bluuebunny/crossref_metadata_2025 huggingface dataset:
Unique Cortical Physiology Associated With Ipsilateral Hand Movements and Neuroprosthetic Implications
Authors: Wisneski Kimberly J. , Anderson Nicholas , Schalk Gerwin , Smyth Matt , Moran Daniel , Leuthardt Eric C.
Published: October 2008

Background and Purpose—

Brain computer interfaces (BCIs) offer little direct benefit to patients with hemispheric stroke because current platforms rely on signals derived from the contralateral motor cortex (the same region injured by the stroke). For BCIs to assist hemiparetic patients, the implant must use unaffected cortex ipsilateral to the affected limb. This requires the identification of distinct electrophysiological features from the motor cortex associated with ipsilateral hand movements.

Methods—

In this study we studied 6 patients undergoing temporary placement of intracranial electrode arrays. Electrocorticographic (ECoG) signals were recorded while the subjects engaged in specific ipsilateral or contralateral hand motor tasks. Spectral changes were identified with regards to frequency, location, and timing.

Results—

Ipsilateral hand movements were associated with electrophysiological changes that occur in lower frequency spectra, at distinct anatomic locations, and earlier than changes associated with contralateral hand movements. In a subset of 3 patients, features specific to ipsilateral and contralateral hand movements were used to control a cursor on a screen in real time. In ipsilateral derived control this was optimal with lower frequency spectra.

Conclusions—

There are distinctive cortical electrophysiological features associated with ipsilateral movements which can be used for device control. These findings have implications for patients with hemispheric stroke because they offer a potential methodology for which a single hemisphere can be used to enhance the function of a stroke induced hemiparesis.
Target Lesion Revascularization After Wingspan
Authors: Fiorella David J. , Levy Elad I. , Turk Aquilla S. , Albuquerque Felipe C. , Pride G. Lee , Woo Henry H. , Welch Babu G. , Niemann David B. , Purdy Phillip D. , Aagaard-Kienitz Beverly , Rasmussen Peter A. , Hopkins L. Nelson , Masaryk Thomas J. , McDougall Cameron G.
Published: October 2008

Background and Purpose—

In-stent restenosis (ISR) occurs in approximately one-third of patients after the percutaneous transluminal angioplasty and stenting of intracranial atherosclerotic lesions with the Wingspan system. We review our experience with target lesion revascularization (TLR) for ISR after Wingspan treatment.

Methods—

Clinical and angiographic follow-up results were recorded for all patients from 5 participating institutions in our US Wingspan Registry. ISR was defined as >50% stenosis within or immediately adjacent (within 5 mm) to the implanted stent and >20% absolute luminal loss.

Results—

To date, 36 patients in the registry have experienced ISR after percutaneous transluminal angioplasty and stenting with Wingspan. Of these patients, 29 (80.6%) have undergone TLR with either angioplasty alone (n=26) or angioplasty with restenting (n=3). Restenting was performed for in-stent dissections that occurred after the initial angioplasty. Of the 29 patients undergoing TLR, 9 required ≥1 interventions for recurrent ISR, for a total of 42 interventions. One major complication, a postprocedural reperfusion hemorrhage, was encountered in the periprocedural period (2.4% per procedure; 3.5% per patient). Angiographic follow-up is available for 22 of 29 patients after TLR. Eleven of 22 (50%) demonstrated recurrent ISR at follow-up angiography. Nine patients have undergone multiple retreatments (2 retreatments, n=6; 3 retreatments, n=2; 4 retreatments, n=1) for recurrent ISR. Nine of 11 recurrent ISR lesions were located within the anterior circulation. The mean age for patients with recurrent anterior circulation ISR was 57.9 years (vs 81 years for posterior circulation ISR).

Conclusions—

TLR can be performed for the treatment of intracranial Wingspan ISR with a relatively high degree of safety. However, the TLR results are not durable in ≈50% of patients, and multiple revascularization procedures may be required in this subgroup.
An Oscillatory Hebbian Network Model of Short-Term Memory
Authors: Winder Ransom K. , Reggia James A. , Weems Scott A. , Bunting Michael F.
Published: October 2008

Recurrent neural architectures having oscillatory dynamics use rhythmic network activity to represent patterns stored in short-term memory. Multiple stored patterns can be retained in memory over the same neural substrate because the network's state persistently switches between them. Here we present a simple oscillatory memory that extends the dynamic threshold approach of Horn and Usher ( 1991 ) by including weight decay. The modified model is able to match behavioral data from human subjects performing a running memory span task simply by assuming appropriate weight decay rates. The results suggest that simple oscillatory memories incorporating weight decay capture at least some key properties of human short-term memory. We examine the implications of the results for theories about the relative role of interference and decay in forgetting, and hypothesize that adjustments of activity decay rate may be an important aspect of human attentional mechanisms.
Recurrent Infomax Generates Cell Assemblies, Neuronal Avalanches, and Simple Cell-Like Selectivity
Authors: Tanaka Takuma , Kaneko Takeshi , Aoyagi Toshio
Published: October 2008

Recently multineuronal recording has allowed us to observe patterned firings, synchronization, oscillation, and global state transitions in the recurrent networks of central nervous systems. We propose a learning algorithm based on the process of information maximization in a recurrent network, which we call recurrent infomax (RI). RI maximizes information retention and thereby minimizes information loss through time in a network. We find that feeding in external inputs consisting of information obtained from photographs of natural scenes into an RI-based model of a recurrent network results in the appearance of Gabor-like selectivity quite similar to that existing in simple cells of the primary visual cortex. We find that without external input, this network exhibits cell assembly–like and synfire chain–like spontaneous activity as well as a critical neuronal avalanche. In addition, we find that RI embeds externally input temporal firing patterns to the network so that it spontaneously reproduces these patterns after learning. RI provides a simple framework to explain a wide range of phenomena observed in in vivo and in vitro neuronal networks, and it will provide a novel understanding of experimental results for multineuronal activity and plasticity from an information-theoretic point of view.
Whose Rights and Which Rights? The Continuing Story of Non-Refoulement under the European Convention on Human Rights
Authors: den Heijer Maarten
Published: October 2008

This article challenges the assumption that under the European Convention of Human Rights only Articles 2 and 3 bear relevance in cases of refoulement. By unraveling the explicit and implicit principles applied by the European Court of Human Rights and elaborating upon earlier theoretical attempts to ascertain the impact of the Soering judgment on extradition and expulsion cases, it is argued that there is no clear dichotomy of rights within the European Convention and that the higher threshold for applying Convention standards to cases of expulsion in which maltreatment is suffered in the receiving country is dependent on the notion of a 'fundamental value'. Albeit a somewhat nebulous concept, this notion is likely to encompass not only Articles 2 and 3, but also norms protected by other provisions, or at the least certain intrinsic components of those other provisions.
Item Selection in Computerized Classification Testing
Authors: Thompson Nathan A.
Published: October 2008

Several alternatives for item selection algorithms based on item response theory in computerized classification testing (CCT) have been suggested, with no conclusive evidence on the substantial superiority of a single method. It is argued that the lack of sizable effect is because some of the methods actually assess items very similarly through different calculations and will usually select the same item. Consideration of methods that assess information across a wider range is often unnecessary under realistic conditions, although it might be advantageous to utilize them only early in a test. In addition, the efficiency of item selection approaches depend on the termination criteria that are used, which is demonstrated through didactic example and Monte Carlo simulation. Item selection at the cut score, which seems conceptually appropriate for CCT, is not always the most efficient option. A broad framework for item selection in CCT is presented that incorporates these points.
Modeling Socially Desirable Responding and Its Effects
Authors: Ziegler Matthias , Buehner Markus
Published: October 2008

The impact of socially desirable responding or faking on noncognitive assessments remains an issue of strong debate. One of the main reasons for the controversy is the lack of a statistical method to model such response sets. This article introduces a new way to model faking based on the assumption that faking occurs due to an interaction between person and situation. The technique combines a control group design with structural equation modeling and allows a separation of trait and faking variance. The model is introduced and tested in an example. The results confirm a causal influence of faking on means and covariance structure of a Big 5 questionnaire. Both effects can be reversed by the proposed model. Finally, a real-life criterion was implemented and predicted by both variance sources. In this example, it was the trait but not the faking variance that was predictive. Implications for research and practice are discussed.
Population Pharmacokinetics of Cyclophosphamide and Metabolites in Children With Neuroblastoma: A Report From the Children's Oncology Group
Authors: McCune Jeannine S. , Salinger David H. , Vicini Paolo , Oglesby Celeste , Blough David K. , Park Julie R.
Published: October 2008

Cyclophosphamide‐based regimens are front‐line treatment for numerous pediatric malignancies; however, current dosing methods result in considerable interpatient variability in tumor response and toxicity. In this pediatric population, the authors' objectives were (1) to quantify and explain the pharmacokinetic variability of cyclophosphamide and 2 of its metabolites, hydroxycyclophosphamide (HCY) and carboxyethylphosphoramide mustard (CEPM), and (2) to apply a population pharmacokinetic model to describe the disposition of cyclophosphamide and these metabolites. A total of 196 blood samples were obtained from 22 children with neuroblastoma receiving intravenous cyclophosphamide (400 mg/m2/d) and topotecan. Blood samples were quantitated for concentrations of cyclophosphamide, HCY, and CEPM using liquid chromatography—mass spectrometry and analyzed using nonlinear mixed‐effects modeling with the NONMEM software system. After model building was complete, the area under the concentration‐time curve (AUC) was computed using NONMEM. Cyclophosphamide elimination was described by noninducible and inducible routes, with the latter producing HCY. Glomerular filtration rate was a covariate for the fractional elimination of HCY and its conversion to CEPM. Considerable interpatient variability was observed in the AUC of cyclophosphamide, HCY, and CEPM. These results represent a critical first step in developing pharmacokinetic‐linked pharmacodynamic studies in children receiving cyclophosphamide to determine the clinical relevance of the pharmacokinetic variability in cyclophosphamide and its metabolites.
Polling Students About Conditions of Learning
Authors: Strom Paris , Strom Robert , Wing Charlotte
Published: October 2008

Online polling was examined as a procedure for decision makers to find out how students perceive conditions of learning at their school. Students in Grades 7-12 from eight schools completed online polls about learning on the Internet, time management, and tutoring. Principals favorably evaluated polling as a method for gathering information and changed certain policies and practices based on input from students. Local school context was determined to be the most significant influence in shaping perceptions regarding improvement.
The Effect of Ankle Taping on Detection of Inversion-Eversion Movements in Participants with Recurrent Ankle Sprain
Authors: Refshauge Kathryn M. , Raymond Jacqueline , Kilbreath Sharon L. , Pengel Liset , Heijnen Inger
Published: October 2008

Background

Taping is often used to counter the proprioceptive deficit after joint injury such as ankle sprain. However, the effect of taping on proprioceptive acuity at the ankle is unclear, with conflicting findings.

Hypothesis

Application of tape improves detection of inversion and eversion movements at the ankle.

Study Design

Controlled laboratory study.

Methods

The 70% threshold for movement detection was measured in 16 participants with recurrent ankle sprain under 2 conditions: with the ankle taped or untaped. The threshold for movement detection was examined at 3 velocities (0.1 deg/s, 0.5 deg/s, and 2.5 deg/s) and in 2 directions (inversion and eversion).

Results

Application of tape significantly decreased the ability to detect movements at the ankle (P <. 023). For example, at 0.5 deg/s, the 70% detection threshold was 3.40° ± 1.05° in inversion and 3.49° ± 1.15° in eversion at the untaped ankle, and 4.02° ± 0.86° in inversion and 4.04° ± 0.89° in eversion at the taped ankle.

Conclusion

Taping the ankle decreased the ability to detect movement in the inversion-eversion plane in participants with recurrent ankle sprain.

Clinical Relevance

The findings suggest that the efficacy of taping is unlikely to be explained by an enhanced ability to detect inversion or eversion movements. However, because it has been found effective in reducing the incidence of ankle sprain, clinicians should continue taping to reduce the likelihood of resprain.
Exploring Family Environment Characteristics and Multiple Abuse Experiences Among Homeless Youth
Authors: Ferguson Kristin M.
Published: October 2008

This qualitative study used data from the Social Enterprise Intervention (SEI) pilot study, a comprehensive vocational training program with integrated clinical services for homeless youth. In-depth interviews were conducted with 28 homeless youth participating in the SEI study to explore their perceptions of family environment characteristics and abuse experiences. The constant comparative method was used to analyze transcripts from in-depth interviews with the youth participants. Emergent themes related to family characteristics include home instability, abandonment, and caregiver substance abuse. Abuse-related subthemes include intrafamilial abuse, caregiver abuse, rejection, and deprecation by caregivers. Grounded theory is used to interpret findings and develop working hypotheses to guide future studies of multitype maltreatment among homeless youth.
Democracy and Leadership: Does Every Vote Count?
Authors: Helterbran Valeri R.
Published: October 2008

Good judgment and ethics in decision making are important criteria in all areas of teaching and administration. This case study chronicles the actions of a class sponsor whose decisions modify the results of a high school's senior class elections and the fallout that results. The principal must assess the problem, take appropriate action to ethically resolve the situation for the sake of the students involved, restore integrity to the election process, and ameliorate attending problems created by the circumstances of this case. Because of the complexity of the situation, ramifications exist well beyond the election, affecting the school in general and the community at large.
Phase I study of obatoclax mesylate (GX15-070), a small molecule pan–Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia
Authors: O'Brien Susan M. , Claxton David F. , Crump Michael , Faderl Stefan , Kipps Thomas , Keating Michael J. , Viallet Jean , Cheson Bruce D.
Published: October 2008

Obatoclax mesylate is a small molecule pan–Bcl-2 antagonist with in vitro activity against chronic lymphocytic leukemia (CLL) cells. Obatoclax was administered to patients with advanced CLL at doses ranging from 3.5 to 14 mg/m2 as a 1-hour infusion and from 20 to 40 mg/m2 as a 3-hour infusion every 3 weeks. Twenty-six patients received a total of 74 cycles. Dose-limiting reactions were neurologic (somnolence, euphoria, ataxia) and associated with the infusion. The maximum tolerated dose (MTD) was 28 mg/m2 over 3 hours every 3 weeks. One (4%) of 26 patients achieved a partial response. Patients with anemia (3/11) or thrombocytopenia (4/14) experienced improvements in hemoglobin and platelet counts. Circulating lymphocyte counts were reduced in 18 of 26 patients with a median reduction of 24%. Overall, the maximum plasma concentration (Cmax) and area under the curve (AUC) values of obatoclax were dose proportional. Activation of Bax and Bak was demonstrated in peripheral blood mononuclear cells, and induction of apoptosis was related to overall obatoclax exposure, as monitored by the plasma concentration of oligonucleosomal DNA/histone complexes. Obatoclax mesylate has biologic activity and modest single-agent activity in heavily pretreated patients with advanced CLL. Further evaluation in less heavily pretreated patients and in combination with other therapeutic agents is warranted. This trial has been registered with http://clinicaltrials.gov under identifier NCT00600964.
Integrin αvβ3 on human endothelial cells binds von Willebrand factor strings under fluid shear stress
Authors: Huang Jing , Roth Robyn , Heuser John E. , Sadler J. Evan
Published: October 2008

Acutely secreted von Willebrand factor (VWF) multimers adhere to endothelial cells, support platelet adhesion, and may induce microvascular thrombosis. Immunofluorescence microscopy of live human umbilical vein endothelial cells showed that VWF multimers rapidly formed strings several hundred micrometers long on the cell surface after stimulation with histamine. Unexpectedly, only a subset of VWF strings supported platelet binding, which depended on platelet glycoprotein Ib. Electron microscopy showed that VWF strings often consisted of bundles and networks of VWF multimers, and each string was tethered to the cell surface by a limited number of sites. Several approaches implicated P-selectin and integrin αvβ3 in anchoring VWF strings. An RGDS peptide or a function-blocking antibody to integrin αvβ3 reduced the number of VWF strings formed. In addition, integrin αv decorated the VWF strings by immunofluorescence microscopy. Furthermore, lentiviral transduction of shRNA against the αv subunit reduced the expression of cell-surface integrin αvβ3 and impaired the ability of endothelial cells to retain VWF strings. Soluble P-selectin reduced the number of platelet-decorated VWF strings in the absence of Ca2+ and Mg2+ but had no effect in the presence of these cations. These results indicate that VWF strings bind specifically to integrin αvβ3 on human endothelial cells.
Reductive isolation from bone marrow and blood implicates common lymphoid progenitors as the major source of thymopoiesis
Authors: Serwold Thomas , Richie Ehrlich Lauren I. , Weissman Irving L.
Published: October 2008

Ongoing thymopoiesis requires continual seeding from progenitors that reside within the bone marrow (BM), but the identity of the most proximate prethymocytes has remained controversial. Here we take a comprehensive approach to prospectively identify the major source of thymocyte progenitors that reside within the BM and blood, and find that all thymocyte progenitor activity resides within a rare Flk2+CD27+ population. The BM Flk2+CD27+ subset is predominantly composed of common lymphoid progenitors (CLPs) and multipotent progenitors. Of these 2 populations, only CLPs reconstitute thymopoiesis rapidly after intravenous injection. In contrast, multipotent progenitor-derived cells reconstitute the thymus with delayed kinetics only after they have reseeded the BM, self-renewed, and generated CLPs. These results identify CLPs as the major source of thymocyte progenitors within the BM.
Ploidy status and copy number aberrations in primary glioblastomas defined by integrated analysis of allelic ratios, signal ratios and loss of heterozygosity using 500K SNP Mapping Arrays
Authors: Gardina Paul J , Lo Ken C , Lee Walter , Cowell John K , Turpaz Yaron
Published: October 2008

Background

Genomic hybridization platforms, including BAC-CGH and genotyping arrays, have been used to estimate chromosome copy number (CN) in tumor samples by detecting the relative strength of genomic signal. The methods rely on the assumption that the predominant chromosomal background of the samples is diploid, an assumption that is frequently incorrect for tumor samples. In addition to generally greater resolution, an advantage of genotyping arrays over CGH arrays is the ability to detect signals from individual alleles, allowing estimation of loss-of-heterozygosity (LOH) and allelic ratios to enhance the interpretation of copy number alterations. Copy number events associated with LOH potentially have the same genetic consequences as deletions.

Results

We have utilized allelic ratios to detect patterns that are indicative of higher ploidy levels. An integrated analysis using allelic ratios, total signal and LOH indicates that many or most of the chromosomes from 24 glioblastoma tumors are in fact aneuploid. Some putative whole-chromosome losses actually represent trisomy, and many apparent sub-chromosomal losses are in fact relative losses against a triploid or tetraploid background.

Conclusion

These results suggest a re-interpretation of previous findings based only on total signal ratios. One interesting observation is that many single or multiple-copy deletions occur at common putative tumor suppressor sites subsequent to chromosomal duplication; these losses do not necessarily result in LOH, but nonetheless occur in conspicuous patterns. The 500 K Mapping array was also capable of detecting many sub-mega base losses and gains that were overlooked by CGH-BAC arrays, and was superior to CGH-BAC arrays in resolving regions of complex CN variation.
SHIV-1157i and passaged progeny viruses encoding R5 HIV-1 clade C env cause AIDS in rhesus monkeys
Authors: Humbert Michael , Rasmussen Robert A , Song Ruijiang , Ong Helena , Sharma Prachi , Chenine Agnès L , Kramer Victor G , Siddappa Nagadenahalli B , Xu Weidong , Else James G , Novembre Francis J , Strobert Elizabeth , O'Neil Shawn P , Ruprecht Ruth M
Published: October 2008

Background

Infection of nonhuman primates with simian immunodeficiency virus (SIV) or chimeric simian-human immunodeficiency virus (SHIV) strains is widely used to study lentiviral pathogenesis, antiviral immunity and the efficacy of AIDS vaccine candidates. SHIV challenges allow assessment of anti-HIV-1 envelope responses in primates. As such, SHIVs should mimic natural HIV-1 infection in humans and, to address the pandemic, encode HIV-1 Env components representing major viral subtypes worldwide.

Results

We have developed a panel of clade C R5-tropic SHIVs based upon env of a Zambian pediatric isolate of HIV-1 clade C, the world's most prevalent HIV-1 subtype. The parental infectious proviral clone, SHIV-1157i, was rapidly passaged through five rhesus monkeys. After AIDS developed in the first animal at week 123 post-inoculation, infected blood was infused into a sixth monkey. Virus reisolated at this late stage was still exclusively R5 tropic and mucosally transmissible. Here we describe the long-term follow-up of this initial cohort of six monkeys. Two have remained non-progressors, whereas the other four gradually progressed to AIDS within 123–270 weeks post-exposure. Two progressors succumbed to opportunistic infections, including a case of SV40 encephalitis.

Conclusion

These data document the disease progression induced by the first mucosally transmissible, pathogenic R5 non-clade B SHIV and suggest that SHIV-1157i-derived viruses, including the late-stage, highly replication-competent SHIV-1157ipd3N4 previously described (Song et al., 2006), display biological characteristics that mirror those of HIV-1 clade C and support their expanded use for AIDS vaccine studies in nonhuman primates.
Human prion disease with a G114V mutation and epidemiological studies in a Chinese family: a case series
Authors: Ye Jing , Han Jun , Shi Qi , Zhang Bao-Yun , Wang Gui-Rong , Tian Chan , Gao Chen , Chen Jian-Min , Li Cun-Jiang , Liu Zheng , Li Xian-Zhang , Zhang Lai-Zhong , Dong Xiao-Ping
Published: October 2008

Introduction

Transmissible spongiform encephalopathies are a group of neurodegenerative diseases of humans and animals. Genetic Creutzfeldt-Jakob diseases, in which mutations in the PRNP gene predispose to disease by causing the expression of abnormal PrP protein, include familial Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia.

Case presentation

A 47-year-old Han-Chinese woman was hospitalized with a 2-year history of progressive dementia, tiredness, lethargy and mild difficulty in falling asleep. On neurological examination, there was severe apathy, spontaneous myoclonus of the lower limbs, generalized hyperreflexia and bilateral Babinski signs. A missense mutation (T to G) was identified at the position of nt 341 in one PRNP allele, leading to a change from glycine (Gly) to valine (Val) at codon 114. PK-resistant PrPSc was detected in brain tissues by Western blotting and immunohistochemical assays. Information on pedigree was collected notably by interviews with family members. A further four suspected patients in five consecutive generations of the family have been identified. One of them was hospitalized for progressive memory impairment at the age of 32. On examination, he had impairment of memory, calculation and comprehension, mild ataxia of the limbs, tremor and a left Babinski sign. He is still alive.

Conclusion

This family with G114V inherited prion disease is the first to be described in China and represents the second family worldwide in which this mutation has been identified. Three other suspected cases have been retrospectively identified in this family, and a further case with suggestive clinical manifestations has been shown by gene sequencing to have the causal mutation.
Evidence that molecular changes in cells occur before morphological alterations during the progression of breast ductal carcinoma
Authors: Castro Nadia P , Osório Cynthia ABT , Torres César , Bastos Elen P , Mourão-Neto Mário , Soares Fernando A , Brentani Helena P , Carraro Dirce M
Published: October 2008

Introduction

Ductal carcinoma in situ (DCIS) of the breast includes a heterogeneous group of preinvasive tumors with uncertain evolution. Definition of the molecular factors necessary for progression to invasive disease is crucial to determining which lesions are likely to become invasive. To obtain insight into the molecular basis of DCIS, we compared the gene expression pattern of cells from the following samples: non-neoplastic, pure DCIS, in situ component of lesions with co-existing invasive ductal carcinoma, and invasive ductal carcinoma.

Methods

Forty-one samples were evaluated: four non-neoplastic, five pure DCIS, 22 in situ component of lesions with co-existing invasive ductal carcinoma, and 10 invasive ductal carcinoma. Pure cell populations were isolated using laser microdissection. Total RNA was purified, DNase treated, and amplified using the T7-based method. Microarray analysis was conducted using a customized cDNA platform. The concept of molecular divergence was applied to classify the sample groups using analysis of variance followed by Tukey's test.

Results

Among the tumor sample groups, cells from pure DCIS exhibited the most divergent molecular profile, consequently identifying cells from in situ component of lesions with co-existing invasive ductal carcinoma as very similar to cells from invasive lesions. Additionally, we identified 147 genes that were differentially expressed between pure DCIS and in situ component of lesions with co-existing invasive ductal carcinoma, which can discriminate samples representative of in situ component of lesions with co-existing invasive ductal carcinoma from 60% of pure DCIS samples. A gene subset was evaluated using quantitative RT-PCR, which confirmed differential expression for 62.5% and 60.0% of them using initial and partial independent sample groups, respectively. Among these genes, LOX and SULF-1 exhibited features that identify them as potential participants in the malignant process of DCIS.

Conclusions

We identified new genes that are potentially involved in the malignant transformation of DCIS, and our findings strongly suggest that cells from the in situ component of lesions with co-existing invasive ductal carcinoma exhibit molecular alterations that enable them to invade the surrounding tissue before morphological changes in the lesion become apparent.
A candidate molecular signature associated with tamoxifen failure in primary breast cancer
Authors: Vendrell Julie A , Robertson Katherine E , Ravel Patrice , Bray Susan E , Bajard Agathe , Purdie Colin A , Nguyen Catherine , Hadad Sirwan M , Bieche Ivan , Chabaud Sylvie , Bachelot Thomas , Thompson Alastair M , Cohen Pascale A
Published: October 2008

Introduction

Few markers are available that can predict response to tamoxifen treatment in estrogen receptor (ER)-positive breast cancers. Identification of such markers would be clinically useful. We attempted to identify molecular markers associated with tamoxifen failure in breast cancer.

Methods

Eighteen initially ER-positive patients treated with tamoxifen requiring salvage surgery (tamoxifen failure [TF] patients) were compared with 17 patients who were disease free 5 years after surgery plus tamoxifen adjuvant therapy (control patients). cDNA microarray, real-time quantitative PCR, and immunohistochemistry on tissue microarrays were used to generate and confirm a gene signature associated with tamoxifen failure. An independent series of 33 breast tumor samples from patients who relapsed (n = 14) or did not relapse (n = 19) under tamoxifen treatment from a different geographic location was subsequently used to explore the gene expression signature identified.

Results

Using a screening set of 18 tumor samples (from eight control patients and 10 TF patients), a 47-gene signature discriminating between TF and control samples was identified using cDNA arrays. In addition to ESR1/ERα, the top-ranked genes selected by statistical cross-analyses were MET, FOS, SNCG, IGFBP4, and BCL2, which were subsequently validated in a larger set of tumor samples (from 17 control patients and 18 TF patients). Confirmation at the protein level by tissue microarray immunohistochemistry was observed for ER-α, γ-synuclein, and insulin-like growth factor binding protein 4 proteins in the 35 original samples. In an independent series of breast tumor samples (19 nonrelapsing and 14 relapsing), reduced expression of ESR1/ERα, IGFBP4, SNCG, BCL2, and FOS was observed in the relapsing group and was associated with a shorter overall survival. Low mRNA expression levels of ESR1/ERα, BCL2, and FOS were also associated with a shorter relapse-free survival (RFS). Using a Cox multivariate regression analysis, we identified BCL2 and FOS as independent prognostic markers associated with RFS. Finally, the BCL2/FOS signature was demonstrated to have more accurate prognostic value for RFS than ESR1/ERα alone (likelihood ratio test).

Conclusions

We identified molecular markers including a BCL2/FOS signature associated with tamoxifen failure; these markers may have clinical potential in the management of ER-positive breast cancer.
Selective Elevation of Adiponectin Production by the Natural Compounds Derived from a Medicinal Herb Alleviates Insulin Resistance and Glucose Intolerance in Obese Mice
Authors: Xu Aimin , Wang Hongbing , Hoo Ruby L. C. , Sweeney Gary , Vanhoutte Paul. M. , Wang Yu , Wu Donghai , Chu Wenjing , Qin Guowei , Lam Karen S. L.
Published: October 2008

Adiponectin is an adipocyte-derived insulin-sensitizing hormone with antidiabetic, antiinflammatory, and antiatherosclerotic properties. A decreased serum level of adiponectin in obesity has been identified as an independent risk factor for diabetes and cardiovascular complications, suggesting that pharmacological intervention aimed at elevating adiponectin production might hold promise for the treatment and/or prevention of these diseases. Here we report the identification of two structurally related natural compounds (astragaloside II and isoastragaloside I) from the medicinal herb Radix Astragali that possess such an activity. Astragaloside II and isoastragaloside I selectively increased adiponectin secretion in primary adipocytes without any obvious effects on a panel of other adipokines. Furthermore, an additive effect on induction of adiponectin production was observed between these two compounds and rosiglitazone, a thiazolidinedione class of insulin-sensitizing drugs. Chronic administration of astragaloside II and isoastragaloside I in both dietary and genetic obese mice significantly elevated serum levels of total adiponectin and selectively increased the composition of its high molecular weight oligomeric complex. These changes were associated with an alleviation of hyperglycemia, glucose intolerance, and insulin resistance. By contrast, the beneficial effects of these two compounds on insulin sensitivity and glucose metabolism were diminished in adiponectin knockout mice. In conclusion, our results suggest that pharmacological elevation of circulating adiponectin alone is sufficient to ameliorate insulin resistance and diabetes and support the use of adiponectin as a biomarker for future drug discovery. The two natural compounds might provide the lead as a novel class of therapeutics for obesity-related diseases.

Natural compounds alleviate insulin resistance by inducing adiponectin production.
Pharmacokinetics and pharmacodynamics of Phor21-βCG(ala), a lytic peptide conjugate
Authors: Jia Lee , Noker Patricia E , Piazza Gary A , Leuschner Carola , Hansel William , Gorman Gregory S , Coward Lori U , Tomaszewski Joseph
Published: October 2008

Phor21-βCG(ala), a 36-amino acid peptide comprised of a lytic peptide (Phor21) conjugated to a modified 15-amino acid segment of the β-chain of chorionic gonadotropin (βCG(ala)), selectively kills cancer cells that over-express luteinizing hormone/chorionic gonadotropin (LH/CG) receptors by disrupting cellular membrane structure. These studies were designed to further characterize its in-vitro inhibition and in-vivo destruction of prostate cancer cells, biostability and pharmacokinetics to determine its pharmacokinetic and pharmacodynamic profile. Inhibitory effects of Phor21-βCG(ala) were tested in PC-3 and Caco-2 cells as well as in nude mice bearing PC-3 cells transfected with the luciferase gene (PC-3.luc). Plasma stability, protease hydrolysis and pharmacokinetics of Phor21-βCG(ala) were measured by using liquid chromatography mass spectrometry (LC/MS/MS). Phor21-βCG(ala) selectively inhibited proliferation in-vitro and in-vivo metastases of PC-3 cells. Phor21-βCG(ala) was relatively stable in mouse, rat, dog and human plasma. Its degradation was partially due to protease hydrolysis and thermodynamic catalysis. Intravenous administration of Phor21-βCG(ala) showed its blood Cmax and AUC0→∞ around the in-vitro effective levels. In the tested rodents, Phor21-βCG(ala) displayed a moderate volume of distribution at steady state (VdSS) and slow clearance (Cl) in the rodents. In conclusion, Phor21-βCG(ala) displayed promising in-vitro and in-vivo anti-cancer activity with favourable pharmacokinetics, and may offer a novel approach to metastatic cancer chemotherapy.
Restriction of retinoic acid activity by Cyp26b1 is required for proper timing and patterning of osteogenesis during zebrafish development
Authors: Laue Kathrin , Jänicke Martina , Plaster Nikki , Sonntag Carmen , Hammerschmidt Matthias
Published: October 2008

Skeletal syndromes are among the most common birth defects. Vertebrate skeletogenesis involves two major cell types: cartilage-forming chondrocytes and bone-forming osteoblasts. In vitro, both are under the control of retinoic acid (RA), but its exact in vivo effects remained elusive. Here, based on the positional cloning of the dolphin mutation, we have studied the role of the RA-oxidizing enzyme Cyp26b1 during cartilage and bone development in zebrafish. cyp26b1 is expressed in condensing chondrocytes as well as in osteoblasts and their precursors. cyp26b1 mutants and RA-treated wild-type fish display a reduction in midline cartilage and the hyperossification of facial and axial bones, leading to fusions of vertebral primordia, a defect not previously described in the context of RA signaling. Fusions of cervical vertebrae were also obtained by treating mouse fetuses with the specific Cyp26 inhibitor R115866. Together with data on the expression of osteoblast markers, our results indicate that temporal and spatial restriction of RA signaling by Cyp26 enzymes is required to attenuate osteoblast maturation and/or activity in vivo. cyp26b1 mutants may serve as a model to study the etiology of human vertebral disorders such as Klippel-Feil anomaly.
Ovarian development in mice requires the GATA4-FOG2 transcription complex
Authors: Manuylov Nikolay L. , Smagulova Fatima O. , Leach Lyndsay , Tevosian Sergei G.
Published: October 2008

We have demonstrated previously that mammalian sexual differentiation requires both the GATA4 and FOG2 transcriptional regulators to assemble the functioning testis. Here we have determined that the sexual development of female mice is profoundly affected by the loss of GATA4-FOG2 interaction. We have also identified the Dkk1 gene, which encodes a secreted inhibitor of canonical β-catenin signaling, as a target of GATA4-FOG2 repression in the developing ovary. The tissue-specific ablation of theβ-catenin gene in the gonads disrupts female development. In Gata4ki/ki; Dkk1-/- or Fog2-/-;Dkk1-/- embryos, the normal ovarian gene expression pattern is partially restored. Control of ovarian development by the GATA4-FOG2 complex presents a novel insight into the cross-talk between transcriptional regulation and extracellular signaling that occurs in ovarian development.
Notch signaling maintains Leydig progenitor cells in the mouse testis
Authors: Tang Hao , Brennan Jennifer , Karl Jeannie , Hamada Yoshio , Raetzman Lori , Capel Blanche
Published: October 2008

During testis development, fetal Leydig cells increase their population from a pool of progenitor cells rather than from proliferation of a differentiated cell population. However, the mechanism that regulates Leydig stem cell self-renewal and differentiation is unknown. Here, we show that blocking Notch signaling, by inhibiting γ-secretase activity or deleting the downstream target gene Hairy/Enhancer-of-split 1, results in an increase in Leydig cells in the testis. By contrast, constitutively active Notch signaling in gonadal somatic progenitor cells causes a dramatic Leydig cell loss, associated with an increase in undifferentiated mesenchymal cells. These results indicate that active Notch signaling restricts fetal Leydig cell differentiation by promoting a progenitor cell fate. Germ cell loss and abnormal testis cord formation were observed in both gain- and loss-of-function gonads, suggesting that regulation of the Leydig/interstitial cell population is important for male germ cell survival and testis cord formation.
Wnt5a and Wnt11 interact in a maternal Dkk1-regulated fashion to activate both canonical and non-canonical signaling inXenopusaxis formation
Authors: Cha Sang-Wook , Tadjuidje Emmanuel , Tao Qinghua , Wylie Christopher , Heasman Janet
Published: October 2008

Wnt signaling in development and adult tissue homeostasis requires tight regulation to prevent patterning abnormalities and tumor formation. Here, we show that the maternal Wnt antagonist Dkk1 downregulates both the canonical and non-canonical signaling that are required for the correct establishment of the axes of the Xenopus embryo. We find that the target Wnts of Dkk activity are maternal Wnt5a and Wnt11, and that both Wnts are essential for canonical and non-canonical signaling. We determine that Wnt5a and Wnt11 form a previously unrecognized complex. This work suggests a new aspect of Wnt signaling: two Wnts acting in a complex together to regulate embryonic patterning.
The response of the honeybee dance to uncertain rewards
Authors: Seefeldt Sandra , De Marco Rodrigo J.
Published: October 2008

This work focuses on the responses of dancing bees to uncertain rewards. We varied the distribution of a fixed amount of sugar solution among the several flowers of a patch and recorded the foraging and subsequent dance behaviour of single honeybees collecting such a reward at that patch. Concurrently, we aimed to minimize the well-known modulatory effects of sugar reward on both the probability and the strength of a honeybee's dance. It was under these circumstances that we conceived the honeybee dance as an autonomous information-processing system and asked whether or not such a system is sensitive to uncertainty of reward. Our results suggest that bees can tune their dancing according to the distribution of sugar reward among the several flowers of a patch, and that they seemingly do this based on the number– or the frequency – of their non-rewarding inspections to these flowers: the higher the number of non-rewarding inspections the lower the probability of dancing. As a result, a honeybee's dance appears as`risk-averse', meaning that dances for uncertain resources are less likely. Presumably, the ultimate result of having `risk-averse' dances is a colony's ability to diminish delayed rewards and the effects of competition with other flower visitors for limited resources. We conclude that a systems approach to the honeybee dance will help to further analyse the regulation of a honeybee's threshold for dancing, and that theoretical accounts of `risk-sensitive'dances would prove fruitful in broader studies of honeybee foraging,particularly if one were to examine how recruitment actually translates into fitness.
Non-linear intramolecular interactions and voltage sensitivity of a KV1 family potassium channel fromPolyorchis penicillatus(Eschscholtz 1829)
Authors: Klassen Tara L. , O'Mara Megan L. , Redstone Megan , Spencer Andrew N. , Gallin Warren J.
Published: October 2008

Voltage sensitivity of voltage-gated potassium channels (VKCs) is a primary factor in shaping action potentials in excitable cells. Variation in the amino acid sequence of the channel proteins is responsible for differences in the voltage range over which the channel opens. Thus, understanding how changes in voltage sensitivity are effected by changes in channel protein sequence illuminates the functional evolution of excitability. The KV1-family channel jShak1, from the jellyfish Polyorchis penicillatus, differs from most other KV1 channels in ways that are useful for studying the problem of how voltage sensitivity is related to channel sequence. We assessed the contributions of changes in sequence of the S4, voltage sensing, helix and changes in one asparagine residue in the S2 helix, to the relative stability of the open and closed states of the channel. Mutation of the neutral S2 residue (Asn227) to glutamate stabilized the open conformation of the channel. Different modifications of charge and length in S4 favoured either the closed conformation or the open conformation. The interactions between pairs of mutations revealed that some of the S4 mutations alter the conformation of the voltage-sensing domain such that the S4 helix is constrained to be closer to the S2 helix than in the wild-type conformation. These results, taken in conjunction with three-dimensional models of the channel, identify intra-molecular interactions that control the balance between open and closed states. These interactions are likely to be relevant to understanding the functional characteristics of members of this channel family from other organisms.
Alanine aminotransferase levels are not significantly elevated in patients with HIV/HBV co-infection and lamivudine resistance
Authors: Bhattacharya D , Katzenstein D , Wong A , Israelski D , Imperial J C , Keeffe E B , Donovan R M
Published: October 2008

In hepatitis B virus (HBV) monoinfection, alanine aminotransferase (ALT) levels are linearly correlated with HBV DNA levels and lamivudine resistance. In human immunodeficiency virus (HIV)/HBV co-infection, little is known about the association between ALT, HBV DNA, and lamivudine resistance. We assessed HBV DNA, lamivudine resistance and ALT levels in 45 time points in 11 patients with HIV/HBV co-infection during lamivudine-containing antiretroviral therapy. High HBV DNA levels (>106 copies/mL) and lamivudine resistance developed in 45% and 91% of patients, respectively. However, ALT levels were not elevated in the setting of high HBV DNA levels (mean ALT, 48 IU/mL) or lamivudine resistance (mean ALT, 44 IU/mL). HBV viraemia and lamivudine resistance during extended lamivudine-containing antiretroviral therapy are common in HIV/HBV co-infection, occurring in the absence of significant ALT elevations. In HIV/HBV co-infection, measurement of HBV DNA and HBV resistance mutations may identify HBV virological failure before biochemical changes and should be routinely used in the management of HIV/HBV co-infection.
Condom use among high-risk heterosexual women with concurrent sexual partnerships, Houston, Texas, USA
Authors: Richards J E , Risser J M , Padgett P M , Rehman H U , Wolverton M L , Arafat R R
Published: October 2008

Concurrent sexual partnerships allow for enhanced transmission of sexually transmitted infections (STIs). Condom use dynamics in this context may be an important factor for transmission of HIV. We conducted a cross-sectional study to describe the frequency of concurrency among high-risk heterosexual women in Houston, Texas and determine the factors associated with condom use. A total of 553 participants were recruited using respondent-driven sampling and completed an anonymous questionnaire; 256 (49%) were identified as having a concurrent partnership. The prevalence of condom use at last sexual encounter was 26%. Women were significantly more likely to use condoms if their sexual encounter was with a casual partner and if alcohol and/or drugs were not used. The high prevalence of concurrent partnerships suggests the presence of a dense sexual network which may enable the rapid spread of STIs and HIV. The risk of transmission may be additionally increased due to the low prevalence of condom use.