Specific inhibition of FGF5-induced cell proliferation by RNA aptamers.

Fibroblast growth factor 5 (FGF5) is a crucial regulator of hair growth and an oncogenic factor in several human cancers. To generate FGF5 inhibitors, we performed Systematic Evolution of Ligands by EXponential enrichment and obtained novel RNA aptamers that have high affinity to human FGF5. These aptamers inhibited FGF5-induced cell proliferation, but did not inhibit FGF2-induced cell proliferation. Surface plasmon resonance demonstrated that one of the aptamers, F5f1, binds to FGF5 tightly (Kd = 0.7 ± 0.2 nM), but did not fully to FGF1, FGF2, FGF4, FGF6, or FGFR1. Based on sequence and secondary structure similarities of the aptamers, we generated the truncated aptamer, F5f1_56, which has higher affinity (Kd = 0.118 ± 0.003 nM) than the original F5f1. Since the aptamers have high affinity and specificity to FGF5 and inhibit FGF5-induced cell proliferation, they may be candidates for therapeutic use with FGF5-related diseases or hair disorders.

Nuclear localization of Meis1 in dermal papilla promotes hair matrix cell proliferation in the anagen phase of hair cycle.

The dermal papilla (DP) is a key mesenchymal compartment of hair follicles that orchestrates mesenchymal-epithelial interaction regulating hair growth cycles. In the present study, we demonstrate that a TALE-family transcription factor, Meis1, is selectively localized in the nucleus of the DP in the anagen phase of the hair cycle. By using an ex vivo organ culture of vibrissae follicles, conditional Meis1 loss causes retardation in hair growth, accompanied by defects in cell proliferation of hair matrix cells. This cell proliferation defect is partly rescued by the addition of culture supernatants derived from Meis1-sufficient but not -deficient DP cells. These findings indicate that nuclear Meis1 in DP activate genes involved in secretion of some unknown factors, which promote proliferation of hair matrix cells in the anagen phase of the hair cycle.

Promotion of anagen, increased hair density and reduction of hair fall in a clinical setting following identification of FGF5-inhibiting compounds via a novel 2-stage process.

BACKGROUND: There are very few effective, scientifically validated treatments with known mechanisms of action for treatment of hair loss in both men and women. Fibroblast growth factor 5 (FGF5) is an important factor in the irreversible transition from anagen to catagen, and inhibition of FGF5 prolongs anagen phase and reduces hair loss. OBJECTIVE: We aimed to screen botanically derived molecules for FGF5 inhibitory activity in vitro and assess efficacy in a clinical setting. METHODS: We screened for FGF5 inhibitory efficacy via a novel 2-step in vitro pipeline consisting of an engineered FGF5 responsive cell line, followed by an activated dermal papillae (DP) cell method. Efficacy in a clinical setting was assessed in a randomized, single-blind, placebo-controlled trial against early- to mid-stage pattern hair loss in men and women. RESULTS: We observed FGF5 inhibitory activity for a number of compounds from the monoterpenoid family, many showing greater inhibitory efficacy than our previously reported crude plant extracts. Evaluation of a lead candidate in a clinical study over 112 days showed a significant improvement in anagen:telogen (AT) ratio (p = 0.002), reduced hair fall (p = 0.007) and improved visual grading (p = 0.004). Scientifically matched photography on a subgroup of randomly chosen participants highlighted significant improvement in hair density, with increases evident in all tested participants compared to baseline. CONCLUSION: Isolates from the monoterpenoid family displayed efficacy in FGF5 inhibition in vitro. A topical formulation containing a leading isolate significantly improved AT ratio, reduced hair fall and increased apparent hair density in the tested population of men and women.

Postoperative displacement of hydroxyapatite spacers implanted during double-door laminoplasty.

OBJECT: Double-door laminoplasty using hydroxyapatite (HA) spacers has been widely performed for compressive cervical myelopathy and has provided good neurological outcome. Although HA spacers are used for preventing reclosure of the opened laminae, they are often displaced or dislocated from their original position. The authors investigated the incidence and patterns of postoperative HA spacer displacement to determine the reasons for this unfavorable event. METHODS: Eighty-six patients with compressive myelopathy underwent double-door laminoplasty in which a total of 278 HA spacers were used. The displacement of HA spacers and opened laminae were assessed using postoperative lateral radiographs and CT scans. RESULTS: Postoperative dorsal migration > 2 mm was found in 116 (42%) of 278 implanted HA spacers. In addition, 33 (38%) of 86 HA spacers rotated > 10 degrees and 29 (34%) of the 86 opened laminae tilted > 10 degrees. Moreover, deformation of the newly formed spinal canal was observed in 51 (59%) of 86 cases, and bone fusion between the HA spacer and spinous process was achieved in only 15 (8.7%) of 172 cases. Neurological worsening and neck pain, however, were not associated with displacement of HA spacers or deformation of the spinal canal. CONCLUSIONS: In double-door laminoplasty, postoperative displacement of the HA spacer with deformation of the enlarged spinal canal occurred frequently. Hydroxyapatite spacers tend to become displaced after surgery. Placing the HA spacer at the base of the spinous process close to the dura mater may prevent postoperative displacement.

Perioperative complications of primary posterior lumbar interbody fusion for nonisthmic spondylolisthesis: analysis of risk factors.

OBJECT: Although posterior lumbar interbody fusion (PLIF) is an excellent procedure to attain circumferential decompression, it is technically demanding and can lead to various surgical complications. The authors retrospectively reviewed consecutive patients with nonisthmic spondylolisthesis who underwent PLIF to reveal the incidence and risk factors for perioperative complications of PLIF. METHODS: A total of 240 patients underwent PLIF. The fusion level was at L4-5 in 220, L3-4 in 18, and L5-S1 in 2. The medial walls of the fusion segment's facet joints were resected, and the VSP Spine System was used for the pedicle screw instrumentation. The operations were performed by 7 surgeons, who were divided into 4 groups according to their level of experience with spinal surgery. RESULTS: The average operation time was 175 +/- 49 minutes, and the estimated blood loss was 746 +/- 489 ml. A total of 90 patients (37.5%) experienced complications; 41 (17%) experienced transient neurological complications, and 18 (7.5%) experienced permanent neurological complications. The mean neurological score according to the Japanese Orthopaedic Association improved from 14.3 +/- 3.8 to 24.7 +/- 4.0 in the patients without complications and from 14.8 +/- 3.6 to 24.0 +/- 3.9 in the patients with complications. Multivariate analysis concerning the relationship between complications and risk factors (operation time, estimated intraoperative blood loss, and surgeon experience) revealed that operation time was the only significant risk factor for complications. CONCLUSIONS: Perioperative complications of PLIF were more frequent in this homogeneous study group than in other studies of various implants. Total excision of the facet joints might preclude neurological complications.