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Old 07-09-2010, 08:15 PM   #1
gdpawel
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Johns Hopkins is viewing cell behavior in three dimensions (3D)

One of the most important advances in cancer research at Johns Hopkins is viewing cell behavior in three dimensions (3D). Looking at cells in 3D yields more accurate information.

http://www.medicalnewstoday.com/articles/192565.php
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Old 07-10-2010, 01:46 PM   #2
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Re: Johns Hopkins is viewing cell behavior in three dimensions (3D)

I'm picturing the lab workers running around with those cheap cardboard glasses going "Ooohhhh. Ahhhhh."
But really, better simulation/understanding of how cells move seems critical. The antimitotic tentacle issue seems to be related to this.
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Old 07-10-2010, 03:08 PM   #3
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Re: Johns Hopkins is viewing cell behavior in three dimensions (3D)

In cell-based assay labs using functional profiling, they throw away the single cells and work exclusively with three dimensional, floating, tumor spheroids. If you test the same cells as three dimensional spheroids, they are not many-fold resistant in vitro, just as they are in vivo.

Once they have their proper comparison database, they then stratify the database, based on deviations from the median, for each assay system and at each drug concentration. One half standard deviation more "sensitive" than the median is the cut-off for a "sensitive result. One half standard deviation more "resistant" than the median is the cut-off for a "resistant" result.

Upgrading clinical therapy by using drug sensitivity assays measuring "cell death" of three dimensional microclusters of live "fresh" tumor cells improves the conventional situation by allowing more drugs to be considered. The more anti-cancer drug types there are in the selective arsenal, the more likely the system is to prove beneficial.

Because older assay types and peripheral blood assays test on subcultured cells (as opposed to fresh tumor cultures) and test the cells in monolayers (as opposed to three dimensional cell clusters), the cell grown in the lab will not behave the same way as the actual cancer cells do in your body' own environment.

However, all the work in the past twenty years in the cell culture field has been carried out largely on three dimensional clusters of cells (not monolayers). Solid tumor specimens are cultured in concical polypropylene microwells for 96 hours to increase the proportion of tumor cells, relative to normal cells.

Polypropylene is a slippery material which prevents the attachment of fibroblasts and epithelial cells and encourages the tumor cells to remain in the form of three dimensional, floating clusters. Real life 3D analysis makes chemoresponse assays indicative of what will happen in the body.

And since you got me started Rich, the "deviations" have to do with the Bayesian method of science, which Dr. Donald Berry, Ph.D., professor and chair of the Department of Biostatistics and Applied Mathematics at MD Anderson, says is more in line with how science works. They are putting the Bayesian approach (which is no stranger to cell culture assays) to test with more than 100 cancer-related phase I and II clinical trials planned or carried out.

In fact, the Bayesian methodology is what gives credit to the accuracy of cell culture assay testing. Bayes theorem has been used to describe the relationship between the accuracy of a predictive test (post-test probability) and the overall incidence of what is being tested (pre-test probability). Bayes' theorem indicates that cell death laboratory assays will be accurate in the prediction of clinical drug sensitivity and resistance in tumors.

Funny how some scientists think they have reinvented the wheel.
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Old 07-10-2010, 10:15 PM   #4
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Re: Johns Hopkins is viewing cell behavior in three dimensions (3D)

Yeah, yeah. Talk about the glasses...and when they will be able to simulate chemo's effects on circulating cells.
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Old 07-11-2010, 05:46 AM   #5
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Re: Johns Hopkins is viewing cell behavior in three dimensions (3D)

The evolutionary nature of cancer implies that the required target for the consistent and specific cure or control of cancer is the set of all malignant cells that could evolve. Targeting a lesser set will fail. It will act as a selective pressure that changes the course, but not the flow of tumor cell evolution.

The consistent and specific cure or control of cancer will require developing a set of drugs, given in combination, targeted to patterns of normal cellular machinery related to proliferation and invasiveness.

A sufficient number of independent methods of cell killing must be employed so that it is too improbable for a cancer cell to evolve that can escape death or inactivation. It must examine every cell in the body and must do so for a prolonged period of time.
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Old 08-24-2010, 05:48 PM   #6
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Three-dimensional tissue culture models in cancer biology

Semin Cancer Biol. 2005 Oct;15(5):365-77.

Three-dimensional tissue culture models in cancer biology.
Kim JB.

Ludwig Institute for Cancer Research, First Floor - Breast Cancer Laboratory, Department of Surgery, Royal Free and University College London Medical School, Charles Bell House, 67-73 Riding House Street, London W1W 7EJ, UK. jongbkim2001@yahoo.co.uk

Abstract

Three-dimensional (3D) tissue culture models have an invaluable role in tumour biology today providing some very important insights into cancer biology. As well as increasing our understanding of homeostasis, cellular differentiation and tissue organization they provide a well defined environment for cancer research in contrast to the complex host environment of an in vivo model. Due to their enormous potential 3D tumour cultures are currently being exploited by many branches of biomedical science with therapeutically orientated studies becoming the major focus of research. Recent advances in 3D culture and tissue engineering techniques have enabled the development of more complex heterologous 3D tumour models.

PMID: 15975824 PubMed
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Old 09-24-2010, 03:42 PM   #7
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Microspheroids - Microclusters

There are any number of variables that affect drugs. These include the rate of excretion of the drugs by the kidneys and liver, protein binding and a myriad of other biological factors.

Some anticancer drugs are actually pro-drugs: they need to be first activated in the liver before becoming biologically active. So in vitro testing must administer the active forms of these agents, not the pro-drug form that is given to patients.

In the body, these cells interact with and supported by other living cells, both malignant and non-malignant cells. That is why cell-death functional profiling assays study cancer cells in small clusters, or microspheroids.

Analysis of these microspheroids provides a snapshot of cancer's behavior within the human body and provides a more accurate representation of how cancer cells are likely to respond to treatment in the clinic.

It is crucial that there is no manipulation of isolated cancer cells to make them grow, which was an important point of distinction with earlier cell-growth assays.

Drs. Larry Weisenthal and Robert Nagourney adopted this concept and began applying the term microclusters.

Real-life cancers grow as a complex organism that includes both malignant and non-malignant components. It may include fibrous tissue, mesothelial cells, fibroblasts, endothelial cells, etc.

In order to exhibit its most characteristic behavior patterns, a cancer cell needs to be surrounded by a colony of other cells, both normal and malignant.

Human tumors represent micro-ecosystems composed of transformed cells, stroma, fibroblasts, vascular elements, extra-cellular protein matrices and inflammatory elements.

The behavior of human cancers and their reponse to therapy reflect the complex interplay between humoral, vascular, adhesion and cytokine-mediated events acting in concert.

Tumors are very complex organisms. Ignoring this complexity, most studies of human cancer in culture have focused upon individual tumor cells that have been removed from their complex microenvironoment.

Cells are routinely broken up by mechanical and enzymatic means, which alters their subsequent behavior. Some previous methods of assays limited their analysis only to isolated tumor cells and failed to incorporate the crucial contribution of non-tumorous elements to the cancer phenomenon.

When allowed to grow in vitro, living cancer cells develop into these tiny micro-spheroid clusters that form a complex biosystem in which each malignant cell reacts upon its fellow colonists in subtle but important ways.

Each of these microspheres contains all the complex elements of tumor biosytems that are found in the human body and which can impact clinical reponse.

Source: Nagourney RA, Kollin CA, Sommers B, Su Y-Z, Evans SS. Functional profiling of human tumors in primary culture: a platform for drug discovery and therapy selection, AACR abstract #1546, 2008
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