3D Multi-Scale Behavior of Granular Materials using Experimental and Numerical Techniques

Constitutive modeling of granular material behavior has generally been based on global response of laboratory-size specimens or larger models with little understanding of the fundamental mechanics that drive the global response. Many studies have acknowledged the importance of micro-scale and meso-scale mechanics on the constitutive behavior of granular materials. However, much knowledge is still missing to develop and improve robust micromechanical constitutive models. The research in this dissertation contributes to this knowledge gap for many potential applications using novel experimental techniques to investigate the three-dimensional (3D) behavior of granular materials. Critical micromechanics measurements at multiple scales are investigated by combining 3D synchrotron micro-computed tomography (SMT), 3D image analysis, and finite element analysis (FEA). At the single particle level (micro-scale), particle fracture was examined at strain rates of 0.2 mm/min and 2 m/s using quasi-static unconfined compression, unconfined mini-Kolsky bar, and x-ray imaging techniques. Surface reconstructions of particles were generated and exported to Abaqus FEA software, where quasi-static and higher rate loading curves and crack propagation were simulated with good accuracy. Stress concentrations in oddly shaped particles during FEA simulations resulted in more realistic fracture stresses than theoretical models. A nonlinear multivariable statistical model was developed to predict force required to fracture individual particles with known internal structure and loading geometry. At the meso-scale, 3D SMT imaging during in-situ triaxial testing of granular materials were used to identify particle morphology, contacts, kinematics and interparticle behavior. Micro shear bands (MSB) were exposed during pre-peak stress using a new relative particle displacement concept developed in this dissertation. MSB for spherical particles (glass beads) had larger thickness (3d50 to 5d50) than that of angular sands (such as F35 Ottawa sand, MSB thickness of 1d50 to 3d50). Particle morphology also plays a significant role in the onset and growth of shear bands and global fabric evolution of granular materials. More spherical particles typically exhibit more homogeneous internal anisotropy. Fabric of particles within the shear band (at higher densities and confining pressures) exhibits a peak and decrease into steady-state. Also, experimental fabric produces more accurate strength and deformation predictions in constitutive models that incorporate fabric evolution

Micro shear bands: Precursor for strain localization in sheared granular materials

Recent studies have shown that detection of the onset and evolution of micro shear bands (MSBs) in granular materials can be improved using measurements of the kinematic behavior of particles. Different methods such as the discrete-element method (DEM) or threedimensional (3D) imaging techniques have been used to measure the kinematics of individual particles within triaxial specimens. However, conventional kinematic techniques that use particle translation and/or rotation cannot detect the onset and growth of MSBs during the hardening phase of axisymmetric triaxial experiments. In order to expose the localized shearing and particle-scale behavior of triaxial specimens, a relative particle translation gradient (RPTG) concept is used to detect and expose the onset of strain localization before the peak principal stress ratio (PSR). RPTG measurements for four different granular materials are reported in this paper. The RPTG concept is used to expose the onset of MSBs during the hardening phase of the experiments. In addition, the contact number of individual particles is quantified and discussed in relation to particle rotation to investigate a particle-scale relationship between particle contacts and rotation. The effects of density, confining pressure, and particle shape on contact number are examined.The research is funded by the US National Science Foundation (NSF) under Grant Nos. CMMI-1266230 and CMMI-1362510. Any opinions, findings, and conclusions or recommendations expressed in this paper are those of the authors and do not necessarily reflect the views of the NSF. The SMT images presented in this paper were collected using the X-Ray Operations and Research Beamline Station 13-BMD at Argonne Photon Source (APS), a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. The authors acknowledge the support of GeoSoilEnviroCARS (Sector 13), which is supported by NSF-Earth Sciences (EAR-1128799), and DOE, Geosciences (DE-FG02-94ER14466). The authors thank Dr. Mark Rivers of APS for help performing the SMT scans

Wirkung carcinostatischer äthylenimin-verbindungen auf den DPN-gehalt therapieresistener tumoren

Preliminary experiments with the ascites form of the relatively therapeutic-resistant DS-tumour demonstrated that the decrease in DPN content and the inhibition of glycolysis in the neoplastic cells under the influence of ethylenimine compounds were delayed, in comparison with the rapid changes observed in Ehrlich-ascites carcinomas. Extending these observations, the therapeutic effect of carcinostatic ethylenimine compounds was studied in rats bearing solid forms of either the Jensen sarcoma or the therapeutic-resistant DS-tumour. During the course of the experiments the DPN content of the tumours was followed. In the Jensen sarcoma the DPN content decreased sharply as early as the first day following administration of the carcinostatic, while the DS-tumour, in contrast, showed no clear change during the first six days. A cure was obtained in nine out of thirteen cases of the Jensen-sarcoma rats, while no cure was observed in six DS-tumour-bearing rats. These experiments further support our hypothesis, that carcinostatic ethylenimine compounds are therapeutically effective though they depress the DPN content in the tumour

A qualitative study on people with opioid use disorders’ perspectives on smoking and smoking cessation interventions

Introduction: Smoking-related diseases are major contributors to disability and shorter life expectancy among opioid-dependent patients. Smoking prevalence is considerably higher for opioid-dependent persons than among the general population, and only a minority quit smoking in treatment settings. Studies show that pharmacological smoking cessation interventions have modest success rates. This study aimed to investigate patients’ receiving opioid agonist therapy perspectives on factors affecting behavior and decisions related to smoking cessation, and their experiences with smoking cessation. Methods: This is a qualitative study using semi-structured individual interviews. The participants were asked, among others, to elaborate on the participants’ thoughts about smoking, previous attempts to quit tobacco use, and what could prompt a smoking cessation attempt. We analyzed the transcripts with systematic text condensation. The Standards for Reporting Qualitative Research and the Consolidated Criteria for Reporting Qualitative Research guidelines were followed. Opioid-dependent patients receiving opioid agonist therapy in outpatient clinics were invited to participate using a purposive sampling method. In total, fourteen individuals participated in this study. Results: We identified six themes which were: (1) reflections on how smoking affected decisions, (2) smoking and its impact on physical and mental health, (3) the economy as a motivator to stop smoking, (4) emotions, desires, and habits related to smoking, (5) knowledge of smoking, smoking cessation, and quit attempts, and (6) social factors influencing the participants’ choices and activities. The participants were well informed about the consequences of smoking and had some knowledge and experience in quitting. The participants’ pulmonary health was an important motivational factor for change. Withdrawal symptoms, anxiety, and fear of using other substances discouraged several from attempting to quit smoking. In contrast, social support from partners and access to meaningful activities were considered important factors for success. Few reported being offered help from health professionals to make a smoking cessation attempt. Discussion: Experiencing social support, being encouraged to quit smoking, and patients’ concerns for their physical health were important reasons for wanting to quit smoking. Smoking cessation interventions based on patient preferences and on the behavior change wheel may enable a higher success rate among patients receiving opioid agonist therapy.publishedVersio

Effect of fruit smoothie supplementation on psychological distress among people with substance use disorders receiving opioid agonist therapy: protocol for a randomised controlled trial (FruktBAR)

Background: People with substance use disorders generally have unhealthy diets, including limited intake of fruit and vegetables. Evidence shows substantial health benefits from increasing fruit and vegetable consumption on various indicators and possibly also psychological distress. A pilot study has indicated that supplementation with fruit smoothie could be promising also among people receiving opioid agonist therapy for opioid dependence. FruktBAR will compare the efficacy of added fruit smoothie supplementation to people receiving opioid agonist therapy compared to standard treatment without added supplementation. Methods: FruktBAR is a multicentre, randomised controlled trial. The trial will aim to recruit 302 patients receiving opioid agonist therapy. The intervention involves daily supplementation with 250 ml fruit smoothie including a variety of fruits such as apple, pineapple, mango, bananas, orange, blueberries, passion fruit, coconut, lime, and blackcurrant. The main endpoints are 16 weeks after intervention initiation. Participants will be included and followed up during and after the intervention. The target group will be patients with opioid dependence receiving opioid agonist therapy from involved outpatient clinics in Bergen and Stavanger, two of the largest cities in Norway. The main outcome is psychological distress assessed with Hopkins Symptom Checklist (SCL-10) at the end of the intervention period 16 weeks after initiation, and will be compared between the intervention and control arms. Secondary outcome measures are changes in fatigue, physical functioning assessed with a 4-minute step-test, health-related quality of life, biochemical indicators of inflammation, and biochemical indicators of fruit intake. Discussion: This study will inform on the relative advantages or disadvantages of fruit supplementation in addition to the current medically and psychologically oriented treatment of people receiving opioid agonist therapy. If the supplementation is efficacious, it can be considered for further scale-up.publishedVersio

Impact of liver fibrosis and clinical characteristics on dose-adjusted serum methadone concentrations

Background There is limited knowledge on the causes of large variations in serum methadone concentrations and dose requirements. Objectives We investigated the impact of the degree of liver fibrosis on dose-adjusted steady-state serum methadone concentrations. Methods We assessed the clinical and laboratory data of 155 Norwegian patients with opioid use disorder undergoing methadone maintenance treatment in outpatient clinics in the period 2016–2020. A possible association between the degree of liver fibrosis and dose-adjusted serum methadone concentration was explored using a linear mixed-model analysis. Results When adjusted for age, gender, body mass index, and genotypes of CYP2B6 and CYP3A5, the concentration-to-dose ratio of methadone did not increase among the participants with liver fibrosis (Coefficient: 0.70; 95% CI: −2.16, 3.57; P: 0.631), even among those with advanced cirrhosis (−0.50; −4.59, 3.59; 0.810). Conclusions Although no correlation was found between the degree of liver stiffness and dose-adjusted serum methadone concentration, close clinical monitoring should be considered, especially among patients with advanced cirrhosis. Still, serum methadone measurements can be considered a supplement to clinical assessments, taking into account intra-individual variations.publishedVersio

Efficacy of EGFR Inhibition Is Modulated by Model, Sex, Genetic Background and Diet: Implications for Preclinical Cancer Prevention and Therapy Trials

Molecule-targeted therapies are being widely developed and deployed, but they are frequently less effective in clinical trials than predicted based upon preclinical studies. Frequently, only a single model or genetic background is utilized using diets that are not relevant to that consumed by most cancer patients, which may contribute to the lack of predictability of many preclinical therapeutic studies. Inhibition of epidermal growth factor receptor (EGFR) in colorectal cancer was used to investigate potential causes for low predictive values of many preclinical studies. The efficacy of the small molecule EGFR inhibitor AG1478 was evaluated using two mouse models, ApcMin/+ and azoxymethane (AOM), both sexes on three genetic backgrounds, C57BL/6J (B6) and A/J (A) inbred strains and AB6F1 hybrids, and two diets, standard chow (STD) or Western-style diet (WD). AG1478 has significant anti-tumor activity in the B6-ApcMin/+ model with STD but only moderately on the WD and in the AOM model on an A background with a WD but not STD. On the F1 hybrid background AG1478 is effective in the ApcMin/+ model with either STD or WD, but has only moderate efficacy in the AOM model with either diet. Sex differences were also observed. Unexpectedly, the level of liver EGFR phosphorylation inhibition by AG1478 was not positively correlated with inhibition of tumor growth in the AOM model. Model-dependent interactions between genetic background and diet can dramatically impact preclinical results, and indicate that low predictive values of preclinical studies can be attributed to study designs that do not account for the heterogeneous patient population or the diets they consume. Better-designed preclinical studies should lead to more accurate predictions of therapeutic response in the clinic

Histological and Molecular Evaluation of Patient-Derived Colorectal Cancer Explants

Mouse models have been developed to investigate colorectal cancer etiology and evaluate new anti-cancer therapies. While genetically engineered and carcinogen-induced mouse models have provided important information with regard to the mechanisms underlying the oncogenic process, tumor xenograft models remain the standard for the evaluation of new chemotherapy and targeted drug treatments for clinical use. However, it remains unclear to what extent explanted colorectal tumor tissues retain inherent pathological features over time. In this study, we have generated a panel of 27 patient-derived colorectal cancer explants (PDCCEs) by direct transplantation of human colorectal cancer tissues into NOD-SCID mice. Using this panel, we performed a comparison of histology, gene expression and mutation status between PDCCEs and the original human tissues from which they were derived. Our findings demonstrate that PDCCEs maintain key histological features, basic gene expression patterns and KRAS/BRAF mutation status through multiple passages. Altogether, these findings suggest that PDCCEs maintain similarity to the patient tumor from which they are derived and may have the potential to serve as a reliable preclinical model that can be incorporated into future strategies to optimize individual therapy for patients with colorectal cancer