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1.  Toward patient-specific articular contact mechanics 
Journal of biomechanics  2014;48(5):779-786.
The mechanics of contacting cartilage layers is fundamentally important to understanding the development, homeostasis and pathology of diarthrodial joints. Because of the highly nonlinear nature of both the materials and the contact problem itself, numerical methods such as the finite element method are typically incorporated to obtain solutions. Over the course of five decades, we have moved from an initial qualitative understanding of articular cartilage material behavior to the ability to perform complex, three-dimensional contact analysis, including multiphasic material representations. This history includes the development of analytical and computational contact analysis methods that now provide the ability to perform highly nonlinear analyses. Numerical implementations of contact analysis based on the finite element method are rapidly advancing and will soon enable patient-specific analysis of joint contact mechanics using models based on medical image data. In addition to contact stress on the articular surfaces, these techniques can predict variations in strain and strain through the cartilage layers, providing the basis to predict damage and failure. This opens up exciting areas for future research and application to patient-specific diagnosis and treatment planning applied to a variety of pathologies that affect joint function and cartilage homeostasis.
doi:10.1016/j.jbiomech.2014.12.020
PMCID: PMC4416416  PMID: 25698236
2.  Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias 
Nature genetics  2015;47(5):496-504.
The diaphragm is an essential mammalian skeletal muscle, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDH), a common and often lethal birth defect. The diaphragm is derived from multiple embryonic sources, but how these give rise to the diaphragm is unknown and, despite the identification of many CDH-associated genes, the etiology of CDH is incompletely understood. Using mouse genetics, we show that the pleuroperitoneal folds (PPFs), transient embryonic structures, are the source of the diaphragm’s muscle connective tissue, regulate muscle development, and their striking migration controls diaphragm morphogenesis. Furthermore, Gata4 mosaic mutations in PPF-derived muscle connective tissue fibroblasts result in the development of localized amuscular regions that are biomechanically weaker and more compliant and lead to CDH. Thus the PPFs and muscle connective tissue are critical for diaphragm development and mutations in PPF-derived fibroblasts are a source of CDH.
doi:10.1038/ng.3250
PMCID: PMC4414795  PMID: 25807280
3.  Computational modeling of chemical reactions and interstitial growth and remodeling involving charged solutes and solid-bound molecules 
Mechanobiological processes are rooted in mechanics and chemistry, and such processes may be modeled in a framework that couples their governing equations starting from fundamental principles. In many biological applications, the reactants and products of chemical reactions may be electrically charged, and these charge effects may produce driving forces and constraints that significantly influence outcomes. In this study, a novel formulation and computational implementation are presented for modeling chemical reactions in biological tissues that involve charged solutes and solid-bound molecules within a deformable porous hydrated solid matrix, coupling mechanics with chemistry while accounting for electric charges. The deposition or removal of solid-bound molecules contributes to the growth and remodeling of the solid matrix; in particular, volumetric growth may be driven by Donnan osmotic swelling, resulting from charged molecular species fixed to the solid matrix. This formulation incorporates the state of strain as a state variable in the production rate of chemical reactions, explicitly tying chemistry with mechanics for the purpose of modeling mechanobiology. To achieve these objectives, this treatment identifies the specific theoretical and computational challenges faced in modeling complex systems of interacting neutral and charged constituents while accommodating any number of simultaneous reactions where reactants and products may be modeled explicitly or implicitly. Several finite element verification problems are shown to agree with closed-form analytical solutions. An illustrative tissue engineering analysis demonstrates tissue growth and swelling resulting from the deposition of chondroitin sulfate, a charged solid-bound molecular species. This implementation is released in the open-source program FEBio (www.febio.org). The availability of this framework may be particularly beneficial to optimizing tissue engineering culture systems by examining the influence of nutrient availability on the evolution of inhomogeneous tissue composition and mechanical properties, the evolution of construct dimensions with growth, the influence of solute and solid matrix electric charge on the transport of cytokines, the influence of binding kinetics on transport, the influence of loading on binding kinetics, and the differential growth response to dynamically loaded versus free-swelling culture conditions.
doi:10.1007/s10237-014-0560-1
PMCID: PMC4141041  PMID: 24558059
Chemical reactions; Charged reactants and products; Growth and remodeling; Mechanobiology; Finite element modeling
4.  Continuum Description of the Poisson's Ratio of Ligament and Tendon Under Finite Deformation 
Journal of biomechanics  2014;47(12):3201-3209.
Ligaments and tendons undergo volume loss when stretched along the primary fiber axis, which is evident by the large, strain-dependent Poisson's ratios measured during quasi-static tensile tests. Continuum constitutive models that have been used to describe ligament material behavior generally assume incompressibility, which does not reflect the volumetric material behavior seen experimentally. We developed a strain energy equation that describes large, strain dependent Poisson's ratios and nonlinear, transversely isotropic behavior using a novel method to numerically enforce the desired volumetric behavior. The Cauchy stress and spatial elasticity tensors for this strain energy equation were derived and implemented in the FEBio finite element software (www.febio.org). As part of this objective, we derived the Cauchy stress and spatial elasticity tensors for a compressible transversely isotropic material, which to our knowledge have not appeared previously in the literature. Elastic simulations demonstrated that the model predicted the nonlinear, upwardly concave uniaxial stress-strain behavior while also predicting a strain-dependent Poisson's ratio. Biphasic simulations of stress relaxation predicted a large outward fluid flux and substantial relaxation of the peak stress. Thus, the results of this study demonstrate that the viscoelastic behavior of ligaments and tendons can be predicted by modeling fluid movement when combined with a large Poisson's ratio. Further, the constitutive framework provides the means for accurate simulations of ligament volumetric material behavior without the need to resort to micromechanical or homogenization methods, thus facilitating its use in large scale, whole joint models.
doi:10.1016/j.jbiomech.2014.05.011
PMCID: PMC4179457  PMID: 25134434
ligament; Poisson's ratio; soft tissue mechanics
5.  Stem Cell Ophthalmology Treatment Study (SCOTS) for retinal and optic nerve diseases: a case report of improvement in relapsing auto-immune optic neuropathy 
Neural Regeneration Research  2015;10(9):1507-1515.
We present the results from a patient with relapsing optic neuropathy treated within the Stem Cell Ophthalmology Treatment Study (SCOTS). SCOTS is an Institutional Review Board approved clinical trial and has become the largest ophthalmology stem cell study registered at the National Institutes of Health to date (www.clinicaltrials.gov Identifier NCT 01920867). SCOTS utilizes autologous bone marrow-derived stem cells (BMSCs) for treatment of retinal and optic nerve diseases. Pre-treatment and post-treatment comprehensive eye exams of a 54 year old female patient were performed both at the Florida Study Center, USA and at The Eye Center of Columbus, USA. As a consequence of a relapsing optic neuritis, the patient's previously normal visual acuity decreased to between 20/350 and 20/400 in the right eye and to 20/70 in the left eye. Significant visual field loss developed bilaterally. The patient underwent a right eye vitrectomy with injection of BMSCs into the optic nerve of the right eyeand retrobulbar, subtenon and intravitreal injection of BMSCs in the left eye. At 15 months after SCOTS treatment, the patient's visual acuity had improved to 20/150 in the right eye and 20/20 in the left eye. Bilateral visual fields improved markedly. Both macular thickness and fast retinal nerve fiber layer thickness were maximally improved at 3 and 6 months after SCOTS treatment. The patient also reduced her mycophenylate dose from 1,500 mg per day to 500 mg per day and required no steroid pulse therapy during the 15-month follow up.
doi:10.4103/1673-5374.165525
PMCID: PMC4625519  PMID: 26604914
nerve regeneration; stem cells; optic nerve; autoimmune; optic neuropathy; ophthalmology; bone marrow-derived stem cells; blindness; visual loss; Stem Cell Ophthalmology Treatment Study; neural regeneration
6.  Multiple Low-Dose Challenges in a Rhesus Macaque AIDS Vaccine Trial Result in an Evolving Host Response That Affects Protective Outcome 
Clinical and Vaccine Immunology : CVI  2014;21(12):1650-1660.
Using whole-blood transcriptional profiling, we investigated differences in the host response to vaccination and challenge in a rhesus macaque AIDS vaccine trial. Samples were collected from animals prior to and after vaccination with live, irradiated vaccine cells secreting the modified endoplasmic reticulum chaperone gp96-Ig loaded with simian immunodeficiency virus (SIV) peptides, either alone or in combination with a SIV-gp120 protein boost. Additional samples were collected following multiple low-dose rectal challenges with SIVmac251. Animals in the boosted group had a 73% reduced risk of infection. Surprisingly, few changes in gene expression were observed during the vaccination phase. Focusing on postchallenge comparisons, in particular for protected animals, we identified a host response signature of protection comprised of strong interferon signaling after the first challenge, which then largely abated after further challenges. We also identified a host response signature, comprised of early macrophage-mediated inflammatory responses, in animals with undetectable viral loads 5 days after the first challenge but with unusually high viral titers after subsequent challenges. Statistical analysis showed that prime-boost vaccination significantly lowered the probability of infection in a time-consistent manner throughout several challenges. Given that humoral responses in the prime-boost group were highly significant prechallenge correlates of protection, the strong innate signaling after the first challenge suggests that interferon signaling may enhance vaccine-induced antibody responses and is an important contributor to protection from infection during repeated low-dose exposure to SIV.
doi:10.1128/CVI.00455-14
PMCID: PMC4248781  PMID: 25274805
7.  Stem Cell Ophthalmology Treatment Study (SCOTS) for retinal and optic nerve diseases: a preliminary report 
Neural Regeneration Research  2015;10(6):982-988.
In this report, we present the results of a single patient with optic neuropathy treated within the Stem Cell Ophthalmology Treatment Study (SCOTS). SCOTS is an Institutional Review Board approved clinical trial and is the largest ophthalmology stem cell study registered at the National Institutes of Health to date- www.clinicaltrials.gov Identifier NCT 01920867. SCOTS utilizes autologous bone marrow-derived stem cells in the treatment of optic nerve and retinal diseases. Pre- and post-treatment comprehensive eye exams were independently performed at the Wilmer Eye Institute at the Johns Hopkins Hospital, USA. A 27 year old female patient had lost vision approximately 5 years prior to enrollment in SCOTS. Pre-treatment best-corrected visual acuity at the Wilmer Eye Institute was 20/800 Right Eye (OD) and 20/4,000 Left Eye (OS). Four months following treatment in SCOTS, the central visual acuity had improved to 20/100 OD and 20/40 OS.
doi:10.4103/1673-5374.158365
PMCID: PMC4498363  PMID: 26199618
stem cells; optic nerve; optic neuropathy; ophthalmology; bone marrow-derived stem cells; blindness; visual loss
8.  Formation of microvascular networks: role of stromal interactions directing angiogenic growth 
In the adult, angiogenesis leads to an expanded microvascular network as new vessel segments are added to an existing microcirculation. Necessarily, growing neovessels must navigate through tissue stroma as they locate and grow towards other vessel elements. We have a growing body of evidence demonstrating that angiogenic neovessels reciprocally interact with the interstitial matrix of the stroma resulting in directed neovascular growth during angiogenesis. Given the compliance and the viscoelastic properties of collagen, neovessel guidance by the stroma is likely due to compressive strain transverse to the direction of primary tensile forces present during active tissue deformation. Similar stromal strains control the final network topology of the new microcirculation, including the distribution of arterioles, capillaries and venules. In this case, stromal-derived stimuli must be present during the post-angiogenesis remodeling and maturation phases of neovascularization in order to have this effect. Interestingly, the pre-existing organization of vessels prior to the start of angiogenesis has no lasting influence on the final, new network architecture. Combined, the evidence describes interplay between angiogenic neovessels and stroma that is important in directed neovessel growth and invasion. This dynamic is also likely a mechanism by which global tissue forces influence vascular form and function.
doi:10.1111/micc.12115
PMCID: PMC4032604  PMID: 24447042
9.  Specimen-specific predictions of contact stress under physiological loading in the human hip: validation and sensitivity studies 
Hip osteoarthritis may be initiated and advanced by abnormal cartilage contact mechanics, and finite element (FE) modeling provides an approach with the potential to allow the study of this process. Previous FE models of the human hip have been limited by single specimen validation and the use of quasi-linear or linear elastic constitutive models of articular cartilage. The effects of the latter assumptions on model predictions are unknown, partially because data for the instantaneous behavior of healthy human hip cartilage are unavailable. The aims of this study were to develop and validate a series of specimen-specific FE models, to characterize the regional instantaneous response of healthy human hip cartilage in compression, and to assess the effects of material nonlinearity, inhomogeneity and specimen-specific material coefficients on FE predictions of cartilage contact stress and contact area. Five cadaveric specimens underwent experimental loading, cartilage material characterization and specimen-specific FE modeling. Cartilage in the FE models was represented by average neo-Hookean, average Veronda Westmann and specimen- and region-specific Veronda Westmann hyperelastic constitutive models. Experimental measurements and FE predictions compared well for all three cartilage representations, which was reflected in average RMS errors in contact stress of less than 25%. The instantaneous material behavior of healthy human hip cartilage varied spatially, with stiffer acetabular cartilage than femoral cartilage and stiffer cartilage in lateral regions than in medial regions. The Veronda Westmann constitutive model with average material coefficients accurately predicted peak contact stress, average contact stress, contact area and contact patterns. The use of subject- and region-specific material coefficients did not increase the accuracy of FE model predictions. The neo-Hookean constitutive model underpredicted peak contact stress in areas of high stress. The results of this study support the use of average cartilage material coefficients in predictions of cartilage contact stress and contact area in the normal hip. The regional characterization of cartilage material behavior provides the necessary inputs for future computational studies, to investigate other mechanical parameters that may be correlated with OA and cartilage damage in the human hip. In the future, the results of this study can be applied to subject-specific models to better understand how abnormal hip contact stress and contact area contribute to OA.
doi:10.1007/s10237-013-0504-1
PMCID: PMC3859708  PMID: 23736783
Hip; Finite element; Validation; Constitutive models; Cartilage
10.  Clinical and biochemical outcomes of men undergoing radical prostatectomy or radiation therapy for localized prostate cancer 
Radiation Oncology Journal  2015;33(1):21-28.
Purpose
We analyzed outcomes of patients with prostate cancer undergoing either radical retropubic prostatectomy (RRP) +/- salvage radiation or definitive radiation therapy (RT) +/- androgen deprivation.
Materials and Methods
From 2003-2010 there were 251 patients who underwent RRP and 469 patients who received RT (≥7,560 cGy) for prostate cancer. Kaplan-Meier analysis was performed with the log-rank test to compare biochemical control (bCR), distant metastatic-free survival (DMPFS), and prostate cancer-specific survival (PCSS) between the two groups.
Results
The median follow-up was 70 months and 61.3% of the men were African American. For low risk disease the 6-year bCR were 90.3% for RT and 85.6% for RRP (p = 0.23) and the 6-year post-salvage bCR were 90.3% vs. 90.9%, respectively (p = 0.84). For intermediate risk disease the 6-year bCR were 82.6% for RT and 59.7% for RRP (p < 0.001) and 82.6% vs. 74.0%, respectively, after including those salvaged with RT (p = 0.06). For high risk disease, the 6-year bCR were 67.4% for RT and 41.3% for RRP (p < 0.001) and after including those salvaged with RT was 67.4% vs. 43.1%, respectively (p < 0.001). However, there were no significant differences between the two groups in regards to DMPFS or PCSS.
Conclusion
Treatment approaches utilizing RRP +/- salvage radiation or RT +/- androgen deprivation yielded equivalent DMPFS and PCSS outcomes. Biochemical control rates, using their respective definitions, appeared equivalent or better in those who received treatment with RT.
doi:10.3857/roj.2015.33.1.21
PMCID: PMC4394065  PMID: 25874174
Prostate cancer; Radiation therapy; Radical prostatectomy; Outcomes; Dose escalation; Comparative effectiveness
11.  Deep Transcriptional Sequencing of Mucosal Challenge Compartment from Rhesus Macaques Acutely Infected with Simian Immunodeficiency Virus Implicates Loss of Cell Adhesion Preceding Immune Activation 
Journal of Virology  2014;88(14):7962-7972.
ABSTRACT
Pathology resulting from human immunodeficiency virus (HIV) infection is driven by protracted inflammation; the primary loss of CD4+ T cells is caused by activation-driven apoptosis. Recent studies of nonhuman primates (NHPs) have suggested that during the acute phase of infection, antiviral mucosal immunity restricts viral replication in the primary infection compartment. These studies imply that HIV achieves systemic infection as a consequence of a failure in host antiviral immunity. Here, we used high-dose intrarectal inoculation of rhesus macaques with simian immunodeficiency virus (SIV) SIVmac251 to examine how the mucosal immune system is overcome by SIV during acute infection. The host response in rectal mucosa was characterized by deep mRNA sequencing (mRNA-seq) at 3 and 12 days postinoculation (dpi) in 4 animals for each time point. While we observed a strong host transcriptional response at 3 dpi, functions relating to antiviral immunity were absent. Instead, we observed a significant number of differentially expressed genes relating to cell adhesion and reorganization of the cytoskeleton. We also observed downregulation of genes encoding members of the claudin family of cell adhesion molecules, which are coexpressed with genes associated with pathology in the colorectal mucosa, and a large number of noncoding transcripts. In contrast, at 12 dpi the differentially expressed genes were enriched in those involved with immune system functions, in particular, functions relating to T cells, B cells, and NK cells. Our findings indicate that host responses that negatively affect mucosal integrity occur before inflammation. Consequently, when inflammation is activated at peak viremia, mucosal integrity is already compromised, potentially enabling rapid tissue damage, driving further inflammation.
IMPORTANCE The HIV pandemic is one of the major threats to human health, causing over a million deaths per year. Recent studies have suggested that mucosal antiviral immune responses play an important role in preventing systemic infection after exposure to the virus. Yet, despite their potential role in decreasing transmission rates between individuals, these antiviral mechanisms are poorly understood. Here, we carried out the first deep mRNA sequencing analysis of mucosal host responses in the primary infection compartment during acute SIV infection. We found that during acute infection, a significant host response was mounted in the mucosa before inflammation was triggered. Our analysis indicated that the response has a detrimental effect on tissue integrity, causing increased permeability, tissue damage, and recruitment of SIV target cells. These results emphasize the importance of mucosal host responses preceding immune activation in preventing systemic SIV infection.
doi:10.1128/JVI.00543-14
PMCID: PMC4097788  PMID: 24807713
12.  Impact of hepatitis C treatment initiation on adherence to concomitant medications 
Our study investigated whether initiating hepatitis C virus (HCV) treatment affected adherence to concomitant medications. Mixed effects linear regression was used to analyze data from 57 patients (29 co-infected with HIV) in a prospective study of HCV treatment-naïve patients initiating HCV treatment. Adherence was assessed using structured self-report at the time of treatment initiation, 12 weeks, and 24 weeks into treatment. There was no change in adherence to concomitant medications over the first 24 weeks of HCV treatment. There was a significant interaction effect such that the change in adherence to concomitant medications between baseline and 12 weeks differed between the HIV-infected and HIV-uninfected patients. Adherence to concomitant medications in the HIV-infected patients was found to decrease, whereas adherence in the HIV-uninfected patients was found to increase. HIV-infected patients may be more at risk for adherence problems in the first 12 weeks of HCV treatment as compared to HIV-uninfected patients.
doi:10.1016/j.jana.2013.07.004
PMCID: PMC3947339  PMID: 24070644
adherence; concomitant medications; HCV; HIV; treatment initiation
13.  Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance 
Science (New York, N.Y.)  2014;346(6212):987-991.
Existing mouse models of lethal Ebola virus infection do not reproduce hallmark symptoms of Ebola hemorrhagic fever, neither delayed blood coagulation and disseminated intravascular coagulation, nor death from shock, thus restricting pathogenesis studies to non-human primates. Here we show that mice from the Collaborative Cross exhibit distinct disease phenotypes following mouse-adapted Ebola virus infection. Phenotypes range from complete resistance to lethal disease to severe hemorrhagic fever characterized by prolonged coagulation times and 100% mortality. Inflammatory signaling was associated with vascular permeability and endothelial activation, and resistance to lethal infection arose by induction of lymphocyte differentiation and cellular adhesion, likely mediated by the susceptibility allele Tek. These data indicate that genetic background determines susceptibility to Ebola hemorrhagic fever.
doi:10.1126/science.1259595
PMCID: PMC4241145  PMID: 25359852
14.  Formation of Microvascular Networks: Role of Stromal Interactions Directing Angiogenic Growth 
In the adult, angiogenesis leads to an expanded microvascular network as new vessel segments are added to an existing microcirculation. Necessarily, growing neovessels must navigate through tissue stroma as they locate and grow toward other vessel elements. We have a growing body of evidence demonstrating that angiogenic neovessels reciprocally interact with the interstitial matrix of the stroma resulting in directed neovascular growth during angiogenesis. Given the compliance and the viscoelastic properties of collagen, neovessel guidance by the stroma is likely due to compressive strain transverse to the direction of primary tensile forces present during active tissue deformation. Similar stromal strains control the final network topology of the new microcirculation, including the distribution of arterioles, capillaries, and venules. In this case, stromal-derived stimuli must be present during the post-angiogenesis remodeling and maturation phases of neovascularization to have this effect. Interestingly, the preexisting organization of vessels prior to the start of angiogenesis has no lasting influence on the final, new network architecture. Combined, the evidence describes interplay between angiogenic neovessels and stroma that is important in directed neovessel growth and invasion. This dynamic is also likely a mechanism by which global tissue forces influence vascular form and function.
doi:10.1111/micc.12115
PMCID: PMC4032604  PMID: 24447042
angiogenesis; stroma; matrix; neovessel; remodeling
15.  Tissue-specific transcriptome sequencing analysis expands the non-human primate reference transcriptome resource (NHPRTR) 
Nucleic Acids Research  2014;43(Database issue):D737-D742.
The non-human primate reference transcriptome resource (NHPRTR, available online at http://nhprtr.org/) aims to generate comprehensive RNA-seq data from a wide variety of non-human primates (NHPs), from lemurs to hominids. In the 2012 Phase I of the NHPRTR project, 19 billion fragments or 3.8 terabases of transcriptome sequences were collected from pools of ∼20 tissues in 15 species and subspecies. Here we describe a major expansion of NHPRTR by adding 10.1 billion fragments of tissue-specific RNA-seq data. For this effort, we selected 11 of the original 15 NHP species and subspecies and constructed total RNA libraries for the same ∼15 tissues in each. The sequence quality is such that 88% of the reads align to human reference sequences, allowing us to compute the full list of expression abundance across all tissues for each species, using the reads mapped to human genes. This update also includes improved transcript annotations derived from RNA-seq data for rhesus and cynomolgus macaques, two of the most commonly used NHP models and additional RNA-seq data compiled from related projects. Together, these comprehensive reference transcriptomes from multiple primates serve as a valuable community resource for genome annotation, gene dynamics and comparative functional analysis.
doi:10.1093/nar/gku1110
PMCID: PMC4383927  PMID: 25392405
16.  Micromechanical Model of a Surrogate for Collagenous Soft Tissues: Development, Validation and Analysis of Mesoscale Size Effects 
Aligned, collagenous tissues such as tendons and ligaments are composed primarily of water and type I collagen, organized hierarchically into nanoscale fibrils, microscale fibers and mesoscale fascicles. Force transfer across scales is complex and poorly understood. Since innervation, the vasculature, damage mechanisms and mechanotransduction occur at the microscale and mesoscale, understanding multiscale interactions is of high importance. This study used a physical model in combination with a computational model to isolate and examine the mechanisms of force transfer between scales. A collagen-based surrogate served as the physical model. The surrogate consisted of extruded collagen fibers embedded within a collagen gel matrix. A micromechanical finite element model of the surrogate was validated using tensile test data that was recorded using a custom tensile testing device mounted on a confocal microscope. Results demonstrated that the experimentally measured macroscale strain was not representative of the microscale strain, which was highly inhomogeneous. The micromechanical model, in combination with a macroscopic continuum model, revealed that the microscale inhomogeneity resulted from size effects in the presence of a constrained boundary. A sensitivity study indicated that significant scale effects would be present over a range of physiologically relevant inter-fiber spacing values and matrix material properties. The results indicate that the traditional continuum assumption is not valid for describing the macroscale behavior of the surrogate, and that boundary-induced size effects are present.
doi:10.1007/s10237-013-0475-2
PMCID: PMC3676693  PMID: 23400805
Collagen; soft tissue; ligament; tendon; composites; biomechanics; finite element method
17.  A comprehensive collection of systems biology data characterizing the host response to viral infection 
Scientific Data  2014;1:140033.
The Systems Biology for Infectious Diseases Research program was established by the U.S. National Institute of Allergy and Infectious Diseases to investigate host-pathogen interactions at a systems level. This program generated 47 transcriptomic and proteomic datasets from 30 studies that investigate in vivo and in vitro host responses to viral infections. Human pathogens in the Orthomyxoviridae and Coronaviridae families, especially pandemic H1N1 and avian H5N1 influenza A viruses and severe acute respiratory syndrome coronavirus (SARS-CoV), were investigated. Study validation was demonstrated via experimental quality control measures and meta-analysis of independent experiments performed under similar conditions. Primary assay results are archived at the GEO and PeptideAtlas public repositories, while processed statistical results together with standardized metadata are publically available at the Influenza Research Database (www.fludb.org) and the Virus Pathogen Resource (www.viprbrc.org). By comparing data from mutant versus wild-type virus and host strains, RNA versus protein differential expression, and infection with genetically similar strains, these data can be used to further investigate genetic and physiological determinants of host responses to viral infection.
doi:10.1038/sdata.2014.33
PMCID: PMC4410982  PMID: 25977790
18.  Neoadjuvant Concurrent Chemoradiation for Curative Treatment of Penile Squamous Cell Carcinoma 
Introduction. Penile cancer is a rare malignancy often treated with neoadjuvant chemotherapy followed by surgery. However, the utility of neoadjuvant chemoradiation, particularly when the tumor is resistant to chemotherapy alone, has not been established. In this study, we report a case of pT3cN3M0 penile squamous cell carcinoma with progression of nodal disease on chemotherapy, which was cured with use of neoadjuvant concurrent chemoradiation. Case Report. A 65-year-old male presented with a fixed left inguinal lymph node with associated firmness of the penile glans. Biopsies of both sites revealed evidence of squamous cell carcinoma. The patient underwent partial penectomy for the primary lesion and began neoadjuvant chemotherapy to reduce the size of the unresectable left inguinal node. However, he displayed disease progression in the left inguinal node. As such, we attempted concurrent chemoradiation therapy with regression of his nodal disease. The patient was able to undergo left inguinal node dissection and has no evidence of disease 18 months since his initial surgery. Conclusion. The use of neoadjuvant chemoradiation for bulky cN2-3 disease seems appropriate in the setting of progressive disease. Further studies are necessary to assess the utility of concurrent chemoradiation both in the neoadjuvant and salvage setting.
doi:10.1155/2014/479376
PMCID: PMC4220572  PMID: 25400960
19.  Effects of Decorin Proteoglycan on Fibrillogenesis, Ultrastructure, and Mechanics of Type I Collagen Gels 
The proteoglycan decorin is known to affect both the fibrillogenesis and the resulting ultrastructure of in vitro polymerized collagen gels. However, little is known about its effects on mechanical properties. In this study, 3D collagen gels were polymerized into tensile test specimens in the presence of decorin proteoglycan, decorin core protein, or dermatan sulfate (DS). Collagen fibrillogenesis, ultrastructure, and mechanical properties were then quantified using a turbidity assay, 2 forms of microscopy (SEM and confocal), and tensile testing. The presence of decorin proteoglycan or core protein decreased the rate and ultimate turbidity during fibrillogenesis and decreased the number of fibril aggregates (fibers) compared to control gels. The addition of decorin and core protein increased the linear modulus by a factor of 2 compared to controls, while the addition of DS reduced the linear modulus by a factor of 3. Adding decorin after fibrillogenesis had no effect, suggesting that decorin must be present during fibrillogenesis to increase the mechanical properties of the resulting gels. These results show that the inclusion of decorin proteoglycan during fibrillogenesis of Type I collagen increases the modulus and tensile strength of resulting collagen gels. The increase in mechanical properties when polymerization occurs in the presence of the decorin proteoglycan is due to a reduction in the aggregation of fibrils into larger order structures such as fibers and fiber bundles.
doi:10.1016/j.matbio.2013.04.004
PMCID: PMC3795835  PMID: 23608680
decorin; collagen; fibrillogenesis; mechanics; ultrastructure
20.  Evaluation of a Post-Processing Approach for Multiscale Analysis of Biphasic Mechanics of Chondrocytes 
Understanding the mechanical behavior of chondrocytes as a result of cartilage tissue mechanics has significant implications for both evaluation of mechanobiological function and to elaborate on damage mechanisms. A common procedure for prediction of chondrocyte mechanics (and of cell mechanics in general) relies on a computational post-processing approach where tissue level deformations drive cell level models. Potential loss of information in this numerical coupling approach may cause erroneous cellular scale results, particularly during multiphysics analysis of cartilage. The goal of this study was to evaluate the capacity of 1st and 2nd order data passing to predict chondrocyte mechanics by analyzing cartilage deformations obtained for varying complexity of loading scenarios. A tissue scale model with a sub-region incorporating representation of chondron size and distribution served as control. The postprocessing approach first required solution of a homogeneous tissue level model, results of which were used to drive a separate cell level model (same characteristics as the subregion of control model). The 1st data passing appeared to be adequate for simplified loading of the cartilage and for a subset of cell deformation metrics, e.g., change in aspect ratio. The 2nd order data passing scheme was more accurate, particularly when asymmetric permeability of the tissue boundaries were considered. Yet, the method exhibited limitations for predictions of instantaneous metrics related to the fluid phase, e.g., mass exchange rate. Nonetheless, employing higher-order data exchange schemes may be necessary to understand the biphasic mechanics of cells under lifelike tissue loading states for the whole time history of the simulation.
doi:10.1080/10255842.2013.809711
PMCID: PMC4157590  PMID: 23809004
multiscale; computational modeling; finite element; cartilage; chondrocyte; poroelastic; biphasic; tissue mechanics; cell mechanics; homogenization
21.  Finite element predictions of cartilage contact mechanics in hips with retroverted acetabula 
BACKGROUND
A contributory factor to hip osteoarthritis (OA) is abnormal cartilage mechanics. Acetabular retroversion, a version deformity of the acetabulum, has been postulated to cause OA via decreased posterior contact area and increased posterior contact stress. Although cartilage mechanics cannot be measured directly in-vivo to evaluate the causes of OA, they can be predicted using finite element (FE) modeling.
OBJECTIVE
The objective of this study was to compare cartilage contact mechanics between hips with normal and retroverted acetabula using subject-specific FE modeling. METHODS: Twenty subjects were recruited and imaged: ten with normal acetabula and ten with retroverted acetabula. FE models were constructed using a validated protocol. Walking, stair ascent, stair descent and rising from a chair were simulated. Acetabular cartilage contact stress and contact area were compared between groups.
RESULTS
Retroverted acetabula had superomedial cartilage contact patterns, while normal acetabula had widely distributed cartilage contact patterns. In the posterolateral acetabulum, average contact stress and contact area during walking and stair descent were 2.6 to 7.6 times larger in normal than retroverted acetabula (p ≤ 0.017). Conversely, in the superomedial acetabulum, peak contact stress during walking was 1.2 to 1.6 times larger in retroverted than normal acetabula (p ≤ 0.044). Further differences varied by region and activity.
CONCLUSIONS
This study demonstrated superomedial contact patterns in retroverted acetabula versus widely distributed contact patterns in normal acetabula. Smaller posterolateral contact stress in retroverted acetabula than in normal acetabula suggests that increased posterior contact stress may not be the link between retroversion and OA.
doi:10.1016/j.joca.2013.06.008
PMCID: PMC3779536  PMID: 23792188
hip; cartilage mechanics; finite element; acetabular retroversion; osteoarthritis
22.  Long-term tolerance and outcomes for dose escalation in early salvage post-prostatectomy radiation therapy 
Radiation Oncology Journal  2014;32(3):179-186.
Purpose
To study the long-term outcomes and tolerance in our patients who received dose escalated radiotherapy in the early salvage post-prostatectomy setting.
Materials and Methods
The medical records of 54 consecutive patients who underwent radical prostatectomy subsequently followed by salvage radiation therapy (SRT) to the prostate bed between 2003-2010 were analyzed. Patients included were required to have a pre-radiation prostate specific antigen level (PSA) of 2 ng/mL or less. The median SRT dose was 70.2 Gy. Biochemical failure after salvage radiation was defined as a PSA level >0.2 ng/mL. Biochemical control and survival endpoints were analyzed using the Kaplan-Meier method. Univariate and multivariate Cox regression analysis were used to identify the potential impact of confounding factors on outcomes.
Results
The median pre-SRT PSA was 0.45 ng/mL and the median follow-up time was 71 months. The 4- and 7-year actuarial biochemical control rates were 75.7% and 63.2%, respectively. The actuarial 4- and 7-year distant metastasis-free survival was 93.7% and 87.0%, respectively, and the actuarial 7-year prostate cancer specific survival was 94.9%. Grade 3 late genitourinary toxicity developed in 14 patients (25.9%), while grade 4 late genitourinary toxicity developed in 2 patients (3.7%). Grade 3 late gastrointestinal toxicity developed in 1 patient (1.9%), and grade 4 late gastrointestinal toxicity developed in 1 patient (1.9%).
Conclusion
In this series with long-term follow-up, early SRT provided outcomes and toxicity profiles similar to those reported from the three major randomized trials studying adjuvant radiation therapy.
doi:10.3857/roj.2014.32.3.179
PMCID: PMC4194301  PMID: 25324990
Dose escalation; Prostate cancer; Radiation therapy; Salvage
23.  Effect of Elastin Digestion on the Quasi-static Tensile Response of Medial Collateral Ligament 
Elastin is a structural protein that provides resilience to biological tissues. We examined the contributions of elastin to the quasi-static tensile response of porcine medial collateral ligament through targeted disruption of the elastin network with pancreatic elastase. Elastase concentration and treatment time were varied to determine a dose response. Whereas elastin content decreased with increasing elastase concentration and treatment time, the change in peak stress after cyclic loading reached a plateau above 1 U/ml elastase and 6 hr treatment. For specimens treated with 2 U/ml elastase for 6 hr, elastin content decreased approximately 35%. Mean peak tissue strain after cyclic loading (4.8%, p≥0.300), modulus (275 MPa, p≥0.114) and hysteresis (20%, p≥0.553) were unaffected by elastase digestion, but stress decreased significantly after treatment (up to 2 MPa, p≤0.049). Elastin degradation had no effect on failure properties, but tissue lengthened under the same pre-stress. Stiffness in the linear region was unaffected by elastase digestion, suggesting that enzyme treatment did not disrupt collagen. These results demonstrate that elastin primarily functions in the toe region of the stress-strain curve, yet contributes load support in the linear region. The increase in length after elastase digestion suggests that elastin may pre-stress and stabilize collagen crimp in ligaments.
doi:10.1002/jor.22352
PMCID: PMC4112956  PMID: 23553827
ligament; elastin; elastase; tensile; quasi-static
24.  Manipulating the Microvasculature and Its Microenvironment 
The microvasculature is a dynamic cellular system necessary for tissue health and function. Therapeutic strategies that target the microvasculature are expanding and evolving, including those promoting angiogenesis and microvascular expansion. When considering how to manipulate angiogenesis, either as part of a tissue construction approach or a therapy to improve tissue blood flow, it is important to know the microenvironmental factors that regulate and direct neovessel sprouting and growth. Much is known concerning both diffusible and matrix-bound angiogenic factors, which stimulate and guide angiogenic activity. How the other aspects of the extravascular microenvironment, including tissue biomechanics and structure, influence new vessel formation is less well known. Recent research, however, is providing new insights into these mechanisms and demonstrating that the extent and character of angiogenesis (and the resulting new microcirculation) is significantly affected. These observations and the resulting implications with respect to tissue construction and microvascular therapy are addressed.
PMCID: PMC4096003  PMID: 24580565
angiogenesis; microvessels; microvascular orientation; microvascular remodeling; microvessel guidance; three-dimensional (3D) vascular constructs; matrix mechanics
25.  A Computational Model of In Vitro Angiogenesis based on Extracellular Matrix Fiber Orientation 
Recent interest in the process of vascularization within the biomedical community has motivated numerous new research efforts focusing on the process of angiogenesis. Although the role of chemical factors during angiogenesis has been well documented, the role of mechanical factors, such as the interaction between angiogenic vessels and the extracellular matrix, remain poorly understood. In vitro methods for studying angiogenesis exist, however measurements available using such techniques often suffer from limited spatial and temporal resolution. For this reason, computational models have been extensively employed to investigate various aspects of angiogenesis. This manuscript outlines the formulation and validation of a simple and robust computational model developed to accurately simulate angiogenesis based on length, branching, and orientation morphometrics collected from vascularized tissue constructs. Excellent agreement was observed between computational and experimental morphometric data over time. Computational predictions of microvessel orientation within an anisotropic matrix correlated well with experimental data. The accuracy of this modeling approach makes it a valuable platform for investigating the role of mechanical interactions during angiogenesis.
doi:10.1080/10255842.2012.662678
PMCID: PMC3459304  PMID: 22515707
Angiogenesis; computational model; tissue engineering; extracellular matrix; fiber orientation; matrix anisotropy

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