bluuebunny/crossref_metadata_2025 huggingface dataset:
Firearm Ownership, Means Safety, and Suicidality
Authors: Anestis Michael D. , Daruwala Samantha , Capron Daniel W.
Published: August 2018

Objective

Means safety interventions are effective at reducing suicide rates. This study examined beliefs about firearm ownership or storage and suicide risk, lifetime suicidal thoughts, and openness to means safety.

Method

A community sample of 107 American adult firearm owners (51.4% male; 82.2% White; mage = 37.46) completed a series of self‐report questionnaires via Amazon's Mechanical Turk.

Results

Hierarchical linear regressions indicated that beliefs regarding firearm ownership or storage were associated with openness to means safety measures to prevent a suicide attempt by someone else, but not to prevent one's own suicide attempt. Additionally, results from analyses of covariance indicated that firearm owners with lifetime ideation had stronger beliefs regarding the association between firearm ownership or storage and suicide risk.

Conclusions

Findings indicate firearm owners’ willingness to engage in means safety may be influenced by the degree to which they believe firearm storage is associated with suicide. Furthermore, firearm owners with prior suicide ideation are more open to the idea that firearm ownership and storage are related to suicide risk. Viewing suicide as salient to one's own life may serve as a focal point in efforts to increase openness to means safety among firearm owners.
Undisciplined: Tracing Criminology's Growing Divergence From Sociology
Authors: Dooley Brendan D.
Published: August 2018

Several influential sociologists have questioned the wisdom of criminology's departure from sociology. Omitted from these reflections are the rationale explaining the schism. The present work grants a historical account to fill that absence. Oral histories with 17 leading criminologists, 13 of whom trained as sociologists, have been collected and analyzed. Two domains are explored, professional/organizational and informal/intellectual. First, the departments evidence different hiring patterns, journal content preferences, and journal structures over the past half‐century. Second, there are contrasts regarding ideology; sociology trends leftward. Criminological research concentrates on a dependent variable; sociology links to a unifying orientation. There are concerns that the field's training and research may be too narrow and that the lure of influencing policy could undermine its opportunity to offer critical commentary. Criminology's focus on addressing crime as a practical concern serves some advantages. However, many respondents were conflicted over the loss of an abiding identity. If the field fails to confront its preference for multitheoretical, policy‐driven discussion, it risks being pruned or subsumed without a more fixed sense of identity.
The new allele HLA‐DRB1*14:54:01:04 in a Chinese family identified using next‐generation sequencing
Authors: Peng Dan , Li Haixia , Wang Zhiyuan , Wu Riga , Sun Hongyu
Published: August 2018

DRB1*14:54:01:04 has five nucleotide differences from DRB1*14:54:01:01 at 10544 (G > A) and 9068 (TGAG insertion).
Communication training for inter‐specialty clinicians
Authors: October Tessie W , Dizon Zoelle B , Hamilton Melinda F , Madrigal Vanessa N , Arnold Robert M
Published: August 2018

Background

Inter‐specialty clinicians often co‐lead family conferences for hospitalised patients. Families frequently report receiving different messages from different clinicians. We developed a communication training workshop that crosses disciplines and co‐trains clinicians in one setting to create a culture of delivering a unified message.

Methods

We developed a 2‐day paediatric communication skills workshop to teach the skills necessary to conduct a family conference. The workshop was targeted at nurse‐practitioners and faculty clinicians representing the different specialties that co‐manage children in an intensive care unit. Our primary outcomes were learner self‐assessment of skills attainment and workshop satisfaction. We also evaluated the feasibility of recruiting busy clinicians.

Results

Fifteen clinicians, including eight critical care faculty members (80% of eligible participants), three subspecialty faculty members (100% of eligible participants) and four nurse‐practitioners (100% of eligible participants), participated. Learners' self‐reported confidence improved in all communication metrics assessed. From pre‐ to post‐workshop, confidence increased from 39% to 94% for ‘giving bad news’ (p < 0.05), from 50% to 83% for ‘conducting a family conference’ (p < 0.05), and from 39% to 100% for ‘eliciting a family’s values/preferences (p < 0.05). Every learner rated the workshop as important to their clinical practice and 100% would strongly recommend it to others. All reported the time commitment was not burdensome and 74% would choose this 2‐day format over shorter formats.

When clinicians learn together, they are more likely to speak the same language when communicating with each other, and ultimately to deliver the same message to families

Conclusions

An inter‐specialty communication training workshop for different types of clinician was well received. It is feasible to co‐train different types of clinician in a joint session. When clinicians learn together, they are more likely to speak the same language when communicating with each other, and ultimately to deliver the same message to families.
Validation of three‐dimensional wound measurements using a novel 3D‐WAM camera
Authors: Jørgensen Line Bisgaard , Skov‐Jeppesen Sune Møller , Halekoh Ulrich , Rasmussen Benjamin Schnack , Sørensen Jens Ahm , Jemec Gregor B.E. , Yderstræde Knud Bonnet
Published: August 2018

To monitor wound healing, it is essential to obtain accurate and reliable wound measurements. Various methods have been used to measure wound size including three‐dimensional (3D) measurement devices enabling wound assessment from a volume perspective. However, the currently available methods are inaccurate, costly, or complicated to use. As a consequence, we have developed a 3D‐wound assessment monitor (WAM) camera, which is able to measure wound size in three‐dimension and to assess wound characteristics. The aim of the study was to assess the intrarater and interrater reliability of the 3D wound measurements using the 3D camera and to compare these with traditional measurement methods. Four raters measured 48 wounds using the 3D camera, digital imaging method (2D area), and gel injection into the wound cavity (volume). The data were analyzed using linear mixed effect model. Intraclass and interclass correlation coefficient (ICC) and Bland–Altman plots were used to assess intrarater and interrater reliability for the 3D camera and agreement between the methods. The Bland–Altman plots for intrarater reliability showed minor differences between the measurements, especially the 3D area and perimeter measurements. Moreover, ICCs were very high for both the intrarater and interrater reliability for the 2D area, 3D area, and perimeter measurements (ICCs > 0.99), although slightly lower for the volume measurements (ICC = 0.946–0.950). Finally, a high agreement was found between the 3D camera and the traditional methods (2D area and volume) assessed by narrow 95% prediction intervals and high ICCs above 0.97. In conclusion, the 3D‐WAM camera is an accurate and reliable method, which is useful for several types of wounds. However, the volume measurements were primarily useful in large, deep wounds. Moreover, the 3D images are based on digital technology and therefore carry the possibility for use in remote settings.
Team Katniss? Adolescent Girls’ Participation in a Voluntary Archery After-School Program
Authors: Crookston Shara
Published: August 2018

According to USA Archery, the National Governing Body for the Olympic and Paralympic sport of archery, since December of 2011, the number of archery clubs has nearly doubled and individual membership is up 25%. Owners of archery ranges across the United States are experiencing long waiting lists of adolescents who are interested in learning the sport, and many owners contribute this surge in popularity to The Hunger Games (2008–2010) franchise, a dystopian series featuring Katniss Everdeen, a bow and arrow wielding teenage girl who becomes a reluctant revolutionary instrumental in destroying a totalitarian government. The link between the series and the recent surge in archery is explored here. In this feminist, qualitative study, nine girls (n = 9) between the ages of 11 and 14 were interviewed about their experience participating in at least one 6-week after-school archery program. The results of this study suggest that The Hunger Games series influenced the girls, both directly and indirectly, to participate in the archery program. Additionally, this study found that archery is a sport where both active and less active girls feel they can compete with boys on a level playing field. Lastly, the participants did not report experiencing sexism or bullying as a result of their archery participation. The author provides applications and recommendations for further research.
Race and Exercise Engagement: Investigating the High-Calorie-Burning Activities of White and Black Collegiate Women
Authors: Longmire-Avital Buffie , Madzima Takudzwa , Bierut Elyse
Published: August 2018

Previous research has documented the comprehensive health benefits of regular physical activity. However, just over a third of Black women report meeting the suggested amount of physical activity per week. Research also indicates that collegiate emerging adults often reduce their physical activity as well. Given that Black collegiate women represent the intersection of two groups that report a reduction in physical activity, the primary purpose of this descriptive study was to examine whether or not the rate of engagement in high-calorie-burning (HCB) activity by collegiate females differed by race. A secondary purpose was to explore how the chronic stress of racism for Black women was related to their HCB activity. Three hundred and eighty-three collegiate females between the ages of 18 and 25 (M = 19.67, SD = 1.45) participated; (61.1% [n = 234] self-identified as White, while the remaining 38.9% [n = 149] self-identified as Black). All eligible participants took a 10–15 min anonymous online survey. Results from a chi-squared analysis (χ2 [1] = 8.40, p = .004) revealed that White collegiate women (70.3%) were more likely to report participation in weekly HCB activity than Black collegiate women (55.7%). Additional analyses also suggested that chronic experience with racism (F [1, 147] = 5.13, p = .03) was associated with more frequent HCB activity for the Black women sampled. Campus health promotion campaigns should not overlook how the experience of race may shape health behaviors for their racial minority students and sustain emerging health disparities.
Gender Integration in Collegiate Combative Physical Education Classes
Authors: Bedard Alexander J. , Bigelman Kevin A. , Fielitz Lynn R. , Coelho Jeffrey D. , Kobbe William B. , Barone Renard O. , Gist Nicholas H. , Palmer John E.
Published: August 2018

Collegiate combative physical education classes, such as boxing, grappling, wrestling, and martial arts, offer many positive benefits to students and institutions. There has been an increased interest in combative sports in recent years. As a result of media focus on high-profile female athletes in combative sports, combative physical education classes have become increasingly popular with women. Physical education programs stand to greatly benefit from gender integration of combative classes. Educators and administrators, however, need to consider a number of social, psychological, physiological, and medical factors in order to ensure successful gender integration. Approaching gender integration with a careful and deliberate process that involves physical educators, administrators, and medical personnel will ensure programs maintain an authentic yet safe environment contributing to the attainment of course objectives. When executed in a prudent and deliberate manner, gender integration of combative course offerings has been anecdotally observed to improve women’s self-confidence, sense of inclusion, teamwork, and to enhance cohesion among students of both genders.
Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement
Authors: Lofano Giuseppe , Gorman Matthew J. , Yousif Ashraf S. , Yu Wen-Han , Fox Julie M. , Dugast Anne-Sophie , Ackerman Margaret E. , Suscovich Todd J. , Weiner Joshua , Barouch Dan , Streeck Hendrik , Little Susan , Smith Davey , Richman Douglas , Lauffenburger Douglas , Walker Bruce D. , Diamond Michael S. , Alter Galit
Published: August 2018

HIV-specific antibody sialylation enhances humoral immunity via increased antigen deposition within B cell follicles in a complement-dependent manner.
Localization and Regulation of the T1 Unimolecular Spanin
Authors: Kongari Rohit , Snowden Jeffrey , Berry Joel D. , Young Ry
Published: August 2018

Spanins have been proposed to fuse the cytoplasmic and outer membranes during phage lysis. Recent work with the lambda spanins Rz-Rz1, which are similar to class I viral fusion proteins, has shed light on the functional domains and requirements for two-component spanin function. Here we report, for the first time, a genetic and biochemical approach to characterize unimolecular spanins, which are structurally and mechanistically different from two-component spanins. Considering similar predicted secondary structures within the ectodomains, unimolecular spanins can be regarded as a prokaryotic version of type II viral membrane fusion proteins. This study not only adds to our understanding of regulation of phage lysis at various levels but also provides a prokaryotic genetically tractable platform for interrogating class II-like membrane fusion proteins.
Renewal properties of the d = 1 Ising model
Authors: Cassandro Marzio , Merola Immacolata , Presutti Errico
Published: August 2018

We consider the [Formula: see text] Ising model with Kac potentials at inverse temperature [Formula: see text] where the mean field predicts a phase transition with two possible equilibrium magnetizations [Formula: see text], [Formula: see text]. We show that when the Kac scaling parameter [Formula: see text] is sufficiently small, typical spin configurations are described (via a coarse graining) by an infinite sequence of successive plus and minus intervals where the empirical magnetization is “close” to [Formula: see text], and respectively, [Formula: see text]. We prove that the corresponding marginal of the unique DLR measure is a renewal process.
A refinement of Walker’s inequality
Authors: Horváth Gábor
Published: August 2018

The aim of this paper is to give a refinement of Walker’s inequality. To this, we will use a “self-improvement” of the Cauchy–Schwarz inequality for random variables.
Poststroke cognitive impairment and hippocampal neurovascular remodeling: the impact of diabetes and sex
Authors: Ward Rebecca , Valenzuela John Paul , Li Weiguo , Dong Guangkuo , Fagan Susan C. , Ergul Adviye
Published: August 2018

Diabetes increases the risk and severity of cognitive impairment, especially after ischemic stroke. Pathological remodeling of the cerebrovasculature has been postulated to contribute to poor neuronal repair and worsened cognitive deficits in diabetes. However, little is known about the effect of diabetes on the vascularization of hippocampus, a domain critical to memory and learning. Therefore, we had two aims for this study: 1) to determine the impact of diabetes on hippocampal neurovascular remodeling and the resulting cognitive impairment after stroke using two models with varying disease severity, and 2) to compare the effects of ischemia on hippocampal neurovascular injury in diabetic male and female animals. Stroke was induced by middle cerebral artery occlusion (MCAO) by either the suture or embolic method in control and diabetic age-matched male and female Wistar rats. Hippocampal neuronal density, vascular architecture, and microglial activation as well as cognitive outcomes were measured. Embolic MCAO induced greater neuronal degeneration, pathological vascularization, microglial activation, and cognitive impairment in diabetes as compared with control animals or 60-min MCAO. Although diabetic males had lower neuronal density at baseline, diabetic females had more neurodegeneration after stroke. Control animals recovered cognitive function by day 14 after stroke; diabetic animals showed deficits regardless of sex. These results suggest that mechanisms underlying cognitive decline in diabetes may differ in males and females and provide further insight to the impact of diabetes on stroke severity and poststroke cognitive impairment.

NEW & NOTEWORTHY The present study is the first to provide comparative information on the effects of diabetes and ischemia on cognitive outcomes in both sexes while also evaluating the neurovascular structure in the hippocampus, a critical region for cognitive and memory-related tasks.
Mutant voltage-gated Na+ channels can exert a dominant negative effect through coupled gating
Authors: Clatot Jérôme , Zheng Yang , Girardeau Aurore , Liu Haiyan , Laurita Kenneth R. , Marionneau Céline , Deschênes Isabelle
Published: August 2018

Mutations in voltage-gated Na+ channels have been linked to several channelopathies leading to a wide variety of diseases including cardiac arrhythmias, epilepsy, and myotonia. We have previously demonstrated that voltage-gated Na+ channel (Nav)1.5 trafficking-deficient mutant channels could lead to a dominant negative effect by impairing trafficking of the wild-type (WT) channel. We also reported that voltage-gated Na+ channels associate as dimers with coupled gating properties. Here, we hypothesized that the dominant negative effect of mutant Na+ channels could also occur through coupled gating. This was tested using cell surface biotinylation and single channel recordings to measure the gating probability and coupled gating of the dimers. As previously reported, coexpression of Nav1.5-L325R with WT channels led to a dominant negative effect, as reflected by a 75% reduction in current density. Surprisingly, cell surface biotinylation showed that Nav1.5-L325R mutant is capable of trafficking, with 40% of Nav1.5-L325R reaching the cell surface when expressed alone. Importantly, even though a dominant negative effect on the Na+ current is observed when WT and Nav1.5-L325R are expressed together, the total Nav channel cell surface expression was not significantly altered compared with WT channels alone. Thus, the trafficking deficiency could not explain the 75% decrease in inward Na+ current. Interestingly, single channel recordings showed that Nav1.5-L325R exerted a dominant negative effect on the WT channel at the gating level. Both coupled gating and gating probability of WT:L325R dimers were drastically impaired. We conclude that dominant negative suppression exerted by Nav1.5 mutants can also be caused by impairing the WT gating probability, a mechanism resulting from the dimerization and coupled gating of voltage-gated Na+ channel α-subunits.

NEW & NOTEWORTHY The presence of dominant negative mutations in the Na+ channel gene leading to Brugada syndrome was supported by our recent findings that Na+ channel α-subunits form dimers. Up until now, the dominant negative effect was thought to be caused by the interaction of the wild-type Na+ channel with trafficking-deficient mutant channels. However, the present study demonstrates that coupled gating of voltage-gated Na+ channels can also be responsible for the dominant negative effect leading to arrhythmias.
Abstract A002: Evidence of pazopanib-induced epithelial-mesenchymal transition (EMT) in human tumors
Authors: Navas Tony , Srivastava Apurva K. , Ferry-Galow Katherine , Makhlouf Hala , Chuaqui Rodrigo , Kinders Robert J. , Bottaro Donald P. , Chen Alice P. , Parchment Ralph E. , Kummar Shivaani , Doroshow James H.
Published: August 2018

Background: VEGFR inhibition by pazopanib slows tumor growth through vascular pruning, although compensatory factors associated with angiogenic inhibitors (e.g., induced HIF1-α from increased hypoxia) can lead to enhanced tumor invasion and metastasis by triggering EMT in some preclinical models (Sennino et al., 2012, Cancer Discovery 2(3);270-87). The development of a clinically suitable, validated assay for EMT has made possible the analysis of EMT in a clinical trial of the VEGFR inhibitor pazopanib. Methods: Paired tumor biopsies were obtained at baseline and on cycle 1, day 7 during a phase I trial (NCT01468922) of single-agent pazopanib (800 mg/day, PO). Biopsies were formalin fixed and paraffin embedded, and tissue sections were evaluated for EMT using a multiplex immunofluorescence assay (EMT-IFA) to quantify E-cadherin (E) and vimentin (V) expression and co-localization in tumor-segmented β-catenin+ regions of interests (ROIs) using Definiens software (Navas et al., NCI-EORTC 2015). EMT-IFA quantitative data were calculated from a minimum of 8 ROIs and 2 tissue sections per biopsy. Results: Paired biopsies from 7 patients (pts) with advanced cancer were evaluable for EMT based on H&E pathologist evaluation. As expected, the mesenchymal phenotype of a patient with chondrosarcoma was stable during treatment, but 4 of 6 carcinomas exhibited significant levels of drug-associated EMT towards more transitional (E+V+) or mesenchymal (V+) phenotypes (increased ratio of V+ to E+ area, log10 V:E; P = 0.0030 to < 0.0001). Two of 4 pts with drug-induced EMT additionally displayed significant increases in the area of V+E+ co-localization (um2/cell) in individual tumor cells (P <0.0001), while the other 2 pts did not show evidence of active transitional cells, but only showed increased E+ or decreased V+ tissue areas (um2/cell) within tumor regions. These results indicate that EMT occurs in some carcinoma of pts treated with pazopanib, consistent with results from preclinical models (Navas et al., 2017, AACR). Conclusions: We report for the first time pazopanib-induced EMT and direct evidence of tumor adaptation to anti-angiogenic therapy in clinical samples. Funded by NCI Contract No. HHSN261200800001E.

Citation Format: Tony Navas, Apurva K. Srivastava, Katherine Ferry-Galow, Hala Makhlouf, Rodrigo Chuaqui, Robert J. Kinders, Donald P. Bottaro, Alice P. Chen, Ralph E. Parchment, Shivaani Kummar, James H. Doroshow. Evidence of pazopanib-induced epithelial-mesenchymal transition (EMT) in human tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A002.
Abstract A006: Preclinical tumor models in humanized mice for translational immuno-oncology research
Authors: Stecklum Maria , Wulf-Goldenberg Annika , Paterka Magdalena , Brzezicha Bernadette , Fichtner Iduna , Hoffmann Jens
Published: August 2018

The recent clinical success of immune checkpoint modulators has stimulated immune-oncology research leading to the identification of new tumor immunology targets. However, both target validation and drug development require appropriate humanized preclinical models. Translational research further urgently needs such models for identification of clinically relevant biomarkers and defining rational combination strategies. In previous studies, we have demonstrated that hematopoietic stem cells (HSC) can proliferate and differentiate in immunodeficient mice and establish a functional human immune system with T cells, B cells, NK cells, monocytes, and dendritic cells. Further, we have shown engraftment of patient- (PDX) and cellline-derived xenografts (CDX) on these humanized mice. All CDX and most of the PDX showed no difference in tumor growth compared to non-humanized mice (fully immune resistant). However, some PDX showed a delayed tumor growth on the humanized mice (partly immune resistant), whereas only one model did not grow at all (immune sensitive). This model is demonstrating the functionality of the established human immune system against a PDX. In the next step, we determined PD-L1 expression on different CDX and PDX on RNA and on protein level. Engraftment seems to be dependent on PD-L1 expression on the PDX, with a higher PD-L1 expression correlating with a stronger tumor growth delay. In the last step the PDX/humanized mice system was evaluated for response to the treatment with checkpoint inhibitors alone and in combination therapy with radiation. So far we treated over 20 PDX and CDX models (lung, colon, melanoma, mammary, ovarian, lymphoma) with ipilimumab, nivolumab, and radiation. In most cases we observed a slight tumor growth delay and increased numbers of T cells in the blood and in the tumor. In our fully humanized model system we identified a correlation between response to checkpoint inhibitor treatment and PD-L1 expression on the PDX or CDX. These results demonstrate that fully humanized PDX models enable appropriate preclinical studies on tumor immune biology, evaluation of new immune therapies and combinations, as well as the identification and validation of biomarkers for immune therapy.

Citation Format: Maria Stecklum, Annika Wulf-Goldenberg, Magdalena Paterka, Bernadette Brzezicha, Iduna Fichtner, Jens Hoffmann. Preclinical tumor models in humanized mice for translational immuno-oncology research [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A006.
Abstract A027: Analytic validation of a pan-cancer tumor mutational burden assay
Authors: Nesselbush Monica , Jones Sian , Keefer Laurel , Sengamalay Naomi , Velculescu Victor , Diaz Luis , Sausen Mark , Angiuoli Samuel
Published: August 2018

Checkpoint inhibitors (CPIs) have been approved for front-line or subsequent therapies in several indications over the last few years. While patient response can be remarkably durable, many patients do not benefit. Current clinical biomarkers of response to CPIs include microsatellite instability (MSI) and PD-L1 expression. While a proportion of many solid tumor display microsatellite instability, the prevalence is often very low. Similarly, while clinically informative, PD-L1 expression alone is not sufficient to predict therapeutic outcomes. The lack of predictive biomarkers for response highlights the need for improved biomarkers with greater prevalence across tumor types to predict response to CPIs. Multiple clinical studies have revealed that high tumor mutational burden (TMB) is associated with better clinical response. Here, we describe the development of an assay and system that can be used to infer mutational burden from a discrete targeted region of interest in the exome. The assay has been analytically validated across several different solid tumor types, and provides proof-of-concept for the pan-cancer approach. Determining mutational burden on this fit-for-purpose assay was compared to whole exome sequencing, and high concordance was observed across a large dynamic range of mutations per megabase of coding sequence. Our data indicate that the assay can be used to accurately determine mutational burden in a range of tumor types, across a spectrum of potential mutational burden cut-offs using automated, complex mutation-identification algorithms.

Citation Format: Monica Nesselbush, Sian Jones, Laurel Keefer, Naomi Sengamalay, Victor Velculescu, Luis Diaz, Mark Sausen, Samuel Angiuoli. Analytic validation of a pan-cancer tumor mutational burden assay [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A027.
Abstract A035: CRC MRD detection using Accu-ActTM NGS technology
Authors: Li Xinxing , Zhao Grace , Zhang Xianwen , Sun Yanping , Wang Yi , Ruan Canping , Tang Paul , Faham Malek , Lin Shengrong , Ying Kang , Hu Zhiqian
Published: August 2018

Circulating tumor DNA (ctDNA) is a promising biomarker for detecting minimal residual disease (MRD) and for monitoring treatment of patients with colorectal cancers (CRC). Any technology used for this purpose, however, will face extreme performance demands. In order to build a high-performance multiplex next-generation sequencing (NGS) platform suitable for cancer MRD using ctDNA, we developed Accu-ActTM, an NGS-based assay capable of detecting low-frequency variants in plasma ctDNA with high precision. In our protocol, rolling-circle amplification is used to circularize denatured double-stranded cell-free DNA (cfDNA) and convert it into long tandem repeats, thus enabling consensus-based concatemer error correction. We demonstrated Accu-ActTM’s sensitivity and specificity by testing it on cfDNA samples with known variant frequencies and cfDNA collected from healthy individuals (n = 100). Our results showed that the sensitivity of Accu-Act was 0.1% with an error rate of 1 in 1 million for 20ng of input cfDNA. Concordance analysis was performed using Accu-Act, a 61-gene assay, on 152 tumor/plasma pairings of preoperative samples derived from patients with CRC (stage I-IV). Depending on stage, we report 66-92% patient detection rate. Post-surgery ctDNA profiling was performed on 52 patients (stage I-IV) enrolled in our prospective MRD study. The results showed that 26% of patients had detectable postoperative ctDNA, among whom 72% had disease progression within two years. Only one out of the 41 patients without detectable postoperative ctDNA went on to relapse, and one patient died of a lung infection. Our study showed that ctDNA is a promising prognostic biomarker for CRC relapse after R0 resection (HR (95%CI) 33.00 (4.05 - 270), P<0.001). The Accu-ActTM NGS-based ctDNA assay has high accuracy and is suitable for MRD in CRC patients. Accu-ActTM should make a significant contribution in the development of personalized cancer treatment.

Citation Format: Xinxing Li, Grace Zhao, Xianwen Zhang, Yanping Sun, Yi Wang, Canping Ruan, Paul Tang, Malek Faham, Shengrong Lin, Kang Ying, Zhiqian Hu. CRC MRD detection using Accu-ActTM NGS technology [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A035.
Abstract A046: miR-199a-3p induces BRCA1 dysfunction in triple-negative breast cancer
Authors: Ho John C. , Shin Vivian Y. , Chen Jiawei , Siu Man T. , Cheuk Isabella , Kwong Ava
Published: August 2018

Background: BRCA1 mutations are highly susceptible to familial breast and ovarian cancer, as well as the more aggressive triple-negative breast cancer (TNBC). However, DNA repair defects caused by BRCA dysfunction were reported to have better response to platinum-based chemotherapy and PARP inhibitors. Increasing evidence suggest the roles of miRNAs in regulating BRCA1 functions, with emphasis on cancer progression and therapeutic sensitivity. We previously identified miR-199a-3p as a potential TNBC biomarker, and BRCA1 is the putative downstream target based on in silico prediction. In this study, we aim to investigate the functionalities of miR-199a-3p in TNBC. Methods: The correlation between BRCA1 and miR-199a-3p was investigated through expression analysis of 32 TNBC tumor specimens, and further confirmed by dual-luciferase reporter assay. The functionalities of miR-199a-3p in TNBC cells were assessed by MTT cell proliferation, migration, and clonogenic assays. The effects of miR-199a-3p on cisplatin and PARP inhibitor veliparib sensitivities were determined by MTT assays, followed by apoptosis and cell cycle analyses. Results: An inverse correlation between miR-199a-3p and BRCA1 expressions was observed in TNBC tumor specimens. miR-199a-3p was demonstrated to directly target BRCA1, and caused downregulation of BRCA1 protein expression, and suppressed luciferase activity mediated by BRCA1-3’-UTR in reporter assays. Overexpression of miR-199a-3p in TNBC cell lines (MDA-MB-231 and MDA-MB-468) was shown to inhibit cell proliferation, migration, and clonogenic ability, suggesting tumor-suppressive functions. On the other hand, cisplatin treatment induced BRCA1 expression, concurrent with reduced miR-199a-3p, in TNBC cells. Restoration of miR-199a-3p expression sensitized the cells to cisplatin and PARP inhibitor veliparib. Ectopic expression of miR-199a-3p also suppressed aldehyde dehydrogenase (ALDH)-positive stem cell-like population in cisplatin-resistant TNBC cells. Conclusions: Our results suggest that miR-199a-3p is involved in TNBC progression and chemotherapeutic sensitivity, at least partially through regulation of BRCA1.

Citation Format: John C. Ho, Vivian Y. Shin, Jiawei Chen, Man T. Siu, Isabella Cheuk, Ava Kwong. miR-199a-3p induces BRCA1 dysfunction in triple-negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A046.
Abstract A059: Targeted RNA expression profiling for biomarker discovery in complex biologic samples
Authors: Chenchik Alex , Frangou Costa , Makhanov Mikhail
Published: August 2018

New rapid and robust transcriptome-based methods for cellular characterization of the tumor microenvironment and biomarker discovery are required to improve prognosis and treatment of cancer and other diseases. However, challenges with current approaches for the above applications include high sample requirements, poor sensitivity, low dynamic range, and limited throughput. To address these limitations, we have developed the DriverMap targeted RNA expression profiling assay using a genome-wide set of 19,000 validated primer pairs that leverages the sensitivity of multiplex RT-PCR with the throughput and digital readout depth of next-generation sequencing (NGS). Starting from just 10pg (single-cell) to 100ng (10,000 cells) of total RNA is sufficient to quantify over 5 orders of magnitude variation in gene expression levels with performance similar to conventional qRT-PCR. Further, the use of gene-specific primers enables direct analysis of total RNA isolate and obviates the need for globin and rRNA depletion from whole blood samples. In this study, we present the performance of the assay for immunophenotyping of immune cells in whole blood samples from sepsis patients and assess the immune responses to complex immunomodulatory stimuli in an ex vivo model system. We will also present profiling results that demonstrate how this assay can be used to analyze the level of immune cell infiltration in tumor samples, and identify active pathways in tumor and xenograft samples. Preliminary studies demonstrate the assay’s unparalleled specificity and sensitivity, resulting in better detection of low-abundance mRNA transcripts as well as an improved cost-effectiveness for high-throughput clinical applications.

Citation Format: Alex Chenchik, Costa Frangou, Mikhail Makhanov. Targeted RNA expression profiling for biomarker discovery in complex biologic samples [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A059.
Abstract A074: Killing late-stage cancer cells by coupling DNA damage induction with MAPK pathway activation
Authors: Bhattacharjee Vikram
Published: August 2018

Acquired resistance of metastatic melanoma (MM) tumors to BRAF V600E inhibitors (BRAFis) is commonplace in the clinic. Habitual relapse of patients contributes to <20% 5-year survival rates in MM. We previously identified serine synthesis as a critical mechanism of late-stage cancer cell resistance to BRAFis. Pretreatment with DNA-damaging agent and nucleoside analog gemcitabine resensitized drug-resistant cancer cells to BRAFis dabrafenib (Tafinlar) and vemurafenib (Zelboraf). The combination treatments were effective against BRAF wild type cancer cells, potentially expanding the clinical reach of BRAFis. In this study, we identify two additional DNA-damaging agents that resensitized drug-resistant MM and pancreatic cancer cells to BRAFis dabrafenib and encorafenib. We identify the antifolate and DNA-damaging agent methotrexate (MTX), and the topoisomerase 1 inhibitor and DNA-damaging agent camptothecin (Camp) as sensitizers of late-stage, drug-resistant cancer cells to BRAFis dabrafenib and encorafenib (LGX818). Importantly, we show a novel positive correlation between DNA repair delay and and allosteric MAPK activation via BRAFi treatment in BRAF wild type cells. Cells arrest in G1/S following DNA-damaging agent + BRAFi combination treatments and ultimately, cell death is triggered via apoptosis, presumably due to DNA damage repair delays. Additionally, we have identified activating KRAS codon 12 mutations as critical to the efficacy of combination treatments. In summary, we have elucidated a novel method of cell death induction via DNA-damaging agent + BRAFi combination treatments that has the potential to significantly impact late-stage MM and pancreatic cancer therapy in the clinic.

Citation Format: Vikram Bhattacharjee. Killing late-stage cancer cells by coupling DNA damage induction with MAPK pathway activation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A074.
Abstract A075: Metabolic targeting of hypoxia and HIF-1α in colorectal cancer potentiates the therapeutic efficacy of oxaliplatin
Authors: Chen Ching-Chow
Published: August 2018

The stabilization of hypoxia inducible factor-1α (HIF-1α) protein plays an important role in the gene transcription in hypoxia. Overexpression of HIF-1α has been reported in various human cancers. It is degraded under normoxic conditions by proline hydroxylation through prolyl hydroxylase domain-containing protein (PHD), leading to von Hippel-Lindau (VHL) E3-ubiquitin ligase-mediated ubiquitination and rapid degradation by proteasome. Succinate is produced when PHD hydroxylates HIF-1α, implying that elevated succinate in normoxia represents an increase in PHD activity. We found that DNA methyltransferase (DNMT) inhibitor zebularine could downregulate HIF-1α expression in various colorectal cancer (CRC) cells. Zebularine enhanced the degradation of HIF-1α protein through inducing its hydroxylation. Metabolomic analysis showed that zebularine reversed the reduced succinate level in hypoxia, indicating an increase in PHD activity. Zebularine also reduced angiogenesis in CRC. Furthermore, zebularine potentiated the anticancer effect of oxaliplatin in CRC cells and in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC mouse model. This finding provides a new pharmacologic strategy to increase HIF-1α hydroxylation and overcome oxaliplatin resistance to enhance the anti-CRC therapy.

Citation Format: Ching-Chow Chen. Metabolic targeting of hypoxia and HIF-1α in colorectal cancer potentiates the therapeutic efficacy of oxaliplatin [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A075.
Abstract A076: Potent and water-soluble C-3’ modified docetaxel analogs by enthalpic driven optimization
Authors: Fang Weishuo , Wang Hongbo , Gago Federico
Published: August 2018

A dual strategy aimed at enhancing the binding affinity for microtubules and improving the water solubility of docetaxel led to the design and synthesis of a series of novel C-2 and C-3' modified analogs. Among the latter, a compound demonstrated a higher affinity constant for microtubules that resulted in the ability to overcome resistance in cultured P-gp overexpressing tumor cells and a superior activity to docetaxel in drug-resistant A2780/AD ovarian cancer cells xenografted in mice. In addition, the considerably lower hydrophobicity of this compound relative to both docetaxel and paclitaxel led to a 3-fold better aqueous solubility. A molecular modelling was performed to explain its potent activity at structural level.

Citation Format: Weishuo Fang, Hongbo Wang, Federico Gago. Potent and water-soluble C-3’ modified docetaxel analogs by enthalpic driven optimization [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A076.
Abstract A097: Phase II trial of the c-Met inhibitor tepotinib in patients with advanced non-small cell lung cancer harboring MET exon 14-skipping mutations
Authors: Felip Enriqueta , Veillon Remi , Viteri Santiago , Scheele Jürgen , Bruns Rolf , Paik Paul K.
Published: August 2018

Background: Approximately 3-4% of non-small cell lung cancers (NSCLCs) harbor activating mutations of the MET proto-oncogene that cause exon 14 skipping (METex14) and accumulation of c-Met lacking a juxtamembrane domain. Such tumors are sensitive to nonselective kinase inhibitors with activity against c-Met, so selective c-Met inhibitors may have greater efficacy and/or tolerability. This single-arm phase II trial (NCT02864992) is investigating the efficacy and safety of the potent and selective c-Met inhibitor tepotinib in patients (pts) with NSCLC harboring METex14. Methods: Eligible patients (pts) are adults with stage IIIB/IV NSCLC and METex14 mutations identified in tumor and/or circulating tumor DNA (ctDNA) in plasma (liquid biopsy) by a central laboratory. Pts with EGFR-activating mutations, ALK rearrangements, or >2 lines of prior therapy are excluded. Pts receive tepotinib 500 mg QD on a 21-day cycle until disease progression, intolerable toxicity, or withdrawal from treatment for other reasons. Primary endpoint: objective response rate (ORR). Secondary endpoints: progression-free and overall survival, safety, pharmacokinetics, and quality of life. Recruitment of up to 120 (minimum 60 tumor, 60 ctDNA METex14-positive) pts in Europe, USA, and Japan is planned. Results: Five pts (age 55-77 years; 4 stage IV, 1 stage IIIB; all male; 4 Caucasian, 1 Asian) have been enrolled. Pts have currently completed 0-8 cycles of tepotinib therapy. Most adverse events observed to date have been grade 1/2 in severity, mostly unrelated to tepotinib treatment. One grade ≥3 tepotinib-related AE has occurred: grade 3 increased serum amylase. One pt has died due to his disease. Of the four pts with post-baseline tumor evaluations, two have confirmed partial response, one unconfirmed partial response, and one (with only one post-baseline assessment) stable disease. Conclusions: Initial data suggest that tepotinib 500 mg QD has promising activity in METex14 NSCLC. The safety profile of tepotinib appears favorable. Recruitment to the trial is ongoing.

Citation Format: Enriqueta Felip, Remi Veillon, Santiago Viteri, Jürgen Scheele, Rolf Bruns, Paul K. Paik. Phase II trial of the c-Met inhibitor tepotinib in patients with advanced non-small cell lung cancer harboring MET exon 14-skipping mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A097.
Abstract A110: Hypoxia-selective DNA-PK inhibitor
Authors: Kyle Alastair H. , Baker Jennifer H.E. , Fryer Karen H. , Banaáth Judit , Wang Taixiang , Porres Soraya S. , Mann Sam E. , Hynd George , Menear Keith , Minchinton Andrew I.
Published: August 2018

Targeting tumor hypoxia continues to be a goal of translational radiation oncology owing to overwhelming preclinical and clinical validation of the importance of tumor oxygenation to radiation sensitivity. We describe a rational, structure-based drug development and characterization program for novel prodrugs that can target DNA-PK selectively within hypoxic tumor cells. The dual selectivity of these prodrugs has the potential to substantially improve the therapeutic index of radiation therapy used to treat numerous cancers. Using several biochemical, cell and novel tissue-based screening systems we explored the mechanistic and biologic activity of two new classes of DNA-PK inhibitors. Iterative improvements in molecular activity were driven by high-throughput assays utilizing both immunostaining and clonogenic survival endpoints. Kinase selectivity and in vitro ADME assays facilitated the identification of drug-like compounds with the potential for good oral bioavailability. 3D-tissue culture models helped explore tissue penetration and bystander effects and experiments analyzing the oxygen dependence of prodrug cleavage to the active DNA-PK inhibitors guided the selection of hypoxic trigger moieties. Novel parental compounds and hypoxia-activated prodrugs in two distinct chemical classes that are potent inhibitors of DNA-PK have been developed. Lead compounds exhibit high in vitro potency and good oral drug-like properties and show significant enhancement of radiation-induced cytotoxicity. In vivo experiments indicate excellent oral bioavailability with plasma T½‘s exceeding 30 minutes and significant antitumor activity against human xenografts.

Citation Format: Alastair H. Kyle, Jennifer H.E. Baker, Karen H. Fryer, Judit Bana áth, Taixiang Wang, Soraya S. Porres, Sam E. Mann, George Hynd, Keith Menear, Andrew I. Minchinton. Hypoxia-selective DNA-PK inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A110.