bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I Trial of Pelvic Radiation, Weekly Cisplatin, and 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP, NSC #663249) for Locally Advanced Cervical Cancer
Authors: Kunos Charles A. , Waggoner Steven , von Gruenigen Vivian , Eldermire Elisa , Pink John , Dowlati Afshin , Kinsella Timothy J.
Published: February 2010

Purpose: This study assessed the safety/tolerability, pharmacokinetics, and clinical activity of three times weekly i.v. 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in combination with once-weekly i.v. cisplatin and daily pelvic radiation in patients with gynecologic malignancies. 3-AP is a novel small-molecule inhibitor of ribonucleotide reductase (RNR) and is being tested as a potential radiosensitizer and chemosensitizer.

Experimental Design: Patients with stage IB2 to IVB cervical cancer (n = 10) or recurrent uterine sarcoma (n = 1) were assigned to dose-finding cohorts of 2-hour 3-AP infusions during 5 weeks of cisplatin chemoradiation. Pharmacokinetic and methemoglobin samples and tumor biopsy for RNR activity were obtained on day 1 and day 10. Clinical response was assessed.

Results: The maximum tolerated 3-AP dose was 25 mg/m2 given three times weekly during cisplatin and pelvic radiation. Two patients experienced manageable 3-AP–related grade 3 or 4 electrolyte abnormalities. 3-AP pharmacokinetics showed a 2-hour half-life, with median peak plasma concentrations of 277 ng/mL (25 mg/m2) and 467 ng/mL (50 mg/m2). Median methemoglobin levels peaked at 1% (25 mg/m2) and 6% (50 mg/m2) at 4 hours after initiating 3-AP infusions. No change in RNR activity was found on day 1 versus day 10 in six early complete responders, whereas elevated RNR activity was seen on day 10 as compared with day 1 in four late complete responders (P = 0.02). Ten (100%) patients with stage IB2 to IVB cervical cancer achieved complete clinical response and remained without disease relapse with a median 18 months of follow-up (6-32 months).

Conclusions: 3-AP was well tolerated at a three times weekly i.v. 25 mg/m2 dose during cisplatin and pelvic radiation. Clin Cancer Res; 16(4); 1298–306
Blockade of the Extracellular Signal-Regulated Kinase Pathway Enhances the Therapeutic Efficacy of Microtubule-Destabilizing Agents in Human Tumor Xenograft Models
Authors: Watanabe Kazushi , Tanimura Susumu , Uchiyama Aya , Sakamoto Toshiaki , Kawabata Takumi , Ozaki Kei-ichi , Kohno Michiaki
Published: February 2010

Purpose: The extracellular signal-regulated kinase (ERK) pathway is upregulated in human cancers and represents a target for mechanism-based approaches to cancer treatment. However, specific blockade of the ERK pathway alone induces mostly cytostatic rather than proapoptotic effects, resulting in a limited therapeutic efficacy of inhibitors that target the mitogen-activated protein kinase/ERK kinase (MEK). Given the cytoprotective role of the ERK pathway, we examined whether its blockade by the MEK inhibitor PD184352 might enhance the therapeutic efficacy of anticancer drugs in human tumor xenograft models.

Experimental Design: We recently showed that blockade of the ERK pathway by MEK inhibitors enhances the induction of apoptosis by microtubule-destabilizing agents, including TZT-1027 and vinorelbine, in various tumor cells with aberrant activation of the ERK pathway in vitro. We here examined the therapeutic efficacy of the combination of PD184352 with TZT-1027 or vinorelbine in nude mice harboring HT-29 or HT1080 tumor xenografts, in which the ERK pathway is activated as a result of mutations of BRAF and NRAS, respectively.

Results: Coadministration of PD184352 markedly sensitized HT-29 or HT1080 tumor xenografts to TZT-1027–induced or vinorelbine-induced cytotoxicity. Low doses of TZT-1027 or vinorelbine that by themselves showed little or moderate cytotoxicity thus suppressed the growth of HT-29 xenografts almost completely and induced essentially complete regression of HT1080 xenografts when administered with PD184352. The enhanced therapeutic efficacy of the drug combinations was achieved by a relatively transient blockade of the ERK pathway.

Conclusions: Administration of both a MEK inhibitor and a microtubule-destabilizing agent represents a promising chemotherapeutic strategy with improved safety for cancer patients. Clin Cancer Res; 16(4); 1170–8
Potential Clinical Significance of a Plasma-Based KRAS Mutation Analysis in Patients with Advanced Non–Small Cell Lung Cancer
Authors: Wang Shuhang , An Tongtong , Wang Jie , Zhao Jun , Wang Zhijie , Zhuo Minglei , Bai Hua , Yang Lu , Zhang Yan , Wang Xin , Duan Jianchun , Wang Yuyan , Guo Qingzhi , Wu Meina
Published: February 2010

Purpose: Non–small cell lung cancer (NSCLC) with KRAS mutation may be resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). This study aims to evaluate a plasma-based KRAS mutation analysis and the clinical significance of plasma KRAS mutation as a predictive marker for tumor resistance to EGFR-TKIs in patients with NSCLC.

Experimental Design: DNA extracted from plasma and matched tumor tissues were obtained from 273 patients with advanced stage NSCLC. Patients were followed up prospectively for treatment outcomes. KRAS mutations in codon 12 and 13 were detected using PCR-restriction fragment length polymorphism. Mutations in plasma and matched tumors were compared. Associations between KRAS mutation status and patients' clinical outcomes were analyzed.

Results: KRAS mutation was found in 35 (12.8%) plasma samples and 30 (11.0%) matched tumor tissues. The consistency of KRAS mutations between plasma and tumors is 76.7% (23 of 30; κ = 0.668; P < 0.001). Among 120 patients who received EGFR-TKI treatment, the response rate was only 5.3% (1 of 19) for patients with plasma KRAS mutation compared with 29.7% for patients with no KRAS mutation in plasma DNA (P = 0.024). The median progression-free survival time of patients with plasma KRAS mutation was 2.5 months compared with 8.8 months for patients with wild-type KRAS (P < 0.001).

Conclusions: KRAS mutation in plasma DNA correlates with the mutation status in the matched tumor tissues of patients with NSCLC. Plasma KRAS mutation status is associated with a poor tumor response to EGFR-TKIs in NSCLC patients and may be used as a predictive marker in selecting patients for such treatment. Clin Cancer Res; 16(4); 1324–30
Phase I Oncology Studies: Evidence That in the Era of Targeted Therapies Patients on Lower Doses Do Not Fare Worse
Authors: Jain Rajul K. , Lee J. Jack , Hong David , Markman Maurie , Gong Jing , Naing Aung , Wheler Jennifer , Kurzrock Razelle
Published: February 2010

Purpose: To safely assess new drugs, cancer patients in initial cohorts of phase I oncology studies receive low drug doses. Doses are successively increased until the maximum tolerated dose (MTD) is determined. Because traditional chemotherapy is often more effective near the MTD, ethical concerns have been raised about administration of low drug doses to phase I patients. However, a substantial portion of oncology trials now investigate targeted agents, which may have different dose-response relationships than cytotoxic chemotherapies.

Experimental Design: Twenty-four consecutive trials treating 683 patients between October 1, 2004, and June 30, 2008, at MD Anderson Cancer Center were analyzed. Patients were assigned to a low-dose (≤25% MTD), medium-dose (25-75% MTD), or high-dose (≥75% MTD) group, and groups were compared for response rate, time-to-treatment failure, progression-free survival, overall survival, and toxicity. To remove negatively biasing data from the high-dose group, in a second analysis, patients treated above the MTD were excluded (high-dose group, 75-100% MTD). Of the 683 patients, 97.7% received targeted agents.

Results: Even when excluding patients above the MTD, there was an early trend favoring the low- versus high-dose group in time-to-treatment failure, with 32.9% versus 25.2% of patients on therapy at 3 months (P = 0.08). In addition, the low-dose group fared at least as well as the other groups in all other outcomes, including response rate, progression-free survival, overall survival, and toxicity.

Conclusions: These data may help alleviate concerns that patients who receive low drug doses on contemporary phase I oncology trials fare worse and suggest targeted agents may have different dose-response relationships than cytotoxic chemotherapies. Clin Cancer Res; 16(4); 1289–97
Targeting the Cytoprotective Chaperone, Clusterin, for Treatment of Advanced Cancer
Authors: Zoubeidi Amina , Chi Kim , Gleave Martin
Published: February 2010

Many strategies used to kill cancer cells induce stress-responses that activate survival pathways to promote emergence of a treatment resistant phenotype. Secretory clusterin (sCLU) is a stress-activated cytoprotective chaperone up-regulated by many varied anticancer therapies to confer treatment resistance when overexpressed. sCLU levels are increased in several treatment recurrent cancers including castrate resistant prostate cancer, and therefore sCLU has become an attractive target in cancer therapy. sCLU is not druggable with small molecule inhibitors, therefore nucleotide-based strategies to inhibit sCLU at the RNA level are appealing. Preclinical studies have shown that antisense oligonucleotide (ASO) or siRNA knockdown of sCLU have preclinical activity in combination with hormone- and chemotherapy. Phase I and II clinical trial data indicate that the second generation ASO, custirsen (OGX-011), has biologic and clinical activity, suppressing sCLU expression in prostate cancer tissues by more than 90%. A randomized study comparing docetaxel-custirsen to docetaxel alone in men with castrate resistant prostate cancer reported improved survival by 7 months from 16.9 to 23.8 months. Strong preclinical and clinical proof-of-principle data provide rationale for further study of sCLU inhibitors in randomized phase III trials, which are planned to begin in 2010. Clin Cancer Res; 16(4); 1088–93
Proanthocyanidins Inhibit In vitro and In vivo Growth of Human Non–Small Cell Lung Cancer Cells by Inhibiting the Prostaglandin E2 and Prostaglandin E2 Receptors
Authors: Sharma Som D. , Meeran Syed M. , Katiyar Santosh K.
Published: February 2010

Overexpression of cyclooxygenase-2 (COX-2) and prostaglandins (PG) is linked to a wide variety of human cancers. Here, we assessed whether the chemotherapeutic effect of grape seed proanthocyanidins (GSP) on non–small cell lung cancer (NSCLC) cells is mediated through the inhibition of COX-2 and PGE2/PGE2 receptor expression. The effects of GSPs on human NSCLC cell lines in terms of proliferation, apoptosis, and expression of COX-2, PGE2, and PGE2 receptors were determined using Western blotting, fluorescence-activated cell sorting analysis, and reverse transcription-PCR. In vitro treatment of NSCLC cells (A549, H1299, H460, H226, and H157) with GSPs resulted in significant growth inhibition and induction of apoptosis, which were associated with the inhibitory effects of GSPs on the overexpression of COX-2, PGE2, and PGE2 receptors (EP1 and EP4) in these cells. Treatment of cells with indomethacin, a pan-COX inhibitor, or transient transfection of cells with COX-2 small interfering RNA, also inhibited cell growth and induced cell death. The effects of a GSP-supplemented AIN76A control diet fed to nude mice bearing tumor xenografts on the expression of COX-2, PGE2, and PGE2 receptors in the xenografts were also evaluated. The growth-inhibitory effect of dietary GSPs (0.5%, w/w) on the NSCLC xenograft tumors was associated with the inhibition of COX-2, PGE2, and PGE2 receptors (EP1, EP3, and EP4) in tumors. This preclinical study provides evidence that the chemotherapeutic effect of GSPs on lung cancer cells in vitro and in vivo is mediated, at least in part, through the inhibition of COX-2 expression and subsequently the inhibition of PGE2 and PGE2 receptors. Mol Cancer Ther; 9(3); 569–80
Repression of Human Telomerase Reverse Transcriptase Using Artificial Zinc Finger Transcription Factors
Authors: Sohn Joon Hyung , Yeh Byung-Il , Choi Jong-Whan , Yoon Joonho , Namkung Jun , Park Kwang-Kyun , Kim Hyun-Won
Published: February 2010

Telomerase activation is a key step in the development of human cancers. Expression of the catalytic subunit, human telomerase reverse transcriptase (hTERT), represents the limiting factor for telomerase activity. In this study, we have used artificial zinc finger protein (ZFP) transcription factors (TF) to repress the expression of hTERT in human cancer cell lines at the transcriptional level. We have constructed four-fingered ZFPs derived from the human genome which binds 12-bp recognition sequences within the promoter of the hTERT gene and fused them with a KRAB repressor domain to create a potent transcriptional repressor. Luciferase activity was decreased by >80% in all of the transcriptional repressors with luciferase reporter assay. When they were transfected into the telomerase-positive HEK293 cell line, a decrease of mRNA level and telomerase activity together with shortening of telomere length was observed. Actual growth of HEK293 cells was also inhibited by transfection of artificial ZFP-TFs. The repression was maintained for 100 days of culture. The repression of telomerase expression by artificial ZFP-TFs targeting the promoter region of the hTERT presents a new promising strategy for inhibiting the growth of human cancer cells. Mol Cancer Res; 8(2); 246–53
Sec5 and Exo84 Foster Oncogenic Ras-Mediated Tumorigenesis
Authors: Issaq Sameer H. , Lim Kian-Huat , Counter Christopher M.
Published: February 2010

The genes encoding the Ras family of small GTPases are mutated to yield constitutively active GTP-bound oncogenic proteins in one third of all human cancers. Oncogenic Ras binds to and activates a number of proteins that promote tumorigenic phenotypes, including the family of Ral guanine nucleotide exchange factors (RalGEF). Activated RalGEFs convert the Ral family of small GTPases, composed of RalA and RalB, from an inactive GDP-bound state to an active GTP-bound state. As both RalA and RalB have been implicated in a variety of tumorigenic phenotypes, we sought to determine which proteins downstream of Rals promote transformation and tumorigenesis. Here, we report that shRNA-mediated knockdown of the Ral effector proteins Sec5 and Exo84, but less so in the case of RalBP1, reduced oncogenic RalGEF-mediated transformation and oncogenic Ras-driven tumorigenic growth of human cells. These results suggest that Rals promote oncogenic Ras-mediated tumorigenesis through, at least in part, Sec5 and Exo84. Mol Cancer Res; 8(2); 223–31
Sustained c-Jun-NH2-Kinase Activity Promotes Epithelial-Mesenchymal Transition, Invasion, and Survival of Breast Cancer Cells by Regulating Extracellular Signal-Regulated Kinase Activation
Authors: Wang Jinhua , Kuiatse Isere , Lee Adrian V. , Pan Jingxuan , Giuliano Armando , Cui Xiaojiang
Published: February 2010

The c-Jun NH2-terminus kinase (JNK) mediates stress-induced apoptosis and the cytotoxic effect of anticancer therapies. Paradoxically, recent clinical studies indicate that elevated JNK activity in human breast cancer is associated with poor prognosis. Here, we show that overexpression of a constitutively active JNK in human breast cancer cells did not cause apoptosis, but actually induced cell migration and invasion, a morphologic change associated with epithelial-mesenchymal transition (EMT), expression of mesenchymal-specific markers vimentin and fibronectin, and activity of activator protein transcription factors. Supporting this observation, mouse mammary tumor cells that have undergone EMT showed upregulated JNK activity, and the EMT was reversed by JNK inhibition. Sustained JNK activity enhanced insulin receptor substrate-2–mediated ERK activation, which in turn increased c-Fos expression and activator protein activity. In addition, hyperactive JNK attenuated the apoptosis of breast cancer cells treated by the chemotherapy drug paclitaxel, which is in contrast to the requirement for inducible JNK activity in response to cytotoxic chemotherapy. Blockade of extracellular signal-regulated kinase activity diminished hyperactive JNK-induced cell invasion and survival. Our data suggest that the role of JNK changes when its activity is elevated persistently above the basal levels associated with cell apoptosis, and that JNK activation may serve as a marker of breast cancer progression and resistance to cytotoxic drugs. Mol Cancer Res; 8(2); 266–77
Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer
Authors: Mudduluru Giridhar , Vajkoczy Peter , Allgayer Heike
Published: February 2010

Myeloid zinc finger 1 (MZF1) is a member of the SCAN domain family transcription factors that form dimers through their highly conserved SCAN motifs. Silencing of MZF1 inhibits cell proliferation, and abnormal expression of MZF1 results in cancer development. However, a potential role of MZF1 in metastasis remains unclear. Axl is a receptor tyrosine kinase and was first identified as a transforming gene in chronic myeloid leukemia. Axl overexpression induces proliferation, migration, and invasion and is highly expressed in different human cancers. In this study, we show that overexpression of MZF1 induces migration and invasion in colorectal (Rko, SW480) and cervical (HeLa) cancer cells. In addition, we show that MZF1 binds to the Axl promoter, transactivates promoter activity, and enhances Axl-mRNA and protein expression in a dose-dependent manner. In vitro, sh-RNA knockdown of Axl reduced MZF1-induced migration and invasion in HeLa and Rko cells (P = 0.05). Additionally, Rko cells overexpressing MZF1 showed increased tumor formation and liver metastasis in the chicken-embryo-metastasis assay in vivo. Furthermore, the expression of MZF1 and Axl was significantly higher in resected colorectal tumors compared with corresponding normal tissues (P = 0.02; P = 0.05), and MZF1 expression was positively correlated with Axl gene expression in tumor tissues (P < 0.01). Taken together, this is the first study to show that MZF1 induces invasion and in vivo metastasis in colorectal and cervical cancer, at least in part by regulating Axl gene expression. Mol Cancer Res; 8(2); 159–69.
Targeted Drug Delivery to Hepatocarcinoma In vivo by Phage-Displayed Specific Binding Peptide
Authors: Du Bing , Han Honghui , Wang Ziqiang , Kuang Lisha , Wang Lei , Yu Liping , Wu Miao , Zhou Zhongliang , Qian Min
Published: February 2010

Hepatocellular carcinoma is one of the deadliest cancers in the world. In this study, a hepatocarcinoma-specific binding peptide, which could be used for drug delivery in targeting therapy, was obtained by in vivo phage display technology. After three rounds of panning, only the potential motif Pro-Ser was found in 80 sequenced phage clones. Phage A54 (sequence AGKGTPSLETTP) was shown to be the most effective and specific to the liver cancer cells by cell-based ELISA in all 130 tested clones. After phage A54 was injected i.v. into the xenograft-bearing mice for in vivo distribution, phage enrichment was found in tumor tissues compared with control phage C10 and normal liver tissues through phage titering and immunohistochemical staining. Next, the specific binding ability of synthesized peptide A54 was further confirmed by fluorescence microscopy, competition binding, and fluorescence-activated cell sorting assay. A54 and A54M (sequence AGKGTAALETTP) were synthesized and coupled to doxorubicin (DOX) to do the preliminary targeting therapy. After the treatment, the proliferation of liver cancer cells treated with A54-DOX was restrained significantly in vitro when compared with A54M-DOX–treated group. Reduction in tumor size and prolongation of long-term survival were also found in xenograft-bearing models compared with free DOX–treated group. In conclusion, the specific binding peptide A54, which was screened from phage display library, represents a promising approach for the development of novel target therapy strategies against hepatocellular carcinoma. Mol Cancer Res; 8(2); 135–44
Differential Inhibition of Protein Translation Machinery by Curcumin in Normal, Immortalized, and Malignant Oral Epithelial Cells
Authors: Chakravarti Nitin , Kadara Humam , Yoon Do-Jun , Shay Jerry W. , Myers Jeffrey N. , Lotan Dafna , Sonenberg Nahum , Lotan Reuben
Published: February 2010

Curcumin has shown some promise in the prevention of oral carcinogenesis by mechanism(s) that are still not completely resolved. Messenger RNA translation is mediated in eukaryotes by the eIF4F complex composed of eukaryotic translation initiation factors eIF4E, eIF4G, and eIF4A. Overexpression of some of these components or the inactivation of initiation repressor proteins (4E-BP1) has been implicated in cancer development including oral carcinogenesis by affecting cell survival, angiogenesis, and tumor growth and invasion. In this study, we examined the possibility that curcumin affects the translational machinery differently in normal, immortalized normal, leukoplakia, and malignant cells. Curcumin treatment in vitro inhibited the growth of immortalized oral mucosa epithelial cells (NOM9-CT) and the leukoplakia cells (MSK-Leuk1s) as well as in the UMSCC22B and SCC4 cells derived from head and neck squamous cell carcinoma. Curcumin only exerted minor effects on the growth of normal oral epithelial cells (NOM9). In the immortalized, leukoplakia, and cancer cells, curcumin inhibited cap-dependent translation by suppressing the phosphorylation of 4E-BP1, eIF4G, eIF4B, and Mnk1, and also reduced the total levels of eIF4E and Mnk1. Our findings show that immortalized normal, leukoplakia, and malignant oral cells are more sensitive to curcumin and show greater modulation of protein translation machinery than the normal oral cells, indicating that targeting this process may be an important approach to chemoprevention in general and for curcumin in particular. Cancer Prev Res; 3(3); 331–8
RAGE Does Not Affect Amyloid Pathology in Transgenic ArcAβ Mice
Authors: Vodopivec Ivana , Galichet Arnaud , Knobloch Marlen , Bierhaus Angelika , Heizmann Claus W. , Nitsch Roger M.
Published: February 2010

Background: Alzheimer’s disease (AD) is characterized by brain accumulation of the amyloid-β peptide (Aβ) that triggers a cascade of biochemical and cellular alterations resulting in the clinical phenotype of the disease. While numerous experiments addressed Aβ toxicity, the mechanisms are still not fully understood. The receptor for advanced glycation end products (RAGE) binds Aβ and was suggested to be involved in the pathological processes of AD. Objective: Our purpose was to assess the effect of RAGE deletion on Aβ-related pathology. Methods: We crossed RAGE knockout (RAGE–/–) mice with transgenic mice harboring both the Swedish and Arctic Aβ precursor protein mutations (arcAβ mice). We assessed Aβ levels, Aβ brain deposition, Aβ-degrading enzyme activities, Aβ precursor protein expression and processing, number and morphology of microglia as well as cognitive performance of 6- and 12-month-old RAGE–/–/arcAβ, RAGE–/–, arcAβ and wild-type mice. Results: RAGE–/–/arcAβ mice had significantly lower levels of SDS- and formic-acid-extracted Aβ in the cortex and hippocampus, with concomitantly increased activity of insulin-degrading enzyme at the age of 6 months. However, RAGE deletion could neither prevent the decline in cognitive performance nor the age-related cerebral accumulation of Aβ peptide. Furthermore, histological analysis revealed no difference in the microglia-occupied brain areas or microglial morphologies between RAGE–/–/arcAβ and arcAβ mice. Conclusions: Together, our results indicate that while the absence of RAGE was associated with increased insulin-degrading enzyme activity in the brain, it was not sufficient to prevent or ameliorate cognitive deterioration, Aβ accumulation and microglial activation in the arcAβ mouse model of AD.
Cutaneous Richter’s Syndrome, Prognosis, and Clinical, Histological and Immunohistological Patterns: Report of Four Cases and Review of the Literature
Authors: Duong T. , Grange F. , Auffret N. , Aractingi S. , Bodemer C. , Brousse N. , Hermine O. , Fraitag S.
Published: February 2010

Background: Richter’s syndrome (RS) corresponds to the transformation of chronic lymphocytic leukemia (CLL) into high-grade lymphoma. RS can involve extranodal sites including the gastrointestinal tract, lungs and skin. Cutaneous RS is rare, we describe 4 cases with clinical manifestations, histological and immunohistological patterns, and outcome. Methods: Clinical data were analyzed and all patients’ skin biopsy samples stained with HE for the CD20, CD5, CD3 and CD30 antigens. Epstein-Barr-virus (EBV)-encoded early RNA and clonal rearrangements were also analyzed. Results: The patients’ mean age at CLL diagnosis was 57 years (53–62 years), with a male/female sex ratio of 3:1. The transformation to cutaneous RS occurred between 8 and 75 months after initial diagnosis and progressed to a fatal systemic disease in 3 cases, between 24 and 129 months. Cutaneous CLL was associated with earlier transformation in our series and could not be distinguished from RS on clinical grounds alone. All patients had a large-cell infiltrate and clonal rearrangements. Conclusions: The precise mechanism of RS is unclear, but a role of EBV has been suggested in fludarabine-treated CLL. For all our patients, the diagnosis of transformation was made on the basis of cutaneous localizations and led to intensified CLL treatment.
Ethnic Variations in Dementia: The Contributions of Cardiovascular, Psychosocial and Neuropsychological Factors
Authors: Ng Tze Pin , Leong Terence , Chiam Peak Chiang , Kua Ee-Heok
Published: February 2010

Background: Ethnic variations in dementia rate have been reported worldwide. Understanding these differences is vital for aetiological research, clinical care and health service planning. While age and gender have been consistently implicated, the reasons behind interethnic variation remain unclear. Method: We used data from the Singapore National Mental Health Survey (Elderly) in 2003, a cross-sectional population-based study to investigate the extent to which differences in cardiovascular risk factors, psychosocial factors and cognitive functional status contributed to ethnic differences in dementia prevalence among Chinese, Malays and Indians. Results: Ethnic differences in dementia prevalence (4.2% in Chinese, 9.4% in Malays and 8.8% in Indians) were not explained by differences in gender, age and education (Malays vs. Chinese: adjusted OR = 3.11; Indians vs. Chinese: OR = 4.30). Differences in cardiovascular factors, depression or leisure time activities contributed modestly to the differences, but the OR remained significantly elevated. Differences in Mini-Mental State Examination scores contributed the most to explaining the ethnic differences (Malays vs. Chinese: adjusted OR = 0.73; Indians vs. Chinese: OR = 1.18). Conclusion: Cognitive functional reserve accounted for much of the ethnic differences in dementia prevalence and its assessment has implications for the detection and treatment of dementia in multiethnic populations.
Attention Network Functioning in Patients with Dementia with Lewy Bodies and Alzheimer’s Disease
Authors: Fuentes Luis J. , Fernández Pedro J. , Campoy Guillermo , Antequera Martirio M. , García-Sevilla Julia , Antúnez Carmen
Published: February 2010

Background: Attention deficits are at the core of the defects in neuropsychological performance which define both dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). Most studies have used separate tasks to test different attention abilities in patients with these diagnoses, precluding the assessment of any interaction among the different attention components. Methods: We used a version of the Attention Network Test in which the alerting, orienting and executive attention networks, along with their interactions, could be assessed with a single task. Three groups of participants were tested: DLB patients (n = 13), AD patients (n = 18) and healthy controls (n = 18). Results: The alerting signal improved orienting attention and increased the conflict effect in the healthy controls, but they had no effect on these networks in the AD patients. The DLB patients only showed preserved orienting and conflict effects when the alerting signal was present, indicating that there was regulation of the orienting and executive attention networks by the alerting signal. Conclusions: The most important differences among the 3 groups were observed in the attention network interactions, where alerting played a more relevant role in the DLB than in the AD patients. Under alerting states, the DLB patients showed evidence of certain regulation in the orienting and executive attention networks.
Neuroprotection in Diabetic Encephalopathy
Authors: Fazeli Seyyed Amirhossein
Published: February 2010

Increasing evidence has shown that diabetes may be associated with learning and memory deficits in humans. These cognitive disorders, called ‘diabetic encephalopathy’, can impair the daily performance of diabetic individuals. In recent years, some neuroprotective measures have been proposed to prevent diabetic neuropathology. This review attempts to show a summary of different experimental measures that have been described to improve the burden of diabetes in the central nervous system, particularly hippocampal formation.
Macronutrient Intake and Metabolic Syndrome in Subjects at High Cardiovascular Risk
Authors: Cabello-Saavedra Elizabeth , Bes-Rastrollo Maira , Martínez Jose Alfredo , Diez-Espino Javier , Buil-Cosiales Pilar , Serrano-Martinez Manuel , Martinez-Gonzalez Miguel Angel
Published: February 2010

Background: The effect of macronutrient intake on the metabolic syndrome (MS) is still controversial. Our aim in this study was to assess the relationships between macronutrient intake and the risk of developing the MS in subjects at high cardiovascular risk. Methods: In this cross-sectional study, 967 high-risk men and women (55–80 years) were assessed according to the MS criteria defined by the National Cholesterol Education Program Adult Treatment Panel III (ATP3) and those established by the International Diabetes Federation (IDF). A 137-item validated food frequency questionnaire was used. Odds ratios (OR) for macronutrient intake and MS were calculated and adjustments were made for potential confounders. Results: When applying the ATP3 criteria, an inverse association was found for fiber and polyunsaturated fatty acid (PUFAs) intake, with ORs of 0.55 (95% CI: 0.35–0.86) and 0.60 (95% CI: 0.39–0.94), respectively, for the 5th versus the 1st quintile. Using the IDF criteria, an inverse association between fiber intake and the MS was obtained whereas a direct association was found between carbohydrate intake and the MS: OR = 1.71 (95% CI: 1.05–2.79) for the highest versus the lowest quintile. Conclusions: A diet rich in fiber and PUFAs is correlated with a reduced risk of MS in subjects at high cardiovascular risk.
Injectable Hydrogel Helps Bone Marrow-Derived Mononuclear Cells Restore Infarcted Myocardium
Authors: Li Xiao-Yan , Wang Tao , Jiang Xue-Jun , Lin Tao , Wu De-Qun , Zhang Xian-Zheng , Okello Emmy , Xu Hong-Xin , Yuan Ming-Jie
Published: February 2010

Backgrounds: Experimental and clinical studies have suggested that cell implantation could improve cardiac function after myocardial infarction (MI). However, this technique was limited by decreased engraftment and survival of transplanted cells within the ischemic tissue. The present study was performed to investigate whether implantation of bone marrow-derived mononuclear cells (BMMNCs) encapsulated in hydrogel could increase cell engraftment and help to restore cardiac function of MI rabbits. Methods: MI was induced in rabbits by coronary artery ligation. One week later, cell culture medium, Dex-PCL-HEMA/PNIPAAm hydrogel, BMMNCs in medium or BMMNCs in hydrogel were injected into the infarcted area of the left ventricle (LV). Results: Increased cell engraftment was observed 48 h after injection when cells were encapsulated in hydrogel; 30 days after treatment, echocardiographic studies showed that injection of BMMNCs in hydrogel preserved LV ejection fraction and attenuated LV dilatation compared with other groups. Histological analysis indicated that injection of BMMNCs in hydrogel enhanced neovascular formation and prevented scar expansion compared with the other groups. Conclusion: Injection of hydrogel-encapsulated BMMNCs increased cell engraftment and improved LV function; this technique may serve as an effective approach to restore infarcted myocardium.
Distribution of Core Fragments from the Major Cat Allergen Fel d 1 Is Maintained among the Main Anatomical Sites of Production
Authors: Bienboire-Frosini Cécile , Lebrun Régine , Vervloet Daniel , Pageat Patrick , Ronin Catherine
Published: February 2010

Background: Polymorphism of Fel d 1 has long been observed, but structural characterization of Fel d 1 variants among the various sites of production and animals is still missing. This study was aimed at elucidating the structural polymorphism of this protein as a function of the site of production and the resulting influence on the immunological behavior of the allergen. Methods: Fel d 1 was water-extracted from the 4 main sites of production, i.e. cheek zone, interdigital zone, anal sac (AS), and chest area and a panel of 10 cats. Fel d 1-like materials were immunoblotted, immunopurified and characterized by MALDI-TOF MS. Immunoreactivity was studied using ELISA dose-dependent curves at equilibrium. Results: In all areas, 4–10 isoforms ranging from 7 to 40 kDa were detected by MS. Essentially two truncated heterodimers of 13–14 and 16–17 kDa were identified together with intact Fel d 1 in all compartments and they were largely predominant in AS. These core fragments were found to contribute to a variable recognition by antibodies in a panel of ELISA. Conclusions: Our study identified truncated dimers of Fel d 1, probably resulting from proteolytic degradation of both chains and present in all cats. Core fragments are largely distributed among anatomical sites of production and especially well represented in AS. They are recognized as intact allergens by antibodies and may therefore introduce discrepancies in allergen measurement depending on the variable amount of intact and degraded Fel d 1 produced by the cat.
The Effect of Brushing Time and Dentifrice Quantity on Fluoride Delivery in vivo and Enamel Surface Microhardness in situ
Authors: Zero D.T. , Creeth J.E. , Bosma M.L. , Butler A. , Guibert R.G. , Karwal R. , Lynch R.J.M. , Martinez-Mier E.A. , González-Cabezas C. , Kelly S.A.
Published: February 2010

While the clinical anticaries efficacy of fluoride toothpaste is now without question, our understanding of the relation of fluoride efficacy to brushing time and dentifrice quantity is limited. The aim of this in situ study was to determine how differences in brushing time and dentifrice quantity influence (i) fluoride distribution immediately after brushing, (ii) clearance of fluoride in saliva, (iii) enamel fluoride uptake (EFU) and (iv) enamel strengthening, via the increase in surface microhardness. The study compared brushing times of 30, 45, 60, 120 and 180 s with 1.5 g of dentifrice containing 1,100 µg/g fluoride as sodium fluoride. In addition, 60 s of brushing with 0.5 g dentifrice was evaluated. A longer brushing time progressively reduced retention of dentifrice in the brush, thereby increasing the amount delivered into the mouth. A longer brushing time also increased fluoride concentrations in saliva for at least 2 h after the conclusion of brushing, showing that increased contact time promoted fluoride retention in the oral cavity. There was a statistically significant positive linear relationship between brushing time and both enamel strengthening and EFU. Compared to 0.5 g dentifrice, brushing with 1.5 g dentifrice more than doubled the fluoride recovered in saliva after brushing and increased EFU. In conclusion, the results of this preliminary, short-term usage study suggest for the first time that both brushing time and dentifrice quantity may be important determinants both of fluoride retention in the oral cavity and consequent enamel remineralization.
C-Reactive Protein Promotes Cardiac Fibrosis and Inflammation in Angiotensin II–Induced Hypertensive Cardiac Disease
Authors: Zhang Rongxin , Zhang Yuan Yuan , Huang Xiao R. , Wu Yin , Chung Arthur C.K. , Wu Ed Xuekui , Szalai Alexander J. , Wong Benjamin C.Y. , Lau Chu-Pak , Lan Hui Y.
Published: February 2010

C-reactive protein (CRP) is a risk factor or biomarker for cardiovascular diseases, including hypertension. The present study investigated the functional importance of human CRP in hypertensive cardiac remodeling by a chronic infusion of angiotensin II (Ang II) into mice that express human CRP. Compared with the wild-type mice, although Ang II infusion caused an equally high systolic blood pressure, levels of human CRP were further elevated, and cardiac remodeling was markedly exacerbated in mice that express human CRP, resulting in a significant reduction in the left ventricular ejection fraction and fractional shortening and an increase in cardiac fibrosis (collagen I and III and α-smooth muscle actin) and inflammation (interleukin 1β and tumor necrosis factor-α). The enhancement in cardiac remodeling in mice that express human CRP was associated with further upregulation of the Ang II type I receptor and transforming growth factor-β1 and overactivation of both transforming growth factor-β/Smad and nuclear factor-κB signaling pathways. Furthermore, in vitro studies in cardiac fibroblasts revealed that CRP alone was able to significantly induce expression of the Ang II type I receptor, collagen I/III, and α-smooth muscle actin, as well as proinflammation cytokines (interleukin 1β and tumor necrosis factor-α), which was further enhanced by addition of Ang II. In conclusion, CRP is not only a biomarker but also a mediator in Ang II–mediated cardiac remodeling. Enhanced upregulation of the Ang II type I receptor and activation of the transforming growth factor-β/Smad and nuclear factor-κB signaling pathways may be the mechanisms by which CRP promotes cardiac fibrosis and inflammation under high Ang II conditions.
UNEP in Global Environmental Governance: Design, Leadership, Location
Authors: Ivanova Maria
Published: February 2010

As debates on reform of global environmental governance intensify, the future of the United Nations Environment Programme (UNEP) has come into acute political focus. Many argue that the organization has faltered in its role as the UN's leading agency for the environment. In this article, I use historical institutional analysis in combination with current international relations and management theory to explain UNEP's creation and evolution. Having described how the creators of UNEP envisioned the nascent organization, I analyze its subsequent performance, identifying the key factors that have shaped its record. I argue that the original vision for UNEP was ambitious but fundamentally pragmatic, and that the organization's mixed performance over the years can be explained by analysis of three factors: its design, leadership, and location. Thus, this article clarifies the record on UNEP's intended function, and lays the foundation for a systematic methodology for evaluating international organizations.
Preparing for a Warmer World: Towards a Global Governance System to Protect Climate Refugees
Authors: Biermann Frank , Boas Ingrid
Published: February 2010

Climate change threatens to cause the largest refugee crisis in human history. Millions of people, largely in Africa and Asia, might be forced to leave their homes to seek refuge in other places or countries over the course of the century. Yet the current institutions, organizations, and funding mechanisms are not sufficiently equipped to deal with this looming crisis. The situation calls for new governance. We outline and discuss in this article a blueprint for a global governance architecture for the protection and voluntary resettlement of climate refugees—defined as people who have to leave their habitats because of sudden or gradual alterations in their natural environment related to one of three impacts of climate change: sea-level rise, extreme weather events, and drought and water scarcity. We provide an extensive review of current estimates of likely numbers and probable regions of origin of climate refugees. With a view to existing institutions, we argue against the extension of the definition of refugees under the 1951 Geneva Convention Relating to the Status of Refugees. Key elements of our proposal are, instead, a new legal instrument specifically tailored for the needs of climate refugees—a Protocol on Recognition, Protection, and Resettlement of Climate Refugees to the United Nations Framework Convention on Climate Change—as well as a separate funding mechanism.
Cue Competition Affects Temporal Dynamics of Edge-assignment in Human Visual Cortex
Authors: Brooks Joseph L. , Palmer Stephen E.
Published: February 2010

Edge-assignment determines the perception of relative depth across an edge and the shape of the closer side. Many cues determine edge-assignment, but relatively little is known about the neural mechanisms involved in combining these cues. Here, we manipulated extremal edge and attention cues to bias edge-assignment such that these two cues either cooperated or competed. To index their neural representations, we flickered figure and ground regions at different frequencies and measured the corresponding steady-state visual-evoked potentials (SSVEPs). Figural regions had stronger SSVEP responses than ground regions, independent of whether they were attended or unattended. In addition, competition and cooperation between the two edge-assignment cues significantly affected the temporal dynamics of edge-assignment processes. The figural SSVEP response peaked earlier when the cues causing it cooperated than when they competed, but sustained edge-assignment effects were equivalent for cooperating and competing cues, consistent with a winner-take-all outcome. These results provide physiological evidence that figure–ground organization involves competitive processes that can affect the latency of figural assignment.
Early Stages of Figure–Ground Segregation during Perception of the Face–Vase
Authors: Pitts Michael A. , Martínez Antígona , Brewer James B. , Hillyard Steven A.
Published: February 2010

The temporal sequence of neural processes supporting figure–ground perception was investigated by recording ERPs associated with subjects' perceptions of the face–vase figure. In Experiment 1, subjects continuously reported whether they perceived the face or the vase as the foreground figure by pressing one of two buttons. Each button press triggered a probe flash to the face region, the vase region, or the borders between the two. The N170/vertex positive potential (VPP) component of the ERP elicited by probes to the face region was larger when subjects perceived the faces as figure. Preceding the N170/VPP, two additional components were identified. First, when the borders were probed, ERPs differed in amplitude as early as 110 msec after probe onset depending on subjects' figure–ground perceptions. Second, when the face or vase regions were probed, ERPs were more positive (at ∼150–200 msec) when that region was perceived as figure versus background. These components likely reflect an early “border ownership” stage, and a subsequent “figure–ground segregation” stage of processing. To explore the influence of attention on these stages of processing, two additional experiments were conducted. In Experiment 2, subjects selectively attended to the face or vase region, and the same early ERP components were again produced. In Experiment 3, subjects performed an identical selective attention task, but on a display lacking distinctive figure–ground borders, and neither of the early components were produced. Results from these experiments suggest sequential stages of processing underlying figure–ground perception, each which are subject to modifications by selective attention.
Assembly and Use of New Task Rules in Fronto-parietal Cortex
Authors: Dumontheil Iroise , Thompson Russell , Duncan John
Published: February 2010

Severe capacity limits, closely associated with fluid intelligence, arise in learning and use of new task rules. We used fMRI to investigate these limits in a series of multirule tasks involving different stimuli, rules, and response keys. Data were analyzed both during presentation of instructions and during later task execution. Between tasks, we manipulated the number of rules specified in task instructions, and within tasks, we manipulated the number of rules operative in each trial block. Replicating previous results, rule failures were strongly predicted by fluid intelligence and increased with the number of operative rules. In fMRI data, analyses of the instruction period showed that the bilateral inferior frontal sulcus, intraparietal sulcus, and presupplementary motor area were phasically active with presentation of each new rule. In a broader range of frontal and parietal regions, baseline activity gradually increased as successive rules were instructed. During task performance, we observed contrasting fronto-parietal patterns of sustained (block-related) and transient (trial-related) activity. Block, but not trial, activity showed effects of task complexity. We suggest that, as a new task is learned, a fronto-parietal representation of relevant rules and facts is assembled for future control of behavior. Capacity limits in learning and executing new rules, and their association with fluid intelligence, may be mediated by this load-sensitive fronto-parietal network.
Decreased Visual Attention Further from the Perceived Direction of Gaze for Equidistant Retinal Targets
Authors: Balslev Daniela , Gowen Emma , Miall R. Chris
Published: February 2010

The oculomotor and spatial attention systems are interconnected. Whereas a link between motor commands and spatial shifts in visual attention is demonstrated, it is still unknown whether the recently discovered proprioceptive signal in somatosensory cortex impacts on visual attention, too. This study investigated whether visual targets near the perceived direction of gaze are detected more accurately than targets further away, despite the equal eccentricity of their retinal projections. We dissociated real and perceived eye position using left somatosensory repetitive transcranial magnetic stimulation (rTMS), which decreases cortical processing of eye muscle proprioceptive inflow and produces an underestimation of the rotation of the right eye. Participants detected near-threshold visual targets presented in the left or right visual hemifield at equal distance from fixation. We have previously shown that when the right eye is rotated to the left of the parasagittal plane, TMS produces an underestimation of this rotation, shifting perceived eye position to the right. Here we found that, in this condition, TMS also decreased target detection in the left visual hemifield and increased it in the right. This effect depended on the direction of rotation of the right eye. When the right eye was rotated rightward and TMS, we assume, shifted perceived gaze direction in opposite direction, leftward, visual accuracy decreased now in the right hemifield. We suggest that the proprioceptive eye position signal modulates the spatial distribution of visual processing resources, producing “pseudo-neglect” for objects located far relative to near the perceived direction of gaze.