bluuebunny/crossref_metadata_2025 huggingface dataset:
CCL2 Blockade Augments Cancer Immunotherapy
Authors: Fridlender Zvi G. , Buchlis George , Kapoor Veena , Cheng Guanjun , Sun Jing , Singhal Sunil , Crisanti M. Cecilia , Wang Liang-Chuan S. , Heitjan Daniel , Snyder Linda A. , Albelda Steven M.
Published: December 2009

Altering the immunosuppressive microenvironment that exists within a tumor will likely be necessary for cancer vaccines to trigger an effective antitumor response. Monocyte chemoattractant proteins (such as CCL2) are produced by many tumors and have both direct and indirect immunoinhibitory effects. We hypothesized that CCL2 blockade would reduce immunosuppression and augment vaccine immunotherapy. Anti-murine CCL2/CCL12 monoclonal antibodies were administered in three immunotherapy models: one aimed at the human papillomavirus E7 antigen expressed by a non–small cell lung cancer (NSCLC) line, one targeted to mesothelin expressed by a mesothelioma cell line, and one using an adenovirus-expressing IFN-α to treat a nonimmunogenic NSCLC line. We evaluated the effect of the combination treatment on tumor growth and assessed the mechanism of these changes by evaluating cytotoxic T cells, immunosuppressive cells, and the tumor microenvironment. Administration of anti-CCL2/CCL12 antibodies along with the vaccines markedly augmented efficacy with enhanced reduction in tumor volume and cures of approximately half of the tumors. The combined treatment generated more total intratumoral CD8+ T cells that were more activated and more antitumor antigen–specific, as measured by tetramer evaluation. Another important potential mechanism was reduction in intratumoral T regulatory cells. CCL2 seems to be a key proximal cytokine mediating immunosuppression in tumors. Its blockade augments CD8+ T-cell immune response to tumors elicited by vaccines via multifactorial mechanisms. These observations suggest that combining CCL2 neutralization with vaccines should be considered in future immunotherapy trials. Cancer Res; 70(1); 109–18
OTX2 Is Critical for the Maintenance and Progression of Shh-Independent Medulloblastomas
Authors: Adamson David C. , Shi Qun , Wortham Matthew , Northcott Paul A. , Di Chunhui , Duncan Christopher G. , Li Jianjun , McLendon Roger E. , Bigner Darell D. , Taylor Michael D. , Yan Hai
Published: December 2009

OTX2 is a developmentally regulated transcription factor involved in early morphogenesis of the central nervous system. This gene is amplified and overexpressed in medulloblastoma cell lines, but the nature and extent of its genetic alterations in primary tumors have not been evaluated. Analysis of a large cohort of primary medulloblastomas revealed frequent focal copy number gain of a region minimally containing OTX2 as a single gene. OTX2 copy number gain was restricted to tumor subtypes that did not express a molecular signature of Wnt or Shh pathway activation. FISH analysis revealed copy number gain in a subset of cells within medulloblastoma samples, suggesting a late event in tumor progression. Gain of OTX2 copy number was associated with the presence of anaplastic histologic features and shorter survival in medulloblastoma patients. In support of a functional role, ectopic OTX2 expression enhanced proliferation and tumorigenicity of immortalized primary cells, whereas OTX2 knockdown in medulloblastoma cells prolonged the survival of animals bearing xenograft tumors. Mechanistic investigations revealed upregulation of MYC as a potential mechanism whereby OTX2 promotes tumor progression. Our findings define OTX2 as an important oncogenic driver in medulloblastoma. Cancer Res; 70(1); 181–91
Evaluation of MicroRNA Expression Profiles That May Predict Recurrence of Localized Stage I Non–Small Cell Lung Cancer after Surgical Resection
Authors: Patnaik Santosh K. , Kannisto Eric , Knudsen Steen , Yendamuri Sai
Published: December 2009

Prognostic markers that can predict the relapse of localized non–small cell lung cancer (NSCLC) have yet to be defined. We surveyed expression profiles of microRNA (miRNA) in stage I NSCLC to identify patterns that might predict recurrence after surgical resection of this common deadly cancer. Small RNAs extracted from formalin-fixed and paraffin-embedded tissues were hybridized to locked nucleic acid probes against 752 human miRNAs (representing 82% of the miRNAs in the miRBase 13.0 database) to obtain expression profiles for 37 cases with recurrence and 40 cases without recurrence (with clinical follow-up for at least 32 months). Differential expression between the two case groups was detected for 49% of the miRNAs (Wilcoxon rank sum test; P < 0.01). The performance of expression profiles at differentiating the two case groups was assessed by leave-one-out and Monte Carlo cross-validations. In leave-one-out cross-validation using support vector machines- or top-scoring gene pair classifier methods, which looked for six- or two-miRNA-based classifiers, the identified miRNA expression pattern predicted recurrence with an accuracy of 70% and 83%, and hazard ratio of 3.6 [95% confidence interval (95% CI), 1.8–7.1] and 9.0 (95% CI, 4.4–18.2), respectively. Mean accuracy in Monte Carlo cross-validation using 1,000 random 60–17 splits was 69% (95% CI, 68–70) and 72% (95% CI, 71–72), respectively. The specific miRNAs mir-200b*, mir-30c-1*, mir-510, mir-630, mir-657, and mir-146b-3p and mir-124*, mir-585, and mir-708, respectively, represented most commonly among the 1,000 classifiers identified in Monte Carlo cross-validation by the two methods. MiRNAs mir-488, mir-503, and mir-647 were identified as potential reference miRNAs for future studies, based on the stability of their expression patterns across the 77 cases and the two case-groups. Our findings reinforce efforts to profile miRNA expression patterns for better prognostication of stage I NSCLC. Cancer Res; 70(1); 36–45
Changes in the Mouse Estrus Cycle in Response to Brca1 Inactivation Suggest a Potential Link between Risk Factors for Familial and Sporadic Ovarian Cancer
Authors: Hong Hao , Yen Hai-Yun , Brockmeyer Amy , Liu Ying , Chodankar Rajas , Pike Malcolm C. , Stanczyk Frank Z. , Maxson Robert , Dubeau Louis
Published: December 2009

Menstrual cycle activity is the most important risk factor for sporadic serous ovarian carcinoma, whereas a germ-line mutation in BRCA1 is the most important risk factor for the familial form. Given the rarity of BRCA1 mutations in sporadic ovarian cancers, we hypothesized that BRCA1 influences the menstrual cycle in a way that mimics the factors underlying sporadic ovarian cancer predisposition, making BRCA1 mutations redundant in such cancers. We compared the length of each phase of the estrus cycle (equivalent to the human menstrual cycle) and of circulating levels of estradiol in control mice and in mice carrying a Brca1 mutation in their ovarian granulosa cells, two thirds of which develop ovarian or uterine epithelial tumors. We also compared the length of the different phases of the cycle in mutants that subsequently developed tumors with those in mutants that remained tumor-free. Mutant mice as well as oophorectomized wild-type mice harboring mutant ovarian grafts showed a relative increase in the average length of the proestrus phase of the estrus cycle, which corresponds to the estrogen-dominated follicular phase of the human menstrual cycle. Total circulating levels of estradiol were also increased in mutant mice injected with pregnant mare serum gonadotropins. The relative increase in proestrus length was highest in mutant mice that subsequently developed reproductive epithelial tumors. We conclude that loss of a functional Brca1 increases murine ovarian epithelial tumor predisposition by increasing estrogen stimulation in the absence of progesterone, recapitulating conditions associated with sporadic ovarian cancer predisposition in humans. Cancer Res; 70(1); 221–8
P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 Determine the Pharmacokinetics of Etoposide
Authors: Lagas Jurjen S. , Fan Lin , Wagenaar Els , Vlaming Maria L.H. , van Tellingen Olaf , Beijnen Jos H. , Schinkel Alfred H.
Published: December 2009

Purpose: Despite the extensive use of etoposide for the treatment of different malignant neoplasms, its main pharmacokinetic determinants are not completely defined. We aimed to study the impact of P-glycoprotein (P-gp/ABCB1) and the multidrug resistance proteins ABCC2 (MRP2) and ABCC3 (MRP3) on the pharmacokinetics of etoposide.

Experimental Design: Abcb1a/1b−/−, Abcc2−/−, Abcc3−/−, Abcb1a/1b;Abcc2−/−, and Abcc2;Abcc3−/− mice were used to investigate the separate and combined impact of P-gp, Abcc2, and Abcc3 on the in vivo behavior of etoposide.

Results: P-gp restricted the oral (re)uptake of unchanged etoposide, and mediated its excretion across the gut wall. In contrast, hepatobiliary excretion was almost entirely dependent on Abcc2. Yet, complete loss of Abcc2 did not result in elevated liver or plasma concentrations of etoposide. Instead, Abcc2−/− mice displayed an increased hepatic formation of etoposide glucuronide, which was secreted via Abcc3 from the liver to the blood circulation and eliminated with the urine. Combination Abcc2;Abcc3−/− mice had highly increased accumulation of etoposide glucuronide in their livers, whereas both single knockouts did not, indicating that Abcc2 and Abcc3 provide alternative pathways for the hepatic elimination of etoposide glucuronide.

Conclusions: P-gp, ABCC2, and ABCC3 significantly affect the pharmacokinetics of etoposide and/or etoposide glucuronide. Variation in transporter expression or activity may explain the high variation in oral availability of etoposide (25-80%) among cancer patients. However, despite the fact that substantial variations in transporter activity can occur, we believe that cancer patients are often relatively protected from etoposide toxicity due to overlapping functions of these transporters in the elimination of etoposide. Clin Cancer Res; 16(1); 130–40
Activation of WD Repeat and High-Mobility Group Box DNA Binding Protein 1 in Pulmonary and Esophageal Carcinogenesis
Authors: Sato Nagato , Koinuma Junkichi , Fujita Masahiro , Hosokawa Masao , Ito Tomoo , Tsuchiya Eiju , Kondo Satoshi , Nakamura Yusuke , Daigo Yataro
Published: December 2009

Purpose: We attempted to identify novel biomarkers and therapeutic targets for lung and esophageal cancers.

Experimental Design: We screened for genes that were overexpressed in a large proportion of lung and esophageal carcinomas using a cDNA microarray representing 27,648 genes or expressed sequence tags. A gene encoding WDHD1, a WD repeat and high-mobility group box DNA binding protein 1, was selected as a candidate. Tumor tissue microarray containing 267 archival non–small cell lung cancers and 283 esophageal squamous cell carcinomas (ESCC) was used to investigate the clinicopathologic significance of WDHD1 expression. The role of WDHD1 in cancer cell growth and/or survival was examined by small interfering RNA experiments and cell growth assays. The mechanism of WDHD1 activation through its phosphorylation in cancer cells was examined by immunoprecipitation and kinase assays.

Results: Positive WDHD1 immunostaining was associated with a poor prognosis for patients with non–small cell lung cancer (P = 0.0403) as well as ESCC (P = 0.0426). Multivariate analysis indicated it to be an independent prognostic factor for ESCC (P = 0.0104). Suppression of WDHD1 expression with small interfering RNAs effectively suppressed lung and esophageal cancer cell growth. In addition, induction of the exogenous expression of WDHD1 promoted the growth of mammalian cells. AKT1 kinase seemed to phosphorylate and stabilize the WDHD1 protein in cancer cells.

Conclusions: WDHD1 expression is likely to play an important role in lung and esophageal carcinogenesis as a cell cycle regulator and a downstream molecule in the phosphoinositide 3-kinase/AKT pathway, and that WDHD1 is a candidate biomarker and a promising therapeutic target for cancer. Clin Cancer Res; 16(1); 226–39
Microarray-Based Response Prediction in Esophageal Adenocarcinoma
Authors: Schauer Matthias , Janssen Klaus-Peter , Rimkus Caroline , Raggi Matthias , Feith Marcus , Friess Helmut , Theisen Joerg
Published: December 2009

Purpose: In locally advanced (uT3, N+) adenocarcinomas of the esophagus, neoadjuvant chemotherapy improves patient outcome. However, only a subgroup of patients responds. Therefore, in the present study, we evaluated whether the response to neoadjuvant chemotherapy can be predicted by a pretreatment tumor biopsy analysis.

Experimental Design: Biopsies of 47 patients with locally advanced (uT3, N+) adenocarcinoma of the esophagus were obtained during primary staging. All patients underwent neoadjuvant chemotherapy with cisplatin, 5-fluorouracil, and leucovorin and subsequent resection of the esophagus. Biopsies were used for microarray analysis. The predominance of tumor cells within the specimens was >70%. Affymetrix U133 plus 2.0 gene chips with 54675 probe sets were used. A statistical comparison of patients responding to chemotherapy versus nonresponding patients was done. All patients were examined with immunohistology against Ephrin B3 receptor and Ki-67.

Results: A total of 86 genes were at least 2-fold differentially regulated comparing responding with nonresponding adenocarcinomas of the esophagus. The predominant genes encoded for the regulation of the cell cycle, transduction, translation, cell-cell interaction, cytoskeleton, and the signal transduction. The strongest difference was seen for the Ephrin B3 receptor. This result could be confirmed by immunhistology. A statistical significant correlation between the Ephrin B3 receptor, chemotherapy response, pathologic staging, and grading could be shown.

Conclusions: There were significant differences in the gene profile between patients with adenocarcinoma of the esophagus responding to neoadjuvant chemotherapy compared with nonresponding patients. This suggests that it could be possible to characterize patients responding to chemotherapy even before starting the treatment using customized microarray analysis. Clin Cancer Res; 16(1); 330–7
Immunotherapy for Human Renal Cell Carcinoma by Adoptive Transfer of Autologous Transforming Growth Factor β–Insensitive CD8+ T Cells
Authors: Wang Longxin , Wen Weihong , Yuan Jianlin , Helfand Brian , Li Yu , Shi Changhong , Tian Feng , Zheng Jia , Wang Fuli , Chen Lin , Liang Lili , Zhou Liqun , Lee Chung , Chen Zhinan , Guo Yinglu , Wang He , Zhang Qiang , Qin Weijun
Published: December 2009

Purpose: Transforming growth factor-β (TGF-β) is a potent immunosuppressor that has been associated with tumor evasion from the host immune surveillance and, thus, tumor progression. We tested a novel immunotherapy for human renal cell cancer (RCC) using a technique that involves the adoptive transfer of autologous tumor–reactive, TGF-β–insensitive CD8+ T cells into human RCC–challenged immunodeficient mice to identify its potent antitumor responses.

Experimental Design: The present study was conducted using a one-to-one adoptive transfer strategy to treat tumor-bearing severe combined immunodeficient (SCID/beige) mouse. The SCID/beige mice were humanized with peripheral blood mononuclear cells from patients with RCC (Hu-PBMC-SCID) before adoptive transfer. Autologous CD8+ T cells were expanded ex vivo using autologous patient's dendritic cells pulsed with the tumor lysate and rendered TGF-β insensitive by dominant-negative TGF-β type II receptor. In addition, human RCC cell lines were generated using patients' tumor cells injected into SCID/beige mice.

Results: Using flow cytometry analysis, we confirmed the expression of the tumor-reactive, TGF-β–insensitive CD8+ T cells were the effector CD8+ cells (CD27−CDRA+). Adoptive transfer of autologous TGF-β–insensitive CD8+ T cells into tumor-bearing Hu-PBMC-SCID mice induced robust tumor-specific CTL responses in vitro, were associated with tumor apoptosis, suppressed lung metastasis, and prolonged survival times in vivo.

Conclusion: The one-to-one adoptive transfer strategy is an ideal in vivo murine model for studying the relationship between TGF-β and immunosurveillance in RCC in vivo. Furthermore, this technique may offer the promise of a novel therapeutic option for the treatment of human patients with RCC. Clin Cancer Res; 16(1); 164–73
Phase 1 Study of Aflibercept Administered Subcutaneously to Patients with Advanced Solid Tumors
Authors: Tew William P. , Gordon Michael , Murren John , Dupont Jakob , Pezzulli Sandra , Aghajanian Carol , Sabbatini Paul , Mendelson David , Schwartz Lawrence , Gettinger Scott , Psyrri Amanda , Cedarbaum Jesse M. , Spriggs David R.
Published: December 2009

Purpose: To determine the maximum tolerated dose or maximal administered dose and pharmacokinetic and safety profiles of s.c. administered vascular endothelial growth factor Trap (aflibercept), a novel antiangiogenic agent.

Experimental Design: In this open-label, dose-escalation study, patients with advanced solid tumors were treated with subcutaneous doses of aflibercept at seven dose levels. Patients received a single dose of aflibercept and then underwent safety and pharmacokinetic assessments over the next 4 weeks. Patients then received weekly or biweekly treatment over the subsequent 6 weeks. Patients tolerating and benefiting could continue on aflibercept at the same dose and schedule until progression of disease.

Results: Thirty-eight patients received at least one dose of aflibercept. Maximum tolerated dose was not reached. Due to solubility/dosing limits with the subcutaneous formulation, 1,600 μg/kg/week was the maximal administered dose. The most common toxicities were proteinuria (37%), fatigue (32%), injection site reactions (18%), nausea (17%), myalgia and anorexia (16% each), hypertension (13%), and voice hoarseness (11%). Drug-related grade 3 to 4 toxicity was uncommon (7%) and reversible: dehydration, cerebral ischemia, proteinuria, hypertension, leukopenia, and pulmonary embolism. We identified dose-proportional increases in plasma concentrations of aflibercept bound to vascular endothelial growth factor with a t1/2 of 18 days. No antiaflibercept antibodies were detected. Stable disease was maintained for at least 10 weeks in 18 patients (47%), and 2 patients maintained on study for >1 year.

Conclusion: Subcutaneous aflibercept was well tolerated and had manageable side effects. Its favorable pharmacokinetic profile and potential antitumor activity warrants further evaluation. Clin Cancer Res; 16(1); 358–366
Evaluating a Marker's Contribution to a Nomogram: The GEMCaP Example
Authors: Kattan Michael W.
Published: December 2009

A postoperative nomogram developed in 1999 by Kattan et al. has been externally validated, but needs improvement. This tool predicts well but not perfectly. The Genomic Evaluators of Metastatic Prostate Cancer (GEMCaP) biomarkers hold promise for improving this tool; however, a larger data set that permits more involved analyses is needed. Clin Cancer Res; 16(1); 1–3
Caspase-4 Activation in Association with Decreased Adenosine Deaminase Activity May Be a Factor for Gastric Ulcer
Authors: Yaguchi Takahiro , Saito Masaru , Yasuda Yoshiyuki , Nishizaki Tomoyuki
Published: December 2009

Background/Aims: Adenosine deaminase (ADA)-deficient disease, a severe combined immunodeficiency, is most commonly associated with gastrointestinal disorders such as ulcer. The present study investigated the role of ADA in the pathogenesis of gastric ulcer. Methods: ADA activity was measured in a variety of organs and tissues from rats and in human gastric biopsy samples from patients who underwent gastrofiberscope. An MTT assay and TUNEL staining were carried out, and activity of caspase-3 and -4 was enzymatically measured in MKN45 human gastric cancer cells. In the Western blot analysis, caspase-4 activation was identified in gastric biopsy samples. Results: In rat organs and tissues, the epithelium of the gastrointestine exhibited higher ADA activity. The ADA inhibitor EHNA reduced cell viability, increased TUNEL-positive cells, and activated caspase-3 and -4 in MKN45 cells. For gastric biopsy samples, much lower ADA activity was found in gastric ulcer tissues, with a tendency of caspase-4 activation. Conclusion: A decline in ADA activity and the ensuing increase in intracellular adenosine concentrations for the stomach could induce gastric epithelial cell apoptosis by activating caspase-4 and the effector caspase-3. This may represent a fresh pathogenetical pathway for gastric ulcer relevant to ADA activity and caspase-4 activation.
The Interaction of the Neuroprotective Compounds Riluzole and Phenobarbital with AMPA-Type Glutamate Receptors: A Patch-Clamp Study
Authors: Jin Ling-Jing , Schlesinger Friedrich , Song Yun-Ping , Dengler Reinhard , Krampfl Klaus
Published: December 2009

Background: Blockade of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors is a promising pharmacological strategy in the treatment of neurodegenerative diseases. The aim of the study is to elucidate if there are direct interactions of riluzole and phenobarbital with AMPA-type receptor channels and to determinethe molecular pharmacological mechanisms. Methods: The patch-clamp technique was used combining an ultrafast solution exchange system to investigate the interaction of riluzole and phenobarbital with recombinant AMPA-type glutamate receptor channels (homomeric GluR2flipGQ or nondesensitizing GluR2L504Y). Results: A dose-dependent decrease in the relative peak current amplitude (rAmp) and the relative area-under-the-current curve (rAUC) were found after preincubation with 0.1 mmol/l or higher concentrations of riluzole. Furthermore, in coapplication experiments with GluR2L504Y, the application of 1 or 3 mmol/l riluzole showed a decrease in the current decay time constant, and a reopening current was observed at 3 mmol/l riluzole. Phenobarbital blocks AMPA receptor channels dose-dependently in the coapplication experiments, and reopening currents after removing glutamate and blocker were observed. A slight block effect after preincubation should indicate an additional competitive block effect. Conclusion: Riluzole and phenobarbital modulate AMPA-type receptor channels separately, which could be both characterized as a combination of open-channel block and competitive-block mechanism.
Identification of Novel in vitro Test Systems for the Determination of Glucocorticoid Receptor Ligand-Induced Skin Atrophy
Authors: Schoepe S. , Schäcke H. , Bernd A. , Zöller N. , Asadullah K.
Published: December 2009

Topical glucocorticoids (GCs) demonstrate good anti-inflammatory effects but are limited by their side effect potential, with skin atrophy being the most prominent one. Thus, determining the atrophogenic potential of novel compounds is important. The aim of this study was to establish an in vitro skin atrophy model. A screening cascade was applied and GCs with a known atrophogenic potential were used as tool compounds. Five rodent and human cutaneous cell types/cell lines and 2 human skin equivalents were tested. Known and suspected atrophy markers related to collagen metabolism and epidermal thickness were measured. Altogether, a combination of 7 different cellular assays with up to 16 markers each were investigated. A reproducible, more than 2-fold, regulation of the candidate markers by dexamethasone or clobetasol was found for: (a) matrix metalloproteinase (MMP) 1, 2, 3 and 9 expression in human keratinocytes, (b) COL1A1 and COL3A1 expression in 3T3 fibroblasts, and (c) epidermal thickness, collagen and MMP synthesis in the full-thickness skin model (FTSM). These 3 models were further investigated with a panel of 4–5 GCs, demonstrating dose dependency and correlation with the atrophogenic potential of the tool compounds, qualifying them as potentially suitable. Finally, the predictability of these models for the in vivo situation was analyzed, testing a novel selective GC receptor agonist (SEGRA) in comparison to clobetasol. The results from the in vitro models suggested less atrophogenic effects for the SEGRA compound, which indeed was confirmed in the hr/hr rat skin atrophy model. In conclusion, a combination of 3 in vitro models based on 3T3 cells, human keratinocytes and FTSM with several readouts is recommended to determine atrophogenicity of GC receptor ligands. Further experiments are necessary to eventually reduce this panel and to demonstrate the true predictability for the clinic.
A Revised Activities of Daily Living/Instrumental Activities of Daily Living Instrument Increases Interpretive Power: Theoretical Application for Functional Tasks Exercise
Authors: Fieo Robert , Watson Roger , Deary Ian J. , Starr John M.
Published: December 2009

Background: As the number of adults in older age groups expands, difficulty performing usual activities of daily life is a rising health concern. A common exercise regimen employed to attenuate functional decline and disability has been resistance strength training. However, recent evidence suggests that functional tasks exercise may be more effective in preventing disability. Objective: Activities of Daily Living (ADL) measures are one of the most widely used tools in gerontology, and yet the full sensitivity of these instruments is often not realized. The purpose of this study is to enhance the interpretive power of ADL by formally confirming a hierarchy of decline, assessing discriminatory power, and examining option characteristic curves. Theoretically, a revised ADL instrument can improve the efficacy of functional tasks training programs. Methods: This was a cross-sectional study that employed Item Response Theory (IRT) to interpret ADL outcomes. Participants consisted of community-dwelling older adults (n = 548, aged 79) living in Scotland. Results: A Mokken scale with ρ = 0.77 was obtained, indicating good reliability, and satisfying the IRT assumption that a single unidimensional scale is present. The set H coefficient of 0.48 indicated that the scale may be ordered by decreasing difficulty, with the ‘Cut your own toe-nails?’ item being the most difficult and ‘Tie a good knot in a piece of string?’ being the least difficult. Discriminatory and option characteristic parameters revealed ‘Get on a bus?’ to be the task most closely related to the latent construct and that item options can be used to ascertain critical thresholds for prevention type strategies. Conclusions: Examining parameters relating to difficulty, discriminatory power, and option characteristics facilitated the identification of ADL/Instrumental ADL items that may serve to enhance functional task training in community-dwelling older adults. These analyses demonstrated that functional tasks have differing levels of discriminatory power, and that a task’s discriminatory power is likely to change with varying levels of disability. This observation reinforces the notion that exercises based on functional tasks may differ significantly in their therapeutic effect. Lastly, this study was able to highlight statistically meaningful cut-points relating to when older adults should begin ‘prehabilitation’ interventions.
Novel Method to Process Cystic Fibrosis Sputum for Determination of Oxidative State
Authors: Hector A. , Jonas F. , Kappler M. , Feilcke M. , Hartl D. , Griese M.
Published: December 2009

Background: Induced sputum is the most commonly used method to analyze airway inflammation in cystic fibrosis (CF) patients ex vivo. Due to the complex matrix of the sample material, precise and reliable analysis of sputum constituents depends critically on preanalytical issues. Objectives: Here we compared the commonly used method for sputum processing by dithiothreitol (DTT) with a novel mechanical method in regard to basal cellular parameters, neutrophil markers and glutathione (GSH) levels. Methods: Sputum samples from CF patients were processed in parallel with or without the use of DTT. The key improvement of the mechanical method was the processing in many very small aliquots. Cellular and humoral markers were assessed and compared according to Bland-Altman. Results: Total cell count, cell viability, differential cell count, neutrophil elastase levels and flow cytometrically analyzed neutrophil markers (CD63, CD11b, DHR) did not differ between the two methods. Intracellular and extracellular GSH levels were significantly higher in DTT-treated samples (p = 0.002). Conclusion: The mechanical sputum-processing method presented had a similar yield of cells and fluids as the conventional DTT method and the advantage of omitting the introduction of reducing agents. This method allows a more reliable analysis of redox-dependent airway inflammation in sputum cells and fluid from CF patients than methods utilizing DTT.
Response to Spray Cryotherapy in a Patient with Adenocarcinoma in the Parietal Pleura
Authors: Downie Gordon , Krimsky William
Published: December 2009

Malignancies of the parietal pleura, whether primary or metastatic, are a therapeutic challenge, and current therapies target their symptoms and not their tumor burden. Therefore, alternatives to standard approaches seem warranted. A patient with a parietal pleura-based adenocarcinoma was treated with low-pressure spray cryotherapy after failing more traditional approaches. The patient underwent therapeutic pleuroscopy with moderate sedation and local analgesia of the right chest. She was treated with the CSA Medical spray cryotherapy system, which was introduced into the chest via the working channel of a semi-rigid pleuroscope. Pleuroscopic examination 3 days after spray cryotherapy revealed >50% reduction in tumor size. No adverse events or complications occurred as a result of treatment. At the 3-month follow-up, a slightly raised mound of tissue was noted at the treatment site. This area was biopsied and found to be negative for tumor, containing only chronic inflammatory tissue. No evidence of residual cancer was observed. Initial observations include lack of a bystander effect on lung and pleura; no significant side effects or symptoms; a 50% tumoricidal response 3 days after treatment, and a complete tumoricidal response 90 days after treatment without evidence of tumor on the parietal pleura.
Terrorist Spectaculars: Backlash Attacks and the Focus of Intelligence
Authors: Arce Daniel G. , Sandler Todd
Published: December 2009

This article presents a signaling model of terrorist attacks, where the target government faces a trade-off from its counterterrorism responses and the backlash (counterreaction) that such responses incite. An endogenous characterization of terrorist spectaculars is specified, given a government’s counterterrorism stance and the potential for backlash attacks. In particular, spectacular attacks are pooling, rather than separating, phenomena, whereby the government cannot discern, based on past attacks, the militancy of the terrorist group. The definition for ‘‘spectacular’’ terrorist attacks is inversely related to the government’s toughness and its belief that it confronts a militant group. Policy recommendations are specified for non-event-specific intelligence in relation to the avoidance of spectacular attacks or unnecessary concessions. Intelligence must be focused on the propensity for counterterrorism to give rise to a backlash attack.
“Loss of Connections Is Death”
Authors: Lim Soh-Leong
Published: December 2009

This qualitative study on Sudanese refugees’ lived experiences and perceptions of transnationalism involved face-to-face in-depth interviewing with a sample of 21 adult Southern Sudanese refugees who immigrated to San Diego in the 1990s. Through inductive analysis, the author sought an understanding of the nature and motivations of the refugees’ transnational family ties. Findings reveal the relational and affective aspects of these ties and show how social conditions and cultural imperatives drive the motivations and meanings. The author discusses the transnational behaviors of the Southern Sudanese within the context of forced migration and the Sudanese cultural value system. The author also discusses the role of trust, access, and relational context as they relate to research among refugee communities.
Whispering on the Water
Authors: Penny Elizabeth , Newton Elizabeth , Larkin Michael
Published: December 2009

In the context of one of the United Kingdom's Early Intervention Services (EIS) for psychosis, we set out to explore the treatment experiences of families of Pakistani origin, and their beliefs about treatment and psychosis. We took a phenomenological and hermeneutic approach. In-depth interviews were conducted with 11 British Pakistanis, from six families. All participants were involved in caring for family members who were being treated within an EIS. Data were subjected to Interpretative Phenomenological Analysis. We identified three super-ordinate themes: ‘A Story of Loss, ‘A Social Illness,’ and ‘Divergent Points on the Path to Change.’ These reflected the impact on participants' lives; their understandings of the problem and possible solutions; and their use of a range of cultural resources. Some aspects of these caregivers' understandings of psychosis, caring, and treatment overlap with those ascribed to caregivers generally. We discuss their culturally-specific understandings, and the implications for practice and policy.
The Multiple Worlds of Successful Cambodian American Students
Authors: Chhuon Vichet , Hudley Cynthia , Brenner Mary E. , Macias Roseanne
Published: December 2009

Educational policy usually overlooks Cambodian American students as a unique ethnic group, attending instead to the positive statistics that aggregate Asian American students into a single group of successful students. Through ethnographic interviews, this article examines how successful Cambodian American students interpreted values from their multiple worlds in relation to their paths into the university and provides insight into the academically supportive features of their different worlds. Family obligation emerged as a coherent theme that figured prominently in their school experiences. This study complicates the simplistic view of how traditional cultural values influence immigrant ethnic minority school achievement.
Value-Laden Technocratic Management and Environmental Conflicts
Authors: Glenna Leland L.
Published: December 2009

Environmental controversies are often framed as conflicts between environmentalist and antienvironmentalist positions. The underlying dimensions of ethics and justice tend to be overlooked. This article seeks to integrate insights from environmental ethics and sociological observations through a case study of a watershed conflict. A controversy emerged in the 1990s when residents of the New York City (NYC) watershed filed a lawsuit to block NYC’s proposed regulations for the land surrounding the streams and reservoirs that supply NYC’s drinking water. The conflict was resolved after NYC agreed to provide economic development funds to the watershed towns in exchange for accepting the regulations. An analysis of interviews with NYC watershed town supervisors reveals that the conflict was resolved because underlying competing theories of justice were addressed. This contradicts the popular narrative that an environmental conflict can be resolved when competing parties come to the realization that natural ecosystems provide valuable water-purification services.
Revision Ulnar Collateral Ligament Reconstruction Using a Suspension Button Fixation Technique
Authors: Lee Gregory H. , Limpisvasti Orr , Park Maxwell C. , McGarry Michelle H. , Yocum Lewis A. , Lee Thay Q.
Published: December 2009

Background

Revision ulnar collateral ligament reconstruction remains a challenging problem. The objective of this study was to biomechanically evaluate an ulnar collateral ligament reconstruction technique using a suspension button fixation technique that can be used even in the case of ulnar cortical bone loss.

Hypothesis

An ulnar suspension fixation technique for ulnar collateral ligament reconstruction can restore elbow kinematics and demonstrate failure strength comparable to that of currently available techniques.

Study Design

Controlled laboratory study.

Methods

Nine pairs of cadaveric elbows were dissected free of soft tissue and potted. After simulating ulnar cortical bone loss, ulnar collateral ligament reconstruction was performed in 1 elbow of each pair using palmaris longus autograft and a 30-mm RetroButton suspended from the far (lateralmost) ulnar cortex. A docking technique was used for humeral fixation of the graft. Elbow valgus angle was quantified using a Microscribe 3DLX digitizer at multiple elbow flexion angles. Valgus angle was measured with the ulnar collateral ligament intact, transected, and reconstructed. In addition, load-to-failure testing was performed in 1 elbow of each pair.

Results

Release of the ulnar collateral ligament caused a significant increase in valgus angle at each flexion angle tested (P < .002). Reconstructed elbows demonstrated no significant differences in valgus angle from the intact elbow at all flexion angles tested. Load-to-failure tests showed that reconstructed elbows had an ultimate torque (10.3 ± 5.7 N·m) significantly less than intact elbows (26.4 ± 10.6 N·m) (P = .001).

Conclusion

Ulnar collateral ligament reconstruction using a suspension button fixation technique reliably restored elbow kinematics to the intact state. Load-to-failure testing demonstrated comparable fixation strength to several historic controls of primary reconstruction techniques despite the simulated ulnar cortical bone loss.

Clinical Relevance

Ulnar collateral ligament reconstruction using a suspension button fixation technique can be considered in the case of ulnar cortical bone loss in a primary or revision setting.
Layers of Influence: Important Contextual Factors in Directing Dementia Care Programs
Authors: Jarrott Shannon E. , Gigliotti Christina M.
Published: December 2009

Researchers have documented the powerful influence of the physical and social environment on persons with dementia; however, most intervention studies fail to include contextual assessments when exploring outcomes. As part of a larger study assessing a horticultural therapy (HT) intervention, the authors explored the contextual and procedural factors that impacted results. Guided by the theory of environmental press, interviews were conducted with five of the study’s activity facilitators who worked in seven dementia care programs possessing varied social and physical environments. Findings indicated that the theory of environmental press should be expanded beyond the person with dementia and applied to program facilitators. A hierarchical relationship became evident; for program participants to achieve congruence between their competence and their environment, the facilitator must first achieve such a fit. Facilitators with fewer competencies were more vulnerable to the shortcomings of their environments; supportive environments can minimize deficits in competence.
Memory for Category Information Is Idealized Through Contrast With Competing Options
Authors: Davis Tyler , Love Bradley C.
Published: December 2009

We suggest that human category formation relies on contrastive learning mechanisms that seek to reduce prediction error. In keeping with this view, manipulating category contrast leads to systematic distortions in people’s memory for category information. Simply by changing the basis of comparison (i.e., the available response options), we can systematically distort people’s perceptions of novel, energy-source, and political categories. Our proposal explains perceived variations in category members’ typicality, including cases in which average items are judged as highly typical and cases in which extreme or ideal members are judged as highly typical of the category. Although straightforward, our account spans findings from studies in goal-derived, cross-cultural, and object-based categorization and suggests ways in which society’s perception of key issues is distorted by political discourse.
L-Ascorbate protects rat hepatocytes against sodium arsenite—induced cytotoxicity and oxidative damage
Authors: Asit Kumar Bera  , Rana Tanmoy , Das Subhashree , Bandyopadhyay Subhasish , Bhattacharya Debasis , Pan Diganta , De Sumanta , Subrata Kumar Das
Published: December 2009

Sodium arsenite—exposed hepatocytes of rat showed higher production of nitric oxide (NO) and increased lipid peroxidation (LPO) level vis-a-vis activity of superoxide dismutase (SOD) and catalase (CAT) were significantly lowered. Subsequently, the cell proliferation index (CPI) and cell viability were also reduced. Treatment with L-ascorbate was found effective in normalizing the arsenic-induced alteration of SOD and CAT activity and LPO level in rat hepatocytes. These observations indicated that L-ascorbate also has potent cytoprotective role as it could reduce the NO production and normalize the cell proliferation and viability of hepatocytes. Therefore, the in vitro study suggested that ascorbic acid is helpful to ameliorate the arsenic-induced cytotoxicity and oxidative stress of rat hepatocytes.
Adverse effects of lactational exposure to chlorpyrifos in suckling rats
Authors: Mansour SA , Mossa AH
Published: December 2009

The present study was undertaken to evaluate the oxidative damage, biochemical and histopathological alterations in sucking rats whose mothers were exposed to the insecticide chlorpyrifos (CPF). Dams were administered CPF, via oral route. Doses equalled 0.01 mg kg—1 body weight (b.wt.; acceptable daily intake, ADI), 1.00 mg kg—1 b.wt. (no observed adverse effects level, NOAEL) and 1.35 mg kg—1 b.wt. (1/100 lethal dose [LD50]) from postnatal day 1 until day 20 after delivery. At two high doses of CPF, the body weight gain and relative liver and kidney weight of suckling pups were significantly decreased. Exposure of the mothers to CPF caused increase in lipid peroxidation (LPO) and decrease in superoxide dismutase (SOD) and glutathione-s-transferase (GST) in lactating pups. CPF altered the level of the marker parameters related to the liver and kidneys. Consistent histological changes were found in the liver and kidneys of the subjected pups, especially at the higher doses. The results suggested that the transfer of CPF intoxication through the mother’s milk has resulted in oxidative stress and biochemical and histopathological alterations in the suckling pups. The data of this study may be considered as a contribution to the problem of lactational transfer of the relatively less persistent OP pesticides, such as CPF.
Carvedilol-induced elevation in cytosolic free Ca2+ level and apoptosis in SIRC corneal epithelial cells
Authors: Shieh Pochuen , Lee Chih-Hung , Ng Ling Yi  , Jan Chung-Ren
Published: December 2009

The effect of the cardiovascular drug carvedilol on cytosolic free Ca2+ concentrations ([Ca 2+]i) and viability was examined in Statens Seruminstitut rabbit cornea (SIRC) corneal epithelial cells. [Ca2+]i and cell viability were measured using the fluorescent dyes fura-2 and 4-[3-[4-lodophenyl]-2-4(4-nitrophenyl)-2H-5-tetrazolio-1,3-benzene disulfonate] (WST-1), respectively. Carvedilol at concentrations between 1 and 30 μM increased [Ca 2+]i in a concentration-dependent manner. The Ca2+ signal was reduced partly by removing extracellular Ca2+. Carvedilol induced Mn2+ quench of fura-2 fluorescence implicating Ca2+ influx. The Ca2+ influx was inhibited by suppression of protein kinase C activity. In Ca2+-free medium, after pretreatment with 1 μM thapsigargin (an endoplasmic reticulum Ca 2+ pump inhibitor), carvedilol-induced [Ca2+]i rise was reduced; and conversely, carvedilol pretreatment inhibited a major part of thapsigargin-induced [Ca 2+]i rise. Addition of the phospholipase C inhibitor 1-[6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino] hexyl]-1H-pyrrole-2,5-dione (U73122; 2 μM) did not change carvedilol-induced [Ca2+]i rise. At concentrations between 5 and 70 μM, carvedilol killed cells in a concentration-dependent manner. The cytotoxic effect of 20 μM carvedilol was not reversed by prechelating cytosolic Ca2+ with BAPTA/AM. Apoptosis was induced by 5—70 μM carvedilol. Collectively, in SIRC corneal epithelial cells, carvedilol-induced [Ca2+]i rises by causing Ca2+ release from the endoplasmic reticulum in a phospholipase C-independent manner, and Ca 2+ influx via protein kinase C-regulated Ca2+ channels. Carvedilol-caused cytotoxicity was mediated by Ca2+-independent apoptosis in a concentration-dependent manner.
Bereaved Parents’ and Siblings’ Reports of Legacies Created by Children With Cancer
Authors: Foster Terrah L. , Gilmer Mary Jo , Davies Betty , Barrera Maru , Fairclough Diane , Vannatta Kathryn , Gerhardt Cynthia A.
Published: December 2009

This qualitative study explored bereaved parents’ and siblings’ reports of legacies created by children with advanced cancer. Participants included 40 families of children who died from cancer, with 36 mothers, 27 fathers, and 40 siblings (ages 8-18 years). Individual interviews were completed at home approximately 10.68 months (SD = 3.48) after the child’s death. Content analysis of interviews indicated that many children living with cancer did specific things to be remembered, such as making crafts for others, willing away belongings, writing letters to loved ones, and giving special gifts. Some children, particularly those who were very ill or died unexpectedly, did not intentionally do or say anything to be remembered. Legacies included bereaved individuals remembering children’s qualities, concern for family, and beliefs about afterlife. Having advanced cancer appeared to motivate children to influence others’ lives and prepare for their own deaths. Children’s advice about how to live life inspired bereaved family members. Findings contribute to the current knowledge of legacy-making in children and offer implications for practice and future research.
Nonlinear Structural Vibration Suppression Using Dynamic Neural Network Observer and Adaptive Fuzzy Sliding Mode Control
Authors: Li L. , Song G. , Ou J.
Published: December 2009

Nonlinear vibration control of structures has attracted much attention in recent years. In this paper, the adaptive fuzzy sliding mode (AFSM) control algorithm is adopted to actively control nonlinear structural vibration. Since the AFSM control algorithm needs the full state feedback of the structure, a dynamic neural network (DNN) observer is proposed, considering the nonlinearity of the structure. The neural network weights are adapted on-line, and no off-line learning is required. Furthermore, no exact knowledge of structural nonlinearities is needed. The weight training algorithm is established based on Lyapunov stability theory in the presence of modeling error. A semi-active control algorithm is used for MR damper to track the active control force, which is computed by the AFSM control algorithm based on the DNN observer. Results of the numerical simulation of semi-active control of a 20-story nonlinear building using MR dampers verify the performance of the DNN observer and the effectiveness of the proposed AFSM control.
Lesbian/Bisexual Mothers and Intimate Partner Violence: Help Seeking in the Context of Social and Legal Vulnerability
Authors: Hardesty Jennifer L. , Oswald Ramona F. , Khaw Lyndal , Fonseca Carol
Published: December 2009

Mothers in same-sex relationships face unique challenges when help seeking for intimate partner violence (IPV). Formal helping systems often invalidate their family relationships, leaving them vulnerable and distrustful when help seeking. To better understand their experiences, the authors interviewed 24 lesbian/bisexual mothers who were either in or had left abusive same-sex relationships. Increasing severity of violence, effects of violence on children and families, and “being tired” influenced their definitions of the situation. Decisions to seek formal help appeared to be influenced by their support from informal networks and perceived stigma related to the intersection of IPV and being lesbian or bisexual.