bluuebunny/crossref_metadata_2025_split huggingface dataset:
Somatostatin Receptor sst2 Decreases Cell Viability and Hormonal Hypersecretion and Reverses Octreotide Resistance of Human Pituitary Adenomas
Authors: Acunzo Julie , Thirion Sylvie , Roche Catherine , Saveanu Alexandru , Gunz Ginette , Germanetti Anne Laure , Couderc Bettina , Cohen Richard , Figarella-Branger Dominique , Dufour Henry , Brue Thierry , Enjalbert Alain , Barlier Anne 
Published: December 2008

Abstract
In human somatotroph adenomas, growth hormone (GH) hypersecretion can be inhibited by somatostatin analogues such as octreotide. Unfortunately, serum GH levels reach normal values in only 60% of treated patients. The decreased sensitivity to octreotide is strongly related to a lower expression of somatostatin receptor sst2. In this present study, the sst2 gene was transferred by an adenoviral vector (Ad-sst2) in human somatotroph (n = 7) and lactotroph (n = 2) adenomas in vitro. Sst2 mRNA levels and sst2 immunostaining dramatically increased after infection. Ten days after infection at 20 multiplicity of infection (MOI), sst2 gene transfer decreased cell viability from 19% to 90% by caspase-dependent apoptosis. At low viral doses (5 MOI), Ad-sst2 decreased GH or prolactin (PRL) basal secretion and mRNA expression. Somatotroph tumors were classified in three groups according to their octreotide sensitivity. Four days after infection by 5 MOI Ad-sst2, the maximal GH suppression by octreotide increased from 31% to 57% in the octreotide partially resistant group and from 0% to 27% in the resistant ones. In the octreotide-sensitive group, EC50 values significantly decreased from 1.3 × 10−11 to 6.6 × 10−13 mol/L without improving maximal GH suppression. Finally, lactotroph tumors, nonresponding to octreotide in basal conditions, became octreotide sensitive with a maximal PRL suppression of 43% at 10−8 mol/L. Therefore, sst2 reexpression is able to improve octreotide sensitivity. Sst2 gene transfer may open new theapeutic strategies in treatment combined with somatostatin analogues. [Cancer Res 2008;68(24):10163–70]
Timosaponin A-III Induces Autophagy Preceding Mitochondria-Mediated Apoptosis in HeLa Cancer Cells
Authors: Sy Lai-King , Yan Siu-Cheong , Lok Chun-Nam , Man Ricky Y.K. , Che Chi-Ming 
Published: December 2008

Abstract
Timosaponin A-III (TAIII), a saponin isolated from the rhizome of Anemarrhena asphodeloides, exhibits potent cytotoxicity and has the potential to be developed as an anticancer agent. Here, we provide evidence that TAIII induces autophagy in HeLa cells followed by apoptotic cell death. TAIII-induced autophagy was morphologically characterized by the formation of membrane-bound autophagic vacuoles recognizable at the ultrastructural level. TAIII-treated cells expressing green fluorescent protein (GFP)–labeled microtubule-associated protein 1 light chain 3 (LC3) displayed punctate fluorescence indicative of LC3 recruitment to the autophagosome. This was associated with the conversion of LC3-I (the cytosolic form) into LC3-II (the lipidated form located on the autophagosome membrane). TAIII treatment also induced mitochondrial dysfunction involving overproduction of reactive oxygen species and reduction of mitochondrial membrane potential accompanied by induction of mitochondrial permeability transition. Prolonged exposure to TAIII resulted in cytochrome c release and caspase-3 activation, events that signified the onset of apoptotic cell death. TAIII-induced autophagy preceded apoptosis, as evidenced by early autophagic vacuole formation, GFP-LC3 translocation, and LC3-II increase in the absence of caspase-3 cleavage. Notably, TAIII-mediated apoptotic cell death was potentiated by treatment with autophagy inhibitor 3-methyladenine or small interfering RNA against the autophagic gene beclin 1. These findings suggest that TAIII-elicited autophagic response plays a protective role that impedes the eventual cell death. In terms of structure-activity relationship, the sugar chain in TAIII is indispensable to the drug action, as the sugar-lacking aglycone sarsasapogenin did not induce autophagy and exhibited weaker cytotoxicity. [Cancer Res 2008;68(24):10229–37]
Overexpression of OATP1B3 Confers Apoptotic Resistance in Colon Cancer
Authors: Lee Wooin , Belkhiri Abbes , Lockhart A. Craig , Merchant Nipun , Glaeser Hartmut , Harris Elizabeth I. , Washington M. Kay , Brunt Elizabeth M. , Zaika Alex , Kim Richard B. , El-Rifai Wael 
Published: December 2008

Abstract
Organic anion transporting polypeptide 1B3 (OATP1B3, SLCO1B3) is normally expressed in hepatocytes. In this study, we showed frequent overexpression of OATP1B3 in colorectal adenocarcinomas. Quantitative reverse transcription-PCR analysis of 17 colon tumors indicated tumoral overexpression of OATP1B3 by ∼100-fold, compared with 20 normal colon samples (P &lt; 0.0001). Using immunohistochemistry on a tissue microarray containing 93 evaluable colon tumor specimens, we detected immunostaining of OATP1B3 in 75 colon adenocarcinomas (81%) and no immunostaining in normal samples. To determine the functional effects of OATP1B3 expression on drug-induced apoptosis, we used camptothecin and oxaliplatin on a panel of colorectal cancer cell lines stably overexpressing OATP1B3. The results indicated that OATP1B3 overexpression enhanced cell survival in RKO, HCT-8, and HCT116p53+/+ cells that harbor wild-type p53 but not in Caco-2 and HCT116p53−/− cells that lack p53, compared with the respective empty vector controls (P &lt; 0.01). The terminal deoxynucleotidyl transferase-mediated nick-end labeling assay confirmed that HCT116p53+/+ cells overexpressing OATP1B3 had significantly lower apoptotic levels compared with empty vector control (P &lt; 0.001). The overexpression of OATP1B3 reduced the transcriptional activity of p53, with subsequent reductions in transcript and protein levels of its downstream transcription targets (P21WAF1 and PUMA). Overexpression of a point mutation (G583E) variant of OATP1B3 lacking transport activity did not confer an antiapoptotic effect or affect p53 transcriptional activity, suggesting that the antiapoptotic effect of OATP1B3 may be associated with its transport activity. Taken together, our results suggest that OATP1B3 overexpression in colorectal cancer cells may provide a survival advantage by altering p53-dependent pathways. [Cancer Res 2008;68(24):10315–23]
A Transcription-Independent Function of FOXO1 in Inhibition of Androgen-Independent Activation of the Androgen Receptor in Prostate Cancer Cells
Authors: Liu Ping , Li Shangwei , Gan Lu , Kao Timothy P. , Huang Haojie 
Published: December 2008

Abstract
Increasing evidence suggests that aberrant activation of the androgen receptor (AR) plays a pivotal role in the development and progression of androgen depletion–independent prostate cancer (PCa) after androgen deprivation therapy. Here, we show that loss of the PTEN tumor suppressor gene is associated with hyperactivation of the AR in human PCa cell lines. This effect is mediated primarily by its downstream effector FOXO1. In addition to the inhibition of androgenic activation of the AR, forced expression of FOXO1 in PTEN-negative PCa cells also inhibits androgen-independent activation of the AR in a manner independent of FOXO1 transcriptional function. In contrast, silencing of FOXO1 in PTEN-positive cells not only increases the basal activity of the AR in the absence of androgens, it also markedly sensitizes the AR activation by low levels of androgens or nonandrogenic factors such as interleukin-6. FOXO1-mediated inhibition of the AR is partially attenuated by the histone deacetylase (HDAC) inhibitor trichostatin A. Accordingly, FOXO1 interacts with HDAC3 as shown by coimmunoprecipitation assays, and cotransfection of cells with FOXO1 and HDAC3, but not HDAC1 and HDAC2, results in a greater inhibition of AR activity than in cells transfected with FOXO1 or HDAC3 individually. Together, our findings define a novel corepressor function of FOXO1 in inhibition of androgen-independent activation of the AR. [Cancer Res 2008;68(24):10290–9]
Molecular Mechanisms of Patupilone Resistance
Authors: Mozzetti Simona , Iantomasi Raffaella , De Maria Ilaria , Prislei Silvia , Mariani Marisa , Camperchioli Alessia , Bartollino Silvia , Gallo Daniela , Scambia Giovanni , Ferlini Cristiano 
Published: December 2008

AbstractPatupilone is an epothilone in advanced clinical development that has shown promising efficacy in heavily pretreated patients. This study aimed at characterizing the mechanisms of patupilone activity in resistant patients. To this end, we generated patupilone-resistant cells using two cellular models, the first characterized by high chemosensitivity and low class III β-tubulin (TUBB3) expression (A2780), and the second by low chemosensitivity and high TUBB3 expression (OVCAR-3). The obtained cell lines were named EPO3 and OVCAR-EPO, respectively. The same selection procedure was done in A2780 cells to generate a paclitaxel-resistant cell line (TAX50). Factors of resistance are expected to increase in the drug-resistant cell lines, whereas factors of drug sensitivity will be down-regulated. Using this approach, we found up-regulation of TUBB3 in TAX50, but not EPO3, cells, showing that TUBB3 mediates the resistance to paclitaxel but not to patupilone. Moreover, TUBB3 was a factor of patupilone sensitivity because OVCAR-EPO cells exhibited a dramatic reduction of TUBB3 and a concomitant sensitization to hypoxia and cisplatin-based chemotherapy. To identify the mechanisms underlying patupilone resistance, tubulin genes were sequenced, thereby revealing that a prominent mechanism of drug resistance is represented by point mutations in class I β-tubulin. Overall, these results suggest that paclitaxel and patupilone have nonoverlapping mechanisms of resistance, thus allowing the use of patupilone for those patients relapsing after paclitaxel-based chemotherapy. Furthermore, patupilone represents a promising first-line option for the treatment of high-risk ovarian cancer patients, who exhibit high TUBB3 levels and poor response to standard paclitaxel-platin chemotherapy. [Cancer Res 2008;68(24):10197–204]
A Mutant Collagen XIII Alters Intestinal Expression of Immune Response Genes and Predisposes Transgenic Mice to Develop B-Cell Lymphomas
Authors: Tuomisto Anne , Sund Malin , Tahkola Jenni , Latvanlehto Anne , Savolainen Eeva-Riitta , Autio-Harmainen Helena , Liakka Annikki , Sormunen Raija , Vuoristo Jussi , West Anne , Lahesmaa Riitta , Morse Herbert C. , Pihlajaniemi Taina 
Published: December 2008

AbstractEpithelial cells of mucosal surfaces are critical for maintaining immune homeostasis by aiding in the discrimination of pathogenic and commensal microorganisms and modulating the activities of antigen-presenting cells and lymphocytes. Functional breakdowns resulting in chronic infection and inflammation are associated with the development of hematologic and solid neoplasms for which detailed pathogenetic mechanisms are poorly understood. Mice heterozygous for a transgene Col13a1del expressing a mutant collagen XIII developed clonal mature B-cell lineage lymphomas originating in mesenteric lymph nodes (MLN). The tumors were associated with T cells and macrophages. The incidence of disease was reduced 2-fold in transgenic mice raised under specific pathogen-free conditions, suggesting a role for infectious agents. The lymphomas did not express the mutant collagen XIII, indicating that its influence on tumorigenesis was B-cell extrinsic and likely to be associated with collagen XIII–positive tissues drained by the MLN. Studies of the small intestines of transgenic mice showed that the subepithelial basement membranes (BM) were highly abnormal and that they exhibited heightened expression of genes involved in immune responses. These results define collagen XIII–dependent maintenance of the intestinal BM as a previously unappreciated component of immune responses and a critical determinant of cancer susceptibility. [Cancer Res 2008;68(24):10324–31]
Confirmation of Gene Expression–Based Prediction of Survival in Non–Small Cell Lung Cancer
Authors: Guo Nancy L. , Wan Ying-Wooi , Tosun Kursad , Lin Hong , Msiska Zola , Flynn Daniel C. , Remick Scot C. , Vallyathan Val , Dowlati Afshin , Shi Xianglin , Castranova Vincent , Beer David G. , Qian Yong 
Published: December 2008

Abstract
Purpose: It is a critical challenge to determine the risk of recurrence in early stage non–small cell lung cancer (NSCLC) patients. Accurate gene expression signatures are needed to classify patients into high- and low-risk groups to improve the selection of patients for adjuvant therapy.
Experimental Design: Multiple published microarray data sets were used to evaluate our previously identified lung cancer prognostic gene signature. Expression of the signature genes was further validated with real-time reverse transcription-PCR and Western blot assays of snap-frozen lung cancer tumor tissues.
Results: Our previously identified 35-gene signature stratified 264 patients with NSCLC into high- and low-risk groups with distinct overall survival rates (P &lt; 0.05, Kaplan-Meier analysis, log-rank tests). The 35-gene signature further stratified patients with clinical stage 1A diseases into poor prognostic and good prognostic subgroups (P = 0.0007, Kaplan-Meier analysis, log-rank tests). This signature is independent of other prognostic factors for NSCLC, including age, sex, tumor differentiation, tumor grade, and tumor stage. The expression of the signature genes was validated with real-time reverse transcription-PCR analysis of lung cancer tumor specimens. Protein expression of two signature genes, TAL2 and ILF3, was confirmed in lung adenocarcinoma tumors by using Western blot analysis. These two biomarkers showed correlated mRNA and protein overexpression in lung cancer development and progression.
Conclusions: The results indicate that the identified 35-gene signature is an accurate predictor of survival in NSCLC. It provides independent prognostic information in addition to traditional clinicopathologic criteria.
Cancer Stem Cell Analysis and Clinical Outcome in Patients with Glioblastoma Multiforme
Authors: Pallini Roberto , Ricci-Vitiani Lucia , Banna Giuseppe Luigi , Signore Michele , Lombardi Dario , Todaro Matilde , Stassi Giorgio , Martini Maurizio , Maira Giulio , Larocca Luigi Maria , De Maria Ruggero 
Published: December 2008

Abstract
Purpose: Cancer stem cells (CSC) are thought to represent the population of tumorigenic cells responsible for tumor development. The stem cell antigen CD133 identifies such a tumorigenic population in a subset of glioblastoma patients. We conducted a prospective study to explore the prognostic potential of CSC analysis in glioblastoma patients.
Experimental Design: We investigated the relationship between the in vitro growth potential of glioblastoma CSCs and patient death or disease progression in tumors of 44 consecutive glioblastoma patients treated with complete or partial tumorectomy followed by radiotherapy combined with temozolomide treatment. Moreover, we evaluated by immunohistochemistry and immunofluorescence the prognostic value of the relative presence of CD133+ and CD133+/Ki67+ cells in patient tumors.
Results: In vitro CSC generation and the presence of ≥2% CD133+ cells in tumor lesions negatively correlated with overall (P = 0.0001 and 0.02, respectively) and progression-free (P = 0.0002 and 0.01, respectively) survival of patients. A very poor overall (P = 0.007) and progression-free (P = 0.001) survival was observed among patients whose tumors contained CD133+ cells expressing Ki67. Taking into account symptom duration, surgery type, age, O6-methylguanine-DNA methyltransferase promoter methylation, and p53 status, generation of CSCs and CD133/Ki67 coexpression emerged as highly significant independent prognostic factors, with an adjusted hazard ratio of 2.92 (95% confidence interval, 1.37-6.2; P = 0.005) and 4.48 (95% confidence interval, 1.68-11.9; P = 0.003), respectively.
Conclusions: The analysis of CSCs may predict the survival of glioblastoma patients. In vitro CSC generation and presence of CD133+/Ki67+ cells are two considerable prognostic factors of disease progression and poor clinical outcome.
Effects of High-Dose IFNα2b on Regional Lymph Node Metastases of Human Melanoma: Modulation of STAT5, FOXP3, and IL-17
Authors: Wang Wenjun , Edington Howard D. , Rao Uma N.M. , Jukic Drazen M. , Radfar Arash , Wang Hong , Kirkwood John M. 
Published: December 2008

Abstract
Purpose: Signal transducer and activator of transcription 5 (STAT5) and STAT3 oppose one another in regulation of the reciprocal development of CD4+CD25+FOXP3+ regulatory T cells (Treg) and T helper 17 (Th17). A reduction in STAT3 is associated with up-regulation of Treg, and STAT5 activation promotes Treg differentiation or function while constraining Th17 generation. The effects of IFNα on STAT signaling in relation to tumor tissue Treg and Th17 have not been documented in humans beyond the observations that IFNα2b down-regulates STAT3.
Experimental Design: Following diagnostic biopsy and before definitive surgery, 20 doses of high-dose IFNα2b (HDI) were administered to patients with stage IIIB melanoma who gave written informed consent. Lymph node biopsies, in which both total STAT3 and phosphorylated STAT3 were down-regulated by HDI, were probed with STAT5, FOXP3, CD4, and interleukin 17 (IL-17) with immunohistochemistry and/or immunofluorescence techniques.
Results: The percentage of FOXP3+ lymphocytes determined by immunohistochemistry was up-regulated from 3.06 ± 0.65% to 9.86 ± 1.27% (n = 13, P = 0.0002), and this observation was confirmed by immunofluorescence evaluation of CD4+FOXP3+ Tregs. HDI induced STAT5 up-regulation (five cases observed) in melanoma cells and lymphocytes but did not induce the generation of IL-17–expressing lymphocytes. Increased STAT5 expression was associated with increased FOXP3 expression among lymphocytes, and STAT5 was constitutively activated among both melanoma cells and lymphocytes.
Conclusion: IFNα2b up-regulates STAT5 and down-regulates STAT3, in conjunction with up-regulation of Treg and inhibition of IL-17–expressing lymphocytes in melanoma tissues. These findings suggest that the effects of IFNα may be potentiated through interference with the response of Tregs and/or STAT5.
A Synovial Sarcoma-Specific Preoperative Nomogram Supports a Survival Benefit to Ifosfamide-Based Chemotherapy and Improves Risk Stratification for Patients
Authors: Canter Robert J. , Qin Li-Xuan , Maki Robert G. , Brennan Murray F. , Ladanyi Marc , Singer Samuel 
Published: December 2008

Abstract
Purpose: To identify prognostic factors related to outcome in 255 patients with synovial sarcoma and to construct a preoperative nomogram to predict the risk of disease-specific death.
Design: Between July 1982 and June 2006, 301 patients underwent treatment at our institution for primary synovial sarcoma of all anatomic sites and 255 patients with localized disease at presentation were resected with curative intent. Data were collected prospectively and analyzed retrospectively.
Results: Five-, 10-, and 15-year disease-specific survival (DSS) was 72%, 60%, and 53%, respectively. Multivariate analysis revealed size and primary tumor site as the only independent adverse predictors of disease-specific death. A nomogram based on preoperative data for surgical patients not receiving anthracycline-ifosfamide (AI) chemotherapy (n = 196) estimates 3- and 5-year DSS with a concordance index of 77.3%. For the first 3 years following diagnosis, the observed DSS for patients treated with AI chemotherapy (n = 59) was greater than that predicted by the preoperative nomogram based on patients not receiving AI chemotherapy. SYT-SSX fusion transcript data were available for 132 patients. Multivariate analysis of this subset showed that SYT-SSX1 fusion type was predictive of early, but not late, distant recurrence.
Conclusion: Size and location govern prognosis in primary synovial sarcoma resected with curative intent. A nomogram based on preoperative variables provides individualized patient survival estimates and shows an early survival benefit to chemotherapy that may dissipate over time. This nomogram may improve decision-making with regards to selecting patients most likely to benefit from neoadjuvant/adjuvant chemotherapy.
Genetic Susceptibility Loci for Breast Cancer by Estrogen Receptor Status
Authors: Garcia-Closas Montserrat , Chanock Stephen 
Published: December 2008

Abstract
Breast cancer is a heterogeneous disease, and risk factors could be differentially associated with the development of distinct tumor subtypes that manifest different biological behavior and progression. In support of this view, there is growing evidence that known breast cancer risk factors vary by hormone receptor status and perhaps other pathologic characteristics of disease. Recent work from large consortial studies has led to the discovery of novel breast cancer susceptibility loci in genic (CASP8, FGFR2, TNRC9, MAP3K1, LSP1) and nongenic regions (8q24, 2q35, 5p12) of the genome, and to the finding of substantial heterogeneity by tumor characteristics. In particular, susceptibility loci in FGFR2, TNRC9, 8q24, 2q35, and 5p12 have stronger associations for estrogen receptor–positive (ER+) disease than estrogen receptor–negative (ER−) disease. These findings suggest that common genetic variants can influence the pathologic subtype of breast cancer, and provide further support for the hypothesis that ER+ and ER− disease result from different etiologic pathways. Current studies had limited power to detect susceptibility loci for less common tumor subtypes, such as ER− disease including triple-negative and basal-like tumors. Ongoing work targeting uncommon subtypes is likely to identify additional tumor-specific susceptibility loci in the near future. Characterization of etiologic heterogeneity of breast cancer may lead to improvements in the understanding of the biological mechanisms for breast cancer, and ultimately result in improvements in prevention, early detection, and treatment.