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Elevated levels of chemokine receptor CCR9 expression in solid tumors may contribute to poor patient prognosis. In this study, we characterized a novel CCR9-mediated pathway that promotes pancreatic cancer cell invasion and drug resistance, indicating that CCR9 may play a critical role in cancer progression through activation of β-catenin. We noted that the CCL25/CCR9 axis in pancreatic cancer cells induced the activation of β-catenin, which enhanced cell proliferation, invasion, and drug resistance. CCR9-mediated activation of β-catenin and the resulting downstream effects were effectively inhibited by blockade of the PI3K/AKT pathway, but not by antagonism of Wnt. Importantly, we discovered that CCR9/CCL25 increased the lethal dose of gemcitabine, suggesting decreased efficacy of anti-cancer drugs with CCR9 signaling. Through in silico computational modeling, we identified candidate CCR9 antagonists and tested their effects on CCR9/β-catenin regulation of cell signaling and drug sensitivity. When combined with gemcitabine, it resulted in synergistic cytotoxicity. Our results show that CCR9/β-catenin signaling enhances pancreatic cancer invasiveness and chemoresistance, and may be a highly novel therapeutic target. [ABSTRACT FROM AUTHOR]

The purpose of this article is to propose a framework to facilitate the achievement of greater economies of scope in economics research and undergraduate teaching. A four-year research plan is proposed, followed by discussion of practical strategies for overcoming barriers to undergraduate research in economics. Emphasis is placed on (i) bringing undergraduates into research programs as soon as the first semester and (ii) encouraging and incentivizing faculty members to participate in undergraduate research initiatives. [ABSTRACT FROM AUTHOR]

The generalized Newton-Euler inverse mass operator (GNEIMO) method is an advanced method for internal coordinates molecular dynamics (ICMD). GNEIMO includes several theoretical and algorithmic advancements that address longstanding challenges with ICMD simulations. In this article, we describe the GneimoSim ICMD software package that implements the GNEIMO method. We believe that GneimoSim is the first software package to include advanced features such as the equipartition principle derived for internal coordinates, and a method for including the Fixman potential to eliminate systematic statistical biases introduced by the use of hard constraints. Moreover, by design, GneimoSim is extensible and can be easily interfaced with third party force field packages for ICMD simulations. Currently, GneimoSim includes interfaces to LAMMPS, OpenMM, and Rosetta force field calculation packages. The availability of a comprehensive Python interface to the underlying C11 classes and their methods provides a powerful and versatile mechanism for users to develop simulation scripts to configure the simulation and control the simulation flow. GneimoSim has been used extensively for studying the dynamics of protein structures, refinement of protein homology models, and for simulating large scale protein conformational changes with enhanced sampling methods. GneimoSim is not limited to proteins and can also be used for the simulation of polymeric materials. [ABSTRACT FROM AUTHOR]

We propose a consumption model that captures the impact that perceived price ambiguities may have upon decision-making in green markets in general and in active transportation markets in particular. The basic intuition for the model is that a consumer who may be misperceiving the price of the green good (the active transportation mode) would be willing to pay a positive amount from her income in the current period to resolve the misperception going forward. We posit that the basis for the price misperception in the active transportation context is misperception of the relative risks involved in taking that mode. The compensating variation that aligns perceived and objective risk is derived. We show how raising green consumption via price misperception correction can be superior to traditional economic policy instruments. The results shed light on the more general family of situations in which agents may consistently misperceive aspects of the decision environment. [ABSTRACT FROM AUTHOR]

Internal coordinate molecular dynamics (ICMD) methods provide a more natural description of a protein by using bond, angle, and torsional coordinates instead of a Cartesian coordinate representation. Freezing high-frequency bonds and angles in the ICMD model gives rise to constrained ICMD (CICMD) models. There are several theoretical aspects that need to be developed to make the CICMD method robust and widely usable. In this article, we have designed a new framework for (1) initializing velocities for nonindependent CICMD coordinates, (2) efficient computation of center of mass velocity during CICMD simulations, (3) using advanced integrators such as Runge-Kutta, Lobatto, and adaptive CVODE for CICMD simulations, and (4) cancelling out the 'flying ice cube effect' that sometimes arises in Nosé-Hoover dynamics. The Generalized Newton-Euler Inverse Mass Operator (GNEIMO) method is an implementation of a CICMD method that we have developed to study protein dynamics. GNEIMO allows for a hierarchy of coarse-grained simulation models based on the ability to rigidly constrain any group of atoms. In this article, we perform tests on the Lobatto and Runge-Kutta integrators to determine optimal simulation parameters. We also implement an adaptive coarse-graining tool using the GNEIMO Python interface. This tool enables the secondary structure-guided 'freezing and thawing' of degrees of freedom in the molecule on the fly during molecular dynamics simulations and is shown to fold four proteins to their native topologies. With these advancements, we envision the use of the GNEIMO method in protein structure prediction, structure refinement, and in studying domain motion. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

BACKGROUND: Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare, nearly universally fatal complication from transfusion of nonirradiated cellular blood components, occurring when a recipient's immune system is unable to recognize and destroy transfused T lymphocytes. Irradiation of cellular components eliminates this risk. We present an unusual case of a liver transplant recipient developing TA-GVHD 13 weeks after transfusion of a random unit of nonirradiated red blood cells (RBCs) that happened to be from a donor homozygous for an HLA haplotype shared by the patient. STUDY DESIGN AND METHODS: This study was a single case review of a liver transplant recipient who developed skin GVHD and marrow aplasia. Clinical course and the chimerism studies involving the patient, the liver donor, and the blood donor are detailed. RESULTS: The patient presented 3 months posttransplant with GVHD of his skin and marrow aplasia. In addition to standard antigraft immunosuppression, this patient had started the interleukin-1 receptor antagonist anakinra on Posttransplant Day 13 for an acute gout flare. Chimerism studies on the patient's peripheral blood identified a population of CD3 cells that did not originate with either the patient or his liver donor. HLA studies and microsatellite profiling of the unknown CD3 population identified the source of the patient's TA-GVHD, a unit of nonirradiated, nonleukoreduced apheresis RBCs. CONCLUSION: Use of an immunomodulating agent may have contributed to the development of TA-GVHD in a liver transplant patient who received a random unit of nonirradiated RBCs by chance from an unrelated haploidentical donor. [ABSTRACT FROM AUTHOR]

The metropolitan Seattle area has utilized a centralized transfusion service model throughout the modern era of blood banking. This approach has used four laboratories to serve over 20 hospitals and clinics, providing greater capabilities for all at a lower consumption of resources than if each depended on its own laboratory and staff for these functions. In addition, this centralized model has facilitated wider use of the medical capabilities of the blood center's physicians, and a county-wide network of transfusion safety officers is now being developed to increase the impact of the blood center's transfusion expertise at the patient's bedside. Medical expectations and traffic have led the blood center to evolve the centralized model to include on-site laboratories at facilities with complex transfusion requirements (e.g., a children's hospital) and to implement in all the others a system of remote allocation. This new capability places a refrigerator stocked with uncrossmatched units in the hospital but retains control over the dispensing of these through the blood center's computer system; the correct unit can be electronically cross-matched and released on demand, obviating the need for transportation to the hospital and thus speeding transfusion. This centralized transfusion model has withstood the test of time and continues to evolve to meet new situations and ensure optimal patient care. [ABSTRACT FROM AUTHOR]

The article discusses the transfusion methods at several blood centers in the U.S. in 2011. These blood centers include Community Blood Center/Community Tissue Services (CBC/CTS) of Dayton, Ohio, BloodCenter of Wisconsin Inc. (BCW) of Milwaukee, Wisconsin and Puget Sound Blood Center (PSBC) of Seattle, Washington. It also tackles the role of transfusion safety officer (TSO) in improving transfusion safety.

Study Objective. To estimate an appropriate once-daily gentamicin dose and dosing interval for non-critical care pediatric patients older than 3 months of age without cystic fibrosis. Design. Pharmacokinetic analysis of data from a retrospective medical record review. Setting. Large academic children's hospital. Patients. One hundred fourteen non-critical care pediatric patients older than 3 months of age without cystic fibrosis who received multiple-daily dosing regimens of gentamicin between September 2007 and April 2008. Measurements and Main Results. Patient-specific pharmacokinetic parameters were calculated using drug concentrations obtained at steady state. Once-daily doses were extrapolated for each patient to achieve goal peak and trough concentrations. Using the average of these doses and the patient-specific pharmacokinetic parameters, theoretical once-daily peak and trough concentrations were calculated for each patient. Patient characteristics were analyzed to determine differences between patients who did and those who did not achieve adequate peak concentrations. Mean ± SD pharmacokinetic parameters were as follows: elimination rate constant 0.32 ± 0.06 hour-1, half-life 2.28 ± 0.54 hours, and volume of distribution 0.24 ± 0.08 L/kg. The only patient demographic characteristic found to have a significant effect on the extrapolated peak concentration was age. The following age-specific once-daily doses were calculated: 3 months to less than 2 years, 9.5 mg/kg; 2 years to less than 8 years, 8.5 mg/kg; and 8-18 years, 7 mg/kg. Conclusion. Age was the primary factor in determining the once-daily dose of gentamicin in our pediatric population. Further prospective research is necessary to determine the safety and efficacy of these age-based, once-daily doses for gentamicin. [ABSTRACT FROM AUTHOR]

Background Both increases and decreases in the incidence of subsequent malignancies in melanoma patients have been reported. We examined the database of the Indiana University Cancer Center to determine whether there is an association between malignant melanoma and noncutaneous malignancies. Objective We searched for evidence of noncutaneous malignancies in a cohort of melanoma patients. Methods Patients with microscopically confirmed malignant melanoma diagnosed between January 1987 and March 2001 were analyzed. This cohort was investigated for noncutaneous malignancies occurring either before or after the diagnosis of melanoma. The standardized incidence ratios (SIR) were calculated as the ratio of the observed to the expected number of patients with second malignancies, and 95% confidence intervals (95% CI) around the SIR were estimated from the cumulative Poisson distribution. Results A total of 955 patients with melanoma (498 males and 457 females) were documented over the 14-year period. Sixty-nine noncutaneous malignancies were identified in 59 (6.2%) melanoma patients (39 males and 20 females). There was a higher risk of non-Hodgkin's lymphoma (SIR = 1.91; 95% CI, 0.88–3.62) in men and renal cell carcinoma (SIR = 2.41, 95% CI, 0.97–4.97) in men. In female patients, however, there was no higher risk of noncutaneous malignancies. Conclusions This study did not show a higher risk of prostate cancer, gastrointestinal cancer, leukemia, endometrial cancer, or cancer of the nerve and neuroendocrine systems in melanoma patients. No female patients incurred a higher risk of noncutaneous cancers. The increased risk of non-Hodgkin's lymphoma and renal cell carcinoma in men might be attributed to a mutual carcinogenic exposure, an aberration of cell-mediated immunity, a shared genetic susceptibility, increased medical surveillance among cancer patients, a post-therapy effect after cancer management, or factors not as yet clear. Close monitoring of melanoma patients for signs of second malignancy is warranted. [ABSTRACT FROM AUTHOR]

Evidence-Based Medicine (EBM) is the practice of integrating best research evidence with clinical expertise and patent values. 1 The term, Evidence-Based Medicine, was named in 1992 by a group led by Gordon Guyatt at McMaster University in Canada. The practice of EBM arose from the awareness of: 1 the daily need for valid information pertinent to clinical practice; 2 the inadequacy of traditional sources, like textbooks, for such information; 3 the disparity between clinical enhancing skills and declining up-to-date knowledge and eventually, clinical performance; and 4 the inability to spend more time in finding and assimilating evidence pertinent to clinical practice. EBM simply emphasizes three As: Access , Appraisal and Application . Access requires refining a clinical question into a searchable term and an answerable question and using search engines to track down the information. Appraisal is using epidemiological principles and methods to critically review evidence for its validity and applicability. Application is integrating the critically appraised evidence with clinical expertise and each patient's unique situation. The outcomes following such practices are then assayed. The last step involves evaluating the effectiveness and efficiency in executing the first two As and seeking ways for improvement. In this article, we describe the concept and steps of practising EBM and utilize melanoma as an example to illustrate how we integrate the best evidence to outline the management plan for stage I-II melanoma. [ABSTRACT FROM AUTHOR]