bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A26: Pimozide, an antipsychotic derivative, targets the STAT signaling pathway in osteosarcoma
Authors: Angulo Pablo , Chastain Katherine , Subramaniam Dharmalingam , Anant Shrikant 
Published: August 2018

Abstract
Objective: Osteosarcoma (OS) is the most common pediatric bone cancer worldwide with an annual US incidence of 800. Chemotherapy and surgery have resulted in a marginal increase in survival of localized OS. However, that same treatment regimen has not been as successful for improving metastatic OS, as it yields an abysmal 5-year overall survival of less than 30% in patients afflicted with the disease. There have not been new successful standardized treatment agents in the last 2 decades for OS. Current standard practice still implements the same chemotherapeutic agents: cisplatin, doxorubicin, and methotrexate. These nonspecific agents have failed to yield optimal survival in metastatic OS patients. Hence, there is a need to utilize different agents that can specifically target signaling pathways involved in the pathogenesis of OS. One such pathway that has been found to be instrumental in the pathogenesis of OS is the JAK/STAT pathway, and the antipsychotic medication pimozide appears to be able to halt OS growth through inhibiting this pathway. Herein, we investigated the effects of pimozide on OS cancer growth and elucidated its mechanistic action through STAT signaling pathway.
Methods: Human OS cell lines KHOS, MG63, and SJSA cell lines and normal osteoblast cells were used in the study. The effects of pimozide on cell proliferation were assessed by hexosaminidase and clonogenicity assays. Effects of pimozide on stem cells were evaluated by colonosphere formation. Furthermore, the effect of pimozide on OS cells was evaluated by live cell fluorescent staining. Western blot was utilized to evaluate the effect on STAT protein expression.
Results: Pimozide treatment resulted in a dose- and time-dependent inhibition of proliferation and colony formation in all three osteosarcoma cell lines but not in osteoblast cells. It induces caspase 3 and 7 activity. Pimozide also showed reduced live cell fluorescent staining. Pimozide significantly reduced the number and size of spheroid formation. In addition, pimozide inhibits OS stem cell marker protein CD44 expression. Moreover, pimozide treatment decreased the expression of STAT5 signaling proteins on Western blot, which suggests that pimozide inhibits OS growth through STAT signaling pathway.
Conclusion: Together, these data suggest that pimozide inhibits OS cancer growth by inhibiting the STAT signaling pathway. Pimozide could serve as a potential therapeutic agent for OS.
Citation Format: Pablo Angulo, Katherine Chastain, Dharmalingam Subramaniam, Shrikant Anant. Pimozide, an antipsychotic derivative, targets the STAT signaling pathway in osteosarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A26.
Abstract B09: Novel sarcoma treatments identified via drug sensitivity/resistance screening of sarcoma cell lines
Authors: Grad Iwona , Ayuda Pilar , Hanes Robert , Enserink Jorrit , Myklebost Ola 
Published: August 2018

Abstract
Sarcomas comprise a plethora of subtypes and each should be regarded as ultra-orphan malignancy. Over the last century incremental improvements of sarcoma therapies have provided better survival; however, treatment options appear to have been exhausted and new alternatives beyond traditional chemotherapeutic regimens are much needed. To broaden the repertoire of antisarcoma drugs, we applied a direct drug testing approach. Using a library of 349 anticancer compounds (FDA-approved/under clinical trial) and panels of liposarcoma and osteosarcoma cell lines, we selected a group of potential novel antisarcoma therapeutics and retested them against cells from primary tumors. We are also investigating genomic and molecular features to find potential drug response biomarkers. Since all those compounds have been approved or are under clinical trials, they present a unique shortcut repurposing opportunity for personalized sarcoma treatment.
Citation Format: Iwona Grad, Pilar Ayuda, Robert Hanes, Jorrit Enserink, Ola Myklebost. Novel sarcoma treatments identified via drug sensitivity/resistance screening of sarcoma cell lines [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B09.
Abstract B22: Uncovering the role of lysyl oxidase-like 2 in rhabdomyosarcoma
Authors: Rabaiget Olga Almacellas , Martínez Juan Huertas , Monclús Silvia Garcia , Varona Santiago Rello , Martín Herrero , Alemany Roser López , Tirado Oscar M. 
Published: August 2018

Abstract
Rhabdomyosarcoma (RMS) is the most common soft-tissue malignancy in childhood and adolescence that originates as a consequence of regulatory disruption in the growth and differentiation of muscle precursor cells. Members of the lysyl oxidase family of proteins (LOX and LOXL1-4) are amine oxidases that catalyze the covalent crosslinking of collagen and elastin in the extracellular matrix. Apart from their traditional role, novel functions have been attributed to these proteins related to tumor progression. In this study we sought to unravel the potential role of this family of proteins during the progression of RMS. By qRT-PCR and Western blot, lysyl oxidase-like 2 (LOXL2) was found overexpressed in RMS cell lines compared to other sarcoma cells. Then we characterized LOXL2 in RMS cell lines by analyzing the subcellular localization by immunofluorescence and subcellular fractionation. Post-translational modifications were also analyzed: glycosylation and proteolytic processing by tunicamycin treatment and secretion by analysis of the conditioned media by Western blot. Moreover, we characterized the neoplastic phenotype after silencing LOXL2 in two RMS cell lines (RH4 and CW9019). Stable LOXL2 knockdown resulted in a decrease in their clonogenic, proliferative, and cell migratory capabilities. On the other hand, reexpression of LOXL2 in RH28 cells using wild-type or mutated (catalytically inactive) constructs resulted in an increase in cell proliferation and migration, independently of its catalytic activity. Finally, in vivo experiments using an orthotopic model of tumor generation inside the muscle will be carried out to further evaluate the tumorigenic role of LOXL2. Taking all into consideration, our results suggest an oncogenic role of LOXL2 in RMS.
Citation Format: Olga Almacellas Rabaiget, Juan Huertas Martínez, Silvia Garcia Monclús, Santiago Rello Varona, David Herrero Martín, Roser López Alemany, Oscar M. Tirado. Uncovering the role of lysyl oxidase-like 2 in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B22.
Abstract IA05: Genomic approaches to drug discovery
Authors: Golub Todd 
Published: August 2018

Abstract
It is now becoming possible to bring powerful genomic methods to bear on the process of drug discovery. This talk will illustrate 1) the use of the Connectivity Map, a large-scale effort to develop a compendium of gene expression signatures of cellular state; 2) the use of PRISM, a new multiplexed, high-throughput approach to screening cancer cell lines for anticancer activity; and 3) the use of cancer models (cell lines and patient-derived xenografts) in discovery, with particular focus on clonal drift in these models and the impact of that drift on drug sensitivity.
Citation Format: Todd Golub. Genomic approaches to drug discovery [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA05.
Abstract IA07: Cancer drug target identification using domain-focused CRISPR screening
Authors: Vakoc Christopher 
Published: August 2018

Abstract
In my presentation, I will describe an experimental strategy to reveal actionable protein domains that sustain the growth of cancer cells, which relies on CRISPR-Cas9-based indel mutagenesis of exons encoding protein domains.
Citation Format: Christopher Vakoc. Cancer drug target identification using domain-focused CRISPR screening [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA07.
Abstract IA18: Integrin-α10 drives metastasis and sarcomagenesis in mxyofibrosarcoma and undifferentiated pleomorphic sarcoma
Authors: Singer Samuel 
Published: August 2018

Abstract
Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) are the most common and aggressive types of genetically complex sarcoma. The development of new targeted therapies is vital for improving patients' outcomes; however, the complexity of alterations in these sarcomas has made it difficult to find the true drivers of oncogenesis. To investigate the molecular basis of MFS and UPS oncogenesis and progression, we undertook gene expression and copy number profiling of a well-characterized set of 94 primary untreated high-grade MFS and UPS. Unsupervised clustering identified a subgroup associated with poor clinical outcome. This subgroup had strikingly higher expression of the integrin-α10 gene, ITGA10, and its expression was also independently associated with outcome. We therefore investigated the role of integrin-α10 in MFS and UPS cells, defined the pathways by which it exerts its effects, and tested pharmacologic inhibition of these pathways for antitumor effects both in vitro and in vivo. Silencing of integrin-α10 induces growth suppression through apoptosis in MFS and UPS cells but not in normal mesenchymal cells. Integrin-α10 transmitted its tumor-specific signal via TRIO and RICTOR, two oncoproteins that are frequently co-overexpressed through gene amplification on chromosome 5p. TRIO and RICTOR activated RAC/PAK and AKT/mTOR to promote sarcoma cell survival. Inhibition of these proteins with EHop-016 (RAC inhibitor) and INK128 (mTOR inhibitor) had antitumor effects in tumor-derived cell lines and mouse xenografts, and combining the drugs enhanced the effects. Our results demonstrate the importance of integrin-α10/TRIO/RICTOR signaling for driving myxofibrosarcoma progression and provide the basis for promising targeted treatment strategies for patients with high-risk disease.
Citation Format: Samuel Singer. Integrin-α10 drives metastasis and sarcomagenesis in mxyofibrosarcoma and undifferentiated pleomorphic sarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA18.
Abstract IA23: Variation in the immune cell infiltrate and expression of PD-L1 in sarcoma subtypes
Authors: Andrulis Irene L. 
Published: August 2018

Abstract
The presence of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment has been associated with clinical characteristics and prognosis in various cancers, although the role of TILs in sarcoma is unclear. Adult soft tissue sarcomas are a heterogeneous group of tumors that would benefit from the identification of new prognostic markers and novel therapeutic strategies. The purpose of this study was to determine whether there are specific subgroups of soft tissue sarcomas that contain TILs and/or express immune checkpoint proteins, and if so, the clinical importance. We performed immunohistochemistry (IHC) on sections from 99 tumors and found that certain soft tissue sarcomas such as leiomyosarcoma and liposarcoma exhibit little or no immune infiltrate and immune checkpoint proteins. In contrast, a subset of undifferentiated pleomorphic sarcomas (UPS) and myxofibrosarcomas contain TILs and express PD-L1 and PD-1. Evaluation of expression of PD-L1 by IHC has been controversial; however, we observed a significant positive correlation comparing the levels of PD-L1 determined by IHC on tumor sections and RT-qPCR of mRNA from quick frozen primary tumors. We detected PD-L1 expression in a well-characterized group of osteosarcomas in addition to UPS and myxofibrosarcoma. We are now integrating data from RNA-sequencing and next-generation sequencing to investigate the molecular differences in tumors with and without PD-L1 expression. These studies suggest that there may be individuals with specific sarcomas who may be good candidates to benefit from immunotherapies targeting PD-L1/PD-1 based on their tumor characteristics.
Citation Format: Irene L. Andrulis. Variation in the immune cell infiltrate and expression of PD-L1 in sarcoma subtypes [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA23.
Abstract PR10: Development and characterization of novel/genetically defined mouse models of malignant peripheral nerve sheath tumor for preclinical therapeutics testing
Authors: Patel Amish J. , Sher Jessica J. , Chen Yu , Chi Ping 
Published: August 2018

Abstract
Malignant peripheral nerve sheath tumor (MPNST) represents 5-10% of soft-tissue sarcomas, and can develop either sporadically, in patients with neurofibromatosis Type I (NF1), or in association with radiotherapy. Limited genetic information regarding their pathogenesis in humans has posed a challenge to developing authentic mouse models more reflective of the human disease. Recently, we discovered that these clinically distinct MPNST subtypes commonly share inactivating mutations in tumor suppressors NF1, CDKN2A, and PRC2 (Polycomb Repressive Complex 2). Using a combination of Cre-loxP-based genetically engineered mouse models (GEMMs) and stem/progenitor transplantation models, we show that inactivation of these tumor suppressors is sufficient to promote development of bona fide MPNSTs. We envision that further characterization of these models will provide a solid foundation for investigating MPNST biology and developing therapies in a genetically defined context more closely resembling the human disease.
This abstract is also being presented as Poster B18.
Citation Format: Amish J. Patel, Jessica J. Sher, Yu Chen, Ping Chi. Development and characterization of novel/genetically defined mouse models of malignant peripheral nerve sheath tumor for preclinical therapeutics testing [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr PR10.
Abstract PR14: Immune cell transcript levels, metastatic progression, and survival in osteosarcoma: A comparative transcriptome analysis
Authors: Scott Milcah , Temiz Nuri , Sarver Anne , LaRue Rebecca , Rathe Susan , Varshney Jyotika , Wolf Natalie , Moriarity Branden , Obrien Timothy , Spector Logan , Largaespada David , Modiano Jaime , Subramanian Subbaya , Sarver Aaron 
Published: August 2018

Abstract
Background: Human osteosarcoma (OS) is a rare bone disease primarily affecting children and adolescents that has proven challenging to study, due both to its rarity and its genetic heterogeneity. OS is very common in large-breed dogs and can be genetically induced in mice, making the disease ideal for comparative genomic analyses across species. The overall survival rate of patients with OS is ~60% in patients under 30 years old and only ~30% for patients aged 50 years or older---rates that have not significantly improved over the past two decades. Understanding how intertumor transcriptional variation is conserved across species and associated with progression to metastasis resulting in patient death will enable us to more efficiently develop effective strategies to manage OS and improve therapy.
Methods and Findings: Transcriptional profiles of OS tumors and cell lines derived from humans (n=49), mice (n=103), and dogs (n=34) were generated using RNA sequencing. We identified conserved intertumor transcriptional variation present in tumor sets from all 3 species, comprising gene clusters associated with cell cycle/mitosis and with the presence/absence of immune cells. Further, we developed a novel Gene Cluster Expression Summary Score (GCESS) technique to quantify intertumor transcriptional variation and demonstrate that these GCESS values are
associated with patient outcome. Specifically, we show that human OS tumors with GCESS values indicative of decreased immune cell presence are associated with metastasis and poor survival. These results were validated in an independent human OS tumor cohort and in 15 different tumor data sets obtained from The Cancer Genome Atlas (TCGA).
Conclusions: Utilizing GCESS-based analyses of primary OS tumors to characterize the extent to which immune cells are absent and the tumor cells are undergoing mitosis may provide key information to identify novel drug targets, better inform therapeutic decisions, and improve overall survival for OS patients.
This abstract is also being presented as Poster A07.
Citation Format: Milcah Scott, Nuri Temiz, Anne Sarver, Rebecca LaRue, Susan Rathe, Jyotika Varshney, Natalie Wolf, Branden Moriarity, Timothy Obrien, Logan Spector, David Largaespada, Jaime Modiano, Subbaya Subramanian, Aaron Sarver. Immune cell transcript levels, metastatic progression, and survival in osteosarcoma: A comparative transcriptome analysis [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr PR14.
Relationship between serum thyrotropin and urine albumin excretion in euthyroid subjects with diabetes
Authors: Das Gautam , Taylor Peter N , Abusahmin Hussam , Ali Amer , Tennant Brian P , Geen John , Okosieme Onyebuchi 
Published: August 2018

Background Microalbuminuria represents vascular and endothelial dysfunction. Thyroid hormones can influence urine albumin excretion as it exerts crucial effects on the kidney and on the vascular system. This study explores the relationship between serum thyrotropin and urine albumin excretion in euthyroid patients with diabetes. Methods A total of 433 patients with type 1 or 2 diabetes were included in this retrospective cross-sectional study. Data included anthropometric measurements and biochemical parameters from diabetes clinic. Males with urine albumin creatinine ratio >2.5 and female’s >3.5 mg/mmoL were considered to have microalbuminuria. Results 34.9% of the patients had microalbuminuria. Prevalence of microalbuminuria increased according to TSH quartiles (26.9, 34.6, 38.5 and 44.9%, P for trend = 0.02). In a fully adjusted logistic regression model, higher TSH concentrations were associated with high prevalence of microalbuminuria (adjusted odds ratio 2.06 [95% CI: 1.14–3.72]; P = 0.02), while comparing the highest with the lowest quartile of TSH. Multiple linear regression analysis showed an independent association between serum TSH and urine albumin creatinine ratio (β = 0.007, t = 2.03 and P = 0.04). The risk of having microalbuminuria was higher with rise in TSH concentration in patients with younger age (<65 years), raised body mass index (≥25 kg/m2), hypertension, type 2 diabetes and hyperlipidaemia and age was the most important determinant ( P for interaction = 0.02). Conclusion Serum TSH even in the euthyroid range was positively associated with microalbuminuria in euthyroid patients with diabetes independent of traditional risk factors. This relationship was strongest in patients with components of the metabolic syndrome.
A Panel Data Analysis of Foreign Direct Investment Inflows into India Since 1991 to 2015
Authors: Javed Roohi , Javed Farheen 
Published: August 2018

At the outset, this study dwells on the ambiguities surrounding the definition of foreign direct investment (FDI) and the non-adherence to international norms in measuring the FDI inflows by India. The study finds that portfolio investors and round-tripping investments have been important contributors to India’s reported FDI inflows, thus, blurring the distinction between direct and portfolio investors on the one hand and foreign and domestic investors on the other. These investors were also the ones who have exploited the tax haven route the most. These observations acquire added significance in the context of the substantial fall in the inflows seen during 1991–1992 to April 2015–December 2015. FDI as a strategic component of investment is needed by India for achieving the economic reforms and maintaining the pace of growth and development of the economy. The government should design the FDI policy in such a way where FDI inflow can be utilised as a means of enhancing domestic production, savings and exports through the equitable distribution among states by providing much freedom to states, so that they can attract FDI inflows at their own level. The impact of FDI inflows into India in recent years is highly significant. JEL: C40, C82, E44, F210, G15
Industrial Location Policy in India
Authors: Ramaul Nalin Kumar , Ramaul Pinki 
Published: August 2018

The article provides a broad overview of the industrial location policy in India since Independence. In India, the glaring regional imbalances and inequalities have arisen through a complex set of historical, socio-economic, demographic and cultural factors. The pre-reform approach to industrial location policy involved top-down identification of lagging areas and targeting them with interventionist and regulatory measures. In the post-reform period, the process of liberalisation has curtailed the role of government as industrial owner and location regulator, and restricted policy space. Thus, the focus shifted to a targeted approach and subnational strategies. Package for industrial development are in operation for the special category states, namely northeastern states, Jammu and Kashmir (J&K), Himachal Pradesh and Uttarakhand. In other regions, the development of industries adopted a cluster development approach. However, the peripheral lagging regions continue to stagnate despite the industrial location policy having tried virtually everything. The persistently growing regional disparity in post-reform period is a matter of grave concern. JEL Classification: R3, L5
Economies of Scale in Public Sector Banks
Authors: Bishnoi Tulchha Ram , Sh. Sofia Devi 
Published: August 2018

The present study attempts to analyse the cost analysis of the banking industry with special focus on optimum size of a bank. It studies the cost structure, economies/diseconomies as well as the optimum size of public sector banks for the period 1991–1992 to 2013–2014. Economies of scale relating to 26 public sector banks are worked out for selected years. The large banks operated at a scale, reaping economies in all the years, the exception being the year 2004–2005 achieving position of the minimum AC—. For the small banks, there are economies of scale in all the selected years. Both the banks groups did not show diseconomies with respect to total cost, even though there were diseconomies associated with other individual cost items. The minimum efficient size (MES) was attained by all the public sector banks in each of the years selected. JEL codes: D24, D210, D220, D240, D240, D250