bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interpretation of genome-wide infinium methylation data from ligated DNA in formalin-fixed, paraffin-embedded paired tumor and normal tissue
Authors: Jasmine Farzana , Rahaman Ronald , Roy Shantanu , Raza Maruf , Paul Rupash , Rakibuz-Zaman Muhammad , Paul-Brutus Rachelle , Dodsworth Charlotte , Kamal Mohammed , Ahsan Habibul , Kibriya Muhammad G 
Published: February 2012

Abstract

Background
Formalin-fixed, paraffin-embedded (FFPE) samples are a highly desirable resource for epigenetic studies, but there is no suitable platform to assay genome-wide methylation in these widely available resources. Recently, Thirlwell et al. (2010) have reported a modified ligation-based DNA repair protocol to prepare FFPE DNA for the Infinium methylation assay. In this study, we have tested the accuracy of methylation data obtained with this modification by comparing paired fresh-frozen (FF) and FFPE colon tissue (normal and tumor) from colorectal cancer patients. We report locus-specific correlation and concordance of tumor-specific differentially methylated loci (DML), both of which were not previously assessed.

Methods
We used Illumina's Infinium Methylation 27K chip for 12 pairs of FF and 12 pairs of FFPE tissue from tumor and surrounding healthy tissue from the resected colon of the same individual, after repairing the FFPE DNA using Thirlwell's modified protocol.

Results
For both tumor and normal tissue, overall correlation of β values between all loci in paired FF and FFPE was comparable to previous studies. Tissue storage type (FF or FFPE) was found to be the most significant source of variation rather than tissue type (normal or tumor). We found a large number of DML between FF and FFPE DNA. Using ANOVA, we also identified DML in tumor compared to normal tissue in both FF and FFPE samples, and out of the top 50 loci in both groups only 7 were common, indicating poor concordance. Likewise, while looking at the correlation of individual loci between FFPE and FF across the patients, less than 10% of loci showed strong correlation (r ≥ 0.6). Finally, we checked the effect of the ligation-based modification on the Infinium chemistry for SNP genotyping on an independent set of samples, which also showed poor performance.

Conclusion
Ligation of FFPE DNA prior to the Infinium genome-wide methylation assay may detect a reasonable number of loci, but the numbers of detected loci are much fewer than in FF samples. More importantly, the concordance of DML detected between FF and FFPE DNA is suboptimal, and DML from FFPE tissues should be interpreted with great caution.
Phase I Trial of Anti-CD22 Recombinant Immunotoxin Moxetumomab Pasudotox (CAT-8015 or HA22) in Patients With Hairy Cell Leukemia
Authors: Kreitman Robert J. , Tallman Martin S. , Robak Tadeusz , Coutre Steven , Wilson Wyndham H. , Stetler-Stevenson Maryalice , FitzGerald David J. , Lechleider Robert , Pastan Ira 
Published: February 2012

Purpose To conduct a phase I dose-escalation trial assessing safety and response of recombinant immunotoxin moxetumomab pasudotox (CAT-8015, HA22) in chemotherapy-resistant hairy cell leukemia (HCL). Patients and Methods Eligible patients had relapsed/refractory HCL after ≥ two prior therapies and required treatment because of abnormal blood counts. Patients received moxetumomab pasudotox 5 to 50 μg/kg every other day for three doses (QOD ×3), with up to 16 cycles repeating at ≥ 4-week intervals if patients did not experience disease progression or develop neutralizing antibodies. Results Twenty-eight patients were enrolled, including three patients each at 5, 10, 20, and 30 μg/kg, four patients at 40 μg/kg, and 12 patients at 50 μg/kg QOD ×3 for one to 16 cycles each (median, four cycles). Dose-limiting toxicity was not observed. Two patients had transient laboratory abnormalities consistent with grade 2 hemolytic uremic syndrome with peak creatinine of 1.53 to 1.66 mg/dL and platelet nadir of 106,000 to 120,000/μL. Drug-related toxicities in 25% to 64% of the 28 patients included (in decreasing frequency) grade 1 to 2 hypoalbuminemia, aminotransferase elevations, edema, headache, hypotension, nausea, and fatigue. Of 26 patients evaluable for immunogenicity, 10 patients (38%) made antibodies neutralizing more than 75% of the cytotoxicity of 1,000 ng/mL of immunotoxin, but this immunogenicity was rare (5%) after cycle 1. The overall response rate was 86%, with responses observed at all dose levels, and 13 patients (46%) achieved complete remission (CR). Only 1 CR lasted less than 1 year, with the median disease-free survival time not yet reached at 26 months. Conclusion Moxetumomab pasudotox at doses up to 50 μg/kg QOD ×3 has activity in relapsed/refractory HCL and has a safety profile that supports further clinical development for treatment of this disease.
Reflex Immunohistochemistry and Microsatellite Instability Testing of Colorectal Tumors for Lynch Syndrome Among US Cancer Programs and Follow-Up of Abnormal Results
Authors: Beamer Laura C. , Grant Marcia L. , Espenschied Carin R. , Blazer Kathleen R. , Hampel Heather L. , Weitzel Jeffrey N. , MacDonald Deborah J. 
Published: February 2012

Purpose Immunohistochemistry (IHC) for MLH1, MSH2, MSH6, and PMS2 protein expression and microsatellite instability (MSI) are well-established tools to screen for Lynch syndrome (LS). Although many cancer centers have adopted these tools as reflex LS screening after a colorectal cancer diagnosis, the standard of care has not been established, and no formal studies have described this practice in the United States. The purpose of this study was to describe prevalent practices regarding IHC/MSI reflex testing for LS in the United States and the subsequent follow-up of abnormal results. Materials and Methods A 12-item survey was developed after interdisciplinary expert input. A letter of invitation, survey, and online-survey option were sent to a contact at each cancer program. A modified Dillman strategy was used to maximize the response rate. The sample included 39 National Cancer Institute–designated Comprehensive Cancer Centers (NCI-CCCs), 50 randomly selected American College of Surgeons–accredited Community Hospital Comprehensive Cancer Programs (COMPs), and 50 Community Hospital Cancer Programs (CHCPs). Results The overall response rate was 50%. Seventy-one percent of NCI-CCCs, 36% of COMPs, and 15% of CHCPs were conducting reflex IHC/MSI for LS; 48% of the programs used IHC, 14% of the programs used MSI, and 38% of the programs used both IHC and MSI. One program used a presurgical information packet, four programs offered an opt-out option, and none of the programs required written consent. Conclusion Although most NCI-CCCs use reflex IHC/MSI to screen for LS, this practice is not well-adopted by community hospitals. These findings may indicate an emerging standard of care and diffusion from NCI-CCC to community cancer programs. Our findings also described an important trend away from requiring written patient consent for screening.
Linking patterns and processes across scales: the application of scale-transition theory to algal dynamics on rocky shores
Authors: Benedetti-Cecchi Lisandro , Tamburello Laura , Bulleri Fabio , Maggi Elena , Gennusa Vincenzo , Miller Matthew 
Published: February 2012

SUMMARYUnderstanding how species and environments respond to global anthropogenic disturbances is one of the greatest challenges for contemporary ecology. The ability to integrate modeling, correlative and experimental approaches within individual research programs will be key to address large-scale, long-term environmental problems. Scale-transition theory (STT) enables this level of integration, providing a powerful framework to link ecological patterns and processes across spatial and temporal scales. STT predicts the large-scale (e.g. regional) behavior of a system on the basis of nonlinear population models describing local (e.g. patch-scale) dynamics and the interaction between these nonlinearities and spatial variation in population abundance or environmental conditions. Here we use STT to predict the dynamics of turf-forming algae on rocky shores at Capraia Island, in the northwest Mediterranean. We developed a model of algal turf dynamics based on density-dependent growth that included the effects of local interactions with canopy algae. The model was parameterized with field data and used to scale up the dynamics of algal turfs from the plot scale (20×20 cm) to the island scale (tens of km). The interaction between nonlinear growth and spatial variance in cover of turfing algae emerged as a key term to translate the local dynamics up to the island scale. The model successfully predicted short-term and long-term mean values of turf cover estimated independently from a separate experiment. These results illustrate how STT can be used to identify the relevant mechanisms that drive large-scale changes in ecological communities. We argue that STT can contribute significantly to the connection between biomechanics and ecology, a synthesis that is at the core of the emerging field of ecomechanics.
Methodological advances in predicting flow-induced dynamics of plants using mechanical-engineering theory
Authors: de Langre Emmanuel 
Published: February 2012

SummaryThe modeling of fluid–structure interactions, such as flow-induced vibrations, is a well-developed field of mechanical engineering. Many methods exist, and it seems natural to apply them to model the behavior of plants, and potentially other cantilever-like biological structures, under flow. Overcoming this disciplinary divide, and the application of such models to biological systems, will significantly advance our understanding of ecological patterns and processes and improve our predictive capabilities. Nonetheless, several methodological issues must first be addressed, which I describe here using two practical examples that have strong similarities: one from agricultural sciences and the other from nuclear engineering. Very similar issues arise in both: individual and collective behavior, small and large space and time scales, porous modeling, standard and extreme events, trade-off between the surface of exchange and individual or collective risk of damage, variability, hostile environments and, in some aspects, evolution. The conclusion is that, although similar issues do exist, which need to be exploited in some detail, there is a significant gap that requires new developments. It is obvious that living plants grow in and adapt to their environment, which certainly makes plant biomechanics fundamentally distinct from classical mechanical engineering. Moreover, the selection processes in biology and in human engineering are truly different, making the issue of safety different as well. A thorough understanding of these similarities and differences is needed to work efficiently in the application of a mechanistic approach to ecology.
Biophysics, environmental stochasticity, and the evolution of thermal safety margins in intertidal limpets
Authors: Denny M. W. , Dowd W. W. 
Published: February 2012

SummaryAs the air temperature of the Earth rises, ecological relationships within a community might shift, in part due to differences in the thermal physiology of species. Prediction of these shifts – an urgent task for ecologists – will be complicated if thermal tolerance itself can rapidly evolve. Here, we employ a mechanistic approach to predict the potential for rapid evolution of thermal tolerance in the intertidal limpet Lottia gigantea. Using biophysical principles to predict body temperature as a function of the state of the environment, and an environmental bootstrap procedure to predict how the environment fluctuates through time, we create hypothetical time-series of limpet body temperatures, which are in turn used as a test platform for a mechanistic evolutionary model of thermal tolerance. Our simulations suggest that environmentally driven stochastic variation of L. gigantea body temperature results in rapid evolution of a substantial ‘safety margin’: the average lethal limit is 5–7°C above the average annual maximum temperature. This predicted safety margin approximately matches that found in nature, and once established is sufficient, in our simulations, to allow some limpet populations to survive a drastic, century-long increase in air temperature. By contrast, in the absence of environmental stochasticity, the safety margin is dramatically reduced. We suggest that the risk of exceeding the safety margin, rather than the absolute value of the safety margin, plays an underappreciated role in the evolution of thermal tolerance. Our predictions are based on a simple, hypothetical, allelic model that connects genetics to thermal physiology. To move beyond this simple model – and thereby potentially to predict differential evolution among populations and among species – will require significant advances in our ability to translate the details of thermal histories into physiological and population-genetic consequences.
Plankton distribution and ocean dispersal
Authors: McManus Margaret Anne , Woodson C. Brock 
Published: February 2012

Summary
Plankton are small organisms that dwell in oceans, seas and bodies of fresh water. In this review, we discuss life in the plankton, which involves a balance between the behavioral capabilities of the organism and the characteristics and movement of the water that surrounds it. In order to consider this balance, we discuss how plankton interact with their environment across a range of scales – from the smallest viruses and bacteria to larger phytoplankton and zooplankton. We find that the larger scale distributions of plankton, observed in coastal waters, along continental shelves and in ocean basins, are highly dependent upon the smaller scale interactions between the individual organism and its environment. Further, we discuss how larger scale organism distributions may affect the transport and/or retention of plankton in the ocean environment. The research reviewed here provides a mechanistic understanding of how organism behavior in response to the physical environment produces planktonic aggregations, which has a direct impact on the way marine ecosystems function.
Linking biomechanics and ecology through predator–prey interactions: flight performance of dragonflies and their prey
Authors: Combes S. A. , Rundle D. E. , Iwasaki J. M. , Crall J. D. 
Published: February 2012

SUMMARYAerial predation is a highly complex, three-dimensional flight behavior that affects the individual fitness and population dynamics of both predator and prey. Most studies of predation adopt either an ecological approach in which capture or survival rates are quantified, or a biomechanical approach in which the physical interaction is studied in detail. In the present study, we show that combining these two approaches provides insight into the interaction between hunting dragonflies (Libellula cyanea) and their prey (Drosophila melanogaster) that neither type of study can provide on its own. We performed &gt;2500 predation trials on nine dragonflies housed in an outdoor artificial habitat to identify sources of variability in capture success, and analyzed simultaneous predator–prey flight kinematics from 50 high-speed videos. The ecological approach revealed that capture success is affected by light intensity in some individuals but that prey density explains most of the variability in success rate. The biomechanical approach revealed that fruit flies rarely respond to approaching dragonflies with evasive maneuvers, and are rarely successful when they do. However, flies perform random turns during flight, whose characteristics differ between individuals, and these routine, erratic turns are responsible for more failed predation attempts than evasive maneuvers. By combining the two approaches, we were able to determine that the flies pursued by dragonflies when prey density is low fly more erratically, and that dragonflies are less successful at capturing them. This highlights the importance of considering the behavior of both participants, as well as their biomechanics and ecology, in developing a more integrative understanding of organismal interactions.
Biomechanics meets the ecological niche: the importance of temporal data resolution
Authors: Kearney Michael R. , Matzelle Allison , Helmuth Brian 
Published: February 2012

SUMMARYThe emerging field of mechanistic niche modelling aims to link the functional traits of organisms to their environments to predict survival, reproduction, distribution and abundance. This approach has great potential to increase our understanding of the impacts of environmental change on individuals, populations and communities by providing functional connections between physiological and ecological response to increasingly available spatial environmental data. By their nature, such mechanistic models are more data intensive in comparison with the more widely applied correlative approaches but can potentially provide more spatially and temporally explicit predictions, which are often needed by decision makers. A poorly explored issue in this context is the appropriate level of temporal resolution of input data required for these models, and specifically the error in predictions that can be incurred through the use of temporally averaged data. Here, we review how biomechanical principles from heat-transfer and metabolic theory are currently being used as foundations for mechanistic niche models and consider the consequences of different temporal resolutions of environmental data for modelling the niche of a behaviourally thermoregulating terrestrial lizard. We show that fine-scale temporal resolution (daily) data can be crucial for unbiased inference of climatic impacts on survival, growth and reproduction. This is especially so for species with little capacity for behavioural buffering, because of behavioural or habitat constraints, and for detecting temporal trends. However, coarser-resolution data (long-term monthly averages) can be appropriate for mechanistic studies of climatic constraints on distribution and abundance limits in thermoregulating species at broad spatial scales.
Integrating physiological and biomechanical drivers of population growth over environmental gradients on coral reefs
Authors: Madin Joshua S. , Hoogenboom Mia O. , Connolly Sean R. 
Published: February 2012

SUMMARY
Coral reefs exhibit marked spatial and temporal variability, and coral reef organisms exhibit trade-offs in functional traits that influence demographic performance under different combinations of abiotic environmental conditions. In many systems, trait trade-offs are modelled using an energy and/or nutrient allocation framework. However, on coral reefs, differences in biomechanical vulnerability have major demographic implications, and indeed are believed to play an essential role in mediating species coexistence because highly competitive growth forms are vulnerable to physical dislodgment events that occur with high frequency (e.g. annual summer storms). Therefore, an integrated energy allocation and biomechanics framework is required to understand the effect of physical environmental gradients on species’ demographic performance. However, on coral reefs, as in most ecosystems, the effects of environmental conditions on organisms are measured in different currencies (e.g. lipid accumulation, survival and number of gametes), and thus the relative contributions of these effects to overall capacity for population growth are not readily apparent. A comprehensive assessment of links between the environment and the organism, including those mediated by biomechanical processes, must convert environmental effects on individual-level performance (e.g. survival, growth and reproduction) into a common currency that is relevant to the capacity to contribute to population growth. We outline such an approach by considering the population-level performance of scleractinian reef corals over a hydrodynamic gradient, with a focus on the integrating the biomechanical determinants of size-dependent coral colony dislodgment as a function of flow, with the effects of flow on photosynthetic energy acquisition and respiration.
Successful Use of Fondaparinux for Bridging Early After Aortic and Mitral Mechanical Heart Valve Replacement
Authors: Perissinotti Anthony J , Dotson Bryan , Baciewicz Frank A , Tennenberg Steven D 
Published: February 2012

Objective: To report a case of successful use of fondaparinux for bridging early after aortic and mitral mechanical heart valve replacement (MHVR). Case Summary: A 71-year-old female underwent aortic and mitral valve replacements with St. Jude medical bileaflet prostheses, as well as DeVega tricuspid annuloplasty and coronary artery bypass graft. Anticoagulation was initially withheld following the procedure because of thrombocytopenia, large amount of chest tube drainage (~1 L/day), and concerns regarding postoperative bleeding. The thrombocytopenia (baseline platelet count 183 × 103/μL; postoperative platelet count 44 × 103/μL) was thought to be a consequence of the cardiopulmonary bypass; there was a low probability of heparin-induced thrombocytopenia. However, the care team preferred to avoid heparin products and initiated fondaparinux 7.5 mg subcutaneously once daily on postoperative day 8 once the patient's platelet count had recovered to >100 × 103/μL. The treatment was bridged to warfarin on postoperative day 13 and the patient was discharged home after receiving 8 days of fondaparinux. Throughout the patient's hospitalization and upon follow-up on postoperative day 31, there were no signs or symptoms of thromboembolic events or bleeding. Discussion: Unfractionated heparin and low-molecular-weight heparins are the standard of care for bridging to warfarin in patients with MHVR. The use of fondaparinux following MHVR has not been studied in randomized controlled trials. In vitro studies support the effectiveness of fondaparinux in preventing thrombus formation on mechanical heart valves. However, the only data available in humans as of December 2011 are 3 case reports. Two of these case reports described the successful use of fondaparinux for anticoagulation in a patient with an aortic valve replacement. In the third case report, the patient had an aortic and mitral valve replacement. Our case report is novel because it describes the use of fondaparinux early after MHVR, which is the most critical time period (or effective thromboprophylaxis. Conclusions: The use of fondaparinux for postoperative bridging in our patient early alter combined aortic and mitral MHVR was effective. However, until studies evaluate the efficacy and safety of fondaparinux in patients with MHVR, its use should be considered only when heparin products are contraindicated.