bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 588: Neutrophil to lymphocyte ratio as strongest predictor of early death in metastatic triple negative breast cancer
Authors: Ku Gabriel A. De la Cruz , Morante Zaida , Pinto Joseph , Araujo Jhajaira , Enriquez Daniel , Eyzaguirre Eduardo , Saavedra Antonella , Lujan Maria , Luque Renato , Rázuri Cesar , Fuentes Hugo , Neciosup Silvia , Moreno Henry Gómez 
Published: August 2018

Abstract
Background: Metastatic triple-negative breast cancer (mTNBC) is a heterogeneous disease with poor prognosis where recent studies suggest that the immune system plays a critical role the mechanisms of disease progression and metastasis. In the other hand, a high Neutrophil to Lymphocyte Ratio (NLR) is associated with poor survival in patients diagnosed with several types of cancer. Our aim was to evaluate the prognostic value of NLR in mTNBC.
Methods: We retrospectively reviewed 130 patients diagnosed with mTNBC between 2000-2014 at “Instituto Nacional de Enfermedades Neoplasicas”. NLR group was divided in &lt;2.5 and ≥2.5. Sites of metastasis were identified by TAC or magnetic resonance imaging. Survival rates were estimated by the Kaplan-Meier method and differences were calculated by Log-rank test. The Cox Regression was used for prognostic factors.
Results: The median age was 50 years (range: 23-92 years). From our study population, 41.2% were premenopausal, and just 10 patients (9.5%) had a breast-ovary cancer familiar background, 62.5% were diagnosed at clinical stage T3-T4 and 86.1% had lymph node involvement. From 130 patients, 41 and 64 had NLR &lt;2.5 and ≥2.5, respectively, while there was no association between characteristics and NLR, only patients with malnutrition had NLR ≥2.5 (9.1% vs 40.8%, p=0.002) and solid organ involvement (62.4% vs 81.3%, p=0.04). Furthermore, lung and bone were the most frequent sites of metastasis. Those patients with lower ratio (&lt;2.5) had better response to chemotherapy (p &lt;0.001). With a median follow-up of 6.25 years, at 1-year OS was lower among patients with NLR ≥2.5 (59% vs 20%, HR: 2.77, 95%CI:1.77-4.33, p&lt;0.001). In addition, at univariate analysis malnutrition also showed an impact on OS (HR: 1.79, 95%CI: 1.20-2.67, p=0.005). At multivariate analysis, between age, T stage, N stage, NLR and solid organ involvement, just NLR was the best and only predictor of worse OS (HR: 3.12, 95%CI:1.94-5.03, p&lt;0.001).
Conclusion: In mTNBC, an NLR ≥2.5 was a strong and accessible biomarker of poor OS. Lower values of NLR could help us to predict chemotherapy response.
Citation Format: Gabriel A. De la Cruz Ku, Zaida Morante, Joseph Pinto, Jhajaira Araujo, Daniel Enriquez, Eduardo Eyzaguirre, Antonella Saavedra, Maria Lujan, Renato Luque, Cesar Rázuri, Hugo Fuentes, Silvia Neciosup, Henry Gómez Moreno. Neutrophil to lymphocyte ratio as strongest predictor of early death in metastatic triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 588.
Abstract 5880: Small-molecule modulators of PDE3/SLFN12 to kill cancer cells
Authors: Lewis Timothy A. , Waal Luc de , Wu Xiaoyun , Ellerman Manuel , Kopitz Charlotte , Wengner Antje , Eis Knut , Lange Martin , Tersteegen Adrian , Lienau Philip , Greulich Heidi , Meyerson Matthew 
Published: August 2018

Abstract
We have previously reported1 our results with a small molecule called DNMDP which kills certain cancer cells by modulating the interaction of PDE3A and Schlafen 12 (SLFN12), a more recently discovered protein of unknown function. While DNMDP selectively inhibits PDE3, most PDE3 inhibitors have no cell killing effects and in fact rescue cancer cells from DNMDP-induced death. DNMDP is not suitable for advanced studies due to structural liabilities. Optimization of DNMDP to both increase activity and improve pharmacokinetic properties resulted in enantiomerically pure, low molecular weight, metabolically stable compounds which are active at low doses in animal models of cervical cancer and melanoma. While these compounds are selective PDE3A inhibitors and their biochemical activity mirrors their cellular activity, the activity of the compounds results not from PDE3 inhibition and increased cAMP levels, but from increased compound-induced binding of PDE3A to SLFN12, which most PDE3 inhibitors do not effect. Our results suggest that small molecule modulators of PDE3/SLFN12 binding may provide a novel treatment for the treatment of certain cancers.
1Nat. Chem. Bio. 2016, 12, 102-108.
Citation Format: Timothy A. Lewis, Luc de Waal, Xiaoyun Wu, Manuel Ellerman, Charlotte Kopitz, Antje Wengner, Knut Eis, Martin Lange, Adrian Tersteegen, Philip Lienau, Heidi Greulich, Matthew Meyerson. Small-molecule modulators of PDE3/SLFN12 to kill cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5880.
Abstract 5896: Downregulation of calcium-sensing receptor enhances MET-mediated prostate cancer chemosensitivity
Authors: Huang Luying , Wang Fuhao , Tong Haibo , Mizokami Atsushi , Keller Evan T. , Lu Yi , Zhang Jian 
Published: August 2018

Abstract
Chemoresistance, in various types of cancer including prostate cancer (PCa), is one of the major challenges in cancer therapy. Others and our lab have reported that the epithelial-to-mesenchymal transition (EMT) plays critical roles in development of chemoresistance and metastasis. The calcium-sensing receptor (CaSR) plays important roles in maintenance of calcium homeostasis and altered CaSR expression, and functional changes are involved in certain diseases, including tumorigenesis and its development. However, the mechanism of CaSR in PCa chemoresistance remains unclear. In current study, the CaSR expression level was detected in parental PC3 and DU145 cells and their chemoresistant PC3-TxR and DU145-TxR cells. We found the CaSR was highly expressed in chemoresistant PC3-TxR and DU145-TxR cells. Then by using siRNA technique, CaSR expression was transiently knocked down in chemoresistant cells. The tumor cell migration, invasion, and colony formation were evaluated by wound healing, transwell, and colony formation assays, respectively. The drug sensitivity was evaluated using MTS assay. We observed that the abilities of tumor cell migration and invasion were significantly diminished in CaSR knockdown PC3-TxR and DU145-TxR cells. The ability of colony formation was also reduced. Interestingly, the sensitivity to paclitaxel was reactivated in CaSR knockdown PC3-TxR and DU145-TxR cells. We finally observed that E-cadherin expression was increased in CaSR knockdown chemoresistant cells, and Snail, Vimentin and β-catenin were decreased; these results are consistent with EMT phenotypic alterations. Taken together, we conclude that downregulation of CaSR enhances MET-mediated prostate cancer chemosensitivity.
Supported by NSFC Key Project 81130046; NSFC projects 81773146,81272415; JCYJ20170412152943794, JCYJ20170412154619484, JCYJ20170307105128101, JCYJ2017030711041760; Guangxi Key Projects 2013GXNSFEA053004.
Citation Format: Luying Huang, Fuhao Wang, Haibo Tong, Atsushi Mizokami, Evan T. Keller, Yi Lu, Jian Zhang. Downregulation of calcium-sensing receptor enhances MET-mediated prostate cancer chemosensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5896.
Abstract 590: Marital status and survival among breast cancer patients
Authors: Lu Yan , Jackson Bradford E. , Ghabach Bassam , Ojha Rohit P. 
Published: August 2018

Abstract
Background: Recent evidence suggests improved survival for married breast cancer patients compared with unmarried patients, but unclear is whether this survival benefit extends to socioeconomically disadvantaged women. We aimed to assess the association between marital status and breast cancer survival among socioeconomically disadvantaged breast cancer patients and breast cancer patients from the general population.
Methods: We used data from the John Peter Smith (JPS) Oncology Registry, which comprises cancer patients in Tarrant County, TX treated at a safety-net institution, and the Texas Cancer Registry (TCR), a statewide population-based registry. Our eligible population included females aged 18 – 64 years diagnosed with primary breast cancer between January 2008 and June 2013 with follow-up through 2016. We categorized marital status into three groups: single, married, or separated/divorced/widowed. We estimated the 36-month restricted mean survival time, which allows survival comparisons within a specified period.
Results: Our study populations comprised 614 JPS and 32,985 TCR patients. The age distribution at diagnosis was similar for both groups (JPS: median=51 years; TCR: median=52 years). JPS patients were more often non-White (JPS=62%; TCR=42%) and uninsured (JPS=56%; TCR=9.6%). A higher frequency of TCR patients were married (TCR=65%; JPS=39%). Survival was shorter for JPS patients (JPS=33.1 months; TCR =34.8 months) after 36-months (Table 1). Married women had longer survival than unmarried women in both populations.
Conclusion: Our results suggest similar magnitudes of improved survival for married women with breast cancer compared with unmarried women in both populations, but socioeconomically disadvantaged patients have consistently lower survival estimates across marital subgroups compared with patients from the general population. Our findings warrant further studies that explore mechanisms of how marital status influences breast cancer survival in different populations.
Table 1. Restricted mean survival time (RMST) after breast cancer diagnosis based on marital statusDisadvantaged Cancer PatientsaCancer Patients from General PopulationbRMSTc (months)Difference in RMST (95% CLd) (months)RMST (months)Difference in RMST (95% CL) (months)Separated/Divorced/Widowed32.2-0.89 (-2.8, 1.0)34.10.01 (-0.23, 0.25)Married33.80.56 (-0.96, 2.1)35.10.54 (0.36, 0.71)Single33.00 (Reference)34.10 (Reference)aCancer patients from JPS Oncology RegistrybCancer patients in the Texas Cancer RegistrycBased on 36-month restricted mean survivaldCL: Confidence limits
Citation Format: Yan Lu, Bradford E. Jackson, Bassam Ghabach, Rohit P. Ojha. Marital status and survival among breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 590.
Abstract 5901: The role of POU3F2 in the aggressive behavior of neuroendocrine prostate cancer
Authors: Kobayashi Naoko , Hong Dai , Wang Chun , Yamashiro Joyce , Guan Johnny , Reiter Robert E. 
Published: August 2018

Abstract
Neuroendocrine and Small Cell Prostate Cancer (NEPC) is a lethal disease emerging from Castrate Resistant Prostate Cancer (CRPC) after treatment with next-generation anti-androgen therapies such as abiraterone and enzalutamide. The mechanisms by which treatment resistant prostate epithelial cancer cells trans-differentiate to poorly differentiated small cell cancer are not well understood. We and others found that Nervous System-Specific Octamer-Binding Transcription Factor (POU3F2) expression is induced in NEPC. POU3F2 is a reprogramming transcription factor that controls cellular differentiation and can induce stem-like cells from differentiated glioblastoma. POU3F2 also plays a critical role in melanoma progression and in small cell carcinoma of the lung. NEPC shares similarities with small cell carcinoma from other organs. We hypothesized that POU3F2 may be a key transcription factor that is required for transdifferentiation and the survival of NEPC cells. We further hypothesize that the underlying mechanism of therapy resistance in NEPC is that NEPC consists of stem-like cells that were reprogrammed from differentiated prostate cancer cells under the selective pressure of androgen receptor (AR) pathway-targeted therapy. We elucidated the functional role of POU3F2 in the aggressive cancer behavior of NEPC —including stem-cell properties, tumorigenesis, invasion, and chemo-resistance. We also characterized the mechanisms that regulate POU3F2 expression in therapy-resistant NEPC. The study provides a rational for targeted therapy for treatment of NEPC. It could also be used to design a strategy to halt the emergence of NEPC from CRPC.
Citation Format: Naoko Kobayashi, Dai Hong, Chun Wang, Joyce Yamashiro, Johnny Guan, Robert E. Reiter. The role of POU3F2 in the aggressive behavior of neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5901.
Abstract 5903: The molecular mechanism for producing BQ323636.1 in Tamoxifen resistance breast cancer cells
Authors: Mok Ka Chun , Tsoi Ho , Khoo Ui-Soon , Man Ellen 
Published: August 2018

Abstract
Breast cancer is one of the prevalent causes of cancer in women. Two thirds of breast cancer patients are ER-positive and can be benefited from tamoxifen treatment. However, 50% of the patients will eventually develop the resistance. Identifying molecular targets associated with tamoxifen resistance would help in designing better therapeutic strategies. Previous study from our group identify a novel factor BQ323636.1 (BQ), a spliced variant of NCOR2, could confer tamoxifen resistance. From our in vivo study, nuclear enrichment of BQ in primary breast tumor was found to be associated with tamoxifen resistance. However, the molecular mechanism governed the nuclear import of BQ and was not clear. From bioinformatics prediction, we identified a functional nuclear localization signal (NLS) on BQ. We therefore performed a protein screening to search for the import receptor which could interact with BQ. KPNA1 was found to interact with BQ. To further validate such an interaction, we fused the NLS to GPF reporter protein (GFP-NLS) and performed a co-immunoprecipitation. The result showed that the GFP-NLS was able to interact with KPNA1. Knockdown of KPNA1 by RNAi could prevent the nuclear import of BQ. This confirmed the functional role of KPNA1 in the nuclear import of BQ. In addition, knockdown of KPNA1 in BQ overexpressing breast cancer cells could reverse the tamoxifen resistance. The results highlighted the functional significance of KPNA1 in the tamoxifen resistance. Subsequently, we investigated the functional role of BQ in the nucleus. We found BQ could deplete the gene repressive function of NCOR2. We found that NCOR2 could interact with HSF4 and should repress the expression of HIF1α. In the presence of BQ, the repressive function of NCOR2 on HIF1α was compromised, leading to up-regulation of HIF1α. To further validate the effect of HIF1α in the tamoxifen resistance, HIF1α inhibitor was employed and found that the treatment of the inhibitor could reduce the resistance in BQ overexpressing breast cancer cells. Therefore, our study uncovered the role of KPNA1 in the development of tamoxifen resistance through which KPNA1 could promote the nuclear import of BQ. Subsequently, BQ could lead to the up-regulation of HIF1α which also play significant role in the development of tamoxifen resistance.
Citation Format: Ka Chun Mok, Ho Tsoi, Ui-Soon Khoo, Ellen Man. The molecular mechanism for producing BQ323636.1 in Tamoxifen resistance breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5903.
Abstract 5908: Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen
Authors: Chapeau Emilie A. 
Published: August 2018

Abstract
Inhibitors of MDM2-TP53 interaction are predicted to be effective in tumors where the TP53 gene is wild-type by preventing TP53 protein degradation. One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor. Here we utilized piggyBac transposon insertional mutagenesis to anticipate resistance mechanisms that occur under intermittent high dose treatment with the MDM2-TP53 inhibitor HDM201. Constitutive piggyBac mutagenesis in Arf-/- mice provided a collection of spontaneous tumors with characterized insertional genetic landscapes. Tumors were allografted in large cohorts of mice to assess HDM201 pharmacological effects. 16 out of 21 allograft models were sensitive to HDM201 but ultimately relapsed under treatment. When tumors with acquired resistance to HDM201 were compared to untreated tumors, 87 genes were found differentially and significantly targeted by piggyBac transposon. Resistant tumors displayed a complex clonality pattern suggesting emergence of several resistant subclones. Among the most frequent alterations conferring resistance, we observed somatic and insertional loss-of-function mutations in Trp53 in 54% of tumors, and transposon-mediated gain-of-function alterations in Bcl-xL, Mdm4, and two TP53-family members, resulting in expression of the TP53 dominant negative truncations ΔNTrp63 and ΔNTrp73. Enhanced BCL-xL and MDM4 proteins expression was confirmed in resistant tumors, as well as in HDM201 resistant patient-derived tumor xenografts. Interestingly, concomitant inhibition of MDM2 and BCL-xL demonstrated significant synergy in p53 wild-type cell lines in vitro.
Moreover, we performed an additional piggyBac screen with daily HDM201 treatment, at lower dose. Surprisingly, we identified Bcl-XL expression as a unique mechanism of resistance in intermittent high dose scheduling. These data suggested that different apoptotic inductions between the two HDM201 dose regimens (intermittent high dose/daily lower dose) likely play a role in the way the resistance to HDM201 takes place.
Collectively, our study has identified several potential mechanisms by which TP53 wild-type tumors may escape MDM2 targeted therapy, and provide evidence that Bcl-XL inhibition may be beneficial for relapsing patients that were treated with HDM201 intermittent scheduling.
Citation Format: Emilie A. Chapeau. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5908.
Abstract 5922: "Gammora": Selective killing of cancer cells bearing CD24 by viral integrase
Authors: Shapira Shiran , Finkelshtein Eynat , Loyter Abraham , Arber Nadir 
Published: August 2018

Abstract
The HIV integrase is important in the integration of viral DNA to the host genome resulting in double-stranded breaks (DSB). Only 1-2 copies are integrated, due to inhibition of HIV-1 Rev protein, making the cells invisible to the immune system. CD24 is mostly expressed on cancer and not normal cells. We hypothesize that specific targeting of the viral particles using mAb to CD24 together with stimulating the enzyme activity and increasing the frequency of integration events, would increase the occurrence of DSB, that will lead to genomic instability, and ultimately to apoptosis of the target cells.
Aim
To develop a therapeutic platform, for selective eradication of cancer cells, which consists of targeted lentivirus particles and IN-derived peptides.
Methods
Integrase derived peptides (designated as INR2 and INS) were synthesized. Humanized anti-CD24 antibody (scFv) was engineered and fused to the lentivirus envelope. Stability, solubility and toxicity of the peptides were analyzed by HPLC-MS and MTD, respectively, as well as their activity and permeability into cells. Cell death was measured qualitatively by fluorescent microscopy and quantified by the enzymatic MTT assay. Colorectal, pancreatic and lung cancer cells were used for testing the potency of the lentiviral-based system. The efficacy of the suggested system was assessed in vivo, in nude mice bearing xenografts of lung cancer. The mice were treated systemically twice weekly.
Results
INS and INR2 stimulate viral integrase in vitro. A single IV administration of INR2 and INS was well tolerated without adverse effects. These lentivirus particles contain nonfunctional DNA with flanked LTRs allowing their integration into the target cells DNA and formation of DSB due to the action of the integrase whose activity was stimulated by the IN-derived peptides. Massive cell death (40-70%) in a dose-
dependent manner was achieved. Raltegravir, an antiretroviral FDA-approved drug, was able to inhibit cell death (2-3 times). In vivo, the INR2 and INS combination led to a significant reduction (50%) in tumor volume. Live imaging (IVIS device) of the tumors and selected organs confirmed that the viruses indeed reach the tumor after systemic injection and that the anti-CD24 enhanced the selectivity of infection.
Conclusions
The use of IN-derived peptides together with the CD24-targeted lenti-therapy approach suggests a novel strategy that specifically promotes killing and removal of a wide range of cancer cells.
Citation Format: Shiran Shapira, Eynat Finkelshtein, Abraham Loyter, Nadir Arber. "Gammora": Selective killing of cancer cells bearing CD24 by viral integrase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5922.