bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR1: Genomic discovery of CD44-SLC1A2 gene fusions in gastric cancer
Authors: Tao Jiong , Ramnarayanan Kalpana , Huang Baohua , Tan Iain Beehuat , Ooi Chia Huey , Lee Minghui , Zhang Shenli , Leong Siew Hong , Ivanova Tatiana , Ganesan Kumaresan , Gopalakrishnan Veena , Rha Sun Young , Chung Hyun Cheol , Yap Celestial , Palanisamy Nallasivam , Tan Patrick 
Published: June 2012

Abstract
Among the various genomic abnormalities associated with cancers, fusion genes and transcripts are particularly notable due to their cancer-specific nature and translational potential as diagnostic and therapeutic targets. In pediatric acute lymphoblastic leukemia (ALL), assays detecting the AML-ETO and PML-RAR fusion genes are routinely used to diagnose particular clinical subtypes, and treatment of chronic myelogenous leukemia (CML), a disease once associated with extremely poor prognosis, has been revolutionized by imatinib, an inhibitor of the BCR-ABL fusion gene. While fusion genes are well- known in hematological malignancies, our knowledge of recurrent fusion events in solid epithelial tumors is far less mature. To date, only two fusion genes have been identified in solid tumors, including TMPRSS2-ERG in prostate cancer, and EML4-ALK in non-small cell lung cancer. No recurrent fusion genes have been so far identified in common gastrointestinal cancers such as stomach, colon and esophageal adenocarcinoma. In this study, to identify genes affected by genome rearrangements in gastric cancer (GC), which is the second highest cause of global cancer mortality, we analyzed chromosomal imbalances in a cohort of 123 primary GCs and cell lines, and discovered several tumors exhibiting recurrent genomic breakpoints in the SLC1A2/EAAT2 glutamate transporter. 5’ RNA ligase mediated rapid amplification of cDNA ends (RLM-RACE) analysis of a GC cell line with SLC1A2 breakpoints (SNU16) revealed expression of a CD44-SLC1A2 fusion transcript, computationally predicted to result in a truncated but functional SLC1A2 protein. In an independent tumor panel, CD44-SLC1A2 gene fusions were detected in 4% to 5% of GCs (2/43), but not in adjacent matched normal gastric tissues. Using custom-designed fusion-specific siRNAs, we show that silencing of CD44-SLC1A2 in fusion-positive SNU16 cells significantly reduced cellular proliferation, invasion, and colony formation, but not in cell lines lacking CD44-SLC1A2 expression. CD44-SLC1A2 silencing also significantly reduced intracellular glutamate levels and sensitized SNU16 cells to cisplatin. Fusions of SLC1A2 to upstream CD44 regulatory elements likely causes SLC1A2 transcriptional dysregulation, as tumors expressing abnormally high SLC1A2 levels also tended to be CD44-SLC1A2 positive. CD44-SLC1A2 gene fusions may be one mechanism used by cancers to establish a pro-oncogenic metabolic milieu favoring tumor growth and survival. We believe that our study will be of great interest to the gastric cancer community, as it represents the first recurrent fusion transcript identified in this disease (and for that matter any common gastrointestinal cancer).
Citation Information: Clin Cancer Res 2010;16(14 Suppl):PR1.
Abstract PR2: Therapeutic intervention targeting a Hedgehog-dependent barrier to drug delivery in pancreatic cancer
Authors: Olive Kenneth P. , Jacobetz Michael , Gopinathan Aarthi , Goldgraben Mae , Ireland Heather , Reichelt Stefanie , Howat William J. , Whitebread Nigel , McGovern Karen , Adams Julian , Iacobuzio-Donahue Christine , Griffiths John , Tuveson David 
Published: June 2012

Abstract
Ductal pancreatic tumors are unusually resistant to chemotherapy, exhibiting primary resistance to each of the numerous regimens tested to date. These tumors are also unusually desmoplastic and harbor a sparse and inefficient vasculature. The resulting lack of perfusion appears to play a role in the inefficient delivery of numerous chemotherapeutic agents to the parenchyma of pancreatic tumors. Recent evidence has implicated the sonic hedgehog pathway in promoting desmoplasia through a paracrine signaling mechanism active in pancreatic tumors of both humans and the Kras/p53/PdxCre (KPC) mouse model. We sought to evaluate the dependence of stromal desmoplasia on Hedgehog (Hh) pathway signaling and, by extension, assess the effects of Hh pathway inhibition on drug delivery and chemoresistance.
Using IPI-926, a semisynthetic inhibitor of the Smoothened protein, we found that stromal contribution was markedly diminished within 10 days of inhibition of the Hh pathway. Paradoxically, the depletion of stromal cells was coincident with an increase in microvessel density, despite previous data indicating a pro-angiogenic role for the Hh pathway. These non-cell autonomous changes resulted in an increase in the delivery of small molecules to KPC pancreatic tumors and an increase in apoptosis when administered in combination with gemcitabine. Ultimately, mice treated with both IPI-926 and gemcitabine had a significant extension of survival and a decrease in the incidence of liver metastases. We conclude that the Hh pathway plays an important role in the maintenance of pancreatic tumor stroma and that this contributes to the primary chemoresistance of pancreatic tumors. These data also support the clinical evaluation of agents that target the stroma in pancreatic cancer.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):PR2.
Abstract PR3: Preclinical and molecular profiling data suggest LumB breast cancer as a potential indication for co-targeting IGF1R and mTOR with MK-0646 and MK-8669
Authors: Zhang Theresa , Feldman Igor , Sathyanarayanan Sriram , Haines Brian , Paweletz Cloud , Nebozhyn Michael , Shumway Stuart , Roberts Brian , Arthur William , Strack Peter , Huang Pearl , Dai Hongyue , Buser-Doepner Carolyn , Loboda Andrey , Watters James 
Published: June 2012

Abstract
There has been increasing interest in developing cancer therapies targeting PI3K pathway nodes. However, inhibition of a single node in PI3K pathway such as mTOR by rapamycin analogues results in compensatory activation of survival signaling pathway such as AKT and thereby limiting monotherapy activity. Therefore, in most tumor types, multipathway inhibition, guided by an in-depth understanding of feedback and crosstalk between pathways, may be required for tumor regression. It is well known that that mTOR inhibition upregulates pAKT via the S6K-IRS2 negative feedback loop. Inhibiting both mTOR and IGF1R may therefore ablate such feedback upregulation and lead to clinical response. However, it is unclear which tumor types will respond to the combination in the clinic. Here, we present preclinical and molecular profiling data that supports LumB breast cancer as a potential indication for MK-8669/MK-0646 (mTOR/IGF1 R inhibitor combination). When a panel of over 60 breast cancer cell lines was treated with MK-8669, ER+ cell lines and HER2+ cell lines were clearly more responsive than the triple negative ones. Meanwhile, the status of the MAPK pathway, as captured by a RAS gene expression signature, correlated with resistance to MK-8669 across the panel. Moreover, MK-8669 treatment unregulated multiple key nodes of the IGF1R pathway in the breast cell line panel, especially IRS2, whose upregulation correlated with the response to MK-8669. Furthermore, IGF1R, whose mRNA level correlates with the response to MK-0646 (IGF1 Ri) in multiple internal and external studies, is the highest in a subset of LumB tumors, suggesting a potential dependency on the IGF1R pathway in those tumors. Finally, a comparison between the gene expression profiles of breast cancer cell lines and tumors revealed that the ER+ breast cancer cell lines only represented the LumB, not LumA, subtype of human breast tumors. Taken together, these findings allow us to hypothesize that LumB breast cancer may be enriched in responders to the MK-0646/MK-8669 combination. In 2009, Merck initiated a phase I trial of MK-8669/MK-0646 in which clinical response was observed in LumB breast cancer patients. A phase II clinical trial has been initiated to test the hypothesis retrospectively.
This talk is also presented as Poster A52.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):PR3.
Abstract PR5: Prediction of survival in diffuse large B-cell lymphoma based on the expression of two genes integrating tumor and microenvironment
Authors: Gentles Andrew J. , Alizadeh Ash A. , Alencar Alvaro J. , Kohrt Holbrook E. , Houot Roch , Goldstein Matthew J. , Natkunam Yasodha , Advani Ranjana H. , Gascoyne Randy D. , Briones Javier , Plevritis Sylvia K. , Lossos Izidore S. , Levy Ronald 
Published: June 2012

Abstract
Several gene expression signatures are predictive of prognosis in diffuse large B cell lymphoma (DLBCL), but the lack of practical methods for a genome scale analysis has restricted their clinical applicability. Towards construction of a molecular predictor amenable to rapid testing on routinely obtained diagnostic clinical specimens, we studied genes previously reported to be associated with survival in DLBCL, testing and validating risk scoring models with robust survival associations in the current therapeutic era.
We identified LMO2 expression as a robust univariate predictor of survival and cell of origin classification of DLBCL, with independent prognostic value. We examined bivariate models combining expression of LMO2 with other genes, and identified TNFRSF9 as a tumor microenvironment gene with independent prognostic influence. A combined model integrating both LMO2 and TNFRSF9 expression was independent of “cell of origin” classification, “stromal signatures,” International Prognostic Index (IPI), and added to the predictive power of IPI. A composite model was validated in multiple independent patient cohorts using public microarray data. Using routinely obtained formalin fixed, paraffin embedded diagnostic specimens from an independent cohort, we developed a simple assay validating the clinical utility of this 2-gene model, as well as a composite model integrating the IPI. In conclusion, measurement of a single gene expressed by tumor cells and a single gene expressed by the immune microenvironment is sufficient to predict overall survival in patients with DLBCL treated with R-CHOP. A combined model serves as a robust clinical risk assessment tool.
This talk is also presented as Poster A27.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):PR5.
Abstract PR6: Resistance to EGFR inhibition via the emergence of EGFRvIII-independent tumor growth-promoting mechanisms in glioblastoma
Authors: Wykosky Jill , Mukasa Akitake , Chin Lynda , Cavenee Webster , Furnari Frank 
Published: June 2012

Abstract
A major hurdle in the clinical success of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the treatment of glioblastoma multiforme (GBM) is the occurrence of resistance, the mechanisms for which remain largely unknown. Amplification of EGFR and/or expression of its constitutively active mutant, EGFRvIII, are among the most frequently found molecular alterations in GBMs. Recently, we have shown that U373 cells engineered to express doxycycline (dox)-repressible EGFRvIII were dependent upon the expression of this receptor not only for tumor initiation, but also for maintenance and progression of tumors in a xenograft mouse model. Interestingly, following a period of growth stasis in vivo due to silencing of EGFRvIII, some tumors regained the ability to grow rapidly, which is strikingly similar to the clinical scenario of resistance. These aggressive breakthrough tumors, termed “escapers,” remained silenced for EGFRvIII and employed distinctly different signaling pathways when collectively compared to the initial EGFRvIII-dependent tumors. Escapers exhibited elevated activity of components of the MAPK signaling pathway, and cell lines established from the tumors were significantly more sensitive to inhibition of Mek than cells derived from EGFRvIII-dependent tumors. Removal of dox and reexpression of EGFRvIII in escapers markedly suppressed tumor growth, suggesting that the unique signaling pathway preferences of escapers are not compatible with those pathways preferentially utilized by EGFRvIII. Genes were identified by microarray analysis that were specifically expressed at higher levels in the escapers. These genes represent candidates for involvement in the process of overcoming EGFRvIII-dependence and, thus, may also contribute to resistance to EGFR inhibition. Significantly, escaper cells that reexpressed EGFRvIII were resistant to the in vitro growth- inhibitory effects of the TKI gefitinib as measured by colony formation in soft agar. Thus, the emergence of EGFRvIII-independent tumor growth-promoting mechanisms in escapers is characterized by a switch in pathway signaling preferences and upregulation of novel genes, and confers resistance to EGFR inhibition. The genes and pathways identified may shed light on novel mechanisms of TKI resistance and point towards potential targets for the development of agents that could be used in combination with TKIs to circumvent resistance while improving clinical response.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):PR6.
Calciolangbeinite, K2Ca2(SO4)3, a new mineral from the Tolbachik volcano, Kamchatka, Russia
Authors: Pekov I. V. , Zelenski M. E. , Zubkova N. V. , Yapaskurt V. O. , Chukanov N. V. , Belakovskiy D. I. , Pushcharovsky D. Y. 
Published: July 2012

AbstractThe new mineral calciolangbeinite, ideally K2Ca2(SO4)3, is the Ca-dominant analogue of langbeinite. It occurs in sublimates at the Yadovitaya fumarole on the Second scoria cone of the Northern Breakthrough of the Great Tolbachik Fissure eruption, Tolbachik volcano, Kamchatka, Russia. The mineral is associated with langbeinite, piypite, hematite, rutile, pseudobrookite, orthoclase, lyonsite, lammerite, cyanochroite and chlorothionite. Calciolangbeinite occurs as tetrahedral to pseudooctahedral crystals, which are bounded by {111} and {11}, and as anhedral grains up to 1 mm in size, aggregated into clusters up to 2 mm across, and forming crusts covering areas of up to 1.5x1.5 cm on the surface of volcanic scoria. Late-stage calciolangbeinite occurs in complex epitaxial intergrowths with langbeinite. Calciolangbeinite is transparent and colourless with white streak and vitreous lustre. Its Mohs' hardness is 3–3½. It is brittle, has a conchoidal fracture and no obvious cleavage. The measured and calculated densities are Dmeas = 2.68(2) and Dcalc = 2.74 g cm–3, respectively. Calciolangbeinite is optically isotropic with n = 1.527(2). The chemical composition of the holotype specimen is Na2O 0.38, K2O 21.85, MgO 6.52, CaO 16.00, MnO 0.27, FeO 0.08, Al2O3 0.09, SO3 55.14, total 100.63 wt.%. The empirical formula, calculated on the basis of twelve oxygen atoms per formula unit, is K2.01(Ca1.24Mg0.70Na0.05Mn0.02Fe0.01Al0.01)S 2.03S3.00O12. Calciolangbeinite is cubic, space group P213, a = 10.1887(4) Å, V = 1057.68(4) Å3 and Z = 4. The strongest reflections in the X-ray powder pattern [listed as (d, Å (I)(hkl)] are 5.84(8)(111); 4.54(9)(120); 4.15(27)(211); 3.218 (100) (310, 130); 2.838 (8) (230, 320), 2.736 (37) (231, 321), 2.006 (11) (431, 341) , 1.658(8)(611,532,352). The crystal structure was refined from single-crystal X-ray diffraction data to R = 0.0447. The structure is based on the langbeinite-type three-dimensional complex framework, which is made up of (Ca,Mg)O6 octahedra (Ca and Mg are disordered) and SO4 tetrahedra. Potassium atoms occupy two sites in voids in the framework; K(1) cations are located in ninefold polyhedra whereas K(2) cations are sited in significantly distorted octahedra. Calciolangbeinite and langbeinite are isostructural and form a solid-solution series.
Computational identification and analysis of novel sugarcane microRNAs
Authors: Thiebaut Flávia , Grativol Clícia , Carnavale-Bottino Mariana , Rojas Cristian Antonio , Tanurdzic Milos , Farinelli Laurent , Martienssen Robert A , Hemerly Adriana Silva , Ferreira Paulo Cavalcanti Gomes 
Published: July 2012

Abstract

Background
MicroRNA-regulation of gene expression plays a key role in the development and response to biotic and abiotic stresses. Deep sequencing analyses accelerate the process of small RNA discovery in many plants and expand our understanding of miRNA-regulated processes. We therefore undertook small RNA sequencing of sugarcane miRNAs in order to understand their complexity and to explore their role in sugarcane biology.

Results
A bioinformatics search was carried out to discover novel miRNAs that can be regulated in sugarcane plants submitted to drought and salt stresses, and under pathogen infection. By means of the presence of miRNA precursors in the related sorghum genome, we identified 623 candidates of new mature miRNAs in sugarcane. Of these, 44 were classified as high confidence miRNAs. The biological function of the new miRNAs candidates was assessed by analyzing their putative targets. The set of bona fide sugarcane miRNA includes those likely targeting serine/threonine kinases, Myb and zinc finger proteins. Additionally, a MADS-box transcription factor and an RPP2B protein, which act in development and disease resistant processes, could be regulated by cleavage (21-nt-species) and DNA methylation (24-nt-species), respectively.

Conclusions
A large scale investigation of sRNA in sugarcane using a computational approach has identified a substantial number of new miRNAs and provides detailed genotype-tissue-culture miRNA expression profiles. Comparative analysis between monocots was valuable to clarify aspects about conservation of miRNA and their targets in a plant whose genome has not yet been sequenced. Our findings contribute to knowledge of miRNA roles in regulatory pathways in the complex, polyploidy sugarcane genome.
Somato-dendritic morphology and dendritic signal transfer properties differentiate between fore- and hindlimb innervating motoneurons in the frog Rana esculenta
Authors: Stelescu András , Sümegi János , Wéber Ildikó , Birinyi András , Wolf Ervin 
Published: June 2012

Abstract

Background
The location specific motor pattern generation properties of the spinal cord along its rostro-caudal axis have been demonstrated. However, it is still unclear that these differences are due to the different spinal interneuronal networks underlying locomotions or there are also segmental differences in motoneurons innervating different limbs. Frogs use their fore- and hindlimbs differently during jumping and swimming. Therefore we hypothesized that limb innervating motoneurons, located in the cervical and lumbar spinal cord, are different in their morphology and dendritic signal transfer properties. The test of this hypothesis what we report here.

Results
Discriminant analysis classified segmental origin of the intracellularly labeled and three-dimensionally reconstructed motoneurons 100% correctly based on twelve morphological variables. Somata of lumbar motoneurons were rounder; the dendrites had bigger total length, more branches with higher branching orders and different spatial distributions of branch points. The ventro-medial extent of cervical dendrites was bigger than in lumbar motoneurons. Computational models of the motoneurons showed that dendritic signal transfer properties were also different in the two groups of motoneurons. Whether log attenuations were higher or lower in cervical than in lumbar motoneurons depended on the proximity of dendritic input to the soma. To investigate dendritic voltage and current transfer properties imposed by dendritic architecture rather than by neuronal size we used standardized distributions of transfer variables. We introduced a novel combination of cluster analysis and homogeneity indexes to quantify segmental segregation tendencies of motoneurons based on their dendritic transfer properties. A segregation tendency of cervical and lumbar motoneurons was detected by the rates of steady-state and transient voltage-amplitude transfers from dendrites to soma at all levels of synaptic background activities, modeled by varying the specific dendritic membrane resistance. On the other hand no segregation was observed by the steady-state current transfer except under high background activity.

Conclusions
We found size-dependent and size-independent differences in morphology and electrical structure of the limb moving motoneurons based on their spinal segmental location in frogs. Location specificity of locomotor networks is therefore partly due to segmental differences in motoneurons driving fore-, and hindlimbs.
Capsule endoscopy with flexible spectral imaging color enhancement reduces the bile pigment effect and improves the detectability of small bowel lesions
Authors: Sakai Eiji , Endo Hiroki , Kato Shingo , Matsuura Tetsuya , Tomeno Wataru , Taniguchi Leo , Uchiyama Takashi , Hata Yasuo , Yamada Eiji , Ohkubo Hidenori , Higrashi Takuma , Hosono Kunihiro , Takahashi Hirokazu , Nakajima Atsushi 
Published: July 2012

Abstract

Background
Capsule endoscopy with flexible spectral imaging color enhancement (CE-FICE) has been reported to improve the visualization and detection of small-bowel lesions, however, its clinical usefulness is still not established. Therefore, we conducted a study to evaluate whether CE-FICE contributes to improve the detectability of small-bowel lesions by CE trainees.

Methods
Four gastroenterology trainees without prior CE experience were asked to read and interpret 12 CE videos. Each of the videos was read by conventional visualization method and under three different FICE settings. To evaluate whether the lesion recognition ability of the CE trainees could be improved by the FICE technology, the lesion detection rate under each of the three FICE settings was compared with that by conventional CE. CE trainees tend to miss small-bowel lesions in bile-pigment-positive condition, therefore we evaluated whether CE-FICE contributes to reducing the bile-pigment effect. The bile-pigment condition was determined by the color values around the small-bowel lesions according to the results of the receiver-operating-characteristic analysis. Moreover, we also evaluated whether poor bowel preparion might affect the accuracy of lesion recognition by CE-FICE.

Results
Of a total of 60 angioectasias, CE trainees identified 26 by conventional CE, 40 under FICE setting 1, 38 under FICE setting 2, and 31 under FICE setting 3. Of a total of 82 erosions/ulcerations, CE trainees identified 38 by conventional CE, 62 under FICE setting 1, 60 under FICE setting 2, and 20 under FICE setting 3. Compared with conventional CE, FICE settings 1 and 2 significantly improved the detectability of angioectasia (P = 0.0017 and P = 0.014, respectively) and erosions/ulcerations (P = 0.0012 and P = 0.0094, respectively). Although the detectability of small-bowel lesions by conventional CE (P = 0.020) and under FICE setting 2 (P = 0.0023) was reduced by the presence of bile-pigments, that under FICE setting 1 was not affected (P = 0.59). Our results also revealed that in poor bowel visibility conditions, CE-FICE yielded a high rate of false-positive findings.

Conclusions
CE-FICE may reduce the bile-pigment effect and improve the detectability of small-bowel lesions by CE trainees; the reliability of CE-FICE may be improved by good bowel preparation.