Tumor Associated Macrophages

Tumor associated macrophages (TAMs) have been known as cells which have protected and supported tumor cells. TAMs have been examined by many researchers and there seems to be a slow but advancing opportunity to address them and eliminate their influence[1].

From a recent paper by Etzerodt et al[2]:

Tumor-associated macrophages (TAMs) play critical roles in tumor progression but are also capable of contributing to antitumor immunity. Recent studies have revealed an unprecedented heterogeneity among TAMs in both human cancer and experimental models. Nevertheless, we still understand little about the contribution of different TAM subsets to tumor progression. Here, we demonstrate that CD163-expressing TAMs specifically maintain immune suppression in an experimental model of melanoma that is resistant to anti–PD-1 checkpoint therapy. Specific depletion of the CD163+ macrophages results in a massive infiltration of activated T cells and tumor regression. Importantly, the infiltration of cytotoxic T cells was accompanied by the mobilization of inflammatory monocytes that significantly contributed to tumor regression. Thus, the specific targeting of CD163+ TAMs reeducates the tumor immune microenvironment and promotes both myeloid and T cell–mediated antitumor immunity, illustrating the importance of selective targeting of tumor-associated myeloid cells in a therapeutic context.

 This is a powerful observation and adds greatly to how these protective macrophages can be handled. From Eureka[3]:

…new form of immunotherapy that has so far been tested on mice makes it probable, that oncologists in the future may be able to treat some of the patients who are not responding to existing types of immunotherapy. Instead of attacking the cancer cells directly, the new technique target and remove a subtype of immune cells known as macrophages, after which the immune system itself begins to attack the cancer. This is shown by a new study published in the Journal of Experimental Medicine in which researchers from Aarhus University, Denmark, have collaborated with colleagues in France, the UK and USA, to show that the serious form of skin cancer 'malignant melanoma' can be defeated by using the new method. This variant of skin cancer accounts for eighty per cent of all deaths from melanomas. "We've studied what happens to the tumour when it is exposed to targeted treatment that removes precisely ten per cent of the macrophages that are supporting the cancer tumour instead of fighting it," says Anders Etzerodt, PhD and assistant professor in cancer immunology at the Department of Biomedicine at Aarhus University…"The most important result is that the depletion of this specific type of macrophage causes the tumour to shrink, which is triggered by a subsequent mobilisation of new macrophages and, ultimately, also an activation of the so-called T cells which attack the tumour," says Anders Etzerodt. The type of macrophages which the researchers have removed express a specific receptor, CD163, on the cell surface. Unlike other macrophages, these are known to have an undesirable effect in connection with cancer. Instead of recognising cancer cells as unwanted tissue, the macrophage sees the tumours as normal tissue that needs help with regeneration. It is also widely recognised that survival rates are worse if there are many macrophages, which express the CD163 receptor in the tumour.

This capability may be significant in addressing a wide variety of cancers.

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[1] https://www.researchgate.net/publication/334959399_Immunotherapy_Possible_Directions

[2] Etzerodt et al, Specific targeting of CD163+ TAMs mobilizes inflammatory monocytes and promotes T cell–mediated tumor regression, Jrl Experimental Medicine, August 2019

[3] https://www.eurekalert.org/pub_releases/2019-08/au-rda082719.php

An Interesting Location

Biarritz is an interesting place for the meeting. It was part of Aquataine, recall Eleanor of that land and then was called Gascony and was the landing place for Edward III and his son the Black Prince from which the rode their horses sowing death and destruction at the beginning of the 100 years war.

I wonder if anyone recalls history?

More Employment Mid 2019

We have again been looking at the monthly stats.

First the above is the gap between actual and maximum employment and surprise it is negative for the past few months.

The above details all along with the percent employed. Note it exceeds the number before the Bush Depression.

This is the growth in population and employment and we finally seem to have made the gap close.

Finally as above we see a full recovery. No anticipation of any collapse. Will see what Tariffs do.

Employment Mid 2019

I thought it would be useful to examine employment data since we have not done so in a few years since the Great Bush Recession. Here goes.

The above is the total employment. Now below is the total normalized by population.

Note in the above that we are now well above where we were in mid 2006, the high point. Thus the economy is doing quite well.

The above is the change in Core (real work) and Government and the ratio of Govt to Core. The ratio is down but no where near where we were. Reason is explosion in health care costs! We can show you this in a bit.

The above is that growth. Health and Ed, mostly health, has grown from 17 million to almost 25 million! This is due we believe to a variety of factors not just the ACA.

The above is the stats on the Core workers. Mining is highly variable and reflects the economy more than most. Financial has grown. Construction is nearing the 2006 peak. Note the canary in the coal mine is construction stats, we do not see any here.

The above the is previous chart normalized by PoP. Ed and Health shows the ongoing explosion. Thus the deficit.

Here we have the percents in each and Ed and Health and professional are the two growth areas.

The above shows the growth in each as percent and we see Leisure as well. Manufacturing is still down 20% or so.Thus if we are looking for a recession we clearly do not find it here. Will be tracking.

The Canary in the Bookstore

The NY Times has a piece on problems arising in Amazon. They note:

Over the last few weeks I got a close-up view of this process when I bought a dozen fake and illegitimate Orwell books from Amazon. Some of them were printed in India, where the writer is in the public domain, and sold to me in the United States, where he is under copyright.Others were straightforward counterfeits, like the edition of his memoir “Down and Out in Paris and London” that was edited for high school students. The author’s estate said it did not give permission for the book, printed by Amazon’s self-publishing subsidiary. Some counterfeiters are going as far as to claim Orwell’s classics as their own property, copyrighting them with their own names.Catch up and prep for the week ahead with this newsletter of the most important business insights, delivered Sundays. What unites all these books is that none of them paid the author anything, which means they could compete with legal Orwell titles as a lower-cost alternative. After all, if you need a copy of “Animal Farm” or “1984” for school, you’re not going to think too much about who published it. Because all editions of “1984” are the same, right? Not always, not on Amazon.

In my recent experience this is but the tip of a massive iceberg, or a large canary shouting at the top of its lungs before it perishes.

Having been an avid a trusting Amazon user for well over two decades I have found it often indispensable, until now. What is happening? Third Party vendors. Originally Amazon sold the product and stood behind it. In the past year in my experience almost half the third party vendors I tried to use were a near disaster. They say they have something, collect your money, and never deliver. Then you read the fine print on Amazon and they disavow any and all responsibility. That is, the one great Amazon reputation is being despoiled by the third party vendors whose reps and warranties are worthless in my opinion.

It is not only fake books, it is also medical supplies that should not have been sold through the channel. For example is you were to purchase glucose test strips you get ones to be sold only through a Medicare channel and not Amazon. But Amazon third party players sell these in unauthorized channels. Batteries from China, with knock off labels, Knock off books, not to be sold in the US. Multiple types of defective merchandise.

Perhaps this is profitable for the time for Amazon but then there is the FTC which if it gets enough complaints could become a costly strategy. Trust is a very valuable asset. Loss of trust can destroy a business. Hopefully someone at Amazon is listening.

My only short term solution is to buy only what Amazon sells, any other seller is a risk in my opinion and in my experience.

Communicating Science

Science can at times be exceedingly complex. At others somewhat simple. Take lung cancer as an example. It took decades to have people know that smoking caused lung cancer. Why? Well in my opinion having lived through the period and never having smoked, it was twofold. The media promoted the habit as something that made one "cool". Second, medical scientists used complex statistical analyses which no one could understand. One could scare people but that did not work. Frankly it required a ready acceptance of DNA and the impact of genetic mutations that allowed many, not all obviously, to see that they got it. Not that they really got it but the paradigm had shifted and once you knew about DNA you had a new paradigm, independent of statistics, to grab hold of.

Needless to say, this also applied to various cancers, almost to an extreme. Patients come in armed with their DNA demanding pre-emptive care. You then have to tell them that germ line DNA and the DNA in a tumor are different but if you have a BRCA mutation your risk is indeed higher. However there may be no reason to look for a BRAF V600 in the excised mole after the pathologist deemed it benign. Yet this current state of affairs demonstrates the taking hold of a real paradigm shift, the double helix, even if the patient understands nothing more than its existence.

The same holds with X rays and excessive use. Likewise, for HIV and its transmission. However if one were to take measles, and other communicable disease preventable by vaccines, one can see a dual paradigm, namely believe they work or believe they are harmful. In this case I suggest the paradigm of immunology and the antibodies is lacking. Most individuals have no clue. Yet perhaps as we see immunotherapy in cancers, we may expect a shift there also.

Now to climate change or whatever the current term is. Carbon dioxide and methane can be shown to retain solar heat as it strikes the earth. That may be a fact but the paradigm for it is lacking. The promulgators tried to use the term "greenhouse gasses" but as a paradigm it has not caught fire.

Let us consider some early work on this topic[1]. The authors note:

Methane (CH4) is the most abundant organic gas in Earth’s atmosphere. .. Since the early 1970s a variety of roles of methane in atmospheric chemistry and climate have been identified. For example, methane affects tropospheric ozone, hydroxyl radicals and carbon monoxide concentrations, stratospheric chlorine and ozone chemistry and, through its infrared properties, Earth’s energy balance…

They continue:

Atmospheric methane exerts influence over Earth’s climate in several different ways, both direct and indirect. The more direct roles involve interaction with planetary infrared radiation, warming Earth’s surface and near-surface atmosphere and cooling the stratosphere, i.e., the roles of an effective greenhouse gas. The most important infrared spectral feature of methane molecules is their 7.66-μm absorption band; quantitative models of the impact of methane’s role in Earth’s energy budget focus on this band. …calculated that the presence of 1.5 ppm of CH4 in the atmosphere causes the globally averaged surface temperature to be about 1.3 K higher than it would be with zero methane and that larger effects would apply to polar latitudes.…have computed the global heating due to an increase of CH4 concentrations from various deduced preindustrial levels to contemporary values and the future heating effects of several methane scenarios. For example, the infrared radiative heating effect of a methane increase from 0.7 ppm (preindustrial revolution) to 1.7 ppm (1988 concentration) is about half as large as the comparable effect of simultaneously increasing C02 from 275 ppm to 345 ppm. Future growth in atmospheric methane concentrations, while not clearly predictable, is likely to contribute more to future climatic change than any other gas except C02. …In the paleoatmosphere of 4.25 billion years ago when the Sun was perhaps 30% less luminous, relatively high concentrations of atmospheric gases such as C02 and CH4 could have served to maintain Earth temperatures above freezing (evidence suggests that Earth was not frozen over) …. Methane concentrations of about 100 ppm could have decreased the amount of C02 required for maintenance of a warm Earth by about a factor of 2 … The direct radiative effect of atmospheric methane also extends into the stratosphere; at altitudes above about 20 km, CH4 molecules act to cool the atmosphere through radiative losses to space. There are also several interesting and potentially important indirect ways that methane can affect climate. One that has not received much attention is that the atmospheric oxidation of CH4 produces CO which is converted further to C02. Methane oxidation produces about 8 x 1014 g CO/yr …. CO molecules survive two to three months on average before conversion to C02 by (R16). In this way, about 0.34 x 1015 g C/yr as C02 is produced globally. By comparison, total human release of C02 due to combustion and cement use is about 5.3 x1015 g C/yr. Thus, we calculate that the atmospheric production of C02 from atmospheric CH4 is about 6% as much as the direct annual release of C02 from anthropogenic sources. Other indirect effects of increasing atmospheric CH4 Eire the chemical production of tropospheric O3 (a greenhouse gas) and increases in tropospheric water vapor. The latter effect is not proven, but it is a common and plausible assumption in climate model sensitivity and a result of some general circulation models that as temperature rises, atmospheric relative humidity will remain rather constant. Accordingly, absolute H20 amounts would increase. In this way the effect of a greenhouse warming from CH4 or other causes leads to an amplification of perhaps 50% due to increased H20 vapor concentrations … Tropospheric O3 increases that can result from CH4 increases in the presence of NO2 … are also able to affect climate, especially if ozone concentrations should increase in the upper troposphere where O3 is a particularly effective greenhouse gas.

 

Needless to say this is not a paradigm. Furthermore, this is one of the better non-paradigms. The issue is simple. The sun sends radiation to the earth, the CO2 and CH4 absorb it and the outer electron levels jump with the increase in energy and they decay converting it to heat, most of which falls down to the earth. Thus these gasses are energy converters, taking one level and turning it into another thus increasing temperature. Secondly when the heat is reradiated outward it is reduced again by these molecules which absorb and reflect back in a somewhat endless process. There is a little quantum mechanics here but at high school  level.

Now along come the teenagers. As Nature notes[2]:

As each of the UN conventions faces continuing challenges, the IPCC can at least be assured of support from the next generation. It has garnered a following among the growing international youth climate movement. Members keenly absorb every new report, including participants in the school strike for climate, led by Swedish teenage activist Greta Thunberg. Thunberg makes a point of namechecking the IPCC and quoting paragraph and page numbers in speeches, as she did in an address to the French parliament at the end of last month. As government delegates get ready for Delhi, Nairobi and New York, they must prepare to answer why, if children can understand the meaning of the IPCC assessments, adults cannot do the same? The youth climate movement’s members are brave, and they are right. It has been almost three decades since the three UN conventions — on biodiversity, climate and desertification — were agreed at the Earth Summit in Rio de Janeiro. And it has been 31 years since the IPCC was created to advise decision makers. Yet environmental promises have not been matched by meaningful action. Younger generations know, perhaps better than the adults, that the world might not have another three decades to prevent climate impacts that will be even more serious than those we face now. Politicians must act now.

Politically, when one has a group of uneducated children evoking politically pontificated pronouncements the masses will rebel. If, however, you had a simple and understandable paradigm you can win. The paradigm; why ae roses red? Simple, the white light is reflected off the leaf and everything but red is absorbed so what we see reflected is red. Why is the earth getting warmer? Simple, we have CO2 and CH4 absorbing light from the sun and converting it to infrared for warming and then blocking it from leaving.

If one can get the simple paradigm across then most people can understand and respond. The solution then is the reduction of these gasses via technology not politics. Unlike Nature, younger generations really do not "know" since it is most likely they have not been taught.

The challenge is for Scientists to explain simply and correctly, give people paradigms to hold on to. People like good paradigms. Scientists should not try to explain as if we must understand every detail. Furthermore, Government reports all too often miss everything trying to be totally inclusive of every "good" idea. To paraphrase Amadeus, "too many words".

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[1] BIO GEO CHEMICAL ASPECTS OF ATMOSPHERIC METHANE, R. J. Cicerone, National Center for Atmospheric Research, Boulder, Colorado and R. S. Oremland, U.S. Geological Survey, Menlo Park, California. Global Biogeochemical Cycles, Vol. 2, No. 4, Pages 299-327, December 1988

[2] https://www.nature.com/articles/d41586-019-02425-7