An Open-Source Mesh Generation Platform for Biophysical Modeling Using Realistic Cellular Geometries.

Advances in imaging methods such as electron microscopy, tomography, and other modalities are enabling high-resolution reconstructions of cellular and organelle geometries. Such advances pave the way for using these geometries for biophysical and mathematical modeling once these data can be represented as a geometric mesh, which, when carefully conditioned, enables the discretization and solution of partial differential equations. In this work, we outline the steps for a naïve user to approach the Geometry-preserving Adaptive MeshER software version 2, a mesh generation code written in C++ designed to convert structural data sets to realistic geometric meshes while preserving the underlying shapes. We present two example cases: 1) mesh generation at the subcellular scale as informed by electron tomography and 2) meshing a protein with a structure from x-ray crystallography. We further demonstrate that the meshes generated by the Geometry-preserving Adaptive MeshER software are suitable for use with numerical methods. Together, this collection of libraries and tools simplifies the process of constructing realistic geometric meshes from structural biology data.

The Implementation of the Colored Abstract Simplicial Complex and its Application to Mesh Generation.

We introduce CASC: a new, modern, and header-only C++ library which provides a data structure to represent arbitrary dimension abstract simplicial complexes (ASC) with user-defined classes stored directly on the simplices at each dimension. This is accomplished by using the latest C++ language features including variadic template parameters introduced in C++11 and automatic function return type deduction from C++14. Effectively CASC decouples the representation of the topology from the interactions of user data. We present the innovations and design principles of the data structure and related algorithms. This includes a metadata aware decimation algorithm which is general for collapsing simplices of any dimension. We also present an example application of this library to represent an orientable surface mesh.

Statin use in cancer patients with brain metastases: a missed communication opportunity at the end of life.

PURPOSE: Preventive care, referring to medical interventions with anticipated long-term benefits, is often inappropriately continued near the end of life. We examined the use of statin medications in patients with brain metastases receiving whole brain radiation therapy to determine the effect of short life expectancy and regular interaction with oncology providers on statin discontinuation. We propose reasons for the unnecessary continuation of preventive care and suggest that it is a frequently missed communication opportunity to discuss prognosis in a concrete manner. METHODS: This is a retrospective study examining statin use in patients receiving whole brain radiotherapy for brain metastases. A total of 206 patients at two cancer centers were studied, and information on statin use and clinical characteristics was obtained from review of the medical record. RESULTS: Of the 206 patients, 53 (26 %) were on a statin at their initial radiation oncology consultation. Of these patients, 13 (25 %) had their statin discontinued by the time of their last follow-up visit, but 40 patients (75 %) were continued on their statin despite their limited life expectancy and low likelihood of benefit. CONCLUSIONS: The majority of patients who were on statins prior to starting palliative whole brain radiation therapy remained on a statin after completing treatment despite an estimated survival of months and regular visits with an oncologist. This represents a missed opportunity for doctors and patients to discuss the appropriateness of continuing preventive care as part of an important conversation about prognosis.

Post-fire temporal trends in soil-physical and -hydraulic properties and simulated runoff generation: Insights from different burn severities in the 2013 Black Forest Fire, CO, USA.

Burn severity influences on post-fire recovery of soil-hydraulic properties controlling runoff generation are poorly understood despite the importance for parameterizing infiltration models. We measured soil-hydraulic properties of field-saturated hydraulic conductivity (Kfs), sorptivity (S), and wetting front potential (ψf) for four years after the 2013 Black Forest Fire, Colorado, USA, at six sites across a gradient of initial remotely sensed burn severity using the change in the normalized burn ratio (dNBR). These measurements were correlated with soil-physical property measurements of bulk density (ρb), loss on ignition (LOI, a measure of soil organic matter), and ground cover composition to provide insight into causal factors for temporal changes in Kfs, S, and ψf. Modeled infiltration using the Smith-Parlange approach parameterized with measured Kfs, S, and ψf further discerned the role of precipitation intensity on runoff generation. Temporal trends of soil-physical properties and ground cover showed influences from initial burn severity. Trends in soil-hydraulic properties, surprisingly, were not strongly influenced by initial burn severity despite inferred effects of ρb, LOI, and ground cover on trends in Kfs and S. Calculations of dNBR at the time of sampling showed strong correlations with Kfs and S, demonstrating a new approach for estimating long-unburned Kfs and S values, infiltration model parameters after fire, and assessing the time of return to pre-fire values. Simulated infiltration-excess runoff, in contrast, did depend on initial burn severity. Time series of the ratio S2/Kfs ≈ ψf tended to converge between 1 and 10 mm four years after wildfire, potentially (i) defining a long-unburned forest domain of S2/Kfs and ψf from 1 to 10 mm with relatively high Kfs values, and (ii) providing a new post-fire soil-hydraulic property recovery metric (i.e. S2/Kfs ≈ ψf in the range of 1 to 10 mm) for sites in the Rocky Mountains of the USA.

Dynamics of laser-generated magnetic fields using long laser pulses.

We report on the experimental investigation of magnetic field generation with a half-loop gold sheet coil driven by long-duration (10 ns) and high-power (0.5 TW) laser pulses. The amplitude of the magnetic field was characterized experimentally using proton deflectometry. The field rises rapidly in the first 1 ns of laser irradiation, and then increases slowly and continuously up to 10 ns during further laser irradiation. The transient dynamics of current shape were investigated with a two-dimensional (2D) numerical simulation that included Ohmic heating of the coil and the resultant change of electrical resistivity determined by the coil material temperature. The numerical simulations show rapid heating at the coil edges by current initially localized at the edges. This current density then diffuses to the central part of the sheet coil in a way that depends both on normal current diffusion as well as temporal changes of the coil resistance induced by the Ohmic heating. The measured temporal evolution of the magnetic field is compared with a model that determines a solution to the coil current and voltage that is consistent with a plasma diode model of the drive region and a 2D simulation of current diffusion and dynamic resistance due to Ohmic heating in the laser coil.

A new tri-particle backlighter for high-energy-density plasmas (invited).

A new tri-particle mono-energetic backlighter based on laser-driven implosions of DT3He gas-filled capsules has been implemented at the OMEGA laser. This platform, an extension of the original D3He backlighter platform, generates 9.5 MeV deuterons from the T3He reaction in addition to 14.7 and 3.0 MeV protons from the deuterium and helium-3 reactants. The monoenergetic 14.7 and 3.0 MeV protons have been used with success at OMEGA and the NIF for both radiography and stopping-power studies. There are several advantages of having a third particle to diagnose plasma conditions: an extra time-of-flight-separated radiograph and an improved ability to discern between electric and magnetic fields. In cases where the 3.0 MeV protons cannot penetrate an experiment, the benefit of the additional 9.5 MeV deuterons is magnified. This capability is well-suited for NIF experiments, where large fields and plasma densities often preclude useful 3.0 MeV proton data. The advantages are demonstrated with radiographs of OMEGA plasmas with magnetic and electric fields. Tests using backlighter-scale 420 µm diameter thin glass capsules validate the platform's extended backlighting capability. The performance characteristics of this backlighter, such as source size and timing, are discussed.

Adult gliosarcoma: epidemiology, natural history, and factors associated with outcome.

The epidemiology and natural history of adult gliosarcomas (GSMs), as well as patient and treatment factors associated with outcome, are ill defined. Patients over 20 years of age with GSM diagnosed from 1988 to 2004 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier survival analysis and Cox models were used to examine outcomes. Similar analyses were conducted for patients diagnosed with glioblastoma (GBM) over the same time period. GSM represented 2.2% of the 16,388 patients identified with either GSM or GBM. No significant differences between GSM and GBM were identified with respect to age, gender, race, tumor size, or use of adjuvant radiation therapy (RT). Patients with GSM were more likely to have temporal lobe involvement and undergo some form of tumor resection. The most important analyzed factors influencing GSM overall survival were age, extent of resection, and use of adjuvant RT. After adjusting for factors impacting overall survival, the prognosis for GSM appears slightly worse than for GBM (HR = 1.17, 95% CI, 1.05-1.31). GSM is a rare malignancy that presents very similarly to GBM with a slightly greater propensity for temporal lobe involvement. Optimal treatment remains to be defined. However, these retrospective findings suggest tumor excision, as opposed to biopsy only, and adjuvant RT may improve outcome. Despite therapy, prognosis remains dismal and outcomes may be inferior to those seen in GBM patients.

Adjuvant radiotherapy for pancreatic cancer is associated with a survival benefit primarily in stage IIB patients.

BACKGROUND: The role of adjuvant radiotherapy (RT) for pancreatic cancer remains controversial despite the completion of three multi-institutional randomized trials. This study examines the survival impact of postoperative RT in a large population-based database. METHODS: Patients with pancreatic cancer diagnosed from 1988 to 2003 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. The cohort was limited to patients who underwent resection of nonmetastatic disease to yield a population of 3252 patients. The primary end point was overall survival. Survival analyses were conducted using corrections for perioperative mortality as well as a propensity score analysis to account for baseline differences in patient characteristics. RESULTS: Multiple independent factors were associated with RT use, including patient age and disease stage (P < 0.0001). In general, younger patients and those with more advanced disease were more likely to receive RT. Disease stage significantly affected survival (P < 0.0001). For patients who survived at least 6 months, adjuvant RT was associated with increased survival [hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.80-0.96]. On subgroup analysis, only stage IIB (T1-3N1) patients enjoyed a statistically significant benefit associated with RT (HR, 0.70; 95% CI, 0.62-0.79). CONCLUSIONS: Adjuvant RT is frequently given to patients in the United States after resection of their pancreatic cancer. Although RT is associated with a survival benefit for nonmetastatic patients as a whole, this trend appears to predominantly derive from a survival benefit in patients with stage IIB disease.

A comprehensive approach to managing a neglected, neglected tropical disease; The Myanmar Snakebite Project (MSP).

Snakebite is predominantly an occupational disease affecting poor rural farmers in tropical regions and was recently added to the World Health Organisation list of Neglected Tropical Diseases (NTD). We document an overview of methodologies developed and deployed in the Myanmar Snakebite Project, a foreign aid project largely funded by the Australian Government, with the core aim to "improve outcomes for snakebite patients". A multidisciplinary team of experts was assembled that worked in a collaborative manner with colleagues in Myanmar, first to identify problems related to managing snakebite and then develop interventions aimed to improve selected problem areas. A broad approach was adopted, covering antivenom production, antivenom distribution and health system management of snakebite. Problems identified in antivenom production included poor snake husbandry resulting in poor survival of captive specimens, lack of geographical diversity; poor horse husbandry, resulting in high mortality, inadequate stock acquisition protocols and data collection, and inappropriate immunisation and bleeding techniques; and inadequate production capacity for freeze dried antivenoms and quality control systems. These problems were addressed in various ways, resulting in some substantial improvements. Antivenom distribution is being reorganised to achieve better availability and utilisation of stock. Health system management of snakebite was assessed across all levels within the area selected for the study, in Mandalay region. A comprehensive community survey indicated that hospital statistics substantially underestimated the snakebite burden, and that access to care by local villagers was delayed by transport and cost issues compounded by lack of antivenom at the most peripheral level of the health service. A health system survey confirmed under-resourcing at the local village level. Prospective case data collection initiated at tertiary hospitals indicated the extent of the snakebite burden on health resources. Interventions initiated or planned include training of health staff, development of a core of senior trainers who can "train the trainers" nationwide in a sustainable way, development and deployment of management guidelines and algorithms for snakebite and a distribution of solar powered fridges to remote health facilities to allow storage of antivenom and prompt treatment of snakebite cases before transfer to major hospitals, thereby reducing the "bite to needle" time.

The survival impact of the intergroup 0116 trial on patients with gastric cancer.

PURPOSE: The Intergroup 0116 (INT 0116) trial demonstrated a survival benefit for a broad group of fully resected gastric cancer patients. This study examined the impact on survival of the release of this landmark trial. METHODS AND MATERIALS: Patients with gastric carcinoma diagnosed between 1995 and 2004 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Patients from the overall population as well as those potentially eligible for the INT 0116 trial were classified as having been diagnosed either before (1995-1999) or after (2000-2004) this trial. Both Kaplan-Meier survival analysis and Cox models were used to examine survival trends within these cohorts. RESULTS: For the overall population of 22,982 patients, the use of radiotherapy (RT) significantly changed after the INT 0116 trial (p < 0.0001), with postoperative RT increasing from 6.5% to 13.3%. For the two periods of interest, overall survival significantly improved in recent years (p = 0.00008). A similar improvement was also seen for patients who were potentially eligible for the INT 0116 trial (p = 0.004), with 3-year survival rates improving from 32.2% to 34.5%. On both univariate and multivariate analysis, use of RT was associated with a significant survival improvement (HR, 0.65 [0.48-0.88]; p = 0.005). CONCLUSION: Use of postoperative RT for gastric cancer has significantly increased after the release of the INT 0116 trial, likely reflecting increased use of adjuvant chemoradiotherapy. This change has been associated with improved survival in gastric cancer patients, suggesting that the improved outcome seen in this trial has been successfully translated to the community.

The impact of T and N stage on long-term survival of rectal cancer patients in the community.

BACKGROUND AND OBJECTIVES: Use of the TNM staging system has been encouraged for rectal cancer patients. This study examined the impact of T and N stages on long-term survival as well as the performance of associated risk classification systems. METHODS: Patients who underwent surgery for rectal adenocarcinoma from 1988 to 2004 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier survival analysis was performed for subgroups of patients defined by T and N stage. RESULTS: For the overall population of 30,826 patients, both T and N stage significantly impacted overall survival (P < 0.001). N stage variably affected survival for subgroups of patients based on T stage, whereas T stage significantly affected survival regardless of N stage. A previously developed risk classification system that assigns one of four risk levels outperformed AJCC group staging in this cohort. Based on long-term outcomes, a modified risk classification system was constructed which was highly prognostic for long-term overall survival (P < 0.001). CONCLUSIONS: Rectal cancer patients experience widely varying survival rates based on extent of disease. A new risk classification system is proposed that provides better prognostic information than AJCC group staging, suggesting current rectal cancer staging systems may be improved with appropriate revisions.

Mutations of the PU.1 Ets domain are specifically associated with murine radiation-induced, but not human therapy-related, acute myeloid leukaemia.

Murine radiation-induced acute myeloid leukaemia (AML) is characterized by loss of one copy of chromosome 2. Previously, we positioned the critical haematopoietic-specific transcription factor PU.1 within a minimally deleted region. We now report a high frequency (>65%) of missense mutation at codon 235 in the DNA-binding Ets domain of PU.1 in murine AML. Earlier studies, outside the context of malignancy, determined that conversion of arginine 235 (R235) to any other amino-acid residue leads to ablation of DNA-binding function and loss of expression of downstream targets. We show that mutation of R235 does not lead to protein loss, and occurs specifically in those AMLs showing loss of one copy of PU.1 (P=0.001, Fisher's exact test). PU.1 mutations were not found in the coding region, UTRs or promoter of human therapy-related AMLs. Potentially regulatory elements upstream of PU.1 were located but no mutations found. In conclusion, we have identified the cause of murine radiation-induced AML and have shown that loss of one copy of PU.1, as a consequence of flanking radiation-sensitive fragile domains on chromosome 2, and subsequent R235 conversion are highly specific to this mouse model. Such a mechanism does not operate, or is extremely rare, in human AML.

Adenoma multiplicity in irradiated Apc(Min) mice is modified by chromosome 16 segments from BALB/c.

Ionizing radiation (IR) is a well-characterized carcinogen in humans and mice. The BALB/c mouse strain is unusually sensitive to IR-induced tissue damage and cancer development in a range of organs, suggestive of a partial defect in DNA damage response. This has been confirmed by finding BALB/c-specific functional polymorphism in Prkdc, a gene on mouse chromosome 16 that encodes the catalytic subunit of DNA-dependent protein kinase. Prkdc(BALB) has been associated with increased susceptibility to IR-induced mammary and lymphatic neoplasia. Here, we provide evidence that chromosome 16 segments from BALB/c interact with Apc(Min) (multiple intestinal neoplasia) and specifically enhance IR-induced adenoma development in the upper part of the small intestine.

Gastrointestinal bleeding associated with concurrent capecitabine and radiotherapy in patients with pancreatic cancer.

CONTEXT: Capecitabine is currently being evaluated for the treatment of a variety of gastrointestinal malignancies. OBJECTIVE: The aim of this study is to report on the incidence of late gastrointestinal bleeding in patients with pancreatic cancer who received concurrent capecitabine and abdominal irradiation followed by prolonged capecitabine therapy. PATIENTS: We reviewed the medical records of 24 patients (13 female, 11 males; median age of 64.5 years): 22 cases of adenocarcinoma and 2 cases of neuroendocrine carcinoma. Initially, 4 patients underwent surgical resection. Median follow-up was 10.3 months. INTERVENTIONS: Patients received capecitabine (600-800 mg/m2 orally twice daily) with concurrent radiation (50.4-54.0 Gy). Patients who were resected received an additional 2-4 cycles of capecitabine; otherwise, capecitabine was given indefinitely until disease progression occurred. MAIN OUTCOME MEASURE: Incidence of late gastrointestinal bleeding. RESULTS: Three patients developed gastro-intestinal bleeding after concurrent capecitabine and irradiation and 2 of these patients died as a result of this toxicity. CONCLUSIONS: Our study indicates that serious gastrointestinal bleeding is a possible late complication associated with concurrent capecitabine and irradiation therapy for pancreatic cancer followed by additional capecitabine therapy. Caution and close monitoring should therefore be used when continuing capecitabine therapy in this setting.

Development of the Ion Exchange-Gravimetric Method for Sodium in Serum as a Definitive Method.

An ion exchange-gravimetric method, previously developed as a National Committee for Clinical Laboratory Standards (NCCLS) reference method for the determination of sodium in human serum, has been re-evaluated and improved. Sources of analytical error in this method have been examined more critically and the overall uncertainties decreased. Additionally, greater accuracy and repeatability have been achieved by the application of this definitive method to a sodium chloride reference material. In this method sodium in serum is ion-exchanged, selectively eluted and converted to a weighable precipitate as Na2SO4. Traces of sodium eluting before or after the main fraction, and precipitate contaminants are determined instrumentally. Co-precipitating contaminants contribute less than 0.1 % while the analyte lost to other eluted ion-exchange fractions contributes less than 0.02 % to the total precipitate mass. With improvements, the relative expanded uncertainty (k = 2) of the method, as applied to serum, is 0.3 % to 0.4 % and is less than 0.1 % when applied to a sodium chloride reference material.

Angiosarcoma outcomes and prognostic factors: a 25-year single institution experience.

OBJECTIVE: Angiosarcoma is an aggressive malignancy with endothelial differentiation and notoriously poor prognosis despite aggressive therapy. Limited data are available to guide management decisions. To address this limitation, we present a large retrospective analysis of angiosarcoma patients treated at a single institution over a 25-year period. METHODS: To identify factors that impact angiosarcoma outcomes, we reviewed demographic, tumor, and treatment characteristics of angiosarcoma patients evaluated at the University of Wisconsin Hospital between 1987 and 2012. RESULTS: The cohort included 81 patients diagnosed at ages 19 to 90 years (median, 67 y). Fifty-five (68%) patients presented with localized disease, whereas 26 (32%) presented with metastases. The primary sites were visceral/deep soft tissue (42%), head and neck/cutaneous (37%), breast (16%), and limbs in the setting of Stewart-Treves (5%). The 5-year overall survival was 40% with a median of 16 months. By univariate analysis, significant adverse predictors of survival included metastases at presentation, visceral/deep soft tissue tumor location, tumor size > 5 cm, tumor necrosis, and the absence of surgical excision. A trend toward prolonged survival was observed with radiation therapy and for chemotherapy in patients with metastases. Age, sex, and prior radiation showed no correlation with survival. CONCLUSIONS: Our large single institution series confirms the poor prognosis of angiosarcoma, supports a central role for surgical excision in management, and highlights the need for novel therapies particularly in patients who present with metastatic disease.

Bladder preservation for localized muscle-invasive bladder cancer: the survival impact of local utilization rates of definitive radiotherapy.

PURPOSE: This study examines the management and outcomes of muscle-invasive bladder cancer in the United States. METHODS AND MATERIALS: Patients with muscle-invasive bladder cancer diagnosed between 1988 and 2006 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Patients were classified according to three mutually exclusive treatment categories based on the primary initial treatment: no local management, radiotherapy, or surgery. Overall survival was assessed with Kaplan-Meier analysis and Cox models based on multiple factors including treatment utilization patterns. RESULTS: The study population consisted of 26,851 patients. Age, sex, race, tumor grade, histology, and geographic location were associated with differences in treatment (all p < 0.01). Patients receiving definitive radiotherapy tended to be older and have less differentiated tumors than patients undergoing surgery (RT, median age 78 years old and 90.6% grade 3/4 tumors; surgery, median age 71 years old and 77.1% grade 3/4 tumors). No large shifts in treatment were seen over time, with most patients managed with surgical resection (86.3% for overall study population). Significant survival differences were observed according to initial treatment: median survival, 14 months with no definitive local treatment; 17 months with radiotherapy; and 43 months for surgery. On multivariate analysis, differences in local utilization rates of definitive radiotherapy did not demonstrate a significant effect on overall survival (hazard ratio, 1.002; 95% confidence interval, 0.999-1.005). CONCLUSIONS: Multiple factors influence the initial treatment strategy for muscle-invasive bladder cancer, but definitive radiotherapy continues to be used infrequently. Although patients who undergo surgery fare better, a multivariable model that accounted for patient and tumor characteristics found no survival detriment to the utilization of definitive radiotherapy. These results support continued research into bladder preservation strategies and suggest that definitive radiotherapy represents a viable initial treatment strategy for those who wish to attempt to preserve their native bladder.

Efficacy of Tie2 receptor antagonism in angiosarcoma.

Angiosarcomas are malignant endothelial cell tumors with few effective systemic treatments. Despite a unique endothelial origin, molecular candidates for targeted therapeutic intervention have been elusive. In this study, we explored the tunica internal endothelial cell kinase 2 (Tie2) receptor as a potential therapeutic target in angiosarcoma. Human angiosarcomas from diverse sites were shown to be universally immunoreactive for Tie2. Tie2 and vascular endothelial growth factor receptor (VEGFR) antagonists inhibited SVR and MS1-VEGF angiosarcoma cell survival in vitro. In the high-grade SVR cell line, Tie2 and VEGF antagonists inhibited cell survival synergistically, whereas effects were largely additive in the low-grade MS1-VEGF cell line. Xenograft modeling using these cell lines closely recapitulated the human disease. In vivo, Tie2 and VEGFR inhibition resulted in significant angiosarcoma growth delay. The combination proved more effective than either agent alone. Tie2 inhibition seemed to elicit tumor growth delay through increased tumor cell apoptosis, whereas VEGFR inhibition reduced tumor growth by lowering tumor cell proliferation. These data identify Tie2 antagonism as a potential novel, targeted therapy for angiosarcomas and provide a foundation for further investigation of Tie2 inhibition, alone and in combinations, in the management of this disease.