Endoscopic Medial Reepithelization for Inflammatory Canal Stenosis.

OBJECTIVE: Inflammatory external auditory canal (EAC) Stenosis arises from infiltration of inflammatory cells, edema and eventual sclerosing of the medial EAC, leading to complete obstruction and conductive hearing loss. Current treatment includes surgical resection of the affected area with widening and reepithelization of the EAC via postauricular incision, but the condition is reported to recur with high frequency. Our aim was to assess the feasibility of endoscopic transcanal treatment as an alternative to postauricular canalplasty and understand its effect on recurrence rates. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Four patients were included who had bilateral conductive hearing loss and inflammatory canal stenosis, all with gross thickening of the tympanic membrane. INTERVENTIONS: Patients underwent endoscopic removal of obstructive tissue and reepithelization with split-thickness skin grafting. MAIN OUTCOME MEASURES: Postoperative air-bone gap (ABG), lack of recurrence, subjective reporting of hearing improvement, and lack of drainage. RESULTS: Eight of 8 ears (n = 4 patients) had significant improvement in hearing. No recurrence has been observed in any of the patients over a mean follow-up time of 90 months (range, 42-189 mo). Average reduction in ABG was 13.40 dB (SD = 9.0 dB) with a statistically significant difference between the pure tone average preoperative and postoperative ABG (p = 0.0008; n = 7). CONCLUSIONS: Endoscopic treatment of Inflammatory EAC stenosis obviates the need for postauricular incision and results in clinical improvement with a favorable recurrence rate.

SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway.

mTOR complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple environmental cues. Nutrients signal via the Rag guanosine triphosphatases (GTPases) to promote the localization of mTORC1 to the lysosomal surface, its site of activation. We identified SAMTOR, a previously uncharacterized protein, which inhibits mTORC1 signaling by interacting with GATOR1, the GTPase activating protein (GAP) for RagA/B. We found that the methyl donor S-adenosylmethionine (SAM) disrupts the SAMTOR-GATOR1 complex by binding directly to SAMTOR with a dissociation constant of approximately 7 µM. In cells, methionine starvation reduces SAM levels below this dissociation constant and promotes the association of SAMTOR with GATOR1, thereby inhibiting mTORC1 signaling in a SAMTOR-dependent fashion. Methionine-induced activation of mTORC1 requires the SAM binding capacity of SAMTOR. Thus, SAMTOR is a SAM sensor that links methionine and one-carbon metabolism to mTORC1 signaling.

KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1.

The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth that responds to diverse environmental signals and is deregulated in many human diseases, including cancer and epilepsy. Amino acids are a key input to this system, and act through the Rag GTPases to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. Multiple protein complexes regulate the Rag GTPases in response to amino acids, including GATOR1, a GTPase activating protein for RAGA, and GATOR2, a positive regulator of unknown molecular function. Here we identify a protein complex (KICSTOR) that is composed of four proteins, KPTN, ITFG2, C12orf66 and SZT2, and that is required for amino acid or glucose deprivation to inhibit mTORC1 in cultured human cells. In mice that lack SZT2, mTORC1 signalling is increased in several tissues, including in neurons in the brain. KICSTOR localizes to lysosomes; binds and recruits GATOR1, but not GATOR2, to the lysosomal surface; and is necessary for the interaction of GATOR1 with its substrates, the Rag GTPases, and with GATOR2. Notably, several KICSTOR components are mutated in neurological diseases associated with mutations that lead to hyperactive mTORC1 signalling. Thus, KICSTOR is a lysosome-associated negative regulator of mTORC1 signalling, which, like GATOR1, is mutated in human disease.