bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Cystatin B as a Potential Serum Marker in Hepatocellular Carcinoma
Authors: Lee Mi-Jin , Yu Gyung-Ran , Park Seon-Hwa , Cho Baik-Hwan , Ahn Jong-Seong , Park Hae-Joon , Song Eun-Young , Kim Dae-Ghon
Published: February 2008

Purpose: The poor survival rate of hepatocellular carcinoma (HCC) is in part due to the inability to diagnose patients at an early stage. Therefore, the aim of this study was to search for candidate serum marker for HCC and to test their ability to distinguish a HCC from benign liver disease.

Experimental Design: Genome-wide analysis by a microarray in 40 HCC patients was done between HCC and paired nontumor liver tissues. Expression of cystatin B (CSTB) was examined by mRNA expression analysis and immunohistochemistry. The serum CSTB levels were measured using a sandwich ELISA method in four groups, including normal healthy subjects (group 1, n = 52) and patients with noncirrhotic chronic hepatitis (group 2, n = 53), cirrhosis (group 3, n = 43), and HCC (group 4, n = 62).

Results: Microarray and statistical analyses identified 248 genes that were expressed differently between HCC and nontumor liver tissues. One of them, CSTB, was expressed preferentially in the HCCs compared with the nontumor tissues, 36 of 45 specimens (80%) by Northern blot and semiquantitative reverse transcription-PCR analyses. The serum CSTB level was much higher in HCC patients than in those with nonmalignant chronic liver disease (groups 2 and 3; P < 0.0001). The receiver operating characteristic curve indicated 5.34 ng/mL to be the optimal value for CSTB, and the sensitivity and specificity for this CSTB value were 85.5% (95% confidence interval, 74.2-93.1%) and 53.1% (95% confidence interval, 42.7-63.4%), respectively, in distinguishing between patients with HCC and those with nonmalignant chronic liver disease.

Conclusion: CSTB is specifically overexpressed in most HCCs and is also elevated in the serum of a large proportion of HCC patients. CSTB or the combination of CSTB and α-fetoprotein may be a useful marker for diagnosing patients with HCC with a high sensitivity.
Trastuzumab Activates Allogeneic or Autologous Antibody-Dependent Cellular Cytotoxicity against Malignant Rhabdoid Tumor Cells and Interleukin-2 Augments the Cytotoxicity
Authors: Katsumi Yoshiki , Kuwahara Yasumichi , Tamura Shinichi , Kikuchi Ken , Otabe Osamu , Tsuchiya Kunihiko , Iehara Tomoko , Kuroda Hiroshi , Hosoi Hajime , Sugimoto Tohru
Published: February 2008

Purpose: Malignant rhabdoid tumor (MRT) is an early childhood cancer with poor prognosis. Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor-2 (HER-2), has been shown to be effective against breast cancer and other cancers. We investigated the effect of trastuzumab on MRT cell lines.

Experimental Design: We examined expression of HER-2 on four MRT cell lines and two tumor tissues by indirect immunofluorescence, flow cytometry, and immunohistochemistry. The effect of trastuzumab against MRT cells was examined by cell growth assay. To observe the antibody-dependent cellular cytotoxicity of effector cells, we examined the cytotoxicity of trastuzumab in combination with allogeneic or autologous human peripheral blood mononuclear cells with and without IL-2 using the chromium release assay.

Results: All four MRT cell lines and both MRT tissues expressed HER-2 protein. Trastuzumab alone did not reduce the viability of the MRT cell lines. On the other hand, the cytotoxicity of trastuzumab against each of the MRT cell lines was significantly increased by the presence of allogeneic and autologous peripheral blood mononuclear cells (P < 0.01). There was a strong correlation coefficient (r = 0.825) between HER-2 expression and the cytotoxicity enhanced by trastuzumab. Moreover, trastuzumab in combination with peripheral blood mononuclear cells augmented by interleukin-2 (IL-2) was significantly more cytotoxic than trastuzumab alone or IL-2 alone (P < 0.01).

Conclusions: Our results indicate that (1) trastuzumab can exert antitumor effects on MRT cells by using the antibody-dependent cellular cytotoxicity of effector cells and (2) IL-2 can enhance the cytotoxicity of trastuzumab against MRT cells.
Enhanced Immune System Regeneration in Humans Following Allogeneic or Autologous Hemopoietic Stem Cell Transplantation by Temporary Sex Steroid Blockade
Authors: Sutherland Jayne S. , Spyroglou Lisa , Muirhead Jennifer L. , Heng Tracy S. , Prieto-Hinojosa Adria , Prince H. Miles , Chidgey Ann P. , Schwarer Anthony P. , Boyd Richard L.
Published: February 2008

Purpose: To determine if temporarily blocking sex steroids prior to stem cell transplantation can increase thymus function and thus enhance the rate of T cell regeneration.

Experimental Design: This was a pilot study of luteinizing hormone–releasing hormone agonist (LHRH-A) goserelin given 3 weeks prior to allogeneic or autologous hemopoietic stem cell transplantation and administered up to 3 months posttransplantation. Patients (with or without LHRH-A administration) were assessed from 1 week to 12 months posttransplantation for multiple immunologic variables by flow cytometry (particularly naïve T cells), quantitative PCR to assess T-cell receptor excision circle levels (as a correlate of thymus function), CDR3 length analysis to determine the variability of the TCR repertoire, and in vitro assays to determine functional T cell responses.

Results: LHRH-A administration prior to stem cell transplantation significantly increased neutrophil and lymphocyte numbers within the first month of posttransplantation. Most importantly, total and naïve CD4+ T cell regeneration together with T-cell receptor excision circle production, T cell repertoire regeneration, and peripheral T cell function were also significantly enhanced at multiple time points posttransplant. In addition, an increase in disease-free survival (P = 0.04) was seen in the autologous setting. Although LHRH-A administration increased T cell responses in vitro, it did not exacerbate graft-versus-host disease in the allogeneic setting.

Conclusions: This study provides an important new approach to the improvement of immune reconstitution in patients undergoing hemopoietic stem cell transplantation and may have generic applications in many T cell–based disorders.
Enhanced Functionality of CD4+CD25highFoxP3+ Regulatory T Cells in the Peripheral Blood of Patients with Prostate Cancer
Authors: Yokokawa Junko , Cereda Vittore , Remondo Cinzia , Gulley James L. , Arlen Philip M. , Schlom Jeffrey , Tsang Kwong Y.
Published: February 2008

Purpose: CD4+CD25highFoxP3+ regulatory T cells (Treg) have been shown to inhibit the activation and function of T cells that participate in antigen-specific immune responses. Higher levels of Tregs have been reported in the peripheral blood of patients with several types of tumors. In this study, we investigated the number and functionality of CD4+CD25highFoxP3+ Tregs in patients with prostate cancer (PCa), and their potential role in inhibiting antitumor immune responses.

Experimental Design: Levels of Tregs in the peripheral blood of healthy donors and patients with biochemically progressive, localized, and metastatic PCa were each measured by flow cytometry. The functional activity of Tregs was determined by their ability to suppress the proliferation of CD4+CD25− T cells. Data were analyzed using Wilcoxon rank sum test and unpaired Student's t test.

Results: Although levels of Tregs in the peripheral blood of patients with PCa were not significantly higher than those in healthy donors, Tregs in patients with PCa had significantly greater suppressive functionality than Tregs from healthy donors (P < 0.05). Additionally, there was a direct correlation between the serum levels of prostaglandin E2 and Treg functionality in patients with localized PCa, using Pearson's product-moment correlation coefficient (R).

Conclusions: These findings further show the potential importance of Tregs in modifying immune responses in patients with PCa. Although longer studies are necessary to confirm these findings, these studies also show for the first time the differences in Treg populations in patients with various stages of PCa, and thus, provide a basis for determining which PCa patient populations are best suited for immunotherapy trials involving the inhibition of Tregs.
Medulloblastoma: From Molecular Pathology to Therapy
Authors: Rossi Alessandra , Caracciolo Valentina , Russo Giuseppe , Reiss Krzysztof , Giordano Antonio
Published: February 2008

Medulloblastoma is the most common malignant tumor of central nervous system in children. Patients affected by medulloblastoma may be categorized as high-risk and standard-risk patients, based on the clinical criteria and histologic features of the disease. Currently, multimodality treatment, including surgery, radiotherapy, and chemotherapy is considered as the most effective strategy against these malignant cerebellar tumors of the childhood. Despite the potential poor outcomes of these lesions, the 5-year survival stands, at present, at 70% to 80% for standard-risk patients, whereas high-risk patients have a 5-year survival of 55% to 76%. Attempts to further reduce the morbidity and mortality associated with medulloblastoma have been restricted by the toxicity of conventional treatments and the infiltrative nature of the disease. Over the past decade, new discoveries in molecular biology have revealed new insights in signaling pathways regulating medulloblastoma tumor formation. Recent advances in the molecular biology of medulloblastoma indicate that the classification of these embryonal tumors, solely based on histology and clinical criteria, may not be adequate enough. Better understanding of the growth control mechanisms involved in the development and progression of medulloblastoma will allow a better classification, leading to the improvement of the existing therapies, as well as to the development of new therapeutic approaches.
Hypoxia-Selective Targeting by the Bioreductive Prodrug AQ4N in Patients with Solid Tumors: Results of a Phase I Study
Authors: Albertella Mark R. , Loadman Paul M. , Jones Philip H. , Phillips Roger M. , Rampling Roy , Burnet Neil , Alcock Chris , Anthoney Alan , Vjaters Egils , Dunk Chris R. , Harris Peter A. , Wong Alvin , Lalani Alshad S. , Twelves Chris J.
Published: February 2008

Purpose: AQ4N is a novel bioreductive prodrug under clinical investigation. Preclinical evidence shows that AQ4N penetrates deeply within tumors and undergoes selective activation to form AQ4, a potent topoisomerase II inhibitor, in hypoxic regions of solid tumors. This proof-of-principle, phase I study evaluated the activation, hypoxic selectivity, and safety of AQ4N in patients with advanced solid tumors.

Experimental Design: Thirty-two patients with cancer (8 glioblastoma, 9 bladder, 8 head and neck, 6 breast, and 1 cervix) received a single 200 mg/m2 dose of AQ4N before elective surgery. AQ4 and AQ4N levels in 95 tissues (tumor, healthy tissue) were assessed by liquid chromatography-tandem mass spectrometry. Tissue sections were also analyzed for AQ4 fluorescence using confocal microscopy, and for expression of the hypoxia-regulated glucose transporter, Glut-1.

Results: Activated AQ4 was detected in all tumor samples with highest levels present in glioblastoma (mean 1.2 μg/g) and head and neck (mean 0.65 μg/g) tumors; 22 of 32 patients had tumor AQ4 concentrations ≥0.2 μg/g, levels previously shown to be active in preclinical studies. In 24 of 30 tumor samples, AQ4 was detected at higher concentrations than in adjacent normal tissue (tumor to normal ratio range 1.1-63.6); distant skin samples contained very low concentrations of AQ4 (mean 0.037 μg/g). Microscopic evaluation of tumor sections revealed that AQ4 colocalized within regions of Glut-1+ hypoxic cells.

Conclusions: AQ4N was activated selectively in hypoxic regions in human solid tumors. Intratumoral concentrations of AQ4 exceeded those required for activity in animal models and support the evaluation of AQ4N as a novel tumor-targeting agent in future clinical studies.
ETV6-NCOA2: A Novel Fusion Gene in Acute Leukemia Associated with Coexpression of T-Lymphoid and Myeloid Markers and Frequent NOTCH1 Mutations
Authors: Strehl Sabine , Nebral Karin , König Margit , Harbott Jochen , Strobl Herbert , Ratei Richard , Struski Stephanie , Bielorai Bella , Lessard Michel , Zimmermann Martin , Haas Oskar A. , Izraeli Shai
Published: February 2008

Purpose: The ETV6 gene has been reported to be fused to a multitude of partner genes in various hematologic malignancies with 12p13 aberrations. Cytogenetic analysis of six cases of childhood acute lymphoblastic leukemia revealed a novel recurrent t(8;12)(q13;p13), suggesting involvement of ETV6.

Experimental Design: Fluorescence in situ hybridization was used to confirm the involvement of ETV6 in the t(8;12)(q13;p13) and reverse transcription-PCR was used to identify the ETV6 partner gene. Detailed immunologic characterization was done, and owing to their lineage promiscuity, the leukemic blast cells were analyzed for NOTCH1 mutations.

Results: We have identified a novel recurrent t(8;12)(q13;p13), which results in a fusion between the transcriptional repressor ETV6 (TEL) and the transcriptional coactivator NCOA2 (TIF2) in six cases of childhood leukemia expressing both T-lymphoid and myeloid antigens. The ETV6-NCOA2 transcript encodes a chimeric protein that consists of the pointed protein interaction motif of ETV6 that is fused to the COOH terminus of NCOA2, including the cyclic AMP–responsive element binding protein–binding protein (CBP) interaction and the AD2 activation domains. The absence of the reciprocal NCOA2-ETV6 transcript in one of the cases suggests that the ETV6-NCOA2 chimeric protein and not the reciprocal NCOA2-ETV6 is responsible for leukemogenesis. In addition, ETV6-NCOA2 leukemia shows a high frequency of heterozygous activating NOTCH1 mutations, which disrupt the heterodimerization or the PEST domains.

Conclusions: The ETV6-NCOA2 fusion may define a novel subgroup of acute leukemia with T-lymphoid and myeloid features, which is associated with a high prevalence of NOTCH1 mutations.
Methylseleninic Acid Enhances Taxane Drug Efficacy against Human Prostate Cancer and Down-Regulates Antiapoptotic Proteins Bcl-XL and Survivin
Authors: Hu Hongbo , Li Guang-xun , Wang Lei , Watts Jennifer , Combs Gerald F. , Lü Junxuan
Published: February 2008

Purpose: Our previous work has shown that methylseleninic acid (MSeA) sensitized hormone refractory prostate cancer (HRPCa) cells to apoptosis induced by paclitaxel (Taxol) through enhancing multiple caspases. This study aimed to (a) determine the general applicability of the sensitization effect for taxane drugs in vitro, (b) establish the enhancement of paclitaxel efficacy by MSeA in vivo, and (c) investigate Bcl-XL and survivin as molecular targets of MSeA to augment apoptosis.

Experimental design: DU145 and PC-3 HRPCa cell lines were used to evaluate the in vitro apoptosis effects of paclitaxel, docetaxel and their combination with MSeA, and the molecular mechanisms. DU145 xenograft growth in athymic nude mice was used to evaluate the in vivo efficacy of paclitaxel and its combination with MSeA. The tumor samples were used to examine Bcl-XL and survivin protein abundance.

Results: MSeA combination with paclitaxel or docetaxel exerted a greater than additive apoptosis effect on DU145 and PC-3 cells. In nude mice, paclitaxel and MSeA combination inhibited growth of DU145 subcutaneous xenograft with the equivalent efficacy of a four-time higher dose of paclitaxel alone. MSeA decreased the basal and paclitaxel-induced expression of Bcl-XL and survivin in vitro and in vivo. Ectopic expression of Bcl-XL or survivin attenuated MSeA/paclitaxel-induced apoptosis.

Conclusions: MSeA enhanced the efficacy of paclitaxel against HRPCa in vitro and in vivo, at least in part, by down-regulating the basal and paclitaxel-induced expression of both Bcl-XL and survivin to increase caspase-mediated apoptosis. MSeA may be a novel agent to improve taxane combination therapy.
A Phase I Study of ABT-751, an Orally Bioavailable Tubulin Inhibitor, Administered Daily for 21 Days Every 28 Days in Pediatric Patients with Solid Tumors
Authors: Fox Elizabeth , Maris John M. , Widemann Brigitte C. , Goodspeed Wendy , Goodwin Anne , Kromplewski Marie , Fouts Molly E. , Medina Diane , Cohn Susan L. , Krivoshik Andrew , Hagey Anne E. , Adamson Peter C. , Balis Frank M.
Published: February 2008

Purpose: To determine the toxicity profile, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) of ABT-751 administered orally once daily for 21 days, repeated every 28 days in a pediatric population.

Experimental Design: Patients who were ≤18 years with relapsed or refractory solid tumors and who were able to swallow capsules were eligible. The starting dose was 75 mg/m2/d (n = 3) and was escalated to 100 (n = 6), 130 (n = 5), and 165 (n = 3) mg/m2/d in cohorts of three to six patients. The MTD was determined from DLTs occurring during the first treatment cycle.

Results: Nineteen children (median age, 13 years; range, 5-18 years) were enrolled, and 17 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 9), sarcomas (n = 9), and other solid tumors (n = 1). DLTs included fatigue, sensory neuropathy, transient hypertension, neutropenia, thrombocytopenia, nausea, vomiting, dehydration, abdominal pain, and constipation. The MTD of ABT-751 administered daily for 21 days every 28 days was 100 mg/m2/d. Non-DLT at the MTD included bone marrow suppression, gastrointestinal toxicities (anorexia, abdominal pain, nausea, vomiting, and constipation), and sensory and motor neuropathies. The median number of cycles administered was one (range, one to five). Tolerance of repeated treatment cycles was poor.

Conclusion: Fatigue, hematologic, and gastrointestinal toxicities limited the tolerability of ABT-751 administered to children on the once daily for 21 days every 28 days schedule. The MTD in children with solid tumors (100 mg/m2/d daily for 21 days) was similar to the recommended dose in adults with solid tumors (200 mg fixed dose) receiving the same dosing schedule.
Phase I Clinical Study of Atacicept in Patients with Relapsed and Refractory B-Cell Non–Hodgkin's Lymphoma
Authors: Ansell Stephen M. , Witzig Thomas E. , Inwards David J. , Porrata Luis F. , Ythier Arnaud , Ferrande Lee , Nestorov Ivan , DeVries Todd , Dillon Stacey R. , Hausman Diana , Novak Anne J.
Published: February 2008

Purpose: B-lymphocyte stimulator and a proliferation-inducing ligand regulate B-cell homeostasis and immunoglobulin production and are overexpressed in B-cell malignancies. Atacicept (TACI-Ig), a recombinant fusion protein that inhibits both B-lymphocyte stimulator and a proliferation-inducing ligand, may be a novel treatment for B-cell malignancies.

Experimental Design: A phase 1, open-label, dose-escalation study of atacicept in patients with relapsed or refractory B-cell lymphoma was done. Atacicept was given s.c. weekly for 5 weeks to sequential patient cohorts at doses of 2, 4, 7, or 10 mg/kg. Patients responding or with stable disease were eligible for treatment on an extension study for up to 24 weeks or until disease progression.

Results: All patients were heavily pretreated (median number of previous treatments, 5; range, 1-10), and four patients had previously received a stem cell transplant. Four patients were treated at the 2, 4, or 7 mg/kg dose levels, and three patients received 10 mg/kg of atacicept. Atacicept was well tolerated at all doses. Three adverse events with grade 3 severity were reported for one patient, including jaw pain, gastrointestinal hemorrhage, and sepsis; all were considered unrelated to atacicept. Pharmacokinetic results were nonlinear, and treatment with atacicept resulted in dose-dependent decreases in immunoglobulin concentrations. Two patients had stable disease at 8 weeks, entered the extension study, and received additional doses of atacicept with no safety or tolerability concerns.

Conclusion: Atacicept at doses of up to 10 mg/kg was well tolerated and showed biological activity by decreasing immunoglobulin concentrations, although tumor responses were not observed.
Calcitrol (1α,25-dihydroxyvitamin D3) inhibits androgen glucuronidation in prostate cancer cells
Authors: Kaeding Jenny , Bélanger Julie , Caron Patrick , Verreault Mélanie , Bélanger Alain , Barbier Olivier
Published: February 2008

Calcitriol (1α,25-dihydroxyvitamin D3), the active metabolite of vitamin D, has recently emerged as a promising therapeutic agent in the treatment of prostate cancer, the second most common cause of cancer death in American males. In the present study, we have analyzed the effects of calcitriol treatment on the expression and activity of the UDP-glucuronosyltransferase (UGT) 2B15 and 2B17 in prostate cancer LNCaP and 22Rv1 cells. These two enzymes share a crucial role in the inactivation of androgens in the human prostate. We report that calcitriol treatment results in lower glucuronide conjugation of the active androgen dihydrotestosterone and its reduced metabolites androstane-3α-diol and androsterone in LNCaP cells. The same treatment also drastically decreased the mRNA and protein levels of UGT2B15 and UGT2B17 in LNCaP and 22Rv1 cells. Using casodex, an androgen receptor (AR) antagonist, and AR-specific small interfering RNA probes, we show that calcitriol requires a functional AR to inhibit the expression of the UGT2B17 gene in LNCaP cells. By contrast, transient transfection and site-directed mutagenesis experiments revealed that calcitriol down-regulates UGT2B15 promoter activity through a responsive region between positions -171 and -113 bp. In conclusion, the present study identifies the vitamin D receptor activator calcitriol as a negative regulator of the UGT2B15- and UGT2B17-dependent inactivation of androgens in prostate cancer LNCaP cells. Androgens promote prostate cancer cell proliferation; thus, the reduction of their inactivation could have a limiting effect of the calcitriol antiproliferative properties in prostate cancer cells. [Mol Cancer Ther 2008;7(2):380–90]
Dual mechanisms of action of the 5-benzylidene-hydantoin UPR1024 on lung cancer cell lines
Authors: Cavazzoni Andrea , Alfieri Roberta R. , Carmi Caterina , Zuliani Valentina , Galetti Maricla , Fumarola Claudia , Frazzi Raffaele , Bonelli Mara , Bordi Fabrizio , Lodola Alessio , Mor Marco , Petronini Pier Giorgio
Published: February 2008

In this study, we examined the mechanism of action of the novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor 5-benzylidene-hydantoin UPR1024, whose structure was designed to interact at the ATP-binding site of EGFR. The compound had antiproliferative and proapoptotic effects when tested on the non–small cell lung cancer cell line A549. The growth inhibitory effect was associated with an accumulation of the cells in the S phase of the cell cycle. Moreover, UPR1024 induced significant level of DNA strand breaks associated with increased expression of p53 and p21WAF1 proteins, suggesting an additive mechanism of action. The presence of wild-type p53 improved the drug efficacy, although the effect was also detectable in p53 null cells. We also noted apoptotic cell death after treatment with UPR1024 at concentrations above 10 μmol/L for >24 h, with involvement of both the extrinsic and intrinsic pathways. The present data show that UPR1024 may be considered a combi-molecule capable of both blocking EGFR tyrosine kinase activity and inducing genomic DNA damage. UPR1024 or its derivatives might serve as a basis for development of drugs for the treatment of lung cancer in patients resistant to classic tyrosine kinase inhibitors. [Mol Cancer Ther 2008;7(2):361–70]
DNAzyme technology and cancer therapy: cleave and let die
Authors: Dass Crispin R. , Choong Peter F.M. , Khachigian Levon M.
Published: February 2008

Novel molecules are constantly being discovered and developed to find better means of managing debilitating and fatal diseases, which include cancer in its multiple forms. Among these molecules, and as a direct consequence of a better understanding of the molecular basis of diseases, are those falling within the class of gene therapeutics. Among these players, deoxyribozymes (DNAzymes) have come a long way from being just another analytic tool available to molecular biologists. Recent studies have shown the potential DNAzymes to serve as drugs both in cell-based assays and preclinical models of cancer. It is anticipated that with the development of smart delivery systems for DNAzymes, better pharmacokinetics and pharmacodynamics will be possible, expediting DNAzyme march toward the clinic. Also, the ability of DNAzymes to yield to such phenomena as light-induced activation may be exploited for targeted therapy. This review documents the rise of DNAzymes in the fight against cancer and serves as a forecast for this promising biotechnology in this context. [Mol Cancer Ther 2008;7(2):243–51]
Identification of Trop-2 as an oncogene and an attractive therapeutic target in colon cancers
Authors: Wang Jianbo , Day Ryan , Dong Yiyu , Weintraub Steven J. , Michel Loren
Published: February 2008

The cell surface protein Trop-2 is highly expressed in a wide variety of epithelial cancers. In contrast, there is little or no expression of Trop-2 in adult somatic tissue. Because it is a cell surface protein that is selectively expressed in tumor cells, Trop-2 is a potential therapeutic target. However, whether Trop-2 is actively involved in tumorigenesis and whether its targeting for treatment would be effective have not been examined. Here, we show that Trop-2 expression is necessary for tumorigenesis and invasiveness of colon cancer cells, as both are inhibited when Trop-2 expression is suppressed by RNA interference. Conversely, ectopic expression of Trop-2 in colon cancer cells enhances their capacity for anchorage-independent growth and ectopic expression of Trop-2 in NIH3T3 cells is sufficient to promote both anchorage-independent growth and tumorigenesis. Importantly, we show that an antibody against the extracellular domain of Trop-2 reduces tumor cell invasiveness. Therefore, we have identified Trop-2 as an oncogene that has potential as a therapeutic target. Given the restricted expression of Trop-2 in normal tissue, anti–Trop-2 therapeutics would be predicted to have limited toxicity. [Mol Cancer Ther 2008;7(2):280–5]
Defective p53 signaling in p53 wild-type tumors attenuates p21waf1 induction and cyclin B repression rendering them sensitive to Chk1 inhibitors that abrogate DNA damage-induced S and G2 arrest
Authors: Levesque Aime A. , Fanous Andrew A. , Poh Alissa , Eastman Alan
Published: February 2008

DNA damage induces cell cycle arrest to provide time for repair and enhance cell survival. The Chk1 inhibitor 7-hydroxystaurosporine (UCN-01) can overcome both S and G2 arrest and drive cells through a lethal mitosis. S-phase arrest induced by the topoisomerase I inhibitor SN38 results from activation of Chk1 and degradation of Cdc25A phosphatase that occurs independent of p53 status. However, p53-mediated induction of p21waf1 and repression of cyclin B prevent abrogation of S and G2 arrest, respectively. Surprisingly, incubation of MCF10A immortalized breast cells with UCN-01 fails to elevate Cdc25A protein due to p53-mediated inhibition of Cdc25A transcription. Suppression of p21waf1 in MCF10A cells overcame this transcriptional inhibition, and the S-phase-arrested cells became sensitive to UCN-01, although they now arrested in G2 as cyclin B expression remained suppressed. We also compared the response of p53 wild-type tumors to the combination of SN38 and UCN-01. In CAKI-1, U87MG, and SUM102, SN38 induced p21waf1 and the cells were resistant to UCN-01. In contrast, HCT116 and MCF7 cells had markedly attenuated induction of p21waf1 and failed to repress cyclin B. Accordingly, these cells were susceptible to UCN-01-mediated abrogation of both S and G2 arrest. SN38 induced expression of another p53-inducible gene, 14-3-3σ, suggesting selective dysregulation of p53 response genes. In summary, several cell lines commonly considered wild-type for p53 appear to have defects in expression of selected p53 response genes following DNA damage, and this makes them sensitive to the combination of DNA damage plus Chk1 inhibitor. [Mol Cancer Ther 2008;7(2):252–62]
Caspase-, cathepsin-, and PERK-dependent regulation of MDA-7/IL-24-induced cell killing in primary human glioma cells
Authors: Yacoub Adly , Park Margaret A. , Gupta Pankaj , Rahmani Mohammed , Zhang Guo , Hamed Hossein , Hanna David , Sarkar Devanand , Lebedeva Irina V. , Emdad Luni , Sauane Moira , Vozhilla Nicollaq , Spiegel Sarah , Koumenis Costas , Graf Martin , Curiel David T. , Grant Steven , Fisher Paul B. , Dent Paul
Published: February 2008

Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a novel cytokine displaying selective apoptosis-inducing activity in transformed cells without harming normal cells. The present studies focused on defining the mechanism(s) by which a GST-MDA-7 fusion protein inhibits cell survival of primary human glioma cells in vitro. GST-MDA-7 killed glioma cells with diverse genetic characteristics that correlated with inactivation of ERK1/2 and activation of JNK1-3. Activation of JNK1-3 was dependent on protein kinase R–like endoplasmic reticulum kinase (PERK), and GST-MDA-7 lethality was suppressed in PERK−/− cells. JNK1-3 signaling activated BAX, whereas inhibition of JNK1-3, deletion of BAX, or expression of dominant-negative caspase-9 suppressed lethality. GST-MDA-7 also promoted a PERK-, JNK-, and cathepsin B–dependent cleavage of BID; loss of BID function promoted survival. GST-MDA-7 suppressed BAD and BIM phosphorylation and heat shock protein 70 (HSP70) expression. GST-MDA-7 caused PERK-dependent vacuolization of LC3-expressing endosomes whose formation was suppressed by incubation with 3-methyladenine, expression of HSP70 or BiP/GRP78, or knockdown of ATG5 or Beclin-1 expression but not by inhibition of the JNK1-3 pathway. Knockdown of ATG5 or Beclin-1 expression or overexpression of HSP70 reduced GST-MDA-7 lethality. Our data show that GST-MDA-7 induces an endoplasmic reticulum stress response that is causal in the activation of multiple proapoptotic pathways, which converge on the mitochondrion and highlight the complexity of signaling pathways altered by mda-7/IL-24 in glioma cells that ultimately culminate in decreased tumor cell survival. [Mol Cancer Ther 2008;7(2):297–313]
The Development of Children’s Orientations toward Moral, Social, and Personal Orders: More than a Sequence in Development
Authors: Turiel Elliot
Published: February 2008

Lawrence Kohlberg first published details of his research on the development of moral judgments in Vita Humana (later titled Human Development). Along with a series of other articles and essays, he greatly influenced research on moral development. He was instrumental in moving the field out of the narrow confines of analyses of psychological mechanisms to inclusion of substantive philosophical definitions of the domain. He persuaded many researchers to take morality seriously as a realm pertaining to people’s thinking about how they ought to relate to each other and how social systems should be organized. Although several aspects of Kohlberg’s theoretical formulations are now not widely accepted, most researchers (though not all) are concerned with combining epistemological considerations with psychological analyses and view children as possessing moral capacities not solely imposed by adults. One of these theoretical perspectives, discussed in this essay, is based on distinctions among social domains. Problems in current research, especially on morality and neuroscience, that fails to attend to epistemological considerations are discussed.
Reflections on J.V. Wertsch’s ‘From Social Interaction to Higher Psychological Processes,’ Human Development, 1979
Authors: Saxe Geoffrey B.
Published: February 2008

In his 1979 Human Development article reprinted in this anniversary issue, James Wertsch presented an approach to genetic analysis of the shifting regulation of problem-solving behavior in early childhood. In my reflections on Wertsch’s seminal contribution, I discuss ways that subsequent inquiry built upon ideas he elaborated in the 1979 article, using my own work as an illustrative case. One strand of my discussion focuses on method. Wertsch’s treatment involved lab-based studies, and I discuss how, in my research on early number development, I coordinated laboratory methods similar to Wertsch’s with field methods. The second strand broadens the scope of Wertsch’s approach to genetic analyses. Wertsch presented a compelling case for the utility of genetic analysis in investigations of the emergence of forms of problem solving. I discuss the importance of extending genetic explanation by incorporating sociogenetic analysis of the reproduction and alteration of collective systems of representation in the social history of communities. As an illustration I present my research on numerical representations used by a remote Papua New Guinea cultural group. I conclude by considering the utility of a genetic analysis of collective forms of representation and the functions these forms serve, in ontogeny as well as in social history.
Taxonomic Attribution of the Olduvai Hominid 7 Manual Remains and the Functional Interpretation of Hand Morphology in Robust Australopithecines
Authors: Moyà-Solà Salvador , Köhler Meike , Alba David M. , Almécija Sergio
Published: February 2008

In this paper, we test the currently accepted taxonomic hypothesis that the hand of theHomo habilisholotype Olduvai hominid 7 (OH7) from Olduvai Gorge can be unambiguously assigned toHomo. Morphometric and morphological comparison with humans and australopithecines(AustralopithecusandParanthropus)indicate that the OH7 hand most likely belongs toP. boisei. The morphological adaptations ofParanthropusare thus further evaluated in the light of the alternative taxonomic hypothesis for OH7. Functional analyses suggest that morphological features related to human-like precision grasping, previously considered diagnostic of toolmaking by some, may be alternatively attributed to specialized manual feeding techniques in robust australopithecines.
Benefit of Percutaneous Injection of Autologous Platelet-Leukocyte-Rich Gel in Patients with Delayed Union and Nonunion
Authors: Bielecki T. , Gazdzik T.S. , Szczepanski T.
Published: February 2008

This article reports the efficacy of percutaneous autologous platelet-leukocyte-rich gel (PLRG) injection as a minimally invasive method alternative to open grafting techniques. Each of 32 participants was followed on a regular basis with clinical examinations, roentgenograms, dual-energy X-ray absorptiometry examinations. In the delayed union group, the average time to union was 9.3 weeks after PLRG injection and the union was achieved in all cases. In the nonunion group, the union was observed in 13 of 20 cases and the average time to union was 10.3 weeks after PLRG injection. Interestingly, in patients in whom union was not achieved, the average time from the fracture and/or from the last operation was >11 months. This is our initial experience with the use of PLRG as biologic treatment for delayed union or nonunion. Our investigation showed that percutaneous PLRG injection in delayed union is a sufficient method to obtain union, which is less invasive procedure than bone marrow injection. Percutaneous PLRG grafting can be also an effective method for the treatment of selected cases of nonunion. The essential factor is the average time from the initial surgery to PLRG injection for nonunion; <11 months seems to be critical for good outcomes.
Influence of Beverage Composition on the Results of Erosive Potential Measurement by Different Measurement Techniques
Authors: Jager D.H.J. , Vieira A.M. , Ruben J.L. , Huysmans M.C.D.N.J.M.
Published: February 2008

The influence of beverage composition on the measurement of erosive potential is unclear. The aim of this study was to evaluate whether beverage composition influences the measurement of erosive potential and to evaluate the influence of exposure in small and large volumes. Eleven beverages were included: water (control), 3 alcopops, 2 beers and 5 soft drinks. For each beverage 15 bovine enamel samples were used: 5 for chemical and 10 for profilometric analysis. After exposure to the beverages (63 min) the resulting solutions were analyzed for Ca and inorganic phosphorus (Pi) content. The samples for optical profilometry were submersed sequentially in 500 ml or in 1 ml of the drinks for 3, 6, 9, 15 and 30 min (total 63 min). For some of the beverages high baseline concentrations of Ca (energy drink) or Pi (cola drink, cola lemon drink, beer, beer lemon) were found. Some of the beverages showed a good correlation between the chemical methods. Profilometry (both for 1 and 500 ml) showed generally lower enamel losses than the chemical methods. Lower enamel losses were found for the profilometry 1 ml compared to the profilometry 500 ml only for the cola drinks. It can be concluded that the composition of the beverages had a significant effect on the determination of the erosive potential with chemical analyses. Drink composition also influenced the effect of small versus large exposure volumes, indicating the need for standardization of exposure parameters.
Mental Health Care Use in Parkinson’s Disease: A Record Linkage Study
Authors: Leentjens A.F.G. , Driessen G. , Weber W. , Drukker M. , van Os J.
Published: February 2008

Background/Aim: Parkinson’s disease (PD) is often complicated by psychiatric comorbidity, which is likely to lead to a higher use of mental health care facilities. In addition, psychiatric symptomatology and associated mental health care use may be present even before motor symptoms and PD are diagnosed, as the pathophysiology of PD and its psychiatric consequences are likely to overlap to a degree. This will be reflected in an increasing mental health care use prior to the diagnosis of PD. The aim of this study is to compare the level of mental health care use of PD patients with that of a matched control population, and to assess possible fluctuations in mental health care use in the years surrounding the diagnosis of PD. Methods: Record linkage study comparing the number of mental health care contacts by PD patients with that of a matched control population. Results: Mental health care use by PD patients already increased before the time of diagnosis of PD, and decreased again after diagnosis. The relative risk for mental health care use was increased from 3 years prior (RR 1.41; 95% CI 1.27–1.57) to 2 years after (RR 1.83; 95% CI 1.63–2.05) diagnosing PD. This increase was higher for women than for men, and higher for younger than older individuals. Conclusion: The early pathophysiology of PD is expressed in part as mental health problems, suggesting the possibility of early detection in particular demographic groups and a proactive approach to early intervention for comorbid psychopathology.
Prevalence of Primary Chronic Headache in a Population-Based Sample of 30- to 44-Year-Old Persons
Authors: Grande Ragnhild Berling , Aaseth Kjersti , Gulbrandsen Pål , Lundqvist Christofer , Russell Michael Bjørn
Published: February 2008

Background: Prevalence data on primary chronic headache in the general population based on clinical interviews by physicians are lacking. Methods: In a cross-sectional epidemiological survey, a random sample of 30,000 persons from Akershus County, aged 30–44 years, were sent a postal questionnaire. Those with self-reported chronic headache within the last month and/or year were invited to a semi-structured diagnostic interview and a physical and neurological examination conducted by 2 neurological residents with experience in headache diagnostics. The diagnoses were made according to the International Classification of Headache Disorders, 2nd edition, 2004, and relevant revisions. Results: The questionnaire response rate was 71%, and the participation rate of the interview was 74%. The 1-year prevalence of primary chronic headache was 2.9%. Chronic tension-type headache (CTTH) and probable chronic tension-type headache (pCTTH) had 1-year prevalences of 1.6 and 1.2%, respectively. The prevalences of other primary chronic headaches were: chronic migraine (CM) 0.01%, probable CM 0.09% and other subtypes 0.04%. Co-occurrence of migraine was frequent, as 42% with CTTH and 55% with pCTTH had migraine. Conclusion: Primary chronic headache is prevalent in the general population. The majority has CTTH or pCTTH, while CM and other primary chronic headaches are rare.
Normal and Pathological Aging of Attention in Presymptomatic Huntington’s, Huntington’s and Alzheimer’s Disease, and Nondemented Elderly Subjects
Authors: Peretti Charles-Siegfried , Ferreri Florian , Blanchard François , Bakchine Serge , Peretti Charles Roger , Dobrescu Andrei , Chouinard Virginie-Anne , Chouinard Guy
Published: February 2008

Background: Attention models view attention as having at least two components: endogenous attention defined as executive and directed by voluntary acts, and exogenous attention defined as automatic and directed by external stimulation. Methods: Three studies (2 of our own) were designed to evaluate the decline of these two components of attention in normal aging and two neurodegenerative diseases. Standardized tests derived from Posner’s model of visuospatial attention were administered to normal healthy elderly participants (n = 13), patients suffering from Huntington’s disease (HD; n = 17) and Alzheimer’s disease (n = 15), and matched control subjects (n = 57). Outcome measures were reaction time (RT) and RT difference score (defined as invalid RT minus valid RT). Results: In healthy elderly participants, the decline was more pronounced for endogenous attention in situations of perceptual conflict. In Alzheimer’s disease, there was a significant decline in both attention components, while in HD, voluntary attention was markedly impaired and automatic attention preserved. Conclusions: Normal aging and HD are characterized by decreased endogenous attention in situations of perceptual conflict. Our data support previous findings that older people display impairment of attention in complex perceptual situations. We propose a model which allows for the separation of attention pathologies, thus improving therapeutic strategies for patients and elderly.
Effectiveness of Distant Healing for Patients with Chronic Fatigue Syndrome: A Randomised Controlled Partially Blinded Trial (EUHEALS)
Authors: Walach Harald , Bösch Holger , Lewith George , Naumann Johannes , Schwarzer Barbara , Falk Sonja , Kohls Niko , Haraldsson Erlendur , Wiesendanger Harald , Nordmann Alain , Tomasson Helgi , Prescott Phil , Bucher Heiner C.
Published: February 2008

Background: Distant healing, a form of spiritual healing, is widely used for many conditions but little is known about its effectiveness. Methods: In order to evaluate distant healing in patients with a stable chronic condition, we randomised 409 patients with chronic fatigue syndrome (CFS) from 14 private practices for environmental medicine in Germany and Austria in a two by two factorial design to immediate versus deferred (waiting for 6 months) distant healing. Half the patients were blinded and half knew their treatment allocation. Patients were treated for 6 months and allocated to groups of 3 healers from a pool of 462 healers in 21 European countries with different healing traditions. Change in Mental Health Component Summary (MHCS) score (SF-36) was the primary outcome and Physical Health Component Summary score (PHCS) the secondary outcome. Results: This trial population had very low quality of life and symptom scores at entry. There were no differences over 6 months in post-treatment MHCS scores between the treated and untreated groups. There was a non-significant outcome (p = 0.11) for healing with PHCS (1.11; 95% CI –0.255 to 2.473 at 6 months) and a significant effect (p = 0.027) for blinding; patients who were unblinded became worse during the trial (–1.544; 95% CI –2.913 to –0.176). We found no relevant interaction for blinding among treated patients in MHCS and PHCS. Expectation of treatment and duration of CFS added significantly to the model. Conclusions: In patients with CFS, distant healing appears to have no statistically significant effect on mental and physical health but the expectation of improvement did improve outcome.
Minireview on Regulation of Intestinal Calcium Absorption
Authors: Pérez Adriana V. , Picotto Gabriela , Carpentieri Agata R. , Rivoira María A. , Peralta López María E. , Tolosa de Talamoni Nori G.
Published: February 2008

An overview of current information on the mechanisms by which intestinal calcium absorption occurs is described in this article. Both paracellular and transcellular pathways are analyzed. Special emphasis focuses on molecules participating in the latter pathway, such as TRPV5 and TRPV6 channels, located in the apical region of the enterocytes, CB9k and CB28k, presumably involved in the cation movement from the apical to the basolateral pole of the cell, and PMCA1b and Na+/Ca2+ exchanger, proteins that extrude Ca2+ from the cells. Current concepts on the relative importance of paracellular and transcellular calcium transport and the vitamin D dependence of each pathway are referred and analyzed showing the contrasting views on this issue. More detailed information is given regarding the stimulatory effect of vitamin D on intestinal Ca2+ absorption either in animal models or in the human intestine. The possible mechanisms triggered by hormones such as PTH, calcitonin, estrogen, thyroid hormone, glucocorticoids and different nutritional factors on intestinal calcium absorption are also reviewed. Finally, the influence of physiological conditions such as growth, pregnancy, lactation and aging on intestinal calcium absorption are discussed.
Responses of the Hypothalamopituitary Adrenal Axis and the Sympathoadrenal System to Isolation/Restraint Stress in Sheep of Different Adiposity
Authors: Tilbrook Alan J. , Rivalland Elizabeth A.T. , Turner Anne I. , Lambert Gavin W. , Clarke Iain J.
Published: February 2008

There is evidence that levels of adipose tissue can influence responses of the hypothalamopituitary-adrenal (HPA) axis to stress in humans and rats but this has not been explored in sheep. Also, little is known about the sympathoadrenal responses to stress in individuals with relatively different levels of adipose tissue. We tested the hypothesis that the stress-induced activation of the HPA axis and sympathoadrenal system is lower in ovariectomized ewes with low levels of body fat (lean) than ovariectomized ewes with high levels of body fat (fat). Ewes underwent dietary manipulation for 3 months to yield a group of lean ewes (n = 7) with a mean (±SEM) live weight of 39.1 ± 0.9 kg and body fat of 8.9 ± 0.6% and fat ewes (n = 7) with a mean (±SEM) live weight of 69.0 ± 1.8 kg and body fat of 31.7 ± 3.4%. Fat ewes also had higher circulating concentrations of leptin than lean ewes. Blood samples were collected every 15 min over 8 h when no stress was imposed (control day) and on a separate day when 4 h of isolation/restraint was imposed after 4 h of pretreatment sampling (stress day). Plasma concentrations of adrenocorticotropic hormone (ACTH), cortisol, epinephrine and norepinephrine did not change significantly over the control day and did not differ between lean and fat ewes. Stress did not affect plasma leptin levels. All stress hormones increased significantly during isolation/restraint stress. The ACTH, cortisol and epinephrine responses were greater in fat ewes than lean ewes but norepinephrine responses were similar. Our results suggest that relative levels of adipose tissue influence the stress-induced activity of the hypothalamopituitary-adrenal axis and some aspects of the sympathoadrenal system with fat animals having higher responses than lean animals.