Finite element modeling of 3D human mesenchymal stem cell-seeded collagen matrices exposed to tensile strain

The use of human mesenchymal stem cells (hMSCs) in tissue engineering is attractive due to their ability to extensively self-replicate and differentiate into a multitude of cell lineages. It has been experimentally established that hMSCs are influenced by chemical and mechanical signals. However, the combined chemical and mechanical in vitro culture conditions that lead to functional tissue require greater understanding. In this study, finite element models were created to evaluate the local loading conditions on bone marrow derived hMSCs seeded in three dimensional collagen matrices exposed to cyclic tensile strain. Mechanical property and geometry data used in the models were obtained experimentally from a previous study in our laboratory and from mechanical testing. Eight finite element models were created to simulate three-dimensional hMSC-seeded collagen matrices exposed to different levels of cyclic tensile strain (10% and 12%), culture media (complete growth and osteogenic differentiating), and durations of culture (7 and 14 days). Through finite element analysis, it was determined that globally applied uniaxial tensile strains of 10% and 12% resulted in local strains up to 18.3% and 21.8%, respectively. Model results were also compared to experimental studies in an attempt to explain observed differences between hMSC response to 10% and 12% cyclic tensile strain

Computational micromagnetics with Commics

We present our open-source Python module Commics for the study of the magnetization dynamics in ferromagnetic materials via micromagnetic simulations. It implements state-of-the-art unconditionally convergent finite element methods for the numerical integration of the Landau–Lifshitz–Gilbert equation. The implementation is based on the multiphysics finite element software Netgen/NGSolve. The simulation scripts are written in Python, which leads to very readable code and direct access to extensive post-processing. Together with documentation and example scripts, the code is freely available on GitLab. Program summary: Program title: Commics Program Files doi: http://dx.doi.org/10.17632/29wv9h78h7.1 Licensing provisions: GPLv3 Programming language: Python3 Nature of problem: Numerical integration of the Landau–Lifshitz–Gilbert equation in three space dimensions Solution method: Tangent plane scheme [1]: original first-order version, projection-free version, second-order version, efficient second-order IMEX version; Midpoint scheme [2]: original version, IMEX version; Magnetostatic Maxwell equations are treated by the hybrid FEM–BEM method [3] Additional comments including restrictions and unusual features: An installation of the finite element software Netgen/NGSolve and an installation of the boundary element library BEM++ are required. References [1] F. Alouges. A new finite element scheme for Landau–Lifchitz equations. Discrete Contin. Dyn. Syst. Ser. S, 1(2):187–196, 2008. [2] S. Bartels and A. Prohl. Convergence of an implicit finite element method for the Landau–Lifshitz–Gilbert equation. SIAM J. Numer. Anal., 44(4):1405–1419, 2006. [3] D. R. Fredkin and T. R. Koehler. Hybrid method for computing demagnetization fields. IEEE Trans. Magn., 26(2):415–417, 1990

Conservation risks and benefits of establishing monarch butterfly (Danaus plexippus) breeding habitats close to maize and soybean fields in the north central United States: A landscape‐scale analysis of the impact of foliar insecticide on nonmigratory monarch butterfly populations

Establishing habitat in agricultural landscapes of the north central United States is critical to reversing the decline of North America\u27s eastern monarch butterfly (Danaus plexippus) population. Insecticide use could create population sinks and threaten recovery. Discouraging habitat establishment within a 38‐m zone around crop fields is a suggested risk mitigation measure. In Story County, Iowa, United States, this mitigation would discourage habitat establishment in 84% of roadsides and 38% of noncrop land. It is unclear if the conservation benefits from establishing habitat close to crop fields outweigh suppression of population growth owing to insecticide exposure. Consequently, monarch conservation plans require spatially and temporally explicit landscape‐scale assessments. Using an agent‐based model that incorporates female monarch movement and egg laying, the number and location of eggs laid in Story County were simulated for four habitat scenarios: current condition, maximum new establishment, moderate establishment, and moderate establishment only outside a 38‐m no‐plant zone around crop fields. A demographic model incorporated mortality from natural causes and insecticide exposure to simulate adult monarch production over 10 years. Assuming no insecticide exposure, simulated adult production increased 24.7% and 9.3%, respectively, with maximum and moderate habitat establishment and no planting restrictions. A 3.5% increase was simulated assuming moderate habitat establishment with a 38‐m planting restriction. Impacts on adult production were simulated for six representative insecticides registered for soybean aphid (Aphis glycines) management. Depending on the frequency of insecticide applications over a 10‐year period, simulated production increased 8.2%–9.3%, assuming moderate habitat establishment with no planting restrictions. Results suggest that the benefits of establishing habitat close to crop fields outweigh the adverse effects of insecticide spray drift; that is, metapopulation extirpation is not a concern for monarchs. These findings are only applicable to species that move at spatial scales greater than the scale of potential spray‐drift impacts

Genetic background influences fluoride's effects on osteoclastogenesis

Excessive fluoride (F) can lead to abnormal bone biology. Numerous studies have focused on the anabolic action of F yet little is known regarding any action on osteoclastogenesis. Little is known regarding the influence of an individual’s genetic background on the responses of bone cells to F. Four-week old C57BL/6J (B6) and C3H/HeJ (C3H) female mice were treated with NaF in the drinking water (0ppm, 50ppm and 100ppm F ion) for 3 weeks. Bone marrow cells were harvested for osteoclastogenesis and hematopoietic colony-forming cell assays. Sera were analyzed for biochemical and bone markers. Femurs, tibiae and lumbar vertebrae were subjected to microCT analysis. Tibiae and femurs were subjected to histology and biomechanical testing, respectively. The results demonstrated new actions of F on osteoclastogenesis and hematopoietic cell differentiation. Strain specific responses were observed. The anabolic action of F was favored in B6 mice exhibiting dose dependent increases in serum ALP activity (p < 0.001); in proximal tibia trabecular and vertebral BMD (tibia at 50&100ppm, p = 0.001; vertebrae at 50&100ppm, p = 0.023&0.019, respectively); and decrease in intact PTH and sRANKL (p = 0.045 and p < 0.001, respectively). F treatment in B6 mice also resulted in increased numbers of CFU-GEMM colonies (p = 0.025). Strain specific accumulations in bone [F] were observed. For C3H mice, dose dependent increases were observed in osteoclast potential (p < 0.001), in situ trabecular osteoclast number (p = 0.007), hematopoietic colony forming units (CFU-GEMM: p < 0.001, CFU-GM: p = 0.006, CFU-M: p < 0.001), and serum markers for osteoclastogenesis (intact PTH: p = 0.004, RANKL: p = 0.022, TRAP5b: p < 0.001). A concordant decrease in serum OPG (p = 0.005) was also observed. Fluoride treatment had no significant effects on bone morphology, BMD and serum PYD crosslinks in C3H suggesting a lack of significant bone resorption. Mechanical properties were also unaltered in C3H. In conclusion, short term F treatment at physiological levels has strain specific effects in mice. The expected anabolic effects were observed in B6 and novel actions hallmarked by enhanced osteoclastogenesis shifts in hematopoietic cell differentiation in the C3H strain

Distinct surveillance pathway for immunopathology during acute infection via autophagy and SR-BI

The mechanisms protecting from immunopathology during acute bacterial infections are incompletely known. We found that in response to apoptotic immune cells and live or dead Listeria monocytogenes scavenger receptor BI (SR-BI), an anti-atherogenic lipid exchange mediator, activated internalization mechanisms with characteristics of macropinocytosis and, assisted by Golgi fragmentation, initiated autophagic responses. This was supported by scavenger receptor-induced local increases in membrane cholesterol concentrations which generated lipid domains particularly in cell extensions and the Golgi. SR-BI was a key driver of beclin-1-dependent autophagy during acute bacterial infection of the liver and spleen. Autophagy regulated tissue infiltration of neutrophils, suppressed accumulation of Ly6C(+) (inflammatory) macrophages, and prevented hepatocyte necrosis in the core of infectious foci. Perifocal levels of Ly6C(+) macrophages and Ly6C(-) macrophages were unaffected, indicating predominant regulation of the focus core. SR-BI-triggered autophagy promoted co-elimination of apoptotic immune cells and dead bacteria but barely influenced bacterial sequestration and survival or inflammasome activation, thus exclusively counteracting damage inflicted by immune responses. Hence, SR-BI-and autophagy promote a surveillance pathway that partially responds to products of antimicrobial defenses and selectively prevents immunity-induced damage during acute infection. Our findings suggest that control of infection-associated immunopathology can be based on a unified defense operation

Body mass index and circulating oestrone sulphate in women treated with adjuvant letrozole

Background: Obesity is an independent adverse prognostic factor in early breast cancer patients, but it is still controversial whether obesity may affect adjuvant endocrine therapy efficacy. The aim of our study (ancillary to the two clinical trials Gruppo Italiano Mammella (GIM)4 and GIM5) was to investigate whether the circulating oestrogen levels during treatment with the aromatase inhibitor letrozole are related to body mass index (BMI) in postmenopausal women with breast cancer. Methods: Plasma concentration of oestrone sulphate (ES) was evaluated by radioimmunoassay in 370 patients. Plasma samples were obtained after at least 6 weeks of letrozole therapy (steady-state time). Patients were divided into four groups according to BMI. Differences among the geometric means (by ANOVA and ANCOVA) and correlation (by Spearman's rho) between the ES levels and BMI were assessed. Results: Picomolar geometric mean values (95% confidence interval, n=patients) of circulating ES during letrozole were 58.6 (51.0-67.2, n=150) when BMI was <25.0 kg m-2; 65.6 (57.8-74.6, n=154) when 25.0-29.9 kg m-2; 59.3 (47.1-74.6, n=50) when 30.0-34.9 kg m -2; and 43.3 (23.0-81.7, n=16) when 6535.0 kg m-2. No statistically significant difference in terms of ES levels among groups and no correlation with BMI were observed. Conclusions: Body mass index does not seem to affect circulating oestrogen levels in letrozole-treated patient

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

Background: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. Methods: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. Results: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93–1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89–1.06, P=0.5) mutation carriers. Conclusion: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out. A Osorio1, R L Milne2, G Pita3, P Peterlongo4,5, T Heikkinen6, J Simard7, G Chenevix-Trench8, A B Spurdle8, J Beesley8, X Chen8, S Healey8, KConFab9, S L Neuhausen10, Y C Ding10, F J Couch11,12, X Wang11, N Lindor13, S Manoukian4, M Barile14, A Viel15, L Tizzoni5,16, C I Szabo17, L Foretova18, M Zikan19, K Claes20, M H Greene21, P Mai21, G Rennert22, F Lejbkowicz22, O Barnett-Griness22, I L Andrulis23,24, H Ozcelik24, N Weerasooriya23, OCGN23, A-M Gerdes25, M Thomassen25, D G Cruger26, M A Caligo27, E Friedman28,29, B Kaufman28,29, Y Laitman28, S Cohen28, T Kontorovich28, R Gershoni-Baruch30, E Dagan31,32, H Jernström33, M S Askmalm34, B Arver35, B Malmer36, SWE-BRCA37, S M Domchek38, K L Nathanson38, J Brunet39, T Ramón y Cajal40, D Yannoukakos41, U Hamann42, HEBON37, F B L Hogervorst43, S Verhoef43, EB Gómez García44,45, J T Wijnen46,47, A van den Ouweland48, EMBRACE37, D F Easton49, S Peock49, M Cook49, C T Oliver49, D Frost49, C Luccarini50, D G Evans51, F Lalloo51, R Eeles52, G Pichert53, J Cook54, S Hodgson55, P J Morrison56, F Douglas57, A K Godwin58, GEMO59,60,61, O M Sinilnikova59,60, L Barjhoux59,60, D Stoppa-Lyonnet61, V Moncoutier61, S Giraud59, C Cassini62,63, L Olivier-Faivre62,63, F Révillion64, J-P Peyrat64, D Muller65, J-P Fricker65, H T Lynch66, E M John67, S Buys68, M Daly69, J L Hopper70, M B Terry71, A Miron72, Y Yassin72, D Goldgar73, Breast Cancer Family Registry37, C F Singer74, D Gschwantler-Kaulich74, G Pfeiler74, A-C Spiess74, Thomas v O Hansen75, O T Johannsson76, T Kirchhoff77, K Offit77, K Kosarin77, M Piedmonte78, G C Rodriguez79, K Wakeley80, J F Boggess81, J Basil82, P E Schwartz83, S V Blank84, A E Toland85, M Montagna86, C Casella87, E N Imyanitov88, A Allavena89, R K Schmutzler90, B Versmold90, C Engel91, A Meindl92, N Ditsch93, N Arnold94, D Niederacher95, H Deißler96, B Fiebig97, R Varon-Mateeva98, D Schaefer99, U G Froster100, T Caldes101, M de la Hoya101, L McGuffog49, A C Antoniou49, H Nevanlinna6, P Radice4,5 and J Benítez1,3 on behalf of CIMB

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

Modeling on fluid flow and inclusion motion in centrifugal continuous casting strands

During the centrifugal continuous casting process, unreasonable casting parameters can cause violent level fluctuation, serious gas entrainment, and formation of frozen shell pieces at the meniscus. Thus, in the current study, a three-dimensional multiphase turbulent model was established to study the transport phenomena during centrifugal continuous casting process. The effects of nozzle position, casting and rotational speed on the flow pattern, centrifugal force acting on the molten steel, level fluctuation, gas entrainment, shear stress on mold wall, and motion of inclusions during centrifugal continuous casting process were investigated. Volume of Fluid model was used to simulate the molten steel-air two-phase. The level fluctuation and the gas entrainment during casting were calculated by user-developed subroutines. The trajectory of inclusions in the rotating system was calculated using the Lagrangian approach. The results show that during centrifugal continuous casting, a large amount of gas was entrained into the molten steel, and broken into bubbles of various sizes. The greater the distance to the mold wall, the smaller the centrifugal force. Rotation speed had the most important influence on the centrifugal force distribution at the side region. Angular moving angle of the nozzle with 8° and keeping the rotation speed with 60 revolutions per minute can somehow stabilize the level fluctuation. The increase of angular angle of nozzle from 8 to 18 deg and rotation speed from 40 to 80 revolutions per minute favored to decrease the total volume of entrained bubbles, while the increase of distance of nozzle moving left and casting speed had reverse effects. The trajectories of inclusions in the mold were irregular, and then rotated along the strand length. After penetrating a certain distance, the inclusions gradually moved to the center of billet and gathered there. More work, such as the heat transfer, the solidification, and the inclusions entrapment during centrifugal continuous casting, will be performed

Obesity and survival in operable breast cancer patients treated with adjuvant anthracyclines and taxanes according to pathological subtypes: a pooled analysis

IntroductionObesity is an unfavorable prognostic factor in breast cancer (BC) patients regardless of menopausal status and treatment received. However, the association between obesity and survival outcome by pathological subtype requires further clarification.MethodsWe performed a retrospective analysis including 5,683 operable BC patients enrolled in four randomized clinical trials (GEICAM/9906, GEICAM/9805, GEICAM/2003–02, and BCIRG 001) evaluating anthracyclines and taxanes as adjuvant treatments. Our primary aim was to assess the prognostic effect of body mass index (BMI) on disease recurrence, breast cancer mortality (BCM), and overall mortality (OM). A secondary aim was to detect differences of such prognostic effects by subtype.ResultsMultivariate survival analyses adjusting for age, tumor size, nodal status, menopausal status, surgery type, histological grade, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, chemotherapy regimen, and under-treatment showed that obese patients (BMI 30.0 to 34.9) had similar prognoses to that of patients with a BMI < 25 (reference group) in terms of recurrence (Hazard Ratio [HR] = 1.08, 95% Confidence Interval [CI] = 0.90 to 1.30), BCM (HR = 1.02, 0.81 to 1.29), and OM (HR = 0.97, 0.78 to 1.19). Patients with severe obesity (BMI ≥ 35) had a significantly increased risk of recurrence (HR = 1.26, 1.00 to 1.59, P = 0.048), BCM (HR = 1.32, 1.00 to 1.74, P = 0.050), and OM (HR = 1.35, 1.06 to 1.71, P = 0.016) compared to our reference group. The prognostic effect of severe obesity did not vary by subtype.ConclusionsSeverely obese patients treated with anthracyclines and taxanes present a worse prognosis regarding recurrence, BCM, and OM than patients with BMI < 25. The magnitude of the harmful effect of BMI on survival-related outcomes was similar across subtypes