bluuebunny/crossref_metadata_2025 huggingface dataset:
Promising thermoelectric materials of Cu3VX4 (X=S, Se, Te): A Cu-V-X framework plus void tunnels
Authors: Liu Xiao-Peng , Feng Zhen-Zhen , Guo Shu-Ping , Xia Yi , Zhang Yongsheng
Published: May 2019

Skutterudites and half-Heusler compounds are well-studied promising thermoelectric (TE) materials due to favorable electrical properties. However, their intrinsic lattice thermal conductivities are so high that various methodologies have been developed to decrease them. Based on our first-principles phonon calculations, we find that thermodynamically stable Cu3VX4 ([Formula: see text], Se, Te) compounds exhibit good thermoelectric properties due to their special crystal structure (a Cu-V-X framework plus large void tunnels). The mechanically stable framework is the favorite pathway for the carrier conduction, which induces high electrical conductivity and power factor (comparative to those of filled-skutterudites and half-Heusler systems). Moreover, the void tunnels in the crystal structure result in unsaturated coordinations at the X sites and corresponding lone-pair electrons, which lower the lattice thermal conductivity. The calculated intrinsic lattice thermal conductivity of Cu3VX4 is much lower than those of the well-studied skutterudites and half-Heusler compounds. Thus, the maximum ZT values approach 1.6 (at 900[Formula: see text]K, [Formula: see text][Formula: see text][Formula: see text]) and 1.2 (at 1000[Formula: see text]K, [Formula: see text][Formula: see text][Formula: see text]) for the p- and n-type Cu3VTe4 compounds, respectively. Our work provides not only distinctive high-performance TE materials (Cu3VX4), but also a guideline for future promising thermoelectric discoveries.
How the node’s vital and tie strength effect rumor spreading on social network
Authors: Huo Liang’an , Lin Tingting , Liu Chen , Fang Xing
Published: May 2019

The spread of rumors on complex networks has attracted wide attention in the field of management. In this paper, the generalized rumor spreading model is modified to take into account the vital of the spreader and the tie strength for the pairwise contacts between nodes in complex networks at degree-dependent spreading rate. Concretely, we introduce the infectivity exponent [Formula: see text], and the degree influenced real exponent [Formula: see text] into the analytical rumor spreading model. Rumor infectivity, [Formula: see text], where [Formula: see text], defines that each spreader node may contact [Formula: see text] neighbors within one time step. The tie strength between two nodes with degrees [Formula: see text] and [Formula: see text] are measured by [Formula: see text], [Formula: see text] is the degree influenced real exponent which depends on the type of complex networks and [Formula: see text] is a positive quantity. We use a tuning parameter [Formula: see text] to combine both the effect of the vital nodes and the strength of connectivity between nodes. We use analytical and numerical solutions to examine the threshold behavior and dynamics of the model on several models of social network. It was found that the infectivity exponent [Formula: see text], the degree influenced real exponent [Formula: see text] and tuning parameter [Formula: see text] affect the rumor threshold, one can adjust the parameters to control the rumor threshold which is absent for the standard rumor spreading model.
Round Robin Thread Selection Optimization in Multithreaded Processors
Authors: Carroll Shane , Lin Wei-Ming
Published: May 2019

We propose a variation of round-robin ordering in an multi-threaded pipeline to increase system throughput and resource distribution fairness. We show that using round robin with a typical arbitrary ordering results in inefficient use of shared resources and subsequent thread starvation. To address this but still use a simple round-robin approach, we optimally and dynamically sort the order of the round robin periodically at runtime. We show that with 4-threaded workloads, throughput can be improved by over 9% and harmonic throughput by over 3% by sorting thread order at run time. We experiment with multiple stages of the pipeline and show consistent results throughout several experiments using the SPEC CPU 2006 benchmarks. Furthermore, since the technique is still a simple round robin, the increased performance requires little overhead to implement.
Characteristics of information entropy in spin–orbit coupled spin-1 Bose–Einstein condensates
Authors: Zhao Qiang , Mi Bin-Zhou , Li Yushan
Published: May 2019

In this paper, we study the properties of information entropy in spin–orbit coupled spin-1 Bose–Einstein condensates. Our discussion is divided into two parts, stationary state and dynamics. For the former, we find that the coordinate component Sr and total entropy S increase with the strength of the spin–orbit coupling [Formula: see text]. The momentum component Sk shows a discontinuity behavior, it increases with [Formula: see text] when [Formula: see text] is lesser than a critical value [Formula: see text], while it decreases with [Formula: see text] when [Formula: see text] is greater than [Formula: see text]. In order to characterize the disorder-to-order transition, we introduce an order parameter [Formula: see text]. Numerical results display that [Formula: see text] gradually increases with increasing [Formula: see text] and reaches its saturation, which implies that the system becomes more and more ordered. For the latter, the Sr increases and Sk decreases with increasing [Formula: see text] at the same time. The entropic uncertainty relation is well obeyed at fixed [Formula: see text]. Moreover, [Formula: see text] decreases as a function of t. The strength effect of spin–orbit coupling on order-to-disorder transition becomes weak.
Is the world small enough? — A view from currencies
Authors: Baydilli Yusuf Yargi , Türker İlker
Published: May 2019

Exchange rates are important indicators of the economic power of countries, directly affected by the international trading patterns and relations. Since almost every pair of countries in the globalized world are economically and financially related, exchange rates can be evaluated as nodes of a global financial network to make meaningful inferences.

In this study, a financial network approach is conducted by evaluating the movements of the most traded 35 currencies against gold between years 2005 and 2017. Using graph theory and statistical methods, the analysis of economic relations between currencies is carried out, supported with geographical and cultural inferences. A risk map of currencies is generated through the portfolio optimization. Another approach of applying various threshold levels for correlations to determine connections between currencies is also employed. Results indicate that there exists a saddle point for correlation threshold as 0.9 which results in a robust network topology that is highly modular and clustered, also dominantly displaying small-world and scale-free properties.
2-Adic valuations of Stirling numbers of the first kind
Authors: Qiu Min , Hong Shaofang
Published: May 2019

Let [Formula: see text] and [Formula: see text] be positive integers. We denote by [Formula: see text] the 2-adic valuation of [Formula: see text]. The Stirling numbers of the first kind, denoted by [Formula: see text], count the number of permutations of [Formula: see text] elements with [Formula: see text] disjoint cycles. In recent years, Lengyel, Komatsu and Young, Leonetti and Sanna, and Adelberg made some progress on the study of the [Formula: see text]-adic valuations of [Formula: see text]. In this paper, by introducing the concept of [Formula: see text]th Stirling numbers of the first kind and providing a detailed 2-adic analysis, we show an explicit formula on the 2-adic valuation of [Formula: see text]. We also prove that [Formula: see text] holds for all integers [Formula: see text] between 1 and [Formula: see text]. As a corollary, we show that [Formula: see text] if [Formula: see text] is odd and [Formula: see text]. This confirms partially a conjecture of Lengyel raised in 2015. Furthermore, we show that if [Formula: see text], then [Formula: see text] and [Formula: see text], where [Formula: see text] stands for the [Formula: see text]th elementary symmetric functions of [Formula: see text]. The latter one supports the conjecture of Leonetti and Sanna suggested in 2017.
A thorough study on genetic algorithms in feedback-based wavefront shaping
Authors: Wu Daixuan , Luo Jiawei , Li Zhaohui , Shen Yuecheng
Published: May 2019

Feedback-based wavefront shaping focuses light through scattering media by employing phase optimization algorithms. Genetic algorithms (GAs), inspired by the process of natural selection, are well suited for phase optimization in wavefront shaping problems. In 2012, Conkey et al. first introduced a GA into feedback-based wavefront shaping to find the optimum phase map. Since then, due to its superior performance in noisy environment, the GA has been widely adopted by lots of implementations. However, there have been limited studies discussing and optimizing the detailed procedures of the GA. To fill this blank, in this study, we performed a thorough study on the performance of the GA for focusing light through scattering media. Using numerical tools, we evaluated certain procedures that can be potentially improved and provided guidance on how to choose certain parameters appropriately. This study is beneficial in improving the performance of wavefront shaping systems with GAs.
The intersection graph of ideals of ℤm
Authors: Khojasteh S.
Published: May 2019

Let [Formula: see text] be an integer, and let [Formula: see text] be the set of all non-zero proper ideals of [Formula: see text]. The intersection graph of ideals of [Formula: see text], denoted by [Formula: see text], is a graph with the vertex set [Formula: see text] and two distinct vertices [Formula: see text] are adjacent if and only if [Formula: see text]. Let [Formula: see text] be an integer and [Formula: see text] be a [Formula: see text]-module. In this paper, we study a kind of graph structure of [Formula: see text], denoted by [Formula: see text]. It is the undirected graph with the vertex set [Formula: see text], and two distinct vertices [Formula: see text] and [Formula: see text] are adjacent if and only if [Formula: see text]. Clearly, [Formula: see text]. Let [Formula: see text] and [Formula: see text], where [Formula: see text]’s are distinct primes, [Formula: see text]’s are positive integers, [Formula: see text]’s are non-negative integers, and [Formula: see text] for [Formula: see text] and let [Formula: see text], [Formula: see text]. The cardinality of [Formula: see text] is denoted by [Formula: see text]. Also, let [Formula: see text], [Formula: see text] and [Formula: see text] denote the independence number, the domination number and the set of all isolated vertices of [Formula: see text], respectively. We prove that [Formula: see text] and we show that if [Formula: see text] is not a null graph, then [Formula: see text] and [Formula: see text] We also compute some of its numerical invariants, namely maximum degree and chromatic index. Among other results, we determine all integer numbers [Formula: see text] and [Formula: see text] for which [Formula: see text] is Eulerian.
A Comparative Analysis on Hindi and English Extractive Text Summarization
Authors: Verma Pradeepika , Pal Sukomal , Om Hari
Published: May 2019

Text summarization is the process of transfiguring a large documental information into a clear and concise form. In this article, we present a detailed comparative study of various extractive methods for automatic text summarization on Hindi and English text datasets of news articles. We consider 13 different summarization techniques, namely, TextRank, LexRank, Luhn, LSA, Edmundson, ChunkRank, TGraph, UniRank, NN-ED, NN-SE, FE-SE, SummaRuNNer, and MMR-SE, and we evaluate their performance using various performance metrics, such as precision, recall,F1, cohesion, non-redundancy, readability, and significance. A thorough analysis is done in eight different parts that exhibits the strengths and limitations of these methods, effect of performance over the summary length, impact of language of a document, and other factors as well. A standard summary evaluation tool (ROUGE) and extensive programmatic evaluation using Python 3.5 in Anaconda environment are used to evaluate their outcome.
Guest editor's introduction
Authors: Hopton Sarah Beth
Published: May 2019

Dear Reader,

You've probably heard the story of the city of pigs before, that lovely allegory in Book II of the
Republic
, where Socrates attempts to prove that justice is not only desirable, but belongs to the highest class of desirable things: those desired for their own sake and consequence. But this is an important story to retell, as it frames the consequence of the scholarship contained in this issue on environmental justice and technical communication in a way that perhaps few other stories can.
Shades of denialism
Authors: Cagle Lauren E. , Herndl Carl
Published: May 2019

This article explores rhetorical practices underlying productive deliberation about climate change. We analyze discussion of climate change on a Reddit subforum to demonstrate that good-faith deliberation---which is essential to deliberative democracy---exists online. Four rhetorical concepts describe variation among this subforum's comments: William Keith's distinction between 'discussion' and 'debate,' William Covino's distinction between good and bad magic, Kelly Oliver's notion of ethical response/ability, and Krista Ratcliffe's notion of rhetorical listening. Using a three-part taxonomy based on these concepts, we argue that collaborative climate change deliberation exists and that forum participation guidelines can promote productive styles of engagement.
Rhetoric, risk, and hydraulic fracturing
Authors: Ballentine Brian
Published: May 2019

Claims for America's potential for energy independence are substantiated largely thanks to advancements in an extraction process known as hydraulic fracturing or "fracking." This article focuses on the negotiations among individual landowners and oil and gas companies as they enter into leasing agreements to permit fracking. The author draws on his own experiences as a landowner in the Marcellus and Utica shale region. Of primary concern is how landowners construct their own understanding of risk amidst a network of local, regional, and global actors. Landowner and oil and gas company relationships are analyzed using theories of rhetoric and risk communication.
Abstract 2098: The effect of in utero folic acid supplementation on colorectal cancer risk in the offspring in a chemical carcinogen rodent model
Authors: Sie Karen K , Medline Alan , Sohn Kyoung-Jin , Croxford Ruth , Kim Young-In
Published: May 2019

Background: Epidemiologic studies suggest that dietary intake and blood levels of folate are inversely related to colorectal cancer (CRC) risk. However, animal studies and recent human intervention trials have suggested that although folate supplementation may decrease the risk of developing de novo CRC, folate supplementation may promote the progression of existing, undiagnosed preneoplastic lesions in the colorectum to CRC. Total intake and blood levels of folate in North America have dramatically increased over the past decade owing to mandatory folic acid (FA; the synthetic form of folate) fortification and 30-40% of the population taking multivitamins containing FA. It is unknown whether high folate in the intrauterine environment may affect CRC risk in the offspring. We therefore investigated the effect of FA supplementation provided in utero and postnatally on CRC risk in the offspring in the azoxymethane (AOM) rat model of CRC.

Methods: Female Sprague-Dawley rats were placed on either a control diet (2mg FA/kg diet) or a supplemented diet (5mg FA) for 3 weeks prior to breeding, and remained on the diet throughout pregnancy and lactation. Male pups from each maternal diet group were randomized to either the control or supplemented diet (n=55 per group) at weaning (21 days of age). At 5 and 6 weeks of age, 2 weekly s.c. injections of AOM were given. At 34 weeks of age, all rats were sacrificed and tumor incidence, multiplicity and burden as well as plasma folate and homocysteine (Hcy; an accurate inverse indicator of folate status) and liver folate concentrations were determined.

Results: Plasma and liver folate concentrations accurately reflected dietary FA levels (p<0.001), and a significant interaction was found between maternal and pup diets (p< 0.02). Plasma Hcy was lower in pups fed the 5mg diet (p=0.036). Maternal FA supplementation significantly decreased the risk of developing CRC in the offspring (p=0.003) whereas postnatal FA supplementation had no significant effect. Pups from dams on the control diet had a nearly 3-fold increased risk of developing CRC compared with those from dams on FA supplementation (odds ratio=2.78; 95% CI, 1.41-5.50). There was no significant effect of interaction between maternal and pup diets on CRC incidence. Total number of tumors and sum of tumor diameter were significantly different among the diet groups (p=0.014 and p=0.006, respectively) with FA supplemented pups from dams on the control diet bearing a higher number of tumors and a larger tumor diameter than other groups (p<0.03).

Conclusions: Notwithstanding the limitations associated with this model, our data suggest that FA supplementation provided in utero, but not postnatally, may protect the offspring from developing CRC. Although FA supplementation may promote the progression of established precursors of CRC, FA supplementation may decrease the risk of developing de novo CRC.
Abstract 225: The first use of a live listeria cancer vaccine in man
Authors: Rothman John
Published: May 2019

We report herein on the first in man use of a live Listeria cancer vaccine. 15 women with progressive, recurrent, or advanced cervical cancer who had failed prior chemotherapy, and/or radiotherapy and/or surgery were treated with Lovaxin C (Lm-LLO-E7) in a phase I/II assessment of safety. Lm-LLO-E7 is a living bioengineered strain of Listeria based upon the parent strain 10403S that has been attenuated by the excision of prfA, and modified by plasmid insertion to secrete a fusion protein comprised of the tumor specific antigen HPV-16-E7 fused to a non-hemolytic fragment of the endogenous Listeria protein Listeriolysin O (LLO). This results in a bacterial vector attenuated by approximately 105.

Listeria in general, and this vector in specific, has been shown to have numerous effects presumed to be efficacious in the treatment of cancer including; induction of strong innate immunity, strong activation of both CD4+ and CD8+ lymphocytes, stimulated release of a variety of salutary cytokines and chemokines, the upregulation of co-stimulatory molecules, the generation of an inter-tumor environment conducive to tumor cell killing, the stimulation of myelopoesis and maturation of immature myeloid cells, and a lack of T regulatory cell activation.

In this study, 5 patients each received two doses of either 1x109, 3.3x109, or 1x1010 cfu separated by 3 weeks. Ampicillin was given 5 days after each dose IV and then orally for 10 days. Follow-up assessments were made at 3 weeks and 3 months subsequent to the second vaccination. Patients had metastatic disease and most were stage IVb at the time of their first vaccination.

All 15 treated patients were evaluable for safety analysis and 13 were evaluable in an intent-to-treat analysis of efficacy. Lovaxin C resulted in a flu-like syndrome in all patients comprised of fever, chills, and nausea with or without vomiting. In the 2 lower dose cohorts these symptoms were treated adequately with non-prescription NSAIDs and anti-emetics. At the dose of 1x1010 the same symptoms were observed, however they were dose limiting in severity, with fevers of 40-41oC and associated severe hypotensive diastolic BP. Other side effects observed were likely associated with prior therapies or disease severity. No serum, urine or stool Listeria was detectable.

Tumors were assessed by scan using RECIST criteria. At the end of the study 5 patients had progressive disease, 7 patients were stable, and one patient demonstrated a PR by objective criteria. Of the 7 stable patients, 3 demonstrated tumor reductions of approximately 20%. The PR, who was IVb at dosing, was subsequently given 6 courses of chemotherapy and a radical hysterectomy. At the time of this writing she is tumor free, with normal hematology, and all labs WNL.

It is concluded that Lovaxin C is safe to use therapeutically.
Abstract 3836: A tracking and feedback registry to reduce disparities in breast cancer care
Authors: Bickell Nina , Shastri Kruti , Fei Kezhen , Oluwole Soji , Godfrey Henry , Srinivasan Anitha , Hiotis Karen , Guth Amber
Published: May 2019

Background: Despite the existence of effective adjuvant treatment for early stage breast cancer, women do not always receive it, particularly, minority women. Primary treatment for breast cancer, surgery and varying combinations of radio-, chemo- and hormonal therapy, is delivered by different specialists and is often fragmented. Underuse of post-surgical adjuvant treatment occurs more commonly among women who do not see a medical oncologist despite surgeons’ referral request. To reduce underuse of adjuvant treatment due to failed connections, we tracked and fedback to surgeons information about whether their newly diagnosed breast cancer patients connected with an oncologist.

Methods: We compared oncology referral rates and underuse among pre-intervention (N=677) and intervention (N=300) patients undergoing breast cancer surgery at 6 NYC hospitals. All surgeons consented to the intervention. Each surgeon chose an office person to verify eligibility and identify patient’s oncology referrals. Patients identified upcoming oncology appointment sites and times. Following scheduled visits, oncologists were called to verify patients’ connection & these data were fedback to surgeons & their office staff. Six months later, we abstracted in- & outpatient charts. We compared rates of: completed oncology consultations and underuse of radiotherapy after breast conserving surgery, of chemotherapy for ER negative and hormonal therapy for ER positive tumors >1cm between pre- and intervention women with newly diagnosed early-stage breast cancer.

Results: There was a significant increase in oncology consultations completed (83% to 97%; p<0.0001) and decrease in underuse of adjuvant treatment (21% to 14%; p<0.001); specifically, underuse of chemotherapy (22% to 11%; p=0.05) and hormonal therapy (20% to 8%; p=0.0004) declined. Among black and Hispanic women, underuse of radiotherapy significantly decreased (23% to 10%; p=0.02). Multivariate models, adjusting for clustering by hospital, patient age, race, stage and insurance, found the intervention increased rates of oncology consultation (OR=5.33; 95%CI: 2.68-10.60), and reduced adjuvant underuse (OR= 0.62; 95%CI: 0.42-0.93). Minority race was no longer a risk factor for an oncology consultation (OR=1.20; 95%CI: 0.69-2.08) or underuse of adjuvant therapy (OR= 1.13; 95%CI: 0.73-1.75).

Conclusions: A tracking and feedback registry which closes the referral loop between surgeons and oncologists appears to improve rates of medical oncology consultation, reduces rates of adjuvant treatment underuse and eliminates the racial disparity in treatment.
Abstract 4179: Promising clinical activity of a NAB paclitaxel plus gemcitabine combination in a disease-specific phase I trial in patients with advanced pancreatic cancer
Authors: Von Hoff Daniel D. , Borad Mitesh , Ramanathan Ramesh K. , Smith Lon S. , Drengler Ronald L. , Wood Tina E. , Laheru Daniel , Hidalgo Manuel
Published: May 2019

Patients (pts) with pancreatic cancer have very poor survival. A substantial percentage of pancreatic cancers have increased expression of SPARC (Secreted Protein And Rich in Cysteine) (Guweidhi et al., Annals of Surgery, 2005; 242: 224-234,Von Hoff et al., J Clin Oncol 2006; 24(18s): 138, Infante et al., J Clin Oncol 2007; 25 (3): 319.) Increased SPARC expression has been correlated with improved response to nanoparticle albumin-bound paclitaxel(nab-paclitaxel) due to a SPARC-albumin interaction (Trieu et al., New Targets in Delivery System for Diagnosis and Treatment (SKCC), 2007; abstract 53). Based on this observation, SPARC may play a role in selectively concentrating nab-paclitaxel in pancreatic tumors. Therefore a disease specific modified phase I trial of nab-paclitaxel + gemcitabine in pts with advanced pancreatic cancer was performed. Tumor samples were obtained for SPARC evaluation and CA19-9 levels were monitored as a drop in CA19-9 has been correlated with improved survival.

In this study, pts with advanced pancreatic cancer with no prior chemotherapy except as a radiation sensitizer received nab-paclitaxel + gemcitabine on days 1, 8, 15 every 28 days with a starting dose of 100 mg/m2 and 1000 mg/m2 respectively. Subsequent dose escalations of nab-paclitaxel were planned at 125 and 150mg/m2.

To date, 20 pts have been recruited for this study. All of the pts received nab-paclitaxel 100mg/m2 + gemcitabine 1000 mg/m2. 18/20 patients completed at least one cycle of treatment and were considered evaluable. Independent review of the patient’s measurable disease on CAT and PET scans is ongoing with many of the patients continuing to have radiographic regression of disease. 17/18 evaluable subjects had paired CA19-9 levels available for analysis. Clinical activity has been demonstrated by CA19-9 reduction of greater than 20% from baseline in 82% (14/17pts) and more than 70% from baseline in 59% (10/17 pts). A decrease of CA19-9 of at least 20% has been associated with improvement in patient survival (AH Ko et al., BJC 2005; 93, 195-199, Park BB et al., Cancer Chemother Pharmacol 2007 Sep; 60 (4): 489-94, and Boeck S et al., Oncology 2006; 70 (4): 255-64).

The most common Grade 3/4 adverse event (AE) was neutropenia (n=3, 2, respectively). Other grade 3 AEs include febrile neutropenia (1), fatigue (1) and hyperglycemia (1). In addition, 2 cases of grade 2 anemia and 2 cases of thrombocytopenia were observed.

Based on these results, the combination of nab-paclitaxel and gemcitabine in pancreatic cancer warrants further study. Dose escalation to cohort 2 is proceeding. When the MTD is determined, that cohort will be expanded. The optimum dose as determined in this study will be used in a larger, randomized phase II/III study.
Abstract 4740: Selective ablation of metastatic disease with integrin ανβ3 targeted nanoparticle drug delivery
Authors: Majeti Bharat K , Murphy Eric A , Barnes Leo , Makale Milan , Lutu-Fuga Kimberly , Weis Sara , Bouvet Michael , Wrasidlo Wolfgang , Cheresh David A
Published: May 2019

Angiogenic blood vessels found within growing tumors express high levels of integrin ανβ3 while mature vessels fail to express this integrin. Based on this we developed a ανβ3-targeted nanoparticle (NP) in an attempt to selectively deliver therapeutics to the tumor neovasculature. A cyclic peptide ligand (cRGDfK) coupled to a phospholipid and incorporated into a nanoparticle demonstrated specific binding to ανβ3 on cultured endothelial cells. To characterize the in vivo targeting capacity of these NPs, we monitored NP accumulation using intravital microscopy of tumor neovasculature. A dorsal skin-fold window chamber implanted with GFP-labeled melanoma cells lacking integrin ανβ3 were imaged at various times after NP injection into the bloodstream. By 5h post injection, the cRGDfK NPs targeted the neovasculature at the angiogenic tips adjacent to the tumor margin, whereas untargeted (cRADfK) NPs failed to bind. After establishing in vivo targeting, these ανβ3-targeted NPs were loaded with doxorubicin via an ammonium phosphate gradient for therapeutic studies. The cRGD-Dox particles disrupted angiogenesis in the mouse matrigel model leaving only small fragments of disrupted vessels within the FGF loaded plugs. Next, we utilized an orthotopic pancreatic cancer model to study the ability of the NPs to target the vasculature of both primary pancreatic tumors as well as metastatic sites including the hepatic hilar lymph node and mesenteric lymph nodes. cRGD-Dox particles injected systemically at 1 mg/kg produced a profound anti-metastatic effect while only marginally influencing the pre-established primary tumor within the pancreas. This is much improved compared to the free doxorubicin treatments in which 1 mg/kg of free doxorubicin had no effect and 15 mg/kg of free doxorubicin was required for a similar therapeutic effect in this orthotopic model. Animals treated with 15 mg/kg of free doxorubicin lost over 20% of their body weight within 7 days, whereas no decrease in body weight was observed in the cRGD-Dox treated animals, confirming the reduction in overall toxicity. Histology confirmed that the cRGD-Dox particles induced apoptosis in regions co-localized with β3 expressing tumor vasculature. Additionally, we tested the cRGD-Dox particles in an orthotopic renal cell carcinoma model. Similar to the pancreatic carcinoma, the cRGD-Dox particles had a slight effect on primary tumor growth but greatly reduced metastasis to several sites including the pancreas, liver, spleen, and diaphragm. These findings reveal that ανβ3 targeted NP drug delivery may preferentially disrupt newly forming metastatic lesions by delivery of chemotherapeutic agents to sites of active angiogenesis in which the endothelium expresses high levels of ανβ3.
Abstract 4997: Prospective identification, tracking, and targeting of cancer-initiating cells in breast cancer and glioma via low proteasome activity
Authors: Vlashi Erina , Kim Kwanhgee , Della Donna Lorenza , McDonald Tyson , Lagadec Chann , McBride William H , Frank Pajonk
Published: May 2019

Cancer initiating cells (CICs) in breast cancer and glioma are resistant to radiation and chemotherapy. Complete elimination of these cells from the tumor mass determines therapeutic success. Thus, prospective identification of this cell population is key to developing novel targeting strategies for CICs. The current surface marker combinations employed in identifying CICs have several shortcomings. Here we report a novel marker for CICs that allows identification, tracking, and targeting of CICs in-vitro and in-vivo.

Proteasome activities of human (U87 and U87viii) and murine (GL261) glioma cells, as well as human (MCF-7 and MDA-MB-231) and murine (67NR) breast cancer cells were analyzed using fluorogenic peptide substrates. Stable cell lines were generated with retroviruses coding for fusion proteins of ZsGreen and the degron of murine ornithine decarboxylase (ODC), or in combimation with thymidine kinase (TK). Accumulation of ZsGreen was monitored by fluorescence microscopy and flow cytometry. Self-renewal capacity was assessed in sphere forming assays, and tumorgenicity was determined by injection of sorted tumor cells into nude mice.

Cell populations enriched for CICs demonstrated significantly reduced activities of the 26S proteasome and showed differential expression of proteasome subunits. Accumulation of ZsGreen corresponded with the CD24-/low/CD44+ phenotype in MCF-7 cells, and glioma ZsGreen-positive cells expressed high levels of the stem cell marker, nestin. Cells with low proteasome function exhibited a 5-fold increased sphere forming capacity, and 3-log increased tumorgenicity.

Histologically, ZsGreen-positive U87 cells resided in a perivascular niche, and stained negative for Ki67. Optical in-vivo imaging revealed a significant increase in the number of ZsGreen-positive cells after treatment with sublethal doses of radiation. Fractionated sublethal irradiation of these xenografts caused induction of jagged-1 and notch-1 expression, and induced Ki67 expression in the zsGreen-positive population. Treatment of TK-ZsGreenODC-expressing U87 cells with ganciclovir eliminated cells with low proteasome activity, and subsequently prevented sphere formation in-vitro, and caused complete regression of tumors in-vivo.

We conclude that low proteasome activity is a unique characteristic of CICs. Cell lines infected with reporter constructs for proteasome activity can be utilized to identify CICs and track their response to cancer treatments. Most importantly, this feature of CICs can be exploited as a specific target for selective elimination of CICs, leading to improved tumor control.
Abstract LB-242: Aberrant crypt foci (ACF) are not surrogate biomarkers of sporadic adenoma prevention with celecoxib: Results from the Adenoma Prevention with Celecoxib (APC) trial
Authors: Cho Nancy L , Redston Mark , Zauber Ann G. , Carothers Adelaide M , Hornick Jason L , Wilton Andrew , Sontag Stephen , Nishioka Norman , Giardiello Frances , Saltzman John R , Gostout Chris , Eagle Craig J , Hawk Ernest T. , Bertagnolli Monica M
Published: May 2019

Aberrant crypt foci (ACF) are the earliest visible neoplastic lesions in the colorectum. The natural history of these lesions and their role in the adenoma-carcinoma sequence are unknown. We studied ACF in a subset of patients enrolled in the Adenoma Prevention with Celecoxib (APC) Trial to determine whether the presence of ACF in the rectum correlated with that of adenomas in the entire large intestine. Participants were randomized to placebo (n=17), celecoxib 200 mg bid (n=15), or celecoxib 400 mg bid (n=13). Magnification chromoendoscopy (MCE) was performed to identify and biopsy ACF within the rectum at baseline and after 8-12 months of medication use. A total of 670 ACF were identified in 45 patients, and 70 of these were examined histologically. All of the ACF examined were non-dysplastic. Analysis showed no differences in ACF number between baseline and post-treatment studies (8.3±1.0 vs. 6.3±1.1) and no modulation by treatment (celecoxib vs placebo; p=0.77). Immunohistochemical studies showed that ACF contained cells exhibiting increased proliferation, but lacked other features of neoplasia such as increased Cox-2 expression and microvascular density, nuclear localization of β-catenin, or decreased expression of the tumor suppressors SMAD4, estrogen receptor (ERα) or MGMT. Of the secondary markers assessed at baseline, only SMAD4 expression correlated with post-treatment adenoma recurrence. Taken together, these data showed that non-dysplastic ACF are not accurate surrogate endpoint biomarkers of colorectal adenoma risk or NSAID chemoprevention response.
Abstract LB-248: A single-institution prospective study evaluating the functional diffusion map (fDM) as an early imaging biomarker for overall survival in high-grade glioma
Authors: Ross Brian D , Hamstra Daniel A , Galban Craig J , Meyer Charles R , Johnson Timothy D , Sundgren Pia C , Tsien Christina , Junck Larry , Ross David J , Rehemtulla Alnawaz , Chenevert Thomas L , Lawrence Theodore S
Published: May 2019

Introduction: Standard assessment of radiologic response in patients with malignant glioma is traditionally carried out using T1 gadolinium-enhanced MRI at approximately 10 weeks following treatment initiation. Diffusion-weighted MRI of gliomas, analyzed by the functional diffusion map (fDM), may provide an early measure of response during treatment to predict patient survival (OS). Tumor cells restrict the random diffusion of water molecules within a tumor; therefore, diffusion will increase during successful therapy. The fDM imaging biomarker is a voxel-wise method for analysis of DW-MRI data providing for quantification of treatment-associated spatial alterations in tumor diffusion values earlier than radiologic response.

Methods: A prospective single-institution trial of early assessment of brain tumor response by MRI was performed early during radiation therapy. Sixty patients with high grade glioma undergoing radiation therapy were enrolled in an IRB-approved study of intra-treatment MRI 1, 3, and 10 weeks after the initiation of treatment. Receiver operating characteristic curve analysis was used to evaluate imaging parameters as a function of patient survival at one-year. Log Rank and Cox Proportional Hazards models were utilized to assess OS.

Results: Measurable changes in diffusion MRI were observed as early as one week into treatment. The volume of tumor with increased diffusion as assessed by fDM 3 weeks after the start of therapy was the strongest predictor of patient survival at one year, with larger fDM predicting longer median survival [52.6 vs. 10.9 months, log-rank, P<0.003, HR 2.7 (95% CI: 1.5-5.9)]. Radiologic response at 10 weeks was of similar prognostic value [log-rank, P<0.0007, HR 2.9 (95% CI: 1.7-7.2)]. Pre-treatment age (<50 vs. 50+, P<0.007), pathologic grade (III vs. IV, P<0.05), and the use of concurrent temozolomide (yes vs. no, P<0.05) all predicted for increased survival on univariate analysis. On multivariate analysis only age (P<0.03) and fDM (P<0.04) retained prognostic significance for overall survival. Radiologic response and fDM agreed in their stratification for 75% of patients. However, a composite index of response including both fDM at 3 weeks and RR at 10 weeks provided a more robust predictor of patient survival and may help identify patients where RR does not correlate with clinical outcome.

Conclusions: Compared to conventional neuro-imaging, fDM provided an earlier assessment of equal predictive value during the course of treatment, providing the opportunity to individualize therapy. The combination of fDM and RR provided a more accurate prediction of patient survival than either metric alone.
Abstract LB-303: Berubicin, a brain tumor targeting anthracycline: Discovery and clinical evaluation
Authors: Priebe Waldemar , Madden Timothy , Conrad Charles A.
Published: May 2019

Development of effective chemotherapeutic strategies to treat brain tumors has been limited in part by the inaccessibility of the CNS to pharmacological intervention. Topoisomerase II (topo II) overexpression has been well documented in human gliomas and is correlated to poor survival, but to date no effective topo II poison, capable of reaching the target tissue after systemic administration, has been developed. We hypothesized that the presence of ATP-binding cassette (ABC) transporters in the blood-brain barrier (BBB) might, in part, be responsible for limiting the CNS penetration of most anticancer drugs including topo II poisons like doxorubicin (DOX). To identify new agents effective in vivo against brain tumors, we have used our innovative modular design of DNA-binding agents to create unique libraries of potential topo II poisons. By systematically screening such libraries, we have identified highly apoptotic compounds that can circumvent P-gp and MRP1-mediated resistance mechanisms, suggesting that such compounds will be potent cytotoxins against gliomas, through their ability to cross the BBB.Synthesis and in vitro screening of a library of over 400 DNA binding agents in a panel of cells overexpressing P-gp and MRP1 led to identification of 10 compounds possessing the necessary characteristics from which the compound Berubicin (RTA744, WP744) was selected for detailed preclinical evaluation. Berubicin (BRB) is structurally related to the well-known anticancer drug DOX, but is significantly more apoptotic than DOX against multidrug-resistant tumor cell lines with the MDR1 and MRP1 phenotypes and can cross the BBB, achieving CNS and brain tumor concentrations exceeding that of plasma. Subsequent preclinical development led to IND and Phase I clinical studies in humans. In the first Phase I trial dose escalation of BRB proceeded according to an accelerated titration design, with single patient cohorts and 100% dose escalations until evidence of drug-related Grade 2 or greater toxicities were observed. The MTD of berubicin administered on a qd X 3 schedule was 7.5 mg/m2/day (22.5 mg/m2/cycle). Toxicities appear consistent with the anthracycline class, with no unexpected toxicities observed. Of interest no neurotoxicity or cardiotoxicity have been reported. Median time to progression in the Phase I study as of 5/21/ 2007 was 7.4 weeks with one complete response (CR), one partial response (PR)) and 7 minor response or stable disease patients, observed. Because of the unique biological characteristics of BRB (potent topo II poison, ability to cross BBB, activity against multidrug resistant tumors) and the results of Phase I clinical studies this agent is uniquely placed to become an effective therapeutic agent for the treatment of brain tumors.
Abstract LB-304: Evaluation of the effects of anti-VEGF therapy in a multidisciplinary phase I/II study of neoadjuvant bevacizumab with chemoradiation therapy in rectal cancer
Authors: Willett Christopher G , Xu Lei , Duda Dan G , di Tomaso Emmanuelle , Boucher Yves , Lahdenranta Johanna , Ancukiewicz Marek , Bendell Johanna , Czito Brian , Blaszkowsky Lawrence , Clark Jeffrey , Jain Rakesh K
Published: May 2019

Background: A phase I/II study of neoadjuvant bevacizumab with 5-fluorouracil and radiation therapy in patients with locally advanced rectal cancer is underway to assess the clinical benefits of bevacizumab enhancement of chemo-radiation therapy.

Methods: 24 patients with endoscopic ultrasound or surface coil MRI staged T3/T4 non-metastatic rectal cancer were enrolled from 2001-2007. All patients completed 4 cycles of neoadjuvant therapy including: 1) bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; 2) peripheral venous infusion 5-FU (225 mg/m2/24 hours) administration each treatment week of cycles 2 - 4; 3) external beam irradiation delivery (50.4 Gy in 28 fractions over 5.5 weeks); and 4) surgery 7 to 9 weeks after completion of all neoadjuvant therapy. Correlative studies are undertaken before and during the trial. We collected serial tumor biopsies, PET-FDG scans, and analyzed blood and urine for potential biomarkers.

Results: Histologic examination showed no residual primary cancer in 5 patients (ypT0). Of 19 patients with residual disease, microscopic disease usually occurred as malignant glands embedded in fibrosis (ypT1 in 3 patients, ypT2 in 4 patients, ypT3-4 in 12 patients). Downstaging was seen in 12/22 tumors. Nine patients had microscopic nodal metastases. Bevacizumab alone and combined treatment were both associated with increased plasma VEGF, PlGF and SDF1alpha levels in analyzed patients (P<0.01 at all 4 timepoints compared to baseline). Viable CECs were decreased by VEGF blockade at day 3 (P<0.01 compared to baseline), and CEC levels correlated with histologic tumor response (T3 vs T0, p <0.05). Laser-capture micro-dissection identified a set of genes changed by anti-VEGF therapy in cancer cells as well as in tumor-associated macrophages. Actuarial 4 year local control and disease-free are 100% and 88%, respectively.

Conclusions: Addition of bevacizumab at a dose of 5 mg/kg to standard chemo-radiation shows activity and the combined regimen yields promising results.
Abstract LB-333: Antagonistic interaction effects of aspirin and folic acid on inflammatory markers
Authors: Ho Gloria Y , Xue Xiaonan , Saibil Fred , Rohan Thomas , Baron John
Published: May 2019

This ancillary study to the Aspirin/Folate Polyp Prevention Trial examined the effects of low dose aspirin and folic acid (FA) supplementation on reducing the levels of inflammatory markers- CRP, IL-6, and TNF-α. The Aspirin/Folate Trial was a randomized, double-blind trial of aspirin and folate to prevent recurrent colorectal adenomas. In a 3x2 factorial design, patients were randomized to receive 81 mg/d or 325 mg/d of aspirin or placebo, and to receive 1 mg/d of FA or placebo. In this ancillary study, blood samples collected at baseline and year 3 were assayed for the 3 inflammation markers. Marker levels at year 3 were analyzed by linear regression, with main effects of the randomization groups and interaction between aspirin and FA modeled as independent variables. In the FA-placebo stratum, mean CRP at year 3 decreased with increasing dosage of aspirin, and it was 0.58 μg/mL lower in the aspirin-325 mg group than aspirin-placebo group (P=0.048). However, in the FA-1 mg stratum, the aspirin-325 mg group actually had a higher mean CRP than aspirin-placebo. Similarly, among individuals not given aspirin, the FA-1 mg group had a 0.58 μg/mL reduction in mean CRP as compared to the FA-placebo group (P=0.045), but in individuals who were also given 325 mg of aspirin, mean CRP was higher in FA-1 mg than FA-placebo. Therefore, 325 mg of aspirin or FA alone decreased CRP levels, but together they attenuated the effects of each single regimen (P=0.033 for interaction). There were also antagonistic interaction effects on TNF-α (P=0.019) and the overall proinflammatory index (P=0.009) calculated by combining the levels of the 3 markers. Similar results were obtained when adjusting for other covariates, including baseline marker levels. Long-term use of low dose aspirin or FA supplementation alone has a modest anti-inflammatory effect, but the two regimens together eliminate such beneficial effects, and the mechanism needs to be elucidated.

Table 1.Geometric mean of inflammation markers at year 3 by randomization groupAspirin: PlaceboAspirin: 81 mgAspirin: 325 mgFolic Acid: PlaceboCRP (μg/mL)2.452.141.87*IL-6 (pg/mL)2.102.012.01TNF-α (pg/mL)2.161.511.63Folic Acid: 1 mgCRP (μg/mL)1.87**2.172.15IL-6 (pg/mL)1.942.112.15TNF-α (pg/mL)1.661.652.42*P=0.048, mean CRP levels between aspirin-325 mg and aspirin-placebo in the FA-placebo subgroup. **PP=0.045, mean CRP levels between FA-1 mg and FA-placebo in the aspirin-placebo subgroup.
Abstract P1-06-08: Improved endocrine therapy response prediction using a whole slide digital ER and PR staining score to assess local ER pathway activity in hormone receptor positive breast cancer patients
Authors: van Ooijen H , van Hemert F , van der Ven J , de Inda MA , Velter R , Halter D , den Biezen-Timmermans E , van Brussel A , van de Wiel P , Wimberger-Friedl R , van de Stolpe A
Published: May 2019

This abstract was withdrawn by the authors.