Inundated With Introduction To Cancer And Lots Of Terminology

This week of my course is devoted entirely to cancer. The previous week was devoted entirely to inflammation. Combined, these two weeks make up the translation portion of our cell biology and genetics course, Block 2. Translation is a big buzz word, especially here at Cornell where the dean of the veterinary school is a researcher (_not_ a clinician at all mind you!) keen on translational research (which is essentially applied research-- or applying research to come up with better treatments for clinical problems). My experience as a patient at UCSF had already convinced me of the power of 'bench-t0-bedside' medicine long before I arrived at Cornell. My doctors there implemented the latest research in treating me, and were not only skilled surgeons and diagnosticians, but good researchers, or at the very least well educated on the most recent breakthroughs in their field.

I've had a few epiphanies during this week, I am beginning to understand the basics of cancer. For one thing, cancer comes about because of mutations in stem cells or other progenitor-type cells capable of proliferation. I never really understood this before. Non-stem cells/non-progenitor cells do not have the limitless replicative potential necessary for cancerous growth, which is one of six hallmarks of cancer (the other five are-- sustained angiogenesis, evading apoptosis/programmed cell death, self-sufficiency in growth signals, insensitivity to anti-growth signals, tissue invasion and metastasis).

Furthermore, the mutations that occur are usually in growth regulatory genes, typically oncogenes or tumor repressor genes. My professor, Dr. Levine, defines an oncogene as 'an altered gene whose product can act to help make a cell cancerous. It is generally a positive regulator of cell proliferation and is dominant... Mutations that activate proto-oncogenes are dominant, gain-of-function mutations, in which the oncoprotein is no longer tightly regulated.' The mutation does not have to be in the coding region of the gene itself, simple over-expression of a normal pro-proliferation cellular gene can turn it into an oncogene!

Chronic proliferation is a risk factor for cancer because every time a stem cell divides it is at risk for acquiring mutations that predispose it to cancer. I say mutations-- plural-- because in order to become cancerous, a cell must acquire multiple mutations since there are multiple characteristics/strategies/traits that are necessary for malignant cell growth and one mutation will not meet all the criterion needed to produce a cancer cell (see above for the six hallmarks of cancer). The need for multiple mutations helps explain why there is often a long latency period between exposure to a carcinogen and the development of cancer. It also is one reason that the risk for cancer is increased in older individuals-- they have had more time to accumulate mutations.

Here are some things that now make more sense to me-- you are more at risk for developing cancer under a scar than in unblemished skin (why is that? in order to heal and form a scar, the stem cells in that area were forced to divide, predisposing them to developing malignant mutations). The slide in my notes that says, 'The prevalence of growth disturbances depends on capacity of cells to reproduce' makes sense for the same reason. Most cancers originate from continuously replicating cells such as epidermis, GI tract epithelium and immune system cells. Some cancers come from stable cells that do not typically replicate but possess the ability to regenerate, i.e. liver/hepatocytes. Cells that have very little regenerative cancer like cardiac myocytes and neurons rarely become cancerous because they don't have stem cells that divide frequently (or at all in some cases).

My understanding of the importance of the role of proliferation in cancer also allowed me to understand aspects of my lecture on viral oncogenesis. Bovine leukemia virus is non-transducing long latency retrovirus that causes lymphocytosis (an increased number of lymphocytes) in about a third of cows one year after infection (technically this is leukemia but cows are hardy animals and don't show any clinical signs of disease unlike many other species). 5% develop bovine lymphosarcoma after 8 years. The tumors do not show viral expression and there is no viral oncogene activated by integration of bovine leukemia virus. The cancer stems from accumulated mutations due to the increased rate of replication of the lymphocytes.

Right now I'm studying pathology, how one identifies a malignant neoplasm. It turns out that it is not that easy! The three major differentials for a swelling/tumor are neoplasia (benign or malignant), inflammation and hyperplasia. Hyperplasia is defined in my notes as an increase in size due to an increase in the number of cells. It can be a protective response that regresses completely or it can go on to become cancer. As if that isn't complicated enough, there is no _one_ criterion for distinguishing benign neoplasias from malignant neoplasias. Malignant neoplasias are, according to my pathology notes, typically infiltrative, destructive, anaplastic (i.e. poorly differentiated), mitotically active, rapidly growing sometimes with necrosis, may have a desmoplastic response (lots of immature fibrous connective tissue) and the only dead ringer (no pun intended) is metastasis. The characteristics of a malignant cells' morphology are cellular pleomorphism-- anisocytosis, anisokaryosis, increased number of nucleoli and loss of nuclear polarity. Beyond identifying a tumor as cancerous, one is also expected to differentiate it based on the type of tissue it is derived from (as well as the actual structure or organ). Epithelial-derived tumors have polygonal cells and are called carcinomas (or adenocarcinoma if they are derived from glandular epithelial tissue). Mesenchymal-derived tumors are spindle shaped or round cells, may form rafts/streams and are called sarcomas.

And then there are all the details that make veterinary medicine so very fun and challenging. For example-- the area of a lymph node that is first colonized by metastatic cancer cells is the subscapular sinus, except in pigs and dolphins. (Right, got that!)

I have yet to study several lectures I've had recently-- 1. on cancer and immunology (trying to use the immune system to combat cancer-- mostly how to activate cytotoxic T cells with pathogen molecular associated pattern molecules but also a bit on DNA vaccines), 2. a very dense lecture on angiogenesis, invasiveness and metastasis that went into specific homing/anchorage factors such as the chemokine receptor CXCR4 which is involved in bone metastases (and is only one of several molecules that make up the bone-metastatic signature), 3. tumor suppressor genes, 4. oncogenes, 5. understanding cancer risk and management which includes risk factors for animal cancers (number of estrus cycles before spay and breast cancer in dogs, age at spay and breast cancer in cats, uv exposure, lack of pigmentation (white fur color) and squamous cell carcinoma of the skin in dogs and cats, herbicide and lymphoma in dogs, second hand smoke and lymphoma in cats-- this is interesting, they think the correlation is meaningful because cats groom so they ingest the particulate matter of second hand smoke and expose their GI tract to those carcinogenic molecules).

And that's not counting the lectures I have yet to get tomorrow on cancer imaging and cancer therapy.

If I had more time I'd write about Philadelphia chromosome for my mom (maybe another night, or perhaps it will be a dinner discussion next week). Cancer is fascinating and fun as long as you aren't the one who has it. Or your pet. It's the leading cause of death overall in dogs-- regardless of age 1 in 4 dogs dies of cancer.

As for the vocabulary-- I ran out of time. But try this-- telangiectasias means veins appearing on the eyes and skin (Ataxia Telangiectasia is a human disease that is linked to high rates of cancer). And pathology is always good for a few terms-- agenesis, aplasia, metaplasia, dysplasia, anaplasia (and I'm purposefully leaving out all the obvious -plasias like hyperplasia and hypoplasia). My favorite for the night-- papillary, used to describe patterns formed by tumor cells, means pertaining to or resembling a nipple or forming a rounded mass.

Note-- if you made it all the way to the end of this post kudos to you. Sorry it is so incredibly long, just didn't have time to condense it to something less wordy.

The Silent Killer In Our Midst And Post-Mortem (i.e. Midterm Exam) Results Are Back

I'm referencing an immune response, which isn't always pathological or part of a disease process. Yes, folks, the silent killer in our midst is... inflammation-- dum da dum! In Chapter 2 of the eighth edition of Robbins and Cotran's _Pathologic Basis Of Disease_ they state:

Inflammation may contribute to a variety of diseases that are not thought to be primarily due to abnormal host responses. For instance, chronic inflammation may play a role in atherosclerosis, type 2 diabetes, degenerative disorders like Alzheimer's disease, and cancer. In recognition of the wide-ranging harmful consequences of inflammation, the lay press has rather melodramatically referred to it as "the silent killer."

I remember reading a very interesting Scientific American article called "Heart Health In The Inflammation Age" about the role of inflammation in heart disease (and how inflammation stemming from dental disease may even be a risk factor for myocardial infarction).

More than that didn't make much sense to me until today, when we started our section on cancer. Dr. Levine explains the link between chronic inflammation and cancer in my 'Cancer Principles' handout:

Proliferating cells are more susceptible to acquiring mutations that contribute to tumor progression. Any factor that promotes chronic proliferation will increase the likelihood that an individual will develop cancer. Examples include: estrogen, which stimulates the proliferation of mammary and ovarian tissue; toxic chemicals including ethanol, which kills cells thereby promoting the proliferation of stem cells and hepatitis C virus, which promotes chronic inflammation of the liver, thereby stimulating hepatocyte proliferation. These factors act as indirect carcinogens because they don't directly mutagenize DNA. Chronic inflammation is especially dangerous because in addition to growth factors (promoters) secreted by neutrophils and macrophages, these cells also produce large amounts of reactive oxygen species which can act as initiators and mutagenize DNA.

What reactive oxygen species is he speaking of? I can flip to Dr. Clark's lecture (or Robbins and Cotran) and see that neutrophils produce superoxide, which is turned into hydrogen peroxide, which undergoes a further reaction to become hyperchlorous acid, i.e. bleach via myeloperoxidase. Macrophages form hydroxyl radicals rather than bleach (since they lack myeloperoxidase) and these react with reactive nitrogen intermediates to form the powerful peroxynitrite intermediate. (Cool aside: myeloperoxidase has a heme group which when combined with its bromine cofactor gives neutrophil rich secretions the greenish hue that you may be familiar with in substances such as pus or mucus).

What can you do about all this to prevent yourself from being struck down by the silent killer in our midst? Besides brushing your teeth and not sharing blood or bodily fluids (which will prevent you from contracting hepatitis C and a whole lot of other nasty viruses)? Robbins and Cotran illuminate:

Another approach to manipulating inflammatory responses has been to modify the intake and content of dietary lipids by increasing the consumption of fish oil. The proposed explanation for the effectiveness of this approach is that the polyunsaturated fatty acids in fish oil serve as poor substrates for conversion to active metabolites by both the cyclooxygenase and lipoxygenase pathways but are excellent substrates for the production of anti-inflammatory lipid products called resolvins and protectins.

Hence the big deal over omega-3 and -6 supplements, eating fish being good for your heart, and the many cereals and even peanut butter products that have flaxseed in them (I don't know if flaxseed is just as good as fish oil-- it is high in omega-3 but I'm not sure how bioavailable it is).

So brush your teeth, pratice safe sex, eat fish or take supplements with fish oil and you may evade the silent killer.

But lest you forget the original function of inflammation, I leave you with this pearl of wisdom from Dr. Buckle's lecture notes: As a clinican or pathologist remember, inflammation is the morphological manifestation of the immune response.

Now, back to the post-mortem. I'm thrilled with my midterm results. I'm very motivated to study hard for the final in hopes of getting a truly good grade. I guess my seasonal affective disorder can't keep me from succeeding academically. Phew.

The Gendering Of Animals In Children's Clothing: Feminine Cats and Masculine Dogs

On my way back to Ithaca I stopped over in New York city to see my one year old niece, Talia (above). She's wearing a sweater that I picked up for her in San Jose. It has a stylized cat on it (in case you can't tell from the picture) and says 'Meow' (all you can see is the 'M').

I've noticed an interesting trend in infant clothing-- boys' clothing features lots of dogs and girls' clothing features far fewer animals, only an occasional cat. I'm fascinated that as a society we not only go to great lengths to identify infants' gender from day one (and if a baby is somehow dressed in an ambiguous, gender-neutral outfit then people inevitably inquire as to its sex) but also have denoted certain animals as masculine or feminine.

I wonder how dogs got to be masculine and cats got to be feminine? Women are sometimes derogatorily referrred to as catty. Could that have something to do with it?
Some rap singers refer to themselves as big dogs in their songs. (Akon has a song titled 'Big Dog' and Cordazar Calvin Broadus goes by the name 'Snoop Dogg'). Some little boys' clothing even says 'Big Dog' on it, although I doubt they are specifically referencing any rap songs.

I think it's fascinating that even in a language where objects/nouns are not gendered, we manage to assign a gender to animals.

That said, I did manage to find one top for Ian featuring a jaguar (that's a _big_ cat, not a big dog) and an older girls' top with a Scottish terrier (albeit wearing a jeweled collar). You know me, I like to be subversive!

Goodbye 2009, Goodbye California

Above: Sunset in San Martin on my last day in California 2009.

It's the end of a long year. I'm going to take a break from blogging for awhile. I'll update in a few weeks, until then I'll be hard at work in my second semester of vet school.
Hermit Thrush

Updated-- I'll do my best to keep writing. It's a nice way to keep in touch with people and I love that some complete strangers read me and offer support. Thanks all. But it is tough when faced with the onslaught of my second semester.

San Martin-- Arabians, Bucks And Cowboys

Above: View of San Martin from SelfSustainableNurse's kitchen. It's not easy to piece together a panoramic view like that from multiple photos-- I'm sure there has to be an easier way to do it than how I did it.

I plan to spend my last hours in the Bay in San Martin. I've roamed the Bay, from San Martin to San Anselmo (given a few more days I would have extended my range South to Monterey, possibly even to Big Sur, and to Point Reyes in the North). The two ends of the Bay are my favorite-- the coast of Monterey bay and Point Reyes National Seashore. Two of my favorite places on this planet. (My other two being the forest in central North Carolina where I grew up and Maayan Tsvi in Northern Israel, overlooking the Mediterranean ocean). And of course I love San Jose, the perfect mid-point, in particular the trails and hills of Almaden Quicksilver.

I made SelfSustainableNurse and her husband laugh a good deal on my visit. I wasn't even trying to be funny. I was just studying. Part of what I have to learn for my 'Veterinarians and Society' course, which specializes in ethics this block/semester, are the different breeds of horses, cows, sheep, goats and pigs (do not ask what this has to do with ethics-- I've long since stopped trying to make sense of my courses and accepted that they are beyond ecclectic in the mix of material covered). I've always found horse breeds especially difficult to distinguish, even way back in tech school. While looking over Arabians, I asked SelfSustainableNurse if she'd ever owned an Arabian. She and her husband just about fell off their chairs in the kitchen laughing. When she regained her breath she explained that both her horse, Percy, and her husband's horse, Phoenix, are Arabians. So yes, two of the horses that I looked at all winter and spring are Arabians. Oops. SelfSustainableNurse loves Arabians because she says they have such distinct individual personalities. But she admits that they are easily spooked/very reactive, which is why I am wary of them.

Next, I was looking out the back kitchen window and saw the new, registered Nigerian Dwarf goat that SelfSustainableNurse recently purchased. I commented, "There's your new ram!" To which she replied, laughing, "You mean buck!" Right. I do remember memorizing that, as well as other livestock terms. Obviously it didn't stick.

One thing I love about San Martin-- the cowboys. There are lots of people out on horseback. SelfSustainableNurse distinguishes between the real cowboys and the macho Mexicans on stallions foolishly showing off just to be cool. She assured me that the photo below was of a real cowboy.

Working Emergency Over The Holidays

Above: That's how I felt at the end of three shifts in a row at the emergency clinic!

I worked Wednesday, Christmas Eve and Christmas. Although everyone has been complaining that business has been slow this year, it was pretty busy. I had a hard time keeping up with the pace-- it's been a year since I've worked as a technician and to top that off everything had moved (those of you who have worked emergency know that there is nothing more frustrating than not being able to find what you need quickly-- I couldn't even find the muzzles as they were in a completely different place than last time I had worked there!)

We saw a lot of chocolate toxicities, which is typical of this time of year. Giving charcoal or UAA gel to animals is one of my least favorite things to do as a technician. Not because it is messy but because I am terrified of my patients aspirating. I've seen a few charcoal aspiration pneumonias that have been referred to us for overnight care and none of them have lived. I especially dislike giving charcoal when my patient is still heavily sedated from the drugs used to induce emesis or is struggling with me fiercely. In fact, I had one very stubborn (but otherwise totally sweet) chihuahua fight me so much that I told the veterinarian I could not get the full dose into her patient. She then came over to help me and found the same thing to be true with both of us working on getting the charcoal into this dog. She commented that one way to get veterinarians to realize that what they are asking is impossible is to make them help. I know that I am just working relief and so I don't really have the doctors' trust the way a regular employee would... but still I hope that if/when someday I am a veterinarian that I trust my technicians' judgment and don't push them to do things that might jeopardize my patients' health.

I also saw one marijuana toxicity. Classic signs-- ataxic, acting as if it is reacting to something when there is no stimuli, low heart rate, peeing all over the floor. The receptionist asked me to triage the dog and after doing a quick once over (pink mm, normal capillary refill time, low heart rate, acted like it had neurological disease and/or was hallucinating) I asked the owners point blank, "Do you have any marijuana in your house?" I think my bluntness caught one of the teenagers off guard and she nodded. Mom was ready to kill. I felt badly and explained we had no interest in the legality of the matter but that it would be much easier to treat her dog if we knew what it had eaten.

What I enjoyed the most on my shifts was the two things I've always liked best as a technician-- lab work and anesthesia. It was rewarding to find that after not working for so long I still knew what I was seeing under a microscope. I found tons of giardia on a direct fecal smear from a puppy that had projectile, watery diarrhea and had just been treated (suprise, surprise) for giardia. It's been a long time since I've seen that alien face-like trophozoite staring back at me through the microscope, flagella undulating wildly. I also found schistocytes on a blood smear from another patient when doing a differential-- I called out from lab to the vet, "Hey, has this dog had a splenectomy?" To which she replied from her desk, "No, why?" Well, it turns out the dog had splenomegaly. Hmm...

I had a cat with rouleaux on the blood smear, differential was a classic stress leukogram. Nothing too remarkable in my book as far as blood work goes in an emergency clinic. The vet later told me she suspected FIP based on a constellation of signs-- uveitis, high globulins, not responding to treatment. When I showed her the lab work she noted that rouleaux is often found in cats with FIP, has something to do with the elevated globulins. I thought that was interesting.

I also got to be the anesthetist for two difficult anesthesias. The first was a geriatric dog, which made me nervous as after not doing any anesthesia for a full year the last thing I wanted was for my first patient to be old and sick! And it was not a smooth anesthesia-- the dog was too light once the vet started doing something painful, and when I deepened the anesthesia the dog got too deep and so we partially reversed its premed dose of hydromorphone. The vet joked, "This dog either wants to walk off the table or die." No fun. But the veterinarian got her job done in a hurry and I turned off the anesthetic gas expecting a fast recovery. Twenty-five minutes later I was still monitoring an intubated patient on oxygen. Realizing that the patient was not going to wake up on its own, I asked the veterinarian if we could reverse the rest of the hydromorphone. She agreed. About one minute after I gave the naloxone to the dog intraveneously, it woke up. Amazing. In all the years I've worked emergency this is the _only_ case where I've ever had to reverse a premedication.

My other anesthesia was a c-section. I had trouble intubating (super elongated soft palate!) and was nervous because there were no premedications on board and a masked induction, which can make for a rocky anesthesia. Plus, I wanted to keep my patient as light as possible so that the puppies would not be too anesthetized themselves when delivered. My patient's blood pressure tanked and wouldn't come back up no matter what I did-- lighten the anesthesia, bolus fluids, give hetastach... you name it. So finally, once all the puppies were out, the veterinarian had me give a dose of hydromorphone to see if that would help. As soon as I had injected the hydro IV, the dog began to tremor violently. I don't know what was going on. I've never seen anything quite like it (although I did once have a dog seize on a propofol induction). My first panicked thought was that my patient was going agonal, but the continuous, steady heart rate and regular, spontaneous respirations did not support that. Eventually she stopped shaking. (Of course then I was shaking from the adrenaline rush that came from thinking my patient was dying). She had a smooth recovery and went home with her pups the next morning.

I went home at 4:30 am Christmas morning after being on since 5:30 pm Christmas eve. That's emergency. And I came back the same day at noon. Now you know why I konked out like the puppy in the picture after I was done working!

Random Useless Information, Results Pending On Post-Mortem

I was extremely lucky to make it back to California last night after an extended stay in the Syracuse airport thanks to the blizzard that wreaked havoc on air travel. I think it is just plain luck that accounts for me getting the last seat on a flight to San Francisco after missing my connection to San Jose.

I'm back, but none the wiser. I find that I know a lot of useless information:

• When I saw a logo with a woodchuck, I thought of what lesions from hepatitis and lymphoma look like on necropsy of a woodchuck. How's that? Cornell has a breeding colony of captive woodchucks that they use for research (apparently a good animal model of hepatitis?)

• When merle coat color in dogs came up, I knew that it arises from a SINE_Cf insertion.

• When a melanoma in a grey horse was mentioned I thought of the connection between grey coat color and the eventuality of developing melanomas and knew that both grey coat color and melanomas also result from a specific insertion (read more here).

• When my dad mentioned an epidemiological study on statins to me on, I immediately thought of how statins are contraindicated during pregnancy based on the discovery (by Cornell veterinarians) that Veratrum californicum is the cause of cyclopia in ewes that ingested it around the second week of gestation. The biological mechanism underlying the teratogenicity of Veratrum has to do with hedgehog and patched signaling and cholesterol hence the concern that statins would also be teratogenic.

• Perhaps most disturbing of all, while watching a TV documentary on Jack the Ripper (article here), I understood why the coroner estimated that it took at least fifteen minutes for Jack the Ripper to severely mutilate his victims' bodies. It's not that easy to cut up a dead body. It takes skill. Which is perhaps why profilers also suggest that Jack the Ripper knew some basic anatomy and perhaps worked in a mortuary. Kind of disturbing that I followed all the profilers' thought processes. If you've never cut up a large dead body (I'm thinking alpaca, horse or cow) then you don't know what hard work you're in for. You have to repeatedly sharpen your knife with that kind of sustained effort (which is another reason the profilers suspect Jack worked in a mortuary-- he'd have access to the kind of instruments needed to quickly and effectively disfigure a body).

And speaking of post-mortems... Back when I was a first year in college I got placed in a special advanced chemistry intro class that was mostly quantum mechanics. It was legendary for being incredibly difficult and for being next to impossible to get an A in (though I did achieve that much to my surprise). The first exam was so tough I still remember questions off of it-- like this one "Prove that orbitals are symmetrical." Uh-huh. I was convinced that I had flunked and I remember telling that to my professor as he prepared to leave the exam room with our stack of papers. He said coolly, "Wait and see what the post-mortem shows." Which, like most exams in my life, yielded a grade much better than my wildest expectations.

So now I always associate grading exams with the word "post-mortem." The problem with Cornell is the time it takes them to do a post-mortem is maddeningly long. I took a midterm at the beginning of December. I will not get it back until I return to school in January. Given that this waiting game makes me extremely anxious, I decided to institute some ground rules for myself to help manage this anxiety. Rule one: do not look up answers after leaving the exam. I can often recall almost every question on an exam just after finishing and would look up ones I was unsure of. This only heightened my anxiety when looking up something made me realize I got that question wrong, especially if I realized I had gotten several questions wrong. Rule two: do not, DO NOT, think about the exam. At all (if possible). Forcing myself to stop thinking about the exam when I find myself worrying about my grade also helps.