You Can't Make This Up

From the National Post we have the following:

The voracious use of toilet paper in the United States — with the average American using almost three rolls each week and major manufacturers spurning alternative fibres — is destroying Canada’s forests and causing widespread environmental damage, two international environmental groups say. A report on tissue paper use gave failing grades to the leading toilet paper, tissue and paper towel brands for using only virgin fibre pulp, mostly from Canada’s old boreal forests. “Forests are too vital to flush away,” says the report, called The Issue With Tissue, released Wednesday by Natural Resources Defense Council and Stand.earth, international nonprofit environmental organizations that cooperated on the study.

Yep, back to the old sandpaper material I remember from the Navy. This is part of the Green New Deal stuff we are hearing about. How about the bucket and left hand routine, corn cobs, oak leaves?

What I do not understand is that trees are plants. In fact I have in process some 72 Ginkgo seedlings which are to be transported to New Hampshire next year for my tree farm. Yes, I may not live to see their full growth, takes 300-400 years, but those trees outlive Hiroshima! Try a wipe on that paper!

Now tree farms are everywhere. It takes about 30 years to get a mature white pine suitable for harvesting. That is in New England. Now there are millions of acres and each tree needs just a small fraction for maturity, some 1,000 square feet. Thus 40 trees per acre for good growth. Play the math, it works, most of northern Maine is covered this way, not to mention much of Canada.

So plants have been farmed by humans now for well over 10,000 years and we are pretty good at t. I guess, except for TP! Oh Canada!

Exosomes and Cancer: A New Paradigm?

Exosomes and small vesicles, less than 100 nm, released by cells and containing parts of DNA or RNA, miRNAs, proteins, and other matter released by the cell. They become free in the extracellular areas and can find their way to other cell sites. The exosomes with miRNA may find other cells, attach, enter, and activate the cell in such a manner to result in the damage in the originating cell.

This paper is a combination of fact and speculation. It attempts to refer to many significant works presented in the literature while attempting to knit together an alternative view of metastasis. There is a great deal of evidence for this new paradigm, but the reader should be warned that there is no definitive acceptance. Thus the speculation. Paradigm shifts are always difficult. Kuhn and his followers have posited ways in which this occurs. I am hardly suggesting that there is any sudden or great insight, I am merely suggesting an alternative view. This view looks at the exosome and miRNA.

One could look at this as an example of a cancer cell of origin and metastatic cells at distant points. In this paradigm the cancer stem cell, "cell of origin", just sends out exosomes of miRNA which somehow float about until the find a cell to attach to. If one accepts this paradigm, it changes in material ways how we see metastasis and more importantly how we see possible therapeutics. Namely if a melanoma mets to the lung, does it do so via an miRNA in an exosome and moreover is it the lung because the lung tissue has a receptor that allows the entry of the miRNA.

Thus exosomes with miRNA can be powerful transmitters of cancers. The actual malignant cell does not have to move, it just has to send out the right miRNA.

As Rak noted regarding the work of Leyden and his Lab:

The metastatic dissemination of cancer cells from their site of origin through the bloodstream to distant organs is a major cause of cancer-related deaths. This process is not random1; instead, certain populations of cancer cells preferentially seek out and colonize specific organs, under the control of a range of molecular programs. Such homing implicitly involves interactions between cancer cells that escape the primary tumour, sometimes known as seeds, and the microenvironment, or ‘soil’, of target sites.

But less intuitive is the discovery by Hoshino et al. that seeds can influence the soil before their arrival, sending out extracellular vesicles called exosomes that precondition specific organs for metastatic invasion. There is growing support for the provocative notion that a build-up of systemic responses to a primary tumour might precede, and even enable, the eruption of metastatic cancer.

These responses might involve complex alterations in the body’s vascular, coagulation and inflammatory systems — for example, cancer-related changes in the composition of soluble proteins, in cell populations or in the characteristics of exosomes5in the blood. Hoshino et al. define exosomes as small extracellular vesicles — membrane-bounded compartments that transport proteins, lipids and nucleic acids from one cell to another, and which can travel considerable distances in bodily fluids or the bloodstream.

This information- transfer process has attracted considerable interest in cancer research, because some extracellular vesicles carry cancer causing genes called oncogenes, or oncogenic proteins that promote cancer formation and disease progression. The involvement of extracellular vesicles, including exosomes, in metastasis has been studied for some time, and contributes to several key events that prepare a distant site for colonization — a process called premetastatic niche formation.

Simply stated, it could be postulated that it is the exosome that initiates and facilitates metastatic growth, not necessarily the flow of the cells to new locations.

A great deal of effort is underway to resolve the extent of the functions of EVs in cancer metastasis and in turn the possibility of targeting them as a therapeutic.

There are two paradigms that we now work with in metastasis. The classic involves the movement of the malignant cell across the body. The second, the EV model, is the movement of EVs across the body, influencing distant phenotypes. The EV model makes sense in many cancers, because of the ease of the EV going into and out of the circulatory systems; blood and lymph.

We demonstrate these two paradigms below:

1.1        Classic Paradigm

The classic paradigm is shown below. It fundamentally assumes that a single cell mutates and becomes malignant and then that cell proliferates as a cell and enters and leaves the blood system and finds a location where it can again proliferate, perhaps undergoing additional genetic changes. The key here in the classic paradigm is that the malignant cell is the mechanism for proliferation. The literature here is significant.

 

Key to this Classic Paradigm, is the belief that it is the malignant cell itself which migrates, and even more so, the cell is a stem cell. Namely it can migrate and do so in a manner that allows it to establish its own outpost of a malignancy. The cell maintains and carries with it the identical genetic flaws which made it what it is at its site of origin. Then as part of this paradigm, it is this cell which must go into and out of the blood stream. This behavior of the Classic Paradigm is a complex and oftentimes highly questionable type of behavior.

1.2        EV or Neo-Classical Paradigm

The new EV paradigm is shown below. It is not the actual cell but elements of the cell such as miRNA which go forth and multiplies. Note it first does a phenotype change still requiring fueling and then may actually have a genotype change resulting in the classic "whack a mole" results in metastasis.

 The essence of the Neo Classical paradigm conjecture is severalfold:

1. A malignant cell is changed and produces exosomes which contain, for want of a better alternative, miRNAs which if and when absorbed by target cells are oncogenetic in nature. The malignant cell can best be called a stem cell.

2. The target cells absorbing and activating the miRNAs phenotypically become malignant. Their genetic structure has not changed but they are responding to the miRNA exosome. The target cells may be local or distant.

3. The target cells are targeted by ligands or receptors on the exosome that match those of the target cells. Thus there is a specificity of targeting, much like what we see in many metastatic events.

4. The exosomes are small enough and unencumbered with surface proteins that they are easily sent into and out of the blood stream. In addition they are almost invisible to the immune system.

5. Long term exposure is inducive to a genotypic change of the target cell, thus enabling it to become its own stem like cell.

6. Properly characterize exosomes may be targetable.

7. Early extraction of the stem cell before genotypic change can be curative. Once the target cell genotypically changes that cell must be excised or deactivated.

8. However, if the exosome itself is identifiable then perhaps an immune targeting may be achieved.

If the above conjecture, which we argue may have some validity, is correct, it argues for a dramatically different approach to cancer treatment.

1.3        Issues

Exosomes have become a significant factor in examining cancer metastasis. One could argue that they are paradigm shifting. Our focus herein is to examine exosomes as a significant if not primary diver of many metastases. This is a dramatically different view of cancer progression. It does allow for the explanation of many of the issue that we see in examining such progression.

1.3.1       What are exosomes

We use the literature to examine the exosomes and its kindred spirits. Exosomes are fundamentally ad double wall lipid carriers of cellular elements, predominantly parts of DNA, RNA, proteins, and most importantly miRNA.

1.3.2       What are the theories of metastasis

What is metastasis and how does it work. Again in a simplified sense, metastasis if the propagation of malignant behavior to other sites in addition to the primary site. Now trees and other plants get tumors. But these tumors do not spread. Large galls on the sides of trees are compartmentalized tumors plus viral materials. Thus what makes animals have such diseases and how do they function?

1.3.3       What are miRNAs and how do they relate to Exosomes

Micro RNAs are small RNA strips, about 22 base pairs in length, that can target and suppress mRNA inhibiting translation.

1.3.4       What is the impact of epigenetic factors on Exosomes

Epigenetic factors such as the impact of miRNAs can be significant. They silence or activate genes, they can also impact histones which in turn may silence or activate genes. We examine both to a degree. There is a complex network of positive feedback where miRNAs can induce via other genes favorable growth environments.

1.3.5       How do we understand the dynamics of cancers using the Neo Classical Model

In the Classical model we have the mutation of genes, the creation of a putative cancer stem cell, and the movement from one place to another via initially an EMT and then intra and extra-vasation. Now the Neo-Classical model assumes that it is the exosome and its contents, putatively the miRNA, that moves about. This can be a fundamental paradigm shift but arguably verifiable. Thus how then does one consider the dynamics of metastasis in this case?

1.3.6       What is the impact on therapeutics

Dealing with the exosomes one considers ways to block them via multiple therapeutics. If one can block them after initial tumor recognition then is there a way to mitigate metastasis?

1.3.7       How does Immunotherapy get applied

Immunotherapy has made great strides however to be effective the cells targeted must be recognizable. Thus understanding the surface of the exosomes or even more so to be able to target them and insert markers may be effective. One wonders if CAR-T approaches may be effective.

1.3.8       What can we do with diagnostics and prognostics

This is a key question which may be easier to deal with. We can now access many of the exosomes, examine their contents and then assess the specific malignancy and ascertain its progression.

We proceed to review, examine, and consider these issues. This is not a fundamental research paper since it relies on the work of others, it is not a review paper since it does not present a summary of others, but it is an attempt to consider a new paradigm. This may or may not prove to have sustainable capacity but the author believes it is worth the consideration in light of recent investigations.

We have published a paper discussing this topic in detail.

Voting Rights in New Jersey?

Since New Jersey has been taken over completely by the Democrats, we are well into bankruptcy, technically, we see taxes exploding, roads collapsing, new government entities and entitlements exploding, and now the folks in Trenton want to delimit our rights to vote! Mussolini must be turning over in his grave, he never got this far. At least he got the trains to run on time, our folks keep having them fall off the tracks!

The latest, reported by North Jersey News, notes:

New Jersey Democrats are reviving a controversial effort to force President Donald Trump to release his tax returns or be denied a spot on the state's 2020 ballot. The state Senate on Thursday approved a bill — which the Legislature passed once before, in 2017, but which then-Gov. Chris Christie blocked by issuing a scathing veto — that would prohibit candidates for president and vice president from appearing on the ballot unless they make their tax returns public. Similar legislation has been introduced in at least 30 states but never enacted, according to the National Conference of State Legislatures, meaning New Jersey would be the first to impose such a disclosure requirement if its measure is also approved by the Assembly and signed by Gov. Phil Murphy, a Democrat. 

The Governor will in my opinion sign this attempt to delimit the vote. Why not, he seems to be doing whatever will enshrine a one party system. Voting is a classic right. Boston is known for electing mayors while in prison. In New Jersey we have mayors who are getting multiple pensions while imprisoned. 

So why not just go all the way, abolish voting and let the Democrats in Trenton decide for all of us! And I was concerned when in Russia!

Well Said

The Telegraph has an interesting piece which I agree with. They note:

Teaching children coding is a waste of time, the OECD’s education chief has said, as he predicts the skill will soon be obsolete. Andreas Schleicher, director of education and skills at the Organisation for Economic Co-operation and Development, said that the skill is merely “a technique of our times” and will become irrelevant in the future. "Five hundred years ago we might have thought about pen literacy,” Mr Schleicher said. "In a way coding is just one technique of our times. And I think it would be a bad mistake to have that tool become ingrained. "You teach it to three-year-olds and by the time they graduate they will ask you 'Remind me what was coding'. That tool will be outdated very soon." Comparing it to trigonometry, he said: "We are going to get into the same dilemma. I think is very important that we strike a better balance about those kinds of things. "For example, I would be much more inclined to teach data science or computational thinking than to teach a very specific technique of today." The Government has championed the teaching of coding and computing skills, with the Chancellor allocating £84 million to treble the number of computing science teachers in 2017’s Autumn Budget. A new National Centre for Computing was set up to train up the 8,000 new teachers in the subject.   Computing became part of the national curriculum in 2014, and the GCSE in Information and Computer Technology (ICT) was axed in favour of a new qualification in computing which includes more coding and programming.  

Let me provide a simple example which counters a recent press release with one of my own:

The new Purpleperson College of Typing has selected is new Dean, Prof Swifty Fingers, a world renowned expert in the new field of typing and more importantly shorthand. Prof. Fingers is a known leader in STEM, the "Shorthand, Typing, Erasing, and Margins" field, for which there is an explosion of new opportunities. Prof Fingers also is an advocate of the new field of shorthand, also known as Automated Inscription, or "AI", an exciting new technology that allows for the capture of human utterances and placing them in a coded manner on small pieces of paper, which in turn may be readily transcribed using the new typewriter technology currently infusing every academic discipline.

This new technology accompanied by AI has become an indispensable element of every field of knowledge from classic Greek to Botany, to the study of Law. As such the new Purpleperson College of Typing will have all of these Departments subsumed under it new Dean and a major thrust will be the training of STEM to a multicultural groups  as an essential part of the country's global competitiveness.

As Prof. Fingers had noted in the inaugural address"

"There has been no other technology that has spanned all areas of knowledge in such a short period of time as the typewriter and no adjunct to that technology such as AI which will create a competitive edge to every field."

Prof. Fingers then demonstrated his own ability to copy from a record produced by Mr. Edison a speech of President Grant at some 90 words per minute and then he had one of his post doc students use the newest Remington typewriter to type it in the same 90 words per minute. The audience was aghast as such a technological breakthrough.

The White House issued its own typed press release saying that the US would remain at the forefront of this new revolution.

 Yes the above is fiction, but not that much of fiction. You see, a hundred plus years ago young men were trained on these devices. Then as they needed more and more they created secretaries, and we all know where that ended. Any reasonable person now does their own typing most likely on some highly sophisticated electronic device.

Thus the who coding thing is a waste of time. I spent years on Latin, and I actually still use it. I spent time on Greek, it helped when I was in Athens, still took a year to catch up. I use trigonometry, I use algebra, calculus, and use data manipulation and calculation skills. 

Teaching skills such as BASIC is now defunct, Python, may have use for specific purposes. Who knows COBOL, FORTRAN, and the list goes on. Critical thinking and organizational skills are useful. C++++++ may not be, for all.