bluuebunny/crossref_metadata_2025 huggingface dataset:
Registration of Brain MRI/PET Images Based on Adaptive Combination of Intensity and Gradient Field Mutual Information
Authors: Liu Jiangang , Tian Jie
Published: April 2007

Traditional mutual information (MI) function aligns two
multimodality images with intensity information, lacking spatial
information, so that it usually presents many local maxima that can
lead to inaccurate registration. Our paper proposes an algorithm of
adaptive combination of intensity and gradient field mutual
information (ACMI). Gradient code maps (GCM) are constructed by
coding gradient field information of corresponding original images.
The gradient field MI, calculated from GCMs, can provide
complementary properties to intensity MI. ACMI combines intensity MI
and gradient field MI with a nonlinear weight function, which can
automatically adjust the proportion between two types MI in
combination to improve registration. Experimental results
demonstrate that ACMI outperforms the traditional MI and it is much
less sensitive to reduced resolution or overlap of images.
Joint Spectra of Generators in Topological Algebras
Authors: Wawrzyńczyk Antoni
Published: April 2007

Let𝒜be a complex topological algebra with unit 1 and𝒰a family of proper closed ideals in𝒜. For an arbitraryS⊂𝒜we define a globally defined joint spectrumσ𝒰(S)={(λs)s∈S∈ℂS  |  ∃ I  ∈𝒰(s−λs)∈I ∀s∈S}. We prove that forSgenerating𝒜the spectrumσ𝒰(S)can be identified with the set𝔐𝒰of continuous multiplicative functionalsfon𝒜such that kerf∈𝒰. The relation is given by the formulaσ𝒰(S)={(f(s))s∈S  |   f∈𝔐𝒰}. If𝒜is aQ-algebra, the setσ𝒰(S)is rationally convex.
Modification of the Quasilinearization Method for the Inverse Problem
Authors: Celechovská-Kozáková Lenka
Published: April 2007

We propose a new modification of Bellman's quasilinearization method such that at any iteration step, it works with an approximate solution of the original nonlinear system and with new approximation of parametersα(k+1)which are close enough to the previous ones. As an output, this approach provides a construction of a convergent sequence of parameters where the limit is the best approximation of parameters of a given system. We apply this method to a mathematical model describing BSP-kinetics in the human liver.
Androgen-Independent Growth and Tumorigenesis of Prostate Cancer Cells Are Enhanced by the Presence of PKA-Differentiated Neuroendocrine Cells
Authors: Deeble Paul D. , Cox Michael E. , Frierson Henry F. , Sikes Robert A. , Palmer Jodie B. , Davidson Robert J. , Casarez Eli V. , Amorino George P. , Parsons Sarah J.
Published: April 2007

The neuroendocrine status of prostatic adenocarcinomas is considered a prognostic indicator for development of aggressive, androgen-independent disease. Neuroendocrine-like cells are thought to function by providing growth and survival signals to surrounding tumor cells, particularly following androgen ablation therapy. To test this hypothesis directly, LNCaP cells were engineered to inducibly express a constitutively activated form of the cyclic AMP–dependent protein kinase A catalytic subunit (caPKA), which was previously found upon transient transfection to be sufficient for acquisition of neuroendocrine-like characteristics and loss of mitotic activity. Clonal cells that inducibly expressed caPKA enhanced the growth of prostate tumor cells in anchorage-dependent and anchorage-independent in vitro assays as well as the growth of prostate tumor xenografts in vivo, with the greatest effects seen under conditions of androgen deprivation. These results suggest that neuroendocrine-like cells of prostatic tumors have the potential to enhance androgen-independent tumor growth in a paracrine manner, thereby contributing to progression of the disease. [Cancer Res 2007;67(8):3663–72]
Coordinated Regulation of Pathways for Enhanced Cell Motility and Chemotaxis Is Conserved in Rat and Mouse Mammary Tumors
Authors: Wang Weigang , Wyckoff Jeffrey B. , Goswami Sumanta , Wang Yarong , Sidani Mazen , Segall Jeffrey E. , Condeelis John S.
Published: April 2007

Correlating tumor cell behavior in vivo with patterns of gene expression has led to new insights into the microenvironment of tumor cells in the primary tumor. Until now, these studies have been done with cell line–derived tumors. In the current study, we have analyzed, in polyoma middle T oncogene (PyMT)–derived mammary tumors, tumor cell behavior and gene expression patterns of the invasive subpopulation of tumor cells by multiphoton-based intravital imaging and microarray-based expression profiling, respectively. Our results indicate that the patterns of cell behavior that contribute to invasion and metastasis in the PyMT tumor are similar to those seen previously in rat MTLn3 cell line–derived mammary tumors. The invasive tumor cells collected from PyMT mouse mammary tumors, like their counterparts from rat xenograft mammary tumors, are a population that is relatively nondividing and nonapoptotic but chemotherapy resistant and chemotactic. Changes in the expression of genes that occur uniquely in the invasive subpopulation of tumor cells in the PyMT mammary tumors that fall on the Arp2/3 complex, capping protein and cofilin pathways show a pattern like that seen previously in invasive tumor cells from the MTLn3 cell line–derived tumors. These changes predict an enhanced activity of the cofilin pathway, and this was confirmed in isolated invasive PyMT tumor cells. We conclude that changes in gene expression and their related changes in cell behavior, which were identified in the invasive tumor cells of cell line–derived tumors, are conserved in the invasive tumor cells of PyMT-derived mouse mammary tumors, although these tumor types have different genetic origins. [Cancer Res 2007;67(8):1–6]
In vitroandIn vivoMolecular Evidence for Better Therapeutic Efficacy of ABT-627 and Taxotere Combination in Prostate Cancer
Authors: Banerjee Sanjeev , Hussain Maha , Wang Zhiwei , Saliganan Allen , Che Mingxin , Bonfil Daniel , Cher Michael , Sarkar Fazlul H.
Published: April 2007

Bone is the key metastatic site for prostate cancer. Endothelin 1 (ET-1) produced abundantly by prostate cancer cells binds to its receptor present on bone marrow stromal cells and favors osteoblastic response during bone metastases of prostate cancer. This suggests that interrupting ET-1 interaction with its endothelin A (ETA) receptor could be useful for inhibiting prostate cancer bone metastasis and, as such, may enhance the therapeutic activity of docetaxel (Taxotere), the most commonly used drug for the treatment of metastatic prostate cancer. Therefore, the goal of our study was to obtain preclinical data supporting our hypothesis that the combined use of ETA receptor antagonist (ABT-627; Atrasentan) with Taxotere will be superior in inducing apoptosis in vitro and inhibiting tumor growth in vivo in a SCID-hu model of experimental bone metastasis induced by C4-2b prostate cancer cells. In vitro studies were done on a panel of prostate cancer cell lines to understand the molecular basis of combination therapy, and we found that the combination was more effective in the inhibition of cell viability and induction of apoptosis in LNCaP and C4-2b cells (androgen receptor positive) but not in PC-3 cells. These results were correlated with inactivation of Akt/nuclear factor-κB and its target genes. For in vivo studies, the therapeutic regimen was initiated when the tumor began showing signs of growth and treatment was continued for 5 weeks. Tumor volume and serum prostate-specific antigen were used as terminal index to evaluate the therapeutic advantage of combination therapy relative to a single regimen and untreated control. At termination, we found a 90% reduction in tumor volume by combination treatment relative to the untreated control group. Most importantly, the antitumor activity was associated with the down-regulation of molecular markers in tumor tissues that were similar to those observed in vitro. [Cancer Res 2007;67(8):3818–25]
Enhanced Antitumor Activity of T Cells Engineered to Express T-Cell Receptors with a Second Disulfide Bond
Authors: Cohen Cyrille J. , Li Yong F. , El-Gamil Mona , Robbins Paul F. , Rosenberg Steven A. , Morgan Richard A.
Published: April 2007

Adoptive transfer of genetically T-cell receptor (TCR)–modified lymphocytes has been recently reported to cause objective cancer regression. However, a major limitation to this approach is the mispairing of the introduced chains with the endogenous TCR subunits, which leads to reduced TCR surface expression and, subsequently, to their lower biological activity. We here show that it is possible to improve TCR gene transfer by adding a single cysteine on each receptor chain to promote the formation of an additional interchain disulfide bond. We show that cysteine-modified receptors were more highly expressed on the surface of human lymphocytes compared with their wild-type counterparts and able to mediate higher levels of cytokine secretion and specific lysis when cocultured with specific tumor cell lines. Furthermore, cysteine-modified receptors retained their enhanced function in CD4+ lymphocytes. We also show that this approach can be employed to enhance the function of humanized and native murine receptors in human cells. Preferential pairing of cysteine-modified receptor chains accounts for these observations, which could have significant implications for the improvement of TCR gene therapy. [Cancer Res 2007;67(8):3898–903]
Degrasyn Activates Proteasomal-Dependent Degradation of c-Myc
Authors: Bartholomeusz Geoffrey , Talpaz Moshe , Bornmann William , Kong Ling-Yuan , Donato Nicholas J.
Published: April 2007

c-Myc is a highly unstable transcription factor whose deregulation and increased expression are associated with cancer. Degrasyn, a small synthetic molecule, induces rapid degradation of c-Myc protein in MM-1 multiple myeloma and other tumor cell lines. Destruction of c-Myc by degrasyn requires the presence of a region of c-Myc between amino acid residues 316 and 378 that has not previously been associated with c-Myc stability. Degrasyn-induced degradation of c-Myc depends on proteasomes but is independent of the degron regions previously shown to be important for ubiquitin-mediated targeting and proteasomal destruction of the protein. Degrasyn-dependent c-Myc proteolysis is not mediated by any previously identified c-Myc regulatory mechanism, does not require new protein synthesis, and does not depend on the nuclear localization of c-Myc. Degrasyn reduced c-Myc levels in A375 melanoma cells and in A375 tumors in nude mice, and this activity correlated with tumor growth inhibition. Together, these results suggest that degrasyn reduces the stability of c-Myc in vitro and in vivo through a unique signaling process that uses c-Myc domains not previously associated with c-Myc regulation. [Cancer Res 2007;67(8):3912–8]
Phase I Study of Aerosolized SLIT Cisplatin in the Treatment of Patients with Carcinoma of the Lung
Authors: Wittgen Bart P.H. , Kunst Peter W.A. , van der Born Kasper , van Wijk Atie W. , Perkins Walter , Pilkiewicz Frank G. , Perez-Soler Roman , Nicholson Susan , Peters Godefridus J. , Postmus Pieter E.
Published: April 2007

Purpose: To investigate the safety and pharmacokinetics of aerosolized Sustained Release Lipid Inhalation Targeting (SLIT) Cisplatin in patients with lung carcinoma.

Experimental Design: Phase I, dose-escalating study of SLIT Cisplatin given in two sessions daily. Safety data, including laboratory variables, adverse events, pulmonary function tests, and radiographic imaging, were collected and analyzed for all patients to determine toxicity. Pharmacokinetic monitoring was done during the first course.

Results: Seventeen patients and one tracheostomy patient on compassionate use received treatment. Aerosolized cisplatin was well tolerated. No dose-limiting toxicity was observed at the maximum delivered dose. Safety data showed no hematologic toxicity, nephrotoxicity, ototoxicity, or neurotoxicity. Most common adverse events were nausea (64.7%), vomiting (47.1%), dyspnea (64.7%), fatigue (64.7%), and hoarseness (47.1%). Pharmacokinetic data showed very low plasma platinum levels only with the longest repeated inhalations. Common Toxicity Criteria grade 2 decrease in forced expiratory volume in one second and diffusing lung capacity for carbon monoxide after one course occurred both in two patients and grade one decrease in forced expiratory volume in one second and diffusing lung capacity for carbon monoxide in six and five patients, respectively. Direct airway deposition via the tracheostomy resulted in clinical deterioration after two cycles best described as bronchitis, completely reversible within days. Overall response: stable disease in 12 patients and progressive disease in 4 patients (one patient received one cycle).

Conclusions: Aerosolized liposomal cisplatin was found to be feasible and safe.
Multiplex Analysis of Serum Cytokines in Melanoma Patients Treated with Interferon-α2b
Authors: Yurkovetsky Zoya R. , Kirkwood John M. , Edington Howard D. , Marrangoni Adele M. , Velikokhatnaya Lyudmila , Winans Matthew T. , Gorelik Elieser , Lokshin Anna E.
Published: April 2007

Purpose: Interferon (IFN)-α2b is the only Food and Drug Administration–approved treatment for operable high-risk melanoma that has been shown to significantly and durably prolong relapse-free survival (RFS) of patients with stage IIB-III melanoma. Development of reliable serum assays may contribute to the development of methods for earlier detection of melanoma and the selection of patients who may be most susceptible to current available interventions with IFNα.

Experimental Design: A powerful high-throughput xMAP multiplex immunobead assay technology (Luminex Corp., Austin, TX) was used to simultaneously test 29 cytokines, chemokines, angiogenic as well as growth factors, and soluble receptors in the sera of 179 patients with high-risk melanoma and 378 healthy individuals.

Results: Serum concentrations of interleukin (IL)-1α, IL-1β, IL-6, IL-8, IL-12p40, IL-13, granulocyte colony-stimulating factor, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein (MIP)-1α, MIP-1β, IFNα, tumor necrosis factor (TNF)-α, epidermal growth factor, vascular endothelial growth factor (VEGF), and TNF receptor II were found to be significantly higher in patients with resected high-risk melanoma compared with healthy controls. Bayesian Network algorithm classification of the data offered 90% sensitivity at 98% specificity with 96.5% of melanoma patients distinguished from healthy individuals. IFN-α2b therapy resulted in a significant decrease of serum levels of immunosuppressive and tumor angiogenic/growth stimulatory factors (VEGF, epidermal growth factor, and hepatocyte growth factor) and increased levels of antiangiogenic IFN-γ inducible protein 10 (IP-10) and IFN-α. Pretreatment levels of proinflammatory cytokines IL-1β, IL-1α, IL-6, TNF-α, and chemokines MIP-1α and MIP-1β were found to be significantly higher in the serum of patients with longer RFS values of 1 to 5 and >5 years when compared with patients with shorter RFS of <1 year.

Conclusion: These data show that multiplexed analysis of serum biomarkers is useful for the evaluation of prognostic markers of clinical outcome and potential predictive markers of response to IFN-α2b in patients with high-risk operable melanoma.
Predicting Hepatocellular Carcinoma by Detection of Aberrant Promoter Methylation in Serum DNA
Authors: Zhang Yu-Jing , Wu Hui-Chen , Shen Jing , Ahsan Habibul , Tsai Wei Yann , Yang Hwai-I , Wang Li-Yu , Chen Shu-Yuan , Chen Chien-Jen , Santella Regina M.
Published: April 2007

Purpose: Most hepatocellular carcinomas (HCC) are diagnosed at an advanced stage. Hypermethylation of CpG islands in promoter regions is now recognized as an important early event in carcinogenesis and detection of methylated DNA has been suggested as a potential biomarker for early detection of cancer. There are no studies on epigenetic changes in samples from HCC patients before diagnosis. We explored the possible diagnostic value of aberrant promoter hypermethylation of three tumor suppressor genes in serum DNA for early detection of HCC.

Experimental Design: Aberrant promoter hypermethylation was investigated in DNA isolated from the serum of 50 HCC patients who provided repeated blood samples before diagnosis and 50 controls enrolled in a cancer screen program in Taiwan. Methylation-specific PCR was used to determine the methylation status of p16, p15, and ras association domain family 1A (RASSF1A).

Results: Among cases, aberrant methylation was found in serum DNA 1 to 9 years before clinical HCC diagnosis. RASSF1A had the highest frequency of hypermethylation with 35 (70%) cases having at least one positive sample compared with 22 (44%) for p16 and 12 (22%) for p15. Six subjects were hypermethylation negative for all three genes. For the 50 controls, promoter hypermethylation was found in three and two subjects for RASSF1A and p16, respectively; none had methylation of p15. A receiver operating characteristic curve that included clinical risk factors (age, HBsAg status, anti–hepatitis C virus status, smoking, and alcohol status) and hypermethylation biomarkers gave an overall predictive accuracy of 89% with sensitivity and specificity 84% and 94%, respectively.

Conclusions: The analysis of epigenetic changes on RASSF1A, p16, and p15 tumor suppressor genes in serum DNA may be a valuable biomarkers for early detection in populations at high risk of HCC.
Effect of Epidermal Growth Factor Receptor Inhibitor Class in the Treatment of Head and Neck Cancer with Concurrent Radiochemotherapy In vivo
Authors: Feng Felix Y. , Lopez Carlos A. , Normolle Daniel P. , Varambally Sooryanarayana , Li Xiaoxin , Chun Patrick Y. , Davis Mary A. , Lawrence Theodore S. , Nyati Mukesh K.
Published: April 2007

Purpose: To optimally integrate epidermal growth factor receptor (EGFR) inhibitors into the clinical treatment of head and neck cancer, two important questions must be answered: (a) does EGFR inhibition add to the effects of radiochemotherapy, and (b) if so, which method of inhibiting EGFR is superior (an EGFR antibody versus a small molecule tyrosine kinase inhibitor)? We designed an in vivo study to address these questions.

Experimental Design: Nude mice with UMSCC-1 head and neck cancer xenografts received either single, double, or triple agent therapy with an EGFR inhibitor (either cetuximab or gefitinib), gemcitabine, and/or radiation for 3 weeks. Tumor volumes and animal weights were measured for up to 15 weeks. Immunoblotting and immunofluorescent staining were done on tumors treated with either cetuximab or gefitinib alone.

Results: The addition of an EGFR inhibitor significantly delayed the tumor volume doubling time, from a median of 40 days with radiochemotherapy (gemcitabine and radiation) alone, to 106 days with cetuximab and 66 days with gefitinib (both P < 0.005). Cetuximab resulted in significantly less weight loss than gefitinib. Immunoblot analysis and immunofluorescent staining of tumors show that although levels of phosphorylated AKT and extracellular signal–regulated kinase were decreased similarly in response to cetuximab or gefitinib, cetuximab caused prolonged suppression of pEGFR, pSTAT3, and BclXL compared with gefitinib.

Conclusions: EGFR inhibition, particularly with cetuximab, improves the effectiveness of radiochemotherapy in this model of head and neck cancer. The correlation of response with prolonged suppression of EGFR, STAT3, and BclXL offers the possibility that these may be candidate biomarkers for response.
Role ofCD14Promoter Polymorphisms inHelicobacter pyloriInfection–Related Gastric Carcinoma
Authors: Zhao Dan , Sun Tong , Zhang Xuemei , Guo Yongli , Yu Dianke , Yang Ming , Tan Wen , Wang Guiqi , Lin Dongxin
Published: April 2007

Purpose: Genetic variation in CD14 may affect CD14 expression and susceptibility to Helicobacter pylori infection–related cancers. This study examined functional single nucleotide polymorphisms (SNP) in the CD14 promoter and their associations with risk of developing gastric carcinoma in relation to H. pylori infection.

Experimental Design: Thirty individual DNAs were sequenced to identify variants, and the function of the variants was examined by reporter gene assays. Genotypes and haplotypes were analyzed in 470 patients and 470 controls, and odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by logistic regression. Serologic H. pylori antibody and soluble CD14 (sCD14) levels were measured by ELISA.

Results: Two SNPs (−651C>T and −260C>T) were identified, of which the −260CT and −260TT genotypes were associated with elevated risk of gastric carcinoma (OR, 1.77; 95% CI, 1.09-2.85 and OR, 1.95; 95% CI, 1.20-3.16, respectively). Haplotype analysis suggested a synergistic effect of the two SNPs (OR for the T−651-T−260 haplotype, 3.39 versus OR for the C−651-T−260 haplotype, 1.45; P = 0.02), which is consistent with reporter gene assays. A multiplicative joint effect between H. pylori infection and −260C>T polymorphism was observed (OR for the presence of both −260TT genotype and H. pylori infection, 4.03; 95% CI, 1.80-9.04). Patients had significantly higher sCD14 than controls (1,866 ± 2,535 ng/mL versus 1,343 ± 2,119 ng/mL; P < 0.001), and this difference was associated with the CD14 −260 polymorphism and H. pylori infection.

Conclusions: Functional polymorphism in CD14 is associated with greater risk of H. pylori–related gastric carcinoma, which might be mediated by elevated sCD14.
Vorinostat for Treatment of Cutaneous Manifestations of Advanced Primary Cutaneous T-Cell Lymphoma
Authors: Mann Bhupinder S. , Johnson John R. , He Kun , Sridhara Rajeshwari , Abraham Sophia , Booth Brian P. , Verbois Leigh , Morse David E. , Jee Josephine M. , Pope Sarah , Harapanhalli Ravi S. , Dagher Ramzi , Farrell Ann , Justice Robert , Pazdur Richard
Published: April 2007

Purpose: To discuss vorinostat approval for treatment of cutaneous manifestations of advanced cutaneous T-cell lymphoma (CTCL).

Experimental Design: Data from 1 single-arm, open-label, multicenter pivotal trial and 11 other trials submitted to support the new drug application for vorinostat in the treatment of advanced primary CTCL were reviewed. The pivotal trial assessed responses by changes in overall skin disease score using a severity-weighted assessment tool (SWAT). Vorinostat could be considered active in CTCL if observed response rate was at least 20% and the lower bound of the corresponding 95% confidence interval (95% CI) excluded 5%. Patients reported pruritis relief using a questionnaire and a visual analogue scale.

Results: The pivotal trial enrolled 74 patients with stage IB or higher CTCL. Median number of prior treatments was 3, and 61 patients (82%) had stage IIB or higher disease. The objective response rate in the skin disease assessed by change in the overall SWAT score from the baseline was 30% (95% CI, 18.5 to 42.6) in patients with stage IIB or higher disease. Median response duration (end of response defined by 50% increase in SWAT score from the nadir) was 168 days. Median time to tumor progression was 148 days for overall population and 169 days for patients with stage IIB or higher disease. Assessment of pruritis relief was considered unreliable.

Conclusions: Vorinostat showed activity in CTCL, and skin responses were a clinical benefit. Vorinostat was approved for treatment of cutaneous manifestations of CTCL. A nonblinded, single-arm trial did not allow a reliable assessment of pruritis relief.
Proteomics of Canine Lymphoma Identifies Potential Cancer-Specific Protein Markers
Authors: McCaw Dudley L. , Chan Arvan S. , Stegner Andrew L. , Mooney Brian , Bryan Jeffrey N. , Turnquist Susan E. , Henry Carolyn J. , Alexander Hannah , Alexander Stephen
Published: April 2007

Purpose: Early diagnosis of cancer is crucial for the success of treatment of the disease, and there is a need for markers whose differential expression between disease and normal tissue could be used as a diagnostic tool. Spontaneously occurring malignancies in pets provide a logical tool for translational research for human oncology. Lymphoma, one of the most common neoplasms in dogs, is similar to human non–Hodgkin's lymphoma and could serve as an experimental model system.

Experimental Design: Thirteen lymph nodes from normal dogs and 11 lymph nodes from dogs with B-cell lymphoma were subjected to proteomic analysis using two-dimensional PAGE separation and matrix-assisted laser desorption/ionization time-of-flight analysis.

Results: A total of 93 differentially expressed spots was subjected to matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry analysis, and several proteins that showed differential expression were identified. Of these, prolidase (proline dipeptidase), triosephosphate isomerase, and glutathione S-transferase were down-regulated in lymphoma samples, whereas macrophage capping protein was up-regulated in the lymphoma samples.

Conclusions: These proteins represent potential markers for the diagnosis of lymphoma and should be further investigated in human samples for validation of their utility as diagnostic markers.
Targeting TRAIL Agonistic Receptors for Cancer Therapy
Authors: Carlo-Stella Carmelo , Lavazza Cristiana , Locatelli Alberta , Viganò Lucia , Gianni Alessandro M. , Gianni Luca
Published: April 2007

Based on preclinical studies demonstrating that tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) exerts a potent and cancer cell–specific proapoptotic activity, recombinant TRAIL as well as agonistic anti–TRAIL-R1 and anti–TRAIL-R2 antibodies recently entered clinical trials. Additionally, gene therapy approaches using TRAIL-encoding adenovirus (Ad-TRAIL) are currently being developed to overcome the limitations inherent to TRAIL receptor targeting, i.e., pharmacokinetic of soluble TRAIL, pattern of receptor expression, and tumor cell resistance. To optimize gene therapy approaches, CD34+ cells transduced with Ad-TRAIL (CD34-TRAIL+) have been investigated as cellular vehicles for TRAIL delivery. Transduced cells exhibit a potent tumor killing activity on a variety of tumor cell types both in vitro and in vivo and are also cytotoxic against tumor cells resistant to soluble TRAIL. Studies in tumor-bearing nonobese diabetic/severe combined immunodeficient mice suggest that the antitumor effect of CD34-TRAIL+ cells is mediated by both direct tumor cell killing due to apoptosis and indirect tumor cell killing due to vascular-disrupting mechanisms. The clinical translation of cell and gene therapy approaches represent a challenging strategy that might achieve systemic tumor targeting and increased intratumor delivery of the therapeutic agent.
HLA-DQB1*02–Restricted HPV-16 E7 Peptide–Specific CD4+ T-Cell Immune Responses Correlate with Regression of HPV-16–Associated High-Grade Squamous Intraepithelial Lesions
Authors: Peng Shiwen , Trimble Cornelia , Wu Lee , Pardoll Drew , Roden Richard , Hung Chien-Fu , Wu T.-C.
Published: April 2007

Purpose: The fact that up to 30% of established high-grade squamous intraepithelial lesions (HSIL) of the cervix regress spontaneously presents the opportunity to identify clinically relevant human papillomavirus (HPV) viral epitopes associated with disease outcome. Two human HPV antigens, E6 and E7, are functionally required for initiation and maintenance of cervical cancer precursor lesions and invasive cervical cancer. The identification and characterization of endogenously processed HPV antigenic epitopes in closely characterized patient cohorts will provide insight into the reasons for success or failure of therapeutic approaches.

Experimental Design: We characterized the HPV-16 E6/E7–specific T-cell epitopes using E6/E7 overlapping peptide pools with peripheral blood lymphocytes obtained from normal healthy donors. We then analyzed the difference in the HPV-16 T-cell immune responses in HPV-16+ HSIL patients with or without spontaneous regression of lesions using the statistical methods.

Results: We have identified an HPV-16 E7–specific CD4+ T-cell epitope [amino acids (aa) 71-85] that was restricted by HLA-DQB1*0201. Analysis of peripheral blood lymphocytes obtained from 14 HLA-DQB1*02 patients with HPV-16+ HSILs showed that the HPV-16+ E7 peptide (aa 71-85)–specific CD4+ T-cell immune response was significantly higher in the group of patients with regression compared with the patients without regression (P value <0.05).

Conclusions: The HPV-16 E7 peptide–specific CD4+ T-cell immune response correlates with spontaneous regression of established HPV16+ HSILs. Thus, this E7 epitope may be useful for the characterization of HPV-specific immune responses in patients infected with HPV-16 or immunized with HPV vaccines.
Neuregulin-1 Attenuates Neointimal Formation following Vascular Injury and Inhibits the Proliferation of Vascular Smooth Muscle Cells
Authors: Clement Ceiléssia M. , Thomas LaReese K. , Mou Yongsang , Croslan DaJoie R. , Gibbons Gary H. , Ford Byron D.
Published: April 2007

Neuregulin-1 (NRG-1) is expressed in vascular endothelial cells, and its receptors are localized to the underlying smooth muscle cells. However, the role of NRG-1 in vascular function and injury is largely unknown. First, the expression of NRG-1 and its receptors (erbB receptors) was analyzed after balloon injury to the rat carotid artery. NRG-1 and erbB expression levels were low in uninjured vessels; however, NRG-1 and erbB4 were upregulated following injury. We then examined the effect of NRG-1 on neointimal formation following balloon injury. NRG-1 was administered by tail-vein injection prior to injury and every 2 days following injury. Two weeks after injury, NRG-1-treated animals demonstrated a 50% reduction in lesion size compared with controls receiving the vehicle. To examine possible mechanisms for NRG-1 action, we examined its effects on vascular smooth muscle cell (VSMC) function. Rat VSMC cultures were pretreated with NRG-1 for 24 h and then stimulated with platelet-derived growth factor. NRG-1 significantly decreased platelet-derived growth factor-stimulated VSMC proliferation and migration. These findings suggest that NRG-1 may be a novel therapeutic candidate for the treatment of restenosis and atherosclerosis.
Activity of Endothelium-Derived Hyperpolarizing Factor Is Augmented in Monocrotaline-Induced Pulmonary Hypertension of Rat Lungs
Authors: Morio Yoshiteru , Homma Noriyuki , Takahashi Hideki , Yamamoto Akihito , Nagaoka Tetsutaro , Sato Koichi , Muramatsu Masashi , Fukuchi Yoshinosuke
Published: April 2007

The mechanism of endothelium-dependent vasodilator signaling involves three components such as nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). Although EDHF is distinct from nitric oxide and prostacyclin, it requires activation of Ca2+-sensitive K+ channels (KCa) and cytochrome P450 metabolites. However, the physiological role of EDHF in the pulmonary circulation is unclear. Thus, we tested if EDHF would regulate vascular tone in rat lungs of control and monocrotaline (MCT)-induced pulmonary hypertension. Inhibition of EDHF with a combination of KCa blockers, charybdotoxin (50 nM) plus apamin (50 nM), increased baseline vascular tone in MCT-induced hypertensive lungs. Thapsigargin (TG; 100 nM), an inhibitor of Ca-ATPase, caused greater EDHF-mediated vasodilation in MCT-induced hypertensive lungs. TG-induced vasodilation was abolished with the charybdotoxin-apamin combination. Sulfaphenazole (10 µM), a cytochrome P450 inhibitor, reduced the TG-induced vasodilation in MCT-induced hypertensive lungs. RT-PCR analysis exhibited an increase in KCa mRNA in MCT-treated lungs. These results indicate the augmentation of tonic EDHF activity, at least in part, through the alteration in cytochrome P450 metabolites and the upregulation of KCa expression in MCT-induced pulmonary hypertension.
Heredity of Endothelin Secretion
Authors: Lillie Elizabeth O. , Mahata Manjula , Khandrika Srikrishna , Rao Fangwen , Bundey Richard A. , Wen Gen , Chen Yuqing , Taupenot Laurent , Smith Douglas W. , Mahata Sushil K. , Ziegler Michael G. , Cockburn Myles , Schork Nicholas J. , O’Connor Daniel T.
Published: April 2007

Background—

Endothelial dysfunction predisposes to vascular injury in association with hypertension. Endothelin (ET-1) is a potent vasoactive peptide that is synthesized and released by the vascular endothelium and is a marker of endothelial function. Chromogranin A (CHGA) regulates the storage and release of catecholamines and may have direct actions on the microvasculature.
CHGA
, a candidate gene for intermediate phenotypes that contribute to hypertension, shows a pattern of single nucleotide polymorphism variations that alter the expression and function of this gene both in vivo and in vitro.

Methods and Results—

In a study of twins (n=238 pairs), plasma ET-1 was 58±5% (
P
<0.0001) heritable. Plasma ET-1 was both correlated and associated with chromogranin fragment levels, and the 2 were influenced by shared genetic determination (pleiotropy [ρ
G
]; for the CHGA precursor, ρ
G
=0.318±0.105;
P
=0.0032). We therefore hypothesized that variation in the
CHGA
gene may influence ET-1 secretion. Carriers of the
CHGA
promoter −988G, −462A, and −89A minor alleles showed significantly higher mean plasma ET-1 than their major allele homozygote counterparts (
P
=0.02,
P
=0.006,
P
=0.03, respectively). Analysis of a linkage disequilibrium block that spans these 3 single nucleotide polymorphisms showed a significant association between the GATACA haplotype and plasma ET-1 (
P
=0.0075). In cultured human umbilical vein endothelial cells, CHGA caused dose-dependent secretion of ET-1 over a brief (<1 hour) time course at relatively low concentrations of CHGA (10 to 100 nmol/L) with a threshold concentration (10 nmol/L) in the range found circulating in humans in vivo.

Conclusions—

These results suggest that common, heritable variation in expression of the human
CHGA
gene influences endothelial ET-1 secretion in vivo, explained by a CHGA stimulus/ET-1 secretion coupling in endothelial cells in vitro. The findings document a previously unsuspected interaction between the sympathochromaffin system and the endothelium and suggest novel genetic and cell biological approaches to the prediction, diagnosis, and mechanism of endothelial dysfunction in human disease.
Modeling the Interactions between Aerosols and Liquid Water Clouds with a Self-Consistent Cloud Scheme in a General Circulation Model
Authors: Ming Yi , Ramaswamy V. , Donner Leo J. , Phillips Vaughan T. J. , Klein Stephen A. , Ginoux Paul A. , Horowitz Larry W.
Published: April 2007

To model aerosol–cloud interactions in general circulation models (GCMs), a prognostic cloud scheme of cloud liquid water and amount is expanded to include droplet number concentration (Nd) in a way that allows them to be calculated using the same large-scale and convective updraft velocity field. In the scheme, the evolution of droplets fully interacts with the model meteorology. An explicit treatment of cloud condensation nuclei (CCN) activation enables the scheme to take into account the contributions to Nd of multiple aerosol species (i.e., sulfate, organic, and sea-salt aerosols) and to consider kinetic limitations of the activation process. An implementation of the prognostic scheme in the Geophysical Fluid Dynamics Laboratory (GFDL) AM2 GCM yields a vertical distribution of Nd with a characteristic maximum in the lower troposphere; this feature differs from the profile that would be obtained if Nd is diagnosed from the sulfate mass concentration based on an often-used empirical relationship. Prognosticated Nd exhibits large variations with respect to the sulfate mass concentration. The mean values are generally consistent with the empirical relationship over ocean, but show negative biases over the Northern Hemisphere midlatitude land, perhaps owing to the neglect of subgrid variations of large-scale ascents and inadequate convective sources. The prognostic scheme leads to a substantial improvement in the agreement of model-predicted present-day liquid water path (LWP) and cloud forcing with satellite measurements compared to using the empirical relationship.

The simulations with preindustrial and present-day aerosols show that the combined first and second indirect effects of anthropogenic sulfate and organic aerosols give rise to a steady-state global annual mean flux change of −1.8 W m−2, consisting of −2.0 W m−2 in shortwave and 0.2 W m−2 in longwave. The ratios of the flux changes in the Northern Hemisphere (NH) to that in Southern Hemisphere (SH) and of the flux changes over ocean to that over land are 2.9 and 0.73, respectively. These estimates are consistent with the averages of values from previous studies stated in a recent review. The model response to higher Nd alters the cloud field; LWP and total cloud amount increase by 19% and 0.6%, respectively. Largely owing to high sulfate concentrations from fossil fuel burning, the NH midlatitude land and oceans experience strong radiative cooling. So does the tropical land, which is dominated by biomass burning–derived organic aerosol. The computed annual, zonal-mean flux changes are determined to be statistically significant, exceeding the model’s natural variations in the NH low and midlatitudes and in the SH low latitudes. This study reaffirms the major role of sulfate in providing CCN for cloud formation.
Vortex Street Dynamics: The Selection Mechanism for the Areas and Locations of Jupiter’s Vortices
Authors: Humphreys Tom , Marcus Philip S.
Published: April 2007

With the exception of the Great Red Spot, Jupiter’s long-lived vortices are not isolated, but occur in east–west rows. Each row is centered about a westward-going jet stream with anticyclones on the poleward side and cyclones on the equatorial. Vortices are staggered so that like-signed vortices are never longitudinally adjacent. These double rows of vortices, called here Jovian vortex streets (JVSs) are robust. Calculations with no forcing and no dissipation (i.e., Hamiltonian dynamics) allow a continuum of JVS solutions, so they cannot be used to determine the physics that selects the observed values of the areas, circulations, and locations of Jupiter’s vortices. Constraints imposed by stability put few bounds on these values. When small amounts of dissipation and forcing are added to the governing equations, there is no longer a continuum of solutions; an initial JVS that was a solution of the Hamiltonian equations is now out of equilibrium and evolves to an attractor. For fixed forcing, all initial JVS evolve to the same attractor, so that the area of the vortices in the late-time JVS is selected uniquely as is the separation width in latitude between the row of cyclones and row of anticyclones. The separation width of the attracting JVS is nearly independent of the forcing, but the areas of the vortices in the attracting JVS depend strongly on the strength of the forcing, which is a measure of the ambient Jovian turbulence. Results are compared with observations.
Vertical-Mode and Cloud Decomposition of Large-Scale Convectively Coupled Gravity Waves in a Two-Dimensional Cloud-Resolving Model
Authors: Tulich Stefan N. , Randall David A. , Mapes Brian E.
Published: April 2007

This paper describes an analysis of large-scale [O(1000 km)] convectively coupled gravity waves simulated using a two-dimensional cloud-resolving model. The waves develop spontaneously under uniform radiative cooling and approximately zero-mean-flow conditions, with wavenumber 2 of the domain appearing most prominently and right-moving components dominating over left-moving components for random reasons. The analysis discretizes the model output in two ways. First, a vertical-mode transform projects profiles of winds, temperature, and heating onto the vertical modes of the model’s base-state atmosphere. Second, a cloud-partitioning algorithm sorts sufficiently cloudy grid columns into three categories: shallow convective, deep convective, and stratiform anvil.

Results show that much of the tilted structures of the waves can be captured by just two main vertical spectral “bands,” each consisting of a pair of vertical modes. The “slow” modes have propagation speeds of 16 and 18 m s−1 (and roughly a full-wavelength vertical structure through the troposphere), while the “fast” modes have speeds of 35 and 45 m s−1 (and roughly a half-wavelength structure). Deep convection anomalies in the waves are more or less in phase with the low-level cold temperature anomalies of the slow modes and in quadrature with those of the fast modes. Owing to the characteristic life cycle of deep convective cloud systems, shallow convective heating peaks ∼2 h prior to maximum deep convective heating, while stratiform heating peaks ∼3 h after. The onset of deep convection in the waves is preceded by a gradual deepening of shallow convection lasting a period of many hours.

Results of this study are in broad agreement with simple two-mode models of unstable large-scale wave growth, under the name “stratiform instability.” Differences here are that 1) the key dynamical modes have speeds in the range 16–18 m s−1, rather than 23–25 m s−1 (owing to a shallower depth of imposed radiative cooling), and 2) deep convective heating, as well as stratiform heating, is essential for the generation and maintenance of the slow modes.
Assessing Predictability with a Local Ensemble Kalman Filter
Authors: Kuhl David , Szunyogh Istvan , Kostelich Eric J. , Gyarmati Gyorgyi , Patil D. J. , Oczkowski Michael , Hunt Brian R. , Kalnay Eugenia , Ott Edward , Yorke James A.
Published: April 2007

In this paper, the spatiotemporally changing nature of predictability is studied in a reduced-resolution version of the National Centers for Environmental Prediction (NCEP) Global Forecast System (GFS), a state-of-the-art numerical weather prediction model. Atmospheric predictability is assessed in the perfect model scenario for which forecast uncertainties are entirely due to uncertainties in the estimates of the initial states. Uncertain initial conditions (analyses) are obtained by assimilating simulated noisy vertical soundings of the “true” atmospheric states with the local ensemble Kalman filter (LEKF) data assimilation scheme. This data assimilation scheme provides an ensemble of initial conditions. The ensemble mean defines the initial condition of 5-day deterministic model forecasts, while the time-evolved members of the ensemble provide an estimate of the evolving forecast uncertainties. The observations are randomly distributed in space to ensure that the geographical distribution of the analysis and forecast errors reflect predictability limits due to the model dynamics and are not affected by inhomogeneities of the observational coverage.

Analysis and forecast error statistics are calculated for the deterministic forecasts. It is found that short-term forecast errors tend to grow exponentially in the extratropics and linearly in the Tropics. The behavior of the ensemble is explained by using the ensemble dimension (E dimension), a spatiotemporally evolving measure of the evenness of the distribution of the variance between the principal components of the ensemble-based forecast error covariance matrix.

It is shown that in the extratropics the largest forecast errors occur for the smallest E dimensions. Since a low value of the E dimension guarantees that the ensemble can capture a large portion of the forecast error, the larger the forecast error the more certain that the ensemble can fully capture the forecast error. In particular, in regions of low E dimension, ensemble averaging is an efficient error filter and the ensemble spread provides an accurate prediction of the upper bound of the error in the ensemble-mean forecast.
A Combined Eddy-Diffusivity Mass-Flux Approach for the Convective Boundary Layer
Authors: Siebesma A. Pier , Soares Pedro M. M. , Teixeira João
Published: April 2007

A better conceptual understanding and more realistic parameterizations of convective boundary layers in climate and weather prediction models have been major challenges in meteorological research. In particular, parameterizations of the dry convective boundary layer, in spite of the absence of water phase-changes and its consequent simplicity as compared to moist convection, typically suffer from problems in attempting to represent realistically the boundary layer growth and what is often referred to as countergradient fluxes. The eddy-diffusivity (ED) approach has been relatively successful in representing some characteristics of neutral boundary layers and surface layers in general. The mass-flux (MF) approach, on the other hand, has been used for the parameterization of shallow and deep moist convection. In this paper, a new approach that relies on a combination of the ED and MF parameterizations (EDMF) is proposed for the dry convective boundary layer. It is shown that the EDMF approach follows naturally from a decomposition of the turbulent fluxes into 1) a part that includes strong organized updrafts, and 2) a remaining turbulent field. At the basis of the EDMF approach is the concept that nonlocal subgrid transport due to the strong updrafts is taken into account by the MF approach, while the remaining transport is taken into account by an ED closure. Large-eddy simulation (LES) results of the dry convective boundary layer are used to support the theoretical framework of this new approach and to determine the parameters of the EDMF model. The performance of the new formulation is evaluated against LES results, and it is shown that the EDMF closure is able to reproduce the main properties of dry convective boundary layers in a realistic manner. Furthermore, it will be shown that this approach has strong advantages over the more traditional countergradient approach, especially in the entrainment layer. As a result, this EDMF approach opens the way to parameterize the clear and cumulus-topped boundary layer in a simple and unified way.
Choosing the Smoothing Parameters within a Multiple-Pass Barnes Objective Analysis Scheme: A Cautionary Note
Authors: Spencer Phillip L. , Askelson Mark A. , Doswell Charles A.
Published: April 2007

Various combinations of smoothing parameters within a two-pass Barnes objective analysis scheme are applied to analytic observations obtained by regular and irregular sampling of a one-dimensional sinusoidal analytic wave to obtain gridded fields. Each of these various combinations of smoothing parameters would produce equivalent analyses if the observations were continuous and infinite (unbounded). The authors demonstrate that owing to the discreteness of the analytic observations, the actual analyses resulting from these various combinations of smoothing parameters are different. When derivatives are computed and as stations become more irregularly distributed, these differences increase. An awareness of these potentially significant analysis differences should prompt the analyst to consider carefully the choice of smoothing parameters when applying an objective analysis scheme to real observations.