adam Julien , Le Cesne Axel
Published: September 2020

Purpose:

Desmoid-type fibromatosis (DF) are locally aggressive neoplasms, with a need for effective systemic treatment in case of progression to avoid the short- and long-term complications of local treatments.

Experimental Design:

We retrospectively analyzed the outcomes of adult patients with DF treated with oral vinorelbine (90 mg once weekly) at Gustave Roussy Cancer Institute (Villejuif, Paris, France). Only patients with documented progressive disease according to RECIST v1.1 for more than 3 months (±2 weeks) before treatment initiation were included.

Results:

From 2009 to 2019, 90 out of 438 patients with DF were eligible for this analysis. Vinorelbine was given alone in 56 patients (62%), or concomitantly with endocrine therapy in 34 patients, for a median duration of 6.7 months. A partial response was observed in 29% and stable disease in another 57%. With a median follow-up of 52.4 months, the median time to treatment failure (TTF) was not reached. Progression-free rates at 6 and 12 months were 88.7% and 77.5%, respectively. Concomitant endocrine therapy was associated with longer TTF in women [HR, 2.16; 95% confidence interval (CI), 1.06–4.37; P = 0.03). Among 64 patients with documented CTNNB1 mutational status, p.S45F or p.S45P mutations were associated with longer TTF compared with p.T41A or wild-type tumors (HR, 2.78; 95% CI, 1.23–6.27; P = 0.04). Toxicity profile was favorable, without grade 3–4 toxicity, except for one grade 3 neutropenia.

Conclusions:

Oral vinorelbine is an effective, affordable, and well-tolerated regimen in patients with advanced, progressive DF. Prolonged activity was observed in patients with tumors harboring CTNNB1 p.S45F or p.S45P mutations.
Abstract A006: Multi-modal estimation of causal influences of environmental agents on colorectal cancer in an understudied population
Authors: Galadima Hadiza , Adunlin Georges , Blando James
Published: September 2020

Background: While there is a well-established causal relationship between several individual factors and contextual socioeconomic status with colorectal cancer, there is still a lack of strong evidence that the prevalence of environmental agents is independently associated with colorectal cancer in various geographical areas. Population-based studies assessing the causal relationship between environmental agents and colorectal cancer are limited by the scarcity of comprehensive data. Most previous studies have relied on the recall of self-reported exposures. Objective: In this study, we provide new and important insights by integrating publicly available ‘big data’ resources with hospital data to identify causal influences on colorectal cancer in an understudied rural population in Virginia. Methods: Data linkage was achieved by geocoding patients zip codes at diagnosis and spatially assigning contextual and environmental data to the hospital cancer records. Machine learning imputation methods were used to fill in the missing values that resulted from the linkage. A “Big Data” science approach was used to develop a multi-scale modeling of individual and contextual data with national and local exposomes from environmental exposures sources. The methodology is based on training a Bayesian causal network to better understand the causal inference from individual and contextual level data, as well as environmental exposures data on the outcomes of colorectal cancer. The primary source of data for this project is the Sentara Cancer Registry (SCR). The SCR collects data on cancer cases from eight Sentara hospitals. The information collected by SCR includes patient characteristics and clinical outcomes. The secondary source of data come from the U.S. Census Bureau (Census 2010). This data source is used to determine zip-code level socioeconomic status of each colorectal cancer case. Environmental data such as water quality, Superfund site locations, toxic release sites, and heavy metals were obtained from the Virginia Department of Environmental Quality. Environmental data was supplemented with Toxics Release Inventory (TRI) database, considered to be the most comprehensive data source on industrial toxic emissions in the US. Conclusion: This study contributed to the scientific innovation of leveraging mixed-methods data collection by building a comprehensive database for cancer research in an understudied population.

Citation Format: Hadiza Galadima, Georges Adunlin, James Blando. Multi-modal estimation of causal influences of environmental agents on colorectal cancer in an understudied population [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A006.
Abstract C081: Introduction of a randomized controlled trial on areca nut/betel quid cessation: The Betel Nut Intervention Trial (BENIT)
Authors: Paulino Yvette C , Wilkens Lynne R , Sotto Patrick P , Franke Adrian A , Kawamoto Crissy T , Chennaux Jade SN , Mendez Ana J , Tenorio Lynette F , Badowski Grazyna , Pokhrel Pallav , Herzog Thaddeus A
Published: September 2020

Areca nut, the seed of the Areca catechu L. palm evaluated to be a Group 1 carcinogen, is still chewed by 10-20% of the world population. It is often chewed with Piper betle L. leaf and other ingredients such as slaked lime and tobacco, to form a betel quid. Globally, areca nut/betel quid is the fourth most commonly used psychoactive substance after tobacco, alcohol, and caffeine. Unlike tobacco cessation, systematic research on areca nut/betel quid cessation is rare. The negative health effects associated with areca nut/betel quid consumption warrant the need for an evidence-based cessation program. Consequently, the Betel Nut Intervention Trial (BENIT) was initiated in August 2016. The BENIT is a randomized, controlled, superiority trial designed to test the efficacy of an intensive areca nut/betel quid cessation program, and to quantify the efficacy through bio-verification. The trial is ongoing in Guam and Saipan in the Mariana Islands. Adult areca nut/betel quid chewers, 18 years and older who include tobacco in their betel quid, are being enrolled into the trial. Those enrolled are assessed for the primary outcome (chewing status) and the secondary outcome (saliva bio-verification) at baseline, at 22 days, and at 6 months. The areca nut/betel quid chewers randomized into the control arm receive an educational booklet only. The areca nut/betel quid chewers randomized into the intervention arm receive the educational booklet and a 22-day cessation program modeled after a smoking cessation program and led by trained facilitators. To date, 224 chewers have been enrolled into the BENIT. The current quit percentages are 18% in the experimental group and 8% in the control group, though these results may change as the trial progresses. The BENIT is designed to provide evidence of the efficacy of a cessation program to help areca nut/betel quid with tobacco chewers to quit chewing. Although the current intervention trial focuses on Guam and Saipan, it has the potential for greater regional and global importance. TRIAL REGISTRATION: Clinical Trial # NCT02942745.

Citation Format: Yvette C Paulino, Lynne R Wilkens, Patrick P Sotto, Adrian A Franke, Crissy T Kawamoto, Jade SN Chennaux, Ana J Mendez, Lynette F Tenorio, Grazyna Badowski, Pallav Pokhrel, Thaddeus A Herzog. Introduction of a randomized controlled trial on areca nut/betel quid cessation: The Betel Nut Intervention Trial (BENIT) [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C081.
Abstract B20: STK3/4-mediated phosphorylation of LC3B regulates directional intracellular transport of autophagic vesicles
Authors: Nieto-Torres Jose L. , Shanahan Sean-Luc , Chassefeyre Romain , Landeras-Bueno Sara , Lee Lee R. , Zaretski Sviatlana , Encalada Sandra , Hansen Malene
Published: September 2020

Autophagy is a fundamental catabolic process that allows the degradation of cytosolic components to supply the cell with nutrients in response to starvation, among other functions. Recently, our lab discovered that the Hippo pathway members, STK3 and STK4, phosphorylate the autophagy protein LC3B, a key component of autophagic vesicles that participates in specifying their content and their intracellular transport. Depletion of STK3/4 kinases or generation of an LC3B phospho-null mutant (T50A) causes a block of the autophagy process evidenced by an accumulation of autophagic vesicles throughout the cell. However, these studies did not clarify which step of the autophagy process was impaired. To address this question, we employed proteomics to analyze LC3B-binding partners affected by LC3B phosphorylation, and identified multiple proteins implicated in intracellular vesicle transport. Accordingly, we hypothesized that LC3B phosphorylation may affect transport of autophagic vesicles. We tested this hypothesis directly by live-cell imaging in multiple cell types and found that the absence of LC3B phosphorylation was accompanied by an aberrantly high transport of LC3B-positive autophagic vesicles toward the periphery of the cell, and a low transport of the vesicles toward the perinuclear area, where the autophagy process is normally completed. Moreover, starvation-induced perinuclear positioning of autophagic vesicles was prevented in the absence of LC3B phosphorylation. Collectively, these findings indicate that STK3/4-mediated phosphorylation of LC3B regulates the directional transport of autophagic vesicles and this may promote autophagy completion. Notably, this regulatory axis may be triggered when the nutrient availability is low and autophagy is induced. Understanding how input signals regulate STK3/4, and in turn control autophagy, may prove important to develop therapies against diseases such as cancer.

Citation Format: Jose L. Nieto-Torres, Sean-Luc Shanahan, Romain Chassefeyre, Sara Landeras-Bueno, Lee R. Lee, Sviatlana Zaretski, Sandra Encalada, Malene Hansen. STK3/4-mediated phosphorylation of LC3B regulates directional intracellular transport of autophagic vesicles [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B20.
Abstract B22: The origin of the Hippo pathway
Authors: Chen Yuxuan , Wang Wenqi
Published: September 2020

First discovered in Drosophila, the Hippo signaling pathway plays a crucial role in organ size control from fly to human. Interestingly, there are many paralog genes in the mammalian Hippo pathway, which were developed through duplication from fly to human. Tracked in evolution, the Hippo pathway originated from unicellular organism. In this study, we primarily focused on how the Hippo pathway evolved to establish its conserved function in tissue/organ homeostasis, which may shed light on its dysregulation in cancer development from a new perspective.

Citation Format: Yuxuan Chen, Wenqi Wang. The origin of the Hippo pathway [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B22.
Abstract B28: Cep55 regulates YAP/TAZ expression and localization during cell cycle progression
Authors: Lin Yen-Ming , Wu Chu-Han , Ouyang Pin
Published: September 2020

Cell cycle regulation plays a pivotal role in controlling cell proliferation and survival. Aberrant expression of cell cycle-associated genes generally afflicts cells with tumor-prone characteristics and promotes chromosome instability. Cep55 (Centrosome Protein 55kDa; also known as c10orf3 and FLJ10540) was identified as an important regulator of cytokinesis involved in cell growth and proliferation. It is associated with central spindle and midbody during cell cycle progression and cooperates with members of endosomal sorting complex required for transport (ESCRT) machinery to constrict intracellular bridge for cell abscission. In addition to cytokinesis, Cep55 is involved in regulating the PI3K/AKT pathway as well as promoting tumorigenesis. In search of novel Cep55 interplayers that may abrogate their expression upon loss of cep55 expression, we set out experiments with cultured cells exogenously expressed Flag-tagged wild type (wt) Cep 55 versus shRNAs against Cep55 and subjected immunoprecipitates to LC-MS/MS. The Hippo pathway components YAP and its paralogue TAZ were found to be diminished apparently in Cep55 null sample compared with wt counterpart. To confirm if Cep55 knockdown affects expression of Hippo pathway, we transfected 293T cells with Cep55 shRNAs and detected expression of Hippo core components with Western blots. Hippo components such as Merlin, Mst, and Lats are without effect in expression level, with the exception of YAP/TAZ whose expression was decreased extensively. Immunofluorescent microscopy reveals YAP/TAZ colocalized with Cep55 at central spindle and midbody during mitosis; however, depletion of Cep55 results in diffusion of YAP/TAZ at midbody, suggesting cep55 is required for midbody localization of YAP/TAZ. In contrast, knockdown of YAP/TAZ did not significantly alter Cep55 localization to the midbody ring but displays phenotype, such as multinuclear cells and micronuclei, similar to that observed in Cep55-depleted cells. Together our data provide evidence that Cep55-YAP/TAZ interaction plays an important role in cytokinesis and may support a biologic interplay between the Hippo-YAP and PI3K-AKT-mTOR pathways.

Note: This abstract was not presented at the conference.

Citation Format: Yen-Ming Lin, Chu-Han Wu, Pin Ouyang. Cep55 regulates YAP/TAZ expression and localization during cell cycle progression [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B28.
Abstract B35: FLT3-TAZ signaling induces drug resistance in leukemia
Authors: Shin Ji Eun , Park Hyun Woo
Published: September 2020

YAP/TAZ, the transcriptional coactivators of TEAD and major transducers of the Hippo pathway, has been studied only in solid tumors. Interestingly, YAP/TAZ are consistently upregulated in adherent tumor cell lines, but hardly expressed in hematologic malignancies including lymphoma and leukemia. However, we identified significant upregulation of TAZ in specific leukemia mouse models driven by FLT3 (AML) or Bcr-Abl (blast crisis-CML; bc-CML). We observed strong correlation between TAZ and FLT3 induction in bc-CML patients as well as leukemia cells, which led us to investigate the role of FLT3-TAZ signaling in imatinib-induced drug resistance in CML. FLT3 expression induced imatinib resistance (IR) in K562 CML cells. In K562-IR cells, transcription of TAZ mRNA is significantly increased, but not YAP. Our data show that target gene induction by TAZ-TEAD interaction promotes imatinib resistance. Importantly, inhibition of FLT3-TAZ signaling resensitized K562-IR cell to imatinib treatment and caused cell death. Therefore, we propose that combination therapy targeting both FLT3-TAZ and Bcr/abl signaling could trigger synthetic lethality in bc-CML cells.

Citation Format: Ji Eun Shin, Hyun Woo Park. FLT3-TAZ signaling induces drug resistance in leukemia [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B35.