1/26/2019

Biopharma/Investing
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I don’t think Evenity will sell well. Aimovig might be a monster, though. More on Amgen very soon.

The web media layoffs remind us that there is no money in virtue signaling. Major media will get back to real news. The ‘fakeout’ caused by companies like Vice and Buzzfeed will retract and the CBS/ABC/NBCs of the world will realize ‘woke’ culture and uber-progressivism won’t pay the bills. People want the news, not preaching. Companies like Buzzfeed (hungry for a merger) are still upside down on cost structure and will go bankrupt. Startups, such as Gawker’s latest iteration, actually have a risk of imploding on their own smug, before they prove they’re not viable businesses, either. More 20-somethings will realize that their calling of ‘speaking truth to power’ (by trying to usurp power itself) is a distant second to operating profit. No operating profit, no whining about the benefits of socialism, sorry.

Clinical Trials I Noticed
—————————-
Drug Interaction Study Between Dorzagliatin and Empagliflozin. Hua Medicine Limited.
Drug Interaction Study Between Dorzagliatin and Sitagliptin. Hua Medicine Limited.
Hua is 2552 HK. It’s a true Chinese biotech with nothing but this glucokinase activator. But are you trading it? No, because it’s easy to go long some consensus stock and underperform.

Exploratory Study to Investigate the Bioactivity, Ocular and Systemic Safety, Tolerability and Pharmacokinetics Following Single and Multiple Intravitreal Administrations of KSI-301 in Subjects w/AMD, DME, and RVO. Kodiak Sciences.
KOD is a freshly public company worth around $300 million. A putative fourth entrant into the ocular VEGF space would be welcome, I think. This one is kind of interesting and worth watching IMO. No relation to Codiak, one of the more valuable private companies.

RUCONEST as a Therapeutic Strategy to Reduce the Incidence of Delayed Graft Function. Pharming Technologies.
Remember PHARM NA? Seems cheap, only around 4-5x sales and they seem to be focused on expanding Ruconest outside of HAE as soon as they can. Changes abound in the HAE space but there is usually therapeutic inertia, so they just might be okay. Worth watching this European stock.

ANAVEX2-73 for Treatment of Early Alzheimer’s Disease. Anavex Life Sciences Corp.
Remember these guys? AVXL, I think. They ran a SINGLE-ARM phase 2 and tried to make some efficacy claims. No joke. Better luck with a placebo-controlled study.

BrUOG 379 Phase Ib/II Trial ONC201 + Nivolumab in MSS mCRC. Oncoceutics. Brown University.
This tiny private company is developing this “ERK/AKT” inhibitor. I haven’t looked into it enough to tell if it actually binds ERK or AKT or simply reduces their activity (major difference!). Worth looking further.

Papers I’ve Read
——————–
Antitumor properties of RAF709, a highly selective and potent inhibitor of RAF kinase dimers, in tumors driven by mutant RAS or BRAF. Shao et al. Cancer Res 2018.
0.3-1.5nM doesn’t get Novartis out of the woods here, unfortunately, as other new RAF “dimer-inhibitors” like LY3009120 and lifiratenib show weak clinical data. The RAF monomer-inhibitor craze got started with Roche-Plexxikon (Plexxikon acquired by Daiichi in 2011 for $800 million) and Taflinar. All of these drugs have been underwhelming. The subtext is the main goal is to inhibit the “undruggable” RAS via RAF inhibition attenuating the downstream signal. With AMG510, a true RAS inhibitor with clinical activity has been advanced. Anyway, a slew of new drugs inhibiting both dimer and monomer formations of RAF were discovered. Here, the phase 1 demonstrated 2 PRs out of 75, all but ending the short life of what is now known as LXH254.

Personal
———–
I’ll root for the Patriots. Just for Patty!

1/25/2019

Biopharma/Investing
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Lots of interesting personnel changes: EDIT, VRTX.
Gossamer going public is fascinating.

Papers I’ve Read
——————–
The Structural Violence of Hyperincarceration – A 44-Year-Old Man with Back Pain. Karandinos & Bourgois. NEJM 2019.
Funny last name of the second author. The paper walks through the odyssey of one inner-city Spanish-speaker. The article notes 70 million US citizens have a criminal record (we can do better! why not 270 million!?), but wrongly places blame on incarceration as a cause of “structural violence”, an imaginary construct.
I am actually in prison, right now. Prison doesn’t create “structural violence”. The BOP has an efficient system of allocating violent people–you get classified to the appropriate security-level according to your actions. Healthcare has been fairly good, even relative to the care I receive “on the outside” with my millionaire lifestyle. The issue with this man’s distrust of the healthcare system is his lack of education and inability to speak English. He’s 44, likes to deal drugs and break rules. He distrusts doctors because he has a poor grasp on reality in general, not because he has “institutional distrust”. He doesn’t understand the world around him. He doesn’t want to.

The Imperative for Climate Action to Protect Health. Haines, Ebi. NEJM 2019;380:263-73.
Here we go. Surface temperature has increased by 0.7 degrees (Celsius) since the 1961-1990 mean. In 1850 it was negative 0.4 degrees. This is an abysmally poor data set to draw conclusions–without at least 50 periods similar in length one cannot even calculate the effect size of this change without information on temperature’s volatility (standard deviation). This lowly review articles relies on other similarly flawed data sets and their interpretations. Temperatures are probably increasing but give me a solid study that proves that. What inferences can we really draw? Do we assume humans stand there and do nothing, or react accordingly? Protecting health from possible climate change impacts is very important, and sounding alarms of danger is important too. But let’s not put weak meteorological data in the best medical journal.

Personal
———–
Anyone else having a bout of seasonal affective disorder? Yeesh, January has always been rough for me. At least spring is almost here!
There was an article in WIRED (thank you) about Elon Musk which is a must-read. In my first major CEO job, I was a lot like Musk. Impatient, full of expletives and outbursts, basically unprofessional. I’m really happy that I grew out of that behavior. If you are yelling at your colleagues, you’re not only alienating your important partners but also you should simply be reflecting on your own inability to properly allocate human resources. That person in chemistry is an idiot? You hired them! Or, you hired the person who hired them. Your fault, buddy. Save your breath.

Becoming a “celebrity” overnight also happened to Musk and you can see what it did to him. Thankfully a lot of my celebrity came after being arrested and I resigned, but the overlap period was still harmful. I understand, to some extent, what Musk is going through. It’s probably best for him to stay CEO, for the sake of the employees, but turn off his outside life. There comes a pressure of feeding ‘fans’ that starts to distract–and I felt that despite modest fame. He also has SpaceX and other interests to manage. If the company has another good quarter, all the naysayers will be proven wrong, but in the meantime for his own health he should focus 100% on the businesses and turn off the media and any celebrity-type activities.

1/22/2019

947-951 days to go

Biopharma/Investing
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JNJ’s results are interesting. Their portfolio has never been this volatile. Remicade is plummeting, run-rating at just under $5 billion now, with Stelara and Tremfya still growing. This doesn’t bode well for AMGN–they have no next-generation autoimmune drugs (not even a stinking JAK inhibitor). Still no Zytiga generic–something will probably launch this quarter.

Read an article about an amyloid-beta vaccine. I actually met the husband-wife team around 10 years ago. Very nice couple, did not think the drug would work then, do not think it works now. There is a lot going on in the AD world right now that I perhaps will write up shortly.

Papers I’ve Read
———————-
In Vitro Pharmacological Characterization of Buprenorphine, Samidorphan, and Combinations Being Developed as an Adjunctive Treatment for Major Depressive Disorder. Bidlack et al. JPET 2018.
As we prepare for the FDA rejection of ALKS5461, this article came across my ‘desk’. The article begins by suggesting there is evidence of an effect of buprenorphine in depression. I disagree. As my jail colleagues point out, the three citations supporting this claim are unfounded. First, Bodkin in 1995 trialed only 10 patients with buprenorphine in an acute setting–far too few to draw reliable conclusions, especially without a control. In a review article, Kosten pointed to two studies, principally the horrific Alkermes phase 2 which suggested 2mg/2mg of ALKS5461 “worked” (-2.8 vs placebo on HAM-D) and 8mg/8mg failed (-0.5 vs placebo HAM-D). Of course it is fun to throw away data that doesn’t support your claim and rely on this evanescent and unpredictable (and untenable) dose window where ALKS5461 has a treatment effect but at only 4x the dose, it disappears. The rational thing to do is group the data–doing so would result in failure, of course. The phase 3s were no better. Kosten also calls out the Yovell, et al. trial of ultra-low-dose buprenorphine with a p=0.04 result and unclear (to me, at least) statistical treatment of dropouts. The Ehrich, et al. phase 1/2 tested a 4mg–>8mg dose which provided the ironic impetus to go to phase 2, where that dose had no effect.
Moving forward, we have an addictive opioid and a proprietary antagonist/partial agonist (samidorphan). The theory is samidorphin will somehow limit the abuse liability of buprenorphine while sparing the alleged anti-depressant effect. How or why this is possible is not really discussed nor accessible to the imagination. The actual experimental results here are not interesting–buprenorphine is a partial agonist at the triad of opioid receptors. The workers found a difference between the high-affinity state/low-affinity state binding of our favorite ligand, with unclear implications. There were no obvious conclusions to be drawn from the fairly advanced BRET assay used to interrogate specific G-protein coupling (Galphai/o). One is left wondering if there is a therapeutic effect here at all (and there is not), then why not just use opioids? In fact, one paper suggests before the 1950s, opioids were the mainstay treatment for “melancholia”. And why do we need a new opioid partial agonist/antagonist in samidorphin? Isn’t naloxone or naltrexone enough? Right, patents. Samidorphin is a “new chemical entity” and would protect the “invention” here. But what is the attenuation of samidorphin really worth, even assuming a therapeutic effect? Couldn’t you achieve the same outcome with a lower dose of buprenorphine or an even weaker opioid agonist? This is pharmacology done wrong. Thankfully ALKS5461 is headed to the wastebasket of drug ideas.

Personal
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Great NFL weekend! Algorithms found the games too close to call, and I guess they were! I hope the Patriots lose.

I really want to learn Spanish. I just have no time… it’s funny how quickly “this bid” is going. I’m going to miss it!

1/16/2019

953-956 days to go – 31 months

Biopharma/Investing
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Not surprised APTX doesn’t work. The depression stuff doesn’t work either.

Papers I’ve Read
———————-
Discovery and characterization of AZD6738, a potent inhibitor of ataxia telangiectasia mutated and rad3 related (ATR) kinase with application as an anti-cancer agent. Foote et al. J Med Chem 2018.
AstraZeneca’s ATR project has yielded a clinical candidate. 6738 is a suloximine (S=N), replacing the sulfonamide moiety of the hit AZ20. Apparently, this SNOH- moiety hanging off the cyclopropyl did the trick to improve solubility and eliminate CYP3A4 liability (that and one atom on the heterocycle). Anyway, ATR is part of DNA damage repair. You’ve probably heard of it from Vertex, who sold their VX-970 to Merck KgaA (now M-6620 or berzosertib) for a pretty penny. I don’t trust anything from Vertex Cambridge drug discovery (including and especially Derek Lowe). So far I don’t think anyone is bowled over by the data for ATRs–no monotherapy efficacy. There’s a Bayer compound out there, too. It seems like the AZ predecessor compound was around for a while.

6-Benzhydryl-4-amino-quinolin-2-ones as Potent Cannabinoid Type 1 (CB1) Receptor Inverse Agonists and Chemical Modifications for Peripheral Selectivity. Zhang et al. J Med Chem 2018.
J&J researchers produce a peripherally-restricted CB1 agonist to avoid the AE profile of the storied Accomplia. I didn’t know GC1 was the MOST abundant GPCR in the brain–kind of amazing, huh?

Cytokine-Induced Expression of HIV-1 in a Chronically Infected Promonocyte Cell Line. Folks, Fauci, et al. Science 1987.
Human Immunodeficiency Virus-Infected Individuals Contain Provirus in Small Numbers of Perpiheral Mononuclear Cells and at Low Copy Numbers. Simmonds, et al. J Virol 1990.

Still in the way-back-machine for HIV.

Personal
———–
Lauren Duca divorced her husband and is gay now. Just 2 and a half years ago she thought it was wise to marry a man. Now all she tweets about is how terrible and useless men are. Play to your audience, I guess. Perhaps she will even become an author, selling her book to a like-minded left-wing gnat (or nut?) at a publishing company that doesn’t realize they’ve been appropriated by ideology. Maybe I should rollup that industry and instill some libertarianism. People should be able to read whatever is appealing, not what some self-anointed anti-business SJW gatekeeper decides.

I wrote more on this and recent revelations that Duca is a body-shamer (the body-shaming posts are awful) and even an ablist/classist as she panned community colleges in a recent Facebook post if you’d like to read it. Evidently even further revelations are forthcoming. Guess her book deal may be off-the-table.

1/12/2018

957 days left

Biopharma/Investing
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Biomarin’s CEO said there is no drug pricing crisis or problem and this issue is “all politics”. He is 100% correct. If you analyze disposable income, funds spent on pharmaceuticals vs. entertainment, poverty rates, insurance coverage rates and other data sets, you cannot possibly reach any other conclusion. As I said in my Ivy League tour, think with facts and reasoning, not with emotion, and you’ll discover the truth–assuming it is the truth you were seeking in the first place.

Papers I’ve Read
———————
Vpu Mediates Depletion of Interferon Regulatory Factor 3 during HIV Infection by a Lysosome-Dependent Mechanism. Doehle et al. J Vir 2012:86;8367-8374.
6 years ago, Vpu was discovered to label a core host viral defense mechanism, IRF3, “garbage”, prompting the obsequious cell to digest its comrade in the greedy lyosome. The conniving interloper wins.

Hydroxyurea for Children with Sickle Cell Anemia in Sub-Saharan Africa. Tshilolo et al. NEJM 2019:380;2
Why? A single-arm study of a well-known drug. Just why?

Next-Generation Sequencing to Diagnose Suspected Genetic Disorders. Adams, Eng. NEJM 2018;379:14
Simple backgrounder for anyone who has been asleep.

Personal
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Keep the government shut down until our debt is retired. It will balance the budget. Just 10 years? Keep collecting taxes. In 2035, no taxes, no government. Perfect answer, and it worked in the 1800s 🙂

1/11/2019

958 days left

Biopharma/Investing
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Carl Icahn (or any other large swashbuckling investor) should take a stake in BMY, scuttle the CELG deal, which is suboptimal at best and wasteful at worst, and sell the company to PFE instead. Buying 100-200 million shares at $45 and cancelling the deal makes you $1-2 billion alone. Then, if PFE, Novartis or JNJ, who no doubt would want Opdivo, would be interested in a $100 billion or higher offer for BMY, one could net $2 to $4 billion on the trade.

What can be said about Bezos that hasn’t been already said?
Vinik coming back to hedge funds is interesting news.

Papers I’ve Read
——————–
A Conserved Role for Serotonergic Neurotransmission in Mediating Social Behavior in Octopus. Eric Edsinger, Gul Dolen. Curr Biol 2018.
Nature advertised Octopi on Ecstasy, so I had to look this paper up. It’s about as weird as expected, with some fairly high p-values. Octopi (and virtually all other species) express SERT and the MDMA-binding site on SERT is fairly homologous to human SERT, although homology on a small part of a huge transmembrane protein shouldn’t get one too excited. Anyway, they use a “three chamber” study design often used with rodents and find MDMA has a very weak effect size, driving male octopi to females as opposed to their unaffected state where they prefer examining a unique object. What does this tell us about behavior? Who knows, I’m just a drug guy.

Theoretical Prediction of the Creation and Observation of a Ghost Trilobite Chemical Bond. Eiles, Tong & Greene. Phys Rev Lett 2018.
Rydberg atoms can form bizarre “trilobite” bonds. The electron probability functions look like actual trilobites from eons ago. These Purdue physicists demonstrate a “ghost bond”, where such a Rydberg electron exists in a strange (>100nm bond length!) state WITHOUT the other atom present. Ghost bonds. Truth stranger than fiction…

In vivo fate of HIV-1-infected T cells: Quantitative analysis of the transition to stable latency. Chun, et al. Nature Medicine 1995.
A seminal paper, 23 years old, on identifying the latent ‘reservoir’ of CD4+ proviral T cells.

Personal
———–
In a few days (the 13th) my monthly jailiversary will be here. Celebrating 16 months in and 31 to go.

1/10/2018

Biopharma/Investing
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I don’t think LLY gets their money’s worth with LOXO.
BLUE comments on gene therapy very interesting: 5-year payment plan sounds reasonable. $2.1 million cap on pricing also interesting to note.

Papers I’ve Read
———————-
Polyamine modulation of anticonvulsant drug response: A potential mechanism contributing to pharmacoresistance in chronic epilepsy. Beckonert et al. J Neurosci 2018. DOI: 10.1523/JNEUROSCI.0640-18.2018
U Bonn (Germany) researchers suggest spermidine (just a polyamine, don’t get too excited) concentrations are linked to CBZ resistance in epilepsy. The data don’t convince me too much but it is interesting–the uM/mM concentrations should scare readers. Nonetheless, there is a catabolism inhibitor opportunity here if one was so inclined.

New Promise for Vaccines against Tuberculosis. Barry Bloom. NEJM.
I wouldn’t call the GSK vaccine promising. p=0.04 shouldn’t be in NEJM.

Antisense Gene Therapy for Neurodegenerative Disease? Haque & Isacson. Exp Neur 1997.
Early huntingtin antisense experimental failure. A fun attempt at oligos from circa 20 years ago by Harvard workers probably sheds zero light on the Isis/Roche product candidate, but is a fun time warp.

Personal
———–
I have such weird dreams in here. One feature that has carried over from from my apartment to this group home is my dreams are long-running narratives with active and developing plots. There are some obvious themes: the progression from adolescence to adulthood still clearly haunts/taunts me if I give any credence to these semi-lucid moments at all. Does anyone keep a “dream diary”? Isn’t it all the subconscious regurgitation of nonsense? Neurons misfiring their engrams into the dark gaps of synapses–an uncoordinated melody of discharged waves: read into it at your own risk.

I purchased a SAT test-prep book for the guys in my room. We’re having fun preparing for a world without drug dealing and guns–whenever we get out.

If any medicinal chemists are out there and interested in being a penpal, I have a lot of topics to discuss–martin@thotpatrol.com is my email that is rapidly copied sent to my email here at Fort Dix. I’m working on prodrugs of quinone molecules among other interesting ideas.

1/7/2019

962-964 days to go

Biopharma/Investing
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The BMY-CELG deal is not too unexpected. I had modeled a AMGN-CELG merger and felt it was too long-term dilutive to AMGN and it is probably also long-term dilutive to BMY, unless luspatercept does more than $3bn and the CARTs do more than $4bn combined, which is possible. Ozanimod also adds to the puzzle. My estimates were reasonable and the deal was too dilutive. BMY is betting that their commercial execution will outpace their R&D execution, which is basically a fair bet across all of pharma. With LAG, IDO and TIGIT looking disappointing, might as well launch new products that actually work. With very low debt costs, it is a reasonable transaction from a practical perspective. One can pontificate about theoretical alternative investment rates, but how many opportunities to deploy $75 billion are really out there? Nevertheless, BMY has waded into the REMSphere, where they will encounter a staunch opponent in the current FDA. Any attempts to delay generic entrance of Revlimid will be encountered by fierce resistance. Given the near-term generics for CELG’s top 3 drugs, BMY will regain their weird lumpy revenue/earnings profile (no kidding the deal is ‘accretive’ in the next few years!), resulting in a return to the Avapro/Abilify cliff story of the past.

During the year and especially at the end of the year I like to sort my universe’s stocks by YTD performance. I’ll try to present the winners and losers of 2018 in an upcoming blog post. Invariably some moron hedge fund manager says “this was a tough year”. No, stupid. This was a year where you failed to do your job–buy the stocks which appear at the top of the list and short the stocks at the bottom. I’m looking at Greenlight, -30% for the year. The list proves *someone* made money in this zero-sum game, and if you can’t spot the sucker at the table… I like pharmaceuticals because of the heterogeneity of the space, which allows for a no-excuses approach for the player, despite changes in alpha and its accessibility.

Hansa Bio (HMED in Sweden) is one of my favorite stocks. Maybe I’ll do a writeup!
Amgen is fairly valued. Detailed writeup soon!

Papers I’ve Read
——————–
I’ve spent the last few weeks reviewing most (!!!) of the scientific literature of 2018, at least from the preeminent journals. There were a lot of great advances in 2018, especially in biomedical science. Here are some:

1) The evolution from CRISPR to Base Editors.
2) The clearer evidence that microglia is responsible for the pathogenesis of many CNS maladies.
3) CRISPR babies are out there.
4) Further CART successes, including BCMA.
5) Progress towards HIV clearance.
6) Further gene therapy successes, including SMA and hemophilia.
7) VRTX CF advances.
8) A stop codon read-through experiment actually works.
9) AlphaGo and other AI successes.
10) Microbiome successes and failures, further fleshing out of the reality of this niche.
11) Spooky action confirmed, again.
12) Success in quantum satellites/cryptography.
13) Quiet year for math as Goldbach theorem fizzles out and the ABC scandal remind us of the frailty of human logic.
14) Continued success in spinal cord injury restoration/rehabilitation.

Missed anything?

Hemoglobinopathies in the Fetal Position. Pasricha & Drakesmith. NEJM 2018 379;17.
Another “clinical implications of basic research”, a dumbed-down abstract form of another journal’s paper. In this case, Science published a dynamic paper on HRI kinase controlling fetal hemoglobin expression through adulthood. This will undoubtedly herald a race to synthesize a selective HRI inhibitor (send me crystal structure in the mail please). But, again, do us putatively dumb readers of the NEJM need this helping translational hand to read Science?

Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Meisel et al.
Finally, a microbiome paper that isn’t… full of shit. UChicago researchers working with Tet-/- mice found pre-leukemic disorders where expansion of some myeloid cells are highly correlated with driving tumor progression. What is driving that expansion? Amazingly, they find some Lactobacillus snuck into the vivarium, colonizing mice gut microbiomes. This then resulted in IL-6 expression which drove the leukemia. Amazing! It is worth attempting Actemra, Roche’s IL-6 antibody, in some of these human conditions and seeing if the experiment replicates. There are some methodological issues with the experiment, but in general, it is very convincing and exciting.

TAS05567, A Novel Potent and Selective Spleen Tyrosine Kinaase Inhibitor, Abrogates Immunoglobulin-Mediated Autoimmune and Allergic Reactions in Rodent Models. Hayashi et al.
Taiho, not to be confused with Taisho, researchers outline their Syk inhibitor. The thinking here is the Syk inhibitors advanced heretofore have been too sloppy and this more selective kinase inhibitor will avoid the promiscuity seen in the past. I think this class of molecules will remain dead as the therapeutic impact just is not there.

Personal
———–
Saturday NFL match-ups look too close to call. Sunday I chose the Eagles, who came through 🙂 I really like this team. They’re unlikely to proceed further, but they are far stronger than most think.
I sort of like the new Meek Mill album, an artist I mostly panned in the past.

12/31/2018

969 days left.

Biopharma/Investing
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Have been finding lots of cool things. Things I can’t tell you about.
Anyone following the Egalet/Iroko deal? Interesting times in specialty pharmaceuticals as usual.
Or how about the Concordia recap?
I may also attempt a list of 2018 private companies by valuation. Never seen before data! Largely my guesses! Perhaps it can be an open Google doc (maintained by one of my trusty followers) that is a resource for the biopharma community.

Papers I’ve Read
——————–
I’ll be releasing my favorite journals of 2018 soon. I’m not sure if I should do top 10, top 20 or top 50-200. I read a lot.

Books I’ve Read
——————–
Nightfall and Other Stories – Asimov
I was never a science fiction fan. When I read some Asimov a few years ago, I didn’t like it. No patience, I guess. This collection of “Nightfall” and twenty other stories, all briefly introduced by the author, is spectacular. One forgets the delineation of science fiction as Asmiov plunges the reader into deep reservoirs of human existence. Highly recommended.

Code – Petzold
I read this in 2014 and again at the MDC about 9 months ago. A sort of introduction to the world of computers, Petzold sews hardware with software in several mediums, demonstrating the duality (or unity, if you prefer) of computer engineering. One can’t help but get bogged down in increasingly complex schematics, but if you stick with it, Code takes you one of the most enjoyable reading journeys I’ve ever been on. Thank God for overzealous prosecutors!?

Personal
———–
Can’t thank Trump and his team enough for CJ reform. All 4,000 of us at FCI Fort Dix and the tens of thousands of friends and families are so appreciative. I have rarely met a prisoner with a “fair” sentence–I’d say 75% of inmates’ sentences are too long, being as objective as possible. The majority of incarceration is related to illegal drugs and guns, punitive ideas whose time may come and should be going. Happy New Year to my fellow “criminals”. We’ll be home soon.

12/24/2018

Biopharma/Investing
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Stay market neutral! Stocks fall, too. 10 years of stocks rising has to get reversed at some point. “When the tide goes out, we see who has been swimming naked.”

Papers I’ve Read
——————–
Mutations in TOP3a Cause a Bloom Syndrome-like Disorder. Martin et al. Am J Hum Genet 103, 2018.
The BTRR complex repairs double Holliday junctions. Without any of the BTRR members, this phenotype involving growth destriction, microcephaly and cancer predisposition is seen. TopoIIIalpha is a component of BTRR and these researchers identify 12 patients with TOP3A and RMI1 (another component of BTRR) mutations. It appears TOP3A homozygous LOF is incompatible with life (Li et al, PNAS 1998) and the authors speculate that these are severe hypomorphic alleles. I don’t see much of a therapeutic strategy here, perhaps gene therapy could reduce sister chromatid exchanges and other chromosomal abnormalities seen in this family of diseases, potentially reducing new onset neoplasms, but with no benefit towards dysmorphic symptoms.

Signalling Pathways and Cellular Mechanisms Regulating Mossy Fiber Sprouting in the Development of Epilepsy. Godale & Danzer. Front Neurol 2018.
As is my reaction to many neuroscience papers, I’m more confused on the subject matter after reading this one.

Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder. Liu et al. Hum Mol Genet 2018.
I didn’t know much about the T-box transcription factors going into this paper, so it was helpful to get acquainted with these powerful developmental regulators. DiGeorge syndrome is a somewhat well-known rare disease caused by TBX1 deletion, and it appears there are a slew of other T-box disorders, including now, TBX2 variants. TBX2 seems extremely sensitive to gene dosage, with heterozygote hypomorphs and duplication variants both causing disease. The workers here use similar tools to ones I’ve highlighted before including GeneMatcher and the Undiagnosed Diseases Network. Without giving away my own secrets, the bioinformatics tools used in this paper are comprehensive and impressive. The ortholog work is not–drosophila are clearly not the best species to test TBX variants. Anyway, with only 4 patients found (3 in one family), it’s a little hard to get excited about this work or even think about a therapeutic given the extreme gene dosage sensitivity and the developmental nature of the disorder.

Brief Book Review – The Big Con by David M. Maurer
————————————————————–
“A feast of language” boasts the front cover. Indeed, should you desire satiety from a diet of anachronistic cant, TBC will not disappoint. Maurer is a splendid writer outside of the confidence man’s argot, which is disappointingly dated. One cannot envision the last time someone took “a touch” off of the “rag”. Yet, it is still fun to get a glimpse of the early part of last century’s underworld dialect. With fascinating stories/examples of these touches (confidence games run to successful completion), Maurer keeps his work alive despite a fatally boring premise. In some subtextual senses, the book is about human nature and good vs. evil. But the dreary meta-premise is that perhaps the greedy victim, who Maurer posits is so blinded by cupidity that he is invariably willing to join in connivance with the confidence man (of course only to be fleeced at the end), is really the bad guy. Building sympathy for con artists is hard, and Maurer doesn’t intentionally do so, but his wry commentary and somewhat unbelievable access to this cohort of miscreants makes one wonder which side he’s on. The reality is he is just a linguistics enthusiast, so much so, he was willing to dive head-first into this unknown world to simply learn new usages. There is precious little technical discussion of semantics in the style of a, say, Chomsky. Maurer is just the real deal word guy, giving an incidental window of the lives of the con vernacular.

Clinical Trials I’ve Noticed
——————————-
Study of Potential for Drug Interactions Mediated by CYP3A4 Inhibition With Aramchol in Healthy Volunteers. Galmed Pharmaceuticals.
I had almost forgotten about bile acids since I had built Retrophin’s bile acid business in 2014 (which should be going generic soon, by the way). Galmed has a cholic acid combination product I was a bit worried about. Not sure what they’re up to. $GLMD

Safety and Efficacy of Autologous Umbilical Cord Stem Cells Infusion for Preterm Infants. Guangdong Women and Children Hospital.
I’m confused about what is so wrong with preterm infants that they need ‘stem cells’. Oh, China.

The Effects of Microgravity on Human Sperm. Parabolic Flight. Institut Universitari Dexeus.
God bless these intrepid researchers.

Personal
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Half of all US adults have had a family member sent to prison. So, obviously, criminal “justice” is a disaster in the US and we have to make major rollbacks. But why not also acknowledge the professional failure of the law enforcement apparatus that includes the FBI, DOJ (DC and USA/AUSAs), etc.? Grand juries, juries and judges are to blame as well. The U.S. didn’t become a police state by accident–everyone is culpable. I’m not frustrated–I think that comes clear in these blog pages. I just feel terrible for all the guys here with truly undeserved long-term sentences. The accusers are often more guilty than the accused!

Government shutdown? Sounds great to me. Some of it should be permanently shut down!

Is Ruth Bader Ginsberg okay? Can someone check please?

Glossary
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I’m going to make this section iterative. We’ll start with simple definitions for some terms and “update” them over time.

dentate gyrus (updated): Part of the hippocampus, the DG receives input related to new stimuli from the entorhinal cortex. The DG is thought to be instrumental in forming new memories and spatial processing. The DG has granule cells with unique axonal projections called mossy fibers. Mossy cells constitute a substantial population of DG cells.

ribosome – The translation apparatus of the cell, using tRNA and mRNA to create proteins. Exceptionally complex, future definitions will build details.

syntenic – on the same chromosome, usually used when comparing conservation across organisms/orthologs