Is Meaningful Use Meaningful?

The EHR/EHR is moving forward in its Government mandated manner but signs of revolt may still be simmering. In MedPageToday they report:

...Amherst, Mass, said that three of the physicians who left her practice in the last year did so because of frustration with the Meaningful Use requirements. She said the practice underwent an expensive audit associated with the program that lasted more than a year, which had the ironic effect of delaying other programs aimed at improving patients' health. If Stage 3 goes into effect, ... said, she will be obliged to stop accepting Medicare patients, leaving 1,500 elderly and disabled patients without a primary care doctor. "I couldn't take care of my patients and take care of myself," she said. Another physician mocked the requirement for a certain percentage of patients to use online patient portals to communicate with doctors. He said he has his secretary log in his patients, most of whom are geriatric, so that they can send "a note of clinical relevance... which says 'hi'."

There are levels of problems here. First is the ability of the physician to enter "meaningful" data. For the most part it is cut and paste. Second is the ability to look at trends. Medicine often is seeing if anything has changed; HbA1c, PSA, BP, weight, etc. Change and rates of change are critical. I see this in monitoring HbA1c and PSA levels, yes PSA levels. Sample blood glucose are useless, HbA1c is a 90 day average. It has value. Single PSA is meaningless, velocity is prognostic. Most EHR make one fumble for those metrics. Third, try and get them to interconnect! Even in an integrated hospital system. Take New York Presbyterian. Cornell does not communicate with Columbia, and patient portals are separate and patient appointments are catch as catch can.

They continue

...a pediatrician from Leominster, Mass., agreed that certain metrics were inappropriate for certain specialties. "I think of this every time I check the blood pressure on a screaming 3-year-old who has an ear infection." And a number of physicians, ..., commented on the futility of punishing providers for the failures of technology vendors. Stack said he has the knowledge and expertise to take a patient whose liver has ruptured through numerous protocols and into the operating room in just enough time to keep the patient from bleeding to death internally. " I shoudn't have to write the software code for the electronic health record at the same time."

 It continues:

a professor at Harvard University and a researcher for the Children's Hospital Informatics Program at Boston Children's Hospital, said EHRs should be as adaptable as the apps on an iPhone. "If the makers of Angry Birds want to add a new bird they don't have to fly to Cupertino... to figure out how to do that."

 I could not have said it better myself!

Got Your Goat

I like the Canadians. They seem to give us our best comedians and good stories.

In the National Post we have the one about the goat:

A goat that bunkered down at the Tim Hortons in Martensville, Saskatchewan, has been reunited with its owners. Warman RCMP were called to the coffee shop Sunday around 4 a.m. The goat had walked into the entranceway of the building through the automatic doors and settled down for a nap. Police arrived and loaded the animal into their cruiser.

Yep, police called for a goat. Now for those not familiar with goats, this is not uncommon.

How to Spend Money, Ours!

It was not enough for the FEDs under the Stimulus to dump billions into broadband, with questionable results at best, but now NY State appears to be jumping in as well with State Taxpayer money.

The New Yrok Broadband plan will, it appears, give away some $500 million to build out broadband. They state:

Governor Cuomo has launched the largest and most ambitious investment in statewide broadband deployment in the country. Through the creation of the $500 million New NY Broadband Program, the State of New York will incentivize broadband provide rs to expand and upgrade networks to ensure that they reach all underserved and unserved communities in the State . The Program is designed to ensure that every New Yorker has access to high - speed Internet . The Program will be implemented by the end of 2018.

They also do address wireless which we believe is the only solution to such areas as rural New York State. BUT, who has the license? You just can't do wireless, you need a license, and most have been given out already. Any why 25 Mbps and 100 Mbps. I am always amazed at why someone who decides to live in the wilderness need our taxpayer money for 100 Mbps access when they most likely do not have indoor toilets!

Perhaps a state voter referendum would help here.

Detecting Prostate Cancer

Prostate Cancer is a high incidence cancer in men with a small percentage being very aggressive and potentially lethal. PSA has been used for over two decades and despite the USPTF negative stand it still finds use, especially in men with a family history of aggressive PCa.

However the next step in diagnosis is a biopsy, and the classic multi core approach has its own problems. Namely it samples at best 2-3% of the prostate and for early stage PCa this may not be adequate.

Fused MRI and TRUS is now coming of age and is used more frequently. In a recent paper by Bodman et al the authors have examined the performance of such tests.

They report:

MRI/TRUS fusion–assisted targeted biopsy improves the detection rate of prostate cancer after a previous negative biopsy. Targeted biopsy is more likely to reveal clinically significant cancer than systematic biopsy; nevertheless, systematic biopsy should still be performed, even if the MRI findings are negative...The MRI/TRUS fusion biopsy approach is a promising method for detecting prostate cancer after a prior negative histological result. Combining MRI-guided targeted biopsies of suspicious lesions with a systematic 12-core biopsy protocol increases the overall cancer detection rate and leads to more clinically relevant cancers being found. Our data suggests that taking additional fusion-guided biopsies from lesions with a low risk score, based on MRI analysis,  is not necessary.

Systematic biopsy remains necessary even when MRI results in inconspicuous images. The strategy of a single targeted biopsy without a systematic biopsy is not to be recommended. MRI-guided   fusion biopsy holds great promise for the future but must still undergo careful verification. As no unified technical standardization or systematic training exist for this method to date, a high amount of examiner experience is necessary. Finally, because the MRI/TRUS fusion strategy has not yet been considered in the current S3 guidelines for primary diagnosis of prostate cancer, the value of this method should be analyzed in large multicenter studies.

Overall the results indicated:

Grayscale TRUS: Senstivity % 18.3, Specificity % 90.4
MRI/TRUS: Senstivity % 58, Specificity % 93

This can be a substantial improvement. It would be useful to have a similar model as we had developed for Grayscale TRUS using a Bayesian model.

More on CRISPRs

We have examined CRISPRs for the past few years since their introduction. Initially we had a CRISPR with a Cas9 molecule which managed to cut DNA at specific spots. The CRISPR was designed to match a specific sequence and the Cas9 was able to recognize the PAM sequences and using certain portions of the Cas9 it could then “break” both strands at opposite positions of the DNA, a specific set of base pairs from the end of the PAM.

This then becomes a useful tool in an ever growing tool-box for DNA modification. In bacteria this cut is applied to viral DNA or RNA and it is a “natural” immune system in the bacteria. In other cells, plants and animals, it enables precise and specific gene editing.

In a recent paper from Zhang’s Lab at Broad they have identified another protein which acts like Cas9. This new system is called CRISPR-Cpf1 and is identified as a class 2 CRISPR system[1]. Specifically Cpf1 is a CRISPR-associated two-component RNA-programmable DNA nuclease. It functions in a manner similar to Cas9 and targeted DNA is cleaved as a 5-nt staggered cut distal to a 5′ T-rich PAM. They have also identified two Cpf1 orthologs exhibit robust nuclease activity in human cells. In the paper in Cell they state:

The microbial adaptive immune system CRISPR mediates defense against foreign genetic elements through two classes of RNA-guided nuclease effectors. Class 1 effectors utilize multi-protein complexes, whereas class 2 effectors rely on single-component effector proteins such as the well-characterized Cas9. Here, we report characterization of Cpf1, a putative class 2 CRISPR effector. We demonstrate that Cpf1 mediates robust DNA interference with features distinct from Cas9. Cpf1 is a single RNA-guided endonuclease lacking tracrRNA, and it utilizes a T-rich protospacer-adjacent motif. Moreover, Cpf1 cleaves DNA via a staggered DNA double-stranded break. Out of 16 Cpf1-family proteins, we identified two candidate enzymes from Acidominococcus and Lachnospiraceae, with efficient genome-editing activity in human cells. Identifying this mechanism of interference broadens our understanding of CRISPR-Cas systems and advances their genome editing applications.

The figure below depicts their interpretation of its functioning.

It is worth comparing these two mechanisms. The Cas9 is a bit more rigid than Cpf1. As noted above and as discussed in the paper and elsewhere, this new protein complex does what Cas9 did but with many more attractive features.

In an MIT press release they state[2]:

The newly described Cpf1 system differs in several important ways from the previously described Cas9, with significant implications for research and therapeutics, as well as for business and intellectual property:

    First: In its natural form, the DNA-cutting enzyme Cas9 forms a complex with two small RNAs, both of which are required for the cutting activity. The Cpf1 system is simpler in that it requires only a single RNA. The Cpf1 enzyme is also smaller than the standard SpCas9, making it easier to deliver into cells and tissues.

    Second, and perhaps most significantly: Cpf1 cuts DNA in a different manner than Cas9. When the Cas9 complex cuts DNA, it cuts both strands at the same place, leaving “blunt ends” that often undergo mutations as they are rejoined. With the Cpf1 complex the cuts in the two strands are offset, leaving short overhangs on the exposed ends. This is expected to help with precise insertion, allowing researchers to integrate a piece of DNA more efficiently and accurately.

    Third: Cpf1 cuts far away from the recognition site, meaning that even if the targeted gene becomes mutated at the cut site, it can likely still be recut, allowing multiple opportunities for correct editing to occur.

    Fourth: The Cpf1 system provides new flexibility in choosing target sites. Like Cas9, the Cpf1 complex must first attach to a short sequence known as a PAM, and targets must be chosen that are adjacent to naturally occurring PAM sequences. The Cpf1 complex recognizes very different PAM sequences from those of Cas9. This could be an advantage in targeting some genomes, such as in the malaria parasite as well as in humans.

The above four properties are quite compelling and worthy of note. Cas9 did have the problem of cutting at opposite sites and trusting that a competent and non-aberrant re-fusion was made. This discovery, assumedly after hundreds of attempts, opens the door on another dimension of the CRISPR world.

As is noted in Xcomony they state[3]:

… the Cpf1 work is still in its infancy. It’s well behind CRISPR/Cas9—which researchers have used to make changes in the cells of all types of organisms, including humans. Several companies are working with CRISPR/Cas9 to create therapeutics for genetic disease. None have reached clinical trials yet.

The issue here is just how extensive is Cpf1 development and how readily available is the technology. The above presentation seems to imply an early stage. They continue:

But work with CRISPR/Cas9 to modify the human germline—eggs, sperm, and embryos—is also coming faster than expected, sparking ethical concerns. An international summit on the topic is scheduled for December in Washington, DC.

Meanwhile, researchers around the world are working to find new versions of Cas9, or new enzymes entirely, like Cpf1, to make the whole enterprise easier. “There is little doubt that… there are additional systems with distinctive characteristics that await exploration and could further enhance genome editing and other areas of biotechnology as well as shed light on the evolution of these defense systems,” Zhang (pictured above speaking at a 2014 Xconomy event) and his coauthors write in the Cell paper.

In other words, Cpf1 is the tip of the iceberg. I’ll outline three differences between Cpf1 and Cas9 that the paper’s authors have highlighted as potentially important for the field. First, for those unfamiliar with CRISPR and gene editing, it helps to think of these enzymes as molecular scissors. Bacteria use them in the wild to defend themselves against invading viruses, cutting up the viral RNA and storing the pieces in a kind of immune system memory bank.

It was only in recent years that the natural system has been modified and harnessed as a gene editing tool. The enzyme—a protein—and its guide—made from RNA—need to be sent into a cell (that’s one difficult trick) and hit the right spot (that’s another difficult trick).

The following is the Xconomy author’s description. It is a restatement of what was in the MIT release but rephrases the key differences:

Here’s why Zhang and his co-authors think Cpf1 could have advantages over Cas9:

—Cpf1 only uses one strand of RNA as a guide to reach its target gene. Cas9 uses two strands. A single-strand system might lead to simpler, cheaper designs and easier delivery of the enzyme-guide complex into cells.

—Once delivered into the cell’s nucleus, Cpf1 makes staggered double-stranded cuts in the target DNA, whereas Cas9 cuts both DNA strands in the same location. This could be important, Zhang and colleagues write, because the staggered ends make it easier to insert a new gene after the old one is removed. That could help get around one of the hurdles of Cas9: Scientists say using Cas9 to replace an old gene with a new one has proven far more difficult than simply cutting out a gene.

—When Cpf1 homes in on a gene, it actually makes the cut off to the side, relatively speaking—farther down the DNA strand. (Imagine your friend holding a string in the exact location that needs snipping. You don’t cut her finger; you cut off to the side.) Zhang and colleagues write that this could be a “potentially useful feature” because it preserves the target site for subsequent rounds of editing.

The off-setting of the splices is a significantly better method. It gives the “sticky” ends approach and tends to much fewer errors. This alone could make this much more attractive.

In a Nature discussion of these results they state[4]:

But now one of the technique's pioneers thinks that he has found a way to make CRISPR even simpler and more precise. In a paper published in Cell on 25 September, a team led by synthetic biologist Feng Zhang of the Broad Institute in Cambridge, Massachusetts, reports the discovery of a protein1 called Cpf1 that may overcome one of CRISPR-Cas9’s few limitations; although the system works well for disabling genes, it is often difficult to truly edit them by replacing one DNA sequence with another.

The CRISPR/Cas9 system evolved as a way for bacteria and archaea to defend themselves against invading viruses. It is found in a wide range of these organisms, and uses an enzyme called Cas9 to cut DNA at a site specified by 'guide' strands of RNA. Researchers have turned CRISPR/Cas9 into a molecular-biology powerhouse that can be used in other organisms. The cuts made by the enzyme are repaired by the cell’s natural DNA-repair processes.

Good, better, best?

CRISPR is much simpler than previous gene-editing methods, but Zhang thought there was still room for improvement.

So he and his colleagues searched the bacterial kingdom to find an alternative to the Cas9 enzyme commonly used in laboratories. In April, they reported that they had discovered a smaller version of Cas9 in the bacterium Staphylococcus aureus2. The small size makes the enzyme easier to shuttle into mature cells — a crucial destination for some potential therapies.

The team was also intrigued by Cpf1, a protein that looks very different from Cas9, but is present in some bacteria with CRISPR. The scientists evaluated Cpf1 enzymes from 16 different bacteria, eventually finding two that could cut human DNA.

They also uncovered some curious differences between how Cpf1 and Cas9 work. Cas9 requires two RNA molecules to cut DNA; Cpf1 needs only one. The proteins also cut DNA at different places, offering researchers more options when selecting a site to edit. “This opens up a lot of possibilities for all the things we could not target before,” says epigeneticist Luca Magnani of Imperial College London.

Cpf1 also cuts DNA in a different way. Cas9 cuts both strands in a DNA molecule at the same position, leaving behind what molecular biologists call ‘blunt’ ends. But Cpf1 leaves one strand longer than the other, creating a 'sticky' end. Blunt ends are not as easy to work with: a DNA sequence could be inserted in either end, for example, whereas a sticky end will only pair with a complementary sticky end.

“The sticky ends carry information that can direct the insertion of the DNA,” says Zhang. “It makes the insertion much more controllable.”

Zhang’s team is now working to use these sticky ends to improve the frequency with which researchers can replace a natural DNA sequence. Cuts left by Cas9 tend to be repaired by sticking the two ends back together, in a relatively sloppy repair process that can leave errors. Although it is possible that the cell will instead insert a designated, new sequence at that site, that kind of repair occurs at a much lower frequency. Zhang hopes that the unique properties of how Cpf1 cuts may be harnessed to make such insertions more frequent.

In contrast we also have an article in The Economist which states[5]:

CRISPR-Cpf1 may also be better than CRISPR-Cas9 in other ways. Cpf1 is a smaller and simpler enzyme (known technically as an endonuclease) than Cas9, which means it will be easier to deliver to the cells whose genes need modifying. And its slightly offset cuts to double-stranded DNA will help researchers to insert genetic patches more efficiently and accurately.

Its discovery also raises the question of how many other endonuclease-based systems are out there in the world’s bacteria. Viral infection is a serious threat to these microbes, and the natural job of both CRISPR-Cas9 and CRISPR-Cpf1 is to recognise viral genes and chop them up before they can do any harm. Conversely, viruses are constantly evolving to escape the antiviral systems’ attentions, meaning bacteria need to generate new ones. The chances are good, therefore, that CRISPR-Cas9 and CRISPR-Cpf1 are not alone. …

The tools to carry out that exploration now exist. CRISPR-Cpf1, for instance, was found not by searching in bacteria directly, but by scrutinising a published database of bacterial genetic sequences, which yielded two species that contain it. Further searches might be equally rewarding—and the more gene-editing systems are discovered, the harder it will be to monopolise their use.

Despite the optimism of those who think the new techniques may calm qualms about genetic engineering, however, some people are bound to have ethical worries—certainly when it comes to applying them to human beings. Earlier this year, for example, when Chinese scientists used CRISPR-Cas9 gene editing on a human embryo (albeit one that was unviable, and could not therefore have developed into a person) there was much brouhaha and several calls for a moratorium on this line of inquiry.

There may not only be ethical worries but as we have discussed previously there is a weaponization approach also readily available.

In a report in Nature World they state[6]:

The CRISPR/Cas9 system evolved as a way for bacteria and archaea to defend themselves against invading viruses. It is found in a wide range of these organisms, and uses an enzyme called Cas9 to cut DNA at a site specified by ‘guide’ strands of RNA. Researchers have turned CRISPR/Cas9 into a molecular-biology powerhouse that can be used in other organisms. The cuts made by the enzyme are repaired by the cell’s natural DNA-repair processes…

The newly described Cpf1 system differs in several important ways from the previously described Cas9, with significant implications for research and therapeutics, as well as for business and intellectual property.

In its natural form, the DNA-cutting enzyme Cas9 forms a complex with two small RNAs, both of which are required for the cutting activity. The Cpf1 system is simpler in that it requires only a single RNA.

Cpf1 cuts DNA in a different manner than Cas9. When the Cas9 complex cuts DNA, it cuts both strands at the same place, leaving ‘blunt ends’ that often undergo mutations as they are rejoined. With the Cpf1 complex the cuts in the two strands are offset, leaving short overhangs on the exposed ends.

Cpf1 cuts far away from the recognition site, meaning that even if the targeted gene becomes mutated at the cut site, it can likely still be re-cut, allowing multiple opportunities for correct editing to occur.

The Cpf1 system provides new flexibility in choosing target sites. Like Cas9, the Cpf1 complex must first attach to a short sequence known as a PAM, and targets must be chosen that are adjacent to naturally occurring PAM sequences.

Finally, in a discussion in Wired the reporting is as follows[7]:

The discovery comes at a time when CRISPR/Cas9 is sweeping through biology labs. So revolutionary is this new genome editing technique that rival groups, who each claim to have been first to the tech, are bitterly fighting over the CRISPR/Cas9 patent. This new gene-editing protein called Cpf1—and maybe even others yet to be discovered—means that one patent may not be so powerful after all…

Many different proteins are associated with CRISPR. But in the early 2010s, Emmanuelle Charpentier, who was studying the flesh-eating bacteria Streptococcus pyogenes, stumbled onto one with special powers. Her bacteria happen to carry Cas9 proteins, which have the remarkable ability to precisely cut DNA based on a RNA guide sequence. In 2012, Charpentier and UC Berkeley biologist Jennifer Doudna published a paper describing the CRISPR/Cas9 system and speculated about its genome editing capabilities. And they filed a patent application. Much more on that patent later.

The patent issue is something we spoke about when the PTO pushed the Broad version through in less than six months, an unheard of process time.

While Cas9 has driven thousands of lab experiments and millions of dollars in funding for startups trying to capitalize on the technology, Cpf1 has remained relatively obscure. This study drags Cpf1 into the limelight. “It’s a very comparable to Cas9 and it has a few different features which could be quite useful,” says Dana Carroll, a biochemist at the University of Utah.

That’s because Cas9 isn’t perfect, despite its hype as a laser-precise genome editing tool. Cpf1 offers some slight advantages. For example, when it cuts double-stranded DNA, it snips the two strands in slightly different locations, resulting in overhang that molecular biologists call “sticky ends.” Sticky ends can make it easier to insert a snippet of new DNA—say, a different version of a gene—though the Cell paper does not actually show data directly comparing Cas9 and Cpf1 when inserting DNA.

Cpf1 is also physically a smaller protein, so it may be easier to put into human cells. It requires only one RNA molecule instead of two, with Cas9. But it’s not a rival so much as a complementary tool: The two proteins favor binding to different locations in the genome, so together, they might allow more flexibility in where scientist want to cut.

The writer then returns to the patent issues:

Not long after Doudna and UC Berkeley filed a patent, the Broad Institute and MIT filed their own patent on behalf of Zhang for the CRISPR/Cas9 system. Zhang had been working on actually showing that CRISPR/Cas9 can edit mammalian genomes in mammalian cells, an application he published in 2013 and says he came up with independently. The Broad’s and MIT’s attorney paid a fee to accelerate their application. Ultimately, the US Patent and Trademark Office awarded the patent to Zhang, MIT, and the Broad Institute. The University of California, obviously unhappy with the decision, filed an application for an interference proceeding to get the USPTO to reconsider. That process is ongoing.

But biotech companies have raced ahead to develop therapeutics and techniques with the system. Feng and Doudna have since licensed their technology to rival companies, Editas and Caribou. Charpentier also cofounded Crispr Therapeutics in Switzerland. Whoever wins the patent dispute will have a monopoly on CRISPR/Cas9 technology, the hottest new thing in biotech.

But with Cfp1, the stakes of that specific patent dispute go down. A lab or company could use Cfp1 without infringing on the CRISPR/Cas9 patent. “It takes power away from whoever the winner is going to be,” says Jacob Sherkow, a NYU law professor. (Zhang has indicated the rights to Cpf1 may not necessarily go to the company he cofounded, Editas.) Whether a CRISPR/Cfp1 system is patentable as a separate invention—Sherkow says it probably is—perhaps isn’t even relevant because its very existence means Cas9 is no longer the only game in town.

This latter observation is of significant value. Namely Cpf1 if it is truly better makes Cas9 battles of less value.

It is of continuing interest to follow the dimensions of this new “tool box” available to those of us working on gene changes.

References

1.     Zetsche, B., et al, Cpf1 Is a Single RNA-Guided Endonuclease of a Class 2 CRISPR-Cas System, Cell DOI: http://dx.doi.org/10.1016/j.cell.2015.09.038

2.     Ledford, H., Alternative CRISPR system could improve genome editing, Nature News, 25 September 2015

---

[1] http://www.cell.com/cell/abstract/S0092-8674%2815%2901200-3

[2] http://mcgovern.mit.edu/news/news/system-for-genome-editing-could-increase-power-of-genome-engineering/

 

[3] http://www.xconomy.com/boston/2015/09/25/crispr-update-could-make-gene-edits-easier-discoverers-say/

[4] http://www.nature.com/news/alternative-crispr-system-could-improve-genome-editing-1.18432

[5] http://www.economist.com/news/science-and-technology/21668031-scientists-have-found-yet-another-way-edit-genomes-suggesting-such-technology-will

[6] http://www.natureworldreport.com/2015/09/cpf1-for-precise-genome-engineering/

[7] http://www.wired.com/2015/09/war-genome-editing-just-got-lot-interesting/

The Canadian Wall

One is always amused when reading the Canadian Press view of Americans. The National Post has an article speaking to the desire by some 40% of Americans to build a wall between the US and Canada.

They state:

Failed Republican presidential candidate Scott Walker may feel some vindication in this number: 41 per cent of Americans say that if a wall is built along the Mexican border, one should also be erected on the Canadian one. And yes, the same percentage favors a wall erected along the nation’s southern border. The latest Bloomberg Politics poll that also shows that immigration, a flashpoint in the 2016 presidential campaign thanks in large point to the incendiary rhetoric of Republican front-runner Donald Trump, is an issue that stirs strong emotions among Americans, some of them contradictory.

Now I just returned from a business trip from my New Hampshire home to Laval in Quebec City. The return was via the NH Route 3 "Moose Alley" entry point. Now this is a single lane road in the northern most point in NH and it was empty going north and south. When you approach the border there is a gate on the Canadian side, open, but on the US side there is a multimillion dollar bunker. It is an enormous facility and out came two HS men with weapons. Here we were, two mid 70 year old in a 10 year old Caddy from New Jersey. Clearly a major threat.

We presented our passports. They had my wife remove her sunglasses, show her face in the sun. Then they inspected the underside of the car, all packages in the back seat, the trunk, the contents of our luggage. They asked where we went, why we returned this way, the "moose" dummy, everyone comes down here to see the moose!

Twenty minutes, no other vehicles in sight coming south or going north! I guess they were just bored. I have returned from Russia, Thailand, Bulgaria with less inspection.

Guess they heard I spoke French! Yes, also my wife's family is from Nova Scotia! Yikes.

Then about a mile south of the border is a massive sign just on the edge of the uninhabited forest, "Trump". I guess the moose vote!

Maybe the Canadians should build that border.

Why It is NOT STUPID

The Telegraph lists 20 "stupid" questions asked by passengers. One is:

"Excuse me, what's in the ham and cheese sandwich?"

All you have to do is look and see it is already more than "ham and cheese". That is the problem. Culturally say in New York, ask for "ham and cheese" and get just that, you want bread, ask for the bread, "stupid". In California when you ask for "ham and cheese" on rye, you get some amalgam of fruits, nuts, plants, and who knows what that the cook, owner or someone thinks you should have and never intends to inform you. Kind of like Republicans versus Democrats.

So to paraphrase Forest Gump, "Life is like a hand and cheese sandwich."

CTCs, PCa, and WNT

Circulating Tumor Cells, CTCs, are now capable of being extracted efficiently from patients. From Haber's Lab at Dana Farber his team has published a paper in Science describing the results. The results are worth examining.

They state in an earlier version on breast cancer:

Circulating tumor cells (CTCs) are present at low concentrations in the peripheral blood of patients with solid tumors. It has been proposed that the isolation, ex vivo culture, and characterization of CTCs may provide an opportunity to noninvasively monitor the changing patterns of drug susceptibility in individual patients as their tumors acquire new mutations. In a proof-of-concept study, we established CTC cultures from six patients with estrogen receptor–positive breast cancer. Three of five CTC lines tested were tumorigenic in mice. Genome sequencing of the CTC lines revealed preexisting mutations in the PIK3CA gene and newly acquired mutations in the estrogen receptor gene (ESR1), PIK3CA gene, and fibroblast growth factor receptor gene (FGFR2), among others. Drug sensitivity testing of CTC lines with multiple mutations revealed potential new therapeutic targets. With optimization of CTC culture conditions, this strategy may help identify the best therapies for individual cancer patients over the course of their disease. 

We have examined the pathways above extensively in the past and WNT is a well known target. I hear Haber talk this past week at NYAS and his talk was quite informative. I was especially impressed by the means used to extract CTCs, that alone is worth a look.

My general concern however is several fold:

1. CTCs can come from anywhere. As we have discussed before the work of Gundem et al demonstrated a complex proliferation of genetic profiles in AR PCa. Thus one may be able to gain some prognostic information but not localization.

2. There is always the issue of stem cells. Again what cells may get extravasated is not the same as what cells are proliferating.

3. Cell communication via exosomes is a concern as is the ECM issues of localized growth.

This is an extraordinary useful tool and definitely worth following. The current Science work on PCa states:

Prostate cancer is initially responsive to androgen deprivation, but the effectiveness of androgen receptor (AR) inhibitors in recurrent disease is variable. Biopsy of bone metastases is challenging; hence, sampling circulating tumor cells (CTCs) may reveal drug-resistance mechanisms. We established single-cell RNA-sequencing (RNA-Seq) profiles of 77 intact CTCs isolated from 13 patients (mean six CTCs per patient), by using microfluidic enrichment. Single CTCs from each individual display considerable heterogeneity, including expression of AR gene mutations and splicing variants. Retrospective analysis of CTCs from patients progressing under treatment with an AR inhibitor, compared with untreated cases, indicates activation of noncanonical Wnt signaling (P = 0.0064). Ectopic expression of Wnt5a in prostate cancer cells attenuates the antiproliferative effect of AR inhibition, whereas its suppression in drug-resistant cells restores partial sensitivity, a correlation also evident in an established mouse model. Thus, single-cell analysis of prostate CTCs reveals heterogeneity in signaling pathways that could contribute to treatment failure. 

 The last sentence is the most powerful and disturbingly consistent observation. PCa is just "too sneaky". It does not follow simple lines of development. It is not a BRAF V600 melanoma, it is not a Vogelstein colon cancer progression.

Frankly, it is for this reason alone that the USPTF recommendations on PSA testing are cruel and unusual. It is clear that PCa is a highly complex cancer and one that lends itself to multiple parallel paths resulting in some significantly high mortality rates. The very thought of taking the only tool and refusing to use it may, in my opinion, almost border on the criminal.

Where is Mussolini When He is Needed?

Getting the trains to run on time into and out of Penn Station, or anywhere in New York these days, needs a strong hand. Amtrak seems never to be on time. When at Penn Station I rarely see a on time departure, it seems 50 minutes is de rigeur.

But now we have power losses in the tunnel almost daily. What are we waiting for? Possible disasters. There is not a single politician addressing the issue. However this is what happens when Government runs something, anything, except Defense it appears.

I feel for the poor folks who try to use Public Transport only to be deceived by those who "provide" the service.

Let us see what Friday delivers. As of now they are still stumbling along. At least NJ Transit posts updates. If one looks at Amtrak; all is well........Pity.

Oh yes, and that low carbon stuff, won't work this way folks!

Programming, Computer Science, or What?

The NY Times recounts the current Mayor's intent to introduce Computer Science into the Grammar and Secondary School programs.

They state:

To ensure that every child can learn the skills required to work in New York City’s fast-growing technology sector, Mayor Bill de Blasio will announce on Wednesday that within 10 years all of the city’s public schools will be required to offer computer science to all students. Meeting that goal will present major challenges, mostly in training enough teachers. There is no state teacher certification in computer science, and no pipeline of computer science teachers coming out of college. Fewer than 10 percent of city schools currently offer any form of computer science education, and only 1 percent of students receive it, according to estimates by the city’s Department of Education.

Now this raises several questions.

First, does he understand what Computer Science means? Doubt it but lets continue. 

Second, I think he means programming. Computer Science is a much broader discipline, from architecture to language structures.

Third, and this is a key point, coding can be counter productive. Let me explain.

In 1962 I started teaching Fortran on an IBM 709 computer to students. I first had to learn some, FAP, Fortran Assembly Programming. Recently I came up to speed with Python on an MIT MOOC. What I noticed what that the focus was on using Python to "manipulate" the solution. The underlying mathematics was not even discussed. When I did Apollo guidance calculations we used an assembly program and that was only after we had done the mathematical analyses and reduced the steps to a minimum, after all we only had 64K memory!

Over the years I have picked up probably a couple of dozen languages, depending what I needed them for. Pascal for an options trading station, C for a communications protocol, Python for DNA string analysis, SNOBOL for modelling switching networks, FORTRAN for scientific stuff, BASIC to run my old Atari, and the list goes on. More than two dozen languages, each to solve a specific set of problems. Programming is implementing a logical set of commands to achieve a result from a potential complex mathematical problem. It is a means to an end, NOT and end in itself.

Learning a language is secondary to understanding the application and its related mathematics. Cluster analysis for genomic testing, or time series analysis for Kalman Filtering. 

Thus the issue is that programming is a tool, and there are many tools available. So what are we trying to teach a student. If we had a spectrophotometer, we use it to help solve a chemical problem, not to known how to use a tool. Programming should be viewed first as a tool, not as an end.

Yet Computer Science is NOT programming. Hematologists are not Phlebotomists. 

The final issue is who are the teachers? If good programming is a means to and end and if the end is the solution of some putatively complex mathematical problem, that we do a mass disservice to students in "teaching" them to code. We need to facilitate their thinking process. Not turn them into coders.

Misbehavior at Microsoft

Now I am no fan of Microsoft. They in my opinion exude an arrogance based upon an internally generated self image. Then there is Windows 10, which kind of works, and can almost be put back into an XP type OS where things are somewhat understood. I still cannot figure out how to effect the old cmd files but that is another story.

Yes, they have tried dozens of time to download w10 onto my office systems. Multiple times a day, I think I have blocked them. I have a W10 pad and it works kind of OK. It does not deal with Bluetooth well, wrong drivers, and try and get the right ones, and the WiFi is iffy at best. Again I suspect a driver problem.

Now Inquirer reports that they are actually loading W10 even if you did not ask for it. Imagine what that would do to a production machine! Bring it to a total halt. All drivers would be dead on arrival. They do NOT work on W10. It would almost in my opinion be a terrorist act. But they keep hitting my updates. The article states:

WHEN WE REVEALED last Thursday that Microsoft has started downloading Windows 10 indiscriminately to anyone who qualifies for an upgrade, whether they want one or not, we knew it was kind of a big deal. We're proud to be recognised as a credible news source and our articles are often cited and quoted. What we didn't expect was that this would be picked up first by the tech press, then the national press, then the world press in droves. To say that it struck a nerve is an understatement. It's like the keylogger story last year, but much, much, much bigger. There are several factors here. At a basic level, there's the privacy and intrusion aspect. After all, it's one thing to agree to receive updates to your operating system automatically, especially given that many of them relate to keeping the system locked down, but this isn't an update, it's a whole new operating system. Then there's the sneakiness. Microsoft offers an opt-in scheme to Windows 10. Remember all that stuff about reserving your copy? If you didn't reserve a copy and it just goes ahead and downloads it anyway, it's going directly against your wishes. And let's remember, it's going into a hidden folder that you actually have to change settings to be able to see. That says a lot.

I can see a great Class Action suit here! Where are the lawyers when you need them?

The damages could be astronomical!  For example, let us say I have a time constraint on getting out a report of legal filing. Down comes W10, now I have to reassemble all my files, none of my software will work, bad drivers or incompatible, no peripherals and the list goes on. Not to mention getting rid of all the "nice" graphics to get the presentation back some where near what you were used to. Do any of the folks at Microsoft even think? Perhaps not.

Let's wait and see what happens next.

Turn Arounds and Politics

Back in the 80s I did a few turn arounds. There was a simple formula:

1. Fire half the people. I used SSNs to make the decision, even numbers out. That reduced costs.

2. Raise the prices, that gave you some revenue for a short time.

3. Rush to find a buyer.

It works and private equity folks do it all the time. I left that when I did one in Memphis. I got to see what firing some of these folks meant. People with a spouse in the midst of cancer treatment, a child needing extensive care, etc. The stories were too many to take. They were real.

Now we have the tale of a couple of Private Equity folks taking companies like Kraft off the market. Guess what; they fired a ton of people and now are cutting off the health care plans for all the retirees. As reported in insurancenewsnet they state:

Global food giant Kraft Heinz Co. is going after retiree benefits as the recently merged company accelerates cost cutting to try to boost profitability. The company, which was created through the July combination of Kraft Foods Group and H.J. Heinz Co., is eliminating a group health insurance plan for about 15,000 Kraft retirees and will give them money to buy coverage on a private exchange. The company is also allowing some retirees to cash out their pension plans. Heinz retirees experienced similar cuts in 2013 and 2014. The moves are the latest efforts by Kraft Heinz and Highlight the belt-tightening that is typical of corporate shake-ups implemented by Brazilian investment firm 3G Capital, which partnered in 2013 with Warren Buffett's Berkshire Hathaway to buy Heinz. Berkshire and 3G engineered the merger of Kraft and Heinz to create the world's fifth largest food and beverage company, which is expected to have annual sales of about $28 billion.

Yes indeed, one of the folks on the Private Equity side is that bastion of Liberal Democrat doctrine, the man from Nebraska. So what do we see? Tens of thousands of folks now scrambling to get coverage  and many in the midst of life threatening situations. A quick calculation shows that these poor folks will go from a costs 0f approzimately $2,000 per year plus out of pocket per person to well over $10,000 per year per person, assuming they can even get a plan. And what of that poor person in the midst of cancer therapy? I remebered that, I got the guy another job, and carried his plan. I guess I am just not cold enough for that business.

One is reminded of Tennessee Williams and "relying on the kindness of strangers". Blanche DuBois did not make it through so well. Thus one should think twice when some well heeled Private Equity person tells us how we should manage our lives; what of the impact they had on the lives of the many?

What could or should have been done? Tell the folks a year ahead of time, give them so room to maneuver, but don't drop it on them at the end of the year. Will one year cost that much? Especially if the tax rate for these guys is so low.

Caveat Emptor

The current President had some two years ago proposed that the Federal Government in its wisdom provide a list of some to be determined quality metrics and evaluations of the Nation's Universities. According to the NY Times the same folks have decided not to go with that idea.

The Times states:

(the President) on Saturday abandoned his two-year effort to have the government create a system that explicitly rates the quality of the nation’s colleges and universities, a plan that was bitterly opposed by presidents at many of those institutions. Under the original idea, announced by (the President)  with fanfare in 2013, all of the nation’s 7,000 institutions of higher education would have been assigned a ranking by the government, with the aim of publicly shaming low-rated schools that saddle students with high debt and poor earning potential. Instead, the White House on Saturday unveiled a website that does not attempt to rate schools with any kind of grade, but provides information to prospective students and their parents about annual costs, graduation rates and salaries after graduation. (The President) praised the new website in his weekly address, saying that by using the new College Scorecard, “Americans will now have access to reliable data on every institution of higher education.”

Now we thought it was a rather dumb idea at the outset. Imagine a group of GS-9s beholding to their politically appointed leaders deciding on how to rank say MIT, Stanford, and Cal Tech. You think they would understand the courses? How about what people do?

Now take MIT as an example. Frankly if some Junior drops out of school to do a start up which in turn changes the world for the better, is that drop out bad or good? By the way this happens all the time. So to the good old GS-9, who may have made it through a Community College somewhere, it would be bad.

Just think, the same folks who brought you the ACA wanted to drop a bomb on Higher Education!

But wait, look at the Web Site. I looked for Engineering and ranked them by highest salary upon Graduation. What one was highest? SUNY Down State Medical School! Are you nuts! They are graduating MDs, in Medicine. Best I know MDs and Engineers are a bit different, been there done that. The The Merchant Marine Academy! That is not engineering, it is ship steering and maintenance. It is not Annapolis. Then fourth comes Harvard. What happened to Stanford, Cal Tech. Keep going and going!

When one puts a list like this together one should try it out on real people to see if it makes sense. Not the Government! Who cares about reality!

Unemployment: September 2015

Some thoughts on employment. That chart above depicts the unemployment numbers with and without the change in participation rates. Clearly there is a sustained gap.

The above details this a bit more.

The above is the gap in some specific detail.

The above shows the gap per month from what it should be. There is a growing and systematic gap in employment. This means that we have more people on the dole and less taxes. Making things worse is that more employment is related to Government funded work; Government, Education, Health Care.

This is the actual gaps per month.

Overall people are being added to the payrolls but not at a large enough rate and not in value creating jobs.

After the seven years we have been tracking these numbers we still see systemic weakness in the economy.

FED Balance Sheet

The above is the current Fed Balance Sheet. Note that it has remained constant somewhat since Q1. Specifically as shown below:

The two main components have remained with minimal change. This appears to be a significant factor and may be a key reason for increasing the rates.

MIT Weight Loss?

It appears that MIT had added a "weight loss" program to its ever growing list of advantages. The article states:

the program helps participants learn to love foods that support weight loss and maintain a healthy lifestyle. It includes meal plans, a high-fiber regime, and portion control. There is also a weekly online support group that provides nutrition education and helps dieters form new, healthy habits that promote weight loss sustainability. There is also weekly check-ins and weight tracking with various Web tools. Unlike many other weight-loss programs, iDiet requires daily weigh-ins — “an important and effective way to see and appreciate your success” according to the program’s website — but there are no set exercise requirements. Meal planning on the program is simple. You can buy the cookbook or find simple recipes online. Recipes include vegetarian options; others are designed to address special dietary concerns such as high blood pressure or cholesterol, diabetes, or gluten and lactose intolerance.

 Well here is my take:

1. Get rid of the high carb fast food "food courts". They are everywhere. One could in the past walk over to Walker Memorial, sit at a large table and have a conversation while eating a reasonably priced balanced meal. You got exercise, reasonable food, low prices, and you actually met people. Now we have the solitary fast food outlets selling high carb and high priced food just a few steps away from one's computer, or they now actually have it on the table.

2. Get rid of the refrigerators and food storage units in all of the "labs" It appears that there is always someone bringing cookies from "mom" in Bangalore and a constant flow of consumption. n my old days in Building 20, the wooden remnants of the Rad Lab any loose food was consumed by the resident rodents. Perhaps we should bring back the rodents!

3. Watch out for those Chinese Restaurants. Now I like Chinese food but it is so high in calories that the almost daily routine of going out to eat with the team gets a bit much, as well as adding to the waist line.

Adding another costly program will not change the above. It will just shall we say "put lipstick on the pig".