bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting the PI3K p110α Isoform Inhibits Medulloblastoma Proliferation, Chemoresistance, and Migration
Authors: Guerreiro Ana S. , Fattet Sarah , Fischer Barbara , Shalaby Tarek , Jackson Shaun P. , Schoenwaelder Simone M. , Grotzer Michael A. , Delattre Olivier , Arcaro Alexandre 
Published: November 2008

Abstract
Purpose: The phosphoinositide 3-kinase (PI3K)/Akt pathway is frequently activated in human cancer and plays a crucial role in medulloblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K/Akt signaling as a novel antiproliferative approach in medulloblastoma.
Experimental Design: The expression pattern and functions of class IA PI3K isoforms were investigated in medulloblastoma tumour samples and cell lines. Effects on cell survival and downstream signaling were analyzed following down-regulation of p110α, p110β, or p110δ by means of RNA interference or inhibition with isoform-specific PI3K inhibitors.
Results: Overexpression of the catalytic p110α isoform was detected in a panel of primary medulloblastoma samples and cell lines compared with normal brain tissue. Down-regulation of p110α expression by RNA interference impaired the growth of medulloblastoma cells, induced apoptosis, and led to decreased migratory capacity of the cells. This effect was selective, because RNA interference targeting of p110β or p110δ did not result in a comparable impairment of DAOY cell survival. Isoform-specific p110αinhibitors also impaired medulloblastoma cell proliferation and sensitized the cells to chemotherapy. Medulloblastoma cells treated with p110α inhibitors further displayed reduced activation of Akt and the ribosomal protein S6 kinase in response to stimulation with hepatocyte growth factor and insulin-like growth factor-I.
Conclusions: Together, our data reveal a novel function of p110α in medulloblastoma growth and survival.
Bendamustine Is Effective in p53-Deficient B-Cell Neoplasms and Requires Oxidative Stress and Caspase-Independent Signaling
Authors: Roué Gaël , López-Guerra Mónica , Milpied Pierre , Pérez-Galán Patricia , Villamor Neus , Montserrat Emili , Campo Elias , Colomer Dolors 
Published: November 2008

Abstract
Purpose: Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are two incurable B-cell lymphoid neoplasms characterized by distinct clinical presentation and evolution. Bendamustine hydrochloride is a multifunctional, alkylating agent with a purine-like ring system that exhibits activity in multiple cancer models, including CLL and MCL, but whose mechanism is only partially described. Our aim was to analyze the apoptotic pathways activated by bendamustine in CLL and MCL together with the relevance of p53 mutation in determining the response to this drug.
Experimental Design: Thirteen CLL/MCL cell lines and primary tumor cells from 8 MCL and 25 CLL patients were cultured for up to 24 h with bendamustine followed by cytotoxic assays, flow cytometry, immunofluorescence, and Western blot analysis of p53 response pathway and apoptosis-related factors.
Results: Bendamustine displayed cytotoxic activity on most CLL and MCL primary cells and cell lines irrespective of ZAP-70 expression and p53 status. Bendamustine was found to act synergistically with nucleoside analogues in both CLL and MCL, this combination being effective in p53 mutated cases resistant to standard chemotherapy. Bendamustine cytotoxicity was mediated by the generation of reactive oxygen species and triggering of the intrinsic apoptotic pathway involving up-regulation of PUMA and NOXA, conformational activation of BAX and BAK, and cytosolic release of caspase-related and caspase-unrelated mitochondrial apoptogenic proteins.
Conclusions: Our findings support the use of bendamustine as a therapeutic agent, alone or in combination, for CLL and MCL with p53 alterations and describe the molecular basis of its activity in these entities.
Increased Risk of Cancer Other Than Melanoma in CDKN2A Founder Mutation (p16-Leiden)-Positive Melanoma Families
Authors: de Snoo Femke A. , Bishop D. Timothy , Bergman Wilma , van Leeuwen Inge , van der Drift Clasine , van Nieuwpoort Frans A. , Out-Luiting Coby J. , Vasen Hans F. , ter Huurne Jeanet A.C. , Frants Rune R. , Willemze Rein , Breuning Martijn H. , Gruis Nelleke A. 
Published: November 2008

Abstract
Purpose: We report the largest study to date analyzing the risk of cancers other than melanoma in melanoma families positive for the same CDKN2A mutation.
Experimental Design: We studied family members of 22 families positive for the p16-Leiden founder mutation who had attended a surveillance clinic or were their close relatives. Within this cohort, observed and expected rates of cancer were computed by mutation status consisting of 221 (proven plus obligate) carriers, 639 (proven plus obligate) noncarriers, and 668 first-degree relatives whose carrier risk was estimated from the relationship to known carriers and the age and melanoma status of that person and their relatives.
Results: Our analysis shows a relative risk (RR) of cancer other than melanoma and nonmelanoma skin cancer of 4.4 [95% confidence interval (95% CI), 3.3-5.6], predominantly attributable to the increased risk for pancreatic cancer (RR, 46.6; 95% CI, 24.7-76.4), but also for other cancers. We provide substantial proof for pancreatic cancer being a key component of the p16-Leiden phenotype. Inclusion of this cancer in a penetrance analysis leads to an estimated RR of pancreatic cancer for mutation carriers of 47.8 (95% CI, 28.4-74.7).
Conclusions: This study shows clear evidence of increased risk of cancers other than melanoma in CDKN2A families carrying the p16-Leiden mutation. Further research is necessary to determine if similar risks apply to families with CDKN2A mutations other than p16-Leiden.
Insulin-Like Growth Factor Binding Protein-2 Is a Novel Therapeutic Target Associated with Breast Cancer
Authors: So Alan I. , Levitt Randy J. , Eigl Bernhard , Fazli Ladan , Muramaki Motosugu , Leung Sam , Cheang Maggie C.U. , Nielsen Torsten O. , Gleave Martin , Pollak Michael 
Published: November 2008

AbstractPurpose: Insulin-like growth factor (IGF) binding proteins (IGFBP) modulate interactions of IGF ligands with the IGF-I receptor. The role of IGFBPs, and specifically IGFBP-2, in breast cancer progression has been poorly defined. This study assesses the effect of IGFBP-2 on the behavior of human breast cancer using clinical specimens as well as in vitro and in vivo experimental systems.Experimental Design: 4,181 primary invasive breast cancers and 120 benign breast tissue samples were identified for tumor tissue microarray construction and immunostained with IGFBP-2 antibody. Estrogen receptor-negative MDA-MB-231 cells constitutively overexpressing IGFBP-2 (MDA-MB-231BP-2) were created to assess the effect of IGFBP-2 gain-of-function. MDA-MB-468 cells, naturally expressing IGFBP-2, were used to determine the effect of IGFBP-2 loss-of-function using OGX-225, an antisense oligonucleotide drug candidate.Results: IGFBP-2 expression was significantly higher in breast cancer tissue compared with benign breast tissue. MDA-MB-231BP-2 cells grew more rapidly and were more resistant to paclitaxel both in vitro and in vivo compared with parental cells. OGX-225 decreased IGFBP-2 expression and attenuated the associated aggressive phenotype of MDA-MB-231BP-2 cells both in vitro and in vivo. Furthermore, OGX-225 inhibited the in vitro and in vivo growth of MDA-MB-468 cells.Conclusions: This study provides evidence that IGFBP-2 expression is associated with breast cancer. Novel therapeutics targeting IGFBP-2, such as OGX-225, merit further evaluation.
PXR Pharmacogenetics: Association of Haplotypes with Hepatic CYP3A4 and ABCB1 Messenger RNA Expression and Doxorubicin Clearance in Asian Breast Cancer Patients
Authors: Sandanaraj Edwin , Lal Suman , Selvarajan Viknesvaran , Ooi London Lucien , Wong Zee Wan , Wong Nan Soon , Ang Peter Cher Siang , Lee Edmund J.D. , Chowbay Balram 
Published: November 2008

Abstract
Purpose: To characterize pregnane X receptor (PXR) polymorphic variants in healthy Asian populations [Chinese, Malay and Indian (n = 100 each)], and to investigate the association between PXR haplotypes and hepatic mRNA expression of PXR and its downstream target genes, CYP3A4 and ABCB1, as well as their influence on the clearance of doxorubicin in Asian breast cancer patients.
Experimental Design: PXR genotyping was done by direct DNA sequencing, and PXR haplotypes and haplotype clusters were derived by expectation-maximization algorithm. Genotype-phenotype correlations were done using Mann-Whitney U test and Kruskal-Wallis test.
Results: Significant interethnic variations were observed in PXR pharmacogenetics among the three Asian ethnic groups. The expression of PXR mRNA in liver tissues harboring the PXR*1B haplotype clusters was 4-fold lower compared with the non-PXR*1B (*1A + *1C) haplotype clusters [PXR*1B versus PXR*1A; P = 0.015; PXR*1B versus PXR*1C; P = 0.023]. PXR*1B-bearing liver tissues were associated with significantly lower expression of CYP3A4 (PXR*1B versus non-PXR*1B, P = 0.030) and ABCB1 (PXR*1B versus non-PXR*1B, P = 0.060) compared with non–PXR*1B-bearing liver tissues. Doxorubicin clearance in breast cancer patients harboring the PXR*1B haplotypes was significantly lower compared with patients carrying the non-PXR*1B haplotypes [PXR*1B versus non-PXR*1B, CL/BSA (L h−1 m−2): 20.84 (range, 8.68-29.24) versus 24.85 (range, 13.80-55.66), P = 0.022].
Conclusions: This study showed that PXR*1B was associated with reduced hepatic mRNA expression of PXR and its downstream targets, CYP3A4 and ABCB1. Genotype-phenotype correlates in breast cancer patients showed PXR*1B to be significantly associated with lower doxorubicin clearance, suggesting that PXR haplotype constitution could be important in influencing interindividual and interethnic variations in disposition of its putative drug substrates.
Identification of an Immunogenic CTL Epitope of HIFPH3 for Immunotherapy of Renal Cell Carcinoma
Authors: Sato Eiji , Torigoe Toshihiko , Hirohashi Yoshihiko , Kitamura Hiroshi , Tanaka Toshiaki , Honma Ichiya , Asanuma Hiroko , Harada Kenji , Takasu Hideo , Masumori Naoya , Ito Naoki , Hasegawa Tadashi , Tsukamoto Taiji , Sato Noriyuki 
Published: November 2008

AbstractPurpose: CD8+ CTLs have an essential role in immune response against tumor. Although tumor-associated antigens have been identified in renal cell carcinoma (RCC), few of these are commonly shared and investigated as therapeutic targets in the clinical medicine. In this report, we show that HIFPH3, a member of prolyl hydroxylases that function as oxygen sensor, is a novel tumor antigen and HIFPH3-specific CTLs are induced from peripheral blood lymphocytes of RCC patients.Experimental Design: Expression of HIFPH3 was examined by reverse transcription-PCR and immunostaining with anti-HIFPH3 antibody. To identify HLA-A24-restricted T-cell epitopes of HIFPH3, eight peptides were selected from the amino acid sequence of this protein and screened for their binding affinity to HLA-A24. Peptide-specific CTLs were induced by stimulating peripheral blood lymphocytes of HLA-A24-positive RCC patients with these peptides in vitro. HLA-A24-restricted cytotoxicity of the CTLs against HIFPH3+ RCC lines was assessed by chromium release assay.Results: HIFPH3 was overexpressed in many RCC cell lines and primary RCC tissues, whereas it was not detectable in normal adult tissues by reverse transcription-PCR. Of the eight peptides that contained HLA-A24-binding motif, HIFPH3-8 peptide (amino acid sequence, RYAMTVWYF) could induce the peptide-specific CTLs from 3 of 6 patients with HIFPH3-positive RCC. Furthermore, HIFPH3-8 peptide-specific CTLs showed cytotoxicity against HIFPH3+ RCC cell lines in a HLA-A24-restricted manner.Conclusions: HIFPH3 may be a target antigen in immunotherapy for RCC and HIFPH3-8 peptide could be used as a peptide vaccine for HLA-A*2402+/HIFPH3+ RCC patients.
A Phase 1 Open-Label, Accelerated Dose-Escalation Study of the Hypoxia-Activated Prodrug AQ4N in Patients with Advanced Malignancies
Authors: Papadopoulos Kyriakos P. , Goel Sanjay , Beeram Murali , Wong Alvin , Desai Kavita , Haigentz Missak , Milián María L. , Mani Sridhar , Tolcher Anthony , Lalani Alshad S. , Sarantopoulos John 
Published: November 2008

Abstract
Purpose: AQ4N is a novel prodrug that is selectively bioreduced to AQ4, a topoisomerase II inhibitor, in hypoxic tumor. This study assessed the maximum tolerated dose and pharmacokinetics of AQ4N when administered weekly in patients with advanced cancers.
Experimental Design: AQ4N was administered as a 30-minute i.v. infusion on days 1, 8, and 15 of a 28-day cycle in eight dose cohorts ranging from 12 to 1,200 mg/m2. Accelerated titration design was used and the maximum tolerated dose was defined as the highest dose at which fewer than two of six patients had a dose-limiting toxicity.
Results: Sixteen patients were treated with cumulative doses of AQ4N ranging from 61.6 through 9,099.1 mg/m2. A single patient per cohort was treated up to 384 mg/m2 without toxicities. At 1,200 mg/m2, two of five patients experienced a dose-limiting toxicity (grade 5 respiratory failure and grade 3 fatigue). Five cohort assigned patients were treated without toxicity at 768 mg/m2, establishing this dose as the maximum tolerated dose. Among the most common adverse events observed were fatigue (38%), diarrhea (31%), nausea (25%), vomiting (25%), and anorexia (13%). Anticipated blue coloration of body fluids or skin was observed in all patients. The pharmacokinetics of AQ4N were dose proportional over all doses studied. Three patients experienced stable disease, including a patient with collecting duct renal cancer stable for 25 months.
Conclusion: AQ4N is well tolerated when administered weekly on a 3-of-4-week schedule at 768 mg/m2. Further combination studies investigating the safety and efficacy of AQ4N are ongoing.
Oral Human Papillomavirus Infection Before and After Treatment for Human Papillomavirus 16–Positive and Human Papillomavirus 16–Negative Head and Neck Squamous Cell Carcinoma
Authors: Agrawal Yuri , Koch Wayne M. , Xiao Weihong , Westra William H. , Trivett Anna L. , Symer David E. , Gillison Maura L. 
Published: November 2008

Abstract
Purpose: Oral human papillomavirus (HPV) infection is a risk factor for head and neck squamous cell carcinoma (HNSCC), and is a concern for patients with HPV-positive HNSCC and their partners. The prevalence of oral HPV infection before and after cancer therapy was investigated among patients with HPV16-positive and HPV16-negative HNSCC.
Experimental Design: Serial oral rinse samples (ORS) were collected from a cohort of 135 HNSCC cases as frequently as every 3 months for up to 3 years. Tumor HPV status was determined by HPV16 in situ hybridization. HPV was detected in ORS by consensus PCR and line blot hybridization. The HPV16 variants in positive oral rinse–tumor pairs were determined by sequencing. The odds of oral HPV infection among HPV16-positive and HPV16-negative cases were compared by use of generalized estimating equations.
Results: Patients were followed for a median of 21 months and provided a median of 4 samples. Forty-four of 135 patients had HPV16-positive tumors. HPV16-positive cases were more likely than HPV16-negative cases to have an oral HPV infection detected before (odds ratio, 8.6; 95% confidence interval, 3.5-21) and after therapy (OR, 2.9; 95% confidence interval, 1.1-7.4). Oral infections by HPV16 and other high-risk, but not low-risk, types were more common among HPV16-positive cases both before and after therapy. Most HPV16 variants in ORS were European, unique, and identical to that in the tumor. Persistence of a type-specific oral infection was demonstrable for as long as 5 years.
Conclusion: Oral high-risk HPV infections are more frequent among patients with HPV16-positive than HPV16-negative HNSCC, consistent with a behavioral and/or biological disposition to infection.
Phase II Trial of Short-Course CHOP-R Followed by 90Y-ibritumomab Tiuxetan and Extended Rituximab in Previously Untreated Follicular Lymphoma
Authors: Jacobs Samuel A. , Swerdlow Steven H. , Kant Jeffrey , Foon Kenneth A. , Jankowitz Rachel , Land Stephanie R. , DeMonaco Nicholas , Joyce Judith , Osborn Jennifer L. , Evans Terry L. , Schaefer Patricia M. ,   The Minh Luong
Published: November 2008

Abstract
Purpose: Radioimmunotherapy has been approved for relapsed follicular lymphoma (FL), including rituximab-refractory FL. This study was designed to determine the CR rate with short-course chemoimmunotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R) followed by 90-Y ibritumomab tiuxetan (RIT) with extended rituximab as first-line treatment.
Experimental Design: Between March 2004 and February 2007, 60 patients with stage II to IV symptomatic or bulky FL from a single institution supported by a large community network entered this phase II trial. Patients received CHOP-R for three treatment cycles before RIT followed by four additional weekly treatments with rituximab. Response was determined using fusion [18 F] fluorodeoxyglucose-positron emission tomography (PET)-computed tomography (CT) imaging.
Results: Of the 60 patients entering this trial, 55 patients completed all protocol therapy. The median follow up was 19.7 months (range, 0.26-35.9 months). For intent-to-treat analysis, the complete response (CR) rate after CHOP-R, as assessed by CT and PET imaging, was 40% and 46%, respectively. After RIT, the CR rate improved, as assessed by CT and PET imaging, to 82% and 89%, respectively. Ten patients have progressed, including eight from best response of CR. Seven of 18 patients who were PET positive after CHOP-R progressed compared with 3 of 37 patients who were PET negative (P = 0.010).
Conclusions: In patients with previously untreated, symptomatic or bulky FL, short-course chemoimmunotherapy and consolidation RIT and extended rituximab resulted in a high CR rate. Failure to achieve an early PET CR after CHOP-R indicated high risk of relapse.
Recurrence of Urothelial Carcinoma of the Bladder: A Role for Insulin-Like Growth Factor-II Loss of Imprinting and Cytoplasmic E-Cadherin Immunolocalization
Authors: Gallagher Emma M. , O'Shea Deirdre M. , Fitzpatrick Patricia , Harrison Michèle , Gilmartin Breege , Watson Jenny A. , Clarke Trevor , Leonard Martin O. , McGoldrick Aloysius , Meehan Maria , Watson Chanel , Furlong Fiona , O'Kelly Patrick , Fitzpatrick John M. , Dervan Peter A. , O'Grady Anthony , Kay Elaine W. , McCann Amanda 
Published: November 2008

Abstract
Purpose: This study documents the frequency of insulin-like growth factor-II (IGF-II) loss of imprinting (LOI) in a series of 87 bladder tissues. E-cadherin (CDH1) immunolocalization was also investigated due to the known redistribution of this adherence protein to the cytoplasm following exogenous exposure to IGF-II.
Experimental Design: Informative IGF-II cases were identified following DNA-PCR amplification and subsequent sequencing of the transcribable ApaI RFLP in exon 9 of IGF-II. Similar approaches using primer-specific cDNA templates identified the imprinting status of IGF-II in these informative cases. CDH1 cellular localization was assessed on a tissue microarray platform of 114 urothelial carcinoma of the bladder (UCB) cases (70 pTa noninvasive and 44 pT1 lamina propria invasive) using the commercially available Novocastra antibody.
Results: IGF-II LOI was evident in 7 of 17 (41%) UCB tumors and 4 of 11 (36%) tumor-associated normal urothelial samples. Two of four pT1 grade 3 tumors, the subject of much debate concerning their suitability for radical cystectomy, showed LOI at the IGF-II locus. In those tumors showing IGF-II LOI, 4 of 7 (57%) displayed concomitant CDH1 cytoplasmic staining. In contrast, only 3 of 10 (30%) IGF-II maintenance of imprinting tumors had concomitant CDH1 cytoplasmic localization. UCB cell lines displaying cytoplasmic CDH1 immunolocalization expressed significantly higher levels of IGF-II (CAL29, HT1376, and RT112) compared with RT4, a cell line displaying crisp membranous CDH1 staining. Finally, cytoplasmic CDH1 staining was an independent predictor of a shorter time to recurrence independent of tumor grade and stage.
Conclusions: We suggest that CDH1 cytoplasmic immunolocalization as a result of increased IGF-II levels identifies those nonmuscle invasive presentations most likely to recur and therefore might benefit from more radical nonconserving bladder surgery.
Aberrant Polo-Like Kinase 1-Cdc25A Pathway in Metastatic Hepatocellular Carcinoma
Authors: Wang Xiao Qi , Zhu Yong Qiang , Lui Karen S. , Cai Qi , Lu Ping , Poon Ronnie T. 
Published: November 2008

AbstractPurpose: Most studies on pathogenesis of tumor metastasis focus on cell adhesion and migration. Little is understood of how cell cycle pathways critically affect cell fate of metastatic cells and their sensitivity to anticancer drugs. In this study, we investigated cell cycle checkpoint progression and regulation in the presence of cisplatin in metastatic hepatocellular carcinoma (HCC) cells.Experimental Design: Cisplatin-mediated cell cycle progression and Polo-like kinase 1 (Plk1)-Cdc25A pathway were compared between metastatic and nonmetastatic HCC cells by flow cytometry, Western blots, and reverse transcription-PCR. Cdc25A expression in clinical HCC samples was detected using immunohistochemistry and its association with clinical HCC metastasis was analyzed.Results: Cisplatin induced degradation of Cdc25A in nonmetastatic HCC cells but not in metastatic HCC cells. Hence, metastatic HCC cells showed defective S-M cell cycle phase arrest and continued to enter mitosis. Tumor expression of Cdc25A was strongly associated with metastatic diseases in HCC patients, and elevated Cdc25A expression significantly correlated with HCC tumor-node-metastasis staging and venous invasion. Metastatic HCC cells did not show down-regulation of Plk1 that was normally induced by DNA damage. Blockage of Plk1 expression in metastatic HCC cells initiated Cdc25A degradation in response to DNA damage, suggesting that Plk1 could be an upstream regulator of Cdc25A. Deregulated Plk1-Cdc25A pathway in metastatic HCC cells and primary tumors did not result in drug-induced mitotic catastrophe but rather in accumulation of damaged DNA due to checkpoint adaptation.Conclusions: Metastatic HCC cells showed a defective S-M checkpoint following cisplatin treatment and potential aberrant checkpoint adaptation, which might result from deregulation of Plk1-Cdc25A pathway.