bluuebunny/crossref_metadata_2025 huggingface dataset:
The syndecan-1 heparan sulfate proteoglycan is a viable target for myeloma therapy
Authors: Yang Yang , MacLeod Veronica , Dai Yuemeng , Khotskaya-Sample Yekaterina , Shriver Zachary , Venkataraman Ganesh , Sasisekharan Ram , Naggi Annamaria , Torri Giangiacomo , Casu Benito , Vlodavsky Israel , Suva Larry J. , Epstein Joshua , Yaccoby Shmuel , Shaughnessy John D. , Barlogie Bart , Sanderson Ralph D.
Published: May 2007

The heparan sulfate proteoglycan syndecan-1 is expressed by myeloma cells and shed into the myeloma microenvironment. High levels of shed syndecan-1 in myeloma patient sera correlate with poor prognosis and studies in animal models indicate that shed syndecan-1 is a potent stimulator of myeloma tumor growth and metastasis. Overexpression of extracellular endosulfatases, enzymes which remove 6-O sulfate groups from heparan sulfate chains, diminishes myeloma tumor growth in vivo. Together, these findings identify syndecan-1 as a potential target for myeloma therapy. Here, 3 different strategies were tested in animal models of myeloma with the following results: (1) treatment with bacterial heparinase III, an enzyme that degrades heparan sulfate chains, dramatically inhibited the growth of primary tumors in the human severe combined immunodeficient (SCID-hu) model of myeloma; (2) treatment with an inhibitor of human heparanase, an enzyme that synergizes with syndecan-1 in promoting myeloma progression, blocked the growth of myeloma in vivo; and (3) knockdown of syndecan-1 expression by RNAi diminished and delayed myeloma tumor development in vivo. These results confirm the importance of syndecan-1 in myeloma pathobiology and provide strong evidence that disruption of the normal function or amount of syndecan-1 or its heparan sulfate chains is a valid therapeutic approach for this cancer.
Inhibition of apoptosis prevents West Nile virus induced cell death
Authors: Kleinschmidt Malte C , Michaelis Martin , Ogbomo Henry , Doerr Hans-Wilhelm , Cinatl Jindrich
Published: May 2007

Background

West Nile virus (WNV) infection can cause severe meningitis and encephalitis in humans. Apoptosis was recently shown to contribute to the pathogenesis of WNV encephalitis. Here, we used WNV-infected glioma cells to study WNV-replication and WNV-induced apoptosis in human brain-derived cells.

Results

T98G cells are highly permissive for lytic WNV-infection as demonstrated by the production of infectious virus titre and the development of a characteristic cytopathic effect. WNV replication decreased cell viability and induced apoptosis as indicated by the activation of the effector caspase-3, the initiator caspases-8 and -9, poly(ADP-ribose)polymerase (PARP) cleavage and the release of cytochrome c from the mitochondria. Truncation of BID indicated cross-talk between the extrinsic and intrinsic apoptotic pathways. Inhibition of the caspases-8 or -9 inhibited PARP cleavage, demonstrating that both caspases are involved in WNV-induced apoptosis. Pan-caspase inhibition prevented WNV-induced apoptosis without affecting virus replication.

Conclusion

We found that WNV infection induces cell death in the brain-derived tumour cell line T98G by apoptosis under involvement of constituents of the extrinsic as well as the intrinsic apoptotic pathways. Our results illuminate the molecular mechanism of WNV-induced neural cell death.
High resolution crystal structure of PedB: a structural basis for the classification of pediocin-like immunity proteins
Authors: Kim In-Kwon , Kim Min-Kyu , Kim Ji-Hye , Yim Hyung-Soon , Cha Sun-Shin , Kang Sa-Ouk
Published: May 2007

Background

Pediocin-like bacteriocins, ribosomally-synthesized antimicrobial peptides, are generally coexpressed with cognate immunity proteins in order to protect the bacteriocin-producer from its own bacteriocin. As a step for understanding the mode of action of immunity proteins, we determined the crystal structure of PedB, a pediocin-like immunity protein conferring immunity to pediocin PP-1.

Results

The 1.6 Å crystal structure of PedB reveals that PedB consists of an antiparallel four-helix bundle with a flexible C-terminal end. PedB shows structural similarity to an immunity protein against enterocin A (EntA-im) but some disparity to an immunity protein against carnobacteriocin B2 (ImB2) in both the C-terminal conformation and the local structure constructed by α3, α4, and their connecting loop. Structure-inspired mutational studies reveal that deletion of the last seven residues of the C-terminus of PedB almost abolished its immunity activity.

Conclusion

The fact that PedB, EntA-im, and ImB2 share a four-helix bundle structure strongly suggests the structural conservation of this motif in the pediocin-like immunity proteins. The significant difference in the core structure and the C-terminal conformation provides a structural basis for the classification of pediocin-like immunity proteins. Our mutational study using C-terminal-shortened PedBs and the investigation of primary sequence of the C-terminal region, propose that several polar or charged residues in the extreme C-terminus of PedB which is crucial for the immunity are involved in the specific recognition of pediocin PP-1.
A real-time view of the TAR:Tat:P-TEFb complex at HIV-1 transcription sites
Authors: Molle Dorothée , Maiuri Paolo , Boireau Stéphanie , Bertrand Edouard , Knezevich Anna , Marcello Alessandro , Basyuk Eugenia
Published: May 2007

HIV-1 transcription is tightly regulated: silent in long-term latency and highly active in acutely-infected cells. Transcription is activated by the viral protein Tat, which recruits the elongation factor P-TEFb by binding the TAR sequence present in nascent HIV-1 RNAs. In this study, we analyzed the dynamic of the TAR:Tat:P-TEFb complex in living cells, by performing FRAP experiments at HIV-1 transcription sites. Our results indicate that a large fraction of Tat present at these sites is recruited by Cyclin T1. We found that in the presence of Tat, Cdk9 remained bound to nascent HIV-1 RNAs for 71s. In contrast, when transcription was activated by PMA/ionomycin, in the absence of Tat, Cdk9 turned-over rapidly and resided on the HIV-1 promoter for only 11s. Thus, the mechanism of trans-activation determines the residency time of P-TEFb at the HIV-1 gene, possibly explaining why Tat is such a potent transcriptional activator. In addition, we observed that Tat occupied HIV-1 transcription sites for 55s, suggesting that the TAR:Tat:P-TEFb complex dissociates from the polymerase following transcription initiation, and undergoes subsequent cycles of association/dissociation.
Low E2F1 transcript levels are a strong determinant of favorable breast cancer outcome
Authors: Vuaroqueaux Vincent , Urban Patrick , Labuhn Martin , Delorenzi Mauro , Wirapati Pratyaksha , Benz Christopher C , Flury Renata , Dieterich Holger , Spyratos Frédérique , Eppenberger Urs , Eppenberger-Castori Serenella
Published: May 2007

Introduction

We investigated whether mRNA levels of E2F1, a key transcription factor involved in proliferation, differentiation and apoptosis, could be used as a surrogate marker for the determination of breast cancer outcome.

Methods

E2F1 and other proliferation markers were measured by quantitative RT-PCR in 317 primary breast cancer patients from the Stiftung Tumorbank Basel. Correlations to one another as well as to the estrogen receptor and ERBB2 status and clinical outcome were investigated. Results were validated and further compared with expression-based prognostic profiles using The Netherlands Cancer Institute microarray data set reported by Fan and colleagues.

Results

E2F1 mRNA expression levels correlated strongly with the expression of other proliferation markers, and low values were mainly found in estrogen receptor-positive and ERBB2-negative phenotypes. Patients with low E2F1-expressing tumors were associated with favorable outcome (hazard ratio = 4.3 (95% confidence interval = 1.8–9.9), P = 0.001). These results were consistent in univariate and multivariate Cox analyses, and were successfully validated in The Netherlands Cancer Institute data set. Furthermore, E2F1 expression levels correlated well with the 70-gene signature displaying the ability of selecting a common subset of patients at good prognosis. Breast cancer patients' outcome was comparably predictable by E2F1 levels, by the 70-gene signature, by the intrinsic subtype gene classification, by the wound response signature and by the recurrence score.

Conclusion

Assessment of E2F1 at the mRNA level in primary breast cancer is a strong determinant of breast cancer patient outcome. E2F1 expression identified patients at low risk of metastasis irrespective of the estrogen receptor and ERBB2 status, and demonstrated similar prognostic performance to different gene expression-based predictors.
Mammographic density does not correlate with Ki-67 expression or cytomorphology in benign breast cells obtained by random periareolar fine needle aspiration from women at high risk for breast cancer
Authors: Khan Qamar J , Kimler Bruce F , O'Dea Anne P , Zalles Carola M , Sharma Priyanka , Fabian Carol J
Published: May 2007

Background

Ki-67 expression is a possible risk biomarker and is currently being used as a response biomarker in chemoprevention trials. Mammographic breast density is a risk biomarker and is also being used as a response biomarker. We previously showed that Ki-67 expression is higher in specimens of benign breast cells exhibiting cytologic atypia that are obtained by random periareolar fine needle aspiration (RPFNA). It is not known whether there is a correlation between mammographic density and Ki-67 expression in benign breast ductal cells obtained by RPFNA.

Methods

Included in the study were 344 women at high risk for developing breast cancer (based on personal or family history), seen at The University of Kansas Medical Center high-risk breast clinic, who underwent RPFNA with cytomorphology and Ki-67 assessment plus a mammogram. Mammographic breast density was assessed using the Cumulus program. Categorical variables were analyzed by χ2 test, and continuous variables were analyzed by nonparametric test and linear regression.

Results

Forty-seven per cent of women were premenopausal and 53% were postmenopausal. The median age was 48 years, median 5-year Gail Risk was 2.2%, and median Ki-67 was 1.9%. The median mammographic breast density was 37%. Ki-67 expression increased with cytologic abnormality (atypia versus no atypia; P ≤ 0.001) and younger age (≤50 years versus >50 years; P ≤ 0.001). Mammographic density was higher in premenopausal women (P ≤ 0.001), those with lower body mass index (P < 0.001), and those with lower 5-year Gail risk (P = 0.001). Mammographic density exhibited no correlation with Ki-67 expression or cytomorphology.

Conclusion

Given the lack of correlation of mammographic breast density with either cytomorphology or Ki-67 expression in RPFNA specimens, mammographic density and Ki-67 expression should be considered as potentially complementary response biomarkers in breast cancer chemoprevention trials.
Epidermal Growth Factor Receptor Copy Number Alterations Correlate With Poor Clinical Outcome in Patients With Head and Neck Squamous Cancer
Authors: Temam Stephane , Kawaguchi Hidetoshi , El-Naggar Adel K. , Jelinek Jaroslav , Tang Hongli , Liu Diane D. , Lang Wenhua , Issa Jean-Pierre , Lee J. Jack , Mao Li
Published: May 2007

Purpose

Overexpression of epidermal growth factor receptor (EGFR) is common in head and neck squamous cell carcinoma (HNSCC). Recent studies showed that EGFR inhibitors are effective for patients with HNSCC. This study analyzed the genetic nature of EGFR gene in HNSCC and its clinical correlations.

Patients and Methods

The EGFR gene copy numbers in 134 HNSCC tumors were determined using quantitative real-time polymerase chain reaction. The status of EGFR gene copy numbers was analyzed with clinical parameters including clinical outcome. Mutation status of EGFR exons 18, 19, and 21 was determined in the HNSCC tumors.

Results

Aberrant EGFR copy numbers were found in 32 (24%) of 134 tumors, including 22 (17%) with increased copy number and 10 (7%) with decreased copy number. Patients whose tumors had EGFR copy number alterations (particularly patients with increased copy numbers) had significantly poorer overall, cancer-specific, and disease-free survivals compared with patients with normal copy numbers (P < .0001). At 5 years after initial diagnosis, 20 (91%) of the 22 patients with increased copy numbers died of disease compared with 30 (29%) of the 102 patients with normal copy number. No mutations on EGFR exons 18, 19, and 21 were detected in any of the tumors.

Conclusion

A subset of HNSCC manifests EGFR copy number alterations, and this is associated with a poor clinical outcome, suggesting a biologic role of the alterations. The rare mutation or small deletion at EGFR exons 18 to 21 indicates a minimal role of these events in HNSCC.
Trastuzumab, Paclitaxel, Carboplatin, and Gemcitabine in Advanced Human Epidermal Growth Factor Receptor-2/neu–Positive Urothelial Carcinoma: Results of a Multicenter Phase II National Cancer Institute Trial
Authors: Hussain Maha H.A. , MacVicar Gary R. , Petrylak Daniel P. , Dunn Rodney L. , Vaishampayan Ulka , Lara Primo N. , Chatta Gurkamal S. , Nanus David M. , Glode L. Michael , Trump Donald L. , Chen Helen , Smith David C.
Published: May 2007

Purpose

We investigated the safety and efficacy (response rates, time to disease progression, survival) of trastuzumab, carboplatin, gemcitabine, and paclitaxel in advanced urothelial carcinoma patients and prospectively evaluated human epidermal growth factor receptor-2 (Her-2/neu) overexpression rates.

Patients and Methods

Advanced urothelial carcinoma patients were screened for Her-2/neu overexpression. Eligibility for therapy required human epidermal growth factor receptor-2 (Her-2/neu) overexpression by immunohistochemistry (IHC), gene amplification and/or elevated serum Her-2/neu, no prior chemotherapy for metastasis, and adequate organ function including a normal cardiac function. Treatment consisted of trastuzumab (T) 4 mg/kg loading dose followed by 2 mg/kg on days 1, 8, and 15; paclitaxel (P) 200 mg/m2 on day 1; carboplatin (C; area under the curve, 5) on day 1; and gemcitabine (G) 800 mg/m2 on days 1 and 8. The primary end point was cardiac toxicity.

Results

Fifty-seven (52.3%) of 109 registered patients were Her-2/neu positive, and 48.6% were positive by IHC. Her-2/neu–positive patients had more metastatic sites and visceral metastasis than did Her-2/neu negative patients. Forty-four of 57 Her-2/neu–positive patients were treated with TPCG. The median number of cycles was six (range, 1 to 12 cycles). The most common grade 3/4 toxicity was myelosuppression. Grade 3 sensory neuropathy occurred in 14% of patients, and 22.7% experienced grade 1 to 3 cardiac toxicity (grade 3, n = 2: one left ventricular dysfunction, one tachycardia). There were two therapy-related deaths. Thirty-one (70%) of 44 patients responded (five complete and 26 partial), and 25 (57%) of 44 were confirmed responses. Median time to progression and survival were 9.3 and 14.1 months, respectively.

Conclusion

We prospectively characterized Her-2/neu status in advanced urothelial carcinoma patients. TPCG is feasible; cardiac toxicity rates were higher than projected, but the majority were grade two or lower. Determining the true contribution of trastuzumab requires a randomized trial.
Phase I Clinical Trial of Oxaliplatin in Children and Adolescents With Refractory Solid Tumors
Authors: Spunt Sheri L. , Freeman Burgess B. , Billups Catherine A. , McPherson Valerie , Khan Raja B. , Pratt Charles B. , Stewart Clinton F.
Published: May 2007

Purpose

To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors and to determine whether carbamazepine reduces oxaliplatin-induced neurotoxicity.

Patients and Methods

Three regimens of oxaliplatin (given intravenously over 2 hours) were tested: regimen A (100 mg/m2, 130 mg/m2, or 160 mg/m2 every 3 weeks to determine the MTD of oxaliplatin); regimen B (to determine whether carbamazepine starting 24 hours before and ending 48 hours after oxaliplatin reduced the dose-limiting neurotoxicity and increased the MTD of regimen A); and regimen C (to evaluate the safety of a fixed dose two-thirds the MTD of regimen A given every 2 weeks [more frequent administration but comparable dose intensity]).

Results

Twenty-six patients were enrolled on regimens A (n = 11), B (n = 6), and C (n = 9). The DLT was grade 3 pharyngolaryngeal dysesthesia, sensory neuropathy, and ataxia at 160 mg/m2. The MTD was 130 mg/m2 every 3 weeks. At the MTD, the median clearance rate of ultrafiltrable platinum was 9.7 L/h/m2 (range, 6.5 to 15.5 L/h/m2). Addition of carbamazepine permitted dose escalation to 160 mg/m2 without DLT. DLT was not observed with a fixed dose of 85 mg/m2 given every 2 weeks. On all regimens, hematologic toxicity was mild. No significant nephrotoxicity, ototoxicity, or cumulative neurologic toxicity was observed.

Conclusion

The DLT, MTD, PK, and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors are similar to those observed in adults. Carbamazepine may reduce the dose-limiting neurotoxicity of oxaliplatin.
Whole Genome Oligonucleotide-Based Array Comparative Genomic Hybridization Analysis Identified Fibroblast Growth Factor 1 As a Prognostic Marker for Advanced-Stage Serous Ovarian Adenocarcinomas
Authors: Birrer Michael J. , Johnson Michael E. , Hao Ke , Wong Kwong-Kwok , Park Dong-Choon , Bell Aaron , Welch William R. , Berkowitz Ross S. , Mok Samuel C.
Published: May 2007

Purpose

To identify markers that can predict overall survival in patients with high-grade advanced stage serous adenocarcinomas.

Patients and Methods

Oligonucleotide array comparative genomic hybridization (aCGH) was performed on 42 microdissected high-grade serous ovarian tumor samples. aCGH segments were obtained and a prediction Cox model was built and validated by the standard leave one out analysis. Both DNA and mRNA copy numbers of selected genes located on the candidate aCGH segments were determined by quantitative polymerase chain reaction (qPCR) and quantitative reverse transcriptase PCR (qRT-PCR) analyses. The gene that showed the highest correlation was further validated on an independent set of specimens and was selected for further functional studies.

Results

Two chromosomal regions, 4p16.3 and 5q31-5q35.3, exhibited the strongest correlation with overall survival (P < .01). From the 5q31 region, fibroblast growth factor 1 (FGF-1) was selected for further validation study. FGF-1 mRNA copy number was significantly correlated with DNA copy number and protein expression levels (P = .021 and < .001), and both FGF-1 mRNA and protein levels were significantly associated with overall survival (P = .018 and .042). This association was validated for protein expression on an independent set of 81 samples, significant to P = .006. Further studies showed significant correlation between FGF-1 protein expression and CD31+ staining in the tumor stroma (P = .024). Finally, both cancer cells and endothelial cells treated with exogenous FGF-1 showed a significant increase in cell motility and survival.

Conclusion

Amplification of FGF-1 at 5q31 in ovarian cancer tissues leads to increased angiogenesis, and autocrine stimulation of cancer cells, which may result in poorer overall survival in patents with high-grade advanced stage serous ovarian cancer.
Superiority of Fluorodeoxyglucose Positron Emission Tomography to Other Functional Imaging Techniques in the Evaluation of Metastatic SDHB-Associated Pheochromocytoma and Paraganglioma
Authors: Timmers Henri J.L.M. , Kozupa Anna , Chen Clara C. , Carrasquillo Jorge A. , Ling Alexander , Eisenhofer Graeme , Adams Karen T. , Solis Daniel , Lenders Jacques W.M. , Pacak Karel
Published: May 2007

Purpose

Germline mutations of the gene encoding subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB) predispose to malignant paraganglioma (PGL). Timely and accurate localization of these aggressive tumors is critical for guiding optimal treatment. Our aim is to evaluate the performance of functional imaging modalities in the detection of metastatic lesions of SDHB-associated PGL.

Patients and Methods

Sensitivities for the detection of metastases were compared between [18F]fluorodopamine ([18F]FDA) and [18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), iodine-123- (123I) and iodine-131 (131I) -metaiodobenzylguanidine (MIBG), 111In-pentetreotide, and Tc-99m-methylene diphosphonate bone scintigraphy in 30 patients with SDHB-associated PGL. Computed tomography (CT) and magnetic resonance imaging (MRI) served as standards of reference.

Results

Twenty-nine of 30 patients had metastatic lesions. In two patients, obvious metastatic lesions on functional imaging were missed by CT and MRI. Sensitivity according to patient/body region was 80%/65% for 123I-MIBG and 88%/70% for [18F]FDA-PET. False-negative results on 123I-MIBG scintigraphy and/or [18F]FDA-PET were not predicted by genotype or biochemical phenotype. [18F]FDG-PET yielded a by patient/by body region sensitivity of 100%/97%. At least 90% of regions that were false negative on 123I-MIBG scintigraphy or [18F]FDA-PET were detected by [18F]FDG-PET. In two patients, 111In-pentetreotide scintigraphy detected liver lesions that were negative on other functional imaging modalities. Sensitivities were similar before and after chemotherapy or 131I-MIBG treatment, except for a trend toward lower post- (60%/41%) versus pretreatment (80%/65%) sensitivity of 123I-MIBG scintigraphy.

Conclusion

With a sensitivity approaching 100%, [18F]FDG-PET is the preferred functional imaging modality for staging and treatment monitoring of SDHB-related metastatic PGL.
Mechanisms Regulating Oocyte Meiotic Resumption: Roles of Mitogen-Activated Protein Kinase
Authors: Liang Cheng-Guang , Su You-Qiang , Fan Heng-Yu , Schatten Heide , Sun Qing-Yuan
Published: May 2007

Oocyte meiotic maturation is one of the important physiological requirements for species survival. However, little is known about the detailed events occurring during this process. A number of studies have demonstrated that MAPK plays a pivotal role in the regulation of meiotic cell cycle progression in oocytes, but controversial findings have been reported in both lower vertebrates and mammals. In this review, we summarized the roles of MAPK cascade and related signal pathways in oocyte meiotic reinitiation in both lower vertebrates and mammals. We also tried to reconcile the paradoxical results and highlight the new findings concerning the function of MAPK in both oocytes and the surrounding follicular somatic cells. The unresolved questions and future research directions regarding the role of MAPK in meiotic resumption are addressed.
Steroid Receptor Phosphorylation: A Key Modulator of Multiple Receptor Functions
Authors: Weigel Nancy L. , Moore Nicole L.
Published: May 2007

Steroid receptors are hormone-activated transcription factors, the expression and activities of which are also highly dependent upon posttranslational modifications including phosphorylation. The remarkable number of phosphorylation sites in these receptors and the wide variety of kinases participating in their phosphorylation facilitate integration between cell-signaling pathways and steroid receptor action. Sites have been identified in all of the functional domains although the sites are predominantly in the amino-terminal portions of the receptors. Regulation of function is receptor specific, site specific, and often dependent upon activation of a specific cell-signaling pathway. This complexity explains, in part, the early difficulties in identifying roles for phosphorylation in receptor function. With increased availability of phosphorylation site-specific antibodies and better means to measure receptor activities, numerous roles for site-specific phosphorylation have been identified including sensitivity of response to hormone, DNA binding, expression, stability, subcellular localization, and protein-protein interactions that determine the level of regulation of specific target genes. This review summarizes current knowledge regarding receptor phosphorylation and regulation of function. As functional assays become more sophisticated, it is likely that additional roles for phosphorylation in receptor function will be identified.
Estrogen Deprivation and Inhibition of Breast Cancer Growth in Vivo through Activation of the Orphan Nuclear Receptor Liver X Receptor
Authors: Gong Haibiao , Guo Ping , Zhai Yonggong , Zhou Jie , Uppal Hirdesh , Jarzynka Michael J. , Song Wen-Chao , Cheng Shi-Yuan , Xie Wen
Published: May 2007

Estrogen plays an important role in normal physiology. It is also a risk factor for breast cancer, and antiestrogen therapies have been shown to be effective in the treatment and prevention of breast cancers. The liver is important for estrogen metabolism, and a compromised liver function has been linked to hyperestrogenism in patients. In this report, we showed that the liver X receptor (LXR) controls estrogen homeostasis by regulating the basal and inducible hepatic expression of estrogen sulfotransferase (Est, or Sult1e1), an enzyme critical for metabolic estrogen deactivation. Genetic or pharmacological activation of LXR resulted in Est induction, which in turn inhibited estrogen-dependent uterine epithelial cell proliferation and gene expression, as well as breast cancer growth in a nude mouse model of tumorigenicity. We further established that Est is a transcriptional target of LXR, and deletion of the Est gene in mice abolished the LXR effect on estrogen deprivation. Interestingly, Est regulation by LXR appeared to be liver specific, further underscoring the role of liver in estrogen metabolism. Activation of LXR failed to induce other major estrogen-metabolizing enzymes, suggesting that the LXR effect on estrogen metabolism is Est specific. In summary, our results have revealed a novel mechanism controlling estrogen homeostasis in vivo and may have implications for drug development in the treatment of breast cancer and other estrogen-related cancerous endocrine disorders.
Specters of the Real: Documentary Time and Art
Authors: Cowie Elizabeth
Published: May 2007

elizabeth cowie is Professor of Film Studies at the School of Drama, Film, and Visual Arts at the University of Kent, Canterbury. She published Representing the Woman: Cinema and Psychoanalysis (University of Minnesota Press, 1997), and has recently written on the horror of the horror film; on cinematic dream-work; and on documentary film, memory, and trauma in Alain Resnais's Hiroshima mon amour, and on Jean Rouch and surrealism. Her essay in Camera Austria on the work of Milica Tomić, a Yugoslav video artist committed to working politically in art, focuses on the role of trauma as the unrepresentable figured in Tomić's work. A similar focus arises in her commentary accompanying Juan delGado's video work “Who are you entertaining to?” in Aspect: The Chronicle of New Media Art. She is currently completing a book on documentary film and video theory and practice.
The Indexical and the Concept of Medium Specificity
Authors: Doane Mary Ann
Published: May 2007

mary ann doane is George Hazard Crooker Professor of Modern Culture and Media at Brown University. She is the author of The Emergence of Cinematic Time: Modernity, Contingency, the Archive (Harvard University Press, 2002), Femmes Fatales: Feminism, Film Theory, Psychoanalysis (Routledge, 1991), and The Desire to Desire: The Woman's Film of the 1940s (Indiana University Press, 1987). Currently, she is researching the use of the close-up in film practice and theory and the way in which screen size and its corresponding scale have figured in the negotiation of the human body's relation to space in modernity.
Notch signalling is needed to maintain, but not to initiate, the formation of prosensory patches in the chick inner ear
Authors: Daudet Nicolas , Ariza-McNaughton Linda , Lewis Julian
Published: May 2007

Notch signalling is well-known to mediate lateral inhibition in inner ear sensory patches, so as to generate a balanced mixture of sensory hair cells and supporting cells. Recently, however, we have found that ectopic Notch activity at an early stage can induce the formation of ectopic sensory patches. This suggests that Notch activity may have two different functions in normal ear development, acting first to promote the formation of the prosensory patches, and then later to regulate hair-cell production within the patches. The Notch ligand Serrate1 (Jag1 in mouse and humans) is expressed in the patches from an early stage and may provide Notch activation during the prosensory phase. Here, we test whether Notch signalling is actually required for prosensory patch development. When we block Notch activation in the chick embryo using the gamma-secretase inhibitor DAPT, we see a complete loss of prosensory epithelial cells in the anterior otocyst, where they are diverted into a neuroblast fate via failure of Delta1-dependent lateral inhibition. The cells of the posterior prosensory patch remain epithelial, but expression of Sox2 and Bmp4 is drastically reduced. Expression of Serrate1 here is initially almost normal, but subsequently regresses. The patches of sensory hair cells that eventually develop are few and small. We suggest that,in normal development, factors other than Notch activity initiate Serrate1 expression. Serrate1, by activating Notch, then drives the expression of Sox2 and Bmp4, as well as expression of the Serrate1 gene itself. The positive feedback maintains Notch activation and thereby preserves and perhaps extends the prosensory state,leading eventually to the development of normal sensory patches.
Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage
Authors: Val Pierre , Martinez-Barbera Juan-Pedro , Swain Amanda
Published: May 2007

It has been proposed that the mammalian adrenal cortex and gonad are derived from the same primordium present during early urogenital development. Molecular pathways involved in the differentiation of the adrenal cortex from the adrenogonadal primordium (AGP) have yet to be determined. Here we show in mice that the transcription co-factor Cited2 is required for the specification of the adrenal cortex from the AGP. We present genetic and molecular evidence demonstrating that Cited2 interacts with the transcription factor Wt1 to stimulate expression of the nuclear hormone receptor Sf-1 (Nr5a1) in the AGP prior to the separation between gonad and adrenal cortex. We show a direct correlation between the expression levels of Sf-1 in the AGP and the defects in adrenal development found in mice with different Cited2 and Wt1 mutant backgrounds. Analysis of embryos heterozygous for mutations in both Sf-1 and Cited2 confirmed that these genes act in the same pathway during adrenal development. Our studies reveal a regulatory mechanism in which Cited2 acts as a Wt1 co-factor to increase, at a critical time in embryogenesis, the levels of the essential transcription factor Sf-1 in the AGP above the threshold required to determine adrenal development. These results highlight the importance of transcription factor dosage in organogenesis and the role of transcription co-factors such as Cited2 in determining the levels of these factors.
Hrk/DP5 contributes to the apoptosis of select neuronal populations but is dispensable for haematopoietic cell apoptosis
Authors: Coultas Leigh , Terzano Susanna , Thomas Tim , Voss Anne , Reid Kate , Stanley Edouard G. , Scott Clare L. , Bouillet Philippe , Bartlett Perry , Ham Jonathan , Adams Jerry M. , Strasser Andreas
Published: May 2007

The pro-apoptotic BH3-only members of the Bcl2 family, crucial initiators of cell death, are activated by a diverse array of developmental cues or experimentally applied stress stimuli. We have investigated, through gene targeting in mice, the biological roles for the BH3-only family member HRK (also known as DP5) in apoptosis regulation. Hrk gene expression was found to be restricted to cells and tissues of the central and peripheral nervous systems. Sensory neurons from mice lacking Hrk were less sensitive to apoptosis induced by nerve growth factor (NGF) withdrawal, consistent with the induction of Hrk following NGF deprivation. By contrast, cerebellar granule neurons that upregulate Hrk upon transfer to low-K+ medium underwent apoptosis normally under these conditions in the absence of Hrk. Furthermore, loss of Hrk was not sufficient to rescue the neuronal degeneration in lurcher mutant mice. Despite previous reports, no evidence was found for Hrk expression or induction in growth-factor-dependent haematopoietic cell lines following withdrawal of their requisite cytokine, and haematopoietic progenitors lacking HRK died normally in response to cytokine deprivation. These results demonstrate that HRK contributes to apoptosis signalling elicited by trophic factor withdrawal in certain neuronal populations but is dispensable for apoptosis of haematopoietic cells.
Naturally occurring erysipelas in rats
Authors: Feinstein R. E. , Eld K.
Published: May 2007

Erysipelothrix rhusiopathiae was isolated from the main limb joints of two Sprague Dawley rats affected by spontaneous lesions of chronic fibrinopurulent polyarthritis, endocarditis and mycocarditis.
CBXC: A set of recombinant inbred strains between CBA/Ca and BALB/c
Authors: Fernandez J.L. , Peters A. G. , Cossens I. A. , Weeks M. , Festing M. F. W.
Published: May 2007

A new set of nine recombinant inbred strains designated CBXC-l to CBXC-9 has been developed from a cross between CBA/Ca female and BALB/c male mice. All of the strains have been brother × sister mated for more than 20 generations, and have been characterized at eight electrophoretic, one immunological and two coat colour loci at which the progenitor strains differ. This set of strains should be useful in investigating the genetics of any characters which differ between the two progenitor strains.
Long-term anaesthesia with alfentanil and midazolam for lung transplantation in the dog
Authors: Flecknell P. A. , Hooper T. L. , Fetherstony G. , Locke T. J. , McGregor C. G. A.
Published: May 2007

An anaesthetic regime was developed for lung transplantation in the dog using a continuous infusion of alfentanil and midazolam. This combination of agents provided excellent analgesia and also produced loss of consciousness. Cardiovascular stability was well maintained over a 24-h period of anaesthesia following lung transplantation. Although no animals were allowed to recover from anaesthesia in the present series, the regime described is likely to be suitable for recovery anaesthesia, particularly since both of the agents used can be reversed with specific antagonists.
Use of cage space by guineapigs
Authors: White W. J. , Balk M. W. , Lang C. M.
Published: May 2007

Cage space requirements for laboratory animals have been established by Government Regulation and Recommendations. In order to test the adequacy of these space allocations, the use of cage floor area by breeding groups of guineapigs was studied. A computer-coupled video tracking system capable of imaging in low light intensity as well as total darkness was used to determine the average per cent occupancy by guineapigs in all portions of a cage over 12-h light and dark cycles. Simultaneous time synchronized slow motion video recordings permitted an analysis of activity to be coordinated with cage use data. Results of the study revealed that breeding groups of guinea pigs utilize the periphery of the cage almost to the total exclusion of the centre of the cage. Approximately 75-85% of all occupancy in both the day and evening hours occurred in 47% of the cage floor area located along the periphery. Analysis of video recordings revealed that the animals remained active throughout the day and night with no prolonged period of quiescence that could be associated with sleep. Results of this study suggest that while guidelines for housing guineapigs based on area allocation per animal can be formulated and are easy to administer, they cannot be supported by the behavioural characteristics of these animals or careful quantitation of their pattern of cage space utilization.
On Scheduling Fees to Prevent Merging, Splitting, and Transferring of Jobs
Authors: Moulin Hervé
Published: May 2007

A deterministic server is shared by users with identical linear waiting costs, requesting jobs of arbitrary lengths. Shortest jobs are served first for efficiency. The server can monitor the length of a job but not the identity of the job’s user, thus merging, splitting, or partially transferring jobs offer cooperative strategic opportunities. Can we design cash transfers to neutralize such manipulations? We prove that mergeproofness and splitproofness are not compatible, and that it is similarly impossible to prevent all transfers of jobs involving three or more agents. On the other hand, robustness against pairwise transfers is feasible and essentially characterizes a one-dimensional set of scheduling methods. This line is borne by two outstanding methods: the merge-proof S+ and the split-proof S−. Splitproofness, unlike mergeproofness, is not compatible with several simple tests of equity. Thus, the two properties are far from equally demanding.
Risk-Sensitive and Risk-Neutral Multiarmed Bandits
Authors: Denardo Eric V. , Park Haechurl , Rothblum Uriel G.
Published: May 2007

For the multiarmed bandit, the classic result is probabilistic: each state of each bandit (Markov chain with rewards) has an index that is determined by an optimal stopping time for that state’s bandit, and expected discounted income is maximized by playing at each epoch a bandit whose current state has the largest index. Our approach is analytic, not probabilistic. It uses pairwise comparison in place of stopping times. A simple recursion assigns to each state of each bandit a utility and an amplification of future utility that depend solely on the data for that state’s bandit. These utilities and amplifications determine whether or not one state dominates another. We show that it is optimal to play at each epoch any bandit whose current state is not dominated by the current states of the other bandits. We obtain this result by a coherent analysis that encompasses three models—one with risk-averse exponential utility, one with risk-seeking exponential utility, and one with linear utility and either stopping or discounting. We also show that the risk-seeking case and a model of Nash [Nash, P. 1980. A generalized bandit problem. J. Roy. Statist. Soc. B 42 165–169] are equivalent to each other.
On the Closedness of the Linear Image of a Closed Convex Cone
Authors: Pataki Gábor
Published: May 2007

When is the linear image of a closed convex cone closed? We present very simple and intuitive necessary conditions that (1) unify, and generalize seemingly disparate, classical sufficientconditions such as polyhedrality of the cone, and Slater-type conditions; (2) are necessary and sufficient, when the dual cone belongs to a class that we call nice cones (nice cones subsume all cones amenable to treatment by efficient optimization algorithms, for instance, polyhedral, semidefinite, and p-cones); and (3) provide similarly attractive conditions for an equivalent problem: the closedness of the sum of two closed convex cones.
Oral Antidiabetic Agents in Pregnancy and Lactation: A Paradigm Shift?
Authors: Feig Denice S , Briggs Gerald G , Koren Gideon
Published: May 2007

Objective:

To provide information on the use of oral antidiabetic agents in pregnancy and breast-feeding.

Data Sources:

Primary articles were identified by a MEDLINE search (1966–March 2007) using the MeSH headings: pregnancy in diabetics, pregnancy, polycystic ovary syndrome, hypoglycemic agents, glipizide, glyburide, metformin, rosiglitazone, pioglitazone, clinical trial, controlled clinical trial, multicenter study, randomized controlled trial, case–control studies, and cohort studies.

Study Selection and Data Extraction:

All studies using oral antidiabetic agents in pregnancy were evaluated and relevant data were included in the discussion.

Data Synthesis:

Studies of glyburide and glipizide have found little or no transfer of these drugs across the placenta, whereas metformin and rosiglitazone cross readily. Animal studies have found no evidence to suggest that glyburide, glipizide, metformin, or rosiglitazone are teratogenic. In gestational diabetes, glyburide was safe and efficacious; however, 16–19% of women failed to achieve optimal glucose control. No developmental toxicity in infants was observed when metformin was used before and throughout pregnancy in women with polycystic ovarian syndrome (PCOS). Some of the studies involving patients with type 2 diabetes had methodological problems. A randomized controlled trial using metformin for gestational diabetes in the third trimester is underway. The human information is inadequate to evaluate the risk of glipizide or the thiazolidinediones in pregnancy. In breast milk, 3 studies measured nonsignificant amounts of metformin and one study was unable to detect either glyburide or glipizide.

Conclusions:

Neither glyburide nor metformin has caused developmental toxicity in humans. Glyburide has been used for the treatment of gestational diabetes, and metformin has been used in women with PCOS who eventually became pregnant. Additional trials are needed to better define the benefits and risks of oral antidiabetic agents in pregnancy. Metformin, glyburide, and glipizide appear to be compatible with breast-feeding.
Evaluation of Fall Arrest Harness Sizing Schemes
Authors: Hsiao Hongwei , Whitestone Jennifer , Kau Tsui-Ying
Published: May 2007

Objective: This paper evaluated harness sizing schemes and anthropometric criteria for harness design applications. Background: Updated harness sizing systems are needed to accommodate diverse populations in the current workforce. Method: Three-dimensional torso scan data and human-harness interfaces from 108 women and 108 men were digitally captured. Abounding box approach was employed to quantify the effect of torso shape and size on fall harness fit. Results: A logistic regression model with eight equations was developed and tested to classify more than 96% of participants to the best-fitting size. Conclusion: Study outcomes suggested an alternative system of two sizes for women and three sizes for men over the current four-size unisex system. In addition, thigh strap angle and back D ring location could be utilized along with current harness static fit test criteria to further enhance postfall harness fit predictions. Application: This research could help reduce the risk of worker injury resulting from poor fit, improper size selection, or failure to don the harness properly.
Interaction With an Immersive Virtual Environment Corrects Users' Distance Estimates
Authors: Richardson Adam R. , Waller David
Published: May 2007

Objective: Two experiments examined whether prior interaction within an immersive virtual environment (VE) enabled people to improve the accuracy of their distance judgments and whether an improved ability to estimate distance generalized to other means of estimating distances. Background: Prior literature has consistently found that users of immersive VEs underestimate distances by approximately 50%. Method: In each of the two experiments, 16 participants viewed objects in an immersive VE and estimated their distance to them by means of blindfolded walking tasks before and after interacting with the VE. Results: The interaction task significantly corrected users' underestimation bias to nearly veridical. Differences between pre- and postinteraction mean distance estimation accuracy were large ( d = 4.63), and significant ( p < .001), and they generalized across response task. Conclusion: This finding limits the generality of the underestimation effect in VEs and suggests that distance underestimation in VEs may not be a roadblock to the development of VE applications. Application: Potential or actual applications of this research include the improvement of VE systems requiring accurate spatial awareness.
Evaluation of Six Night Vision Enhancement Systems: Qualitative and Quantitative Support for Intelligent Image Processing
Authors: Mahlke Sascha , Rösler Diana , Seifert Katharina , Krems Josef F. , Thüring Manfred
Published: May 2007

Objective: An evaluation study was conducted to answer the question of which system properties of night vision enhancement systems (NVESs) provide a benefit for drivers without increasing their workload. Background: Different infrared sensor, image processing, and display technologies can be integrated into an NVES to support nighttime driving. Because each of these components has its specific strengths and weaknesses, careful testing is required to determine their best combination. Method: Six prototypical systems were assessed in two steps. First, a heuristic evaluation with experts from ergonomics, perception, and traffic psychology was conducted. It produced a broad overview of possible effects of system properties on driving. Based on these results, an experimental field study with 15 experienced drivers was performed. Criteria used to evaluate the development potential of the six prototypes were the usability dimensions of effectiveness, efficiency, and user satisfaction (International Organization for Standardization, 1998). Results: Results showed that the intelligibility of information, the easiness with which obstacles could be located in the environment, and the position of the display presenting the output of the system were of crucial importance for the usability of the NVES and its acceptance. Conclusion: All relevant requirements are met best by NVESs that are positioned at an unobtrusive location and are equipped with functions for the automatic identification of objects and for event-based warnings. Application: These design recommendations and the presented approach to evaluate the systems can be directly incorporated into the development process of future NVESs.
Development and Plasticity of Spontaneous Activity and Up States in Cortical Organotypic Slices
Authors: Johnson Hope A. , Buonomano Dean V.
Published: May 2007

Cortical computations are an emergent property of neural dynamics. To understand how neural dynamics emerges within local cortical networks, we characterized the development and underlying mechanisms of spontaneous dynamics in cortical organotypic slices. We observed not only a quantitative increase in the levels of spontaneous dynamics, but a qualitative transition from brief bursts of activity to well defined Up states during the first 4 weeksin vitro. Analysis of cellular and synaptic properties indicates that these changes are driven by increasing excitatory drive accompanied by changes in the balance of excitation and inhibition. Examination of the structure of spontaneous dynamics revealed no evidence of precisely repeating patterns. Slices exposed to chronic patterned stimulation exhibited decreased levels of spontaneous activity, suggesting homeostatic control of the levels of network activity. Together, these results suggest that Up states reflect a fundamental mode of network dynamics that emerges through the orchestrated regulation of multiple cellular and synaptic properties in parallel.