Novel ALK5 inhibitor TP0427736 reduces TGF-ß　induced growth inhibition in human outer root sheath cells and elongates anagen phase in mouse hair follicles.

BACKGROUND: Androgenic alopecia (AGA) occurs as a result of the contraction of the anagen phase because of the action of androgens on hair follicles. TGF-ß production from dermal papillae is enhanced by androgens, and growth inhibition of hair-follicle cells is induced by TGF-ß, and the hair cycle progresses from the anagen phase to the catagen phase. We investigated both the in vitro and in vivo potency of the newly identified ALK5 inhibitor TP0427736 {6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole}. METHODS: For in vitro study, kinase inhibitory activity was evaluated with ELISA, and inhibitory activity against TGF-ß-induced Smad2/3 phosphorylation in A549 cells and TGF-ß-induced growth inhibition of human outer root sheath cells were assayed using ELISA. For in vivo study, we used a mouse model that had been synchronized through dorsal hair depilation. RESULTS: TP0427736 inhibited ALK5 kinase activity with an IC50 of 2.72nM; this effect was 300-fold higher than the inhibitory effect on ALK3. In cell-based assays, TP0427736 inhibited Smad2/3 phosphorylation in A549 cells and decreased the growth inhibition of human outer root sheath cells. The topical application of TP0427736 significantly decreased Smad2 phosphorylation in mouse skin, and its repeated application suppressed the shortening of average hair follicle length during the transition from the late anagen phase to the catagen phase. CONCLUSIONS: TP0427736, a potent ALK5 inhibitor with appropriate in vitro and in vivo profiles, may serve as a potential new therapy for AGA.　.

Bimatoprost 0.03% for the Treatment of Eyelash Hypotrichosis: A Pooled Safety Analysis of Six Randomized, Double-masked Clinical Trials.

OBJECTIVE: Describe the safety profile of bimatoprost 0.03% ophthalmic solution as once-daily topical treatment for idiopathic or chemotherapy-induced eyelash hypotrichosis. DESIGN: Pooled data from six randomized, multicenter, double-masked, parallel-group clinical studies of at least three-months' duration with at least one bimatoprost treatment group. SETTING: Study sites in the United States, Canada, United Kingdom, and Japan from 2007 to 2012. PARTICIPANTS: Adults with eyelash hypotrichosis, defined as baseline Global Eyelash Assessment of minimal or moderate, who received bimatoprost 0.03% (n=680) or vehicle, with no prior exposure to bimatoprost (n=379). MEASUREMENTS: Safety assessments included adverse events, vital sign measurements, and physical examinations. Common (≥2%) and treatment-related adverse events were analyzed at time points up to four months and through end of treatment, up to 12 months. RESULTS: Similar overall adverse events incidence was reported in bimatoprost and vehicle groups for subjects with idiopathic hypotrichosis; a higher incidence in both groups was reported for postchemotherapy subjects. Common adverse events included conjunctival hyperemia, eyelid pruritus, blepharal pigmentation, nasopharyngitis, eyelid erythema, and punctate keratitis. Most adverse events occurred early in treatment, were mild in intensity, localized to treatment site, and reversible with treatment cessation. Discontinuations due to adverse events were low (3.2% for bimatoprost and 2.4% for vehicle). CONCLUSION: Adverse events were consistent with the known pharmacologic mechanism of bimatoprost. The safety profile was similar across the studies and no new safety signals were observed. Once-daily bimatoprost 0.03% for treatment of eyelid hypotrichosis has a favorable safety and tolerability profile when applied topically to the upper eyelid margin.

Sebaceous carcinoma: an immunohistochemical reappraisal.

The rates of distant metastases and tumor death in sebaceous carcinoma (SC) have been reported to be higher than those of other cutaneous carcinomas, such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), regardless of whether they occur in ocular or extraocular regions. Therefore, strict differentiation of SC from SCC and BCC is required. In this article, we report immunohistochemical findings of SC and compare these data to those of SCC, BCC, and sebaceoma. An immunohistochemical study was performed using 7 antibodies [anti-carcinoembryonic antigen (CEA), anti-epithelial membrane antigen (EMA), anti-CA15-3, anti-CA19-9, anti-androgen receptor (AR), anti-epithelial antigen (Ber-EP4), and anti-adipophilin (ADP)] on 35 cases of SC (16 cases in ocular and 19 cases in extraocular regions) and 10 cases of each SCC (5 cases in ocular and 5 cases in extraocular regions), BCC (5 cases in ocular and 5 cases in extraocular regions), and sebaceoma (no cases arose on the eyelids). In summary, the typical immunophenotypes of SC were EMA+, CA15-3+, AR+, Ber-EP4-, and ADP+; those of sebaceoma were CEA-, EMA+, Ber-EP4-, and ADP+; those of SCC were CEA-, EMA+, CA19-9-, AR-, Ber-EP4-, and ADP-; and those of BCC were CEA-, EMA-, CA15-3-, Ber-EP4+, and ADP-. Other antibody tests for each neoplasm were positive in about half of the cases. The detection of AR and ADP was useful for differentiating SC from SCC, whereas the determination of EMA, CA15-3, Ber-EP4, and ADP was valuable in differentiating SC from BCC.

Immunohistochemical findings of sebaceous carcinoma and sebaceoma: retrieval of cytokeratin expression by a panel of anti-cytokeratin monoclonal antibodies.

This study examined immunohistochemical findings of sebaceous carcinoma and sebaceoma. An immunohistochemical study using 13 anti-cytokeratin (CK) antibodies (anti-CK1, 5-8, 10 and 14-20) and 35 cases of sebaceous carcinoma (16 cases on ocular and 19 cases on extraocular regions) and 10 cases of sebaceoma (no cases arose on the eyelids) was performed. Overall, those in ocular lesions were almost the same as those for extraocular lesions in sebaceous carcinoma other than CK8. The findings in sebaceous carcinoma were almost equal to those of sebaceoma. Over 75% of cases with sebaceous carcinoma were positive with anti-CK5 and anti-CK14 antibodies and negative with anti-CK1, CK10, CK15, CK17, CK18 and CK20 antibodies. Most cases (50-75%) of those were positive with CK7 and negative with CK6, CK16, CK19 and CK8. The sensitivity and specificity of immunohistochemical detection of sebaceous carcinoma using the panel of anti-cytokeratin antibodies were lower than those of other antibodies. Immunohistochemical detection of cytokeratins in diagnosing sebaceous carcinoma should be considered to be ancillary to conventional microscopic findings and those of other antibodies.

Coexistence of giant blue nevus of the scalp with hair loss and alopecia areata.

A 43-year-old Japanese man presented with a 13-year history of a grayish macule measuring 7 cm in diameter with sparse hairs on the vertex. Histopathological examination demonstrated two types of melanocytes, spindle-shaped and ovoid cells, with abundant melanin aggregated around the upper part of the pilosebaceous apparatus. Fibrous, thick collagen bundles were also seen surrounding the upper part of the small hair follicles. There was no infiltration of melanocytes or lymphocytes in the lower dermis or adipose tissue. Based on these findings, a diagnosis of blue nevus, cellular type, was made. Giant cellular blue nevi on the scalp are rare, and 11 cases reported in the published work have shown characteristic features such as hair loss and cranial invasion of nevus cells. It should be noted that melanocytes of giant blue nevi have a high potential to damage other organs such as underlying bone and hair follicles. The patient also showed a typical lesion of alopecia areata on the left temporal which was successfully treated with topical corticosteroid.

Diltiazem-associated photodistributed hyperpigmentation: report of two Japanese cases and published work review.

Scherschum et al. proposed diltiazem-associated photodistributed hyperpigmentation as a novel type of drug-induced photosensitive lichenoid eruption. The characteristic clinical features were slate-gray reticulated hyperpigmentation on sun-exposed areas, while lichenoid dermatitis with prominent pigmentary incontinence was noted histologically. Although the clinical and histological features were similar to those of lichen planus pigmentosus, the histological features did not show either compact hyperkeratosis or wedge-shaped hypergranulosis, which are typical histological features of lichen planus. We describe two Japanese cases of diltiazem-associated photodistributed hyperpigmentation, who were successfully treated with topical tacrolimus, and review the published work.

Resin splint as a new conservative treatment for ingrown toenails.

Several conservative as well as surgical methods are used for the treatment of ingrown toenails until date. The conservative methods are either based on nail splinting or on orthonyxia, but no methods employing both principles have been reported thus far. Moreover, surgical methods usually involve postoperative pain, prolonged wound healing and restricted activities of daily living. Therefore, considering the need of a simplified, non-invasive method, in this study, we applied a novel splint to treat patients with ingrown toenails and estimated the clinical efficacy as well as rate of recurrence following treatment. The splint is a plate made of resin that is attached to the lateral edge of the nail using a bandage. We studied 61 patients (19 men and 42 women; mean age 36 years), with an average application duration of 9.3 months and an average follow-up period of 10 months in all patients. All patients experienced pain relief within a week of splint application and a decrease in the degree of nail deformity. Moreover, follow-up revealed a recurrence rate of 8.2%. Therefore, we believe that this new device is an excellent conservative treatment method for patients with ingrown toenails.

Real-time in vivo imaging of p16Ink4a reveals cross talk with p53.

Expression of the p16(Ink4a) tumor suppressor gene, a sensor of oncogenic stress, is up-regulated by a variety of potentially oncogenic stimuli in cultured primary cells. However, because p16(Ink4a) expression is also induced by tissue culture stress, physiological mechanisms regulating p16(Ink4a) expression remain unclear. To eliminate any potential problems arising from tissue culture-imposed stress, we used bioluminescence imaging for noninvasive and real-time analysis of p16(Ink4a) expression under various physiological conditions in living mice. In this study, we show that oncogenic insults such as ras activation provoke epigenetic derepression of p16(Ink4a) expression through reduction of DNMT1 (DNA methyl transferase 1) levels as a DNA damage response in vivo. This pathway is accelerated in the absence of p53, indicating that p53 normally holds the p16(Ink4a) response in check. These results unveil a backup tumor suppressor role for p16(Ink4a) in the event of p53 inactivation, expanding our understanding of how p16(Ink4a) expression is regulated in vivo.

Centrifugal lipodystrophy of the scalp presenting with an arch-form alopecia: a 10-year follow-up observation.

We describe a 10-year follow-up observation of progressive arch-form alopecia caused by centrifugal lipodystrophy (CLD) in a Japanese boy. A 2.5-year-old boy developed a slightly depressed lesion demarcated by a horseshoe-shaped erythematous border on his right neck, which then extended to the scalp. Four years later, arch-form alopecia became apparent in the right temporal region along with an erythematous border. The arch-form alopecia gradually expanded centrifugally, leaving a slight residual depression, but hair regrowth was seen within the area of alopecia. Histological examination of the erythematous border revealed non-specific inflammatory changes in the subcutaneous fat. Magnetic resonance imaging findings revealed a loss of subcutaneous fat inside the lesion. The alopecia continuously extended until he was 12 years old, but, thereafter, expansion ceased and hair regrowth gradually occurred in the arch-form alopecia. A linear non-hairy lesion 5 cm in length still remained when he was 13 years old. CLD might involve the scalp and cause linear, arch-form alopecia.

Primary dermal melanoma: A case report and molecular characterization.

Swetter et al. proposed primary dermal melanoma (PDM) as a distinct entity based on an excellent prognosis. The histopathological features of PDM are extremely similar to those of metastatic melanoma or clear cell sarcoma (CCS). We describe a 38-year-old woman with a subcutaneous tumor in her left thigh. Physical and imaging examinations showed no evidence of metastatic melanoma. The lesion showed obvious strong expression of KIT by immunohistochemistry, but no EWS-ATF1 fusion transcript specific for CCS was detected by reverse transcription polymerase chain reaction. In further analyses of KIT expression in other tumors, three of four primary melanomas (75%) and six of 12 metastatic melanomas (50%) were moderately or strongly positive, however, both the primary and metastatic lesions of CCS tested negative. We believe this to be a case of PDM, and emphasize the distinctiveness of PDM.