A possible revival of population-representing digital human manikins in static work situations - exemplified through an evaluation of a prototype console for robotic surgery

BACKGROUND: In the 90s, digital human manikins (DHMs) were introduced in planning ofworkstations, by static or semi-static simulations. Modern DHMs can simulate dynamic work and offer a rapid way for a virtual pre-production ergonomic evaluation. Work-related musculoskeletal disorders may affect surgical performance and patient safety. A prototype of an open console, which is contrary to the conventional closed consoles and may be seen as a representative for a new generation, has been designed to reduce workload for robotic surgery surgeons. OBJECTIVE: The aim of this project was to test a new DHM tool with improved usability to evaluate the ergonomics of a console of a robotic surgical system in a pre-production stage. METHODS: The DHM tool IMMA was used together with a 3D model of the prototype console. Twelve manikins who represented females and males from two national populations were introduced. Manikin-console distances, after console adjustments per manikin, were compared with a US checklist and Swedish standard for VDU work. RESULTS: The DHM tool was useful for this case, but the distances of the checklist and the standard were needed to be obtained "manually". The automatic functions of the DHM worked smoothly but were not optimized for VDU work. The prototype fulfilled most, but not all, of the ergonomic criteria of the checklist and the standard. CONCLUSIONS: There is room for improvements of the adjustable ranges of the console prototype. DHMs may facilitate rapid pre-production evaluation of workstations for static work; if ergonomic assessment models for VDU work are built-in, there may be a revival of DHMs in static work situations

Plasma protein biomarkers for the detection of pancreatic neuroendocrine tumors and differentiation from small intestinal neuroendocrine tumors

There is an unmet need for novel biomarkers to diagnose and monitor patients with neuroendocrine neoplasms. The EXPLAIN study explores a multi-plasma protein and supervised machine learning strategy to improve the diagnosis of pancreatic neuroendocrine tumors (PanNET) and differentiate them from small intestinal neuroendocrine tumors (SI-NET). At time of diagnosis, blood samples were collected and analyzed from 39 patients with PanNET, 135 with SI-NET (World Health Organization Grade 1-2) and 144 controls. Exclusion criteria were other malignant diseases, chronic inflammatory diseases, reduced kidney or liver function. Prosed Oncology-II (i.e., OLink) was used to measure 92 cancer related plasma proteins. Chromogranin A was analyzed separately. Median age in all groups was 65-67 years and with a similar sex distribution (females: PanNET, 51%; SI-NET, 42%; controls, 42%). Tumor grade (G1/G2): PanNET, 39/61%; SI-NET, 46/54%. Patients with liver metastases: PanNET, 78%; SI-NET, 63%. The classification model of PanNET versus controls provided a sensitivity (SEN) of 0.84, specificity (SPE) 0.98, positive predictive value (PPV) of 0.92 and negative predictive value (NPV) of 0.95, and area under the receiver operating characteristic curve (AUROC) of 0.99; the model for the discrimination of PanNET versus SI-NET providing a SEN 0.61, SPE 0.96, PPV 0.83, NPV 0.90 and AUROC 0.98. These results suggest that a multi-plasma protein strategy can significantly improve diagnostic accuracy of PanNET and SI-NET.Peer reviewe

Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors.

Patients with small intestinal neuroendocrine tumors (SI-NETs) frequently develop spread disease; however, the underlying molecular mechanisms of disease progression are not known and effective preventive treatment strategies are lacking. Here, protein expression profiling was performed by HiRIEF-LC-MS in 14 primary SI-NETs from patients with and without liver metastases detected at the time of surgery and initial treatment. Among differentially expressed proteins, overexpression of the ubiquitin-like protein NEDD8 was identified in samples from patients with liver metastasis. Further, NEDD8 correlation analysis indicated co-expression with RBX1, a key component in cullin-RING ubiquitin ligases (CRLs). In vitro inhibition of neddylation with the therapeutic agent pevonedistat (MLN4924) resulted in a dramatic decrease of proliferation in SI-NET cell lines. Subsequent mass spectrometry-based proteomics analysis of pevonedistat effects and effects of the proteasome inhibitor bortezomib revealed stabilization of multiple targets of CRLs including p27, an established tumor suppressor in SI-NET. Silencing of NEDD8 and RBX1 using siRNA resulted in a stabilization of p27, suggesting that the cellular levels of NEDD8 and RBX1 affect CRL activity. Inhibition of CRL activity, by either NEDD8/RBX1 silencing or pevonedistat treatment of cells resulted in induction of apoptosis that could be partially rescued by siRNA-based silencing of p27. Differential expression of both p27 and NEDD8 was confirmed in a second cohort of SI-NET using immunohistochemistry. Collectively, these findings suggest a role for CRLs and the ubiquitin proteasome system in suppression of p27 in SI-NET, and inhibition of neddylation as a putative therapeutic strategy in SI-NET

Genetic characterization of adrenocortical tumors

Adrenocortical cancer is a rare tumor form. However, adrenal tumors are today often found incidentally when using imaging techniques on the upper abdomen and should then be investigated. With the advance in molecular understanding of cancer new approaches to manage the disease may become available. We screened malignant and benign adrenocortical tumors (ACT) for gross genetic alterations using comparative genomic hybridization and microsatellite markers with the aim to find chromosomal regions that may harbour oncogenes, tumor suppressor genes, or mutator genes. Chromosomes 4 and 5 were found to possibly harbour oncogenes whereas chromosomes 2, 11, 17 and 18 may harbour tumor suppressor genes of importance for the development and progression of ACT. Furthermore, the study indicates that fundamental genetic changes take place in ACT larger than 4 cm. Because the tumor syndromes, Carney complex (CC) and Multiple endocrine neoplasia type I (MEN 1), are located on chromosome 2p16 and 11q13, respectively, these regions were further investigated. A one centi Morgan region, located distal to the CC locus, was defined by deletion mapping and may harbour TSGs of importance for the malignant transition of ACT. Furthermore, the 11q13 locus was frequently deleted in malignant ACT but no mutations were found in the MEN1 gene. It will be appropriate to investigate the transcriptional regulating region of the gene as well as epigenetic changes, such as the imprinting status. However, another gene(s) with TSG function may show to cause the frequent percentage of deletions at this locus. Another candidate gene, the IGF2 gene (11pl5) has been suggested to contribute to neoplastic cell proliferation and increase of its transcripts has been found in ACT. Studies of the IGF2 gene showed two novel splicing events which was also found in a Hep 3B cell line. The function of these splicing events is unknown. The suspected high prevalence of undiagnosed mild congenital adrenal hyperplasia (CAH), together with the high frequency of sporadic ACT in the population, has led to the speculation that mild undiagnosed CAH, or the heterozygous carrier state, is a predisposing factor for the development and/or progression of this tumor form. To investigate if mild CAH may be overrepresented in patients with apparently sporadic ACT we screened for constitutional mutations in the CYP21 gene. As no mutations were found we conclude that patients with ACT do not need to be screened for CAH. Gelatinase A is a metalloproteinase important in the process of tumor invasion and metastasis. Analyzes of mRNA expression of gelatinase A and its activator MT1-MMP showed increased levels in malignant as compared with benign ACT. These findings suggests that proteolytic enzymes are important for the malignant behaviour of ACT

IWW transport of recycling volumes

As a part of the Interreg Baltic Sea Region project “EMMA”, M4Traffic has been given the task to investigate certain goods flows in the Mälaren Valley to find whether it is possible to use Inland Waterway (IWW) as a part of the transport chain. In collaboration with the Swedish Transport Administration, three such flows were identified; • Return-packaging - Paper, glass, newspaper, metal and plastic - Aluminium cans and PET-bottle• Household waste• Sand and gravel as well as snow cleared from the streets during winter.After consideration it was decided that this report will be focusing on return packaging, more specifically general household packages and newspapers (FTIAB) and aluminium cans and plastic bottles (Returpack). In addition, a short survey of existing academic literature was conducted to give some supplementary context, as well as a brief cost benefit analysis in order to compare costs related to different transport systems.EMMA - inre vattenväga

Initial clinical presentation and spectrum of pheochromocytoma: a study of 94 cases from a single center

Background: With the increasing access to imaging more pheochromocytomas are diagnosed in the workup of adrenal incidentalomas. This may have changed the occurrence of the classic presentation with hypertension and the classic triad (headaches, sweating and palpitation). Methods: We reviewed 94 consecutive cases of pheochromocytomas. Two cases of ectopic ACTH-syndrome were subsequently excluded. Results: Of the 92 cases included 64% had presented as an incidentaloma, 32% as a suspected pheochromocytoma and 4% had been screened because of previously diagnosed MEN2A. Those screened were youngest while those with incidentalomas were oldest. The females were more common in the incidentaloma and the screening groups, and males in the suspected pheochromocytoma group. Measurements of noradrenaline/ normetanephrine levels were highest in the suspected pheocromocytoma group and lowest in the screening group. Hypertension was present in 63% of the incidentalomas, 79% of suspected pheochromocytomas and in none of the screening group. Paroxysmal symptoms were present in almost all with suspected pheochromocytoma while only in half of the other groups. The suspected pheocromocytoma group had most symptoms and the screening group least. The classic triad was present in 14% of the incidentalomas, in 28% of the suspected and in none of the screening group, while no symptoms at all was present in 12%, 0% and 25%, respectively. Pheochromocytoma crisis occurred in 5%. There was a positive correlation between tumor size vs hormone levels, and catecholamine levels vs blood pressure. Conclusion: Clinicians need to be aware of the modern presentation of pheochromocytomas since early identification can be life-saving

Chemokine-directed migration of tumor-inhibitory neural progenitor cells towards an intracranially growing glioma.

We have earlier shown that the rat neural progenitor cell line HiB5 is capable of suppressing intracranial growth of glioma cells in Fisher rats. Unlike some neural progenitor cells, HiB5 cells have not shown homing capacity towards glioma cells growing intracranially. In this study, we have genetically modified HiB5 progenitor cells to over-express the chemokine receptor CXCR3. We show that the introduced receptor is functionally responding to ligand stimulation with increased phosphorylation levels of ERK and SAPK/JNK and a transcriptional response of an AP-1 reporter system introduced into HIB5 cells. These transfected progenitor cells migrate in vitro in response to IP-10 and I-TAC. Further, we show an enhanced in vivo migration of the CXCR3 transfected HiB5 cells over the corpus callosum towards an IP-10 and I-TAC expressing glioma, as compared to wild type HiB5 cells. Our data indicate that it is possible to take advantage of chemokines natural capacity to initiate migratory responses, and to use this ability to enhance tumor-inhibitory neural progenitor cells to target an intracranially growing glioma