3D beam-column finite element under non-uniform shear stress distribution due to shear and torsion

The paper discusses the application of a 2-node, three-dimensional (3D) beam-column finite element with an enhanced fiber cross-section model to the inelastic response analysis of concrete members. The element accounts for the local distribution of strains and stresses under the coupling of axial, flexural, shear, and torsional effects with an enriched kinematic description that accounts for the out-of-plane deformations of the cross-section. To this end the warping displacements are interpolated with the addition of a variable number of local degrees of freedom. The material response is governed by a 3D nonlinear stress-strain relation with damage that describes the degrading mechanisms of typical engineering materials under the coupling of normal and shear stresses. The element formulation is validated by comparing the numerical results with measured data from the response of two prismatic concrete beams under torsional loading and with standard beam formulations

3D beam-column finite elements under tri-axial stess-strain states: non-uniform shear stress distribution and warping

In many engineering structures, the effects of shear and torsional loads are an important aspect of both the analysis and the design process. These effects are usually neglected in typical framed structures. However, in some relevant cases, such as bridges, shear walls or thin-walled frames, it is essential to account for the shear and torsional loads and their interaction with the other loading conditions to correctly reproduce the structural response. In this framework, the main task is to accurately describe the nonlinear structural response in terms of global behavior and local stress-strain distributions, reproducing the coupling of the stress components and its influence on the global response. This results even more important in large scale structures made of cementitious and/or innovative composite materials, widely adopted in nowadays professional practice. Indeed, these structures usually show degrading mechanisms and softening behavior. Hence, they require sophisticated computational models and ad hoc analysis strategies to predict the structure capacity under severe loading conditions. A standard approach to analyze these structures is the adoption of beam-column finite element (FE) models, which are often preferred with respect to two-dimensional (2D) plate/shell or three-dimensional (3D) FEs, because of their efficiency and low computational cost. However, most beam-column FE formulations are based on theclassical Euler-Bernoulli or Timoshenko theory, assuming the cross-sections to remain plane during the loading process. This assumption requires specific corrective measures, when the shear and torsion and the related warping effects are pronounced. This work discusses the simulation of RC members with a 3D 2-node beam FE that includes warping effects. The FE formulation in [1] is extended to allow the description of structural members with softening material behavior. The governing equations are derived from a four-field Hu-Washizu variational principle, with independent interpolation of the warping displacement field from the rigid section displacements, the generalized section deformations and the material stress fields. In particular, the warping of the cross-section is described by interpolating the out-of-plane displacement with the addition of a variable number of local degrees of freedom to those commonly used for the beam FE. The global nonlinear response and the local distributions of strains and stresses are described introducing a fiber cross-section discretization. Hence, the coupling of axial, flexural, shear and torsional effects in terms of material response is automatically taken into account. Focusing on RC structures, the damaging mechanisms of the concrete material is described by adopting a new 3D nonlinear constitutive relationship with plasticity and damage. This is an enhanced version of that proposed in [2] and introduces the description of the unilateral effects typically appearing in concrete-like materials, due to the crack opening and closure. A Drucker-Prager type plastic model is coupled with a two-parameter isotropic damage model, where two scalar variables are used to describe the damage in tension and compression, respectively. The localization problems and the related mesh-dependency, due to the softening material behavior, are controlled through a regularization technique based on a properly modified nonlocal integral procedure. For beam-column FEs, the nonlocal strain measures are evaluated performing the integration of the local generalized section deformations along the element axis, whereas for 2D FEs the nonlocal integration is performed considering the generalized membrane/plate deformations. The proposed model is implemented and validated through some correlation studies. These consider the numerical analysis of a series of plain concrete and RC beams subjected to torsional loads and of two RC shear walls. The results are compared with experimental measurements and with those of standard FE beam models

Discovery of novel mutations in the dihydropyrimidine dehydrogenase gene associated with toxicity of fluoropyrimidines and viewpoint on preemptive pharmacogenetic screening in patients

Background: Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of the metabolic pathway of 5-fluorouracil (5-FU) and other fluoropyrimidines to inactive compounds. For this reason, severe, life-threatening toxicities may occur in patients with deficient DPD activity when administered standard doses of 5-FU and its prodrugs. Materials and methods: We selected three patients with colorectal adenocarcinoma who displayed unexpected severe adverse reactions after treatment with 5-FU and capecitabine. To investigate the possible involvement of deficient variants of the DPD gene (DPYD), a denaturing HPLC (dHPLC) approach followed by target exon sequencing of DPYD was performed on DNA extracted from peripheral blood. Results: Three novel non-synonymous mutations of DPYD, c.2509-2510insC, c.1801G>C, and c.680G>A, were detected in these subjects. Due to the absence of other deficient variants of DPYD and the compatibility of adverse reactions with fluoropyrimidine treatment, the novel variants were associated with a poor-metabolizer phenotype. Conclusions: Stratification of patients on the basis of their genotype may help prevent toxicity, and the large body of evidence about the pathogenesis of fluoropyrimidine-induced adverse reactions strongly encourages the adoption of best practice recommendations to appropriately address this important clinical issue. This approach is of utmost importance within a preventive, prognostic, and personalized approach to patient care in the oncology setting

Concise Review: Chronic Myeloid Leukemia: Stem Cell Niche and Response to Pharmacologic Treatment

Nowadays, more than 90% of patients affected by chronic myeloid leukemia (CML) survive with a good quality of life, thanks to the clinical efficacy of tyrosine kinase inhibitors (TKIs). Nevertheless, point mutations of the ABL1 pocket occurring during treatment may reduce binding of TKIs, being responsible of about 20% of cases of resistance among CML patients. In addition, the presence of leukemic stem cells (LSCs) represents the most important event in leukemia progression related to TKI resistance. LSCs express stem cell markers, including active efflux pumps and genetic and epigenetic alterations together with deregulated cell signaling pathways involved in self-renewal, such as Wnt/β-catenin, Notch, and Hedgehog. Moreover, the interaction with the bone marrow microenvironment, also known as hematopoietic niche, may influence the phenotype of surrounding cells, which evade mechanisms controlling cell proliferation and are less sensitive or frankly resistant to TKIs. This Review focuses on the role of LSCs and stem cell niche in relation to response to pharmacological treatments. A literature search from PubMed database was performed until April 30, 2017, and it has been analyzed according to keywords such as chronic myeloid leukemia, stem cell, leukemic stem cells, hematopoietic niche, tyrosine kinase inhibitors, and drug resistance. Stem Cells Translational Medicine 2018

Kidney biopsy findings in a critically ill COVID-19 patient with dialysis-dependent. acute kidney injury: a case against \u201cSARS-CoV-2 nephropathy

NO abstract available- Case repor

Inhibition of N-linked glycosylation impairs ALK phosphorylation and disrupts pro-survival signaling in neuroblastoma cell lines

<p>Abstract</p> <p>Background</p> <p>The Anaplastic Lymphoma Kinase (ALK) is an orphan receptor tyrosine kinase, which undergoes post-translational N-linked glycosylation. The catalytic domain of ALK was originally identified in the t(2;5) translocation that produces the unglycosylated oncogenic protein NPM-ALK, which occurs in Anaplastic Large Cell Lymphoma (ALCL). Recently, both germline and somatic activating missense mutations of ALK have been identified in neuroblastoma (NB), a pediatric cancer arising from neural crest cells. Moreover, we previously reported that ALK expression is significantly upregulated in advanced/metastatic NB. We hypothesized that ALK function may depend on N-linked glycosylation and that disruption of this post-translational modification would impair ALK activation, regardless the presence of either gene mutations or overexpression.</p> <p>Methods</p> <p>We employed tunicamycin to inhibit N-linked glycosylation. The following ALK-positive NB cell lines were used: SH-SY5Y and KELLY (ALK mutation F1174L), UKF-NB3 (ALK mutation R1275Q) and NB1 (ALK amplification). As a control, we used the NB cell lines LA1-5S and NB5 (no ALK expression), and the ALCL cell line SU-DHL1 (NPM-ALK).</p> <p>Results</p> <p>Tunicamycin treatment of ALK-positive NB cells resulted in a hypoglycosylated ALK band and in decreased amounts of mature full size receptor. Concomitantly, we observed a marked reduction of mature ALK phosphorylation. On the contrary, tunicamycin had no effects on NPM-ALK phosphorylation in SU-DHL1 cells. Moreover, phosphorylation levels of ALK downstream effectors (AKT, ERK1/2, STAT3) were clearly impaired only in ALK mutated/amplified NB cell lines, whereas no significant reduction was observed in both ALK-negative and NPM-ALK-positive cell lines. Furthermore, inhibition of N-linked glycosylation considerably impaired cell viability only of ALK mutated/amplified NB cells. Finally, the cleavage of the Poly-ADP-ribose-polymerase (PARP) suggested that apoptotic pathways may be involved in cell death.</p> <p>Conclusions</p> <p>In this study we showed that inhibition of N-linked glycosylation affects ALK phosphorylation and disrupts downstream pro-survival signaling, indicating that inhibition of this post-translational modification may be a promising therapeutic approach. However, as tunicamycin is not a likely candidate for clinical use other approaches to alter N-linked glycosylation need to be explored. Future studies will assess whether the efficacy in inhibiting ALK activity might be enhanced by the combination of ALK specific small molecule and N-linked glycosylation inhibitors.</p

IGEC2: A 17-month search for gravitational wave bursts in 2005-2007

We present here the results of a 515 days long run of the IGEC2 observatory, consisting of the four resonant mass detectors ALLEGRO, AURIGA, EXPLORER and NAUTILUS. The reported results are related to the fourfold observation time from Nov. 6 2005 until Apr. 14 2007, when Allegro ceased its operation. This period overlapped with the first long term observations performed by the LIGO interferometric detectors. The IGEC observations aim at the identification of gravitational wave candidates with high confidence, keeping the false alarm rate at the level of 1 per century, and high duty cycle, namely 57% with all four sites and 94% with at least three sites in simultaneous observation. The network data analysis is based on time coincidence searches over at least three detectors: the four 3-fold searches and the 4-fold one are combined in a logical OR. We exchanged data with the usual blind procedure, by applying a unique confidential time offset to the events in each set of data. The accidental background was investigated by performing sets of 10^8 coincidence analyses per each detector configuration on off-source data, obtained by shifting the time series of each detector. The thresholds of the five searches were tuned so as to control the overall false alarm rate to 1/century. When the confidential time shifts was disclosed, no gravitational wave candidate was found in the on-source data. As an additional output of this search, we make available to other observatories the list of triple coincidence found below search thresholds, corresponding to a false alarm rate of 1/month.Comment: 10 pages, 8 figures Accepted for publication on Phys. Rev.

Candidate germline biomarkers of lenalidomide efficacy in mantle cell lymphoma: the FIL MCL0208 trial

In the FIL MCL0208 phase III trial, lenalidomide maintenance (LEN) after transplantation (ASCT) in mantle cell lymphoma (MCL) improved progression-free survival (PFS) vs observation (OBS). The host pharmacogenetic background was analyzed to decipher whether single nucleotide polymorphisms (SNPs) of genes encoding transmembrane transporters, metabolic enzymes, or cell surface receptors might predict drug efficacy. Genotypes were obtained by real-time polymerase chain reaction (RT-PCR) in peripheral blood (PB) germ line DNA. Polymorphisms of either ABCB1 or VEGF were found in 69% and 79% of 278 patients and predicted favorable PFS vs homozygous wild type (WT) in the LEN arm: 3-year PFS 85% vs 70% (p < 0.05) and 85% vs 60% (p < 0.01), respectively. Patients carrying both ABCB1 and VEGF WT had the poorest 3-year PFS (46%) and overall survival (OS, 76%): in fact, in these patients LEN did not improve PFS vs OBS (3-year PFS 44% vs 60%, p = 0.62). Moreover, CRBN polymorphism (n = 28) was associated with lenalidomide dose reduction or discontinuation. Finally, ABCB1, NCF4, and GSTP1 polymorphisms predicted lower hematological toxicity during induction, while ABCB1 and CRBN polymorphisms predicted lower risk of grade ≥3 infections. This study demonstrates that specific SNPs represent candidate predictive biomarkers of immunochemotherapy toxicity and LEN efficacy after ASCT in MCL. This trial is registered at eudract.ema.europa.eu as 2009-012807-25

Results of the IGEC-2 search for gravitational wave bursts during 2005

The network of resonant bar detectors of gravitational waves resumed coordinated observations within the International Gravitational Event Collaboration (IGEC-2). Four detectors are taking part in this collaboration: ALLEGRO, AURIGA, EXPLORER and NAUTILUS. We present here the results of the search for gravitational wave bursts over 6 months during 2005, when IGEC-2 was the only gravitational wave observatory in operation. The network data analysis implemented is based on a time coincidence search among AURIGA, EXPLORER and NAUTILUS, keeping the data from ALLEGRO for follow-up studies. With respect to the previous IGEC 1997-2000 observations, the amplitude sensitivity of the detectors to bursts improved by a factor about 3 and the sensitivity bandwidths are wider, so that the data analysis was tuned considering a larger class of detectable waveforms. Thanks to the higher duty cycles of the single detectors, we decided to focus the analysis on three-fold observation, so to ensure the identification of any single candidate of gravitational waves (gw) with high statistical confidence. The achieved false detection rate is as low as 1 per century. No candidates were found.Comment: 10 pages, to be submitted to Phys. Rev.