The development of a finite elements based springback compensation tool for sheet metal products

Springback is a major problem in the deep drawing process. When the tools are released after the forming stage, the product springs back due to the action of internal stresses. In many cases the shape deviation is too large and springback compensation is needed: the tools of the deep drawing process are changed so, that the product becomes geometrically accurate after springback. In this paper, two different ways of geometric optimization are presented, the smooth displacement adjustment (SDA) method and the surface controlled overbending (SCO) method. Both methods use results from a finite elements deep drawing simulation for the optimization of the tool shape. The methods are demonstrated on an industrial product. The results are satisfactory, but it is shown that both methods still need to be improved and that the FE simulation needs to become more reliable to allow industrial application

Bmi1 loss produces an increase in astroglial cells and a decrease in neural stem cell population and proliferation

The polycomb transcriptional repressor Bmi1 promotes cell cycle progression, controls cell senescence, and is implicated in brain development. Loss of Bmi1 leads to a decreased brain size and causes progressive ataxia and epilepsy. Recently, Bmi1 was shown to control neural stem cell (NSC) renewal. However, the effect of Bmi1 loss on neural cell fate in vivo and the question whether the action of Bmi1 was intrinsic to the NSCs remained to be investigated. Here, we show that Bmi1 is expressed in the germinal zone in vivo and in NSCs as well as in progenitors proliferating in vitro, but not in differentiated cells. Loss of Bmi1 led to a decrease in proliferation in zones known to contain progenitors: the newborn cortex and the newborn and adult subventricular zone. This decrease was accentuated in vitro, where we observed a drastic reduction in NSC proliferation and renewal because of NSC-intrinsic effects of Bmi1 as shown by the means of RNA interference. Bmi1(-/-) mice also presented more astrocytes at birth, and a generalized gliosis at postnatal day 30. At both stages, colocalization of bromodeoxyuridine and GFAP demonstrated that Bmi1 loss did not prevent astrocyte precursor proliferation. Supporting these observations, Bmi1(-/-) neurospheres generate preferentially astrocytes probably attributable to a different responsiveness to environmental factors. Bmi1 is therefore necessary for NSC renewal in a cell-intrinsic mode, whereas the altered cell pattern of the Bmi1(-/-) brain shows that in vivo astrocyte precursors can proliferate in the absence of Bmi1

Epigenetics as a mechanism driving polygenic clinical drug resistance

Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such 'one gene : one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance

Springback Compensation: Fundamental Topics and Practical Application

Now that the simulation of deep drawing processes has become more reliable the virtual compensation of the forming tools has become reality. In literature, the Displacement Adjustment (DA) algorithm has proved to be most effective. In this article it is shown how the compensation factor, required for (one-step) DA depends on material, process and geometrical parameters. For this an analytical bar stretchbending model was used. A compensation factor is not required when DA is applied iteratively and the products geometrical accuracy is improved further. This was demonstrated on an industrial part. The compensation varies over the product, leading to a reduction in shape deviation of 90% and more, a result that could not have been achieved with one-step compensatio

An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors

Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear, however, whether these phenotypic similarities reflect the activity of common molecular pathways. Here, we analyze the enrichment patterns of gene sets associated with embryonic stem (ES) cell identity in the expression profiles of various human tumor types. We find that histologically poorly differentiated tumors show preferential overexpression of genes normally enriched in ES cells, combined with preferential repression of Polycomb-regulated genes. Moreover, activation targets of Nanog, Oct4, Sox2 and c-Myc are more frequently overexpressed in poorly differentiated tumors than in well-differentiated tumors. In breast cancers, this ES-like signature is associated with high-grade estrogen receptor (ER)-negative tumors, often of the basal-like subtype, and with poor clinical outcome. The ES signature is also present in poorly differentiated glioblastomas and bladder carcinomas. We identify a subset of ES cell-associated transcription regulators that are highly expressed in poorly differentiated tumors. Our results reveal a previously unknown link between genes associated with ES cell identity and the histopathological traits of tumors and support the possibility that these genes contribute to stem cell–like phenotypes shown by many tumors

Effects of Sea-Level Rise on Dredging and Dredged Estuary Morphology

Estuaries and deltas worldwide are facing land loss and drowning due to sea-level rise (SLR). Commonly home to ports, their channels are dredged and deepened for navigation. However, little is known about how such sediment management will interact with changing sediment transport patterns due to SLR. Using scale experiments, empirical relations and real world examples from global estuaries and deltas, we identify that dredging and SLR combined enhance bend migration whereas SLR alone leads to decentralizing of channels and drowning of intertidal area. In estuaries where channels are fixed, excess energy due to increasing tidal prism will manifest as bed and bank erosion, placing flood safety measures like dikes at risk. SLR increases dredging volumes in upstream reaches due to the rapid collapse of shoals and river banks along the whole estuary. Channel deepenings are ineffective under SLR conditions due to sediment import induced by increasingly flood-dominant tides. Non-dredged systems which have more regular and level elevations will lose intertidal area more quickly than dredged systems that have disconnected higher intertidal flats and a single deep channel. Mid-size dredged European systems are more likely to drown due to dredging in the present century than from SLR. Effects can be avoided by pursuing sediment management strategies that help restore the morphology disrupted by dredging

CD44+CD24− prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis

Recent evidence supports the hypothesis that cancer stem cells are responsible for tumour initiation and formation. Using flow cytometry, we isolated a population of CD44+CD24− prostate cells that display stem cell characteristics as well as gene expression patterns that predict overall survival in prostate cancer patients. CD44+CD24− cells form colonies in soft agar and form tumours in NOD/SCID mice when as few as 100 cells are injected. Furthermore, CD44+CD24− cells express genes known to be important in stem cell maintenance, such as BMI-1 and Oct-3/4. Moreover, we can maintain CD44+CD24− prostate stem-like cells as nonadherent spheres in serum-replacement media without substantially shifting gene expression. Addition of serum results in adherence to plastic and shifts gene expression patterns to resemble the differentiated parental cells. Thus, we propose that CD44+CD24− prostate cells are stem-like cells responsible for tumour initiation and we provide a genomic definition of these cells and the differentiated cells they give rise to. Furthermore, gene expression patterns of CD44+CD24− cells have a genomic signature that is predictive of poor patient prognosis. Therefore, CD44+CD24− LNCaP prostate cells offer an attractive model system to both explore the biology important to the maintenance and differentiation of prostate cancer stem cells as well as to develop the therapeutics, as the gene expression pattern in these cells is consistent with poor survival in prostate cancer patients

Molecular subtypes of breast cancer are associated with characteristic DNA methylation patterns

Introduction: Five different molecular subtypes of breast cancer have been identified through gene expression profiling. Each subtype has a characteristic expression pattern suggested to partly depend on cellular origin. We aimed to investigate whether the molecular subtypes also display distinct methylation profiles. Methods: We analysed methylation status of 807 cancer-related genes in 189 fresh frozen primary breast tumours and four normal breast tissue samples using an array-based methylation assay. Results: Unsupervised analysis revealed three groups of breast cancer with characteristic methylation patterns. The three groups were associated with the luminal A, luminal B and basal-like molecular subtypes of breast cancer, respectively, whereas cancers of the HER2-enriched and normal-like subtypes were distributed among the three groups. The methylation frequencies were significantly different between subtypes, with luminal B and basal-like tumours being most and least frequently methylated, respectively. Moreover, targets of the polycomb repressor complex in breast cancer and embryonic stem cells were more methylated in luminal B tumours than in other tumours. BRCA2-mutated tumours had a particularly high degree of methylation. Finally, by utilizing gene expression data, we observed that a large fraction of genes reported as having subtype-specific expression patterns might be regulated through methylation. Conclusions: We have found that breast cancers of the basal-like, luminal A and luminal B molecular subtypes harbour specific methylation profiles. Our results suggest that methylation may play an important role in the development of breast cancers