Turbulent blood flow in a cerebral artery with an aneurysm.

Unruptured intracranial aneurysms are common in the general population, and many uncertainties remain when predicting rupture risks and treatment outcomes. One of the cutting-edge tools used to investigate this condition is computational fluid dynamics (CFD). However, CFD is not yet mature enough to guide the clinical management of this disease. In addition, recent studies have reported significant flow instabilities when refined numerical methods are used. Questions remain as to how to properly simulate and evaluate this flow, and whether these instabilities are really turbulence. The purpose of the present study is to evaluate the impact of the simulation setup on the results and investigate the occurrence of turbulence in a cerebral artery with an aneurysm. For this purpose, direct numerical simulations were performed with up to 200 cardiac cycles and with data sampling rates of up to 100,000 times per cardiac cycle. Through phase-averaging or triple decomposition, the contributions of turbulence and of laminar pulsatile waves to the velocity, pressure and wall shear stress fluctuations were distinguished. For example, the commonly used oscillatory shear index was found to be closely related to the laminar waves introduced at the inlet, rather than turbulence. The turbulence energy cascade was evaluated through energy spectrum estimates, revealing that, despite the low flow rates and Reynolds number, the flow is turbulent near the aneurysm. Phase-averaging was shown to be an approach that can help researchers better understand this flow, although the results are highly dependent on simulation setup and post-processing choices.

Real world data on outcomes of anti-CD38 antibody treated, including triple class refractory, patients with multiple myeloma: a multi-institutional report from the Canadian Myeloma Research Group (CMRG) Database.

Multiple myeloma (MM) remains incurable despite the availability of novel agents. This multi-center retrospective cohort study used the Canadian Myeloma Research Group Database to describe real-world outcomes of patients withanti-CD38 monoclonal antibody (mAb) refractory MM subsequently treated with standard of care (SoC) regimens. Patients with triple class refractory (TCR) disease (refractory to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 mAb) were examined as a distinct cohort. Overall, 663 patients had disease progression on anti-CD38 mAb therapy, 466 received further treatment (346 with SoC regimens were included, 120 with investigational agents on clinical trial and were excluded). The median age at initiation of subsequent SoC therapy of 67.9 (range 39.6-89.6) years with a median of 3 prior lines (range 1-9). The median PFS and OS from the start of subsequent therapy was 4.6 (95% CI 4.1-5.6) months and 13.3 (95% CI 10.6-16.6) months, respectively. The median PFS and OS of patients with TCR disease (n = 199) was 4.4 (95% CI 3.6-5.3) months and 10.5 (95% CI 8.5-13.8) months. Our results reinforce that real-world patients with relapsed MM, particularly those with TCR disease, have dismal outcomes. There remains an urgent unmet need for the development of and access to effective therapeutics for these patients.

Outcomes and interventions in patients transported to hospital with ongoing CPR after out-of-hospital cardiac arrest - An observational study.

INTRODUCTION: The main objective was to present characteristics and outcome of patients without sustained field return of spontaneous circulation (ROSC) transported to hospital with ongoing cardiopulmonary resuscitation (CPR). Our secondary objectives were to investigate hospital-based interventions and the performance of the universal Termination of Resuscitation-rule (uTOR). METHODS: In this retrospective observational cohort study, out-of-hospital cardiac arrest (OHCA) patients arriving to the emergency department of a university hospital in Sweden during a six-year period (2010-2015) were identified using a prospectively recorded hospital-based registry. Additional data were retrieved from medical records and from the Swedish cardiopulmonary resuscitation registry. RESULTS: Among 409 patients transported with ongoing CPR, 7 survived to hospital discharge (1.7%). Hospital-based interventions against a suspected cause of arrest were attempted during ongoing resuscitation in 34 patients (8.3%), of whom 3 survived to hospital discharge. The remaining 4 survivors had spontaneous in-hospital ROSC. Survivors presented with either a shockable rhythm (n = 4) or pulseless electrical activity (n = 3). The uTOR identified non-survivors with a positive predictive value (PPV) of 98.4% and a specificity of 71.4% for termination. CONCLUSION: Survival after OHCA where sustained prehospital ROSC is not achieved is rare and available in-hospital interventions are rarely utilised. No patient with asystole as the first recorded rhythm survived. The uTOR identified non-survivors with a PPV of 98.4% but showed poor specificity.

An accessible pharmacodynamic transcriptional biomarker for notch target engagement.

γ-Secretase mediates amyloid production in Alzheimer's disease (AD) and oncogenic activity of Notch. γ-Secretase inhibitors (GSIs) are thus of interest for AD and oncology. A peripheral biomarker of Notch activity would aid determination of the therapeutic window and dosing regimen for GSIs, given toxicities associated with chronic Notch inhibition. This study examined the effects of GSI MK-0752 on blood and hair follicle transcriptomes in healthy volunteers. The effects of a structurally diverse GSI on rhesus blood and hair follicles were also compared. Significant dose-related effects of MK-0752 on transcription were observed in hair follicles, but not blood. The GSI biomarker identified in follicles exhibited 100% accuracy in a clinical test cohort, and was regulated in rhesus by a structurally diverse GSI. This study identified a translatable, accessible pharmacodynamic biomarker of GSI target engagement and provides proof of concept of hair follicle RNA as a translatable biomarker source.

A mathematical model and computational framework for three-dimensional chondrocyte cell growth in a porous tissue scaffold placed inside a bi-directional flow perfusion bioreactor.

The in vitro chondrocyte cell culture for cartilage tissue regeneration in a perfusion bioreactor is a complex process. Mathematical modeling and computational simulation can provide important insights into the culture process, which would be helpful for selecting culture conditions to improve the quality of the developed tissue constructs. However, simulation of the cell culture process is a challenging task due to the complicated interaction between the cells and local fluid flow and nutrient transport inside the complex porous scaffolds. In this study, a mathematical model and computational framework has been developed to simulate the three-dimensional (3D) cell growth in a porous scaffold placed inside a bi-directional flow perfusion bioreactor. The model was developed by taking into account the two-way coupling between the cell growth and local flow field and associated glucose concentration, and then used to perform a resolved-scale simulation based on the lattice Boltzmann method (LBM). The simulation predicts the local shear stress, glucose concentration, and 3D cell growth inside the porous scaffold for a period of 30 days of cell culture. The predicted cell growth rate was in good overall agreement with the experimental results available in the literature. This study demonstrates that the bi-directional flow perfusion culture system can enhance the homogeneity of the cell growth inside the scaffold. The model and computational framework developed is capable of providing significant insight into the culture process, thus providing a powerful tool for the design and optimization of the cell culture process.

Computational modelling of the scaffold-free chondrocyte regeneration: a two-way coupling between the cell growth and local fluid flow and nutrient concentration.

The in vitro chondrocyte cell culture process in a perfusion bioreactor provides enhanced nutrient supply as well as the flow-induced shear stress that may have a positive influence on the cell growth. Mathematical and computational modelling of such a culture process, by solving the coupled flow, mass transfer and cell growth equations simultaneously, can provide important insight into the biomechanical environment of a bioreactor and the related cell growth process. To do this, a two-way coupling between the local flow field and cell growth is required. Notably, most of the computational and mathematical models to date have not taken into account the influence of the cell growth on the local flow field and nutrient concentration. The present research aimed at developing a mathematical model and performing a numerical simulation using the lattice Boltzmann method to predict the chondrocyte cell growth without a scaffold on a flat plate placed inside a perfusion bioreactor. The model considers the two-way coupling between the cell growth and local flow field, and the simulation has been performed for 174 culture days. To incorporate the cell growth into the model, a control-volume-based surface growth modelling approach has been adopted. The simulation results show the variation of local fluid velocity, shear stress and concentration distribution during the culture period due to the growth of the cell phase and also illustrate that the shear stress can increase the cell volume fraction to a certain extent.

Modelling and simulation of the chondrocyte cell growth, glucose consumption and lactate production within a porous tissue scaffold inside a perfusion bioreactor.

Mathematical and numerical modelling of the tissue culture process in a perfusion bioreactor is able to provide insight into the fluid flow, nutrients and wastes transport, dynamics of the pH value, and the cell growth rate. Knowing the complicated interdependence of these processes is essential for optimizing the culture process for cell growth. This paper presents a resolved scale numerical simulation, which allows one not only to characterize the supply of glucose inside a porous tissue scaffold in a perfusion bioreactor, but also to assess the overall culture condition and predict the cell growth rate. The simulation uses a simplified scaffold that consists of a repeatable unit composed of multiple strands. The simulation results explore some problematic regions inside the simplified scaffold where the concentration of glucose becomes lower than the critical value for the chondrocyte cell viability and the cell growth rate becomes significantly reduced.

Prediction of cell growth rate over scaffold strands inside a perfusion bioreactor.

Mathematical and computational modeling of the dynamic process where tissue scaffolds are cultured in perfusion bioreactors is able to provide insight into the cell and tissue growth which can facilitate the design of tissue scaffolds and selection of optimal operating conditions. To date, a resolved-scale simulation of cell growth in the culture process, by taking account of the influences of the supply of nutrients and fluid shear stress on the cells, is not yet available in the literature. This paper presents such a simulation study specifically on cartilage tissue regeneration by numerically solving the momentum, scalar transport and cell growth equations, simultaneously, based on the lattice Boltzmann method. The simulation uses a simplified scaffold that consists of two circular strands placed in tandem inside a microchannel, with the object of identifying the effect of one strand on the other. The results indicate that the presence of the front strand can reduce the cell growth rate on the surface of the rear strand, depending on the distance between them. As such, the present study allows for investigation into the influence of the scaffold geometry on the cell growth rate within scaffolds, thus providing a means to improve the scaffold design and the culture process.

A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial.

BACKGROUND: The main objective was to study the effect on progression-free survival (PFS) of adding erlotinib to bevacizumab as maintenance treatment following chemotherapy and bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with untreated mCRC received doublet chemotherapy + bevacizumab during 18 weeks and those without tumor progression were eligible for randomization to bevacizumab + erlotinib (arm A) or bevacizumab alone (arm B), until progression or unacceptable toxic effect. RESULTS: Of the 249 patients enrolled, 80 started maintenance treatment in arm A and 79 in arm B. The rate of any grade 3/4 toxic effect was 53% in arm A and 13% in arm B. Median PFS was 5.7 months in arm A and 4.2 months in arm B (HR = 0.79; 95% confidence interval 0.55-1.12; P = 0.19). Overall survival (OS) from start of induction chemotherapy was 26.7 months in the randomized population, with no difference between the two arms. CONCLUSIONS: The addition of erlotinib to bevacizumab as maintenance treatment after first-line chemotherapy in mCRC did not improve PFS significantly. On-going clinical and translational studies focus on identifying subgroups of patients that may benefit from erlotinib in the maintenance setting. CLINICAL TRIALS NUMBER: NCT00598156.

MK-0457, an Aurora kinase and BCR-ABL inhibitor, is active in patients with BCR-ABL T315I leukemia.

MK-0457, an Aurora kinase and BCR-ABL inhibitor, was studied on a Phase I/II study in 77 patients with refractory hematologic malignancies. The average number of cycles per patient was 3 (range 1-21). Maximum tolerated doses for a 5-day short infusion and continuous infusion regimens were 40 mg/m(2)/h and 144 mg/m(2)/h, respectively. Drug-related adverse events (AEs) included transient mucositis and alopecia. Eight of 18 patients with BCR-ABL T315I-mutated chronic myelogenous leukemia (44%) had hematologic responses and one of three patients (33%) with Philadelphia chromosome-positive acute lymphoblastic leukemia obtained complete remission. MK-0457 has important activity in patients with leukemias expressing the highly resistant T315I BCR-ABL mutation.

Modeling of cell cultures in perfusion bioreactors.

Cultivating cells and tissues in bioreactors is a critical step in forming artificial tissues or organs prior to transplantation. Among various bioreactors, the perfusion bioreactor is known for its enhanced convection through the cell-scaffold constructs. Knowledge of mass transfer is essential for controlling the cell culture process; however, obtaining this information remains a challenging task. In this research, a novel mathematical model is developed to represent the nutrient transport and cell growth in a 3-D scaffold cultivated in a perfusion bioreactor. Numerical methods are employed to solve the equations involved, with a focus on identifying the effect of factors such as porosity, culturing time, and flow rate, which are controllable in the scaffold fabrication and culturing process, on cell cultures. To validate the new model, the results from the model simulations were compared to the experimental results extracted from the literature. With the validated model, further simulations were carried out to investigate the glucose and oxygen distribution and the cell growth within the cell-scaffold construct in a perfusion bioreactor, thus providing insight into the cell culture process.

Investigation of the in vitro culture process for skeletal-tissue-engineered constructs using computational fluid dynamics and experimental methods.

The in vitro culture process via bioreactors is critical to create tissue-engineered constructs (TECs) to repair or replace the damaged tissues/organs in various engineered applications. In the past, the TEC culture process was typically treated as a black box and performed on the basis of trial and error. Recently, computational fluid dynamics (CFD) has demonstrated its potential to analyze the fluid flow inside and around the TECs, therefore, being able to provide insight into the culture process, such as information on the velocity field and shear stress distribution that can significantly affect such cellular activities as cell viability and proliferation during the culture process. This paper briefly reviews the CFD and experimental methods used to investigate the in vitro culture process of skeletal-type TECs in bioreactors, where mechanical deformation of the TEC can be ignored. Specifically, this paper presents CFD modeling approaches for the analysis of the velocity and shear stress fields, mass transfer, and cell growth during the culture process and also describes various particle image velocimetry (PIV) based experimental methods to measure the velocity and shear stress in the in vitro culture process. Some key issues and challenges are also identified and discussed along with recommendations for future research.

Paclitaxel, Epirubicin and Capecitabine (TEX) as First-Line Treatment for Metastatic Breast Cancer: a Pilot Phase I/II Feasibility Study.

Thirteen patients with untreated metastatic breast cancer received epirubicin 60 mg/m(2), paclitaxel 155 mg/m(2) (both day 1) and capecitabine 665 mg/m(2) twice daily (days 1-14) every 21 days, with intra-patient dose escalation/reduction. Grade 3/4 events were infrequent. Nine patients (69%) achieved an objective response. Median time to progression and overall survival were 6.6 and 23.5 months, respectively.

Validation of large-scale, monochromatic UV disinfection systems for drinking water using dyed microspheres.

Dyed microspheres have been developed as a new method for validation of ultraviolet (UV) reactor systems. When properly applied, dyed microspheres allow measurement of the UV dose distribution delivered by a photochemical reactor for a given operating condition. Prior to this research, dyed microspheres had only been applied to a bench-scale UV reactor. The goal of this research was to extend the application of dyed microspheres to large-scale reactors. Dyed microsphere tests were conducted on two prototype large-scale UV reactors at the UV Validation and Research Center of New York (UV Center) in Johnstown, NY. All microsphere tests were conducted under conditions that had been used previously in biodosimetry experiments involving two challenge bacteriophage: MS2 and Qbeta. Numerical simulations based on computational fluid dynamics and irradiance field modeling were also performed for the same set of operating conditions used in the microspheres assays. Microsphere tests on the first reactor illustrated difficulties in sample collection and discrimination of microspheres against ambient particles. Changes in sample collection and work-up were implemented in tests conducted on the second reactor that allowed for improvements in microsphere capture and discrimination against the background. Under these conditions, estimates of the UV dose distribution from the microspheres assay were consistent with numerical simulations and the results of biodosimetry, using both challenge organisms. The combined application of dyed microspheres, biodosimetry, and numerical simulation offers the potential to provide a more in-depth description of reactor performance than any of these methods individually, or in combination. This approach also has the potential to substantially reduce uncertainties in reactor validation, thereby leading to better understanding of reactor performance, improvements in reactor design, and decreases in reactor capital and operating costs.

Absorptance of nonferrous alloys to Nd:YLF and Nd:YAG laser light at room temperature.

The measurement of absorptance is important for the analysis and modeling of laser-material interactions. Unfortunately, most of the absorptance data currently available consider only polished pure metals rather than the commercially available (unpolished, oxidized) alloys that are actually being processed in manufacturing. We present the results of absorptance measurements carried out at room temperature on as-received engineering grade nonferrous metals (Al, Cu, and Zn alloys). The measurements were made using an integrating sphere with a Nd:YLF laser at two wavelengths (1053 and 527 nm, which means that the results are also valid for Nd:YAG radiation at 1064 and 532 nm). The absorptance results obtained differ considerably from the existing data for polished, pure metals and should help improve the accuracy of laser-material interaction models. Some clear trends were identified. For all 22 cases studied the absorptance was higher than for ideal pure, polished metals. For all Al and Cu samples the absorptance was higher for the green than it was for the infrared wavelength, while for all Zn coatings this trend was reversed. No clear correlation between absorptance and surface roughness was found at low roughness values (Sa 0.15-0.60), but one rougher set of samples (Sa 2.34) indicated a roughness-absorptance correlation at higher roughness levels.

Phase relationships support a role for coordinated activity in the indirect pathway in organizing slow oscillations in basal ganglia output after loss of dopamine.

The goal of the present study was to determine the phase relationships of the slow oscillatory activity that emerges in basal ganglia nuclei in anesthetized rats after dopamine cell lesion in order to gain insight into the passage of this oscillatory activity through the basal ganglia network. Spike train recordings from striatum, subthalamic nucleus (STN), globus pallidus (GP), and substantia nigra pars reticulata (SNpr) were paired with simultaneous local field potential (LFP) recordings from SNpr or motor cortex ipsilateral to a unilateral lesion of substantia nigra dopamine neurons in urethane-anesthetized rats. Dopamine cell lesion induced a striking increase in incidence of slow oscillations (0.3-2.5 Hz) in firing rate in all nuclei. Phase relationships assessed through paired recordings using SNpr LFP as a temporal reference showed that slow oscillatory activity in GP spike trains is predominantly antiphase with oscillations in striatum, and slow oscillatory activity in STN spike trains is in-phase with oscillatory activity in cortex but predominantly antiphase with GP oscillatory activity. Taken together, these results imply that after dopamine cell lesion in urethane-anesthetized rats, increased oscillatory activity in GP spike trains is shaped more by increased phasic inhibitory input from the striatum than by phasic excitatory input from STN. In addition, results show that oscillatory activity in SNpr spike trains is typically antiphase with GP oscillatory activity and in-phase with STN oscillatory activity. While these observations do not rule out additional mechanisms contributing to the emergence of slow oscillations in the basal ganglia after dopamine cell lesion in the anesthetized preparation, they are compatible with 1) increased oscillatory activity in the GP facilitated by an effect of dopamine loss on striatal 'filtering' of slow components of oscillatory cortical input, 2) increased oscillatory activity in STN spike trains supported by convergent antiphase inhibitory and excitatory oscillatory input from GP and cortex, respectively, and 3) increased oscillatory activity in SNpr spike trains organized by convergent antiphase inhibitory and excitatory oscillatory input from GP and STN, respectively.

Correlated multisecond oscillations in firing rate in the basal ganglia: modulation by dopamine and the subthalamic nucleus.

Previous studies from this laboratory have shown that many neurons in the basal ganglia have multisecond (<0.5 Hz) periodicities in firing rate in awake rats. The frequency and regularity of these oscillations are significantly increased by systemically injected dopamine (DA) agonists. Because oscillatory activity should have greater functional impact if shared by many neurons, the level of correlation of multisecond oscillations was assessed by recording pairs of neurons in the globus pallidus and substantia nigra pars reticulata in the same hemisphere, or pairs of globus pallidus neurons in opposite hemispheres in awake, immobilized rats. Cross-correlation (90-180 s lags) and spectral analysis were used to characterize correlated oscillations. Thirty-eight percent of pairs recorded in baseline (n=50) demonstrated correlated multisecond oscillations. Phase relationships were near 0 or 180 degrees. DA agonist injection significantly increased the incidence of correlation (intra- and interhemispheric) to 94% (n=17). After DA agonist injection, phase relationships of globus pallidus/substantia nigra neuron pairs were exclusively concentrated near 180 degrees, and phases of interhemispheric pairs of globus pallidus neurons were concentrated near 0 degrees. After subthalamic nucleus lesion (n=8), the incidence of correlated multisecond oscillations (or of multisecond oscillations per se) was not changed, although the consistent phase relationship between the globus pallidus and substantia nigra pars reticulata was disrupted. Subthalamic lesion also blocked apomorphine-induced decreases in oscillatory period and increases in oscillation amplitude, and significantly attenuated apomorphine-induced changes in mean firing rate. The data demonstrate that multisecond oscillations in the basal ganglia can be correlated between nuclei, and that DA receptor activation increases the level of correlation and organizes internuclear phase relationships at these multisecond time scales. While the subthalamic nucleus is not necessary for generating or transmitting these slow oscillations, it is involved in DA agonist-induced modulation of mean firing rate, oscillatory period, and internuclear phase relationship. These data further support a role for DA in modulating coherent oscillatory activity in the basal ganglia, and for the subthalamic nucleus in shaping the effects of DA receptor stimulation on basal ganglia output.

How to MEK muscle.

Myogenesis is inhibited by receptor activation of Ras through the MEK and ERK kinases, but the underlying mechanism is unclear. In this issue of Molecular Cell, Perry et al. show that activated MEK1 forms an inhibitory complex with myogenic transcription factors in the nucleus.