bluuebunny/crossref_metadata_2025 huggingface dataset:
CXCL12 Mediates Immunosuppression in the Lymphoma Microenvironment after Allogeneic Transplantation of Hematopoietic Cells
Authors: Dürr Christoph , Pfeifer Dietmar , Claus Rainer , Schmitt-Graeff Annette , Gerlach Ulrike V. , Graeser Ralph , Krüger Sophie , Gerbitz Armin , Negrin Robert S. , Finke Jürgen , Zeiser Robert
Published: December 2010

Clinical studies indicate a role of allogeneic hematopoietic cell transplantation (alloHCT) for patients with refractory or recurrent B-cell lymphoma (BCL) indicative of a graft-versus-tumor effect. However, the relevance of local immunosuppression in the BCL microenvironment by donor-derived regulatory T cells (Treg) after alloHCT is unclear. Therefore, we studied Treg recruitment after alloHCT in different murine BCL models and the impact of lymphoma-derived chemoattractive signals. Luciferase transgenic Tregs accumulated in murine BCL microenvironment and microarray-based analysis of BCL tissues revealed increased expression of CXCL9, CXCL10, and CXCL12. In vivo blocking identified the CXCR4/CXCL12 axis as being critical for Treg attraction toward BCL. In contrast to Tregs, effector T cells displayed low levels of CXCR4 and were not affected by the pharmacologic blockade. Most important, blocking CXCR4 not only reduced Treg migration toward tumor tissue but also enhanced antitumor responses after alloHCT. CXCL12 production was dependent on antigen-presenting cells (APC) located in the lymphoma microenvironment, and their diphtheria-toxin receptor (DTR)-based depletion in CD11c.DTR-Tg mice significantly reduced Treg accumulation within BCL tissue. CXCL12 was also detected in human diffuse, large BCL tissues indicative of its potential clinical relevance. In conclusion, we demonstrate that Tregs are recruited toward BCL after alloHCT by infiltrating host APCs in a CXCL12-dependent fashion. Blocking CXCR4 enhanced antitumor effects and prolonged survival of tumor-bearing mice by reducing local Treg accumulation, indicating that CXCR4 is a potential target to interfere with tumor escape after alloHCT. Cancer Res; 70(24); 10170–81. ©2010 AACR.
NEDD8-Targeting Drug MLN4924 Elicits DNA Rereplication by Stabilizing Cdt1 in S Phase, Triggering Checkpoint Activation, Apoptosis, and Senescence in Cancer Cells
Authors: Lin Jie Jessie , Milhollen Michael A. , Smith Peter G. , Narayanan Usha , Dutta Anindya
Published: December 2010

MLN4924 is a first-in-class experimental cancer drug that inhibits the NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and stabilizing many cullin substrates. The mechanism by which MLN4924 inhibits cancer cell proliferation has not been defined, although it is accompanied by DNA rereplication and attendant DNA damage. Here we show that stabilization of the DNA replication factor Cdt1, a substrate of cullins 1 and 4, is critical for MLN4924 to trigger DNA rereplication and inhibit cell proliferation. Even only 1 hour of exposure to MLN4924, which was sufficient to elevate Cdt1 for 4–5 hours, was found to be sufficient to induce DNA rereplication and to activate apoptosis and senescence pathways. Cells in S phase were most susceptible, suggesting that MLN4924 will be most toxic on highly proliferating cancers. Although MLN4924-induced cell senescence seems to be dependent on induction of p53 and its downstream effector p21Waf1, we found that p53−/− and p21−/− cells were even more susceptible than wild-type cells to MLN4924. Our results suggested that apoptosis, not senescence, might be more important for the antiproliferative effect of MLN4924. Furthermore, our findings show that transient exposure to this new investigational drug should be useful for controlling p53-negative cancer cells, which often pose significant clinical challenge. Cancer Res; 70(24); 10310–20. ©2010 AACR.
Coexpression Network Analysis Identifies Transcriptional Modules Related to Proastrocytic Differentiation and Sprouty Signaling in Glioma
Authors: Ivliev Alexander E. , 't Hoen Peter A.C. , Sergeeva Marina G.
Published: December 2010

Gliomas are primary brain tumors with high mortality and heterogeneous biology that is insufficiently understood. In this study, we performed a systematic analysis of the intrinsic organization of complex glioma transcriptome to gain deeper knowledge of the tumor biology. Gene coexpression relationships were explored in 790 glioma samples from 5 published patient cohorts treated at different institutions. We identified 20 coexpression modules that were common to all the data sets and associated with proliferation, angiogenesis, hypoxia, immune response, genomic alterations, cell differentiation phenotypes, and other features inherent to glial tumors. A collection of high-quality signatures for the respective processes was obtained using cross-data set summarization of the modules' gene composition. Individual modules were found to be organized into higher order coexpression groups, the two largest of them associated with glioblastoma and oligodendroglioma, respectively. We identified a novel prognostic gene expression signature (185 genes) linked to a proastrocytic pattern of tumor cell differentiation. This “proastrocytic” signature was associated with long survival and defined a subgroup of the previously established “proneural” class of gliomas. A strong negative correlation between proastrocytic and proneural markers across differentiated tumors underscored the distinction between these subtypes of glioma. Interestingly, one further novel signature in glioma was identified that was associated with EGFR (epidermal growth factor receptor) gene amplification and suggested that EGF signaling in glioma may be a subject to regulation by Sprouty family proteins. In summary, this integrated analysis of the glioma transcriptome provided several novel insights into molecular heterogeneity and pathogenesis of glial tumors. Cancer Res; 70(24); 10060–70. ©2010 AACR.
Coexpression of Oct4 and Nanog Enhances Malignancy in Lung Adenocarcinoma by Inducing Cancer Stem Cell–Like Properties and Epithelial–Mesenchymal Transdifferentiation
Authors: Chiou Shih-Hwa , Wang Mong-Lien , Chou Yu-Ting , Chen Chi-Jen , Hong Chun-Fu , Hsieh Wang-Ju , Chang Hsin-Tzu , Chen Ying-Shan , Lin Tzu-Wei , Hsu Han-Sui , Wu Cheng-Wen
Published: December 2010

Epithelial–mesenchymal transition (EMT), a critical process of cancer invasion and metastasis, is associated with stemness property of cancer cells. Though Oct4 and Nanog are homebox transcription factors essential to the self-renewal of stem cells and are expressed in several cancers, the role of Oct4/Nanog signaling in tumorigenesis is still elusive. Here microarray and quantitative real-time PCR analysis showed a parallel, elevated expression of Oct4 and Nanog in lung adenocarcinoma (LAC). Ectopic expressions of Oct4 and Nanog in LACs increased the percentage of CD133-expressing subpopulation and sphere formation, enhanced drug resistance, and promoted EMT. Ectopic expressions of Oct4 and Nanog activated Slug and enhanced the tumor-initiating capability of LAC. Furthermore, double knockdown of Oct4 and Nanog suppressed the expression of Slug, reversed the EMT process, blocked the tumorigenic and metastatic ability, and greatly improved the mean survival time of transplanted immunocompromised mice. The immunohistochemical analysis demonstrated that expressions of Oct4, Nanog, and Slug were present in high-grade LAC, and triple positivity of Oct4/Nanog/Slug indicated a worse prognostic value of LAC patients. Our results support the notion that the Oct4/Nanog signaling controls epithelial–mesenchymal transdifferentiation, regulates tumor-initiating ability, and promotes metastasis of LAC. Cancer Res; 70(24); 10433–44. ©2010 AACR.
Identification of PP2A Complexes and Pathways Involved in Cell Transformation
Authors: Sablina Anna A. , Hector Melissa , Colpaert Nathalie , Hahn William C.
Published: December 2010

The simian virus 40 small t (SV40ST) oncoprotein interacts with protein phosphatase 2A (PP2A), an abundantly expressed family of serine–threonine phosphatases. This interaction is essential for the transformation of human cells by SV40, and several PP2A subunits have been implicated as tumor suppressor genes. However, the pathways controlled by specific PP2A complexes involved in cell transformation remain incompletely understood. Using a comprehensive loss-of-function approach, we identified 4 PP2A regulatory subunits [B56α, B56γ, PR72/PR130, and PTPA (protein phosphatase 2A activator)], which when suppressed replaced the expression of SV40ST in human cell transformation. We found that manipulation of complexes containing PP2A B56α, B56γ, and PR72/PR130 activates the pathways regulated by c-Myc, Wnt, and PI3K (phosphoinositide 3-kinase)/Akt in a manner that depends on their specific phosphatase activity. In contrast, suppression of PTPA disrupts the assembly of PP2A heterotrimeric complexes, which leads to the activation of these same oncogenic pathways. These observations delineate the PP2A family members and pathways perturbed by SV40ST during human cell transformation. Cancer Res; 70(24); 10474–84. ©2010 AACR.
Twenty-Second Annual Pezcoller Symposium: RNA Biology and Cancer
Authors: Bernards René , Filipowicz Witold , Livingston David M. , Mihich Enrico
Published: December 2010

The 22nd annual Pezcoller Symposium titled “RNA Biology and Cancer” was held in Trento, Italy, on June 10–12, 2010. The program of the symposium was developed by Drs. Rene Bernards, Witold Filipowicz, and David Livingston; they cochaired the meeting in cooperation with Dr. Enrico Mihich. The topics discussed included the opportunities offered by small RNA as tools for cancer drug development, the role of noncoding RNAs, the biochemistry of small RNAs, the function of micro RNA in cancer, and RNAs as diagnostics and therapeutics in cancer. Cancer Res; 70(24); 10034–7. ©2010 AACR.
Histone H3 Lysine 79 Methyltransferase Dot1 Is Required for Immortalization by MLL Oncogenes
Authors: Chang Ming-Jin , Wu Hongyu , Achille Nicholas J. , Reisenauer Mary Rose , Chou Chau-Wen , Zeleznik-Le Nancy J. , Hemenway Charles S. , Zhang Wenzheng
Published: December 2010

Chimeric oncoproteins resulting from fusion of MLL to a wide variety of partnering proteins cause biologically distinctive and clinically aggressive acute leukemias. However, the mechanism of MLL-mediated leukemic transformation is not fully understood. Dot1, the only known histone H3 lysine 79 (H3K79) methyltransferase, has been shown to interact with multiple MLL fusion partners including AF9, ENL, AF10, and AF17. In this study, we utilize a conditional Dot1l deletion model to investigate the role of Dot1 in hematopoietic progenitor cell immortalization by MLL fusion proteins. Western blot and mass spectrometry show that Dot1-deficient cells are depleted of the global H3K79 methylation mark. We find that loss of Dot1 activity attenuates cell viability and colony formation potential of cells immortalized by MLL oncoproteins but not by the leukemic oncoprotein E2a-Pbx1. Although this effect is most pronounced for MLL-AF9, we find that Dot1 contributes to the viability of cells immortalized by other MLL oncoproteins that are not known to directly recruit Dot1. Cells immortalized by MLL fusions also show increased apoptosis, suggesting the involvement of Dot1 in survival pathways. In summary, our data point to a pivotal requirement for Dot1 in MLL fusion protein–mediated leukemogenesis and implicate Dot1 as a potential therapeutic target. Cancer Res; 70(24); 10234–42. ©2010 AACR.
Peroxisome Proliferator-Activated Receptor-γ Activation Inhibits Tumor Metastasis by Antagonizing Smad3-Mediated Epithelial-Mesenchymal Transition
Authors: Reka Ajaya Kumar , Kurapati Himabindu , Narala Venkata R. , Bommer Guido , Chen Jun , Standiford Theodore J. , Keshamouni Venkateshwar G.
Published: December 2010

Epithelial-mesenchymal transition (EMT) was shown to confer tumor cells with abilities essential for metastasis, including migratory phenotype, invasiveness, resistance to apoptosis, evading immune surveillance, and tumor stem cell traits. Therefore, inhibition of EMT can be an important therapeutic strategy to inhibit tumor metastasis. Here, we show that activation of peroxisome proliferator-activated receptor γ (PPAR-γ) inhibits transforming growth factor β (TGF-β)-induced EMT in lung cancer cells and prevents metastasis by antagonizing Smad3 function. Activation of PPAR-γ by synthetic ligands (troglitazone and rosiglitazone) or by a constitutively active form of PPAR-γ prevents TGF-β–induced loss of E-cadherin expression and inhibits the induction of mesenchymal markers (vimentin, N-cadherin, fibronectin) and matrix metalloproteases. Consistently, activation of PPAR-γ also inhibited EMT-induced migration and invasion of lung cancer cells. Furthermore, effects of PPAR-γ ligands were attenuated by siRNA-mediated knockdown of PPAR-γ, indicating that the ligand-induced responses are PPAR-γ dependent. Selective knockdown of Smad2 and Smad3 by siRNA showed that TGF-β–induced EMT is Smad3 dependent in lung cancer cells. Activation of PPAR-γ inhibits TGF-β–induced Smad transcriptional activity but had no effect on the phosphorylation or nuclear translocation of Smads. Consistently, PPAR-γ activation prevented TGF-β–induced transcriptional repression of E-cadherin promoter and inhibited transcriptional activation of N-cadherin promoter. Finally, treatment of mice with troglitazone or knockdown of Smad3 in tumor cells significantly inhibited TGF-β–induced experimental metastasis in SCID-Beige mice. Together, with the low toxicity profile of PPAR-γ ligands, our data show that these ligands may serve as potential therapeutic agents to inhibit metastasis. Mol Cancer Ther; 9(12); 3221–32. ©2010 AACR.
The Transmembrane Adaptor Cbp/PAG1 Controls the Malignant Potential of Human Non–Small Cell Lung Cancers That Have c-Src Upregulation
Authors: Kanou Takashi , Oneyama Chitose , Kawahara Kunimitsu , Okimura Akira , Ohta Mitsunori , Ikeda Naoki , Shintani Yasushi , Okumura Meinoshin , Okada Masato
Published: December 2010

The tyrosine kinase c-Src is upregulated in various human cancers, although the precise regulatory mechanism underlying this upregulation is unclear. We previously reported that a transmembrane adaptor Csk-binding protein (Cbp; PAG1) plays an important role in controlling the cell transformation that is induced by the activation of c-Src. To elucidate the in vivo role of Cbp, we examined the function of Cbp in lung cancer cell lines and tissues. In this study, we found that Cbp was markedly downregulated in human non–small cell lung cancer (NSCLC) cells. The ectopic expression of Cbp suppressed the anchorage-independent growth of the NSCLC cell lines (A549 and Lu99) that had upregulated c-Src, whereas the Cbp expression had little effect on other NSCLC cell lines (PC9 and Lu65) that express normal levels of c-Src. The expression of Cbp suppressed the kinase activity of c-Src in A549 cells by recruiting c-Src and its negative regulator, C-terminal Src kinase (Csk), to lipid rafts. The treatment with Src inhibitors, such as PP2, dasatinib, and saracatinib, also suppressed the growth of A549 cells. Furthermore, Cbp expression attenuated the ability of A549 cells to form tumors in nude mice, invade in vitro, and metastasize in vivo. In addition, we found a significant inverse correlation between the level of Cbp expression and the extent of lymph node metastasis in human lung cancers. These results indicate that Cbp is required for the Csk-mediated inactivation of c-Src and may control the promotion of malignancy in NSCLC tumors that are characterized by c-Src upregulation. Mol Cancer Res; 9(1); 103–14 ©2010 AACR.
Anticytokine Therapy in Preterm Labor: Current Knowledge and Future Perspectives
Authors: Sado Toshiyuki , Kitanaka Takashi , Naruse Katsuhiko , Oi Hidekazu , Noguchi Taketoshi , Yoshida Shozo , Kajihara Hirotaka , Shigetomi Hiroshi , Oonogi Akira , Kobayashi Hiroshi
Published: December 2010

Aims: Up to 10% of pregnant women have preterm birth that might be refractory to current therapy. Infections and asphyxia related to preterm birth are the causes of death in the majority of neonates and therefore represent an urgent clinical need. Methods: The present article reviews the English language literature for preclinical and clinical trials and promising molecular targets on preterm labor. Results: Preterm birth is a complex heterogeneous condition. There is no current treatment for the fetal membranes once they have ruptured; therefore, essentially any treatment has to be preventative to quiesce preterm labor and prevent any spread of infection to the fetus. Modulating the pro-inflammatory process-mediated cytokine network may present a new paradigm for preterm labor treatment. There are many reports on the role of β-adrenergic agonists (betamimetics), magnesium sulfate, progesterone, oxytocin antagonist, calcium channel blocker or the Kunitz inhibitor bikunin in the treatment of preterm labor. In the present review, we have focused on the preclinical and clinical anticytokine therapy for preterm labor. The preclinical and clinical trials with bikunin reducing preterm labor exacerbations have raised the importance of usefulness and safety considerations related to this novel therapy. Conclusion: Anticytokine therapy is ready for the clinic.
Spinal Cord Injuries without Radiographic Abnormality at Two Pediatric Trauma Centers in Ontario
Authors: Trigylidas T. , Yuh S.J. , Vassilyadi M. , Matzinger M.A. , Mikrogianakis A.
Published: December 2010

Background: Spinal cord injury without radiographic abnormality (SCIWORA) represents a traumatic myelopathy, either transient or permanent, that is not associated with visible vertebral fractures or ligamentous abnormalities on plain radiographs or CT. MRI has become essential in the diagnosis and evaluation of trauma patients and in predicting the long-term neurological outcome. Methods: The medical charts of 578 children with vertebral trauma at the Children’s Hospital of Eastern Ontario and the Hospital for Sick Children were retrospectively reviewed. Results: Forty-five patients were identified as having traumatic myelopathy. Three of these patients had SCIWORA. Two sustained thoracic spinal cord injuries as a result of motor vehicle accidents and permanent neurological deficits. The third was involved in a sports-related injury and sustained a cervical spine injury that improved in 48 h. Conclusions: SCIWORA is uncommon. The serious neurological sequelae that can result from a missed diagnosis merit more attention in identifying a spinal lesion in children with traumatic myelopathy. MRI has played a valuable role in this respect and may be even more predictive of outcome than the presenting neurological findings. The SCIWORA acronym can be modified to SCIWONA (spinal cord injury without neuroimaging abnormality) in order to highlight the importance of MRI in the prognosis.
Urinary Neutrophil Gelatinase-Associated Lipocalin and Progression of Diabetic Nephropathy in Type 1 Diabetic Patients in a Four-Year Follow-Up Study
Authors: Nielsen Stine Elkjaer , Hansen Henrik Post , Jensen Berit Ruud , Parving Hans-Henrik , Rossing Peter
Published: December 2010

Background: Neutrophil gelatinase-associated lipocalin (NGAL), a marker of renal tubular damage, predicts progression in non-diabetic chronic kidney. We evaluated urinary (u)-NGAL as a predictor of progression in diabetic nephropathy in type 1 diabetic (T1D) patients. Methods: As a substudy of a 4-year randomized, intervention study evaluating low-protein diet in T1D patients with diabetic nephropathy, 78 patients were studied with yearly measurements of u-NGAL (ELISA, BioPorto). Outcome: Decline in glomerular filtration rate (GFR) (51Cr-EDTA), and end-stage renal disease (ESRD) or death. Results: Mean age 40.7 (8.2) years and 50 men. 13 patients developed ESRD or died. Baseline GFR (mean, SD): 68 (31) ml/min/1.73 m2. Baseline u-NGAL [geometric mean (95% CI)] and GFR were 15.6 ng/24 h (11.8–20.7) and 68 (31) ml/min/1.73 m2. During follow-up, an increase in u-NGAL [geometric mean (95% CI)] of 15%/year (4–27) and a decline in GFR of 3.7 (3.0) ml/min/year were observed. Baseline u-NGAL was not associated with the decline in GFR. Elevated u-NGAL at baseline (log-transformed) predicted death and ESRD (HR 3.8, 95% CI 1.04–14.0), however not after adjustment for known progression promoters (HR 2.0, p = 0.6). Conclusion: Elevated u-NGAL was not related to decline in GFR during a 4-year follow-up. Elevated u-NGAL was associated with the development of ESRD and death, but not after adjustment.
RAR-Beta Expression Is Associated with Early Volumetric Changes to Radiation Therapy in Cervical Cancer
Authors: Kim Woo Young , Lee Jeong-Won , Park Young-Ae , Choi Jung-Joo , Sung Chang Ohk , Song Sang Yong , Choi Chel Hun , Kim Tae-Joong , Huh Seung Jae , Kim Byoung-Gie , Bae Duk-Soo
Published: December 2010

Background: To identify a molecular marker associated with volumetric changes to radiotherapy (RT) in cervical cancer, we compared gene expression profiles of an early response (ER) group with a late response (LR) group, which are defined by complete and partial disappearance of a primary cervical lesion on MRI performed 1 month after completion of RT. Methods: Microarray analysis of mRNA expression profiles was performed in 17 patients (11 in the ER and 6 in the LR group). After selection of the genes with significant differential expression, we evaluated the association of the selected genes with radioresistance in clinical specimens. Results: We identified 53 genes with differential expression on microarray analysis using the permutation test with t statistics (p ≤ 0.01). Using immunohistochemistry, we evaluated the expression of RAR-β, one of the genes selected among the differentially expressed genes. RAR-β expression was significantly down-regulated in the LR group compared with the ER group (p = 0.02). However, this gene did not predict permanent radioresistance (p = 0.19). Conclusions: RAR-β expression might be a valuable marker for the prediction of early volumetric changes to RT in cervical carcinomas. Further search for additional genes associated with early volumetric changes and radioresistance may aid in refining individual treatment strategies.
Ultrasound for Ovarian Cancer Screening: Are We Throwing the Baby out with the Bath Water?
Authors: Bignardi T. , Condous G.
Published: December 2010

The lack of standardization in gynaecological scanning is worrying, especially with regard to the sonographic evaluation of adnexal masses. The results of ongoing trials on the use of ultrasound as a screening test for ovarian cancer are likely to be affected by this lack of standardization in terminology and classifications. The lack of high-quality gynaecological ultrasound, combined with the low prevalence of ovarian cancer, may yield to a poor performance of transvaginal ultrasound as a screening test for ovarian cancer in large trials. In order to increase the specificity of ultrasound in a screening program, thus reducing unnecessary surgeries, a uniform, reproducible and accurate method for the sonographic evaluation of ovarian masses must be implemented. This move to improve and standardize reporting in gynaecological ultrasound should negate the need to use the phrase ‘complex ovarian mass’. In this paper, we will critically evaluate current terminology, newly proposed accepted morphological classification of ovarian cysts as well as the ability for ultrasound to discriminate between benign and malignant ovarian masses.
Efficacy of Corticosteroids in Hearing Preservation after Radiosurgery for Vestibular Schwannoma: A Prospective Study
Authors: Kim Jin Wook , Kim Dong Gyu , Paek Sun Ha , Chung Hyun-Tai , Kim Yong Hwy , Han Jung Ho , Park Chul-Kee , Jung Hee-Won
Published: December 2010

Objectives: We prospectively investigated the efficacy of corticosteroid medication in salvaging acute hearing deterioration after radiosurgery for vestibular schwannoma (VS) and analyzed prognostic factors for hearing preservation. Methods: Forty-one patients with serviceable hearing treated with gamma knife radiosurgery between 2004 and 2006 were included. Nineteen patients who suffered acute hearing deterioration after radiosurgery were treated with oral corticosteroids. The efficacy of corticosteroids was compared with the results of a historical observation group of 15 patients who had experienced hearing deterioration but who had not taken corticosteroids. Results: The tumor control rate and serviceable hearing preservation rate at the last follow-up were 97.6 and 61%, respectively. There was no significant difference in the actuarial serviceable hearing preservation rates between the corticosteroid treatment group and the historical observation group (p = 0.519). However, the mean pure-tone averages were significantly different between the 2 groups (51.5 vs. 63.7 dB; p = 0.025). Multivariate analysis revealed that preradiosurgery hearing status and transient volume expansion were prognostic factors for hearing preservation (p = 0.013 and p = 0.029, respectively). Conclusions: This study demonstrates the possibility that corticosteroid medication may improve acute hearing deterioration after radiosurgery in VS patients. Further studies on optimal corticosteroid medication for managing acute hearing deterioration after radiosurgery are mandatory.
Customized, Miniature Rapid-Prototype Stereotactic Frames for Use in Deep Brain Stimulator Surgery: Initial Clinical Methodology and Experience from 263 Patients from 2002 to 2008
Authors: Konrad Peter E. , Neimat Joseph S. , Yu Hong , Kao Chris C. , Remple Michael S. , D’Haese Pierre-François , Dawant Benoit M.
Published: December 2010

Background: The microTargeting™ platform (MTP) stereotaxy system (FHC Inc., Bowdoin, Me., USA) was FDA approved in 2001 utilizing rapid-prototyping technology to create custom platforms for human stereotaxy procedures. It has also been called the STarFix (surgical targeting fixture) system since it is based on the concept of a patient- and procedure-specific surgical fixture. This is an alternative stereotactic method by which planned trajectories are incorporated into custom-built, miniature stereotactic platforms mounted onto bone fiducial markers. Our goal is to report the clinical experience with this system over a 6-year period. Methods: We present the largest reported series of patients who underwent deep brain stimulation (DBS) implantations using customized rapidly prototyped stereotactic frames (MTP). Clinical experience and technical features for the use of this stereotactic system are described. Final lead location analysis using postoperative CT was performed to measure the clinical accuracy of the stereotactic system. Results: Our series included 263 patients who underwent 284 DBS implantation surgeries at one institution over a 6-year period. The clinical targeting error without accounting for brain shift in this series was found to be 1.99 mm (SD 0.9). Operating room time was reduced through earlier incision time by 2 h per case. Conclusion: Customized, miniature stereotactic frames, namely STarFix platforms, are an acceptable and efficient alternative method for DBS implantation. Its clinical accuracy and outcome are comparable to those associated with traditional stereotactic frame systems.
Speech Perception after Early-Life Otitis Media with Fluctuating Hearing Loss
Authors: Zumach Anne , Chenault Michelene N. , Anteunis Lucien J.C. , Gerrits Ellen
Published: December 2010

The present study examined the effect of early-life otitis media and its associated fluctuating hearing loss on categorical speech perception in 7-year-old Dutch children. The middle ear status of these children had been followed prospectively in their first 2 years of life. Identification and discrimination of speech sounds differing in place of articulation were tested at school age and outcomes were significantly related to otitis media-related hearing loss. Results revealed that phoneme identification and discrimination were affected by early-life hearing loss. It is not otitis media per se, but rather the relative severity of hearing loss resulting from early-life otitis media which is related to poorer categorical speech perception abilities in school-age children.
Surgery of Ovarian Tumors in Children
Authors: Sarnacki Sabine , Brisse Hervé
Published: December 2010

Surgery of ovarian tumors in children requires a good knowledge of these lesions. Complete resection is mandatory for malignant lesions, and in the case of benign tumors preservation of healthy ovarian tissue is crucial. Diagnosis is based on clinical features (age and hormonal status), imaging and tumor marker levels. Laparoscopy is of great help in making a diagnosis and staging when the lesion is malignant. Laparotomy by a supra-pubic approach is, however, the only way to ensure a safe treatment of the lesion by avoiding any risk of tumor spillage, which constitutes a chance loss. Surgical treatment consists of complete ovariectomy for a malignant tumor and partial ovariectomy when the lesion is surely benign. Preservation of fertility is based on conservative surgery for uni- or bilateral benign lesions, and may be discussed in some selected cases of bilateral malignant tumors. When the remaining ovarian tissue predicts precocious ovarian failure, ovarian tissue or oocyte cryopreservation may be proposed to patients and their families.
The Many Faces of Endothelial Microparticles
Authors: Dignat-George Françoise , Boulanger Chantal M.
Published: December 2010

Endothelial microparticles (EMP) are complex vesicular structures shed from activated or apoptotic endothelial cells. They play a remarkable role in coagulation, inflammation, endothelial function, and angiogenesis and thus disturb the vascular homeostasis, contributing to the progression of vascular diseases. As a cause or a consequence, elevated levels of EMP were found in plasma from patients with vascular diseases, where they serve as a surrogate marker of endothelial function. More recent data challenged the presumed deleterious role of EMP because they could promote cell survival, exert antiinflammatory effects, counteract coagulation processes, or induce endothelial regeneration. This review focuses on the ambivalent role of EMP in vascular homeostasis.
Impact of Independent Data Adjudication on Hospital-Specific Estimates of Risk-Adjusted Mortality Following Percutaneous Coronary Interventions in Massachusetts
Authors: Barringhaus Kurt G. , Zelevinsky Katya , Lovett Ann , Normand Sharon-Lise T. , Ho Kalon K.L.
Published: December 2010

Background—

As part of state-mandated public reporting of outcomes after percutaneous coronary interventions (PCIs) in Massachusetts, procedural and clinical data were prospectively collected. Variables associated with higher mortality were audited to ensure accuracy of coding. We examined the impact of adjudication on identifying hospitals with possible deficiencies in the quality of PCI care.

Methods and Results—

From October 2005 to September 2006, 15 721 admissions for PCI occurred in 21 hospitals. Of the 864 high-risk variables from 822 patients audited by committee, 201 were changed, with reassignment to lower acuities in 97 (30%) of the 321 shock cases, 24 (43%) of the 56 salvage cases, and 73 (15%) of the 478 emergent cases. Logistic regression models were used to predict patient-specific in-hospital mortality. Of 241 (1.5%) patients who died after PCI, 30 (12.4%) had a lower predicted mortality with adjudicated than with unadjudicated data. Model accuracy was excellent with either adjudicated or unadjudicated data. Hospital-specific risk-standardized mortality rates were estimated using both adjudicated and unadjudicated data through hierarchical logistic regression. Although adjudication reduced between-hospital variation by one third, risk-standardized mortality rates were similar using unadjudicated and adjudicated data. None of the hospitals were identified as statistical outliers. However, cross-validated posterior-predicted
P
values calculated with adjudicated data increased the number of borderline hospital outliers compared with unadjudicated data.

Conclusions—

Independent adjudication of site-reported high-risk features may increase the ability to identify hospitals with higher risk-adjusted mortality after PCI despite having little impact on the accuracy of risk prediction for the entire population.
Comparing MODIS and AIRS Infrared-Based Cloud Retrievals
Authors: Nasiri Shaima L. , Van T. Dang H. , Kahn Brian H. , Fetzer Eric J. , Manning Evan M. , Schreier Mathias M. , Frey Richard A.
Published: December 2010

Comparisons are described for infrared-derived cloud products retrieved from the Moderate Resolution Imaging Spectroradiometer (MODIS) and the Atmospheric Infrared Sounder (AIRS) using measured spatial response functions obtained from prelaunch AIRS calibration. One full day (1 January 2005) of global collection-5 MODIS and version-5 AIRS retrievals of cloud-top temperature Tc, effective cloud fraction f, and derived effective brightness temperature Tb,e is investigated. Comparisons of Tb,e demonstrate that MODIS and AIRS are essentially radiatively consistent and that MODIS Tb,e is 0.62 K higher than AIRS Tb,e for all scenes, increasing to 1.43 K for cloud described by AIRS as single layer and decreasing to 0.50 K for two-layer clouds. Somewhat larger differences in Tc and f are observed between the two instruments. The magnitudes of differences depend partly on whether MODIS uses a CO2-slicing or 11-μm brightness temperature window retrieval method. Some cloud- and regime-type differences and similarities between AIRS and MODIS cloud products are traceable to the assumptions made about the number of cloud layers in AIRS and also to the MODIS retrieval method. This (partially) holistic comparison approach should be useful for ongoing algorithm refinements, rigorous assessments of climate applicability, and establishment of the capability of synergistic MODIS and AIRS retrievals for improved cloud quantities and also should be useful for future observations to be made by the National Polar-Orbiting Operational Environmental Satellite System (NPOESS) Preparatory Project (NPP).
Wind Profiler Observations of Mountain Waves and Rotors during T-REX
Authors: Cohn Stephen A. , Grubišić Vanda , Brown William O. J.
Published: December 2010

A network of three boundary layer radar wind profilers is used to study characteristics of mountain waves and rotors and to explore the utility of such a network. The data employed were collected as part of the Terrain-Induced Rotor Experiment (T-REX), which took place in Owens Valley, California, in early 2006. The wind profilers provide a continuous time–height representation of wave and rotor structure. During intensive observing period 3 (IOP 3), the profiler network was positioned in an L-shaped configuration, capturing key features of the mountain waves and rotor, including the boundary layer vortex sheet (or shear layer), turbulence within this shear layer, the classical lower turbulence zone (LTZ), and wave motion above the LTZ. Observed features were found to be in good agreement with recent high-resolution numerical simulations. Using the wind profiler with superior time resolution (Multiple Antenna Profiler Radar), a series of updraft–downdraft couplets were observed beneath the first downwind wave crest. These are interpreted as signatures of subrotors. Such detailed observations of subrotors are rare, even though subrotors are believed to be a common feature of rotor circulations in Owens Valley. During IOP 6, the network was repositioned to form a line across the valley. A simple algorithm was used to determine the amplitude, wavelength, and phase of the primary wave over the valley and to observe their changes over time and height. In the IOP-6 case, the wavelength increased over time, the phase indicated an eastward-shifting wave crest, and the amplitude increased with height and also varied over time.
Atmospheric Local Energetics and Energy Interactions between Mean and Eddy Fields. Part II: An Example for the Last Glacial Maximum Climate
Authors: Murakami Shigenori , Ohgaito Rumi , Abe-Ouchi Ayako
Published: December 2010

The atmospheric local energy cycle in the Last Glacial Maximum (LGM) climate simulated by an atmosphere–ocean GCM (AOGCM) is investigated using a new diagnostic scheme. In contrast to existing ones, this scheme can represent the local features of the Lorenz energy cycle correctly, and it provides the complete information about the three-dimensional structure of the energy interactions between mean and eddy fields. The diagnosis reveals a significant enhancement of the energy interactions through the barotropic processes in the Atlantic sector at the LGM. Energy interactions through the baroclinic processes are also enhanced in the Atlantic sector, although those in the Pacific sector are rather weakened. These LGM responses, however, are not evident in the global energy cycle except for an enhancement of the energy flow through the stationary eddies.
Projected Changes in Mean and Extreme Precipitation in Africa under Global Warming. Part II: East Africa
Authors: Shongwe Mxolisi E. , van Oldenborgh Geert Jan , van den Hurk Bart , van Aalst Maarten
Published: December 2010

Probable changes in mean and extreme precipitation in East Africa are estimated from general circulation models (GCMs) prepared for the Intergovernmental Panel on Climate Change Fourth Assessment Report (AR4). Bayesian statistics are used to derive the relative weights assigned to each member in the multimodel ensemble. There is substantial evidence in support of a positive shift of the whole rainfall distribution in East Africa during the wet seasons. The models give indications for an increase in mean precipitation rates and intensity of high rainfall events but for less severe droughts. Upward precipitation trends are projected from early this (twenty first) century. As in the observations, a statistically significant link between sea surface temperature gradients in the tropical Indian Ocean and short rains (October–December) in East Africa is simulated in the GCMs. Furthermore, most models project a differential warming of the Indian Ocean during boreal autumn. This is favorable for an increase in the probability of positive Indian Ocean zonal mode events, which have been associated with anomalously strong short rains in East Africa. On top of the general increase in rainfall in the tropics due to thermodynamic effects, a change in the structure of the Eastern Hemisphere Walker circulation is consistent with an increase in East Africa precipitation relative to other regions within the same latitudinal belt. A notable feature of this change is a weakening of the climatological subsidence over eastern Kenya. East Africa is shown to be a region in which a coherent projection of future precipitation change can be made, supported by physical arguments. Although the rate of change is still uncertain, almost all results point to a wetter climate with more intense wet seasons and less severe droughts.
Can the Increase in the Eddy Length Scale under Global Warming Cause the Poleward Shift of the Jet Streams?
Authors: Kidston Joseph , Vallis G. K. , Dean S. M. , Renwick J. A.
Published: December 2010

The question of whether an increase in the atmospheric eddy length scale may cause a poleward shift of the midlatitude jet streams is addressed. An increase in the length scale of the eddy reduces its zonal phase speed and so causes eddies to dissipate farther from the jet core. If the eddy dissipation region on the poleward flank of the jet overlaps with the eddy source latitudes, shifting this dissipation to higher latitudes will alter which latitudes are a net source of baroclinic eddies, and hence the eddy-driven jet stream may shift poleward. This behavior does not affect the equatorward flank of the jet in the same way because the dissipation region on the equatorward flank is well separated from the source latitudes. An experiment with a barotropic model is presented in which an increase in the length scale of a midlatitude perturbation results in a poleward shift in the acceleration of the zonal flow. Initial investigations indicate that this behavior is also important in both observational data and the output of comprehensive general circulation models (GCMs). A simplified GCM is used to show that the latitude of the eddy-driven jet is well correlated with the eddy length scale. It is argued that the increase in the eddy length scale causes the poleward shift of the jet in these experiments, rather than vice versa.
Subseasonal Variation in ENSO-Related East Asian Rainfall Anomalies during Summer and Its Role in Weakening the Relationship between the ENSO and Summer Rainfall in Eastern China since the Late 1970s
Authors: Ye Hong , Lu Riyu
Published: December 2010

The findings of the study reported in this paper show that, during ENSO decaying summers, rainfall and circulation anomalies exhibit clear subseasonal variation. Corresponding to a positive (negative) December–February (DJF) Niño-3.4 index, a positive (negative) subtropical rainfall anomaly, with a southwest–northeast tilt, appears in South China and the western North Pacific (WNP) in the subsequent early summer (from June to middle July) but advances northward into the Huai River Basin in China as well as Korea and central Japan in late summer (from late July to August). Concurrently, a lower-tropospheric anticyclonic anomaly over the WNP extends northward from early to late summer. The seasonal change in the basic flows, characterized by the northward shift of the upper-tropospheric westerly jet and the WNP subtropical high, is suggested to be responsible for the differences in the above rainfall and circulation anomalies between early and late summer by inducing distinct extratropical responses even under the almost identical tropical forcing of a precipitation anomaly in the Philippine Sea.

A particular focus of the study is to investigate, using station rainfall data, the subseasonal variations in ENSO-related rainfall anomalies in eastern China since the 1950s, to attempt to examine their role in weakening the relationship between the ENSO and summer mean rainfall in eastern China since the late 1970s. It is found that the ENSO-related rainfall anomalies tend to be similar between early and late summer before the late 1970s, that is, the period characterized by a stronger ENSO–summer mean rainfall relationship. After the late 1970s, however, the anomalous rainfall pattern in eastern China is almost reversed between early and late summer, resulting accordingly in a weakened relationship between the ENSO and total summer rainfall in eastern China.
Longwave 3D Benchmarks for Inhomogeneous Clouds and Comparisons with Approximate Methods
Authors: Kablick George P. , Ellingson Robert G. , Takara Ezra E. , Gu Jlujing
Published: December 2010

The purpose of this study is twofold: to (i) establish three-dimensional (3D) longwave radiative transfer benchmarks for inhomogeneous cloud fields and (ii) compare the results with three approximate, 1D methods. The benchmark results are calculated using a correlated-k three-dimensional Monte Carlo (3DMC) algorithm that is validated via comparisons to line-by-line calculations for simple atmospheres. The approximate methods include an independent column approximation (ICA) and two cloud-overlap schemes: maximum/random (MRO) and random (RO). Six inhomogeneous cloudy-sky test cases are used and encompass a wide range of domain sizes used by general circulation models. Domain-averaged fluxes and heating rates from these atmospheres show that the ICA is consistently more accurate than the cloud-overlap models with respect to the 3D benchmarks. For example, comparisons of model results for the Atlantic Trade Wind Experiment (ATEX), a marine boundary layer cumulus field, yield a maximum cloud-layer heating rate error of 15.73 K day−1 from using cloud-overlap models, whereas the ICA error is only 2.17 K day−1. This paper presents results showing that these differences are attributed to the 3D effects of unresolved clouds and indicate that there is an inherent deficiency in the ability of 1D models to accurately calculate radiative quantities in these atmospheres.
Representing Grass– and Shrub–Snow–Atmosphere Interactions in Climate System Models
Authors: Liston Glen E. , Hiemstra Christopher A.
Published: December 2010

A vegetation-protruding-above-snow parameterization for earth system models was developed to improve energy budget calculations of interactions among vegetation, snow, and the atmosphere in nonforested areas. These areas include shrublands, grasslands, and croplands, which represent 68% of the seasonally snow-covered Northern Hemisphere land surface (excluding Greenland). Snow depth observations throughout nonforested areas suggest that mid- to late-winter snowpack depths are often comparable or lower than the vegetation heights. As a consequence, vegetation protruding above the snow cover has an important impact on snow-season surface energy budgets. The protruding vegetation parameterization uses disparate energy balances for snow-covered and protruding vegetation fractions of each model grid cell, and fractionally weights these fluxes to define grid-average quantities. SnowModel, a spatially distributed snow-evolution modeling system, was used to test and assess the parameterization. Simulations were conducted during the winters of 2005/06 and 2006/07 for conditions of 1) no protruding vegetation (the control) and 2) with protruding vegetation. The spatial domain covered Colorado, Wyoming, and portions of the surrounding states; 81% of this area is nonforested. The surface net radiation, energy, and moisture fluxes displayed considerable differences when protruding vegetation was included. For shrubs, the net radiation, sensible, and latent fluxes changed by an average of 12.7, 6.9, and −22.7 W m−2, respectively. For grass and crops, these fluxes changed by an average of 6.9, −0.8, and −7.9 W m−2, respectively. Daily averaged flux changes were as much as 5 times these seasonal averages. As such, the new parameterization represents a major change in surface flux calculations over more simplistic and less physically realistic approaches.
Radar Nowcasting of Cloud-to-Ground Lightning over Houston, Texas
Authors: Mosier Richard M. , Schumacher Courtney , Orville Richard E. , Carey Lawrence D.
Published: December 2010

Ten years (1997–2006) of summer (June–August) daytime (1400–0000 UTC) Weather Surveillance Radar-1988 Doppler data for Houston, Texas, were examined to determine the best radar-derived predictors of the first cloud-to-ground lightning flash from a convective cell. Convective cells were tracked using a modified version of the Storm Cell Identification and Tracking (SCIT) algorithm and then correlated to cloud-to-ground lightning data from the National Lightning Detection Network (NLDN). Combinations of three radar reflectivity values (30, 35, and 40 dBZ) at four isothermal levels (−10°, −15°, −20°, and updraft −10°C) and a new radar-derived product, vertically integrated ice (VII), were used to optimize a radar-based lightning forecast algorithm. Forecasts were also delineated by range and the number of times a cell was identified and tracked by the modified SCIT algorithm. This study objectively analyzed 67 384 unique cells and 1 028 510 lightning flashes to find the best lightning forecast criteria. Results show that using 30 dBZ at the −15° or −20°C isotherm on cells within 75 km of the radar that have been tracked for at least two consecutive scans produces the best lightning forecasts with a critical success index (CSI) of 0.68. The best VII predictor values were 0.42 or 0.58 kg m−2 on cells within 75 km of the radar that have been tracked for at least two consecutive scans, producing a CSI of 0.67. Lead times for these predictors were 10.0 and 13.4 min, respectively. Lead times greater than 10 min occurred with less stringent predictors (e.g., 30 dBZ at −10°C or VII greater than 0.25 kg m−2 on cells within 125 km with a minimum track count of 2), but lower CSI values result. In general, cells tracked for multiple scans provide higher CSIs and lead times than decreasing the range from the radar or changing the reflectivity threshold and height.