bluuebunny/crossref_metadata_2025 huggingface dataset:
A Phase I Trial of Liposomal Doxorubicin, Bevacizumab, and Temsirolimus in Patients with Advanced Gynecologic and Breast Malignancies
Authors: Moroney John W. , Schlumbrecht Matthew P. , Helgason Thorunn , Coleman Robert L. , Moulder Stacy , Naing Aung , Bodurka Diane C. , Janku Filip , Hong David S. , Kurzrock Razelle
Published: September 2011

Purpose: Liposomal doxorubicin (D) and bevacizumab (A) are active single agents in gynecologic and breast malignancies which share a resistance mechanism: upregulation of hypoxia inducible factor (HIF-1α). We, therefore, added temsirolimus (T), which inhibits HIF-1α, to D and A (DAT). Trial objectives were assessment of safety, preliminary efficacy, and identification of biological response correlates.

Patients and Methods: Cycle length was 21 days, with IV D, A, and T on day 1; T on days 8 and 15 (3+3 dose-escalation design with expansion cohorts). Mutational assays for PIK3CA, BRAF, KRAS, and immunhistochemistry for PTEN loss were conducted.

Results: This article details 74 patients with gynecologic and breast malignancies who received at least one dose of drug on study. Median patient age: 52 (27–79); prior regimens: 4 (1–11). Responses: 1 (1.4%) complete response (CR), 14 (18.9%) partial responses (PR), and 13 (17.6%) with stable disease (SD) ≥ 6 months (total = 37.9%). The most common grade 1 toxicities were fatigue (27%) and anemia (20.2%). Notable grade 3/4 toxicities: thrombocytopenia (9.5%), mucositis (6.7%), and bowel perforation (2.7%). PIK3CA mutations or PTEN loss were identified in 25 of 59 (42.3%) of tested patients. Among these, nine (36%) achieved CR/PR and four (16%) had SD ≥ 6 months (CR+PR+SD ≥ 6 months = 52%).

Conclusions: DAT is well tolerated with manageable side effects. Responses observed warrant further evaluation. Mutational analyses were notable for a high percentage of responders with phosphoinositide-3-kinase pathway aberrations. Clin Cancer Res; 17(21); 6840–6. ©2011 AACR.
The Prognostic Significance of Various 13q14 Deletions in Chronic Lymphocytic Leukemia
Authors: Ouillette Peter , Collins Roxane , Shakhan Sajid , Li Jinghui , Li Cheng , Shedden Kerby , Malek Sami N.
Published: September 2011

Purpose: To further our understanding of the biology and prognostic significance of various chromosomal 13q14 deletions in chronic lymphocytic leukemia (CLL).

Experimental Design: We analyzed data from SNP 6.0 arrays to define the anatomy of various 13q14 deletions in a cohort of 255 CLL patients and have correlated two subsets of 13q14 deletions (type I exclusive of RB1 and type II inclusive of RB1) with patient survival. Furthermore, we measured the expression of the 13q14-resident microRNAs by quantitative PCR (Q-PCR) in 242 CLL patients and subsequently assessed their prognostic significance. We sequenced all coding exons of RB1 in patients with monoallelic RB1 deletion and have sequenced the 13q14-resident miR locus in all patients.

Results: Large 13q14 (type II) deletions were detected in approximately 20% of all CLL patients and were associated with shortened survival. A strong association between 13q14 type II deletions and elevated genomic complexity, as measured through CLL-FISH or SNP 6.0 array profiling, was identified, suggesting that these lesions may contribute to CLL disease evolution through genomic destabilization. Sequence and copy number analysis of the RB1 gene identified a small CLL subset that is RB1 null. Finally, neither the expression levels of the 13q14-resident microRNAs nor the degree of 13q14 deletion, as measured through SNP 6.0 array-based copy number analysis, had significant prognostic importance.

Conclusions: Our data suggest that the clinical course of CLL is accelerated in patients with large (type II) 13q14 deletions that span the RB1 gene, therefore justifying routine identification of 13q14 subtypes in CLL management. Clin Cancer Res; 17(21); 6778–90. ©2011 AACR.
Species D Adenoviruses as Oncolytics against B-cell Cancers
Authors: Chen Christopher Y. , Senac Julien S. , Weaver Eric A. , May Shannon M. , Jelinek Diane F. , Greipp Philip , Witzig Thomas , Barry Michael A.
Published: September 2011

Purpose: Oncolytic viruses are self-amplifying anticancer agents that make use of the natural ability of viruses to kill cells. Adenovirus serotype 5 (Ad5) has been extensively tested against solid cancers, but less so against B-cell cancers because these cells do not generally express the coxsackie and adenoviral receptor (CAR). To determine whether other adenoviruses might have better potency, we “mined” the adenovirus virome of 55 serotypes for viruses that could kill B-cell cancers.

Experimental Design: Fifteen adenoviruses selected to represent Ad species B, C, D, E, and F were tested in vitro against cell lines and primary patient B-cell cancers for their ability to infect, replicate in, and kill these cells. Select viruses were also tested against B-cell cancer xenografts in immunodeficient mice.

Results: Species D adenoviruses mediated most robust killing against a range of B-cell cancer cell lines, against primary patient marginal zone lymphoma cells, and against primary patient CD138+ myeloma cells in vitro. When injected into xenografts in vivo, single treatment with select species D viruses Ad26 and Ad45 delayed lymphoma growth.

Conclusions: Relatively unstudied species D adenoviruses have a unique ability to infect and replicate in B-cell cancers as compared with other adenovirus species. These data suggest these viruses have unique biology in B cells and support translation of novel species D adenoviruses as oncolytics against B-cell cancers. Clin Cancer Res; 17(21); 6712–22. ©2011 AACR.
Lysophosphatidic Acid–Induced p21Waf1 Expression Mediates the Cytostatic Response of Breast and Ovarian Cancer Cells to TGFβ
Authors: Wu Jinhua , Mukherjee Abir , Lebman Deborah A. , Fang Xianjun
Published: September 2011

Lysophosphatidic acid (LPA) is a multifunctional intercellular phospholipid mediator present in blood and other biological fluids. In cancer cells, LPA stimulates expression or activity of inflammatory cytokines, angiogenic factors, matrix metalloproteinases, and other oncogenic proteins. In this study, we showed that LPA upregulated expression of the cyclin-dependent kinase inhibitor p21Waf1 in TGFβ-sensitive breast and ovarian cancer cells, but not in TGFβ-resistant ones. We examined the possibility that LPA-induced p21 might contribute to the cytostatic response to TGFβ. In serum-free conditions, TGFβ alone induced p21 expression weakly in TGFβ-sensitive cells. Serum or serum-borne LPA cooperated with TGFβ to elicit the maximal p21 induction. LPA stimulated p21 via LPA1 and LPA2 receptors and Erk-dependent activation of the CCAAT/enhancer binding protein beta transcription factor independent of p53. Loss or gain of p21 expression led to a shift between TGFβ-sensitive and -resistant phenotypes in breast and ovarian cancer cells, indicating that p21 is a key determinant of the growth inhibitory activity of TGFβ. Our results reveal a novel cross-talk between LPA and TGFβ that underlies TGFβ-sensitive and -resistant phenotypes of breast and ovarian cancer cells. Mol Cancer Res; 9(11); 1562–70. ©2011 AACR.
Hunting for the Causes of Meningioma—Obesity Is a Suspect
Authors: Rajaraman Preetha
Published: September 2011

In this issue of the journal, Michaud and colleagues report a 48% increased risk of meningioma in obese individuals compared with individuals with a normal body mass index (BMI). This large prospective cohort study adds weight to the suggested link between BMI and meningioma, thus contributing to the growing number of cancer sites likely associated with body fatness. Although the exact mechanisms underlying the BMI–meningioma link are unclear, possible mediators include hormonal factors, immunologic response, and levels of insulin or insulin-like growth factors, each of which has been implicated by various levels of evidence in meningioma risk. Understanding the relationships between body fatness, height, and hormonal and immunologic factors could provide important clues to the etiology of meningioma and may have implications for the early detection and prevention of these tumors. Cancer Prev Res; 4(9); 1353–5. ©2011 AACR.
Brush-based Cytology Screening in the Tonsils and Cervix: There Is a Difference!
Authors: Lingen Mark W.
Published: September 2011

This perspective on the report by Fakhry and colleagues in this issue of the journal (beginning on page 1378) examines the diagnostic accuracy of a “Pap-test equivalent” for screening for human papillomavirus (HPV)-associated cancers in the tonsils. HPV infection is strongly associated with cancer development in the oropharynx (tonsils and base of tongue) and cervix; the data discussed here underscore the differences in screening for cervical versus oropharyngeal malignancies and discuss some of the challenges and limitations associated with screening for tonsillar premalignancy and early cancers. Cancer Prev Res; 4(9); 1350–2. ©2011 AACR.
Personalizing CA125 Levels for Ovarian Cancer Screening
Authors: Dorigo Oliver , Berek Jonathan S.
Published: September 2011

Screening trials for the early detection of ovarian cancer in the general population and in patients at a high risk for this disease have so far failed to show a reduction of ovarian cancer–specific mortality. Current screening modalities include pelvic examinations, transvaginal ultrasounds, and cancer antigen 125 (CA125) serum marker levels, which are associated with a high false-positive rate. The last decade has witnessed significant modifications in the interpretation of serum CA125 that extend beyond a static CA125 cutoff point. The Risk of Ovarian Cancer Algorithm (ROCA) incorporates changes of CA125 levels over time and an individual's age-specific risk. Ongoing screening trials have incorporated ROCA, but it is still unclear whether the algorithm will increase the sensitivity and specificity of early ovarian cancer diagnosis. A very recent study analyzed baseline CA125 serum marker levels from high-risk patients included in ovarian cancer screening trials conducted by the Cancer Genetics Network and the Gynecologic Oncology Group. The findings show that the distribution of CA125 serum marker levels in this population is significantly affected by various demographic and clinical factors, in particular menopausal status and oral contraceptive use in premenopausal patients. The data suggest that CA125 cutoff points might have to be stratified for subgroups of patients to reduce false-positive results. These intriguing observations will need to be validated in future screening trials for ovarian cancer. Cancer Prev Res; 4(9); 1356–9. ©2011 AACR.
HPV-associated Oropharyngeal Cancers—Are They Preventable?
Authors: Kreimer Aimée R. , Chaturvedi Anil K.
Published: September 2011

It is not known whether a human papillomavirus (HPV)-induced oropharyngeal precancerous lesion could be identified by screening with a pap test equivalent or whether one even exists. In this issue of the journal (beginning on page 1378), Fakhry and colleagues report their results showing that cytologic evaluation of the oropharynx, although useful in detecting invasive oropharyngeal cancers, may have limited utility as a screening modality for detecting precancer. These findings argue against the potential for secondary prevention of HPV-associated oropharyngeal cancers through screening for and preventing the progression of precancer and highlight the opportunity for primary prevention through prophylactic HPV vaccination, if proven efficacious and cost-effective. Cancer Prev Res; 4(9); 1346–9. ©2011 AACR.
Predicting Adherence to Tamoxifen for Breast Cancer Adjuvant Therapy and Prevention
Authors: Lin Jennifer H. , Zhang Shumin M. , Manson JoAnn E.
Published: September 2011

Treatment with the selective estrogen receptor modulator (SERM) tamoxifen for 5 years has produced dramatic breast cancer–related benefits in (a) the adjuvant setting, with 30% to 50% reductions in recurrence, contralateral disease, and mortality and (b) the prevention setting of healthy high-risk women, where tamoxifen reduces the risk of invasive and noninvasive breast cancer by 50%. Despite these striking data, adherence to tamoxifen is low, and low adherence is associated with poor survival. Although toxicity is a major predictor of poor adherence after starting therapy, pretreatment (baseline) predictors of poor tamoxifen adherence have been minimally studied. The adherence–survival link underscores the critical need to identify early predictors of poor adherence, and recent work is beginning to address this need. A major baseline predictor of poor adherence to prevention is current smoking, which is interestingly absent from studies of adherence to adjuvant therapy. Other important prevention adherence factors include breast cancer risk, extremes of age, non-white ethnicity, low socioeconomic status, and alcohol use. The strongest adjuvant therapy predictors are age (especially very young), ethnicity, and socioeconomic status. Future studies involving prospective systematic evaluation of these and other potential predictors in endocrine chemoprevention (e.g., other SERMs and aromatase inhibitors) are critical, as is the development of effective/targeted interventions to improve adherence and thus treatment outcomes in at-risk women. Cancer Prev Res; 4(9); 1360–5. ©2011 AACR.
TGF-β Receptor II Loss Promotes Mammary Carcinoma Progression by Th17-Dependent Mechanisms
Authors: Novitskiy Sergey V. , Pickup Michael W. , Gorska Agnieszka E. , Owens Philip , Chytil Anna , Aakre Mary , Wu Huiyun , Shyr Yu , Moses Harold L.
Published: September 2011

We report that interleukin (IL)-17 significantly increases the secretion of CXC chemokine ligand 1 and 5 (CXCL1/5) from mammary carcinoma cells, and that stimulated secretion of CXCL1/5 by IL-17 is down-regulated by TGF-β through the type II TGF-β receptor (TβRII). Carcinoma cells with conditional knockout of TβRII (Tgfbr2KO) have enhanced sensitivity to IL-17a in the stimulation of chemokine secretion. During polyoma middle T (PyMT)–induced tumor progression, levels of Th17-inducing cytokines TGF-β, IL-6, and IL-23 were increased in PyMT/Tgfbr2KO tumors, which was associated with an increased number of Th17 cells. IL-17 increased the suppressive function of myeloid-derived suppressor cells (MDSC) on T cells through the up-regulation of Arg, IDO, and cyclooxygenase-2. Treatment of PyMT/Tgfbr2KO mice with anti-IL-17 Ab decreased carcinoma growth and metastatic burden. Analysis of human breast cancer transcriptome databases demonstrated a strong association between IL-17 gene expression and poor outcome in lymph node-positive, estrogen receptor-negative, or luminal B subtypes, suggesting potential therapeutic approaches.

Significance: TGF-β signaling is a major tumor suppressor pathway and is therefore difficult to target therapeutically. Understanding the downstream effects of abrogation of TGF-β signaling in tumor cells may identify processes that can be targeted therapeutically. We present data indicating that targeting IL-17 signaling, a pathway that is greatly enhanced by loss of TGF-β signaling, could provide a therapeutic benefit. Analysis of human databases indicated a specific group of patients in whom treatment could be more efficient. Cancer Discovery; 1(5): 430–41. © 2011 AACR

This article is highlighted in the In This Issue feature, p. 367
A Molecularly Annotated Platform of Patient-Derived Xenografts (“Xenopatients”) Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer
Authors: Bertotti Andrea , Migliardi Giorgia , Galimi Francesco , Sassi Francesco , Torti Davide , Isella Claudio , Corà Davide , Di Nicolantonio Federica , Buscarino Michela , Petti Consalvo , Ribero Dario , Russolillo Nadia , Muratore Andrea , Massucco Paolo , Pisacane Alberto , Molinaro Luca , Valtorta Emanuele , Sartore-Bianchi Andrea , Risio Mauro , Capussotti Lorenzo , Gambacorta Marcello , Siena Salvatore , Medico Enzo , Sapino Anna , Marsoni Silvia , Comoglio Paolo M. , Bardelli Alberto , Trusolino Livio
Published: September 2011

Only a fraction of patients with metastatic colorectal cancer receive clinical benefit from therapy with anti-epidermal growth factor receptor (EGFR) antibodies, which calls for the identification of novel biomarkers for better personalized medicine. We produced large xenograft cohorts from 85 patient-derived, genetically characterized metastatic colorectal cancer samples (“xenopatients”) to discover novel determinants of therapeutic response and new oncoprotein targets. Serially passaged tumors retained the morphologic and genomic features of their original counterparts. A validation trial confirmed the robustness of this approach: xenopatients responded to the anti-EGFR antibody cetuximab with rates and extents analogous to those observed in the clinic and could be prospectively stratified as responders or nonresponders on the basis of several predictive biomarkers. Genotype–response correlations indicated HER2 amplification specifically in a subset of cetuximab-resistant, KRAS/NRAS/BRAF/PIK3CA wild-type cases. Importantly, HER2 amplification was also enriched in clinically nonresponsive KRAS wild-type patients. A proof-of-concept, multiarm study in HER2-amplified xenopatients revealed that the combined inhibition of HER2 and EGFR induced overt, long-lasting tumor regression. Our results suggest promising therapeutic opportunities in cetuximab-resistant patients with metastatic colorectal cancer, whose medical treatment in the chemorefractory setting remains an unmet clinical need.

Significance: Direct transfer xenografts of tumor surgical specimens conserve the interindividual diversity and the genetic heterogeneity typical of the tumors of origin, combining the flexibility of preclinical analysis with the informative value of population-based studies. Our suite of patient-derived xenografts from metastatic colorectal carcinomas reliably mimicked disease response in humans, prospectively recapitulated biomarker-based case stratification, and identified HER2 as a predictor of resistance to anti-epidermal growth factor receptor antibodies and of response to combination therapies against HER2 and epidermal growth factor receptor in this tumor setting. Cancer Discovery; 1(6); 508–23. ©2011 AACR.

Read the Commentary on this article by Ciardiello and Normanno, p. 472

This article is highlighted in the In This Issue feature, p. 457
Shrimp Allergy in Italian Adults: A Multicenter Study Showing a High Prevalence of Sensitivity to Novel High Molecular Weight Allergens
Authors: Asero R. , Mistrello G. , Amato S. , Ariano R. , Colombo G. , Conte M.E. , Crivellaro M. , De Carli M. , Della Torre F. , Emiliani F. , Lodi Rizzini F. , Longo R. , Macchia D. , Minale P. , Murzilli F. , Nebiolo F. , Quercia O. , Senna G.E. , Villalta D.
Published: September 2011

Background: Shrimp is a frequent cause of food allergy worldwide. Besides tropomyosin, several allergens have been described recently. Objective: We investigated which allergens are involved in Italian shrimp-allergic adults. Methods: Sera from 116 shrimp-allergic patients selected in 14 Italian allergy centers were studied. Skin prick tests with house dust mite (HDM) as well as measurements of IgE to Pen a 1 (shrimp tropomyosin) and whole shrimp extract were performed. All sera underwent shrimp immunoblot analysis, and inhibition experiments using HDM extract as inhibitor were carried out on some Pen a 1-negative sera. Results: Immunoblots showed much variability. IgE reactivity at about 30 kDa (tropomyosin) was found in <50% of cases, and reactivity at about 67 kDa and >90 kDa was frequent. Further reactivities at 14–18, 25, 43–50, about 60 and about 80 kDa were detected. Most subjects had a history of shrimp-induced systemic symptoms irrespective of the relevant allergen protein. IgE to Pen a 1 were detected in sera from 46 (41%) patients. Skin reactivity to HDM was found in 43/61 (70%) Pen 1-negative subjects and inhibition studies showed that pre-adsorption of sera with HDM extract induced a marked weakening of the signal at >67 kDa. Conclusions: Several allergens other than tropomyosin are involved in shrimp allergy in adult Italian patients. Some hitherto not described high molecular weight allergens seem particularly relevant in this population and their cross-reactivity with HDM allergens makes them novel potential panallergens of invertebrates.
Preliminary Studies on the Prevention of the Ovalbumin-Induced Allergic Response by Enterococcus faecalis CECT7121 in Mice
Authors: Castro M.S. , Azpiroz M.B. , Molina M.A. , Mourelle A.C. , Alaniz F.S. , Maldonado A.M. , Manghi M.A.
Published: September 2011

Background: Allergic diseases are featured by an increased production of IgE due to an imbalance in the immune response towards a Th2 profile. In this work, the ability of Enterococcus faecalis CECT7121 to regulate this Th2-exaggerated response in a murine model of ovalbumin (OVA)-induced allergy was studied. Methods: BALB/c mice intragastrically inoculated with E. faecalis CECT7121 before and during a subcutaneous immunization protocol with OVA were studied in comparison with an immunized control group. The allergen-specific immune response (IgE, IgG, IgG1 and IgG2a) was assessed. The proliferative activity of memory splenocytes and the levels of IL-4, IL-5, IL-13, IL-10, IL-12 and IFN-γ were also determined. Results: Upon treatment with E. faecalis CECT7121 the following effects were observed: (1) a decrease in specific IgE levels, (2) an increase in anti-OVA IgG2a levels, (3) the levels of anti-OVA IgG and IgG1 remained unaltered, (4) a reduction in the proliferation rate of memory cells, (5) a decrease in the levels of the Th2 cytokines IL-4, IL-5 and IL-13, and (6) the secretion of IL-10, IL-12 and IFN-γ remained unchanged. Moreover, the incubation of human basophils with non-viable E. faecalis CECT7121 together with an allergen preparation induced the release of β-hexosaminidase at levels that were lower than control reactions and similar i.g. the spontaneous release. Conclusions: In this model, the i.g. administration of E. faecalis CECT7121 hampers the establishment of the OVA-induced allergic immune response, suggesting that this strain could be useful for the treatment of IgE-mediated allergic diseases.
Effect of Respiratory Syncytial Virus Infection on Plasmacytoid Dendritic Cell Regulation of Allergic Airway Inflammation
Authors: Tsuchida Tomoko , Matsuse Hiroto , Fukahori Susumu , Kawano Tetsuya , Tomari Shinya , Fukushima Chizu , Kohno Shigeru
Published: September 2011

Background: Respiratory syncytial virus (RSV) can infect myeloid dendritic cells (mDCs) and regulate their function in the development of allergy. It has been widely reported that plasmacytoid DCs (pDCs) play a critical role in antiviral innate immunity. In contrast, not much is known about the role of pDCs in the interaction between allergy and viral infection. The purpose of the present study was to investigate the effect of RSV infection on pDC function in the regulation of allergic airway inflammation in a murine model of Dermatophagoides farinae-sensitized allergic asthma. Methods: Splenic pDCs isolated from D. farinae-sensitized donor mice were infected with live RSV ex vivo. Subsequently, these pDCs were inoculated into the airways of D. farinae-sensitized recipient mice. Lung pathology, lung tissue cytokine profiles, the number of regulatory T cells (Treg) and mDCs as well as the effects of IL-10 neutralization in the lung tissue of recipient mice were determined. Results: Intranasal inoculation of D. farinae-sensitized pDCs significantly inhibited the development of allergic airway inflammation and both Th1 and Th2 immunity. Live RSV infection of these pDCs prior to inoculation interfered with their inhibitory effects through decreasing Treg and IL-10 and increasing mDCs. Conclusions: In asthmatic airways, pDCs mediate tolerance to inhaled allergens through the regulation of Treg, IL-10 and mDCs. RSV infection of pDCs potentially inhibits their immunotolerogenic effects and thus exacerbates allergic airway inflammation.
Epitope Mapping of Atlantic Salmon Major Allergen by Peptide Microarray Immunoassay
Authors: Perez-Gordo Marina , Lin Jing , Bardina Ludmilla , Pastor-Vargas Carlos , Cases Barbara , Vivanco Fernando , Cuesta-Herranz Javier , Sampson Hugh A.
Published: September 2011

Background: IgE epitope mapping of allergens reveals important information about antigen elicitors involved in allergic reactions. The peptide-based microarray immunoassay offers an advantage of scale and parallel design over previous methods of epitope mapping. It has been used to map epitopes of some food allergens but has never been used with fish allergens. Objective: We sought to develop a peptide microarray immunoassay to map allergenic fish epitopes of two isoforms of Atlantic salmon (Salmo salar) parvalbumin, Sal s 1 beta 1 and Sal s 1 beta 2. Methods: Sera from 16 fish-allergic patients with specific IgE to salmon parvalbumin were used. Twelve healthy volunteers were used as negative controls. A library of overlapping peptides was synthesized commercially, representing the primary sequence of Sal s 1 beta 1 and Sal s 1 beta 2. Peptides were used to analyze allergen-specific IgE antibodies by immunolabeling with patient sera. Results: Three antigenic regions, not previously described, were identified in Sal s 1 beta 1. Two of them correlated with those previously reported in Gad c 1, parvalbumin from Baltic cod (Gadus callarias). No allergenic regions were found in Sal s 1 beta 2. This could be explained by crucial amino acid substitutions between isoforms. Conclusions: We have identified three antigenic regions in Sal s 1 beta 1 using a peptide microarray immunoassay. These three sequential epitopes formed a unique antigenic determinant in the three-dimensional model of the protein. In addition, we proved that isoforms from the same protein might have a different allergenic behavior.
Detection of Four Germ Cell Markers in Rats during Testis Morphogenesis: Differences and Similarities with Mice
Authors: Encinas Giselly , Zogbi Camila , Stumpp Taiza
Published: September 2011

Germ cells are the only cells capable of transmitting genetic information from generation to generation. Germ cell development has been widely studied in different species. Among mammals, the mouse is the model used in the majority of studies on germ cell differentiation, sex determination and genetics. In the present study, we suggest that the rat is also a very important model for the investigation of the mechanisms of germ cell development. To study rat germ cell development and compare it with that of mouse, the germ cell markers germ cell nuclear antigen 1 (GCNA1), OCT4, mouse vasa homologue (MVH) and specific surface embryonic antigen 1 (SSEA1) were immunolabeled at different phases of embryonic and postnatal development. SSEA1 and GCNA1 were not detected in rat primordial germ cells and fetal gonocytes. GCNA1 was detected postnatally and was present only in leptotene, zygotene and early pachytene spermatocytes. On the other hand, in mice, these markers were detected in germ cells as soon as 11.5 days postcoitum (dpc). MVH was detected in migrating rat primordial germ cells as well as in those that have already colonized the gonads, whereas in mice, MVH is detected only in germ cells that have reached the gonads. In rats, OCT4-positive germ cells were detected from 13 to 17 dpc, but not at 19 dpc or in postnatal testes. This is in contrast with mice that show OCT4 labeling in both embryonic and adult testes. These data suggest that primordial germ cell development in rats and mice shows considerable differences and that the rat may also be an important model to study the embryonic development of germ cells.
The Effect of Serial Passaging on the Proliferation and Differentiation of Bovine Adipose-Derived Stem Cells
Authors: Zhao Yimu , Waldman Stephen D. , Flynn Lauren E.
Published: September 2011

Adipose-derived stem cells (ASCs) represent an excellent cell source for the development of regenerative therapies for a broad variety of tissue disorders. Commonly, in vitro expansion is necessary to obtain sufficient cell populations for research purposes and clinical applications. Although it has been demonstrated that human ASCs can maintain their adipogenic, chondrogenic and osteogenic potential in long-term culture (up to 15 passages), it is not guaranteed that a satisfactory level of differentiation is achievable in later passages. In this study, we investigated the self-renewal and multilineage differentiation capacity of bovine ASCs, isolated from the interdigital fat pad, and explored how serial passaging influences the cells. A proliferation study examined the changes in growth kinetics from passage 1 to 5, and multilineage (adipogenesis, chondrogenesis and osteogenesis) differentiation studies were conducted to compare the potential between passage 2 (P2) and passage 5 (P5). From the proliferation study, a statistically significant change in the doubling time did not appear until P5. In the differentiation study, both P2 and P5 ASCs could be stimulated to undergo multilineage differentiation under specific culturing conditions. However, adipogenic and chondrogenic cultures showed significantly lower levels of differentiation in the P5-induced cultures. In contrast, P5-induced osteogenic cultures had higher alkaline phosphatase enzyme activity than P2-induced cultures, suggesting an increase in the osteogenic response with serial passaging. Overall, bovine ASCs are capable of self-renewal and multilineage differentiation; however, long-term in vitro expansion has a negative effect on adipogenic and chondrogenic differentiation, while potentially favoring osteogenesis.
Quality of Health Care of Rosacea in Germany from the Patient’s Perspective: Results of the National Health Care Study RosaReal 2009
Authors: Langenbruch A.K. , Beket E. , Augustin M.
Published: September 2011

Objectives: To obtain reliable data on quality of care of rosacea and to compare care indicators with those found in atopic dermatitis and psoriasis. Patients and Methods: In this cross-sectional study, clinical history, health-related quality of life (HrQoL), medication and treatment benefit of patients with rosacea were assessed by standardized questionnaires. Data were compared to patients with atopic dermatitis and psoriasis. Results: Almost all 475 participants (96.4%) had received topical therapy. 24% had used cortisone ointments. The mean Dermatology Life Quality Index (DLQI) was 4.3 ± 4.6 (atopic dermatitis: 8.5 ± 6.0, psoriasis: 6.7 ± 6.2). The Patient Benefit Index (patient-defined therapeutic benefit) was 1.9 ± 1.2 (psoriasis: 2.3 ± 1.1, atopic dermatitis: 2.1 ± 1.1). Conclusions: Only a small proportion of the rosacea patients had substantial impairments in HrQoL. Overall, their burden appears to be lower than in patients with atopic dermatitis or psoriasis. However, the lower therapeutic benefit and the high proportion of topical steroid use indicate a need for optimized therapy.
Enhanced-MRI and Ultrasound Evaluation of Painful Shoulder in Patients after Stroke: A Pilot Study
Authors: Pompa Alessandra , Clemenzi Alessandro , Troisi Elio , Di Mario Marco , Tonini Angelo , Pace Luca , Casillo Paolo , Cuccaro Alessandro , Grasso Maria Grazia
Published: September 2011

Background: Epidemiological and radiological studies have previously been performed to identify the possible causes of hemiplegic shoulder pain (HSP). Many different etiologies have been postulated, though no clear correlations have emerged, and a multifactorial pathogenesis of HSP has been proposed. Recently, two MRI-based studies have described different shoulder findings as possible causes of pain in chronic stroke survivors. Purpose: The aim of this study was to describe the structural abnormalities of the painful shoulder in the first months after stroke by ultrasound and enhanced MRI. The secondary aims were to identify possible predisposing factors for HSP and to evaluate its impact on motor recovery. Methods: One hundred and fifty-three first-time stroke patients, admitted to the Santa Lucia Foundation for rehabilitation, were investigated for HSP. Twenty-five stroke patients with HSP and 16 stroke patients without shoulder pain were included. An ultrasound evaluation and enhanced shoulder MRI were performed for all the patients. Results: Among the shoulder abnormalities detected by both imaging studies, only capsulitis, which was detected by enhanced shoulder MRI in 88% of the HSP patients, was independently associated with pain (p < 0.001) and proven to be predictive of pain intensity as expressed by the VAS score (p < 0.003). HSP correlated with a worse global recovery (p < 0.05) as well as with male sex (p = 0.006), neglect (p = 0.02) and subluxation (p = 0.03), although none of these features were found to be independent predictors of pain. Conclusion: Adhesive capsulitis was found to be a possible cause of HSP. However, MRI, which is more expensive than other diagnostic tools, may be considered the gold standard tool for understanding the etiology of HSP.
Directional Asymmetries of Saccadic Hypometria in Patients with Early Parkinson’s Disease and Unilateral Symptoms
Authors: Choi Seong-Min , Lee Seung-Han , Choi Kang-Ho , Nam Tai-Seung , Kim Joon-Tae , Park Man-Seok , Kim Byeong-Chae , Kim Myeong-Kyu , Cho Ki-Hyun
Published: September 2011

Background: Saccade may be abnormal in Parkinson’s disease (PD), but there have been no systematic studies on directional asymmetries of horizontal saccades in early PD. The aims of this study were to determine the saccadic abnormalities and their directional asymmetries. Methods: We recorded visually guided horizontal prosaccades with random (random amplitudes and irregular time intervals) and regular (fixed amplitude and regular time interval) paradigms using video-oculography in 44 patients with unilateral symptoms and signs from early PD and in 26 controls. Results: PD patients showed decreased saccadic amplitude compared to the controls, especially during regular paradigm while the saccadic latency did not differ between the groups. Patients with unilateral PD tended to show more severe saccadic hypometria toward the symptomatic side during the regu- lar paradigm, compared to normal control. Conclusion: Even in early PD patients, saccadic accuracy may be abnormal. Asymmetries in saccadic hypometria are more likely to be detected during the anticipatable saccadic paradigm, which could be a useful adjunct in the diagnosis of early-stage PD.
Bacterial Heat Shock Protein 60, GroEL, Can Induce the Conversion of Naïve T Cells into a CD4+ CD25+ Foxp3-Expressing Phenotype
Authors: Ohue Ryuji , Hashimoto Kei , Nakamoto Masahiro , Furukawa Yuichi , Masuda Tetsuya , Kitabatake Naofumi , Tani Fumito
Published: September 2011

Recent publications report that heat shock proteins (HSPs) can endow regulatory responses to the systemic immune system when administered via the mucosal route, leading to an amelioration of atherosclerosis and allergy. However, it remains poorly understood if HSP antigens exist in the luminal contents of the gastrointestinal tract and which types of HSP induce regulatory responses. Here we addressed these problems, considering that numerous gut microflora and foods are natural sources of HSPs. SDS-PAGE and immunoblotting with the anti-HSP60 antibody demonstrated the intact and degraded forms of HSP60 mainly in appendix and large intestine of the gastrointestinal tract. No reactivity with this antibody was observed for any of the luminal contents derived from germ-free animals, suggesting gut microflora to be a source of the intestinal HSPs because of lack of HSPs in animal chow diet. GroEL, a typical member of bacterial HSP60, showed a tendency to stimulate splenocytes in germ-free mice, compared to that in conventional mice, suggesting that resident commensal bacterial GroEL may stimulate HSP-reactive T cells as regulatory cells in conventional animals. Importantly, GroEL, but not mouse-derived HSP60, caused naïve T cells to differentiate into CD4+ CD25+ Foxp3+ T cells, indicating that the production of regulatory T cells depends on the type of HSP. Thus, HSPs derived from commensal microbes can be utilized to stimulate immunoregulatory pathways for the maintenance of intestinal homeostasis.
Immunoadsorption in Patients with Chronic Inflammatory Demyelinating Polyradiculoneuropathy with Unsatisfactory Response to First-Line Treatment
Authors: Galldiks Norbert , Burghaus Lothar , Dohmen Christian , Teschner Sven , Pollok Manfred , Leebmann Josef , Frischmuth Nikolaus , Hollinger Peter , Nazli Nahed , Fassbender Cordula , Klingel Reinhard , Benzing Thomas , Fink Gereon R. , Haupt Walter F.
Published: September 2011

Background/Aims: First-line treatment options for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are corticosteroids, intravenous immunoglobulin, and plasma exchange. In a significant number of patients, first-line therapy fails, and long-term maintenance treatment still remains a therapeutic challenge. Immunoadsorption (IA) may be an alternative to classical plasma exchange in the therapy of immune-mediated neurologic diseases. The aim of this investigation was to evaluate efficacy and safety of IA in patients with CIDP with unsatisfactory response to first-line treatment options. Methods: CIDP patients received adjunct IA treatment using tryptophan-immune adsorbers. The inflammatory neuropathy cause and treatment disability (INCAT) score was used to grade disability and monitor treatment effects. Results: In total, 14 CIDP patients were analyzed. Ten patients were treated in hospital. After one IA treatment series, the INCAT score decreased significantly in all 10 patients. Four of these 14 patients were treated in outpatient clinics using long-term maintenance IA with 1–2 treatments per week. In these 4 patients, effects of long-term maintenance IA resulted in an improvement of overall disability. In all patients, IA was safe, well tolerated, and no severe adverse effects occurred. Conclusion: IA could be an effective and safe option for CIDP patients with unsatisfactory response to first-line treatment options and for long-term maintenance treatment.
T-communities and Sense of Community in a University Town: Evidence from a Student Sample using a Spatial Ordered-response Model
Authors: Whalen Kate E. , Páez Antonio , Bhat Chandra , Moniruzzaman Md , Paleti Rajesh
Published: September 2011

An emerging interest in transport research concerns the factors that can help to create strong, sustainable and ‘livable’ communities; however, relatively limited empirical work has been conducted to date. In this paper the perception of sense of community among neighbourhood residents is investigated. Drawing from research on tertiary street-communities ( t-communities), the paper explores the effect of the urban landscape, particularly street networks, and neighbourhood and individual characteristics on sense of community. A sample of students at McMaster University in Hamilton, Canada, is used for the analysis. In addition to providing an opportunity to study sense of community, a student sample is interesting in its own right, as students are often a component of essential but at times uneasy relations between universities and towns. Analysis is based on the application of an ordered probit model with a spatial lag. The results provide evidence that t-community membership can influence sense of community.
Network Accessibility and Employment Centres
Authors: Giuliano Genevieve , Redfearn Chris , Agarwal Ajay , He Sylvia
Published: September 2011

This research examines the impact of accessibility on the growth of employment centres in the Los Angeles region between 1990 and 2000. There is extensive empirical documentation of polycentricity—the presence of multiple concentrations of employment—in large metropolitan areas. However, there is limited understanding of the determinants of growth of employment centres. It has long been held that transport investments influence urban structure, particularly freeways and airports. Using data on 48 employment centres, the effects are tested of various measures of accessibility on centre employment growth: highway accessibility, network accessibility and two measures of labour force accessibility. Access to airports is also tested. It is found that, after controlling for centre size, density, industry mix, location within the region and spatial amenities, labour force accessibility and network accessibility are significantly related to centre growth. It is concluded that accessibility continues to play an important role in urban spatial structure.
The Price of Victory
Authors: Kontokosta Constantine
Published: September 2011

The Olympic Games have come to be viewed as an unprecedented opportunity to leverage a short-term event into a long-term positive legacy. Although the Olympics are assumed to yield economic benefits, there has been no rigorous analysis of the impact of hosting on residential real estate markets. Utilising a substantial dataset for six host cities and comparable cities between 1984 and 2000, this paper employs an adjusted interrupted time-series approach to estimate the house price impacts of hosting the Olympic Games. The results suggest that the Olympics are not a ‘one size fits all’ economic development strategy and that potential outcomes are dependent on a number of factors, including the co-ordination of planning and Olympic-related development and the relative scale of the total Olympic investment.
An Evaluation of the Layering and Legacy of Area-based Regeneration Initiatives in England: The Case of Wolverhampton
Authors: Henderson Steven
Published: September 2011

In England, there have been 40 years of area-based initiatives (ABIs) involving strategic national government intervention in local authority areas with significant regeneration needs. Whilst they have been examined individually, less consideration has been given to the layering and legacy of ABIs. Uncertainties include whether local authorities have institutionalised new ways of operating or whether layering complexities have acted as significant barriers. Focusing on Wolverhampton, in the West Midlands, this paper examines recent ABI experiences and discusses why support for City Challenge (1992–98) appeared stronger than the more recent New Deal for Communities programme (2001–11). Important ABI legacies include greater diversity of neighbourhood structures, anxiety towards ABIs where property markets are depressed and the realisation that, whilst partnership working has intensified, traditional exclusionary aspects remain. Achieving the most effective governance structures to facilitate urban regeneration remains an on-going challenge, including within emerging Coalition government policy frameworks.
Risk in International Relations
Authors: Clapton William
Published: September 2011

Risk is a concept that has recently filtered through into International Relations (IR). However, the literature on risk, risk management and IR is still comparatively small and there is still significant scope for the theorisation of these concepts in an IR context. Thus far, the literature on risk and IR has been largely characterised by the debate between critical realist, constructivist and post-structuralist approaches to risk. At the core of these debates is the ontological question of whether risks are ‘real’ or not. However, this article will suggest that these ontological debates have grown stale and are unhelpful to furthering the research agenda on risk and IR. As this article will demonstrate, we need to systematically develop ways for both explaining risk identification, assessment and management –what might be termed ‘riskisation’ – and why particular forms of risk management emerge in particular situations and not others.
After the ‘War on Terror’: Regulatory States, Risk Bureaucracies and the Risk-Based Governance of Terror
Authors: Heng Yee-Kuang , McDonagh Kenneth
Published: September 2011

In March 2009, the Obama administration sent a message to senior Pentagon staff instructing them to refrain from using either of the terms ‘Long War’ or ‘Global War on Terror’ and to replace these terms with ‘Overseas Contingency Operations’. The change in tone and, potentially, substance, from the Obama White House by ending the ‘war on terror’ at the rhetorical level suggests a need to shift our academic attention towards developing more appropriate analytical frameworks for examining alternative strategies for countering terrorism. This paper seeks to explore what it terms an emerging risk-based approach being deployed by states. Our framework proposed here deploys the twin concepts of ‘risk bureaucracies’ and risk regulatory regimes (RRRs) in examining terrorist financing and aviation security regulations.
Theorising Risk and Uncertainty in International Relations
Authors: Jarvis Darryl S. L.
Published: September 2011

Frank Knight was one of the twentieth century’s most illustrious economic thinkers. His writings and enquiry into the nature of method, theory and knowledge in relation to the activities of social actors, and under what circumstances and with what limitations we might adequately theorise social agency, bequeathed a rich tradition of theoretical and practical insight. Many of his writings centred on the issue of risk and uncertainty, how social actors anticipate the future and manage and mediate terrains of uncertainty and risk, and in doing so change the outcomes that obtain. Knight’s contributions essentially constructed a means for assessing and measuring risk in various facets of social activity, seeding insights which remain pertinent today. As the article notes, however, despite Knight’s insights and the methodological schema he constructed for probability analysis, remarkably few social sciences – including international relations – have mined his work. Ironically, much that we need to know to more effectively theorise and accommodate the conundrums of risk and uncertainty into social scientific methods Knight long ago handed down to us.
Managing Climate Risks or Risking a Managerial Climate
Authors: Rothe Delf
Published: September 2011

Current international climate governance from a risk-political perspective points to a paradoxical moment in world risk society. While the probability of negative climate impacts increases and we can see the emergence of a common risk perception among international decision-makers, nation states in the international climate regime fail to agree on effective preventive measures that could mitigate the harming effects of global warming. While at the discursive level climate change is constructed as one of the major risks in the twenty-first century, the focus in international climate governance remains on voluntary measures and market-based instruments. Drawing on discourse theory, this paradox can be explained as the outcome of a discursive struggle in climate politics. Risk, in this perspective, is a political technology to govern the future that is embedded within broader political rationalities. Until 2007, risk management in climate governance was established as a form of advanced liberal government based on individualisation and self-responsibility. The growing consensus on dangerous climate change ultimately reinforces this advanced liberal risk management by presenting climate change as a ‘naturalised’ de-bounded risk and blurring its socio-economic causes.