bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4280: FH (rs367543046, chr1:241661227 A/ATTT) heterozygous carrier status does not confer risk to hereditary leiomyomatosis and renal cell cancer (HLRCC) and prostate cancer
Authors: Walsh Michael F. , Mandelker Diana , Vijai Joseph , Musheyev David , Kennedy Jennifer , Stadler Zsofia , Kemel Yelena , Topka Sabine , Cadoo Karen , Carlo Maria , Ladanyi Marc , Robson Mark , Offit Kenneth , Zhang Liying 
Published: July 2017

Abstract
Fumarate Hydratase (FH) mutations underpin the autosomal recessive syndrome Fumarate Hydratase deficiency and the autosomal dominant syndrome Hereditary Leiomyomatous and Renal Cell Carcinoma (HLRCC). The variant rs367543046, a duplication leading to p. Lys477_Asn478insLys in FH has strong evidence for risk towards fumarate hydratase deficiency when occurring in trans to another germline alteration in the FH gene. In addition, this variant in the heterozygous state has been reported in ClinVar to predispose to the autosomal dominant condition HLRCC, given other heterozygous mutations have shown to be pathogenic. Population level data is sparse to determine the variant’s impact in the heterozygous state. Here, we show in a series of 1375 cancer cases the (rs367543046, chr1: 241661227 A/ATTT), variant detected in 7 (0.5%) individuals with cancer. One patient with bladder cancer had a history of uterine leiomyomas, but the immunohistochemistry for 2SC was negative, suggesting that the leiomyomas were not associated with HLRCC. None of the other 6 carriers of this variant had any features of HLRCC. Notably, this variant was not detected in any of the patients with renal cancer (n=178) participating in the study. Since 4/7 prostrate cancer patients of Ashkenazi ethnicity harbored this variant, we performed a genetic epidemiology study using 856 Ashkenazi Jewish prostate cancer patients. The allele frequencies were compared with 557 Ashkenazi Jewish non-cancer controls. A fisher’s two sided exact test showed that the variant is not associated with prostate cancer in Jews (P=1, OR 1.12(CI 95% 0.21-7.25). Our findings suggest that the variant, which is pathogenic for autosomal recessive fumarate hydratase deficiency does not confer pathogenicity in the heterozygous form for Hereditary Leiomyomatous and Renal Cell Carcinoma or prostate cancer.
Ashkenazi Jewish Prostate Cancer Patients vs Ashkenazi Jewish Non-Cancer PatientsAttributeAshkenazi Jewish Prostate Cancer PatientsAshkenazi Jewish Non-Cancer patientsCT53CC17071151
Citation Format: Michael F. Walsh, Diana Mandelker, Joseph Vijai, David Musheyev, Jennifer Kennedy, Zsofia Stadler, Yelena Kemel, Sabine Topka, Karen Cadoo, Maria Carlo, Marc Ladanyi, Mark Robson, Kenneth Offit, Liying Zhang. FH (rs367543046, chr1:241661227 A/ATTT) heterozygous carrier status does not confer risk to hereditary leiomyomatosis and renal cell cancer (HLRCC) and prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4280. doi:10.1158/1538-7445.AM2017-4280
Abstract 4283: BRCA1 and BRCA 2 mutation predictions using BRACAPRO and MYRIAD models in patients with Korean ethnicity
Authors: Eoh Kyung Jin , Park Hyung Seok , Park Ji Soo , Lee Seung-Tae , Han Jeongwoo , Lee Jung-Yun , Kim Sunghoon , Kim Sang Wun , Kim Young Tae , Nam Eun Ji 
Published: July 2017

Abstract
Introduction: This study is aimed to compare the predictive efficacy of BRCAPRO and MYRIAD BRCA risk calculator in patients tested in Korean ethnicity.
Methods: Individuals, who received gene test on BRCA mutation from November 2010 to August 2016, were recruited from database of department of obstetrics and gynecology at a single institute in Korea. Observed BRCA1 and BRCA2 mutation status was compared with predicted carrier probabilities under the BRCAPRO, and MYRIAD BRCA risk calculator. Risk assessment for all patients was calculated using the CancerGene assessment software.
Results: Total of 279 patients was recruited, and 99.3% (277 out of 279) had Korean ethnicity. The mean age at presentation was 52 years. Out of the 279 individuals, 206 had ovarian cancer, 36 had breast cancer, 26 had double primary ovarian/breast cancer, and 11 had no cancer. Fifty five individuals had family history of ovarian/breast cancer in first degree relatives. Sixty three patients (22.6%) tested positive for a BRCA mutation (45 BRCA1, 18 BRCA2). The mean BRCAPRO and MYRIAD score for all patients was 6.4% and 7.7%, respectively. The BRCAPRO and MYRIAD scores were significantly higher for patients who tested positive for a BRCA mutation (30.4% vs. 6.3%, P &lt; 0.001, 12.1% vs. 7.7%, P &lt; 0.001, respectively). The area under the receiver operating characteristics curves were 0.762, and 0.751 for all patients for the BRCAPRO and MYRIAD score to predict the risk of carrying a BRCA mutation.
Conclusion: BRCAPRO and MYRIAD appear to be valid risk assessment tools for determining the risk of carrying a BRCA mutation in Korean ethnicity.
Citation Format: Kyung Jin Eoh, Hyung Seok Park, Ji Soo Park, Seung-Tae Lee, Jeongwoo Han, Jung-Yun Lee, Sunghoon Kim, Sang Wun Kim, Young Tae Kim, Eun Ji Nam. BRCA1 and BRCA 2 mutation predictions using BRACAPRO and MYRIAD models in patients with Korean ethnicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4283. doi:10.1158/1538-7445.AM2017-4283
Abstract 4287: HABP2 p.G534E variant in patients with family history of thyroid and breast cancer
Authors: Pinheiro Maisa , Drigo Sandra A. , Marchi Fabio A. , Tonhosolo Renata , Andrade Sonia C. , Jurisica Igor , Kowalski Luiz P. , Achatz Maria Isabel W. , Rogatto Silvia R. 
Published: July 2017

Abstract
Background. Familial Papillary Thyroid Carcinoma (PTC) has been recently associated with the HABP2 p.G534E mutation. In this study we evaluated the putative association of the HABP2 p.G534E mutation and familial history of PTC and Breast Carcinoma (BC) in the Brazilian population.
Methods. Germline mutations of twenty unrelated individuals with personal and/or family history of PTC and/or BC were identified by whole exome sequencing (WES), using Nextera Exome Enrichment kit and HiSeq200 platform (Illumina). Two cases were positive for p.G534E. Family members from both positive cases (seven from Family 1 and three from Family 2) were recruited for segregation analysis. An additional patient and three relatives (Family 3) with history of PTC and BC were included for validation. Fifty frozen PTC tumor samples and 170 healthy Brazilian individuals were also screened for the HABP2 variant. Confirmation and validation were performed by Sanger sequencing.
Results. Interestingly, Family 1 reported a consanguineous history, reflected in two homozygous cases: the proband (PTC) and his unaffected sister. Also, only one (BC) out of eight tested members was negative for p.G534E. In the Family 2, the only patient diagnosed with PTC was negative for the mutation, while three relatives were positive for the same loci. The index case (PTC) from Family 3, was wild type for HABP2 and three relatives tested were positive carriers. In PTC tumor samples the Allele Frequency (AF) was 0.04: two heterozygous and one homozygous for p.G534E. Among 170 healthy individuals, five were heterozygous for the variant, representing an AF of 0.0147. The two index patients evaluated by WES also presented interesting pathogenic variants in genes potentially associated with deregulation of the extracellular matrix organization pathway (CTSB, TNXB, COL4A3, COL16A1, COL24A1, COL5A2, NID1, LOXL2, MMP11, TRIM24 and MUSK) and DNA repair function (NBN and MSH2).
Conclusion. Our findings suggest that HABP2 is not a predisposition gene involved in familial PTC and BC.
Financial Support: FAPESP (2013/01867-8 and 2014/03983-8) and CNPq (481132/2012-0)
Note: This abstract was not presented at the meeting.
Citation Format: Maisa Pinheiro, Sandra A. Drigo, Fabio A. Marchi, Renata Tonhosolo, Sonia C. Andrade, Igor Jurisica, Luiz P. Kowalski, Maria Isabel W. Achatz, Silvia R. Rogatto. HABP2 p.G534E variant in patients with family history of thyroid and breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4287. doi:10.1158/1538-7445.AM2017-4287
Abstract 4292: Indole-3-carbinol (I3C) enhances efficacy of Gemcitabine in leiomyosarcoma
Authors: Suwal Sujit , Moran Alexandra , Paz-Mejia Ana , Flor Lorena , Picado Omar , Azab Basem , Trent Jonathan , Pendola Fiorella , Livingstone Alan S. , Yakoub Danny 
Published: July 2017

Abstract
Introduction: Adjuvant Gemcitabine have recently been shown to improve progression free survival in some types of leiomyosarcoma. Adequate cellular uptake of the drug remains a challenge. We aimed to evaluate the role of nucleoside transporter activator (I3C) in increasing the in vitro efficacy of gemcitabine in the treatment of leimyosarcoma.
Methods: Leiomyosarcoma cells (SKLMS) were incubated with DMEM+10% FBS + 1% Antibiotics. Dose response curves were generated for gemcitabine and I3C to identify the IC-50 values. Triplicates of cells were then plated in 96 well plates (3000 cells/well) and allowed to adhere. The adherent cells were further treated with gemcitabine in the presence or absence of I3C and compared with controls (DMSO treatment). MTS cell viability assays were done and absorbance was monitored in a micro-plate reader. Flow cytometry was performed with Propidium Iodide (PI) staining. Scratch assays were done to assess cell migration.
Results: Viability assay showed significant increase in the cytotoxicity of gemcitabine in presence of I3C compared to controls. Flow cytometry data showed gemcitabine alone treatment has arrested the cell cycle at G0/G1 phase without increase of cell death. On the contrary, use of gemcitabine in combination with I3C increased the cell death by at least three folds compared to control as well as gemcitabine alone treated cell population. Scratch assay over a 16 hour period showed that the rate of cellular migration significantly dropped by 1.5 folds upon treatment with gemcitabine combined with I3C compared to gemcitabine alone. Western blots showed increased expression of membrane transporter hENT-1 with I3C treatment.
Conclusion: The use of I3C enhanced cellular uptake, transport and cytotoxicity of gemcitabine in SKLMS cells. Further studies are warranted and underway to elaborate on intracellular mechanisms of action to optimize the use of I3C as a potential adjunct in preclinical and clinical leiomyosarcoma treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Sujit Suwal, Alexandra Moran, Ana Paz-Mejia, Lorena Flor, Omar Picado, Basem Azab, Jonathan Trent, Fiorella Pendola, Alan S. Livingstone, Danny Yakoub. Indole-3-carbinol (I3C) enhances efficacy of Gemcitabine in leiomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4292. doi:10.1158/1538-7445.AM2017-4292
Abstract 4297: ADCs inhibiting the all-powerful osmotic transducer
Authors: Prudent James R. , Marshall David , Malavasi Fabio , Chillemi Antonella 
Published: July 2017

Abstract
Purpose
Extracellular drug conjugates (or EDCs) are a new type of ADC that selectively inhibit the all-powerful Na,K-ATPase, an extracellular membrane ion pump required for life . To determine if EDCs may be valuable clinical candidates, we further assessed their safety, efficacy and mode of action.
Experimental Design
Cynomolgus monkeys were infused with EDCs at various levels and monitored by heart telemetry, blood cell levels and serum examination. Additionally, cultured cells were subjected to EDCs and monitored in real time and by high resolution dual fluorescent labeling to better understand the mechanism of cell death.
Results
We tested the efficacy of the EDCs in a number of xenografts models and observed strong activity (regression and cures). Little to no tumor reduction was observed for the free antibodies or with control-EDCs where the antibody target was not expressed.
To test for safety, each cynomolgus monkey were infused with one of three EDCs to better understand the MTD of each EDC. In all cases, MTD was determined to be between 5 and 10mgs/kg where EDC serum levels reached between 100 and 200ugs/ml. At the maximum safe dose tested (5mgs/kg), heart beat and other observed parameters were found to be normal with the exception of the blood cells expressing the EDC targets (EDC targeting CD20 at this high level was found to drop all B-cells to a nondetectable level which rebounded to normal on day 58).
To further understand the EDC mechanism, cells exposed to the EDCs and monitored visually in real-time or by dual fluorescence microscopies. All cells exposed to the EDCs showed membrane swelling and extracellular localization of the EDC.
Conclusion
These results show that targeted inhibitors of the Na,K-ATPase ion pump have promise as future anticancer medicines. First, EDCs appear safe in nonhuman primates at efficacious doses in rodent xenografts. In addition, an identified mechanism of extracellular necrotic death is novel in the field of oncology. Our hope is that cancers that up-regulate MDR and/or anti-apoptotic mechanisms will be sensitive to EDCs. Continuing efforts to identify the full death pathway of this new type of ADC should lead to identifying patients most likely to respond to EDC based therapies.
Citation Format: James R. Prudent, David Marshall, Fabio Malavasi, Antonella Chillemi. ADCs inhibiting the all-powerful osmotic transducer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4297. doi:10.1158/1538-7445.AM2017-4297
Abstract 4298: FTY720 induces necroptosis in lung cancer by modulating ceramide signaling at the plasma membrane
Authors: Nganga Rose 
Published: July 2017

Abstract
Sphingolipids are important signaling molecules in cells and have recently been explored as cancer therapy targets. FTY720 (Fingolimod, Gilenya) is an FDA approved sphingosine analogue drug used for the treatment of multiple sclerosis (MS). FTY720 is phosphorylated by sphingosine kinase 2 (SK2), to generate P- FTY720 to exert its immunosuppressive properties through binding to sphingosine -1 phosphate receptors (S1PRs). FTY720 also exhibits anti-cancer properties. Our previous studies indicated that one of the mechanism by which FTY720 induces cell death is through necroptosis. FTY720 directly binds to I2PP2A/SET (Inhibitor 2 of PP2A), consequently activating the tumor suppressor protein phosphatase 2A (PP2A). The activated PP2A then induces cell death by stimulating the activity of Receptor-Interacting Protein kinase-1 (RIPK1), involved in necroptosis signaling. Previous studies have shown that FTY720 can modulate sphingolipids metabolism in cells. However, little is known about the roles of FTY720 in ceramide signaling and regulation of necroptosis in lung cancer. We hereby seek to investigate the mechanisms of FTY720 in inducing necroptosis with regard to ceramide signaling. Preliminary data indicate that inhibitors of ceramide generation partially protect cells against FTY720-induced cell death. Interestingly, FTY720 and non-phosphorylated FTY720 analogues do not affect ceramide generation, but lead to the formation of cancer specific ceramide-multi-protein complexes at the plasma membrane. Our studies show a role of these complexes in inducing plasma membrane rupture, a key phenomenon in necroptosis. Further elucidation of these novel structures will be helpful in improving cancer therapeutics that further promote the formation these structures hence more cell death.
Citation Format: Rose Nganga. FTY720 induces necroptosis in lung cancer by modulating ceramide signaling at the plasma membrane [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4298. doi:10.1158/1538-7445.AM2017-4298
Abstract 4306: Combined effects of chemotherapy to reduce metastasis caused by insufficient hyperthermia
Authors: Lee Tae Hee , Bu Jiyoon , Kim Byoung Hyuck , Kim Young Jun , Kang Yoon-Tae , Moon Jung Eun , Cho Young-Ho 
Published: July 2017

Abstract
Hyperthermia therapy is one of the most widely studied non-surgical methods for breast tumors, which eliminates tumor by inducing acute stress on tumor cells. However, it has been extensively known that the viability of the tumor cells is highly influenced by the applied temperature. Insufficient thermal stress during hyperthermia treatments may alter tumor microenvironment by promoting epithelial to mesenchymal-like transition (EMT) and as a result, enhancing the outgrowth of residual tumor cells. Therefore, cells that have survived from sublethal thermal stress and experienced EMT may cause substantial clinical problems. In this case, hyperthermia requires additional therapy in order to promote cell death of more invasive tumor cells that have resisted to the thermal stimulus. In this study, we confirmed that the co-treatment of chemotherapy with hyperthermia may overcome the phenotypical transition caused by insufficient heat treatment. After exposing breast cancer cells (MCF-7) into two different temperature conditions (42°C and 47°C) for an hour, we have verified that 10.51 ± 1.71% and 18.27 ± 10.66% of cells experienced apoptosis or necrosis when the cells were exposed to 42°C and 47°C, respectively. At the same time, cancer cells showed higher invasiveness, spear-like morphology, and enhanced migratory behaviors as the exposed temperature increases, which is mainly shown among the cells that have experienced EMT. Further western blot assay and quantitative real-time polymerase chain reaction (qRT-PCR) using mesenchymal marker (vimentin) and epithelial marker (E-cadherin) also support that the mesenchymal-like phenotype has been highly increased on the cells that have resisted to the thermal stress. However, when chemotherapy was conducted after the heat treatment, cell viability was highly reduced. Paclitaxel (11.7 nM), cisplatin (3.3 μM), and combination of two anticancer drugs were treated for 24 hours on the cells that have been exposed to different temperatures, respectively. As a result, death rate of tumor cells has increased from 11.31 to 66.69%. Especially, when paclitaxel and cisplatin were co-treated, the death rate was up to 73.75 ± 4.37% after cells were exposed to 47°C. In conclusion, cancer cells that have survived from insufficient hyperthermia showed high potential to promote metastasis or recurrence but additional chemotherapy can successfully reduce the side effects induced by insufficient hyperthermia treatment.
Citation Format: Tae Hee Lee, Jiyoon Bu, Byoung Hyuck Kim, Young Jun Kim, Yoon-Tae Kang, Jung Eun Moon, Young-Ho Cho. Combined effects of chemotherapy to reduce metastasis caused by insufficient hyperthermia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4306. doi:10.1158/1538-7445.AM2017-4306
Abstract 431: IDH1-mutated gliomas rely on anaplerosis of glutamate and lactate whereas IDH1 wild-type gliomas rely on glycolysis and acetate anaplerosis
Authors: Khurshed Mohammed , Lenting Krissie , Molenaar Remco J. , Leenders William P. , Noorden Cornelis J. van 
Published: July 2017

Abstract
Hotspot mutations in isocitrate dehydrogenase 1 (IDH1MT) initiate low grade glioma (LGG) and secondary glioblastoma and induce neomorphic activity that converts α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2-HG). This causes metabolic rewiring that is not fully understood and in vitro studies have shown that IDH1MT cancer cells rely on glutaminolysis, providing cells with α-KG via activities of glutaminase (GLS) and glutamate dehydrogenase (GLUD). Here, we first show by in silico analysis of 269 IDH1 wild-type (IDH1WT) and 408 IDH1MT gliomas, obtained from the The Cancer Genome Atlas (TCGA) database, that IDH1WT gliomas have high expression levels of genes encoding for enzymes that are involved in glycolysis and acetate anaplerosis. On the other hand, the tricarboxylic acid (TCA) cycle, rather than glycolytic lactate production, is the predominant metabolic pathway in IDH1MT gliomas and is driven by lactate and glutamate anaplerosis to facilitate production of α-KG, and ultimately D-2-HG. IDH1WT- and IDH1MT-related differences in expression were found in both LGG and glioblastoma. Furthermore, via in situ enzymatic activity mapping, we show in human gliomas and in xenocraft models that GLUD activity is increased and GLS activity is decreased in IDH1MT glioma, indicating that IDH1MT gliomas depend on glutamatolysis, rather than glutaminolysis. We show that transcript levels in our xenocraft models are in good agreement with our in silico analysis of the TCGA database. Finally, we confirmed the glutamate dependency of IDH1MT gliomas by MRS-flux analysis, whereas IDH1WT gliomas show high lactate production. Taken together, we show that IDH1WT gliomas have a typical Warburg phenotype and rely on acetate anaplerosis whereas IDH1MT gliomas are glutamate and lactate dependent. This metabolic rewiring in IDH1MT glioma, enables targeting of glutaminolysis rather than direct inhibition of IDH1MT for therapy. It diminishes the supply of glutamate-derived α-KG and directly inhibits the production of D-2-HG and simultaneously worsen the redox status of the glioma cells by inhibiting NAD(P)H production by GLUD. A candidate drug to inhibit GLUD is epigallocatechin-3-gallate gallate, a component of green tea that is currently receiving high interest as anti-cancer agent.
Note: This abstract was not presented at the meeting.
Citation Format: Mohammed Khurshed, Krissie Lenting, Remco J. Molenaar, William P. Leenders, Cornelis J. van Noorden. IDH1-mutated gliomas rely on anaplerosis of glutamate and lactate whereas IDH1 wild-type gliomas rely on glycolysis and acetate anaplerosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 431. doi:10.1158/1538-7445.AM2017-431