Magic mushroom rapid reset

The hallucinogenic drug psilocybin has a long history of religious and medicinal use, and is currently being tested in combination with therapy to treat a number of psychiatric conditions including addictions, obsessive compulsive disorder and treatment-resistant major depression. Modern psychopharmacological studies are bearing out historical evidence that the drug, which is a serotonin receptor agonist and can be found in the mushroom genus Psilocybe, can rapidly and durably improve mental functioning. Researchers from the British University College London have shown that psilocybin had long-term effects on cerebral blood flow and brain connectivity, increasing the connectivity between some brain regions and decreasing it between others. Changes in blood flow were apparent five weeks after treatment, when roughly half of treated patients still had improved mood as well. “These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients,” the authors wrote. “The post-treatment brain changes are different to previously observed acute effects of psilocybin and other ‘psychedelics’ yet were related to clinical outcomes.” The team reported its findings in the Oct. 13, 2017, issue of Scientific Reports.

Cutting communications starves glioblastoma cells

Both oncogenic signaling pathways and altered metabolism are basic mechanisms that fuel the growth of tumor cells. Using glioblastoma as a model, researchers at the University of California at Los Angeles have gained new insights into the relationship between the two, linking the effects of several household names in oncology research. The team showed that inhibiting epidermal growth factor (EGFR) signaling reduced glucose metabolism. This activated the anti-apoptotic protein Bcl-XL, which prevented p53 from initiating programmed cell death programs. The team then showed that glioblastoma cells had a synthetic lethal vulnerability to inhibiting EGFR signaling in combination with stabilizing p53. The authors concluded that “together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies.” Their work appeared in the Oct. 9, 2017, issue of Nature Medicine.

Sinking cancer’s SHIP

SHIP1 is an immune checkpoint, and as such, a potential target for immuno-oncology efforts. But in previous experiments, knocking out the protein led to reduced rather than increased activity of both T cells and Natural Killer (NK) cells. Now, researchers from the SUNY Upstate Medical Center have shown that reversible inhibition of SHIP1, rather than knocking the protein out altogether, was effective at increasing the antitumor activity of both T cells and NK cells. The team looked at transient inhibition of SHIP1 because permanent activation can ultimately backfire, leading to immune cell exhaustion. “Transient SHIP1 inhibition in mouse models of lymphoma and colon cancer improved the median and long-term tumor-free survival rates,” the authors wrote. “The findings suggest that a pulsatile regimen of SHIP1 inhibition might be an effective immunotherapy in some cancer patients.” Their work appeared in the Oct. 10, 2017, issue of Science Signaling.

14 tons, and what do you get

20 grams per year does not sound like a large amount, but even that much of the experimental drug bryostatin has been hard to come by. Bryostatin, which is in clinical trials for HIV, Alzheimer’s disease, and cancer, was originally isolated from the marine animal bugula neritina, but to get the National Institute of Health’s original supply of 18 g took 14 tons of source material. Artificial synthesis of the compound is currently possible, but also at vanishingly low yields. Now, researchers from Stanford University have developed a simpler method to synthesize bryostatin that could be completed in 29 steps, instead of the shortest currently known synthesis route, which requires almost twice as many steps. The researchers said that their method could be “scaled to meet clinical needs (~20 grams per year).” Additionally, “this practical solution to the bryostatin supply problem also opens broad, facile, and efficient access to derivatives and potentially superior analogs.” Their work appeared in the Oct. 13, 2017, issue of Science.

Nobody’s perfect, including patient-derived xenografts

Cancer cell lines have been cultured, sometimes for decades, in an environment that is very different from their natural microenvironment. One attempt at understanding tumor evolution in more realistic animal models has involved the use of growing patient-derived xenografts in mice, which provides a microenvironment that cell cultures can’t. However, researchers from the Dana-Farber Cancer Institute and the Broad Institute have shown that such patient-derived xenografts, too, do not fully mimic the natural tumor environment. The authors looked at the evolution of copy number alterations (CNAs) in more than 1,000 patient-derived xenografts representing two dozen tumor types. They found that “several CNAs recurrently observed in primary tumors gradually disappeared in PDXs, indicating that events undergoing positive selection in humans can become dispensable during propagation in mice.” The authors concluded that “these findings have major implications for PDX-based modeling of human cancer.” Their work appeared in the Oct. 9, 2017, online issue of Nature Genetics.

Gene editing how-to

Gene editing of blood-forming stem cells to treat inherited diseases has been responsible for some of gene therapy’s greatest triumphs, and some of its greatest tragedies as well. But mostly, it has been the scene of much more mundane ongoing frustrations with respect to developing successful protocols for gene editing. Partly, this is due to the fact that homology-directed repair, which is the more precise gene editing method, is inefficient in blood-forming stem cells, Researchers from the Italian San Raffaele Telethon Gene Therapy Institute have developed translatable methods to achieve clinically relevant gene correction while transplanting small numbers of edited cells. The authors wrote that “overall, our results pave the way toward clinical translation of targeted [blood-forming stem cell] gene editing by drafting a roadmap of preclinical studies to interrogate the efficacy and safety of the procedure and establishing clinically compatible processes for efficient manufacturing of the therapeutic cell product.” Their work appeared in the Oct. 11, 2017, issue of Science Translational Medicine.

‘Eating cells’ and obesity

Macrophages are the body’s big eaters, devouring all manner of dead cells and debris. Researchers from the Portuguese Institut Gulbenkian have shown that a subtype of macrophages eats the neurotransmitter norepinephrine (NE) in the sympathetic nervous system, and that this particular form of feeding contributed to obesity. These sympathetic neuron-associated macrophages (SAMs) increased their activity with activation of the sympathetic nervous system, and when they did, they shifted to a more proinflammatory state. In animal models of obesity, decreasing the NE-metabolizing activity of SAMs led to “substantial and sustained weight loss in obese mice” by browning white fat and increasing energy dissipation via heat. “The team found that “human sympathetic ganglia also contain SAMs expressing the analogous molecular machinery for NE clearance, which thus constitutes a potential target for obesity treatment.” They reported their results in the Oct. 9, 2017, issue of Nature Medicine.

The lives of a cell

The Genotype-Tissue Expression (GTEx) Consortium has published a comprehensive map of regulatory variants or expression quantitative trait loci (eQTL) in dozens of different tissues, giving new insight into how DNA sequence variants play out in different tissues. Sequence variants that are common to all cells interact with cell-specific gene expression programs, and as a result, sequence variants can have noticeable effects in specific cell types and be immaterial in others. The authors analyzed more than 7,000 tissue samples from about 450 individuals to understand the effects of regulatory variants. Among the insights gained from the analysis were that regulatory variants that were near genes affected gene expression in more tissues than those far from them, and showed how such variants affected RNA editing and X chromosome inactivation. A commentary accompanying the papers noted that the work needs to be extended both by looking at different cell types within tissues, and using tissue samples that have not been frozen. Nevertheless, “the extensive catalogue generated by the GTEx Consortium takes us a step closer to decoding the regulatory code of the genome. The consequences of genetic variation on gene expression are gradually becoming clearer.” Papers and commentary were published in the Oct. 12, 2017, issue of Nature.

How food and gut immunity interact

The intestines need to let nutrients and electrolytes in while keeping toxins and the gut microbiome out. Previous work had identified the metabolism of dietary beta-carotene into either vitamin A, which is transported elsewhere, or retinoic acid, which affects gut immunity locally. Researchers from Case Western Reserve University have identified the transcription factor ISX as critical for controlling beta-carotene metabolism. Mice lacking ISX produced too much retinoic acid, which led to a dysregulated immune system and autoimmune attacks on pancreatic cells. The authors noted that “genetic polymorphisms in the Isx gene have been associated with inflammatory disorders in humans, indicating that our findings in mice have clinical implications.” Their work appeared in the Oct. 9, 2017, online issue of the Proceedings of the National Academy of Sciences.

How the thyroid affects the liver

Hypothyroidism increases the risk of nonalcoholic fatty liver disease (NAFLD), but how it does so has been unknown to date. Scientists from Yale University have shown that thyroid hormones affected insulin secretion and increased fat breakdown, leading to higher levels of fatty acids in the liver. Unexpectedly, however, severely lowered levels of thyroid hormones inhibited fat breakdown and was protective against NAFLD. The authors summarized that their work “reveal key metabolic differences between mild and severe hypothyroidism,” as well as the mechanisms linking thyroid function and NAFLD in both cases. They reported their findings in the Oct. 10, 2017, online issue of the Proceedings of the National Academy of Sciences.