bluuebunny/crossref_metadata_2025_split huggingface dataset:
Depression and anxiety in pet owners after a diagnosis of cancer in their pets: a cross-sectional study in Japan
Authors: Nakano Yuko , Matsushima Masato , Nakamori Azusa , Hiroma Junshiro , Matsuo Eiji , Wakabayashi Hidetaka , Yoshida Shuhei , Ichikawa Hiroko , Kaneko Makoto , Mutai Rieko , Sugiyama Yoshifumi , Yoshida Eriko , Kobayashi Tetsuya 
Published: February 2019

ObjectiveTo determine the presence and predictors of depression and anxiety in pet owners after a diagnosis of cancer in their pets.DesignCross-sectional study.SettingA veterinary medical centre specialised in oncology for dogs and cats and two primary veterinary clinics in Japan.ParticipantsThe participants for analysis were 99 owners of a pet with cancer diagnosis received in the past 1–3 weeks and 94 owners of a healthy pet.Main outcome measuresSelf-reported questionnaires were used to assess depression and anxiety. Depression was assessed using the Center of Epidemiologic Studies Depression Scale, and anxiety was measured by using the State–Trait Anxiety Inventory-Form JYZ.ResultsDepression scores were significantly higher in owners of a pet with cancer than owners of a healthy pet, even after adjustment for potential confounders (p<0.001). Within the owners of a pet with cancer, depression was significantly more common in those who were employed than those who were unemployed (p=0.048). State anxiety scores were significantly higher in owners of a pet with cancer than owners of a healthy pet, even after adjustment for potential confounders, including trait–anxiety scores (p<0.001). Furthermore, in owners of a pet with cancer, state anxiety was higher in owners with high trait anxiety (p<0.001) and in owners whose pets had a poor prognosis (p=0.027).ConclusionThe results indicate that some owners tended to become depressed and anxious after their pets had received a diagnosis of cancer. Employment may be a predictor of depression. High trait anxiety and a pet with a poor prognosis may increase owners’ state anxiety. Including the pet in a family genogram and attention to the pet’s health condition may be important considerations for family practice.
Folding during soft-sediment deformation
Authors: Alsop G. I. , Weinberger R. , Marco S. , Levi T. 
Published: February 2019

Abstract
The detailed analysis of folding in rocks was in part pioneered by John Ramsay, and resulted in a range of techniques and criteria to define folds. Although folding of unlithified or ‘soft’ sediments is typically assumed to produce similar geometries to those in ‘hard rocks’, there has to date been little detailed analysis of such folds. The aim of this paper is therefore to investigate folds developed during soft-sediment deformation (SSD) by applying techniques established for the analysis of tectonic folds during hard-rock deformation (HRD). We use the Late Pleistocene Lisan Formation exposed around the Dead Sea as our case study, as the laminated lake sediments record intricacies of fold detail generated during seismically triggered slumping of mass transport deposits (MTDs) towards the depocentre of the basin. While it is frequently assumed that folds created during SSD are chaotic and form disharmonic structures, we provide analyses that show harmonic fold trains may form during slumping, although larger upright folds cannot be traced for significant distances and are more typically disharmonic. Our analysis also reveals a range of fold styles, with more competent detrital-rich layers displaying buckles (Class 1B), as well as upright Class 1A folds marked by thickened limbs. Class 1A buckle folds are generally considered to be created by flattening that overprints folds with an original Class 1B geometry. As thickened fold limbs are truncated by overlying erosive surfaces, the vertical flattening is considered to have occurred during the slump event. Different fold shapes may partially reflect variable flattening, depending on the original orientation of upright or recumbent folds, together with continued downslope-directed simple-shear deformation that modifies the fold geometry. Analysis of fold wavelength, amplitude and bed thickness allows us to plot strain contour maps, and indicates that beds defining slump folds display viscosity contrasts in the range of 50–250, which are similar to values estimated from folds created during HRD in metamorphic rocks. A range of refold patterns, similar to those established by John Ramsay in metamorphic rocks, are observed within slumps, and are truncated by the overlying sediments, indicating that they formed during a single progressive slump event rather than distinct ‘episodes’ of superimposed deformation. This study confirms that techniques developed for the analysis of folds created during HRD are equally applicable to those formed during SSD, and that resulting folds are generally indistinguishable from one another. Extreme caution should therefore be exercised when interpreting the origin of folds in the rock record where the palaeogeographical and tectonic contexts become increasingly uncertain, thereby leading to potential misidentification of folds created during SSD.
Abstract A28: Donor lymphocyte infusion after allogeneic stem cell transplantation is a feasible therapy option with acceptable toxicity rates in patients with refractory Ewing’s sarcoma and rhabdomyosarcoma
Authors: Schober Sebastian J. , Steinhauser Maximilian , Wawer Angela , Luettichau Irene Teichert-von , Salat Christoph , Issels Rolf D. , Schwinger Wolfgang , Ussowicz Marek , Antunovic Petar , Castagna Luca , Kolb Hans-Jochem , Burdach Stefan E.G. , Thiel Uwe 
Published: February 2019

Abstract
Background: New therapy options are urgently needed for patients with treatment-refractory Ewing’s sarcoma (ES) or rhabdomyosarcoma (RMS). In these subgroups, the role of allogeneic stem cell transplantation (allo-SCT) to induce a graft-versus-tumor effect (GvT) remains unclear. Here, we describe our experience and the general feasibility of donor lymphocyte infusion (DLI) following allo-SCT for those patients.
Patients and Methods: We retrospectively evaluated data of eight patients with treatment-refractory ES (ES #1-4) and RMS (RMS #1-4) after DLI following allo-SCT. Data were individually evaluated for presence of graft-versus-host disease (GvHD), relapse-free survival (RFS), and overall survival (OS). Three of four ES and one of four RMS patients had received haploidentical grafts; the remaining patients received HLA-matched grafts prior to DLI. Patients received donor lymphocytes ranging from 2.5 x 104 to 1 x 108 CD3+ cells/kg body weight.
Results: ES #4 and RMS #4 developed acute GvHD after DLI. Limited chronic GvHD was observed in RMS #3. In two patients, DLI was associated with stable disease for nine (ES #2) and six months (ES #4), respectively. RMS #4 showed partial remission lasting for eight months after one dose of DLI with 1 x 106 CD3+ cells/kg combined with local hyperthermia and chemotherapy. ES #4 had residual disease before allo-SCT and was converted to CR after DLI. Altogether, seven patients died of disease and none of toxicity. RMS #2 received seven doses up to 1 x 108 CD3+ cells/kg and IL-2 including surgery and chemotherapy and remained in CR for 97 months at the date of data assessment. Median follow-up after allo-SCT was 27.5 months.
Conclusion: DLI after allo-SCT is a feasible therapy option for treatment-refractory ES and RMS patients. In this analysis, DLI-related toxicity is acceptable. These findings have to be evaluated in prospective analyses.
Citation Format: Sebastian J. Schober, Maximilian Steinhauser, Angela Wawer, Irene Teichert-von Luettichau, Christoph Salat, Rolf D. Issels, Wolfgang Schwinger, Marek Ussowicz, Petar Antunovic, Luca Castagna, Hans-Jochem Kolb, Stefan E.G. Burdach, Uwe Thiel. Donor lymphocyte infusion after allogeneic stem cell transplantation is a feasible therapy option with acceptable toxicity rates in patients with refractory Ewing’s sarcoma and rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A28.
Abstract A42: Prexasertib (LY2606368) is highly active as a monotherapy or in combination with chemotherapy in preclinical models of pediatric bone and soft tissue sarcoma
Authors: Lowery Caitlin D. , Blosser Wayne , Dowless Michele , Renschler Matthew , Stephens Jennifer , Beckmann Richard , Stancato Louis 
Published: February 2019

Abstract
The serine/threonine kinase checkpoint kinase 1 (CHK1) is a crucial mediator of replication stress and helps maintain genome integrity by governing the S-phase and G2/M cell cycle checkpoints following DNA damage, facilitating DNA repair through homologous recombination, and licensing replication forks during S phase. The CHK1 small-molecule inhibitor prexasertib (LY2606368) is currently under clinical investigation in pediatric cancer patients with recurrent or refractory solid tumors (NCT02808650). Reduced proliferation was observed at low nanomolar concentrations in a panel of pediatric bone and soft tissue sarcoma cell lines. In addition, prexasertib caused DNA damage and cell death in vitro as measured by Western blot analysis and high content imaging. Prexasertib as a monotherapy was superior to doxorubicin or actinomycin D in several cell line-derived and patient-derived xenograft (PDX) models of pediatric soft tissue sarcoma, with two models of alveolar rhabdomyosarcoma (aRMS) demonstrating a complete response to prexasertib; however, acquired resistance to prexasertib was observed. In addition, preclinical PDX mouse models of Ewing’s sarcoma and osteosarcoma typically demonstrated intrinsic resistance to single-agent prexasertib. Importantly, combination with cytotoxic chemotherapy could not only overcome intrinsic prexasertib resistance in vivo, as would be expected given the potential for prexasertib to act as a chemopotentiator, but also prevented the emergence of acquired resistance following single-agent prexasertib treatment. In vitro experiments were performed to evaluate the effect of prexasertib plus chemotherapy on cell proliferation. Future preclinical studies include genomic analysis of pediatric bone and soft tissue sarcoma models to delineate the molecular underpinnings of sensitivity and acquired resistance to prexasertib and to identify predictive biomarkers for response.
Citation Format: Caitlin D. Lowery, Wayne Blosser, Michele Dowless, Matthew Renschler, Jennifer Stephens, Richard Beckmann, Louis Stancato. Prexasertib (LY2606368) is highly active as a monotherapy or in combination with chemotherapy in preclinical models of pediatric bone and soft tissue sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A42.
Abstract A46: Heterotypic nucleosomes and PRC2 role in diffuse intrinsic pontine gliomas
Authors: Piunti Andrea 
Published: February 2019

Abstract
Diffuse intrinsic pontine gliomas (DIPG) harbor a characteristic lysine-to-methionine mutation on histone H3 (H3K27M) that potently inhibits Polycomb Repressive Complex 2 (PRC2) enzymatic activity; however, the precise roles of H3K27M and PRC2 in tumorigenesis remain elusive. Here we perform epigenomic profiling of patient-derived H3K27M mutant DIPG cell lines and demonstrate that H3K27M resides in nucleosomes with H3K27acetylation (H3K27ac) and colocalizes with bromodomain proteins at actively transcribed genes. In contrast, PRC2 is excluded from H3K27M occupied regions but, strikingly, the PRC2 complex is required for maintaining oncogenic potential. Finally, we demonstrate that pharmacologic bromodomain inhibition suppresses tumor growth in vivo. Altogether our results indicate that H3K27M drives accumulation of H3K27ac and point to bromodomain proteins inhibition as a powerful clinical strategy against DIPG.
Citation Format: Andrea Piunti. Heterotypic nucleosomes and PRC2 role in diffuse intrinsic pontine gliomas [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A46.
Abstract B02: Distinct CD8+ T-cell recognition profiles driven by conformational plasticity of recurrent neuroblastoma neoepitopes
Authors: Salama Sofie R. , Toor Jugmohit S. , Rao Arjun A. , McShan Andrew C. , Yarmarkovich Mark , Tripathi Sarvind , Nerli Santrupti , Madejska Ada A. , Nguyen Son , Yamaguchi Karissa , Maris John M. , Haussler David , Sgourakis Nikolaos G. 
Published: February 2019

Abstract
The identification of tumor neoantigens driving T-cell responses for immunotherapy poses a significant bottleneck in the development of approaches for precision cancer therapeutics. Here, we employ a bioinformatics method, Prediction Of T Cell Epitopes for Cancer Therapy (ProTECT), using sequencing data from neuroblastoma patients to identify a recurrent Anaplastic Lymphoma Kinase mutation (ALK R1275Q) that leads to two high-affinity neoepitopes when expressed in complex with common HLA alleles. Analysis of the x-ray structures of nonamer and decamer peptides bound to HLA-B*15:01 reveals that the neoepitopes adopt distinct conformations that confer measurable differences in stability in vitro, while the self-antigen is excluded from binding due to steric hindrance. MHC tetramer staining of peripheral blood mononuclear cells from HLA-matched donors shows that the two neoepitopes elicit distinct CD8+ T-cell recognition profiles. To expand the range of patients who could mount a T-cell response to our ALK neoepitopes, we additionally characterize HLA binding repertoire using Rosetta comparative modeling simulations. Subsequent determination of the x-ray structure of decamer-bound HLA-A*01:01 further validates the Rosetta predictions. This work provides a novel approach towards robust, high-throughput identification and detailed characterization of highly stable neoantigen/HLA targets with desired T-cell recognition features for cancer immunotherapy.
Citation Format: Sofie R. Salama, Jugmohit S. Toor, Arjun A. Rao, Andrew C. McShan, Mark Yarmarkovich, Sarvind Tripathi, Santrupti Nerli, Ada A. Madejska, Son Nguyen, Karissa Yamaguchi, John M. Maris, David Haussler, Nikolaos G. Sgourakis. Distinct CD8+ T-cell recognition profiles driven by conformational plasticity of recurrent neuroblastoma neoepitopes [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B02.
Abstract B09: IL6 and CXCL8 mediate redundant tumor-host signaling pathways that facilitate osteosarcoma lung metastasis
Authors: Roberts Ryan D. , Cam Hakan , Gross Amy C. , Winget Sarah , Phelps Doris , Houghton Peter J. 
Published: February 2019

Abstract
Osteosarcoma (OS) kills patients through aggressive metastatic spread, primarily to lung tissues. Our lab has sought to understand that tumor-host interactions that mediate this propensity for OS cells to colonize and grow in the lung. We identified two factors, IL6 and CXCL8, that become overexpressed in metastatic OS nodules relative to the same patient’s primary lesions. Expression of these factors correlates strongly with capacity to colonize lung tissue in murine models of OS metastasis. Aberrant expression of ΔNp63 drives production of IL6 and CXCL8 and can endow poorly metastatic OS tumors with increased metastatic potential. This effect can be completely reversed by blocking IL6 and CXCL8. Treating mice inoculated with circulating OS cells with inhibitors of IL6 and CXCL8 signaling reduces lung metastasis. This effect completely blocks lung colonization in some models, but only when used in combination. The effects of IL6 and CXCL8 inhibition endure for many months beyond discontinuation of therapy. Genetic manipulation studies confirm that these effects result from on-target effects of the drugs. Clinical studies performed in canine patients will help determine whether these treatments might be effective adjuvants for the treatment of patients with OS.
Citation Format: Ryan D. Roberts, Hakan Cam, Amy C. Gross, Sarah Winget, Doris Phelps, Peter J. Houghton. IL6 and CXCL8 mediate redundant tumor-host signaling pathways that facilitate osteosarcoma lung metastasis [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B09.
Abstract B17: ADGRB3 is a novel tumor suppressor epigenetically silenced in WNT medulloblastoma
Authors: Bhattacharya Debanjan , Zhu Dan , Devi Narra , Meir Erwin G. Van 
Published: February 2019

Abstract
Medulloblastoma (MB) is the most aggressive primary malignant brain tumor in children and arises from neural progenitor cells in the developing cerebellum. Although some subtypes of MB show a favorable prognosis with treatment, still one third of patients succumb to this disease and the children who survive suffer from long-term side effects of the aggressive treatments. ADGRB3 (formerly called BAI3) is a member of the ADGRB1-3 subfamily of adhesion GPCR transmembrane proteins, which are highly expressed in the brain specially in cerebellum and hippocampal neurons. The ADGRB3 gene was recently found to undergo somatic mutations in several cancers, but nothing is known about the functional role of ADGRB3 in medulloblastoma. Our recent findings based on analysis of a published microarray dataset and RT-PCR experiments showed that ADGRB3 mRNA expression was selectively repressed in WNT-MB tumor tissue compared to other three molecular subgroups and normal human cerebellar tissue. Using bisulfite sequencing we have detected hypermethylation of the ADGRB3 promoter exclusively in WNT-MB subgroup of human MB tissue but not in the other three molecular subgroups and normal human cerebellar tissue. These results clearly indicate that ADGRB3 is epigenetically silenced in WNT-MB via promoter hypermethylation. In vitro experiments showed that restoration of ADGRB3 expression in ADGRB3-silenced MB cell lines slows cell growth and inhibits WNT signaling targets. We further analyzed whether methyl CpG binding proteins and histone modifications modulate transcriptional repression of ADGRB3 in WNT-MB. ChIP assays revealed enrichment of repressive MBD2 protein in the ADGRB3 promoter region. siRNA mediated knockdown of ADGRB3 in ADGRB3-silent MB cell line (UW288-1) was found to reactivate ADGRB3 expression. We found that in vitro treatment with KCC-07, a recently discovered MBD2 inhibitor, reactivates ADGRB3 mRNA expression in ADGRB3-silent but not expressing MB cells. We are currently investigating whether ADGRB3 can negatively regulate the WNT/beta-catenin pathway or acts via an independent pathway that synergizes with it to facilitate transformation. Altogether, our findings define an epigenetic mechanism for ADGRB3 silencing in WNT-MB and indicate a novel role of ADGRB3 as a potent suppressor of oncogenic cerebellar transformation. Our findings also highlight the potential of epigenetic reactivation of ADGRB3 as a less toxic therapeutic intervention for the children suffering from WNT-MB.
Citation Format: Debanjan Bhattacharya, Dan Zhu, Narra Devi, Erwin G. Van Meir. ADGRB3 is a novel tumor suppressor epigenetically silenced in WNT medulloblastoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B17.
Abstract B18: Modeling renal medullary carcinomas identifies druggable vulnerabilities in SMARCB1-deficient cancers
Authors: Hong Andrew L. , Tseng Yuen-Yi , Kynnap Bryan D. , Doshi Mihir B. , Wala Jeremiah , Sandoval Gabriel , Church Alanna J. , Mullen Elizabeth , Kadoch Cigall , Roberts Charles W.M. , Beroukhim Rameen , Boehm Jesse S. , Hahn William C. 
Published: February 2019

Abstract
Renal medullary carcinomas (RMCs) are thought to be driven by the loss of tumor suppressor, SMARCB1. These rare kidney cancers carry a very poor prognosis and primarily affect African American adolescents and young adults with sickle cell trait. From two patients with RMC, we have identified by whole-genome sequencing mechanisms of SMARCB1 loss (e.g., inactivating fusion events involving SMARCB1). We developed in vitro models of primary and relapsed metastatic disease. We performed biochemical and functional studies to conclusively show that RMC is dependent on loss of SMARCB1, similar to rhabdoid tumors and atypical teratoid/rhabdoid tumors. Furthermore, we performed small-molecule screens, pooled CRISPR-Cas9 knockout, and RNAi suppression screens focused on druggable cancer targets. Integration of these orthogonal methods identifies a core set of targets that may provide a rational approach to therapeutic targeting for this rare kidney cancer and other SMARCB1-deficient cancers.
Citation Format: Andrew L. Hong, Yuen-Yi Tseng, Bryan D. Kynnap, Mihir B. Doshi, Jeremiah Wala, Gabriel Sandoval, Alanna J. Church, Elizabeth Mullen, Cigall Kadoch, Charles W.M. Roberts, Rameen Beroukhim, Jesse S. Boehm, William C. Hahn. Modeling renal medullary carcinomas identifies druggable vulnerabilities in SMARCB1-deficient cancers [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B18.