tbuckley/cabot-search huggingface dataset:
Abstract 718: Macrophage PI3Kgamma signaling promotes cancer immune suppression
Authors: Megan M. Kaneda, Judith A. Varner
Journal: Cancer Research (2016)

Abstract Innate immune cells can switch from a pro-inflammatory state that defends against pathogens and to an anti-inflammatory state that repairs damaged tissue. Pro-inflammatory 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 the 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, but suppress NFkappaB-dependent expression of pro-inflammatory 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 pro-inflammatory 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: Megan M. Kaneda, Judith A. Varner. Macrophage PI3Kgamma signaling promotes 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 718.
Abstract 5208: Trends in fatal prostate cancer incidence by race among US men
Authors: Scott P. Kelly, Philip S. Rosenberg, William F. Anderson, Sean D. Cleary, Naji Younes, Gabriella Andreotti, Michael B. Cook
Journal: Cancer Research (2016)

Abstract Background: Prostate-specific antigen testing (PSA) has dramatically changed the composition of prostate cancer, making it difficult to assess incidence trends. By defining fatal prostate cancer as the underlying cause of death from disease within 10 years of diagnosis, we have been able to conduct an in-depth analysis of “clinically relevant” prostate cancer incidence trends. Methods: We extracted incident prostate cancer cases, causes of death and survival among men aged 45-84 years using the US Surveillance, Epidemiology, and End Results (SEER) database (1975-2002). In addition to standard descriptive analyses, the ability to distinguish prostate cancer cases that were ultimately fatal enabled us to fit age-period-cohort models. Results: Among 51,682 fatal prostate cancer cases, incidence increased 1% per year prior to 1992, declined 15% per year from 1992-1995, and further declined by 5% per year through 2002. Age-specific incidence rates of fatal disease decreased over 2% per year among men aged 55 years and older, yet increased up to 1% per year among younger men. Fatal disease rates were more than 2-fold higher in black men compared with white men, a racial disparity that increased to 3-6 fold among younger men. Conclusion: In the United States, after widespread use of PSA screening and advances in prostate cancer treatment, fatal prostate cancer rates have substantially declined. Yet, rates of fatal prostate cancer among younger men have remained relatively stable, suggesting the need for additional attention to early-onset prostate cancer that has the potential to result in death. This study also highlights the persistent black-to-white racial disparity in fatal prostate cancer, underscoring the need for a greater understanding of the causes of this difference so that strategies may be implemented to reduce, and ultimately eliminate, racial disparities in prostate cancer. Citation Format: Scott P. Kelly, Philip S. Rosenberg, William F. Anderson, Sean D. Cleary, Naji Younes, Gabriella Andreotti, Michael B. Cook. Trends in fatal prostate cancer incidence by race among US men. [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 5208.
Abstract 695: SHP-2-upregulated ZEB1 is important for PDGFRá-driven glioma epithelial-mesenchymal transition and invasion in mice and humans
Authors: Lei Zhang, Weiwei Zhang, Yanxin Li, Zuoqing Li, Yinfang Wang, Lina Song, Deguan Lv, Ichiro Nakano, Bo Hu, Shi-Yuan Cheng, Haizhong Feng
Journal: Cancer Research (2016)

Abstract A critical clinical challenge in glioblastoma therapy is robust tumor growth and invasion driven by aberrant activation of oncogenic tyrosine receptor kinases (RTKs) including PDGFRá. Here, we report that a SHP-2-upregulated epithelial-mesenchymal transition (EMT)-inducer, ZEB1 is important for PDGFRá-driven glioma EMT, invasion and glioma stem cell renewal in mice and humans. ZEB1 and activated PDGFRá were co-expressed in invasive regions of mouse glioma xenografts and human clinical glioma specimens. Glioma patients with high levels of both p-PDGFRá and ZEB1 had significantly shorter overall survival compared with those with low expression of p-PDGFRá and ZEB1. Knockdown of ZEB1 inhibited PDGF-A/PDGFRá-stimulated glioma EMT, tumor growth, invasion and glioma stem cell renewal. PDGFRá mutant deficient of SHP-2 binding (PDGFRá-F720) or PI3K binding (PDGFRá-F731/42), knockdown of SHP-2 or treatments of pharmacological inhibitor for PDGFRá-signaling effectors attenuated PDGF-A/PDGFRá-stimulated ZEB1 expression, cell migration and glioma stem cell proliferation. Importantly, SHP-2 acts together with PI3K/Akt to regulate a ZEB1-miR-200 feedback loop in PDGFRá-driven gliomas. Together, our findings uncover a new pathway in which ZEB1 functions as a key regulator for PDGFRá-driven glioma EMT, invasion and glioma stem cell renewal, suggesting that ZEB1 as a potential therapeutic target for human gliomas with high PDGFRá activation. Citation Format: Lei Zhang, Weiwei Zhang, Yanxin Li, Zuoqing Li, Yinfang Wang, Lina Song, Deguan Lv, Ichiro Nakano, Bo Hu, Shi-Yuan Cheng, Haizhong Feng. SHP-2-upregulated ZEB1 is important for PDGFRá-driven glioma epithelial-mesenchymal transition and invasion in mice and humans. [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 695.
Risk of hospitalization with pegfilgrastim versus filgrastim prophylaxis: A retrospective cohort study
Authors: D. Weycker, J. Malin, J. Kim, R. Barron, J. Edelsberg, A. Kartashov, G. Oster
Journal: Journal of Clinical Oncology (2008)

6580 Background: Risk of febrile neutropenia has been reported to be lower with pegfilgrastim (PEG) than filgrastim (FIL) in controlled trials in cancer patients receiving myelosuppressive chemotherapy. It is unknown whether risk of hospitalization for neutropenic complications also differs between these agents in a real-world setting. Methods: A retrospective cohort study was undertaken using a US healthcare claims database. The source population included cancer patients who underwent a course of chemotherapy between January 2002 and December 2005, and who also received PEG or FIL during their first course. For each such patient, each unique cycle of chemotherapy was identified, as was each cycle in which PEG or FIL was administered by cycle day 5 (ie, as prophylaxis). Risk of hospitalization for neutropenia, fever, or infection (“neutropenic complications”) and any reason, respectively, was then examined on a cycle-specific basis, including all patient-cycles in which PEG or FIL was administered as prophylaxis. Unadjusted and adjusted odds of hospitalization were estimated using generalized estimating equations (GEE), the latter controlling for patient and treatment characteristics. Results: A total of 15,763 patient-cycles were identified in which patients received prophylaxis either with PEG (n=14,570) or FIL (n=1,193); mean (SD) number of days of FIL prophylaxis was 4.5 (3.3). Crude risk of hospitalization for neutropenic complications was 4.8% for FIL and 3.1% for PEG; corresponding figures for all-cause hospitalization were 8.7% and 6.3%. Unadjusted and adjusted odds of hospitalization were consistently lower (by 28%-36%) with PEG (vs FIL) (Table). Conclusions: In comparison with FIL, risk of hospitalization appears to be approximately one-third lower with PEG prophylaxis in cancer patients receiving myelosuppressive chemotherapy in a real-world setting. Odds ratios for hospitalization with PEG versus FIL (referent) Hospitalization for Neutropenic Complications Hospitalization for Any Reason Odds Ratio 95% CI p-value Odds Ratio 95% CI p-value Unadjusted 0.64 0.48–0.85 0.002 0.70 0.57–0.87 0.001 Adjusted 0.68 0.51–0.91 0.008 0.72 0.58–0.90 0.003 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Amgen Amgen
Combination Pharmacotherapy for Cardiovascular Disease
Journal: Annals of Internal Medicine (2005)

Cardiovascular disease (CVD) is the major cause of death in developed countries and is rapidly becoming the major cause of death in the developing world. The increasing rates of obesity and type 2 diabetes, however, may slow the current favorable trends for deaths attributable to CVD in many developed countries. To improve control of risk factors for CVD, Wald and Law proposed a "polypill," containing a statin, a diuretic, a beta-blocker, an angiotensin-converting enzyme inhibitor, aspirin, and folic acid. This combination pharmacotherapy (CP) could be made widely available without treating specific risk factors or individuals. A workshop sponsored by the Centers for Disease Control and Prevention reviewed the concept of CP for both primary and secondary prevention. Combination pharmacotherapy may prove to be efficacious but may also have side effects and poor adherence, which may be greater than or less than that of other preventive approaches. Randomized trials are needed to study these issues, although the design for such trials is uncertain. The ability of CP to prevent CVD in a cost-effective manner must be demonstrated. Minority groups and people with low socioeconomic status in the United States have an increased risk for CVD, and the effectiveness of such pharmacotherapy must be considered for these populations. Combination pharmacotherapy may prove especially effective in the developing world, where studies of CP may precede those done in wealthier countries. Combination pharmacotherapy may have tremendous potential, but additional study and detailed evaluation are necessary.
Abstract 3548: <i>In vivo</i> CRISPR reveals dual activation of apoptosis and necroptosis as means to eradicate drug resistant leukemia
Authors: Júlia Aguadé-Gorgorió, Scott McComb, Gunnar Cario, Martin Stanulla, Cornelia Eckert, Jean-Pierre Bourquin, Beat C. Bornhauser
Journal: Cancer Research (2016)

Abstract Dysregulation of apoptosis constitutes a general mechanism for refractory acute lymphoblastic leukemia (ALL) to escape cell death during chemotherapy. We have assessed the potential of SMAC mimetic compounds (SM) to eradicate drug resistant ALL by blocking the pro-survival cellular inhibitor of apoptosis proteins (cIAPs). On the basis of a large xenograft bank of primary ALL samples, obtained by xenotransplantation in immunodeficient NSG mice, we detected exquisite sensitivity to SM in vitro in a third of the cases tested, including drug-resistant and relapsed samples. Potent in vitro activity was highly predictive of in vivo efficacy in the xenograft model. Treatment of transplanted mice with SM not only delayed leukemia progression, but also completely eliminated leukemia burden in established disease for several weeks following treatment. SM activity required the presence of RIP1, since lentiCRISPR mediated gene knockout of RIP1 in patient-derived ALL cells blocked SM-induced cell death in vivo and in vitro. In contrast, RIP1 loss had no significant impact on the response to standard antileukemic therapies, supporting a view that RIP1-dependent death pathways are not likely to be selected against by front line chemotherapy. Furthermore, using a multicolor lentiCRISPR approach for simultaneous disruption of multiple genes, we found that downstream of RIP1, the response to SM was dependent on simultaneous execution of apoptosis and necroptosis, since genetic targeting of both cell death pathways was required to block SM-induced death. Upstream of RIP1, expression levels of TNF receptor II (TNFR2) in primary ALL correlated with sensitivity to SM, and genetic disruption of TNFR2 conferred resistance to SM treatment in vivo. Thus, SM treatment circumvents drug resistance through parallel activation of RIP1-dependent apoptosis and necroptosis, providing a strong rationale for application in salvage treatment of refractory childhood ALL. Citation Format: Júlia Aguadé-Gorgorió, Scott McComb, Gunnar Cario, Martin Stanulla, Cornelia Eckert, Jean-Pierre Bourquin, Beat C. Bornhauser. In vivo CRISPR reveals dual activation of apoptosis and necroptosis as means to eradicate drug resistant leukemia. [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 3548.
The T Cell Receptor (TCR) Repertoire Is a Key Determinant of the Tumour Microenvironment (TME) in Diffuse Large B Cell Lymphoma (DLBCL)
Authors: Colm Keane, Kimberly Jones, Clare Gould, David Hamm, Peter Wood, Simone Birch, Pauline Crooks, Michael R Green, Dipti Taulaulikar, Sanjiv Jain, Josh Tobin, Maher K Gandhi
Journal: Blood (2015)
The Optimal Duration of Anticoagulant Therapy In Patients with Cancer-Related Deep Vein Thrombosis: The Advantage of Using Residual Vein Thrombosis (the Cancer-DACUS Study)
Authors: Sergio Siragusa, Alessandra Malato, Doris Mascheroni, Walter Ageno, Eugenio Bucherini, Pietro Spadaro, Davide Imberti, Giorgia Saccullo, Lucio Lo Coco, Stefano Rotondo, Rita Santoro, Pierpaolo Di Micco, Vincenzo Oriana, Oreste Urbano, Tullio Prantera, Francesco Recchia, Andrea D'Alessio, Pina Gallucci, Angelo Ghirarduzzi, Oreste Cormaci, Clementina Caracciolo, Vincenzo Abbadessa
Journal: Blood (2010)
Abstract 1170: EphA3 maintains radioresistance in head and neck cancers
Authors: Myung Woul Han, Song Hee Kim, Hyo Won Chang, Hae Yun Nam, Myungjin Lee, Gui Chul Kim, Yoon sun Lee, Mi Ra Kim
Journal: Cancer Research (2016)

Abstract Radiotherapy is a well-established therapeutic modality used in treatment of many cancers. However, radioresistance remains a serious obstacle to successful treatment. Radioresistance can cause local recurrence and distant metastases in some patients after treatment by radiation. Thus, special emphasis has been given to the discovery of effective radiosensitizers. EphA3 receptors functions contribute to tumor development, modulating cell-cell adhesion, invasion, neo-angiogenesis, tumor growth and metastasis. However, the role of EphA3 in radioresistance remains to be elucidated. Here, we established the stable radioresistant head and neck cancer cell line (AMC HN3R cell line) and identified that EphA3 was overexpressed predominantly in the AMC HN3R cancer cell line through DNA microarray, real time PCR and Western blotting. Additionally, we identified that EphA3 was overexpressed in recurred laryngeal cancer specimen after radiation therapy. And we found that EphA3 mediated the tumor invasiveness and migration and EMT (epithelial mesenchymal transition) related protein expression in AMC HN3R cancer cell line. To investigate the role of EphA3 in modulating the radiosensitivity, we observed the change of survival fraction after transfection EphA3 siRNA. And we found that inhibition of EphA3 enhances radiosensitivity in AMC HN 3R cell line. In conclusion, these results suggest that EphA3 is overexpressed in radioresistant head and neck cancer and can play a crucial role in development radioresistance in head and neck cancers through regulation of EMT pathway. Citation Format: Myung Woul Han, Song Hee Kim, Hyo Won Chang, Hae Yun Nam, Myungjin Lee, Gui Chul Kim, Yoon sun Lee, Mi Ra Kim. EphA3 maintains radioresistance in head and neck cancers. [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 1170.
Abstract 749: Betaglycan-mediated regulation of mesenchymal stromal cell behavior in the prostate tumor-bone microenvironment
Authors: Leah M. Cook, Jeremy J. McGuire, Conor C. Lynch
Journal: Cancer Research (2016)

Abstract Prostate cancer frequently metastasizes to bone, resulting in increased risk of fractures and severe pain that significantly impacts patient quality of life. Bone metastatic prostate cancer is currently incurable with standard of care therapies being mainly palliative. In bone, prostate cancer generates extensive osteogenic lesions by promoting osteoblast activity. Osteoblasts are specialized bone forming cells derived from mesenchymal stem cells. In a bid to find new molecular targets through which prostate cancer induces osteogenesis, we incubated naïve MSCs with osteogenic bone metastatic prostate cancer cell line C4-2B conditioned media. Gene expression analysis revealed a 3-fold increase in expression of the TGFâ co-receptor, betaglycan. Given the critical role of TGFâ in the context of bone metastatic disease, we examined the role of betaglycan in MSC behavior. To this end, we utilized shRNA to knockdown betaglycan gene expression in mouse bone marrow-derived primary MSCs. Reduced betaglycan expression in knockdown (KD) MSCs had little to no impact on the expression of TGFâ signaling receptors, TGFâRI and TGFâRII, or pan-TGFâ ligand expression. However, using PAI promoter activity, a readout for TGFâ signaling, we observed a 3-fold increase in luminescence in KD-MSCs compared to controls. Likewise, phosphorylated Smad 2 was significantly increased in Betaglycan KD-MSCs in response to TGFâ treatment, collectively demonstrating increased TGFâ signaling in MSCs with reduced betaglycan expression. Using modified Boyden chamber assays, we found that 50% more Betaglycan-KD MSCs migrated towards recombinant TGFâ than controls (100 KD-MSCs cells migrated towards recombinant TGFâ vs. 50 control cells); this change was reversed with the addition of recombinant betaglycan. Using osteogenic differentiation assay, we found that Betaglycan KD-MSC differentiation was reduced by approximately 70% compared to control MSCs as measured by alizarin red staining. Addition of recombinant TGFâ further suppressed differentiation in both KD-MSCs and Control MSCs. This phenomenon was rescued by the addition of recombinant betaglycan, suggesting that MSC-derived betaglycan is critical for driving the osteogenic program. We are currently determining the impact of betaglycan on MSC behavior in the tumor bone microenvironment using in vivo models of bone metastatic prostate cancer. Collectively, these findings suggest that prostate cancer-induced MSC osteogenic programs are regulated in part via the induction of betaglycan. Citation Format: Leah M. Cook, Jeremy J. McGuire, Conor C. Lynch. Betaglycan-mediated regulation of mesenchymal stromal cell behavior in the prostate tumor-bone microenvironment. [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 749.
Cost-Effectiveness Analysis of Arsenic Trioxide in Combination with All-Trans Retinoic Acid in Acute Promyelocytic Leukemia with Pretreatment White Blood Counts &lt;10G/L
Authors: Richard F. Schlenk, Stefan Schönsteiner, Katharina Krempel, Anja Neumann, Walter Fiedler, Peter Brossart, Bernd Hertenstein, Helmut R. Salih, Mohammed Wattad, Michael Lübbert, Stefan Kremers, Christian H. Brandts, Mathias Hänel, Norbert Schmitz, Hartmut Link, Arnold Ganser, Gerhard Ehninger, Hartmut Döhner, Francesco Lo Coco, Uwe Platzbecker
Journal: Blood (2014)
Worse prognosis of <i>KRAS</i> C.35 G &gt; A mutant metastatic colorectal cancer (MCRC) patients treated with first-line triplet chemotherapy plus bevacizumab (FIr-B/FOx) and post-progression.
Authors: Gemma Bruera, Katia Cannita, Daniela Di Giacomo, Aude Lamy, Aldo Victor Giordano, Roberto Vicentini, Paolo Marchetti, Thierry Frébourg, Jean-Christophe Sabourin, Mario Tosi, Edoardo Alesse, Corrado Ficorella, Enrico Ricevuto
Journal: Journal of Clinical Oncology (2013)

e14596 Background: Prognosis of MCRC patients (pts) treated with bevacizumab (BEV) and chemotherapy (CT) is not significantly different according to KRAS genotype. Specificmutations confer different aggressiveness. Prognostic relevance of the prevalent c.35 G &gt; A KRAS mutation was retrospectively evaluated in pts treated with first line FIr-B/FOx, and post-progression. Methods: KRAS codon 12/13 and BRAF mutations were screened by SNaPshot and/or sequencing. FIr-B/FOx: weekly 2 days/12h-timed-flat-infusion/5-fluorouracil 900 mg/m 2 , weekly alternating irinotecan 160 mg/m 2 /BEV 5 mg/kg, or oxaliplatin 80 mg/m 2 . Second-line treatment was selected according to fitness, KRAS genotype, previous efficacy and safety. Efficacy was evaluated and compared according to treatment or KRAS genotype, using log-rank. Results: At 21.5 months, 59 pts were evaluated. KRAS mutant pts: c.35 G &gt; A, 15 (25.4%); c.35 G &gt; T, 7 (11.8%); c.38 G &gt; A, 3 (5%); other, 3 (5%). KRAS wild-type, 31 pts (52.7%). ORR, PFS, OS were, respectively: c.35 G &gt; A, 71%, 9 months, 14 months; other mutants, 61%, 12 months, 39 months. OS was significantly worse in c.35 G &gt; A pts compared to KRAS wild-type (p = 0.002), KRAS/BRAFwild-type (p = 0.03), other pts (p = 0.002), other mutants (p = 0.05), other codon 12 (p = 0.03) mutant pts; PFS was not significantly different. Post-progression, at 14 months follow-up, PFS and OS were significantly worse in c.35 G &gt; A compared to wild-type and/or other mutant pts. ORR of second line treatments was 38%, metastasectomies 12.5%, PFS 10 months, OS 14 months. PFS and OS were significantly favourable in pts treated with triplet CT plus targeted agent compared to triplet, respectively: PFS 13 months versus 8 months; OS not reached versus 11 months. Conclusions: KRAS c.35 G &gt; A mutation may significantly affect worse OS of MCRC pts. It does not significantly affect worse PFS of intensive first line FIr-B/FOx, while after progression significantly affect worse efficacy of second line treatments. Re-challenge of intensive regimens may affect significantly favourable PFS and OS.