bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2963: Pharmacologic Chk2-inhibition promotes increased killing of human colorectal cancer cells and protects from gastrointestinal toxicity following Irinotecan/trail death-receptor agonists (TDRA)
Authors: Finnberg Niklas K. , Arunasalam Navaraj , Lang Krystle , Cerniglia George , Motoyama Noboru , Zhou Bin-Bing , El-Deiry Wafik S. 
Published: June 2012

Abstract
Dose-limiting gastrointestinal toxicity following systemic chemotherapy-based treatment regimen is associated with increased cost and reduced cure-rate. Pharmacologic inhibition of Chk2 has the potential to sensitize cancer cells to cancer therapy while at the same time protect normal tissues from toxicity. Cell death in normal tissues and cells is blocked by inhibition or loss of chk2 in a DNA damage-specific manner whereas tumors cells with check-point aberrations are sensitized to death. We show that inhibiting Chk2-by the use the pharmacologic inhibitors of the Chk2-kinase “Chk2 Inhibitor II” (CI-II) and PV-1019 has the potential to both protect the GI mucosa and improve cell-kill of colorectal cancer cells when Irinotecan is combined with trail death-receptor agonists (TDRA). HCT116-Chk2-/- cells were increasingly sensitive to Irinotecan, TDRA and the combination thereof and PV-1019 had single agent activity towards SW620 cells at 10µM and caused sensitization to Irinotecan at lower doses. Gastrointestinal (GI) toxicity in mice following treatment with the TDRA-antibody MD5-1 in combination with high-dose Irinotecan is completely mediated by chk2 since Chk2-deficient mice are protected and pharmacologic inhibition of Chk2 using CI-II following Irinotecan/TDRA reduced the extent of weight loss and lethality associated with GI-toxicity in the mice. Interestingly, chk2-inhibition only conferred significant protection following Irinotecan/TDRA but not fluorouracil/TDRA, suggesting an Irinotecan-specific protection from GI-toxicity. Concomitant pharmacologic inhibition in conjunction with Irinotecan-based therapy may improve the therapeutic window by reducing GI-toxicity and increasingly promote colorectal cancers cell death.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2963. doi:10.1158/1538-7445.AM2011-2963
Abstract 2965: hSSB1 binds and protects p21 from ubiquitin-mediated degradation and positively correlates with p21 in human hepatocellular carcinomas
Authors: Kang Tiebang , Xu Shuangbing , Zeng Yi-Xin 
Published: June 2012

Abstract
Down-regulation of hSSB1, a single-stranded DNA-binding protein, causes increased radiosensitivity, defective checkpoint activation and genomic instability. However, the mechanisms of hSSB1 function in these responses remain to be uncovered. Here, we present evidence that hSSB1 and p21 interact through their N-terminal domains and that this interaction may prevent p21 from ubiquitin-mediated degradation. Furthermore, both promotion of the G1/S transition and abrogation of the G2/M checkpoints induced by hSSB1 knockdown are substantially rescued by overexpressing p21. Most importantly, hSSB1 and p21 levels are positively correlated in human hepatocellular carcinomas, as determined by immunostaining. Therefore, hSSB1 may positively modulate p21 to regulate cell cycle progression and DNA damage response, implicating hSSB1 as a novel, promising therapeutic target for cancers such as hepatocellular carcinomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2965. doi:10.1158/1538-7445.AM2011-2965
Abstract 2969: A Wee1 kinase inhibitor, MK-1775, sensitizes cervical carcinoma cell lines to cisplatin and topotecan
Authors: Shumway Stuart D. , Kubica Jamie L. , Guertin Amy D. , Hurd Melissa S. , Wexler Roseanne S. , Demuth Tim , Toniatti Carlo 
Published: June 2012

Abstract
The Wee1 tyrosine kinase plays a key role in checkpoint arrest by phosphorylating and inhibiting cyclin-dependent kinases 1 and 2, two CDKs that drive S-phase and G2- to M-phase transitions, respectively. Interfering with Wee1 leads to elevated CDK1 and 2 activity, which in turn overcomes checkpoint arrest and causes cells to progress through the cell cycle in the presence of DNA damage. Wee1 inhibitors are therefore expected to sensitize cancer cells to DNA damaging chemotherapeutics. In particular, p53-deficient cells are postulated to be particularly sensitive to Wee1 inhibition because they lack a G1-checkpoint and rely more on S- and G2-phase checkpoints where Wee1 activity is critical. The p53 pathway is frequently inactivated in cervical carcinoma either through TP53 mutation or through functional inactivation by Human PapillomaVirus (HPV) gene products. We thus investigated the capability of MK-1775, a selective and potent inhibitor of Wee1, to sensitize cervical cancer cell lines to cisplatin and topotecan. We have evaluated the potential of the Wee1 inhibitor MK-1775 to sensitize cervical cancer cells to standard-of-care treatments both in vitro and in vivo. Using a panel of cervical cancer cell lines, we demonstrated that MK-1775 at clinically relevant concentrations potentiates the cytotoxic activity of cisplatin and topotecan in vitro as indicated by the average 3-fold and 2-fold shift in the CC50s for cisplatin and topotecan, respectively. Chemosenstization was observed in both HPV-negative/p53 mutant and HPV-positive p53/wild-type cervical cancer cell lines. Finally, we have demonstrated that MK-1775 significantly increases the in vivo efficacy of a cisplatin-topotecan combination therapy in xenograft models of HPV+ cervical carcinoma. Based on these data, MK-1775 is currently undergoing clinical evaluation in a phase 1b/2 trial in platinum combination for the treatment of cervical carcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2969. doi:10.1158/1538-7445.AM2011-2969
Abstract 2974: Regulation of cyclin dependent kinase 7 through a phosphotidylinositol 3-kinase/PKC-ι mediated cell proliferation cascade
Authors: Desai Shraddha , Acevedo-Duncan Mildred 
Published: June 2012

Abstract
PKC-ι is highly over expressed in the transformed phenotype of human glioma and benign and malignant meningioma however little is understood about its role in glioma cell proliferation. Several upstream molecular aberrations and/or loss of PTEN have been implicated that lead to constitutive activation in phosphotidylinositol (PI) 3-kinase pathway. PKC-ι is one of the important downstream targeted mediators which are often up regulated by PI3-kinase. Cyclin dependent kinase activating kinase (CAK) which comprises of cyclin dependent kinase 7 (Cdk7), cyclin H and MAT1, is the master cell regulator which phosphorylates cyclin dependent kinases (cdks) and promotes cell proliferation. We studied a potential function of PKC-ι in cell cycle progression and proliferation in two human glial tumor derived cells T98G and U87MG. Results show that PKC-ι directly associate and phosphorylate Cdk7 at Thr-170, which is required for Cdk activation and G1/S cell cycle transition. Furthermore, Cdk7 phosphorylated its downstream target, cyclin dependent kinase 2 (cdk2) at Thr-160. Purified PKC-ι was also observed to phosphorylate endogenous as well as exogenous Cdk7. PKC-ι knockdown with silencing RNA (siRNA) as well as PI3-kinase inhibitors, Wortmannin and LY294002 treatment exhibited corresponding reduction in phosphorylation of Cdk7 and subsequently cdk2. Collectively, these findings suggest presence of a novel PI3-kinase/PKC-ι/Cdk7/cdk2 cell proliferation pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2974. doi:10.1158/1538-7445.AM2011-2974
Abstract 2985: CHD1L upregulates TCTP and induces mitotic defects and chromosome missegregation through decreasing Cdk1 activity by Cdc25C ubiquitination
Authors: Chan Tim Hon Man , Chen Leilei , Guan Xin-Yuan 
Published: June 2012

Abstract
CHD1L is a target oncogene responsible for the 1q21 amplification event in hepatocellular carcinoma (HCC). Here, TCTP was found to be a CHD1L target gene. CHD1L protein directly binds to the promoter region (−733/-1027) of TCTP and upregulates the latter's expression in both cell lines and clinical specimens. Overexpression of TCTP, detected in 41.9% of human HCCs, was significantly associated with heavy liver cirrhosis and advanced tumor stage. During mitosis, the elevated expression of TCTP could accelerate the ubiquitin-proteasome degradation of Cdc25C, which in turn led to the failure in the dephosphorylation of Cdk1 on Tyr15 and the decreased Cdk1 activity, finally causing a faster mitosis exit and chromosome missegregation. Depletion experiments confirmed that TCTP accelerates M phase progression and induces tumorigenicity. Overall, we reveal a novel molecular pathway (CHD1L)-(TCTP)-(Cdc25C)-(Cdk1) during hepatocarcinogenesis which causes the malignant transformation of hepatocytes with the phenotypes of accelerated mitotic progression and the production of aneuploidy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2985. doi:10.1158/1538-7445.AM2011-2985
Abstract 2991: ATM is activated in mitosis and required for the spindle checkpoint
Authors: Yang Chunying , Tang Xi , Guo Xiaojing , Wong Stephen , Fu Li , Xu Bo 
Published: June 2012

Abstract
The ATM kinase, mutation of which leads to the human autosomal recessive disorder Ataxia-Telangiectasia (A-T), plays a critical role in the maintenance of genetic stability. ATM is activated in response to DNA double strand breaks and essential for cell cycle checkpoints. However, ATM function outside the DNA damage response is less clear. Here we report that ATM is activated in mitosis in the absence of DNA damage and is required for the spindle assembly checkpoint. We generated stable cell lines expressing either control shRNA or ATM shRNA and monitored chromosome dynamics and the timing of mitosis by time-lapse video microscopy. The results reveal that ATM-depleted cells proceed into anaphase despite the presence of maloriented and unaligned chromosomes; whereas control cells do not proceed into anaphase until the completion of chromosome alignment on the metaphase plate. We also find ATM-depleted cells exit mitosis much earlier than control cells. In addition, we found ATM-depleted cells do not arrest in mitosis after nocodazole treatment, indicating a spindle assembly checkpoint (SAC) defect. Enzymatic assays indicate that ATM kinase activity is enhanced during mitosis. Further, mitotic ATM activation is mechanistically distinct from that induced by ionizing radiation. Next we demonstrate that mitotic-dependent ATM activation relies on the Aurora-B kinase, a chromosome passenger protein, which is implicated in chromosomal alignment, spindle checkpoint and cytokinesis. Aurora-B phosphorylates ATM at Serine 1403 both in vitro and in vivo. Immunofluorescence experiments show that ATM-Ser1403 phosphorylation has a similar localization pattern to Aurora B during mitosis. More interestingly, we find that ATM Ser1403 phosphorylation is evident in malignant breast cancer tissues and is highly correlated with the mitotic index (p=0.001, Pearson Correlation Test). Cells expressing the mutation of Serine 1403 to Alanine show a defective SAC and accelerated mitotic progression, similar to that of ATM-depleted cells. Collectively, our data demonstrate the functional significance of ATM activation in mitosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2991. doi:10.1158/1538-7445.AM2011-2991
Abstract 3006: A novel method for locus specific detection of 5-hydroxymethylcytosine
Authors: Yen James L. , Choi Stella , Van Eden Marc E. , Jia Xi Yu 
Published: June 2012

Abstract
Epigenetic mis-regulation leading to diseases such as cancer is classically understood in terms of aberrant DNA methylation patterns. For decades, 5-methylcytosine (5-mC) has been the focus of epigenetic DNA modification studies. But recently, a novel epigenetic DNA modification, 5-hydroxymethylcytosine (5-hmC), has been shown to be present in mammalian brain and ES cells. Current tools available to map DNA methylation (e.g. bisulfite conversion) cannot distinguish between 5-mC and 5-hmC. Here we describe a new method for locus specific interrogation of 5-hmC within DNA.
Treatment of DNA with a 5-hmC glucosyltransferase enzyme specifically adds a glucose moiety onto preexisting 5-hmC residues, yielding glucosyl-5-hydroxymethylcytosine (glu-5-hmC). Subsequent digestion of DNA with glu-5-hmC sensitive restriction endonucleases effectively cleaves DNA with cytosine, 5-mC, or 5-hmC within their recognition site. But when glu-5-hmC is present, DNA is not able to be cleaved. Exploiting this difference in “cleavability”, 5-hmC can be detected at loci of interest using qPCR.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3006. doi:10.1158/1538-7445.AM2011-3006
Abstract 3008: Genome-wide siRNA screening identifies epigenetic silencing factor networks as potential targets for cancer therapy
Authors: Poleshko Andrey S. , Einarson Margret B. , Skalka Anna Marie , Katz Richard A. 
Published: June 2012

Abstract
Epigenetic processes control the binary on-off states of specific gene sets, thereby creating heritable transcription patterns that drive development, and maintain cellular identity. The prominent epigenetic regulatory marks on eukaryotic chromatin are histone modifications and DNA cytosine methylation (5meCpG). These marks are placed by protein complexes, including members of the histone modifying and DNA methyltransferase (DNMT) enzyme families. It is hypothesized that errors in placement, removal, or reading of epigenetic marks can cause human disease through inappropriate silencing of specific genes. As the epigenetic marks that mediate gene silencing are reversible, there is interest in devising therapeutic strategies to reactivate epigenetically silent genes. Inhibitors of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) enzyme families can reverse epigenetic silencing and produce anti-tumor effects, possibly through reactivation of silent tumor suppressor genes (so-called epigenetic therapy). As these inhibitors show limited specificity within enzyme families, their precise mechanisms of action are not well understood.
To identify cellular factors involved in maintenance of epigenetic silencing, we constructed a population of human cells harboring epigenetically silent GFP reporter genes. Using this cell population we have implemented a GFP reporter-based siRNA knockdown screen to identify novel factors and networks that maintain epigenetic silencing in human cells. We have now completed a genome-wide, high throughput siRNA-based screen (21,122 siRNA targets). The screen has produced 128 gene hits that have satisfied several validating criteria. The output of this screen was of high quality, as several of the factors were identified in an earlier independent screen. Among the newly identified hits, there was a significant enrichment for factors that mediate SUMOylation, as well as 25 factors corresponding to novel genes, including 9 with no predicted functions.
This screen has the potential to identify novel cellular pathways and reveal new targets for epigenetic therapy of cancer and other diseases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3008. doi:10.1158/1538-7445.AM2011-3008
Abstract 3009: Genetic and epigenetic variations resulting from Alu retrotransposition
Authors: de Andrade Alexandre , Xie Hehuang , Wang Min , Bonaldo Maria F. , Soares Marcelo B. 
Published: June 2012

Abstract
Alu repeats are the most prevalent retrotransposons, comprising approximately 10% of the human genome. Alu retrotransposons have amplified during primate evolution by an RNA-mediated copy and paste mechanism. Among the Alu subfamilies, AluY elements and its variants exhibit the highest rates of retrotransposition. De novo retrotransposition of active Alu elements have given rise to insertion polymorphisms in human populations. While generating methylation maps of Alu elements in human normal cerebellum and in ependymoma tumors, Xie and colleagues (2009, 2010) also identified putative new Alu element insertions. In this study, we explored these Alu libraries to identify recent Alu element insertions and to understand the (epi)genetic variations that result from such events. This study may also enable identification of DNA structural variation that may occur at the onset of tumorigenesis and/or during tumor progression.
A total of 327 putative recent Alu element insertions represented by 1,762 sequence reads were identified, including 316 events that have not yet been documented in either dbSNP or dbRIP. Forty-seven out of a total of forty-nine randomly selected events representing nineteen genomic loci were sequence-verified. Alu element insertions remained heterozygous for sixteen out of nineteen genomic loci in one or more individuals. The polymorphic Alu elements are enriched for young Alu families and they present some characteristic sequence features, such as longer poly(A) tails. In addition, they also present the TT/AAAA consensus sequence at their 3’-flanking regions, and AT-rich target site duplications. Despite being homozygous or heterozygous insertions, these Alu elements are heavily methylated. Further methylation analysis on two genomic loci revealed no methylation difference in two heterozygous alleles and also no methylation difference at CpG dinucleotides flanking the Alu insertion sites. These results indicate that the recently integrated Alu elements have not influenced the methylation status of their neighboring CpG dinucleotides.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3009. doi:10.1158/1538-7445.AM2011-3009
Abstract 301: 67-kDa laminin receptor as prognostic marker and therapeutic target in epithelial ovarian carcinoma
Authors: Lee Jeong-Won , Cho Young-Jae , Choi Chel-Hun , Park Young Ae , Choi Jung-Joo , Jeon Hye-Kyeong , Kim Byoung-Gie , Bae Duk-Soo 
Published: June 2012

Abstract
Objectives: The 67-kDa laminin receptor (67LR) is a non-integrin cell surface receptor with high affinity for laminin, which plays a key role in tumor invasion and metastasis.
We investigated the clinical significance of 67LR expression including roles of prognostic marker or therapeutic target in epithelial ovarian carcinoma.
Methods: The expression of 67LR was evaluated by immunohistochemistry in 71 patients with ovarian carcinomas including 54 serous, 13 endometrioid and 4 mucinous types. We assessed the correlation of 67LR expression with clinical characteristics including histology, tumor grade, FIGO stage, and survival. In vitro experiment was performed for 67LR with inhibition using siRNA to evalute its role in cell growth control and sensitivity to chemotherapeutic agents in ovary carcinoma cell line.
Results: The expression of 67LR protein with mainly membranous location was observed in majority (45/62, 73 %) of the EOCs but not in normal ovarian tissues (P&lt;0.001). Thirty (48.4%) of 62 specimens were scored as cytoplasmic-67LR-positive. The 67-LR membranous expression was correlated with poorer progression-free survival (HR = 2.14, 95% CI 1.08-4.23, P = 0.028), though it was not an independent prognostic factor. And interestingly, cytoplasmic expression without membranous expression was correlated with poorer overall survival (P = 0.002). When 67-LR siRNA was transfected to several ovarian cancer cells, there was significant in vitro effect on cell survival and proliferation assessd by MTT assay.
Conclusion: These finding suggest that 67LR expression might be a prognostic marker for survival and it may play possible target for experimental treatment of epithelial ovary carcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 301. doi:10.1158/1538-7445.AM2011-301
Abstract 3011: Evaluation of a high throughput platform for chromatin immunoprecipitation
Authors: Li Zirong 
Published: June 2012

Abstract
Expression of eukaryotic genes during development requires complex spatial-temporal regulation. This complex regulation is often achieved through the coordinated interaction of transcription regulatory elements in the promoters of the target genes. The identification and mapping of regulatory elements in genome scale is crucial to understand how gene expression is regulated
Chromatin immunoprecipitation is a standard method for assessing the occupancy of DNA binding proteins in vivo in their native chromatin context using antibodies. However, standard chromatin immunoprecipitation procedure is time consuming, labor intensive and not suited for analyzing many samples simultaneously.
Recently, we have developed a simple chromatin immunoprecipitation protocol, which utilizes high capacity protein A/G coated magnetic beads and 96 well plate. This protocol requires fewer steps, little hands-on time and is compatible with multi-channel pipetting and liquid handling robot. This protocol allows genome wide mapping of transcription regulatory network in a high throughput manner.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3011. doi:10.1158/1538-7445.AM2011-3011