Memory of the Unjamming Transition during Cyclic Tiltings of a Granular Pile

Discrete numerical simulations are performed to study the evolution of the micro-structure and the response of a granular packing during successive loading-unloading cycles, consisting of quasi-static rotations in the gravity field between opposite inclination angles. We show that internal variables, e.g., stress and fabric of the pile, exhibit hysteresis during these cycles due to the exploration of different metastable configurations. Interestingly, the hysteretic behaviour of the pile strongly depends on the maximal inclination of the cycles, giving evidence of the irreversible modifications of the pile state occurring close to the unjamming transition. More specifically, we show that for cycles with maximal inclination larger than the repose angle, the weak contact network carries the memory of the unjamming transition. These results demonstrate the relevance of a two-phases description -strong and weak contact networks- for a granular system, as soon as it has approached the unjamming transition.Comment: 13 pages, 15 figures, soumis \`{a} Phys. Rev.

Solid behavior of anisotropic rigid frictionless bead assemblies

We investigate the structure and mechanical behavior of assemblies of frictionless, nearly rigid equal-sized beads, in the quasistatic limit, by numerical simulation. Three different loading paths are explored: triaxial compression, triaxial extension and simple shear. Generalizing recent results [1], we show that the material, despite rather strong finite sample size effects, is able to sustain a finite deviator stress in the macroscopic limit, along all three paths, without dilatancy. The shape of the yield surface is adequately described by a Lade-Duncan (rather than Mohr-Coulomb) criterion. While scalar state variables keep the same values as in isotropic systems, fabric and force anisotropies are each characterized by one parameter and are in one-to-one correspondence with principal stress ratio along all three loading paths.The anisotropy of the pair correlation function extends to a distance between bead surfaces on the order of 10% of the diameter. The tensor of elastic moduli is shown to possess a nearly singular, uniaxial structure related to stress anisotropy. Possible stress-strain relations in monotonic loading paths are also discussed

Formation of bone-like apatite layer on chitosan fiber mesh scaffolds by a biomimetic spraying process

Bone-like apatite coating of polymeric substrates by means of biomimetic process is a possible way to enhance the bone bonding ability of the materials. The created apatite layer is believed to have an ability to provide a favorable environment for osteoblasts or osteoprogenitor cells. The purpose of this study is to obtain bone-like apatite layer onto chitosan fiber mesh tissue engineering scaffolds, by means of using a simple biomimetic coating process and to determine the influence of this coating on osteoblastic cell responses. Chitosan fiber mesh scaffolds produced by a previously described wet spinning methodology were initially wet with a Bioglass"–water suspension by means of a spraying methodology and then immersed in a simulated body fluid (SBF) mimicking physiological conditions for one week. The formation of apatite layer was observed morphologically by scanning electron microscopy (SEM). As a result of the use of the novel spraying methodology, a fine coating could also be observed penetrating into the pores, that is clearly within the bulk of the scaffolds. Fourier Transform Infrared spectroscopy (FTIRATR), Electron Dispersive Spectroscopy (EDS) and X-ray diffraction (XRD) analysis also confirmed the presence of apatite-like layer. A human osteoblast-like cell line (SaOs-2) was used for the direct cell contact assays. After 2 weeks of culture, samples were observed under the SEM. When compared to the control samples (unmodified chitosan fiber mesh scaffolds) the cell population was found to be higher in the Ca–P biomimetic coated scaffolds, which indicates that the levels of cell proliferation on this kind of scaffolds could be enhanced. Furthermore, it was also observed that the cells seeded in the Ca–P coated scaffolds have a more spread and flat morphology, which reveals an improvement on the cell adhesion patterns, phenomena that are always important in processes such as osteoconduction

Secreted and tumour targeted human carboxylesterase for activation of irinotecan

Irinotecan (CPT-11) is an anticancer agent for the treatment of colon cancer. CPT-11 can be considered as a prodrug, since it needs to be activated into the toxic drug SN-38 by the enzyme carboxylesterase. An approach to achieve tumour specific activation of CPT-11 is to transduce the cDNA encoding carboxylesterase into tumour cells. A secreted form of carboxylesterase may diffuse through a tumour mass and may activate CPT-11 extracellularly. This could enhance the antitumour efficacy by exerting a bystander effect on untransduced cells. In addition a secreted tumour-targeted form of carboxylesterase should prevent leakage of the enzyme from the site of the tumour into the circulation. We have constructed a secreted form of human liver carboxylesterase-2 by deletion of the cellular retention signal and by cloning the cDNA downstream of an Ig kappa leader sequence. The protein was secreted by transfected cells and showed both enzyme activity and efficient CPT-11 activation. To obtain a secreted, tumour-targeted form of carboxylesterase-2 the cDNA encoding the human scFv antibody C28 directed against the epithelial cell adhesion molecule EpCAM, was inserted between the leader sequence and carboxylesterase-2. This fusion protein showed CPT-11 activation and specific binding to EpCAM expressing cells. Importantly, in combination with CPT-11 both recombinant carboxylesterase proteins exerted strong antiproliferative effects on human colon cancer cells. They are, therefore, promising new tools for gene directed enzyme prodrug therapy approaches for the treatment of colon carcinoma with CPT-11

Fanconi anemia genes are highly expressed in primitive CD34(+ )hematopoietic cells

BACKGROUND: Fanconi anemia (FA) is a complex recessive genetic disease characterized by progressive bone marrow failure (BM) and a predisposition to cancer. We have previously shown using the Fancc mouse model that the progressive BM failure results from a hematopoietic stem cell defect suggesting that function of the FA genes may reside in primitive hematopoietic stem cells. METHODS: Since genes involved in stem cell differentiation and/or maintenance are usually regulated at the transcription level, we used a semiquantitative RT-PCR method to evaluate FA gene transcript levels in purified hematopoietic stem cells. RESULTS: We show that most FA genes are highly expressed in primitive CD34-positive and negative cells compared to lower levels in more differentiated cells. However, in CD34(- )stem cells the Fancc gene was found to be expressed at low levels while Fancg was undetectable in this population. Furthermore, Fancg expression is significantly decreased in Fancc -/- stem cells as compared to wild-type cells while the cancer susceptibility genes Brca1 and Fancd1/Brac2 are upregulated in Fancc-/- hematopoietic cells. CONCLUSIONS: These results suggest that FA genes are regulated at the mRNA level, that increased Fancc expression in LTS-CD34(+ )cells correlates with a role at the CD34(+ )differentiation stage and that lack of Fancc affects the expression of other FA gene, more specifically Fancg and Fancd1/Brca2, through an unknown mechanism

TGF-β promotes microtube formation in glioblastoma through Thrombospondin 1

International audienceAbstract Background Microtubes (MTs), cytoplasmic extensions of glioma cells, are important cell communication structures promoting invasion and treatment resistance through network formation. MTs are abundant in chemoresistant gliomas, in particular, glioblastomas (GBMs), while they are uncommon in chemosensitive IDH-mutant and 1p/19q co-deleted oligodendrogliomas. The aim of this study was to identify potential signaling pathways involved in MT formation. Methods Bioinformatics analysis of TCGA was performed to analyze differences between GBM and oligodendroglioma. Patient-derived GBM stem cell lines were used to investigate MT formation under transforming growth factor-beta (TGF-β) stimulation and inhibition in vitro and in vivo in an orthotopic xenograft model. RNA sequencing and proteomics were performed to detect commonalities and differences between GBM cell lines stimulated with TGF-β. Results Analysis of TCGA data showed that the TGF-β pathway is highly activated in GBMs compared to oligodendroglial tumors. We demonstrated that TGF-β1 stimulation of GBM cell lines promotes enhanced MT formation and communication via calcium signaling. Inhibition of the TGF-β pathway significantly reduced MT formation and its associated invasion in vitro and in vivo. Downstream of TGF-β, we identified thrombospondin 1 (TSP1) as a potential mediator of MT formation in GBM through SMAD activation. TSP1 was upregulated upon TGF-β stimulation and enhanced MT formation, which was inhibited by TSP1 shRNAs in vitro and in vivo. Conclusion TGF-β and its downstream mediator TSP1 are important mediators of the MT network in GBM and blocking this pathway could potentially help to break the complex MT-driven invasion/resistance network

Prehospital Stroke Triage:A Modeling Study on the Impact of Triage Tools in Different Regions

Background and purpose: Direct transportation to a thrombectomy-capable intervention center is beneficial for patients with ischemic stroke due to large vessel occlusion (LVO), but can delay intravenous thrombolytics (IVT). The aim of this modeling study was to estimate the effect of prehospital triage strategies on treatment delays and overtriage in different regions. Methods: We used data from two prospective cohort studies in the Netherlands: the Leiden Prehospital Stroke Study and the PRESTO study. We included stroke code patients within 6 h from symptom onset. We modeled outcomes of Rapid Arterial oCclusion Evaluation (RACE) scale triage and triage with a personalized decision tool, using drip-and-ship as reference. Main outcomes were overtriage (stroke code patients incorrectly triaged to an intervention center), reduced delay to endovascular thrombectomy (EVT), and delay to IVT. Results: We included 1798 stroke code patients from four ambulance regions. Per region, overtriage ranged from 1-13% (RACE triage) and 3-15% (personalized tool). Reduction of delay to EVT varied by region between 24 ± 5 min (n = 6) to 78 ± 3 (n = 2), while IVT delay increased with 5 (n = 5) to 15 min (n = 21) for non-LVO patients. The personalized tool reduced delay to EVT for more patients (25 ± 4 min [n = 8] to 49 ± 13 [n = 5]), while delaying IVT with 3-14 min (8-24 patients). In region C, most EVT patients were treated faster (reduction of delay to EVT 31 ± 6 min (n = 35), with RACE triage and the personalized tool. Conclusions: In this modeling study, we showed that prehospital triage reduced time to EVT without disproportionate IVT delay, compared to a drip-and-ship strategy. The effect of triage strategies and the associated overtriage varied between regions. Implementation of prehospital triage should therefore be considered on a regional level.</p

Pancreatitis of biliary origin, optimal timing of cholecystectomy (PONCHO trial):Study protocol for a randomized controlled trial

Background: After an initial attack of biliary pancreatitis, cholecystectomy minimizes the risk of recurrent biliary pancreatitis and other gallstone-related complications. Guidelines advocate performing cholecystectomy within 2 to 4 weeks after discharge for mild biliary pancreatitis. During this waiting period, the patient is at risk of recurrent biliary events. In current clinical practice, surgeons usually postpone cholecystectomy for 6 weeks due to a perceived risk of a more difficult dissection in the early days following pancreatitis and for logistical reasons. We hypothesize that early laparoscopic cholecystectomy minimizes the risk of recurrent biliary pancreatitis or other complications of gallstone disease in patients with mild biliary pancreatitis without increasing the difficulty of dissection and the surgical complication rate compared with interval laparoscopic cholecystectomy.Methods/Design: PONCHO is a randomized controlled, parallel-group, assessor-blinded, superiority multicenter trial. Patients are randomly allocated to undergo early laparoscopic cholecystectomy, within 72 hours after randomization, or interval laparoscopic cholecystectomy, 25 to 30 days after randomization. During a 30-month period, 266 patients will be enrolled from 18 hospitals of the Dutch Pancreatitis Study Group. The primary endpoint is a composite endpoint of mortality and acute re-admissions for biliary events (that is, recurrent biliary pancreatitis, acute cholecystitis, symptomatic/obstructive choledocholithiasis requiring endoscopic retrograde cholangiopancreaticography including cholangitis (with/without endoscopic sphincterotomy), and uncomplicated biliary colics) occurring within 6 months following randomization. Secondary endpoints include the individual endpoints of the composite endpoint, surgical and other complications, technical difficulty of cholecystectomy and costs.Discussion: The PONCHO trial is designed to show that early laparoscopic cholecystectomy (within 72 hours) reduces the combined endpoint of mortality and re-admissions for biliary events as compared with interval laparoscopic cholecystectomy (between 25 and 30 days) after recovery of a first episode of mild biliary pancreatitis.</p