bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II Trial of OGX-011 in Combination with Docetaxel in Metastatic Breast Cancer
Authors: Chia Stephen , Dent Susan , Ellard Susan , Ellis Peter M. , Vandenberg Ted , Gelmon Karen , Powers Jean , Walsh Wendy , Seymour Lesley , Eisenhauer Elizabeth A. 
Published: January 2009

AbstractPurpose: Clusterin is an antiapoptotic protein activated in response to cellular stress. OGX-011 is a second-generation antisense oligonucleotide that inhibits clusterin expression. The primary objective of this phase II trial was to assess the safety and efficacy of the combination of OGX-011 and docetaxel for metastatic breast cancer.Experimental Design: Women with measurable metastatic breast cancer and ≤1 chemotherapy regimen were eligible. Three loading doses of OGX-011 640 mg i.v. followed by weekly OGX-011 and docetaxel 75 mg/m2 (every 3 weeks) were given. A two-stage design was used with a hypothesis of H0 ≤35% and Ha ≥55%. Objective response in ≥6 of the first 14 patients was required for the trial to continue to the second stage.Results: Fifteen patients were enrolled. A median of six cycles were delivered (range, 2-10). Five partial responses were confirmed for a 33% response rate (95% confidence interval, 11.8-61.6%) with a further 9 (60%) patients showing stable disease. The median duration of stable disease was 9.3 months. The median time to progression was 8 months (95% confidence interval, 5.62-9.43 months). Toxic effects were similar to those with single agent docetaxel. Although serum clusterin decreased on treatment, there was no relationship observed between the magnitude of decrease and response.Conclusion: The combination of OGX-011 and docetaxel at 75 mg/m2 is well tolerated and clinical activity was seen in these patients with metastatic breast cancer, but there was an insufficient number of responses to meet the criteria for proceeding to the second stage of accrual.
Enhancement of Docetaxel Anticancer Activity by a Novel Diindolylmethane Compound in Human Non–Small Cell Lung Cancer
Authors: Ichite Nkechi , Chougule Mahavir B. , Jackson Tanise , Fulzele Suniket V. , Safe Stephen , Singh Mandip 
Published: January 2009

Abstract
Purpose: This study was conducted to examine the cytotoxic effects of a peroxisome proliferator-activated receptor γ (PPARγ) agonist, 1,1-bis (3′-indolyl)-1-(p-biphenyl) methane (DIM-C-pPhC6H5), alone and in combination with docetaxel in vitro in A549 lung cancer cells and in vivo in nude mice bearing A549 orthotopic lung tumors.
Experimental Design: Isobolographic method was used to calculate combination index values from cell viability data. Apoptosis was evaluated in A549 cells by terminal deoxynucleotidyl transferase-mediated nick end labeling assay and measurement of cleaved poly(ADP-ribose) polymerase level. Expression of proteins was studied by Western blotting. A549 cells were implanted to induce orthotopic lung tumors in nude mice and the efficacy of docetaxel, DIM-C-pPhC6H5, or combination was determined. Apoptosis and cleaved caspase-3 expression in the harvested tissues were studied by terminal deoxynucleotidyl transferase-mediated nick end labeling and immunohistochemistry, respectively.
Results: The combination index values (0.36-0.9) suggested synergistic to additive effects of docetaxel + DIM-C-pPhC6H5 and resulted in the highest increase in percentage of apoptotic cells and expression of cleaved poly(ADP-ribose) polymerase, Bax, and N-cadherin compared with treatment with either agent. The combination also enhanced procaspase-3 and -9 cleavage. In vivo, docetaxel + DIM-C-pPhC6H5 reduced lung weights by 57% compared with 39% by docetaxel or 22% by DIM-C-pPhC6H5 alone, induced apoptosis in 43% of the tumor cells compared with 29% and 22% in tumors treated with docetaxel and DIM-C-pPhC6H5, respectively, and increased procaspase-3 cleavage compared with either agent alone.
Conclusions: These findings suggest potential benefit for use of docetaxel and DIM-C-pPhC6H5 combination in lung cancer treatment.
Improved Systemic Delivery of Oncolytic Reovirus to Established Tumors Using Preconditioning with Cyclophosphamide-Mediated Treg Modulation and Interleukin-2
Authors: Kottke Timothy , Thompson Jill , Diaz Rosa Maria , Pulido Jose , Willmon Candice , Coffey Matt , Selby Peter , Melcher Alan , Harrington Kevin , Vile Richard G. 
Published: January 2009

Abstract
Purpose: The goals of this study were (a) to investigate whether preconditioning of immunocompetent mice with PC-61-mediated regulatory T-cell (Treg) depletion and interleukin-2 (IL-2) would enhance systemic delivery of reovirus into subcutaneous tumors and (b) to test whether cyclophosphamide (CPA), which is clinically approved, could mimic PC-61 for modification of Treg activity for translation into the next generation of clinical trials for intravenous delivery of reovirus.
Experimental Design: C57Bl/6 mice bearing subcutaneous B16 tumors were treated with CPA or PC-61 followed by 10 injections of low-dose IL-2. Mice were then treated with intravenous reovirus. Virus localization to tumor and other organs was measured along with tumor growth and systemic toxicity.
Results: Preconditioning with PC-61 and IL-2 enhanced localization of intravenous oncolytic reovirus to tumors with significantly increased antitumor therapy compared with controls (P &lt; 0.01). However, with the maximal achievable dose of reovirus, Treg modification + IL-2 was also associated with systemic toxicity. CPA (100 mg/kg) did not deplete, but did functionally inhibit, Treg. CPA also mimicked PC-61, in combination with IL-2, by inducing “hyperactivated” NK cells. Consistent with this, preconditioning with CPA + IL-2 enhanced therapy of intravenously delivered, intermediate-dose reovirus to a level indistinguishable from that induced by PC-61 + IL-2, without any detectable toxicity.
Conclusion: With careful reference to ongoing clinical trials with dose escalation of reovirus alone and in combination with CPA, we propose that future clinical trials of CPA + IL-2 + reovirus will allow for both improved levels of virus delivery and increased antitumor efficacy.
Delta-Crystallin Enhancer Binding Factor 1 Controls the Epithelial to Mesenchymal Transition Phenotype and Resistance to the Epidermal Growth Factor Receptor Inhibitor Erlotinib in Human Head and Neck Squamous Cell Carcinoma Lines
Authors: Haddad Yasmine , Choi Woonyoung , McConkey David J. 
Published: January 2009

Abstract
Purpose: Although the epidermal growth factor receptor (EGFR) is overexpressed in a majority of head and neck squamous cell carcinomas (HNSCC), only a minority of patients derive substantial clinical benefit from EGFR inhibitors. We initiated the present study to identify the mechanisms underlying erlotinib resistance in a panel of HNSCC cell lines.
Methods: We used [3H]thymidine incorporation to characterize the heterogeneity of responsiveness to erlotinib-mediated growth inhibition in a panel of 27 human HNSCC cells. We characterized the molecular mechanisms involved in resistance using a representative subset of six erlotinib-sensitive and erlotinib-resistant HNSCC lines.
Results: Erlotinib had heterogeneous effects on DNA synthesis in HNSCC cells that correlated closely with molecular markers of epithelial to mesenchymal transition (EMT). Specifically, the drug-sensitive lines expressed high levels of E-cadherin and showed limited invasion and migration capabilities. In contrast, the erlotinib-resistant HNSCC lines expressed high levels of the E-cadherin repressor delta-crystallin enhancer binding factor 1 (deltaEF1; Zeb-1) and other mesenchymal markers and low levels of E-cadherin, and they were highly invasive and migratory. Small interfering RNA–mediated knockdown of deltaEF1 in the erlotinib-resistant cell lines (1386LN and UMSCC1) resulted in up-regulation of E-cadherin and increased sensitivity to erlotinib in an E-cadherin–dependent manner.
Conclusions: DeltaEF1 controls the mesenchymal phenotype and drives erlotinib resistance in HNSCC cells. E-cadherin and deltaEF1 may prove to be useful markers in predicting EGFR inhibitor responsiveness.
Disseminated Tumor Cells in Prostate Cancer Patients after Radical Prostatectomy and without Evidence of Disease Predicts Biochemical Recurrence
Authors: Morgan Todd M. , Lange Paul H. , Porter Michael P. , Lin Daniel W. , Ellis William J. , Gallaher Ian S. , Vessella Robert L. 
Published: January 2009

AbstractPurpose: Men with apparently localized prostate cancer often relapse years after radical prostatectomy. We sought to determine if epithelial-like cells identified from bone marrow in patients after radical prostatectomy, commonly called disseminated tumor cells (DTC), were associated with biochemical recurrence.Experimental Design: We obtained bone marrow aspirates from 569 men prior to radical prostatectomy and from 34 healthy men with prostate-specific antigens &lt;2.5 ng/mL to establish a comparison group. Additionally, an analytic cohort consisting of 98 patients with no evidence of disease (NED) after radical prostatectomy was established to evaluate the relationship between DTC and biochemical recurrence. Epithelial cells in the bone marrow were detected by magnetic bead enrichment with antibodies to CD45 and CD61 (negative selection) followed by antibodies to human epithelial antigen (positive selection) and confirmation with FITC-labeled anti-BerEP4 antibody.Results: DTC were present in 72% (408 of 569) of patients prior to radical prostatectomy. There was no correlation with pathologic stage, Gleason grade, or preoperative prostate-specific antigens. Three of 34 controls (8.8%) had DTC present. In patients with NED after radical prostatectomy, DTC were present in 56 of 98 (57%). DTC were detected in 12 of 14 (86%) NED patients after radical prostatectomy who subsequently suffered biochemical recurrence. The presence of DTC in NED patients was an independent predictor of recurrence (hazard ratio 6.9; 95% confidence interval, 1.03-45.9).Conclusions: Approximately 70% of men undergoing radical prostatectomy had DTC detected in their bone marrow prior to surgery, suggesting that these cells escape early in the disease. Although preoperative DTC status does not correlate with pathologic risk factors, persistence of DTC after radical prostatectomy in NED patients was an independent predictor of recurrence.
Loss-of-Function Fibroblast Growth Factor Receptor-2 Mutations in Melanoma
Authors: Gartside Michael G. , Chen Huaibin , Ibrahimi Omar A. , Byron Sara A. , Curtis Amy V. , Wellens Candice L. , Bengston Ana , Yudt Laura M. , Eliseenkova Anna V. , Ma Jinghong , Curtin John A. , Hyder Pilar , Harper Ursula L. , Riedesel Erica , Mann Graham J. , Trent Jeffrey M. , Bastian Boris C. , Meltzer Paul S. , Mohammadi Moosa , Pollock Pamela M. 
Published: January 2009

Abstract
We report that 10% of melanoma tumors and cell lines harbor mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. These novel mutations include three truncating mutations and 20 missense mutations occurring at evolutionary conserved residues in FGFR2 as well as among all four FGFRs. The mutation spectrum is characteristic of those induced by UV radiation. Mapping of these mutations onto the known crystal structures of FGFR2 followed by in vitro and in vivo studies show that these mutations result in receptor loss of function through several distinct mechanisms, including loss of ligand binding affinity, impaired receptor dimerization, destabilization of the extracellular domains, and reduced kinase activity. To our knowledge, this is the first demonstration of loss-of-function mutations in a class IV receptor tyrosine kinase in cancer. Taken into account with our recent discovery of activating FGFR2 mutations in endometrial cancer, we suggest that FGFR2 may join the list of genes that play context-dependent opposing roles in cancer. (Mol Cancer Res 2009;7(1):41–54)
Boswellic Acid Blocks Signal Transducers and Activators of Transcription 3 Signaling, Proliferation, and Survival of Multiple Myeloma via the Protein Tyrosine Phosphatase SHP-1
Authors: Kunnumakkara Ajaikumar B. , Nair Asha S. , Sung Bokyung , Pandey Manoj K. , Aggarwal Bharat B. 
Published: January 2009

AbstractActivation of signal transducers and activators of transcription-3 (STAT-3) has been linked with survival, proliferation, chemoresistance, and angiogenesis of tumor cells, including human multiple myeloma (MM). Thus, agents that can suppress STAT3 activation have potential as cancer therapeutics. In our search for such agents, we identified acetyl-11-keto-β-boswellic acid (AKBA), originally isolated from Boswellia serrata. Our results show that AKBA inhibited constitutive STAT3 activation in human MM cells. AKBA suppressed IL-6–induced STAT3 activation, and the inhibition was reversible. The phosphorylation of both Jak 2 and Src, constituents of the STAT3 pathway, was inhibited by AKBA. Interestingly, treatment of cells with pervanadate suppressed the effect of AKBA to inhibit the phosphorylation of STAT3, thus suggesting the involvement of a protein tyrosine phosphatase. We found that AKBA induced Src homology region 2 domain–containing phosphatase 1 (SHP-1), which may account for its role in dephosphorylation of STAT3. Moreover, deletion of the SHP-1 gene by small interfering RNA abolished the ability of AKBA to inhibit STAT3 activation. The inhibition of STAT3 activation by AKBA led to the suppression of gene products involved in proliferation (cyclin D1), survival (Bcl-2, Bcl-xL, and Mcl-1), and angiogenesis (VEGF). This effect correlated with the inhibition of proliferation and apoptosis in MM cells. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the AKBA-induced apoptosis. Overall, our results suggest that AKBA is a novel inhibitor of STAT3 activation and has potential in the treatment of cancer. (Mol Cancer Res 2009;7(1):118–28)
Management of the Athlete With Acute Anterior Cruciate Ligament Deficiency
Authors: Hurd Wendy , Axe Michael , Snyder-Mackler Lynn 
Published: January 2009

Background: Identification of highly active individuals early after acute anterior cruciate ligament deficiency who are good candidates for nonoperative management is a clinical challenge. The University of Delaware has developed and validated a treatment algorithm and screening examination to distinguish between nonoperative and surgical candidates. Study Design: Review. Evidence Acquisition: A description of the decision-making rules and rehabilitation protocol for highly active individuals with anterior cruciate ligament deficiency is provided. Results from clinical trials, outcome studies, and biomechanical investigations conducted using the treatment algorithm and screening examination are also reviewed. Results: Patients identified as nonoperative rehabilitation candidates using these clinical guidelines have a far greater success rate than what has been reported when patients self-select nonoperative management. Furthermore, nonoperative outcomes are improved when patients participate in a perturbation-enhanced rehabilitation protocol. Divergent lower extremity movement patterns are consistent with the different functional abilities of the dichotomous patient groups identified with the screening examination. Conclusion: Given the differential patient response to anterior cruciate ligament injury, implementation of the decision-making guidelines discussed in this review offers clinicians the opportunity to provide individualized patient care rather than continuing with a blanket surgical treatment strategy.
Dynamic evolution of bitter taste receptor genes in vertebrates
Authors: Dong Dong , Jones Gareth , Zhang Shuyi 
Published: January 2009

Abstract

Background
Sensing bitter tastes is crucial for many animals because it can prevent them from ingesting harmful foods. This process is mainly mediated by the bitter taste receptors (T2R), which are largely expressed in the taste buds. Previous studies have identified some T2R gene repertoires, and marked variation in repertoire size has been noted among species. However, the mechanisms underlying the evolution of vertebrate T2R genes remain poorly understood.

Results
To better understand the evolutionary pattern of these genes, we identified 16 T2R gene repertoires based on the high coverage genome sequences of vertebrates and studied the evolutionary changes in the number of T2R genes during birth-and-death evolution using the reconciled-tree method. We found that the number of T2R genes and the fraction of pseudogenes vary extensively among species. Based on the results of phylogenetic analysis, we showed that T2R gene families in teleost fishes are more diverse than those in tetrapods. In addition to the independent gene expansions in teleost fishes, frogs and mammals, lineage-specific gene duplications were also detected in lizards. Furthermore, extensive gains and losses of T2R genes were detected in each lineage during their evolution, resulting in widely differing T2R gene repertoires.

Conclusion
These results further support the hypotheses that T2R gene repertoires are closely related to the dietary habits of different species and that birth-and-death evolution is associated with adaptations to dietary changes.
The relationship between magnetic and electrophysiological responses to complex tactile stimuli
Authors: Zhu Zhao , Zumer Johanna M , Lowenthal Marianne E , Padberg Jeff , Recanzone Gregg H , Krubitzer Leah A , Nagarajan Srikantan S , Disbrow Elizabeth A 
Published: January 2009

Abstract

Background
Magnetoencephalography (MEG) has become an increasingly popular technique for non-invasively characterizing neuromagnetic field changes in the brain at a high temporal resolution. To examine the reliability of the MEG signal, we compared magnetic and electrophysiological responses to complex natural stimuli from the same animals. We examined changes in neuromagnetic fields, local field potentials (LFP) and multi-unit activity (MUA) in macaque monkey primary somatosensory cortex that were induced by varying the rate of mechanical stimulation. Stimuli were applied to the fingertips with three inter-stimulus intervals (ISIs): 0.33s, 1s and 2s.

Results
Signal intensity was inversely related to the rate of stimulation, but to different degrees for each measurement method. The decrease in response at higher stimulation rates was significantly greater for MUA than LFP and MEG data, while no significant difference was observed between LFP and MEG recordings. Furthermore, response latency was the shortest for MUA and the longest for MEG data.

Conclusion
The MEG signal is an accurate representation of electrophysiological responses to complex natural stimuli. Further, the intensity and latency of the MEG signal were better correlated with the LFP than MUA data suggesting that the MEG signal reflects primarily synaptic currents rather than spiking activity. These differences in latency could be attributed to differences in the extent of spatial summation and/or differential laminar sensitivity.
Unsuspected and extensive transmission of a drug-susceptible Mycobacterium tuberculosisstrain
Authors: López-Calleja Ana Isabel , Gavín Patricia , Lezcano Ma Antonia , Vitoria Ma Asunción , Iglesias Ma José , Guimbao Joaquín , Lázaro Ma Ángeles , Rastogi Nalin , Revillo Ma José , Martín Carlos , Samper Sofia 
Published: January 2009

Abstract

Background
A large and unsuspected tuberculosis outbreak involving 18.7% of the total of the tuberculosis cases studied, was detected in a population-based molecular epidemiological study performed in Zaragoza (Spain) from 2001 to 2004.

Methods
The Mycobacterium tuberculosis drug-susceptible strain, named MTZ strain, was genetically characterized by IS6110-RFLP, Spoligotyping and by MIRU-VNTR typing and the genetic patterns obtained were compared with those included in international databases. The characteristics of the affected patients, in an attempt to understand why the MTZ strain was so highly transmitted among the population were also analyzed.

Results
The genetic profile of the MTZ strain was rare and not widely distributed in our area or elsewhere. The patients affected did not show any notable risk factor for TB.

Conclusion
The M. tuberculosis strain MTZ, might have particular transmissibility or virulence properties, and we believe that greater focus should be placed on stopping its widespread dissemination.
Minor contribution of mutations at iniA codon 501 and embC-embA intergenic region in ethambutol-resistant clinical Mycobacterium tuberculosis isolates in Kuwait
Authors: Jaber Al-Anoud , Ahmad Suhail , Mokaddas Eiman 
Published: January 2009

AbstractBackgroundEthambutol (EMB) is a first-line drug for the treatment of tuberculosis (TB). Resistance to EMB inMycobacterium tuberculosisisolates is mediated by mutations in several genes involved in arabinan synthesis notably threeemb(arabinosyl transferase) andiniA(isoniazid-inducible) genes. Most epidemiologically unrelated EMB-resistantM. tuberculosisstrains contain mutations atembBcodons 306, 406 and 497,embC-embAintergenic region (IGR) andiniAcodon 501 (iniA501).ObjectiveTo develop a more comprehensive molecular screen for EMB-resistance detectioamong epidemiologically unrelated EMB-resistantM. tuberculosisstrains previously analyzed forembBcodon 306, 406 and 497 mutations by including analysis of mutations atiniA501and inembC-embAIGR.MethodsFifty consecutive and phenotypically documented EMB-resistant and 25 pansusceptibleM. tuberculosisstrains isolated from 75 different TB patients over a four-year period in Kuwait were analyzed. Mutations atiniA501were detected by PCR amplification followed by restriction fragment length polymorphism (RFLP) patterns generated withHpy99 I. Direct DNA sequencing was used to confirm RFLP results and for detecting mutations inembC-embAIGR.ResultsNearly same number of EMB-resistantM. tuberculosisstrains were resistant to EMB alone and EMB together with additional resistance to rifampicin and isoniazid (9 of 50, 18% and 11 of 50, 22%, respectively). All the 25 pansusceptible strains contained wild-type sequences atiniA501and inembC-embAIGR. The analysis of 50 EMB-resistantM. tuberculosisisolates showed that only one strain contained a mutatediniA501while no mutation was detected inembC-embAIGR in any of the isolate.ConclusionAnalysis ofiniA501andembC-embAIGR in epidemiologically unrelated EMB-resistantM. tuberculosisisolates in Kuwait indicate that mutations at these locations occur very infrequently and their inclusion for the development of a comprehensive molecular screen will make only minor contribution towards rapid EMB resistance detection.
Hepatic hydatid disease: four case reports
Authors: Elshazly Attef M , Azab Manar S , ElBeshbishi Samar N , Elsheikha Hany M 
Published: January 2009

Abstract
We report four cases who were referred to Mansoura University Teaching Hospital, Egypt suffering from abdominal pain and gastrointestinal manifestations. The patients' history was unremarkable, except that they had contact with dogs and live in rural communities. Laboratory findings showed peripheral blood eosinophilia, leucocytosis, and elevated liver enzymes. Serological tests were positive in three cases. Ultrasonography showed well-circumscribed cystic masses in the liver. Diagnosis of hydatid cysts was confirmed by computed tomography (CT). Surgical treatment along with chemotherapy was performed and all patients recovered well. The results of these cases support the notion that CT scan can led to increased clarity, regarding surgical management, because of discordance between radiographic and laboratory findings.