bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1180: Activation of antisense transcription by Top1cc in human colon cancer cells
Authors: Marinello Jessica , Bertozzi Davide , Bueno Susana , Iurlaro Raffaella , Sordet Olivier , Chillemi Giovanni , Capranico Giovanni 
Published: June 2012

Abstract
Camptothecin (CPT) and derivatives are effective anti-cancer agents exerting their activity through the inhibition of DNA topoisomerase I (Top1). The cascade of events following the collision of a replication fork with CPT-trapped Top1 (TopIcc) has been deeply studied. Recently, strong evidence demonstrated that Top1cc affects specific transcriptional mechanisms as well. In particular, Top1ccs specifically favor RNA polymerase II escape from promoter-proximal pausing sites, and can alter chromatin structure and accessibility. We have also demonstrated that the CPT-induced transcriptional stress determines a changed balance between sense and antisense transcripts at the human HIF-1α locus in cancer cells [Capranico et al., BBA 2010]. Here, we have further investigated the Top1cc-related antisense transcriptional activation at the single gene locus and genome-wide. CPT treatments promote the transcription, in normal as well as hypoxic conditions, of a novel long non-coding antisense RNA at the 5’ of the human HIF-1α mRNA (5’aHIF1α), which is 5’-capped and polyadenylated, indicating that is transcribed by RNA polymerase II. The 5’aHIF1α RNA localizes preferentially in the nuclear compartment, in particular RNA FISH experiments show that it accumulates mainly in the perinuclear region of human HCT116 cells. Thus, the data may suggest that it may have a regulatory role in membrane RNA/protein trafficking. To investigate whether the described effect at HIF-1α locus is a general event after Top1cc, we have carried out a genome-wide analyses of cellular transcripts. rRNA-depleted total RNA samples from CPT-treated and untreated HCT116 cells were subjected to bisulfite C&gt;T conversion to maintain the information of the strand polarity of transcripts, and then sequenced on the Illumina platform (Solexa). Initial analyses of the ratio between sense and antisense sequence tags indicate that Top1cc induces the activation of antisense transcription at several gene loci. The results thus indicate that activation of antisense transcription may be a general response to the transcriptional stress caused by Top1ccs, possibly contributing to the pharmacological activity of camptothecins.
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 1180. doi:10.1158/1538-7445.AM2011-1180
Abstract 1193: Guanylate binding protein-1, a novel oncogenic gene in glioblastoma
Authors: Li Ming , Cavenee Webster , Furnari Frank 
Published: June 2012

Abstract
Glioblastoma multiforme (GBM) is the most common and deadly primary malignant brain tumor in adults. The most frequent genetic lesion associated with GBM, found at 40-60% frequency, is amplification and mutation of the EGFR gene. Here we report that guanylate binding protein-1 (GBP1), an immune response large GTPase, is involved in EGFR-mediated glioblatoma invasion through the modulation of matrix metallopeptidase-1 (MMP1) expression and show that GBP1 is upregulated in human GBM tumors relative to normal brain tissues, especially in EGFRvIII-positive samples. We further show that EGFRvIII promotes GBP1 expression at the transcriptional level through stimulation of the p38 MAPK signaling pathway and targeting GBP1 by lentivirus shRNA transduction significantly reduces EGFRvIII-mediated tumorigenicity of orthotopic xenografts in the mouse. Reciprocally, overexpression of GBP1 alone in glioma cells was sufficient to enhance glioma tumorigenesis by increasing cell proliferation, angiogenesis and decreasing cell apoptosis. Taken together, these results reveal that GBP1 is a novel oncogenic gene downstream of EGFRvIII signaling and suggest that GBP1 may serve as a promising therapeutic target for the treatment of GBM patients.
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 1193. doi:10.1158/1538-7445.AM2011-1193
Abstract 1224: Repression of cancer cell senescence by PKCι
Authors: Restall Ian J. , Paget Judith A. , Daneshmand Manijeh , Amin Md. Shahrier , Islam Shahidul , Lorimer Ian A.J. 
Published: June 2012

Abstract
Senescence is an irreversible growth arrest phenotype adopted by cells that has a key role in protecting organisms from cancer. There is now considerable interest in therapeutic strategies that reactivate this process to control the growth of cancer cells. Protein kinase C iota (PKCι) is a member of the atypical protein kinase C family and an important downstream mediator in the phosphoinositide pathway. PKCι expression was found to be upregulated in a subset of breast cancers and breast cancer cell lines. Introduction of mutant, oncogenic PIK3CA, but not wild-type PIK3CA, into breast mammary epithelial cells increased both the expression and activation of PKCι. In breast cancer cell lines overexpressing PKCι, depletion of PKCι increased the number of senescent cells, as assessed by senescence-associated β-galactosidase, morphology and bromodeoxyuridine incorporation. This phenomenon was not restricted to breast cancer cells, as it was also seen in glioblastoma cells. Senescence induction did not require p53, p16 or Arf and was not associated with activation of the DNA damage response. Depletion of PKCι had no effect on senescence in normal mammary epithelial cell lines. We conclude that PKCι is overexpressed in a subset of cancers where it functions to suppress premature senescence. This function appears to be restricted to cancer cells and inhibition of PKCι may therefore be an effective way to selectively activate premature senescence in cancer cells.
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 1224. doi:10.1158/1538-7445.AM2011-1224
Abstract 123: miR-145 function as a tumor suppressor targeting multiple oncogenes in prostate cancer
Authors: Fuse Miki , Nohata Nijiro , Mutallip Muradil , Kikkawa Naoko , Sakamoto Shinichi , Kojima Satoko , Chiyomaru Takeshi , Kawakami Kazumori , Enokida Hideki , Nakagawa Masayuki , Ichikawa Tomohiko , Seki Naohiko 
Published: June 2012

Abstract
Prostate cancer remains one of the most prevalent cancers and a major cause of morbidity and mortality in the western world. Disease progression and the development of hormone refractory disease remain major causes of cancer-related death. The understanding of the new molecular pathways of hormone refractory would be helpful in improving diagnosis and therapy of the disease.
microRNAs (miRNAs) are small, non-coding RNAs with a length of approximately 22 nucleotides. They regulate gene expression by promoting mRNA cleavage and at the posttranscriptional level by translational suppression. They play important roles in various biological and metabolic processes, including development, differentiation, signal transduction, cell maintenance, and cancer. Bioinformatic predictions indicate that miRNAs regulate more than 30% of the protein coding genes. It is estimated that approximately 1,000 miRNAs exist in the vertebrate genome.
An important role for miRNAs in the development of cancer has emerged in recent years. miRNAs are aberrantly expressed in many human cancers, and they may function as oncogenes or tumor suppressors. Up-regulated miRNAs could function as oncogenes by negatively regulating tumor suppressor genes, while down-regulated miRNAs could act as tumor suppressors, inhibiting cancers by regulating oncogenes.
Down-regulation of miR-145 has been reported in many types of human cancer, including prostate cancer, suggesting that miR-145 function as a tumor suppressor. In this study, we focused on target identification of miR-145 in prostate cancer, based on gene-wide gene expression analysis of miR-145 transfection cells. According to our expression analysis showed that down-regulated genes (FSCN1, UNG and EIF4EBP2) were identified. Loss-of-function assays revealed that FSCN1 inhibited cell proliferation, migration, and invasion in PC3 and DU145 cells, suggesting FSCN1 function as an oncogene.
The identification of tumor suppressive miRNA and their target genes could provide new insights into potential mechanisms of prostate carcinogenesis.
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 123. doi:10.1158/1538-7445.AM2011-123
Abstract 1235: Induction of a p21 mediated senescence program by p53 impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer
Authors: Jackson James G. , Chang Leslie L. , Quintás-Cardama Alfonso , El-Naggar Adel K. , Lozano Guillermina 
Published: June 2012

Abstract
How p53 mediates response to DNA damage induced by chemotherapy treatment of breast cancer is not well understood with few mechanistic studies addressing the conflicting reports in the literature. We have used the MMTV-Wnt1 mouse model of breast cancer to examine the role of the p53 pathway in the biochemical, cellular and clinical response to doxorubicin. We found that treatment of p53 wild type breast tumors, or heterozygous tumors that retained the wild type allele, resulted in an initial mean tumor regression of only 35%, followed by stable disease (∼1 to 2 weeks) and relapse by 11 days. Surprisingly, we found that breast tumors with mutant p53 responded better to treatment, with regression of 70% and 24 days to relapse (p&lt;0.001). Investigating the mechanism of these responses, we found that p53 mutant tumors harvested 24 hours after final treatment did not induce p53 targets after treatment when compared to untreated tumors, did not enter proliferative arrest, but did undergo p53-independent apoptosis, consistent with tumor regression data. Conversely, treated p53 wild type tumors induced p53 targets such as p21 and Puma, were negative for the proliferation marker Ki67, and did not induce apoptosis. Further characterization of the partial response in p53 wild type tumors revealed that tumors harvested in the stable arrest phase (7-14 days after treatment) had elevated markers of senescence, including p21, Dec1, Dcr2, p15, p16 and PML, compared to relapsed or resistant tumors. To more precisely address which of the myriad p53 functions was responsible for the poor response in p53 wild type tumors, we bred the MMTV-Wnt1 mice into a p21 null background and treated and monitored mice that formed tumors. We found that genetic loss of p21 in the tumors was sufficient to achieve the dramatic response observed in p53 null tumors. These data show that p53 mediated activation of a senescence program via p21 is the primary outcome in treated MMTV-Wnt1tumors, resulting in an incomplete response, stable disease and eventual early relapse, while treated p53 mutant or p21 null tumors undergo cell death and tumor regression.
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 1235. doi:10.1158/1538-7445.AM2011-1235
Abstract 1239: Smurf2-mediated ubiquitination and degradation of Id1 regulates p16 expression during senescence
Authors: Kong Yahui , Zhang Hong 
Published: June 2012

Abstract
The cyclin-dependent kinase inhibitor p16INK4A (p16) plays a critical role in senescence, cancer and aging. Its expression increases in senescent cells and with aging in many tissues of rodents and humans. The regulation of p16 expression during senescence and aging is of great interest, but is not well understood. Here we report that Smurf2, an E3 ubiquitin ligase previously found to activate senescence, can regulate p16 expression during senescence. We find that Smurf2 is required for the elevation of p16 in senescent cells, while ectopic expression of Smurf2 is sufficient to induce p16 expression dependent on its E3 ligase activity. This ligase-dependent regulation of p16 contrasts with previously identified ligase-independent regulation of p21 by Smurf2. Interestingly, we find that Smurf2 expression increases with aging in a number of tissues in mouse, providing a possible mechanism of increased p16 expression during aging. Furthermore, we identify Id1, a transcriptional repressor of p16, as a novel ubiquitination target of Smurf2's E3 ligase activity. Ubiquitination and degradation of Id1 by Smurf2 is the mediator through which Smurf2 regulates p16 expression. As the expression of Smurf2 increases in senescent cells in response to telomere shortening, our finding provides a possible link between telomere shortening and p16 expression during senescence. Further, the regulation of p16 by Smurf2 through Id1 ubiquitination and degradation will help us to understand the underlying mechanism of senescence provoked by Smurf2, and provide insight into tumor suppression or aging regulated by Smurf2.
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 1239. doi:10.1158/1538-7445.AM2011-1239
Abstract 1242: Induction and targeting of polyploid senescent cells in cancer therapeutics
Authors: Wang Qin , Wu Peter , Ivanova Iana , Chu Elizabeth , Wu Daniel Y. 
Published: June 2012

Abstract
Therapy-induced cellular senescence (TCS), an emerging concept in cancer therapeutics, describes an in vivo response of human tumors to chemotherapy and radiation. These treatments elicit a coordinated response that results in prolonged cell cycle arrest, characteristic senescence morphology and expression of senescence-specific markers. In the past decade, a growing body of evidence has supported the hypothesis that “senescence response occurs in treated human cancers and the response is reversible.” We now present evidence that TCS may be adverse to cancer therapeutics based on a clinicopatholgical study conducted in patients with advanced non-small cell lung cancer following induction therapy prior to surgery. To further define how a subpopulation of senescent cells could escape terminal arrest, our work now implicates a polyploid state through which senescent cells can survive and eventually resume proliferation. In H1299 lung cancer cells, we show that mitotic kinase Cdk1 facilitates endoreplication and formation of polyplid senescent cells (PSCs) following chemotherapy as the genetic modulation of Cdk1 activity profoundly affect the prevalence of these polyploid cells. Importantly, senescence escape occurs from the PSCs at 2.5 times the frequency of escape observed from diploid (2/4n) cells through novel non-canonical cell division mechanisms. Furthermore, we also demonstrate distinct functions of p21 and p27, two members of KIP family in TCS. While both interact with endogenous cyclin B1-Cdk1 complex in senescent cells, only p27 directly inhibits Cdk1 kinase activity and modulates PSC formation, whereas the knockdown of p21 leads to massive apoptosis. Finally, we show that statins, HMG-CoA inhibitors, currently approved for treatment of dyslipidemia down-regulate several key targets of the Cdk1 pathway, including Cdk1 itself, cyclin B1, and survivin, while up-regulating p27. Statins both decrease polyploid cells and abrogate escape of several cancer cell lines from TCS. Altogether, our work here challenges the current cancer treatment paradigm and supports the incorporation of novel strategies to enforce irreversible cell cycle exit in senescent tumor cells following treatment.
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 1242. doi:10.1158/1538-7445.AM2011-1242
Abstract 1244: The requirement of autophagy pathway for drug-induced senescence in human melanoma cells by AZD1152
Authors: Zhang Gao , Herlyn Meenhard 
Published: June 2012

Abstract
Oncogene-induced senescence (OIS) is a well-documented phenomenon both in vitro and in vivo as a tumor-suppression mechanism. It functions as a barrier to tumor initiation and progression. However, tumor cells quickly develop a sophisticated yet not well-understood mechanism to overcome and subsequently repress cellular senescence to facilitate its progression. Here we have focused on the drug-induced senescence in human melanoma cells by inhibition of Aurora B kinase (AURKB) through either small molecule AZD1152 or shAURKB. By implementing a systems biology approach, we have uncovered the necessity of mTOR, and autophagy/lysosome pathways for the drug-induced senescence in human melanoma cells. Particularly, the mTOR inhibitor Rapamycin suppresses the senescence phenotype by converting senescence to quiescence, whereas the autophagy inhibitor Bafilomycin A1 or Hydroxychloroquine can induce cell death in senescent melanoma cells induced by AZD1152, suggesting that autophagy is an important survival mechanism for senescent melanoma cells. Thus our study can potentially lead to a framework of utilizing the pro-senescence therapy followed by inhibition of autophagy as a novel clinic approach toward melanoma prevention and cure.
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 1244. doi:10.1158/1538-7445.AM2011-1244
Abstract 1283: Phase I and pharmacokinetic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine: A California Cancer Consortium study
Authors: Newman Edward M. , Morgan Robert J. , Beumer Jan H. , Blanchard Suzette M. , El-Khoueiry Anthony B. , Kummar Shivaani , Carroll Mary I. , Synold Timothy W. , Lenz Heinz J. , Doroshow James H. 
Published: June 2012

Abstract
Background: The California Cancer Consortium conducted the first-in-human clinical trial of the investigational new drug 5-fluoro-2′-deoxycytidine (FdC), a DNA methyltransferase inhibitor stable in aqueous solution, as a 3-hour infusion concurrent with 350 mg/m2 of the cytidine deaminase inhibitor tetrahydrouridine (THU), included to prolong the half-life of FdC in vivo. Methods: A 3+3 design was used; initial FdC dose doubling ended when two moderate toxicities or one severe toxicity were observed. Pharmacokinetics of FdC and THU were obtained. Results: On the initial schedule, daily (QD) × 5 every 21 days (d), FdC was escalated from 2.5 to 80 mg/m2/d without treatment-related grade 3 toxicity other than anemia and lymphopenia. At FdC doses ≥20 mg/m2/d, peak plasma FdC concentrations were above those that inhibit DNA methylation in vitro (Beumer, et al., Cancer Chemother Pharmacol 62:363-8, 2008). The schedule was amended to QD × 5 for 2 consecutive weeks every 28 d, and patients (pts) were enrolled at 40, 67, 100, 134, and 180 mg/m2/d. Overall, 51 pts were treated [28 M; 23 F; median (range): age 63 (30-85), KPS 80 (60-100)]; 44 pts were evaluable for toxicity (1 cycle). 1/6 pts at 134 mg/m2/d had dose-limiting toxicity (DLT) (grade 3 colitis) and 2/2 pts at 180 mg/m2/d had DLT (1-grade 3 fatigue + LFT; 1-grade 4 mucositis + ANC + platelets). Of the 31 pts on 28-d cycles, 8 had clinical progression prior to the first scheduled evaluation at 8 weeks and 5 did not complete 2 cycles for other reasons; 7 pts had progressive disease at 8 weeks; and 10 pts had stable disease for ≥8 weeks. In addition, 1 heavily-pretreated pt with breast cancer, treated at 67 mg/m2/d, had a partial response lasting 1 year. Conclusions: The Maximum Tolerated Dose was 134 mg/m2/d FdC + 350 mg/m2/d THU QD × 5 for 2 consecutive weeks every 28 d. An expansion cohort is being accrued to determine the pharmacokinetics of oral FdC and THU. Based on the nature of the toxicities and the observed response at 67 mg/m2/d, a multi-histology Phase II trial has been initiated at 100 mg/m2/d QD × 5 for 2 consecutive weeks every 28 d. Supported by U01 CA62505, P30 CA33572, N01-CM-52202, and P30CA47904. The authors acknowledge the invaluable contribution of Dr. M. J. Egorin.
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 1283. doi:10.1158/1538-7445.AM2011-1283
Abstract 1295: Relationship between pharmacokinetic (PK) sampling schema and reported PK variability of liposomes in patients
Authors: Schell Ryan F. , Caron Whitney P. , Walsh Mark D. , Zamboni Beth A. , Ramanathan Ramesh K. , Zamboni William C. 
Published: June 2012

Abstract
Introduction: Liposomal formulations offer advantages over small molecules including increased solubility, selective targeting potential and prolonged drug exposure. Compared with conventional formulations, these agents often have greater PK and pharmacodynamic variability, which is attributed to the role of the mononuclear phagocyte system in the clearance of liposomes. Inter-patient variability in drug exposure, represented by area under the curve (AUC), of encapsulated drug can be 20- to 100-fold. However, some nanoparticle and liposomal agents report lower inter-patient PK variability. Study design and sampling schema may affect the documentation of PK variability, due to the prolonged systemic exposure of encapsulated drug. Thus, we evaluated the reported PK variability of PEGylated CKD-602 (S-CKD602) and non-liposomal CKD-602 (NL-CKD-602) using a short (0-24 h) and long (0-336 h) sampling schema.
Methods: S-CKD602 and NL-CKD-602 were administered at doses ranging from 0.5 to 2.1 mg/m2 in phase I studies of patients with advanced solid tumors. Blood samples were obtained from baseline to 336 h for S-CKD602 and from baseline to 24 h for NL-CKD-602. Plasma concentration of total (lactone + hydroxy acid) encapsulated CKD-602 from S-CKD602 and total CKD-602 from NL-CKD-602 were measured by LC-MS/MS. AUC from 0 to 24 h (AUC0-24) and 0 to 336 h (AUC0-336) were calculated. The coefficient of variance % (CV%) in AUC0-24 and AUC0-336 at each dose level were calculated for S-CKD602 and NL-CKD-602. Results:

Conclusion: The inter-patient variability of exposure of S-CKD602 is 2.5- to 3.4-fold greater than that of NL- CKD-602. Current PK study designs limited to 24 h underestimate the inter-patient variability of exposure of S-CKD602. PK study design of liposomal agents requires an extended PK sampling schema to accurately describe its PK disposition. A limited sampling strategy that may be applied for all nanoparticles is under development to address this issue.
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 1295. doi:10.1158/1538-7445.AM2011-1295