Wednesday, December 13, 2017

Healthcare in New Jersey

NJBIZ reports on demands of the incoming Governor as to how to "improve" the State's Healthcare system.

Some observations:

Amend state law so that health care related state boards are not self-governed. Instead, require that at least half of any of these individual board’s memberships be comprised of individuals whose professions are not directly regulated by that board, and who would be representative of consumers that utilize the services overseen by the board. In addition, the state should examine and issue a report on best practices utilized by other states for health care related state boards.

That would mean politically appointed and motivated individuals having no knowledge of or interest in medicine but promulgating a politically supported agenda.

Revise state law to allow for the electronic delivery of insurance materials and provide for such delivery as the default method, while allowing consumers to opt in to the delivery of paper materials if they wish.

Opt out seems to be pervasive in NJ. Especially with the Democrats. This would make every older person require electronic delivery and thus open it up to massive data fraud.

Amend state law (through the Division of Consumer Affairs) to expand the kinds of services nurses, physician assistants or therapists can perform without supervision and in general.

This is the Nurses full employment act. They are cheaper and even thought not qualified they become your only choice!

That New Jersey adopt a standard that imposes requirements that providers offering services at hospitals participate in the same networks as such hospitals, and that providers and facilities publicly disclose the networks in which they participate.

 If you are a specialist and the hospital at which you have privileges serves Medicaid then you must also! This will drive all specialists to private "clinics".

If you did not like Obama Care your will really thrill to Murphy Care! Another gift from Goldman Sachs.

Cancer Treatment and Unintended Consequences

The recent explosion in immunotherapy targeting such elements as PD-1 or PD-L! and others has demonstrated a significant positive step forward. However recent results indicate that there may also be a dark side to this process.

As Sarkizova and Hacohen have noted:

The T cells of the immune system have a key role in the identification and elimination of cells that pose a threat to the body, such as infected cells and cancer cells. ….(authors) propose a framework to assess how effectively tumours can be detected by T cells — a tumour property known as immunogenicity. The authors demonstrate that their models for assigning tumour-immunogenicity scores can be used to predict clinical responses to a type of cancer immunotherapy called checkpoint blockade.

Most cells in the body present peptide fragments known as antigens on their cell surface, which are generated from intracellular proteins. Each peptide is bound in a complex with a specialized receptor called an MHC class I protein (HLA class I in humans). T cells known as cytotoxic T cells police the body in search of cells displaying specific antigens, especially antigens from infectious organisms, or in the case of cancer, antigens known as neoantigens that have arisen as a result of a mutation. If the T-cell receptor (TCR) of a cytotoxic T cell recognizes and binds an antigen that is not normally present, the T cell will often unleash an attack that kills the cell displaying that antigen. TCRs are highly variable and have slightly different antigen-binding regions, enabling the immune system to recognize millions of antigens. Antigen binding to MHC proteins and TCR recognition of antigen–MHC complexes are key determinants of an immune response.

They continue with the discussion of checkpoints as follows:

Tumour cells often fight back against this immune-system surveillance by hijacking the natural mechanisms that dampen immune responses, which are normally intended to block autoimmmune attacks against healthy tissue. Checkpoint-blockade therapies can block these immuno-inhibitory signals, such as those generated by the ‘checkpoint’ PD-L1 protein4. However, only a subset of tumours treated with such therapies regress. Therefore, approaches are needed to identify the tumours that are most likely to respond to immunotherapy.

Current ways of predicting the effectiveness of checkpoint-blockade therapy rely on measuring the level of PD-L1 protein expressed by tumour cells, counting the number of T cells in a tumour, and estimating the number of different neoantigens that a tumour contains5. The work by Ɓuksza and Balachandran and their respective colleagues offers a new type of integrated model to predict whether a tumour will be attacked by T cells, a characteristic that they refer to as tumour fitness (low fitness being associated with a strong immune response against the tumour).

Thus in the best of worlds we see the result below. As Ludin and Zon note:

PD-1 is expressed on the surface of immune cells called T cells. When PD-1 is bound by a ligand produced by tumour cells, PD-1 signalling renders the T cell inactive, preventing immune responses that would destroy the tumour. Treatment with an antibody to PD-1 blocks ligand binding and so PD-1 signalling, instead promoting the PI3K signalling pathway, which is involved in T-cell activation. As such, anti-PD-1 treatment triggers an immune response,

Wartewig et al. have demonstrated that PD-1 signalling in a mouse model o f T cell non- Hodgkin’s lymphoma prevents proliferation of cancerous T cells (the source of the PD-1 ligand was not defined). In these mice, anti-PD-1 treatment can aggravate disease by reactivating the cancerous cells to enable then continuous proliferation.

Namely a tumor cell having a PD-L1 can be attacked by the T cells when we block this suppressor. We demonstrate this below. If PD-1 is matched with a PD-L1 then the T cell remains inactive. If we have an antibody used to block either PD-1 or PD-L1 then we can get T cell activation.

  In contrast if the bad cell is the T cell, or if there is such a cell present in addition to the other tumor, then removing this block may activate the malignant T cell and off we go with a second malignancy. The example we show below.

As Wartewig et al note:

By contrast, a homo- or heterozygous deletion of PD-1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Thus, the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T cell lymphomas that is frequently altered in human disease. These findings extend the known physiological functions of PD-1 beyond the prevention of immunopathology after antigen-induced T cell activation, and have implications for T cell lymphoma therapies and for current strategies that target PD-1 in the broader context of immuno-oncology

Namely we have the potential that certain cells have managed to block malignant T cells from multiplying and thus keep a hematological cancer under control. When attacking another cancer with a blockade it may then allow this blocked cell to proliferate.

As Giladi and Amit note:

The cells of the immune system, which patrol the blood and dwell in tissues, have many functions. They protect the body from pathogens and cancer, and orchestrate metabolism and the formation of organs. They are involved in almost every activity that regulates the body’s internal environment, from the development and remodelling of tissues to the clearance of dying cells and debris. So their dysfunction can cause many problems

This may be an obvious statement but it sets the path for what is to follow. The more one learns about the immune system the more we find a complexity of cells, not just T or B cells but T cells which perform different sets of functions. To understand this we need tools that allow us to ascertain what happens on a single cell basis. The authors continue:

First, it is clear that many of the current categories of immune cells, such as T cells or monocytes, encompass heterogeneous populations. To probe cellular complexity, researchers must therefore cast their nets wide, and try to collect all immune cells within a tissue or region of interest. This is a very different approach from that used with methods based on cell-surface markers, which aim to obtain as pure a sample as possible.

Second, success will depend, in part, on the extent to which researchers preserve the states of cells and the original composition of a tissue. Cell stress or death should be minimized to ensure that tissue preparation does not favour specific cell types. …

Third, bioinformaticians will need to develop scalable and robust algorithms to cope with greater numbers of cells, conflicting or overlapping programs of gene expression and fleeting developmental stages.

Fourth, after researchers have characterized all of the immune cells in a sample, they will need to find molecular markers that can be used to either enrich or deplete certain cell types in further samples.

The issue then is that it is essential to have in the "tool box" methods to carefully examine individual cells in situ. There are clear indications that cell interactions are complex, and also are extremely dynamic. The real question is: what level of depth of differentiation is essential for what level of patient care? As we noted above, there are cases where PD-1 blockage can on the one hand activate the immune system against the cancer and on the other hand suddenly activate dormant malignancies. Is this then just a "whack a mole" strategy against cancer, namely attacking one only to have then to attack a second resulting from the success of the first?

Fox and Loeb had previously attacked this issue from the perspective of breast cancer. They noted:

The total number of mutations that a tumour genome carries, including those present in only a small subset of cells, may in fact underlie the aggressiveness of different cancer subtypes. For example, the extent of genetic diversity within a tumour, and its divergence from normal tissue, probably influences the ability of the immune system to distinguish malignant cells from normal cells. Identifying the mechanisms by which cancer cells generate mutational heterogeneity may therefore present previously unexplored targets.

Single-cell sequencing will allow us to detect rare mutant subpopulations hidden within cancers that could expand and lead to drug resistance, and thus to avoid unnecessary and potentially harmful administration of ineffective, toxic therapies. Ultimately, the exceptional plasticity of the tumour genome may well prove to be a key characteristic of cancer11 and a major, as yet untapped, therapeutic vulnerability.

There clearly is a growing need to perform a multiplicity of single cell analyses. However this is a complex spatio-temporal result, with a great deal of extraneous information. We should understand how cells genetic makeup changes as a function of time and of location. Location is itself complex because it refers to what cells are adjacent and even just close. Furthermore many gene expressions or suppressions are irrelevant, just chaff in an attempt to track a target. The desire to measure single cells is but a first step. A "model" or paradigm of what is essential for understanding the "system" is essential.

1.     Fox and Loeb, One cell at a time, Nature, August 2014.
2.     Giladi and Amit, Immunology, one cell at a time, 6 July 2017 | Vol 547  | Nature | 2 7
3.     Ludin and Zon, The dark side of PD-1 receptor inhibition, Nature, 7 December 2017, VOL 552, p 41
4.     Lukasz et al, A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy , Nature November 2017
5.     Sarkizova and Hacohen, How T cells spot tumour cells, Nature November 23 2017.
6.     Wartewig et al, PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis, 7 December 2017, Vol 552, Nature, p. 121

Monday, December 11, 2017

The Accidental Suffragette

Dorothy Day had a rather idiosyncratic life. She started out as a reporter on one of the many issue oriented papers in the early part of the twentieth century and that in New York managed to associate with a mix of the bohemian and left wing crowds of the day. She was involved with several different men, having first an abortion for a pregnancy and then giving birth out of wed-lock on what may have been the second. After that she converted to Catholicism and aggressively pursued the Social Justice movement popular at the time. This included a focus on seeking better conditions for labor and immigrants.

The book by Hennessy, her granddaughter, is a well written and somewhat balanced presentation of her life. Now for Day there have been a multiplicity of biographies as well as autobiographies so that one approaching Hennessy from that perspective will see a great deal of repetition of events. But Hennessy presents them in a fresh and readily readable manner.

One may ask why Day still plays an interesting role. First, it is the movement amongst Social Justice activists in the Catholic Church to seek Sainthood for her. Support is coming from many directions, such as Dolan in New York and Francis in Rome. This book by Hennessy is not a plea for Sainthood but a balanced presentation of her life. The second reason is that Day was a Social Justice advocate and as such one can examine her life and through it try to obtain a better understanding of just what that entails.

Now from my personal perspective I approached Day tangentially. In writing about my grandmother, Hattie Kruger, a Socialist in New York, a Suffragette, a woman who rand for Congress in 1918 and for New York State Office with Eugene Debs in 1920, I found that Hattie was arrested with Day and the two were in the first batch of women arrested in November 1917 by order of President Wilson and sent to Occoquan Prison where they were brutalized and force fed, again by orders of Wilson. Thus my grandmother spent time with Day and thus I wondered what type of person she was. Furthermore Day lived three blocks from my Grandmother on State Island and my parents are buried a few grave sites from Day in the same Cemetery. So much for coincidences!

I was writing a piece on my Grandmother and her time as a Suffragette. I especially was focused on her time being arrested under the direct orders of Woodrow Wilson, that misogynistic, racist, anti-Semite, anti-Catholic, all around good guy. And we worry about Robert E. Lee, but I digress. Wilson hated these women walking around with signs asking for the right to vote. After all, he was a Virginian, a man, and more importantly the President. So off with their heads, or the next best thing was to arrest them and ship them off to prison. Get them past a friendly judge, and then to Occoquan Prison, now Lorton. Throw them in cells, host then down, let them starve! Yes indeed a real nice fellow Wilson was. After all he had just gotten us into WW I, sent a few hundred thousand to France, no uniforms though, but what the heck, let them figure out how to deal with the French snows.

My Grandmother was in the first batch of women on that cold November day thrown into the back of the Black Marias, the police wagons. There were no Paddy Wagons in DC, not enough Irish. Along with her was a young lady called Dorothy Day. I had originally thought Day was there as a Suffragette. Not really. She was sent down as a reporter to cover the protest for her New York newspaper. She just happened to "be on the corner when the bus went by" so to speak. She became an "accidental Suffragette". Now Day recalls but one of the people with her and Day recalls that they joyfully discussed literature in the prison. Day at this time seems to have been more interested in the "adventure" of the moment and somewhat apart from the underlying cause,  the right to vote for women. That surprised me, at least until I discovered a bit more about Day.

Days life during the teens and twenties was somewhat that of a libertine. In Day's writing and in that of Hennessy there are no holds barred regarding this period. One could surmise that this period is a bit like that of Augustine of Hippo, who took his concubine to Italy to study, abandoned her, then let his child loose, and then his son died. Augustine then returned to Hippo and had a career writing against the likes of the Donatists and Pelagians. The theme may have some parallel.

What did this "accidental Suffragette" do after her exposure to this world? It seems that she found God in the Catholic Church. Like many converts I have known, my mother having been one, they often move aggressively into their new found faith, and accept it in all its deepest dimensions. For Day is was a move which led to the founding of the Catholic Worker, a rather left wing but "Catholic" weekly. It focused on helping the oppressed, especially during the Depression period. Day indicates that the naming was in contradistinction to that of the Daily Worker, the paper of the Communist Party.

She then was accompanied by a French intellect and wanderer who convinced her to leverage this paper into a full blown mission, a mission to the poor and homeless, for which there were many in the 1930s. She soon found herself at the center of a movement, dedicated to this new found faith and its focus on human equality and justice.

By the 1940s she had also become an avowed pacifist and was strongly opposed the US entry into WW II, especially after Pearl Harbor. In the 1950s, she vehemently opposed the use of nuclear weapons and the execution of the Rosenbergs. By the 1960s she had a multiplicity of "farms" and similar places where people assembled and had what we called "Retreats", which were week-long "spiritual" get-togethers where they contemplated and listened to religious lectures. During this period she strongly opposed the Vietnam War, was pro-integration, and supported the farm workers actions and other similar equal rights movements.

She developed a wide cadre of admirers and fellow movement supporters ranging from labor leaders to religious figures such as Thomas Merton, the Trappist monk. By the 1970s, in her later years, she saw a slow reduction of many of these ventures, especially as she aged and was in poor health.

There is often comparison of Day to such figures as Francis of Assisi and others yet one can see Francis as the founder of a sustained Order of Friars who had a substantial impact on Catholic teaching. It is not clear what the sustained influence of Day will be. But it is worth the while to see through the eyes of her grand daughter what Day did, why, and to examine the consequences of her efforts.

Saturday, December 9, 2017

Microbiome and Cancer

We wrote a piece a few weeks back on the Microbiome and Cancer. Some recent papers as summarized in Nature have discussed the progress in understanding this phenomenon. Now the Nature piece states: 

Preclinical mouse models have shown that the gut microbiome can modulate therapeutic responses to cancer therapies. Yet, this has not been extensively characterized in humans. Two studies now propose that the gut microbiome is an important host factor that determines the response and primary resistance to anti-programmed cell death protein 1 (PD1) immunotherapy in patients with cancer. “the clinical response to PD1 blockade could be predicted by the composition of the gut microbiome” Both groups initially sought to determine whether the clinical response to PD1 blockade could be predicted by the composition of the gut microbiome. To achieve this, faecal samples were collected from patients with either melanoma, non-small-cell lung cancer (NSCLC) or renal cell carcinoma (RCC) before and after commencement of immunotherapy. Metagenomic shotgun sequencing was then used to quantify bacterial species. A common finding was that high diversity of the gut microbiome correlated with prolonged progression-free survival (PFS) following PD1 inhibition.

The papers are by Routy et al and the other by Gopalakrishnan et al. Routy et al note:

Immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizeable minority of cancer patients. Here, we show that primary resistance to ICI can be due to abnormal gut microbiome composition. Antibiotics (ATB) inhibited the clinical benefit of ICI in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICI (but not from non-responding patients) into germ-free or ATB-treated mice ameliorated the antitumor effects of PD-1 blockade. Metagenomics of patient stools at diagnosis revealed correlations between clinical responses to ICI and the relative abundance of Akkermansia muciniphila. Oral supplementation with A. muciniphila post-FMT with non-responder feces restored the efficacy of PD-1 blockade in an IL-12-dependent manner, by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into tumor beds.

 There clearly are a multiplicity of dimensions in using the immune system to combat cancers. It is essential to view this as a systems problem, understanding that we are a bit ignorant of all of its dimensions.

Thursday, December 7, 2017

reCAPTCHA and Knowledge

One should read Theaetetus a few times, even if Plato was a bit off, lacking any scientific basis. But then again these are techys I will be speaking of and worse they are millennials. But in trying to deal with reCAPTCHA, that device which says it can tell if you are a human, I suspect Plato would not agree.

Let me pose a simple example. The ask to show street signs. Then there is a photo with a street sign on a pole, and a bit overlapping another frame, just a wee bit. Now to me the pole is a part of the street sign. The sign would not function without the pole. But not to reCAPTCHA. So on to another picture asking the same question. How about that structure holding the sign above the highway? Nope, I guess not.

Language and meaning are complex, and despite the best efforts of those isolated mammals inhabiting some complex in California, I would guess, humans, the real kind, can understand the word "sign" in a multifaceted manner.

This is a simple but powerful example of the lack of human understanding, especially of others. Plato in his Socratic tales spent a great deal of time on this issue. Google seems clueless.

Just an Observation

From time to time I have bemoaned the USPS. Now, they look great compared to UPS! UPS seems to be sending its packages, no they are my packages, around the world a few times before they get where they are supposed to go. Perhaps someone in management could try to find out what is happening. After all they are a union shop and aren't they supposed to be better?