Background: About 20 000 patients are diagnosed with muscle-invasive UC annually, where the five-year survival rate is approximately 5% in metastatic cases. The transcription factor PPARG is associated with the luminal lineage subtype reflecting ∼65% of all advanced UC patients. Recurrent genetic alterations in PPARG, including focal amplification, missense mutations, and fusions, as well as hotspot mutations in its obligate heterodimer, retinoid X receptor alpha (RXRA) are characteristic of this molecular subtype. Materials and Methods: We analyzed tumor tissue collected from over 3000 patients with muscle-invasive UC sequenced using the Tempus xT assay (DNA-seq of 648 genes at 500x coverage; RNA-seq; 3262pt DNA, 2685pt both). Molecular classification as luminal (luminal papillary, luminal, and luminal infiltrated subtypes) or non-luminal (basal-squamous and neuronal subtypes) was performed using non-negative matrix factorization (NMF) rank 5 following the Robertson method, excluding PPARG from the gene set to eliminate the inference of bias. Mean expression was reported as Log2[TPM+1]. Mutations were reported as single nucleotide variants or insertion/deletions (SnvIndel). Results: We determined that luminal-papillary (669pt), luminal (449pt), and luminal-infiltrated (621pt) UC subtypes comprised 65% of the real-world cohort, consistent with subtype distribution as reported in the Robertson TCGA data set. Higher PPARG expression was associated with luminal subtypes (7.78 Log2[TPM+1], p < 0.00001) compared to non-luminal subtypes (5.47 Log2[TPM+1]). The prevalence of mutations in PPARG, RXRA, and fibroblast growth factor receptor 3 (FGFR3) was also significantly higher in the luminal subtype, where the frequency of PPARG amp (copy number 4–7) was 10% (p < 0.05), PPARG SnvIndel was 2.0% (p = 0.8), RXRA hotspot SnvIndel was 3.3% (p < 0.00005) and FGFR3 SnvIndel was 14% (p < 0.005). Collectively 1 in 3 advanced UC patients in a real-world population harbored mutations in PPARG, RXRA or FGFR3. A PPARG expression threshold (7.75 Log2[TPM+1]) was derived from logistic regression comparing amplified and diploid patients, where gain of even one copy of PPARG is associated with overexpression. Many diploid patients exhibit PPARG expression (7.49 Log2[TPM+1]) comparable to amplified patients. High PPARG expression was sustained in metastatic samples (7.55 Log2[TPM+1]), and expression did not significantly vary by metastatic tissue site (p > 0.05). Conclusion: To the best of our knowledge, this represents the largest real-world dataset from patients with advanced and metastatic UC evaluated to date. Stratification of advanced UC patients based upon PPARG status as a defining feature of the luminal phenotype supports targeting of this pathway with novel agents under development. Conflict of interest: Ownership: Flare-affiliated authors are shareholders of Flare Therapeutics.

•SULT1A inhibition in the gut can increase plasma tyrosine and brain dopamine.•Artificial colors are SULT1A inhibitors, as are many natural polyphenols in foods.•Prior ADHD trials were compromised by including multiple SULT1A inhibitors.•Prior trials show evidence of SULT1A inhibition causing ADHD symptoms.•Prior trials support an inverted-U ADHD response to SULT1A inhibition.

In the January 2012 issue of Headache, Dr. Ahn and Dr. Brennan posed the question “How does a migraine attack stop?”1 It has long been hypothesized that dopamine is involved in the genesis of migraines. Given that dopamine is normally present in the body, while migraines are sporadic, this hypothesis implies that something causes elevated levels of dopamine that can, in turn, lead to a migraine in susceptible patients. There is also extensive evidence linking various triggers, such as red wine, citrus, coffee, and chocolate, to migraines. Unfortunately, there has been little evidence to tie the ingestion of these foods and drinks to the creation of dopamine. Various vasoactive monoamines in these substances, including tyramine, octopamine, synephrine, and caffeine, are often blamed for the resulting migraine, but without a mechanistic bridge other than a possible indirect link through effects on blood pressure. There is, however, a direct mechanism connecting the ingested triggers to dopamine. The triggers listed above contain phenols and polyphenols that have been shown in vitro to inhibit the human sulfotransferase enzymes SULT1A1 and SULT1A3. These enzymes, along with monoamine oxidase and catechol-O-methyltransferase, are normally responsible for deactivating catecholamines in humans. Any in vivo inhibition of the SULT1A enzymes would allow catecholamines, including dopamine, to build up in the body. Evidence of such in vivo inhibition is presented in a recent paper.2 Many patients believe their migraines are triggered by stress. A better explanation, consistent with a SULT1A inhibition mechanism, is that in response to stress, the body releases catecholamines that a normal enzyme system would quickly deactivate; SULT1A inhibition significantly slows this deactivation, and the resulting buildup of dopamine causes the migraine. The proximate trigger of the migraine is indeed the stress, but the root cause was the SULT1A inhibition. Given that this inhibition could have occurred hours or even days earlier, and asymptomatically, it is not surprising that the patient reports the stress as the cause of the migraine. This mechanism also explains why triggers do not act consistently, either for a given patient or across patients.3 The glass of red wine does not create the dopamine that triggers the migraine, but only sets the stage by reducing the remaining SULT1A activity. Whether a migraine actually results will depend on (1) the particular SULT1A genotypes; (2) the extent of SULT1A inhibition from the wine and whatever was previously ingested; (3) the magnitude and composition of any released catecholamines; and (4) the patient's susceptibility to the resulting dopamine. In this construct, it is likely that the migraine stops when sufficient SULT1A capacity becomes available to reduce dopamine concentration back to normal levels. Depending on the nature of the inhibition, this could occur through a combination of diminishing phenol/polyphenol concentrations that cause a reversible inhibition to release, or when new SULT1A is generated in the case of irreversible inhibition.

SULT1A enzymes protect humans from catecholamines, but natural substances in many foods have been found to inhibit these enzymes in vitro. Given the hormonal roles of catecholamines, any in vivo SULT1A inhibition could have serious consequences. This paper uses a re-analysis of published data to confirm that SULT1A inhibitors have effect in vivo in at least some patients. Nineteen studies are cited that show ingestion of SULT1A inhibitors leading to catecholamine increases, blood pressure changes, migraine headaches, or atrial fibrillation. SULT1A inhibition does not create the catecholamines, but prevents normal catecholamine deactivation. Susceptible patients probably have lower-activity SULT1A alleles. The paper discusses new hypotheses that SULT1A inhibition can cause "holiday heart" arrhythmias and type 2 diabetes in susceptible patients. Subgroup analysis based on SULT1A alleles, and addition of a catecholamine source, should improve the consistency of results from tests of SULT1A inhibitors. SULT1A inhibition may be a key contributor to cheese-induced migraines (via annatto), false positives in metanephrine testing, and the cardiovascular impacts of recreational alcohols.

ABSTRACTSudden cardiac death is a significant health issue, causing millions of deaths worldwide annually. Studies have found that the likelihood of such death is higher in winter. Further studies identified that the highest likelihood occurs on Christmas Day and New Years Day, but not the interim period. Thanksgiving, Independence Day and the Islamic holiday Eid Al‐Fitr also show significant increases in the rate of cardiac events or death. A number of mechanisms have been proposed, but none have satisfactorily explained the evidence. This article reviews the data supporting the existence of a holiday cardiac death phenomenon, the involvement of catecholamines and the normal modes of human catecholamine deactivation. Further evidence is reviewed that supports a hypothesized mechanism whereby critical SULT1A catecholamine deactivation enzymes can in some patients be inhibited by naturally‐occurring phenols and polyphenols in foods and alcohols. If deactivation is inhibited by holiday consumption excesses, holiday stress or excitement could lead to a buildup of catecholamines that can cause fatal arrhythmias. Awareness of this mechanism could reduce deaths, both through doctor/patient education leading to a moderation in consumption and through the potential identification of patients with a predisposition to SULT1A inhibition. This hypothesis also raises parallels between sudden cardiac death in adults and Sudden Infant Death Syndrome (SIDS). The possible involvement of SULT1A inhibition in SIDS is discussed. Copyright © 2012 John Wiley & Sons, Ltd.

Oil companies often have large backlogs of drilling opportunities. Optimizing this portfolio is critical. I used a simulated annealing algorithm to schedule drilling rigs for BP Exploration by making an analogy to the vehicle-routing problem, and I estimated the value of acquiring additional drilling rigs. By considering the perishability of projects' benefits in optimizing over a multi-period planning horizon, I increased the value of portfolios by deferring attractive projects in favor of less attractive ones. This violates the standard practice of maximizing value by sorting projects by such attractiveness measures as net present value or internal rate of return. My program is BP's primary planning tool in the Prudhoe Bay field. The first year's application improved portfolio net present value by approximately $30 million over traditional planning methods.