Its the ECONOMY Stupid!

Its the ECONOMY Stupid!

Its the ECONOMY Stupid!

Its the ECONOMY Stupid!

Dissecting the innards of the largest economy in the world is like David battling against a 100 Goliaths! But in the quiet peaceful doldrums of summer, one can sit down under the shade of a tree, let the breezes fill the space and cajole the mind into contemplation.

My take on the Quantitative Easing and its impact on the economy and how the experts continue to make it worse by injecting more of their unwanted and un-needed help. The Too Big to Fail concept has burdened the citizenry in ways that we have not fully felt yet, except in the slow drip of job losses. Although the unemployment remains at 4.9% and one has to ask about those 95 million sitting on their hands as well as how does one count and keep a straight face...but then I digress. Indeed at the end of the day the unfunded liability can be defaulted on and the Debt can be defaulted on and what will be left is a Third World Global Order...to the delight of some!

Wall Street continues to sell stocks at higher highs due to the cheap money available for stock buybacks, but at what costs...CAPEX? The future? main Street struggles to keep people employed, but demand decreases because the consumer is tapped out. If 70% of the economy is fueled by the consumer in the U.S. and 40% of the U.S. consumer fuels the world economy, a tapped out U.S. consumer with limited discretionary income and no job is not the answer anymore.

While Regulations continue to place a stranglehold on businesses the art of negotiating the Policy world costs more than $2 Trillion. The Impact of Regulatory Costs on Small Firms article from Small Business Association written in 2010 placed the cost at $1.75 Trillion.

Take a look at this Mind Map below. The arrows point to the influencer of the influenced. The tentacles of the FED's Quantitive Easing Trap continues to unfold and affect the Economy in ways that were never imagined. Of course the expert economists will find fault to protect their turf, but for us simple people with limited knowledge, this is a good place to start.

If you have opinions please convey them…it will make for a robust discussion. Thank you!

"WHAT WILL IT TAKE?"

In the matter of writing, exclamation points are used for varying degrees of expressions. Sometime we mean, “look how horrible!” and other times we think, “Can you believe it!” But each exclamation point has a story to tell. Some saucy, some sticky, some plain vanilla wonderful. Sometime with exclamation points, we want to invite the attention of another to come in and enter our thoughts - a difficult proposition indeed. But what about the curly exclamation point that we call the question mark? Where does that take us? And therein lies a tale…

“What will it take?” The answer to that question is not easily available. The answer seems hidden in the last missing page of a well worn mystery novel. Conjuring up ideas of how to answer a question like that one takes skill and wading into an ocean of emotions. Indeed what would it take to fix a problem like Joe’s?

Joe, you see has a medical riddle. He carries a truant gene that seems to create the mischief in his cells. Joe is painfully aware of this for he has been told of the same after three surgeries and countless therapeutic endeavors to salvage his life. He is safe for now. Content at working his daily dose of living as a salesperson in a shoe store. He is on a constant follow up with his oncologist and each visit is marked with the growing fear of the inevitable. He has learned to avoid the downer thoughts but the fog of uncertainty keeps visiting him in times of repose. He is a truly wonderful gentleman. His once blond hair is now gone replaced by a shaved head. his physique is equally diminished after many bouts under the scalpel and chemicals. A once brawny physique, which he claimed he had, is now replaced with the scrawny shadow of the former self that I see. Yet he claims he sees life in a better light now. He walks daily, communes with nature and has a smile that would brighten any dull cloudy day. Faced with the prospects of a hazy future, he has learned the art of living and the wonders of the limits of survival that each one of us take for granted. He is working on a doctorate in psychology. He already has one in physics.

“What will it take?” he asks again. “We shall see Joe, we are working on it.”

“Sorry Sir, but Joe’s plan does not approve the PET/MRI scan without further information and a certified letter from the oncologist.” The tinny voice speaks from the Insurer never-never-land. “But I am the oncologist!”

“We still need documentation Sir.”

“We have received the documentation, but the test is still denied.” a different de-empathized voice responds a week later.

“But I certified the reasoning for the test.”

“Would you like to speak with the supervisor?”

“Sure!”

After the click and the muzak that invites frustration another click and a human voice arrives, “May I help you?”

I am looking for an approval for a PET/MRI scan based on the certified documentation I sent earlier.”

“Could you briefly explain the issue. That will help greatly.”

A ten minute explanation later, we are running in circles.

“Are you a physician?”

“No sir, I am a Registered Nurse.”

“May I speak with physician in your department.”

“Surely.” And the shifting sounds on the telephone cease momentarily and then the infernal muzak comes back to haunt.

“Hello, may I help you?”

“Are you a doctor?”

“Yes, my name is Jane Blah, Blah.”

“I am looking for an approval for a PET/MRI scan.”

“Um, I looked at the records you provided and I am sorry but based on the data, I cannot approve the test.”

“Are you an oncologist?”

“No, I am a pediatrician.”

“Do you have any training in oncology?”

“No.”

“Then how can you deny this request?”

“We have criteria for best practices based on the Choosing Wisely programs and we adhere to that. Besides, we are constantly reviewing the established criteria.”

“Oh! Okay. Do you mind giving me your full name, your position at this Insurance company and your official phone number?”

“Sure, why?

“I will send that information to my attorney and ask the patient to hire an attorney as well so that the future is not as murky for his survival or for an unnecessary litigation. While you adhere to your criteria, a patient's future is at stake that your have promised to help mitigate their financial health needs through premiums. I am sure you will prevail!” The sarcasm and irony was not lost on the receiver.

“There is no need for that!” The voice on the other end has some degree of angst now.

“There is a need for this, when you arbitrarily try to make decisions based on your esteemed guidelines without consideration of your client’s needs.”

“Let me see what I can do.”

The phone goes dead.

And therein lies a tale to ponder upon! This exclamation point has many meanings but only a few very clear expressions!

CANCER CELL CYCLE & the CDK INHIBITORS

Interesting thing about medicine is that knowledge never seems to end. It comes in waves as brilliant folk look upon failures and success with a critical eye and not through the lens of judgment. For both adding to success and learning from failure ultimately defines progress.

We have known about the cell cycle for quite a long time. Lets look upon the cell as it divides from one into two. Such division is required for the growth and well being of the human body. Cyclins are a very Important part of Cell Division and growth!

In short a Cell must go through the cycle of acquiring various agencies of proteins and enzymes before it can divide into two. Cells are in a continuous state of growth and replication. The stages move from G1 —> S —> G2 —> M and back to —>G1

(G1 = Initial state)

(S = Synthesis phase where the cell synthesizes various needed agencies within)

(G2 = Bulking up stage and acquired various agencies)

(M = Mitosis stage or the actual act of division)

There is a G0 cell phase which is interdependent on the G1 phase. G0 cells are quiet but functional, and not surging through the cell cycle. They can recruited into the cycle when need arises.

Chemotherapeutic drugs affect the cells cycle in various stages. eg. Vinca alkaloids and Taxanes in the M phase and the Alkylating agents in the G1 - S phase etc.

We shall focus on the G1 - S Phase inhibitors where most of the mischief seems to take place.

When an external mitogenic stimulus is received, in oncogenesis (tumorogenesis) at the G1 phase, the D1 Cyclins merge with the CDK4 and CDK6 to create a D:CDK4/CDK6 complex. 

(D1 Cyclins + CDK4/CDK6 = D:CDK4/CDK6)

The D:CDK4/CDK6 complex phosphorylates the Retinoblastoma protein (pRb). pRb is a well known tumor suppressor. Thus phosphorylation of the pRb leads to its inactivation. 

The pRb has the unique characteristics of sequestering the E2F family of transcription factors. This inactivation of the pRb leads to release of the E2F family of transcription factors that drive the wayward cancer cell from the G1 through to the S phase.

Although this might seem straightforward and simplistic, let us not forget that there are various Negative feedback loops available to protect us fragile humans. These are the INK family of p16 protein which is encoded by the CDKN2A gene and the CIP/KIP family of p21 and p27 proteins. Provocation by the TGF-beta signaling mechanism via the SMAD3/4 pathway, which leads to expression of the p16 and KIP family of p21 and 27 proteins that act as suppressors of the Cyclin D1 complex formation. Some of the initiators of these negative feedback loos are basic cell senescence and the release of various molecules that trigger the cell growth cessation

The "Ts" suggest blockade and Arrows mean throughput!

The magic being that p16 binds with the CDK4 and CDK6 and prevents them from creating the D:CDK4/CDK6 complex. This binding prevents the cell from going into the next phase of the cell cycle and ultimate division.

Most of the data on the Cycle Dependent Inhibitor activity was determined in Breast Cancer research where the Estrogen Receptor positive cases became resistant to the Anti-estrogenic compounds.

Several drugs have been manufactured as CDK inhibitors. The lead one is Pablociclib, that received FDA approval in Hormone positive Breast Cancer.

Pablociclib by itself was essentially useless as a therapeutic option. But in ER+, HER2- Breast cancer cases that had developed resistance to the antiestrogens, Pablociclib when given with Letrazole there was a substantially higher PFS of 26.1 months versus 7.5 months in (PALOMA-1 trial). PALOMA-2 trial (using Pablociclib + Fulvestrant) confirmed the PALOMA-1 trial data. The dose limiting toxicity, as one might expect, is based on the Neutropenia and Diarrhea. Both organs Bone marrow and the GI tract have fairly robust cell replication. The toxicity seems to have been addressed modestly well with another D:CDK4/CDK6 Inhibitor, Abemaciclib. And Abemaciclib crosses the blood-brain barrier to impact the brain metastatic disease as well. Corroborative data are not yet available on the brain metastatic activity at present.

Lest one thinks that these Inhibitors only work on Breast Cancer, you might not know that animal trials with mice suggest otherwise. Activity is noted in the laboratory in Melanoma, Colorectal Cancer and Non Small Cell Lung Cancer as well. Trials are or will shortly be in progress to prove efficacy in the various malignancies.

The problems that still need to be addressed are whether these “Ciclibs” can be used with chemotherapeutic agents, since both impact the cell cycle dynamics. And whether the combination might reduce the effects of one another. And equally whether they can be used with the Immune check-point Inhibitors (Anti PD-1 and PD-L1) since the growth and proliferation of the T Reg cells is dependent on the Cell Cycle also.
Time, Hard work and Good Basic plus Clinical Research will tell the tale.

Meantime, we have seem to have another arrow in our quiver.

Online References:

1. http://cancerdiscovery.aacrjournals.org/content/6/4/353.full

2. https://genomebiology.biomedcentral.com/articles/10.1186/gb4184

3. http://genesdev.cshlp.org/content/13/12/1501.full

4. http://ac.els-cdn.com/0092867495903852/1-s2.0-0092867495903852-main.pdf?_tid=0e3f1db2-5d7a-11e6-b269-00000aab0f6b&acdnat=1470669128_f251eeee9fd0e65f46702003f67c90e4

SUMMER WEATHER FLYING

We were all at the FBO. The three of us; I was the pilot, with my my two non-pilot college friends. They wanted to go flying and it didn't matter what the weather was. Even after mentioning that it was going to be Instrument conditions, they remain unfazed. “we want to see what it feels like in the clouds in a small aircraft!” is what both grown men chimed simultaneously.

On the other hand there were these beautiful relatively still looking clouds overhead at around 2000 feet with a soft underbelly undulating to the rigors of the Appalachian mountain waves currents. The atmospheric hue was a crisp grey with a bit of a yellowish hue thrown in.

“A bit of a yellowish hue?” My mind raced back many years earlier. I had not quite hit the teens then and there we were the three friends who had promised to remain friends forever, now lost to each other in the sea of human life’s tumult. But there in the Raspberry tree bearing white raspberries in the bushels, we sat crushing the juice out of nature one raspberry at a time. Meanwhile, the yellowish hue deepened a bit, the colors intensified and just as smartly the first raindrop fell. We chose to ignore it and soon drenched in a deluge we sought shelter in the nearby friend's home. The rain it poured and poured till the streets couldn't take it anymore and let go of onrushing waves and waves of water turning gardens and lawns into shallow swimming pools.

It was the same color this day! I mentioned the weather issues and the two daredevils wanted nothing to do with that. Their reaction against my weather reading judgment was; “Dont be a Chump!” “Chicken, “ then there was the “Chicken wing walk around” and a litany of other disparagements that good friends are wont to do. So I suggested that we go have an early lunch and if the weather truly was not changing, then we could continue with our plans. They agreed as long as I paid for the lunch.

Entering the diner, I felt a raindrop on my head. Soon we were seated and I pulled out my smartphone and checked the weather. There were isolated green and yellow spots of radar images suggesting a few scattered cells in the area and one tiny green one overhead. I checked the k-index ("vertical temperature lapse rate, moisture content of the lower atmosphere, and the vertical extent of the moist layer.” - Mathematically speaking: K-INDEX K = (T850 - T500) + Td850 - (T700 - Td700) The result was not heartening to me; The K Index was listed at 36. (K values +20 indicate some potential for air mass thunderstorms. K values +40 indicate almost 100% chance for air mass thunderstorms). I quietly ordered my lunch and launched on a long conversation about other things.

No sooner had the waiter brought our food, we heard a distinct crackle of thunder and a bright light. Ah, I thought, the tiny green cell had reached out for help from the devil’s worksop. The momentary lapse in the conversation was proceeded with a call for dessert and coffee. But the coffee never came. The water broke and the heavens poured down their heavy weight of moisture into a sheet of blur outside the window. The lights in the dinner flickered and then darkness descended for us so we could see nature’s display outside. The torrents continued, the lightening flashes and the constant rumble interspersed with a loud bark from nature’s displeasure. We paid out the handwritten bill presented to us and thought about escape strategies from the diner towards our vehicles.

That we didn’t fly that day, was good thing. The tiny green blobs predictably had grown over the hour we had sat in the diner and merged together with others to create a “train effect,’ that left us helplessly running for our vehicles when we thought the rain was letting down a bit. But it didn't. Not at all!

Some summer days, it just is better sitting in a hanger, a diner or at home and wishing we were flying. That was certainly one of those days.

I often question had I not had the childhood experience, would I have launched in the air given the two major distractions mixed with insinuations of being a wimp? Given the questionable weather forecast of thunderstorm after 8 pm? I cant say. But I am glad, for the experience, to experience another one in complete ground safety.

In these lazy, hazy, crazy days of summer, when humidity is in the 60%, your shirt is sticking to your skin and the temperatures are hovering around the high eighties or higher, check the K-Index, it might save your life.