bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 595: A cell-permeant amiloride derivative induces caspase-independent, AIF-mediated programmed necrotic death of breast cancer cells.
Authors: Leon Leonardo J. , Pasupuleti Nagarekha , Gorin Fredric , Carraway Kermit 
Published: August 2014

Abstract
Amiloride is a potassium-sparing diuretic that has been used as an anti-kaliuretic for the chronic management of hypertension and heart failure. Several studies have identified a potential anti-cancer role for amiloride, however the mechanisms underlying its anti-tumor effects remain to be fully delineated. Our group previously demonstrated that amiloride triggers caspase-independent cytotoxic cell death in human glioblastoma cell lines but not in primary astrocytes. To delineate the cellular mechanisms underlying amiloride's anti-cancer cytotoxicity, cell permeant and cell impermeant derivatives of amiloride were synthesized that exhibit markedly different potencies in cancer cell death assays. Here we compare the cytotoxicities of 5-benzylglycinyl amiloride (UCD38B), and its free acid 5-glycinyl amiloride (UCD74A) toward human breast cancer cells. UCD74A exhibits poor cell permeability and has very little cytotoxic activity, while UCD38B is cell permeant and induces the caspase-independent death of proliferating and non-proliferating breast cancer cells. UCD38B treatment of human breast cancer cells induces autophagy, reflected in LC3 conversion, however this does not appear to be the cause of cell death. Electron microscopy reveals that UCD38B induces a dramatic swelling of intracellular organelles such as the endoplasmic reticulum and mitochondria. Surprisingly UCD38B, but not UCD74A, induces efficient AIF translocation from the mitochondria to the nucleus, and AIF function is necessary for the efficient induction of cancer cell death. Our observations indicate that UCD38B induces programmed necrosis through AIF translocation, and suggest that cytosolic accessibility may facilitate drug action.
Citation Format: Leonardo J. Leon, Nagarekha Pasupuleti, Fredric Gorin, Kermit Carraway. A cell-permeant amiloride derivative induces caspase-independent, AIF-mediated programmed necrotic death of breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 595. doi:10.1158/1538-7445.AM2013-595
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 601: Antioxidant inhibition of GSK-3β stabilizes anti-apoptotic factor Mcl-1 leading to decreased apoptosis and increased cell survival.
Authors: Niture Suryakant K. , Jaiswal Anil K. 
Published: August 2014

Abstract
Antioxidant-mediated stabilization of Nrf2 is known to up-regulate anti-apoptotic factors Bcl-2 and Bcl-xL that leads to reduced apoptosis and increased cell survival. In this report we investigated and found that anti-apoptotic factor Mcl-1 is coordinately induced with Bcl-2 and Bcl-xL factors in response to antioxidants. However, unlike Bcl-2 and Bcl-xL, Nrf2 did not control antioxidant-mediated up-regulation of Mcl-1. Further studies revealed that ERK1/2 phosphorylation of Mcl-1T163 primes Mcl-1 for phosphorylation by GSK3β at position S159. This modification degrades Mcl-1 and contributes to the maintenance of physiological level of Mcl-1 and cellular apoptosis. Exposure of Hep-G2 cells to antioxidant tert-butyl hydroquinone (t-BHQ) for 4-16h led to time dependent Akt-mediated inactivation of GSK3β, decreased Mcl-1S159 phosphorylation resulting in stabilization of Mcl-1 protein. Antioxidant-mediated increased Mcl-1 heterodimerized with Bim and Bax and down regulated cellular apoptosis. The contribution of antioxidant increased Mcl-1 in reduced apoptosis was further confirmed by siRNA-mediated inhibition of Mcl-1 that increased susceptibility to etoposide-mediated cell death and reduced cell survival through the activation of caspases 3/7. These results provided evidence that antioxidant control of GSK-3β led to increase in Mcl-1 that contributed to decreased apoptosis and increased cell survival. The results collectively suggest that antioxidant stabilized Nrf2 and GSK3β both through distinct mechanisms lead to increased anti-apoptotic factors Bcl-2, Bcl-xL and Mcl-1 that reduces apoptosis and promotes cell survival.
Citation Format: Suryakant K. Niture, Anil K. Jaiswal. Antioxidant inhibition of GSK-3β stabilizes anti-apoptotic factor Mcl-1 leading to decreased apoptosis and increased cell survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 601. doi:10.1158/1538-7445.AM2013-601
Abstract 603: CAL-101 acts synergistic with arsenic trioxide in chronic lymphocytic leukemia by preventing p21 phosphorylation through AKT1.
Authors: Merkel Olaf , Sifft Eveline , Schweiggl Simone , Asslaber Daniela , Wacht Nathalie , Greil Richard 
Published: August 2014

Abstract
Chronic lymphocytic leukemia (CLL) is the most abundant leukemia of the elderly in the Western world and characterized by the accumulation of CD5/CD19/CD23 positive cells in the peripheral blood, lymph nodes and spleen. It has a very heterogeneous course of disease with patients living longer than 10 years after diagnosis and others needing immediate treatment. CLL cells of the latter often bear aberrations in the p53 tumor suppressor gene. We have shown before that arsenic trioxide preferentially induces apoptosis in CLL cells deficient for p53 (n = 51, P = 0.029). We now reproduced this finding in mouse embryo fibroblasts (MEF) that are p53 deficient. Next we wanted to clarify the role of p53 downstream targets p21 and PUMA and found that p21 but not PUMA knockout led to increased arsenic trioxide susceptibility. When localized in the cytosol p21 has been described to have and anti-apoptotic function and accordingly is associated with negative prognosis in breast, ovarian and prostate cancer. To clarify p21’s localization in CLL cells we used differential detergent cell fractionation and demonstrate that upon arsenic trioxide treatment p21 is induced, but accumulates in the cytoplasm. This is in contrast to fludarabine treated cells, where p21 is strongly induced and shuttles to the nucleus. Moreover, we show here that arsenic trioxide leads to transient AKT activation and AKT phosphorylation of p21 has been shown to promote cytosolic localization. We next hypothesized that by combining the PI3Kdelta/AKT inhibitor CAL-101 with arsenic trioxide we might prevent cytosolic accumulation of p21. Recently, the idea of therapeutic inhibition of tyrosinse kinases in the B-cell receptor pathway has gained new momentum through pivotal phase-2 clincal studies with CAL-101 and ibrutinib targeting the PI3Kdelta- and the Bruton's tyrosine-kinase, respectively. We show here, that the PI3K inhibitor CAL-101 abrogates AKT activation through arsenic trioxide. This leads to strongly, synergistic apoptosis induction when CAL-101 and arsenic trioxide are combined irrespective of p53 status of CLL cells. Thus, we think that these findings not only shed light on the role of p21 in apoptosis induction in CLL, but open the path to novel therapeutic combination regimens.
Citation Format: Olaf Merkel, Eveline Sifft, Simone Schweiggl, Daniela Asslaber, Nathalie Wacht, Richard Greil. CAL-101 acts synergistic with arsenic trioxide in chronic lymphocytic leukemia by preventing p21 phosphorylation through AKT1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 603. doi:10.1158/1538-7445.AM2013-603
Abstract 61: Use of two-color fluorometric real-time PCR to develop molecular diagnostic tests with intrinsic quality control that augment cytomorphologic diagnosis of lung cancer.
Authors: Yeo Jiyoun , Crawford Erin L. , Blomquist Thomas M. , Stanoszek Lauren M. , Dannemiller Rachel E. , Jordan Laura , Zyrek Jill , de la Casas Luis , Willey James C. 
Published: August 2014

Abstract
Quantitative RT-PCR tests that measure transcript abundance of selected genes in clinical specimens promise to improve cancer diagnostic accuracy and enable “personalized medicine” through selection of the most effective treatment for each cancer. However, most clinical samples are Formalin-Fixed, Paraffin-Embedded (FFPE) and these yield sub-optimal RNA integrity. Thus, there is a need for qPCR tests with increased robustness that also have intrinsic quality control and low cost. To address this need, we developed qPCR methods that enable simultaneous measurement of each target gene and reference gene transcript relative to a known number of gene-specific internal standard (IS) molecules using two-color fluorometric analysis on real-time platform. For each gene, a competitive template IS was synthesized containing 4-6 nucleotide changes relative to the native template (NT). During PCR, NT or IS signal was quantified with sequence-specific FAM-labeled probe or Quasar 670-labeled probe, respectively. To optimize measurement sensitivity for analysis of highly degraded FFPE samples; a) each RNA sample was reverse transcribed (RT) with gene-specific primer and b) cDNA was pre-amplified with 18 PCR cycles in the presence of internal standards. Results obtained with pre-amp or no pre-amp conditions were highly correspondent.
We conducted a validation study of this assay in 38 samples (10 malignant and 10 benign surgical FFPE tissues and 13 malignant and 5 benign fine needle aspirate (FNA) samples. Consistent with previous results in fresh frozen surgical samples, the lung cancer diagnostic test (LCDT) optimal cut-off value discriminated malignant from non-malignant tissues (p = 0.0009), had 92.9% specificity and 75.0% sensitivity, and a receiver operator characteristic area under the curve of 0.87 (95% confidence interval 0.74-0.99). Based on these data, we expect that this quality-controlled two color fluorometric qPCR approach will enable reliable analysis of the LCDT and other promising qPCR-based molecular diagnostic tests in small degraded RNA extracted from clinical FFPE and FNA cell block FFPE samples.
Citation Format: Jiyoun Yeo, Erin L. Crawford, Thomas M. Blomquist, Lauren M. Stanoszek, Rachel E. Dannemiller, Laura Jordan, Jill Zyrek, Luis de la Casas, James C. Willey. Use of two-color fluorometric real-time PCR to develop molecular diagnostic tests with intrinsic quality control that augment cytomorphologic diagnosis of lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 61. doi:10.1158/1538-7445.AM2013-61
Abstract 615: Knock-down of base excision repair genes increases susceptibility to organophospate pesticide toxicity.
Authors: Saulsbury Marilyn D. , Heyliger Simone , Li Feng , Parker-Johnson KiTani A. 
Published: August 2014

Abstract
Organophosphates are chemicals that inhibit cholinesterases and are employed widely as pesticides. Concerns are increasing regarding the relative safety of these chemicals to the environment. Recent studies suggest organophosphate exposure is associated with increased expression of fragile sites and DNA damage at concentrations that are not associated with cholinesterase inhibition. Chronic exposure to the organophosphate has been associated with high incidences of prostate cancer in farm workers as well as leukemia and non-Hodgkin lymphoma in adults and children. Moreover, a higher degree of DNA damage has been reported in pesticide applicators that have polymorphisms in the base excision repair genes XRCC1 and OGG1. Our laboratory reports that cells deficient in BER enzymes APE1 and OGG1 exhibit a higher cytotoxicity when exposed, in a dose-dependent manner, to organophosphates Chlorpyrifos, Chlorpyrifos-oxon and Isofenphos. However, it should be noted that other organophosphates such as Diazinon and Dichlorvos had very little effects on cellular viability within the APE1 and OGG1 deficient cells. It should be noted that Chlorpyrifos, Chlorpyrifos-oxon and Isofenphos also produce significant oxidative stress in cells. Our data is consistent with previous studies which report a higher degree of DNA damage has been reported in pesticide applicators that have polymorphisms in the base excision repair genes XRCC1 and OGG1. Moreover, our data further suggests that only certain organophosphates, particularly those that induce oxidative stress, may be responsible for toxicity in APE1 and OGG1 deficient cells.
Citation Format: Marilyn D. Saulsbury, Simone Heyliger, Feng Li, KiTani A. Parker-Johnson. Knock-down of base excision repair genes increases susceptibility to organophospate pesticide toxicity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 615. doi:10.1158/1538-7445.AM2013-615
Abstract 617: High-throughput screens identify PARP inhibition as being synthetically lethal with ERCC1 deficiency in non-small cell lung cancer cell lines.
Authors: Postel-Vinay Sophie C. , Bajrami Ilirjana , Friboulet Luc , Aarts Marieke , Fontebasso Yari , Andre Fabrice , Olaussen Ken , Soria Jean-Charles , Lord Chris , Ashworth Alan 
Published: August 2014

Abstract
Background: Non-small cell lung cancer (NSCLC) harbors frequent DNA-repair defects that represent therapeutic opportunities. Notably, Excision Repair Cross-Complementation group 1 (ERCC1) deficiency has been described in a subset of tumors and correlated with platinum sensitivity. The use of mechanism-based approaches, such as synthetic lethality, could allow targeting more selectively such DNA repair defects, with reduced systemic toxicity.
Methods: To identify ERCC1-selective synthetic lethal interactions, we adopted an integrated functional and molecular profiling approach. An isogenic model of ERCC1-deficient NSCLC cells, consisting of one parental ERCC1-proficient cell line and 3 ERCC1-deficient clones, was functionally profiled by high throughput drug sensitivity screening using a library containing commonly used oncology agents as well as a large number of in-development targeted agents. This was integrated with data from molecular profiling, including high throughput siRNA screens.
Results: The comparison of functional viability profiles for ERCC1-deficient models enabled the identification of synthetic lethal effects that could represent therapeutic opportunities for ERCC1-deficient tumors. Notably, ERCC1-deficient cells showed increased sensitivity to several PARP inhibitors, representing promising preliminary results that could be translated in the clinical setting. Mechanistic studies revealed a significant delay in double-strand break repair associated with a G2/M arrest following PARP inhibitor treatment in the ERCC1-deficient population only. Further in vitro work is providing deeper insight into the mechanisms underlying this PARP inhibitors sensitivity and in vivo work is underway.
Conclusions: ERCC1-deficiency sensitizes human NSCLC cell lines to PARP inhibitors. In vitro and in vivo revalidations of these results and now underway to further dissect the molecular mechanisms responsible for these ERCC1-deficient selective effects, which could represent therapeutic opportunities.
Citation Format: Sophie C. Postel-Vinay, Ilirjana Bajrami, Luc Friboulet, Marieke Aarts, Yari Fontebasso, Fabrice Andre, Ken Olaussen, Jean-Charles Soria, Chris Lord, Alan Ashworth. High-throughput screens identify PARP inhibition as being synthetically lethal with ERCC1 deficiency in non-small cell lung cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 617. doi:10.1158/1538-7445.AM2013-617
Abstract 622: Degradation of APE1 by the E3 ubiquitin ligase Parkin.
Authors: Scott Timothy L. , Rangaswamy Suganya , Dhar Bithika , Zhi LianTeng , Bueler Hansruedi , Izumi Tadahide 
Published: August 2014

Abstract
The mammalian apurinic/apyrimidinic endonuclease 1 (APE1/Ref1) is a DNA repair/redox regulator protein of which cytoplasmic accumulation has been associated with tumorigenesis and poor survival outcome. APE1 is degraded through the ubiquitin/proteasome pathway and previous studies reported APE1 ubiquitination by the E3 ubiquitin ligases MDM2 and UBR3. Here we report that Parkin efficiently polyubiquitinated and degraded APE1. Parkin, a product of the PARK2 gene, is responsible for a type of early onset Parkinson's disease (PD) and has been identified as a tumor suppressor. Expression of Parkin and Pink1 enhanced APE1 ubiquitination and markedly decreased endogenous APE1 in A549, a lung adenocarcinoma cell line. APE1 degradation was blocked by incubation of the cells with MG132, a potent 26S proteasome inhibitor, and by a PD associated point mutation in the Parkin RING domain. The activity of PTEN induced-kinase 1 (Pink1) was required for APE1 degradation. Co-immunoprecipitation revealed that APE1 interacted with Parkin in the presence of Pink1. These results suggest that APE1 stability is dynamically regulated by Parkin in the cytoplasm through the N-terminal APE1 domain.
Citation Format: Timothy L. Scott, Suganya Rangaswamy, Bithika Dhar, LianTeng Zhi, Hansruedi Bueler, Tadahide Izumi. Degradation of APE1 by the E3 ubiquitin ligase Parkin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 622. doi:10.1158/1538-7445.AM2013-622
Abstract 624: Novel interaction of RECQ1 with Ku70/80 and its potential role in non-homologous end joining.
Authors: Parvathaneni Swetha , Brosh Robert M. , Sharma Sudha 
Published: August 2014

Abstract
Genomic instability is a known precursor to cancer and aging. The RecQ helicases are a highly conserved family of DNA-unwinding enzymes that play key roles in maintaining genome stability in all living organisms. Human RecQ homologs include RECQ1, BLM, WRN, RECQL4, and RECQ5β, three of which have been linked to disease with elevated risk of cancer and growth defects (Bloom Syndrome and Rothmund-Thomson Syndrome) or premature aging (Werner Syndrome). RECQ1, the first RecQ helicase discovered and the most abundant in human cells, is the least well understood of the five human RecQ homologs. We have previously described that knockout of RECQ1 in mice or knockdown of its expression in HeLa cells results in elevated frequency of spontaneous sister chromatid exchanges, chromosomal instability, increased load of DNA damage and heightened sensitivity to ionizing radiation. We have now obtained evidence implicating RECQ1 in the nonhomologous end-joining pathway of DNA double strand break repair. We show that RECQ1 interacts directly with the Ku70/80 subunit of the DNA-PK complex, and depletion of RECQ1 results in reduced end-joining in cell free extracts. In vitro, RECQ1 binds and unwinds the Ku70/80 bound partial duplex DNA substrate efficiently. Linear DNA is co-bound by RECQ1 and Ku70/80, and DNA binding by Ku70/80 is modulated by RECQ1. Collectively, these results provide the first evidence for a role of RECQ1 in nonhomologous end-joining, perhaps through interaction with Ku70/80.
Citation Format: Swetha Parvathaneni, Robert M. Brosh, Sudha Sharma. Novel interaction of RECQ1 with Ku70/80 and its potential role in non-homologous end joining. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 624. doi:10.1158/1538-7445.AM2013-624
Abstract 629: Oddities of DNA damage signaling in mitotic human cells revealed by super-resolution microscopy.
Authors: Mistrik Martin , Bartek Jiri 
Published: August 2014

Abstract
Using an optimized cell-spreading technique combined with immunofluorescence (IF) and super-resolution microscopy we examined in greater detail DNA lesions induced within human mitotic chromosomes. We found some major differences in DNA damage signaling of mitosis-associated lesions induced by different genotoxic insults, such as inducers of DNA replication stress and ionizing radiation. While the former source of DNA damage represents a prominent inducer of genomic instability - a hallmark of cancer, the latter treatment is commonly used in cancer therapy. Differences in the DNA damage signal spreading and participation of various DNA damage-responsive proteins differentially recruited to sites of the DNA lesions are presented and discussed, including our innovative techniques developed for quantitative IF analysis of mitotic cells.
Citation Format: Martin Mistrik, Jiri Bartek. Oddities of DNA damage signaling in mitotic human cells revealed by super-resolution microscopy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 629. doi:10.1158/1538-7445.AM2013-629
Abstract 656: Promoter hypermethylation and silencing of tumor suppressor genes RASSF1A, WIF1, SLIT2 and ROBO1 in triple negative breast carcinomas.
Authors: Alvarez Carolina , Garrido Gloria , Gajardo Patricia , Quiroz Alonso , Cornejo Valeria , Fernandez Wanda , Camus Mauricio , Carvallo Pilar 
Published: August 2014

Abstract
Triple negative breast cancers represent 10-17% of all breast carcinomas. They display a high histological grade, a more aggressive clinical behavior and they lack any specific treatment, thus are associated to a bad prognosis. As other cancer types, this cancer is caused by sequential accumulation of mutations and genomic alterations involving tumor suppressor genes and oncogenes. In this matter, inactivation of tumor suppressor genes may occur by deletion, promoter hypermethylation or point mutations. In previous study by array CGH we found several tumor suppressor candidate genes deleted in a hereditary breast cancer set of tumors. In addition we studied 4 of these tumor suppressor genes RASSF1A, WIF1, SLIT2 and ROBO1 in a non triple negative set of breast cancer tumors, and found a high frequency of promoter methylation, statistically associated with loss of protein expression for RASSF1A and WIF1. In the present study we aimed to extend the analysis to triple negative breast cancer tumors due to their clinical relevance. Methylation analysis through MS-PCR revealed that RASSF1A promoter was hypermethylated in 52.9% of triple negative tumors, and presents loss of expression in 80.6% of the tumors. WIF1 promoter was hypermethylated in 89.1% and its protein expression was downregulated in 63.1% of the tumors. For SLIT2 we found frequent promoter hypermethylation among tumors (82.6%) showing loss of expression in 88% of the tumors. MS-PCR analyses were not informative for ROBO1, but protein expression was reduced in 49% of all tumors. Our results show that a high percentage of tumors present silencing of RASSF1A, WIF1, SLIT2 and/or ROBO1, and therefore implying the impairment of the pathways they represent. This findings support these genes may have an important role in triple negative breast tumor development. Fondecyt 1080595.
Citation Format: Carolina Alvarez, Gloria Garrido, Patricia Gajardo, Alonso Quiroz, Valeria Cornejo, Wanda Fernandez, Mauricio Camus, Pilar Carvallo. Promoter hypermethylation and silencing of tumor suppressor genes RASSF1A, WIF1, SLIT2 and ROBO1 in triple negative breast carcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 656. doi:10.1158/1538-7445.AM2013-656