bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2855: Anti-PSMA x anti-CD3 SCORPIONTM molecule inhibits tumor growth in vivo in mouse models of prostate cancer.
Authors: Miller Robert , Fang Hang , Luke Jessica , Aguilar Megan , Chenault Ruth , Kumer John , Wiens Jennifer , Algate Paul , Bienvenue David , McMahan Catherine , Nguyen Holly , Vessella Robert , Blankenship John 
Published: August 2014

Abstract
Background: Treatment of metastatic, castrate-resistant prostate cancer (CRPC) remains a highly unmet medical need. We have developed a bispecific SCORPIONTM (multi-specific protein therapeutic) molecule that redirects T cell cytotoxicity against cells expressing PSMA (Prostate Specific Membrane Antigen), a common prostate-cancer related antigen. The SCORPION molecule described here contains two pairs of binding domains, each targeting a unique antigen, linked to opposite ends of an immunoglobulin Fc domain to extend the half-life of the molecule in vivo. In these studies, we examine the ability of a SCORPION molecule targeting both CD3 and PSMA, to inhibit the growth of PSMA expressing tumors in vivo.
Materials and Methods: NOD/SCID mice were implanted with the PSMA(+) prostate tumor cell line C4-2B and purified human T cells in one of two models. In a first model of residual disease, C4-2B cells were coimplanted subcutaneously with human T cells, and treatment with drug was initiated immediately. This model was run twice with T cells from two different human donors. In a second model of established disease, C4-2B cells were implanted subcutaneously and allowed to develop for 20 days, after which human T cells were injected intra-peritoneally, with subsequent administration of drug. Tumor growth was assessed by tumor volume and serum PSA, and tumor volume and weight loss were used as endpoints.
Results: SCORPION molecules targeting PSMA and CD3 inhibited growth of PSMA(+) tumors in both model settings and significantly improved overall survival. Reduction in circulating serum PSA was also observed. Repeat studies using a second human T cell donor showed similar inhibition of tumor growth and overall survival. Inhibition of tumor growth was seen at doses in the low pmol range per mouse.
Conclusions: These studies show that anti-PSMA x anti-CD3 SCORPION therapeutics redirect T cell cytotoxicity in in vivo xenograft models and merit further investigation as potential therapeutics in CRPC.
Citation Format: Robert Miller, Hang Fang, Jessica Luke, Megan Aguilar, Ruth Chenault, John Kumer, Jennifer Wiens, Paul Algate, David Bienvenue, Catherine McMahan, Holly Nguyen, Robert Vessella, John Blankenship. Anti-PSMA x anti-CD3 SCORPIONTM molecule inhibits tumor growth in vivo in mouse models of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2855. doi:10.1158/1538-7445.AM2013-2855
Abstract 2865: The significance of Vitamin D deficiency and low grade pathogens in etiology of prostate cancer.
Authors: Oliver Tim R T D 
Published: August 2014

Abstract
Introduction. Estimations of sun exposure (but less so spot serum Vitamin D levels) correlate with risk of prostate cancer occurrence. This suggests that it is due to long term Vitamin D deficiency over 10-40 years as a possible explanation. This, via diminished macrophage function, could allow persistence of low grade pathogens to set up chronic inflammation that could lead to Proliferative Inflammatory Atrophy (PIA) of the prostate, now thought to be an important precursor of cancer. Despite multiple investigations of sexually transmitted infections, there has been no consistently associated organism. However recently infection with two low grade pathogenic organisms, teenage acne associated anaerobic bacterium Propionibacterium.acnes (PA) and protozoan Trichomonas vaginalis (TA), have shown a more consistent association with prostate cancer. This abstract reports the results of a systematic review of publications investigating the association of sun exposure and prostate cancer and of PA and T V with prostate cancer and considers how these observations could lead to improved specificity of PSA screening
Methods. Pubmed searches using terms prostate or prostatic, sunshine or UVB or Vitamin D and acne or PA or TA were performed and the abstracts reviewed and appropriate papers selected for review and data extraction
Results . Amongst 1134 abstracts investigating PC and Vitamin D were two systematic reviews that failed to produce a consistent association. In contrast four of four studies of an index of sun exposure involving 1568 patients (OR 0.75, 0.75, 0.59 & 0.89) and 6 of 7 geographic studies (0.32, 0.38, 0.44, 0.16, 0.52, 1.63 & 0.64) demonstrated an association of high UVB exposure with reduced PC risk. Four of five publications on PA and PC (1.7, 1.67, 2.17 & 0.67) and 2 of 3 publications on TV and PC (1.23, 1.43 & 0.83) from 205 papers reviewed showed consistent increase risk of PC associated with infection.
Conclusion. Lack of association with spot Vitamin D but clear association with index of sun exposure suggest that the association is due to reduced long term Vitamin D mediated non-specific macrophage surveillance that is involved against lowly pathogenic agents of which PA and TV could be lead organisms. Impact on PSA of elimination of these organisms could become an important strategy in future efforts of to improve the specificity of PSA screening and chemoprevention of PC
Citation Format: Tim R T D Oliver. The significance of Vitamin D deficiency and low grade pathogens in etiology of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2865. doi:10.1158/1538-7445.AM2013-2865
Abstract 2872: Image analysis algorithms for whole-slide counting, regional assignment, and subtype classification of tumor-associated macrophages (TAMs).
Authors: Laffin Brian E. , Krueger Joseph , Salama Mohamed 
Published: August 2014

Abstract
Tumor-associated macrophages (TAMs) regulate cancer progression on multiple levels, including angiogenesis, treatment response, and metastasis. Additionally, multiple studies have demonstrated a significant association between clinical outcome and TAM abundance, M1 vs. M2 subtype, and intratumoral distribution into stromal or epithelial compartments. However, manual counting of TAMs and assignment into tumor stroma or epithelial nests is laborious, inaccurate, subjective, and does not provide a statistically optimal sample size. These pitfalls may be limiting its utility as a diagnostic tool or an endpoint in drug efficacy studies. Using tissue sections from human breast cancers as a model, we have developed image analysis algorithms for the rapid automated counting and compartmental assignment of total TAMs (CD68+) and TAMs of the more strongly tumor-promoting M2 subtype (CD163+). Using whole slide scanning and proprietary image analysis tools called Feature Analysis on Consectutive Tissue Sections (FACTS), we have developed an approach to not only tally but also map the location of CD68+ and CD163+ macrophages in serial tissue sections, align those sections, and provide information about regional distribution of these macrophages. These outcomes can also be aligned with other serial sections containing relevant biomarkers associated with macrophage infiltration such as hypoxia or angiongenesis, using our proprietary multivariate correlation analysis tool Multivariatemap. Additionally, we have begun investigations into the association of these regional macrophage densities with clinical outcome using patient data available for the model set. These approaches represent a powerful toolkit for elucidating significant quantitative associations between TAMs and tumor vasculature, hypoxia, or other relevant features or markers, for the determination of prognostic or drug efficacy endpoints.
Citation Format: Brian E. Laffin, Joseph Krueger, Mohamed Salama. Image analysis algorithms for whole-slide counting, regional assignment, and subtype classification of tumor-associated macrophages (TAMs). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2872. doi:10.1158/1538-7445.AM2013-2872
Abstract 2875: NF-κB signaling in myeloid cells limits urethane-induced lung tumorigenesis.
Authors: McLoed Allyson , Zaynagetdinov Rinat , Sherrill Taylor , Yull Fiona , Blackwell Timothy 
Published: August 2014

Abstract
The transcription factor Nuclear Factor κB (NF-κB) is a master regulator of inflammation, and its activation is associated with tumorigenesis in a variety of cancers. Our group has shown that NF-κB signaling in lung epithelial cells is critical for lung tumor formation. However, the role of NF-κB in other cell types, such as myeloid cells, during lung carcinogenesis is uncertain. We hypothesized that NF-κB signaling in myeloid cells (macrophages, monocytes, and neutrophils) promotes lung tumorigenesis by facilitating lung inflammation. Surprisingly, we found that mice with myeloid cell-targeted IKKβ deletion (IKKβΔmye mice) developed significantly more tumors than wild-type (WT) mice 4 months following a single intraperitoneal (IP) injection of the lung carcinogen urethane (1g/kg). IKKβΔmye mice exhibited a paradoxical increase in the proinflammatory cytokines IL-1β, TNFα, and CXCL1 at 1 and 2 weeks after urethane treatment, and a more than 3-fold higher influx of CD11b+Ly-6G+ cells into IKKβΔmye lungs compared to WT lungs was observed by flow cytometry 1 week post-urethane. By 6 weeks after urethane, IKKβΔmye mice developed more lung inflammation than WT mice, which was accompanied by an increased burden of atypical adenomatous hyperplasia lesions. Flow cytometric analysis of inflammatory cell populations at this time point revealed a sustained increase in granulocytic cells, indicated by significantly higher numbers of CD11b+Gr-1hi cells in the lungs of IKKβΔmye mice compared to WT mice. Depletion of granulocytic cells using Ly-6G antibody treatment (50ug/weekly IP injection) during the first 6 weeks of urethane-induced lung carcinogenesis reduced lung NF-κB activation and lung tumor incidence in IKKβΔmye mice to levels observed in urethane-treated WT mice, indicating that granulocytic cells play an important role in lung tumorigenesis during early tumor development and may do so by limiting NF-κB activation in lung epithelial cells. Together, our data suggest that the impact of NF-κB signaling on lung tumorigenesis is cell type specific and that myeloid NF-κB signaling limits urethane-induced inflammation and lung tumorigenesis. Granulocytes are important players during early lung tumor promotion, and we propose that they promote lung carcinogenesis through interactions that increase survival and/or proliferation of mutated lung epithelial cells.
Citation Format: Allyson McLoed, Rinat Zaynagetdinov, Taylor Sherrill, Fiona Yull, Timothy Blackwell. NF-κB signaling in myeloid cells limits urethane-induced lung tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2875. doi:10.1158/1538-7445.AM2013-2875
Abstract 2877: Dual role of mast cells in prostate tumors.
Authors: Colombo Mario P. , Pittoni Paola , Sangaletti Sabina , Tripodo Claudio 
Published: August 2014

Abstract
Prostatic carcinoma is most often a multifocal disease, with areas of localized, well-differentiated adenocarcinomas coexisting with poorly differentiated lesions within the same tumor. Mast cells (MC), classically known as the primary responders in allergic reactions, have been recently indicate of prognostic value in prostate cancer. We have evidence of a dual role of MC in prostate cancer. Within the same human tumor, MC are specifically enriched and degranulated in areas of adenocarcinoma, whereas few around anaplastic foci. This observation has been confirmed in tumors from TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) mice, and in two novel tumor cells lines, derived from them, phenocopying well and poorly differentiated adenocarcinoma: T1525 and T23, respectively. MC promote the growth of the well-differentiated adenocarcinoma T1525 that does not develop when transplanted into MC-deficient mice, or when MC degranulation is pharmacologically inhibited with sodium cromoglycate. In particular, mast cells are essential for the outgrowth of early-stage tumors due to their matrix metalloproteinase-9 production, become dispensable in advanced-stage, post-epithelial-to-mesenchymal transition, and are protective against neuroendocrine prostate tumor variants. Indeed, pharmacological inhibition or genetic ablation of MC in TRAMP mice results in early development of undifferentiated tumors characterized by marked anaplasia, suggesting that the growth of anaplastic clones may be antagonized by MC.
Our data demonstrate that MC can influence the histotype of tumor arising from the prostate and that their targeting may change tumor outcome. As a possible corollary, MC depletion might favor the growth of more undifferentiated and aggressive variants. The common expression of c-Kit by mast cells and neuroendocrine clones suggests a possible competition for the ligand Stem Cell Factor and offers the chance of curing early-stage disease while preventing neuroendocrine tumors using c-Kit-targeted therapy.
Citation Format: Mario P. Colombo, Paola Pittoni, Sabina Sangaletti, Claudio Tripodo. Dual role of mast cells in prostate tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2877. doi:10.1158/1538-7445.AM2013-2877
Abstract 2884: ER stress and autophagy induced in pro-inflammatory mast cells exposed to stimuli associated with a positive energy balance.
Authors: Balajadia Januaria M. , Shimoda Lori , Greineisen William , Turner Helen 
Published: August 2014

Abstract
Over the past two decades there has been an increase in the incidence of obesity and metabolic diseases due to sedentary lifestyles, high caloric intake, genetics and environmental factors. Studies have shown that obesity is linked with multiple co-morbid pathologies, including increases in the incidence of some cancers. We have studied the effect of a nutrient-dense environment upon the mast cell, a pro-inflammatory immunocyte. Our recently published work shows that these immunocytes are sites for ectopic lipid deposition (steatosis) under conditions that mimic high nutrient availability and hyperinsulineamia. Moreover, the steatotic phenotype is associated with phenotypic change in the mast cells, with relative over-production of bioactive eicosanoids and other pro-inflammatory lipid mediators, but suppression of some aspects of the acute Type I hypersensitivity pathway. In the current study we sought to further explore the impact of nutrient abundance upon the cell biology of the mast cell. We observe the induction of ER stress pathways, which is associated with the re-programming of the ER towards lipid synthesis and deposition in lipid bodies. Moreover, we observe the induction of autophagy pathways, which likely reflect cellular attempts to access the dysregulated ER and lipid bodies in an effort to return to homeostasis. These studies deepen our understanding of the degree to which altered nutrient environments can, in turn, cause immunological dysregulation. Of particular interest for future studies will be the links between mast cell dysregulation and the systemic and local inflammatory pathology that is associated with metabolic syndrome.
Citation Format: Januaria M. Balajadia, Lori Shimoda, William Greineisen, Helen Turner. ER stress and autophagy induced in pro-inflammatory mast cells exposed to stimuli associated with a positive energy balance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2884. doi:10.1158/1538-7445.AM2013-2884
Abstract 2885: Features of innate immunity dominate serum and tissue protein and cytokine profiles in both mouse and human inflammatory bowel disease.
Authors: Knutson Charles G. , Mangerich Aswin , Zeng Yu , Raczynski Arkadiusz R. , Liberman Rosa G. , Kang Pilsoo , Ye Wenjie , Gong Guanyu , Prestwich Erin , Lu Kun , Wishnok John S. , Korzenik Joshua R. , Wogan Gerald N. , Gox James G. , Dedon Peter C. , Tannenbaum Steven R. 
Published: August 2014

Abstract
Inflammatory bowel disease (IBD) is a chronic and relapsing intestinal inflammatory disease that arises through unknown genetic, environmental, and bacterial origins. Ulcerative colitis (UC) and Crohn's disease (CD) are the two main forms of IBD, and their incidence is increasing in industrialized countries. Further, IBD is a significant risk factor for the development of colon cancer. Though the specific determinants remain elusive, persistent inflammation is believed to play a significant role in colon cancer carcinogenesis. To better define the molecular mechanisms linking colitis to the identity of disease biomarkers, we performed a translational comparison of protein expression and protein damage products in mouse and human IBD. Helicobacter hepaticus-infected Rag2-/- mice emulate many aspects of human IBD, and our recent work with this model highlights the importance of neutrophils in the pathology of colitis and colon cancer. Analysis of neutrophil- and macrophage-derived damage products revealed accumulation of 3-chlorotyrosine (CTyr) and 3-nitrotyrosine (NTyr) in inflamed mice colons that increased with disease duration. These results were further corroborated in mouse studies by histological evaluation, which demonstrated strong infiltration of neutrophils and macrophages to the site of inflammation. Human studies revealed an increase in CTyr in the colon of UC and CD tissues relative to serum levels. The nucleic acid chlorination damage product, 5-chloro-2′-deoxycytidine (5-Cl-dC), was quantified in human colon and found to be present at similar levels to that of inflamed mice colons. Multivariate analysis of these markers along with serum proteins and cytokines revealed a general signature of activated innate immunity in human IBD. UC sera were strongly suggestive of neutrophil activity while CD and mouse sera were suggestive of macrophage and neutrophil activity. These data point to innate immunity as a major determinant of serum and tissue profiles and provide insight into disease activity in IBD.
Citation Format: Charles G. Knutson, Aswin Mangerich, Yu Zeng, Arkadiusz R. Raczynski, Rosa G. Liberman, Pilsoo Kang, Wenjie Ye, Guanyu Gong, Erin Prestwich, Kun Lu, John S. Wishnok, Joshua R. Korzenik, Gerald N. Wogan, James G. Gox, Peter C. Dedon, Steven R. Tannenbaum. Features of innate immunity dominate serum and tissue protein and cytokine profiles in both mouse and human inflammatory bowel disease. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2885. doi:10.1158/1538-7445.AM2013-2885
Abstract 289: Inhibition of Trk receptor leads to mesenchymal-epithelial transition in human hepatocellular carcinoma cell lines.
Authors: Abe Mitsuhiko , Koga Hironori , Yoshida Takafumi , Masuda Hiroshi , Sakata Masahiro , Ikezono Yu , Nakamura Toru , Taniguchi Eitaro , Kawaguchi Takumi , Yano Hirohisa , Torimura Takuji , Sata Michio 
Published: August 2014

Abstract
Sorafenib, the first molecular targeted agent for HCC, has been shown to be clinically effective in global clinical trials. Although overall survival of HCC patients has been extended by a few months, these results are not satisfactory. Clinical studies involving other molecular targeted therapies and combination therapies are ongoing, but no clearly effective therapy has yet emerged. While we were exploring new targets related to epithelial-mesenchymal transition (EMT), which is involved in metastasis and ivasion of advanced cancers, we found the EMT-inducing potential of the tropo-myosine-related kinase B (TrkB) receptor, whose ligands include brain-derived neurotrophic factor (BDNF).
We observed by phase contrast microscopy that K252a, a Trk inhibitor, induced alterations in cell shape of several HCC cell lines (HAK-1A, HAK-1B, KYN-2, Huh7, and HLF). The morphological change was most obvious in HAK-1B cells, which have been proven to have mesenchymal features: the K252a-treated HAK-1B turned to polygonal epithelial-like cells. In Western blot analysis, the E-cadherin expression level was increased in the K252a-treated HAK-1B cells. Similar findings were demonstrated also in HAK-1A, which is a sister cell line of HAK-1B. The mechanistic basis for the “mesenchymal-epithelial transition (MET)” was down-regulation of E2A, an EMT-regulating transcriptional factor. Although the down-regulation of E2A was universally found in other cell lines, such as KYN-2, Huh7, and HLF, their expression levels of E-cadherin were not apparently increased.
Our findings suggest that inhibition of TrkB signaling may be a new therapeutic approach for advanced HCC, since the inhibition may give rise to “MET” in aggressive tumors. In addition, the present data are impressive insofar as they imply a relationship between the liver and neurosystem.
Citation Format: Mitsuhiko Abe, Hironori Koga, Takafumi Yoshida, Hiroshi Masuda, Masahiro Sakata, Yu Ikezono, Toru Nakamura, Eitaro Taniguchi, Takumi Kawaguchi, Hirohisa Yano, Takuji Torimura, Michio Sata. Inhibition of Trk receptor leads to mesenchymal-epithelial transition in human hepatocellular carcinoma cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 289. doi:10.1158/1538-7445.AM2013-289