bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4327: Nek6 and Hif-1α cooperate with the cytoskeletal gateway of drug resistance to drive outcome in serous ovarian cancer
Authors: De Donato Marta , Fanelli Mara , Mariani Marisa , Raspaglio Giuseppina , Pandya Deep , He Shiquan , Fiedler Paul , Petrillo Marco , Scambia Giovanni , Ferlini Cristiano 
Published: August 2015

Abstract
Hypoxia selects the most aggressive and drug-resistant clones in solid malignancies. One of the pivotal transcription factors induced by hypoxia is Hif-1α. However, in serous ovarian cancer (SEOC), Hif-1α expression is not a prognostic biomarker. This study aims to assess the hypothesis that the serine-threonine kinase Nek6 functions as a downstream effector cooperating with Hif-1α in driving ovarian cancer aggressiveness.
Nek6 was overexpressed and Hif-1α was silenced in A2780 cells. Nek6 was also stably silenced in Hey cells. The dependence of Nek6 expression on Hif-1α was assayed as a function of hypoxic growth conditions. Nek6 interaction with the cytoskeletal gateway of drug resistance was investigated with far western blot. The co-expression of NEK6, HIF1A, TUBB3 and GBP1 transcripts was quantified with qPCR in two cohorts of SEOC patients (346 locally treated patients and 344 from the TCGA dataset).
Nek6 expression is induced by hypoxia in a Hif-1α dependent fashion. Nek6 directly interacts with GBP-1, thus being a component of the cytoskeletal gateway of drug resistance. Nek6 overexpression increases and silencing decreases the anchorage-independent growth of cultured cells. In SEOC patients, NEK6 expression is significantly correlated with HIF1A. Co-expression of NEK6, HIF1A, TUBB3 and GBP1 transcripts identifies a subset of SEOC patients characterized by poor outcome and drug resistance.
This study demonstrates the functional relevance of Nek6 in the context of the adaptive response to hypoxia in SEOC. This finding may help identify a sub-population of patients at high risk of relapse to standard first-line chemotherapy.
Citation Format: Marta De Donato, Mara Fanelli, Marisa Mariani, Giuseppina Raspaglio, Deep Pandya, Shiquan He, Paul Fiedler, Marco Petrillo, Giovanni Scambia, Cristiano Ferlini. Nek6 and Hif-1α cooperate with the cytoskeletal gateway of drug resistance to drive outcome in serous ovarian cancer. [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 4327. doi:10.1158/1538-7445.AM2015-4327
Abstract 4334: Elevated lactic acid is a negative prognostic factor in metastatic lung cancer
Authors: Vlachostergios Panagiotis J. , Parikh Nirav , Oikonomou Katerina , Gibilaro Eugene , Apergis George 
Published: August 2015

Abstract
Introduction: Hyperlactatemia with or without type B lactic acidosis is a rare complication of malignancy, previously observed most often in hematological malignancies. Underlying pathophysiology involves reduced lactic acid metabolism from metastatic liver dysfunction as well as overproduction of lactic acid from aberrant glycolytic metabolism of tumors. Clinical data to evaluate the potential value of arterial or venous lactic acid (LA) level assessment as a predictor of overall survival (OS) or/and response to treatment are lacking. The aim of this study was to assess the prognostic value of LA in patients with metastatic lung cancer.
Methods: Patients diagnosed with stage IV non-small cell lung cancer (NSCLC) or extensive stage small cell lung cancer (SCLC) from 2012 to present, were included in this single center, retrospective study. Patients with sepsis or acute exacerbation of heart failure were excluded from the study. Arterial and venous LA level, bicarbonate, anion gap, urine ketones, serum LDH were recorded for each patient and their associations with demographic and clinical data and OS were analyzed with the Chi-square test, Kaplan-Meier's actuarial method (log-tank test) and Cox proportional hazard model.
Results: 85 patients (43 males, mean age 73.1, range 45-96 years) were studied. The maximal levels of arterial or venous LA were significantly associated with presence of ≥2 metastatic sites (p = 0.001), ICU admission or transfer (p = 0.016), intubation (p = 0.029), elevated serum anion gap (p&lt;0.001) and LDH levels (p&lt;0.001). No significant associations emerged between LA level and gender, age, smoking status, histology, tumor size or grade, previous lung resection, location of metastases, COPD, previous metformin use, ketonuria, and previous or ongoing palliative chemotherapy. Hyperlactatemia (p&lt;0.001), histologic subtype (p = 0.019), ICU admission or transfer (p = 0.014), intubation (p = 0.026), number of metastatic sites (p = 0.01), AG (p&lt;0.01) and LDH (p&lt;0.001) were univariately associated with OS. LDH was the only independent prognostic factor [OR = 0.162 (95% CI: 0038-0.687), p = 0.014].
Conclusion: Our results suggest that elevated LA is a predictor of poor OS in metastatic lung cancer patients, irrespective of chemotherapy. Here lie implications for targeting tumor-derived LA production via manipulation of glycolytic enzymes or lactate transporters, with use of LA as a surrogate marker of response.
Citation Format: Panagiotis J. Vlachostergios, Nirav Parikh, Katerina Oikonomou, Eugene Gibilaro, George Apergis. Elevated lactic acid is a negative prognostic factor in metastatic lung cancer. [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 4334. doi:10.1158/1538-7445.AM2015-4334
Abstract 435: Adipocyte-derived monocyte chemotactic protein-1 (MCP-1) promotes prostate cancer progression through matrix metalloproteinase (MMP-2) mediated extracellular matrix degradation
Authors: Ito Yusuke , Ishiguro Hitoshi , Kobayashi Naohito , Hasumi Hisashi , Watanabe Masatoshi , Yao Masahiro , Uemura Hiroji 
Published: August 2015

Abstract
Background: Obesity is known to be associated with prostate cancer development and progression, but the detailed mechanism is not clear. Monocyte chemotactic protein-1 (MCP-1) is secreted from cancer cells, stromal cells and adipocytes, and it is involved in prostate cancer progression. Here we investigated the biological role of MCP-1 secreted from adipocytes for prostate cancer cells.
Methods: Human pre-adipocytes (HPAds) were cultured and differentiated to mature adipocytes. Conditioned medium (CM) from HPAd cells was obtained using phenol red-free RPMI1640 medium. We performed a cytokine membrane array analysis to detect cytokines in the CM. To characterize the physiological function of MCP-1 in the CM, we performed an MTT-assay, a wound-healing and invasion assay with anti-MCP-1 antibody using three prostate cancer cell lines: DU145, LNCaP, and PC-3. Matrix metalloproteinase (MMP)-2 and MMP-9 activities were evaluated by gelatin zymography. A qPCR and Western blotting were used to examine the mRNA and protein expression levels of MMP-2.
Results: The cytokine membrane array of the CM showed a strong signal of MCP-1compared to the control medium, and we thus focused our attention on MCP-1 in the CM. The CM up-regulated the cancer cell proliferation, and the neutralization by anti-MCP-1 antibody inhibited the proliferative effect of the prostate cancer cell lines. The CM greatly increased the invasive activity in the prostate cancer cell lines, and anti-MCP-1 antibody decreased the invasiveness. Gelatin zymography revealed that the CM markedly enhanced the enzymatic activity of MMP-2, and anti-MCP-1 antibody down-regulated its effect. MMP-2 mRNA expression was undetected and the MMP-2 protein level was unchanged between the control medium and CM in DU145 cells.
Conclusions: MCP-1 from adipocytes enhances the growth and invasion activity of prostate cancer cells. The inhibition of MCP-1 derived from adipocytes might be an effective treatment for prostate cancer.
Citation Format: Yusuke Ito, Hitoshi Ishiguro, Naohito Kobayashi, Hisashi Hasumi, Masatoshi Watanabe, Masahiro Yao, Hiroji Uemura. Adipocyte-derived monocyte chemotactic protein-1 (MCP-1) promotes prostate cancer progression through matrix metalloproteinase (MMP-2) mediated extracellular matrix degradation. [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 435. doi:10.1158/1538-7445.AM2015-435
Abstract 4365: Targeting the SF3B1 spliceosome protein: Development of a reporter for HTS screen and pharmacodynamic profiling of small molecule drug leads
Authors: Shi Yihui , Lagisetti Chandraiah Lagisetti , Joyner Amanda S. , Sambucetti Lidia C. , Webb Thomas R. 
Published: August 2015

Abstract
The spliceosome is an important emerging target for cancer therapy that has only recently been uncovered that represents an exciting new opportunity for therapeutic intervention in cancer. Two naturally occurring bacterial products show striking selective toxicity to tumors and have recently been found to act by targeting the SF3b subunit of the spliceosome, thus modulating pre-mRNA splicing in tumor cells. However, these natural products, and analogs derived from them, are synthetically quite complex. We have designed and optimized a class of novel synthetic small molecules, called sudemycins, which also modulate alternative splicing and have substantial antitumor activity. Previous work in our lab has shown that our lead compound, sudemycin D6 has significant in vivo antitumor activity. We now report the development of a high-throughput cell-based luciferase reporter system that has multiple applications in facilitating splicing modulatory drug discovery and development.
Citation Format: Yihui Shi, Chandraiah Lagisetti Lagisetti, Amanda S. Joyner, Lidia C. Sambucetti, Thomas R. Webb. Targeting the SF3B1 spliceosome protein: Development of a reporter for HTS screen and pharmacodynamic profiling of small molecule drug leads. [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 4365. doi:10.1158/1538-7445.AM2015-4365
Abstract 4379: MPT0B292 enhances acetylation of α-tubulin through up-regulation of acetyltransferase gene, MEC-17 and exhibits potent anti-tumor, anti-angiogenesis and anti-metastatic effects in vitro and in vivo
Authors: Chang Jang-Yang , Cheng Yun-Ching 
Published: August 2015

Abstract
In recent years, epigenetic therapeutics is a new generation of chemotherapeutics for cancer. Microtubule-targeted agents constitute a type of anticancer drugs largely used in the clinics. Cells generate distinct microtubule subtypes through expression of different iso-types and through post-translational modifications, including acetylation, detyrosination, polyglutamination and polyglycylation. The acetylation of α-tubulin K-40 is controlled by the balance between acetyltransferase and de-acetylase expression. MEC-17, one of α-tubulin acetyltransferases, plays an important role in the regulation of acetylation of α-tubulin. Through screening of compounds that is able to selectively acetylate α-tubulin, MPT0B292 was identified.
Our results show that MPT0B292 up-regulate MEC-17 gene and protein expression, which subsequently lead to enhancing α-tubulin acetylation. MPT0B292 exhibits potent anti-proliferative activities toward various human cancer cells with IC50 ranged from 75 to 200 nM. In addition, HUVEC and WI-38 cells were much less susceptibility to the anti-proliferative effect of MPT0B292 with IC50 4 and12 μM, respectively. In FACS analysis of cell cycle, MPT0B292 induces G2/M phase arrest with concomitantly losses from G0/G1 and S phases in a concentration-dependent manner. Furthermore, MPT0B292 induces ROS generation in a concentration-dependent manner by FACS analysis, which leads to damaging mitochondria and triggering cell apoptosis. The effects MPT0B292-induced ROS and cell apoptosis could be significantly rescued by pretreatment with N-acetylcysteine, Diphenyleneiodonium (DPI) and rotenone. Moreover, the amount of ROS induced by MPT0B292 was significantly reduced by knockdown of MEC-17 with siRNA and resulted in rescuing cell viability. In addition, MPT0B292 inhibits cell motility by an increase in cellular focal adhesion area. Moreover, MPT0B292 shows potent activity against the growth of xenograft tumor of lung cancer cell, A549, without significantly compromising the mice body weight. MPT0B292 also decreases lung metastasis in orthotopical breast cancer model. These data indicate MPT0B292 is a promising anticancer compound with unique action of mechanism that has potential for future development.
Citation Format: Jang-Yang Chang, Yun-Ching Cheng. MPT0B292 enhances acetylation of α-tubulin through up-regulation of acetyltransferase gene, MEC-17 and exhibits potent anti-tumor, anti-angiogenesis and anti-metastatic effects in vitro and in vivo. [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 4379. doi:10.1158/1538-7445.AM2015-4379
Abstract 4387: Anti-tumor activity of TNF-gold nanodrugs tagged with tumor vasculature-homing peptides containing the NGR or isoDGR motives
Authors: Curnis Flavio , Gasparri AnnaMaria , Sacchi Angelina , Fiocchi Martina , Corti Angelo 
Published: August 2015

Abstract
Colloidal gold (Au) is a well-tolerated nanomaterial currently exploited for several applications in the field of nanomedicine. In particular, gold nanoparticles loaded with tumor necrosis factor-alpha (TNF), a cytokine endowed with anti tumor activity, have a therapeutic index higher than that of TNF. For this reason TNF-gold nanoparticles are currently tested in cancer patients.
We have addressed the hypothesis that TNF-gold nanoparticles tagged with tumor vasculature homing peptides have improved therapeutic properties.
To this aim we have tagged TNF-gold nanoparticles with albumin-peptide conjugates containing the NGR (Asn-Gly-Arg) or isoDGR (isoAsp-Gly-Arg) motives, i.e. with ligands of CD13 and integrin alphavbeta3, respectively, expressed by the tumor neovasculature.
The therapeutic properties of the resulting nanodrugs (called NGR-HSA/Au/TNF and isoDGR-HSA/Au/TNF) were then investigated in fibrosarcoma- or lymphoma-bearing mice and compared with those a nanodrug lacking the targeting peptide (called HSA/Au/TNF). The results showed that intravenous administration of extremely low doses of NGR-HSA/Au/TNF or isoDGR-HSA/Au/TNF (equivalent to 5 pg of bioactive TNF/mouse) were sufficient to induce anti-tumor effects, whereas similar doses of HSA/Au/TNF were minimally active. Low-dose NGR-HSA/Au/TNF and isoDGR-HSA/Au/TNF, but not HSA/Au/TNF, could also exert synergistic anti-tumor effects with melphalan, a chemotherapeutic drug. These findings support the concept that tagging TNF-gold nanoparticles with tumor vasculature homing peptides have an improved antitumor activity, likely because of an active targeting mechanism.
Citation Format: Flavio Curnis, AnnaMaria Gasparri, Angelina Sacchi, Martina Fiocchi, Angelo Corti. Anti-tumor activity of TNF-gold nanodrugs tagged with tumor vasculature-homing peptides containing the NGR or isoDGR motives. [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 4387. doi:10.1158/1538-7445.AM2015-4387
Abstract 4389: Liposomes containing piperazine compounds inhibit tumor growth in a patient-derived xenograft model of glioblastoma multiforme
Authors: Swindell Elden P. , Ugolkov Andrey , Freguia Christian , Dubrovskyi Oleksii , Hankins Patrick L. , Yang Jeong , Raizer Jeffrey J. , Chandler James P. , James Charles David , Mazar Andrew P. , O'Halloran Thomas V. 
Published: August 2015

Abstract
Glioblastoma multiforme (GBM) is fatal in nearly all instances, and responds poorly to current standards of care. GBMs exhibit resistance to chemotherapy which leads to tumor recurrence following initial surgical debulking. We have recently developed an 80 nm liposome containing a novel hydrophobic microtubule disrupting piperazine. This novel nanostructure, called IM-1 nanobin, contains 500-1000 piperazine drug molecules encapsulated in the hydrophobic inner leaflet of the lipid bilayer in each liposome. This nanoparticle inhibited the proliferation of GBM cells in vitro, although its cytotoxicity was reduced (3-5 fold) compared to free drug dissolved in DMSO. Results from FACS analysis showed that sub-micromolar concentrations of IM-1 caused G2/M phase cell cycle arrest and apoptosis of U87 GBM cells, as well as early passage GBM cells derived from a patient-derived xenograft (PDX). In collaboration with the Northwestern Brain Tumor Institute, we have established a panel of PDX. Since these tumors are not propagated in culture, they preserve the mixture of tumor cells and stroma critical for conducting meaningful therapy response experiments. IM-1 was evaluated in GBM PDX propagated in subcutaneous and intracranial compartments. In mice bearing subcutaneous PDX tumors, IM-1 treatment delayed the growth of the tumors compared to free drug alone; orthotopic GBM PDX studies are ongoing. Our results show that a novel liposome encapsulated piperazine, IM-1, is a promising new nanostructure for development as a therapeutic for treating patients with GBM.
Citation Format: Elden P. Swindell, Andrey Ugolkov, Christian Freguia, Oleksii Dubrovskyi, Patrick L. Hankins, Jeong Yang, Jeffrey J. Raizer, James P. Chandler, Charles David James, Andrew P. Mazar, Thomas V. O'Halloran. Liposomes containing piperazine compounds inhibit tumor growth in a patient-derived xenograft model of glioblastoma multiforme. [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 4389. doi:10.1158/1538-7445.AM2015-4389
Abstract 4394: Selective accumulation and specific tumor damage by folate receptor-targeted CA-4 prodrug as part of a combination of photodynamic therapy and site-specific chemotherapy
Authors: Gregory Nkepang , Bio Moses , Rajaptura Pallavi , Awuah Samuel G. , You Youngjae 
Published: August 2015

Abstract
A non-invasive or minimally invasive tumor ablation regimen is an attractive tool with which to control tumors. This approach is complementary to primary treatment options without causing systemic side effects or severe physical burdens from the treatment itself. Clinically approved photodynamic therapy (PDT) is one such regimen. In PDT, photosensitizers are activated by visible and near IR light to destroy tumors. However, the therapeutic efficacy of PDT is limited due to the spatial and temporal restrictions of the effector of PDT, singlet oxygen. We have been developing a new prodrug strategy that can overcome these limits by using a unique combination of PDT and site-specific chemotherapy. The prodrug is composed of photosensitizer and anticancer drug via a singlet oxygen-cleavable linker. Upon illumination, the prodrugs cause PDT damage and simultaneously release anticancer drugs only at the illuminated target area. In our previous publications, we reported 1) the design and synthesis of prodrugs of combretastatin A-4, 2) visible/ near IR light-controlled release of the drug from the prodrug, 3) bystander effects from the released anticancer drug, and 4) the superior antitumor effect of the prodrug compared to a simple combination of PDT and chemotherapy. Recently, a more advanced CA-4 prodrug was developed to achieve selective delivery to tumors via folate receptors (FRs) overexpressed in numerous cancer cell lines. The targeted prodrug showed FR-mediated uptake to FR-expressing cancer cells (colon 26 cells) in vitro and to FR-expressing tumors in vivo. Notably, the targeted CA-4 prodrug effectively ablated the tumors without causing collateral damage to the surrounding skin.
Citation Format: Nkepang Gregory, Moses Bio, Pallavi Rajaptura, Samuel G. Awuah, Youngjae You. Selective accumulation and specific tumor damage by folate receptor-targeted CA-4 prodrug as part of a combination of photodynamic therapy and site-specific chemotherapy. [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 4394. doi:10.1158/1538-7445.AM2015-4394
Abstract 440: Nicotinamide phosphoribosyltransferase (NAMPT): a new cytokine in tumor progression
Authors: Grolla Ambra , Torretta Simone , Amoruso Angela , Orsomando Giuseppe , Genazzani Armando 
Published: August 2015

Abstract
An important role has been shown for Nicotinamide phosphoribosyltransferase (NAMPT; also known as PBEF or visfatin) in cancer, inflammation and metabolic diseases. Alongside maintaining intracellular NAD levels constant by contributing to the salvage pathway of NAD production, it is now clear that NAMPT is also a pleiotropic player in cell signalling: (i) as a key regulator of NAD consuming-enzymes, including sirtuins and PARPs; and (ii) as an extracellular cytokine that binds to a yet unknown extracellular receptor. It has been shown that a regulated positive secretory process exists, although the exact mechanism of release is at present under investigation. A mounting amount of cell types have been shown to release eNAMPT, including adipocytes, hepatocytes, cardiomyocytes and activated immune cells.
In my work, I verified that eNAMPT is released by different types of tumour cells, specifically by melanoma, neuroblastoma and glioblastoma, mesotelioma, and prostate cancer cells in vitro. In particular, we analysed the mechanisms of its release and we found both classical and non-classical pathway involvement. eNAMPT release could be modulated by tumoural microenvironment conditions and once released by tumour cells, in our hands, eNAMPT has paracrine and autocrine effects: it activates MAPK and Akt pathways in melanoma cells and induces M1 polarization in human monocytes. Mainly, I demonstrated for the first time that eNAMPT levels in plasma of tumour-bearing mice are increased because part of this circulating protein derives directly from tumour itself. This parallels observations that eNAMPT is increased in cancer patients, and indeed this increase can be, at least, in part attributed to the tumour itself. All these data suggested that the tumour microenvironment might be enriched of this cytokine-like protein, which could have a role in tumour progression and severity.
Citation Format: Ambra Grolla, Simone Torretta, Angela Amoruso, Giuseppe Orsomando, Armando Genazzani. Nicotinamide phosphoribosyltransferase (NAMPT): a new cytokine in tumor progression. [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 440. doi:10.1158/1538-7445.AM2015-440