RIP Z’ev

I was listening to a piece of music the other day with some drums in it, and it occurred to me to look up my old landlady’s friend Z’EV.  To my surprise, Z’EV had passed, in 2017.  According to his Wikipedia page, he was a big deal in the SoHo music scene in the 70’s and 80’s, performing in happening places like the Kitchen and Danceteria.  When he died, of lung failure, he was staying with a friend in Chicago.

The lung failure was caused by being severely injured in an Amtrak train derailment the year before, in 2016.  Those of you who think of trains as a safer alternative to flying …. well, not in this case.

The story behind Z’EVs death of lung failure in Chicago involves an unreported accident with a runaway feed truck.  The truck rolled down an incline, crossed a road and slammed into some tracks hard enough to cause a bend in one track.  It was enough to derail the passenger train.  The truck itself rolled over and was then driven back up the hill by the guy who left it idling and unattended to begin with.  He was worried about his job.  He didn’t notice the bend in the track.  He didn’t call 911 or the posted rail emergency number.    His boss laughed when it happened.  For them it was just another day.  They had no idea what would happen next.  The trucking company fought responsibility for several years, and then took responsibility and settled.

There is some Better Call Saul-esque color in the truck story in the judgment, which is an elaborate, lengthy document describing what is ultimately a very simple event (a truck ran down a hill).  It’s a slice of life of some folks in the middle of a giant cornfield:

The morning before the accident, two Cimarron employees were working on the
company’s feed lot, which is located north of Highway 50 and the BNSF rail line. Kevin Ornelas was operating the feed mill and Arturo Carillo was operating a feed truck, a 2004 Kenworth grain hauling truck, which had an empty weight of at least 26,900 lbs. and had gross vehicle weight range of 26,000 to 33,000 pounds.

Carillo had made several feed lot runs that morning before Ornelas asked him for
help unplugging a “soak leg” that had become clogged on the feed mill. Ornelas needed Carillo to open and close a gate at ground level that runs corn up into the soak tanks, so that Ornelas, standing up on a catwalk over the soak tanks, could make sure the downspout was clean.

Carillo parked the truck next to the soak tanks and grain elevators facing south in
the direction of the railroad track. As Carillo left the truck to help Ornelas, it was parked on an incline facing in a downhill direction away from the mill and toward the highway and railroad tracks.

Some time between 10:00 and 11:00 a.m., Ornelas, with a clear view of the truck
from atop the soak tank catwalk, watched the truck start to roll and yelled down to Carillo that the truck was rolling away.  Carillo went to get his personal truck, losing sight of the run-away feed truck in the process.

Ornelas saw the runaway feed truck roll down the hill, across Highway 50, into
the ditch running parallel to the train tracks on the south side of the highway, up the
opposite side of the ditch, and then back down into the ditch where it stopped, still facing south. The momentum of the thirteen-ton truck was enough that when it crossed the highway into the ditch it became airborne.

In the ditch, the truck’s undercarriage bottomed out before it continued, striking
the rail track roadbed. The impact caused a displacement of between seven to ten (but most typically described as a nine) inch displacement of the tracks

To reach the feed truck, Carillo drove his personal truck across Highway 50,
crossed the railroad tracks at a grade crossing on the south side of the highway, and
turned right on a dirt road on the south side of, and running parallel to, the tracks. Carillo  parked his personal truck on the dirt road directly across the tracks from where the Cimarron feed truck had come to rest, and walked right over the damaged track.

Carillo found the still-running feed lot truck in the ditch, sitting perpendicular to
the railroad tracks. He moved the truck away from the tracks and drove it back up to the feed lot where he told Rita Tobyne, Cimarron’s head feed truck driver, what happened.  He asked her to call feed lot manager Maynard Burl and tell him the feed truck had rolled  to the other side of Highway 50. Tobyne said she was not going to call Burl.

Carillo then asked Ornelas to call Burl, which Ornelas did, asking Burl to come out
to the feed lot. Ornelas has testified that, while they were waiting for Burl to arrive, he took Carillo back down to the railroad tracks to retrieve his personal vehicle.

At the time the truck hit the BNSF tracks, there was a railroad crossing sign near
where the truck impacted the tracks, which also contains a blue sign with a 1-800 phone number to report problems or emergencies to BNSF.

Ornelas saw the sign as he crossed over the tracks and was aware of the sign, but
neither he nor any other Cimarron employee called the 1-800 phone number to report the truck runaway incident.

When Burl came to the feed lot, Ornelas showed him the path the truck had taken
down the hill, and told him that the truck had gone across the highway and through the ditch on the south side of the highway, and pointed him to where the truck had come to rest.

Carillo also tried to tell Burl about the path that the truck had taken and where it
had come to rest, but Burl said he did not care and that Carillo would probably get fired.  Burl observed the path that the truck left through the field from the mill to the
highway. After being told what had happened, Burl did not go down to examine the
railroad tracks and did not ask either Ornelas or Carillo whether there had been any
damage to the tracks.

Instead, he yelled at Carillo that he did not care that the truck had crossed the
highway, criticized Ornelas for asking Carillo to help unclog the soak leg, pointed out to both men that the truck had likely suffered several thousand dollars in damage, and told Carillo that he would probably get fired or written up. Burl straightened the feed truck’s bent muffler, and went home.

Later in the afternoon Cimarron assistant manager Jim Fairbank came to the mill.
Ornelas told him that the feed truck had rolled down the hill and across the highway,  and Fairbank laughed about it and made no effort to see for himself where it had rolled.

No one at Cimarron did any further investigation, or contacted the railroad, law
enforcement, or any other party to inform them of the truck roll-away incident.

No word on whether or not Carillo kept his job.  The feed lot is still there.

NF1 -omics

Allergenome

Les pathologies salivaires

Antibodyome

In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells

Bibliome

Haplotype structure enables prioritization of common markers and candidate genes in autism spectrum disorder

Chaperome

Rethinking HSF1 in Stress, Development, and Organismal Health

Connectome

Resting state functional MRI reveals abnormal network connectivity in Neurofibromatosis 1

Cytome

Neurofibromin is a Novel Regulator of Ras-induced Reactive Oxygen Species Production in Mice and Humans

Dynome

NF1 loss disrupts Schwann cell–axonal interactions: a novel role for semaphorin 4F

Editome

Tissue-specific modification of gld-2 mRNA in C. elegans: Likely C-to-U editing

Embryome

Congenital tumours and tumour‐like lesions in domestic animals. 1. Cattle A review

Envirome

Neurofibromas in NF1: Schwann cell origin and role of tumor environment

Epigenome

Epigenetic mechanisms drive the progression of neurofibromas to malignant peripheral nerve sheath tumors

Exome

Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas

Exposome

Ten novel mutations in the human neurofibromatosis type 1 (NF1) gene in Italian patients

Fluxome

The space of enzyme regulation in HeLa cells can be inferred from its intracellular metabolome

Foodome

Nutrient intake in neurofibromatosis type 1: A cross-sectional study

Genome

A porcine model of neurofibromatosis type 1 that mimics the human disease

NF1 Genome Project

Glycome

Glioblastoma extracellular vesicles: reservoirs of potential biomarkers

Hologenome

Identification of de novo deletions at the NF1 gene: no preferential paternal origin and phenotypic analysis of patients

Interactome

Clustered, Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9-coupled Affinity Purification/Mass Spectrometry Analysis Revealed a Novel Role of Neurofibromin in mTOR Signaling

Interferome

An inflammatory gene signature distinguishes neurofibroma Schwann cells and macrophages from cells in the normal peripheral nervous system

Ionome

A systematic assessment of chemical, genetic, and epigenetic factors influencing the activity of anticancer drug KP1019 (FFC14A)

Kinome

Targeting the Kinome in Neurofibromatosis type 1 

Lipidome

Evaluating modified diets and dietary supplement therapies for reducing muscle lipid and improving muscle function in neurofibromatosis type 1 (NF1)

Mechanome

Mechanical Signaling in NF1 Osteoblast Cells

Membranome

SPD – A web-based secreted protein database

Metabolome

Metabolome Profiling by HRMAS NMR Spectroscopy of Pheochromocytomas and Paragangliomas Detects SDH Deficiency: Clinical and Pathophysiological Implications

Metagenome

Gene Expression and Molecular Characterization of a Xylanase from Chicken Cecum Metagenome

Metallome
Methylome

The DNA methylome

Microbiome
Moleculome
ORFeome
Obesidome
Organome
Pharmacogenome
Phenome
Physiome
Phytochemome
Proteome
Regulome
Researchsome
Secretome
Sociome
Speechome
Synaptome
Synthetome
Toponome
Toxome
Transcriptome
Trialome
Variome
Volatilome

A drug to cure cutaneous neurofibroma could be worth $3B

800px-neurofibroma02

According to the NY Times and NPR, drugs for orphan diseases have become big business, partly due to side-effects of a law intended to promote development.  The Times discusses two recent sales:

  1. $3.3 billion for rights to the drug Kalydeco for cystic fibrosis, which has a frequency of 1:3500 births.
  2. $2.85 billion for rights to the drug Tysabri for multiple sclerosis, which has a frequency of 1:750.

Cutaneous neurofibroma is a kind of benign skin tumor suffered by most people with NF1, which means that there is a mutation in the gene which codes for neurofibromin 1, which is a tumor suppressing protein.  NF1 has a frequency of 1:3000 which makes it more frequent than CF and less frequent than MS.  By the numbers above, a drug which prevents or eliminates cutaneous neurofibroma would be worth $3billion.

The drug selumetinib was discovered by Array BioPharma and licensed to  AstroZeneca.  The agreement has had some difficulties.  Selumetinib was approved to treat neurofibroma.  An early phase trial shows tumor reduction but not elimination.   Selumetinib is an MEK inhibitor.

NF1 biomarkers and etc.

CTF has a biobank: http://www.ctf.org/understanding-nf/ctf-biobank  Mt. Sinai is the prime contractor for sample collection, so if you are Med School professor there, this is easy:https://www.synapse.org/#!Synapse:syn4984604/wiki/247965

There are also 43 tissue banks in Europe.

In search of biobanks I found this wonderful summary of pathogenesis clues for NF1, which expands on Korf’s summary:

Diagnostic biomarkers

Predictive and pharmacodynamic biomarkers

Higher melanoma inhibitory activity (MIA)

Candidate genes: SOX5NOL1MLF2FOXM1FKBP1CDK4TSPAN31ERBB2MYC and TP53

Higher adrenomedullin (ADM)

Aurora kinase A

Higher serum fetal antigen 1

Survivin (BIRC5), thymidine kinase 1 (TK1) and topoisomerase 2-a (TOP2A) immunohistochemical staining of malignant peripheral nerve sheath tumors to split patients into high and low risk

Higher serum soluble growth factor receptor Axl (sAxl)

Lower blood circulating levels of hepatocyte growth factor

Significant differences in interleukin-6, interferon-γ, epidermal growth factor receptor, tumor necrosis factor–α, insulin-like growth factor binding protein 1 and RANTES

Survival in NF1 patients with methylated or unmethylated RASSF1A at five years

miR-204 downregulation in patients with NF1 with malignant peripheral nerve sheath tumors

 There are 42 or 43 omics, depending on your count:

Allergenome

Interactome

Phenome

Bibliome

Interferome

Physiome

Connectome

Ionome

Phytochemome

Cytome

Kinome

Proteome

Editome

Lipidome

Regulome

Embryome

Mechanome

Researchsome

Envirome

Metabolome

Secretome

Epigenome

Metagenome

Speechome

Exome

Metallome

Synthetome

Exposome (2005)

Microbiome

Toponome

Exposome (2009)

Obesidome

Transcriptome

Foodome

ORFeome

Trialome

Genome

Organome

Volatilome

Glycome

Pharmacogenetics

Hologenome

Pharmacogenome

For any of these topics, we could ask, “has anybody done something on NF1 xxxics?”  Randomly selecting “proteomics”, I get immediate hits:

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3650346/

https://www.ncbi.nlm.nih.gov/pubmed/15805275

https://www.nature.com/articles/mp201548

Let’s do a blog post inventorying articles under each omic for NF1, on a rainy day.

Also here’s a rather dense but topical article to save for a rainy day:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573439/

 

Pathogenesis of NF1

Bruce Korf wrote this summary of the pathogenesis of NF1 which I will unpack here a little bit.

“NF1 is due to mutations in the NF1 gene, located at chromosome 17q11.2″

“Neurofibromin, the protein product encoded by the gene, is expressed in many tissues, including brain, kidney, spleen, and thymus.”

“It belongs to a family of guanosine triphosphate hydrolase (GTPase)-activating proteins (GAPs)”

“that stimulate intrinsic GTPase activity in the ras p21 family (21 kD rat sarcoma viral oncogene homologs)”

“Ras activates a number of signaling pathways”

“that includes the stem cell factor (SCF)/”

“c-kit signaling, ”

“mechanistic target of rapamycin (mTOR), and ”

“mitogen-activated protein kinase (MAPK) pathways.”

“Mutations in the NF1 gene result in loss of production or reduced function of protein,”

“causing the wide spectrum of clinical findings, including NF1-associated tumors.  ”

“Penetrance, or the likelihood that the individual carrying the mutation will manifest the disorder, is complete.”

“NF1 is highly variable in its expression, however (ie, the severity of and specific manifestations of the disorder vary among affected individuals within the same family and from one family to another) . ”

“Somatic mutation or loss of heterozygosity at the NF1 locus,”

“in combination with a germline NF1 mutation,”

“leads to complete loss of neurofibromin expression that is seen in NF1 lesions such as pseudoarthrosis and neurofibromas.”

” NF1 therefore functions as a tumor suppressor gene.”

How complex is a cell?

I asked a biologist recently how many parts there were to a cell.  I hazily remember pictures of an outside and an inside.  She said “more than 10,000”.  Let’s quantify that:

How many atoms? How about 100 trillion.

How many molecules? Between 5 million and 2 trillion?

How many proteins? About 10 billion?

Why ask?  The real question is: How hard is it to simulate a cell.  At a brute force level, the answer is: hard.  Obviously there is a lot of structure to a cell that I can’t begin to imagine.  It’s something I should study up a bit more.

Tweaking ACH for FARC

bokeh_plot

[Cross post]

ACH is a methodology which scores Inconsistency but doesn’t score Consistency. At most it says that evidence is really not consistent with the outcome, without opining on whether it is consistent.https://en.wikipedia.org/wiki/Analysis_of_competing_hypotheses http://competinghypotheses.org/docs/ACH,_Step_By_Step has Credibility and Relevance scores

The Xerox ACH implementation http://www.pherson.org/PDFFiles/ACHTechnicalDescription.pdf
has Credibility and Relevance scores of Low=1/sqrt(2), Medium = 1 and High = sqrt(2). The Consistency score is Very Inconsistent = -2, Inconsistent=-1, and Neutral, Consistent and Very Consistent are 0. The Weighted Inconsistency Score is Credbility * Relevance * Consistency. So any evidence item which is not inconsistent gets a weight of 0.

For my ACH-ish model, as applied to rationales with comments supplied for forecasts, I will weight as follows. Let the forecast be F. Assign Credibility and Relevance scores of Low=1/(2sqrt(2)), Medium = 1/sqrt(2), and High = 1. Let the Consistency score C be -1,-1/2,0,1/2,1. Let W = Credibility * Relevance. Then my ACH-ish-model weighted forecast will be W100*(C+1)/2 and ignore the original forecast in the formula, just looking at it as a shorthand for the text and how to view the import of the text.

So far I see 74 forecasts for FARC of which 32 have rationales. My model for FARC is ACH-ish as above. The Consensus has been towards 0 on FARC except it just picked up a little. The early comments on FARC anticipated that pick-up.