Nature reviews. Urology
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Nature reviews. Urology · Oct 2015
ReviewMolecular genetics and clinical features of Birt-Hogg-Dubé syndrome.
Birt-Hogg-Dubé (BHD) syndrome is an inherited renal cancer syndrome in which affected individuals are at risk of developing benign cutaneous fibrofolliculomas, bilateral pulmonary cysts and spontaneous pneumothoraces, and kidney tumours. Bilateral multifocal renal tumours that develop in BHD syndrome are most frequently hybrid oncocytic tumours and chromophobe renal carcinoma, but can present with other histologies. Germline mutations in the FLCN gene on chromosome 17 are responsible for BHD syndrome--BHD-associated renal tumours display inactivation of the wild-type FLCN allele by somatic mutation or chromosomal loss, confirming that FLCN is a tumour suppressor gene that fits the classic two-hit model. ⋯ Studies with FLCN-deficient cell and animal models support a role for FLCN in modulating the AKT-mTOR pathway. Emerging evidence links FLCN with a number of other molecular pathways and cellular processes important for cell homeostasis that are frequently deregulated in cancer, including regulation of TFE3 and/or TFEB transcriptional activity, amino-acid-dependent mTOR activation through Rag GTPases, TGFβ signalling, PGC1α-driven mitochondrial biogenesis, and autophagy. Currently, surgical intervention is the only therapy available for BHD-associated renal tumours, but improved understanding of the FLCN pathway will hopefully lead to the development of effective forms of targeted systemic therapy for this disease.
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Nature reviews. Urology · Sep 2015
ReviewCurrent and potential urological applications of botulinum toxin A.
Botulinum toxin subtype A (BoNT-A) is a potent neurotoxin that can selectively modulate neurotransmitter release from nerve endings, resulting in muscular paralysis. BoNT-A might also act on sensory nerves, and have an anti-inflammatory effect. In the first urological use of BoNT-A, injection into the urethral sphincters of patients with detrusor-sphincter dyssynergia resulted in a reduction of urethral resistance and improved voiding efficiency. ⋯ BoNT-A has also been widely used to treat patients with the off-label indications of neurogenic or non-neurogenic voiding dysfunction and male lower urinary tract symptoms owing to BPH and bladder-neck dysfunction. Other indications for which urologists have applied BoNT-A injections include interstitial cystitis/bladder pain syndrome, bladder oversensitivity and chronic pelvic pain syndrome. BoNT-A is currently delivered as an intravesical injection; however, use of liposome encapsulated formulations is also beginning to show some therapeutic potential.