bluuebunny/crossref_metadata_2025_split huggingface dataset:
S100A2 Induces Metastasis in Non–Small Cell Lung Cancer
Authors: Bulk Etmar , Sargin Bülent , Krug Utz , Hascher Antje , Jun Yu , Knop Markus , Kerkhoff Claus , Gerke Volker , Liersch Ruediger , Mesters Rolf M. , Hotfilder Marc , Marra Alessandro , Koschmieder Steffen , Dugas Martin , Berdel Wolfgang E. , Serve Hubert , Müller-Tidow Carsten 
Published: December 2008

Abstract
Purpose: S100 proteins are implicated in metastasis development in several cancers. In this study, we analyzed the prognostic role of mRNA levels of all S100 proteins in early stage non–small cell lung cancer (NSCLC) patients as well as the pathogenetic of S100A2 in the development of metastasis in NSCLC.
Experimental Design: Microarray data from a large NSCLC patient cohort was analyzed for the prognostic role of S100 proteins for survival in surgically resected NSCLC. Metastatic potential of the S100A2 gene was analyzed in vitro and in a lung cancer mouse model in vivo. Overexpression and RNAi approaches were used for analysis of the biological functions of S100A2.
Results: High mRNA expression levels of several S100 proteins and especially S100A2 were associated with poor survival in surgically resected NSCLC patients. Upon stable transfection into NSCLC cell lines, S100A2 did not alter proliferation. However, S100A2 enhanced transwell migration as well as transendothelial migration in vitro. NOD/SCID mice injected s.c. with NSCLC cells overexpressing S100A2 developed significantly more distant metastasis (64%) than mice with control vector transfected tumor cells (17%; P &lt; 0.05). When mice with S100A2 expressing tumors were treated i.v. with shRNA against S100A2, these mice developed significantly fewer lung metastasis than mice treated with control shRNA (P = 0.021).
Conclusions: These findings identify S100A2 as a strong metastasis inducer in vivo. S100A2 might be a potential biomarker as well as a novel therapeutic target in NSCLC metastasis.
Mechanism and Management of AKT Inhibitor-Induced Hyperglycemia
Authors: Crouthamel Ming-Chih , Kahana Jason A. , Korenchuk Susan , Zhang Shu-Yun , Sundaresan Gobalakrishnan , Eberwein Derek J. , Brown Kathleen K. , Kumar Rakesh 
Published: December 2008

Abstract
Purpose: Insulin-like growth factor-I receptor and phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathways are among the most active areas of drug discovery in cancer research. However, due to their integral roles in insulin signaling, inhibitors targeting these pathways often lead to hyperglycemia and hyperinsulinemia. We investigated the mechanism of hyperglycemia induced by GSK690693, a pan-AKT kinase inhibitor in clinical development, as well as methods to ameliorate these side effects.
Experimental Design: The effect of GSK690693 on blood glucose, insulin, and glucagon levels was characterized in mice. We then evaluated the effects of commonly prescribed antidiabetic agents on GSK690693-induced hyperglycemia. The mechanism of blood glucose increase was evaluated using fasting and tracer uptake studies and by measuring liver glycogen levels. Finally, approaches to manage AKT inhibitor-induced hyperglycemia were designed using fasting and low carbohydrate diet.
Results: We report that treatment with antidiabetic agents does not significantly affect GSK690693-induced hyperglycemia in rodents. However, administration of GSK690693 in mice significantly reduces liver glycogen (∼90%), suggesting that GSK690693 may inhibit glycogen synthesis and/or activate glycogenolysis. Consistent with this observation, fasting before drug administration reduces baseline liver glycogen levels and attenuates hyperglycemia. Further, GSK690693 also inhibits peripheral glucose uptake and introduction of a low-carbohydrate (7%) or 0% carbohydrate diet after GSK690693 administration effectively reduces diet-induced hyperglycemia in mice.
Conclusions: The mechanism of GSK690693-induced hyperglycemia is related to peripheral insulin resistance, increased gluconeogenesis, and/or hepatic glycogenolysis. A combination of fasting and low carbohydrate diet can reduce the magnitude of hyperglycemia induced by an AKT inhibitor.
An Immune Response Enriched 72-Gene Prognostic Profile for Early-Stage Non–Small-Cell Lung Cancer
Authors: Roepman Paul , Jassem Jacek , Smit Egbert F. , Muley Thomas , Niklinski Jacek , van de Velde Tony , Witteveen Anke T. , Rzyman Witold , Floore Arno , Burgers Sjaak , Giaccone Giuseppe , Meister Michael , Dienemann Hendrik , Skrzypski Marcin , Kozlowski Miroslaw , Mooi Wolter J. , van Zandwijk Nico 
Published: December 2008

Abstract
Purpose: Current staging methods are imprecise for predicting prognosis of early-stage non–small-cell lung cancer (NSCLC). We aimed to develop a gene expression profile for stage I and stage II NSCLC, allowing identification of patients with a high risk of disease recurrence within 2 to 3 years after initial diagnosis.
Experimental Design: We used whole-genome gene expression microarrays to analyze frozen tumor samples from 172 NSCLC patients (pT1-2, N0-1, M0) from five European institutions, who had undergone complete surgical resection. Median follow-up was 89 months (range, 1.2-389) and 64 patients developed a recurrence. A random two thirds of the samples were assigned as the training cohort with the remaining samples set aside for independent validation. Cox proportional hazards models were used to evaluate the association between expression levels of individual genes and patient recurrence-free survival. A nearest mean analysis was used to develop a gene-expression classifier for disease recurrence.
Results: We have developed a 72-gene expression prognostic NSCLC classifier. Based on the classifier score, patients were classified as either high or low risk of disease recurrence. Patients classified as low risk showed a significantly better recurrence-free survival both in the training set (P &lt; 0.001; n = 103) and in the independent validation set (P &lt; 0.01; n = 69). Genes in our prognostic signature were strongly enriched for genes associated with immune response.
Conclusions: Our 72-gene signature is closely associated with recurrence-free and overall survival in early-stage NSCLC patients and may become a tool for patient selection for adjuvant therapy.
Alemtuzumab Therapy for Hypereosinophilic Syndrome and Chronic Eosinophilic Leukemia
Authors: Verstovsek Srdan , Tefferi Ayalew , Kantarjian Hagop , Manshouri Taghi , Luthra Raja , Pardanani Animesh , Quintás-Cardama Alfonso , Ravandi Farhad , Ault Pat , Bueso-Ramos Carlos , Cortes Jorge E. 
Published: December 2008

Abstract
Purpose: Patients with hypereosinophilic syndrome (HES) or chronic eosinophilic leukemia (CEL) that are refractory to standard therapies are difficult to manage and have significantly shortened life expectancy.
Experimental Design: CD52 is a surface glycoprotein highly expressed on eosinophils. We treated 11 patients with advanced HES/CEL with alemtuzumab, a humanized anti-CD52 monoclonal antibody. Alemtuzumab was administered, in general, first in escalating doses (5, 10, 30 mg i.v. on days 1-3), then at the tolerated dose thrice per week for a total of 12 doses. Patients with complete hematologic response (CHR; normal percent and absolute eosinophil count) were allowed to continue therapy once weekly as maintenance.
Results: Ten patients (91%) achieved CHR after a median of 2 weeks (0.5-5 weeks) of therapy. Bone marrow eosinophilia resolved in four of seven evaluable patients. The median duration of CHR was 3 months (1.5-17+ months). Seven of the 10 CHR patients relapsed, five while off-therapy. Two patients achieved second CHR upon alemtuzumab rechallenge. Three patients experienced mild infusion-related symptoms, two developed cytomegalovirus reactivation requiring therapy, and one developed orbital lymphoma that was successfully treated.
Conclusions: Our limited experience suggests alemtuzumab to be a valuable therapy for advanced HES or CEL, refractory to standard therapies, and supports the clinical evaluation of alemtuzumab in a larger trial.
Induction of Apoptosis in Human Leukemia Cells by Grape Seed Extract Occurs via Activation of c-Jun NH2-Terminal Kinase
Authors: Gao Ning , Budhraja Amit , Cheng Senping , Yao Hua , Zhang Zhuo , Shi Xianglin 
Published: December 2008

Abstract
Purpose: To characterize the functional role of c-Jun NH2-terminal kinase (JNK) and other apoptotic pathways in grape seed extract (GSE)-induced apoptosis in human leukemia cells by using pharmacologic and genetic approaches.
Experimental Design: Jurkat cells were treated with various concentrations of GSE for 12 and 24 h or with 50 μg/mL GSE for various time intervals, after which apoptosis, caspase activation, and cell signaling pathways were evaluated. Parallel studies were done in U937 and HL-60 human leukemia cells.
Results: Exposure of Jurkat cells to GSE resulted in dose- and time-dependent increase in apoptosis and caspase activation, events associated with the pronounced increase in Cip1/p21 protein level. Furthermore, treatment of Jurkat cells with GSE resulted in marked increase in levels of phospho-JNK. Conversely, interruption of the JNK pathway by pharmacologic inhibitor (e.g., SP600125) or genetic (e.g., small interfering RNA) approaches displayed significant protection against GSE-mediated lethality in Jurkat cells.
Conclusions: The result of the present study showed that GSE induces apoptosis in Jurkat cells through a process that involves sustained JNK activation and Cip1/p21 up-regulation, culminating in caspase activation.
BH3 Mimetic Obatoclax Enhances TRAIL-Mediated Apoptosis in Human Pancreatic Cancer Cells
Authors: Huang Shengbing , Okumura Kenji , Sinicrope Frank A. 
Published: December 2008

Abstract
Purpose: Prosurvival Bcl-2 proteins inhibit the mitochondrial and death receptor-mediated apoptotic pathways. Obatoclax is a small-molecule antagonist of the BH3-binding groove of Bcl-2 proteins that may enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity and efficacy.
Experimental Design: Human pancreatic cancer cell lines were incubated with obatoclax and/or TRAIL and cell viability, Annexin V labeling, caspase cleavage, and cytochrome c release were measured. In drug-treated cell lines, protein-protein interactions were studied by immunoprecipitation. Bax/Bak activation was analyzed using conformation-specific antibodies. Lentiviral short hairpin RNA was used to knockdown Bim, Bid, and apoptosis-inducing factor (AIF) expression.
Results: Obatoclax reduced the viability of PANC-1 and BxPC-3 cell lines and synergistically enhanced TRAIL-mediated cytotoxicity. Obatoclax enhanced TRAIL-mediated apoptosis, as shown by Annexin V labeling, which was accompanied by caspase activation (caspase-8, -9, and -3) and cleavage of Bid. Obatoclax potentiated TRAIL-mediated Bax/Bak activation and the release of mitochondrial cytochrome c, Smac, and AIF. Mechanisms underlying the apoptotic effect of obatoclax include displacement of Bak from its sequestration by Bcl-xL or Mcl-1 and release of Bim from Bcl-2 or Mcl-1. Bid knockdown by short hairpin RNA attenuated caspase cleavage and cytotoxicity of obatoclax plus TRAIL. Bim knockdown failed to inhibit the cytotoxic effect of obatoclax alone or combined with TRAIL yet attenuated TRAIL-mediated cytotoxicity. AIF knockdown attenuated cytotoxicity of the drug combination.
Conclusions: Obatoclax potentiates TRAIL-mediated apoptosis by unsequestering Bak and Bim from Bcl-2/Bcl-xL or Mcl-1 proteins. This drug combination enhances Bid-mediated cross-talk between the mitochondrial and death receptor-mediated apoptotic pathways and may represent a novel therapeutic strategy against pancreatic cancer.
Characterization of Genetically Modified T-Cell Receptors that Recognize the CEA:691-699 Peptide in the Context of HLA-A2.1 on Human Colorectal Cancer Cells
Authors: Parkhurst Maria R. , Joo Jayne , Riley John P. , Yu Zhiya , Li Yong , Robbins Paul F. , Rosenberg Steven A. 
Published: December 2008

Abstract
Purpose: Carcinoembryonic antigen (CEA) is a tumor-associated protein expressed on a variety of adenocarcinomas. To develop an immunotherapy for patients with cancers that overexpress CEA, we isolated and genetically modified a T-cell receptors (TCRs) that specifically bound a CEA peptide on human cancer cells.
Experimental Design: HLA-A2.1 transgenic mice were immunized with CEA:691-699. A CEA-reactive TCR was isolated from splenocytes of these mice and was genetically introduced into human peripheral blood lymphocytes via RNA electroporation or retroviral transduction. Amino acid substitutions were introduced throughout the complementarity determining regions (CDR1, CDR2, and CDR3) of both TCR α and β chains to improve recognition of CEA.
Results: Murine lymphocytes bearing the CEA-reactive TCR specifically recognized peptide-loaded T2 cells and HLA-A2.1+ CEA+ human colon cancer cells. Both CD8+ and CD4+ human lymphocytes expressing the murine TCR specifically recognized peptide-loaded T2 cells. However, only gene-modified CD8+ lymphocytes specifically recognized HLA-A2.1+ CEA+ colon cancer cell lines, and tumor cell recognition was weak and variable. We identified two substitutions in the CDR3 of the α chain that significantly influenced tumor cell recognition by human peripheral blood lymphocytes. One substitution, T for S at position 112 (S112T), enhanced tumor cell recognition by CD8+ lymphocytes, and a second dually substituted receptor (S112T L110F) enhanced tumor cell recognition by CD4+ T cells.
Conclusions: The modified CEA-reactive TCRs are good candidates for future gene therapy clinical trials and show the power of selected amino acid substitutions in the antigen-binding regions of the TCR to enhance desired reactivities.
Involvement of Epithelial Cell Transforming Sequence-2 Oncoantigen in Lung and Esophageal Cancer Progression
Authors: Hirata Daizaburo , Yamabuki Takumi , Miki Daiki , Ito Tomoo , Tsuchiya Eiju , Fujita Masahiro , Hosokawa Masao , Chayama Kazuaki , Nakamura Yusuke , Daigo Yataro 
Published: December 2008

Abstract
Purpose: This study aims to isolate potential molecular targets for diagnosis, treatment, and/or prevention of lung and esophageal carcinomas.
Experimental Design: We screened for genes that were frequently overexpressed in the tumors through gene expression profile analyses of 101 lung cancers and 19 esophageal squamous cell carcinomas (ESCC) by cDNA microarray consisting of 27,648 genes or expressed sequence tags. In this process, we identified epithelial cell transforming sequence 2 (ECT2) as a candidate. Tumor tissue microarray was applied to examine the expression of ECT2 protein in 242 archived non–small-cell lung cancers (NSCLC) and 240 ESCC specimens and to investigate its prognostic value. A role of ECT2 in lung and esophageal cancer cell growth and/or survival was examined by small interfering RNA experiments. Cellular invasive activity of ECT2 in mammalian cells was examined using Matrigel assays.
Results: Northern blot and immunohistochemical analyses detected expression of ECT2 only in testis among 23 normal tissues. Immunohistochemical staining showed that a high level of ECT2 expression was associated with poor prognosis for patients with NSCLC (P = 0.0004) as well as ESCC (P = 0.0088). Multivariate analysis indicated it to be an independent prognostic factor for NSCLC (P = 0.0005). Knockdown of ECT2 expression by small interfering RNAs effectively suppressed lung and esophageal cancer cell growth. In addition, induction of exogenous expression of ECT2 in mammalian cells promoted cellular invasive activity.
Conclusions: ECT2 cancer-testis antigen is likely to be a prognostic biomarker in clinic and a potential therapeutic target for the development of anticancer drugs and cancer vaccines for lung and esophageal cancers.
Intratumoral Delivery of β-Lapachone via Polymer Implants for Prostate Cancer Therapy
Authors: Dong Ying , Chin Shook-Fong , Blanco Elvin , Bey Erik A. , Kabbani Wareef , Xie Xian-Jin , Bornmann William G. , Boothman David A. , Gao Jinming 
Published: December 2008

Abstract
Purpose: β-Lapachone (ARQ 501, a formulation of β-lapachone complexed with hydroxypropyl-β-cyclodextrin) is a novel anticancer agent with selectivity against prostate cancer cells overexpressing the NAD(P)H:quinone oxidoreductase-1 enzyme. Lack of solubility and an efficient drug delivery strategy limits this compound in clinical applications. In this study, we aimed to develop β-lapachone–containing polymer implants (millirods) for direct implantation into prostate tumors to test the hypothesis that the combination of a tumor-specific anticancer agent with site-specific release of the agent will lead to significant antitumor efficacy.
Experimental Design: Survival assays in vitro were used to test the killing effect of β-lapachone in different prostate cancer cells. β-Lapachone release kinetics from millirods was determined in vitro and in vivo. PC-3 prostate tumor xenografts in athymic nude mice were used for antitumor efficacy studies in vivo.
Results: β-Lapachone killed three different prostate cancer cell lines in an NAD(P)H:quinone oxidoreductase-1–dependent manner. Upon incorporation of solid-state inclusion complexes of β-lapachone with hydroxypropyl-β-cyclodextrin into poly(d,l-lactide-co-glycolide) millirods, β-lapachone release kinetics in vivo showed a burst release of ∼0.5 mg within 12 hours and a subsequently sustained release of the drug (∼0.4 mg/kg/d) comparable with that observed in vitro. Antitumor efficacy studies showed significant tumor growth inhibition by β-lapachone millirods compared with controls (P &lt; 0.0001; n = 10 per group). Kaplan-Meier survival curves showed that tumor-bearing mice treated with β-lapachone millirods survived nearly 2-fold longer than controls, without observable systemic toxicity.
Conclusions: Intratumoral delivery of β-lapachone using polymer millirods showed the promising therapeutic potential for human prostate tumors.
Preferential Killing of Breast Tumor Initiating Cells by N,N-Diethyl-2-[4-(Phenylmethyl)Phenoxy]Ethanamine/Tesmilifene
Authors: Deng Tao , Liu Jeff C. , Pritchard Kathleen I. , Eisen Andrea , Zacksenhaus Eldad 
Published: December 2008

Abstract
Purpose: N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE; tesmilifene) is thought to potentiate the antineoplastic effect of cytotoxic drugs. In a phase III randomized trial for metastatic breast cancer using doxorubicin with or without DPPE, addition of the latter resulted in a significant improvement in overall survival and a trend toward a difference in progression-free survival but, paradoxically, no difference in objective tumor response. Here we tested the hypothesis that DPPE targets breast tumor-initiating cells (TICs).
Experimental Design: Human breast TICs from pleural effusions were identified as CD44+:CD24−/low cells by flow cytometry and functionally by their ability to form nonadherent spheres in culture. Mouse mammary TICs from two different models of breast cancer were identified as cells capable of initiating spheres in culture and secondary tumors following transplantation into the mammary gland of syngeneic mice.
Results: We show that at physiologically attainable concentrations, treatment with DPPE alone reduced tumorsphere formation and viability of CD44+:CD24−/low breast cancer cells. The kinetics of killing varied for the different breast tumor cells and required continuous exposure to the drug. Whereas doxorubicin killed CD44+:CD24−/low and CD44−:CD24+ cells equally well, DPPE induced apoptosis preferentially in CD44+:CD24−/low cells. Treatment of Her2/Neu+ mammary tumor cells with DPPE in vitro efficiently killed TICs, as determined by flow cytometry and transplantation assays; DPPE further cooperated with doxorubicin to completely eradicate tumorigenic cells.
Conclusions: Our results show that continuous treatment with DPPE alone directly targets breast TICs, and provide rationale to test for cooperation between DPPE and known drugs with efficacy toward breast cancer subtypes.
A Phase I Trial of a Human Papillomavirus DNA Vaccine for HPV16+ Cervical Intraepithelial Neoplasia 2/3
Authors: Trimble Cornelia L. , Peng Shiwen , Kos Ferdynand , Gravitt Patti , Viscidi Raphael , Sugar Elizabeth , Pardoll Drew , Wu T.C. 
Published: December 2008

Abstract
Purpose: To evaluate the safety and immunogenicity of a therapeutic human papillomavirus (HPV)16 DNA vaccine administered to women with HPV16+cervical intraepithelial neoplasia (CIN)2/3.
Experimental Design: This phase I trial incorporated the standard ′3+3″ dose-escalation design with an additional 6 patients allocated to the maximally tolerated dose. Healthy adult women with colposcopically directed, biopsy-proven HPV16+ CIN2/3 received 3 i.m. vaccinations (0.5, 1, or 3 mg) of a plasmid expressing a Sig-E7(detox)-heat shock protein 70 fusion protein on days 0, 28, and 56, and underwent standard therapeutic resection of the cervical squamocolumnar junction at day 105 (week 15). The safety and immunogenicity of the vaccine and histologic outcome based on resection at week 15 were assessed.
Results: Fifteen patients were evaluable (3 each at 0.5 and 1mg, 9 at 3 mg). The vaccine was well tolerated: most adverse events were mild, transient injection-site discomfort; no dose-limiting toxicities were observed. Although HPVE7-specific T-cell responses to E7 detected by enzyme-linked immunospot assays (IFN-γ) were of low frequency and magnitude, detectable increases in response subsequent to vaccination were identified in subjects in the second and third cohorts. Complete histologic regression occurred in 3 of 9 (33%; 7-70% confidence interval) individuals in the highest-dose cohort. Although the difference is not significant, it is slightly higher than would be expected in an unvaccinated cohort (25%).
Conclusions: This HPV16 DNA vaccine was safe and well tolerated. Whereas it seems possible to elicit HPV-specific T-cell responses in patients with established dysplastic lesions, other factors are likely to play a role in lesion regression.
Intracellular MUC1 Peptides Inhibit Cancer Progression
Authors: Bitler Benjamin G. , Menzl Ina , Huerta Carmen L. , Sands Barbara , Knowlton Wendy , Chang Andrew , Schroeder Joyce A. 
Published: December 2008

AbstractPurpose: During cancer progression, the oncoprotein MUC1 binds β-catenin while simultaneously inhibiting the degradation of the epidermal growth factor receptor (EGFR), resulting in enhanced transformation and metastasis. The purpose of this study was to design a peptide-based therapy that would block these intracellular protein-protein interactions as a treatment for metastatic breast cancer.Experimental Design: The amino acid residues responsible for these interactions lie in tandem in the cytoplasmic domain of MUC1, and we have targeted this sequence to produce a MUC1 peptide that blocks the protumorigenic functions of MUC1. We designed the MUC1 inhibitory peptide (MIP) to block the intracellular interactions between MUC1/β-catenin and MUC1/EGFR. To allow for cellular uptake we synthesized MIP adjacent to the protein transduction domain, PTD4 (PMIP).Results: We have found that PMIP acts in a dominant-negative fashion, blocking both MUC1/β-catenin and MUC1/EGFR interactions. In addition, PMIP induces ligand-dependent reduction of EGFR levels. These effects correspond to a significant reduction in proliferation, migration, and invasion of metastatic breast cancer cells in vitro, and inhibition of tumor growth and recurrence in an established MDA-MB-231 immunocompromised (SCID) mouse model. Importantly, PMIP also inhibits genetically driven breast cancer progression, as injection of tumor-bearing MMTV-pyV mT transgenic mice with PMIP results in tumor regression and a significant inhibition of tumor growth rate.Conclusions: These data show that intracellular MUC1 peptides possess significant antitumor activity and have important clinical applications in the treatment of cancer.