Administration of expanded ASCs (20 to 60 million cells) in combination with fibrin glue is an effective and safe treatment for complex perianal fistula and appears to achieve higher rates of healing than fibrin glue alone.
Graphical AbstractHighlights d Loss of PKCl/i promotes basal and NEPC features in vivo d PKCl/i represses mTORC1 activation through LAMTOR2 phosphorylation d Loss of PKCl/i increases the SGOCP through mTORC1/ATF4 to fuel DNA methylation d The mTORC1/ATF4/PHGDH axis is a synthetic vulnerability of NEPC SUMMARY Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)l/i is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCl/i deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.
Long-term follow-up reaffirmed the very good safety profile of the treatment. Nevertheless, a low proportion of the stem cell-treated patients with closure after the procedure remained free of recurrence after more than 3 years of follow-up.
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