bluuebunny/crossref_metadata_2025 huggingface dataset:
On the histogenesis of mixed germ cell-sex cord stromal tumour of the gonads
Authors: Roth Lawrence M , Cheng Liang
Published: July 2016

Aims

The origin of testicular mixed germ cell-sex cord stromal tumour (MGC-SCST) is uncertain, and the nature of this neoplasm is controversial. It has not been established whether the germ cells in testicular MGC-SCST are neoplastic or whether they are merely entrapped within an unclassified sex cord stromal tumour or related testicular neoplasm. In this investigation, we present additional evidence regarding the nature of the germ cells in testicular MGC-SCST.

Methods

We obtained 25 cases of MGC-SCST, 13 of which involved the testis and 12 occurred in the ovary for histological examination. Although the majority of the cases studied were archival, materials were available for immunocytochemical examination in 10 instances.

Results

We found that 10 of 13 testicular MGC-SCSTs studied had a sex cord component resembling unclassified sex cord stromal tumour. In two MGC-SCSTs that had prominent entrapped tubules, an intratubular component was identified. A total of 12 ovarian MGC-SCSTs were examined, and these neoplasms were more diverse in their histological appearance than the testicular examples. The germ cells often resembled those of dysgerminoma. Formation of imperfect follicular-like structures was a frequent feature in ovarian cases.

Conclusions

In this investigation, we provide further evidence that the germ cells in testicular MGC-SCSTs are neoplastic; however, in the great majority of tumours, these cells are low-grade. Some testicular MGC-SCSTs arise from an intratubular component. We believe that the majority of ovarian and some testicular MGC-SCSTs arise more directly from simultaneous transformation of germ cells and sex cord derivatives.
Extracorporeal shockwave therapy and therapeutic exercise for supraspinatus and biceps tendinopathies in 29 dogs
Authors: Leeman J. J. , Shaw K. K. , Mison M. B. , Perry J. A. , Carr A. , Shultz R.
Published: July 2016

Supraspinatus tendinopathy (ST) and biceps tendinopathy (BT) are common causes of forelimb lameness in large‐breed dogs and have historically been treated with conservative management or surgery. Extracorporeal shockwave therapy (ESWT) and therapeutic exercise (TE) are thought to be treatment options for these conditions. The objectives of this study were to report the clinical presentations of dogs treated with ESWT for shoulder tendinopathies, to determine the association between shoulder lesion severity identified on ultrasonography or MRI and outcome, and to compare the outcomes of dogs treated with ESWT with and without TE. Medical records of 29 dogs diagnosed with shoulder tendinopathies and treated with ESWT were reviewed, and 24 dogs were diagnosed with either unilateral BT or BT and ST. None were found to have unilateral ST. Five dogs were diagnosed with bilateral disease. Eighty‐five per cent of dogs had good or excellent outcomes determined by owner assessment 11–220 weeks after therapy. Outcomes were found to be better as tendon lesion severity increased (P=0.0497), regardless if ESWT was performed with or without TE (P=0.92). ESWT should be considered a safe primary therapeutic option for canine shoulder tendinopathies. Larger controlled prospective studies are needed to adequately assess these findings.
A new endophytic species ofNeostagonospora(Pleosporales) from the coastal grassSpinifex littoreusin Taiwan
Authors: Yang Jun-Wei , Yeh Yu-Hung , Kirschner Roland
Published: July 2016

A new species of Neostagonospora associated with Spinifex littoreus was found. Endophytic isolates remained sterile, but a specimen collected on living leaves could be used for morphological characterization and cultivation. The ITS sequences from the cultures as well as from direct total DNA extraction from the plant indicated conspecificity and a broader geographic distribution than the single field collection, but yielded low support on the genus level in phylogenetic analyses. Analysis of the RPB2 sequences, however, sufficiently supported a placement of the species in Neostagonospora. The shape of conidiogenous cells as well as numbers of septa and sizes of conidia are useful characters for distinguishing Neostagonospora species.
Combining bottom trawls and acoustics in a diverse semipelagic environment: What is the contribution of walleye pollock (Gadus chalcogrammus) to near-bottom acoustic backscatter in the eastern Bering Sea?
Authors: Lauffenburger Nathan , De Robertis Alex , Kotwicki Stan
Published: July 2016

The abundance of walleye pollock (Gadus chalcogrammus) in the eastern Bering Sea is estimated in part through fisheries-independent acoustic trawl (AT) surveys, which currently use acoustic backscatter data down to 3 m above the bottom. A large portion of adult pollock are demersal, and these estimates will become more accurate if the survey is extended closer to bottom. The purpose of this project was to assess the feasibility of extending the AT survey closer to the bottom by estimating the contributions of each demersal fish species to observed acoustic backscatter in the highly diverse near-bottom region. This was accomplished by fitting a regression model to simultaneously collected acoustic backscatter and bottom trawl catch data. Pollock were the dominant source of acoustic backscatter among demersal species, accounting for 85.9% ± 4.8% of acoustic backscatter (mean ± standard deviation). A method was developed to extend the AT survey to within 0.5 m of the bottom, and when applied to the 1994–2014 surveys, pollock biomass increased by a mean of 28% ± 9%.
Isotopic tissue turnover and discrimination factors following a laboratory diet switch in Colorado pikeminnow (Ptychocheilus lucius)
Authors: Franssen Nathan R. , Gilbert Eliza I. , James Angela P. , Davis Jason E.
Published: July 2016

Stable isotope ecology has made great strides in quantifying energy transfer through food webs. However, trophic inferences gleaned from field-collected data can be limited when isotopic turnover and isotopic discrimination factors (Δ13C or Δ15N) are unknown. We quantified isotopic turnover and discrimination factors using an isotopic diet switch in the endangered Colorado pikeminnow (Ptychocheilus lucius). The estimated half-life for δ13C was 62 days or a 33% increase in mass and δ15N averaged 133 days or a 52% increase in mass. Growth and metabolic processes both contributed to rates of turnover, but metabolic processes had a stronger effect in δ13C than in δ15N. Lipid-corrected δ13C values resulted in discrimination factors of Δ13C between 0.67 and 0.82 and Δ15N between 2.31 and 2.93, values similar to other fishes. These results suggest sampling fin tissue may be a useful, nonlethal tool for isotopic studies. Fins also demonstrated enrichment in 13C that was not linked to the diet switch, highlighting the importance of controls in isotopic diet switch studies to verify species- and diet-specific estimates of isotopic turnover rates.
Taxonomic bias and international biodiversity conservation research
Authors: Donaldson Michael R. , Burnett Nicholas J. , Braun Douglas C. , Suski Cory D. , Hinch Scott G. , Cooke Steven J. , Kerr Jeremy T.
Published: July 2016

While greater research on threatened species alone cannot ensure their protection, understanding taxonomic bias may be helpful to address knowledge gaps in order to identify research directions and inform policy. Using data for over 10 000 animal species listed on the International Union for Conservation of Nature Red List, we investigated taxonomic and geographic biodiversity conservation research trends worldwide. We found extreme bias in conservation research effort on threatened vertebrates compared with lesser-studied invertebrates in both terrestrial and aquatic habitats at a global scale. Based on an analysis of common threats affecting vertebrates and invertebrates, we suggest a path forward for narrowing the research gap between threatened vertebrates and invertebrates.
Enhancement of second harmonic generation efficiency, laser damage threshold and optical properties of cobalt chloride doped with L-alanine single crystal
Authors: Ignatius I. Cicili , Rajathi S. , Kirubavathi K. , Selvaraju K.
Published: July 2016

In the present study, L-alanine crystal is grown with cobalt chloride as dopant by low temperature solution growth using slow evaporation technique at room temperature. The lattice parameters of the grown pure and cobalt chloride doped L-alanine crystals were determined by the single crystal X-ray diffraction technique. The presence of the elemental composition such as cobalt chloride present in the L-alanine lattice was confirmed by energy dispersive X-ray analysis. The optical transmittance, absorbance, reflectance was measured and used to study the optical properties of the pure and doped L-alanine crystal. The pure L-alanine crystal has high optical transmittance in the whole visible range and UV transparency with lower cutoff wavelength at 240[Formula: see text]nm. By adding cobalt chloride to L-alanine crystal, the transmittance decreases the value of cutoff shifts to the higher wavelengths. Nonlinear optical studies reveal that the SHG efficiency and laser damage threshold energy increases when the L-alanine crystal is doped with cobalt chloride. From microhardness studies, it is observed that the cobalt chloride doped L-alanine crystal is harder than the pure crystal.
Understanding the effect of bound excitons on two photon absorption process in anatase TiO2 nanospheres using ultrafast pulses
Authors: Chakravarthy Giridhar , Allam Srinivasa Rao , Sharan Alok , Ghosh Oriparambil Sivaraman Nirmal , Gayathri Sethuraman , Viswanath Annamraju Kasi , Prabhakar M. N. , Song Jung-Il
Published: July 2016

Nanoparticles of Titanium dioxide [Formula: see text] with its unique optical and electronic characteristics is an important material for photochemical catalysis. The efficiency of catalytic activity of [Formula: see text] anatase nanostructures is greatly influenced by the photo-generated bound excitons. It is found that the interaction of bound excitons generated in [Formula: see text] enhances the cubic nonlinearity of the system due to strong oscillation of photo-generated bound excitons. The trapped electron hole pair concentration is directly proportional to the photocatalytic efficiency of the [Formula: see text] anatase nanostructures. In our report, we show how these photo-generated bound excitons play a significant role in origin of third-order optical nonlinearities. In particular, we have measured large phase shift and seen two photon absorption process through closed and open aperture Z-scan, respectively, using femtosecond pulses at 532[Formula: see text]nm.
A Multicriteria Decision Model for Collaborative Partnerships in Supplier Strategic Management
Authors: Guarnieri Patricia , De Almeida Adiel Teixeira
Published: July 2016

Maintaining relationships with suppliers has become a critical strategic management issue to business. As a consequence, the tasks of evaluating and selecting suppliers are essential, given that companies delegate part of their business to partners. The main purpose of these tasks is to identify suppliers with the highest potential for meeting a buyer’s needs consistently and at an acceptable overall performance. However these tasks are complex since they involve a variety of conflicting criteria, which makes the problem one that can be tackled by an multicriteria decision aid (MCDA) approach. Moreover, companies have suppliers whose features and performance are different and buyers need to decide at each level how they may best collaborate with each type of supplier. Many papers in the literature have addressed this situation involving supplier selection; nevertheless, most of them present methods to solve ranking and choice problems. The objective of this paper is to propose a model for the strategic management of suppliers which uses the ELECTRE TRI method to sort suppliers into classes of collaboration. Therefore, by using this model it is possible for companies to do so in order to define the most appropriate strategies to adopt for each category.
Linear complexity of generalized cyclotomic binary sequences of order 2d and length 2pm
Authors: Zuo Xuewu , Li Xu , Xiao Jin , Tang Yuanyan , Abbasi Rashid , Xu Lixiang
Published: July 2016

In this paper, we construct two new cyclotomic binary sequences of order [Formula: see text] and length [Formula: see text] which include the sequences constructed by Ke et al. in 2012. We also compute their linear complexity. The results show that these sequences have good linear complexity.
3D Porous Graphene/Polyvinyl Alcohol Composites: The Effect of Modification on the Adsorption Properties
Authors: Sun Shuang , Ma Xiaofei
Published: July 2016

Polyvinyl alcohol (PVA) was grafted on graphene nanosheets (GN) in the reduction of graphene oxide with hydrazine hydrate. The obtained GN-PVA (GP) suspension was treated with the freezing–thawing cycle to fabricate 3D porous monolithic GP materials, which were modified with carbon disulfide to introduce xanthan groups on the wall of porous materials, marked as GPCs. The characterization of GPCs confirmed that PVA was attached on the surface of GNs, and xanthan groups were effectively functionalized on the porous structures, which were composed of randomly oriented GNs. The Pb[Formula: see text] adsorption pattern for GPC materials was investigated. The kinetic adsorption and isotherm data fit the pseudo second-order kinetic and the Langmuir isotherm models, respectively. The maximum adsorption capacity of Pb[Formula: see text] reached 242.7[Formula: see text]mg/g. And GPCs for Pb[Formula: see text] adsorption could be regenerated with ethylenediamine tetracetic acid (EDTA) solution for repetitious adsorption.
Fixed point theorems in generalized metric spaces
Authors: Czerwik Stefan , Król Krzysztof
Published: July 2016

In the paper, we shall prove the results on the existence of fixed points of mapping defined on generalized metric space satisfying a nonlinear contraction condition, which is a generalization of Diaz and Margolis theorem (see [A fixed point theorem of the alternative, for contractions on a generalized complete metric space, Bull. Amer. Math. Soc. 74 (1968) 305–309]). We also present local fixed point theorems both in generalized and ordinary metric spaces. Our results are generalizations of Banach fixed point theorem and many other results.
Replicated Computational Results (RCR) Report for “A Distributed-Memory Package for Dense Hierarchically Semi-Separable Matrix Computations Using Randomization”
Authors: Meiser Dominic
Published: July 2016

In this report, we replicate a subset of the performance results in the article “A distributed-memory package for dense Hierarchically Semi-Separable matrix computations using randomization.”
A Support System for Clustering Data Streams with a Variable Number of Clusters
Authors: Silva Jonathan de Andrade , Hruschka Eduardo Raul
Published: July 2016

Many algorithms for clustering data streams that are based on the widely used
k
-Means have been proposed in the literature. Most of these algorithms assume that the number of clusters,
k
, is known and fixed
a priori
by the user. Aimed at relaxing this assumption, which is often unrealistic in practical applications, we propose a support system that allows not only estimating the number of clusters automatically from data but also monitoring the process of the data-stream clustering. We illustrate the potential of the proposed system by means of a prototype that implements eight algorithms for clustering data streams, namely, Stream LSearch-OMR
k
, Stream LSearch-B
k
M, Stream LSearch-IOMR
k
, Stream LSearch-IB
k
M, CluStream-OMR
k
, CluStream-B
k
M, StreamKM++-OMR
k
, and StreamKM++−B
k
M. These algorithms are combinations of three state-of-the-art algorithms for clustering data streams with fixed
k
, namely, Stream LSearch, CluStream, and StreamKM++, with two algorithms for estimating the number of clusters, which are Ordered Multiple Runs of
k
-Means (OMR
k
) and Bisecting
k
-Means (B
k
M). We experimentally compare the performance of these algorithms using both synthetic and real-world data streams. Analyses of statistical significance suggest that the algorithms that are based on OMR
k
yield the best data partitions, while the algorithms that are based on B
k
M are more computationally efficient. Additionally, StreamKM++−OMR
k
and Stream LSearch-IB
k
M provide the best tradeoff relationship between accuracy and efficiency.
From computational thinking to computational participation in K--12 education
Authors: Kafai Yasmin B.
Published: July 2016

Seeking to reframe computational thinking as computational participation.
A Study of Online Review Promptness in a B2C System
Authors: Zhang Junqiang , Li Liangqiang , Qian Yu
Published: July 2016

Web 2.0 technologies have attracted an increasing number of active online writers and viewers. A deeper understanding of when customers will review and what motivates them to write online reviews is of both theoretical and practical significance. In this paper, we present a novel methodological framework, which consists of theoretical modeling and text-mining technologies, to study the relationships among customers’ review promptness, their review opinions, and their review motivations. We first study customers’ online “purchase-review” behavior dynamics; then, we introduce the LDA method to mine customers’ opinion from their review text; finally, we propose a theoretical model to explore some motivations for those people publishing review online. The analytical and experimental results with real data from a Chinese B2C website demonstrate that the behavior dynamics of customers’ online review are influenced by the multidimensional motivations, and some of them can be observed from their review behaviors, such as review promptness.
Isolation of 4,5‐O‐Dicaffeoylquinic Acid as a Pigmentation Inhibitor Occurring in Artemisia capillaris Thunberg and Its Validation In Vivo
Authors: Tabassum Nadia , Lee Ji-Hyung , Yim Soon-Ho , Batkhuu Galzad Javzan , Jung Da-Woon , Williams Darren R.
Published: July 2016

There is a continual need to develop novel and effective melanogenesis inhibitors for the prevention of hyperpigmentation disorders. The plant Artemisia capillaris Thunberg (Oriental Wormwood) was screened for antipigmentation activity using murine cultured cells (B16‐F10 malignant melanocytes). Activity‐based fractionation using HPLC and NMR analyses identified the compound 4,5‐O‐dicaffeoylquinic acid as an active component in this plant. 4,5‐O‐Dicaffeoylquinic acid significantly reduced melanin synthesis and tyrosinase activity in a dose‐dependent manner in the melanocytes. In addition, 4,5‐O‐dicaffeoylquinic acid treatment reduced the expression of tyrosinase‐related protein‐1. Significantly, we could validate the antipigmentation activity of this compound in vivo, using a zebrafish model. Moreover, 4,5‐O‐dicaffeoylquinic acid did not show toxicity in this animal model. Our discovery of 4,5‐O‐dicaffeoylquinic acid as an inhibitor of pigmentation that is active in vivo shows that this compound can be developed as an active component for formulations to treat pigmentation disorders.
Improving the Friction Durability of Magnetic Head-Disk Interfaces by Thin Lubricant Films
Authors: Miyake Shojiro , Suzuki Shota , Miyake Masatoshi
Published: July 2016

Nanowear and viscoelasticity were evaluated to study the nanotribological properties of lubricant films of Z-tetraol, D-4OH, and A20H, including their retention and replenishment properties. For A20H and thick Z-tetraol-coated disks, the disk surface partially protrudes, and the phase lag (tan⁡δ) increases with friction. This result is consistent with replenishment of the lubricant upon tip sliding. For the D-4OH-coated disk, thetan⁡δvalue decreases with tip sliding, similar to the case for the unlubricated disk. The durability of the lubricant-coated magnetic disks was then evaluated by load increase and decrease friction tests. The friction force of the unlubricated disk rapidly increases after approximately 30 reciprocating cycles, regardless of the load. The lubrication state can be estimated by mapping the dependence of friction coefficient on the reciprocating cycle number and load. The friction coefficient can be classified into one of four areas. The lowest friction area constitutes fluid lubrication. The second area constitutes the transition to mixed lubrication. The third area constitutes boundary lubrication. The highest friction of the fourth area results from surface fracture. The boundary lubricating area of the A20H lubricant was wide, because of its good retention and replenishment properties.
Receptor Tyrosine Kinase Phosphorylation Pattern–Based Multidrug Combination Is an Effective Approach for Personalized Cancer Treatment
Authors: Sun Xiaoxiao , Song Qiaoling , He Li , Yan Lei , Liu Jingli , Zhang Qing , Yu Qiang
Published: July 2016

Receptor tyrosine kinases (RTK) are key signaling molecules in regulating cancer cell growth and are important cancer drug targets. Despite the success of specific RTK-targeting therapy in certain cancer treatments, the overall response rates are limited to the drug target–stratified populations. We have systematically studied RTK activations in a panel of cancer cell lines, primary cancers, and cancer xenografts and found that different combinations of RTKs were activated in different cancer cells regardless of their tissue origins. Combinations of specific RTK inhibitors (RTKi) preferentially inhibited proliferation of the cancer cells with corresponding RTK activation profiles. We also found that the activations of RTKs were regulated by both cell-autonomous and environment-dependent mechanisms and demonstrated that inhibition of all activated RTKs was essential to completely block cancer cell proliferation. In addition, c-Myc downregulation was identified as an indicator for the effectiveness of the RTKi combination treatments. Our findings demonstrated that the RTK activation profile is a valid biomarker for diagnosis and stratification of cancers, and a corresponding combination of RTKis is a promising strategy to treat cancers, particularly the single RTKi therapy–resistant cancers, selectively and effectively. Mol Cancer Ther; 15(10); 2508–20. ©2016 AACR.
Abstract 10: Silibinin exhibits anti-cachectic and anti-cancerous property by modulating metabolic properties of pancreatic cancer cells
Authors: Shukla Surendra K. , Dasgupta Aneesha , Mehla Kamiya , Gunda Venugopal , Vernucci Enza , Soucheck Joshua , Goode Gennifer , King Ryan , Mishra Anusha , Rai Ibha , Natrajan Sangeetha , Chaika Nina , Yu Fang , Singh Pankaj K.
Published: July 2016

Cancer cachexia is a systemic syndrome characterized by progressive weight loss of the patient due to muscle wasting and fat depletion with or without anorexia. About 80% of pancreatic ductal adenocarcinoma (PDAC) patients exhibits cachectic phenotype and it significantly contributes in mortality and morbidity of the disease. In present study we have evaluated the effect of bioactive molecule silibinin on pancreatic cancer progression and cachectic properties by utilizing in vitro as well as in vivo models of PDAC. We observed that silibinin inhibits growth and induces apoptosis in multiple pancreatic cancer cell lines in a dose-dependent manner. We also observed silibinin-mediated reduction in the expression of key glycolytic genes and inhibition of glucose uptake and lactate secretion. By performing LC-MS/MS based metabolomics, we observed that silibinin treatment leads to global metabolic alterations in pancreatic cancer cells. Pancreatic cancer cells treated with silibinin exhibited reduced expression of c-MYC level, a key metabolic regulator. Furthermore, we observed that silibinin-mediated STAT3 inhibition leads to reduced c-MYC expression. Ectopic expression of constitutively active STAT3 significantly attenuated the effect of silibinin on c-MYC expression and metabolic phenotype of pancreatic cancer cells. Silibinin treatment also inhibited tumor growth and progression of cachexia. Silibinin treatment to tumor-bearing mice also lead to increased food intake, increased grip strength and body coordination. Overall, our results demonstrate that silibinin exhibits anti-cachectic and anti-cancerous properties by inducing metabolic reprogramming in pancreatic cancer cells.

Citation Format: Surendra K. Shukla, Aneesha Dasgupta, Kamiya Mehla, Venugopal Gunda, Enza Vernucci, Joshua Soucheck, Gennifer Goode, Ryan King, Anusha Mishra, Ibha Rai, Sangeetha Natrajan, Nina Chaika, Fang Yu, Pankaj K. Singh. Silibinin exhibits anti-cachectic and anti-cancerous property by modulating metabolic properties of pancreatic cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 10.
Abstract 1006: Novel adjuvants in triple negative breast cancer chemotherapy
Authors: Rampoldi Antonio , Harbuzariu Adriana , Harmon Tia L. , Gonzalez-Perez Ruben R.
Published: July 2016

Background: Obese patients develop more frequently triple negative breast cancer (TNBC) that has not target therapy and are commonly treated with chemotherapeutics. Leptin, whose levels are elevated in obesity, can induce TNBC proliferation, angiogenesis and resistance to chemotherapeutics. An antagonist for leptin receptor OB-R, leptin peptide receptor antagonist 2 (LPrA2), has been shown to block leptin signaling and decrease tumor progression. LPrA2 also countervails leptin induced resistance to chemotherapeutic agents. We used pegylation or iron oxide nanoparticle (IONPs) as adjuvants to increase LPrA2 solubility, stability and effectiveness.

Hypothesis: Conjugated LPrA2 will decrease TNBC cells proliferation, expression of leptin target molecules and tumorigenesis.

Methods: Human TNBC and murine breast adenocarcinoma derived cell line E0771 (progesterone and HER2 receptor negative) were used. The E0771 cell line was generated from an estrogen receptor positive (ER+) mammary adenocarcinoma isolated from a C57BL/6J mouse. E0771 was made insensitive to estrogen by treatment with drug Tamoxifen (TAM) mimicking TNBC. To specifically assess the role of RBP-Jk (CBS/CSL, an essential transcription factor for Notch signaling) the CRISPR/Cas9 system was used to disrupt RBP-JK gene expression in both wild-type and TAM treated E0771 cells. Cells were treated with chemotherapeutics (Paclitaxel, Doxorubicine, Ciclophosphamide) in presence of leptin and LPrA2-conjugates. The expression of leptin-targeted molecules, Breast Cancer Stem Cells (BCSC) and EMT markers were analyzed after cell treatment.

Results: Chemotherapeutics effects on proliferation, survival and molecular markers were modified by the addition of LPrA2-conjugates. Notch molecules (receptors and ligands) were downregulated by LPrA2 treatment.

Conclusion: The current data indicate that Leptin inhibition could be used as an adjuvant for chemotherapeutic treatments in TNBC patients. LPrA2-conjugates could increase the efficacy of chemotherapy.

Acknowledgements: This work was partially supported by the National Institute of Health and National Cancer Institute Grant U54 CA118638, NIH/SBIR 1R41CA183399-01A1, and DOD Idea Award BC W81XWH-13-1-0382 to RRGP; and facilities, and support services at Morehouse School of Medicine (NIH RR03034 and 1C06 RR18386) and NIH/NCRR grant 1G12RR026250-03.

Citation Format: Antonio Rampoldi, Adriana Harbuzariu, Tia L. Harmon, Ruben R. Gonzalez-Perez. Novel adjuvants in triple negative breast cancer chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1006.
Abstract 1013: Quantification of NADPH balance in cancer
Authors: Liu Ling , Chen Li , Ducker Greg , Park Junyoung , Shah Supriya , Wellen Kathryn E. , Rabinowitz Joshua D.
Published: July 2016

NADPH is a key cofactor involved in antioxidant defense and reductive biosynthesis. The quantitative contribution of different NADPH pathways, either in normal tissues or in tumors, remains unclear. Here we enable tracing of NADPH production using deuterium-labeled nutrients and mass spectrometry, providing methods that for the first time can track each of the major cytosolic pathways: malic enzyme, isocitrate dehydrogenase, folate metabolism, and the pentose phosphate pathway. This is achieved via a battery of different 2H-tracers. A linear algebra method for deducing the fractional contribution of each pathway, even when a specific tracer for that pathway is not available, will be described. Utility of these methods will be illustrated through examples drawn from both normal cellular physiology and cancer. Specifically, we find that most NADPH in differentiating adipocytes is made by malic enzyme. Examining cancer cells, we find that the pentose phosphate pathway is typically the largest cytosolic NADPH source, but that the collective contribution of alternative pathways is often larger than the pentose phosphate pathway. The specific other pathways involved differ strongly depending on the cancer cell type. We also provide examples where NADPH production routes in both normal and cancer cells vary with nutrient availability, including hypoxia. Given the heightened redox stress of cancer cells, understanding NADPH production routes is likely to illuminate new avenues for therapeutic intervention.

Citation Format: Ling Liu, Li Chen, Greg Ducker, Junyoung Park, Supriya Shah, Kathryn E. Wellen, Joshua D. Rabinowitz. Quantification of NADPH balance in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1013.
Abstract 102: Pan-cancer analysis of sex differences in somatic mutation profiles
Authors: Li Constance H. , Haider Syed , Boutros Paul C.
Published: July 2016

Sex influences the clinical and pathological characteristics of a number of cancers including those of the lung, colon and kidney. Men and women differ in incidence rate, response to treatment and survival - even after controlling for confounding factors such as smoking status, age and weight. Some gene-specific sex differences have been identified in these cancers, but there has not been a rigorous, genome-wide analysis of the mutational differences in tumors between men and women. We fill this gap, providing a comprehensive assessment of sex-associated differences in cancer genomics.

We leverage resources from the International Cancer Genome Consortium-The Cancer Genome Atlas pan-cancer project, which includes genomic, transcriptomic and epigenomic profiles of 25,000 tumours and whole genome sequences of 5,000 tumours. Using this data, we analyzed mutational differences between the sexes in 15 tumor types.

We use both univariate (t-test, proportions test) and multivariate (multinomial logistic regression) statistical techniques, along with bioinformatics and pathway analyses. We found distinct sex-associated genomic differences in the copy number aberration (CNA) profiles of six tumor types and in pan-cancer analysis. We observe higher genome instability in male-derived tumors and sex-biased mutations in specific genes and across genomic intervals. Using multivariate modeling to control for confounding variables reinforces the significance of sex in these genomic regions and also reveals additional sex-biased CNAs. Ongoing work with mRNA abundance data suggests an association between sex-differences in CNAs and mRNA abundance both in cis and in trans. Further investigation into affected genes and pathways may reveal fundamental differences in how tumors develop in men and women and provide explanations for reported clinical and pathological sex differences.

Citation Format: Constance H. Li, Syed Haider, Paul C. Boutros. Pan-cancer analysis of sex differences in somatic mutation profiles. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 102.
Abstract 1023: Functional genomics reveals dependency on 6-phosphogluconate dehydrogenase in OXPHOS-deficient tumors
Authors: Sun Yuting , Bandi Madhavi , Lofton Timothy , Smith Melinda , Bristow Christopher , Rogers Norma , Edward Chang , Geck Do Mary , Jiang Yongying , Morlacchi Pietro , Muller Florian , Mseeh Faika , Czako Barbara , Palmer Wylie , Toniatti Carlo , Jones Philip , Draetta Giulio , Heffernan Timothy , Marszalek Joseph
Published: July 2016

Cancer cells display metabolic properties distinct from normal cells and are therefore believed to be dependent on key metabolic enzymes. The effectiveness of targeting metabolism for cancer therapy has been largely restricted due to metabolic adaptability. We postulate that tumors with metabolic vulnerabilities will be limited in such adaptation, thus providing a unique opportunity for therapeutic intervention. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is a metabolically vulnerable cancer, due to mutations in a key TCA cycle enzyme - fumarate hydratase (FH), thus rendering them deficient in oxidative phosphorylation (OXPHOS). We performed a loss-of-function genetic screen in a FH-null HLRCC model (UOK262 cells) and identified 6-phosphogluconate dehydrogenase (6PGD) - a rate-limiting enzyme in the non-oxidative arm of pentose phosphate pathway - as a critical regulator of cell growth. Inhibition of 6PGD using either dox-inducible shRNA or a small molecule inhibitor dramatically blocks the growth of UOK262 cells, and in contrast, has no effect on 6PGD-deficient NB1 cells. The growth inhibition from knockdown is fully rescued by expressing shRNA-resistant 6PGD. Conversely, ectopic expression of 6PGD in NB1 cells results in a gain of function phenotype. Importantly, in vivo, 6PGD knockdown causes robust regression of established UOK262 xenografts. Mechanistically, 6PGD inhibition causes the accumulation of 6-phosphogluconate, blocks glycolysis, and induces ROS production. Furthermore, in tumors with intact TCA cycle, 6PGD inhibition shows synergism with OXPHOS Complex I inhibitor IACS-10759. Together, our data suggest that 6PGD is a bona fide oncology target and provide a strong rationale for developing small molecule inhibitors that could be used to treat OXPHOS-deficient tumors as single agent, or combined with inhibitors of OXPHOS.

Citation Format: Yuting Sun, Madhavi Bandi, Timothy Lofton, Melinda Smith, Christopher Bristow, Norma Rogers, Chang Edward, Mary Geck Do, Yongying Jiang, Pietro Morlacchi, Florian Muller, Faika Mseeh, Barbara Czako, Wylie Palmer, Carlo Toniatti, Philip Jones, Giulio Draetta, Timothy Heffernan, Joseph Marszalek. Functional genomics reveals dependency on 6-phosphogluconate dehydrogenase in OXPHOS-deficient tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1023.
Abstract 1025: A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces cell autophagy and apoptosis in esophageal squamous cell carcinoma cells
Authors: Li Wei , Hou Guixue , Zhou Dianrong , Lou Xiaomin , Xu Yang , Liu Siqi , Zhao Xiaohang
Published: July 2016

The protocatechuic acid ethyl ester ethyl-3,4-dihydroxybenzoate (EDHB) is an antioxidant found in the testa of peanut seeds. The cytotoxic effect of EDHB on esophageal squamous cell carcinoma (ESCC) cells was investigated and 46 up- and down-regulated genes involved in several signaling pathways associated with cell cycle regulation and cellular metabolism were identified. Our studies have shown that EDHB can effectively induce autophagy and apoptosis of esophageal cancer cells by BNIP3 and NDRG1 respectively, and AKR1C family were one of the differentially expressed genes after cells treated with EDHB. We also found that the esophageal cancer cells with higher (KYSE 180) and lower (KYSE 510) AKR1C expressing levels were selected, and the cell proliferation was found inhibited more effectively in KYSE 180 than KYSE 510 cells after treated with EDHB. Furthermore, at the same condition, the effective subunits of AKR1C superfamily, AKR1C1/C2, were identified quantitatively by multiple reaction monitoring (MRM) assays. And the involvement of AKR1C1/C2 in the metabolism of the EDHB in ESCC cells and induced cell death. When autophagy was inhibited using 3-methyladenine (3-MA), KYSE 180 cells exhibited higher sensitivity to EDHB and it may act as metabolic substrate of AKR1C1/C2. These results indicate that esophageal cancer patients with high expression of AKR1C1/C2 are more sensitive to EDHB and facilitate its induced autophagy and apoptosis that providing potential guidance for the chemoprevention of ESCC.

Citation Format: Wei Li, Guixue Hou, Dianrong Zhou, Xiaomin Lou, Yang Xu, Siqi Liu, Xiaohang Zhao. A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces cell autophagy and apoptosis in esophageal squamous cell carcinoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1025.
Abstract 103: Gene expression based subtypes of colorectal cancer
Authors: Berg Kaja G. , Eilertsen Ina A. , Alagaratnam Sharmini , Danielsen Stine A. , Nesbakken Arild , Sveen Anita , Lothe Ragnhild A.
Published: July 2016

Colorectal cancer is a heterogeneous disease and improved molecular stratification of patients is warranted for precise treatment. Several gene expression classification systems are reported in the literature, albeit many have shown low reproducibility in external validation. A robust random forest classification system based on gene expression profiles was recently proposed, suggesting the existence of four biologically different subtypes with associations to prognosis (CMS1, CMS2, CMS3 and CMS4) (Guinney,J., et al., Nat Med, 2015). By applying the CMS classifier to high-quality gene expression profiles from a consecutive series of >400 stage I-IV primary colorectal cancers we are able to reproduce results from Guinney et al in an independent cohort. Analyses of mutational hotspots in BRAF / KRAS and the complete coding sequence of TP53 confirms enrichment of BRAF mutations in CMS1 (p<0.001), TP53 mutations in CMS2 and KRAS mutations in CMS4 (p<0.001). We further validate high levels of somatic copy number aberrations (SCNAs) in CMS2 and CMS4 compared to CMS1 and CMS3 (pair-wise comparisons, fraction of genome affected by SCNAs: CMS1 vs CMS2: p<0.001; CMS1 vs CMS4: p<0.01; CMS2 vs CMS3: p<0.001; CMS3 vs CMS4: p<0.01). Additionally we explore within-subtype variations with respect to SCNAs in the CMS2 and CMS4 subtypes. Altogether our results validate the CMS system as a robust classification system for colorectal cancer.

Citation Format: Kaja G. Berg, Ina A. Eilertsen, Sharmini Alagaratnam, Stine A. Danielsen, Arild Nesbakken, Anita Sveen, Ragnhild A. Lothe. Gene expression based subtypes of colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 103.
Abstract 1032: Characterizing the metabolic dependencies of rhabdomyosarcoma and Ewing's sarcoma cells
Authors: Issaq Sameer , Helman Lee
Published: July 2016

Sarcomas represent a diverse group of malignancies with unique molecular and pathological characteristics. In order to improve sarcoma treatment, a better understanding of the alterations associated with specific sarcoma subtypes is critically important. Renewed interest in the altered metabolic properties of cancer cells has led to an exploration of targeting metabolic dependencies as a novel therapeutic strategy. In this study, we have characterized the dependency of rhabdomyosarcoma (RMS) and Ewing's sarcoma (EWS) cells on key metabolic substrates by examining cell proliferation and bioenergetic properties under varying concentrations of glucose and glutamine. We utilized two alveolar RMS cell lines, one embryonal RMS cell line, and five EWS cell lines. While all cell lines tested were completely growth-inhibited by lack of glucose, individual RMS and EWS cell lines were differentially sensitive to removal of glutamine. Furthermore, glutamine deprivation significantly reduced mitochondrial bioenergetic function, as demonstrated by Seahorse metabolic flux analysis. The observed effects of glutamine deprivation on proliferation and mitochondrial bioenergetics were rescued by the re-introduction of glutamine into the culture media. Our findings suggest that metabolic dependencies of RMS and EWS cells should be further investigated in order to identify metabolic vulnerabilities that could be targeted for potential therapeutic benefit.

Citation Format: Sameer Issaq, Lee Helman. Characterizing the metabolic dependencies of rhabdomyosarcoma and Ewing's sarcoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1032.
Abstract 1040: Differential levels of glycogen in breast cancer cell lines: A potential new target
Authors: Yates Joel A. , Altemus Megan , Wu Zhifen , Wynn Michelle L. , Merajver Sofia D.
Published: July 2016

Cancer cells have been known to alter their metabolic processes in order to survive and proliferate. Normally in muscle and liver, excess glucose is stored within the cells as glycogen. Elevated levels of glycogen have also been found in various cancers, including breast cancers. Recent studies have implicated glycogen metabolism as important in promoting survival of cancer cells, suggesting targeting of glycogen metabolism as a possible treatment to inhibit cancer cell growth. In general, modulation of cancer metabolism is believed to be an attractive adjunct strategy to conventional or targeted therapies. Here we set out to investigate glycogen levels as well as levels of proteins involved in glycogen synthesis and degradation vary across different breast cancer cell lines.

A glucose metabolism qPCR array found differential levels of the alpha subunit of phosphorylase kinase 1, a key enzyme involved in glycogen degradation among three different breast cancer cell lines. Expression levels of glycogen synthesis and degradation enzymes were assessed using qPCR and immunoblot in various breast cancer cell lines. Glycogen levels in these breast cancer cell lines were quantified using an amyloglucosidase reaction coupled with other enzymatic reactions to produce a fluorescent product. It was found that MDA-MB-231, SUM149, and MCF7 cell lines had increased levels of glycogen, between 6.5 and 23.5 μg glycogen per mg protein, whereas SUM190 and normal-like breast epithelial cell line MCF10A had undetectable levels of glycogen. These findings demonstrate that glycogen metabolism can vary widely amongst cancer types, indicating that therapies targeted to disrupt glycogen degradation may produce differential results and that further study of the role of glycogen metabolism in cancer is warranted.

Citation Format: Joel A. Yates, Megan Altemus, Zhifen Wu, Michelle L. Wynn, Sofia D. Merajver. Differential levels of glycogen in breast cancer cell lines: A potential new target. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1040.
Abstract 1046: Statin inhibits malignant mesothelioma cell growth by inactivating YAP1
Authors: Tanaka Kosuke , Kato Taketo , Matsushita Akihiro , Furuta Hiromi , Murakami Yuko , Osada Hirotaka , Sekido Yoshitaka
Published: July 2016

The prognosis of patients with malignant mesothelioma (MM) remains very poor because of highly invasive tumor characteristics and therapeutic resistance of this tumor. Recent studies have shown that MM frequently shows Hippo signaling pathway inactivation, which leads to activation of YAP1 transcriptional co-activator. Although substantial data from clinical trials and epidemiological studies showed promising results for the use of statins in many cancers, few studies have argued about the underlying tumor-suppressive mechanisms of statins. Here, we show that statins act as an inhibitor of YAP1-dependent MM cell growth via mevalonate pathway. In cell culture, statins attenuate migration and invasion of H290 malignant mesothelioma cells with homozygous deletion of NF2, which encodes Merlin, an upstream regulator of Hippo pathway. In contrast, geranylgeranyl diphosphate (GGPP), a down-stream activator of mevalonate pathway, completely rescues H290 cell growth inhibition by statins. We also found that statins accelerate YAP phosphorylation/inactivation, which results in the downregulation of Hippo-pathway targeting gene transcriptions including CTGF, CYR-61 and ANKRD1. Moreover, among 11 MM cell lines, we demonstrated that five out of the six cell lines, which showed significant cell growth inhibition with statins, harbor NF2 and/or LATS2 mutations. Finally, we found that phospho-YAP/YAP ratio was increased in statin-sensitive cells, but not in statin-resistant cells. Together, our findings suggest that mevalonate pathway plays crucial roles in YAP-dependent MM cells by Hippo pathway inactivation, and therefore represents a potential therapeutic target for MM.

Citation Format: Kosuke Tanaka, Taketo Kato, Akihiro Matsushita, Hiromi Furuta, Yuko Murakami, Hirotaka Osada, Yoshitaka Sekido. Statin inhibits malignant mesothelioma cell growth by inactivating YAP1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1046.