Murine 5T multiple myeloma cells induce angiogenesis in vitro and in vivo

Multiple myeloma is a B cell malignancy. Recently, it has been demonstrated that bone marrow samples of patients with multiple myeloma display an enhanced angiogenesis. The mechanisms involved seem to be multiple and complex. We here demonstrate that the murine 5T multiple myeloma models are able to induce angiogenesis in vitro by using a rat aortic ring assay and in vivo by determining the microvessel density. The rat aortic rings cultured in 5T multiple myeloma conditioned medium exhibit a higher number of longer and more branched microvessels than the rings cultured in control medium. In bone marrow samples from 5T multiple myeloma diseased mice, a statistically significant increase of the microvessel density was observed when compared to bone marrow samples from age-matched controls. The angiogenic phenotype of both 5T multiple myeloma cells could be related, at least in part, to their capacity to produce vascular endothelial growth factor. These data clearly demonstrate that the 5T multiple myeloma models are good models to study angiogenesis in multiple myeloma and will allow to unravel the mechanisms of neovascularisation, as well as to test new putative inhibitors of angiogenesis

Functional and molecular characterisation of EO771.LMB tumours, a new C57BL/6-mouse-derived model of spontaneously metastatic mammary cancer.

The translation of basic research into improved therapies for breast cancer patients requires relevant preclinical models that incorporate spontaneous metastasis. We have completed a functional and molecular characterisation of a new isogenic C57BL/6 mouse model of breast cancer metastasis, comparing and contrasting it with the established BALB/c 4T1 model. Metastatic EO771.LMB tumours were derived from poorly metastatic parental EO771 mammary tumours. Functional differences were evaluated using both in vitro assays and spontaneous metastasis assays in mice. Results were compared to non-metastatic 67NR and metastatic 4T1.2 tumours of the 4T1 model. Protein and transcript levels of markers of human breast cancer molecular subtypes were measured in the four tumour lines, as well as p53 (Tp53) tumour-suppressor gene status and responses to tamoxifen in vivo and in vitro. Array-based expression profiling of whole tumours identified genes and pathways that were deregulated in metastatic tumours. EO771.LMB cells metastasised spontaneously to lung in C57BL/6 mice and displayed increased invasive capacity compared with parental EO771. By immunohistochemical assessment, EO771 and EO771.LMB were basal-like, as was the 4T1.2 tumour, whereas 67NR had a luminal phenotype. Primary tumours from all lines were negative for progesterone receptor, Erb-b2/Neu and cytokeratin 5/6, but positive for epidermal growth factor receptor (EGFR). Only 67NR displayed nuclear estrogen receptor alpha (ERα) positivity. EO771 and EO771.LMB expressed mutant p53, whereas 67NR and 4T1.2 were p53-null. Integrated molecular analysis of both the EO771/EO771.LMB and 67NR/4T1.2 pairs indicated that upregulation of matrix metalloproteinase-3 (MMP-3), parathyroid hormone-like hormone (Pthlh) and S100 calcium binding protein A8 (S100a8) and downregulation of the thrombospondin receptor (Cd36) might be causally involved in metastatic dissemination of breast cancer

Organotypic modelling as a means of investigating epithelial-stromal interactions during tumourigenesis

The advent of co-culture approaches has allowed researchers to more accurately model the behaviour of epithelial cells in cell culture studies. The initial work on epidermal modelling allowed the development of reconstituted epidermis, growing keratinocytes on top of fibroblasts seeded in a collagen gel at an air-liquid interface to generate terminally differentiated 'skin equivalents'. In addition to developing ex vivo skin sheets for the treatment of burns victims, such cultures have also been used as a means of investigating both the development and repair of the epidermis, in more relevant conditions than simple two-dimensional culture, but without the use of animals. More recently, by varying the cell types used and adjusting the composition of the matrix components, this physiological system can be adapted to allow the study of interactions between tumour cells and their surrounding stroma, particularly with regards to how such interactions regulate invasion. Here we provide a summary of the major themes involved in tumour progression and consider the evolution of the approaches used to study cancer cell behaviour. Finally, we review how organotypic models have facilitated the study of several key pathways in cancer development and invasion, and speculate on the exciting future roles for these models in cancer research

Fixing Democracy: The Election Security Crisis and Solutions for Mending It (Fall 2020)

The 2000 presidential election debacle in Florida led to the widespread adoption of electronic voting machines in the United States. Yet these machines have proven to be more problematic than the punch card machines that precipitated Florida's crisis. Poorly built and poorly secured electronic voting machines have left U.S. elections vulnerable to software glitches and manipulation — by foreign adversaries or by malicious insiders — for 20 years. An easy solution exists to help restore integrity to the democratic process. But federal lawmakers have failed to act.LBJ School of Public Affair

Countdown to zero Day: stuxnet and the launch of the world's first digital weapon

In January 2010, inspectors with the International Atomic Energy Agency noticed that centrifuges at an Iranian uranium enrichment plant were failing at an unprecedented rate. The cause was a complete mystery—apparently as much to the technicians replacing the centrifuges as to the inspectors observing them. Then, five months later, a seemingly unrelated event occurred: A computer security firm in Belarus was called in to troubleshoot some computers in Iran that were crashing and rebooting repeatedly. At first, the firm’s programmers believed the malicious code on the machines was a simple, routine piece of malware. But as they and other experts around the world investigated, they discovered a mysterious virus of unparalleled complexity. They had, they soon learned, stumbled upon the world’s first digital weapon. For Stuxnet, as it came to be known, was unlike any other virus or worm built before: Rather than simply hijacking targeted computers or stealing information from them, it escaped the digital realm to wreak actual, physical destruction on a nuclear facility. In these pages, Wired journalist Kim Zetter draws on her extensive sources and expertise to tell the story behind Stuxnet’s planning, execution, and discovery, covering its genesis in the corridors of Bush’s White House and its unleashing on systems in Iran—and telling the spectacular, unlikely tale of the security geeks who managed to unravel a sabotage campaign years in the making. But Countdown to Zero Day ranges far beyond Stuxnet itself. Here, Zetter shows us how digital warfare developed in the US. She takes us inside today’s flourishing zero-day “grey markets,” in which intelligence agencies and militaries pay huge sums for the malicious code they need to carry out infiltrations and attacks. She reveals just how vulnerable many of our own critical systems are to Stuxnet-like strikes, from nation-state adversaries and anonymous hackers alike—and shows us just what might happen should our infrastructure be targeted by such an attack. Propelled by Zetter’s unique knowledge and access, and filled with eye-opening explanations of the technologies involved, Countdown to Zero Day is a comprehensive and prescient portrait of a world at the edge of a new kind of war