Science: One thousand pre-cancer lesions in pancreas of pancreatic cancer patients

 Our group investigated prevention methods for pancreatic cancer, using transgenic mice models.

Relevant to the line of work, there was a new paper on precancerous lesions in pancreas. The paper appeared in Nature, a prestigious scientific journal.

So I checked out the paper.

The authors' group was from Johns Hopkins. They recently developed a new methodology that they call CODA. 

Basically, the method can generate 3-dimensional imaging model from a stack of histopathology slides, visualizing tissue structures (fat, duct, smooth muscle, epithelia, etc) as well as precancer lesions and cancers, in a high resolution.

Use of AI was involved in figuring out histopathology from images (e.g., assigning which part is precancer, cancer, or normal part).

By combining microdissection and DNA/RNA extraction, they can analyze genetic/genomic alterations occurring in cancer and precancer lesions.

Nature journal editorial office seems to like papers using new technology to answer old questions. 

In this case, they revealed precancer lesions in normal-looking pancreas from pancreatic (and other) cancer patients with 3D microanatomy and information on genomic mutations.

Precancer lesions in humans are difficult to study. 

 (a) The size is small (<5mm for pre-pancreatic cancer lesions), thus hard to find. 

 (b) Normal(-looking) human tissues are hard to come by for research purposes in general.

 (c) In many cases, precancer lesions do not grow to cancer. As such, treatment may not necessarily be prioritized in clinic.

These were hurdles to investigate precancer lesions.

We did a journal club at our worksite, and the paper's contents were presented.

A few surprises in the report include;

(1) Pancreatic precancer lesions (called PanINs. Another type of lesion called IPMNs was not included in this study) are many, estimated about 1000 (!) in pancreas.

(2) PanINs carry different sets of mutations, suggesting their independent origins. Implicating that they grow like mushrooms in a field.

Below are my impressions. The authors did not spend much of the writing on speculations and translational/therapeutic implications.

(3) As another implication, the various mutations can help PanINs to evade specific mutation-targeting drugs.

Pancreatic cancer (Pancreatic Ductal Adeno Carcinoma PDAC) has been a difficult cancer with 5-year survival rate of 5-8%.

It was known that over 90% of PDAC have a mutation in an oncogene called KRAS, and that the mutation is a driving force for PDAC development. 

Naturally, researchers made efforts to develop drugs inhibiting mutated KRAS. KRAS G12D and KRAS G12C are among most commonly occurring oncogenic mutations, and these mutations were targets to develop specific inhibitors.  After years of struggle, they succeeded in this past few years. 

Specific inhibitors for KRAS G12D and G12C are available, and showing success at laboratory level. There is a hope of using the new drugs for KRAS-mutated cancers (not only for PDAC) in clinic.

Yet, the new results implies that, at least for pancreatic cancer, efficacy of a mutation-specific drug can drop, once cancer or precancer lesions adopt to the specific mutation-targeting drug.

Or, in another scenario, non-responsive cancer/lesions to the drug may start to grow. For example, G12D-specific drug can be overridden by other mutations, rendering the drug ineffective.

The new results indicate that normal-looking parts of pancreas from PDAC patients can carry 1000 PanIN precancer lesions. After treatments, the PanINs, with a mix of different mutations, may develop to another PDAC. 

Perhaps, PanINs work like Hydra's heads, growing back to another PDAC, contributing to the difficulty to beat PDAC in clinic.

Sounds like trouble? Indeed. Well, knowing novel aspects of human precancer lesions will help us to beat them, eventually.

Whether normal people, not cancer patients, have many precancer lesions/PanINs or not is an open question.

Personally, I don't want to believe I have hundreds of PanINs.

Also, the "field effect", whole pancreas developing precancer lesions, was peculiar.  It looks as if entire pancreas is a field to grow precancer lesions and/or cancers.

In other organs like in colon, numbers of precancer lesions are usually much lower, unless there are genetic predispositions.

We saw that hepatocellular carcinomas (liver cancer) develop from heavily fibrotic (cirrhosis) liver. But such "field effects" come into play after healthy liver was affected in some ways, like hepatitis virus infection, aflatoxin (fungus toxin) exposure, alcohol abuse, or fatty liver with inflammation, over many years.

I wonder if environmental carcinogen or virus are in effect for pancreatic cancers as well. 

The paper was, by nature, descriptive. But was also rather thought provoking. 

Braxton et al., "3D genomic mapping reveals multifocality of human pancreatic precancers".

Nature 2024, May 1. online ahead of print.

https://pubmed.ncbi.nlm.nih.gov/38693266/

[Figure 1 from the paper]

Dance: BachAmor Bachata night at Resonant Head 5/11/2024

 Resonant Head is a small (250+ capacity) music live house/event venue at South OKC (400 SW 25th st). 

The venue is well-booked for concerts. It seems they have concerts coming almost every (or every other) night.

A Latin (Salsa/Bachata/Kizomba) party was held there on 5/11/2024. I was curious about the place (never been there), so I went.

There was an elevated stage area, a "mosh pit" floor area where people can dance, a Bar, a DJ booth, and a recessed seating area. 

Not too big, but a neat, nice venue.

[The "Resonant Head" venue. Photos are from their website]

The DJ was Angel from Adelante, and the people seemed to be the same people coming to Adelante party (OU students and former students, I'd say). There were 50-70 people dancing, I think.

The dance was fun. Most people there got basics for Latin social. The "mosh pit" had a good hardwood floor to dance.

I tried out the stage area to dance as well. The stage floor might be of a painted concrete (?) and was a little sticky, but fair for dancers. Glad I brought my shoes with leather sole, instead of suede sole.

About 10 days ago I went to Groovy's, a night club, with my friends' invitation. The place was like Disco of sort, people dance solo to 80's-2000's songs (Vanilla Ice and Shakira, anyone?). Not much of dance skills are required, to be honest. But certainly a fun place.

Latin parties are for partner dances, but for "fun" social dance. Mostly for dancers wanting to have fun for themselves. 

They are mostly beginner-intermediates. Yet, it is fun and amusing to meet someone "energy flow-sensitive".

Community dances infused with contest or show culture would be more technical (something like West Coast Swing, Argentine Tango, or Ballroom).

For these technical dances, dancers' mindsets start to differentiate. Social dancers dancing for fun, or entertainer-dancers who aim at appealing dance (e.g., appealing to judges for contest, appealing to audience for dance as a sport or an art).

There was a recent occasion that made me think about the mindsets. I'd write about it later.

Dance: Gotta be easier on my knees (=Work on better usage, use braces and icing, and take supplements.)

 This past month was somewhat eventful. 

Although I did not go to San Diego for American Association for Cancer Research annual meeting this year, in OKC we had two symposium (geroscience, web of life). There were two two-day online webinar courses. I was finishing up writing two manuscripts. Oh, my.

I have been attending dance parties on weekends as well. I am fine while dancing. But I am making changes in how I treat my knees.

For a couple of months, it went like this.

 (a) On weekend I dance for a couple of nights, 3-4 hours/night. Enjoying it.

 (b) But afterwards, my knees hurt. Not with full on swelling or anything, but a nuisance. 

 (c) I give them some rest for a few days. 

 (d) The pain goes.

 (e) I can dance for the next weekend. 

 (f)  Back to (a).

Obviously, this is not a great cycle. I got to change my way of using my knees.

The cause is simple; strain to ligaments/tendons by overuse.

My body usage for dancing is based on two dances; (1) Argentine Tango (plant on axis and pivot) and (2) West Coast Swing (walk, for which weight shift to the other weight-carrying leg in the end of given two counts, and triple step, for which you stay on the same weight-carrying leg).

Argentine Tango is the dance I practice more. AT is more technical dance and requires fine balancing and controlled pivoting on my axis leg. 

When you want to take a step, a key is how you shift your own body weight. One way to do it efficiently is to relax knee and use the body weight to "fall" toward the direction I want to go.

The fall-based "walk" is an efficient body usage and is used by many athletes (esp. basketball, soccer, martial artists).

But the thing is, if you relax your knee and fall to wrong (or suboptimal) direction for too many times, it can give strain to tendons and ligaments in the knee.

Unlike muscles that are easily gotten tired, tendons and ligaments are connective tissues and transmit mechanical force through them without much complaints. But with overuse or with stretching to suboptimal direction, they can take microinjury, inflame, and hurt.

My knee sending warning pain is likely because my preparation for pivot is insufficient. With the diagnosis, I am working on adding extra caution to position my foot correctly for cleaner pivot on my forefoot, so that I do not strain my knee while pivoting.

Another likely cause is (hate to admit but) my knees are getting old and can take less strain than before. I got to be easier on my knees.

In addition to work on the usage, I bought a few knee braces and testing which ones work well for dancing or for extra support. Also bought gel ice packs for icing after dancing or walk/jog.

 

Read controversy on supplements, but I picked up a bottle of Glucosamine and Chondroitin anyway. 

I have to use my body to dance. Got to be kind to my body, so that it can serve me well.