bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene expression analysis in human osteoblasts exposed to dexamethasone identifies altered developmental pathways as putative drivers of osteoporosis
Authors: Hurson Conor J , Butler Joseph S , Keating Dominic T , Murray David W , Sadlier Denise M , O'Byrne John M , Doran Peter P
Published: February 2007

Background

Osteoporosis, a disease of decreased bone mineral density represents a significant and growing burden in the western world. Aging population structure and therapeutic use of glucocorticoids have contributed in no small way to the increase in the incidence of this disease. Despite substantial investigative efforts over the last number of years the exact molecular mechanism underpinning the initiation and progression of osteoporosis remain to be elucidated. This has meant that no significant advances in therapeutic strategies have emerged, with joint replacement surgery being the mainstay of treatment.

Methods

In this study we have used an integrated genomics profiling and computational biology based strategy to identify the key osteoblast genes and gene clusters whose expression is altered in response to dexamethasone exposure. Primary human osteoblasts were exposed to dexamethasone in vitro and microarray based transcriptome profiling completed.

Results

These studies identified approximately 500 osteoblast genes whose expression was altered. Functional characterization of the transcriptome identified developmental networks as being reactivated with 106 development associated genes found to be differentially regulated. Pathway reconstruction revealed coordinate alteration of members of the WNT signaling pathway, including frizzled-2, frizzled-7, DKK1 and WNT5B, whose differential expression in this setting was confirmed by real time PCR.

Conclusion

The WNT pathway is a key regulator of skeletogenesis as well as differentiation of bone cells. Reactivation of this pathway may lead to altered osteoblast activity resulting in decreased bone mineral density, the pathological hallmark of osteoporosis. The data herein lend weight to the hypothesis that alterations in developmental pathways drive the initiation and progression of osteoporosis.
Novel system uses probasin-based promoter, transcriptional silencers and amplification loop to induce high-level prostate expression
Authors: Woraratanadharm Jan , Rubinchik Semyon , Yu Hong , Dong John Y
Published: February 2007

Background

Despite several effective treatment options available for prostate cancer, it remains the second leading cause of cancer death in American men. Thus, there is a great need for new treatments to improve outcomes. One such strategy is to eliminate cancer through the expression of cytotoxic genes specifically in prostate cells by gene therapy vectored delivery. To prevent systemic toxicity, tissue- and/or cancer-specific gene expression is required. However, the use of tissue- or cancer-specific promoters to target transgene expression has been hampered by their weak activity.

Results

To address this issue, we have developed a regulation strategy that includes feedback amplification of gene expression along with a differentially suppressible tetracycline regulated expression system (DiSTRES). By differentially suppressing expression of the tetracycline-regulated transcriptional activator (tTA) and silencer (tTS) genes based on the cell origin, this leads to the activation and silencing of the TRE promoter, respectively. In vitro transduction of LNCaP cells with Ad/GFP
DiSTRES lead to GFP expression levels that were over 30-fold higher than Ad/CMV-GFP. Furthermore, Ad/FasL-GFPDiSTRES demonstrated cytotoxic effects in prostate cancer cells known to be resistant to Fas-mediated apoptosis.

Conclusion

Prostate-specific regulation from the DiSTRES system, therefore, serves as a promising new regulation strategy for future applications in the field of cancer gene therapy and gene therapy as a whole.
A silent H-bond can be mutationally activated for high-affinity interaction of BMP-2 and activin type IIB receptor
Authors: Weber Dionys , Kotzsch Alexander , Nickel Joachim , Harth Stefan , Seher Axel , Mueller Uwe , Sebald Walter , Mueller Thomas D
Published: February 2007

Background

Bone morphogenetic proteins (BMPs) are key regulators in the embryonic development and postnatal tissue homeostasis in all animals. Loss of function or dysregulation of BMPs results in severe diseases or even lethality. Like transforming growth factors β (TGF-βs), activins, growth and differentiation factors (GDFs) and other members of the TGF-β superfamily, BMPs signal by assembling two types of serine/threonine-kinase receptor chains to form a hetero-oligomeric ligand-receptor complex. BMP ligand receptor interaction is highly promiscuous, i.e. BMPs bind more than one receptor of each subtype, and a receptor bind various ligands. The activin type II receptors are of particular interest, since they bind a large number of diverse ligands. In addition they act as high-affinity receptors for activins but are also low-affinity receptors for BMPs. ActR-II and ActR-IIB therefore represent an interesting example how affinity and specificity might be generated in a promiscuous background.

Results

Here we present the high-resolution structures of the ternary complexes of wildtype and a variant BMP-2 bound to its high-affinity type I receptor BMPR-IA and its low-affinity type II receptor ActR-IIB and compare them with the known structures of binary and ternary ligand-receptor complexes of BMP-2. In contrast to activin or TGF-β3 no changes in the dimer architecture of the BMP-2 ligand occur upon complex formation. Functional analysis of the ActR-IIB binding epitope shows that hydrophobic interactions dominate in low-affinity binding of BMPs; polar interactions contribute only little to binding affinity. However, a conserved H-bond in the center of the type II ligand-receptor interface, which does not contribute to binding in the BMP-2 – ActR-IIB interaction can be mutationally activated resulting in a BMP-2 variant with high-affinity for ActR-IIB. Further mutagenesis studies were performed to elucidate the binding mechanism allowing us to construct BMP-2 variants with defined type II receptor binding properties.

Conclusion

Binding specificity of BMP-2 for its three type II receptors BMPR-II, Act-RII and ActR-IIB is encoded on single amino acid level. Exchange of only one or two residues results in BMP-2 variants with a dramatically altered type II receptor specificity profile, possibly allowing construction of BMP-2 variants that address a single type II receptor. The structure-/function studies presented here revealed a new mechanism, in which the energy contribution of a conserved H-bond is modulated by surrounding intramolecular interactions to achieve a switch between low- and high-affinity binding.
Day care cataract surgery in Central and Southern Italy: a multicentric survey
Authors: Cillino Salvatore , Casuccio Alessandra , Di Pace Francesco , Pillitteri Francesco , Cillino Giovanni , Lodato Gaetano
Published: February 2007

Background

Cataract day surgery has rapidly gained worldwide acceptance, because the new surgical techniques and costs are generally lower than those involved in ordinary hospitalization. Cataract surgery serves as a proxy indicator of the trend towards day surgery hospitalization in Italy and, therefore, of regional variability in health-care delivery and cost. The aim of this study was to update the diffusion of cataract day surgery through various surgical ophthalmological centers in central and southern Italy during 2005.

Methods

A two-stage stratified cluster sampling method was used to draw a sample of Cataract Surgery Unit from Ophthalmic Units of central and southern Italy. A questionnaire was sent to 25 cataract surgery centers in nine health districts that represented the range of establishments (public, private, accredited or otherwise) in which cataract surgery is performed. Data were collected on numbers of procedures performed in 2005, hospital admission type, time from the onset of cataract day surgery, surgical procedure, and presence of other surgical centers.

Results

The response rate was 42% (10 surveys), resulting in at least one completed questionnaire for each of these 9 districts. There is a positive trend towards day surgery hospitalization in all surgical centers. The percentage of patients treated as outpatients during 2005 varied from 50–60% (Avellino, Naples, Campobasso), to 80–90% (Rome, Bari), up to 90–100% (Catania, Palermo, Siracusa and Trapani), with an increasing trend in all the centers studied. Few differences were found in surgical procedures, and these were statistically insignificant.

Conclusion

Our results confirm a positive trend towards day surgery in place of hospital inpatient admission for cataract surgery. This trend is expected to close the existing regional gap in Italy. Increased efficiency is an overriding need for the National Health Service in order to improve the rationalization of resources.
Record linkage research and informed consent: who consents?
Authors: Huang Nicole , Shih Shu-Fang , Chang Hsing-Yi , Chou Yiing-Jenq
Published: February 2007

Background

Linking computerized health insurance records with routinely collected survey data is becoming increasingly popular in health services research. However, if consent is not universal, the requirement of written informed consent may introduce a number of research biases. The participants of a national health survey in Taiwan were asked to have their questionnaire results linked to their national health insurance records. This study compares those who consented with those who refused.

Methods

A national representative sample (n = 14,611 adults) of the general adult population aged 20 years or older who participated in the Taiwan National Health Interview Survey (NHIS) and who provided complete survey information were used in this study. At the end of the survey, the respondents were asked if they would give permission to access their National Health Insurance records. Information given by the interviewees in the survey was used to analyze who was more likely to consent to linkage and who wasn't.

Results

Of the 14,611 NHIS participants, 12,911 (88%) gave consent, and 1,700 (12%) denied consent. The elderly, the illiterate, those with a lower income, and the suburban area residents were significantly more likely to deny consent. The aborigines were significantly less likely to refuse. No discrepancy in gender and self-reported health was found between individuals who consented and those who refused.

Conclusion

This study is the first population-based study in assessing the consent pattern in a general Asian population. Consistent with people in Western societies, in Taiwan, a typical Asian society, a high percentage of adults gave consent for their health insurance records and questionnaire results to be linked. Consenters differed significantly from non-consenters in important aspects such as age, ethnicity, and educational background. Consequently, having a high consent rate (88%) may not fully eliminate the possibility of selection bias. Researchers should take this source of bias into consideration in their study design and investigate any potential impact of this source of bias on their results.
Quantum dot-induced cell death involves Fas upregulation and lipid peroxidation in human neuroblastoma cells
Authors: Choi Angela O , Cho Sung Ju , Desbarats Julie , Lovrić Jasmina , Maysinger Dusica
Published: February 2007

Background

Neuroblastoma, a frequently occurring solid tumour in children, remains a therapeutic challenge as existing imaging tools are inadequate for proper and accurate diagnosis, resulting in treatment failures. Nanoparticles have recently been introduced to the field of cancer research and promise remarkable improvements in diagnostics, targeting and drug delivery. Among these nanoparticles, quantum dots (QDs) are highly appealing due to their manipulatable surfaces, yielding multifunctional QDs applicable in different biological models. The biocompatibility of these QDs, however, remains questionable.

Results

We show here that QD surface modifications with N-acetylcysteine (NAC) alter QD physical and biological properties. In human neuroblastoma (SH-SY5Y) cells, NAC modified QDs were internalized to a lesser extent and were less cytotoxic than unmodified QDs. Cytotoxicity was correlated with Fas upregulation on the surface of treated cells. Alongside the increased expression of Fas, QD treated cells had increased membrane lipid peroxidation, as measured by the fluorescent BODIPY-C11 dye. Moreover, peroxidized lipids were detected at the mitochondrial level, contributing to the impairment of mitochondrial functions as shown by the MTT reduction assay and imaged with confocal microscopy using the fluorescent JC-1 dye.

Conclusion

QD core and surface compositions, as well as QD stability, all influence nanoparticle internalization and the consequent cytotoxicity. Cadmium telluride QD-induced toxicity involves the upregulation of the Fas receptor and lipid peroxidation, leading to impaired neuroblastoma cell functions. Further improvements of nanoparticles and our understanding of the underlying mechanisms of QD-toxicity are critical for the development of new nanotherapeutics or diagnostics in nano-oncology.
Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models
Authors: Zhu Xinmei , Nishimura Fumihiko , Sasaki Kotaro , Fujita Mitsugu , Dusak Jill E , Eguchi Junichi , Fellows-Mayle Wendy , Storkus Walter J , Walker Paul R , Salazar Andres M , Okada Hideho
Published: February 2007

Background

Toll-like receptor (TLR)3 ligands serve as natural inducers of pro-inflammatory cytokines capable of promoting Type-1 adaptive immunity, and TLR3 is abundantly expressed by cells within the central nervous system (CNS). To improve the efficacy of vaccine strategies directed against CNS tumors, we evaluated whether administration of a TLR3 ligand, polyinosinic-polycytidylic (poly-IC) stabilized with poly-lysine and carboxymethylcellulose (poly-ICLC) would enhance the anti-CNS tumor effectiveness of tumor peptide-based vaccinations.

Methods

C57BL/6 mice bearing syngeneic CNS GL261 glioma or M05 melanoma received subcutaneous (s.c.) vaccinations with synthetic peptides encoding CTL epitopes- mEphA2 (671–679), hgp100 (25–33) and mTRP-2 (180–188) for GL261, or ovalbumin (OVA: 257–264) for M05. The mice also received intramuscular (i.m.) injections with poly-ICLC.

Results

The combination of subcutaneous (s.c.) peptide-based vaccination and i.m. poly-ICLC administration promoted systemic induction of antigen (Ag)-specific Type-1 CTLs expressing very late activation antigen (VLA)-4, which confers efficient CNS-tumor homing of vaccine-induced CTLs based on experiments with monoclonal antibody (mAb)-mediated blockade of VLA-4. In addition, the combination treatment allowed expression of IFN-γ by CNS tumor-infiltrating CTLs, and improved the survival of tumor bearing mice in the absence of detectable autoimmunity.

Conclusion

These data suggest that poly-ICLC, which has been previously evaluated in clinical trials, can be effectively combined with tumor Ag-specific vaccine strategies, thereby providing a greater index of therapeutic efficacy.
Progranulin in frontotemporal lobar degeneration and neuroinflammation
Authors: Ahmed Zeshan , Mackenzie Ian RA , Hutton Michael L , Dickson Dennis W
Published: February 2007

Progranulin (PGRN) is a pleiotropic protein that has gained the attention of the neuroscience community with recent discoveries of mutations in the gene for PGRN that cause frontotemporal lobar degeneration (FTLD). Pathogenic mutations in PGRN result in null alleles, and the disease is likely the result of haploinsufficiency. Little is known about the normal function of PGRN in the central nervous system apart from a role in brain development. It is expressed by microglia and neurons. In the periphery, PGRN is involved in wound repair and inflammation. High PGRN expression has been associated with more aggressive growth of various tumors. The properties of full length PGRN are distinct from those of proteolytically derived peptides, referred to as granulins (GRNs). While PGRN has trophic properties, GRNs are more akin to inflammatory mediators such as cytokines. Loss of the neurotrophic properties of PGRN may play a role in selective neuronal degeneration in FTLD, but neuroinflammation may also be important. Gene expression studies suggest that PGRN is up-regulated in a variety of neuroinflammatory conditions, and increased PGRN expression by microglia may play a pivotal role in the response to brain injury, neuroinflammation and neurodegeneration.
Increased sensitivity to cocaine-induced analgesia in Spontaneously Hypertensive Rats (SHR)
Authors: Pamplona Fabrício A , Vendruscolo Leandro F , Takahashi Reinaldo N
Published: February 2007

This study examined the analgesic effect of cocaine in Spontaneously Hypertensive Rats (SHR), which are considered a suitable model for the study of attention deficit hyperactivity disorder (ADHD), and in Wistar (WIS) rats of both sexes using the hot-plate test. In addition, we tested whether habituation to the unheated hot-plate apparatus, that "normalizes" the basal hypoalgesic phenotype of SHR, alters the subsequent cocaine-induced analgesia (CIA) in this strain. SHR of both sexes were hypoalgesic compared to WIS rats in the hot-plate test and showed higher sensitivity to CIA. Habituation to the unheated hot-plate reduced the basal nociceptive latency of SHR, suggesting cognitive/emotional modulation of pain in this strain, but did not alter the magnitude of CIA. The present study shows increased sensitivity to CIA in SHR, which may be related to abnormalities in the mesocorticolimbic dopaminergic system. Further studies using SHR strain may reveal new information on the neurobiological mechanisms underlying ADHD and its co-morbidity with drug addiction.
Clinical findings in two cases of atypical scrapie in sheep: a case report
Authors: Konold Timm , Davis Andrew , Bone Gemma , Bracegirdle John , Everitt Sharon , Chaplin Melanie , Saunders Ginny C , Cawthraw Saira , Simmons Marion M
Published: February 2007

Background

Atypical scrapie is a recently recognised form of transmissible spongiform encephalopathy of sheep that differs from classical scrapie in its neuropathological and biochemical features. Most cases are detected in apparently healthy sheep and information on the clinical presentation is limited.

Case presentation

This report describes the clinical findings in two sheep notified as scrapie suspects and confirmed as atypical scrapie cases by immunohistochemistry and Western immunoblotting. Although both sheep displayed signs suggestive of a cerebellar dysfunction there was considerable variation in the individual clinical signs, which were similar to classical scrapie.

Conclusion

Any sheep presenting with neurological gait deficits should be assessed more closely for other behavioural, neurological and physical signs associated with scrapie and their presence should lead to the suspicion of scrapie.
Decision tree modeling predicts effects of inhibiting contractility signaling on cell motility
Authors: Kharait Sourabh , Hautaniemi Sampsa , Wu Shan , Iwabu Akihiro , Lauffenburger Douglas A , Wells Alan
Published: February 2007

Background

Computational models of cell signaling networks typically are aimed at capturing dynamics of molecular components to derive quantitative insights from prior experimental data, and to make predictions concerning altered dynamics under different conditions. However, signaling network models have rarely been used to predict how cell phenotypic behaviors result from the integrated operation of these networks. We recently developed a decision tree model for how EGF-induced fibroblast cell motility across two-dimensional fibronectin-coated surfaces depends on the integrated activation status of five key signaling nodes, including a proximal regulator of transcellular contractile force generation, MLC (myosin light chain) [Hautaniemi et al, Bioinformatics 21: 2027 {2005}], but we have not previously attempted predictions of new experimental effects from this model.

Results

In this new work, we construct an improved decision tree model for the combined influence of EGF and fibronectin on fibroblast cell migration based on a wider spectrum of experimental protein signaling and cell motility measurements, and directly test a significant and non-intuitive a priori prediction for the outcome of a targeted molecular intervention into the signaling network: that partially reducing activation of MLC would increase cell motility on moderately adhesive surfaces. This prediction was indeed confirmed experimentally: partial inhibition of the activating MLC kinase (MLCK) upstream using the pharmacologic agent ML-7 resulted in increased motility of NR6 fibroblasts. We further extended this exciting finding by showing that partial reduction of MLC activation similarly enhanced the transmigration of the human breast carcinoma cell line MDA-213 through a Matrigel barrier.

Conclusion

These findings specifically highlight a central regulatory role for transcellular contractility in governing cell motility, while at the same time demonstrating the value of a decision tree approach to a systems "signal-response" model in discerning non-intuitive behavior arising from integrated operation a cell signaling network.
Management of bleeding following major trauma: a European guideline
Authors: Spahn Donat R , Cerny Vladimir , Coats Timothy J , Duranteau Jacques , Fernández-Mondéjar Enrique , Gordini Giovanni , Stahel Philip F , Hunt Beverley J , Komadina Radko , Neugebauer Edmund , Ozier Yves , Riddez Louis , Schultz Arthur , Vincent Jean-Louis , Rossaint Rolf
Published: February 2007

Introduction

Evidence-based recommendations can be made with respect to many aspects of the acute management of the bleeding trauma patient, which when implemented may lead to improved patient outcomes.

Methods

The multidisciplinary Task Force for Advanced Bleeding Care in Trauma was formed in 2005 with the aim of developing guidelines for the management of bleeding following severe injury. Recommendations were formulated using a nominal group process and the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) hierarchy of evidence and were based on a systematic review of published literature.

Results

Key recommendations include the following: The time elapsed between injury and operation should be minimised for patients in need of urgent surgical bleeding control, and patients presenting with haemorrhagic shock and an identified source of bleeding should undergo immediate surgical bleeding control unless initial resuscitation measures are successful. A damage control surgical approach is essential in the severely injured patient. Pelvic ring disruptions should be closed and stabilised, followed by appropriate angiographic embolisation or surgical bleeding control, including packing. Patients presenting with haemorrhagic shock and an unidentified source of bleeding should undergo immediate further assessment as appropriate using focused sonography, computed tomography, serum lactate, and/or base deficit measurements. This guideline also reviews appropriate physiological targets and suggested use and dosing of blood products, pharmacological agents, and coagulation factor replacement in the bleeding trauma patient.

Conclusion

A multidisciplinary approach to the management of the bleeding trauma patient will help create circumstances in which optimal care can be provided. By their very nature, these guidelines reflect the current state-of-the-art and will need to be updated and revised as important new evidence becomes available.
Declining Antibiotic Prescriptions for Upper Respiratory Infections, 1993–2004
Authors: Vanderweil Stefan G. , Pelletier Andrea J. , Hamedani Azita G. , Gonzales Ralph , Metlay Joshua P. , Camargo Carlos A.
Published: February 2007

Objectives:
To examine antibiotic prescribing trends for U.S. emergency department (ED) visits with upper respiratory tract infections (URIs) between 1993 and 2004.

Methods:
Data were compiled from the National Hospital Ambulatory Medical Care Survey (NHAMCS). URI visits were identified by using ICD‐9‐CM code 465.9, whereas antibiotics were identified using the National Drug Code Directory class Antimicrobials. A multivariate logistic regression model revealed sociodemographic and geographic factors that were independently associated with receipt of an antibiotic prescription for URIs.

Results:
There were approximately 23.4 million ED visits diagnosed as URIs between 1993 and 2004. Although the proportion of URI diagnoses remained relatively stable (p trend = 0.26), a significant decrease in provision of antibiotic prescriptions for URIs occurred during this 12‐year period, from a maximum of 55% in 1993, to a minimum of 35% in 2004. Patients who were prescribed antibiotics were more likely to be white than African American and to have been treated in EDs located in the southern United States.

Conclusions:
Antibiotic prescribing for URIs continues to decrease, a favorable trend that suggests that national efforts to reduce inappropriate antibiotic usage are having some success. Nevertheless, the frequency of antibiotic treatment for URI in the ED remains high (35%). Future efforts to reduce inappropriate antibiotic prescribing may focus on patients and physicians in southern U.S. EDs. Additional work is needed to address continued evidence of race‐related disparities in care.
Phase II Study of Neoadjuvant Docetaxel, Vinorelbine, and Trastuzumab Followed by Surgery and Adjuvant Doxorubicin Plus Cyclophosphamide in Women With Human Epidermal Growth Factor Receptor 2–Overexpressing Locally Advanced Breast Cancer
Authors: Limentani Steven A. , Brufsky Adam M. , Erban John K. , Jahanzeb Mohammed , Lewis Deborah
Published: February 2007

Purpose

To evaluate the combination of docetaxel, vinorelbine, and trastuzumab as neoadjuvant therapy for human epidermal growth factor receptor 2 (HER2) –overexpressing breast cancer.

Patients and Methods

Patients with stage IIB or III breast cancer, including inflammatory disease, and HER2 overexpression (determined by fluorescent in situ hybridization) were treated with six cycles of docetaxel 60 mg/m2 and vinorelbine 45 mg/m2 administered every 14 days with granulocyte colony-stimulating factor and quinolone prophylaxis. Trastuzumab was administered as a 4 mg/kg loading dose followed by 2 mg/kg weekly for 12 weeks. The primary efficacy end point was pathologic complete response (pCR) in the breast.

Results

Of 31 enrolled patients, 68% had T3 or T4 tumors and 90% were clinically node positive. Twelve patients (39%; 95% CI, 21.6% to 55.9%) achieved pCR in the breast and lymph nodes and 14 patients (45%; 95% CI, 27.6% to 62.7%) achieved pCR in the breast alone, and 19 patients (61%; 95% CI, 44.1% to 78.4%) were node negative after neoadjuvant therapy. Clinical response was documented in 29 patients (94%; 95% CI, 78.6% to 99.2%) with 26 complete responses (84%; 95% CI, 70.9% to 96.8%). The most commonly reported grade 3/4 toxicities were neutropenia (97%), febrile neutropenia (22%), anemia (6%), mucositis/stomatitis (6%), constipation (6%), and skin rash (6%).

Conclusion

With clinical response and pCR rates of 94% and 39%, respectively, docetaxel, vinorelbine, and trastuzumab is a highly active neoadjuvant therapy for HER2-overexpressing locally advanced breast cancer. Although well tolerated overall, significant febrile neutropenia was observed despite prophylactic measures; therefore, evaluating a similar regimen using lower docetaxel and/or vinorelbine doses is warranted.
Efficacy and Safety of Single-Agent Pertuzumab (rhuMAb 2C4), a Human Epidermal Growth Factor Receptor Dimerization Inhibitor, in Castration-Resistant Prostate Cancer After Progression From Taxane-Based Therapy
Authors: Agus David B. , Sweeney Christopher J. , Morris Michael J. , Mendelson David S. , McNeel Douglas G. , Ahmann Frederick R. , Wang Jin , Derynck Mika K. , Ng Kimmie , Lyons Benjamin , Allison David E. , Kattan Michael W. , Scher Howard I.
Published: February 2007

Purpose

Pertuzumab represents a new class of targeted anticancer agents, human epidermal growth factor receptor (HER) dimerization inhibitors. The aim of this single-arm phase II clinical study was to assess the efficacy and safety of single-agent pertuzumab in castration-resistant prostate cancer (CRPC) patients who had experienced progression after prior chemotherapy.

Patients and Methods

Patients received pertuzumab every 3 weeks. All castration-resistant patients had experienced progression after at least one taxane-based regimen. Patients received a loading dose of 840 mg pertuzumab (cycle 1) followed by 420 mg for subsequent cycles. The primary end point was overall response and safety. A separate retrospective analysis of actual survival time versus predicted survival time for a patient population with comparable prognostic features was performed.

Results

Patients were enrolled (N = 42) and treated (n = 41). No patients had complete or partial response (as defined by Response Evaluation Criteria in Solid Tumors Group or ≥ 50% decline in prostate-specific antigen). Of 30 efficacy-assessable patients, five had stable disease (SD) for at least 23 weeks; one of five had SD for 36 weeks. Pertuzumab was well tolerated; diarrhea was the most common adverse effect (61.0%, grades 1 to 3). Retrospective analysis of survival using a validated nomogram suggested that survival was prolonged with pertuzumab treatment, compared with historic controls with similar baseline prognostic features.

Conclusion

Pertuzumab was well tolerated and resulted in no objective responses, but several patients had SD more than 23 weeks from a heavily pretreated population. Retrospective analysis suggested prolonged median survival time with pertuzumab compared with historical controls. Thus, inhibition of HER dimerization may have clinical utility in CRPC patients.
Specific Secondary Genetic Alterations in Mantle Cell Lymphoma Provide Prognostic Information Independent of the Gene Expression–Based Proliferation Signature
Authors: Salaverria Itziar , Zettl Andreas , Beà Sílvia , Moreno Victor , Valls Joan , Hartmann Elena , Ott German , Wright George , Lopez-Guillermo Armando , Chan Wing C. , Weisenburger Dennis D. , Gascoyne Randy D. , Grogan Thomas M. , Delabie Jan , Jaffe Elaine S. , Montserrat Emili , Muller-Hermelink Hans-Konrad , Staudt Louis M. , Rosenwald Andreas , Campo Elias
Published: February 2007

Purpose

To compare the genetic relationship between cyclin D1–positive and cyclin D1–negative mantle cell lymphomas (MCLs) and to determine whether specific genetic alterations may add prognostic information to survival prediction based on the proliferation signature of MCLs.

Patients and Methods

Seventy-one cyclin D1–positive and six cyclin D1–negative MCLs previously characterized by gene expression profiling were examined by comparative genomic hybridization (CGH).

Results

Cyclin D1–negative MCLs were genetically characterized by gains of 3q, 8q, and 15q, and losses of 1p, 8p23-pter, 9p21-pter, 11q21-q23, and 13q that were also the most common alterations in conventional MCLs. Parallel analysis of CGH aberrations and locus-specific gene expression profiles in cyclin D1–positive patients showed that chromosomal imbalances had a substantial impact on the expression levels of the genes located in the altered regions. The analysis of prognostic factors revealed that the proliferation signature, the number of chromosomal aberrations, gains of 3q, and losses of 8p, 9p, and 9q predicted survival of MCL patients. A multivariate analysis showed that the gene expression-based proliferation signature was the strongest predictor for shorter survival. However, 3q gains and 9q losses provided prognostic information that was independent of the proliferative activity.

Conclusion

Cyclin D1–positive and –negative MCLs share the same secondary genetic aberrations, supporting the concept that they correspond to the same genetic entity. The integration of genetic information on chromosome 3q and 9q alterations into a proliferation signature-based model may improve the ability to predict survival in patients with MCL.
Magnetic Resonance Imaging in Multiple Myeloma: Diagnostic and Clinical Implications
Authors: Walker Ronald , Barlogie Bart , Haessler Jeffrey , Tricot Guido , Anaissie Elias , Shaughnessy John D. , Epstein Joshua , van Hemert Rudy , Erdem Eren , Hoering Antje , Crowley John , Ferris Ernest , Hollmig Klaus , van Rhee Frits , Zangari Maurizio , Pineda-Roman Mauricio , Mohiuddin Abid , Yaccoby Shmuel , Sawyer Jeffrey , Angtuaco Edgardo J.
Published: February 2007

Purpose

Magnetic resonance imaging (MRI) permits the detection of diffuse and focal bone marrow infiltration in the absence of osteopenia or focal osteolysis on standard metastatic bone surveys (MBSs).

Patients and Methods

Both baseline MBS and MRI were available in 611 of 668 myeloma patients who were treated uniformly with a tandem autologous transplantation–based protocol and were evaluated to determine their respective merits for disease staging, response assessment, and outcome prediction.

Results

MRI detected focal lesions (FLs) in 74% and MBS in 56% of imaged anatomic sites; 52% of 267 patients with normal MBS results and 20% of 160 with normal MRI results had FL on MRI and MBS, respectively. MRI- but not MBS-defined FL independently affected survival. Cytogenetic abnormalities (CAs) and more than seven FLs on MRI (MRI-FLs) distinguished three risk groups: 5-year survival was 76% in the absence of both more than seven MRI-FLs and CA (n = 276), 61% in the presence of one MRI-FL (n = 262), and 37% in the presence of both unfavorable parameters (n = 67). MRI-FL correlated with low albumin and elevated levels of C-reactive protein, lactate dehydrogenase, and creatinine, but did not correlate with age, beta-2-microglobulin, and CA. Resolution of MRI-FL, occurring in 60% of cases and not seen with MBS-defined FL, conferred superior survival.

Conclusion

MRI is a more powerful tool for detection of FLs than is MBS. MRI-FL number had independent prognostic implications; additionally, MRI-FL resolution identified a subgroup with superior survival. We therefore recommend that, in addition to MBS, MRI be used routinely for staging, prognosis, and response assessment in myeloma.
Selection on the timing of adult emergence results in altered circadian clocks in fruit flies Drosophila melanogaster
Authors: Kumar Shailesh , Kumar Dhanya , Paranjpe Dhanashree A. , R. Akarsh C. , Sharma Vijay Kumar
Published: February 2007

To investigate whether circadian clocks in fruit flies Drosophila melanogaster evolve as a consequence of selection on the timing of adult emergence, we raised four replicate populations each of early(early1..4) and late (late1..4)emerging flies by selecting for adults that emerged during the morning and the evening hours. We estimated the percentage of flies that emerged during the two selection windows to evaluate the direct response to selection, and the circadian phenotypes of adult emergence and locomotor activity rhythms under light/dark (LD) and constant darkness (DD) to assess the correlated response to selection. After 55 generations, the percentage of flies emerging during the morning window increased in the early populations, but decreased in the late populations. The percentage of flies emerging during the evening window increased in the late populations, but decreased in the early populations. The time course and waveform of emergence and locomotor activity rhythms of the selected populations diverged from each other as well as from the controls. Further, the circadian periodicity of the early populations was significantly shorter than the controls, while that of the late populations was significantly longer than the controls. The light-induced phase response curve of the selected populations differed significantly within groups as well as from the controls. Such modifications in the circadian phenotypes of the selected populations due to heritable changes in genetic architecture, in response to imposed selection pressure, suggest that the circadian clocks underlying emergence and locomotor activity rhythms in D. melanogaster evolve as a correlated response to selection on the timing of adult emergence.
Honeybee navigation: distance estimation in the third dimension
Authors: Dacke M. , Srinivasan M. V.
Published: February 2007

Honeybees determine distance flown by gauging the extent to which the image of the environment moves in the eye as they fly towards their goal. Here we investigate how this visual odometer operates when a bee flies along paths that include a vertical component. By training bees to fly to a feeder along tunnels of various three-dimensional configurations, we find that the odometric signal depends only upon the total distance travelled along the path and is independent of its three-dimensional configuration. Hence, unlike walking desert ants, which measure the distance travelled in the horizontal plane whilst traversing undulating terrain, flying bees simply integrate the image motion that is experienced on the way to the goal, irrespective of the direction in which the image moves across the eyes. These findings raise important questions about how honeybee recruits navigate reliably to find the food sources that are advertised by scouts.
Response properties of primary afferents supplying Eimer's organ
Authors: Marasco Paul D. , Catania Kenneth C.
Published: February 2007

The mole's nose is covered with mechanosensory structures called Eimer's organs. Each organ contains Merkel cell-neurite complexes, Paciniform corpuscles and intraepidermal free nerve endings. The function of Eimer's organ has been the subject of speculation since the 1800s, but responses from the afferents have never been investigated. Our goal was to explore the function of Eimer's organ by recording primary afferent responses to a range of mechanosensory stimuli. Unit activity from the trigeminal ganglion was recorded from coast (Scapanus orarius) and star-nosed (Condylura cristata) moles, while stimulating the nose with a Chubbuck mechanosensory stimulator, a piezo-electric sweeping stimulator, and hand-held probes. Stimuli included static indentations, sinusoidal displacements,different indentation velocities, displacement amplitudes, and directional stimuli across the skin. Receptive fields were small, sometimes restricted to single Eimer's organs. Responses were consistent with a slowly adapting Merkel cell-neurite complex-like receptor class and a dynamically sensitive Pacinian-like rapidly adapting class. A second rapidly adapting class was hypothesized to represent activity of prominent free nerve endings within a central cell column. Some receptors were most sensitive to stimuli applied in particular directions across the skin. Most receptors relayed mechanosensory input with high temporal fidelity. In addition some receptors were tuned to respond best when stimulated at a velocity matching the velocity of the nose during foraging. These results support the hypothesis that Eimer's organ functions to detect small surface features and textures by encoding and integrating deflection information for multiple Eimer's organs during brief touches.
A computational investigation of the three-dimensional unsteady aerodynamics ofDrosophilahovering and maneuvering
Authors: Ramamurti Ravi , Sandberg William C.
Published: February 2007

Three-dimensional unsteady computations of the flow past a fruit fly Drosophila under hovering and free flight conditions are computed. The kinematics of the wings and the body of the fruit fly are prescribed from experimental observations. The computed unsteady lift and thrust forces are validated with experimental results and are in excellent agreement. The unsteady aerodynamic origin of the time-varying yaw moment is identified. The differences in the kinematics between the right and the left wings show that subtle change in the stroke angle and deviation angle can result in the yaw moment for the turning maneuver. The computed yaw moment reaches a peak value at the beginning of the maneuver and remains positive throughout the remainder of the maneuver. The origin of the yaw moment is investigated by computing the center of pressures on each wing and the individual moment arms. This investigation leads to the conclusion that it is the forward force and a component of the lift force that combine to produce the turning moment while the side force alone produces the restoring torque during the maneuver. The vorticity shed from the wing's leading edge and the tips show a loop like structure that during stroke reversals pinches off into Λ-like structures that have not been previously observed in the wakes of flapping fliers.
Escape behavior and neuronal responses to looming stimuli in the crabChasmagnathus granulatus(Decapoda: Grapsidae)
Authors: Oliva Damián , Medan Violeta , Tomsic Daniel
Published: February 2007

Behavioral responses to looming stimuli have been studied in many vertebrate and invertebrate species, but neurons sensitive to looming have been investigated in very few animals. In this paper we introduce a new experimental model using the crab Chasmagnathus granulatus, which allows investigation of the processes of looming detection and escape decision at both the behavioral and neuronal levels. By analyzing the escape response of the crab in a walking simulator device we show that: (i) a robust and reliable escape response can be elicited by computer-generated looming stimuli in all tested animals; (ii) parameters such as distance, speed, timing and directionality of the escape run, are easy to record and quantify precisely in the walking device; (iii) although the magnitude of escape varies between animals and stimulus presentations, the timing of the response is remarkably consistent and does not habituate at 3 min stimulus intervals. We then study the response of neurons from the brain of the crab by means of intracellular recordings in the intact animal and show that: (iv) two subclasses of previously identified movement detector neurons from the lobula (third optic neuropil) exhibit robust and reliable responses to the same looming stimuli that trigger the behavioral response; (v) the neurons respond to the object approach by increasing their rate of firing in a way that closely matches the dynamics of the image expansion. Finally, we compare the neuronal with the behavioral response showing that: (vi) differences in the neuronal responses to looming, receding or laterally moving stimuli closely reflect the behavioral differences to such stimuli; (vii) during looming, the crab starts to run soon after the looming-sensitive neurons begin to increase their firing rate. The increase in the running speed during stimulus approach faithfully follows the increment in the firing rate, until the moment of maximum stimulus expansion. Thereafter, the neurons abruptly stop firing and the animal immediately decelerates its run. The results are discussed in connection with studies of responses to looming stimuli in the locust.
Tracking of biogenic hydrodynamic trails in harbour seals (Phoca vitulina)
Authors: Schulte-Pelkum N. , Wieskotten S. , Hanke W. , Dehnhardt G. , Mauck B.
Published: February 2007

For seals hunting in dark and murky waters one source of sensory information for locating prey consists of fish-generated water movements,which they can detect using their highly sensitive mystacial vibrissae. As water movements in the wake of fishes can persist for several minutes,hydrodynamic trails of considerable length are generated. It has been demonstrated that seals can use their vibrissae to detect and track hydrodynamic trails generated artificially by miniature submarines. In the present study, we trained a harbour seal to swim predefined courses, thus generating biogenic hydrodynamic trails. The structure of these trails was measured using Particle Image Velocimetry. A second seal was trained to search for and track the trail after the trail-generating seal had left the water. Our trail-following seal was able to detect and accurately track the hydrodynamic trail, showing search patterns either mostly congruent with the trail or crossing the trail repeatedly in an undulatory way. The undulatory trail-following search pattern might allow a seal to relocate a lost trail or successfully track a fleeing, zigzagging prey fish.
Getting the jump on skeletal muscle disuse atrophy: preservation of contractile performance in aestivatingCyclorana alboguttata(Günther 1867)
Authors: Symonds Beth L. , James Rob S. , Franklin Craig E.
Published: February 2007

Prolonged immobilisation or unloading of skeletal muscle causes muscle disuse atrophy, which is characterised by a reduction in muscle cross-sectional area and compromised locomotory function. Animals that enter seasonal dormancy, such as hibernators and aestivators, provide an interesting model for investigating atrophy associated with disuse. Previous research on the amphibian aestivator Cyclorana alboguttata (Günther 1867)demonstrated an absence of muscle disuse atrophy after 3 months of aestivation, as measured by gastrocnemius muscle contractile properties and locomotor performance. In this study, we aimed to investigate the effect of aestivation on iliofibularis and sartorius muscle morphology and contractile function of C. alboguttata over a longer, more ecologically relevant time-frame of 9 months. We found that whole muscle mass, muscle cross-sectional area, fibre number and proportions of fibre types remained unchanged after prolonged disuse. There was a significant reduction in iliofibularis fibre cross-sectional area (declined by 36% for oxidative fibre area and 39% for glycolytic fibre area) and sartorius fibre density (declined by 44%). Prolonged aestivation had little effect on the isometric properties of the skeletal muscle of C. alboguttata. There was a significant reduction in the isometric contraction times of the relatively slow-twitch iliofibularis muscle, suggesting that the muscle was becoming slower after 9 months of aestivation (time to peak twitch increased by 25%, time from peak twitch to half relaxation increased by 34% and time from last stimulus to half tetanus relation increased by 20%). However, the results of the work-loop analysis clearly demonstrate that, despite changes to muscle morphology and isometric kinetics, the overall contractile performance and power output levels of muscles from 9-month aestivating C. alboguttata are maintained at control levels.