bluuebunny/crossref_metadata_2025 huggingface dataset:
A Modified Bat Algorithm with Conjugate Gradient Method for Global Optimization
Authors: Ahmed Huda I. , Hamed Eman T. , Saeed Chilmeran Hamsa Th.
Published: June 2020

Metaheuristic algorithms are used to solve many optimization problems. Firefly algorithm, particle swarm improvement, harmonic search, and bat algorithm are used as search algorithms to find the optimal solution to the problem field. In this paper, we have investigated and analyzed a new scaled conjugate gradient algorithm and its implementation, based on the exact Wolfe line search conditions and the restart Powell criterion. The new spectral conjugate gradient algorithm is a modification of the Birgin and Martínez method, a manner to overcome the lack of positive definiteness of the matrix defining the search direction. The preliminary computational results for a set of 30 unconstrained optimization test problems show that this new spectral conjugate gradient outperforms a standard conjugate gradient in this field and we have applied the newly proposed spectral conjugate gradient algorithm in bat algorithm to reach the lowest possible goal of bat algorithm. The newly proposed approach, namely, the directional bat algorithm (CG-BAT), has been then tested using several standard and nonstandard benchmarks from the CEC’2005 benchmark suite with five other algorithms and has been then tested using nonparametric statistical tests and the statistical test results show the superiority of the directional bat algorithm, and also we have adopted the performance profiles given by Dolan and More which show the superiority of the new algorithm (CG-BAT).
Automated Localization and Classification of Expressway Pole‐Like Road Facilities from Mobile Laser Scanning Data
Authors: Thanh Ha Tran , Chaisomphob Taweep
Published: June 2020

Mobile LiDAR is an emerging advanced technology for capturing three‐dimensional road information at a large scale effectively and precisely. Pole‐like road facilities are crucial street infrastructures as they provide valuable information for road mapping and road inventory. Thus, the automated localization and classification of road facilities are necessary. This paper proposes a voxel‐based method to detect and classify pole‐like objects in an expressway environment based on the spatially independent and vertical height continuity analysis. First, the ground points are eliminated, and the nonground points are merged into clusters. Second, the pole‐like objects are extracted using horizontal cross section analysis and minimum vertical height criteria. Finally, a set of knowledge‐based rules, which comprise height features and geometric shape, is constructed to classify the detected road poles into different types of road facilities. Two test sites of point clouds in an expressway environment, which are located in Bangkok, Thailand, are used to assess the proposed method. The proposed method extracts the pole‐like road facilities from two datasets with a detection rate of 95.1% and 93.5% and an overall quality of 89.7% and 98.0% in the classification stage, respectively. This shows that the algorithm could be a promising alternative for the localization and classification of pole‐like road facilities with acceptable accuracy.
A Comparison of Strategies to Improve Population Diets: Government Policy versus Education and Advice
Authors: Temple Norman J.
Published: June 2020

Different strategies have been utilized in order to improve the healthiness of the population diet. Many interventions employ education, advice, and encouragement (EAE). Those interventions have been carried out in diverse settings and may achieve modest success; the estimated risk of cardiovascular disease is lowered by about 5–15%. An alternative strategy is action policies carried out by the governments. The removal of trans-fatty acids from food is a model for a successful action policy. Other action policies include requiring a substantial reduction in the amount of salt added to processed foods and ordering schools to cease supplying unhealthy food to students. Taxes and subsidies can be used to increase the price of unhealthy foods, such as sugar-rich foods, and reduce the price of healthy foods, such as fruit and vegetables. It is very probable that action policies are more effective than those based on EAE. They are also much more cost-effective.
Atypical Salmonellosis in a Horse: Implications for Hospital Safety
Authors: Rothers Kristina L. , Hackett Eileen S. , Mason Gary L. , Nelson Brad B.
Published: June 2020

A 17-year-old Quarter Horse mare was evaluated for colic of 24-hour duration. Clinical signs and diagnostic evaluation were consistent with duodenitis-proximal jejunitis. The horse’s clinical condition deteriorated despite medical treatment and was euthanized. Aerobic culture collected from small intestinal ingesta was positive for Salmonella enterica subsp. enterica serovar Hadar. Salmonella sp. is commonly implicated in nosocomial infections in equine veterinary hospitals usually through feces containing the organism. Considering Salmonella sp. was cultured from the jejunal luminal contents and the large volume of nasogastric reflux that was evacuated in this case, a perceived risk of Salmonella sp. transmission from infected gastric reflux to other hospitalized cases was realized. Infectious agent biosecurity precautions should be undertaken in horses with nasogastric reflux to prevent hospital-acquired transmission.
Causal Link between Ventricular Ectopy and Concussion
Authors: Neary J. Patrick , Singh Jyotpal , Christiansen Jonathan P. , Teckchandani Taylor A. , Potter Kirsty L.
Published: June 2020

We present a unique case study report of a male individual with a history of mild nonischaemic cardiomyopathy, with no ventricular ectopy, that at the age of 76 years sustained multiple concussions (i.e., mild traumatic brain injury) within a week of each other. Concussion symptoms included cognitive difficulties, “not feeling well,” lethargy, fatigue, and signs of depression. He was later medically diagnosed with postconcussion syndrome. The patient, WJT, was referred for cardiac and neurological assessment. Structural neuroimaging of the brain (MRI) was unremarkable, but electrocardiography (ECG) assessments using a 24-hour Holter monitor revealed significant incidence of ventricular ectopy (9.4%; 9,350/99,836 beats) over a period of 5–6 months after injury and then a further increase in ventricular ectopy to 18% (15,968/88,189 beats) during the subsequent 3 months. The patient was then prescribed Amiodarone 200 mg, and his ventricular ectopy and concussion symptoms completely resolved simultaneously within days. To the authors’ knowledge, our study is the first to show a direct link between observable and documented cardiac dysregulation and concussion symptomology. Our study has important implications for both cardiac patients and the patients that sustain a concussion, and if medically managed with appropriate pharmacological intervention, it can reverse ventricular ectopy and concussion symptomology. More research is warranted to investigate the mechanisms for this dramatic and remarkable change in cardiac and cerebral functions and to further explore the brain-heart interaction and the intricate autonomic interaction that exists between the extrinsic and intracardiac nervous systems.
Leptin Overexpression as a Poor Prognostic Factor for Colorectal Cancer
Authors: Li Chunxiang , Quan Jichuan , Wei Ran , Zhao Zhixun , Guan Xu , Liu Zheng , Zou Shuangmei , Wang Xishan , Jiang Zheng
Published: June 2020

Leptin acts as an adipocytokine functions via the leptin receptor, which stimulates growth, migration, and invasion of cancer cells. This study is aimed at identifying leptin as a prognostic factor in colorectal cancer (CRC). The differentially expressed genes with prognostic value in CRC tissues either with or without liver metastasis were assessed based on The Cancer Genomic Atlas (TCGA). Leptin was considered a candidate gene for further analysis. Its expression features of 206 CRC patients without liver metastasis and 201 patients with metastasis on tissue microarrays were assessed by immunochemical staining, and the effect of leptin on survival was assessed by Kaplan‐Meier analyses. Overexpressed leptin indicated a poorer prognosis for CRC patients in overall survival (p < 0.05, log‐rank test) based on the TCGA database. The leptin expression significantly correlated with metastasis stage (p < .010) and lymph node involvement (p < .010). Multivariate analysis also indicated that strong leptin expression was an independent adverse prognosticator in CRC (p = .017). Leptin may be valued as a prognostic marker could contribute to predicting a clinical outcome for patients with CRC.
GGTA1/iGb3S Double Knockout Mice: Immunological Properties and Immunogenicity Response to Xenogeneic Bone Matrix
Authors: Shao Anliang , Ling You , Chen Liang , Wei Lina , Fan Changfa , Lei Dan , Xu Liming , Wang Chengbin
Published: June 2020

Background. Animal tissues and tissue‐derived biomaterials are widely used in the field of xenotransplantation and regenerative medicine. A potential immunogenic risk that affects the safety and effectiveness of xenografts is the presence of remnant α‐Gal antigen (synthesized by GGTA1 or/and iGb3S). GGTA1 knockout mice have been developed as a suitable model for the analysis of anti‐Gal antibody‐mediated immunogenicity. However, we are yet to establish whether GGTA1/iGb3S double knockout (G/i DKO) mice are sensitive to Gal antigen‐positive xenoimplants. Methods. α‐Gal antigen expression in the main organs of G/i DKO mice or bovine bone substitutes was detected via a standardized ELISA inhibition assay. Serum anti‐α‐Gal antibody titers of G/i DKO mice after immunization with rabbit red blood cells (RRBC) and implantation of raw lyophilized bone substitutes (Gal antigen content was 8.14 ± 3.17 × 1012/mg) or Guanhao Biotech bone substitutes (50% decrease in Gal antigen relative to the raw material) were assessed. The evaluation of total serum antibody, inflammatory cytokine, and splenic lymphocyte subtype populations and the histological analysis of implants and thymus were performed to systematically assess the immune response caused by bovine bone substitutes and bone substitute grafts in G/i DKO mice. Results. α‐Gal epitope expression was reduced by 100% in the main organs of G/i DKO mice, compared with their wild‐type counterparts. Following immunization with RRBC, serum anti‐Gal antibody titers of G/i DKO mice increased from 80‐ to 180‐fold. After subcutaneous implantation of raw lyophilized bone substitutes and Guanhao Biotech bone substitutes into G/i DKO mice, specific anti‐α‐Gal IgG, anti‐α‐Gal IgM, and related inflammatory factors (IFN‐γ and IL‐6) were significantly increased in the raw lyophilized bone substitute group but showed limited changes in the Guanhao Biotech bone substitute group, compared with the control. Conclusion. G/i DKO mice are sensitive to Gal antigen‐positive xenogeneic grafts and can be effectively utilized for evaluating the α‐Gal‐mediated immunogenic risk of xenogeneic grafts.
Antibiotic Resistance and Virulence Gene Characteristics of Methicillin-ResistantStaphylococcus aureus(MRSA) Isolated from Healthy Edible Marine Fish
Authors: Fri Justine , Njom Henry A. , Ateba Collins N. , Ndip Roland N.
Published: June 2020

Thirty-three (33) isolates of methicillin-resistantStaphylococcus aureus(MRSA) from healthy edible marine fish harvested from two aquaculture settings and the Kariega estuary, South Africa, were characterised in this study. The phenotypic antimicrobial susceptibility profiles to 13 antibiotics were determined, and their antibiotic resistance determinants were assessed. A multiplex PCR was used to determine the epidemiological groups based on the type of SCCmeccarriage followed by the detection of staphylococcal enterotoxin-encoding genessea-sedand the Panton Valentine leucocidin gene (pvl). A high antibiotic resistance percentage (67–81%) was observed for Erythromycin, Ampicillin, Rifampicin, and Clindamycin, while maximum susceptibility to Chloramphenicol (100%), Imipenem (100%), and Ciprofloxacin (94%) was recorded. Nineteen (58%) of the MRSA strains had Vancomycin MICs of ≤2 μg/mL, 4 (12%) with MICs ranging from 4–8 μg/mL, and 10 (30%) with values ≥16 μg/mL. Overall, 27 (82%) isolates were multidrug-resistant (MDR) with Erythromycin-Ampicillin-Rifampicin-Clindamycin (E-AMP-RIP-CD) found to be the dominant antibiotic-resistance phenotype observed in 4 isolates. Resistance genes such astetM,tetA,ermB,blaZ,andfemAwere detected in two or more resistant strains. A total of 19 (58%) MRSA strains possessed SCCmectypes I, II, or III elements, characteristic of healthcare-associated MRSA (HA-MRSA), while 10 (30%) isolates displayed SCCmectype IVc, characteristic of community-associated MRSA (CA-MRSA). Six (18%) of the multidrug-resistant strains of MRSA were enterotoxigenic, harbouring thesee, sea,orsecgenes. A prevalence of 18% (6/33) was also recorded for theluk-PVLgene. The findings of this study showed that marine fish contained MDR-MRSA strains that harbour SCCmectypes, characteristic of either HA-MRSA or CA-MRSA, but with a low prevalence of enterotoxin andpvlgenes. Thus, there is a need for continuous monitoring and implementation of better control strategies within the food chain to minimise contamination of fish with MDR-MRSA and the ultimate spread of the bug.
Abstract A11: Urine sample-derived cerebral organoids suitable for modeling brain development and pathogenesis
Authors: Hu Jiangnan , Lin Victor , Goldberg Mark , Wang Yu-chieh
Published: June 2020

Human cerebral organoids (COs) have been leveraged in many recent studies that led to significant discoveries regarding developmental biology, disease mechanisms, and pharmacologic responses in the central nervous system. Here, we intend to establish cerebral organoids suitable for modeling brain development and pathogenesis based on somatic cells that are isolated noninvasively. The development of such organoids began with the collection of urinary epithelial cells (UECs) from human urine samples. We have obtained multiple lines of human UEC-derived induced pluripotent stem cells (hUEC-iPSCs) by cell reprogramming. COs were generated from hUEC-iPSCs using a protocol optimized by our group. To comprehensively characterize the cellular and molecular features of our COs, we examined samples at different developmental time points. The hUEC-iPSC-developed COs exhibit normal development with neurogenesis and maturation of neuronal cells forming brain layers. These COs produce neurotropic and anti-inflammatory factors that are presumably critical for neurogenesis and neural repair. Several metalloproteases that may facilitate cell migration and microenvironment rearrangement are also present. After transplantation into the mouse cerebrum, vascularization quickly develops in the implanted COs, suggesting their viability and ability to interact with the environment. To gauge cellular plasticity of hUEC-iPSC-developed COs along their development, we exposed the COs that were developed using three different protocols and initially committed to telencephalic development to culture media containing FGF2 and FGF19. Multiple markers of the developing hindbrain were highly upregulated in the COs, indicating that their cellular plasticity and potential to be reprogrammed into noncerebral neural tissue in response to optimized stimuli. Overall, our work begins to reveal the promise of generating personalized COs from cells that are isolated from urine samples. These COs present with cellular plasticity that permits a possibility of generating neural tissue of various brain regions by converting prosencephalic organoids into a mesencephalic or rhombencephalic fate. With further adaptation, this human CO platform could form a unique and personalized model for the investigation of neural development influenced by oncogenic signaling and facilitate the development of novel therapies for treating neurologic malignancy.

Citation Format: Jiangnan Hu, Victor Lin, Mark Goldberg, Yu-chieh Wang. Urine sample-derived cerebral organoids suitable for modeling brain development and pathogenesis [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A11.
Abstract B03: Acute megakaryoblastic leukemia is associated with poor overall survival and enriched in JAK2 variants
Authors: Li Marissa , Binder Moritz , Basha Basma , Zhang Ben , Ferrer Alejandro , Liu Yuanhan , Patnaik Mrinal , Viswanatha David , Gangat Naseema
Published: June 2020

In this study, we aimed to characterize the molecular mechanisms of two very rare subtypes of AML: acute megakaryoblastic leukemia (AMKL) and acute panmyelosis with myelofibrosis (APMF). Our goal is to describe the clinical-pathologic features of APMF and explore the genomic landscape AMKL to further understand these rare malignancies. We identified 35 patients diagnosed with AMKL (n=27) and APMF (n=8) at Mayo Clinic between 1995 and 2015 by retrospective chart review. For 10 of the AMKL patients, tissue was available for whole-exome sequencing and was analyzed in comparison to a published AML reference population. The median overall survival was shorter in patients with AMKL (3.9 months, 95% CI 1.7-7.4) than in patients with APMF (14.3 months, 95% CI 0.7-NE, p = 0.026,). For both AMKL and APMF, patients who underwent allogeneic hematopoietic stem cell transplantation had better overall survival (14.3 months, 95% CI 1.9-NE) compared to those not undergoing transplantation (4.6 months, 95% CI 1.5-7.4, p = 0.003). Patients with AMKL presented more frequently with splenomegaly, with higher peripheral blood blast counts, and with higher serum lactate dehydrogenase concentrations. 9 out of 10 AMKL patients with available tissue for sequencing demonstrated variants in 22 of 35 AML driver genes, with JAK2 V617F as the most common mutation. Although our small study numbers preclude firm conclusions, it does reflect the rarity of these AML subtypes. Furthermore, inferior survival in AMKL (compared to APMF) was reflected in its proliferative disease features such as splenomegaly, high blast counts, and high lactate dehydrogenase. Interestingly, the presence of JAK2 V617F variants in 40% of the interrogated samples was higher than expected. Although JAK2 is a known molecular driver in myeloproliferative neoplasms, it is actually very rare in de novo AML (~1%). Despite improved survival with allogeneic stem cell transplant, we can conclude that treatment outcomes for AMKL and APMF with standard-of-care therapy were sobering and that patients with these rare AML subtypes should undergo molecular evaluation to qualify them for clinical trials with novel targeted therapies.

Citation Format: Marissa Li, Moritz Binder, Basma Basha, Ben Zhang, Alejandro Ferrer, Yuanhan Liu, Mrinal Patnaik, David Viswanatha, Naseema Gangat. Acute megakaryoblastic leukemia is associated with poor overall survival and enriched in JAK2 variants [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B03.
Abstract B17: Modeling genomic complexity of colorectal cancer using multigenic Drosophila models
Authors: Gopinath Sindhura , Cagan Ross , Schadt Eric
Published: June 2020

Colorectal cancer (CRC) is a leading cause of cancer related death worldwide, with an estimated 53,000 deaths in 2019 in the US alone. Despite significant progress made in elucidating mechanisms of tumor initiation and progression, targeted therapies have shown limited efficacy for inoperable or metastatic CRC tumors, especially KRAS or BRAF mutant tumors, which account for more than half (~55%) of CRC tumors. Several targeted inhibitors have failed clinical trials for CRC despite proving effective in preclinical CRC studies and other cancer types. A potential reason for this resistance is the presence of several other mutations in the tumors. CRC patient tumors present significant genetic heterogeneity with mutations in genes in several other major signaling pathways. We address the challenge of genetic complexity by constructing a population of multigenic Drosophila CRC models incorporating 7-15 gene alterations in each line. This population of CRC fly lines models the genetic heterogeneity of CRC by basing the genotype of each fly line on an individual patient’s tumor genotype, with a focus on Ras mutant tumors. Our work has identified multiple combinations of FDA-approved compounds that have shown efficacy in some complex multigenic models and not others. Bangi et al. (2019) discuss the results from the first human CRC patient to be treated with the recommended combination identified from screening the patient-matched fly model. My work aims to uncover the mechanisms of response and resistance presented by the population of heterogeneous CRC genotypes. My results show that there is variability in therapeutic response between different patient genotypes, even when they contain the same known CRC cancer drivers (such as Ras, p53, APC, etc.). I am investigating the downstream transcriptional and signaling networks activated by these genotypes to assess their contribution to resistance or response to specific therapeutic agents.

Citation Format: Sindhura Gopinath, Ross Cagan, Eric Schadt. Modeling genomic complexity of colorectal cancer using multigenic Drosophila models [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B17.
Abstract B50: HnRNP A3 regulates the nuclear EGFR localization and cancer progression
Authors: Chen Chi-Yuan , Lin Yu-Han , Wang Tong-Hong , Wu Chih-Ching
Published: June 2020

Aberrant subcellular translocation and distribution of epidermal growth factor receptor (EGFR) represents a major yet underappreciated cancer development mechanism in non-small cell lung cancer (NSCLC). In this study, we investigated the subcellular interactome of EGFR by free labeling approaches combined with LC-MS/MS, aiming to understand the associated protein networks involved in the tumorigenesis of NSCLC. A total of 54, 77, and 63 EGFR-interacting proteins were identified specifically in the cytosol, mitochondria, and nucleus fractions, respectively. Pathway-wise analyses of these proteins using the KEGG database revealed that the proteins interacting with cytosolic and nuclear EGFR proteins are involved in pathways of ribosome and spliceosome, respectively. The EGFR-interacting proteins in mitochondria are involved in the metabolism of propanoate, fatty acid, valine, leucine, and isoleucine. One of the nuclear EGFR-interacting proteins, hnRNP A3, was shown in this work to modulate the accumulation of nuclear EGFR. Downregulation of hnRNP A3 reduced the nuclear EGFR accumulation and was accompanied with reduced tumor growth ability both in vitro and in vivo. These results suggest that variations in the subcellular translocation and distribution of EGFR within NSCLC cells could affect tumor progression.

Citation Format: Chi-Yuan Chen, Yu-Han Lin, Tong-Hong Wang, Chih-Ching Wu. HnRNP A3 regulates the nuclear EGFR localization and cancer progression [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B50.
Abstract IA04: Stem cells: Coping with stress and cancer
Authors: Fuchs Elaine
Published: June 2020

Adult tissue stem cells have the ability to self-renew long term and differentiate into one or more tissues. Many stem cells are used sparingly to replenish cells during normal homeostasis. However, even stem cells that are quiescent must be able to respond quickly to injury in order to fuel rapid tissue regeneration. How stem cells balance self-renewal and differentiation is of fundamental importance to our understanding of normal tissue maintenance and wound repair. The regulatory circuitry governing this normal balancing act must be intricately regulated in normal homeostasis and then transiently altered to cope with injury responses. Increasing evidence suggests that the mechanism goes awry in inflammation and becomes hijacked in cancers. Skin epithelium is an excellent model system to understand how stem cells remain quiescent during times of minimal wear and tear, how these cells become mobilized during the cyclical bouts of hair growth and wound repair, and how the normal process of stem cell activation goes awry in cancer and inflammation. We have identified and characterized at a molecular level the skin’s stem cells and shown that they reside in distinct niches that impart to the stem cells their behavior both in task and in the molecular properties they display. We use high-throughput genetic and genomic approaches to dissect at a molecular level how stem cell interactions with their niches differ in homeostasis, wound repair, and inflammation, and how heterogeneity in the tumor microenvironment can confer on stem cells resistance to chemotherapy and immunotherapy. Our global objective is to apply our knowledge of the basic science of epithelial stem cells to unfold new avenues for therapeutics.

Citation Format: Elaine Fuchs. Stem cells: Coping with stress and cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA04.
Abstract IA06: The tissue-specific microenvironment in primary tumors and metastases
Authors: Werb Zena , Gonzalez Hugo , Winkler Juliane , Berens Eric
Published: June 2020

Cancer cells within tumors exist in specialized niches in the microenvironment. The tumor cells are heterogeneous and can have properties as divergent as self-renewal, tumor initiation and repopulation potential, dormancy, evasion of cell death, and metastasis. Metastasis is the major cause of poor outcome in breast cancer. The microenvironment is critical for regulating multiple aspects of tumor progression and metastasis. Understanding the processes involved in metastasis is critical for developing new preventative and therapeutic strategies. We have analyzed the matrix environment and its function in tumor progression using in vivo imaging, genetic models of breast cancer, patient-derived xenografts, organotypic cultures, and patient samples. We have found that the matrix environment and the innate immune cells responding to the primary tumor and infiltrating the metastatic sites are critical for regulating tumor invasion and metastasis. Indeed, the inflammatory microenvironment of metastatic sites was distinct from that of the parental tumor and the normal tissue, even before metastasis takes hold. Interplay between nonmetastatic primary breast cancer and innate immune response acts to control metastatic progression. At the single-cell level, early-stage metastatic cells possess a distinct stemlike gene expression signature. The metastatic cells and the microenvironment are distinct in different metastatic sites and from the primary tumor. Micrometastatic cells are distinct due to their increased expression of basal, stem cell, prosurvival, and dormancy-associated genes. In contrast, cells from macrometastases are similar to primary tumor cells, which are more differentiated and heterogeneous. We validated our findings with a large primary breast cancer tissue microarray and pleural effusions from breast cancer patients. These results suggest that novel cancer immunotherapies that activate and augment the function of antitumoral myeloid subpopulations could have therapeutic potential and be clinically important for patients with advanced breast cancer.

Citation Format: Zena Werb, Hugo Gonzalez, Juliane Winkler, Eric Berens. The tissue-specific microenvironment in primary tumors and metastases [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA06.
Abstract IA12: From mouse to man: Dissecting cancer mechanisms using mouse models
Authors: Abate-Shen Cory
Published: June 2020

I have a longstanding interest in understanding how basic cellular mechanisms become co-opted in cancer. I have approached this problem by studying the transcriptional regulatory mechanisms of homeobox genes with the goal of understanding their roles in development, differentiation, and cancer. Over the years, my research program has evolved towards its current focus in which we have undertaken a multidisciplinary approach to investigate genitourinary malignancies, which includes using mechanism-based studies, analyses of genetically engineered mouse models (GEMMs), and state-of-the-art systems biology approaches. My research focus on prostate cancer has its origins in our discovery of Nkx3.1, a prostate-specific homeobox gene that is essential for prostate differentiation and whose loss of function predisposes to prostate cancer. The culmination of our studies over many years has led to a model in which NKX3.1 functions as a gatekeeper that promotes prostate differentiation and protects against prostate cancer initiation. Our recent work has shown that Nkx3.1 is sufficient to fully reprogram non-prostate epithelium to form prostate in vivo. Our work showing that Nkx3.1 mutant mice accurately model indolent prostate cancer led to the discovery of a 3-gene panel that distinguishes indolent and aggressive human prostate cancers, which we are now advancing to the clinic. Moreover, our coclinical prevention study of Nkx3.1 mutant mice led to the identification of a gene signature that predicts response to antiandrogens for men on active surveillance. Furthermore, our analysis of Nkx3.1 mutant mice provided the foundation for our extensive series of GEMMs that are based on genomic alterations that are prevalent in human prostate cancer and that represent the full spectrum of prostate cancer phenotypes, ranging from preinvasive to lethal metastatic disease. To capitalize on these GEMMs, we have generated genome-wide regulatory networks for mouse and human prostate cancer, which have enabled cross-species analyses that have identified key drivers of the specific stages of prostate cancer. We have expanded these computational approaches to integrate preclinical data from GEMMs with human clinical data to predict drug response and optimize drug combinations for human prostate cancer. These studies have identified cellular plasticity as a mechanism of drug resistance in prostate cancer.

Citation Format: Cory Abate-Shen. From mouse to man: Dissecting cancer mechanisms using mouse models [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA12.
Abstract IA13: Identification, validation, and therapeutic targeting of a driver gene in poor-prognosis breast cancer
Authors: Kang Yibin
Published: June 2020

Breast cancer remains a significant health concern worldwide. Integrative genomic analysis of clinical breast cancer samples identified Metadherin (MTDH) as a driver gene that promotes breast cancer initiation, progression, and treatment resistance. Using genetically engineered mouse models, we found that MTDH sustains breast cancer progression and metastasis via interacting with SND1, and acute Mtdh loss inhibits breast cancer development. Using a structure-based small-molecule screen, we obtained a serial of MTDH/SND1 inhibitors. Treatments of the compounds suppress breast tumor growth and metastasis and sensitize breast cancer to chemotherapy by sensitizing cancer cells to stress-induced apoptosis. This series of studies illustrates the use of mouse models to validate clinically relevant novel therapeutic targets for breast cancer and illustrates the functional mechanism of driver genes in cancer progression and metastasis.

Citation Format: Yibin Kang. Identification, validation, and therapeutic targeting of a driver gene in poor-prognosis breast cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA13.
Abstract IA14: Deconstructing the origins of PDAC development
Authors: Flowers Brittany , Xu Hang , Hanson Kathryn , Curtis Christina , Vogel Hannes , Wood Laura , Attardi Laura D.
Published: June 2020

The TP53 gene, which encodes the p53 transcription factor, is mutated in ~75% of human pancreatic ductal adenocarcinomas (PDACs), underscoring the fundamental role of p53 as a barrier to PDAC development. Despite this critical function, however, the cellular and molecular programs through which p53 acts in pancreatic cancer suppression remain poorly understood. To gain a better understanding of the pathways through which p53 acts to suppress PDAC development, which will provide key insight into how the disease develops, we have taken combined mouse genetic and genomic approaches. First, we have sought to determine whether p53 acts in acinar and/or ductal cells to restrain PDAC development. Importantly, for these experiments we have used adult mice to more accurately mimic the development of PDAC in humans. Second, we have sought to systematically deconstruct the role of p53 deletion and p53 missense mutations in driving cancer from these different cells of origin. This comprehensive analysis of large adult mouse cohorts has helped to define the cell of origin for PDAC and the effects of different p53 mutations on spontaneous PDAC development. To gain additional insight into the programs that become dysregulated during pancreatic cancer development, we have performed RNA-sequencing analysis on tumors arising from different compartments and driven by different genetic lesions. These studies have revealed the molecular profiles of tumors arising from acinar versus ductal cells as well those driven by different types of p53 mutations. Through comparison to human pancreatic cancer data, our studies are helping us to better understand the paths to PDAC development in humans and the underlying origins of different subtypes of this disease.

Citation Format: Brittany Flowers, Hang Xu, Kathryn Hanson, Christina Curtis, Hannes Vogel, Laura Wood, Laura D. Attardi. Deconstructing the origins of PDAC development [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA14.
Abstract IA16: The International Human Cancer Models Initiative is generating models annotated with clinical and molecular data
Authors: Gerhard Daniela S.
Published: June 2020

For the past 60 years, cancer research has relied heavily on established cancer cell lines. Their genomes are known to have evolved in vitro and therefore may not reflect well the various salient features of patient tumors (e.g., sensitivity/resistance to cancer therapeutics, etc.). Novel model generation technologies promise to create the next-generation cancer models (NGCMs) to facilitate and enhance studies in various areas of cancer research. The Human Cancer Models Initiative (HCMI) is an international consortium that is developing ~1,000 NGCMs for use in a wide range of cancer-relevant discoveries, from genomic research, cell biology or bio/chemistry studies, to improvements in preclinical and clinical applications. Our goal is to make these models available broadly to the academic and industry researchers (community resource). Therefore, we established a process that ensures the quality of the models and the data associated with them. In my presentation I will describe the Initiative’s pipeline, status (e.g., tumor types, molecular characterization), challenges encountered, and how to obtain the models and associated data.

Citation Format: Daniela S. Gerhard. The International Human Cancer Models Initiative is generating models annotated with clinical and molecular data [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA16.
Abstract IA18: Genetic dissection of breast cancer development and therapy resistance in mouse models
Authors: Jonkers Jos
Published: June 2020

Genetically engineered mouse models (GEMMs) of human cancer not only permit us to gain a detailed insight into the specific genetic changes that drive tumor development and metastasis but also provide powerful tools to study the mechanisms underlying drug response and acquired resistance. Once these processes are understood in sufficient detail, it may be possible to design combination therapies that not only cause complete remissions but also eliminate remnant cells that elicit recurrent disease.

We have developed GEMMs of E-cadherin mutated lobular breast cancer. These mice develop mammary tumors that closely resemble the lobular morphology and the metastatic spectrum of the cognate tumors in humans. Using Sleeping Beauty (SB) transposon-based insertional mutagenesis in conditional E-cadherin mutant mice, we have found that heterozygous loss of MYH9 or overexpression of hyperactive truncated forms of MYPT1/2 and ASPP2 reduces actomyosin contractility and thereby promotes malignant transformation of E-cadherin-deficient mammary epithelial cells, resulting in ILC formation in mice. This work highlights actomyosin hypercontractility induced by E-cadherin loss as a critical barrier to ILC development.

We have also developed several GEMMs for somatic modeling of BRCA1-mutated triple-negative breast cancer using intraductal injection of lentiviral vectors for stable overexpression of exogenous genes and CAS9-mediated disruption or APOBEC-CAS9n-UGI (BE3)-mediated base editing of endogenous genes. We have used these GEMMs to validate RB, PTEN, PIK3CA, MYC, and MCL1 as bona fide driver genes in BRCA1-associated breast cancer. Moreover, MCL1 inhibition potentiated the in vivo efficacy of the PARP inhibitor (PARPi) olaparib, underscoring the therapeutic potential of this combination for treatment of BRCA1-associated cancer patients with poor response to PARPi monotherapy.

The BRCA1-deficient mammary tumors from our mouse models are characterized by genomic instability and hypersensitivity to DNA-damaging agents, including platinum drugs and PARP inhibitors. Nevertheless, none of these drugs are curative: tumors grow back after drug treatment and eventually become resistant. We found that PARPi resistance of BRCA1-deficient GEMM tumors can be induced by several mechanisms, including activation of drug efflux transporters, type of BRCA1 mutation, and loss of components of the 53BP1-RIF1-shieldin and CST complexes that govern end-protection of DNA double-strand breaks.

Citation Format: Jos Jonkers. Genetic dissection of breast cancer development and therapy resistance in mouse models [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA18.
Abstract IA25: Modeling cancer in the CRISPR era
Authors: Ventura Andrea
Published: June 2020

Chromosomal rearrangements are common cancer-associated mutations that often result in the generation of therapeutically actionable gene fusions. Unfortunately, until recently this class of mutations has proved challenging to recapitulate using conventional gene-targeting methods. To overcome this limitation, we have recently developed a CRISPR-based strategy to model a broad range of chromosomal rearrangements, including inversions, deletions, translocations, and tandem duplications (Maddalo et al., 2014). Since this strategy can be used to induce the desired chromosomal rearrangement in somatic cells—ex vivo or directly in vivo—of adult animals, it enables the rapid and cost-effective generation of novel mouse models of human cancer. As proof of concept, we have applied this strategy to generate a novel model of EML4-ALK driven lung adenocarcinoma, and to show that a novel gene fusion observed in a few human gliomas is a potent oncogenic driver and therapeutic target (Cook et al., 2017; Maddalo et al., 2014; Ventura, Dow, 2018). In my presentation, I will discuss how my group is using these novel technologies, as well as conventional gene-targeting methods, to recapitulate the genetic complexity of human cancers in vivo. I will present new and unpublished models of pediatric brain cancers driven by BRAF gene fusions we have recently generated using in vivo and ex vivo CRISPR-mediated chromosomal engineering and show how we are using these models to test novel therapeutic strategies and to gain insights into the molecular pathogenesis of human cancers.

References: Cook PJ, Thomas R, Kannan R, de Leon ES, Drilon A, Rosenblum MK, Scaltriti M, Benezra R, Ventura A. Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target. Nat Commun 2017;8:15987. Maddalo D, Manchado E, Concepcion CP, Bonetti C, Vidigal JA, Han YC, Ogrodowski P, Crippa A, Rekhtman N, de Stanchina E, et al. (2014). In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system. Nature 2014;516: 423-27. Ventura A, Dow LE. (2018). Modeling cancer in the CRISPR era. Annu Rev Cancer Biol 2018;2: 111-31.

Citation Format: Andrea Ventura. Modeling cancer in the CRISPR era [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA25.
Frontal Fibrosing Alopecia Associated with Lichen Planus Pigmentosus: Not Only in Dark Phototypes
Authors: Cappetta María Eugenia , Álvarez Gabriela , Noguera Mónica , D’Atri Gisela , Stengel Fernando
Published: June 2020

The association between frontal fibrosing alopecia and lichen planus pigmetosus was first described in African women. Later, most reports about this association involved dark-skinned patients. Here, we describe 5 cases of frontal fibrosing alopecia associated with lichen planus pigmentosus in light-skinned women from Argentina. Our communication highlights the strength of both entities’ association also in lower Fitzpatrick phototypes.
Cerebral Venous Thrombosis in a Patient with Immune Thrombocytopenia, an Apparent Paradox
Authors: Rasheed Maimoonah A. , Alsaud Arwa E. , Razzaq Sania , Fadul Afraa , Yassin Mohamed A.
Published: June 2020

We present a paradoxical case of immune thrombocytopenia (ITP) that presented with cerebral venous thrombosis. A 39-year-old female patient diagnosed with chronic ITP, who failed treatment on multiple-line agents, was started on eltrombopag (thrombopoietin receptor agonist), which she was not compliant to. The patient later developed extensive cerebral venous thrombosis, along with venous infarcts, and intracranial and subarachnoid hemorrhage. She was treated with intravenous immunoglobulins as well as steroid therapy and was simultaneously started on anticoagulation. The patient improved clinically and radiologically. This case is among few reported cases which signify that patients with ITP are inherently prone to thrombosis despite low platelet count and treating these patients can be a dilemma. Judicious use of anticoagulation and immunosuppressive therapy is recommended based on available evidence pending further recommendations and guidelines about treatment of thrombosis in ITP.
Prostatic Ductal Adenocarcinoma with Papillary Features in a Bladder Washing: A Possible Pitfall in Urinary Cytology – Report of One Case
Authors: Barizzi Jessica , Freguia Stefania , Sarro Rossella , Venzi Giordano , Fulciniti Franco
Published: June 2020

In this article, we report on a case of combined, acinar and ductal prostatic adenocarcinoma affecting the prostatic urethra, which, due to a low degree of cytologic atypia and an exclusive papillary architecture with visible fibrovascular core, was erroneously diagnosed as a low-grade urothelial carcinoma based on its peculiar cytologic presentation in a bladder washing sample.
Serum Calcification Propensity and the Risk of Cardiovascular and All-Cause Mortality in the General Population
Authors: Eelderink Coby , te Velde-Keyzer Charlotte A. , Frenay Anne-Roos S. , Vermeulen Emma A. , Bachtler Matthias , Aghagolzadeh Parisa , van Dijk Peter R. , Gansevoort Ronald T. , Vervloet Marc G. , Hillebrands Jan-Luuk , Bakker Stephan J.L. , van Goor Harry , Pasch Andreas , de Borst Martin H. ,   on behalf of the NIGRAM2+ consortium
Published: June 2020

Objective:

Vascular calcification contributes to the cause of cardiovascular disease. The calciprotein particle maturation time (T
50
) in serum, a measure of calcification propensity, has been linked with adverse outcomes in patients with chronic kidney disease, but its role in the general population is unclear. We investigated whether serum T
50
is associated with cardiovascular mortality in a large general population-based cohort.

Approach and Results:

The relationship between serum T
50
and cardiovascular mortality was studied in 6231 participants of the PREVEND (Prevention of Renal and Vascular End-Stage Disease) cohort. All-cause mortality was the secondary outcome. Mean (±SD) age was 53±12 years, 50% were male, and mean serum T
50
was 329±58 minutes. A shorter serum T
50
is indicative of a higher calcification propensity. Serum T
50
was inversely associated with circulating phosphate, age, estimated glomerular filtration rate, and alcohol consumption, whereas plasma magnesium was positively associated with serum T
50
(
P
<0.001, total multivariable model
R
2
=0.281). During median (interquartile range) follow-up for 8.3 (7.8–8.9) years, 364 patients died (5.8%), of whom 95 (26.1%) died from a cardiovascular cause. In multivariable Cox proportional hazard models, each 60 minutes decrease in serum T
50
was independently associated with a higher risk of cardiovascular mortality (fully adjusted hazard ratio [95% CI], 1.22 [1.04–1.36],
P
=0.021). This association was modified by diabetes mellitus; stratified analysis indicated a more pronounced association in individuals with diabetes mellitus.

Conclusions:

Serum T
50
is independently associated with an increased risk of cardiovascular mortality in the general population and thus may be an early and potentially modifiable risk marker for cardiovascular mortality.