bluuebunny/crossref_metadata_2025 huggingface dataset:
Two Gene Set Variation Index as Biomarker of Bacterial and Fungal Sepsis
Authors: Zheng Xiaowen , Luo Yifeng , Li Qian , Feng Jihua , Zhao Chunling , Lu Junyu , Luo Jiefeng , Zhang Jianfeng
Published: June 2020

Background. The incidence of sepsis has been increasing in recent years. The molecular mechanism of different pathogenic sepsis remains elusive, and biomarkers of sepsis against different pathogens are still lacking. Methods. The microarray data of bacterial sepsis, fungal sepsis, and mock‐treated samples were applied to perform differentially expressed gene (DEG) analysis to identify a bacterial sepsis‐specific gene set and a fungal sepsis‐specific gene set. Functional enrichment analysis was used to explore the body’s response to bacterial sepsis and fungal sepsis. Gene set variation analysis (GSVA) was used to score individual samples against the two pathogen‐specific gene sets, and each sample gets a GSVA index. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic value of sepsis. An independent data set was used to validate the bacterial sepsis‐specific GSVA index. Results. The genes differentially expressed only in bacterial sepsis and the genes differentially expressed only in fungal sepsis were significantly involved in different biological processes (BPs) and pathways. This indicated that the body’s responses to fungal sepsis and bacterial sepsis are varied. Twenty‐two genes were identified as bacterial sepsis‐specific genes and upregulated in bacterial sepsis, and 23 genes were identified as fungal sepsis‐specific genes and upregulated in fungal sepsis. ROC curve analysis showed that both of the two pathogen sepsis‐specific GSVA indexes may be a reliable biomarker for corresponding pathogen‐induced sepsis (AUC = 1.000), while the mRNA of CALCA (also known as PCT) have a poor diagnostic value with AUC = 0.512 in bacterial sepsis and AUC = 0.705 in fungi sepsis. In addition, the AUC of the bacterial sepsis‐specific GSVA index in the independent data set was 0.762. Conclusion. We proposed a bacterial sepsis‐specific gene set and a fungal sepsis‐specific gene set; the bacterial sepsis GSVA index may be a reliable biomarker for bacterial sepsis.
Inner Engineering Practices and Advanced 4‐day Isha Yoga Retreat Are Associated with Cannabimimetic Effects with Increased Endocannabinoids and Short‐Term and Sustained Improvement in Mental Health: A Prospective Observational Study of Meditators
Authors: Sadhasivam Senthilkumar , Alankar Suresh , Maturi Raj , Vishnubhotla Ramana V. , Mudigonda Mayur , Pawale Dhanashri , Narayanan Santhosshi , Hariri Sepideh , Ram Chithra , Chang Tracy , Renschler Janelle , Eckert George , Subramaniam Balachundhar
Published: June 2020

Background. Anxiety and depression are common in the modern world, and there is growing demand for alternative therapies such as meditation. Meditation can decrease perceived stress and increase general well‐being, although the physiological mechanism is not well‐characterized. Endocannabinoids (eCBs), lipid mediators associated with enhanced mood and reduced anxiety/depression, have not been previously studied as biomarkers of meditation effects. Our aim was to assess biomarkers (eCBs and brain‐derived neurotrophic factor [BDNF]) and psychological parameters after a meditation retreat. Methods. This was an observational pilot study of adults before and after the 4‐day Isha Yoga Bhava Spandana Program retreat. Participants completed online surveys (before and after retreat, and 1 month later) to assess anxiety, depression, focus, well‐being, and happiness through validated psychological scales. Voluntary blood sampling for biomarker studies was done before and within a day after the retreat. The biomarkers anandamide, 2‐arachidonoylglycerol (2‐AG), 1‐arachidonoylglycerol (1‐AG), docosatetraenoylethanolamide (DEA), oleoylethanolamide (OLA), and BDNF were evaluated. Primary outcomes were changes in psychological scales, as well as changes in eCBs and BDNF. Results. Depression and anxiety scores decreased while focus, happiness, and positive well‐being scores increased immediately after retreat from their baseline values (P < 0.001). All improvements were sustained 1 month after BSP. All major eCBs including anandamide, 2‐AG, 1‐AG, DEA, and BDNF increased after meditation by > 70% (P < 0.001). Increases of ≥20% in anandamide, 2‐AG, 1‐AG, and total AG levels after meditation from the baseline had weak correlations with changes in happiness and well‐being. Conclusions. A short meditation experience improved focus, happiness, and positive well‐being and reduced depression and anxiety in participants for at least 1 month. Participants had increased blood eCBs and BDNF, suggesting a role for these biomarkers in the underlying mechanism of meditation. Meditation is a simple, organic, and effective way to improve well‐being and reduce depression and anxiety.
Doubly Charged Lepton Search Potential of the FCC-Based Energy-Frontier Electron-Proton Colliders
Authors: Ozansoy A.
Published: June 2020

We search for the doubly charged leptons (L−−) predicted in composite models including extended weak isospin multiplets, namely, IW=1 and IW=3/2, at the Future Circular Collider- (FCC-) based energy-frontier electron-proton colliders with the center-of-mass energies of s=3.46 TeV, s=10 TeV, and s=31.6 TeV, respectively. We deal with the e−p⟶L−−X⟶e−W−X process, calculate the production cross sections, and give the normalized transverse momentum and pseudorapidity distributions of final-state electron to obtain the kinematical cuts for the discovery. We show the statistical significance (SS) of the expected signal yield as a function of doubly charged lepton mass (SS−ML plots) to attain the doubly charged lepton discovery mass limits for both the IW=1 and IW=3/2. It is obtained that discovery mass limits on the mass of doubly charged lepton for IW=1 (IW=3/2) are 2.21 2.73 TeV, 5.46 8.47 TeV, and 12.9 20.0 TeV for s=3.46 TeV, s=10 TeV, and s=31.6 TeV, respectively.
A First Step to a Biomarker of Curative Surgery in Colorectal Cancer by Liquid Biopsy of Methylated Septin 9 Gene
Authors: Leon Arellano M. , García-Arranz M. , Ruiz R. , Olivera R. , Magallares S. , Olmedillas-Lopez S. , Valdes-Sanchez T. , Guadalajara H. , García-Olmo D.
Published: June 2020

Objectives. To confirm that patients affected by colorectal cancer have the V2 region of Septin 9 (SEPT9) gene hypermethylated in the circulating free DNA from a peripheral blood sample before surgery and to determine if this hypermethylated DNA disappears from the patients after complete resection of the tumour. Methods. Plasma from 10 patients with colorectal cancer was collected preoperative and three months after surgery. The analysis of the methylation status of the promoter region of the SEPT9 gene was performed using a 7500 Fast Real-Time PCR System. Results. Hypermethylation of SEPT9 gene was detected in 8 out of 10 preoperative samples (one negative result was probed to be a Lynch syndrome) and in 4 out of 10 postoperative samples matching with the cases of recurrence or persistence of disease. This means that, in this sample, the preoperative sensitivity and specificity of the test were 88.9% and 100%, respectively, and there is 100% correlation between the positive results of the SEPT9 test and a recurrence/persistence of the disease in patients after surgical resection. Conclusions. Our study shows that circulating hypermethylated SEPT9 is a specific colorectal cancer biomarker. This hypermethylated SEPT9 DNA disappears around three months after surgery and that circulating hypermethylated SEPT9 may be the first noninvasive marker for postsurgical diagnosis; this conclusion must be confirmed with a more significant number of patients.
Abstract A08: Modeling melanomagenesis
Authors: Moon Hyeongsun , Donahue Leanne , White Andrew C.
Published: June 2020

Despite recent advances in therapy, cutaneous melanoma remains a deadly form of skin cancer. Ultraviolet radiation is a known risk factor that can be reduced by the use of sunscreen; nevertheless, melanoma incidence continues to rise. Determining how a cell that contains all the mutations required for cancer resists forming a tumor could suggest novel means of prevention. Conversely, understanding an identical cancer cell of origin that has switched to a proliferative expansion state can provide invaluable insight into tumor initiation. We have generated a method of inducing melanoma from melanocyte stem cells in a spatially specific manner by altering the exterior environment, in the context of a previously established genetically engineered mouse model of melanoma. Specifically, exposure to ultraviolet radiation B can provide a proinflammatory microenvironment that stimulates this switch from a quiescent cancer cell of origin to a proliferative cancer cell. Moreover, this model shows tumor development from the interfollicular epidermis, similar to human melanoma initiation and progression. This represents an evolution from previous mouse models of melanoma and presents a new method that can be exploited for stage-specific precision targeting for both initiation prevention and progression intervention.

Citation Format: Hyeongsun Moon, Leanne Donahue, Andrew C. White. Modeling melanomagenesis [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 A08.
Abstract A32: Targeting RON-mediated metabolic vulnerabilities in recurrent/progressive breast cancer
Authors: Hunt Brian G. , Wicker Christina A. , Bourn Jennifer , Lower Elyse , Takiar Vinita , Waltz Susan E.
Published: June 2020

Despite advances in clinical detection, molecular subtyping, and targeted therapeutics, breast cancer (BC) is the second leading cause of cancer-related death in women. Recurrent and metastatic disease is the underlying cause of BC mortality. Due to fear of recurrence, BC is the most overtreated cancer, creating significant ethical and financial burdens. Through a discovery-based genomics approach, the RON receptor tyrosine kinase was identified as a predictor of BC recurrence. We and others have shown that RON overexpression occurs in more than half of all BCs and that RON levels are a predictor of metastasis and poor survival. Through evaluation of human breast tumor tissue, we provide the first line of evidence that RON overexpression occurs independent of molecular subtype and provide prognostic evidence of RON expression as a biomarker of BC recurrence. Further, we identified glycolysis and cholesterol biosynthesis, two potentially therapeutically targetable processes, as being significantly upregulated by RON. To test the efficacy of reducing cholesterol as a therapy for BC with RON expression, we treated two independent, spontaneous murine breast cancer models with inhibitors directed at RON and/or cholesterol biosynthesis (atorvastatin). Our studies show that either RON or cholesterol inhibition reduced BC progression and that combination treatments blocked progression further. Current studies are under way to determine the mechanisms by which RON promotes metabolic pathway dependency and to directly test in a novel murine model of BC recurrence if targeting these pathways provides a survival benefit. We anticipate that our studies will serve as the scientific underpinnings for rationally designed new combinatorial therapeutic strategies to decrease the morbidity and mortality associated with advanced breast cancer.

Citation Format: Brian G. Hunt, Christina A. Wicker, Jennifer Bourn, Elyse Lower, Vinita Takiar, Susan E. Waltz. Targeting RON-mediated metabolic vulnerabilities in recurrent/progressive 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 A32.
Abstract B02: Association of APC, BRAF, and TCF7L2 mutations with tumor mutation load and survival outcomes in patients with metastatic colorectal cancer
Authors: Xu Liang , He Xiao-Sheng , Lan Ping
Published: June 2020

Objective: To investigate whether APC, BRAF, and TCF7L2 mutations are associated with prognosis in patients with mCRC.

Methods: Statistical analysis of genomic data from 980 metastatic colorectal cancer samples obtained from the cbioportal database was performed. The cbioportal cohort was used as a discovery set. Logistic regression models and Kaplan-Meier survival analysis and multivariate analysis and nomogram analysis were applied. The lasso regression was used to identify significantly mutant genes.

Results: We identified 25 mutant genes related to survival outcomes by using lasso regression. These mutated genes were generated to classify mCRC patients into high-risk and low-risk groups. Patients with high-risk scores in the training cohort had shorter survival (hazard ratio [HR] 2.735, 95% CI 2.206-3.390; p<0.0001) than patients with low-risk scores. These 25 genes and mutant gene with mutation frequencies more than 5% were analyzed by univariate and multivariate analysis. Three mutant genes could be regarded as independent prognostic factors for overall survival in mCRC patients: APC, BRAF, and TCF7L2. APC and TCF7L2 mutation were favorable factors, while BRAF mutation was an unfavorable factor. The combined Kaplan-Meier analysis showed 5 groups were significantly associated with prognosis in mCRC and found that these 5 groups were associated with tumor location, molecular subtype, survival, tumor grade, and hypermutation. In TCF7L2 and BRAF mutant group, other mutant gene had a much higher mutation frequency than wild-type group. We speculated that BRAF and TCF7L2 mutation were two important mutation points during CRC metastasis.

Conclusions: These findings indicate that APC, BRAF, and TCF7L2 mutations were associated with tumor mutation load and survival outcomes. These findings may be applicable for patients with mCRC.

Note: This abstract was not presented at the conference.

Citation Format: Liang Xu, Xiao-Sheng He, Ping Lan. Association of APC, BRAF, and TCF7L2 mutations with tumor mutation load and survival outcomes in patients with metastatic colorectal 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 B02.
Abstract B14: Engineering a long-term in vitro model of breast cancer tumor resistance for high-throughput predictive drug screening
Authors: Weathered Rachel , Zhou Ruolan , Swartz Melody A.
Published: June 2020

Solid tumors often show high levels of heterogeneity, making targeted therapeutics especially challenging. In breast cancer, for example, the primary cancer type may be eradicated with targeted therapy, but the minority subclones that are drug resistant can emerge as the new majority clones. Here, we present an in vitro model for long-term culture of ex vivo tumors (e.g., from biopsies) that maintain the tumor microenvironment such that tumors can be dramatically reduced with drugs yet maintained to observe long-term drug resistance. Our in vitro “avatars” (“ivitars”) utilize perfused 3D cultures in a high-throughput, robust, and easily maintained format. We demonstrate in vivo relevance with heterogeneous tumors composed of human breast cancer cell lines MCF-7 and LCC9, with sublines that are tamoxifen sensitive or resistant, in combination with stromal cells. Our results indicate that stromal cells, extracellular matrix components, and relevant biophysical stimuli such as fluid flow in the tumor microenvironment enhance tumor resistance to tamoxifen, even in tamoxifen-sensitive tumor cells. Together, our results suggest that the model can be used as a robust and high-throughput system for studying tumor resistance and will be further investigated for use in patient-specific testing.

Citation Format: Rachel Weathered, Ruolan Zhou, Melody A. Swartz. Engineering a long-term in vitro model of breast cancer tumor resistance for high-throughput predictive drug screening [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 B14.
Abstract B19: Role of cell-cell communication in endocrine therapy-resistant breast cancer
Authors: Sengupta Surojeet , Hu Rong , Susswein Zachary , Fagunloye Adeola , Bansal Shweta , Clarke Robert
Published: June 2020

Endocrine therapy is the mainstay for the treatment of estrogen-receptor positive (ER+) breast cancer. However, frequent emergence of endocrine resistance is a major clinical challenge. Cell-cell cooperation in the tumor microenvironment plays a vital role in acquiring resistance, but its role is poorly understood. We studied the interactions among endocrine-resistant (R) and -sensitive (S) breast cancer cells in the presence and absence of ER-targeted endocrine therapy. We measured changes in admixed cell population remodeling by dual fluorescent labeling of LCC1 (S) with eGFP (green fluorescent protein) and their derived resistant variant (selected against the antiestrogen fulvestrant) LCC9 (R) with mCherry (red fluorescent protein), respectively. Thus, unlike most prior studies, these are genetically related cells, rather than ER+ and ER- cell lines obtained from different patients. Our results revealed that “S”cells (LCC1) acquired the phenotype of “R” cells when cultured in a mixed population. A ratio of 5:1 of S:R cells in mixed population was sufficient to confer resistance to fulvestrant to the S cells within a six-day period. Furthermore, we show that acquirement of this resistant phenotype for the S cells was partially blocked by inhibition of either gap junctions or exosome secretion, suggesting a role of cell-cell contact as well as extracellular vesicles. Global proteomic analysis of pure and admixed S and R cell populations showed that R and S can alter key molecular features of each other when present in mixed cell populations. We used a Bayesian approach to fit single culture cell populations to infer density-dependent growth parameters (growth rate, carrying capacity) and a generalized Lotka-Volterra model to understand how S and R coculture populations may be depressing or supporting growth of the other. Our results identify a net mutualistic interaction between the susceptible and resistant cancer strains, demonstrating that there are ecological dynamics to cancer resistance. In some tumors, ecological dynamics may be more mechanistically relevant than simple Darwinian-based clonal selection in driving tumor heterogeneity and determining response to treatment. Our study strongly indicates that different tumor cell types that may exist in tumors are able to influence each other, which leads to alteration of phenotype.

Note: This abstract was not presented at the conference.

Citation Format: Surojeet Sengupta, Rong Hu, Zachary Susswein, Adeola Fagunloye, Shweta Bansal, Robert Clarke. Role of cell-cell communication in endocrine therapy-resistant 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 B19.
Abstract B26: A novel dietary advanced glycation end product (AGE) model to assess impact on tumor progression
Authors: Schuster Reid K. , Krisanits Bradley A. , Randise Jamie , Nogueira Lourdes M. , Helke Kristi , LaRue Amanda C. , Turner David P. , Findlay Victoria J.
Published: June 2020

Advanced glycation end products, or AGEs, and their corresponding receptor, the receptor for AGE (RAGE), have roles in several chronic diseases such as diabetes and cardiovascular disease due to their proinflammatory properties. Recently AGE: RAGE signaling has been implicated in a number of cancers, including prostate and breast cancer; however, how AGE: RAGE signaling effects these cancers has not been elucidated. To examine this, we have developed a novel dietary AGE tumor model. Our regular and AGE (TestDiet DIO 58G7) diets consist of equal %k/cal from fat, protein, and carbohydrate; however, the predominant source of carbohydrate in the control diet is starch and in the AGE diet is sugar. To generate the high-AGE diet we autoclave at 120°C for 15 min. In the high-AGE diet, the autoclaving mimics the cooking process in foods and induces the formation of AGEs, allowing us to observe the effects of chronic AGE consumption on both normal developmental processes as well as tumor formation and progression. Specifically, we have been able to show the impact of this diet during time periods where the breast is more susceptible to chronic AGE consumption, namely the “windows of susceptibility.” Additionally, we have applied this novel dietary model to the RAGE null (-/-) mice to explore the role of AGE:RAGE signaling further. Specifically, we have shown that chronic consumption of a high-AGE diet disrupts normal pubertal growth in the mammary gland through the recruitment of aberrant stroma, including fibroblasts and macrophages, and that these aberrant changes persist into adulthood. We further show that dietary AGEs promote aggressive tumor growth through manipulation of the tumor microenvironment and that this is RAGE dependent. We propose that this dietary model can be used as an in vivo method to examine the impact of dietary AGEs on the TME and as a mechanism for potential therapeutic and preventative strategies.

Citation Format: Reid K. Schuster, Bradley A. Krisanits, Jamie Randise, Lourdes M. Nogueira, Kristi Helke, Amanda C. LaRue, David P. Turner, Victoria J. Findlay. A novel dietary advanced glycation end product (AGE) model to assess impact on tumor 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 B26.
Abstract B40: Minimal mutational determinants of human squamous cell carcinoma
Authors: Planells-Palop Vicente , Koo Angie , Malave Heydi , Lee Katharine , Tward Aaron
Published: June 2020

Dozens of driver mutations and copy number changes have been implicated in human squamous cell carcinomas (SCCs), and each tumor harbors multiple putative driver mutations. However, the minimal set of mutations sufficient to transform a normal keratinocyte into squamous cell carcinoma is unknown. By analyzing TCGA data and previously published datasets, we have identified common combinations of driver mutations in SCCs. Among the most common driver events are mutations in TP53, CDKN2A, and NOTCH1. Using CRISPR editing at endogenous loci in primary human keratinocytes, we demonstrate that no single driver mutation is sufficient to transform keratinocytes, and in fact many single gene mutations appear toxic to keratinocytes. The combination of loss-of-function mutations in TP53 and CDKN2A is sufficient to immortalize both skin and oral primary human keratinocytes in 2D culture and confer a selective advantage in competition assays. Simultaneous mutation of TP53, CDKN2A, and NOTCH1 demonstrates a very similar phenotype in 2D culture as mutation of TP53 and CDKN2A alone. However, using 3D organotypic squamous epithelial cultures consisting of genome-edited keratinocytes grown on decellularized dermis impregnated with fibroblasts and grown at an air-liquid interface demonstrates that keratinocytes with TP53 and CDKN2A mutation alone are sufficient to induce dysplasia, whereas keratinocytes harboring TP53, CDKN2A, and NOTCH1 mutation exhibit an SCC-like phenotype, including invasion through the basement membrane. RNAseq analysis demonstrates that the transition to SCC by NOTCH1 loss involves a partial EMT-like program. Targeted hybrid capture sequencing of edited keratinocytes revealed no other driver mutations or copy number changes other than the experimentally induced ones, consistent with the notion that TP53, CDKN2A, and NOTCH1 mutations alone are sufficient to reprogram a normal keratinocyte into SCC. Thus, despite a high mutation burden and frequent chromosomal instability, as few as three mutational events appear to be sufficient to induce SCC.

Citation Format: Vicente Planells-Palop, Angie Koo, Heydi Malave, Katharine Lee, Aaron Tward. Minimal mutational determinants of human squamous cell carcinoma [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 B40.
Abstract B47: Mutation of K104 abrogates the oncogenic properties of K-RasG12D
Authors: Yang Moon Hee , Hunt Bethany , Johnson Christian , Simanshu Dhirendra , Haigis Kevin
Published: June 2020

Ras proteins function as small GTPases to regulate a wide range of cellular processes. The activity of Ras is dependent on its nucleotide-binding status, which is modulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Previously, we demonstrated that mutation of K104 to glutamine (K104Q) attenuates the transforming capacity of ectopic oncogenic K-Ras by interrupting GEF-induced nucleotide exchange. In order to assess the biologic relevance of this mutation in vivo, we used CRISPR/Cas9 to generate mouse models carrying the K104Q point mutation in wild-type and conditional K-RasLSL-G12D alleles. Animals homozygous for K104Q were viable, fertile, and arose at Mendelian frequency, indicating that K104Q is not a complete loss-of-function mutation. Consistent with our previous findings from in vitro studies, however, the oncogenic activity of K-RasG12D was significantly attenuated by mutation at K104. These data demonstrate that lysine at position 104 is critical for the full oncogenic activity of mutant K-Ras and suggest that modification at K104, for example acetylation, may also regulate its activity. Using biochemical and structural analysis, we found that the G12D and K104Q mutations cooperate to suppress GEF-mediated nucleotide exchange, explaining the preferential effect of K104Q on oncogenic K-Ras. Finally, we discovered an allosteric regulatory network consisting of K104 and residues on switch II that is key for regulating the stability of the switch II alpha helix. Given the high frequency of KRAS mutations in human cancers, modulation of this network may provide a unique therapeutic approach.

Citation Format: Moon Hee Yang, Bethany Hunt, Christian Johnson, Dhirendra Simanshu, Kevin Haigis. Mutation of K104 abrogates the oncogenic properties of K-RasG12D [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 B47.
Abstract IA17: Defining cancer dependency maps
Authors: Hahn William C.
Published: June 2020

Although molecular profiling of human tumors is becoming increasingly routine, the use of this data to guide remains limited to a subset of patients. To complement genome characterization studies, we have used genome-scale gain- and loss-of-function approaches to identify genes required for cell survival and transformation. Specifically, we have used advances in synthetic gene synthesis to prospectively interrogate all possible alleles of known cancer genes. In parallel, we have performed both genome-scale RNAi and CRISPR-Cas9 screens in hundreds of cancer cell lines to identify differentially essential genes and the context that specifies gene dependency. Integrating these studies with genome characterization of human tumors and protein-protein interaction databases facilitates the identification of genes and pathways required for the survival of specific cancer subtypes. In recent studies, we have expanded these efforts to patient-derived organoids and cell lines, which will expand the number and types of cancers represented and allow for the interrogation of other cancer phenotypes. These studies allow us to define a global cancer dependencies map, which will help further operationalize precision cancer medicine.

Citation Format: William C. Hahn. Defining cancer dependency maps [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 IA17.
Abstract PHA04: A new somatic engineering-based model of small-cell lung cancer development
Authors: Kim Kee-Beom , Kim Dong-Wook , Park Kwon-Sik
Published: June 2020

Defining the cancer genome is essential for understanding the pathogenesis, but it remains challenging due to the paucity of robust models for characterizing recurrent mutations found in cancer. To understand the molecular mechanisms underlying the development of small-cell lung cancer (SCLC), an aggressive type of lung cancer initiated by inactivation of both RB and P53, it is important to determine the functional impact of recurrent mutations found in the patient tumors. To this end, we developed a somatic engineering approach, using a CRISPR/Cre hybrid tool that expresses guide RNA, Cas9 endonuclease, and Cre recombinase from a single adenoviral vector (Ad-target of gRNA-CRISPR/Cre). Intratracheal instillation of this recombinant virus causes mutation in a candidate tumor suppressor gene while recombining floxed alleles of Rb1, Trp53, and Rbl2 in the same epithelial cell. To determine functions of Ep300, Slit2, and Fhit, whose orthologous genes are frequently mutated in SCLC patient tumors, we infect the Rb1/Trp53/Rbl2 conditional mice with the viral vectors carrying gRNAs against these genes. The mice infected with Ad-Ep300-CRISPR/Cre or Ad-Fhit-CRISPR/Cre have higher tumor burden in the lungs than those infected with Ad-lacZ-CRISPR/Cre used as control. Although Slit2 is significantly mutated in SCLC, the mice infected with Ad-Slit2-CRISPR/Cre do not increase tumor burden relative to those with Ad-lacZ-CRISPR/Cre. These results for the first time validate the oncogenic impact of Ep300 and Fhit mutations. This study demonstrates the feasibility and robustness of a new somatic engineering-based model for characterizing candidate mutations, which will facilitate the discovery of key oncogenic drivers and pathways from the large number of novel somatic alterations in SCLC. Ongoing efforts with this new approach are focused on validation of functionally unknown mutations alone or in combinations.

This abstract is also being presented as Poster A39.

Citation Format: Kee-Beom Kim, Dong-Wook Kim, Kwon-Sik Park. A new somatic engineering-based model of small-cell lung cancer 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 PHA04.
Abstract PR01: Developmental reprogramming via Hedgehog pathway activation in nonmyogenic endothelial progenitors drives fusion-negative rhabdomyosarcoma
Authors: Drummond Catherine J. , Gadek Kathrine E. , Bush Madeline , Garcia Matthew R. , Hatley Mark E.
Published: June 2020

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Despite aggressive chemotherapy, radiotherapy, and surgery, clinical outcomes for RMS have not improved for three decades, emphasizing the need to uncover the molecular underpinnings of the disease. RMS has been presumed to originate from derailed muscle progenitors based on the histologic appearance and gene expression pattern of the tumors, resembling embryonic developing skeletal muscle. However, an origin restricted to skeletal muscle does not explain RMS occurring in tissues devoid of skeletal muscle such as the prostate, bladder, salivary gland, biliary tree, and omentum. Previously, we described that activation of Sonic Hedgehog signaling through expression of a conditional, constitutively active Smoothened allele, SmoM2, under control of a presumed adipocyte-restricted adipose protein 2 (aP2)-Cre recombinase transgene in mice, gives rise to aggressive skeletal muscle tumors that display the histologic and molecular characteristics of human embryonal RMS (ERMS). With the short latency and anatomically restricted tumor location in the neck, we sought to leverage this model to explore the cell of origin of ERMS. Lineage tracing experiments identified aP2-Cre labeled cells are distinctly nonmyogenic and were identified as endothelial cells found in the interstitium between muscle fibers. We illustrate that aP2-Cre is not expressed in the quiescent or activated muscle stem cells or satellite cells. Expression of oncogenic SmoM2 with aP2-Cre results in proliferation and expansion of the aP2-Cre labeled muscle interstitial endothelial cells and myogenic transdifferentiation resulting in ERMS. Activation of the hedgehog pathway in aP2-Cre labeled endothelial progenitors results in expression of skeletal muscle specification factors specific in the head and neck development, including TBX1, PITX2, TCF21, and MSC. We illustrate that endothelium and skeletal muscle within the head and neck arise from KDR (VEFGR2)-expressing progenitors. Hedgehog pathway activation in committed KDR+ endothelial progenitors results in Tbx1 expression and subsequent MYOD1 expression driving a partially myogenic program characteristic of ERMS. Our work identifies reprogramming cell fate as a mechanism of transformation in pediatric sarcoma and illustrates that it is dangerous to assume the cell of origin from the characteristics of the tumor cell.

Citation Format: Catherine J. Drummond, Kathrine E. Gadek, Madeline Bush, Matthew R. Garcia, Mark E. Hatley. Developmental reprogramming via Hedgehog pathway activation in nonmyogenic endothelial progenitors drives fusion-negative rhabdomyosarcoma [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 PR01.
Palliative Electrochemotherapy Treatment of Cutaneous Metastases in a Patient with Advanced Thyroid Papillary Carcinoma
Authors: Cavaco Daniela , Carvalhal Sara , Leite Valeriano
Published: June 2020

Advanced papillary thyroid carcinoma (PTC) with cutaneous metastases may cause pain, ulceration, and bleeding. Electrochemotherapy (ECT) is a minimally invasive treatment of tumors located in the skin and subcutaneous tissue. The electric pulses potentiate the toxicity of cytostatic agents entering the tumor cell. It is highly effective especially to relieve pain and improve the quality of life. The adverse events are local and transient. A case of progressive metastatic PTC who developed bleeding cutaneous metastases treated with ECT is described.
Walter Benjamin e o flâneur baudelairiano em Julio Cortázar
Authors: Naletto Pedro De Carvalho
Published: June 2020

Este artigo pretende retomar a relação proposta por Davi Arrigucci Júnior entre o flâneur baudelairiano de “O pintor da vida moderna” e o personagem Roberto-Michel, do conto “Las babas del diablo”, de Julio Cortázar, à luz da análise do flâneur desenvolvida por Walter Benjamin no ensaio “Paris do segundo império”. Baudelaire retira a figura do flâneur do conto “O homem na multidão”, de Edgar Allan Poe, e a descreve em associação às ideias da convalescença e da infância, que exprimem a curiosidade do flâneur em meio à multidão. Na análise de Benjamin, por outro lado, a multidão ganha um caráter negativo, como esconderijo do flâneur, visto que este não se sente seguro no meio social. Ao retomar a análise de Benjamin, este artigo tem como objetivo propor uma possível contribuição à interpretação feita por Arrigucci Jr. do personagem de Cortázar.
Sobre a akrasia e o vínculo entre epistemologia e ética
Authors: Botti Ian Salles
Published: June 2020

Este artigo aborda a incontinência, ou akrasia, sob a perspectiva da epistemologia da virtude de Christopher Hookway a fim de estabelecer uma relação entre epistemologia e ética. A tese é que o fenômeno em questão possui uma contraparte epistêmica, que permite a aproximação entre as disciplinas e promove o debate acerca da validade da distinção entre áreas teóricas e práticas, descritivas e normativas. Pretende-se com isso enfatizar a centralidade do aspecto normativo da epistemologia. Os textos usados são a Ética a Nicômaco, de Aristóteles, no qual a incontinência comum é exposta no contexto de uma ética da virtude; e o artigo “Epistemic akrasia and epistemic virtue”, de Hookway, no qual é defendida a possibilidade da incontinência epistêmica e de uma epistemologia da virtude.
Família, Justica e Política:
Authors: Farhat Pedro Casalotti
Published: June 2020

Partindo da distinção liberal tradicional entre público e privado, nós concebemos a trajetória que inicia com o liberalismo de John Rawls e desemboca nas críticas feministas das filósofas Susan Okin e Seyla Benhabib ao liberalismo de Rawls. Com estas críticas e desenhando seus esforços, nós concebemos um entendimento acerca da distinção inicial, profundamente marcada pela tradição, apenas para indicar ao final um modelo teórico que poderia garantir a participação política de mulheres e outros grupos historicamente excluídos do espaço público e das disputas de poder.
Blockade of PAR‐1 Signaling Attenuates Cardiac Hypertrophy and Fibrosis in Renin‐Overexpressing Hypertensive Mice
Authors: Yokono Yoshikazu , Hanada Kenji , Narita Masato , Tatara Yota , Kawamura Yousuke , Miura Naotake , Kitayama Kazutaka , Nakata Masamichi , Nozaka Masashi , Kato Tomo , Kudo Natsumi , Tsushima Michiko , Toyama Yuichi , Itoh Ken , Tomita Hirofumi
Published: June 2020

Background

Although PAR‐1 (protease‐activated receptor‐1) exerts important functions in the pathophysiology of the cardiovascular system, the role of
PAR
‐1 signaling in heart failure development remains largely unknown. We tested the hypothesis that
PAR
‐1 signaling inhibition has protective effects on the progression of cardiac remodeling induced by chronic renin–angiotensin system activation using renin‐overexpressing hypertensive (Ren‐Tg) mice.

Methods and Results

We treated 12‐ to 16‐week‐old male wild‐type (
WT
) mice and Ren‐Tg mice with continuous subcutaneous infusion of the
PAR
‐1 antagonist
SCH
79797 or vehicle for 4 weeks. The thicknesses of interventricular septum and the left ventricular posterior wall were greater in Ren‐Tg mice than in
WT
mice, and
SCH
79797 treatment significantly decreased these thicknesses in Ren‐Tg mice. The cardiac fibrosis area and monocyte/macrophage deposition were greater in Ren‐Tg mice than in
WT
mice, and both conditions were attenuated by
SCH
79797 treatment. Cardiac
mRNA
expression levels of
PAR
‐1, TNF‐α (tumor necrosis factor‐α), TGF‐β1 (transforming growth factor‐β1), and COL3A1 (collagen type 3 α1 chain) and the ratio of β‐myosin heavy chain (β‐
MHC
) to α‐
MHC
were all greater in Ren‐Tg mice than in
WT
mice;
SCH
79797 treatment attenuated these increases in Ren‐Tg mice. Prothrombin fragment 1+2 concentration and factor Xa in plasma were greater in Ren‐Tg mice than in
WT
mice, and both conditions were unaffected by
SCH
79797 treatment. In isolated cardiac fibroblasts, both thrombin and factor Xa enhanced ERK1/2 (extracellular signal‐regulated kinase 1/2) phosphorylation, and
SCH
79797 pretreatment abolished this enhancement. Furthermore, gene expression of
PAR
‐1,
TGF
‐β1, and
COL
3A1 were enhanced by factor Xa, and all were inhibited by
SCH
79797.

Conclusions

The results indicate that
PAR
‐1 signaling is involved in cardiac remodeling induced by renin–angiotensin system activation, which may provide a novel therapeutic target for heart failure.
Cactodera solani n. sp. (Nematoda: Heteroderidae), a new species of cyst-forming nematode parasitising tomato in Mexico
Authors: Escobar-Avila Ilia Mariana , Subbotin Sergei A. , Tovar-Soto Alejandro
Published: June 2020

A new species of cyst-forming nematode, Cactodera solani n. sp., from Mexico is described. The new species was found in a glasshouse in Mexico City parasitising tomato and common lambsquarter. This cyst nematode has light brown to almost black cysts, presents a small vulval cone with circumfenestra and morphologically it most resembles C. milleri. Cactodera solani n. sp. can be differentiated from C. milleri by having smaller cysts that are 417 (291-581) × 324 (204-505) vs 632 (515-730) × 506 (419-598) μm in size and a longer stylet in the second-stage juveniles of 25 (24-27) vs 22 (21-23) μm. Phylogenetic relationships within populations and species of Cactodera are given based on the analysis of the ITS rRNA and the partial COI gene sequences. The ITS rRNA and COI gene sequences clearly differentiated C. solani n. sp. from other Cactodera species. This new cyst-forming nematode has several generations per year and its life cycle can be completed in 49 days on tomato and in 40 days on common lambsquarter at 20-25°C.
The Terror of Time: The Festival of Dionysus and Saturnalia in Jewish Responses to Foreign Rule
Authors: Bonesho Catherine E.
Published: June 2020

Proper observance of festivals is a major concern in early Jewish literature, but the festivals of the gentiles also figure prominently in this period. Two such festivals are the Greek Festival of Dionysus, described in Second Maccabees, and the Roman festival of Saturnalia, described in the Palestinian Talmud. I show the varied ways in which the authors of these texts, members of different groups, with different textual practices, and living centuries apart, problematize foreign holidays in their responses to imperial rule. Though the polemic against gentiles is heightened in both texts, the epitomator primarily problematizes the Festival of Dionysus because its observance is a violation of ancestral law, while the Palestinian Amoraim stress Saturnalia’s status as a Roman holiday. The different emphases in these discussions of gentile festivals distinguish the prerogatives of these two Jewish communities, their understandings of gentile festivals, and their respective responses to Greek and Roman hegemony.
The New and the Old: A Qualitative Analysis of Modes of Conflict Resolution in the Kingdom of Saudi Arabia
Authors: Pilotti Maura A. E. , El Alaoui Khadija , Salameh Muamar Hasan , Singh Sukhsimranjit , Al Mulhem Huda
Published: June 2020

Using a case study method, we examine how practitioners, including judges, arbitrators and community mediators, view dispute resolution in the Kingdom of Saudi Arabia (KSA). The goal of this study is to assess whether traditional approaches to dispute resolution coexist with or are discarded for imported modes. Participants were selected through convenience sampling. Structured interviews involved (a) participants’ general theoretical foundations, (b) key principles that govern their professional role, (c) their views of different roles, and (d) the extent to which traditional modi operandi persist. The results highlight the dominance of principles and practices of Sharia law over common law. Although the use of formal Western procedures was reported in commercial disputes and rarely in family and tribal matters, implementation was undeniably shaped by religious and kin-based social habits and values.
Ptomaphagus thebeatles n. sp., a previously unrecognized beetle from Europe, with remarks on urban taxonomy and recent range expansion (Coleoptera: Leiodidae)
Authors: Schilthuizen Menno , van Oostenbrugge Wesley , Visser Stefan , van der Meer Marrit , Delval Richard , Dias Claudia , Köster Heko , Maarschall Rudie , Peeters Norbert , Venema Peter , Zaremba Ryan , Beltrami Cristina , Rossato Marzia , Latella Leonardo , Nieuwenhuis Florinda , de Rop Nicole , Njunjić Iva , Perreau Michel , Koene Joris M.
Published: June 2020

Anthropogenic environmental change is leading to changes in distribution for many organisms. While this is frequently discussed for prominent organisms of high conservation value, the same is true for the many cryptic species that rarely figure in debates on the human impact. One such cryptic taxon is the European Ptomaphagus sericatus (Chaudoir, 1845) and related forms. During a citizen science expedition in the Vondelpark, Amsterdam, the Netherlands, we obtained two forms of this species complex. We placed the examination of these specimens in the context of a re-analysis of the species group, and, using DNA barcoding and genital study on material collected thoughout Europe, found that the P. sericatus species complex consists of three distinct, partly sympatric species, one of which was previously undescribed. On the basis of collection data, at least two species, P. medius and P. thebeatles sp. n., show signs of having recently undergone (possibly anthropogenic) range changes, with P. medius even reaching North America. We describe P. thebeatles sp. n.; we raise two subspecies, viz. P. sericatus sericatus (Chaudoir, 1854) and P. sericatus medius (Rey, 1889) to the level of species, and designate a neotype for the former; we identify P. dacicus Jeannel, 1934 and P. pyrenaeus Jeannel, 1934 as junior synonyms of P. sericatus, and P. compressitarsus (Rey, 1889) as a junior synonym of P. subvillosus Goeze, 1777; we identify P. septentrionalis Jeannel, 1934 and P. miser (Rey, 1889) as junior synonyms of P. medius; we designate lectotypes for P. medius and P. miser.
The Term ʿiwaḍ (“Compensation”) and Its Meaning in Sefer ha-Maslul and in the Works of Rabbinic and Arab Grammarians
Authors: Watad Ali
Published: June 2020

Sefer ha-Maslul (“Book of the Path”) is a Hebrew grammar book in the Samaritan tradition. The book, known in Arabic as Kitāb al-Tawṭiya (“Book of Introduction”), was composed in that language during the first half of the twelfth century and is the earliest and only known surviving Samaritan grammatical work. It was first published by Zeʾev Ben-Haim in his monumental book, The Literary and Oral Tradition of Hebrew and Aramaic amongst the Samaritans. Grammatical terminology is key to understanding the theory of a grammarian. One can obtain such understanding by tracking a term throughout a work, examining how it is used and whether its usage is consistent. The term ʿiwaḍ (“compensation”) is a central one in Sefer ha-Maslul. In this article I will examine the outlook of its author, the grammarian Abū Isḥāq b. Mārūṯ, as well as the term ʿiwaḍ and its usages. Sefer ha-Maslul was written following the emergence of scientific grammar among Rabbinic, Arab, and Karaite grammarians. Accordingly, I will compare its author’s approach with those of Judah ben David Ḥayyūǧ (a Rabbanite), Ibn Ǧinnī (a Muslim) and Abū l-Farāǧ Hārūn (a Karaite).