bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxaliplatin neurotoxicity of sensory transduction in rat proprioceptors
Authors: Bullinger Katie L. , Nardelli Paul , Wang Qingbo , Rich Mark M. , Cope Timothy C.
Published: May 2011

Neurotoxic effects of oxaliplatin chemotherapy, including proprioceptive impairments, are debilitating and dose limiting. Here, we sought to determine whether oxaliplatin interrupts normal proprioceptive feedback by impairing sensory transduction of muscle length and force by neurons that are not damaged by dying-back neuropathy. Oxaliplatin was administered over 4 wk to rats in doses that produced systemic changes, e.g., decreased platelets and stunted weight gain, but no significant abnormality in the terminal ends of primary muscle spindle sensory neurons. The absence of neuropathy enabled the determination of whether oxaliplatin caused functional deficits in sensory encoding without the confounding issue of axon death. Rats were anesthetized, and action potentials encoding muscle stretch and contraction were recorded intra-axonally from dorsal roots. In striking contrast with normal proprioceptors, those from oxaliplatin-treated rats typically failed to sustain firing during static muscle stretch. The ability of spindle afferents to sustain and centrally conduct trains of action potentials in response to rapidly repeated transient stimuli, i.e., vibration, demonstrated functional competence of the parent axons. These data provide the first evidence that oxaliplatin causes persistent and selective deficits in sensory transduction that are not due to axon degeneration. Our findings raise the possibility that even those axons that do not degenerate after oxaliplatin treatment may have functional deficits that worsen outcome.
Deletion of a subgroup of ribosome-related genes minimizes hypoxia-induced changes and confers hypoxia tolerance
Authors: Shah Ajit N. , Cadinu Daniela , Henke R. Michael , Xin Xiantong , Ghosh Dastidar Ranita , Zhang Li
Published: May 2011

Hypoxia is a widely occurring condition experienced by diverse organisms under numerous physiological and disease conditions. To probe the molecular mechanisms underlying hypoxia responses and tolerance, we performed a genome-wide screen to identify mutants with enhanced hypoxia tolerance in the model eukaryote, the yeast Saccharomyces cerevisiae . Yeast provides an excellent model for genomic and proteomic studies of hypoxia. We identified five genes whose deletion significantly enhanced hypoxia tolerance. They are RAI1, NSR1, BUD21, RPL20A, and RSM22, all of which encode functions involved in ribosome biogenesis. Further analysis of the deletion mutants showed that they minimized hypoxia-induced changes in polyribosome profiles and protein synthesis. Strikingly, proteomic analysis by using the iTRAQ profiling technology showed that a substantially fewer number of proteins were changed in response to hypoxia in the deletion mutants, compared with the parent strain. Computational analysis of the iTRAQ data indicated that the activities of a group of regulators were regulated by hypoxia in the wild-type parent cells, but such regulation appeared to be diminished in the deletion strains. These results show that the deletion of one of the genes involved in ribosome biogenesis leads to the reversal of hypoxia-induced changes in gene expression and related regulators. They suggest that modifying ribosomal function is an effective mechanism to minimize hypoxia-induced specific protein changes and to confer hypoxia tolerance. These results may have broad implications in understanding hypoxia responses and tolerance in diverse eukaryotes ranging from yeast to humans.
Polarized Raman Spectra of NH4Al(SO4) 2·12H2O
Authors: Boujelbene M. , Mhiri T.
Published: May 2011

The study by spectroscopie Raman relave to compound was interpreted and attributed one being based Theory of group and by comparison with others composed. The current studies of the polarised Raman spectra of give evidence that the disorder is indeed present in the ammonium alum. This is best manifested through the appearance of surplus bands in the spectral regions of vibrations of the sulphate anion.
Effect of One Year of Cryopreservation on the Activity of Lysosomal Hydrolases from EBV‐Transformed Lymphocytes
Authors: de Mello A. S. , Mendes F. B. , Michelin-Tireli K. , Camelier M. V. , Coelho J. C.
Published: May 2011

Background. The Epstein‐Barr virus (EBV) was used as an agent of B lymphocyte proliferation for subsequent diagnosis of lysosomal storage disease.
Due to the constant handling of long‐preserved samples in our cell bank, we decided to observe the behavior and then compare cultured and frozen samples for at least one year′s cryopreservation. Methods. Twenty‐five samples from healthy individuals were used to assess the
possible changes in activity of enzymes β‐galactosidase, β‐glucosidase, α‐iduronidase, α‐galactosidase, and α‐glucosidase. Transmission electron microscopy was used to confirm cell transformation of B lymphocytes into EBV‐infected cells, generating lymphoblastoid cell lines.
Results. Transmission electron microscopy findings confirmed previous reports in the literature that is, significant and evident morphological changes in the nucleus occur after day 12 and the consequent cell transformation into EBV‐infected cells. After thawing and subsequent treatment with the five enzymes utilized, we observed no significant changes in samples cryopreserved for more than one year, as compared to samples cultured for 12 days.
The Structural Basis of Ligand Recognition by Natural Killer Cell Receptors
Authors: Joyce M. Gordon , Sun Peter D.
Published: May 2011

Natural killer cells are a group of lymphocytes which function as tightly controlled surveillance operatives which identify transformed cells through a discrete balance of activating and inhibitory receptors ultimately leading to the destruction of incongruent cells. The understanding of this finely tuned balancing act has been aided by the high‐resolution structure determination of activating and inhibitory receptors both alone and in complex with their ligands. This paper collates these structural studies detailing the aspects which directly relate to the natural killer cell function and serves to inform both the specialized structural biologist reader and a more general immunology audience.
Pricing Variance Swaps for Stochastic Volatilities with Delay and Jumps
Authors: Swishchuk Anatoliy , Xu Li
Published: May 2011

We study the valuation of the variance swaps under stochastic volatility with delay
and jumps. In our model, the volatility of the underlying stock price process not only
incorporates jumps, which are found to be active empirically, but also exhibits past dependence: the behavior of a stock price right after a given time t depends not only on
the situation at t but also on the whole past (history) of the process S(t) up to time t as well.
The jump part in our model is finally represented by a general version of compound
Poisson processes. We provide some analytical closed forms for the expectation of the
realized variance for the stochastic volatility with delay and jumps. We also present a
lower bound for delay as a measure of risk. As applications of our analytical solutions,
a numerical example using S&P60 Canada Index (1998–2002) is then provided to price
variance swaps.
The Effects of Old Age on Hepatic Stellate Cells
Authors: Warren Alessandra , Cogger Victoria C. , Fraser Robin , DeLeve Laurie D. , McCuskey Robert S. , Le Couteur David G.
Published: May 2011

Aging is associated with marked changes in the hepatic sinusoid, yet the effect of old age on hepatic stellate cells (HSC) has not been well described. Transmission electron microscopy and immunohistochemistry were used to study the effects of aging on HSC in livers from rats (3-4 mths versus 24–27 mths) and mice (2-3 mths versus 20–22 mths). Desmin-positive HSC doubled in old age in both mice and rats. Alpha-smooth muscle actin- (αSMA-) positive cells did not increase significantly and remained only a small percentage of desmin-positive cells. Electron microscopy revealed that old age is associated with HSC that have a substantial increase in the number of lipid droplets which are larger in diameter. There was also a marked increase of HSC that protruded into the sinusoidal lumen in old mice. In conclusion, old age is associated with hyperplasia of HSC that are not activated and are engorged with lipid droplets.
Chlamydia trachomatisGenotypes and the Swedish New Variant among UrogenitalChlamydia trachomatisStrains in Finland
Authors: Niemi Suvi , Hiltunen-Back Eija , Puolakkainen Mirja
Published: May 2011

Our aims were to genotypeChlamydia trachomatisstrains present in urogenital samples and to investigate the occurrence of the Swedish new variant ofC. trachomatisin Finland. We genotyped 160C. trachomatispositive samples withompAreal-time PCR and analyzed 495 samples for the new variant. The three most prevalent genotypes were E (40%), F (28%), and G (13%). Only two specimens containing bacteria with the variant plasmid were detected. It seems that in Finland the percentage of infections due to genotypes F and G has slightly increased during the last 20 years. Genotypes E and G appear to be more common, and genotypes J/Ja and I/Ia appear to be less common in Europe than in the USA. Although the genotype E was the most common genotype amongC. trachomatisstrains, the new variant was rarely found in Finland.
Vulvar Merkel Carcinoma: A Case Report
Authors: Iavazzo C. , Terzi M. , Arapantoni-Dadioti P. , Dertimas V. , Vorgias G.
Published: May 2011

This is a new case of Merkel cell carcinoma of the vulva. It is a rare neuroendocrine carcinoma with an aggressive behavior. Because of its rarity in this location, it is not clear whether it behaves differently from the usual neuroendocrine carcinomas of the skin. A case of a 63-year-old patient with vulvar Merkel carcinoma is presented. The clinical presentation, microscopic and immunohistochemical features, and treatment are discussed.
Oxidative Stress and Redox Modulation Potential in Type 1 Diabetes
Authors: Delmastro Meghan M. , Piganelli Jon D.
Published: May 2011

Redox reactions are imperative to preserving cellular metabolism yet must be strictly regulated. Imbalances between reactive oxygen species (ROS) and antioxidants can initiate oxidative stress, which without proper resolve, can manifest into disease. In type 1 diabetes (T1D), T-cell-mediated autoimmune destruction of pancreaticβ-cells is secondary to the primary invasion of macrophages and dendritic cells (DCs) into the islets. Macrophages/DCs, however, are activated by intercellular ROS from resident pancreatic phagocytes and intracellular ROS formed after receptor-ligand interactions via redox-dependent transcription factors such as NF-κB. Activated macrophages/DCs ferryβ-cell antigens specifically to pancreatic lymph nodes, where they trigger reactive T cells through synapse formation and secretion of proinflammatory cytokines and more ROS. ROS generation, therefore, is pivotal in formulating both innate and adaptive immune responses accountable for islet cell autoimmunity. The importance of ROS/oxidative stress as well as potential for redox modulation in the context of T1D will be discussed.
The Thickness Distribution of Oxidation Film on Tapered Pipe Surface in Dieless Drawing
Authors: Qin Fang , Liu Xue-Feng , Mao Hao-En
Published: May 2011

The thickness distribution of oxidation film on the surface of AISI304 stainless steel tapered pipe, its influence factors, and the effect of metal matrix deformation on oxidation behavior during dieless drawing were studied in this paper. The results showed that oxidation rate was affected strongly by induction heating temperature and deformation degree. The thickness distribution of oxidation film was uneven and increased from the larger diameter end to the smaller diameter end along the axial direction of tapered pipe. When induction heating temperature raised or the distance between heat and cold sources was increased, or feed speed was decreased, oxidation rate was accelerated and oxidation film on the tapered pipe surface thickened significantly, due to massive cracks in oxidation film induced by deformation of metal matrix. The density and width of cracks in oxidation film were enlarged, and the thickness of oxidation film increased with the increase in deformation degree.
High‐Resolution Numerical Simulation and Analysis of Mach ReflectionStructures in Detonation Waves in Low‐Pressure H2–O2–Ar Mixtures: A Summary of Results Obtained with the Adaptive Mesh Refinement Framework AMROC
Authors: Deiterding Ralf
Published: May 2011

Numerical simulation can be key to the understanding of the multidimensional nature of transient detonation waves. However, the accurate approximation of realistic detonations is demanding as a wide range of scales needs to be resolved. This paper describes a successful solution strategy that utilizes logically rectangular dynamically adaptive meshes. The hydrodynamic transport scheme and the treatment of the nonequilibrium reaction terms are sketched. A ghost fluid approach is integrated into the method to allow for embedded geometrically complex boundaries. Large‐scale parallel simulations of unstable detonation structures of Chapman‐Jouguet detonations in low‐pressure hydrogen‐oxygen‐argon mixtures demonstrate the efficiency of the described techniques in practice. In particular, computations of regular cellular structures in two and three space dimensions and their development under transient conditions, that is, under diffraction and for propagation through bends are presented. Some of the observed patterns are classified by shock polar analysis, and a diagram of the transition boundaries between possible Mach reflection structures is constructed.
Near‐Infrared Spectroscopy of the Bladder: New Parameters for Evaluating Voiding Dysfunction
Authors: Macnab Andrew , Shadgan Babak , Afshar Kourosh , Stothers Lynn
Published: May 2011

We describe innovative methodology for monitoring alterations in bladder oxygenation and haemodynamics in humans using near‐infrared spectroscopy (NIRS). Concentrations of the chromophores oxygenated (O2Hb) and deoxygenated (HHb) haemoglobin and their sum (total haemoglobin) differ during bladder contraction in health and disease. A wireless device that incorporates three paired light emitting diodes (wavelengths 760 and 850 nanometers) and silicon photodiode detector collects data transcutaneously (10 Hz) with the emitter/detector over the bladder during spontaneous bladder emptying. Data analysis indicates comparable patterns of change in chromophore concentration in healthy children and adults (positive trend during voiding, predominantly due to elevated O2Hb), but different changes in symptomatic subjects with characteristic chromophore patterns identified for voiding dysfunction due to specific pathophysiologies: bladder outlet obstruction (males), overactive bladder (females), and nonneurogenic dysfunction (children). Comparison with NIRS muscle data suggests altered bladder haemodynamics and/or oxygenation may underlie voiding dysfunction offering new insight into the causal physiology.
Recurrent Incisional Hernia due to Pseudomyxoma Peritonei
Authors: Ergul Zafer , Olcucuoglu Engin , Kulacoglu Hakan , Dener Cenap
Published: May 2011

Pseudomyxoma peritonei is a rare but challenging neoplastic disease which is characterized with intraperitoneal mucinous-gelatinous fluid accumulation. It rarely presents as a mass mimicking abdominal wall hernias A recurrent incisional hernia due to pseudomyxoma peritonei is presented here. A 60-year-old female patient had been operated on for a left mucinous ovarian cyst 20 cm in diameter in 1998. Mucinous material had disseminated into interloop spaces through the right subdiaphragmatic region. Total abdominal hysterectomy + bilateral salpingooophorectomy and peritoneal toilet had been performed. She was rehospitalized for abdominal distention and a 4 cm defect over the incision and underwent a hernia repair using polypropylene mesh in 2001. Abdominal distention recurred to give a rise to an incisional hernia in 2006. She was reoperated for decompression and repair, but nothing could be done because of sticky adhesions and the incision were simply closed. The patient was referred to our department for operation. A prosthetic hernia repair with30×30 cm polypropylene mesh was performed. The patient was discharged on the postoperative 5th day following an uneventful recovery. However, she died of disseminated disease after 18 months.
Splicing Factor hnRNP A2/B1 Regulates Tumor Suppressor Gene Splicing and Is an Oncogenic Driver in Glioblastoma
Authors: Golan-Gerstl Regina , Cohen Michal , Shilo Asaf , Suh Sung-Suk , Bakàcs Arianna , Coppola Luigi , Karni Rotem
Published: May 2011

The process of alternative splicing is widely misregulated in cancer, but the contribution of splicing regulators to cancer development is largely unknown. In this study, we found that the splicing factor hnRNP A2/B1 is overexpressed in glioblastomas and is correlated with poor prognosis. Conversely, patients who harbor deletions of the HNRNPA2B1 gene show better prognosis than average. Knockdown of hnRNP A2/B1 in glioblastoma cells inhibited tumor formation in mice. In contrast, overexpression of hnRNP A2/B1 in immortal cells led to malignant transformation, suggesting that HNRNPA2B1 is a putative proto-oncogene. We then identified several tumor suppressors and oncogenes that are regulated by HNRNPA2B1, among them are c-FLIP, BIN1, and WWOX, and the proto-oncogene RON. Knockdown of RON inhibited hnRNP A2/B1 mediated transformation, which implied that RON is one of the mediators of HNRNPA2B1 oncogenic activity. Together, our results indicate that HNRNPA2B1 is a novel oncogene in glioblastoma and a potential new target for glioblastoma therapy. Cancer Res; 71(13); 4464–72. ©2011 AACR.
Imaging DNA Damage In Vivo Using γH2AX-Targeted Immunoconjugates
Authors: Cornelissen Bart , Kersemans Veerle , Darbar Sonali , Thompson James , Shah Ketan , Sleeth Kate , Hill Mark A. , Vallis Katherine A.
Published: May 2011

DNA damage responses (DDR) occur during oncogenesis and therapeutic responses to DNA damaging cytotoxic drugs. Thus, a real-time method to image DNA damage in vivo would be useful to diagnose cancer and monitor its treatment. Toward this end, we have developed fluorophore- and radioisotope-labeled immunoconjugates to target a DDR signaling protein, phosphorylated histone H2A variant H2AX (γH2AX), which forms foci at sites of DNA double-strand breaks. Anti-γH2AX antibodies were modified by the addition of diethylenetriaminepentaacetic acid (DTPA) to allow 111In labeling or the fluorophore Cy3. The cell-penetrating peptide Tat (GRKKRRQRRRPPQGYG) was also added to the immunoconjugate to aid nuclear translocation. In irradiated breast cancer cells, confocal microscopy confirmed the expected colocalization of anti-γH2AX-Tat with γH2AX foci. In comparison with nonspecific antibody conjugates, 111In-anti-γH2AX-Tat was retained longer in cells. Anti-γH2AX-Tat probes were also used to track in vivo DNA damage, using a mouse xenograft model of human breast cancer. After local X-ray irradiation or bleomycin treatment, the anti-γH2AX-Tat probes produced fluorescent and single photon emission computed tomography signals in the tumors that were proportionate to the delivered radiation dose and the amount of γH2AX present. Taken together, our findings establish the use of radioimmunoconjugates that target γH2AX as a noninvasive imaging method to monitor DNA damage, with many potential applications in preclinical and clinical settings. Cancer Res; 71(13); 4539–49. ©2011 AACR.
MicroRNA Sequence and Expression Analysis in Breast Tumors by Deep Sequencing
Authors: Farazi Thalia A. , Horlings Hugo M. , ten Hoeve Jelle J. , Mihailovic Aleksandra , Halfwerk Hans , Morozov Pavel , Brown Miguel , Hafner Markus , Reyal Fabien , van Kouwenhove Marieke , Kreike Bas , Sie Daoud , Hovestadt Volker , Wessels Lodewyk F.A. , van de Vijver Marc J. , Tuschl Thomas
Published: May 2011

MicroRNAs (miRNA) regulate many genes critical for tumorigenesis. We profiled miRNAs from 11 normal breast tissues, 17 noninvasive, 151 invasive breast carcinomas, and 6 cell lines by in-house–developed barcoded Solexa sequencing. miRNAs were organized in genomic clusters representing promoter-controlled miRNA expression and sequence families representing seed sequence–dependent miRNA target regulation. Unsupervised clustering of samples by miRNA sequence families best reflected the clustering based on mRNA expression available for this sample set. Clustering and comparative analysis of miRNA read frequencies showed that normal breast samples were separated from most noninvasive ductal carcinoma in situ and invasive carcinomas by increased miR-21 (the most abundant miRNA in carcinomas) and multiple decreased miRNA families (including miR-98/let-7), with most miRNA changes apparent already in the noninvasive carcinomas. In addition, patients that went on to develop metastasis showed increased expression of mir-423, and triple-negative breast carcinomas were most distinct from other tumor subtypes due to upregulation of the mir∼17–92 cluster. However, absolute miRNA levels between normal breast and carcinomas did not reveal any significant differences. We also discovered two polymorphic nucleotide variations among the more abundant miRNAs miR-181a (T19G) and miR-185 (T16G), but we did not identify nucleotide variations expected for classical tumor suppressor function associated with miRNAs. The differentiation of tumor subtypes and prediction of metastasis based on miRNA levels is statistically possible but is not driven by deregulation of abundant miRNAs, implicating far fewer miRNAs in tumorigenic processes than previously suggested. Cancer Res; 71(13); 4443–53. ©2011 AACR.
STAT3 Plays a Critical Role in KRAS-Induced Pancreatic Tumorigenesis
Authors: Corcoran Ryan B. , Contino Gianmarco , Deshpande Vikram , Tzatsos Alexandros , Conrad Claudius , Benes Cyril H. , Levy David E. , Settleman Jeffrey , Engelman Jeffrey A. , Bardeesy Nabeel
Published: May 2011

The STAT3 transcription factor is an important regulator of stem cell self-renewal, cancer cell survival, and inflammation. In the pancreas, STAT3 is dispensable for normal development, whereas the majority of pancreatic ductal adenocarcinomas (PDAC) show constitutive activation of STAT3, suggesting its potential as a therapeutic target in this cancer. Here, we sought to define the mechanisms of STAT3 activation and its functional importance in PDAC pathogenesis. Large-scale screening of cancer cell lines with a JAK2 inhibitor that blocks STAT3 function revealed a more than 30-fold range in sensitivity in PDAC, and showed a close correlation of sensitivity with levels of tyrosine-phosphorylated STAT3 and of the gp130 receptor, an upstream signaling component. Correspondingly, upregulation of the IL6/LIF-gp130 pathway accounted for the strong STAT3 activation in PDAC subsets. To define functions of STAT3 in vivo, we developed mouse models that test the impact of conditional inactivation of STAT3 in KRAS-driven PDAC. We showed that STAT3 is required for the development of the earliest premalignant pancreatic lesions, acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Moreover, acute STAT3 inactivation blocked PDAC initiation in a second in vivo model. Our results show that STAT3 has critical roles throughout the course of PDAC pathogenesis, supporting the development of therapeutic approaches targeting this pathway. Moreover, our work suggests that gp130 and phospho-STAT3 expression may be effective biomarkers for predicting response to JAK2 inhibitors. Cancer Res; 71(14); 5020–9. ©2011 AACR.
Epidermal Growth Factor Receptor Inhibition Augments the Expression of MHC Class I and II Genes
Authors: Pollack Brian P. , Sapkota Bishu , Cartee Todd V.
Published: May 2011

Purpose: Diverse immune-related effects occur with the use of epidermal growth factor receptor inhibitors (EGFRI). In addition to the cutaneous inflammation induced by EGFRIs, these agents have been associated with the exacerbation of autoimmune skin disease and contact hypersensitivity, antiviral effects, and fatal alveolar damage in the setting of lung transplantation. Because EGFR ligands can modulate MHC class I (MHCI) and II (MHCII) molecule expression, we hypothesized that some of the immune-related effects of EGFRIs are due to direct effects on the expression of MHCI and/or MHCII molecules.

Experimental Design: Primary human keratinocytes and a malignant keratinocyte cell line (A431) were treated with EGFRIs alone or prior to IFN-γ, a potent inducer of MHCI and MHCII molecule expression. CIITA, MHCI, and MHCII RNA expression was measured using quantitative real-time reverse transcriptase PCR, and cell surface MHCI and MHCII protein expression was measured using flow cytometry. Skin biopsies from patients were analyzed for MHCI and MHCII protein expression before and during therapy with an EGFRI using immunohistochemistry.

Results: Both EGFR tyrosine kinase inhibitors and ligand-blocking antibodies (cetuximab) augmented the induction of MHCI and MHCII molecules by IFN-γ in primary and malignant human keratinocytes. Unexpectedly, the increase in MHCI protein expression did not require the presence of IFN-γ. Consistent with these in vitro findings, skin biopsies from cancer patients exhibited increased epidermal MHCI protein expression during therapy with an EGFRI as well as increases in MHCI and MHCII molecule RNA.

Conclusions: These studies suggest that EGFRIs may influence immune/inflammatory responses by directly modulating MHC expression. Clin Cancer Res; 17(13); 4400–13. ©2011 AACR.
Telomerase Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma Patients
Authors: Kyte Jon Amund , Gaudernack Gustav , Dueland Svein , Trachsel Sissel , Julsrud Lars , Aamdal Steinar
Published: May 2011

Purpose: The study is a proof-of-principle trial evaluating toxicity, immune response, and clinical response in melanoma patients after combined therapy with temozolomide and the telomerase peptide vaccine GV1001. Our previous GV1001 trials showed immune responses in approximately 60% of lung or pancreatic cancer patients.

Experimental Design: Twenty-five subjects with advanced stage IV melanoma (M1B or M1C) received concomitant temozolomide and GV1001. Temozolomide was administered 200 mg/m2 orally for 5 days every fourth week, and GV1001 as eight injections over 11 weeks. Immune response was evaluated by delayed type hypersensitivity, T-cell proliferation, and cytokine assays. The immunologic responders continued monthly vaccination.

Results: The treatment was well tolerated. A GV1001-specific immune response was shown in 18 of 23 evaluated subjects (78%). Patients developing long-term T-cell memory survived more than those rapidly losing their responses. The immune response exhibited several characteristics of possible clinical significance including high IFNγ/IL-10 ratios, polyfunctional cytokine profiles, and recognition of naturally processed antigens. Survival compared favorably with matched controls from a benchmark meta-analysis (1 year: 44% vs. 24%, 2 years: 16% vs. 6.6%). The clinical responses developed gradually over years, contrary to what is expected from chemotherapy. Five patients developed partial tumor regression and six more recorded stable disease. One patient has no remaining disease on fluorodeoxyglucose positron emission tomography scans after 5 years.

Conclusions: The immunologic response rate is considerable compared with previous GV1001 trials without concomitant chemotherapy, although low toxicity is retained. The results warrant further studies of GV1001/temozolomide treatment and support the general concept of combining cancer vaccination with chemotherapy. Clin Cancer Res; 17(13); 4568–80. ©2011 AACR.
Early G1 Cyclin-Dependent Kinases as Prognostic Markers and Potential Therapeutic Targets in Esophageal Adenocarcinoma
Authors: Ismail Amin , Bandla Santhoshi , Reveiller Marie , Toia Liana , Zhou Zhongren , Gooding William E. , Kalatskaya Irina , Stein Lincoln , D'Souza Mary , Litle Virginia R. , Peters Jeffrey H. , Pennathur Arjun , Luketich James D. , Godfrey Tony E.
Published: May 2011

Purpose: Chromosomal gain at 7q21 is a frequent event in esophageal adenocarcinoma (EAC). However, this event has not been mapped with fine resolution in a large EAC cohort, and its association with clinical endpoints and functional relevance are unclear.

Experimental Design: We used a cohort of 116 patients to fine map the 7q21 amplification using SNP microarrays. Prognostic significance and functional role of 7q21 amplification and its gene expression were explored.

Results: Amplification of the 7q21 region was observed in 35% of tumors with a focal, minimal amplicon containing six genes. 7q21 amplification was associated with poor survival and analysis of gene expression identified cyclin-dependent kinase 6 (CDK6) as the only gene in the minimal amplicon whose expression was also associated with poor survival. A low-level amplification (10%) was observed at the 12q13 region containing the CDK6 homologue cyclin-dependent kinase 4 (CDK4). Both amplification and expression of CDK4 correlated with poor survival. A combined model of both CDK6 and CDK4 expressions is a superior predictor of survival than either alone. Specific knockdown of CDK4 and/or CDK6 by siRNAs shows that they are required for proliferation of EAC cells and that their function is additive. PD-0332991 targets the kinase activity of both molecules and suppresses proliferation and anchorage independence of EAC cells through activation of the pRB pathway.

Conclusions: We suggest that CDK6 is the driver of 7q21 amplification and that both CDK4 and CDK6 are prognostic markers and bona fide oncogenes in EAC. Targeting these molecules may constitute a viable new therapy for this disease. Clin Cancer Res; 17(13); 4513–22. ©2011 AACR.
Time-Course Imaging of Therapeutic Functional Tumor Vascular Normalization by Antiangiogenic Agents
Authors: Zhang Qingbei , Bindokas Vytas , Shen Jikun , Fan Hanli , Hoffman Robert M. , Xing H. Rosie
Published: May 2011

We describe here new technology that enables noninvasive imaging of therapeutic functional normalization of tumor blood vessels by antiangiogenic agents. Noninvasive variable-magnification in vivo-fluorescence imaging as well as fluorescence tomography was used to visualize functional vessel normalization. Changes in the same vessel before and after drug treatment were imaged with high resolution in real time. Differences in vascular responses to the mTOR inhibitor rapamycin and to an anti-VEGF antibody were functionally imaged. Tumor vessel normalization was shown by significantly reduced leakiness and subsequent improved tumor delivery of Paclitaxel-BODPY as well as by normalized morphology. The tumor vascular pool agent, AngioSense750, was retained only in tumors after either anti-VEGF antibody or rapamycin treatment, as visualized by noninvasive fluorescence tomography. The antiangiogenic therapy normalized vessels, which significantly enhanced the antitumor efficacy of paclitaxel because of increased drug penetration throughout the tumor. The optical imaging technology described here is thus a powerful, noninvasive, time-course imaging tool of functional tumor vessel normalization and its therapeutic consequences. Mol Cancer Ther; 10(7); 1173–84. ©2011 AACR.
Azithromycin Inhibits IL-5 Production of T Helper Type 2 Cells from Asthmatic Children
Authors: Lin Syh-Jae , Lee Wan-Jung , Liang Yu-Wen , Yan Dah-Chin , Cheng Po-Jen , Kuo Ming-Ling
Published: May 2011

Background: Childhood asthma is a type 2 helper T (Th2) cell-driven inflammatory airway disease characterized by recurrent episodes of airway obstruction. Azithromycin (AZM), a macrolide antibiotic exhibiting anti-inflammatory activity aside from its antibacterial effect, may prove beneficial for asthmatic children. This study aimed to determine the effect of AZM on Th2 cells from atopic asthmatic children and non-atopic controls. Methods: CD4+ cells were isolated from peripheral blood mononuclear cells of 9 patients with asthma and 9 non-atopic individuals. Cells were activated as Th0 and differentiated into Th2 cells. The effect of AZM on activated CD4+ cells was evaluated with respective cell proliferation and cytokine production. Results: Th0 and Th2 CD4+ T cells from atopic asthmatic children produced greater interleukin (IL)-5 (Th2 cytokine) but lower interferon (IFN)-γ (Th1 cytokine) compared to the non-atopic controls, respectively. AZM inhibited IL-5 production of Th0 and Th2 cells from atopic asthmatics in a dose-dependent fashion, without significantly affecting their IL-13 and IFN-γ production. A similar effect was observed in non-atopic controls except that AZM did inhibit IFN-γ production of their Th0 cells. AZM at a higher dose decreased cell viability by inhibiting CD4+ T cell proliferation and enhanced their apoptosis, an effect similarly observed in Th0 and Th2 cells, and did not differ between asthmatic children and controls. Conclusion: Our finding that AZM preferentially downregulates IL-5 production suggests its therapeutic potentials in controlling childhood asthma.
Immune Regulation by CD4+CD25+ Regulatory T Cells in Patients with Japanese Cedar Pollinosis
Authors: Yamanishi Takahiro , Chikamatsu Kazuaki , Takahashi Goro , Endo Shuichiro , Masuyama Keisuke
Published: May 2011

Background: Evidence indicating that CD4+CD25+ regulatory T (Treg) cells play a crucial role in the maintenance of peripheral T cell tolerance to allergens has been accumulated. To explore the functional role of Treg cells in patients with Japanese cedar pollinosis, we performed an in vitro investigation of the regulation of immune responses to allergens by Treg cells. Methods: CD4+ and CD4+CD25– T cells obtained from 12 patients with Japanese cedar pollinosis were stimulated with Cry j 1 protein and Cry j 1-derived peptide. On day 6, T cells were tested for allergen-specific reactivity using a CFSE-based proliferation assay and cytokine ELISA assays. The frequency of Cry j 1-specific interleukin (IL)-10-producing Treg cells was assessed by ELISPOT assays. Results: The proportion of proliferated cells induced by allergen stimulation was similar in both CD4+ and CD4+CD25– cell cultures. The production of interferon (IFN)-γ, but not that of IL-5 was significantly enhanced in CD4+CD25– cell cultures compared to that in CD4+ cell cultures. Interestingly, the production of IL-10 was decreased in CD4+CD25– cell cultures. Moreover, Cry j 1-specific IL-10-producing Treg cells were detected in pollen-allergic patients. Conclusion: Our findings suggest that in pollen-allergic patients, Treg cells predominantly suppresses Th1 responses rather than Th2 responses, where allergen-specific IL-10-producing Treg cells may also be responsible for the downregulation of allergen-specific immune responses.
Taut Internal Limiting Membrane Causing Diffuse Diabetic Macular Edema after Vitrectomy: Clinicopathological Correlation
Authors: Gentile Ronald C. , Milman Tatyana , Eliott Dean , Romero Juan M. , McCormick Steven A.
Published: May 2011

Aims: To describe 2 cases of diffuse diabetic macular edema (DME) after diabetic vitrectomy caused by a taut internal limiting membrane (ILM), with clinicopathological correlation. Methods: Interventional case series with immunohistochemical analysis. Results: Two patients were referred for unresponsive diffuse DME after pars plana vitrectomy with removal of the posterior hyaloid. Clinically, a taut ILM was noted over the fovea, and its removal resulted in rapid and long-term resolution of the edema, confirmed by optical coherence tomography with visual acuity improvement. Histopathology with immunostaining revealed a segment of ILM with an inner monolayer of cytokeratin-positive (retinal pigment epithelial cells) and/or glial fibrillary acidic protein-positive cells with smooth muscle actin immunoreactivity. Conclusions: A taut ILM can cause diffuse DME after vitrectomy, and its removal can restore the normal foveal contour and improve visual acuity. Tangential tractional forces from contractile cells propagated across the fovea via the ILM appear to be the etiology.
Sixteen New Cases Contributing to the Characterization of Patients with Distal 22q11.2 Microduplications
Authors: Wincent J. , Bruno D.L. , van Bon B.W.M. , Bremer A. , Stewart H. , Bongers E.M.H.F. , Ockeloen C.W. , Willemsen M.H. , Keays D.A.D. , Baird G. , Newbury D.F. , Kleefstra T. , Marcelis C. , Kini U. , Stark Z. , Savarirayan R. , Sheffield L.J. , Zuffardi O. , Slater H.R. , de Vries B.B. , Knight S.J.L. , Anderlid B.-M. , Schoumans J.
Published: May 2011

The chromosome region 22q11.2 has long been recognized to be susceptible to genomic rearrangement. More recently, this genomic instability has been shown to extend distally (involving LCR22E–H) to the commonly deleted/duplicated region. To date, 21 index cases with ‘distal’ 22q11.2 duplications have been reported. We report on the clinical and molecular characterization of 16 individuals with distal 22q11.2 duplications identified by DNA microarray analysis. Two of the individuals have been partly described previously. The clinical phenotype varied among the patients in this study, although the majority displayed various degrees of developmental delay and speech disturbances. Other clinical features included behavioral problems, hypotonia, and dysmorphic facial features. Notably, none of the patients was diagnosed with a congenital heart defect. We found a high degree of inherited duplications. Additional copy number changes of unclear clinical significance were identified in 5 of our patients, and it is possible that these may contribute to the phenotypic expression in these patients as has been suggested recently in a 2-hit ‘digenic’ model for 16p12.1 deletions. The varied phenotypic expression and incomplete penetrance observed for distal 22q11.2 duplications makes it exceedingly difficult to ascribe pathogenicity for these duplications. Given the observed enrichment of the duplication in patient samples versus healthy controls, it is likely that distal 22q11.2 duplications represent a susceptibility/risk locus for speech and mild developmental delay.
TGIF Mutations in Human Holoprosencephaly: Correlation between Genotype and Phenotype
Authors: Keaton A.A. , Solomon B.D. , Kauvar E.F. , El-Jaick K.B. , Gropman A.L. , Zafer Y. , Meck J.M. , Bale S.J. , Grange D.K. , Haddad B.R. , Gowans G.C. , Clegg N.J. , Delgado M.R. , Hahn J.S. , Pineda-Alvarez D.E. , Lacbawan F. , Vélez J.I. , Roessler E. , Muenke M.
Published: May 2011

Holoprosencephaly (HPE), which results from failed or incomplete midline forebrain division early in gestation, is the most common forebrain malformation. The etiology of HPE is complex and multifactorial. To date, at least 12 HPE-associated genes have been identified, including TGIF (transforming growth factor beta-induced factor), located on chromosome 18p11.3. TGIF encodes a transcriptional repressor of retinoid responses involved in TGF-β signaling regulation, including Nodal signaling. TGIF mutations are reported in approximately 1–2% of patients with non-syndromic, non-chromosomal HPE.We combined data from our comprehensive studies of HPE with a literature search for all individuals with HPE and evidence of mutations affecting TGIF in order to establish the genotypic and phenotypic range. We describe 2 groups of patients: 34 with intragenic mutations and 21 with deletions of TGIF. These individuals, which were ascertained from our research group, in collaboration with other centers, and through a literature search, include 38 probands and 17 mutation-positive relatives. The majority of intragenic mutations occur in the TGIF homeodomain. Patients with mutations affecting TGIFrecapitulate the entire phenotypic spectrum observed in non-chromosomal, non-syndromic HPE. We identified a statistically significant difference between the 2 groups with respect to inheritance, as TGIF deletions were more likely to be de novo in comparison to TGIF mutations (χ2(2) = 6.97, ppermutated = 0.0356). In addition, patients with TGIF deletions were also found to more commonly present with manifestations beyond the craniofacial and neuroanatomical features associated with HPE (p = 0.0030). These findings highlight differences in patients with intragenic mutations versus deletions affecting TGIF, and draw attention to the homeodomain region, which appears to be particularly relevant to HPE. These results may be useful for genetic counseling of affected patients.
Operator Radiation Exposure During Percutaneous Coronary Procedures Through the Left or Right Radial Approach
Authors: Sciahbasi Alessandro , Romagnoli Enrico , Trani Carlo , Burzotta Francesco , Sarandrea Alessandro , Summaria Francesco , Patrizi Roberto , Rao Sunil , Lioy Ernesto
Published: May 2011

Background—

Transradial percutaneous coronary procedures may be effectively performed through the right radial approach (RRA) or the left radial approach (LRA), but data on radiation dose absorbed by operators comparing the two approaches are lacking. The aim of the present study was to evaluate radiation dose absorbed by operators during coronary procedures through the RRA and LRA.

Methods and Results—

Three operators were equipped with 5 different dosimeters (left wrist, shoulder, thorax outside the lead apron, thorax under the lead apron, and thyroid) during RRA or LRA for coronary procedures. Each month, the dosimeters were analyzed to determine the radiation dose absorbed. From February to December 2009, 390 patients were randomly assigned to the RRA (185 patients; age, 66±11 years) or the LRA (185 patients; age, 66±11 years). There were no significant differences in fluoroscopy time (for RRA, 369 seconds; interquartile range, 134 to 857 seconds; for LRA, 362 seconds; interquartile range, 142 to 885 seconds;
P
=0.58) between the 2 groups. There were no significant differences in monthly radiation dose at the thorax (0.85±0.46 mSv for RRA and 1.12±0.78 mSv for LRA,
P
=0.33), at the thyroid (0.36±0.2 mSv for RRA and 0.34±0.3 mSv for LRA,
P
=0.87), and at the shoulder (0.73±0.44 mSv for RRA and 0.94±0.42 mSv for LRA,
P
=0.27). The dose at the wrist was significantly higher for the RRA (2.44±1.12 mSv) compared with the LRA (1±0.8 mSv,
P
=0.002). In both radial approaches, the thoracic radiation dose under the lead apron was undetectable.

Conclusions—

Compared with RRA, LRA for coronary procedures is associated with similar radiation dose for operators at the body, shoulder, or thyroid level, with a possible significant advantage at the wrist. The cumulative radiation dose for both approaches is well under to the annual dose-equivalent limit.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00282646.
Multimodal Optimization Using a Bi-Objective Evolutionary Algorithm
Authors: Deb Kalyanmoy , Saha Amit
Published: May 2011

In a multimodal optimization task, the main purpose is to find multiple optimal solutions (global and local), so that the user can have better knowledge about different optimal solutions in the search space and as and when needed, the current solution may be switched to another suitable optimum solution. To this end, evolutionary optimization algorithms (EA) stand as viable methodologies mainly due to their ability to find and capture multiple solutions within a population in a single simulation run. With the preselection method suggested in 1970, there has been a steady suggestion of new algorithms. Most of these methodologies employed a niching scheme in an existing single-objective evolutionary algorithm framework so that similar solutions in a population are deemphasized in order to focus and maintain multiple distant yet near-optimal solutions. In this paper, we use a completely different strategy in which the single-objective multimodal optimization problem is converted into a suitable bi-objective optimization problem so that all optimal solutions become members of the resulting weak Pareto-optimal set. With the modified definitions of domination and different formulations of an artificially created additional objective function, we present successful results on problems with as large as 500 optima. Most past multimodal EA studies considered problems having only a few variables. In this paper, we have solved up to 16-variable test problems having as many as 48 optimal solutions and for the first time suggested multimodal constrained test problems which are scalable in terms of number of optima, constraints, and variables. The concept of using bi-objective optimization for solving single-objective multimodal optimization problems seems novel and interesting, and more importantly opens up further avenues for research and application.
Supporting Meteorological Field Experiment Missions and Postmission Analysis with Satellite Digital Data and Products
Authors: Hawkins Jeffrey , Velden Christopher
Published: May 2011

Atmospheric and oceanographic field experiments are an important part of research programs aimed at enhancing observational analyses of meteorological and oceanic phenomena, validating new datasets, and/or supporting hypotheses. The Bulletin of the American Meteorological Society (BAMS) has chronicled many field programs, with a primary focus on the enhanced observational assets that were assembled to enable the projects' investigations. However, these field program summaries often overlook the multiple roles that satellite digital data, multispectral imagery, and derived products can play in premission planning, real-time forecasting and mission guidance, and extensive post–field phase analysis. In turn, these intensive observing periods often serve as crucial validation datasets for remotely sensed products and derived fields.
Advanced Concepts on Remote Sensing of Precipitation at Multiple Scales
Authors: Sorooshian Soroosh , AghaKouchak Amir , Arkin Phillip , Eylander John , Foufoula-Georgiou Efi , Harmon Russell , Hendrickx Jan M. H. , Imam Bisher , Kuligowski Robert , Skahill Brian , Skofronick-Jackson Gail
Published: May 2011

No abstract available.
Airborne Intrumentation Needs for Climate and Atmospheric Research
Authors: McFarquhar Greg , Schmid Beat , Korolev Alexei , Ogren John A. , Russell Philip B. , Tomlinson Jason , Turner David D. , Wiscombe Warren
Published: May 2011

No Abstract available.
On the Factors Modulating the Stratocumulus to Cumulus Transitions
Authors: Sandu Irina , Stevens Bjorn
Published: May 2011

Large-eddy simulation (LES) is used to explore the role of various processes in regulating the stratocumulus to cumulus transition (SCT). Simulations are based on a composite case derived from a Lagrangian analysis of 2 yr of data from the northeastern Pacific. The simulations reproduce well the observed transition from a compact stratocumulus layer to more broken fields of cumulus, simply as a response to increasing sea surface temperatures (SSTs) along the transition. In so doing they support earlier theoretical work that argued that the SCT was a response of boundary layer circulations to increased forcing by surface latent heat fluxes. Although the basic features of the SCT imposed by the increase in SST are robust, a variety of other factors affect the detailed character of the SCT. For example, enhanced precipitation or increased downwelling longwave radiative fluxes can accelerate the reduction in cloud cover that accompanies the SCT, while a gradual decrease in the large-scale divergence can make changes in cloud cover that accompany the SCT relatively more modest. The simulations also demonstrate that the pace of the SCT is mainly set by the strength of the temperature inversion capping the initial stratocumulus-topped boundary layer.