bluuebunny/crossref_metadata_2025 huggingface dataset:
BET 1: Give prehospital blood and save a life?
Authors: Scott Nicholas , Sutton Sarah
Published: May 2016

A short cut review was carried out to establish whether prehospital blood transfusion in the trauma patient with active haemorrhage can reduce mortality. 11 directly relevant papers were found using the reported search strategy. Of these two presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that prehospital blood transfusion may reduce short-term mortality in these patients, but that the evidence level is low and further definitive randomised controlled trials are needed to prove benefit.
The application of susceptibility-weighted MRI in pre-interventional evaluation of intracranial dural arteriovenous fistulas
Authors: Jain Narendra Kumar , Kannath Santhosh Kumar , Kapilamoorthy Tirur Raman , Thomas Bejoy
Published: May 2016

Background and purpose

Detection and characterization of intracranial dural arteriovenous fistula (DAVF) is important to plan appropriate therapeutic management. The aim of this study was to analyze the utility of susceptibility-weighted MRI (SWI) in the pre-therapeutic assessment of DAVF in comparison with gold standard digital subtraction angiography (DSA).

Materials and methods

Prospectively, 26 patients with DAVFs underwent a thorough clinical examination and MRI including SWI followed by cerebral DSA. Two observers blinded to the DSA findings evaluated conventional MRI and SWI images and identified the fistulous area (FA), cortical venous reflux (CVR), and cortical venous ectasia (CVE) and compared these observations with the DSA findings documented by a third observer.

Results

Aggressive clinical symptoms were observed in 31% of patients and benign features were noted in 69% of DAVFs. Conventional MRI could identify the FA in only 27% of patients. SWI accurately located 75% of all the FAs in 23 patients. However, SWI failed to identify DAVFs in three patients. CVR was detected in 89.6% of all aggressive DAVFs. The accuracy of SWI to identify CVE was 100% and the extent and degree correlated with DSA observations.

Conclusions

SWI is a reliable non-invasive tool for the localization and characterization of DAVFs and is superior to conventional MRI in the evaluation of DAVFs. This sequence can demonstrate underlying cerebral hemodynamic stresses with a high degree of accuracy and provide valuable pre-therapeutic information.
Endovascular thrombectomy in the setting of aortic dissection
Authors: Reznik Michael E , Espinosa-Morales Aixa Damaris , Jumaa Mouhammad A , Zaidi Syed , Ducruet Andrew F , Jadhav Ashutosh P
Published: May 2016

Background

Recent studies have validated the use of endovascular thrombectomy in large vessel ischemic stroke provided patients are selected appropriately. However, to our knowledge, there have been no previously reported cases of endovascular thrombectomy in patients with aortic dissection. We report three such cases, two with chronic aortic dissections (including one with a history of Marfan syndrome) and another with an acute type B dissection.

Methods

Case studies and review of relevant literature.

Results

Three patients with a history of aortic dissection presented with acute onset right middle cerebral artery syndromes, two of whom had chronic aortic dissections that were status-post graft repair, while a third had an acute type B aortic dissection that had been managed with a femoral-to-femoral bypass. None of the three were candidates for intravenous tissue plasminogen activator. All three were found to have proximal right M1 occlusions on non-invasive imaging and were taken for endovascular thrombectomy via transfemoral, transradial, and transbrachial approaches, respectively. All three had successful recanalization (with Thrombolysis In Cerebral Infarction (TICI) 2b, TICI 3, and TICI 2b flow, respectively) along with clinical improvement, and none had procedure-related complications.

Conclusions

These three cases suggest that endovascular thrombectomy is feasible and can be done safely and efficaciously in patients with aortic dissections and those with Marfan syndrome, although the risks and benefits should be considered as part of any decision-making process. Given that endovascular therapy for acute stroke is now in many situations part of standard care, further studies will be necessary to delineate more precise inclusion and exclusion criteria.
Multimodal imaging findings in normal-appearing white matter of leucoaraiosis: a review
Authors: Zhong Genlong , Lou Min
Published: May 2016

Leucoaraiosis (LA), also referred to as white matter hyperintensities (WMHs), are usually seen as patchy or confluent hyperintense areas on T2-weighted or fluid-attenuated inversion recovery MRI in the elderly. It is often asymptomatic in its early stages, yet its persistent evolution to more advanced stages may lead to substantial neurological dysfunction including dementia, stroke and death. Despite its clinical significance, the pathogenic mechanisms underlying LA development are uncertain. In patients with LA, the pathophysiological changes in white matter (WM) are suggested to be continuous from WMHs to its neighbourhood ‘normal-appearing white matter (NAWM)’ on conventional MRI sequences. Multimodal imaging studies revealed that the so-called ‘NAWM’ was actually abnormal with regard to underlying haemodynamic and microstructural changes. On the basis of positron emission tomography CT, xenon-CT, perfusion MRI, etc, the cerebral blood flow of NAWM was found to be significantly reduced in patients with LA, compared with healthy controls. Meanwhile, the integrity of microstructures and blood–brain barrier in NAWM was also demonstrated to be impaired with diffusion tensor imaging and dynamic contrast-enhanced MRI studies, respectively. In addition,the integrity of NAWM correlated much stronger with cognitive performance than did WMHs load. It is reasonable to assume that the subtle injury of NAWM would be more reversible than WMHs themselves. Therefore, multimodal imaging modalities could be appropriately applied to future interventional studies targeting at early pathophysiological changes of NAWM. In this paper, we summarise current knowledge about NAWM of LA mainly acquired from multimodal imaging studies in vivo, and attempt to give options for future work.
Divergent migratory behaviours associated with body size and ocean entry phenology in juvenile sockeye salmon
Authors: Freshwater Cameron , Trudel Marc , Beacham Terry D. , Godbout Lyse , Neville Chrys-Ellen M. , Tucker Strahan , Juanes Francis
Published: May 2016

Survival during early marine life stages is hypothesized to contribute disproportionately to variation in salmonid recruitment, yet estimates of cumulative mortality are constrained by knowledge of how long juveniles reside in specific regions. We used otolith microstructure techniques to examine the relationship between migratory rate and ocean entry characteristics of juvenile sockeye salmon (Oncorhynchus nerka). We observed differences in migratory rate between catch locations that are consistent with divergent migratory behaviours. Individuals captured in northern regions were typically older, larger at ocean entry, and migrated more rapidly. Migratory rate was also correlated with entry size, phenology, population group, and year. Next, we compared “lingering” individuals captured nearshore during fall surveys to juveniles from the same populations captured during the peak summer migratory period. We determined that individuals that entered after 24 May and at smaller sizes (<85 mm) had a greater probability of being captured late in the year. Our findings demonstrate that the entry characteristics of sockeye salmon are strongly correlated with migratory variation within populations and suggest these traits may directly influence juvenile behaviour.
Age-induced oxidative stress: how does it influence skeletal muscle quantity and quality?
Authors: Baumann Cory W. , Kwak Dongmin , Liu Haiming M. , Thompson LaDora V.
Published: May 2016

With advancing age, skeletal muscle function declines as a result of strength loss. These strength deficits are largely due to reductions in muscle size (i.e., quantity) and its intrinsic force-producing capacity (i.e., quality). Age-induced reductions in skeletal muscle quantity and quality can be the consequence of several factors, including accumulation of reactive oxygen and nitrogen species (ROS/RNS), also known as oxidative stress. Therefore, the purpose of this mini-review is to highlight the published literature that has demonstrated links between aging, oxidative stress, and skeletal muscle quantity or quality. In particular, we focused on how oxidative stress has the potential to reduce muscle quantity by shifting protein balance in a deficit, and muscle quality by impairing activation at the neuromuscular junction, excitation-contraction (EC) coupling at the ryanodine receptor (RyR), and cross-bridge cycling within the myofibrillar apparatus. Of these, muscle weakness due to EC coupling failure mediated by RyR dysfunction via oxidation and/or nitrosylation appears to be the strongest candidate based on the publications reviewed. However, it is clear that age-associated oxidative stress has the ability to alter strength through several mechanisms and at various locations of the muscle fiber.
A Review on Medicinal Properties of Orientin
Authors: Lam Kit Ying , Ling Anna Pick Kiong , Koh Rhun Yian , Wong Ying Pei , Say Yee How
Published: May 2016

Medicinal plants continue to play an important role in modern medications and healthcare as consumers generally believe that most of them cause fewer or milder adverse effects than the conventional modern medicines. In order to use the plants as a source of medicinal agents, the bioactive compounds are usually extracted from plants. Therefore, the extraction of bioactive compounds from medicinal plants is a crucial step in producing plant-derived drugs. One of the bioactive compounds isolable from medicinal plants, orientin, is often used in various bioactivity studies due to its extensive beneficial properties. The extraction of orientin in different medicinal plants and its medicinal properties, which include antioxidant, antiaging, antiviral, antibacterial, anti-inflammation, vasodilatation and cardioprotective, radiation protective, neuroprotective, antidepressant-like, antiadipogenesis, and antinociceptive effects, are discussed in detail in this review.
Genomic Analysis of the Chicken Infectious Anemia Virus in a Specific Pathogen-Free Chicken Population in China
Authors: Li Yang , Wang Yixin , Fang Lichun , Fu Jiayuan , Cui Shuai , Zhao Yingjie , Cui Zhizhong , Chang Shuang , Zhao Peng
Published: May 2016

The antibody to chicken infectious anemia virus (CIAV) was positive in a specific pathogen-free (SPF) chicken population by ELISA test in our previous inspection, indicating a possible infection with CIAV. In this study, blood samples collected from the SPF chickens were used to isolate CIAV by inoculating into MSB1 cells and PCR amplification. A CIAV strain (SD1403) was isolated and successfully identified. Three overlapping genomic fragments were obtained by PCR amplification and sequencing. The full genome sequence of the SD1403 strain was obtained by aligning the sequences. The genome of the SD1403 strain was 2293 bp with a nucleotide identity of 94.8% to 98.5% when compared with 30 referred CIAV strains. The viral proteins VP2 and VP3 were highly conserved, but VP1 was not relatively conserved. Both amino acids 139 and 144 of VP1 were glutamine, which was in accord with the low pathogenic characteristics. In this study, we first reported that CIAV exists in Chinese SPF chicken populations and may be an important reason why attenuated vaccine can be contaminated with CIAV.
A Survey of Seasonal Gastrointestinal Parasitic Infections in Donkeys from a Semiarid Sub-Saharan Region, Sudan
Authors: Ismail Ahmed Abdurhman , Ahmed Nasredin Khogali , Bashar Ahmed Elhag , Seri Hisham Ismail , El Tigani-Asil El Tigani Ahmed , Abakar Adam Dawoud
Published: May 2016

Out of 92 donkeys examined for gastrointestinal parasites, 90 animals were found infected by one or more gastrointestinal parasites with an overall prevalence rate of 97.78%. The distributions of the recovered parasites in the different parts of the body were as follows: stomach, 92.4%, small intestine, 19.6%, caecum, 88%, colon, 80.4%, rectum, 73.9%, and cranial mesenteric artery, 64.1%. A significant difference was found between mean parasite counts and seasons. Hot wet season had higher mean parasites count (5411.5±1694.4) in comparison with hot dry (1795.9±399.6) and cool dry (1719.9±522.4) seasons. Although there was no significant difference between age and mean parasite count, animals more than four years old had high mean count (3361.3±921.8) in comparison with2330±744.3and2030.2±873.1for young and adults animals, respectively. No significant positive or negative correlation was found between total parasite counts of infected animals and any of the climatic factors. The parasites identified wereHabronemaspp. (40.2%),Trichostrongylus axei(30.4%),Parascaris equorum(18.5%),Anoplocephala perfoliata(4.35%),Gastrodiscus aegyptiacus(8.7%), large strongyles (84%), small strongyles (72%), andOxyuris equi(1.1%).
Statistical Analysis of Relationship between Daytime Lidar-Derived Planetary Boundary Layer Height and Relevant Atmospheric Variables in the Semiarid Region in Northwest China
Authors: Dang Ruijun , Li Hong , Liu Zhiguo , Yang Yi
Published: May 2016

Accurate identification of key parameters for data assimilation is important in simulating the planetary boundary layer height (PBLH) and structure evolution in numerical weather prediction models. In this study, surface observational data and lidar-derived PBLH on 42 cloudless days from June 2007 to May 2008 are used to quantify the statistical relationships between surface parameters and the PBLH at a semiarid climate observational site in Northwest China. The results indicate that surface upward long wave radiation, surface temperature, and surface sensible heat fluxes show strong correlations with the PBLH with correlation coefficients at a range of 0.63–0.72. But these parameters show varying correlation response time to the different stages of PBL development. Furthermore, the air temperature shows the highest correlation with the PBLH near the surface and the correlation decreases with increasing height.
Autocrine Acetylcholine, Induced by IL-17A via NFκB and ERK1/2 Pathway Activation, Promotes MUC5AC and IL-8 Synthesis in Bronchial Epithelial Cells
Authors: Montalbano Angela Marina , Albano Giusy Daniela , Bonanno Anna , Riccobono Loredana , Di Sano Caterina , Ferraro Maria , Siena Liboria , Anzalone Giulia , Gagliardo Rosalia , Pieper Michael Paul , Gjomarkaj Mark , Profita Mirella
Published: May 2016

IL-17A is overexpressed in the lung during acute neutrophilic inflammation. Acetylcholine (ACh) increases IL-8 and Muc5AC production in airway epithelial cells. We aimed to characterize the involvement of nonneuronal components of cholinergic system on IL-8 and Muc5AC production in bronchial epithelial cells stimulated with IL-17A. Bronchial epithelial cells were stimulated with recombinant human IL-17A (rhIL-17A) to evaluate the ChAT expression, the ACh binding and production, the IL-8 release, and the Muc5AC production. Furthermore, the effectiveness of PD098,059 (inhibitor of MAPKK activation), Bay11-7082 (inhibitor of IkBαphosphorylation), Hemicholinium-3 (HCh-3) (choline uptake blocker), and Tiotropium bromide (Spiriva®) (anticholinergic drug) was tested in ourin vitromodel. We showed that rhIL-17A increased the expression of ChAT, the levels of ACh binding and production, and the IL-8 and Muc5AC production in stimulated bronchial epithelial cells compared with untreated cells. The pretreatment of the cells with PD098,059 and Bay11-7082 decreased the ChAT expression and the ACh production/binding, while HCh-3 and Tiotropium decreased the IL-8 and Muc5AC synthesis in bronchial epithelial cells stimulated with rhIL-17A. IL-17A is involved in the IL-8 and Muc5AC production promoting, via NFκB and ERK1/2 pathway activation, the synthesis of ChAT, and the related activity of autocrine ACh in bronchial epithelial cells.
Abstract A110: CBP501 suppresses cell migration, invasion and epithelial-mesenchymal transition (EMT) in non-small cell lung carcinoma
Authors: Saito Naoya , Mine Naoki , Kufe Donald W. , Von Hoff Daniel D. , Kawabe Takumi
Published: May 2016

The CBP501 calmodulin-binding peptide is an anti-cancer drug candidate that has completed two Phase II clinical trials for patients with malignant pleural mesothelioma and non-small cell lung carcinoma (NSCLC). CBP501 was previously identified as a unique G2 checkpoint-directed agent and as an enhancer of cisplatin (CDDP) uptake. In post-trial analysis of NSCLC patients, it was found that overall survival (OS) was prolonged in a subpopulation with normal white blood cell counts (WBC) (WBC < 8000).

Here, we show that CBP501 inhibits cell migration (by 42% (A549) and 70% (H1299) with 1μM) and invasion (by 32% (A549) and 49% (H1299) with 1μM) of NSCLC cells in a dose-dependent manner using a transwell assay and a wound healing assay. In addition, inhibition of EMT by CBP501 was assessed by observing 3D spheroid morphology on NanoCulture Plate (NCP). The collapse of the spheroids typically observed upon TGFβ treatment was decreased by CBP501. These results show that CBP501 reduces TGFβ-induced EMT. Furthermore, CBP501 decreases expression of vimentin, a canonical marker of EMT and reduces the up-regulation of vimentin expression by TGFβ. Vimentin protein has important effects on the function of lamellipodia and invadopodia during cell migration and invasion and is related to cancer progression via EMT.

These results suggest that CBP501 may inhibit tumor metastasis through suppression of EMT, which may have contributed to the observed OS prolongation in humans.

Citation Format: Naoya Saito, Naoki Mine, Donald W. Kufe, Daniel D. Von Hoff, Takumi Kawabe. CBP501 suppresses cell migration, invasion and epithelial-mesenchymal transition (EMT) in non-small cell lung carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A110.
Abstract A112: Observed separation of survival curves by WBC in CBP501-treated patients leads to experimental identification of macrophage functions suppressed by CBP501
Authors: MINE NAOKI , Yamamoto Sayaka , Saito Naoya , Sato Takuji , Sakakibara Keiichi , Kufe Donald W. , Von Hoff Daniel D. , Kawabe Takumi
Published: May 2016

The CBP501 calmodulin-binding peptide is an anti-cancer drug candidate that has completed a Phase II clinical trial for patients with non-small cell lung carcinoma (NSCLC). CBP501 was also previously identified as a unique G2 checkpoint-directed agent and as an enhancer of cisplatin (CDDP) uptake.

In a post-trial analysis of the NSCLC patients, it was found that the survival was statistically significantly different between subpopulations with normal white blood cell counts (WBC) (WBC < 8000) and high WBC (WBC > 8000). Notably, treatment by CDDP with or without CBP501 had no effect on the neutrophil oxidative burst or phagocytosis

Here, we show that CBP501 inhibits several functions of macrophages. The LPS-stimulated production of several cytokines (IL-6. TNF-alpha and IL-10) by macrophages were suppressed by CBP501 treatment in vitro. The population of potential cancer stem-like cells was reduced by CBP501 in co-cultures of macrophages and tumor cell lines. In human macrophages isolated from peripheral blood-derived monocytes or THP-1 monocytic cells, phagocytic activity induced by IgG-conjugated beads was suppressed by in vitro CBP501 treatment. The neutrophil extracellular traps (NETs), which are supposed to be cleared by macrophages, were increased by CBP501 in response to leukocyte stimulation. Thrombotic tendency was increased in LPS- and CBP501-treated mice. These results suggest that the inhibition of macrophages by CBP501 could explain the observed dramatic separation of survival curves by WBC in patients with NSCLC.

Many reports (Roy Noy and Jeffrey W. Pollard Immunity. 2014) indicate that tumor associated macrophages (TAMs) promote metastasis. To see if CBP501 might affect this relationship between macrophage activity and metastasis, we performed in vivo mouse study of mice bearing subcutaneous Lewis lung carcinomas. Results showed reduced metastasis to the lung upon CBP501 administration. Further investigation is underway to clarify the role of CBP501 in modulating the earlier characterized TAM-promoted metastasis.

Citation Format: NAOKI MINE, Sayaka Yamamoto, Naoya Saito, Takuji Sato, Keiichi Sakakibara, Donald W. Kufe, Daniel D. Von Hoff, Takumi Kawabe. Observed separation of survival curves by WBC in CBP501-treated patients leads to experimental identification of macrophage functions suppressed by CBP501. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A112.
Abstract A125: Antibody targeted steroids for the treatment of cancer
Authors: Prudent James R. , Marshall David , Murphy John , Hall Chad , Harried Scott
Published: May 2016

Purpose:

The cardiac glycoside family of steroidal drugs has been shown to possess novel and potent antitumor activities in rodents. Yet most likely due to their cardiotoxic nature, these drugs have failed to show clinical efficacy at doses deemed safe to humans. In order to determine if this drug class could be made safer and more efficacious, we assessed the antitumor activity of a new antibody drug conjugate system in which these steroidal compounds are tethered to antibodies that direct them to protein complexes found on various types of cancer cells.

Experimental design:

The activity and safety profiles of these novel antibody drug conjugates were examined using multiple cancer cell lines, normal cells, xenograft models in immunodeficient mice and non-human primates.

Results:

We identified multiple monoclonal antibodies that when conjugated to cardiac glycosides through long stable linkers, could provide cell killing activity independent of effector functions. When tested in vitro on a number of cancer cell lines, these active antibody drug conjugates termed Extracellular Drug Conjugates or EDCs, displayed potent cytotoxic activities with half maximal effective concentration (EC50) in sub-nanomolar ranges via a pathway resembling apoptosis and/or necroptosis. These activities were dependent on the expression of the corresponding antibody, linker length and steroid chemistry. In vivo using various tumor xenograft models, the EDCs were able to partially or completely regress tumor growth when 1 to 10 mgs/kg were administered intravenously. The EDCs were also found to assist various clinically approved therapies regress tumor growth. Finally, because cynomolgus monkeys respond to cardiac glycosides is similar to humans, 5mgs/kg of EDC was slowly infused intravenously into a cynomolgus monkey with no adverse effects observed even though the relative blood concentration of the cardiac glycoside attached reached 1500 nanomolar.

Conclusion:

These results support efforts to further evaluate these unique targeting antibody drug conjugates for the treatment of human cancers.

Citation Format: James R. Prudent, David Marshall, John Murphy, Chad Hall, Scott Harried. Antibody targeted steroids for the treatment of cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A125.
Abstract A138: Targeting activated CRAF fusions in pediatric low-grade gliomas
Authors: Jain Payal , Fierst Tamara , Silva Amanda , Budlow Jake , Boucher Katie , Han Harry , Storm Phillip B. , Waanders Angela , Resnick Adam C.
Published: May 2016

This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 10:00 AM ET Friday, November 6.

Citation Format: Payal Jain, Tamara Fierst, Amanda Silva, Jake Budlow, Katie Boucher, Harry Han, Phillip B. Storm, Angela Waanders, Adam C. Resnick. Targeting activated CRAF fusions in pediatric low-grade gliomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A138.
Abstract A141: A novel inhibitor of malignant signaling in metastatic breast cancer
Authors: Humphries-Bickley Tessa , Castillo-Pichardo Linette , Borrero-Garcia Luis , Forestier-Roman Ingrid , Cubano Luis , Hernandez-O'Farrill Eliud , Vlaar Cornelis , Dharmawardhane Suranganie
Published: May 2016

The Rho GTPase Rac is a pivotal regulator of cancer cell migration and invasion; processes required for metastatic progression. We previously characterized the small molecule EHop-016 as a novel Rac inhibitor in metastatic breast cancer cells and recently reported that EHop-016 was effective at reducing tumor growth, metastasis, and angiogenesis in nude mice at 25 mg/kg bodyweight (BW) (Castillo-Pichardo, et al. 2014). We also determined the pharmacokinetics and bioavailability of EHop-016, and reported that EHop-016 is rapidly cleared from mouse plasma with a half-life of ∼5 hrs and ∼30% bioavailability (Humphries-Bickley, et al., 2015). To improve the bioavailability and efficacy of EHop-016, we synthesized and screened a number of derivatives, from which EHop-016A was identified as a potent Rac inhibitor at nM concentrations. Moreover, as determined from immunofluorescence and brightfield microscopy of several breast cancer cell lines, EHop-016A has a dramatic effect on cell morphology by inducing a loss of cell polarity, and inhibiting cell surface actin-based extensions and focal adhesions, to ultimately result in the detachment of cells from the extracellular matrix (ECM). In addition, EHop-016A reduces breast cancer cell migration in a transwell assay. EHop-016A also decreases mammosphere formation, indicating an inhibitory effect on breast cancer stem cell-like properties. The effect of EHop-016A on metastatic cancer cell viability was determined via MTT assays. EHop-016A decreases cell viability with a GI50 of 150 nM and 110 nM in MDA-MB-435 and MDA-MB-231 human metastatic cancer cell lines respectively. Western blotting demonstrated that EHop-016A decreases anti-apoptotic proteins BCL-2 and BCL-xL without affecting their gene expression, as quantified by qPCR. Consequently, EHop-016A increases pro-apoptotic caspase 3/7 activity. These results indicate that the EHop-016A induced cell rounding and detachment from the substratum results in anoikis (apoptosis due to dissolution of integrin-mediated cell to ECM attachments). Therefore, this new small molecule compound has potential as an inhibitor of metastatic breast cancer progression, and warrants further investigation as an anticancer agent.

Citation Format: Tessa Humphries-Bickley, Linette Castillo-Pichardo, Luis Borrero-Garcia, Ingrid Forestier-Roman, Luis Cubano, Eliud Hernandez-O'Farrill, Cornelis Vlaar, Suranganie Dharmawardhane. A novel inhibitor of malignant signaling in metastatic breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A141.
Abstract A146: Study of anti-leukemia activity of N-(1-pyrenlyl) maleimide in vivo using a bioluminescent mouse model
Authors: Wang Tzu-Chien , Chang Pei-Chi , Chen Chi-Yuan
Published: May 2016

Telomerase plays a pivotal role in cellular immortality and tumorigenesis. Telomerase activity is normally not detectable in most somatic cells, but is activated in the vast majority of cancer cells. Therefore, inhibition of telomerase has been viewed as a promising anticancer approach due to its specificity for cancer cells. During a search for anticancer drugs by screening for small molecules of telomerase inhibitors, we have identified a very promising compound, N-(1-pyrenyl) maleimide, which displays the greatest differential cytotoxicity against hematopoietic Jurkat-T cells in vitro. In this study, we examined the anticancer activity of N-(1-pyrenyl) maleimide against human T-cell acute lymphoblastic leukemia (T-ALL) in vivo. Human T- ALL cells, such as Jurkat cells, were transfected with luciferase-expressing plasmid to establish luciferase-expressing T-ALL cells. The luciferase-expressing T-ALL cells were mixed with matrigel and injected subcutaneously into the nude mice. We have successfully employed such a xenograft method to establish a bioluminescent mouse model for investigating the anti-leukemia activity of N-(1-pyrenyl) maleimide and other classical anti-leukemia drugs. Using the established bioluminescent mouse model, we have begun to examine the anticancer activity of N-(1-pyrenyl) maleimide against T-ALL. We will present our most updated findings in this meeting. (Supported by grant CMRPD3D0171 from Chang Gung Memorial Hospital)

Citation Format: Tzu-Chien Wang, Pei-Chi Chang, Chi-Yuan Chen. Study of anti-leukemia activity of N-(1-pyrenlyl) maleimide in vivo using a bioluminescent mouse model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A146.
Abstract A152: Novel autotaxin inhibitory antibodies block lysophosphatidic acid production in plasma and tumour cell proliferation in vitro
Authors: Ross Sarah , Collins Scott , Jovanovic Jelena , Kendrew Jane , Barry Simon , Rathanaswami Swami , David Blakey , Weir Hazel
Published: May 2016

Autotaxin (ATX) is a secreted phosphodiesterase that cleaves lysophosphatidylcholine (LPC) in serum to produce lysophosphatidic acid (LPA). LPA can signal through a family of GPCR receptors to mediate cell proliferation, migration and survival in cancer cells. Blocking the enzymatic activity of ATX is proposed to have anti-tumour activity by reducing levels of LPA and preventing signaling through the LPA receptor family. A number of synthetic inhibitors have been developed to understand the role in ATX in driving carcinogenesis and these encompass lipid substrate mimetics as well as inhibitors identified from small molecule library screens. Some of these compounds demonstrate low nM activity in vitro and a subset have shown some in vivo activity although none have progressed into the clinic. We sought to identify novel selective ATX antibodies with low nM affinity, which fully inhibited ATX enzyme activity of human, cyno and mouse ATX protein. Using an ATX enzyme inhibition assay we identified and characterised two ATX antibodies, 9E10 and 18B7 which, interestingly, had different binding mechanisms of inhibition and showed potent cross-species inhibition of ATX in vitro. We measured human and mouse ATX expression levels across of panel of xenograft models and verified ATX activity by measuring cleavage of an ATX substrate using conditioned media from these cells. 9E10 and 18B7 antibodies were shown to inhibit the activity of secreted ATX and prevent cleavage of an ATX substrate. 9E10 and 18B7 showed significant inhibition of LPC stimulated cell growth and IL-8 secretion in a range of ATX and/or LPA responsive tumour cell lines. In ex vivo plasma ATX activity assays, treatment of mouse or human plasma with the ATX antibodies inhibited the increase in LPA levels that are observed over time when serum samples are incubated at 37°C. In summary we have identified highly selective ATX antibody inhibitors which will be useful tools to explore the role of ATX in tumour growth and invasion.

Citation Format: Sarah Ross, Scott Collins, Jelena Jovanovic, Jane Kendrew, Simon Barry, Swami Rathanaswami, Blakey David, Hazel Weir. Novel autotaxin inhibitory antibodies block lysophosphatidic acid production in plasma and tumour cell proliferation in vitro. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A152.
Abstract A16: Boosting of in vivo hollow fiber assay by using luciferase-labeled tumor cell lines
Authors: Schaefer-Obodozie Cynthia , Leisegang Ulrike , Ruf Susanne , Giesen Bianca , Schaechtele Christoph , Weber Holger
Published: May 2016

In drug development, predicting in vivo inhibitory drug activity from cellular assay data is difficult due to the complexity of the living system, resulting in the sacrifice of many mice in vain. In order to prescreen compounds for their in vivo activity more efficiently, the hollow fiber assay (HFA) was developed in 1995 by Hollingshead et al. The HFA assay allows the simultaneous evaluation of multiple cell lines implanted in separated drug-(but not cell-) permeable fibers within a single mouse. We herein report on the advancement of this technology by use of luciferase-labeled tumor cell lines. The limits of detection are boosted and disturbing (non-labeled) stroma cells attached to the fibers are excluded enabling a clear separation of drug effects on the tumor cells.

The effect of Gemcitabine and Paclitaxel on growth of luciferase-labeled MDA-MB-231 and A549 cells in HFA was analyzed by MTT in comparison to luciferase activity analysis. The general findings between both read-outs were comparable. The growth of MDA-MB-231 cells was inhibited by both, Paclitaxel and Gemcitabine, whereas inhibition of A549 cell growth was only observed under Paclitaxel treatment. T/C calculation for the MTT analysis predicted a partial response in all cases. In contrast, the luciferase activity analysis clearly distinguished between a complete response for MDA-MB-231 cell growth when treated with Paclitaxel and Gemcitabine and a partial response for Paclitaxel on A549 cell growth. These results correspond to the in vivo xenograft studies: T/C for Gemcitabine using MDA-MB-231 cells was 2-fold lower (16.2%) than T/C in A549 tumors using Paclitaxel (36.3%). In addition, results are shown applying this technology for up to 42 days instead of the typical 14 days, enhancing the possibility to analyze slow-acting drugs.

In summary, the HFA assay for in vivo drug screening with luciferase-labeled tumor cells remarkably increases the power and predictability for drug efficacy in xenograft studies.

Citation Format: Cynthia Schaefer-Obodozie, Ulrike Leisegang, Susanne Ruf, Bianca Giesen, Christoph Schaechtele, Holger Weber. Boosting of in vivo hollow fiber assay by using luciferase-labeled tumor cell lines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A16.
Abstract A170: Preclinical antitumor activity of ASP5878, a novel inhibitor of FGFR1, 2, 3 and 4, in bladder cancer harboring FGFR3-fusion or -mutation
Authors: Suzuki Tomoyuki , Kikuchi Aya , Nakazawa Taisuke , Iizuka Masateru , Nakayama Ayako , Kameda Minoru , Shindoh Nobuaki , Terasaka Tadashi , Hirano Masaaki , Kuromitsu Sadao
Published: May 2016

Background: Fibroblast growth factor (FGF) / FGF receptor (FGFR) gene aberrations such as amplification, mutation and fusion are associated with many types of human cancers. Recently, FGFR3 fusions (FGFR3-TACC3 and FGFR3-BAIAP2L1), which have potent oncogenic activity, have been discovered in bladder and lung cancer. FGFR kinase inhibitors are expected to be a targeted therapy for bladder cancer harboring FGFR3 gene alternations. A phase I clinical trial of ASP5878, a novel inhibitor of FGFR1, 2, 3 and 4, is ongoing (NCT02038673). Method: We tested selectivity of ASP5878 among 128 kinases and sensitivity of ASP5878 on cell proliferation of bladder cancer cell lines. FGFR3 and ERK phosphorylation in FGFR3-dependent bladder cancer cell lines were evaluated with sandwich ELISA or Western blotting. In vivo antitumor effects of ASP5878 were examined in subcutaneously implanted bladder cancer cell lines in nude mice. Results: Among 128 kinases, only 9 kinases including wild-type FGFR1-4 and FGFR3/4 mutants were inhibited more than 50% by ASP5878 (200 nmol/L). The IC50 values of ASP5878 against FGFR1, 2, 3 and 4 kinases are 0.47, 0.60, 0.74 and 3.5 nmol/L, respectively. In addition, ASP5878 suppressed cell growth in several cancer cell lines harboring FGF / FGFR gene alternations. Among 25 bladder cancer cell lines, ASP5878 selectively inhibited cell proliferation of UM-UC-14 [FGFR3 (S249C) positive], RT-112 (FGFR3-TACC3 positive), RT-4 (FGFR3-TACC3 positive) and SW780 (FGFR3-BAIAP2L1 positive). FGFR3 and ERK phosphorylation in UM-UC-14 and RT-112 cell lines were inhibited by ASP5878 in a concentration-dependent manner. Furthermore, ASP5878 inhibited cell proliferation of gemcitabine-resistant RT-112 cells and adriamycin-resistant UM-UC-14 cells. Once-daily oral administration of ASP5878 induced tumor regression at 1 and 3 mg/kg in UM-UC-14 and RT-112 xenograft models, respectively, without body weight loss. Conclusions: These findings suggest that ASP5878 has the potential to be an oral targeted therapy against bladder cancer harboring FGFR3-TACC3 fusion or FGFR3 point mutation even after the acquisition of chemoresistance.

Citation Format: Tomoyuki Suzuki, Aya Kikuchi, Taisuke Nakazawa, Masateru Iizuka, Ayako Nakayama, Minoru Kameda, Nobuaki Shindoh, Tadashi Terasaka, Masaaki Hirano, Sadao Kuromitsu. Preclinical antitumor activity of ASP5878, a novel inhibitor of FGFR1, 2, 3 and 4, in bladder cancer harboring FGFR3-fusion or -mutation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A170.
Abstract A177: Repositioning Bazedoxifene as a novel inhibitor of IL-6/GP130 signaling for pancreatic cancer therapy
Authors: Wu Xiaojuan , Xiao Hui , Li Chenglong , Lin Jiayuh
Published: May 2016

This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 12:15 PM ET Friday, November 6.

Citation Format: Xiaojuan Wu, Hui Xiao, Chenglong Li, Jiayuh Lin. Repositioning Bazedoxifene as a novel inhibitor of IL-6/GP130 signaling for pancreatic cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A177.
Abstract A180: Discovery of furanone derivatives as novel Cdc7 inhibitors with anti-tumor activity
Authors: Irie Takayuki , Asami Tokiko , Sawa Ayako , Taniyama Chika , Funakoshi Yoko , Uno Yuko , Masai Hisao , Sawa Masaaki
Published: May 2016

Introduction>

Cell cycle kinases have been recognized as potential anticancer targets, because loss of regulated cell cycle progression would lead to uncontrolled cell growth and development of cancer. Cdc7 kinase is involved in regulation of the cell cycle and plays important roles in DNA replication. Notably, inhibition of Cdc7 in cancer causes lethal S phase or M phase progression, whereas normal cells can survive, most likely through induction of cell cycle arrest at the DNA replication checkpoints. Therefore Cdc7 kinase has emerged as a promising therapeutic target for the treatment of cancers. Here we present a novel series of furanone derivatives with potent inhibitory effects on Cdc7 kinase.

To identify hit compounds that are insensitive or resistant to high ATP concentration, a high-throughput screening (HTS) was performed in the presence of 100 microM ATP which corresponds to 36-times higher than the Km value of ATP for Cdc7 kinase activity. To characterize inhibitors, ATP dependency and pre-incubation effects were examined. To determine the efficacy of Cdc7 inhibitors, phosphorylation of MCM2 protein in cells were analyzed by western blotting. Selected compounds were subjected to a kinase selectivity panel assay.

Only a single hit compound was identified from the HTS, reflecting extremely low hit rate compared to that of other kinase targets in our past HTS. Subsequent hit to lead studies led to the identification of a novel furanone compound as a potential lead compound for further optimization study. Interestingly, these furanone derivatives showed slow-binding inhibition against Cdc7, and exhibited strong inhibitory activity for Cdc7 even in the presence of 1 mM ATP that was added after the pre-incubation of the kinase and compound. Notably this pre-incubation effect was not observed with other kinases tested. Detailed results using cancer cells will also be presented in this poster.

Citation Format: Takayuki Irie, Tokiko Asami, Ayako Sawa, Chika Taniyama, Yoko Funakoshi, Yuko Uno, Hisao Masai, Masaaki Sawa. Discovery of furanone derivatives as novel Cdc7 inhibitors with anti-tumor activity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A180.
Abstract A184: Activity of plinabulin in tumor models with Kras mutations
Authors: Lloyd George Kenneth , Du Lihua , Lee Gloria , Dalsing-Hernandez Jessica , Kotlarczyk Kari , Gonzales Paul , Nawrocki Steffan , Carew Jennifer , Huang Lan
Published: May 2016

Kras mutations, particularly at codons 12 and 13, are reported to occur in up to one-third of human cancer cells and are considered to be undruggable targets (Stoize et al, 2015). These mutations are especially prevalent in NSCLC and CRC. Plinabulin is a new chemical entity in Phase 3, with a multi-faceted mechanism of action, including anti-angiogenesis, inhibition of tubulin polymerization and activation of JNK, which is downstream of the Kras pathway. The combination of these vascular mechanisms together with activity downstream from Kras, suggests that plinabulin could express anti-tumor activity in the presence of Kras mutations. The present report summarizes the findings with plinabulin on tumors with Kras mutations (p.12V, p.12D, p.D153V, p.G12A, p.G12C, p.G12D, p.G12V or p.G13D) in vitro and in vivo.

In vitro, plinabulin was very potent (IC50 7-33 nM) as a cytotoxic agent against CRC cell lines containing a Kras mutation at p.G13D (LoVo, HCT-15, HCT116) or a BRAF + P53 mutation (HT-29) and against multiple myeloma cell lines (Singh et al, Blood, 2010) with either Nras or p.G12A mutations (IC50<10nM). The active metabolite of irinotecan (SN-38) was less active (2-30 fold) in the CRC cell lines.

In vivo, plinabulin was tested as a single agent and in combination with SOC in the CRC Kras mutation murine models LoVo and HCT-15 and the P53/Braf mutant model HT-29, the NSCLC Kras mutation model A549, the multiple myeloma Kras mutation model MM.1S and the breast Kras mutation model MDA-MB-231. As a single agent plinabulin was at most moderately active in these models, with the greatest activity seen in the LoVo, HCT-15, and MDA-MB-231 models (TGI 21-43%); the exception was a marked single agent activity observed in the MM.1S model. However, in all cases plinabulin significantly increased the anti-tumor activity of the standard of care agents (TGI 59-84%, with several CRs and increased tolerability as compared to SOC alone).

In summary, plinabulin exhibits a potent anti-tumor activity either in vitro, or in vivo as a single agent or in combination with SOC agents. This activity is observed across several tumor types and mutations, but the spectrum of activity does not extend across all tumor types (e.g. inactive in vivo in Kras mutations for pancreatic cancer or melanoma). These findings are encouraging in terms of clinical studies in Kras mutations in MM, NSCLC, CRC and breast cancers.

Citation Format: George Kenneth Lloyd, Lihua Du, Gloria Lee, Jessica Dalsing-Hernandez, Kari Kotlarczyk, Paul Gonzales, Steffan Nawrocki, Jennifer Carew, Lan Huang. Activity of plinabulin in tumor models with Kras mutations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A184.
Abstract A197: Cancer associated fibroblasts are not form by epithelial-to-mesenchymal transition in nu/nu mice
Authors: Szabo Pavol , Smetana Karel , Dvorankova Barbora , Mateu Rosana , Rihova Blanka
Published: May 2016

Cancer-associated fibroblasts are very important players to form specific cancer microenvironmnet and bioactive elements influencing the biological properties of malignant tumors. Their origin from different cell types has been established. It is suppose and under debate that exist three ways of the possibility of their formation: a) by epithelial-to-mesenchymal transition from cancer cells b) by activation of local mesenchymal cells c) by MSC (mesenchymal stem cell), which migrate from bone marrow to tumor. We focused on epithelial-to-mesenchymal transition. This study shows that human cancer cells lines FaDu FaDu (human squamous cell carcinoma isolated from pharynx; HTB-43), Sw620 (human colorectal adenocarcinoma; CCL-227) and HT-29 (human colorectal adenocarcinoma; HTB-38) grafted to nu/nu CD-1 mice induced formation of tumor stroma with the presence of typical smooth muscle actin-containing cancer-associated fibroblasts. These cells seem to be of the host origin because they are not recognized by an antibody specific for human vimentin, as was also verified in vitro. These results suggest that cancer-associated stromal fibroblasts are not formed by epithelial-to-mesenchymal transition from cancer cells.

Citation Format: Pavol Szabo, Karel Smetana, Barbora Dvorankova, Rosana Mateu, Blanka Rihova. Cancer associated fibroblasts are not form by epithelial-to-mesenchymal transition in nu/nu mice. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A197.