Role of the Intercrystalline Tie Chains Network in the Mechanical Response of Semicrystalline Polymers.

We examine the microscopic origin of the tensile response in semicrystalline polymers by performing large-scale molecular dynamics simulations of various chain lengths. We investigate the microscopic rearrangements of the polymers during tensile deformation and show that the intercrystalline chain connections known as tie chains contribute significantly to the elastic and plastic response. These results suggest that the mechanical behavior of semicrystalline polymers is controlled by two interpenetrated networks of entanglements and tie chains.

Nanoscale buckling deformation in layered copolymer materials.

In layered materials, a common mode of deformation involves buckling of the layers under tensile deformation in the direction perpendicular to the layers. The instability mechanism, which operates in elastic materials from geological to nanometer scales, involves the elastic contrast between different layers. In a regular stacking of "hard" and "soft" layers, the tensile stress is first accommodated by a large deformation of the soft layers. The inhibited Poisson contraction results in a compressive stress in the direction transverse to the tensile deformation axis. The hard layers sustain this transverse compression until buckling takes place and results in an undulated structure. Using molecular simulations, we demonstrate this scenario for a material made of triblock copolymers. The buckling deformation is observed to take place at the nanoscale, at a wavelength that depends on strain rate. In contrast to what is commonly assumed, the wavelength of the undulation is not determined by defects in the microstructure. Rather, it results from kinetic effects, with a competition between the rate of strain and the growth rate of the instability.

A novel method for calculating the energy barriers for carbon diffusion in ferrite under heterogeneous stress.

A novel method for accurate and efficient evaluation of the change in energy barriers for carbon diffusion in ferrite under heterogeneous stress is introduced. This method, called Linear Combination of Stress States, is based on the knowledge of the effects of simple stresses (uniaxial or shear) on these diffusion barriers. Then, it is assumed that the change in energy barriers under a complex stress can be expressed as a linear combination of these already known simple stress effects. The modifications of energy barriers by either uniaxial traction/compression and shear stress are determined by means of atomistic simulations with the Climbing Image-Nudge Elastic Band method and are stored as a set of functions. The results of this method are compared to the predictions of anisotropic elasticity theory. It is shown that, linear anisotropic elasticity fails to predict the correct energy barrier variation with stress (especially with shear stress) whereas the proposed method provides correct energy barrier variation for stresses up to ∼3 GPa. This study provides a basis for the development of multiscale models of diffusion under non-uniform stress.

Clinical characteristics and factors associated with acute kidney injury among patients hospitalized with coronavirus disease: an observational retrospective study.

BACKGROUND: Coronavirus disease 19 (COVID-19) is a multisystemic disease with high incidence of acute kidney injury (AKI). OBJECTIVE: To describe the clinical characteristics and factors associated with AKI among patients hospitalized with COVID-19. DESIGN AND SETTING: Retrospective cohort conducted at Hospital Civil de Culiacan, Mexico. METHODS: We included 307 patients hospitalized due to COVID-19. AKI was defined and staged based on serum creatinine levels in accordance with the criteria of the Acute Kidney Injury Network (AKIN). Multivariate logistic regression analysis was used to determine factors associated with AKI. RESULTS: The patients' age was 56 ± 15 years (64.5% male). The incidence of AKI was 33.6% (n = 103). Overall, 53.4% of patients had community-acquired AKI, and 46.6% had hospital-acquired AKI. Additionally, 15.5% of them presented AKIN stage 1; 34% had AKIN stage 2; and 50.5% had AKIN stage 3. Hemodialysis was required for 10.7% of the patients. The factors associated with AKI were chronic kidney disease (odds ratio, OR: 10.8; P = 0.04), use of norepinephrine (OR: 7.3; P = 0.002), diabetes mellitus (OR: 2.9; P = 0.03), C-reactive protein level (OR: 1.005; P = 0.01) and COVID-19 severity index based on chest tomography (OR: 1.09; statistical trend, P = 0.07). Hospital stay (11 ± 7 days; P < 0.001) and mortality (83.5 versus 31.4%; P < 0.05) were greater among patients with AKI. CONCLUSION: AKI was a frequent and serious complication in our cohort of patients hospitalized with COVID-19, which was associated with high mortality and long hospital stay.

Protease-activated receptor-1 antagonist F 16618 reduces arterial restenosis by down-regulation of tumor necrosis factor α and matrix metalloproteinase 7 expression, migration, and proliferation of vascular smooth muscle cells.

Wound healing after angioplasty or stenting is associated with increased production of thrombin and the activation of protease-activated receptor 1 (PAR1). The aim of the present study was to examine the effects of a new selective PAR1 antagonist, 2-[5-oxo-5-(4-pyridin-2-ylpiperazin-1-yl)-penta-1,3-dienyl]-benzonitrile (F 16618), in restenosis and vascular smooth muscle cell (SMC) proliferation and migration using both in vivo and in vitro approaches. Daily oral administration of F 16618 inhibited the restenosis induced by balloon angioplasty on rat carotid artery in a dose-dependent manner. Furthermore, single intravenous administration of F 16618 during the angioplasty procedure was sufficient to protect the carotid artery against restenosis. In vitro, F 16618 inhibited the growth of human aortic SMCs in a concentration-dependent manner with maximal effects at 10 µM. At that concentration, F 16618 also prevented thrombin-mediated SMC migration. In vivo, oral and intravenous F 16618 treatments reduced by 30 and 50% the expression of the inflammatory cytokine tumor necrosis factor α (TNFα) 24 h after angioplasty. However, only acute intravenous administration prevented the induction of matrix metalloproteinase 7 expression. In contrast, F 16618 treatments had no effect on early SMC de-differentiation and transcription of monocyte chemoattractant protein-1 and interleukin-6 and late re-endothelialization of injured arteries. Furthermore, F 16618 compensated for the carotid endothelium loss by inhibiting PAR1-mediated contraction. Altogether, these data demonstrate that PAR1 antagonists such as F 16618 are a highly effective treatment of restenosis after vascular injury, by inhibition of TNFα, matrix metalloproteinase 7, and SMC migration and proliferation in addition to an antithrombotic effect.

Discovery and SAR of small molecule PAR1 antagonists.

High-throughput screening resulted in the identification of a small molecule inhibitor of PAR1. Optimisation of the initial hit led to the discovery of compounds 34 and 49, which displayed antithrombotic activity in an arteriovenous shunt model in the rat after iv administration.

Exploration of a new series of PAR1 antagonists.

Two series of new PAR1 antagonists have been identified. The first incorporates a cinnamoylpiperidine motif and the second a cinnamoylpyridine pattern. The synthesis, biological activity and structure-activity relationship of these compounds are presented. In each series, one analog showed potent in vivo antithrombotic activity in a rat AV shunt model, with up to 53% inhibition at 1.25mpk iv for compound 30.

Efficacy of the Antibody-Drug Conjugate W0101 in Preclinical Models of IGF-1 Receptor Overexpressing Solid Tumors.

The insulin-like growth factor type 1 receptor (IGF-1R) is important in tumorigenesis, and its overexpression occurs in numerous tumor tissues. To date, therapeutic approaches based on mAbs and tyrosine kinase inhibitors targeting IGF-1R have only shown clinical benefit in specific patient populations. We report a unique IGF-1R-targeted antibody-drug conjugate (ADC), W0101, designed to deliver a highly potent cytotoxic auristatin derivative selectively to IGF-1R overexpressing tumor cells. The mAb (hz208F2-4) used to prepare the ADC was selected for its specific binding properties to IGF-1R compared with the insulin receptor, and for its internalization properties. Conjugation of a novel auristatin derivative drug linker to hz208F2-4 did not alter its binding and internalization properties. W0101 induced receptor-dependent cell cytotoxicity in vitro when applied to various cell lines overexpressing IGF-1R, but it did not affect normal cells. Efficacy studies were conducted in several mouse models expressing different levels of IGF-1R to determine the sensitivity of the tumors to W0101. W0101 induced potent tumor regression in certain mouse models. Interestingly, the potency of W0101 correlated with the expression level of IGF-1R evaluated by IHC. In an MCF-7 breast cancer model with high-level IGF-1R expression, a single injection of W0101 3 mg/kg led to strong inhibition of tumor growth. W0101 provides a potential new therapeutic option for patients overexpressing IGF-1R. A first-in-human trial of W0101 is currently ongoing to address clinical safety.

Phase III Trial of Adjuvant Capecitabine After Standard Neo-/Adjuvant Chemotherapy in Patients With Early Triple-Negative Breast Cancer (GEICAM/2003-11_CIBOMA/2004-01).

PURPOSE: Operable triple-negative breast cancers (TNBCs) have a higher risk of relapse than non-TNBCs with standard therapy. The GEICAM/2003-11_CIBOMA/2004-01 trial explored extended adjuvant capecitabine after completion of standard chemotherapy in patients with early TNBC. PATIENTS AND METHODS: Eligible patients were those with operable, node-positive-or node negative with tumor 1 cm or greater-TNBC, with prior anthracycline- and/or taxane-containing chemotherapy. After central confirmation of TNBC status by immunohistochemistry, patients were randomly assigned to either capecitabine or observation. Stratification factors included institution, prior taxane-based therapy, involved axillary lymph nodes, and centrally determined phenotype (basal v nonbasal, according to cytokeratins 5/6 and/or epidermal growth factor receptor positivity by immunohistochemistry). The primary objective was to compare disease-free survival (DFS) between both arms. RESULTS: Eight hundred seventy-six patients were randomly assigned to capecitabine (n = 448) or observation (n = 428). Median age was 49 years, 55.9% were lymph node negative, 73.9% had a basal phenotype, and 67.5% received previous anthracyclines plus taxanes. Median length of follow-up was 7.3 years. DFS was not significantly prolonged with capecitabine versus observation [hazard ratio (HR), 0.82; 95% CI, 0.63 to 1.06; P = .136]. In a preplanned subgroup analysis, nonbasal patients seemed to derive benefit from the addition of capecitabine with a DFS HR of 0.53 versus 0.94 in those with basal phenotype (interaction test P = .0694) and an HR for overall survival of 0.42 versus 1.23 in basal phenotype (interaction test P = .0052). Tolerance of capecitabine was as expected, with 75.2% of patients completing the planned 8 cycles. CONCLUSION: This study failed to show a statistically significant increase in DFS by adding extended capecitabine to standard chemotherapy in patients with early TNBC. In a preplanned subset analysis, patients with nonbasal phenotype seemed to obtain benefit with capecitabine, although this will require additional validation.

Mechanical testing of glassy and rubbery polymers in numerical simulations: role of boundary conditions in tensile stress experiments.

We use coarse-grained molecular dynamics simulations to perform tensile test deformation on glassy and rubbery polymer samples using two types of driving for the deformation. We compare the outcome from a standard homogeneous deformation procedure with that of a boundary driven procedure in which the sample is driven by the nanometric equivalent of grips. No significant difference is observed in both uniaxial and triaxial tensile experiments. Implications for testing the behavior of nonhomogeneous polymer materials are briefly discussed.

Phase Field Modelling of Abnormal Grain Growth.

Heterogeneous grain structures may develop due to abnormal grain growth during processing of polycrystalline materials ranging from metals and alloys to ceramics. The phenomenon must be controlled in practical applications where typically homogeneous grain structures are desired. Recent advances in experimental and computational techniques have, thus, stimulated the need to revisit the underlying growth mechanisms. Here, phase field modelling is used to systematically evaluate conditions for initiation of abnormal grain growth. Grain boundaries are classified into two classes, i.e., high- and low-mobility boundaries. Three different approaches are considered for having high- and low-mobility boundaries: (i) critical threshold angle of grain boundary disorientation above which boundaries are highly mobile, (ii) two grain types A and B with the A-B boundaries being highly mobile, and (iii) three grain types, A, B and C with the A-B boundaries being fast. For these different scenarios, 2D simulations have been performed to quantify the effect of variations in the mobility ratio, threshold angle and fractions of grain types, respectively, on the potential onset of abnormal grain growth and the degree of heterogeneity in the resulting grain structures. The required mobility ratios to observe abnormal grain growth are quantified as a function of the fraction of high-mobility boundaries. The scenario with three grain types (A, B, C) has been identified as one that promotes strongly irregular abnormal grains including island grains, as observed experimentally.

Disentangling and Lamellar Thickening of Linear Polymers during Crystallization: Simulation of Bimodal and Unimodal Molecular Weight Distribution Systems.

We have performed coarse-grained molecular dynamics simulations to study the isothermal crystallization of bimodal and unimodal molecular weight distribution (MWD) polymers with equivalent average molecular weight (Mw). By using primitive path analysis, we can monitor the entanglement evolution during the process of crystallization. We have discovered a quantitative correlation between the degree of disentanglement and crystallinity, indicating that chain disentanglement permits the process of crystallization. In addition, the crystalline stem length also displays a linear relation with the degree of disentanglement at different temperatures. Based on the observation in our simulations, we can build a scenario of the whole process of chain disentangling and lamellar thickening on the basis of chain sliding diffusion. Furthermore, we have enough evidence to infer that the temperature dependence of crystalline stem length is basically a result of temperature dependence of chain sliding diffusion. Our observations are also in agreement with Hikosaka's sliding diffusion theory. Compared to the unimodal system, the disentanglement degree of the bimodal system is more delayed than its crystallinity due to the slower chain sliding of the long-chain component; the bimodal system reaches a larger crystalline stem length at all temperatures due to the promotion of higher chain sliding mobility of the short-chain component.

Protease-activated receptor-1 mediates thrombin-induced persistent sodium current in human cardiomyocytes.

After the thrombus formation in cardiac cavities or coronaries, the serine protease thrombin is produced and can therefore reach the myocardial tissue by the active process of extravasation and binds to the G protein-coupled protease-activated receptor-1 (PAR1) expressed in human myocardium. The role of PAR1 was investigated in the thrombin effect on sodium current (I(Na)). I(Na) was recorded in freshly isolated human atrial myocytes by the whole-cell patch-clamp method. Action potentials (AP) were recorded in guinea pig ventricular tissue by the conventional glass microelectrode technique. Thrombin-activated PAR1 induced a tetrodotoxin-blocked persistent sodium current, I(NaP), in a concentration-dependent manner with an apparent EC(50) of 28 U/ml. The PAR1 agonist peptide SFLLR-NH(2) (50 microM) was able to mimic PAR1-thrombin action, whereas PAR1 antagonists N(3)-cyclopropyl-7-((4-(1-methylethyl)-phenyl)methyl)-7H-pyrrolo(3,2-f)quinazoline-1,3-diamine (SCH 203099; 10 microM) and 1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-3-hydroxy-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanone (ER 112787) (1 microM), completely inhibited it. The activated PAR1 involves the calcium-independent phospholipase-A(2) signaling pathway because two inhibitors of this cascade, bromoenol lactone (50 microM) and haloenol lactone suicide substrate (50 microM), block PAR1-thrombin-induced I(NaP).Asa consequence of I(NaP) activation, in guinea pig right ventricle papillary muscle, action potential duration (APD) were significantly increased by 20% and 15% under the respective action of 32 U/ml thrombin and 50 microM SFLLR-NH(2), and these increases in APD were prevented by 1 microM tetrodotoxin or markedly reduced by application of 1 microM SCH 203099 or ER 112787. Thrombin, through PAR1 activation, increases persistent component of the Na(+) current resulting in an uncontrolled sodium influx into the cardiomyocyte, which can contribute to cellular injuries observed during cardiac ischemia.

Polymer chain generation for coarse-grained models using radical-like polymerization.

A versatile method is proposed to generate configurations of coarse-grained models for polymer melts. This method, largely inspired by chemical "radical polymerization," is divided in three stages: (i) nucleation of radicals (reacting molecules caching monomers), (ii) growth of chains within a solvent of monomers and (iii) termination: annihilation of radicals and removal of residual monomers. The main interest of this method is that relaxation is performed while chains are generated. Pure mono and polydisperse polymer melts are generated and compared to the configurations generated by the push off method from Auhl et al. [J. Chem. Phys. 119, 12718 (2003)]. A detailed study of the static properties (radius of gyration, mean square internal distance, entanglement length) confirms that the radical-like polymerization technique is suitable to generate equilibrated melts. Moreover, the method is flexible and can be adapted to generate nanostructured polymers, namely, diblock and triblock copolymers.

Crystallization of finite-extensible nonlinear elastic Lennard-Jones coarse-grained polymers.

The ability of a simple coarse-grained finite-extensible nonlinear elastic (FENE) Lennard-Jones (LJ) polymer model to be crystallized is investigated by molecular dynamics simulations. The optimal FENE Lennard-Jones parameter combinations (ratio between FENE and LJ equilibrium distances) and the optimal lattice parameters are calculated for five different perfect crystallite structures: simple tetragonal, body-centered tetragonal, body-centered orthorhombic, hexagonal primitive, and hexagonal close packed. It was found that the most energetically favorable structure is the body-centered orthorhombic. Starting with an equilibrated polymer liquid and with the optimal parameters found for the body-centered orthorhombic, an isothermal treatment led to the formation of large lamellar crystallites with a typical chain topology: folded, loop, and tie chains, and with a crystallinity of about 60%-70%, similar to real semicrystalline polymers. This simple coarse-grained Lennard-Jones model provides a qualitative tool to study semicrystalline microstructures for polymers.

Clinical characteristics and factors associated with acute kidney injury among patients hospitalized with coronavirus disease: an observational retrospective study

ABSTRACT BACKGROUND: Coronavirus disease 19 (COVID-19) is a multisystemic disease with high incidence of acute kidney injury (AKI). OBJECTIVE: To describe the clinical characteristics and factors associated with AKI among patients hospitalized with COVID-19. DESIGN AND SETTING: Retrospective cohort conducted at Hospital Civil de Culiacan, Mexico. METHODS: We included 307 patients hospitalized due to COVID-19. AKI was defined and staged based on serum creatinine levels in accordance with the criteria of the Acute Kidney Injury Network (AKIN). Multivariate logistic regression analysis was used to determine factors associated with AKI. RESULTS: The patients' age was 56 ± 15 years (64.5% male). The incidence of AKI was 33.6% (n = 103). Overall, 53.4% of patients had community-acquired AKI, and 46.6% had hospital-acquired AKI. Additionally, 15.5% of them presented AKIN stage 1; 34% had AKIN stage 2; and 50.5% had AKIN stage 3. Hemodialysis was required for 10.7% of the patients. The factors associated with AKI were chronic kidney disease (odds ratio, OR: 10.8; P = 0.04), use of norepinephrine (OR: 7.3; P = 0.002), diabetes mellitus (OR: 2.9; P = 0.03), C-reactive protein level (OR: 1.005; P = 0.01) and COVID-19 severity index based on chest tomography (OR: 1.09; statistical trend, P = 0.07). Hospital stay (11 ± 7 days; P < 0.001) and mortality (83.5 versus 31.4%; P < 0.05) were greater among patients with AKI. CONCLUSION: AKI was a frequent and serious complication in our cohort of patients hospitalized with COVID-19, which was associated with high mortality and long hospital stay.

Pharmacological characterization of protease activated receptor-1 by a serum responsive element-dependent reporter gene assay: major role of calmodulin.

We studied the protease activated receptor-1 coupling to a serum response element (SRE)-dependent luciferase activity readout in transfected COS-7 cells. Thrombin, with a pEC50 of 10.5, was 3000-fold more potent than the peptide agonists SFLLR and its derived compound C721-40 in stimulating luciferase activity, although the three agonists exhibited similar efficacy at the maximal concentration tested. Interestingly, SFLLR- and C721-40-induced luciferase activity was biphasic, suggesting that at least two populations of G proteins couple to the receptor. Further pharmacological characterization of this system was performed using selective protease activated receptor-1 antagonists. SCH203099 and ER-112787 blocked SFLLR-induced luciferase activity with similar potencies (pK(B) of 7), slightly higher than that exhibited by an arylisoxazole derivative compound from Merck (pK(B) of 6.1). These values correlated with their affinities established by competition binding experiments using [3H]-C721-40 as radioligand for protease activated receptor-1. Transduction mechanisms of protease activated receptor-1 coupling to SRE-dependent luciferase activity were examined using specific inhibitors. The Ca2+ chelator BAPTA-AM, as well as the calmodulin inhibitors W-7 and ophiobolin A, robustly inhibited SFLLR-induced SRE activation. Overexpression of RGS2 and a dominant negative rhoA protein abolished the SFLLR signal in an additive manner, suggesting a major role of Gq and G12/13 proteins. Furthermore, inhibition of phospholipase C, MAP-kinases, phosphatidyl inositol-3 kinase, rho-kinase and Ca2+/calmodulin-dependent protein kinases, all downstream effectors of Gq and G12/13, partially blocked the SFLLR-induced luciferase signal. Taken together, this SRE-luciferase assay reveals a complex network of transduction pathways of protease activated receptor-1 in accordance with the pleiotrophic action of thrombin.

A sensitive multidimensional method for the detection, characterization, and quantification of trace free drug species in antibody-drug conjugate samples using mass spectral detection.

Conjugation processes and stability studies associated with the production and shelf life of antibody-drug conjugates (ADCs) can result in free (non-conjugated) drug species. These free drug species can increase the risk to patients and reduce the efficacy of the ADC. Despite stringent purification steps, trace levels of free drug species may be present in formulated ADCs, reducing the therapeutic window. The reduction of sample preparation steps through the incorporation of multidimensional techniques has afforded analysts more efficient methods to assess trace drug species. Multidimensional methods coupling size-exclusion and reversed phase liquid chromatography with ultra-violet detection (SEC-RPLC/UV) have been reported, but offer limited sensitivity and can limit method optimization. The current study addresses these challenges with a multidimensional method that is specific, sensitive, and enables method control in both dimensions via coupling of an on-line solid phase extraction column to RPLC with mass spectral detection (SPE-RPLC/MS). The proposed method was evaluated using an antibody-fluorophore conjugate (AFC) as an ADC surrogate to brentuximab vedotin and its associated parent maleimide-val-cit-DSEA payload and the derived N-acetylcysteine adduct formed during the conjugation process. Assay sensitivity was found to be 2 orders more sensitive using MS detection in comparison to UV-based detection with a nominal limit of quantitation of 0.30 ng/mL (1.5 pg on-column). Free-drug species were present in an unadulterated ADC surrogate sample at concentrations below 7 ng/mL, levels not detectable by UV alone. The proposed SPE-RPLC/MS method provides a high degree of specificity and sensitivity in the assessment of trace free drug species and offers improved control over each dimension, enabling straightforward integration into existing or novel workflows.

Plastic Deformation Mechanisms of Semicrystalline and Amorphous Polymers.

We use large-scale molecular dynamics simulations to investigate plastic deformation of semicrystalline polymers with randomly nucleated crystallites. The strain-softening regime is dominated by deformation of crystallites via reorientation of chain-folded lamellae toward the tensile axis, fragmentation of largest crystalline domains, and a partial loss of crystallinity. The strain-hardening regime coincides with unfolding of chains and recrystallization as a result of strain-induced chain alignment. These observed deformation mechanisms are consistent with experimental findings. We compare the tensile behavior of semicrystalline polymers with their amorphous counterparts at temperatures above and below the glass transition temperature.

Correlation of structure and mechanical response in solid-like polymers.

Employing large scale molecular dynamics simulations, we measure the uniaxial tensile response of amorphous and semicrystalline states of a coarse-grained PVA bead-spring model. The response beyond the elastic limit encompasses strain-softening and strain-hardening regimes. To understand the underlying mechanisms of plastic deformation, we analyse conformational and structural changes of polymers. In particular, we characterise the volume distribution of crystalline domains along the stress-strain curve. The strain-softening regime in semicrystalline samples is dominated by deformation of crystalline parts, while strain-hardening involves unfolding and alignment of chains in both amorphous and crystalline parts. Comparing the tensile response of semicrystalline and amorphous polymers, we find similar conformations of polymers for both systems in the strain-hardening regime.