bluuebunny/crossref_metadata_2025_split huggingface dataset:
Crustal structure and heat-flow history in the UK Rockall Basin, derived from backstripping and gravity-inversion analysis
Authors: Roberts Alan M. , Alvey Andrew D. , Kusznir Nick J. 
Published: May 2018

Seismic data made available by the UK OGA (Oil & Gas Authority) has been used to constrain a model of crustal structure and heat-flow history for the UK Rockall Basin. Top basement/base sediment has been interpreted around the full extent of the seismic dataset. This has produced a model for the thickness of the sediment fill within the basin which is thicker than previous published estimates.

The new sediment-thickness model has been incorporated into a 3D backstripping study, producing maps of subsidence and thinning factor. Analysis of backstripped subsidence shows the thinning factor reaching peak values of
c.
0.8–0.85 (β factor >5) in the south-central axial area, reducing in magnitude northwards to
c.
0.7. The new sediment-thickness model has also been incorporated into a 3D gravity-inversion study, mapping Moho depth, crustal thickness and thinning/stretching factor. The results show crustal-basement thickness reduced to
c.
6 km, thinning factor
c.
0.8, in the south-central area, while it spans the range
c.
6–10 km further north. The results are compatible with previous seismic refraction work in both the UK and Irish sectors of the Rockall Basin. We believe that the extension which created the basin was non-magmatic and that the axial region is underlain by highly-thinned continental crust.

The results from the gravity inversion have been used to make predictions about the top-basement heat-flow history. Heat flow in the basin centre is predicted to have been initially high, reducing with time, associated with cooling of the transient synrift heat-flow anomaly. On the basin flanks heat flow was less variable over time, its magnitude controlled primarily by constant radiogenic heat input from the basement, rather than by the transient geotherm anomaly.
There remain considerable uncertainties associated with our interpretation and analysis. These uncertainties have been addressed with sensitivity analyses.
A regional gravity-inversion model, using the new sediment-thickness data spliced into regional public-domain information, shows that structural and stretching continuity can be mapped at the crustal scale along the full length of the UK/Irish Rockall Basin, contrary to conclusions from some previous studies.
Targeting the Hsp40/Hsp70 Chaperone Axis as a Novel Strategy to Treat Castration-Resistant Prostate Cancer
Authors: Moses Michael A. , Kim Yeong Sang , Rivera-Marquez Genesis M. , Oshima Nobu , Watson Matthew J. , Beebe Kristin E. , Wells Catherine , Lee Sunmin , Zuehlke Abbey D. , Shao Hao , Bingman William E. , Kumar Vineet , Malhotra Sanjay V. , Weigel Nancy L. , Gestwicki Jason E. , Trepel Jane B. , Neckers Leonard M. 
Published: May 2018

Abstract
Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling, in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose expression has been correlated with therapeutic resistance and poor prognosis. In a screen to identify small-molecule dual inhibitors of both androgen-dependent and androgen-independent AR gene signatures, we identified the chalcone C86. Binding studies using purified proteins and CRPC cell lysates revealed C86 to interact with Hsp40. Pull-down studies using biotinylated-C86 found Hsp40 present in a multiprotein complex with full-length (FL-) AR, ARv7, and Hsp70 in CRPC cells. Treatment of CRPC cells with C86 or the allosteric Hsp70 inhibitor JG98 resulted in rapid protein destabilization of both FL-AR and ARv, including ARv7, concomitant with reduced FL-AR- and ARv7-mediated transcriptional activity. The glucocorticoid receptor, whose elevated expression in a subset of CRPC also leads to androgen-independent AR target gene transcription, was also destabilized by inhibition of Hsp40 or Hsp70. In vivo, Hsp40 or Hsp70 inhibition demonstrated single-agent and combinatorial activity in a 22Rv1 CRPC xenograft model. These data reveal that, in addition to recognized roles of Hsp40 and Hsp70 in FL-AR LBD remodeling, ARv lacking the LBD remain dependent on molecular chaperones for stability and function. Our findings highlight the feasibility and potential benefit of targeting the Hsp40/Hsp70 chaperone axis to treat prostate cancer that has become resistant to standard antiandrogen therapy.
Significance:These findings highlight the feasibility of targeting the Hsp40/Hsp70 chaperone axis to treat CRPC that has become resistant to standard antiandrogen therapy. Cancer Res; 78(14); 4022–35. ©2018 AACR.
Preclinical Antitumor Activity of a Novel Anti–c-KIT Antibody–Drug Conjugate against Mutant and Wild-type c-KIT–Positive Solid Tumors
Authors: Abrams Tinya , Connor Anu , Fanton Christie , Cohen Steven B. , Huber Thomas , Miller Kathy , Hong E. Erica , Niu Xiaohong , Kline Janine , Ison-Dugenny Marjorie , Harris Sarah , Walker Dana , Krauser Klaus , Galimi Francesco , Wang Zhen , Ghoddusi Majid , Mansfield Keith , Lee-Hoeflich Si Tuen , Holash Jocelyn , Pryer Nancy , Kluwe William , Ettenberg Seth A. , Sellers William R. , Lees Emma , Kwon Paul , Abraham Judith A. , Schleyer Siew C. 
Published: May 2018

Abstract
Purpose: c-KIT overexpression is well recognized in cancers such as gastrointestinal stromal tumors (GIST), small cell lung cancer (SCLC), melanoma, non–small cell lung cancer (NSCLC), and acute myelogenous leukemia (AML). Treatment with the small-molecule inhibitors imatinib, sunitinib, and regorafenib resulted in resistance (c-KIT mutant tumors) or limited activity (c-KIT wild-type tumors). We selected an anti–c-KIT ADC approach to evaluate the anticancer activity in multiple disease models.
Experimental Design: A humanized anti–c-KIT antibody LMJ729 was conjugated to the microtubule destabilizing maytansinoid, DM1, via a noncleavable linker (SMCC). The activity of the resulting ADC, LOP628, was evaluated in vitro against GIST, SCLC, and AML models and in vivo against GIST and SCLC models.
Results: LOP628 exhibited potent antiproliferative activity on c-KIT–positive cell lines, whereas LMJ729 displayed little to no effect. At exposures predicted to be clinically achievable, LOP628 demonstrated single administration regressions or stasis in GIST and SCLC xenograft models in mice. LOP628 also displayed superior efficacy in an imatinib-resistant GIST model. Further, LOP628 was well tolerated in monkeys with an adequate therapeutic index several fold above efficacious exposures. Safety findings were consistent with the pharmacodynamic effect of neutropenia due to c-KIT–directed targeting. Additional toxicities were considered off-target and were consistent with DM1, such as effects in the liver and hematopoietic/lymphatic system.
Conclusions: The preclinical findings suggest that the c-KIT–directed ADC may be a promising therapeutic for the treatment of mutant and wild-type c-KIT–positive cancers and supported the clinical evaluation of LOP628 in GIST, AML, and SCLC patients. Clin Cancer Res; 24(17); 4297–308. ©2018 AACR.
Abstract A03: Perturbation of proteostasis is lethal in SMARCB1-deficient tumors
Authors: Genovese Giannicola , Carugo Alessandro , Minelli Rosalba , Frederick  , Robinson Scott , Msaouel Pavlos , Heffernan Tim , Viale Andrea , Tannir Nizar , Draetta Giulio 
Published: May 2018

Abstract
Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. The SWI/SNF complex, specifically, is involved in a plethora of biologic functions including cell cycle regulation, terminal differentiation, and regulation of cell metabolism. The crucial chromatin-remodeling function of the SWI/SNF complex during organogenesis and tissue specification is further supported by clinical data showing that the biallelic inactivation of the core subunits SMARCB1 and SMARCA4 results in the emergence of extremely aggressive pediatric malignancies characterized by a dramatic impairment of cell cycle regulation and cellular differentiation programs, resulting in highly lethal diseases characterized by early onset, widespread metastatic dissemination, and resistance to chemotherapy. So far the lack of conditional genetic models of malignant rhabdoid tumors (MRTs) made difficult to investigate the molecular bases of malignant transformation as well as the existence of dependencies associated with SMARCB1 loss. In order to identify the functional vulnerabilities of SMARCB1-deficient cancers, we developed an embryonic mosaic model of malignant rhabdoid tumors (MRTs) that faithfully recapitulates the clinicopathologic features of human disease. By using this novel experimental system we discovered that, upon SMARCB1 ablation, embryonic epithelial progenitors undergo a profound anabolic reprogramming resulting in a global increase in protein biosynthesis and in the adaptive activation of UPR and ER stress response. As a consequence, murine and human SMARCB1-deficient malignancies display an exquisite sensitivity to agents inducing proteotoxic stress and to the pharmacologic and genetic perturbation of autophagy. Our findings, therefore, have immediate clinical implications, paving the way for drug repositioning trials investigating combinations of agents with already known safety profiles targeting simultaneously UPR and the authopagic catabolic machinery in a class of orphan diseases affecting children with limited therapeutic options.
Note: This abstract was not presented at the conference.
Citation Format: Giannicola Genovese, Alessandro Carugo, Rosalba Minelli, Frederick, Scott Robinson, Pavlos Msaouel, Tim Heffernan, Andrea Viale, Nizar Tannir, Giulio Draetta. Perturbation of proteostasis is lethal in SMARCB1-deficient tumors [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A03.
Abstract A05: Investigating mechanisms of obesity-mediated pancreatic cancer progression
Authors: Muzumdar Mandar Deepak , Dorans Kimberly Judith , Chung Katherine Minjee , Bhutkar Arjun , Fuchs Charles , Jacks Tyler 
Published: May 2018

Abstract
Genetically engineered mouse models (GEMMs) that faithfully recapitulate the genetics and histology of human tumors are an underutilized tool to understand how modifiable risk factors influence tumor development. Prospective cohort studies have shown that obesity is associated with an increased risk of developing pancreatic cancer, more advanced disease at diagnosis, and worse survival, though the precise mechanisms behind which obesity contributes to cancer progression remain elusive. We crossed mice harboring loss-of-function mutations in the leptin gene (ob/ob) with Pdx1-Cre; LSL-KrasG12D (KC) mice predisposed to initiate pancreatic cancers. KC; ob/ob mice are obese and exhibit markedly shortened survival (~4 months vs. ~1 year), increased primary tumor burden, and enhanced progression to adenocarcinoma compared to nonobese KC mice. Interestingly, early correction of leptin deficiency using an adeno-associated virus (AAV)-based approach induces rapid normalization of body weight and hyperglycemia and completely prevents the emergence of enhanced tumor burden. In contrast, late leptin restoration following tumor progression does not impact survival. These data suggest a causal and reversible role for obesity in early pancreatic cancer progression. Furthermore, by evaluating the degree by which alternative interventions phenocopy the effects of leptin restoration, we have developed a model to rapidly interrogate mechanisms of obesity-mediated tumor progression. As a proof of principle, we have tested the ability of immunomodulatory (aspirin) and antidiabetic (metformin) agents, observed to impact pancreatic cancer risk and survival in human cohorts, to intercept cancer progression in this model. Finally, combined molecular and biochemical analyses of tumors reveal increased immune cell activation and fibrosis in KC; ob/ob mice compared to nonobese KC and KC; p53 mutant mice and provide specific molecular targets to evaluate for pancreatic cancer therapy and prevention.
Citation Format: Mandar Deepak Muzumdar, Kimberly Judith Dorans, Katherine Minjee Chung, Arjun Bhutkar, Charles Fuchs, Tyler Jacks. Investigating mechanisms of obesity-mediated pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A05.
Abstract A18: Generation of new conditional Kras-alleles by CRISPR-based genome editing
Authors: Zafra Maria Paz , Schatoff Emma M. , Han Teng , Dow Lukas E. 
Published: May 2018

Abstract
KRAS is the most frequently mutated oncogene in human cancers, and specific cancer types show a clear bias in the types and frequency of Kras alterations. However, we do not have a clear understanding of how distinct Kras mutations dictate tumor biology and response to therapy. The generation of conditional animal models, such as Lox-Stop-Lox (LSL) KrasG12D and LSL-KrasG12Vgeo mice, has provided important tools to dissect the impact of Kras mutation in tumor development, but these models alone do not recapitulate the spectrum of Kras alterations in human cancer. To better reflect the Kras mutational landscape in human cancers, we have developed a series of critical LSL-Kras mouse models that recapitulate common Kras alterations observed in colorectal (G13D), pancreatic (G12R), and lung cancer (G12C), allowing the direct interrogation of the effects of these Kras mutations on disease phenotype and treatment response.
To do this, we targeted embryonic stem cells (ESCs) carrying the LSL-KrasG12D allele, by co-transfection of a modified high-fidelity Cas9 (Cas9-HFz), a LSL-Kras-targeted sgRNA, and an HDR template carrying the new mutation. While Cas9-HFz displayed a slight decrease in homology-directed repair (HDR) efficiency in comparison with wild-type Cas9, it enabled high specificity editing of only the LSL allele. Targeted deep sequencing revealed a significant reduction in “off-target” events in wild-type Kras locus in Cas9-HFz transfected samples compared to unmodified Cas9. We next generated transgenic mice by blastocyst injection and produced mice carrying each LSL-Kras variant, a pancreas-specific Cre (p48-Cre), and a far-red fluorescent Cre-reporter (mKate2). We are now analyzing the impact of specific Kras alterations in tumor initiation in distinct tissues such as the pancreas, colon, and lung. Together with available LSL-KrasG12D and LSL-KrasG12V already available, our new alleles will serve as critical tools for better dissecting the genetic factors that dictate disease initiation, progression, and response to therapy.
Citation Format: Maria Paz Zafra, Emma M. Schatoff, Teng Han, Lukas E. Dow. Generation of new conditional Kras-alleles by CRISPR-based genome editing [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A18.
Abstract A19: Phosphorylation results in nuclear translocation of Dicer protein that increases metabolism, accelerates aging, and alters tumorigenesis
Authors: Aryal Neeraj K. , Arur Swathi , Lozano Guillermina 
Published: May 2018

Abstract
Dicer is a well-conserved and essential gene that is required for the production of micro RNAs that play key roles during development and cancer. Several studies have associated aberrant Dicer expression in humans with developmental defects (Dicer1 syndrome) and poor prognosis in various cancers. One important mechanism of controlling protein stability and function is through post-translational modification. Recently, Extracellular signal-Regulated Kinase (ERK) dependent phosphorylation of Dicer during oogenesis has been shown to be essential in C. elegans. The phosphorylation sites in Dicer (Ser1718 and Ser1842 in mice) are well conserved and the phosphorylation is necessary and sufficient for Dicer's translocalization from cytoplasm to nucleus. We are interested in understanding the phosphorylation-mediated control of Dicer function during development and cancer. To understand the role of phospho-Dicer in mammals, we have generated five new Dicer1 alleles including phospho-mimetic mouse models with both serines replaced with aspartic acids (DicerS2D), only Ser1842 replaced with aspartic acid (DicerS1842D), and only Ser1718 replaced with aspartic acid (DicerS1718D).
Phenotypic study shows that &gt;75% of DicerS2D/S2D mutants and &gt;60% of DicerS1842D/S1842D mutants die within five days after birth, while all heterozygous mutants and DicerS1718D/S1718D mice are phenotypically normal. The DicerS2D/S2D and DicerS1842D/S1842D survivors show signs of accelerated aging including smaller size, hunching of backbone, compromised weight gain, infertility, systemic tissue atrophy, and early lethality. We have also observed that DicerS2D/S2D animals and MEFs have increased metabolism as compared with wild type. Since aging and cancer are closely linked and altered metabolism is a hallmark of cancer, we hypothesize that phosphorylated Dicer produces an altered miRNA profile that affects metabolism, leading to developmental defects and tumorigenesis. Transcriptional profiling of MEFs and testes have shown that miRNA profiles are very different in mutants than in wild type, and the most affected pathways are metabolism and cancer. To test the role of phospho-Dicer in tumorigenesis, we crossed the DicerS2D allele into KRasLA1/+ driven nonmetastatic tumor model. The results show that phospho-Dicer reduces tumor-free survival, changes tumor spectrum, and drives metastasis in this tumor model.
Citation Format: Neeraj K. Aryal, Swathi Arur, Guillermina Lozano. Phosphorylation results in nuclear translocation of Dicer protein that increases metabolism, accelerates aging, and alters tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A19.
Abstract A28: Understanding the role of the tumor suppressor p53 in pancreatic cancer development
Authors: Flowers Brittany M. , Garcia Patty B. , Grüner Barbara M. , Winslow Monte M. , Attardi Laura D. 
Published: May 2018

Abstract
In the next decade, pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer-related death. This high rate of mortality is attributed to late-stage diagnosis and lack of effective therapeutic strategies. The tumor-suppressor gene TP53 is mutated in ~75% of PDAC patients. The most frequently observed TP53 mutations in PDAC occur within the DNA binding domain at codons 175 and 273. TP53 mutations may induce loss of wild-type p53 function and gain of novel, oncogenic functions. We aim to use different mouse models of PDAC to identify the molecular pathways deregulated when wild-type p53 is lost and mutant p53 is expressed, to elucidate the molecular mechanisms driving PDAC development. While previous studies have suggested that point mutant p53 drives gain-of-function phenotypes, our studies of aging Pdx1-Cre;KrasLSL-G12D/+;Rosa26LSL-tdTomato/LSL-tdTomato mice with conditional p53 knockout (p53Flox/Flox or p53Flox/Null) or p53 mutation (p53LSL-R172H/Flox or p53LSL-R172H/Null) did not demonstrate a clear mutant p53 gain-of-function phenotype in tumor latency. We hypothesize that tumor latency is too rapid in these models to manifest a clear gain-of-function phenotype, requiring the establishment of different model systems. Indeed, our preliminary studies using tumor-derived p53R172H cell lines and isogenic p53 null cell lines suggest a role for mutant p53 gain of function in later-stage tumorigenesis, specifically in metastatic seeding. Furthermore, we are evaluating the role of the putative PDAC cells of origin, pancreatic acinar and ductal cells, in PDAC development. Using both tumor-derived mouse cell lines and pancreatic lineage-specific genetically engineered mouse models of PDAC, we can evaluate the consequences of loss of wild-type p53 expression and gain of mutant p53 expression in different pancreatic compartments. Ultimately, using these systems we aim to elucidate the target genes and molecular pathways controlled by wild-type p53 or by mutant p53 to regulate PDAC initiation. Understanding the molecular mechanisms driving PDAC initiation is critical for the development of new therapeutic strategies for early detection and effective intervention in PDAC patients.
Citation Format: Brittany M. Flowers, Patty B. Garcia, Barbara M. Grüner, Monte M. Winslow, Laura D. Attardi. Understanding the role of the tumor suppressor p53 in pancreatic cancer development [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A28.
Abstract A31: Biallelic Dicer1 loss in endothelial cells drives angiosarcoma development
Authors: Hanna Jason A. , Drummond Catherine J. , Garcia Matthew R. , Go Jonathan C. , Finkelstein David , Rehg Jerold E. , Hatley Mark E. 
Published: May 2018

Abstract
Angiosarcoma is an aggressive and highly metastatic vascular sarcoma with an extremely poor prognosis. Because of the rarity of the disease, the molecular drivers and optimal treatment strategies for patients remain unclear, highlighting the need for novel genetic and in vivo animal models. MicroRNAs are small RNAs that regulate gene expression and DICER1 is the RNase III endoribonuclease that processes pre-microRNAs into mature microRNAs. DICER1 and microRNAs are central to numerous cellular processes and are often dysregulated in many cancers, including sarcomas. Here we show that biallelic Dicer1 deletion with endothelial expression of aP2-Cre drives aggressive and metastatic angiosarcoma independent of other genetically engineered oncogenes or tumor suppressor loss. Angiosarcomas in aP2-Cre;Dicer1Flox/- mice histologically and genetically resemble human angiosarcoma, and we found microRNA-23 target genes enriched in mouse and human angiosarcoma. Because Ras mutations and Cdkn2a loss are common in angiosarcoma, we interrogated them as angiosarcoma modifiers. Interestingly, we found that both oncogenic LSL-KrasG12D and loss of conditional Cdkn2aFlox decreased tumor latency. In addition, aP2-Cre;LSL-KrasG12D;Cdkn2aFlox/Flox mice developed angiosarcomas, providing a model with Dicer1 expression intact to further study the function of microRNAs in angiosarcoma. Thus, these findings illustrate that Dicer1 can function as a traditional loss-of-function tumor-suppressor gene and provide simple and fully penetrant animal models for the study of angiosarcoma development and metastasis.
Citation Format: Jason A. Hanna, Catherine J. Drummond, Matthew R. Garcia, Jonathan C. Go, David Finkelstein, Jerold E. Rehg, Mark E. Hatley. Biallelic Dicer1 loss in endothelial cells drives angiosarcoma development [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A31.