bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of Copy Number Alterations in Metastatic Melanoma by a DNA FluorescenceIn situHybridization Probe Panel and Array Comparative Genomic Hybridization: A Southwest Oncology Group Study (S9431)
Authors: Moore Stephen R. , Persons Diane L. , Sosman Jeffrey A. , Bobadilla Dolores , Bedell Victoria , Smith David D. , Wolman Sandra R. , Tuthill Ralph J. , Moon Jim , Sondak Vernon K. , Slovak Marilyn L.
Published: May 2008

Purpose: Gene copy number alteration (CNA) is common in malignant melanoma and is associated with tumor development and progression. The concordance between molecular cytogenetic techniques used to determine CNA has not been evaluated on a large set of loci in malignant melanoma.

Experimental Design: A panel of 16 locus-specific fluorescence in situ hybridization (FISH) probes located on eight chromosomes was used to identify CNA in touch preparations of frozen tissue samples from 19 patients with metastatic melanoma (SWOG-9431). A subset (n = 11) was analyzed using bacterial artificial chromosome (BAC) array comparative genomic hybridization (aCGH) of DNA isolated directly from touch-preparation slides.

Results: By FISH, most samples showed loss near or at WISP3/6p21, CCND3/6q22, and CDKN2A/9p21 (>75% of samples tested). More than one third of CDKN2A/9p21 losses were biallelic. Gains of NEDD9/6p24, MET/7q31, and MYC/8q24 were common (57%, 47%, and 41%, respectively) and CNA events involving 9p21/7p12.3 and MET were frequently coincident, suggesting gain of the whole chromosome 7. Changes were confirmed by aCGH, which also uncovered many discreet regions of change, larger than a single BAC. Overlapping segments observed in >45% of samples included many of the loci analyzed in the FISH study, in addition to other WNT pathway members, and genes associated with TP53 pathways and DNA damage response, repair, and stability.

Conclusions: This study outlines a set of CNAs at the gene and regional level, using FISH and aCGH, which may provide a benchmark for future studies and may be important in selection of individual therapy for patients with metastatic malignant melanoma.
Phase I Safety and Pharmacokinetic Study of CT-011, a Humanized Antibody Interacting with PD-1, in Patients with Advanced Hematologic Malignancies
Authors: Berger Raanan , Rotem-Yehudar Rinat , Slama Gideon , Landes Shimon , Kneller Abraham , Leiba Merav , Koren-Michowitz Maya , Shimoni Avichai , Nagler Arnon
Published: May 2008

Purpose: CT-011 is a humanized IgG1 monoclonal antibody that modulates the immune response through interaction with PD-1, a protein belonging to the B7 receptor family present on lymphocytes. The objectives of this phase I study were to assess the dose-limiting toxicities, to determine the maximum tolerated dose, and to study the pharmacokinetics of CT-011 administered once to patients with advanced hematologic malignancies.

Experimental Design: Seventeen patients were treated with escalating doses of CT-011 ranging from 0.2 to 6 mg/kg. For pharmacokinetic analysis, blood samples were withdrawn from the patients before and immediately after treatment and at 24 hours, 48 hours, and on days 7, 14, and 21. CT-011 blood levels were assessed with a specific ELISA and derived concentrations were used to calculate pharmacokinetic parameters. Activation of the immune system was assessed by measuring peripheral blood CD4+, CD8+, and CD69+ lymphocytes.

Results: The study showed the antibody to be safe and well tolerated in this patient population. No single maximum tolerated dose was defined in this study. Clinical benefit was observed in 33% of the patients with one complete remission. Pharmacokinetic analyses show that serum Cmax and the AUC of CT-011 increased proportionally with dose. The median t1/2 of CT-011 ranged from 217 to 410 hours. Sustained elevation in the percentage of peripheral blood CD4+ lymphocytes was observed up to 21 days following CT-011 treatment.

Conclusions: A single administration of 0.2 to 6.0 mg/kg of CT-011 is safe and well tolerated in patients with advanced hematologic malignancies.
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

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

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

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

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

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

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 <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

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

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

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

The 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

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

Histone 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]
KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activityin vitroandin vivo
Authors: Hassig Christian A. , Symons Kent T. , Guo Xin , Nguyen Phan-Manh , Annable Tami , Wash Paul L. , Payne Joseph E. , Jenkins David A. , Bonnefous Céline , Trotter Carol , Wang Yan , Anzola John V. , Milkova Elena L. , Hoffman Timothy Z. , Dozier Sara J. , Wiley Brandon M. , Saven Alan , Malecha James W. , Davis Robert L. , Muhammad Jerry , Shiau Andrew K. , Noble Stewart A. , Rao Tadimeti S. , Smith Nicholas D. , Hager Jeffrey H.
Published: May 2008

Histone deacetylase (HDAC) inhibitors have garnered significant attention as cancer drugs. These therapeutic agents have recently been clinically validated with the market approval of vorinostat (SAHA, Zolinza) for treatment of cutaneous T-cell lymphoma. Like vorinostat, most of the small-molecule HDAC inhibitors in clinical development are hydroxamic acids, whose inhibitory activity stems from their ability to coordinate the catalytic Zn2+ in the active site of HDACs. We sought to identify novel, nonhydroxamate-based HDAC inhibitors with potentially distinct pharmaceutical properties via an ultra-high throughput small molecule biochemical screen against the HDAC activity in a HeLa cell nuclear extract. An α-mercaptoketone series was identified and chemically optimized. The lead compound, KD5170, exhibits HDAC inhibitory activity with an IC50 of 0.045 μmol/L in the screening biochemical assay and an EC50 of 0.025 μmol/L in HeLa cell–based assays that monitor histone H3 acetylation. KD5170 also exhibits broad spectrum classes I and II HDAC inhibition in assays using purified recombinant human isoforms. KD5170 shows significant antiproliferative activity against a variety of human tumor cell lines, including the NCI-60 panel. Significant tumor growth inhibition was observed after p.o. dosing in human HCT-116 (colorectal cancer), NCI-H460 (non–small cell lung carcinoma), and PC-3 (prostate cancer) s.c. xenografts in nude mice. In addition, a significant increase in antitumor activity and time to end-point occurred when KD5170 was combined with docetaxel in xenografts of the PC-3 prostate cancer cell line. The biological and pharmaceutical profile of KD5170 supports its continued preclinical and clinical development as a broad spectrum anticancer agent. [Mol Cancer Ther 2008;7(5):1054–65]
SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells
Authors: Vultur Adina , Buettner Ralf , Kowolik Claudia , Liang Wei , Smith David , Boschelli Frank , Jove Richard
Published: May 2008

Src family kinase activity is elevated in many human tumors, including breast cancer, and is often associated with aggressive disease. We examined the effects of SKI-606 (bosutinib), a selective Src family kinase inhibitor, on human cancer cells derived from breast cancer patients to assess its potential for breast cancer treatment. Our results show that SKI-606 caused a decrease in cell motility and invasion of breast cancer cell lines with an IC50 of ∼250 nmol/L, which was also the IC50 for inhibition of cellular Src kinase activity in intact tumor cells. These changes were accompanied by an increase in cell-to-cell adhesion and membrane localization of β-catenin. By contrast, cell proliferation and survival were unaffected by SKI-606 at concentrations sufficient to block cell migration and invasion. Analysis of downstream effectors of Src revealed that SKI-606 inhibits the phosphorylation of focal adhesion kinase (FAK), proline-rich tyrosine kinase 2 (Pyk2), and Crk-associated substrate (p130Cas), with an IC50 similar to inhibition of cellular Src kinase. Our findings indicate that SKI-606 inhibits signaling pathways involved in controlling tumor cell motility and invasion, suggesting that SKI-606 is a promising therapeutic for breast cancer. [Mol Cancer Ther 2008;7(5):1185–94]
Cash and Kin Go to Court: Legal Families and Chosen Families in Nineteenth-Century Egypt
Authors: Ghazaleh Pascale
Published: May 2008

Court records have offered historians an unparalleled source of information about the Ottoman period, particularly in the Empire's Arab provinces, where abundant documentation tells us about society's material conditions. As far as family history is concerned, Ottoman courts have yielded much important information regarding women's rights and status, as revealed in marriage contracts recorded before the Ottoman qadi. In the field of economic and social history, estate inventories have offered a glimpse of how people lived, what they might have consumed, and how wealthy they were. To date, however, less work has been done on how the family was structured by material relations, as indicated by financial transfers carried out upon a family member's death. In my paper, I will follow some of these transfers, in the form of pre-mortem gifts as well as post-mortem bequests, in an attempt to understand how individuals expressed their sense of obligation toward different elements in their social universe. I will seek to demonstrate that cash flows indicate individual preferences regarding the beneficiaries of wealth. I will also examine the relative importance of different associations, both kin and non-kin, in an individual's social network.
Genesis 1-3 as Source for the Anthropology of Origen
Authors: Lund Jacobsen Anders
Published: May 2008

According to Origen Genesis 1-3 is an anthropological key-text. The account of man's creation in Gen. 1,26f deals with the creation of the inner non-material man in the image of God, whereas Gen. 2,7 deals with the creation of the human body, the outer man, which is not created in the image of God. Some later critics claim that according to Origen Gen. 2,7 is about the creation of a non-material luminous body. In Origen's opinion only the inner man can reach perfection. The outer man can never be perfect, but will be destroyed. To deepen our understanding of, how Origen understands the mortality of the human body, some short sayings about the meaning of Gen. 3,21 are interpreted. In the few places where Origen refers explicitly to Gen. 3,21 there is no clear picture of how he interprets this verse. The most precise observation we can make is that in his view the skin coats denote the mortal corporality that surrounds the inner man.
Le Paraclet dans la notice antimontaniste du PseudoHippolyte, Refutatio omnium haeresium VIII, 19 Les commentaires prophétiques de Priscilla et Maximilla
Authors: Pastorelli David
Published: May 2008

The anti-Montanist notice of Pseudo-Hippolytus, Ref. VIII, 19 is often quoted in research in order to show that the Phrygian prophets wrote numerous books to complete the New Testament. It is, however, marked by an obvious editorial activity: the motive of countless books belongs to the author's heresiological arsenal and should not be counted as a testimony for the history of the New Testament canon. The author is more concerned about the issue of women's ministry : the conflict is on the one hand about the status of Priscilla and Maximilla as prophetic teachers, based on the prophetic office of the Paraclete, and on the other hand about their claims to write « prophetic » commentaries. The underlying principle is the Pauline prohibition that women teach, a fortiori that they write books.
Bilateral Transit Time Assessment of Upper and Lower Limbs as a Surrogate Ankle Brachial Index Marker
Authors: Foo Jong Yong Abdiel
Published: May 2008

Ankle brachial index is useful in monitoring the pathogenesis of peripheral arterial occlusive diseases. Sphygmomanometer is the standard instrument widely used but frequent prolonged monitoring can be less comfortable for patients. Pulse transit time is known to be inversely correlated with blood pressure and a ratio-based pulse transit time measurement has been proposed as a surrogate ankle brachial index marker. In this study, 17 normotensive adults (9 men; aged 25.4 ± 3.9 years) were recruited. Two postural change test activities were performed to induce changes in the stiffness of the arterial wall of the moved periphery. Results showed that only readings from the limbs that adopted a new posture registered significant blood pressure and pulse transit time changes ( P < .05). Furthermore, there was significant correlation between the ankle brachial index and pulse transit time ratio measure for both test activities ( R2 ≥ 0.704). The findings herein suggest that pulse transit time ratio is a surrogate and accommodating ankle brachial index marker.
Structural Equivalence of the Values Domain Across Cultures
Authors: Fontaine Johnny R. J. , Poortinga Ype H. , Delbeke Luc , Schwartz Shalom H.
Published: May 2008

The authors examine the cross-cultural equivalence of the internal structure of the values domain, as measured by the Schwartz Value Survey. Data come from 38 countries, each represented by a student and a teacher sample. In seeking to distinguish lack of fit of the theorized value model from a lack of equivalence in the data and the impact of random sampling fluctuations from valid structural differences, the authors find the following: (a) The Schwartz value theory provides an excellent representation of the average value structure across samples; (b) sampling fluctuation causes deviations from this average structure; (c) sampling fluctuation cannot account for all these deviations; (d) samples of students fit the overall value structure better than samples of teachers, and samples from Western countries better than those from non-Western countries; and (e) the deviations from the average structure exhibit a systematic pattern: the higher the level of societal development of a country, the greater the contrast between protection and growth values.
Applying Response to Intervention Metrics in the Social Domain for Students at Risk of Developing Emotional or Behavioral Disorders
Authors: Cheney Douglas , Flower Andrea , Templeton Tran
Published: May 2008

Response to Intervention (RtI) has become an important element of policy, practice, and research since the 2004 reauthorization of the Individuals with Disabilities Education Act. In this article, five metrics recommended by Gresham (2005) were used to evaluate the progress of 127 students who were at risk of developing emotional disturbance and enrolled in a Tier 2 targeted group intervention. Student progress on a daily behavior report card was used to identify responders and nonresponders. Results suggest that percentage of change and effect size were the most useful metrics and identified 67% of the students as responders to the intervention. Additionally, 91% of the responders were not identified for special education, and over 50% reduced their problem behavior ratings on the Social Skills Rating System Teacher Form. These findings suggest that the intervention reduced the student's at-risk status and helped prevent the development of emotional and behavioral disabilities.
Ethics and Subjectivity
Authors: Luxon Nancy
Published: May 2008

Contemporary accounts of individual self-formation struggle to articulate a mode of subjectivity not determined by relations of power. In response to this dilemma, Foucault's late lectures on the ancient ethical practices of “fearless speech” ( parrhesia) offer a model of ethical self-governance that educates individuals to ethical and political engagement. Rooted in the psychological capacities of curiosity and resolve, such self-governance equips individuals with a “disposition to steadiness” that orients individuals in the face of uncertainty. The practices of parrhesia accomplish this task without fabricating a distinction between internal soul and external body; by creating not a “body of knowledge” but a “body of practices”; and without reference to an external order such as nature, custom, tradition, or religion. The result is an “expressive subject” defined through expressive practices sustained by a simultaneous relationship to herself and to others. Individuals develop themselves not through their ability to “dare to know” but as those who “dare to act.”
Voting the General Will
Authors: Schwartzberg Melissa
Published: May 2008

Scholars exploring the logic of Rousseau's voting rules have typically turned to the connection between Rousseau and the Marquis de Condorcet. Though Condorcet could not have had a direct influence on Rousseau's arguments about the choice of decision rules in Social Contract, the possibility of a connection has encouraged the view that Rousseau's selection of voting rules was based on epistemic reasons. By turning to alternative sources of influence on Rousseau—the work of Hugo Grotius and particularly that of Samuel Pufendorf—a moral, and not purely epistemic, logic of rules governing collective decision making emerges. For Rousseau, as for Pufendorf, the proper choice of voting rule can elicit the appropriate attitude of an individual with respect to the decision of the whole, and can support the morally significant activity of acknowledging error upon discovering that one has voted against the general will.
Politics as a Moderator of the Accountability—Job Satisfaction Relationship: Evidence Across Three Studies
Authors: Breaux Denise M. , Munyon Timothy P. , Hochwarter Wayne A. , Ferris Gerald R.
Published: May 2008

The current study examined the interactive relationship between felt accountability and organizational politics perceptions on job satisfaction in three samples, which included employees in a wide array of work settings. We hypothesized that job satisfaction would decline (increase) as felt accountability became more intense for those perceiving heightened (limited) levels of politics. After controlling for demographic factors (e.g., age, gender, and organizational tenure), affectivity (e.g., negative and positive), and nonlinear main effect terms (e.g., felt accountability2 and politics perceptions2), results supported the study's hypothesized relationship. Namely, findings indicated that accountability predicted unfavorable levels of job satisfaction when coupled with heightened politics perceptions. Implications of results for theory and practice, strengths and limitations, and directions for future research are provided.
Sexual Harassment Isn't Always the Issue
Authors: Mann Stacey , Goodman Doug
Published: May 2008

Discrimination has long been established by the United States Supreme Court to be unconstitutional and illegal. Although the term hostile work environment is not specifically mentioned in the Civil Rights Act of 1964 (CRA), it has been most synonymous with claims of sexual harassment. Have the courts expanded the hostile work environment legal theory to include other protected classes in the CRA? This article analyzes and discusses recent appellate court cases with a claim of hostile work environment with the basis of some action other than sexual harassment. We explain why the courts, in the majority of cases, did not rule in favor of those who claimed hostile work environment, and then we summarize factors the courts used to determine their rulings. In addition, we provide suggestions to both employees and employers.
A useful methodological synergy? Combining critical discourse analysis and corpus linguistics to examine discourses of refugees and asylum seekers in the UK press
Authors: Baker Paul , Gabrielatos Costas , KhosraviNik Majid , Krzyżanowski Michał , McEnery Tony , Wodak Ruth
Published: May 2008

This article discusses the extent to which methods normally associated with corpus linguistics can be effectively used by critical discourse analysts. Our research is based on the analysis of a 140-million-word corpus of British news articles about refugees, asylum seekers, immigrants and migrants (collectively RASIM). We discuss how processes such as collocation and concordance analysis were able to identify common categories of representation of RASIM as well as directing analysts to representative texts in order to carry out qualitative analysis. The article suggests a framework for adopting corpus approaches in critical discourse analysis.
A Multicomponent Intervention to Increase Peer-Directed Communication in Head Start Children
Authors: Stanton-Chapman Tina L. , Kaiser Ann P. , Vijay Prathibha , Chapman Carol
Published: May 2008

The effects of a multicomponent intervention strategy to increase peer-directed social communication in eight Head Start children at risk for poor language and social skill development were examined. The intervention consisted of three components: (a) a planning period, including reading a storybook that illustrated the play theme and use of the social pragmatic communication strategies, practice using vocabulary to be used in play, and choosing roles for the thematic activity; (b) a 10-min play session in which the interventionist coached children to interact while they played with the thematic related toys; and (c) a brief reporting period in which children reviewed their use of the social pragmatic strategies and specific vocabulary. A multiple-baseline design across dyads with pre- and postgeneralization probes was employed. Children increased their use of peer-directed communication over baseline levels, target vocabulary words, and other social pragmatic skills.
Clinicopathologic Features Associated With Cytohistologic Noncorrelation in the Diagnosis of Cervical Dysplasia: A Study of Concurrently Obtained Samples
Authors: Fadare Oluwole , Carns Bhavini , Vos Jeffrey A. , Wang Sa A.
Published: May 2008

On the basis of the unique subset of our database comprising patients who received a Papanicolaou test and a cervical biopsy during the same clinic visit, clinicopathologic factors potentially associated with cytohistologic diagnostic noncorrelation in these concurrently collected samples is investigated. In the first analysis, a selected group of variables potentially associated with noncorrelation relative to the diagnosis of high-grade dysplasia were examined, whereas the second analysis was centered on the effect of varying levels of Papanicolaou test inflammation (below the Bethesda 2001 threshold, ie, partially obscuring inflammation) on noncorrelation regarding the overall diagnosis of dysplasia. For the latter, the overall density of neutrophilic infiltrate on each Papanicolaou test slide was graded in a blinded fashion on a 4-tiered scale (no significant amount, mild, moderate, and severe), followed by a comparison of correlating and noncorrelating cases at each tier. There was no overrepresentation of noncorrelating cases in severe inflammation group. Indeed, correlating and noncorrelating cases did not significantly differ at any level of inflammation. In the first analysis, correlating (n = 17) and noncorrelating (n = 17) cases did not significantly differ in patient age, number of biopsies obtained, endocervical curettage status, glandular involvement by high-grade dysplasia, or frequency of background grade 1 cervical intraepithelial neoplasia. Noncorrelating cases were more likely than correlating cases to be grade 2 cervical intraepithelial neoplasia rather than grade 3 or worse (82% vs 41%, respectively, P = .02), which is probably attributable to the absence of a basaloid proliferation in the most superficial layers of grade 2 lesions. Furthermore, noncorrelating cases showed a comparatively smaller percentage of submitted biopsies involved by high-grade dysplasia (52% vs 75%, respectively, P = .03), consistent with smaller extent of disease. These findings further illustrate that lesional factors are important potential contributors to the false-negative rate of the Papanicolaou test.
Congenital Thrombotic Risk Factors in β-Thalassemia
Authors: Sipahi Tansu , Kara Aslıhan , Kuybulu Ayca , Egin Yonca , Akar Nejat
Published: May 2008

Thalassemia major patients have increased risk for thromboembolic complications because of the chronic hypercoagulable state. The question arising from this is whether thromboembolic complications are the result of genetic polymorphisms of prothrombotic factors. Here, we studied factor V 1691 G-A (FVL), factor II polymorphism (G20210A), methyltetrahydrofolate reductase mutation (MTHFR, C677T), and endothelial cell protein C receptor (EPCR) deletion polymorphism and their relationship with thromboembolic complications. We found significant decrements of protein C and protein S and a slight increased prevalence of congenital thrombophilic mutations when compared with controls. Although 5 of the patients had high soluble EPCR (sEPCR) levels, no significant change was found in sEPCR values between patients and controls.