bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Study and Preliminary Pharmacology of the Novel Innate Immune Modulator rBBX-01 in Gynecologic Cancers
Authors: Rader Janet S. , Aylsworth Charles F. , Juckett David A. , Mutch David G. , Powell Matthew A. , Lippmann Lynne , Dimitrov Nikolay V. 
Published: May 2008

Abstract
Purpose: A recombinant protein product, rBBX-01, is the first innate immunostimulator derived from a protozoan (Eimeria protozoan) and has shown potent preclinical in vivo and in vitro activities. This phase I trial was done to determine the safety and basic pharmacology of rBBX-01.
Experimental Design: Eligible patients had recurrent incurable gynecologic malignancies. The study was divided into three components: a starting low-dose phase (0.85, 2.0, and 4.0 μg/m2), an intrapatient dose acceleration phase (4.0-1,024.0 μg/m2), and a high-dose phase (1,000 and 2,000 μg/m2). All treatment doses were administered daily for 5 days. Patients were allowed a second cycle of treatment if there was evidence of response.
Results: Sixteen patients received a total of 20 cycles of rBBX-01. All patients tolerated the drug well, exhibiting no local or systemic, acute or delayed, adverse reactions. Plasma levels of rBBX-01 were detectable in all patients over the entire dose range, although changes in the pharmacodynamic marker (interleukin-12) exhibited patient-to-patient variability. Of 14 patients with ovarian, primary peritoneal, or endometrial cancer with elevated CA125 biomarkers at the start of treatment, 4 responded with decreased levels of CA125. One patient showed decreasing CA125 levels for 10 months and received no additional chemotherapy for 11 months. Those patients exhibiting reductions in CA125 also exhibited increased levels of plasma interleukin-12 during the week of therapy.
Conclusion: The immunostimulator rBBX-01 was safe in multidose regimens in heavily pretreated women. Of the 14 patients with elevated CA125 levels, a ∼30% response rate was detected. rBBX-01 should receive additional testing in the clinical setting.
Tamoxifen and Aromatase Inhibitors Differentially Affect Vascular Endothelial Growth Factor and Endostatin Levels in Women with Breast Cancer
Authors: Holmes Chris E. , Huang Joe C. , Pace Thomas R. , Howard Alan B. , Muss Hyman B. 
Published: May 2008

Abstract
Purpose: Circulating and cellular proangiogenic and antiangiogenic proteins such as vascular endothelial growth factor (VEGF) and endostatin contribute to the local angiogenic balance. We explored the effects of tamoxifen and aromatase inhibitors on concentrations of VEGF and endostatin in plasma, serum, and platelet releasate (induced by platelet activation).
Experimental Design: VEGF and endostatin concentrations were measured with a quantitative immunoassay before and after 1 to 5 weeks of treatment in 30 women with breast cancer treated with either tamoxifen (n = 14) or aromatase inhibitors (n = 16). Platelet activation was induced by a thrombin receptor agonist.
Results: Tamoxifen therapy resulted in an increase in platelet releasate concentrations of VEGF (P = 0.01) but no change in plasma VEGF. In contrast, aromatase inhibitor therapy did not affect serum, plasma, or platelet releasate VEGF. In univariate analysis, aspirin use attenuated the tamoxifen-associated increase in VEGF in the platelet releasate and decreased serum levels of VEGF (P = 0.03).
Aromatase inhibitor therapy resulted in a decrease in serum endostatin concentrations (P = 0.04), whereas plasma concentrations of endostatin tended to be higher during treatment with aromatase inhibitors (P = 0.06). Tamoxifen therapy resulted in no change in serum or plasma endostatin concentrations. Platelet releasate concentrations of endostatin did not change with either treatment. Interindividual variability was noted among both aromatase inhibitor– and tamoxifen-treated patients.
Conclusions: Tamoxifen and aromatase inhibitor therapy affect VEGF and endostatin levels and likely contribute to the angiogenic balance in breast cancer patients. Aspirin decreased the proangiogenic effects of tamoxifen, suggesting that antiplatelet and/or antiangiogenic therapy might improve the effectiveness of tamoxifen in women with breast cancer.
Analysis of the MammaPrint Breast Cancer Assay in a Predominantly Postmenopausal Cohort
Authors: Wittner Ben S. , Sgroi Dennis C. , Ryan Paula D. , Bruinsma Tako J. , Glas Annuska M. , Male Anitha , Dahiya Sonika , Habin Karleen , Bernards Rene , Haber Daniel A. , Van't Veer Laura J. , Ramaswamy Sridhar 
Published: May 2008

Abstract
Purpose: Most node-negative breast cancer patients are older and postmenopausal and are increasingly being offered adjuvant chemotherapy despite their low overall risk of distant relapse. A molecular diagnostic test with high negative predictive value (NPV) for distant metastasis in this subgroup would spare many older breast cancer patients adjuvant treatment.
Experimental Design: We determined the NPV and positive predictive value of the MammaPrint assay in breast cancer patients who were consecutively diagnosed and treated at the Massachusetts General Hospital between 1985 and 1997. Primary tumors from 100 patients with node-negative, invasive breast cancer (median age, 62.5 years; median follow-up, 11.3 years) were subjected to MammaPrint analysis and classified as being at either low or high risk for distant metastasis.
Results: The MammaPrint 70-gene signature displayed excellent NPV as in previous studies, correctly identifying 100% of women at low risk for distant metastases at 5 years. However, this assay had a lower positive predictive value (12% at 5 years) than previously observed.
Conclusions: The MammaPrint assay was originally designed to identify younger breast cancer patients at low risk for distant metastasis, who might consequently be spared systemic treatment. We show here that the same signature has a very high NPV for distant recurrence after adjuvant treatment in older breast cancer patients.
Clinical and Biological Effects of Neoadjuvant Sargramostim and Thalidomide in Patients with Locally Advanced Prostate Carcinoma
Authors: Garcia Jorge A. , Klein Eric A. , Magi-Galluzzi Cristina , Elson Paul , Triozzi Pierre , Dreicer Robert 
Published: May 2008

Abstract
Purpose: Granulocyte macrophage colony-stimulating factor (GM-CSF) and thalidomide are active agents in prostate cancer. This study assessed the biological effects and safety of GM-CSF and thalidomide in patients with localized prostate cancer before radical prostatectomy.
Experimental Design: Locally advanced prostate cancer patients undergoing radical prostatectomy were recruited for this study. Treatment consisted of two 28-day cycles of GM-CSF (250 μg, s.c., thrice weekly) and thalidomide (200 mg, orally, daily) on days 1 to 28 of each cycle. Radical prostatectomy occurred within 7 to 10 days after completion of therapy. Pretreatment and posttreatment specimens were used to assess the expression of CD3, CD68, Ki-67, S100, PTEN, and CD31. Peripheral blood was examined for dendritic cells, regulatory T cells, and cytokines.
Results: Twenty-eight patients were enrolled. No pathologic responses (P0) were observed and no unexpected toxicities or surgical complications occurred. Eighty-one percent of patients had a prostate-specific antigen decline (mean ± SD decrease was 21.1 ± 15.4%; median, 18.0%). With a median follow-up of 32 months, five patients have experienced progression. Radical prostatectomy tumor tissue specimens showed significant CD3 and S100 overexpression when compared with pretreatment biopsies. No significant changes in tumor macrophage infiltration were observed. Increased number of serum dendritic cell, as well as high serum levels of interleukin-8, basic fibroblast growth factor, and vascular endothelial growth factor, was also observed.
Conclusions: Neoadjuvant GM-CSF and thalidomide was safe and feasible and did not affect the perioperative morbidity of radical prostatectomy. Although no pathologic complete responses were observed, significant posttreatment tumor T-cell and dendritic cell infiltration was noted. No significant changes in serum cytokines, dendritic cells, or regulatory T cells were induced.
Evaluation of the In vitro and In vivo Antitumor Activity of Histone Deacetylase Inhibitors for the Therapy of Retinoblastoma
Authors: Dalgard Clifton Lee , Van Quill Kurtis R. , O'Brien Joan M. 
Published: May 2008

Abstract
Purpose: To evaluate the potential utility of histone deacetylase inhibitors (HDACi) for treatment of retinoblastoma (RB).
Experimental Design: Growth-inhibitory effects of HDACi [trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), or MS-275] were assessed in human and transgenic murine RB cells. Effects of TSA and MS-275 were also assessed in combination with standard therapeutic agents for RB. Proapoptotic effects of MS-275 and TSA were evaluated by caspase-3/7 activity, Annexin V translocation, and/or Bim expression analyses. Effects of MS-275 on cell cycle distribution and reactive oxygen species levels were determined by flow cytometry. Retinal tissue morphology was evaluated in mice after local administration of MS-275. Analysis of retinal acetyl-histone levels was used to assess MS-275 delivery after systemic administration. Therapeutic effects of MS-275 were determined in transgenic mouse and rat ocular xenograft models of RB after i.p. injection of 20 mg/kg every other day for 21 or 13 days, respectively.
Results: TSA, SAHA, and MS-275 dose dependently reduced RB cell survival. TSA and MS-275 showed additive growth-inhibitory effects in combination with carboplatin, etoposide, or vincristine. TSA and MS-275 increased caspase-3/7 activity. MS-275 increased Annexin V membrane translocation and induced G1 arrest. Cytotoxicity of MS-275 was dependent on increased reactive oxygen species levels and was reversed by antioxidant pretreatment. Intraocular administration of 1 μL of 10 μmol/L MS-275 did not alter ocular tissue morphology. Increased acetyl-histone levels confirmed MS-275 delivery to retinal tissue after systemic administration. MS-275 significantly reduced tumor burden in both mouse and rat models of RB.
Conclusions: HDACi should be considered for clinical trials in children with RB.
VDR and SRD5A2 Polymorphisms Combine to Increase Risk for Prostate Cancer in Both Non–Hispanic White and Hispanic White Men
Authors: Torkko Kathleen C. , van Bokhoven Adrie , Mai Phoung , Beuten Joke , Balic Ivana , Byers Tim E. , Hokanson John E. , Norris Jill M. , Barón Anna E. , Lucia M. Scott , Thompson Ian M. , Leach Robin J. 
Published: May 2008

Abstract
Purpose: Vitamin D and dihydrotestosterone pathways interact to promote the growth of prostatic tissue. The nuclear vitamin D receptor (VDR) moderates the actions of vitamin D. 5α-Reductase type II (SRD5A2) codes for the enzyme that converts testosterone to dihydrotestosterone in the prostate. This study tested the interactions of VDR (CDX2, FokI) and SRD5A2 (V89L, A49T) polymorphisms, and their associations with prostate cancer.
Experimental Design: This genetic association study included 932 non–Hispanic White (NHW) men and 414 Hispanic White (HW) men from South Texas. Cases had biopsy-confirmed cancer; controls had normal digital rectal exams and serum prostate-specific antigen levels of &lt;2.5 ng/mL.
Results: Using logistic regression analyses to test associations with prostate cancer, only the V89L polymorphism (VV genotype compared with LL/LV) in HW men was statistically significant [odds ratios (OR), 0.64; 95% confidence intervals (95% CI), 0.41-0.99]. The interaction terms for FokI and V89L in NHW men and CDX2 and V89L in HW men in the logistic model were significant (P = 0.02 and 0.03, respectively). When stratified by V89L genotype, the FokI polymorphism (TT/TC versus CC) was significantly associated with prostate cancer in NHW men with the V89L VV genotype (FokI OR, 1.53; 95% CI, 1.06-2.23). The CDX2 polymorphism (GG versus AG/AA) was significantly associated with prostate cancer only in HW men with the V89L VV genotype (CDX2 OR, 3.16; 95% CI, 1.39-7.19; interaction term P = 0.02).
Conclusion: Our results indicate that the SRD5A2 V89L VV genotype interacts with VDR FokI TT/CT genotypes in NHW men and VDR CDX2 GG genotypes in HW men to increase the risk for prostate cancer.
Divergent Effects of Castration on Prostate Cancer in TRAMP Mice: Possible Implications for Therapy
Authors: Tang Yao , Wang Linbo , Goloubeva Olga , Afnan Khan Mohammad , Zhang Bin , Hussain Arif 
Published: May 2008

Abstract
Purpose: Divergent responses to androgen deprivation have been found in patients and in animal models of prostate cancer. The molecular basis for these different outcomes is unknown. Our aim was to identify the molecular responses of prostate cancer with divergent outcomes to androgen deprivation in TRAMP mice.
Experimental Design: Castrated and noncastrated B6xFVB TRAMP mice were evaluated for survival, tumor development, pathology, and expressions of specific proteins at different time points.
Results: TRAMP mice responded differentially to androgen deprivation. In the majority, primary tumors regressed after castration (positive response), whereas in others the tumors grew even more aggressively than in the noncastrated mice (negative response). Mice with regressed tumors had the highest survival rates. Androgen receptor was elevated in all tumors from castrated mice despite significant differences in tumor sizes. In positively responding tumors, expressions of Bcl-2 and Grp78 were greatly increased by 10 weeks after castration, whereas expressions of Bax, Bcl-xl, SV40 T antigen, and c-myc were lower. These tumors also showed a reduction in proliferating cells compared with noncastrates and negatively responding tumors. Most of these changes disappeared 20 weeks after castration, by which time there was an increase in the size of primary tumors as well as in distant metastasis.
Conclusions: In TRAMP prostate cancer that responded positively to castration, different expression patterns of proteins involved in cellular apoptosis, stress, and proliferation occur ∼10 weeks after castration. This may be an optimal time for targeting Bcl-2, and perhaps Grp78, to enhance the antitumor effects of androgen deprivation.
A Functional Epidermal Growth Factor (EGF) Polymorphism, EGF Serum Levels, and Esophageal Adenocarcinoma Risk and Outcome
Authors: Lanuti Michael , Liu Geoffrey , Goodwin Jonathan M. , Zhai Rihong , Fuchs Bryan C. , Asomaning Kofi , Su Li , Nishioka Norman S. , Tanabe Kenneth K. , Christiani David C. 
Published: May 2008

Abstract
Purpose: The epidermal growth factor (EGF) pathway is important in esophageal adenocarcinoma (EAC) tumorigenesis. We hypothesized that the EGF A61G homozygous variant genotype (GG) is (a) both a risk and poor prognostic factor for EAC and (b) associated with higher EGF serum levels in individuals with gastroesophageal reflux disease (GERD).
Experimental Design: Using unconditional logistic regression, we compared EGF A61G in 312 EAC cases and 447 GERD-free controls, adjusting for age, gender, smoking history, and healthy adult body mass index. Using the method of Kaplan and Meier, log-rank tests, and Cox proportional hazard models, we correlated EGF A61G with overall and failure-free survival in the EAC cases. Serum EGF levels and EGF genotype (G/G versus others) were correlated in 144 GERD patients using Wilcoxon rank sum tests.
Results: The EGF A61G G/G genotype conferred increased EAC risk, with an adjusted odds ratio of 1.81 (95% confidence interval, 1.2-2.7), and was even higher in the subgroup of EAC patients with concurrent Barrett's esophagus (adjusted odds ratio, 2.18; 95% confidence interval, 1.3-3.7). However, EGF A61G was not associated with a more aggressive phenotype or prognosis in EAC patients. Higher serum EGF levels were found in GERD patients carrying G/G compared with A/A or A/G (P = 0.03, Wilcoxon rank sum test).
Conclusion: The EGF A61G G/G genotype is associated with a near 2-fold greater risk of EAC. The G/G allele was also associated with higher EGF levels in tumor-free patients with GERD. EGF genotyping can potentially identify high-risk patients with GERD and Barrett's metaplasia who might benefit from increased surveillance.
Heme oxygenase-1 inhibits breast cancer invasion via suppressing the expression of matrix metalloproteinase-9
Authors: Lin Cheng-Wei , Shen Shing-Chun , Hou Wen-Chi , Yang Liang-Yo , Chen Yen-Chou 
Published: May 2008

Abstract
In the present study, we investigated the antitumor effects of the invasiveness and migration of heme oxygenase 1 (HO-1) in human breast carcinoma cells. 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced matrix metalloproteinase-9 (MMP-9) enzyme activity and gene expression at both protein and mRNA levels were examined in human breast carcinoma cells (MCF-7 and MDA-MB-231), and the addition of the MMP-9 inhibitor, SB3CT, significantly suppressed TPA-induced invasion and migration according to the in vitro Transwell assay. Elevation of HO-1 gene expression by ferric protoporphyrin IX inhibited TPA-induced invasion of MCF-7 cells, which was blocked by adding the heme oxygenase inhibitor, tin protoporphyrin IX, or transfection of cells with HO-1 short hairpin RNA. MCF-7 cells overexpressing HO-1 (MCF-7/HO-1) were established in the present study, and TPA-induced MMP-9 gene expression, tumor invasion, and colony formation were significantly reduced in MCF-7/HO-1 cells, compared with those in Neo-transfected cells. Activation of protein kinase Cα/extracellular signal-regulated kinases/AP-1 with stimulation of reactive oxygen species production was involved in TPA-induced invasion of MCF-7 cells, which was attenuated by HO-1 protein induced by ferric protoporphyrin IX or transfection of HO-1 expression vectors. Additionally, the addition of carbon monoxide, but not ferric ions, biliverdin, or bilirubin, inhibited TPA-induced invasion through suppressing MMP-9, extracellular signal-regulated kinases, and AP-1 activation stimulated by TPA. The beneficial role of HO-1 in blocking tumor invasion was first identified in this study. [Mol Cancer Ther 2008;7(5):1195–1206]
Nucleolus and c-Myc: potential targets of cardenolide-mediated antitumor activity
Authors: Mijatovic Tatjana , De Nève Nancy , Gailly Philippe , Mathieu Véronique , Haibe-Kains Benjamin , Bontempi Gianluca , Lapeira Javier , Decaestecker Christine , Facchini Vincenzo , Kiss Robert 
Published: May 2008

AbstractThe use of cardenolides like ouabain, digitoxin, or oleandrin has been reported previously many times as a means of potentially combating human refractory prostate cancer by inducing apoptosis through an increase in intracellular calcium concentrations. The aims of the current study were to investigate if part of the antitumor effects mediated by cardenolides concerned disorganization of nucleolar structure and whether this was further associated with a marked decrease in c-Myc expression. Accordingly, the antitumor activity of a novel hemisynthetic cardenolide [1R,3aS,3bR,5aS,6aR,7aS,9R,12aR,13aR,15aR]-3a,11a-dihydroxy-13a-(hydroxymethyl)-9,15a-dimethyl-1-(5-oxo-2,5-dihydrofuran-3-yl)icosahydro-1H,4′H-spiro[cyclopenta [7,8]phenanthro[2,3-b]pyrano[3,2-e][1,4]dioxine-11,2′-[1,3]thiazolidin]-4′-one (UNBS1450)] was compared with that of classic cardenolides and reference anticancer agents in prostate cancer cell lines in vitro and in vivo following s.c. and orthotopic prostate cancer cell grafting into mice. The present study indicates that UNBS1450 markedly decreases the in vitro viability/proliferation of human prostate cancer cell lines but not of normal cells. The induced effects are not linked to an increase in intracellular calcium concentrations and subsequent induction of apoptosis. Rather, they appear to relate to the compound's capacity to disorganize nucleolar structure and function (through an impairment of cyclin-dependent kinase and c-Myc expression and related signaling pathways; paralleled by the disorganization of cancer cell-specific perinucleolar bodies as revealed by disruption of Sam68). This nonapoptotic cancer cell death mediated by severe nucleolar targeting and down-regulation of c-Myc expression is a completely new cardenolide-induced mechanism of antitumor action. [Mol Cancer Ther 2008;7(5):1285–96]
Characterisation of the novel apoptotic and therapeutic activities of the histone deacetylase inhibitor romidepsin
Authors: Newbold Andrea , Lindemann Ralph K. , Cluse Leonie A. , Whitecross Kate F. , Dear Anthony E. , Johnstone Ricky W. 
Published: May 2008

Abstract
Histone deacetylase inhibitors (HDACi) are compounds that target the epigenome and cause tumor cell-selective apoptosis. A large number of these agents that have different chemical structures and can target multiple HDACs are being testing in clinical trials and vorinostat is now an approved drug for the treatment of cutaneous T-cell lymphoma. Although these agents are showing promise for the treatment of hematologic malignancies, it is possible that different drugs may have different mechanistic, biological, and therapeutic activities. When comparing an HDACi belonging to the hydroxamic acid class of compounds (vorinostat) with a cyclic tetrapeptide (romidepsin), we showed that these agents regulate the expression of a common set of cellular genes, but certain genes specifically responded to each agent. Using the Eμ-myc mouse model of B-cell lymphoma, we showed previously that overexpression of the prosurvival proteins Bcl-2 and Bcl-XL inhibited the apoptotic and therapeutic activities of the vorinostat. Herein, we compared and contrasted the apoptotic-inducing activities of the hydroxamic acid oxamflatin with romidepsin. Like vorinostat, oxamflatin was unable to kill lymphomas overexpressing Bcl-2 and Bcl-XL, indicating that these proteins can generally protect cells against this class of HDACi. In contrast, romidepsin was able to induce apoptosis in lymphomas overexpressing Bcl-2 with delayed kinetics of cell death and could mediate therapeutic responses against these lymphomas. However, romidepsin was inactive when Bcl-XL was overexpressed. These data provide strong support that HDACi of different chemical classes may have subtle yet potentially important differences in their molecular and biological activities. [Mol Cancer Ther 2008;7(5):1066–79]
Competitive or noncompetitive, that's the question: research toward histone deacetylase inhibitors
Authors: Su Hong , Altucci Lucia , You Qidong 
Published: May 2008

AbstractHistone deacetylase (HDAC) catalyze deacetylation of acetylated lysine residues on histones and a growing number of nonhistone proteins including many transcription factors, playing an important role in the upstream control of gene transcription, cell cycle progression, and apoptosis. It has been wildly recognized that HDACs are promising targets for cancer therapy. At least 10 HDAC inhibitors are currently in clinical evaluation. However, none of them is practically isoform selective. More and more evidence suggests that acetylation modification occurring in ∼85% of eukaryotic proteins should be a general mechanism for altering protein structures or protein-protein interactions. Unselectively inhibiting the deacetylation activity of HDACs and the consequent modulation of the acetylation status of so many substrates might have multiple mechanisms of action in vivo, resulting in both therapeutic responses and unanticipated side effects. Lack of selectivity for the existing HDAC inhibitors is somewhat logical for the highly conserved residues in the catalytic site and the malleable structure in the rim of the active site of HDAC enzymes. For further advancements in the development of HDAC inhibitors, clues for selectivity will have to be considered. [Mol Cancer Ther 2008;7(5):1007–12]