PGC-1α drives small cell neuroendocrine cancer progression towards an ASCL1-expressing subtype with increased mitochondrial capacity.

Adenocarcinomas from multiple tissues can evolve into lethal, treatment-resistant small cell neuroendocrine (SCN) cancers comprising multiple subtypes with poorly defined metabolic characteristics. The role of metabolism in directly driving subtype determination remains unclear. Through bioinformatics analyses of thousands of patient tumors, we identified enhanced PGC-1α-a potent regulator of oxidative phosphorylation (OXPHOS)-in various SCN cancers (SCNCs), closely linked with neuroendocrine differentiation. In a patient-derived prostate tissue SCNC transformation system, the ASCL1-expressing neuroendocrine subtype showed elevated PGC-1α expression and increased OXPHOS activity. Inhibition of PGC-1α and OXPHOS reduced the proliferation of SCN lung and prostate cancer cell lines and blocked SCN prostate tumor formation. Conversely, enhancing PGC- 1α and OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate and promoted commitment to the ASCL1 lineage. These results establish PGC-1α as a driver of SCNC progression and subtype determination, highlighting novel metabolic vulnerabilities in SCNCs across different tissues. STATEMENT OF SIGNIFICANCE: Our study provides functional evidence that metabolic reprogramming can directly impact cancer phenotypes and establishes PGC-1α-induced mitochondrial metabolism as a driver of SCNC progression and lineage determination. These mechanistic insights reveal common metabolic vulnerabilities across SCNCs originating from multiple tissues, opening new avenues for pan-SCN cancer therapeutic strategies.

Marginal Mandibular Nerve Mapping Prior to Nonablative Radiofrequency Skin Tightening.

BACKGROUND: Aging skin and increased skin laxity is a prevalent concern of patients. Nonsurgical treatments, such as radiofrequency, are increasing in popularity due to decreased pain, downtime, and scarring. ThermiRF (Thermi, Irving, TX) is a subdermal radiofrequency treatment for tightening skin. When applying radiofrequency treatments to the neck, it is important to avoid ablating the marginal mandibular nerve and causing nerve trauma. OBJECTIVES: The purpose of this study was to locate and record the position of the marginal mandibular nerve in 72 patients undergoing subdermal radiofrequency skin tightening, to determine how often the nerve correlates to its textbook anatomic position. METHODS: Marginal mandibular nerves were located with a nerve stimulator and marked with the subject in both upright and recumbent positions. Photographs were taken and the nerve position in relation to the mandible was recorded. RESULTS: The marginal mandibular nerve was in its correct anatomic position above the mandible in 18% of patients. Nerve position did not shift between the upright and recumbent positions. Only 10% of patients had left-right nerve symmetry. CONCLUSIONS: To avoid nerve injuries, nerve mapping prior to nonablative radiofrequency treatment is recommended. The marginal mandibular nerve is not always in its correct anatomic position or symmetric to the opposing side. Its location cannot be assumed from the textbook anatomic position or from a single-side mapping.

Long-gap peripheral nerve repair through sustained release of a neurotrophic factor in nonhuman primates.

Severe injuries to peripheral nerves are challenging to repair. Standard-of-care treatment for nerve gaps >2 to 3 centimeters is autografting; however, autografting can result in neuroma formation, loss of sensory function at the donor site, and increased operative time. To address the need for a synthetic nerve conduit to treat large nerve gaps, we investigated a biodegradable poly(caprolactone) (PCL) conduit with embedded double-walled polymeric microspheres encapsulating glial cell line-derived neurotrophic factor (GDNF) capable of providing a sustained release of GDNF for >50 days in a 5-centimeter nerve defect in a rhesus macaque model. The GDNF-eluting conduit (PCL/GDNF) was compared to a median nerve autograft and a PCL conduit containing empty microspheres (PCL/Empty). Functional testing demonstrated similar functional recovery between the PCL/GDNF-treated group (75.64 ± 10.28%) and the autograft-treated group (77.49 ± 19.28%); both groups were statistically improved compared to PCL/Empty-treated group (44.95 ± 26.94%). Nerve conduction velocity 1 year after surgery was increased in the PCL/GDNF-treated macaques (31.41 ± 15.34 meters/second) compared to autograft (25.45 ± 3.96 meters/second) and PCL/Empty (12.60 ± 3.89 meters/second) treatment. Histological analyses included assessment of Schwann cell presence, myelination of axons, nerve fiber density, and g-ratio. PCL/GDNF group exhibited a statistically greater average area occupied by individual Schwann cells at the distal nerve (11.60 ± 33.01 µm2) compared to autograft (4.62 ± 3.99 µm2) and PCL/Empty (4.52 ± 5.16 µm2) treatment groups. This study demonstrates the efficacious bridging of a long peripheral nerve gap in a nonhuman primate model using an acellular, biodegradable nerve conduit.

Prediction of Treatment Outcomes for Neck Rejuvenation Utilizing a Unique Classification System of Treatment Approach Using a 1440-nm Side-Firing Laser.

BACKGROUND: The appearance of a youthful neck is lost with age causing excessive skin laxity, a loss of subcutaneous fat, prominence of platysmal banding, and jowling. In view of the success obtained with laser treatment for neck rejuvenation, the authors have recently taken an algorithmic approach to developing a 7-category classification system of the aging conditions throughout the anatomic spectrum of three areas: skin, fat, and muscle. This system will correlate with specific treatment options. OBJECTIVE: The objective of the study was to confirm the 7-category classification system and treatment approaches based on clinical outcome data for treatment of the mandibular and submandibular areas, specifically for skin tightening and laser lipolysis after a single 1440-nm laser treatment. METHODS: Patients were treated with a single treatment of PrecisionTX™ 1440-nm wavelength laser on their necks. Baseline and posttreatment photographs were taken and evaluated by 3 blinded reviewers using the Cervicomental Angle Scale (CAS). RESULTS: Subjects were rated grades II-III (2.9 ± 0.8) on average at baseline and grades I-II (1.3 ± 0.5) at follow-up. The average improvement was a mean score of 1.5 ± 0.07. Patients, 23/25 (92%), showed at least a 1 score improvement. CONCLUSIONS: This study confirms a new minimally invasive treatment approach based on a unique classification system with no adverse events reported and high patient satisfaction.

Delivery of adipose-derived stem cells in poloxamer hydrogel improves peripheral nerve regeneration.

INTRODUCTION: Peripheral nerve damage is associated with high long-term morbidity. Because of beneficial secretome, immunomodulatory effects, and ease of clinical translation, transplantation with adipose-derived stem cells (ASC) represents a promising therapeutic modality. METHODS: Effect of ASC delivery in poloxamer hydrogel was assessed in a rat sciatic nerve model of critical-sized (1.5 cm) peripheral nerve injury. Nerve/muscle unit regeneration was assessed via immunostaining explanted nerve, quantitative polymerase chain reaction (qPCR), and histological analysis of reinnervating gastrocnemius muscle. RESULTS: On the basis of viability data, 10% poloxamer hydrogel was selected for in vivo study. Six weeks after transection and repair, the group treated with poloxamer delivered ASCs demonstrated longest axonal regrowth. The qPCR results indicated that the inclusion of ASCs appeared to result in expression of factors that aid in reinnervating muscle tissue. DISCUSSION: Delivery of ASCs in poloxamer addresses multiple facets of the complexity of nerve/muscle unit regeneration, representing a promising avenue for further study. Muscle Nerve 58: 251-260, 2018.