bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1587: Stress keratin 17 overexpression downregulates CD8+ T cell infiltration in papillomavirus-associated disease
Authors: Wang Wei , Gronski Ellery , Lambert Paul 
Published: September 2020

Abstract
High-risk human papillomaviruses (HPVs) cause 5% of human cancers. Despite the availability of HPV vaccines, there remains a strong urgency to find ways to treat persistent HPV infections, as current HPV vaccines are not therapeutic for individuals already infected. It has not well understood how papillomaviruses evade host immune surveillance to establish long-term infections, which can lead to neoplastic disease including cancer. Using a mouse papillomavirus (MmuPV1) infection model in immunocompetent FVB/N mice, we found that stress keratins are upregulated in mouse papillomavirus-induced papillomas. In mice deficient for stress keratin K17 (K17KO), we observed early regression of papillomas dependent on T-cells. Expression of cellular genes involved in immune response were significantly upregulated in the papillomas arising on the K17KO mice correlating with increased numbers of infiltrating CD8+T cells and upregulation of IFNγ-related genes, including CXCL9 and CXCL10, prior to complete regression. This T cell-dependent regression also required ligand accessibility to CXCR3, a receptor for CXCL9 and CXCL10. By analyzing public available TCGA data, we found an inverse correlation between K17 mRNA expression and CD8A, GZMB and CXCL9 mRNA expression in a cohort of head and neck cancer patients. We validated these observations by antibody immunofluorescence staining of a tissue microarray (TMA) composed of 380 tumor tissues from head and neck cancer patients (HPV+ n=265, HPV- n=49, HPV unknown n=66). We stained TMA with CD8 and K17. Out of 380 cancer specimens, there are n=46 that had either high percentage of CD8+ cells in tumor (Z score&gt;=1.64, n=14) or a high mean fluorescence intensity of K17 (Z score&gt;=1.64, n=33). The heatmap of these 46 samples showed that the high K17 stained tissue and high CD8+ T cell infiltrated tissues are mutually exclusive, consistent with our prior analysis from TCGA mRNA data from head and neck cancer patients. In the process of exploring the mechanism of K17-mediated immunosuppression, we found that mouse papillomas arising from K17 knockout mice lacked nuclear staining for YAP1 whereas a significant amount of nuclear staining for YAP1 was observed in WT FVB papillomas, suggesting K17 may regulate Yap1 activation to mediate downstream immunosuppressive effect.
Citation Format: Wei Wang, Ellery Gronski, Paul Lambert. Stress keratin 17 overexpression downregulates CD8+ T cell infiltration in papillomavirus-associated disease [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1587.
Abstract 1596: Profiling immune cell populations in the tumor microenvironment with complementary capillary-based and single-cell western assays
Authors: Haitjema Charles , Grant Rainer , Wentz Lindsay , Luhowskyj Stefan , Cooper Jeff , Boge Annegret , Brumbaugh Kathy , Gardner Kelly , Heger Christopher 
Published: September 2020

Abstract
The tumor microenvironment (TME) is a complex mixture of cancerous and non-cancerous cells, including immune cells like T-cells, macrophages, and neutrophils. The TME plays a key role in tumorigenesis and metastasis, and it has recently been recognized that it can dramatically shape a response to therapy. Thus, there is a pressing need to accurately identify and quantify the variety of cell types in any given TME. However, studying the TME presents major challenges. For example, the heterogeneity of the environment requires sensitive and high-resolution techniques to parse subpopulations of different cell types. This challenge is compounded by the severely limited sample size that can be obtained from donor tissues. To address these challenges, we use an in-capillary immunoassay with small sample sizes (3 µL) to identify immune cells commonly found in the TME. We also leverage single-cell western to uncover trends in population heterogeneity. Human peripheral blood mononuclear cells (PBMCs) were differentiated into dendritic cells (DCs) and regulatory T cells (Tregs), and natural killer (NK) cells were expanded from isolated NK cells. These samples were then analyzed by in-capillary immunoassay and single-cell western. These analyses revealed the identification and characterization of cell types, at both the single-cell and population level, based on the differential expression of protein biomarkers. Specifically, in-capillary immunoassay analysis identified mature populations by CD209 and CD83 expression for DCs, a CD56+/CD3- phenotype for NK cells, and CD25 and Foxp3 expression for Tregs. Analysis of single cells provided further detail within these populations, for example, we observed FoxP3low and FoxP3high subpopulations in Tregs, and an unexpectedly large (81%) CD56-/CD3- subpopulation in undifferentiated PBMCs, suggesting the presence of other cell subtypes. We anticipate that the small sample size, automation, single-cell resolution, and multiplexing ability of these assays collectively will enable a more efficient and deeper characterization of the TME not possible with traditional immunoassays like western blot and flow cytometry.
Citation Format: Charles Haitjema, Rainer Grant, Lindsay Wentz, Stefan Luhowskyj, Jeff Cooper, Annegret Boge, Kathy Brumbaugh, Kelly Gardner, Christopher Heger. Profiling immune cell populations in the tumor microenvironment with complementary capillary-based and single-cell western assays [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1596.
Abstract 1616: Elucidating the role of PI3K lipid effectors in BRAF mutant melanoma
Authors: Parkman Gennie , Cho Joseph , Holmen Sheri , McMahon Martin 
Published: September 2020

Abstract
Metastatic melanoma accounts for the highest number of skin cancer deaths, and while current treatments for this disease have progressed significantly in recent years, stage IV melanoma currently has only a 15-20% five-year survival rate. This highlights the critical need for new therapeutics to treat this complex disease. The PI3K/AKT pathway and RAS-RAF-MEK-ERK pathway play a major role in melanoma initiation and progression. Mutations in BRAF are found in around 50% of all human melanomas, and although there has been significant success in the development of therapies for BRAF mutant melanomas, most patients will experience primary or secondary resistance. Furthermore, mutant BRAF has been shown to be insufficient for melanomagenesis, yet the mechanism by which mutationally activated BRAF cooperates with oncogenes and loss of tumor suppressors to promote melanoma tumorigenesis and progression is not well understood. Dysregulated PI3K/AKT signaling is frequently observed concurrently with BRAF mutant melanomas; however, pharmacological inhibitors of AKT have been largely ineffective in clinical trials as single agents. Studies in our lab have shown that there is a discordant effect between pharmacological inhibition and genetic targeting of AKT, suggesting that therapeutic inhibition of this protein kinase is insufficient to block its activity in melanoma. We have shown that genetic knockdown of all three AKT paralogs leads to complete cell lethality in multiple human melanoma cell lines, and overexpression of each of the AKT proteins is able to significantly rescue this deleterious effect, which is dependent on functional kinase activity. Based on these preliminary results, we seek to determine if the PI3K pathway depends solely on AKT signaling for its role in melanoma initiation and progression. Dysregulation of the PI3K lipid signaling cascade in melanoma is conventionally believed to occur through activation of AKT, and we have previously shown that either loss of PTEN or mutationally activated PI3K cooperates with mutant BRAF to promote melanoma formation. However, it has not been shown if constitutively active AKT alone is able to substitute for this effect. Further research will elucidate the role of AKT in the initiating stages of melanoma and provide a more thorough understanding of the PI3K/AKT signaling pathway in promoting BRAF mutant melanomagnesis.
Citation Format: Gennie Parkman, Joseph Cho, Sheri Holmen, Martin McMahon. Elucidating the role of PI3K lipid effectors in BRAF mutant melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1616.
Abstract 1622: Microsatellite instability causes colorectal cancer cell death to trigger anti-tumor immune response
Authors: Lizardo Darleny Y. , Wang Yi-Jun , Yang Liheng , Yu Jian , Zhang Lin 
Published: September 2020

Abstract
Colorectal cancer (CRC) is the second leading cause of cancer deaths in the western world. Approximately 15% of CRCs have defects in DNA mismatch repair (MMR) genes, which lead to frequent mutations in repetitive genomic sequences known as microsatellites. This kind of genomic instability, referred to as microsatellite instability (MSI), contributes to the emergence of highly immunogenic neoantigen peptides that can stimulate an antitumor response. As such, a subset of CRC patients with deficient MMR has a positive response to immune checkpoint blockade immunotherapy. However, the molecular basis of MSI-induced antitumor immune response is not well understood. To address this issue, we used CRISPR to genetically inactivate MutL homolog 1 (MLH1), a key MMR protein, in two microsatellite stable (MSS) murine colorectal cancer cell lines, CT26 and MC-38, which enabled us to directly compare isogenic MSI and MSS tumors in mice with an immuno-deficient or -competent microenvironment. The growth of MLH1-KO cells was comparable to the parental cells in immunocompromised mice. Upon transplantation into syngeneic, immunocompetent mice, the parental CT26 and MC-38 tumors rapidly proliferate. In contrast, the MLH1-KO tumors grew poorly under the same conditions, which was accompanied by apoptotic cell death, upregulation of inflammatory cytokines, and tumor infiltration of CD8+ T lymphocytes. Blocking apoptosis by caspase inhibition suppressed cytokine induction and T lymphocyte infiltration, suggesting a key role of apoptosis in triggering an antitumor immune response. Our current efforts are towards elucidating the mechanism of cell death and defining the associated immune signatures. Ultimately, a better understanding of the immunological consequences of MSI status in CRCs may help to develop more effective CRC therapies.
Citation Format: Darleny Y. Lizardo, Yi-Jun Wang, Liheng Yang, Jian Yu, Lin Zhang. Microsatellite instability causes colorectal cancer cell death to trigger anti-tumor immune response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1622.
Abstract 1632: Long-term maintenance of human mature NK cells from hCD34+HSCs engraftment supported by immune humanized B-NDG hIL15 mice
Authors: Lin Qingcong , Hu Yuting , Zhou Xiaofei , Su Youhong , Shen Yuelei 
Published: September 2020

Abstract
Human HSC (hematopoietic stem cells) engrafted humanized mice are a powerful model that allows researchers to examine the human immune system and evaluate cellular immunotherapy in the preclinical stage. Successful reconstitution of the human immune system in B-NDG mice (a complete immunodeficient mouse model previously developed by Biocytogen) has been accomplished using CD34+ hematopoietic stem cells. However, the species barrier between human immune cells and the mouse microenvironment can obstruct human immunity acquisition, as well as innate immune function development, in the mice upon the reconstitution of immune system.
To address this issue, Biocytogen has developed and validated the B-NDG hIL15 mice that combines a B-NDG mouse background and expresses human IL15 cytokine, which plays important roles in the innate and adaptive cell homeostasis, as well as peripheral immune function. The targeting strategy stipulates the insertion of CDS region of the human IL15 gene after the 5′UTR of the mouse Il15. In this work, human CD34+ hematopoietic stem cells have been successfully grafted in B-NDG hIL15 mice, to reconstitute a functional human immune system. At 4 weeks post CD34+ cell implantation, the percentage of hCD45+ cells reached over 25%, containing human T, B, and NK cells. In summary, these CD34+ reconstituted B-NDG hIL15 mice are validated to be promising tools for the efficacy study of clinically relevant therapeutic agents given the mice's long-term maintenance of human NK cells upon the reconstitution of immune system.
Citation Format: Qingcong Lin, Yuting Hu, Xiaofei Zhou, Youhong Su, Yuelei Shen. Long-term maintenance of human mature NK cells from hCD34+HSCs engraftment supported by immune humanized B-NDG hIL15 mice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1632.
Abstract 1637: ATP-citrate lyase transgenic mice frequently develop lymphoma/leukemia spontaneously
Authors: Kanda Hiroaki , Nomura Kimie , Iizuka Toshihiko , Fujiwara Mutsunori , Ishikawa Yuichi , Migita Toshiro 
Published: September 2020

Abstract
ATP-citrate lyase (ACLY) catalyzes the generation of acetyl-CoA from citrate. ACLY expression is upregulated and/or ACLY is phosphorylated in several types of cancer. We generated ACLY transgenic mice (Tg) to examine the role of ACLY in carcinogenesis.
(Materials and methods)
Using human ACLY cDNA under the ROSA26 promoter, Tg with a C57BL background was established. We observed the Tg without treatment. Statistical analyses were performed using the Chi-square and Fisher's exact test.
(Results)
Of 24 male (M) Tg, aged 24–30 months, 14 (58%), 7 (29%), and 1 (4%) spontaneously developed lymphoma/leukemia (LL), lung carcinoma (LC), and small intestinal carcinoma (SIC), respectively. Since some C57BL mouse colonies are genetically susceptible to LL, and we have previously examined human cases of carcinoma, the Tg were back-crossed with C3H mice, which are resistant to LL and susceptible to carcinoma, especially hepatocellular carcinoma (HCC). A total of 129 (M: 67, female (F): 62) Tg were observed for 18 months. Forty-nine C3H mice (M: 19, F: 30) from the same colony were used as controls. Multiple tumors were counted individually. Seventy-three Tg (57%; M: 41, 61%; F: 32, 52%) and 8 controls (16%; M: 4, 21%; F: 4, 13%) developed cancer. The Tg developed significantly more tumors (total (T), M, F: all p&lt;0.05), including 33 HCC (26%; M: 22, 33%; F: 11, 18%), 28 LL (22%; M: 12, 18%; F: 16, 26%), 7 LC (5%; M: 6, 9%; F: 1, 2%), 4 sarcomas (Sa)(3%; M: 2, 3%; F: 2, 3%), 2 SIC (2%; M: 2, 3%; F: 0), 2 skin appendage carcinomas (SAC) (2%; M: 0; F: 2, 3%), and 1 ovarian cancer (Ov) (1%; F: 1, 2%), than the control mice, which developed 7 HCC (14%; M: 4, 21%; F: 3, 10%), 1 LC (2%; M: 1, 5%; F: 0), and 1 Ov (2%; F: 1, 3%). No LL was seen in the controls. The frequency of HCC did not differ significantly between the Tg and controls (T, M, F: all p&gt;0.05).
(Discussion)
ACLY was reported to be related to the carcinogenesis of anaplastic large cell lymphoma (Basappa J. et al. Blood 2015 126:465). This study suggests that ACLY might contribute to LL development.
Table:Summary of developed cancersNumberTotal cancerHCCLLLCSICSaSACOvACLY12973(57%)*33(26%)28(22%)7(5%)2(2%)4(3%)2(2%)1(1%)Male6741(61%)**22(33%)12(18%)6(9%)2(3%)2(3%)0-Female6232(52%)***11(18%)16(26%)1(2%)02(3%)2(3%)1(2%)Control498(16%)*7(14%)01(2%)0001(2%)Male194(21%)**4(21%)01(5%)000-Female304(13%)***3(10%)000001(3%)*, **, ***; p&lt;0.05
Citation Format: Hiroaki Kanda, Kimie Nomura, Toshihiko Iizuka, Mutsunori Fujiwara, Yuichi Ishikawa, Toshiro Migita. ATP-citrate lyase transgenic mice frequently develop lymphoma/leukemia spontaneously [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1637.
Abstract 1652: Tumor-specific PET imaging with an 18F-labeled tryptophan analogue in a transgenic medulloblastoma mouse model
Authors: Yue Xuyi , Xin Yangchun , Li Hua , Li Zhiqin , Cai Hancheng , Langhans Sigrid A. 
Published: September 2020

Abstract
In vivo positron emission tomography (PET) imaging is a key modality to evaluate disease status of brain tumors. In recent years, tremendous efforts have been made in developing PET imaging methods for pediatric brain tumors. Carbon-11 labelled tryptophan derivatives are feasible as PET imaging probes in brain tumor patients with activation of the kynurenine pathway, but the short half-life of carbon-11 limits its application. Using a transgenic mouse model for the sonic hedgehog (Shh) subgroup of medulloblastoma, here we evaluated the potential of the newly developed 1-(2-[18F]fluoroethyl)-L-tryptophan (1-L-[18F]FETrp) as a PET imaging probe for this common malignant pediatric brain tumor. 1-L-[18F]FETrp was synthesized on a PETCHEM automatic synthesizer with good chemical and radiochemical purities and enantiomeric excess values. Imaging was performed in tumor-bearing Smo/Smo medulloblastoma mice using a Perkin-Elmer G4 PET-X-Ray scanner. Medulloblastoma tumors showed significant and specific accumulation of 1-L-[18F]FETrp. 1-L-[18F]FETrp also showed significantly higher tumor uptake than its D-enantiomer 1-D-[18F]FETrp. The uptake of 1-L-[18F]FETrp in normal brain tissue was low, suggesting that 1-L-[18F]FETrp may prove a valuable PET imaging probe for the Shh subgroup of medulloblastoma and possibly other pediatric and adult brain tumors.
Citation Format: Xuyi Yue, Yangchun Xin, Hua Li, Zhiqin Li, Hancheng Cai, Sigrid A. Langhans. Tumor-specific PET imaging with an 18F-labeled tryptophan analogue in a transgenic medulloblastoma mouse model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1652.
Abstract 1655: Hyperspectral metabolic imaging with a camera
Authors: Hedde Per Niklas , Gratton Enrico 
Published: September 2020

Abstract
New methods to quantify metabolism in cells, organoids, and tissues are highly demanded for cancer diagnosis and treatment. We developed a light sheet-based volumetric imaging platform to rapidly quantify metabolism via fluorescence spectral signatures of intrinsically fluorescent biomolecules.
The ability to quantify metabolism in live cells and tissues can be very powerful as the metabolic activity in rapidly proliferating cells, such as cancer cells, is fundamentally different from non-proliferating cells. Most cancer cells rely on aerobic glycolysis to ferment glucose into lactate independent of the presence of oxygen whereas healthy, differentiated cells primarily rely on oxidative phosphorylation. The rapid generation of cytosolic adenosine triphosphate (ATP) during proliferation results in elevated ratios of the reduced form of nicotinamide adenine dinucleotide (NADH) to NAD+ in cancerous cells that can be detected with fluorescence microscopy of intrinsically (auto)fluorescent molecules such as NADH and flavin adenine dinucleotide (FAD) and its variants. This opens a window to quantify ongoing redox reactions as well as important enzymatic reactions via changes of their fluorescence spectral signatures reporting on the metabolic activity of cells. We developed a light sheet-based hyperspectral imaging platform leveraging custom designed sine/cosine filters and spectral phasor data analysis to directly obtain spectral information with a regular camera. The approach was verified by spectrally resolving 3D reconstructions of fluorescence images of fragments of mouse intestinal crypts. The acquisition speed of light sheet-based hyperspectral imaging is on the order of seconds for one 3D stack allowing for sequential, repeated imaging of several samples over the course of hours to days.
In summary, the overall goal of this project is to develop a modular imaging platform to overcome the limitations of current, laser scanning-based spectral imaging and to make quantification of metabolism viable in live three-dimensional cell, organoid and tissue samples, that can then be used to, for example, to study the effects of cancer chemotherapy reagents on the metabolism of patient-derived organoids.
Citation Format: Per Niklas Hedde, Enrico Gratton. Hyperspectral metabolic imaging with a camera [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1655.
Abstract 1656: Quantifying task performance with photon-processing detectors
Authors: Caucci Luca , Henscheid Nicholas P. , Barrett Harrison H. 
Published: September 2020

Abstract
Purpose. To estimate task performance (e.g., the ability to correctly detect a small lesion in a normal tissue) when the imaging system uses a new class of detectors, called photon-processing detectors.
Experimental Procedure. We simulated a single-photon emission computed tomography (SPECT) system in which multiple cameras image a 3D object from different angles. Each camera uses multiple measurements (e.g., photomultiplier tube outputs) to perform estimation of event parameters (or “attributes”) of each detected gamma-ray photon. Photon attributes, such as position, energy and direction of propagation, are stored at full precision. The likelihood ratio applied to photon-processing data is used to assess task performance for the detection of a signal buried in a random background. Statistical methods (including Markov chain Monte Carlo estimation) are used to calculate the performance of the likelihood ratio on this task.
Results. Our results show an improvement with respect to conventional (i.e., pixelated) detectors when photon-processing detectors are used. The area under the receiver operating characteristic (ROC) curve is used to assess task performance, and we use this figure-of-merit to compare photon-processing detectors with conventional detectors.
Conclusions. Increased performance is observed in the detection of a small lesion when photon-processing detectors are used instead of pixelated detectors. Applications that will benefit from photon-processing detectors include tumor diagnosis, drug development, therapy assessment and the study of tumor metabolism.
Citation Format: Luca Caucci, Nicholas P. Henscheid, Harrison H. Barrett. Quantifying task performance with photon-processing detectors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1656.