bluuebunny/crossref_metadata_2025 huggingface dataset:
Team Identity, Supporter Club Identity, and Fan Relationships: A Brand Community Network Analysis of a Soccer Supporters Club
Authors: Katz Matthew , Baker Thomas A. , Du Hui
Published: July 2019

In this brand community analysis, the authors utilized both the social identity approach and network theory to examine the multiple identities and patterns of interactions among members of an official soccer supporters club. Based on the Multiple In-Group Identity Framework and the brand community triad, the authors differentiated between team and supporter club identity to explore how each affects consumption behaviors. Furthermore, the authors explored the nature of fan relationships based on network principles of multiplexity and homophily as they relate to consumption and socializing ties among fan club members. They also explored the network structure of the brand community. Using both network theory and network methodologies, the authors examined how the multiple identities and many relationships within the brand community affect the consumption behaviors of fan club members. Theoretical and practical implications were considered as they relate to sport consumer behavior and sport marketing.
The Importance of Theorizing Social Change in Sport for Development: A Case Study of Magic Bus in London
Authors: Hills Stephen , Walker Matthew , Dixon Marlene
Published: July 2019

For sport for development practitioners, a theory of change document is a critical first step to map how program inputs yield the desired program outcomes. Yet, in our experience, this document is rarely created in practice. Accordingly, this study makes use of the case of an award-winning sport for development charity that expanded their operations from India to London to illustrate the pejorative implications resulting from failing to create a theory of change. A mixed-methods, quasi-experimental approach was utilized to understand program mechanisms, program processes, and how these influenced the aggregate participant experience. The quantitative analyses yielded no significant effects. Triangulating the qualitative data revealed that personal, social, health, and economic education was a competing product to the program. The limited effects are attributed to a failure to identify and attempt to assuage a local social problem. In addition, alignments with stakeholder expectations, program context, and legal requirements were also derailing. A discussion of the results, implications, and recommendations for establishing and implementing a theory of change are provided.
The Within-Subjects Effects of Practice on Performance of Drop Landing in Healthy, Young Adults
Authors: Hackney James , McFarland Jade , Smith David , Wallis Clinton
Published: July 2019

Most studies of high-speed lower body movements include practice repetitions for facilitating consistency between the trials. We investigated whether 20 repetitions of drop landing (from a 30.5-cm platform onto a force plate) could improve consistency in maximum ground reaction force, linear lower body stiffness, depth of landing, and jump height in 20 healthy, young adults. Coefficient of variation was the construct for variability used to compare the first to the last five repetitions for each variable. We found that the practice had the greatest effect on maximum ground reaction force (p = .017), and had smaller and similar effects on lower body stiffness and depth of landing (p values = .074 and .044, respectively), and no measurable effect on jump height. These findings suggest that the effect of practice on drop landing differs depending upon the variable measure and that 20 repetitions significantly improve consistency in ground reaction force.
Interlimb Coordination During a Combined Gait and Prehension Task
Authors: Bellinger Grace C. , Pickett Kristen A. , Mason Andrea H.
Published: July 2019

Reaching and grasping are often completed while walking, yet the interlimb coordination required for such a combined task is not fully understood. Previous studies have produced contradictory evidence regarding preference for support of the lower limb ipsilateral or contralateral to the upper limb when performing a reaching task. This coordinative aspect of the combined task provides insight into whether the two tasks are mutually modified or if the reach is superimposed upon normal arm swinging. Collectively, 18 right-handed young adults walked slower, took shorter steps, and spent more time in double support during the combined task compared with walking alone. The peak grasp aperture was larger in walking reach-to-grasp trials compared with standing trials. There was not a strong trend for lower limb support preferences at the reach initiation or object contact. The participants could begin walking with either foot and demonstrated variability of preferred gait initiation patterns. There was a range of interlimb coordination patterns, none of which could be generalized to all young adults. The variability with which healthy right-handed young adults execute a combined walking reach-to-grasp task suggests that the cyclical (walking) and discrete (prehension) motor tasks may have separate motor control mechanisms, as proposed in the two primitives theory.
Adipocytes sensitize melanoma cells to environmental TGF-β cues by repressing the expression of miR-211
Authors: Golan Tamar , Parikh Roma , Jacob Etai , Vaknine Hananya , Zemser-Werner Valentina , Hershkovitz Dov , Malcov Hagar , Leibou Stav , Reichman Hadar , Sheinboim Danna , Percik Ruth , Amar Sarah , Brenner Ronen , Greenberger Shoshana , Kung Andrew , Khaled Mehdi , Levy Carmit
Published: July 2019

Fat cells secrete cytokines that enhance pro-metastatic TGF-β signaling in melanoma cells.
Activation of 6-Alkoxy-Substituted Methylenecyclopropane Nucleoside Analogs Requires Enzymatic Modification by Adenosine Deaminase-Like Protein 1
Authors: Vollmer Kathryn J. , Burns Anna C. , Sauer Hannah E. , Williams John D. , Komazin-Meredith Gloria , Cardinale Steve , Butler Michelle , Aron Zachary , Hussein Islam , Busch Marc G. , Bowlin Terry L. , Gentry Brian G.
Published: July 2019

To determine the mechanism of action of third-generation methylenecyclopropane nucleoside analogs (MCPNAs), DNA sequencing of herpes simplex virus 1 (HSV-1) isolates resistant to third-generation MCPNAs resulted in the discovery of G841S and N815S mutations in HSV-1 UL30.
Peptidyl-Prolyl Isomerase
ppiB
Is Essential for Proteome Homeostasis and Virulence in Burkholderia pseudomallei
Authors: Bzdyl Nicole M. , Scott Nichollas E. , Norville Isobel H. , Scott Andrew E. , Atkins Timothy , Pang Stanley , Sarovich Derek S. , Coombs Geoffrey , Inglis Timothy J. J. , Kahler Charlene M. , Sarkar-Tyson Mitali
Published: July 2019

Burkholderia pseudomallei
is the causative agent of melioidosis, a disease endemic to Southeast Asia and northern Australia. Mortality rates in these areas are high even with antimicrobial treatment, and there are few options for effective therapy. Therefore, there is a need to identify antibacterial targets for the development of novel treatments. Cyclophilins are a family of highly conserved enzymes important in multiple cellular processes.
Structural, Biochemical, and
In Vivo
Characterization of MtrR-Mediated Resistance to Innate Antimicrobials by the Human Pathogen
Neisseria gonorrhoeae
Authors: Beggs Grace A. , Zalucki Yaramah M. , Brown Nicholas Gene , Rastegari Sheila , Phillips Rebecca K. , Palzkill Timothy , Shafer William M. , Kumaraswami Muthiah , Brennan Richard G.
Published: July 2019

Neisseria gonorrhoeae
causes a significant disease burden worldwide, and a meteoric rise in its multidrug resistance has reduced the efficacy of antibiotics previously or currently approved for therapy of gonorrheal infections. The multidrug efflux pump MtrCDE transports multiple drugs and host-derived antimicrobials from the bacterial cell and confers survival advantage on the pathogen within the host. Transcription of the pump is repressed by MtrR but relieved by the cytosolic influx of antimicrobials. Here, we describe the structure of induced MtrR and use this structure to identify bile salts as physiological inducers of MtrR. These findings provide a mechanistic basis for antimicrobial sensing and gonococcal protection by MtrR through the derepression of
mtrCDE
expression after exposure to intrinsic and clinically applied antimicrobials.
Porcine Reproductive and Respiratory Syndrome Virus E Protein Degrades Porcine Cholesterol 25-Hydroxylase via the Ubiquitin-Proteasome Pathway
Authors: Ke Wenting , Fang Liurong , Tao Ran , Li Yang , Jing Huiyuan , Wang Dang , Xiao Shaobo
Published: July 2019

CH25H has received significant attention due to its broad antiviral activity, which it mediates by catalyzing the production of 25HC. Most studies have focused on the antiviral mechanisms of CH25H; however, whether viruses also actively regulate CH25H expression has not yet been reported. Previous studies demonstrated that pCH25H inhibits PRRSV replication not only via production of 25HC but also by ubiquitination and degradation of viral nonstructural protein 1α. In this study, we expanded on previous work and found that PRRSV actively degrades pCH25H through the ubiquitin-proteasome pathway. PRRSV E protein, a viral structural protein, is involved in this process. This study reveals a novel mechanism of interaction between virus and host during PRRSV infection.
Identification of ARKL1 as a Negative Regulator of Epstein-Barr Virus Reactivation
Authors: Siddiqi Umama Z. , Vaidya Anup S. , Li Xinliu , Marcon Edyta , Tsao Sai Wah , Greenblatt Jack , Frappier Lori
Published: July 2019

Epstein-Barr virus (EBV) maintains a life-long infection due to the ability to alternate between latent and lytic modes of replication and is associated with several types of cancer. We have identified a cellular protein (ARKL1) that acts to repress the reactivation of EBV from the latent to the lytic cycle. We show that ARKL1 acts to repress transcription of the EBV lytic switch protein by inhibiting the activity of the cellular transcription factor c-Jun. This not only provides a new mechanism of regulating EBV reactivation but also identifies a novel cellular function of ARKL1 as an inhibitor of Jun-mediated transcription.
Statistics in pills: meta-analysis of rare events
Authors: Efthimiou Orestis
Published: July 2019

Meta-analysis of rare events requires special considerations regarding which statistical method to use. This is because standard meta-analytical models are not well suited for the task, especially when some of the identified studies have reported zero events in one or more treatment groups.
Network meta-analysis in a nutshell
Authors: Mavridis Dimitris
Published: July 2019

In most, if not all, healthcare conditions, there is a plethora of competing interventions with few head-to-head comparisons and classical meta-analysis fails to handle simultaneously the multiple comparisons among interventions. Network meta-analysis is an extension of pairwise meta-analysis to accommodate multiple interventions and comparisons.
Use of mixed methods to investigate case definitions to improve the identification of serious injury cases from hospital episode data
Authors: Cryer Colin , Davie Gabrielle , Gulliver Pauline , Samaranayaka Ari
Published: July 2019

Introduction

It has been commonplace internationally, when using hospital data, to use the principal diagnosis to identify injury cases and the first external cause of injury code (E-code) to identify the main cause. Our purpose was to investigate alternative operational definitions of serious non-fatal injury to identify cases of interest for injury surveillance, both overall and for four common causes of injury.

Methods

Serious non-fatal injury cases were identified from New Zealand (NZ) hospital discharge data using an alternative definition: that is, case selection using principal and additional diagnoses. Separately, identification of cause used all E-codes on the discharge record. Numbers of cases identified were contrasted with those captured using the usual definition. Views of NZ government stakeholders were sought regarding the acceptability of the additional cases found using these alternative definitions. Views of international experts were also canvassed.

Results

When using all diagnoses there was a 7% increase in ‘all injury’ cases identified, a 17% increase in self-harm cases and 8% increase in falls cases. Use of all E-codes resulted in a 4% increase in self-harm cases, 2% increase in assault cases and 1% increase in both falls and motor vehicle traffic crash cases.

Discussion

A case definition based solely on principal diagnosis fails to count a material number of serious non-fatal injury cases that are of interest to the injury prevention community. There is a need, therefore, to use an alternative case definition that includes additional diagnoses. Use of multiple E-codes to classify cause of injury should be considered.
Animal farming and the risk of lymphohaematopoietic cancers: a meta-analysis of three cohort studies within the AGRICOH consortium
Authors: El-Zaemey Sonia , Schinasi Leah H , Ferro Gilles , Tual Séverine , Lebailly Pierre , Baldi Isabelle , Nordby Karl-Christian , Kjærheim Kristina , Schüz Joachim , Monnereau Alain , Brouwer Maartje , Koutros Stella , Hofmann Jonathan , Kristensen Petter , Kromhout Hans , Leon Maria E , Beane Freeman Laura E
Published: July 2019

Objective

Animal farming entails a variety of potential exposures, including infectious agents, endotoxins and pesticides, which may play a role in the aetiology of lymphohaematopoietic cancers (LHCs). The aim of this study was to assess whether farming specific animal species is associated with the risk of overall LHC or its subtypes.

Methods

Data from three prospective cohort studies in the USA, France and Norway which are part of the Agricultural Cohort consortium and which collected information about animal farming and cancer were used. Analyses included 316 270 farmers and farm workers. Adjusted Cox models were used to investigate the associations of 13 histological subtypes of LHC (n=3282) with self-reported livestock (cattle, pigs and sheep/goats) and poultry (ever/never and numbers raised) farming. Cohort-specific HRs were combined using random-effects meta-analysis.

Results

Ever animal farming in general or farming specific animal species was not meta-associated with overall LHC. The risk of myeloid malignancies decreased with increasing number of livestock (p trend=0.01). Increased risk of myeloproliferative neoplasms was seen with increasing number of sheep/goats (p trend <0.01), while a decreased risk was seen with increasing number of livestock (p trend=0.02). Between cohorts, we observed heterogeneity in the association of type of animal farmed and various LHC subtypes.

Conclusions

This large-scale study of three prospective agricultural cohorts showed no association between animal farming and LHC risk, but few associations between specific animal species and LHC subtypes were observed. The observed differences in associations by countries warrant further investigations.
Multidisciplinary home-based rehabilitation in inoperable lung cancer: a randomised controlled trial
Authors: Edbrooke Lara , Aranda Sanchia , Granger Catherine L , McDonald Christine F , Krishnasamy Mei , Mileshkin Linda , Clark Ross A , Gordon Ian , Irving Louis , Denehy Linda
Published: July 2019

Background

Lung cancer is associated with poor health-related quality of life (HRQoL) and high symptom burden. This trial aimed to assess the efficacy of home-based rehabilitation versus usual care in inoperable lung cancer.

Methods

A parallel-group, assessor-blinded, allocation-concealed, randomised controlled trial. Eligible participants were allocated (1:1) to usual care (UC) plus 8 weeks of aerobic and resistance exercise with behaviour change strategies and symptom support (intervention group (IG)) or UC alone. Assessments occurred at baseline, 9 weeks and 6 months. The primary outcome, change in between-group 6 min walk distance (6MWD), was analysed using intention-to-treat (ITT). Subsequent analyses involved modified ITT (mITT) and included participants with at least one follow-up outcome measure. Secondary outcomes included HRQoL and symptoms.

Results

Ninety-two participants were recruited. Characteristics of participants (UC=47, IG=45): mean (SD) age 64 (12) years; men 55%; disease stage n (%) III=35 (38) and IV=48 (52); radical treatment 46%. There were no significant between-group differences for the 6MWD (n=92) at 9 weeks (p=0.308) or 6 months (p=0.979). The mITT analyses of 6MWD between-group differences were again non-significant (mean difference (95% CI): 9 weeks: −25.4 m (−64.0 to 13.3), p=0.198 and 6 months: 41.3 m (−26.7 to 109.4), p=0.232). Significant 6-month differences, favouring the IG, were found for HRQoL (Functional Assessment of Cancer Therapy–Lung: 13.0 (3.9 to 22.1), p=0.005) and symptom severity (MD Anderson Symptom Inventory–Lung Cancer: −2.2 (−3.6 to –0.9), p=0.001).

Conclusions

Home-based rehabilitation did not improve functional exercise capacity but there were improvements in patient-reported exploratory secondary outcomes measures observed at 6 months.

Trial registration

Australian New Zealand Clinical Trials Registry (ACTRN12614001268639).
Evaluating whether metapopulation structure benefits endangered diadromous fishes
Authors: Bowlby Heather D. , Gibson A. Jamie F.
Published: July 2019

Metapopulation structure is typically thought to increase regional species abundance, promote population persistence, and aid in the re-establishment of extirpated populations. However, the underlying theoretical models tended to assume high productivity, making the conservation benefit of metapopulation structure uncertain for endangered species with low productivity. We simulated population assemblages (N = 50) of diadromous fishes under high to low productivity scenarios to explicitly assess how straying (movement from natal to non-natal rivers) contributes to changes in species abundance and extinction risk. The population aggregation exhibited greater total abundance from source–sink dynamics and also exhibited the rescue effect when productivity remained moderately high. However, straying did not ensure persistence of nonviable populations or enable population re-establishment when productivity was low. These results were robust to a wide range of alternate spatial and life-history parameterizations of the simulation model. Relative to a real-world population aggregation of endangered Atlantic salmon (Salmo salar), our results would argue for a shift in remediation priorities to prevent extinction. Although there is strong evolutionary justification for maintaining widespread distributions of endangered diadromous species, the immediate numerical consequences of this approach may hinder recovery.
Ambiguïtés des termes q2J4 et q2J5 de la bande v4 de la molécule 70GeF4
Authors: Kaarour Abdelkrim , Meskine Mohamed , Ouardi Okkacha
Published: July 2019

Nous rapportons une nouvelle analyse des positions des raies de la molécule 70GeF4 à partir des spectres rovibrationnels à haute résolution, y compris des raies précises dans la région 250–300 cm−1. Dans cette analyse, 1246 données ont été ajustés en utilisant un Hamiltonien effectif développé à l’ordre six, relatif à la bande fondamentale v4. Pour les attributions et les analyses, nous utilisons les logiciels SPVIEW et XTDS qui implémentent le formalisme tensoriel développé à Dijon pour les molécules tétraédriques. Les transitions expérimentales sont assignées jusqu’à J ≤ 70 pour la bande froide v4. Parmi les 28 paramètres de l’Hamiltonien effectif relatif à la bande fondamentale v4 (dont 1 relatif au niveau de base (GS ou P0) et 27 relatifs à v4), 21 paramètres ont été déterminés. Les 21 paramètres de v4 permettent de bien simuler le spectre. Dans cette étude, 1246 raies ont été utilisées dans l’ajustement de moindres carrés, caractérisé par un écart quadratique moyen dRMS pour les positions des raies : 0,231 × 10−3 cm−1. Sur la base de l’ajustement des 1246 données expérimentales pour v4 de 70GeF4, la théorie des ambiguïtés des paramètres de l’Hamiltonien pour les états triplement dégénérés (F2) des molécules tétraédriques est étudiée. Dans cette théorie, aucun des paramètres de type q2J4 et q2J5 ne peut être déterminé de manière unique à partir de données expérimentales, et ces paramètres ne peuvent pas être considérés comme des constantes spectroscopiques. Le comportement des paramètres ajustés q2J4 et q2J5 obéit à des équations linéaires. Dans notre étude de la bande v4 de 70GeF4, nous avons trouvé que cette théorie et la linéarité sont vérifiées, sauf que les valeurs des angles « expérimentaux » d4(K,Γ) des équations PTZ sont différentes des valeurs théoriques pour Ωmax = 4.
Motion modeling of a non-holonomic wheeled mobile robot based on trajectory tracking control
Authors: Han Xuefeng , Ge Mingda , Cui Jicheng , Wang Hao , Zhuang Wei
Published: July 2019

Trajectory tracking is a problem of emphasis for the mobile robot. In this study, a coordinate transformation method was used to build a kinematic model of the wheeled mobile robot. A traditional proportional-integral-derivative control method was researched and improved by combining it with a neural network. A neural network proportional-integral-derivative trajectory tracking control method was thus designed, and a simulation experiment was performed using Simulink. The results show that in circular trajectory tracking control, the maximum errors of the X axis, Y axis, and θ were approximately 2.1 m, 2.3 m, and 0.4 rad, respectively, and that the system remained stable after running for 10 s. In straight-line trajectory tracking control, the maximum errors of the X axis, Y axis, and θ were approximately −0.8 m, 1.3 m, and 0.3 rad, respectively, and the system remained stable after running for 8 s. The error was relatively small, and the effect of trajectory tracking control was good. The studied method had good performance in terms of wheeled mobile robot trajectory tracking control and is worthy of further promotion and application.
Differential Variation Analysis Enables Detection of Tumor Heterogeneity Using Single-Cell RNA-Sequencing Data
Authors: Davis-Marcisak Emily F. , Sherman Thomas D. , Orugunta Pranay , Stein-O'Brien Genevieve L. , Puram Sidharth V. , Roussos Torres Evanthia T. , Hopkins Alexander C. , Jaffee Elizabeth M. , Favorov Alexander V. , Afsari Bahman , Goff Loyal A. , Fertig Elana J.
Published: July 2019

Tumor heterogeneity provides a complex challenge to cancer treatment and is a critical component of therapeutic response, disease recurrence, and patient survival. Single-cell RNA-sequencing (scRNA-seq) technologies have revealed the prevalence of intratumor and intertumor heterogeneity. Computational techniques are essential to quantify the differences in variation of these profiles between distinct cell types, tumor subtypes, and patients to fully characterize intratumor and intertumor molecular heterogeneity. In this study, we adapted our algorithm for pathway dysregulation, Expression Variation Analysis (EVA), to perform multivariate statistical analyses of differential variation of expression in gene sets for scRNA-seq. EVA has high sensitivity and specificity to detect pathways with true differential heterogeneity in simulated data. EVA was applied to several public domain scRNA-seq tumor datasets to quantify the landscape of tumor heterogeneity in several key applications in cancer genomics such as immunogenicity, metastasis, and cancer subtypes. Immune pathway heterogeneity of hematopoietic cell populations in breast tumors corresponded to the amount of diversity present in the T-cell repertoire of each individual. Cells from head and neck squamous cell carcinoma (HNSCC) primary tumors had significantly more heterogeneity across pathways than cells from metastases, consistent with a model of clonal outgrowth. Moreover, there were dramatic differences in pathway dysregulation across HNSCC basal primary tumors. Within the basal primary tumors, there was increased immune dysregulation in individuals with a high proportion of fibroblasts present in the tumor microenvironment. These results demonstrate the broad utility of EVA to quantify intertumor and intratumor heterogeneity from scRNA-seq data without reliance on low-dimensional visualization.

Significance:

This study presents a robust statistical algorithm for evaluating gene expression heterogeneity within pathways or gene sets in single-cell RNA-seq data
Analysis of Over 140,000 European Descendants Identifies Genetically Predicted Blood Protein Biomarkers Associated with Prostate Cancer Risk
Authors: Wu Lang , Shu Xiang , Bao Jiandong , Guo Xingyi , Kote-Jarai Zsofia , Haiman Christopher A. , Eeles Rosalind A. , Zheng Wei
Published: July 2019

Several blood protein biomarkers have been associated with prostate cancer risk. However, most studies assessed only a small number of biomarkers and/or included a small sample size. To identify novel protein biomarkers of prostate cancer risk, we studied 79,194 cases and 61,112 controls of European ancestry, included in the PRACTICAL/ELLIPSE consortia, using genetic instruments of protein quantitative trait loci for 1,478 plasma proteins. A total of 31 proteins were associated with prostate cancer risk including proteins encoded by GSTP1, whose methylation level was shown previously to be associated with prostate cancer risk, and MSMB, SPINT2, IGF2R, and CTSS, which were previously implicated as potential target genes of prostate cancer risk variants identified in genome-wide association studies. A total of 18 proteins inversely correlated and 13 positively correlated with prostate cancer risk. For 28 of the identified proteins, gene somatic changes of short indels, splice site, nonsense, or missense mutations were detected in patients with prostate cancer in The Cancer Genome Atlas. Pathway enrichment analysis showed that relevant genes were significantly enriched in cancer-related pathways. In conclusion, this study identifies 31 candidates of protein biomarkers for prostate cancer risk and provides new insights into the biology and genetics of prostate tumorigenesis.

Significance:

Integration of genomics and proteomics data identifies biomarkers associated with prostate cancer risk.
Roles and Regulation of Long Noncoding RNAs in Hepatocellular Carcinoma
Authors: Lim Lee Jin , Wong Samuel Y.S. , Huang Feiyang , Lim Sheng , Chong Samuel S. , Ooi London Lucien , Kon Oi Lian , Lee Caroline G.
Published: July 2019

Next-generation sequencing has uncovered thousands of long noncoding RNAs (lncRNA). Many are reported to be aberrantly expressed in various cancers, including hepatocellular carcinoma (HCC), and play key roles in tumorigenesis. This review provides an in-depth discussion of the oncogenic mechanisms reported to be associated with deregulated HCC-associated lncRNAs. Transcriptional expression of lncRNAs in HCC is modulated through transcription factors, or epigenetically by aberrant histone acetylation or DNA methylation, and posttranscriptionally by lncRNA transcript stability modulated by miRNAs and RNA-binding proteins. Seventy-four deregulated lncRNAs have been identified in HCC, of which, 52 are upregulated. This review maps the oncogenic roles of these deregulated lncRNAs by integrating diverse datasets including clinicopathologic features, affected cancer phenotypes, associated miRNA and/or protein-interacting partners as well as modulated gene/protein expression. Notably, 63 deregulated lncRNAs are significantly associated with clinicopathologic features of HCC. Twenty-three deregulated lncRNAs associated with both tumor and metastatic clinical features were also tumorigenic and prometastatic in experimental models of HCC, and eight of these mapped to known cancer pathways. Fifty-two upregulated lncRNAs exhibit oncogenic properties and are associated with prominent hallmarks of cancer, whereas 22 downregulated lncRNAs have tumor-suppressive properties. Aberrantly expressed lncRNAs in HCC exert pleiotropic effects on miRNAs, mRNAs, and proteins. They affect multiple cancer phenotypes by altering miRNA and mRNA expression and stability, as well as through effects on protein expression, degradation, structure, or interactions with transcriptional regulators. Hence, these insights reveal novel lncRNAs as potential biomarkers and may enable the design of precision therapy for HCC.
IL6 Promotes a STAT3-PRL3 Feedforward Loop via SHP2 Repression in Multiple Myeloma
Authors: Chong Phyllis S.Y. , Zhou Jianbiao , Lim Julia S.L. , Hee Yan Ting , Chooi Jing-Yuan , Chung Tae-Hoon , Tan Zea Tuan , Zeng Qi , Waller Daniel D. , Sebag Michael , Chng Wee-Joo
Published: July 2019

Overexpression of PRL-3, an oncogenic phosphatase, was identified as a novel cluster in patients with newly diagnosed multiple myeloma. However, the regulation and oncogenic activities of PRL-3 in multiple myeloma warrant further investigation. Here, we report that IL6 activates STAT3, which acts as a direct transcriptional regulator of PRL-3. Upregulation of PRL-3 increased myeloma cell viability and rephosphorylated STAT3 in a biphasic manner through direct interaction and deactivation of SHP2, thus blocking the gp130 (Y759)-mediated repression of STAT3 activity. Abrogation of PRL-3 reduced myeloma cell survival, clonogenicity, and tumorigenesis, and detailed mechanistic studies revealed “deactivation” of effector proteins such as Akt, Erk1/2, Src, STAT1, and STAT3. Furthermore, loss of PRL-3 efficiently abolished nuclear localization of STAT3 and reduced its occupancy on the promoter of target genes c-Myc and Mcl-1, and antiapoptotic genes Bcl2 and Bcl-xL. PRL-3 also played a role in the acquired resistance of myeloma cells to bortezomib, which could be overcome by PRL-3 silencing. Of clinical relevance, STAT3 and PRL-3 expression was positively correlated in five independent cohorts, and the STAT3 activation signature was significantly enriched in patients with high PRL-3 expression. Furthermore, PRL-3 could be used as a biomarker to identify high-risk patients with multiple myeloma that exhibited poor prognosis and inferior outcome even when treated with novel combinational therapeutics (proteasome inhibitors and immunomodulatory imide drugs). Conclusively, our results support a feedforward mechanism between STAT3 and PRL-3 that prolongs prosurvival signaling in multiple myeloma, and suggest targeting PRL-3 as a valid therapeutic opportunity in multiple myeloma.

Significance:

IL6 promotes STAT3-dependent transcriptional upregulation of PRL-3, which in turn re-phosphorylates STAT3 and aberrantly activates STAT3 target genes, leading to bortezomib resistance in multiple myeloma.
Value of Collaboration among Multi-Domain Experts in Analysis of High-Throughput Genomics Data
Authors: Meerzaman Daoud , Dunn Barbara K.
Published: July 2019

The recent explosion and ease of access to large-scale genomics data is intriguing. However, serious obstacles exist to the optimal management of the entire spectrum from data production in the laboratory through bioinformatic analysis to statistical evaluation and ultimately clinical interpretation. Beyond the multitude of technical issues, what stands out the most is the absence of adequate communication among the specialists in these domains. Successful interdisciplinary collaborations along the genomics pipeline extending from laboratory experiments to bioinformatic analyses to clinical application are notable in large scale, well managed projects such as The Cancer Genome Atlas. However, in certain settings in which the various experts perform their specialized research activities in isolation, the siloed approach to their research contributes to the generation of questionable genomic interpretations. Such situations are particularly concerning when the ultimate endpoint involves genetic/genomic interpretations that are intended for clinical applications. In spite of the fact that clinicians express interest in gaining a better understanding of clinical genomic applications, the lack of communication from upstream experts leaves them with a serious level of discomfort in applying such genomic knowledge to patient care. This discomfort is especially evident among healthcare providers who are not trained as geneticists, in particular primary care physicians. We offer some initiatives that have potential to address this problem, with emphasis on improved and ongoing communication among all the experts in these fields, constituting a comprehensive genomic “pipeline” from laboratory to patient.
Gene Editing of α6 Integrin Inhibits Muscle Invasive Networks and Increases Cell–Cell Biophysical Properties in Prostate Cancer
Authors: Rubenstein Cynthia S. , Gard Jaime M.C. , Wang Mengdie , McGrath Julie E. , Ingabire Nadia , Hinton James P. , Marr Kendra D. , Simpson Skyler J. , Nagle Raymond B. , Miranti Cindy K. , Warfel Noel A. , Garcia Joe G.N. , Arif-Tiwari Hina , Cress Anne E.
Published: July 2019

Human prostate cancer confined to the gland is indolent (low-risk), but tumors outside the capsule are aggressive (high-risk). Extracapsular extension requires invasion within and through a smooth muscle-structured environment. Because integrins respond to biomechanical cues, we used a gene editing approach to determine if a specific region of laminin-binding α6β1 integrin was required for smooth muscle invasion both in vitro and in vivo. Human tissue specimens showed prostate cancer invasion through smooth muscle and tumor coexpression of α6 integrin and E-cadherin in a cell–cell location and α6 integrin in a cell–extracellular matrix (ECM) distribution. Prostate cancer cells expressing α6 integrin (DU145 α6WT) produced a 3D invasive network on laminin-containing Matrigel and invaded into smooth muscle both in vitro and in vivo. In contrast, cells without α6 integrin (DU145 α6KO) and cells expressing an integrin mutant (DU145 α6AA) did not produce invasive networks, could not invade muscle both in vitro and in vivo, and surprisingly formed 3D cohesive clusters. Using electric cell–substrate impedance testing, cohesive clusters had up to a 30-fold increase in normalized resistance at 400 Hz (cell–cell impedance) as compared with the DU145 α6WT cells. In contrast, measurements at 40,000 Hz (cell–ECM coverage) showed that DU145 α6AA cells were two-fold decreased in normalized resistance and were defective in restoring resistance after a 1 μmol/L S1P challenge as compared with the DU145 α6WT cells. The results suggest that gene editing of a specific α6 integrin extracellular region, not required for normal tissue function, can generate a new biophysical cancer phenotype unable to invade the muscle, presenting a new therapeutic strategy for metastasis prevention in prostate cancer.

Significance:

This study shows an innovative strategy to block prostate cancer metastasis and invasion in the muscle through gene editing of a specific α6 integrin extracellular region.
Obesity and Risk for Second Malignant Neoplasms in Childhood Cancer Survivors: A Case–Control Study Utilizing the California Cancer Registry
Authors: Moke Diana J. , Hamilton Ann S. , Chehab Leena , Deapen Dennis , Freyer David R.
Published: July 2019

Background:

Obesity is a known modifiable risk factor associated with adverse outcomes in children with cancer. We sought to determine whether obesity during childhood cancer treatment increases risk for second malignant neoplasms (SMN).

Methods:

In this case–control study, cases (with SMN) and controls (with a single-primary cancer) were selected from the California Cancer Registry who had primary cancer diagnosed <21 years treated at Children's Hospital Los Angeles between 1988 and 2014. Controls were matched 3:1 to cases at the registry level by clinical factors. Medical records were abstracted for cancer treatment exposures, cancer predisposition syndrome, body mass index (BMI), BMI Z-score, and BMI category at diagnosis and end of therapy (EOT).

Results:

A total of 59 cases and 130 controls were included. Median age at primary cancer diagnosis was 6 years, 64.5% were male, median time from primary cancer to SMN was 7.5 years, and 31.7% were obese or overweight. In matched multivariable analyses, there were elevated but nonsignificant associations between SMN and higher BMI Z-score at diagnosis [OR 1.27 (0.99–1.63)] and higher BMI categories at diagnosis [adjusted OR (aOR) overweight, 1.25 (0.55–2.52); aOR obese, 2.51 (1.00–6.29)]. There was a significantly increased risk for SMN among patients who were obese at both diagnosis and EOT [aOR, 4.44 (1.37–14.34)].

Conclusions:

This study suggests that obesity during childhood cancer treatment may be associated with increased risk for SMNs, particularly among those obese throughout therapy.

Impact:

Additional studies to confirm these findings and to develop interventions have the potential to impact SMN development in children with cancer.
Development of a Theranostic Convergence Bioradiopharmaceutical for Immuno-PET Based Radioimmunotherapy of L1CAM in Cholangiocarcinoma Model
Authors: Song In Ho , Jeong Mun Sik , Hong Hyo Jeong , Shin Jong Il , Park Yong Serk , Woo Sang-Keun , Moon Byung Seok , Kim Kwang Il , Lee Yong Jin , Kang Joo Hyun , Lee Tae Sup
Published: July 2019

Purpose:

Cholangiocarcinoma is a malignancy of bile duct with a poor prognosis. Conventional chemotherapy and radiotherapy are generally ineffective, and surgical resection is the only curative treatment for cholangiocarcinoma. L1-cell adhesion molecule (L1CAM) has been known as a novel prognostic marker and therapeutic target for cholangiocarcinoma. This study aimed to evaluate the feasibility of immuno-PET imaging–based radioimmunotherapy using radiolabeled anti-L1CAM antibody in cholangiocarcinoma xenograft model.

Experimental Design:

We prepared a theranostic convergence bioradiopharmaceutical using chimeric anti-L1CAM antibody (cA10-A3) conjugated with 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator and labeled with 64Cu or 177Lu and evaluated the immuno-PET or SPECT/CT imaging and biodistribution with 64Cu-/177Lu-cA10-A3 in various cholangiocarcinoma xenograft models. Therapeutic efficacy and response monitoring were performed by 177Lu-cA10-A3 and 18F-FDG-PET, respectively, and immunohistochemistry was done by TUNEL and Ki-67.

Results:

Radiolabeled cA10-A3 antibodies specifically recognized L1CAM in vitro, clearly visualized cholangiocarcinoma tumors in immuno-PET and SPECT/CT imaging, and differentiated the L1CAM expression level in cholangiocarcinoma xenograft models. 177Lu-cA10-A3 (12.95 MBq/100 μg) showed statistically significant reduction in tumor volumes (P < 0.05) and decreased glucose metabolism (P < 0.01). IHC analysis revealed 177Lu-cA10-A3 treatment increased TUNEL-positive and decreased Ki-67-positive cells, compared with saline, cA10-A3, or 177Lu-isotype.

Conclusions:

Anti-L1CAM immuno-PET imaging using 64Cu-cA10-A3 could be translated into the clinic for characterizing the pharmacokinetics and selecting appropriate patients for radioimmunotherapy. Radioimmunotherapy using 177Lu-cA10-A3 may provide survival benefit in L1CAM-expressing cholangiocarcinoma tumor. Theranostic convergence bioradiopharmaceutical strategy would be applied as imaging biomarker-based personalized medicine in L1CAM-expressing patients with cholangiocarcinoma.
DNA Methylation as a Robust Classifier of Epithelial Ovarian Cancer
Authors: Ishak Charles A. , Lheureux Stephanie , De Carvalho Daniel D.
Published: July 2019

Epithelial ovarian cancers (EOC) can be defined across different histologic subtypes by specific DNA methylation profiles which correlate with outcome. Identification of distinct EOC methylation subgroups emphasizes the role of epigenetic remodeling to establish unique EOC etiology during transformation, and harbors the potential to direct personalized medicine and patient care.

See related article by Bodelon et al., p. 5937
Pharmacologic Ascorbate Primes Pancreatic Cancer Cells for Death by Rewiring Cellular Energetics and Inducing DNA Damage
Authors: Buranasudja Visarut , Doskey Claire M. , Gibson Adrienne R. , Wagner Brett A. , Du Juan , Gordon David J. , Koppenhafer Stacia L. , Cullen Joseph J. , Buettner Garry R.
Published: July 2019

The clinical potential of pharmacologic ascorbate (P-AscH−; intravenous delivery achieving mmol/L concentrations in blood) as an adjuvant in cancer therapy is being reevaluated. At mmol/L concentrations, P-AscH− is thought to exhibit anticancer activity via generation of a flux of H2O2 in tumors, which leads to oxidative distress. Here, we use cell culture models of pancreatic cancer to examine the effects of P-AscH− on DNA damage, and downstream consequences, including changes in bioenergetics. We have found that the high flux of H2O2 produced by P-AscH− induces DNA damage. In response to this DNA damage, we observed that PARP1 is hyperactivated. Using our unique absolute quantitation, we found that P-AscH− mediated the overactivation of PARP1, which results in consumption of NAD+, and subsequently depletion of ATP leading to mitotic cell death. We have also found that Chk1 plays a major role in the maintenance of genomic integrity following treatment with P-AscH−. Hyperactivation of PARP1 and DNA repair are ATP-consuming processes. Using a Seahorse XF96 analyzer, we demonstrated that the severe decrease in ATP after challenging with P-AscH− is because of increased demand, not changes in the rate of production. Genetic deletion and pharmacologic inhibition of PARP1 preserved both NAD+ and ATP; however, the toxicity of P-AscH− remained. These data indicate that disruption of bioenergetics is a secondary factor in the toxicity of P-AscH−; damage to DNA appears to be the primary factor.

Implications:

Efforts to leverage P-AscH− in cancer therapy should first focus on DNA damage.
Outcome of Pancreatic Cancer Surveillance Among High-Risk Individuals Tested for Germline Mutations in BRCA1 and BRCA2
Authors: Saldia Amethyst , Olson Sara H. , Nunes Pamela , Liang Xiaolin , Samson Marguerite L. , Salo-Mullen Erin , Marcell Vanessa , Stadler Zsofia K. , Allen Peter J. , Offit Kenneth , Kurtz Robert C.
Published: July 2019

Germline mutations in BRCA1/2 are risk factors for pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to evaluate whether results of surveillance for PDAC in high risk individuals (HRI) differ between those with and without a pathogenic BRCA1/2 mutation. This prospective study was conducted within the Pancreatic Tumor Registry at a major cancer center. There were 83 HRIs with ≥1 first-degree relative with PDAC who underwent surveillance and testing for pathogenic germline mutations in BRCA1/2. A secondary analysis includes 18 HRIs with known mutations in BRCA1/2 but with weaker family history. HRIs were evaluated over time using magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound when indicated by MRCP findings. We reviewed imaging results, blinded to mutation status. Demographic information was obtained from interviewer-administered questionnaires. The outcome was the proportion with any pancreatic abnormality identified at initial or follow-up surveillance. Among the 83 HRIs in the main analysis, 48 had a mutation in BRCA1/2 and 35 did not. Overall, 16 of 48 (33%) BRCA1/2-positive and 13 of 35 (37%) BRCA1/2-negative participants had pancreatic abnormalities on imaging; in each group, all but one finding was an intraductal papillary mucinous neoplasm. Among those with pathogenic mutations but weaker family history, results were similar: 7 of 18 (39%) with pancreatic abnormalities. Results of surveillance for pancreatic abnormalities on imaging are similar regardless of BRCA1/2 mutation status. While the results from this small study need confirmation in other studies, at present there does not appear to be increased yield from targeting individuals with BRCA1/2 mutations for surveillance.
Uptake of Cervical Cancer Screening in Ethiopia by Self-Sampling HPV DNA Compared to Visual Inspection with Acetic Acid: A Cluster Randomized Trial
Authors: Gizaw Muluken , Teka Brhanu , Ruddies Friederike , Abebe Tamrat , Kaufmann Andreas M. , Worku Alemayehu , Wienke Andreas , Jemal Ahmedin , Addissie Adamu , Kantelhardt Eva Johanna
Published: July 2019

In Ethiopia, the standard method of cervical cancer screening is using Visual Inspection with Acetic Acid (VIA). Self-collection–based human papillomavirus (HPV) testing is assumed to improve the uptake of screening, especially for hard to reach populations. We investigated whether HPV DNA testing with the self-collection of cervical samples would be associated with increased uptake and adherence to procedures at the population level compared with VIA within defined rural population in Ethiopia. A total of 22 clusters (comprising 2,356 women ages 30–49 years) were randomized in two arms. Following the community mobilization, women of the clusters were invited to go either to the local health post for a self-collection–based HPV DNA testing (arm A) or Butajira Hospital for VIA screening (arm B). In the HPV arm, of the 1,213 sensitized women, 1,020 (84.1%) accessed the health post for self-sampling compared with the VIA arm, where 575 of 1,143 (50.5%) visited the hospital for VIA (P < 0.0001). Of those women who attended the VIA and HPV arms, 40% and 65.4% adhered to all procedures expected after screening, respectively. Out of women positive for high risk HPV, 122 (85%) attended VIA as a follow-up test. The trial demonstrated significantly higher levels of population-based uptake and adherence for self-collection HPV testing. Women were more receptive for VIA after their HPV testing result was positive. Self-collection HPV testing can be done at the local health facility and may significantly improve the uptake of cervical cancer screening in Ethiopia.
Primary Choroidal Lymphoma Diagnosed with 27-Gauge Pars Plana Vitrectomy Choroidal Biopsy
Authors: Kam Andrew W. , Galvin Justin , Cherepanoff Svetlana , Miller A. Andrew , Fung Adrian T.
Published: July 2019

Background: Currently, transvitreal fine-needle aspiration biopsy is the most widely used tissue biopsy technique in cases of suspected intraocular lymphoma due to its relative simplicity and low trauma. The small sample produced, however, may be inadequate for diagnostic and prognostic analyses due to mechanical artefacts, insufficient material, or sampling errors. Small case series have demonstrated choroidal biopsy via vitrectomy to be safe and effective. With smaller-gauge vitrectomy instruments, visual recovery is rapid, and post-operative inflammation and conjunctival scarring is minimised. Furthermore, smaller-gauge instrumentation does not appear to affect the diagnostic yield of biopsies for intraocular lymphoma in vitro. We report a case of primary choroidal lymphoma successfully diagnosed with 27-gauge pars plana vitrectomy choroidal biopsy. Case Presentation: A 72-year-old female presented with a 6-month history of painless blurred vision in her right eye. Fundus examination revealed a large pale choroidal mass centred on the posterior pole with overlying exudative retinal detachment. Enhanced depth imaging optical coherence tomography revealed a markedly thickened choroid with an undulating appearance. B-scan ultrasonography demonstrated diffuse, smooth thickening of the choroid, and retrobulbar extrascleral hypoechoic nodules. A 27-gauge pars plana vitrectomy was performed and choroidal biopsy taken. Histopathologic, immunohistochemical, and flow cytometry studies confirmed a diagnosis of extranodal marginal zone B-cell lymphoma. Systemic workup found no evidence of systemic lymphoma. As such, the patient was diagnosed with primary choroidal lymphoma. She underwent intensity-modulated external beam radiotherapy with subsequent resolution of disease. Conclusions: Primary choroidal lymphoma can be safely and effectively diagnosed via 27-gauge vitrectomy choroidal biopsy.