tbuckley/cabot-search huggingface dataset:
Abstract SY03-01: Macrophage PI3Kgamma drives cancer immune suppression
Authors: Judith A. Varner
Journal: Cancer Research (2016)

Abstract Innate immune cells can switch from a proinflammatory state that defends against pathogens and to an anti-inflammatory state that repairs damaged tissue. Proinflammatory myeloid cells activate cytotoxic T cells to eliminate pathogens, but anti-inflammatory myeloid cells inhibit T-cell-mediated immunity, stimulate angiogenesis, and stimulate fibrosis, all of which promote tumor progression. The predominant isoform of PI(3)Kinase in myeloid cells, PI3Kgamma, controls this switch between immune stimulation and immune suppression during inflammation and cancer. Myeloid cell PI3Kgamma and its effectors Akt1, mTor, and S6Kinase stimulate C/EBPbeta-dependent expression of immunosuppressive factors, including Arginase and TGFbeta, while also suppressing NFkappaB-dependent expression of proinflammatory cytokines such as IL12 and IFNgamma, thereby inducing tumor immune suppression and consequent tumor growth and metastasis. In contrast, inhibition of PI3Kgamma activity by genetic or pharmacological means suppresses C/EPBbeta-mediated transcription of anti-inflammatory factors and stimulates NFkappaB-mediated transcription of the proinflammatory cytokines IL12 and IFNgamma, thereby restoring CD8+ T-cell-dependent cytotoxicity that inhibits tumor growth and metastasis. Therefore, inhibitory targeting of PI3Kgamma indirectly restores cytotoxic T-cell immune responses that elicit tumor suppression without unwanted side effects. Our studies highlight the strong therapeutic potential of targeting this kinase to control inflammation and cancer. This work was supported by grants to JAV from the NIH (5R01CA126820), the Landon Foundation-AACR (12-60-27-VARN), the Lustgarten Foundation for Pancreatic Research and the Whitworth Foundation for Cancer Research. Citation Format: Judith A. Varner. Macrophage PI3Kgamma drives cancer immune suppression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY03-01.
Hepatocytes of Donor Origin in Recipients Liver, after Hematopoietic Stem Cell Transplantation in BetaThalassemia Major.
Authors: Ardeshir Ghavamzadeh, Mehrzad Mirzania, Nahid Sedighi, Marjan Yaghmaie, Naser Kamalian, Kamran Alimoghaddam, Seyed Hamidollah Ghaffari, Parisima Azimi
Journal: Blood (2007)
Abstract 1671: Local release of combretastatin A-4 from NIR-light activatable prodrugs overcomes areal and temporal limitations of photodynamic therapy
Authors: Pallavi Rajaputra, Moses Bio, Gregory Nkepang, Pritam Thapa, Sukyung Woo, Youngjae You
Journal: Cancer Research (2016)

Abstract A unique prodrug strategy for treating localized cancers, in which NIR light-illuminated prodrug effectively ablates tumors through the combined effects of photodynamic therapy (i.e., singlet oxygen [SO]) and locally released anticancer drugs has been proposed. Due to short distance of action (&amp;lt; 0.04 μs) and short lifetime (&amp;lt; 0.02 μm) of SO, direct damage of PDT is both areally and temporally limited. We hypothesized that the locally released anticancer drugs would overcome the areal and temporal limits of SO. Near IR-activatable prodrug of combretastatin A-4 (CA4), Pc-(L-CA4)2, and its pseudo-prodrug, Pc-(NCL-CA4)2, were evaluated in vitro and in vivo. After partial illumination of a 24 well, all the cells in the prodrug-treated well were killed by the released CA4. Limited areal damage was observed in the pseudo-prodrug-treated wells. A time-dependent cell survival study revealed more extensive cell death in the prodrug-treated cells, due to the sustained damage from the released CA4. Cell cycle analysis and microscopic imaging data demonstrated the typical damage patterns of CA4 in the prodrug-treated cells. A time-dependent histological study showed that prodrug-treated tumors lacked mitotic bodies. The prodrug caused broader and more long-lasting tumor size reduction than did the pseudo-prodrug. These data consistently support that the released CA4 overcomes the areal and temporal limits of SO, providing far superior antitumor effects. Citation Format: Pallavi Rajaputra, Moses Bio, Gregory Nkepang, Pritam Thapa, Sukyung Woo, Youngjae You. Local release of combretastatin A-4 from NIR-light activatable prodrugs overcomes areal and temporal limitations of photodynamic therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1671.
Graft Versus Leukemia With Little Graft Versus Host Disease? Long Term Follow-Up Of a Study Using Transduced Donor T-Cells For Donor Leukocyte Transfusion
Authors: Eva M Weissinger, Sylvia Borchers, Justyna Ogonek, Kriti Verma, Steve Ehrlich, Christian Koenecke, Patrick Schweier, Chiara Bonini, Fabio Ciceri, Elke Dammann, Susanne Luther, Jürgen Krauter, Michael Stadler, Arnold Ganser
Journal: Blood (2013)
P0968 : Are the type of probiotic strains and their amount equally effective for NAFLD prevention? Experimental comparative study
Authors: N. Kobyliak, O. Virchenko, T. Falalyeyeva, M. Kondro, G. Mykhalchyshyn, M. Spivak, T. Beregova, P. Bodnar
Journal: Journal of Hepatology (2015)
Abstract 3212: Metastatic breast cancer cell communication within a pro-dormancy bone marrow niche
Authors: Trevor T. Price, Clara H. Lee, Qing Cheng, H. Kim Lyerly, William E. Fogler, John L. Magnani, Dorothy A. Sipkins
Journal: Cancer Research (2015)

Abstract Distant metastases are the major cause of death from breast cancer. In estrogen receptor positive (ER+) breast cancer (BC) in particular, metastatic relapse can occur years after initial treatment, suggesting that disseminated tumor cells have a prolonged dormant phase before becoming proliferative. A major site of early disease dissemination and metastatic relapse of ER+ BC is the bone, although the critical signals that allow circulating breast cancer cells (BCCs) to identify bone marrow (BM) vasculature, enter the tissue, and tether to the BM microenvironment (BMM) are little understood. Investigating these interactions of BCCs with the BMM, however, could enable us to target the key biologic determinants allowing safe harbor for metastases within bone. To address the features of breast tumors associated with late recurrence, but not confounded by variations in systemic treatment, we compiled breast tumor gene expression data from 4,767 patients and established a discovery cohort consisting of 743 lymph node-negative patients who did not receive systemic neoadjuvant or adjuvant therapy. Using this data set, we found that expression of E-selectin ligands and CXCR4 were significantly elevated in ER+ tumors that had late recurrences. Based on these observations, we used intravital fluorescence microscopy to study the precise functions of E-selectin ligands and CXCR4 (SDF-1 receptor) in tumor metastasis in in vivo xenograft models and found that these play distinct roles in ER+ BCC migration in the BMM. Using highly specific E-selectin (GMI-1271) and CXCR4 (AMD3100) inhibitors, we determined that E-selectin interactions were critical for BCC entry into bone, while CXCR4/SDF-1 interactions anchored BCCs to the BMM. CXCR4 inhibition led to significant mobilization of BC micrometastases from the BMM into the peripheral circulation. Moreover, we found that dormant and proliferating BCCs occupy distinct regions of the BMM, with dormant BCCs predominantly found in SDF-1 and E-selectin rich regions and thus highly susceptible to AMD3100 mobilization. These findings shed light on how dormant and proliferating BCCs interact with the BMM and suggest new interventions to break the foothold of dormant BC micrometastases in bone. Citation Format: Trevor T. Price, Clara H. Lee, Qing Cheng, H. Kim Lyerly, William E. Fogler, John L. Magnani, Dorothy A. Sipkins. Metastatic breast cancer cell communication within a pro-dormancy bone marrow niche. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3212. doi:10.1158/1538-7445.AM2015-3212
Abstract 121: Analysis and comparison of somatic copy number alterations in gastric cardia adenocarcinoma and gastric non-cardia adenocarcinoma
Authors: Manjiao Liu, Zhen Liu, Jian Bai, Hong Cai, Yang Ke, Changqing Zeng
Journal: Cancer Research (2016)

Abstract Gastric adenocarcinoma is one of the most common cancer type worldwide. Anatomically it may raise from the cardia or non-cardia part of the stomach and previous studies have shown differential susceptibilities loci and prognosis between gastric cardia adenocarcinoma (GCA) and gastric non-cardia adenocarcinoma (GNCA). To better understand the genomic alterations that drive gastric adenocarcinoma and to investigate the differences of genetic aberration between GCA and GNCA, we analyzed somatic copy-number aberrations in 205 gastric adenocarcinomas resected samples, including 114 GCAs and 91 GNCAs using Illumina Human OmniZhongHua BeadChips. We identified 49 significantly recurrent focal alterations in gastric adenocarcinoma. In addition to those previously reported in stomach cancer, several novel focal changes were also observed, including gain of 11p11.2, 6q23.3, 12p11.1, 5p15.33 and loss of 8p11.22, 9p22.2, 18q22.1, 15q21.2, 17q23.3. A few known or potential oncogenes such as TERT, MYB, and IRS2, were included in the focal amplified regions that were not reported in gastric cancer before. Also, a few potential tumor suppressors were seen in these focal loss regions, including DOK6, BRIP1 and NDST4. Especially, HDC, a gene involved in gastric acid secretory, was harbored in the newly identified focal loss region, 15q21.2. Three focal changes, loss of 20p12.1 (containing MACROD2), 6q26 (containing PARK2), and gain of 11p11.2 (containing CRY2), were identified to correlate to the post-surgery overall survival, which may deserve to be further investigated as the potential prognosis markers. Comparison of somatic copy number alternation patterns revealed that in chromosome arm level, 16p and 5q had distinct copy number status between GCA and GNCA samples. The frequencies of three novel focal changes were significantly different between GCA and GNCA. Furthermore, KRAS amplification, a well characterized gastric adenocarcinoma prognosis marker was associated with worse clinical outcome in GNCA, but not in GCA. Taken together, these results provided novel candidate oncogenes or tumor suppressors for gastric adenocarcinoma and different features in structural alterations between GCA and GNCA, which potentially inform novel opportunities for targeted therapeutic interventions. Citation Format: Manjiao Liu, Zhen Liu, Jian Bai, Hong Cai, Yang Ke, Changqing Zeng. Analysis and comparison of somatic copy number alterations in gastric cardia adenocarcinoma and gastric non-cardia adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 121.
Abstract 4762: Gremlin 2 is repressed in invasive endometrial cancer and inhibits cell growth in vitro
Authors: Hiroshi Tsubamoto, Kayo Inoue, Kazuko Sakata, Hiroaki Shibahara, Yasuo Miyoshi
Journal: Cancer Research (2016)

Abstract Background: There are limited therapeutic opportunities for the treatment of advanced or metastatic endometrial cancer (EC), and limited diagnostic tools of myometrial invasion for fertility sparing management of early stage EC. Novel approach based on molecular profiling of EC cells are required. Patients and Methods: We used microarray analysis of EC tumour samples in order to identify tumour-specific changes in gene expression. Identified the most frequently and lowest repressed gene was subjected to immunohistochemistry of tissues of EC. MTT assay and migration assay using EC cells were also conducted to evaluate the antitumor activity of the identified gene. Results: The most significantly suppressed gene in EC compared with the control was Gremlin 2 with an 8.5-fold reduction (p&amp;lt;0.001). Immunohistochemistry revealed that Gremlin 2 was expressed in 4 of 4 tissues of normal endometrium, in 4 of 4 tissues of atypical endometrial hyperplasia and 5 of 5 tissues of low grade EC with FIGO stage IA without myometrial invasion. Among 13 patients with low-grade FIGO stage I with myometrial invasion, Gremlin 2 was partially expressed in the myometrial invasion front in 11 (85%) patients. The MTT assay revealed the proliferation of Ishikawa cells incubated with 1.0 ìg/ml and 5.0 ìg/ml of Gremlin 2 and HEC-1A cells incubated with 5.0 ìg/ml of Gremlin 2 were significantly reduced (P = 0.029, P = 0.025, and P = 0.048, respectively). The proliferation of Ishikawa cells was significantly attenuated after incubation with Gremlin 2 for 72 h (P = 0.024). On the other hand, the migration assay did not show influence of Gremlin 2 on Ishikawa or HEC-1A cells. Conclusion: Gremlin 2, formerly known as protein related to Dan and cerberus (PRDC), has been implicated in development of the embryo and the ovarian follicle in animals, however, there is no report of Gremlin 2 in association with neoplasm or cancer. Gremlin 2 downregulation may lead to carcinogenesis and progression of EC. We suggest that re-activation of Gremlin 2-associated pathways could suppress EC progression, and should thus be explored as a potential novel therapeutic approach as well as diagnostic tool of myometrial invasion. Citation Format: Hiroshi Tsubamoto, Kayo Inoue, Kazuko Sakata, Hiroaki Shibahara, Yasuo Miyoshi. Gremlin 2 is repressed in invasive endometrial cancer and inhibits cell growth in vitro. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4762.
Abstract 2315: Dynamic SPECT imaging of PSMA-specific CAR T cells in mice bearing prostate cancer
Authors: Nia Emami-Shahri, Julie Foster, Jane Sosabowski, John Maher, Sophie Papa
Journal: Cancer Research (2016)

Abstract Immunotherapy using CAR-T-cells is acquiring an expanding role in the treatment of malignant disease. However, efficacy of solid tumour CAR-T-immunotherapy has proven inconsistent. Limitations include poor T-cell trafficking to tumour deposits, insufficient T-cell longevity in-vivo and the occurrence of both predicted and unanticipated on-target and off-target toxicity. To refine this therapeutic approach, it is desirable to develop systems that allow the monitoring of T-cell location and persistence in-vivo. A retroviral vector named PiN-4 was constructed, which co-expresses: (i) an interleukin (IL)-4-responsive chimeric cytokine receptor (4αβ); (ii) a prostate-specific membrane antigen (PSMA)-targeted CAR (P28z) and (iii) hNIS, which promotes the uptake of technetium-99m pertechnetate (99mTcO4−) in viable cells. IL-4 enriched human 4P28zN+ T-cells were administered intravenously to Nod Scid Gamma (NSG) mice bearing prostate tumour xenografts. Measurement of the tumour xenografts by bioluminescent imaging (BLI) found that only PSMA-expressing tumours responded to 4P28zN+ T-cell treatment. Longitudinal SPECT-CT imaging further confirmed this with the preferential accumulation of 4P28zN+ T-cells in PSMA-expressing tumours compared to PSMA-negative tumours. Use of NIS as a T-cell imaging reporter brings several potential advantages. It promotes receptor-mediated uptake of the inexpensive, low toxicity and clinically useful SPECT tracer, technetium-99m pertechnetate (99mTcO4−). In addition, the ectopic expression of NIS is well tolerated by host cells and hNIS functions only in viable cells. These data demonstrate proof of concept for the utility of hNIS as an imaging reporter in genetically engineered T-cells. Citation Format: Nia Emami-Shahri, Julie Foster, Jane Sosabowski, John Maher, Sophie Papa. Dynamic SPECT imaging of PSMA-specific CAR T cells in mice bearing prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2315.
Critical Functions of the Lysosome in Cancer Biology
Authors: Shawn M. Davidson, Matthew G. Vander Heiden
Journal: The Annual Review of Pharmacology and Toxicology (2016)

Lysosomes (or lytic bodies) were so named because they contain high levels of hydrolytic enzymes. Lysosome function and dysfunction have been found to play important roles in human disease, including cancer; however, the ways in which lysosomes contribute to tumorigenesis and cancer progression are still being uncovered. Beyond serving as a cellular recycling center, recent evidence suggests that the lysosome is involved in energy homeostasis, generating building blocks for cell growth, mitogenic signaling, priming tissues for angiogenesis and metastasis formation, and activating transcriptional programs. This review examines emerging knowledge of how lysosomal processes contribute to the hallmarks of cancer and highlights vulnerabilities that might be exploited for cancer therapy.
Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival analysis of KEYNOTE-006.
Authors: Jacob Schachter, Antoni Ribas, Georgina V. Long, Ana Arance, Jean Jacques Grob, Laurent Mortier, Adil Daud, Matteo S. Carlino, Catriona M. McNeil, Michal Lotem, James M. G. Larkin, Paul Lorigan, Bart Neyns, Christian U. Blank, Teresa M. Petrella, Omid Hamid, Honghong Zhou, Scot Ebbinghaus, Nageatte Ibrahim, Caroline Robert
Journal: Journal of Clinical Oncology (2016)

9504 Background: In the phase III KEYNOTE-006 study (NCT01866319), pembro (anti–PD-1) provided superior OS and PFS and a lower incidence of grade 3-5 treatment-related AEs compared with ipi (anti–CTLA-4) in patients (pts) with advanced melanoma and ≤ 1 prior therapy. Here, we present the final OS analysis. Methods: 834 pts were randomized 1:1:1 to 24 mo of pembro 10 mg/kg Q3W or Q2W or to 4 doses of ipi 3 mg/kg Q3W. Clinically stable pts with radiologic progression could receive treatment until confirmed progression. Response was assessed per RECIST v1.1 by central review at wk 12, every 6 wk until wk 48, then every 12 wk thereafter. Survival follow-up was every 12 wk. Final OS analysis occurred after all pts were followed for ≥ 21 mo. Differences in OS were assessed in the intention-to-treat population using the stratified log-rank test with the Hochberg procedure. Results: As of Dec 3, 2015, median follow-up duration was 22.9 mo and 383 pts had died. Pembro continued to provide superior OS, PFS, and ORR over ipi, with no difference between pembro schedules (Table). Median OS was not reached for pembro vs 16.0 mo with ipi; estimated 24-mo OS rates were 55% and 43%, respectively. The PFS KM curves appeared to flatten after ~20 mo for all arms, with estimated 24-mo rates of ~30% for pembro and 14% for ipi. KM estimates suggest ~70% of responding pts have a response lasting ≥ 72 wk. There was 1 treatment-related death (sepsis in the pembro Q2W arm). The safety profile was consistent with that previously reported. Conclusions: With an additional 9 mo of follow-up, median OS was not reached for pembro, and the superiority of pembro over ipi for advanced melanoma was confirmed. Coupled with the durability of response and manageable safety profile, these data support pembro as a standard of care for advanced melanoma. Clinical trial information: NCT01866319. Pembro 10 Q2W N = 279 Pembro 10 Q3W N = 277 Ipi N = 278 OS, median, mo Median, mo NR NR 16.0 24-mo rate, % 55.1 55.3 43.0 HRa (95% CI) 0.68 (0.53-0.87) P = .0008 0.68 (0.53-0.86) P = .0008 — PFS, median, mo Median, mo 5.6 4.1 2.8 24-mo rate, % 31.2 27.8 13.5 HRa (95% CI) 0.61 (0.50-0.75) P < .0001b 0.61 (0.50-0.75) P < .0001b — ORR, % 36.9 P < .0001a,b 36.1 P < .0001a,b 13.3 Responders without further progression, % 72.8 69.0 75.7 aVersus ipi; bNominal.
Abstract 1915: microRNA-320a inhibits cancer cell migration and invasion through targeting LAMP1 in castration-resistant prostate cancer
Authors: Atsushi Okato, Yusuke Goto, Akira Kurozumi, Mayuko Kato, Ryosuke Matsushita, Satoko Kojima, Shinichi Sakamoto, Tomohiko Ichikawa, Naohiko Seki
Journal: Cancer Research (2016)

Abstract BACKGROUND: In early-stage prostate cancer (PCa), more than 90% of patients initially respond to the therapeutic use of androgen deprivation; however, many cases become refractory and progress to castration resistant prostate cancer (CRPC). CRPC is difficult to treat, and most clinical trials for advanced PCa with metastasis to bones or other sites have shown limited benefits. Therefore, understanding the molecular mechanisms of metastatic pathways of CRPC underlying current genomic approaches would help to improve therapies for this disease. Our recent studies of microRNA (miRNA) expression signatures of CRPC revealed that microRNA-320a (miR-320a) was significantly reduced in cancer tissues, suggesting miR-320a acts as a tumor-suppressor in CRPC cells. The aim of this study was to investigate the functional significance of miR-320a in CRPC cells and to identify miR-320a-mediated target genes involved in oncogenesis and metastasis of the disease. METHODS: Gain-of-function studies were performed using transfection of mature miR-320a into cancer cells (DU145 and PC3). Genome-wide gene expression analysis and in silico analysis were applied to identify molecular targets regulated by miR-320a in PCa cells. A luciferase reporter assay was carried out to determine regulation of miR-320a. Loss-of-function studies using siRNA were performed to investigate the functional role of target genes. RESULTS: The expression levels of miR-320a were significantly reduced in PCa tissues and the cell lines. Restoration of mature miR-320a in cancer cells led to significant inhibition of cell migration and invasion activities in PCa cell lines. Lysosomal-associated membrane protein 1 (LAMP1) was identified as a direct target of miR-320a in this assays. Silencing of LAMP1 significantly inhibited cell proliferation, migration and invasion in PCa cells. Moreover, overexpression of LAMP1 was observed in PCa and CRPC clinical specimens. CONCLUSIONS: To the best of our knowledge, this is the first report demonstrating that tumor-suppressive miR-320a directly regulated LAMP1 in PCa cells. The identification of novel target gene regulated by tumor-suppressive miRNAs may lead to a better understanding of molecular mechanisms of CRPC metastatic pathways. Citation Format: Atsushi Okato, Yusuke Goto, Akira Kurozumi, Mayuko Kato, Ryosuke Matsushita, Satoko Kojima, Shinichi Sakamoto, Tomohiko Ichikawa, Naohiko Seki. microRNA-320a inhibits cancer cell migration and invasion through targeting LAMP1 in castration-resistant prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1915.