bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 975: A multiscale computational model for spatio-temporal tumor immune response
Authors: Gong Chang , Milberg Oleg , Wang Bing , Vicini Paolo , Narwal Rajesh , Roskos Lorin , Popel Aleksander S.
Published: July 2017

When the immune system responds to tumor development, patterns of immune infiltrates emerge, highlighted by expression of immune checkpoint-related molecules such as PD-L1 on cancer cells and its receptor PD-1 on cytotoxic T cells. Pre-treatment tumor spatial heterogeneity could bear information on intrinsic characteristics of the tumor lesion for individual patient, and thus has the potential to comprise biomarkers for anti-tumor therapeutics. We developed a systems biology computational multiscale agent-based model to capture the interactions between immune cells and cancer cells during tumor progression. Cytotoxic T cells and cancer cells are modeled as free-moving agents in a 3-dimensional grid, where each cell acts in response to its local microenvironment and carries out functions such as division, apoptosis, cytotoxic killing and switching between states with different PD-1 or PD-L1 expression levels. Subsequently, we analyzed the emergent behavior of tumor progression by looking at all these local interactions as a whole. Using this model, we are able to reproduce temporal dynamics of cytotoxic T cells and cancer cells during general tumor progression, as well as 3-dimensional spatial distributions of these cells over the time course of the simulation. By varying the characteristics of the neoantigen profile of individual patients, such as mutational burden and immunogenicity, a spectrum of pre-treatment spatial patterns of PD-1/PD-L1 expression is generated in our simulations, resembling immune-architectures obtained via immunohistochemistry from patient biopsies. We evaluate potential prognostic biomarkers by correlating these spatial characteristics with in silico treatment results with immune checkpoint inhibitors. Simulation results demonstrate that the percentage of PD-L1 positive cancer cells which are not in close proximity of the tumor boundary or vasculature is more indicative of successful anti-PD1/anti-PD-L1 treatment. Our findings suggest that tumor spatial heterogeneity, especially its immune-architecture, reflects the course of tumor progression as well as patient-specific properties, and is thus likely to carry important information about tumor susceptibility to treatment such as with immune checkpoint inhibitors. We demonstrated how prognostic biomarkers could be realistically simulated in a general cancer scenario. The model is further refined for use to predict treatment/biomarker combinations in specific cancer types.

Citation Format: Chang Gong, Oleg Milberg, Bing Wang, Paolo Vicini, Rajesh Narwal, Lorin Roskos, Aleksander S. Popel. A multiscale computational model for spatio-temporal tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 975. doi:10.1158/1538-7445.AM2017-975
Abstract CT145: A phase I window, dose escalating and safety trial of Metformin in combination with induction chemotherapy (VPLD)in relapsed/refractory acute lymphoblastic leukemia: NCT01324180
Authors: Trucco Matteo , Barredo Julio , Goldberg John , Hale Gregory , Gill Jonathan , Setty Bhuvana , Smith Tiffany , Lee Jae , Reed Damon
Published: July 2017

Background: Relapsed Acute Lymphoblastic Leukemia (ALL) remains a major cause of cancer-related deaths in children. We identified the AMP activated protein kinase (AMPK) as a potential target for ALL therapy due to its regulatory effects on the unfolded protein response (UPR), leading to increased vulnerability of ALL cells to endoplasmic reticulum (ER) stress inducers. In vitro, metformin leads to ALL cell death via AMPK-mediated inhibition of the UPR. Methods: Metformin was administered twice daily continuously on a 28 day cycle in addition to the Vincristine, Dexamethasone, PEG-Asparaginase and Doxorubicin (VPLD) systemic regimen and CNS-directed therapy in pediatric patients with relapsed/refractory ALL. Metformin doses were increased in a standard 3+3 phase I design with three dose levels evaluated, 666, 1,000 and 1,333 mg/m2/day. Pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of the AMPK and ER stress/UPR pathways were ascertained on days 1 and 7, and treatment response was assessed on day 29. Results: Fourteen patients were enrolled, 11 evaluable. DL3 was the maximum administered dose with 2 related DLT’s of diarrhea and acidosis. A single DLT of hypoglycemia and acidosis during an episode of sepsis was observed in DL2. Infectious SAE’s occurred in 7 patients. Two patients had posterior reversible encephalopathy syndrome; both died of disease progression within 30 days of coming off study. A single patient had stable disease, 2 had a partial response, and 3 achieved a complete response. PK studies demonstrated levels within the therapeutic range for patients with diabetes, and PD evaluation showed induction of ER stress and inhibition of the UPR. Conclusions: This trial has been completed. We found induction of ER stress with inhibition of UPR consistent with that observed in vitro leading to metformin-induced apoptosis. The chemotherapeutic backbone was tolerable and the combination with metformin yielded responses in a heavily pretreated population. Toxicities attributable to metformin occurred in all dose levels, but DLT’s were only observed in dose levels above the standard dosing for diabetes. Clinical trial information: NCT01324180

Citation Format: Matteo Trucco, Julio Barredo, John Goldberg, Gregory Hale, Jonathan Gill, Bhuvana Setty, Tiffany Smith, Jae Lee, Damon Reed. A phase I window, dose escalating and safety trial of Metformin in combination with induction chemotherapy (VPLD)in relapsed/refractory acute lymphoblastic leukemia: NCT01324180 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT145. doi:10.1158/1538-7445.AM2017-CT145
Abstract CT159: IFN-γ analysis in blood and tissue as a potential prognostic and/or predictive biomarker
Authors: Kallinteris Nikoletta , Horn Leora , Tang Min , Guennel Tobias , Yin Shen , Lai Jennifer , Shan Joseph , Sanborn Rachel E.
Published: July 2017

Background

SUNRISE, a global, double-bind, Phase III trial of docetaxel (D) plus bavituximab (B) or D plus placebo (P) in previously treated non-squamous non-small cell lung cancer (NSCLC), demonstrated similar overall survival (OS) in both treatment arms. Immune correlate analyses including pre-treatment IFN-γ levels in blood and tumor tissue were used to potentially identify prognostic and/or predictive correlation with clinical outcome.

Methods

Serum was isolated from all randomized NSCLC patients at screening, periodically during treatment and at disease progression for evaluation of IFN-γ levels using the SimoaTM assay (Myriad RBM, Austin, TX, USA). Available archival tissue was also tested for 91- immune gene activation markers, including IFN-γ by the Fluidigm-based gene-expression platform (Sirona Dx, Lake Oswego, OR, USA). Kaplan-Meier statistical methods and Cox proportion hazards models were utilized to evaluate and contrast the correlation of peripheral and intratumoral IFN-γ levels with OS. Patients were classified paradoxically as IFN-γ "low" with a favorable disease prognosis versus "high" associated with more aggressive disease based on the median.

Results

Pretreatment serum results were available for 582 out of the 597 randomized patients. Each patient was classified to be pre-treatment IFN-γ high or low (< cut-off) using cut-off 0.093 pg/ml, which is the median IFN-γ value in the D+B group. Median overall survival (mOS) in all patients with IFN-γ low is 11.3 months (95% confidence interval [CI], 10.1-13.5) versus 10.4 months (95% CI, 8.4-11.3) in all IFN-γ high; p=0.047. mOS of D+B arm is 11.6 months (95% CI, 10.2-13.9) and 11.1 months (95% CI, 9.1-14.7) in the D group; p=0.982 for IFN-γ low. mOS of D+B arm is 9.0 months (95% CI, 6.7-11.2) and 10.6 months (95% CI, 8.9-13.0) in the D group; p=0.252 for IFN-γ high. With the limited intratumoral IFN-γ gene expression data (n=33), no statistically significant correlation with OS was observed.

Conclusions

Correlative approaches identified low peripheral low IFN-γ at pretreatment as a biomarker of interest correlating with more favorable clinical outcomes and is consistent with the hypothesis that bavituximab may demonstrate more immunomodulatory effects in patients with “immune cold” tumors.

Citation Format: Nikoletta Kallinteris, Leora Horn, Min Tang, Tobias Guennel, Shen Yin, Jennifer Lai, Joseph Shan, Rachel E. Sanborn. IFN-γ analysis in blood and tissue as a potential prognostic and/or predictive biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT159. doi:10.1158/1538-7445.AM2017-CT159
Abstract LB-068: From intracellular antibody fragments to small molecule inhibitors of mutant KRAS
Authors: Quevedo Camilo E. , Cruz Abimael , Tulmin Hanna , Bataille Carole J. , Tanaka Tomoyuki , Petch Donna , Russell Angela J. , Phillips Simon , Rabbitts Terence H.
Published: July 2017

Our aim was to develop methods to employ intracellular antibody fragments as lead macromolecules for small compound selections. We have used this approach to identify small molecules binding to mutant RAS with potential to inhibit the RAS-effector interactions. Mutation in RAS family members is among the most frequent in human cancer and the mutant RAS proteins are tumour-specific proteins for therapy. We have previously selected an intracellular antibody single domain fragment that binds to mutant forms of KRAS and HRAS and used this antibody fragment to demonstrate that blocking RAS-effector interaction-dependent signal transduction prevents tumour initiation and overt tumour growth in mouse preclinical models. The antibody fragment binds to GTP-bound RAS with high pM affinity and we have used this property to isolate compounds from a fragment library using a competitive SPR method that places the compounds in the region of the binding site of the antibody fragment. Using a combination of X-ray crystallography and medicinal chemistry, we have obtained a family of compounds that bind adjacent to the KRAS switch I region with nM affinity and that inhibit the downstream phosphorylation of AKT and ERK that results from RAS signaling. The chemical evolution and interaction characteristics of the KRAS-binding compounds will be described and their biochemical and cell-based properties presented. We have validated our approach using an antibody fragment as a screening tool for the

identification of small molecule inhibitors of the RAS-effector interaction. This approach has yielded small compound fragments that are currently being developed as potential RAS-effector inhibitors in our medicinal chemistry programme.

Citation Format: Camilo E. Quevedo, Abimael Cruz, Hanna Tulmin, Carole J. Bataille, Tomoyuki Tanaka, Donna Petch, Angela J. Russell, Simon Phillips, Terence H. Rabbitts. From intracellular antibody fragments to small molecule inhibitors of mutant KRAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-068. doi:10.1158/1538-7445.AM2017-LB-068
Abstract LB-082: Targeted inactivation of STAT3 inhibits proliferation and invasion of breast cancer cells and enhances antitumor activity of doxorubicin through reversion of EMT
Authors: Ding Yi , Jiang Yu , Li Wenqing , Liu Shurong , Lu Zhong , Shi Lihong , Wang Xuejian , Zhang Jian , Wang Lihua
Published: July 2017

Breast cancer is one of the most common malignant diseases in women. Epithelial-mesenchymal transition (EMT) has been documented to play an important role in proliferation, invasion and metastasis of tumor cells as well as drug resistance. Even though the signal transducer and activator of transcription 3 (STAT3) is not a master transcription factor of EMT, STAT3 is involved in the regulation of EMT-related gene expression. However, it remains unclear whether targeted inhibitors of STAT3 affect EMT-mediated proliferation, migration, invasion and drug resistance of tumor cells. In this paper, we investigated the effects of STAT3 and its interaction with Twist, a master transcription factor, in EMT program and subsequent changes in proliferation, migration and invasion of breast cancer cells by interfering STAT3 signaling pathway with different strategies such as STAT3 inactivation and STAT3 silencing. Furthermore, we explored the role of inhibiting STAT3 phosphorylation in the EMT regulation of the sensitivity of tumor cells response to doxorubicin. The results showed that the expression and activation of STAT3 correlated with cell phenotype and invasive ability of breast cancer cells. IL-6 induced phosphorylation of STAT3 can promote the EMT of breast cancer cells. WP1066 completely inhibited STAT3 autophosphorylation and IL-6-induced phosphorylation in breast cancer cells. WP1066 reversed EMT to MET through inhibiting the phosphorylation of STAT3 in breast cancer cells and significantly inhibited the proliferation and invasion in breast cancer cells. Silence STAT3 with siRNA also reversed EMT to MET in breast cancer cells. The expression of EMT transcription factor Twist1 was positively correlated with the activation of STAT3 but not with the expression of STAT3. WP1066 increased doxorubicin antitumor activity through inhibiting the STAT3 phosphorylation. These data provide a proof of concept that targeted inactivation of STAT3 can inhibit proliferation and invasion of breast cancer cells and reduce the resistance of Doxorubicin through reversion of EMT. Support by Natural Science Foundation of China (No.81472489) and Science and Technology Development Plan of Shandong (No.2014GSF118040)

Citation Format: Yi Ding, Yu Jiang, Wenqing Li, Shurong Liu, Zhong Lu, Lihong Shi, Xuejian Wang, Jian Zhang, Lihua Wang. Targeted inactivation of STAT3 inhibits proliferation and invasion of breast cancer cells and enhances antitumor activity of doxorubicin through reversion of EMT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-082. doi:10.1158/1538-7445.AM2017-LB-082
Abstract LB-084: Histone chaperone HIRA is required for Setd1a H3K4 methylation recruited by TAL1 oncoprotein in leukemogenesis
Authors: Li Ying
Published: July 2017

TAL1/SCL is a hematopoietic specific member of the basic Helix-Loop-Helix (bHLH) family of transcription factors important for the development of all hematopoietic lineages and pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL), which plays a coordinating role in establishing the proper chromatin dynamics and gene regulation. We have previously demonstrated that TAL1 associated with H3K4 methyltransferase SETD1A, which mediated epigenetic regulation that regulates hematopoietic transcription and differentiation programs during hematopoiesis and leukemogenesis. We now find that a novel interaction between TAL1 and histone cell cycle regulation defective homolog A (HIRA) histone chaperone. TAL1 directly interacts with HIRA, which is not only essential for promoter H3K4 hypermethylation by Setd1a, but is also critical for the transcriptional activation of target genes mediated by TAL1 and Setd1a in T cell acute lymphoblast leukemia (T-ALL) Jurkat cells, such as CDK6 and NKX3.1. Our data revealed a collaborative role by which transcription factor-directed recruitment of histone chaperone and histone modification enzyme can lead to chromatin structure alterations at specific promoters in leukemogenesis.

Citation Format: Ying Li. Histone chaperone HIRA is required for Setd1a H3K4 methylation recruited by TAL1 oncoprotein in leukemogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-084. doi:10.1158/1538-7445.AM2017-LB-084
Abstract LB-087: Stage specific re-calibration of E2F1 function after RB loss
Authors: Mandigo Amy C. , McNair Christopher , Xu Kexin , Li Fugen , Schiewer Matthew J. , Brown Myles , Knudsen Karen E.
Published: July 2017

Prostate cancer (PCa) is the most frequently diagnosed non-cutaneous malignancy, and the third leading cause of cancer death in males in the United States. The development of the disease is reliant on the activity of the androgen receptor (AR), which promotes proliferation and is required for cell growth and survival. Deregulation of AR leads to the progression of PCa to the incurable form of disease termed castration-resistant prostate cancer (CRPC). One of the underlying mechanisms of AR deregulation is the loss of function of the retinoblastoma (RB) tumor suppressor protein. RB loss is almost exclusively seen in CRPC and is sufficient to induce a CRPC phenotype in primary PCa models. However, RB function is only lost in roughly 30% of tumors. The remaining 70% of tumors that progress to CRPC do so via other mechanisms and retain RB function. A subset of RB positive CRPC tumors progress to lose RB function even in this post-CRPC transition stage of disease. Biological assessment performed in isogenic RB knockdown, both hormone-sensitive and CRPC models, identified distinct functional consequences of RB loss depending on disease state. Transcriptome analysis identified opposing regulated gene signatures between disease stages. Further investigation of the E2F1 cistrome revealed differential E2F1 binding with RB loss in hormone sensitive and CRPC models, identifying distinct roles of E2F1, in the absence of RB, in different disease states. Data to be discussed reveal the stage-specific molecular pathways driven by E2F1 upon RB loss with the potential to promote disease progression.

Citation Format: Amy C. Mandigo, Christopher McNair, Kexin Xu, Fugen Li, Matthew J. Schiewer, Myles Brown, Karen E. Knudsen. Stage specific re-calibration of E2F1 function after RB loss [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-087. doi:10.1158/1538-7445.AM2017-LB-087
Abstract LB-096: SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation
Authors: Wang Xiaofeng , Lee Ryan , Alver Burak , Haswell Jeffrey , Wang Su , Troisi Emma , Bernstein Bradley , Park Peter , Roberts Charles
Published: July 2017

The gene encoding SMARCB1 (SNF5/INI1/BAF47), a core subunit of the SWI/SNF (BAF) chromatin remodeling complex, is biallelically inactivated in nearly all rhabdoid tumors (RTs), highly aggressive and lethal cancers of early childhood. RTs are among the most genomically stable cancers, suggesting an epigenetic mechanism by which SMARCB1 loss drives cancer. Here, we show that despite having indistinguishable mutational landscapes, human RTs show distinct H3K27ac signatures at enhancers that reveal remnants of differentiation programs. In elucidating the mechanism underlying RTs, we find that SMARCB1 is not only essential for the integrity and abundance of SWI/SNF complexes, but also facilitates their targeting to appropriate enhancers. Loss of SMARCB1 alters enhancer targeting—markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers (SEs). We show that these retained SEs are essential for RT survival, including some that are shared across all RT types, such as SPRY1, and other lineage-specific SEs like SOX2 in brain-derived RTs. Taken together, our findings reveal a novel chromatin-based epigenetic mechanism underlying the tumor suppressive activity of SMARCB1.

Citation Format: Xiaofeng Wang, Ryan Lee, Burak Alver, Jeffrey Haswell, Su Wang, Emma Troisi, Bradley Bernstein, Peter Park, Charles Roberts. SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-096. doi:10.1158/1538-7445.AM2017-LB-096
Abstract LB-114: Monogenic autoimmune diseases as a starting point for new immunooncology targets
Authors: Schwartz Benjamin , Hance Kenneth , Freudenberg Johannes , Shelton Christopher , Jing Junping , Yang Jingsong
Published: July 2017

Cyclic dinucleotide (CDN) analogs and small molecule agonists of STING (STimulator of INterferon Genes protein) are currently being developed as immuno-oncology agents based on their ability to stimulate potent anti-tumoral responses in the tumor micro-environment (TME) (1,2). STING agonists act primarily on APCs such as dendritic cells (DCs), resulting in enhanced type I interferon signalling and resulting cytotoxic T cell (CTL) responses (3). Germline gain of function mutations in STING (gene name TMEM173) exist and cause the rare disease SAVI (4). Patients with SAVI present as infants with symptoms such as chronic rash, lesions, and systemic inflammation and eventually succumb to more serious complications such as lung disease. At the functional level, they display elevated levels of interferon responsive genes indicative of constitutive STING activation. Thus, while chronic agonism of this pathway leads to an autoimmune/autoinflammatory phenotype, acute dosing has benefit in a tumor setting as an immunological stimulant. We designed an in silico approach to identify other genes with the same potential disease/phenotype profile as STING. We combined knowledge of Mendelian disease genetics with pathway phenotype associations such as involvement in immune cell anergy, activation, costimulation, chemotaxis, and migration. In addition, we determined a putative set of genes associated with immune privileged sites by combining textmining of biomedical literature with mRNA gene expression analysis. Taken together, these approaches provided a list of potential immuno-oncology targets that also included several well-known targets such as CTLA4, ICOS, and OX40 which are either approved or in clinical trials as immuno-oncology agents. This list was then manually curated and prioritized based on literature, and will be functionally validated in ongoing experimental systems. References: 1) Corrales, L., et. al. “Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity” 2015, Cell Reports, v.11, 1018-1030. 2) Chandra, D., et. al. “STING Ligand c-di-GMP Improves Cancer Vaccination against Metastatic Breast Cancer” 2014, Cancer Immunol. Res., v.2(9), 901-910. 3) Woo, S.-R., et. al. “STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors” 2014, Immunity, v.41, 830-842. 4) Liu, Y., et. al. “Activated STING in a Vascular and Pulmonary Syndrome” 2014, N. Engl. J. Med., v.371(6), 507-518.

Citation Format: Benjamin Schwartz, Kenneth Hance, Johannes Freudenberg, Christopher Shelton, Junping Jing, Jingsong Yang. Monogenic autoimmune diseases as a starting point for new immunooncology targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-114. doi:10.1158/1538-7445.AM2017-LB-114
Abstract LB-138: Runx1 enhancer element marks stem cells in multiple organs
Authors: Yamamura Akihiro , Matsuo Junichi , Lim Yi Hui Melissa , Mon Naing Naing , Heng Dede Liana , Unno Michiaki , Yeoh Khay Guan , Osato Motomi , Ito Yoshiaki
Published: July 2017

Enhancer element (270bp) in the non-coding region between P1 and P2 promoters of Runx1 gene, termed eR1, drives the expression of Runx1 in hematopoietic stem cells (1). This element also targets the expression in stem cells in multiple tissues, including stomach (fundus and corpus) (2), intestine, colon, pancreas, liver, mammary gland and lung. Location of the cells identified by eR1 in each tissue was different from that previously shown by other stem cell markers, such as Lgr5. Nevertheless, in vivo lineage tracing results showed that eR1+ cells are differentiated into all the cell types in the tissue until one year post tamoxifen injection. To demonstrate the stem/progenitor activity in eR1+ cells, we isolated functional units of each organ from eR1-CreERT2; Rosa-tdTomato mice 1 day after tamoxifen injection, dissociated them into single cells and incubated in vitro. Mature organoids were generated from eR1+ cells, suggesting that eR1+ cells have potential to function as stem cells. When we examined the organoids generated from the stomach fundus, all the cells within the organoid showed Tomato color, suggesting they were originated from eR1+ cells. On the contrary, the antral organoids were mixture of Tomato positive and Tomato negative cells. Possible explanation for the mixture of color would be that there are more than one type of stem cells in the antrum and eR1+ and eR1- cells jointly made organoids. Since Lgr5+ stem cells have been described at the base (3) and CCK2R stem cells at +4 position (4) of antrum, whereas eR1+ stem cells are at isthmus of antrum (2), we must examine whether eR1- cells are Lgr5+ cells or CCK2R cells. Interestingly, mixture of eR1+ and eR1- organoids were observed in other GI tract organs. We found that contribution of eR1+ is 100% in proximal stomach and gradually decreased towards rectum (18%). Growth factor requirement of eR1+ stem cells were analyzed by withdrawing each factor. We found that eR1+ stem cells do not require Wnt and jagged1 but eR1- cells require Wnt in antrum. We are studying step-wise carcinogenesis using these organoids.

Reference

1. Ng et al. Stem Cells 2010, 28:1869-81.

2. Matsuo J, Yamamura A et al, Gastroenterology 2016, PMID 27670082.

3. Barker et al, Cell Stem Cells 2010, 6:25-36.

4. Hayakawa et al, Gut 2015, 64:544-553.

Citation Format: Akihiro Yamamura, Junichi Matsuo, Yi Hui Melissa Lim, Naing Naing Mon, Dede Liana Heng, Michiaki Unno, Khay Guan Yeoh, Motomi Osato, Yoshiaki Ito. Runx1 enhancer element marks stem cells in multiple organs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-138. doi:10.1158/1538-7445.AM2017-LB-138
Abstract LB-192: Phenotyping human myeloid derived suppressor cells (MDSC) subsets
Authors: Talmadge James E. , Britton Holly , Dafferner Alicia , Warkentin Phyllis , Cole Kathryn
Published: July 2017

MDSCs are heterogeneous occurring at varying stages of commitment and differentiation. They increase in cancer and other patients with inflammatory diseases and may best be defined based on their ability to suppress T and B cell responses. In recent years these cells have demonstrated clinical relevance, including a negative correlation with prognosis and overall survival in cancer patients increasing with tumor progression and stage. MDSCs were originally described in mice based on a lack of phenotypic markers, i.e. null cells, or predicated on their function, as natural suppressor (NS) cells. Subsequently they were found in humans, based on CD34 expression supporting a hematopoietic progenitor phenotype. The identification of human phenotype(s) is complicated by the association of suppressor cell function with multiple phenotypes. This includes two main subsets defined based on the expression or lack of myeloid and lymphoid markers, with specific phenotypes extent investigator dependent. There is a consensus that MDSCs constitute a continuum of immature to differentiated myeloid cells ranging from multi-potential hematopoietic progenitors to morphologically differentiated granulocytic and monocytic leukocytes. One trending hypothesis is that MDSC phenotypes form three subsets include macrophage (M-) MDSCs with a monocytic morphology, expressing CD14 and no CD15 or CD66b and granulocytic (G)-MDSCs phenotypically characterized by CD15 and/or CD66B expression and no CD14; and an immature (i-) MDSC defined as linage negative, CD33+ cells. Unfortunately, there is no consensus on markers extent to CD14 and CD15 although linage negative and DR- provide a common theme; although not commonly utilized between laboratories and MDSC subset. We provide herein a Flow cytometric strategy utilizing single staining tube and a linear phenotypic characterization that is supported by density and T-cell suppression confirmation. We suggest that staining with Lin, HLA-DR, CD14, CD15, CD11b, CD33 antibodies provides sufficient markers to subset into the three MDSC phenotypes that can be further subset with CD16. PDL1 and CD34 expression. Interestingly the majority of iMDSC express CD34 on the CD33+ cells together with CD14 or CD15 supporting a plastic phenotype with myeloid commitment. All subset can be further, delineated based on CD16 expression further suggesting immaturity. We will note, that some cancer patients express these cell phenotypes at very high levels in the circulation; although the preponderance of G-MDSC vs M-MDSC varies between patients.

Citation Format: James E. Talmadge, Holly Britton, Alicia Dafferner, Phyllis Warkentin, Kathryn Cole. Phenotyping human myeloid derived suppressor cells (MDSC) subsets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-192. doi:10.1158/1538-7445.AM2017-LB-192
Abstract LB-229: Mutation spectra of aflatoxin B1 in vivo establish biomarkers of exposure for human hepatocellualr carcinoma
Authors: Chawanthayatham Supawadee , Valentine Charles C. , Fedeles Bogdan I. , Slocum Stephen L. , Wogan Gerald N. , Croy Robert G. , Essigmann John M.
Published: July 2017

Responding to a need to identify the mutational processes that are responsible for malignant transformation, highly accurate duplex sequencing (DS) was employed to monitor acquisition of context-dependent high-resolution mutational spectra (MS) during the process of hepatocarcinogenesis. Aflatoxin B1 (AFB1) and/or hepatitis B and C viruses are risk factors for human hepatocellular carcinoma (HCC). Available evidence supports the interpretation that formation of AFB1-DNA adducts in hepatocytes seeds a population of mutations, mainly G:C>T:A, and viral processes synergize to accelerate tumorigenesis, perhaps via inflammation. Four-day old male mice were treated with AFB1 using a regimen that induced hepatocellular carcinoma within 72 weeks. The DS technology revealed a distinctive MS of AFB1 at 10 weeks after dosing, well before evidence of neoplasia. Importantly, 25% of all mutations were G>T in one trinucleotide context (5’-CGC-3’), which is also a hotspot mutation in human liver tumors whose incidence correlates with AFB1 exposure. At 72 weeks, livers were separated into tumor tissue and normal surrounding cellular fractions (primarily hepatocytes). The MS in normal cells surrounding the tumors revealed clear evidence of previous AFB1 exposure with predominantly G:C>T:A mutations and strong representation of the CGC>CTC hotspot. Analysis of tumor tissue revealed a more complex pattern than that observed in surrounding hepatocyte fraction; tumor MS were a composite of the 10-week spectrum and a more heterogeneous set of mutations that emerged during tumor outgrowth. The 10-week AFB1-exposed mouse MS was then used as bait to computationally identify human HCC sequences that have similarity to it. This analysis revealed that the mouse spectrum has striking similarity to human HCCs from hepatitis B infected people who have the R249S mutation in P53. The data also provide insight into the molecular basis for the synergism between hepatitis B exposure and AFB1. The MS provided by DS technology provides a method to identify mutational processes in normal and tumor tissues enabling reconstruction of the molecular etiology of human hepatocarcinogenesis and other genetic diseases.

Citation Format: Supawadee Chawanthayatham, Charles C. Valentine III, Bogdan I. Fedeles, Stephen L. Slocum, Gerald N. Wogan, Robert G. Croy, John M. Essigmann. Mutation spectra of aflatoxin B1 in vivo establish biomarkers of exposure for human hepatocellualr carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-229. doi:10.1158/1538-7445.AM2017-LB-229
Abstract LB-245: Immunohistochemical study of MAGI-2 expression in lymphomas and carcinomas from prostate, urinary bladder, ovary, pancreas, liver, and colon
Authors: Liao Zhiming
Published: July 2017

Introduction

MAGI-2 (Membrane Associated Guanylate Kinases Inverted 2) is a scaffolding protein that interacts with PTEN in shutting off the Pi3K/AKT pathway. MAGI-2 suppresses AKT by enhancing PTEN function and its protein stability. In this study, we examined the protein expression of MAGI-2 in normal tissues and various solid tumors by immunohistochemistry (IHC).

Methodology

An IHC study of MAGI-2 was performed on normal tissue and tumor tissues from prostate (34 cases), ovary (95 cases), urinary bladder (92 cases), pancreas (88 cases), liver (2 cases), colon (2 cases), and lymphoma (185 cases). MAGI-2 staining intensity was semi-quantitatively scored using a 0-3 scale. Percent positive rate of MAGI-2 was calculated for carcinomas from prostate, urinary bladder, ovary, pancreas, liver, colon, and lymphoma.

Results

In normal tissues, MAGI-2 was detectable by IHC mostly in follicle area of the tonsil or lymph node and in the cuboidal or columnar epithelium of several organs (skin, urinary bladder, breast, fallopian tube, small intestine, colon, prostate, adrenal gland, and thyroid). The protein expression of MAGI-2 was higher in tumor cells than in their adjacent normal tissues from prostate, urinary bladder, ovary, pancreas, lymph node, liver, and colon. The positive rate of MAGI-2 was 100% for invasive prostate adenocarcinoma (34/34 cases), 82% for ovarian adenocarcinoma (78/95 cases), 76 % for urinary bladder carcinoma (70/92 cases), 62 % of pancreatic adenocarcinoma (55/88 cases), 83 % for diffuse large B-cell lymphoma ( 135/163 cases), 80 % for follicular B-cell lymphoma (8/10 cases), 67% for non-Hodgkin B-cell lymphoma (6/9 cases), 0% for small lymphocytic B-cell lymphoma (0/3 cases), 100% for colon adenocarcinoma (2/2 cases), and 100% for hepatocellular carcinoma (2/2 cases).

Conclusions

MAGI-2 is overexpressed in most lymphomas and carcinomas from prostate, urinary bladder, ovary, pancreas, liver, and colon, but it is not detectable in small lymphocytic B-cell lymphoma by IHC for this study.

Citation Format: Zhiming Liao. Immunohistochemical study of MAGI-2 expression in lymphomas and carcinomas from prostate, urinary bladder, ovary, pancreas, liver, and colon [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-245. doi:10.1158/1538-7445.AM2017-LB-245
Abstract LB-288: An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED
Authors: Qi Wei , Zhao Kehao , Gu Justin , Huang Ying , Wang Youzhen , Zhang Hailong , Zhang Man , Zhang Jeff , Yu Zhengtian , Li Ling , Teng Lin , Chuai Shannon , Zhang Chao , Zhao Mengxi , Chan HoMan , Chen Zijun , Fang Douglas , Qi Fei , Feng Leying , Feng Lijian , Gao Yuan , Ge Hui , Ge Xinjian , Lingel Andreas , Li Guobin , Lin Ying , Liu Yueqin , Luo Fangjun , Shi Minlong , Wang Long , Wang Zhaofu , Yu Yanyan , Zeng Jue , Zeng Chenhui , Zhang Lijun , Zhang Qiong , Zhou Shaolian , Oyang Counde , Atadja Peter , Li En
Published: July 2017

Polycomb repressive complex 2 (PRC2) consists of three core subunits, EZH2, EED and SUZ12 and plays pivotal roles in transcriptional regulation through its histone H3K27 methyltransferase activity. Dysregulation of PRC2 is observed in multiple human cancers, for example, the catalytic subunit EZH2 is overexpressed in a wide range of human cancers and gain-of-function mutations of EZH2 within its catalytic site have been reported in human B-cell lymphoma, parathyroid carcinoma and melanoma. Small molecule inhibitors that compete with the cofactor S-adenosylmethionine (SAM) have been reported and showed anti-lymphoma efficacy in pre-clinical studies. EED within the PRC2 complex allosterically activate the enzymatic activity by binding to tri-methylated H3K27 (H3K27me3). Here we report the discovery of EED226, a potent and selective PRC2 inhibitor directly binding to the H3K27me3 binding pocket of EED. EED226 induces conformational change upon binding EED leading to loss of PRC2 activity. EED226 shows similar activity as SAM-competitive inhibitors in blocking H3K27 methylation of PRC2 target genes and inducing regression of human lymphoma xenograft tumors. Interestingly, EED226 also effectively inhibits PRC2 containing mutant EZH2 protein resistant to SAM-competitive inhibitors. Together, we show EED226 inhibits PRC2 activity via an allosteric mechanism and offers opportunity for treatment of PRC2-dependent cancers.

Citation Format: Wei Qi, Kehao Zhao, Justin Gu, Ying Huang, Youzhen Wang, Hailong Zhang, Man Zhang, Jeff Zhang, Zhengtian Yu, Ling Li, Lin Teng, Shannon Chuai, Chao Zhang, Mengxi Zhao, HoMan Chan, Zijun Chen, Douglas Fang, Fei Qi, Leying Feng, Lijian Feng, Yuan Gao, Hui Ge, Xinjian Ge, Andreas Lingel, Guobin Li, Ying Lin, Yueqin Liu, Fangjun Luo, Minlong Shi, Long Wang, Zhaofu Wang, Yanyan Yu, Jue Zeng, Chenhui Zeng, Lijun Zhang, Qiong Zhang, Shaolian Zhou, Counde Oyang, Peter Atadja, En Li. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-288. doi:10.1158/1538-7445.AM2017-LB-288
Should We Perform Catheter Ablation for Asymptomatic Atrial Fibrillation?
Authors: Kalman Jonathan M. , Sanders Prashanthan , Rosso Raphael , Calkins Hugh
Published: July 2017

Since the original description of atrial fibrillation ablation, numerous studies have demonstrated the superiority of catheter ablation over pharmacological therapy for maintenance of sinus rhythm in patients with both paroxysmal and persistent atrial fibrillation. However, to date, no randomized studies have been powered to demonstrate a mortality or stroke reduction benefit of rhythm control with catheter ablation over a rate control strategy. The results of such ongoing studies are not expected until 2018 or 2019. Thus, the only indication for atrial fibrillation ablation in recent guidelines has been the presence of symptoms. However, up to 40% of an atrial fibrillation population may be asymptomatic. In 2017, in the absence of randomized studies, are there nevertheless data that support atrial fibrillation ablation in asymptomatic patients?
Review of Allanagrus Noyes & Valentine (Hymenoptera: Mymaridae) with a key to species
Authors: PALANIVEL S. , MANICKAVASAGAM S. , HUBER JOHN T.
Published: July 2017

Allanagrus Noyes & Valentine (Hymenoptera: Mymaridae) is reviewed and two new species, A. orientalis Manickavasagam & Palanivel sp. n. and A. montanus Manickavasagam & Palanivel sp. n., are described from Tamil Nadu, India. Allanagrus mayeri (Girault), A. gladius (Girault) and A. aurum (Girault) from Australia are redescribed, the latter only from photographs of the holotype, and the type species, A. magniclava from New Zealand, is illustrated. A key to the seven recognized species is provided.
A new species of Pachycheles (Crustacea: Anomura: Porcellanidae), with taxonomic remarks on two other porcelain crabs from the remote oceanic archipelago of Trindade and Martin Vaz, South Atlantic Ocean
Authors: FERREIRA LUCIANE AUGUSTO DE AZEVEDO , TAVARES MARCOS
Published: July 2017

Three species in two genera of porcelain crabs are reported from the remote oceanic archipelago of Trindade and Martin Vaz one of which, Pachycheles meloi, new to science. The new species is morphologically similar to Pachycheles riisei (Stimpson, 1858) from the inner continental shelf between Florida (USA) and São Paulo (Brazil), of which Pachycheles meloi sp. nov. differs by a suite of carapace and appendage characters, including the presence of a pair of male gonopods on the second abdominal segment (absent in P. riisei). The new species is additionally compared to other congeners. Opportunity is taken to elaborate on the taxonomy of Petrolisthes amoenus (Guérin-Méneville, 1855) and Petrolisthes marginatus (Stimpson, 1859). The Trindade and Martin Vaz Archipelago contain a strongly depauperate porcellanid fauna of western Atlantic affinities.
Additional records of Elasmopus vachoni Mateus & Mateus, 1966 (Crustacea: Amphipoda: Maeridae) from European waters (Tarifa, southern Spain)
Authors: GOUILLIEUX BENOIT , GUERRA-GARCÍA JOSE MANUEL , SORBE JEAN CLAUDE
Published: July 2017

Additional records of Elasmopus vachoni Mateus and Mateus, 1966 together with description of its its poorly-known mouthparts is provided, based on material from Tarifa Island (southern Spain). The known geographical distribution of this species extends from the Gulf of Guinea to the northern part of the Iberian Peninsula, all along its Atlantic and Mediterranean coast, also extending to Canary and Azores Archipelagos. Additionally, an identification key of Elasmopus species mentioned in European waters (ERMS area) is also given.
A new genus and species of Pseudococcidae (Hemiptera: Sternorrhyncha: Coccomorpha) from China
Authors: DONG QIN-GANG , ZHANG JIANG-TAO , WU SAN-AN
Published: July 2017

A new mealybug genus, Dorsoceraricoccus Dong & Wu gen. nov. (Hemiptera: Sternorrhyncha: Coccomorpha: Pseudococcidae), is described to contain Dysmicoccus muajatae Williams as type species, and a new species, Dorsoceraricoccus ningboensis Dong & Wu sp. nov., collected from Zhejiang Province, China on Digitaria sp. (Poaceae). For the new species, the adult female is described and illustrated. In addition, a key to genera of the subfamily Pseudococcinae now known from China and a key to adult female now in Dorsoceraricoccus gen. nov. are provided.
Contemporary Demographic, Treatment, and Geographic Distribution Patterns for Disorders of Sex Development
Authors: Tejwani Rohit , Jiang Ruiyang , Wolf Steven , Adkins Deanna W. , Young Brian J. , Alkazemi Muhammad , Wiener John S. , Pomann Gina-Maria , Purves J. Todd , Routh Jonathan C.
Published: July 2017

This study aimed to describe the demographic characteristics, hospital utilizations, patterns of inpatient surgical management, and the overall state/regional variation in surgery rate among patients with disorders of sex development (DSD). We analyzed the Nationwide Inpatient Sample from 2001 to 2012 for patients younger than 21 years. DSD-related diagnoses and procedures were identified via International Classification of Diseases, Ninth Revision (ICD-9) codes. We identified a total of 43,968 DSD-related admissions. Of these, 73.4% of the admissions were designated as female and 642 (1.9%) were inpatient surgical admissions. Among neonates, less than 1% underwent any type of genital surgery. Nonsurgical admissions were associated with longer length of stay and higher cost. There was no significant regional variation in the rate of DSD surgeries, but we observed higher concentrations of DSD surgeries in states associated with tertiary referral centers.
Explanatory models and distress in primary caregivers of patients with acute psychotic presentations: A study from South India
Authors: Joy Deepa S , Manoranjitham SD , Samuel P , Jacob KS
Published: July 2017

Background:

Emotional distress among caregivers of people with mental illness is common, changes overtime and requires appropriate coping strategies to prevent long-term disability. Explanatory models, which underpin understanding of disease and illness, are crucial to coping.

Aim:

To study the association of explanatory models and distress among caregivers of people with acute psychotic illness.

Method:

A total of 60 consecutive patients and their primary caregivers who presented to the Department of Psychiatry, Christian Medical College, Vellore, were recruited for the study. Positive and Negative Syndrome Scale (PANSS), Short Explanatory Model Interview (SEMI) and the General Health Questionnaire-12 (GHQ-12) were used to assess severity of psychosis, explanatory models of illness and emotional distress. Standard bivariate and multivariable statistics were employed.

Results:

Majority of the caregivers simultaneously held multiple models of illness, which included medical and non-medical perspectives. The GHQ-12 score were significantly lower in people who held multiple explanatory models of illness when compared to the caregivers who believed single explanations.

Conclusion:

Explanatory models affect coping in caregivers of patients with acute psychotic presentations. There is a need to have a broad-based approach to recovery and care.
The effect of risk communication on the acceptance of policies for high-risk facilities in South Korea: with particular focus on the mediating effects of risk perception
Authors: Lee Dae-Woong , Kwon Gi-Heon
Published: July 2017

Continuous technological development has resulted in a new type of risk to human lives: what is now regarded as “socially created risk.” Ideas on risk have increasingly focused on subjective, rather than objective, risk. This shift is clearly observable in the case of location policies for nuclear energy facilities. The South Korean public is often suspicious of new energy facilities; for example, in the case of nuclear power, they are suspicious of the risk of involuntary exposure to dangerous radiation, which cannot be effectively controlled. Therefore, the South Korean government is continuously discussing how to increase the acceptance of such high-risk facilities by managing the public’s risk perceptions. The research question was as follows: “Does the Korean government’s risk communication strategy have a positive impact on the public’s risk perceptions and acceptance of policies?” This study analyzed whether communicating risks helps boost public acceptance of high-risk facilities. A structural equation model and multiple group analyses were used for empirical analysis. The study explores government perspectives in terms of insecurity and conflict caused by scientific advancements, and uncertain public perceptions of high-risk facilities such as nuclear power plants. It provides empirical results regarding risk communication and implications for public policy that decrease risk perception and increase the acceptance of such policies.

Points for practitioners

This study analyzes whether risk communication can solve the problem of low public acceptance of high-risk facilities, based on their risk perception. As a result, this study contributes to policy implications regarding risk communication as a way to control risk perception and increase policy acceptance. In particular, it is critical to develop strategies for risk communication in which the public shares the decision-making process with governmental bodies and energy providers.