bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient sequential consistency via conflict ordering
Authors: Lin Changhui , Nagarajan Vijay , Gupta Rajiv , Rajaram Bharghava
Published: April 2012

Although the sequential consistency (SC) model is the most intuitive, processor designers often choose to support relaxed memory consistency models for higher performance. This is because SC implementations that match the performance of relaxed memory models require post-retirement speculation and its associated hardware costs. In this paper we propose an efficient approach for enforcing SC without requiring post-retirement speculation. While prior SC implementations guarantee SC by explicitly completing memory operations within a processor in program order, we guarantee SC by completing conflicting memory operations, within and across processors, in an order that is consistent with the program order. More specifically, we identify those conflicting memory operations whose ordering is critical for the maintenance of SC and explicitly order them. This allows us to safely (non-speculatively) complete memory operations past pending writes, thus reducing memory ordering stalls. Our experiments with SPLASH-2 programs show that SC can be achieved efficiently, with performance comparable to RMO (relaxed memory order).
Architecture support for disciplined approximate programming
Authors: Esmaeilzadeh Hadi , Sampson Adrian , Ceze Luis , Burger Doug
Published: April 2012

Disciplined approximate programming lets programmers declare which parts of a program can be computed approximately and consequently at a lower energy cost. The compiler proves statically that all approximate computation is properly isolated from precise computation. The hardware is then free to selectively apply approximate storage and approximate computation with no need to perform dynamic correctness checks.

In this paper, we propose an efficient mapping of disciplined approximate programming onto hardware. We describe an ISA extension that provides approximate operations and storage, which give the hardware freedom to save energy at the cost of accuracy. We then propose Truffle, a microarchitecture design that efficiently supports the ISA extensions. The basis of our design is dual-voltage operation, with a high voltage for precise operations and a low voltage for approximate operations. The key aspect of the microarchitecture is its dependence on the instruction stream to determine when to use the low voltage. We evaluate the power savings potential of in-order and out-of-order Truffle configurations and explore the resulting quality of service degradation. We evaluate several applications and demonstrate energy savings up to 43%.
DreamWeaver
Authors: Meisner David , Wenisch Thomas F.
Published: April 2012

Numerous data center services exhibit low average utilization leading to poor energy efficiency. Although CPU voltage and frequency scaling historically has been an effective means to scale down power with utilization, transistor scaling trends are limiting its effectiveness and the CPU is accounting for a shrinking fraction of system power. Recent research advocates the use of full-system idle low-power modes to combat energy losses, as such modes provide the deepest power savings with bounded response time impact. However, the trend towards increasing cores per die is undermining the effectiveness of these sleep modes, particularly for request-parallel data center applications, because the independent idle periods across individual cores are unlikely to align by happenstance.

We propose DreamWeaver, architectural support to facilitate deep sleep for request-parallel applications on multicore servers. DreamWeaver comprises two elements: Weave Scheduling, a scheduling policy to coalesce idle and busy periods across cores to create opportunities for system-wide deep sleep; and the Dream Processor, a light-weight co-processor that monitors incoming network traffic and suspended work during sleep to determine when the system must wake. DreamWeaver is based on two key concepts: (1) stall execution and sleep anytime any core is unoccupied, but (2) constrain the maximum time any request may be stalled. Unlike prior scheduling approaches, DreamWeaver will preempt execution to sleep, maximizing time spent at the systems' most efficient operating point. We demonstrate that DreamWeaver can smoothly trade-off bounded, predictable increases in 99th-percentile response time for increasing power savings, and strictly dominates the savings available with voltage and frequency scaling and timeout-based request batching schemes.
Path-exploration lifting
Authors: Martignoni Lorenzo , McCamant Stephen , Poosankam Pongsin , Song Dawn , Maniatis Petros
Published: April 2012

Processor emulators are widely used to provide isolation and instrumentation of binary software. However they have proved difficult to implement correctly: processor specifications have many corner cases that are not exercised by common workloads. It is untenable to base other system security properties on the correctness of emulators that have received only ad-hoc testing. To obtain emulators that are worthy of the required trust, we propose a technique to explore a high-fidelity emulator with symbolic execution, and then lift those test cases to test a lower-fidelity emulator. The high-fidelity emulator serves as a proxy for the hardware specification, but we can also further validate by running the tests on real hardware. We implement our approach and apply it to generate about 610,000 test cases; for about 95% of the instructions we achieve complete path coverage. The tests reveal thousands of individual differences; we analyze those differences to shed light on a number of root causes, such as atomicity violations and missing security features.
Optic Nerve Hemangioblastoma: A Case Report
Authors: Zywicke Holly , Palmer Cheryl Ann , Vaphiades Michael S. , Riley Kristen O.
Published: April 2012

Hemangioblastomas are World Health Organization (WHO) grade I tumors of uncertain histologic origin. These central nervous system tumors are most often found in the posterior fossa, brainstem, and spinal cord. There are fewer than 20 reported cases of optic nerve hemangioblastomas in the literature. We present a patient with visual decline found to have a mass arising from within the posterior orbital canal that grossly involved the optic nerve sheath. Neuropathologic evaluation showed hemangioblastoma. Although not a common tumor in this location, consideration of hemangioblastoma in the differential diagnosis is important as they can have a more aggressive course than other tumors of this region and have a detrimental effect on visual prognosis.
Prevalence of Drug Resistance and Associated Mutations in a Population of HIV-1+Puerto Ricans: 2006–2010
Authors: Sepúlveda-Torres Lycely del C. , De La Rosa Alexandra , Cumba Luz , Boukli Nawal , Ríos-Olivares Eddy , Cubano Luis A.
Published: April 2012

This is a continuation of our efforts to maintain a record of the evolution of HIV-1 infection in Puerto Rico by monitoring the expression levels of antiretroviral drug-resistance-associated mutations. Samples from 2,500 patients from 2006–2010 were analyzed using the TruGene HIV-1 genotyping kit and the OpenGene DNA sequencing system. Results show that 58.8% of males and 65.3% of females had HIV-1 with resistance to at least one medication. The average number of HIV mutations was 6.0 in males and 6.1 in females. Statistically significant differences between men and women were recorded in the levels of HIV-1 expressed mutations and antiretroviral drug resistance. The most prevalent antiretroviral medication resistance shifted from zalcitabine to nevirapine and efavirenz in the five-year period. M184V and L63P were the dominant mutations for the reverse transcriptase and the protease genes, respectively, but an increase in the incidence of minority mutations was observed.
Stem Cell Therapy for Degenerative Disc Disease
Authors: Drazin Doniel , Rosner Jack , Avalos Pablo , Acosta Frank
Published: April 2012

Low back pain is widely recognized as one of the most prevalent pathologies in the developed world. In the United States, low back pain is the most common health problem for adults under the age of 50, resulting in significant societal and personal costs. While the causes of low back pain are myriad, it has been significantly associated with intervertebral disc (IVD) degeneration. Current first-line therapies for IVD degeneration such as physical therapy and spinal fusion address symptoms, but do not treat the underlying degeneration. The use of tissue engineering to treat IVD degeneration provides an opportunity to correct the pathological process. Novel techniques are currently being investigated and have shown mixed results. One major avenue of investigation has been stem cell injections. Mesenchymal stem cells (MSCs) have shown promise in small animal models, but results in larger vertebrates have been mixed.
Emerging Epigenetic Targets and Therapies in Cancer Medicine
Authors: Popovic Relja , Licht Jonathan D.
Published: April 2012

Abnormalities in the epigenetic regulation of chromatin structure and function can lead to aberrant gene expression and cancer development. Consequently, epigenetic therapies aim to restore normal chromatin modification patterns through the inhibition of various components of the epigenetic machinery. Histone deacetylase and DNA methyltransferase inhibitors represent the first putative epigenetic therapies; however, these agents have pleiotropic effects and it remains unclear how they lead to therapeutic responses. More recently, drugs that inhibit histone methyltransferases were developed, perhaps representing more specific agents. We review emerging epigenetic targets in cancer and present recent models of promising epigenetic therapies.

Significance: The use of DNA methyltransferase and histone deacetylase inhibitors in patients has validated the use of drugs targeted to epigenetic enzymes and strengthened the need for development of additional therapies. In this review, we summarize recently discovered epigenetic abnormalities, their implications for cancer, and the approaches taken for discovering small-molecule inhibitors targeting various properties of the epigenetic machinery. Cancer Discov; 2(5); 405–13. ©2012 AACR.
Receptor Subtypes and Signal Transduction Mechanisms Contributing to the Estrogenic Attenuation of Cannabinoid-Induced Changes in Energy Homeostasis
Authors: Washburn Neal , Borgquist Amanda , Wang Kate , Jeffery Garrett S. , Kelly Martin J. , Wagner Edward J.
Published: April 2012

We examined the receptor subtypes and signal transduction mechanisms contributing to the estrogenic modulation of cannabinoid-induced changes in energy balance. Food intake and, in some cases, O2 consumption, CO2 production and the respiratory exchange ratio were evaluated in ovariectomized female guinea pigs treated s.c. with the cannabinoid receptor agonist WIN 55,212-2 or its cremephor/ethanol/0.9% saline vehicle, and either with estradiol benzoate (EB), the estrogen receptor (ER) α agonist PPT, the ERβ agonist DPN, the Gq-coupled membrane ER agonist STX, the GPR30 agonist G-1 or their respective vehicles. Patch-clamp recordings were performed in hypothalamic slices. EB, STX, PPT and G-1 decreased daily food intake. Of these, EB, STX and PPT blocked the WIN 55,212-2-induced increase in food intake within 1-4 h. The estrogenic diminution of cannabinoid-induced hyperphagia correlated with a rapid (within 15 min) attenuation of cannabinoid-mediated decreases in glutamatergic synaptic input onto arcuate neurons, which was completely blocked by inhibition of protein kinase C (PKC) and attenuated by inhibition of protein kinase A (PKA). STX, but not PPT, mimicked this rapid estrogenic effect. However, PPT abolished the cannabinoid-induced inhibition of glutamatergic neurotransmission in cells from animals treated 24 h prior. The estrogenic antagonism of this presynaptic inhibition was observed in anorexigenic proopiomelanocortin neurons. These data reveal that estrogens negatively modulate cannabinoid-induced changes in energy balance via Gq-coupled membrane ER- and ERα-mediated mechanisms involving activation of PKC and PKA. As such, they further our understanding of the pathways through which estrogens act to temper cannabinoid sensitivity in regulating energy homeostasis in females.
Chlorthalidone Compared With Hydrochlorothiazide in Reducing Cardiovascular Events
Authors: Roush George C. , Holford Theodore R. , Guddati Achuta K.
Published: April 2012

Hydrochlorothiazide (HCTZ) is widely used for hypertension, and prescriptions for HCTZ outnumber those for chlorthalidone (CTDN) by >20-fold in 2 recent surveys. Some have recently expressed a preference for CTDN. However, head-to-head trials testing the effect of the 2 drugs on cardiovascular events (CVEs) are lacking. We conducted a systematic review of randomized trials in which 1 arm was based on either HCTZ or CTDN followed by 2 types of network meta-analyses, a drug-adjusted analysis and an office systolic blood pressure–adjusted analysis. Nine trials were identified: 3 based on HCTZ and 6 based on CTDN. In the drug-adjusted analysis (n=50946), the percentage of risk reduction in congestive heart failure for CTDN versus HCTZ was 23 (95% CI, 2–39;
P
=0.032); and in all CVEs was 21 (95% CI, 12–28;
P
<0.0001). In the office systolic blood pressure–adjusted analysis (n=78350), the percentage of risk reduction in CVEs for CTDN versus HCTZ was 18 (95% CI, 3–30;
P
=0.024). When the reduction in office systolic blood pressure was identical in the 2 arms, the risk for CVEs in HCTZ arms was 19% higher than in its nondiuretic comparator arms (
P
=0.021). Relative to HCTZ, the number needed to treat with CTDN to prevent 1 CVE over 5 years was 27. In conclusion, CTDN is superior to HCTZ in preventing cardiovascular events. This cannot be attributed entirely to the lesser effect of HCTZ on office systolic blood pressure but may be attributed to the pleomorphic effects of alternative medications or to the short duration of action of HCTZ.
A Power-Law Model of Psychological Memory Strength in Short- and Long-Term Recognition
Authors: Donkin Chris , Nosofsky Robert M.
Published: April 2012

A classic law of cognition is that forgetting curves are closely approximated by power functions. This law describes relations between different empirical dependent variables and the retention interval, and the precise form of the functional relation depends on the scale used to measure each variable. In the research reported here, we conducted a recognition task involving both short- and long-term probes. We discovered that formal memory-strength parameters from an exemplar-recognition model closely followed a power function of the lag between studied items and a test probe. The model accounted for rich sets of response time (RT) data at both individual-subject and individual-lag levels. Because memory strengths were derived from model fits to choices and RTs from individual trials, the psychological power law was independent of the scale used to summarize the forgetting functions. Alternative models that assumed different functional relations or posited a separate fixed-strength working memory store fared considerably worse than the power-law model did in predicting the data.
Investigation of penetration mechanics of PW Kevlar fiber reinforced HDPE composites
Authors: Erkendirci Ömer Faruk , Haque Bazle Z (Gama)
Published: April 2012

In this article, a study on the quasi-static penetration resistance behavior of plain weave Kevlar/high density polyethylene composite with varying thicknesses, i.e. HC = 3.1–9.4 mm, is presented using the quasi-static punch shear test methodology for the experiments. The penetration resistance is usually shown by a load–displacement graph, integral of which is the energy dissipated by the composite during penetration. The penetration energy varies with the diameter of the support span which can be equal or higher than the punch diameter. During tests, a flat punch of diameter 7.6 mm with a range of support spans 8.89 to 50.8 mm has been used and quasi-static punch shear test experiments are carried out for varying support span to punch diameter ratios (i.e. SPR = 1.16, 1.33, 1.67, 2.00, 2.33, 2.67, etc.). Their damage mechanisms for different support span to punch diameter ratios and thickness are documented. Stiffness, peak force, deflection, damage area and energy dissipation results are presented in detailed form.
Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides
Authors: Egan Jan B. , Shi Chang-Xin , Tembe Waibhav , Christoforides Alexis , Kurdoglu Ahmet , Sinari Shripad , Middha Sumit , Asmann Yan , Schmidt Jessica , Braggio Esteban , Keats Jonathan J. , Fonseca Rafael , Bergsagel P. Leif , Craig David W. , Carpten John D. , Stewart A. Keith
Published: April 2012

The longitudinal evolution of a myeloma genome from diagnosis to plasma cell leukemia has not previously been reported. We used whole-genome sequencing (WGS) on 4 purified tumor samples and patient germline DNA drawn over a 5-year period in a t(4;14) multiple myeloma patient. Tumor samples were acquired at diagnosis, first relapse, second relapse, and end-stage secondary plasma cell leukemia (sPCL). In addition to the t(4;14), all tumor time points also shared 10 common single-nucleotide variants (SNVs) on WGS comprising shared initiating events. Interestingly, we observed genomic sequence variants that waxed and waned with time in progressive tumors, suggesting the presence of multiple independent, yet related, clones at diagnosis that rose and fell in dominance. Five newly acquired SNVs, including truncating mutations of RB1 and ZKSCAN3, were observed only in the final sPCL sample suggesting leukemic transformation events. This longitudinal WGS characterization of the natural history of a high-risk myeloma patient demonstrated tumor heterogeneity at diagnosis with shifting dominance of tumor clones over time and has also identified potential mutations contributing to myelomagenesis as well as transformation from myeloma to overt extramedullary disease such as sPCL.
Genome-wide analysis of Pax8 binding provides new insights into thyroid functions
Authors: Ruiz-Llorente Sergio , de Pau Enrique Carrillo Santa , Sastre-Perona Ana , Montero-Conde Cristina , Gómez-López Gonzalo , Fagin James A , Valencia Alfonso , Pisano David G , Santisteban Pilar
Published: April 2012

Background

The transcription factor Pax8 is essential for the differentiation of thyroid cells. However, there are few data on genes transcriptionally regulated by Pax8 other than thyroid-related genes. To better understand the role of Pax8 in the biology of thyroid cells, we obtained transcriptional profiles of Pax8-silenced PCCl3 thyroid cells using whole genome expression arrays and integrated these signals with global cis-regulatory sequencing studies performed by ChIP-Seq analysis

Results

Exhaustive analysis of Pax8 immunoprecipitated peaks demonstrated preferential binding to intragenic regions and CpG-enriched islands, which suggests a role of Pax8 in transcriptional regulation of orphan CpG regions. In addition, ChIP-Seq allowed us to identify Pax8 partners, including proteins involved in tertiary DNA structure (CTCF) and chromatin remodeling (Sp1), and these direct transcriptional interactions were confirmed in vivo. Moreover, both factors modulate Pax8-dependent transcriptional activation of the sodium iodide symporter (Nis) gene promoter. We ultimately combined putative and novel Pax8 binding sites with actual target gene expression regulation to define Pax8-dependent genes. Functional classification suggests that Pax8-regulated genes may be directly involved in important processes of thyroid cell function such as cell proliferation and differentiation, apoptosis, cell polarity, motion and adhesion, and a plethora of DNA/protein-related processes.

Conclusion

Our study provides novel insights into the role of Pax8 in thyroid biology, exerted through transcriptional regulation of important genes involved in critical thyrocyte processes. In addition, we found new transcriptional partners of Pax8, which functionally cooperate with Pax8 in the regulation of thyroid gene transcription. Besides, our data demonstrate preferential location of Pax8 in non-promoter CpG regions. These data point to an orphan CpG island-mediated mechanism that represents a novel role of Pax8 in the transcriptional output of the thyrocyte.
Characterization of the transcriptome of an ecologically important avian species, the Vinous-throated Parrotbill Paradoxornis webbianus bulomachus (Paradoxornithidae; Aves)
Authors: Chu Jui-Hua , Lin Rong-Chien , Yeh Chia-Fen , Hsu Yu-Cheng , Li Shou-Hsien
Published: April 2012

Background

Adaptive divergence driven by environmental heterogeneity has long been a fascinating topic in ecology and evolutionary biology. The study of the genetic basis of adaptive divergence has, however, been greatly hampered by a lack of genomic information. The recent development of transcriptome sequencing provides an unprecedented opportunity to generate large amounts of genomic data for detailed investigations of the genetics of adaptive divergence in non-model organisms. Herein, we used the Illumina sequencing platform to sequence the transcriptome of brain and liver tissues from a single individual of the Vinous-throated Parrotbill, Paradoxornis webbianus bulomachus, an ecologically important avian species in Taiwan with a wide elevational range of sea level to 3100 m.

Results

Our 10.1 Gbp of sequences were first assembled based on Zebra Finch (Taeniopygia guttata) and chicken (Gallus gallus) RNA references. The remaining reads were then de novo assembled. After filtering out contigs with low coverage (<10X), we retained 67,791 of 487,336 contigs, which covered approximately 5.3% of the P. w. bulomachus genome. Of 7,779 contigs retained for a top-hit species distribution analysis, the majority (about 86%) were matched to known Zebra Finch and chicken transcripts. We also annotated 6,365 contigs to gene ontology (GO) terms: in total, 122 GO-slim terms were assigned, including biological process (41%), molecular function (32%), and cellular component (27%). Many potential genetic markers for future adaptive genomic studies were also identified: 8,589 single nucleotide polymorphisms, 1,344 simple sequence repeats and 109 candidate genes that might be involved in elevational or climate adaptation.

Conclusions

Our study shows that transcriptome data can serve as a rich genetic resource, even for a single run of short-read sequencing from a single individual of a non-model species. This is the first study providing transcriptomic information for species in the avian superfamily Sylvioidea, which comprises more than 1,000 species. Our data can be used to study adaptive divergence in heterogeneous environments and investigate other important ecological and evolutionary questions in parrotbills from different populations and even in other species in the Sylvioidea.
Individual participant data meta-analysis of prognostic factor studies: state of the art?
Authors: Abo-Zaid Ghada , Sauerbrei Willi , Riley Richard D
Published: April 2012

Background

Prognostic factors are associated with the risk of a subsequent outcome in people with a given disease or health condition. Meta-analysis using individual participant data (IPD), where the raw data are synthesised from multiple studies, has been championed as the gold-standard for synthesising prognostic factor studies. We assessed the feasibility and conduct of this approach.

Methods

A systematic review to identify published IPD meta-analyses of prognostic factors studies, followed by detailed assessment of a random sample of 20 articles published from 2006. Six of these 20 articles were from the IMPACT (International Mission for Prognosis and Analysis of Clinical Trials in traumatic brain injury) collaboration, for which additional information was also used from simultaneously published companion papers.

Results

Forty-eight published IPD meta-analyses of prognostic factors were identified up to March 2009. Only three were published before 2000 but thereafter a median of four articles exist per year, with traumatic brain injury the most active research field. Availability of IPD offered many advantages, such as checking modelling assumptions; analysing variables on their continuous scale with the possibility of assessing for non-linear relationships; and obtaining results adjusted for other variables. However, researchers also faced many challenges, such as large cost and time required to obtain and clean IPD; unavailable IPD for some studies; different sets of prognostic factors in each study; and variability in study methods of measurement. The IMPACT initiative is a leading example, and had generally strong design, methodological and statistical standards. Elsewhere, standards are not always as high and improvements in the conduct of IPD meta-analyses of prognostic factor studies are often needed; in particular, continuous variables are often categorised without reason; publication bias and availability bias are rarely examined; and important methodological details and summary results are often inadequately reported.

Conclusions

IPD meta-analyses of prognostic factors are achievable and offer many advantages, as displayed most expertly by the IMPACT initiative. However such projects face numerous logistical and methodological obstacles, and their conduct and reporting can often be substantially improved.
Increased financial burden among patients with chronic myelogenous leukaemia receiving imatinib in Japan: a retrospective survey
Authors: Kodama Yuko , Morozumi Ryoko , Matsumura Tomoko , Kishi Yukiko , Murashige Naoko , Tanaka Yuji , Takita Morihito , Hatanaka Nobuyo , Kusumi Eiji , Kami Masahiro , Matsui Akihiko
Published: April 2012

Background

The financial burden of medical expenses has been increasing for cancer patients. We investigated the relationship between household income and financial burden among patients with chronic myelogenous leukaemia (CML) who have been treated with imatinib.

Methods

A questionnaire was distributed to 1200 patients between May and August 2009. We retrospectively surveyed their household incomes, out-of-pocket medical expenses, final co-payments after refunds, and the perceived financial burden of their medical expenses in 2000, 2005 and 2008.

Results

A total of 577 patients completed the questionnaire. Their median age was 61 years (range, 15–94). A financial burden was felt by 41.2 % (28 of 68) of the patients treated with imatinib in 2000, 70.8 % (201 of 284) in 2005, and 75.8 % (400 of 528) in 2008. Overall, 182 patients (31.7 %) considered its discontinuation because of the financial burden and 15 (2.6 %) temporarily stopped their imatinib prescription. In 2000, 2005 and 2008, the patients’ median annual household incomes were 49,615 US Dollars (USD), 38,510 USD and 36,731 USD, respectively, with an average currency exchange rate of 104 Yen/USD in 2008. Their median annual out-of-pocket expenses were 11,548, 12,067 and 11,538 USD and their median final annual co-payments were 4,375, 4,327 and 3,558 USD, respectively. Older patients (OR = 0.96, 95 % CI: 0.95–0.98, p ≪ 0.0001 for 1-year increments), and patients with higher household incomes (OR = 0.92, 95 % CI: 0.85–0.99, p = 0.03 for 10,000 USD-increments) were less likely to have considered discontinuing their imatinib treatment. Conversely, patients with higher annual final co-payments (OR = 2.21, 95 % CI: 1.28–4.28, p = 0.004 for 10,000 USD-increments) were more likely to have considered discontinuing their imatinib treatment.

Conclusions

The proportion of CML patients who sensed a financial burden increased between 2000 and 2008. During this period, their annual incomes fell by 13,000 USD, although their medical expenses did not change. Financial support for patients being treated with expensive drugs remains a major problem in Japan.
A high-throughput method to detect Plasmodium falciparum clones in limiting dilution microplates
Authors: Lyko Brian , Hammershaimb Elizabeth A , Nguitragool Wang , Wellems Thomas E , Desai Sanjay A
Published: April 2012

Background

Molecular and cellular studies of Plasmodium falciparum require cloning of parasites by limiting dilution cultivation, typically performed in microplates. The parasite's slow replication rate combined with laborious methods for identification of positive wells has limited these studies. A new high-throughput method for detecting growth without compromising parasite viability is reported.

Methods

In vitro parasite cultivation is associated with extracellular acidification. A survey of fluorescent pH indicators identified 5-(and-6)-carboxy SNARF-1 as a membrane-impermeant dye with a suitable pK

a
value. Conditions for facile detection of viable parasites in 96-well microplates were optimized and used for limiting dilution cloning of genetic cross progeny and transfected parasites.

Results

5-(and-6)-carboxy SNARF-1 is a two-emission wavelength dye that accurately reported extracellular pH in parasite cultures. It readily detected parasite growth in microplate wells and yielded results comparable to labour-intensive examination of Giemsa-stained smears. The dye is non-toxic, allowing parasite detection without transfer of culture material to additional plates for separate assays. This dye was used with high-throughput limiting dilution culture to generate additional progeny clones from the HB3 × Dd2 genetic cross.

Conclusions

This fluorescence-based assay represents a low-cost, efficient method for detection of viable parasites in microplate wells; it can be easily expanded by automation.
Linking genes to diseases with a SNPedia-Gene Wiki mashup
Authors: Good Benjamin M , Clarke Erik L , Loguercio Salvatore , Su Andrew I
Published: April 2012

Background

A variety of topic-focused wikis are used in the biomedical sciences to enable the mass-collaborative synthesis and distribution of diverse bodies of knowledge. To address complex problems such as defining the relationships between genes and disease, it is important to bring the knowledge from many different domains together. Here we show how advances in wiki technology and natural language processing can be used to automatically assemble ‘meta-wikis’ that present integrated views over the data collaboratively created in multiple source wikis.

Results

We produced a semantic meta-wiki called the Gene Wiki+ that automatically mirrors and integrates data from the Gene Wiki and SNPedia. The Gene Wiki+, available at (http://genewikiplus.org/), captures 8,047 distinct gene-disease relationships. SNPedia accounts for 4,149 of the gene-disease pairs, the Gene Wiki provides 4,377 and only 479 appear independently in both sources. All of this content is available to query and browse and is provided as linked open data.

Conclusions

Wikis contain increasing amounts of diverse, biological information useful for elucidating the connections between genes and disease. The Gene Wiki+ shows how wiki technology can be used in concert with natural language processing to provide integrated views over diverse underlying data sources.
Differential activation of human T cells to allogeneic endothelial cells, epithelial cells and fibroblasts in vitro
Authors: Samsonov Dmitry , Geehan Christopher , Woda Craig B , Briscoe David M
Published: April 2012

Background

In the direct pathway, T cells recognize intact donor major histocompatability complexes and allogeneic peptide on the surface of donor antigen presenting cells (APCs). Indirect allorecognition results from the recognition of processed alloantigen by self MHC complexes on self APCs. In this study, we wished to evaluate the relative contribution of different intragraft cells to the alloactivation of nave and memory T cells though the direct and the indirect pathway of allorecognition.

Methods

The processing of membrane fragments from IFN-treated single donor endothelial cells (EC), fibroblasts or renal epithelial cells (RPTEC) was evaluated by DiOC labeling of each cell type and flow cytometry following interaction with PBMC. Direct pathway activation of nave CD45RA+or memory CD45RO+CD4+T cells was evaluated following coculture with IFN-treated and MHC class II-expressing EC, fibroblasts or RPTEC. Indirect pathway activation was assessed using CD45RA+or CD45RO+CD4+T cells cocultured with autologous irradiated APCs in the absence or presence of sonicates derived from IFN-treated allogeneic EC, fibroblasts or RPTEC. Activation of T cells was assessed by [3H]thymidine incorporation and by ELISpot assays.

Results

We find that CD14+APCs readily acquire membrane fragments from fibroblasts and RPTEC, but fail to acquire membrane fragments from intact EC. However, APCs process membranes from EC undergoing apoptosis.There was a notable direct pathway alloproliferative response of CD45RO+CD4+T cells to IFN-treated EC, but not to fibroblasts or RPTEC. Also, there was a minimal direct pathway response of CD45RA+CD4+T cells to all cell types. In contrast, we found that both CD45RA+and CD45RO+CD4+T cells proliferated following coculture with autologous APCs in the presence of sonicates derived from IFN-treated EC, fibroblasts or RPTEC. By ELISpot, we found that these T cells stimulated via the indirect pathway also produced the cytokines IFN, IL-2, IL-4 and IL-5.

Conclusions

Recipient APCs may readily process membrane fragments from allogeneic intragraft cells, but not from EC unless they are undergoing apoptosis. This processing is sufficient for indirect pathway alloactivation of both CD45RA+and CD45RO+CD4+T cells. Only graft vascular EC mediate direct pathway reactivation of CD4+T cells.
Medical image analysis and 3-d modeling to quantify changes and functional restoration in denervated muscle undergoing electrical stimulation treatment
Authors: Gargiulo Paolo , Helgason Thordur , Ingvarsson Páll , Mayr Winfried , Kern Helmut , Carraro Ugo
Published: April 2012

Background and purpose

Muscle tissue composition can be efficiently analyzed and quantified using images from spiral computed tomography technology (SCT) and the associated values of Hounsfield unit (HU) for different tissues. This work propose a novel approaches to monitor muscle condition in denervated muscle undergoing electrical stimulation (ES) treatment based on image segmentation and Three Dimensional (3D) modeling.

Method

Three paraplegic patients with fully denervated muscles in the lower extremities were treated with ES. To follow changes in size, composition and shape of the quadriceps muscle, SCT scans are taken every 6 months from the trochanter major to the knee for 4 years. Using segmentation techniques we isolated rectus femoris muscle (RF) and analyzed its content of fat, connective, and muscle tissue.

Results

The results showed the muscle restoration and growth induced by ES. The amount of normal muscle fibers increased from 45% to 60% of the whole volume while connective tissue and fat was reduced respectively of 30% and 50%. It was also found that muscles undergoing ES were restored in certain areas while declined in others depending on patient’s anatomy and positioning the surface electrodes.

Conclusion

The 3D approach combined with muscle tissue analysis provides information on the whole muscle and on its structural changes during ES treatment otherwise not accessible with other monitoring techniques.
Phase I Study of RO4929097, a Gamma Secretase Inhibitor of Notch Signaling, in Patients With Refractory Metastatic or Locally Advanced Solid Tumors
Authors: Tolcher Anthony W. , Messersmith Wells A. , Mikulski Stanislaw M. , Papadopoulos Kyriakos P. , Kwak Eunice L. , Gibbon Darlene G. , Patnaik Amita , Falchook Gerald S. , Dasari Arvind , Shapiro Geoffrey I. , Boylan John F. , Xu Zhi-Xin , Wang Ka , Koehler Astrid , Song James , Middleton Steven A. , Deutsch Jonathan , DeMario Mark , Kurzrock Razelle , Wheler Jennifer J.
Published: April 2012

Purpose

To determine the maximum-tolerated dose (MTD) and assess safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity of RO4929097, a gamma secretase inhibitor of Notch signaling in patients with advanced solid malignancies.

Patients and Methods

Patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. To assess reversible CYP3A4 autoinduction, the expanded part of the study tested three dosing schedules: (B) as above; modified A, 3 consecutive d/wk for 3 weeks; and (C) continuous daily dosing. Positron emission tomography scans with [18F]fluorodeoxyglucose (FDG-PET) were used to assess tumor metabolic effects.

Results

Patients on schedule A (n = 58), B (n = 47), and C (n = 5; expanded cohort) received 302 cycles of RO4929097. Common grade 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. Transient grade 3 hypophosphatemia (dose-limiting toxicity, one patient) and grade 3 pruritus (two patients) were observed at 27 mg and 60 mg, respectively; transient grade 3 asthenia was observed on schedule A at 80 mg (one patient). Tumor responses included one partial response in a patient with colorectal adenocarcinoma with neuroendocrine features, one mixed response (stable disease) in a patient with sarcoma, and one nearly complete FDG-PET response in a patient with melanoma. Effect on CYP3A4 induction was observed.

Conclusion

RO4929097 was well tolerated at 270 mg on schedule A and at 135 mg on schedule B; the safety of schedule C has not been fully evaluated. Further studies are warranted on the basis of a favorable safety profile and preliminary evidence of clinical antitumor activity.
Adjuvant Chemotherapy for Non–Small-Cell Lung Cancer in the Elderly: A Population-Based Study in Ontario, Canada
Authors: Cuffe Sinead , Booth Christopher M. , Peng Yingwei , Darling Gail E. , Li Gavin , Kong Weidong , Mackillop William J. , Shepherd Frances A.
Published: April 2012

Purpose

Non–small-cell lung cancer (NSCLC) is predominantly a disease of the elderly. Retrospective analyses of the National Cancer Institute of Canada Clinical Trials Group JBR.10 trial and the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis suggest that the elderly benefit from adjuvant chemotherapy. However, the elderly were under-represented in these studies, raising concerns regarding the reproducibility of the study results in clinical practice.

Patients and Methods

By using the Ontario Cancer Registry, we identified 6,304 patients with NSCLC who were treated with surgical resection from 2001 to 2006. Registry data were linked to electronic treatment records. Uptake of chemotherapy was compared across age groups: younger than 70, 70 to 74, 75 to 79, and ≥ 80 years. As a proxy of survival benefit from chemotherapy, we compared survival of patients diagnosed from 2004 to 2006 with survival of those diagnosed from 2001 to 2003. Hospitalization rates within 6 to 24 weeks of surgery served as a proxy of severe chemotherapy-related toxicity.

Results

In all, 2,763 (43.8%) of 6,304 surgical patients were elderly (age ≥ 70 years). Uptake of adjuvant chemotherapy in the elderly increased from 3.3% (2001 to 2003) to 16.2% (2004 to 2006). Among evaluable elderly patients, 70% received cisplatin and 28% received carboplatin-based regimens. Requirements for dose adjustments or drug substitutions were similar across age groups. Hospitalization rates within 6 to 24 weeks of surgery were similar across age groups (28.0% for patients age < 70 years; 27.8% for patients age ≥ 70 years; P = .54). Four-year survival of elderly patients increased significantly (47.1% for patients diagnosed from 2001 to 2003; 49.9% for patients diagnosed from 2004 to 2006; P = .01). Survival improved in all subgroups except patients age ≥ 80 years.

Conclusion

Uptake of adjuvant chemotherapy for NSCLC increased in patients age 70 years or older following reporting of pivotal adjuvant chemotherapy trials, but it remained below that for patients younger than age 70 years. Adoption of adjuvant chemotherapy appears to be associated with significant survival benefit in the elderly (age ≥ 70 years), with tolerability apparently similar to that of patients who are younger than age 70 years.
Adjuvant Therapy in the Treatment of Biliary Tract Cancer: A Systematic Review and Meta-Analysis
Authors: Horgan Anne M. , Amir Eitan , Walter Thomas , Knox Jennifer J.
Published: April 2012

Purpose

The benefit of adjuvant therapy (AT) for biliary tract cancer (BTC) is unclear, with conflicting results from nonrandomized studies. We report a systematic review and meta-analysis to determine the impact of AT on survival.

Methods

Studies published between 1960 and November 2010, which evaluated adjuvant chemotherapy (CT), radiotherapy (RT), or both (CRT) compared with curative-intent surgery alone for resected BTC were included. Only tumors of the gallbladder and bile ducts were assessed. Published data were extracted and computed into odds ratios (ORs) for death at 5 years. Subgroup analyses of benefit based on lymph node (LN) or resection margin positivity (R1) were prespecified. Data were weighted by generic inverse variance and pooled using random-effect modeling.

Results

Twenty studies involving 6,712 patients were analyzed. There was a nonsignificant improvement in overall survival with any AT compared with surgery alone (pooled OR, 0.74; P = .06). There was no difference between gallbladder and bile duct tumors (P = .68). The association was significant when the two registry analyses were excluded. Those receiving CT or CRT derived statistically greater benefit than RT alone (OR, 0.39, 0.61, and 0.98, respectively; P = .02). The greatest benefit for AT was in those with LN-positive disease (OR, 0.49; P = .004) and R1 disease (OR, 0.36; P = .002).

Conclusion

This analysis supports AT for BTC. Prospective randomized trials are needed to provide better rationale for this commonly used strategy. On the basis of our data, such trials could involve two active comparators rather than a no-treatment arm among patients with LN-positive or R1 disease.
OCEANS: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Chemotherapy With or Without Bevacizumab in Patients With Platinum-Sensitive Recurrent Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
Authors: Aghajanian Carol , Blank Stephanie V. , Goff Barbara A. , Judson Patricia L. , Teneriello Michael G. , Husain Amreen , Sovak Mika A. , Yi Jing , Nycum Lawrence R.
Published: April 2012

Purpose

This randomized, multicenter, blinded, placebo-controlled phase III trial tested the efficacy and safety of bevacizumab (BV) with gemcitabine and carboplatin (GC) compared with GC in platinum-sensitive recurrent ovarian, primary peritoneal, or fallopian tube cancer (ROC).

Patients and Methods

Patients with platinum-sensitive ROC (recurrence ≥ 6 months after front-line platinum-based therapy) and measurable disease were randomly assigned to GC plus either BV or placebo (PL) for six to 10 cycles. BV or PL, respectively, was then continued until disease progression. The primary end point was progression-free survival (PFS) by RECIST; secondary end points were objective response rate, duration of response (DOR), overall survival, and safety.

Results

Overall, 484 patients were randomly assigned. PFS for the BV arm was superior to that for the PL arm (hazard ratio [HR], 0.484; 95% CI, 0.388 to 0.605; log-rank P < .0001); median PFS was 12.4 v 8.4 months, respectively. The objective response rate (78.5% v 57.4%; P < .0001) and DOR (10.4 v 7.4 months; HR, 0.534; 95% CI, 0.408 to 0.698) were significantly improved with the addition of BV. No new safety concerns were noted. Grade 3 or higher hypertension (17.4% v < 1%) and proteinuria (8.5% v < 1%) occurred more frequently in the BV arm. The rates of neutropenia and febrile neutropenia were similar in both arms. Two patients in the BV arm experienced GI perforation after study treatment discontinuation.

Conclusion

GC plus BV followed by BV until progression resulted in a statistically significant improvement in PFS compared with GC plus PL in platinum-sensitive ROC.
A Qualitative Study of Rural Black Adolescents’ Perspectives on Primary STD Prevention Strategies
Authors: Akers Aletha Y. , Gold Melanie A. , Coyne‐Beasley Tamera , Corbie‐Smith Giselle
Published: April 2012

CONTEXT:

Primary STD prevention relies on five key strategies: practicing abstinence, choosing low‐risk partners, discussing partners’ sexual history, using condoms consistently and not having multiple partners. Few studies have examined all of these strategies simultaneously, and few have focused on rural black adolescents, whose rates of early sexual initiation and STDs are among the highest in the nation.

METHODS:

In 2006, a sample of 37 black adolescents (20 female, 17 male) from two rural North Carolina counties participated in focus groups that explored their understanding of how primary prevention strategies reduce STD transmission, the common barriers they encounter in trying to adopt these strategies and the risk reduction strategies that they employ. Transcripts were analyzed using a grounded theory approach.

RESULTS:

Adolescents understood how primary prevention strategies reduce STD transmission. However, they perceived sex as normal and abstinence as unlikely during adolescence. Furthermore, they considered the remaining primary prevention strategies difficult to implement because these strategies depend on partner cooperation and incorrectly assume that STD prevention is paramount when adolescents make sexual decisions. Adolescents reported using alternative strategies to reduce their STD risk; the most commonly used approaches were indirect assessments of partner characteristics (e.g., evaluating partners’ physical appearance and sexual history) and STD testing (to identify and treat infections).

CONCLUSION:

Adolescents try to reduce their STD risk, but do so by using ineffective practices. Promoting primary prevention strategies requires helping adolescents to identify opportunities to successfully employ these strategies.
Postabortion Contraception: Qualitative Interviews On Counseling and Provision of Long‐Acting Reversible Contraceptive Methods
Authors: Morse Jessica , Freedman Lori , Speidel J. Joseph , Thompson Kirsten M.J. , Stratton Laura , Harper Cynthia C.
Published: April 2012

CONTEXT:

Long‐acting reversible contraceptive (LARC) methods (IUDs and implants) are the most effective and cost‐effective methods for women. Although they are safe to place immediately following an abortion, most clinics do not offer this service, in part because of the increased cost.

METHODS:

In 2009, telephone interviews were conducted with 20 clinicians and 24 health educators at 25 abortion care practices across the country. A structured topic guide was used to explore general practice characteristics; training, knowledge and attitudes about LARC; and postabortion LARC counseling and provision. Transcripts of the digitally recorded interviews were coded and analyzed using inductive and deductive processes.

RESULTS:

Respondents were generally positive about the safety and effectiveness of LARC methods; those working in clinics that offered LARC methods immediately postabortion tended to have greater knowledge about LARC than others, and to perceive fewer risks and employ more evidence‐based practices. LARC methods often were not included in contraceptive counseling for women at high risk of repeat unintended pregnancy, including young and nulliparous women. Barriers to provision were usually expressed in terms of financial cost—to patients and clinics—and concerns about impact on the smooth flow of clinic procedures. Education and encouragement from professional colleagues regarding LARC, as well as training and adequate reimbursement for devices, were considered critical to changing clinical practice to include immediate postabortion LARC provision.

CONCLUSION:

Despite evidence about the safety and cost‐effectiveness of postabortion LARC provision, many clinics are not offering it because of financial and logistical concerns, resulting in missed opportunities for preventing repeat unintended pregnancies.