SEGMENT 6 SCENE 1 - CONCLUSION

In metastatic bone cancer,

pain does not simply

come from a single source.

Various stresses, be they

mechanical or chemical,

layer upon each other

to create a severe

and unmanageable neuropathy.

Owing to the plasticity

of neurons, pathological

changes soon extend from here

to the central nervous system.

And, to think that

all this starts

with a few cells.

Approximate run time: 31 seconds

UPDATE 09/12/12

So here's the final leg of the film. This segment was animated for the old script. So it WILL BE CHANGED as well. I need to go back to the drafting table and try and tie in the CNS and spinal cord a little more...

But what I have here at the moment, is an attempt to bridge the intro and the end. We start off will a few cells, so I wanted to end on that note. It felt a little... unresolved when I had originally ended with a scene of utter chaos - with nociceptive factors everywhere and things firing like crazy...

Segment 6 Scene 1

SEGMENT 5 SCENE 2 - ACIDOSIS

In the low pH,

acid-sensing ion channels

cause nerves

to readily depolarize.

Constant activation of these channels

lead to gradient imbalances,

priming neurons for spontaneous firing.

With the hypersensitization

of these nociceptors,

chronic pain settles in.

Approximate run time: 22 seconds

This section also needs some expansion.

UPDATE 09/12/11

Currently, I have the acid ions binding to the ASIC receptors (not yet labelled - will be labelled immediately under each structure). Then I have the neuron changing colours to represent the gradient imbalance. This is where I would love to get some feedback. Is it effective? Or not?

The reason I did not show ions passing through the bilayer is that I had already established/introduced H+, which for the purpose of clarity, has been blown up by a lot. To now introduce other ions at that scale would be difficult because they wouldn't be able to flow through all that easily (they would fit through channel). And now, suppose that we make them small dots of light flowing through the channel, then we have a discontinuity between ions and H+.

Also... How exactly does H+ bind or activate ASICs...?

Segment 5 Scene 2

SEGMENT 5 SCENE 1 - OSTEOCLASTS

Like macrophages,

osteoclasts release acids.

They do so in order

to dissolve the

minerals in the bone.

Therefore, osteoclast hyperactivity

aside from resorbing bone,

creates a highly

acidic environment as well.

Approximate run-time: 20 seconds

This sections needs to be expand.

Segment 5 Scene 1

SEGMENT 4 SCENE 2 - INFLAMMATORY NOCICEPTION

And caught in the crossfire

is a sea of nerve endings,

whose surface is littered

by an abundance of receptors

and channels.

Their overstimulation

leads to the inflammatory

pain associated with so

many pathologies.

But, in our case, we have

some cells further

complicating the situation.

Approximate run time: 22 seconds

UPDATE 09/12/09

In the video, I only have protons and ATPs binding so far. But as a continuation from the previous video, I plan on the series of factors introduced previously, floating downwards to activate their respective receptors. The main point I'm trying to get across is that all the factors released in the previous scene will lend itself to the activation of the neurons.

Segment 4 Scene 2

SEGMENT 4 SCENE 1 - INFLAMMATORY SOUP

As the tumour progresses,

nerves become exposed

to an ever-increasing

mixture of nociceptive agents.

This inflammatory soup contains

a host of factors

not limited to cytokines,*

protons, interleukins,**

prostaglandins, growth-factors,***

released by both tumour and immune cells.

And so, as cells fight,

and as cells die,

debris accumulates.****

*On screen, TNF-alpha released by tumour cell.

**H+ by macrophage, IL-2 & IL-10 by T-cell.

***PGE2 and NGF by tumour again.

****ATP from apoptotic cell.

Approximate run time: 31 seconds

UPDATE 09/12/04

I'm still having trouble with this segment. I understand that from a basic science perspective that it is important to list the factors involved, their respective sources, as well as target receptors. However, from a communications and narrative point of view, the use of lists are highly frowned upon, not simply because they are tedious, but for the psychologically-proven fact that most people cannot retain a string of facts presented - in the fashion that our medium will allow - within a short time span.

So, this is the solution that I am proposing: to narrate in brief that factors are released. Visually, however, the various factors will appear one by one on screen. And, each of them will be labeled. By doing so, I am inevitably passing the responsibility of teaching this list of factors to the viewer or lecturer - who has the ability to pause and review this particular sequence.

SEGMENT 3 SCENE 2 - TUMOUR GROWTH & MECHANICAL COMPRESSION

Where the metastasis is

of mammary origins,

there is a great increase

in osteoclastogenesis.

Despite increased osteoblast

hypertrophy and activation,

osteoclast hyperplasia results

in net resorption.

The bone thins,

and its rich

neurovasculature is exposed.

Within the confines

of the marrow cavity,

the tumour expands and

mechanically compresses

the vulnerable vessels.

This is when pain

first settles in.

Approximate run time: 33

UPDATE 09/12/05

Currently, I've posted a short clip of what this scene would original look like. I have yet to include the part where I will show a growing mass that compresses the nerves. The segment below only shows up to the excavation of nerves.

Segment 3 Scene 2 - Net Resorption

(This clip, as mentioned above, is incomplete.)

SEGMENT 3 SCENE 1 - OSTEOCLASTOGENESIS

During the cross-talk,

parathyroid hormone-related protein

is released by cancer cells.

It hyperactivates stromal cells

and osteoblasts,

causing them to increase

surface expression of

the RANK ligand,

which when bound to the

RANK receptor,

causes monocytes

to fuse together

to form multinucleated cells.

With continued exposure

to the RANK ligand,

these cells mature

into osteoclasts.

Approximate run time: 33 seconds