NJ 2020 05 31

It is the end of May and given the other things going on we expect a massive increase in two weeks across major cities and the pattern of infection will most likely lay out a path that will be followed.

Here are the county increase from yesterday. I really wish they were just that. The number for Morris make no sense as you will see shortly.

State wide we see the low end leveling and the highly variable incidence numbers.

County wide we see this big blip as of yesterday. This is a Saturday data as indicated but I can assure you it is a roll up from other factors. Controlling an epidemic demand time and location stamped data which is not what we have ever really gotten.

Deaths are lower but then again it is Saturday data

Still mostly from LTC

County prevalence is flat.

Ferns

There are a few peaceful places left.

Trust Science?

Now we have had a ton of "scientists" opinion on everything during this pandemic. The latest flap is a Lancet study stating the lack of efficacy and even the harm from some medication. The Scientist writes that there is massive opposition to this paper. They note:

The database used for the Lancet study, which the paper states includes 96,032 patients from 671 hospitals across six continents, is accessible only by Surgisphere. But in the week since the paper’s publication, concerns about that dataset have swirled on social media, on the post-publication discussion website PubPeer, and in newspapers.  Initial concerns centered on the paper’s statistical analyses, as well as the fact that COVID-19 patient data were surprisingly homogeneous across continents, despite known differences in demographics and underlying health conditions in those populations. More-recent concerns have broadened to other aspects of the dataset. Desai has since acknowledged one error in an Australian cohort and yesterday published a brief correction. While he has said in an interview with The Scientist that he is looking into clearing up confusion around the study findings, Desai has continued to defend his work and the integrity of the Surgisphere data. But that response has not assuaged the concerns of the scientific community. On May 28, an open letter, which has now accrued more than 180 signatories at research institutions around the world, laid out multiple other problems with the study data and analyses. In addition, readers of the study are beginning to ask about the nature and history of Surgisphere, and how it managed to obtain such a complex dataset in a relatively short period of time. 

It will be interesting to see how this turns out. It does not appear to have a positive ending and the net result will be abject disrespect for the "gang" of scientists. Worse yet will be the Government reliance on "science" will also have lost total trust.

NJ 2020 05 30

The town is low in terms of daily incidence, all from LTC facilities.

The counties still have hot spots where most are cooling down. Now Bergen is negative, hopefully that is some adjustment.

State numbers back to the low levels

County is back to low as well, very low.

Deaths are still higher than I would think but we will see drop tomorrow.

LTC deaths are still the large percent. Strange that after months of warning it persists. Poor management.

State prevalence is leveled, had hope for lower leveling.

NJ 2020 05 29

We still have some county wide pops.

First on a per PoP basis we see Morris is quite low but we continue in Union, Passaic, Mercer and Cumberland.

On an absolute number Union dominates. This is clearly a result due to poor compliance.

The upturn is driven by these three counties and I am a bit surprised. Again we have the noisy data problem.

The county is great.

Deaths see an increase but again a reporting artifact

We still have 60% in LTC. Not clear when this will drop.

Prevalence is flattening which means this may be around for a bit or we just have a lot of hidden infections. We are now testing non symptomatics.

Cancer Associated Fibroblasts

We have recently written a Report on Cancer Associated Fibroblasts which considers a recent Consensus Report. Cancer is much more complex than initially thought. Originally cancer was viewed in the context of the aberrant cell from a specific organ. Namely a cell from an organ had a genetic alteration and the result was aberrant proliferation and loss of function. Not only is a cell genetically changed to promote its aberrant growth but the cell apparently participates with its local environment to facilitate the process as well as developing a shield to prevent attack by the immune system or other entities. In a sense, the malignant cells manage to turn the very cells that protect the body, against the body they are to protect. Thus, the cancer is an amalgam of the aberrant cell and the collection of cells and entities about it that enable the malignant cells to not only survive but to become an entity unto itself. The implications are that any attempt to attack the cell alone may be thwarted by the other entities which are not only enablers but protectors.

In contrast, one can think of wound healing. In certain primitive animals we know that if you tale then, slice them mid body, head and tail, and then allow them to regrow, the net result is two identical regrown entities. There is no scar tissue, just a total regeneration of the original entity. As one goes up the chain in developed animals the ability to regenerate disappears and one is at best left with scar tissues. For the most part the scar tissue is developed by fibroblasts.

Thus, if one were to consider a set of malignant cells as an injury then the application of the fibroblasts and the formation of a putative scar may be a reasonable analogy. However, in this case the "scar" is a mutually self-sustaining entity which facilitates tumor growth and progression.

In this Note we examine some of the recent work regarding Fibroblasts and their association with malignancies. In a recent Consensus Statement, the authors have discussed the ability to gain an understanding of cancer associated fibroblasts. As Sahai et al note[1]:

Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions.

This note is a focus on CAFs as well as other elements of the tumor micro environment. The above remarks from the recent Consensus Statement highlights another set of targets for the treatment of cancers. We have experienced an explosion of ways to target the cancer cell itself. However we know time and again that for a majority of the patients the response is lacking. We address that issue herein where we argue that the TME and its associated cells are the next barrier to breach.

 

Let us begin with the overall stroma, or in Greek, στρομα (packing bed, sack, bedding). The stroma is the collection of elements that surround and support a cell. In cancer cells the stroma can in a sense be identified as the extracellular matrix, plus the cells supporting this such as fibroblasts.

As Maddaluno et al note in their review of fibroblast growth factors, "FGF", they note[2]:

Tissue injury initiates a complex repair process, which in some organisms can lead to the complete regeneration of a tissue. In mammals, However,  the repair of most organs is imperfect and results in scar formation. Both regeneration and repair are orchestrated by a highly coordinated interplay of different growth factors and cytokines. Among the key players are the fibroblast growth factors (FGFs), which control the migration, proliferation, differentiation and survival of different cell types. In addition, FGFs influence the expression of other factors involved in the regenerative response. Here, we summarize current knowledge on the roles of endogenous FGFs in regeneration and repair in different organisms and in different tissues and organs. Gaining a better understanding of these FGF activities is important for appropriate modulation of FGF signaling after injury to prevent impaired healing and to promote organ regeneration in humans.

Thus, FGF in one sense are important in understanding the regrowth of cells injured and also in turn their use in the explosive growth of tumor cells. Cancer cells have a somewhat unique capability in engaging the resources of a multiplicity of other cells, often one which would normally be protective against invaders, and using these cells to assist in its own proliferation. The amalgam of these cells is called the tumor micro environment, TME.

The TME is often overlooked in histological studies where the focus is on the morphology of the aberrant source cells. For example, in examining a thyroid malignancy, one all too often examines the nucleus and nucleolus of the originating thyroid cells. and is the growth of macrophages or fibroblasts which have become an integral part of the malignancy. The same is somewhat true of melanomas and prostate cancers and a wealth of other solid malignancies.

As Biffi and Tuveson have noted[3]:

Stromal cells constitute the tumor microenvironment (TME), a niche where neoplastic cells reside and progress. While the genetic and epigenetic drivers of cancer cells have been extensively investigated, the mechanisms governing the recruitment and activation of a major stromal cell type, cancer-associated fibroblasts (CAFs), are largely unknown.

Investigating the origin and developmental lineage of CAFs is essential for determining their functions and designing means to impede their tumor-supportive roles.

CAFs may be globally viewed as the chief architects of the TME due to their multiple functions. Indeed, they are considered the major source of extracellular matrix components that alter physical-chemical properties, concomitantly impairing vascular function and, therefore, drug delivery.

Furthermore, CAFs secrete paracrine ligands that promote tumor growth, angiogenesis and drug resistance, and directly blunt T cell cytotoxicity while recruiting immunosuppressive populations. Therefore, a multitude of preclinical and clinical studies have attempted to antagonize CAFs as a treatment modality for cancer.

However, the classical view of uniformly pro-tumorigenic CAFs has been modified by the recent identification of subsets with tumor-suppressive properties. This new appreciation that CAFs are a heterogenous population in the TME prompts a reevaluation of CAF identities and functions in efforts to develop more effective therapies.

Changes can be made to cancer cells such as the epithelial to mesenchymal transition process[4].

We can make two basic observations. The first will be the interactions with the cancer cell and the other elements of the tumor micro environment, TME. We show this below:

The above is a simple demonstrative that shows that the cancer cell can control and be controlled by a significant selection of the TME.

In a similar fashion we can look at the CAF and see how it influences the immune environment. This is a critical observation. We show this below:

What is critical to note is that the CAF can control a large set of the immune system. This in effect tends then to block any immunotherapeutic approach to mitigating the cancer cells.

The previous section details some of the key points we will discuss. The driver herein is the Consensus Statement recently issued and referred to herein regarding CAFs. We will present the following:

1. Fibroblasts and FGF. These are the current cells and the growth factors associated somewhat with them. FGF are a large group and a few are fibroblast related whereas the name encompasses a larger set of cells.

2. The ECM and TME: The ECM is the mass of extracellular proteins and the tumor micro environment is the collection of other cells which make up the total tumor mass.

3. Adipocytes: This will be a discussion on another set of cells which are frequently forgotten, The often play a key role in the malignant process.

4. ECM signalling discusses how the TME uses the ECM for intercellular signalling of a holistically defined tumor mass.

5. There is a detailed discussion of the current understanding of the CAF

6. The immune elements are discussed and a specific focus on immunotherapeutic issues.

7. We then consider a specific malignancy, prostate cancer, and the issues of CAF.

Overall, understanding the TME and the elements that make it up is critical to understand the "system" that functions in many cancers. Hematopoietic cancers may be different in that they present themselves bare of any significant TME. On the otherhand somatic cancers often have developed a significant protective environment to sustain themselves.

Fundamentally, we must understand cancers as a set of complex interacting systems. Instead of just targeting one aberrant element of another we must target the system as a whole. Yet to do that we must first truly understand the system. Our goal in the Note is to start with a step in that process.

---

[1] Sahai et al, A framework for advancing our understanding of cancer-associated fibroblasts, Nature Reviews, Cancer, March 2020, Volume 20

[2] Maddaluno, Fibroblast growth factors: key players in regeneration and tissue repair, Development (2017) 144, 4047-4060

[3] Biffi and Tuveson, Deciphering cancer fibroblasts, J. Exp. Med. 2018 Vol. 215 No. 12 2967–2968

[4] https://www.researchgate.net/publication/330222973_EMT_and_Cancers

Pure Speculation?

How does the virus of COVID-19 spread? One would think that as a scientist one would base it upon some well defined and repeatable experiment. Along comes some atmospheric scientist who purports to know the answer.

In and interview in Medscape they state:

Something has been bothering (this person): everything she reads about COVID-19 points to a pathogen that travels through the air.There's how quickly it has spread around the world, studies showing how it spreads through restaurants (maybe by the air conditioning system?), how it attacked a church choir even though they were spread apart while they were singing, how it seems to spread like wildfire on planes and on cruise ships; all of this, she says, ...should know. ...studies aerosols — particles so tiny they float freely through the air, traveling feet or even miles....runs a large, government-funded research center at the University of California San Diego to study how viruses and other things that come out of the ocean float through the air. "A lot of the evidence has been pointing to aerosol transmission of respiratory viruses," she says. Influenza can be passed through the air, as can the virus that causes SARS. "This particular virus, a lot of evidence is mounting." ...says she's been alarmed not to see the CDC or WHO come out with a strong statement that people could catch COVID-19 by breathing it in. "It's just shocking to me, quite honestly, that this has not been factored in." And she believes masks can play a major role in stopping that transmission.

In the Science article written by these folks they state:

Aerosol transmission of viruses must be acknowledged as a key factor leading to the spread of infectious respiratory diseases. Evidence suggests that SARS-CoV-2 is silently spreading in aerosols exhaled by highly contagious infected individuals with no symptoms. Owing to their smaller size, aerosols may lead to higher severity of COVID-19 because virus-containing aerosols penetrate more deeply into the lungs It is essential that control measures be introduced to reduce aerosol transmission. A multidisciplinary approach is needed to address a wide range of factors that lead to the production and airborne transmission of respiratory viruses, including the minimum virus titer required to cause COVID-19; viral load emitted as a function of droplet size before, during, and after infection; viability of the virus indoors and outdoors; mechanisms of transmission; airborne concentrations; and spatial patterns. More studies of the filtering efficiency of different types of masks are also needed. COVID-19 has inspired research that is already leading to a better understanding of the importance of airborne transmission of respiratory disease.

 Now if one reads this final statement it is hardly dispositive. The entire article is speculative relying on bits and pieces of other speculative statements. I have written speculative pieces but I clearly indicate they are speculative. We really do not know. Nor apparently does this individual in my opinion.

The assertions are not based on any first hand reproducible experiments. There is no direct research performed demonstrating intensity of transmission, comparison between methods etc.

Yet in my opinion individuals like this do a gross disservice to science, they make it into an opinion business not a fact business.

NJ 2020 05 28

New cases are down as result of the weekend artifact, not reality.

County has the same effect. They roll the deaths over so one must be very careful looking at any one day.

Deaths are down, that seems like a good sign. The total death curve is flattening.

Still a LTC death problem due to Gov's decision.

14 day is oscillating reflective of a low end stabilization.

This shows the increases in the more distant counties otherwise really good data.

Doubling times are fantastic not like any of those Academic models.

NJ 2020 05 27

State shows a bump up but we suspect it is the noisy data reporting. Shame

The county looks like it is clearing out. So do we get a prize Mr Gov?

Deaths show a peak but again it just the artifact of a 3 day weekend.

The most are nonLTC but again a delayed artifact.

14 day is leveling as we get down the slope.

NJ 2020 05 26

Still in slow decline. There are the typical issues of poor reporting and increases testing. There should be some way to normalize these but lacking data this is the best you can do.

County is really low and seems to be opening despite the lack of leadership from the Gov

Deaths are declining and even thought we have the period behavior of reports the trend is down.

The deaths are still LTC driven thanks to Gov

14 day trends are still good.

NJ 2020 05 25

Let us first look at counties by daily incidence.

The above are the absolute incidence from yesterday by county. Now the incidence per PoP.

Two observations. First the large counties still are seeing infections. Second the smaller counties dominate on a per PoP basis.

The above is the total incidence for the state, we see a pop on the current numbers, perhaps due to more testing

The county saw a similar pop yesterday. Strange since it was a Sunday.

Deaths continue to drop but again that is a Sunday issue and since today is also a holiday we expect an explosion on Tuesday which is Wednesday report.

Deaths show more resurrections such that LTC deaths exceed total reported. One would expect the State to remedy this but alas they are Government employees.

Finally the 14 day running average also popped up. Should be watching this one.

NJ 2020 05 24

The flattening seems due to growth in outlier counties.

Morris is clearly dropping to zero and should be close in a week or so

Deaths remain but remember these are from Saturday

Deaths are dominate by LTC patients due to Gov's mandate

State prevalence is flattening as above

County is still dropping

State 14 day is still negative