tbuckley/cabot-search huggingface dataset:
Abstract 2984: The chemokine CCL2/CCR2 signaling mediated fibroblasts-cancer cells crosstalk promotes basal like breast cancer progression
Authors: Min Yao, Wei Bin Fang, Fang Fan, Nehemiah Alvarez, Patrick E. Fields, Nikki Cheng
Journal: Cancer Research (2017)

Abstract Cancer associated fibroblasts are the most abundant stromal cells in breast cancer, but their function in cancer progression has not been fully understood. We previously identified that the chemokine CCL2 was highly expressed in breast cancer associated fibroblasts, and high stromal CCl2 expression predicted poor outcome in basal like breast cancer. CCL2 is known to recruit monocyte/macrophage and promotes cancer progression. We previously found that recombinant CCL2 can directly signal to breast cancer cells and promote cell survival and invasion in vitro. In this study, we aimed to determine the functional importance of CCL2 signaling mediated fibroblast-cancer cell interactions in breast cancer progression. We used a fibroblast and cancer cell co-graft mouse model as the main functional assay. We generated primary fibroblasts from mouse mammary tumor and human breast cancer, and confirmed most of they expressed high level of CCL2. When co-grafted with the human basal breast cancer cell line MCF10A-CA1D into nude mice, fibroblasts enhanced xenograft growth. Stable knockdown of CCL2 expression from fibroblasts significantly reduced its ability in tumor growth promotion, while knockdown CCL2 from cancer cells did not. Decreased CCL2 production from fibroblasts resulted in increased apoptosis and autophagy in tumor samples. To determine the importance of direct CCL2 signaling to cancer cell, we generated the CCL2 receptor CCR2 mutant CA1D cancer cell lines by CRISPR-Cas9 targeting technology. Mutation of CCR2 in cancer cell significantly reduced tumor growth when co-grafted with CCL2 secreting fibroblasts. Lastly, we tested continuous delivery of CCL2 neutralizing antibody in the co-graft tumor model, but observed minimal therapeutic effect. Further examination of blood CCL2 level revealed an increased production of CCL2 from fibroblasts and mouse host after antibody treatment, which may contribute to the lack of therapeutic effect. In summary, our studies demonstrated the importance of CCL2/CCR2 signaling mediated fibroblasts-cancer cell interaction in basal like breast cancer progression. The CCL2 signaling pathway can be potentially served as therapeutic target, but requires development of efficient targeting strategy. Citation Format: Min Yao, Wei Bin Fang, Fang Fan, Nehemiah Alvarez, Patrick E. Fields, Nikki Cheng. The chemokine CCL2/CCR2 signaling mediated fibroblasts-cancer cells crosstalk promotes basal like breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2984. doi:10.1158/1538-7445.AM2017-2984
Abstract 3141: Combined cetuximab and pemetrexed therapy enhances cytotoxicity against crizotinib-resistant non-small cell lung cancer cells by downregulating thymidylate synthase
Authors: Hwang-Phill Kim, Sae-Won Han, Sang-Hyun Song, Tae-You Kim
Journal: Cancer Research (2017)

Abstract Although non-small cell lung cancer (NSCLC) cells with anaplastic lymphoma kinase (ALK)-rearranged initially show a dramatic response to crizotinib, these cells eventually develop resistance to crizotinib. This resistance is caused by secondary mutations and copy number gain in the ALK gene. However, other resistance mechanisms through activation of the bypass tracts have yet to be clearly elucidated. To investigate the mechanisms of acquired resistance to ALK fusion-directed treatment in NSCLC, we generated crizotinib-resistant NSCLC cell lines in vitro through chronic exposure of an ALK fusion NSCLC line (SNU2292) to crizotinib. Interestingly, the resultant SNU2292-CR cells maintained activation of epidermal growth factor receptor (EGFR) and expressed increased levels of transforming growth factor alpha (TGF-α), an EGFR ligand. Additionally, we found that thymidylate synthase (TS) was overexpressed in SNU2292-CR cells compared with the parental cells. We showed reduction of TS enhanced synergistic inhibition of cell proliferation when cetuximab, an EGFR inhibitor, was combined with pemetrexed, a TS inhibitor. As a result, combined therapy was found to exhibit a synergistic growth inhibitory effect against crizotinib-resistant cells by downregulating TS expression. Taken together, these results support a potential role of activation of the bypass tracts in acquired resistance to ALK-directed treatment in ALK-rearranged NSCLC, and provide insights into strategies for preventing and/or overcoming this resistance in patients Citation Format: Hwang-Phill Kim, Sae-Won Han, Sang-Hyun Song, Tae-You Kim. Combined cetuximab and pemetrexed therapy enhances cytotoxicity against crizotinib-resistant non-small cell lung cancer cells by downregulating thymidylate synthase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3141. doi:10.1158/1538-7445.AM2017-3141
Abstract 5134: Novel trifunctional immunoliposome delivery system to minimize resistance and side effects for anticancer therapy
Authors: Tanaya R. Vaidya, Sihem Ait-Oudhia
Journal: Cancer Research (2017)

Abstract Background: Breast cancer (BC) is the second leading cause of cancer death in women worldwide. About 25% of BCs have overexpression of the HER2 receptor. Although HER2 targeted therapies have shown considerable improvement in HER2-positive BC patients’ outcome, treatment resistance remains a clinical challenge. Here, we sought to develop and evaluate a novel tri-functional immune-liposome (TFIL) that overcomes HER2 treatment resistance and associated cardiotoxicity by dually targeting HER2 on BC cells and CD3 receptors on cytotoxic T-lymphocytes (CTLs). Material and methods: Anti-HER2 (Trastuzumab) and anti-CD3 (OKT-3) antibodies, were conjugated to lipid nanoparticles by the micelle-transfer method, and the resulting formulation was purified by dextran gradient ultra-centrifugation. Targeted lipid nanoparticles were formulated with a fluorescent lipophilic dye, DiD, for studying receptor binding and internalization. Studies were conducted with HER2-positive BT474 cells and CD3-positive Jurkat cells using flow cytometry analyses. Doxorubicin (DXR) was encapsulated in the nanoparticles by the remote-loading technique for cell-kill experiments. In vitro cell-kill studies were conducted by co-culturing BT474 as the target cells, and peripheral blood mononuclear cells as the effector cells, at varying ratios. Results: Purified formulations were successfully characterized for conjugation by determining the protein to lipid ratio. Flow cytometry analyses demonstrated successful cell binding and/or internalization of the TFIL with both the HER2 and CD3-positive cell lines. Moreover, these dual-targeted nanoparticles were able to retarget T cells to kill HER2 positive BC cells, and showed improved efficacy compared to non-targeted and plain HER2-targeted formulations in vitro. Conclusion: A novel drug delivery system, TFIL, that targets HER2 receptors on tumor cells, CD3 on CTLs, and is able to slowly release DXR was successfully developed and evaluated in vitro on HER2 overexpressing BC cells. Our findings show great promise at overcoming resistance and associated cardiotoxicity to present HER2 targeted BC therapies, and may translate into improved anti-tumor activity clinically compared to other treatment options. Citation Format: Tanaya R. Vaidya, Sihem Ait-Oudhia. Novel trifunctional immunoliposome delivery system to minimize resistance and side effects for anticancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5134. doi:10.1158/1538-7445.AM2017-5134
Tularaemia in Berlin – two independent cases in travellers returning from central Anatolia, Turkey, February 2011
Authors: A Schubert, W Splettstoesser, J Bätzing-Feigenbaum
Journal: Eurosurveillance (2011)

Tularaemia, though rare, has recently been increasingly reported in Germany. Most cases are indigenous infections. This report describes two epidemiologically independent infections with Francisella tularensis subspecies holarctica detected in Berlin in February 2011 that were acquired in central Anatolia, Turkey. In Turkey, there have been repeated tularaemia outbreaks since 2000 and the disease should therefore be considered as a differential diagnosis in travellers returning from that country.
Abstract 4182: The two novel BTK-inhibitors M2951 and M7583 show in vivo anti-tumor activity in pre-clinical models of B cell lymphoma
Authors: Eugenio Gaudio, Chiara Tarantelli, Emanuele Zucca, Davide Rossi, Anastasios Stathis, Francesco Bertoni
Journal: Cancer Research (2017)

Abstract Background. Diffuse large B cell lymphoma of the activated B cell like type (ABC DLBCL) is an aggressive lymphoma in which the inhibition of the Bruton’s tyrosine kinase (BTK) has shown biologic and clinical relevance. M7583 and M2951 are two novel highly selective irreversible BTK inhibitors (Fest C et al, 2016). M7583 has shown activity in a mouse model of lupus erythematosus (Bender et al, 2016). Here, we evaluated the anti-tumor activity of M2951 and M7583 in an in vivo ABC DLBCL model. Methods. Xenografts were established by s.c. injecting TMD8 lymphoma cells (100 µL of PBS, 107 cells/mouse) into the left flanks of female NOD-SCID mice (6 weeks of age and around 20g of body weight). Treatments (QD, po) were started with an average tumor volume of 100mm3 on groups of 10 mice each. Results. NOD-SCID mice engrafted with the ABC DLBCL TMD8 were treated with three different concentrations of M7583 (1 mg/Kg; 3 mg/Kg; 10mg/Kg) or M2951 (5 mg/Kg; 15 mg/Kg; 25mg/Kg) or vehicle, as control group. M2951 slowed tumor growth at all doses starting after 10 days of treatment. M7583 at 3 and 10 mg/Kg showed stronger anti-tumor activity than M2951, already evident after 5 days of treatment (P&amp;lt;0.05) and improving with time (after 10 days, P&amp;lt; 0.005). Moreover, while most groups had to be stopped after 2 weeks of treatment (D30 after engraftment) because of the reaching of the maximum tumor volume, allowed by the ethical veterinary committee, mice treated with M7583 at the two highest doses were able to continue treatment for additional six (3 mg/Kg) or ten days (10mg/Kg), when tumors became bigger than 2000 mm3, indicating a high activity of M7583. No body weight losses and sign of toxicity were detected. Conclusion. The two novel BTK inhibitors M2951 and M7583 showed promising in vivo anti-tumor activity in an ABC-DLBCL model. These data provide the rational for further investigating these compounds. Citation Format: Eugenio Gaudio, Chiara Tarantelli, Emanuele Zucca, Davide Rossi, Anastasios Stathis, Francesco Bertoni. The two novel BTK-inhibitors M2951 and M7583 show in vivo anti-tumor activity in pre-clinical models of B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4182. doi:10.1158/1538-7445.AM2017-4182
Low-Density Lipoprotein Cholesterol and Drug Treatment to Lower Atherosclerotic Cardiovascular Disease Risk
Authors: Donald M. Lloyd-Jones
Journal: JAMA Cardiology (2017)

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Abstract 1481: Determination of microRNA profile in lung cancer cell line treated with chemotherapy cisplatin (C), pemetrexed (P) or PC with bevacizumab (B) and its implication in resistance
Authors: Chao H. Huang, Hannah C. Motes, Siddarth Sharma, Jared Kevern, Emma Borrego-Diaz, Mukut Sharma
Journal: Cancer Research (2017)

Abstract Background: Cellular microRNAs (miRNAs) regulate gene expression through modulation of messenger RNA transcription and are involved in epigenetic regulation, metastasis and cancer immunity. They have prognostic and therapeutic significance. The miRNAs associated with resistance in lung cancer without EGFR mutation are not yet known. We sought to determine the profile of miRNA of lung cancer cell lines without EGFR mutation treated with chemotherapy. Methods: lung cancer cell lines HTB177 were treated with PC or PCB (0.05mg/mL Cisplatin, 0.05 mg/mL pemetrexed, 6.25 mg/mL Bevacizumab) for 24, 48, 72 and 144 hours. We obtained baseline miRNA prior to therapy and after treatment to determine the changes in miRNA profile using RT PCR technique. After 144 hours, we obtained miRNA profile of the cells that survived treatment to assess change in the miRNA profile. We chose miRNA that has been reported to influence on the outcome of lung cancer: Let 7 modulates RAS, miRNA 27 is involved as tumor suppressor gene, mir212 negatively regulates antiapoptotic protein PED, miR 375 down regulates ASH1 a transcription factor. Mir21 targets anti-apoptotic genes including PDCD4 and PTEN. Results: We observed down regulation of these miRNA after 24h of treatment with PC and these miRNA then became upregulated after 48 hours, especially let 7f. In contrast, the treatment of PC with B caused upregulation of these miRNA, especially miR 27b and let 7f at 24 h and then decreased levels of upregulation at 48hours. These miRNA were not upregulated at 72h for both groups. The expression of miRNA 21 is upregulated 50 times in cells that survived treatment with PC or PCB at 144h. Conclusions: The treatment using PC and PC with B in lung cancer cell lines regulates change in the profile of miRNA at different time points. There is a difference of the miRNA profile in these 2 treatment groups. miRNA 21 is upregulated in cells resistant to therapy. miRNA could be involved in the activity of chemotherapy and development of resistance. Citation Format: Chao H. Huang, Hannah C. Motes, Siddarth Sharma, Jared Kevern, Emma Borrego-Diaz, Mukut Sharma. Determination of microRNA profile in lung cancer cell line treated with chemotherapy cisplatin (C), pemetrexed (P) or PC with bevacizumab (B) and its implication in resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1481. doi:10.1158/1538-7445.AM2017-1481
Association of Practice-Level Social and Medical Risk With Performance in the Medicare Physician Value-Based Payment Modifier Program
Authors: Lena M. Chen, Arnold M. Epstein, E. John Orav, Clara E. Filice, Lok Wong Samson, Karen E. Joynt Maddox
Journal: JAMA (2017)

Medicare recently launched the Physician Value-Based Payment Modifier (PVBM) Program, a mandatory pay-for-performance program for physician practices. Little is known about performance by practices that serve socially or medically high-risk patients.To compare performance in the PVBM Program by practice characteristics.Cross-sectional observational study using PVBM Program data for payments made in 2015 based on performance of large US physician practices caring for fee-for-service Medicare beneficiaries in 2013.High social risk (defined as practices in the top quartile of proportion of patients dually eligible for Medicare and Medicaid) and high medical risk (defined as practices in the top quartile of mean Hierarchical Condition Category risk score among fee-for-service beneficiaries).Quality and cost z scores based on a composite of individual measures. Higher z scores reflect better performance on quality; lower scores, better performance on costs.Among 899 physician practices with 5 189 880 beneficiaries, 547 practices were categorized as low risk (neither high social nor high medical risk) (mean, 7909 beneficiaries; mean, 320 clinicians), 128 were high medical risk only (mean, 3675 beneficiaries; mean, 370 clinicians), 102 were high social risk only (mean, 1635 beneficiaries; mean, 284 clinicians), and 122 were high medical and social risk (mean, 1858 beneficiaries; mean, 269 clinicians). Practices categorized as low risk performed the best on the composite quality score (z score, 0.18 [95% CI, 0.09 to 0.28]) compared with each of the practices categorized as high risk (high medical risk only: z score, -0.55 [95% CI, -0.77 to -0.32]; high social risk only: z score, -0.86 [95% CI, -1.17 to -0.54]; and high medical and social risk: -0.78 [95% CI, -1.04 to -0.51]) (P < .001 across groups). Practices categorized as high social risk only performed the best on the composite cost score (z score, -0.52 [95% CI, -0.71 to -0.33]), low risk had the next best cost score (z score, -0.18 [95% CI, -0.25 to -0.10]), then high medical and social risk (z score, 0.40 [95% CI, 0.23 to 0.57]), and then high medical risk only (z score, 0.82 [95% CI, 0.65 to 0.99]) (P < .001 across groups). Total per capita costs were $9506 for practices categorized as low risk, $13 683 for high medical risk only, $8214 for high social risk only, and $11 692 for high medical and social risk. These patterns were associated with fewer bonuses and more penalties for high-risk practices.During the first year of the Medicare Physician Value-Based Payment Modifier Program, physician practices that served more socially high-risk patients had lower quality and lower costs, and practices that served more medically high-risk patients had lower quality and higher costs.
Abstract 4696: Development of an inhaled TLR9 agonist for the immunotherapy of lung cancer
Authors: Marilena Gallotta, Hikmat Assi, Robert L. Coffman, Cristiana Guiducci
Journal: Cancer Research (2017)

Abstract CpG-oligonucleotides (CpG-ODN) stimulate innate immune responses through Toll-like receptor-9 (TLR9). Intratumoral (IT) administration of CpG-ODN has been shown to be safe and clinically effective in humans and in multiple animal species. An important feature of local administration of a CpG-ODN is the ability to stimulate immune responses that control the growth of distant, uninjected tumors. Such treatment is especially effective when combined with a complementary mode of immunotherapy, such as anti-PD-1 or radiation. However, repeated IT injection is not practical for many tumor types, including most lung cancers. In mild asthmatic patients and healthy subjects, CpG-ODN have demonstrated safety and pharmacologic activity when delivered by inhalation directly to the lungs. Thus, inhaled CpG presents an alternative to IT injection for primary lung cancers and for other tumor types with prominent lung metastases. In the 4T1 mouse model of metastatic breast cancer, treatment of mice with a CpG-ODN administered intranasally led to a marked reduction in the number of lung metastases. This reduction was accompanied by infiltration of tumors with activated CD8+ and CD4+ T cells and the formation of highly organized tertiary lymphoid structures. These changes are similar to those observed after IT injection of solid tumors growing subcutaneously, and are consistent with changes observed in human tumors responsive to immunotherapy. In the 4T1 model, intranasal CpG-ODN strongly synergized with systemic anti-PD-1 treatment and induced complete clearance of lung tumors, as well as metastases in tissues not exposed to the CpG-ODN, including liver, pancreas and bone. This generation of systemic immunity resulted in long-term survival in the majority of mice. Immune cell subset depletion studies implicate both CD8 and CD4 T cells in the rejection of lung tumors treated with inhaled CpG-ODN plus anti-PD1. Dynavax has developed a CpG-ODN, DV281, that is optimized for aerosol delivery and plans to initiate clinical studies in NSCLC patients in 2017. Citation Format: Marilena Gallotta, Hikmat Assi, Robert L. Coffman, Cristiana Guiducci. Development of an inhaled TLR9 agonist for the immunotherapy of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4696. doi:10.1158/1538-7445.AM2017-4696
Abstract 2482: Inhibition of RAD51 with a cell penetrating antibody, 3E10
Authors: Peter M. Glazer, Audrey Turchick
Journal: Cancer Research (2017)

Abstract Many human malignancies arise in the setting of defective DNA repair pathways, leading to genetic instability, carcinogenesis and tumor progression. However, DNA repair deficiency can provide for a therapeutic window that can be exploited with targeted agents. One such anti-cancer agent is 3E10, a unique cell penetrating, anti-DNA autoantibody. 3E10 by itself is considered non-toxic to normal cells but has been shown to have deleterious effects on cells with DNA repair deficiencies. Specifically, 3E10 has been shown to reduce the efficiency of homologous recombination (HR). This has been attributed to its ability to preferentially binding to ssDNA tails, thereby inhibiting Rad51 mediated strand exchange. Prior work has shown that treatment with 3E10 alone can selectively kill cells with genetic mutations that lead to abnormal DNA repair. For example, 3E10 has been shown to be synthetically lethal in BRCA2 deficient human cancer cells. Additionally, 3E10 sensitizes cells to radiation and other DNA damaging therapies. The goal of this project is to characterize the specific mechanism by which 3E10 inhibits DNA repair pathways. Previously, the mechanism by which 3E10 inhibits HR was attributed to 3E10’s DNA binding ability. Through the biochemical evaluation of 3E10 variants, new evidence now suggests that 3E10 inhibits HR independently of 3E10’s ability to bind DNA. We have found that this HR inhibition is a result of a physical interaction between 3E10 and Rad51. Biochemical analysis revealed that 3E10 binds to the N-terminal domain of Rad51, the domain that plays a role in Rad51 homo-oligomerization and filament formation. This 3E10-Rad51 interaction impairs Rad51’s ability to localize to the nucleus and form repair foci. Taken together, this data suggests that 3E10 inhibits HR by physically interacting with Rad51. Overall, 3E10 holds promise as a novel therapeutic agent for certain subsets of cancer. Citation Format: Peter M. Glazer, Audrey Turchick. Inhibition of RAD51 with a cell penetrating antibody, 3E10 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2482. doi:10.1158/1538-7445.AM2017-2482