The local anisotropic mechanical foam properties of continuously produced polyisocyanurate metal panels were investigated. The main focus was the analysis of the anisotropic cell structure. Based on ...these investigations, a mesoscale FE-model of a representative volume element (RVE) was validated, which can provide a prediction of the mechanical properties of anisotropic foam structures with varying aspect ratios and orientations of the cells based on defined ellipsoid packings and an anisotropic tessellation model. During the validation of the model, the parameters mesh size, RVE size and strut partitioning were investigated. Due to the anisotropic cell structures, a method was developed to determine a directional RVE size, which has distinct advantages over cube-shaped RVEs. Finally, a comparison of experimental to numerical results was performed. Both in the experiment and the simulation, the structures show a strongly anisotropic behavior, whereby the degree of anisotropy tends to be slightly underestimated in the simulation. Despite small deviations, the simulation results are in good agreement with the experimental data. Accordingly, this simulation model is suitable for an estimation of the anisotropic mechanical foam properties.
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•Analysis of the local properties of anisotropic polyisocyanurate foams.•Modeling of anisotropic foam structures with varying aspect ratios and orientations.•Comparison of experimental and numerical results.
Glioblastoma is a highly lethal adult brain tumor with no effective treatments. In this review, we discuss the potential to target cholesterol metabolism as a new strategy for treating glioblastomas. ...Twenty percent of cholesterol in the body is in the brain, yet the brain is unique among organs in that it has no access to dietary cholesterol and must synthesize it de novo. This suggests that therapies targeting cholesterol synthesis in brain tumors might render their effects without compromising cell viability in other organs. We will describe cholesterol synthesis and homeostatic feedback pathways in normal brain and brain tumors, as well as various strategies for targeting these pathways for therapeutic intervention.
Macroautophagy (autophagy) is a regulated catabolic pathway to degrade cellular organelles and macromolecules. The role of autophagy in cancer is complex and may differ depending on tumor type or ...context. Here we show that pancreatic cancers have a distinct dependence on autophagy. Pancreatic cancer primary tumors and cell lines show elevated autophagy under basal conditions. Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. Together, these ultimately result in significant growth suppression of pancreatic cancer cells in vitro. Most importantly, inhibition of autophagy by genetic means or chloroquine treatment leads to robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models. These results suggest that, unlike in other cancers where autophagy inhibition may synergize with chemotherapy or targeted agents by preventing the up-regulation of autophagy as a reactive survival mechanism, autophagy is actually required for tumorigenic growth of pancreatic cancers de novo, and drugs that inactivate this process may have a unique clinical utility in treating pancreatic cancers and other malignancies with a similar dependence on autophagy. As chloroquine and its derivatives are potent inhibitors of autophagy and have been used safely in human patients for decades for a variety of purposes, these results are immediately translatable to the treatment of pancreatic cancer patients, and provide a much needed, novel vantage point of attack.
This prospective nationwide cohort study examined the feasibility of a watchful-waiting protocol for non-functional pancreatic neuroendocrine tumours (NF-pNET) of 2 cm or smaller. In total, 8 of 76 ...patients (11 per cent) with a NF-pNET no larger than 2 cm showed significant tumour progression (more than 0.5 cm/year) during 17 months of follow-up, of whom two opted for resection. No patient developed metastases. Quality of life was poorer than in the reference population. Watchful waiting seems a safe alternative to upfront surgery in patients with a NF-pNET no larger than 2 cm, although longer follow-up is necessary.
Centralization of pancreatic surgery in the Netherlands has been ongoing since 2011. The aim of this study was to assess how centralization has affected the likelihood of resection and survival of ...patients with non-metastatic pancreatic head and periampullary cancer, diagnosed in hospitals with and without pancreatic surgery services.
An observational cohort study was performed on nationwide data from the Netherlands Cancer Registry (2009-2017), including patients diagnosed with non-metastatic pancreatic head or periampullary cancer. The period of diagnosis was divided into three time intervals: 2009-2011, 2012-2014 and 2015-2017. Hospital of diagnosis was classified as a pancreatic or non-pancreatic surgery centre. Analyses were performed using multivariable logistic and Cox regression models.
In total, 10 079 patients were included, of whom 3114 (30.9 per cent) were diagnosed in pancreatic surgery centres. Between 2009-2011 and 2015-2017, the number of patients undergoing resection increased from 1267 of 3169 (40.0 per cent) to 1705 of 3566 (47.8 per cent) (P for trend < 0.001). In multivariable analysis, in 2015-2017, unlike the previous periods, patients diagnosed in pancreatic and non-pancreatic surgery centres had a similar likelihood of resection (odds ratio 1.08, 95 per cent c.i. 0.90 to 1.28; P = 0.422). In this period, however, overall survival was higher in patients diagnosed in pancreatic surgery than in those diagnosed in non-pancreatic surgery centres (hazard ratio 0.92, 95 per cent c.i. 0.85 to 0.99; P = 0.047).
After centralization of pancreatic surgery, the resection rate for patients with pancreatic head and periampullary cancer diagnosed in non-pancreatic surgery centres increased and became similar to that in pancreatic surgery centres. Overall survival remained higher in patients diagnosed in pancreatic surgery centres.
Over the past decades, health care services for pancreatic surgery were reorganized. Volume norms were applied with the result that only a limited number of expert centers perform pancreatic surgery. ...As a result of this centralization of pancreatic surgery, the patient journey of patients with pancreatic tumors has become multi-institutional. To illustrate, patients are referred to a center of expertise for pancreatic surgery whereas other parts of pancreatic care, such as chemotherapy, take place in local hospitals. This fragmentation of health care services could affect continuity of care (COC). The aim of this study was to assess COC perceived by patients in a pancreatic care network and investigate correlations with patient-and care-related characteristics.
This is a pilot study in which patients with (pre) malignant pancreatic tumors discussed in a multidisciplinary tumor board in a Dutch tertiary hospital were asked to participate. Patients were asked to fill out the Nijmegen Continuity of Care-questionnaire (NCQ) (5-point Likert scale). Additionally, their patient-and care-related data were retrieved from medical records. Correlations of NCQ score and patient-and care-related characteristics were calculated with Spearman's correlation coefficient.
In total, 44 patients were included (92% response rate). Pancreatic cancer was the predominant diagnosis (32%). Forty percent received a repetition of diagnostic investigations in the tertiary hospital. Mean scores for personal continuity were 3.55 ± 0.74 for GP, 3.29 ± 0.91 for the specialist and 3.43 ± 0.65 for collaboration between GPs and specialists. Overall COC was scored with a mean 3.38 ± 0.72. No significant correlations were observed between NCQ score and certain patient-or care-related characteristics.
Continuity of care perceived by patients with pancreatic tumors was scored as moderate. This outcome supports the need to improve continuity of care within multi-institutional pancreatic care networks.
To investigate temporal changes in the bias associated with self-reported (as opposed to measured) body mass index (BMI) and explore the relationship of such bias to changing social attitudes towards ...obesity.
Using data from the National Health and Nutrition Examination Survey covering two time periods, 1988-1994 and 2005-2008, discrepancy scores between self-reported vs measured BMI were generated. Changes in the sensitivity of BMI categories based on self-reports were examined for six weight groups, both for the US adult population as a whole and major demographic groups. Linear regression models were used to examine temporal changes in average bias, as well as attitudes about weight within each weight category and by demographic group.
Between 2005-2008 and 1988-1994, the bias towards underestimation of a person's BMI based on interview responses has declined among obese individuals, a trend evident in virtually all demographic subgroups explored. Conversely, most demographic groups showed little change in the extent of bias among underweight and normal-weight individuals. Although the 2005-2008 survey respondents underestimated their measured BMI more than the 1988-1994 respondents, this shift can be entirely explained by the increased prevalence of obesity in more recent years. In fact, obese individuals in 2005-2008 were less likely to overreport their height and underreport their weight than their counterparts in the 1988-1994. Evidence from responses to questions about ideal weight and desire to lose weight point in the direction of a shift in social attitudes, which may make it easier to 'admit' to greater weight in surveys.
Over the past 20 years, the bias in self-reported height and weight has declined leading to more accurate BMI categorizations based on self-report. This change is likely to affect efforts to find correction factors to adjust BMI scores based on self-reported height and weight.
Malignant astrocytic gliomas such as glioblastoma are the most common and lethal intracranial tumors. These cancers exhibit a relentless malignant progression characterized by widespread invasion ...throughout the brain, resistance to traditional and newer targeted therapeutic approaches, destruction of normal brain tissue, and certain death. The recent confluence of advances in stem cell biology, cell signaling, genome and computational science and genetic model systems have revolutionized our understanding of the mechanisms underlying the genetics, biology and clinical behavior of glioblastoma. This progress is fueling new opportunities for understanding the fundamental basis for development of this devastating disease and also novel therapies that, for the first time, portend meaningful clinical responses.
p53 activation prevents the proliferation of genetically unstable cells. Conversely, p53 antagonism by its transcriptional target, the E3 ubiquitin ligase MDM2, is critical for the viability of ...unstressed, cycling cells. We demonstrate that MDM2 induces the degradation of p53 in both the nucleus and the cytoplasm. As p53 and MDM2 accumulate in the nuclei of stressed cells, we investigated mechanisms enabling p53 activation despite the high MDM2 levels generated during a DNA‐damage response. We show that DNA damage destabilized MDM2 by a mechanism involving damage‐activated kinases and MDM2 auto‐ubiquitination. p53 was stable and transcriptionally active when MDM2 was unstable, but became unstable and inactive as the damage response waned and MDM2 stabilized. Importantly, blocking MDM2 destabilization in DNA‐damaged cells prevented p53 target gene activation. Our data reveal that controlled MDM2 degradation is an important new step in p53 regulation.
Adverse events in surgical patients can occur preoperatively, intraoperatively, and postoperatively. Universally accepted classification systems are not yet available for intraoperative adverse ...events (iAEs). ClassIntra has recently been developed and validated as a tool for grading iAEs that occur between skin incision and skin closure irrespective of the origin, that is, surgery, anesthesia, or organizational. The aim of this study is to assess the inter-rater agreement of ClassIntra and assess its predictive value for postoperative complications in elective abdominal surgery.
This study is a secondary use of data from the LAParotomy or LAParoscopy and ADhesiolysis (LAPAD) study, with detailed data on incidence and management of intra-operative and post-operative complications. Data were collected in a cohort of elective abdominal surgeries. Two teams graded all recorded events in the LAPAD study according to ClassIntra. Cohen Kappa coefficient was calculated to determine inter-rater agreement. Uni- and multivariable linear regression was used to assess the predictive value of the ClassIntra grades for postoperative complications.
IAEs were rated in 333 of 755 (44%) surgeries by team 1, and in 324 of 755 (43%) surgeries by team 2. Cohen kappa coefficient for ClassIntra grades was 0.87 95% confidence interval (CI) 0.84-0.90. Discrepancies in grading were most frequent for intraoperative bleeding and adhesions' associated injuries. At least 1 postoperative complication was observed in 278 (37%) patients. The risk of a postoperative complications increased with every increase in severity grade of ClassIntra. Intraoperative hypotension mean difference (MD) 23.41, 95% CI 12.93-33.90 and other organ injuries (MD 18.90, 95% CI -4.22 - 42.02) were the strongest predictors for postoperative complications.
ClassIntra has an almost perfect inter-rater agreement for the classification of iAEs. An increasing grade of ClassIntra was associated with a higher incidence of postoperative complications. Discrepancies in grading related to common complications in abdominal procedures mostly consisted of intraoperative bleeding and adhesion-related injuries. Grading of interoperative events in abdominal surgery might further improve by consensus regarding the definitions of a number of frequent events.
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