Optimised dragline planning model

The presenting company provided data for typical operating parameters used in dragline operation. The problem for the Study Group was to investigate whether an optimal model of dragline operation could be developed. The Study Group modelled the sequence of operations for a typical surface mining strip. Overall, a simulation approach seems necessary to fully represent the dragline operation. Some aspects of the operations that are amenable to optimisation are described in this report

Blending methodologies in talc operations

The problem posed by Western Mining Corporation involves finding a way of improving or optimising the utilisation of batches of lower grade talc when making up orders for products of different grades. During the MISG a number of Linear Programming models were developed. These models addressed the problems of blending batches of talc for a single order and of blending to meet a series of orders for different products over a specified planning horizon. Preliminary versions of the models were tested using data supplied by Western Mining Corporation

Preclinical evaluation of EpCAM-binding designed ankyrin repeat proteins (DARPins) as targeting moieties for bimodal near-infrared fluorescence and photoacoustic imaging of cancer

PURPOSE Fluorescence-guided surgery (FGS) can play a key role in improving radical resection rates by assisting surgeons to gain adequate visualization of malignant tissue intraoperatively. Designed ankyrin repeat proteins (DARPins) possess optimal pharmacokinetic and other properties for in vivo imaging. This study aims to evaluate the preclinical potential of epithelial cell adhesion molecule (EpCAM)-binding DARPins as targeting moieties for near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging of cancer. METHODS EpCAM-binding DARPins Ac2, Ec4.1, and non-binding control DARPin Off7 were conjugated to IRDye 800CW and their binding efficacy was evaluated on EpCAM-positive HT-29 and EpCAM-negative COLO-320 human colon cancer cell lines. Thereafter, NIRF and PA imaging of all three conjugates were performed in HT-29_luc2 tumor-bearing mice. At 24 h post-injection, tumors and organs were resected and tracer biodistributions were analyzed. RESULTS Ac2-800CW and Ec4.1-800CW specifically bound to HT-29 cells, but not to COLO-320 cells. Next, 6 nmol and 24 h were established as the optimal in vivo dose and imaging time point for both DARPin tracers. At 24 h post-injection, mean tumor-to-background ratios of 2.60 ± 0.3 and 3.1 ± 0.3 were observed for Ac2-800CW and Ec4.1-800CW, respectively, allowing clear tumor delineation using the clinical Artemis NIRF imager. Biodistribution analyses in non-neoplastic tissue solely showed high fluorescence signal in the liver and kidney, which reflects the clearance of the DARPin tracers. CONCLUSION Our encouraging results show that EpCAM-binding DARPins are a promising class of targeting moieties for pan-carcinoma targeting, providing clear tumor delineation at 24 h post-injection. The work described provides the preclinical foundation for DARPin-based bimodal NIRF/PA imaging of cancer

Geoarchaeological and palaeontological research in the Maasvlakte 2 sand extraction zone and on the artificially created Maasvlakte 2 beach: a synthesis

Zooarchaeolog

Tissue level, activation and cellular localisation of TGF-β1 and association with survival in gastric cancer patients

Transforming growth factor-β1 (TGF-β1), a tumour suppressing as well as tumour-promoting cytokine, is stored as an extracellular matrix-bound latent complex. We examined TGF-β1 activation and localisation of TGF-β1 activity in gastric cancer. Gastric tumours showed increased stromal and epithelial total TGF-β1 staining by immunohistochemistry. Active TGF-β1 was present in malignant epithelial cells, but most strongly in smooth muscle actin expressing fibroblasts. Normal gastric mucosa from the same patient showed some staining for total, and little for active TGF-β1. Active TGF-β1 levels were determined by ELISA on tissue homogenates, confirming a strong increase in active TGF-β1 in tumours compared to corresponding normal mucosa. Moreover, high tumour TGF-β1 activity levels were significantly associated with clinical parameters, including worse survival of the patients. Total and active TGF-β1 levels were not correlated, suggesting a specific activation process. Of the different proteases tested, active TGF-β1 levels were only correlated with urokinase activity levels. The correlation with urokinase activity suggests a role for plasmin in TGF-β1 activation in the tumour microenvironment, resulting in transformation of resident fibroblasts to tumour promoting myofibroblasts. In conclusion we have shown localisation and clinical relevance of TGF-β1 activity levels in gastric cancer

Identifying Biomarkers in Lymph Node Metastases of Esophageal Adenocarcinoma for Tumor-Targeted Imaging

INTRODUCTION: Tumor-targeted imaging is a promising technique for the detection of lymph node metastases (LNM) and primary tumors. It remains unclear which biomarker is the most suitable target to distinguish malignant from healthy tissue in esophageal adenocarcinoma (EAC). OBJECTIVE: We performed an immunohistochemistry study to identify viable tumor markers for tumor-targeted imaging of EAC. METHODS: We used samples from 72 patients with EAC to determine the immunohistochemical expression of ten potential tumor biomarkers for EAC (carbonic anhydrase IX [CA-IX], carcinoembryonic antigen [CEA], hepatic growth factor receptor, epidermal growth factor receptor, epithelial membrane antigen [EMA], epithelial cell adhesion molecule [EpCAM], human epidermal growth factor receptor 2 [HER-2], urokinase plasminogen activator receptor, vascular endothelial growth factor-A [VEGF-A], and VEGF receptor 2). Immunohistochemistry was performed on tissue microarrays of LNM (n = 48), primary EACs (n = 62), fibrotic tissues (n = 11), nonmalignant lymph nodes (n = 24), and normal esophageal and gastric tissues (n = 40). Tumor marker staining was scored on intensity and percentage of positive cells. RESULTS: EMA and EpCAM showed strong expression in LNM (> 95%) and primary EACs (> 95%). Significant expression was also observed for LNM and EAC using VEGF-A (85 and 92%), CEA (68 and 54%), and CA-IX (4 and 34%). The other tumor biomarkers showed expression of 0-15% for LNM and primary EAC. Except for VEGF-A, nonmalignant lymph node staining was scored as slight or absent. CONCLUSIONS: High expression rates and correlation between LNM in EAC combined with low expression rates in healthy lymph nodes and esophagus tissues were observed for EpCAM and CEA, meaning these are promising targets for tumor-targeted imaging approaches for lymph nodes in patients with EAC

Ativação de neutrófilos de indivíduos saudáveis e imunocomprometidos por promastigotas de Leishmania spp.

Os neutrófilos são as primeiras células polimorfonucleares do sistema imunitário inato a chegar ao local de infeção, constituindo a primeira linha de defesa contra agentes invasores, como no caso do parasita Leishmania. Este parasita é causador da leishmaniose que tem sido reportada em mais de 98 países e que pode afetar animais e seres humanos. As diferentes espécies do parasita podem causar leishmaniose com diferentes apresentações clinicas, das quais salientamos a leishmaniose visceral e a leishmaniose cutânea. O presente trabalho teve como objetivo analisar a resposta imunitária de células polimórficas nucleares (PMN) de indivíduos com diferentes competências imunitárias quando expostas a parasitas de espécies viscerais (L. infantum) e cutâneas (L. amazonensis, L. shawi e L. guyanensis). A internalização parasitária foi confirmada por microscopia optica. A ativação celular foi avaliada através de técnicas laboratoriais que permitaram analisar os mecanismos oxidativos, nomeadamente a produção de ião superóxido, a exocitose de grânulos ricos em enzimas proteolíticas, como é o caso específico da elastase neutrofilica (NE) e da catepsina G (CatG) e a libertação de armadilhas extracelulares (NET). Verificou-se que as espécies de Leishmania induzem a exocitose de CatG e a libertação de NET, independentemente da competência imunitária dos indivíduos estudados. Contudo, idêntica situação não se verifica no caso do stress oxidativo ou da libertação de NE. Leishmania spp. estimulou o stress oxidativo, com produção do ião superóxido, nos PMN de indivíduos saudáveis enquanto os PMN de indivíduos imunocomprometidos apenas parece ficar ativado na presença de L. infantum e de L. amazonensis apontando para mecanismos de ativação diversos decorrentes quer da espécie do parasita quer do nível imunitário do hospedeiro. Situação similar ocorreu na exocitose de grânulos ricos em NE. L. infantum e L. shawi estimularam a libertação de NE por PMN de indivíduos saudáveis e imunocomprometidos. Porém, os PMN de indivíduos com comprometimento da imunidade também responderam aos parasitas da espécie L. amazonensis enquanto que L. guyanensis unicamente induziu a exocitose de NE nos PMN de indivíduos saudáveis. Estes resultados apontam para a existência de especificidades próprias na ativação destes mecanismos relativamente às espécies de Leishmania e ao estado imunitário do hospedeiro. Estudos complementares são necessários para esclarecer o processo de ativação, bem como identificar os eventuais antigénios parasitários (ou até ilhas CpG) que conduzem a ativação de PMN humanos.Neutrophils are the first polymorphonuclear cells of the innate immune system to reach the infection site, providing the first line of defense against invading pathogens, such as the Leishmania parasite. This parasite causes leishmaniasis that has been reported over 98 countries, affecting both animals and human beings. Different species of the parasite can cause leishmaniasis with diverse clinical presentations, as is the case of visceral leishmaniasis and cutaneous leishmaniasis. The present study aimed to evaluate the immune response of polymorphic nuclear cells (PMN) of individuals with different immune competence when exposed to visceral (L. infantum) and cutaneous parasitic species (L. amazonensis, L. guyanensis and L. shawi). Uptake of parasites by PMN was confirmed by optical microscopy. Laboratory techniques were used to evaluate the PMN activation by assessing oxidative mechanisms, namely the production of ion superoxide exocytosis, exocytosis of granules rich in proteolytic enzymes, as is the specific case of neutrophil elastase (NE) and cathepsin G (CatG) and the release of extracellular traps (NET). It was found that the species of Leishmania induce CatG exocytosis and NET release, regardless of the immune competence of the studied subjects. On the contrary, in the case of oxidative stress or the release of NE some differences were observed between PMN from healthy and immuncompromised individuals. All species of Leishmania induced oxidative stress, with production of superoxide ion in PMN of healthy individuals. However, PMN of immunocompromised individuals just seems to be activated in the presence of L. infantum and L. amazonensis parasites, pointing to the possible existence of more than one activation mechanism in association with the immune competence of the host that can be specifically primed by a particular parasite species. A similar situation was observed in the exocytosis of granules rich in NE. L. infantum and L. shawi stimulated the release of NE by PMN isolated from healthy and immunocompromised individuals. However, PMN from individuals with impaired immunity also appeared to respond to L. amazonensis parasites while L. guyanensis only induced PMN from healthy individuals to exocytosis NE. These findings suggest that the presence of specific features in the activation of these particular mechanisms might be related to the species of Leishmania and also to the immune status of the host. Additional studies are needed to clarify the activation process and identify parasitic antigens (or even CpG islands) that direct cell activation

Implant removal associated complications in children with limb fractures due to trauma

Surger

CEA, EpCAM, alpha v beta 6 and uPAR expression in rectal cancer patients with a pathological complete response after neoadjuvant therapy

Rectal cancer patients with a complete response after neoadjuvant therapy can be monitored with a watch-and-wait strategy. However, regrowth rates indicate that identification of patients with a pathological complete response (pCR) remains challenging. Targeted near-infrared fluorescence endoscopy is a potential tool to improve response evaluation. Promising tumor targets include carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), integrin alpha v beta 6, and urokinase-type plasminogen activator receptor (uPAR). To investigate the applicability of these targets, we analyzed protein expression by immunohistochemistry and quantified these by a total immunostaining score (TIS) in tissue of rectal cancer patients with a pCR. CEA, EpCAM, alpha v beta 6, and uPAR expression in the diagnostic biopsy was high (TIS > 6) in, respectively, 100%, 100%, 33%, and 46% of cases. CEA and EpCAM expressions were significantly higher in the diagnostic biopsy compared with the corresponding tumor bed (p < 0.01). CEA, EpCAM, alpha v beta 6, and uPAR expressions were low (TIS < 6) in the tumor bed in, respectively, 93%, 95%, 85%, and 62.5% of cases. Immunohistochemical evaluation shows that CEA and EpCAM could be suitable targets for response evaluation after neoadjuvant treatment, since expression of these targets in the primary tumor bed is low compared with the diagnostic biopsy and adjacent pre-existent rectal mucosa in more than 90% of patients with a pCR.Surgical oncolog