A small-molecule degron with a phenylpropionic acid scaffold.

Targeted protein degradation (TPD), employing proteolysis-targeting chimeras (PROTACs) composed of ligands for both a target protein and ubiquitin ligase (E3) to redirect the ubiquitin-proteasome system (UPS) to the target protein, has emerged as a promising strategy in drug discovery. However, despite the vast number of E3 ligases, the repertoire of E3 ligands utilized in PROTACs remains limited. Here, we report the discovery of a small-molecule degron with a phenylpropionic acid skeleton, derived from a known ligand of S-phase kinase-interacting protein 2 (Skp2), an E3 ligase. We used this degron to design PROTACs inducing proteasomal degradation of HaloTag-fused proteins, and identified key structural relationships. Surprisingly, our mechanistic studies excluded the involvement of Skp2, suggesting that this degron recruits other protein(s) within the UPS.

Cutaneous Vasculitis in Cogan's Syndrome: A Report of Two Cases Associated with Chlamydia Infection.

Cogan's syndrome (CS) is defined by the combination of hearing loss, vertigo, and ocular inflammation of uncertain cause, and can be associated with variable vessel vasculitis. Vasculitic manifestations may include arteritis (affecting large, medium or small arteries), aortitis, and aortic and mitral valvulitis. Cutaneous manifestations including erythema, papules, subcutaneous nodules, and purpura sometimes occur; however, to date, only six cases have been histologically confirmed to have genuine vasculitis. Here, we report two cases of CS, one of which involved a patient who developed the typical symptoms of Takayasu arteritis and purpuric lesions in the legs, with histologic findings consistent with small vessel vaculitis in the dermis. The second case involved a patient who developed subcutaneous nodules in the legs and the axilla, and histologic findings revealed a necrotizing vasculitis of the small arteries in the interlobular area. Both cases were successfully treated with systemic steroid therapy. Based on the clinical features and the examination data, there is a possibility that a Chlamydia trachomatis infection played a pivotal role in the pathogenesis of those vasculitides.

A Case of Infundibulocystic Basal Cell Carcinoma Clinically Mimicking a Melanocytic Nevus Associated with Epidermal Cysts.

A 52-year-old Japanese woman presented with a 1.5-cm black, glossy, flat, pediculated lump that clinically mimicked a melanocytic nevus on the left temporal side of her head. The subcutaneous tumor beneath the nodule was elastic and hard. A histological examination showed that the tumor was well circumscribed with an exo- and endophytic growth 2.4 × 1.9 cm in size. The lesion contained several keratinous cysts and was composed of funicular fascicles containing squamoid cells. Excessive mucinous material deposition was observed around the tumor periphery and a palisading arrangement of nuclei in the tumor periphery was seen in some areas. Based on these findings, a diagnosis of infundibulocystic basal cell carcinoma (IFC-BCC) was made. This report presents a case of IFC-BCC that clinically mimicked a melanocytic nevus and was also associated with epidermal cysts.

Germ cell-specific nucleocytoplasmic shuttling protein, tesmin, responsive to heavy metal stress in mouse testes.

Tesmin 60, a novel testis-specific gene, has been identified to have homology in plant and animal species, sharing a pair of cysteine-rich regions reported to be similar to metallothionein. The functional implications for these homologs, however, are not fully understood. Two plant homologs are involved in regulating transcription or floral development. cDNA was transfected in COS-1 cells using GFP as a tag. The tesmin-GFP chimeric protein revealed its cytoplasmic localization, which is inconsistent with findings for the plant homologs. We hypothesized that the putative regulatory protein tesmin could be under the regulation of the nucleocytoplasmic shuttling by the effect of metal stress. Immunocytochemistry of male germ cells revealed that tesmin mainly locates in the cytoplasm at stages I-VIII of pachytene spermatocytes, while it temporarily translocates into the nucleus in the late pachytene or diplotene stages X-XII under normal conditions. This is one of a few examples of a germ cell-specific protein that undergoes temporal and spatial regulation through the G2/M transition in meiosis. This nucleocytoplasmic translocation of tesmin is also stress-responsive. Administration of cadmium causes loss of temporal regulation in spermatocytes. This observation suggests the testis is more sensitive to stresses than other organs. This is necessary to maintain genetic integrity.

Efficacy and safety of a topical carbon suspension photoenhancer adjunctive to intense pulsed light treatment for pigmented lesions in Japanese patients: A pilot study.

BACKGROUND AND AIMS: Pigmented lesions, e.g., senile lentigo and seborrheic keratosis are commonly seen in photodamaged skin in the Japanese general population. The use of the laser to treat such lesions is often painful, and intense pulsed light (IPL) systems have become widely used. Clearly demarcated pigmented lesions may be identified easily and treated with IPL. Less well demarcated lesions, however, which are very difficult to identify or thick melanogesic lesions like seborrheic keratosis represent one of the most challenging conditions to be treated using IPL. This pilot study evaluated carbon suspension-assisted IPL treatment of such lesions. SUBJECTS AND METHODS: Three female Japanese patients, Fitzpatrick skin type III-IV, comprised the subjects, aged 58, 78 and 85, with indistinct senile lentigines or thick seborrheic keratoses. The lesions were painted or demarcated with a carbon-based ink from a commercially-available Japanese writing instrument (Fude-pen™, Pentel, Japan) consisting of a brush-like pen nib with a refillable or replaceable ink reservoir, and then treated with a broadband (560 - 1200 nm) IPL system. RESULTS: The poorly-demarcated lesions were quickly and easily marked with the pen, and the IPL treatments were well-tolerated. All patients had good improvement in their painted pigmented lesions based on the overall evaluation, compared with unpainted ones. Side effects after treatment, such as hyperpigmentation, persistent erythema, and scarring, were minimal. CONCLUSIONS: Topical carbon suspension-assisted IPL treatment could be a good option for patients with indistinct pigmented or thick melanogenesic lesions. Adverse reactions to this treatment were minimal and the results acceptable, though appropriate lesions need to be chosen carefully.

Treatment for crusted scabies: limitations and side effects of treatment with ivermectin.

Skin eruption with mild itching of the hands and feet developed in a man in his 90s 1 month after he was hospitalized following a traffic accident. Scabies was diagnosed in an attending nurse 3 months after the patient's hospitalization, and infection from the patient was suspected. Cornification of the patient's soles and marked hypertrophy of the nails of both feet were observed. After a large number of scabies mites were detected on microscopic examination, crusted scabies was diagnosed. The patient was given oral ivermectin, 6 mg, once per week for 3 weeks, and crotamiton topical ointment containing 30% benzyl benzoate was applied on the body from the neck down. However, because a large number of scabies mites were detected again on microscopic examination, the dose of ivermectin was increased to 12 mg and administered 3 times. One week after the sixth dose of ivermectin was administered, hemorrhagic scabs around the mouth and erosion of the tongue developed. Mucosal drug eruption was suspected, and eruptions around the mouth and on the tongue resolved within 1 week after ivermectin being discontinued. 1% gamma-benzene hexachloride ointment was applied topically on the body from the neck down once a week, crotamiton ointment containing benzyl benzoate was applied daily, and the hypertrophic parts of the nails were removed. The patient subsequently achieved a full recovery.

Native tesmin is a 60-kilodalton protein that undergoes dynamic changes in its localization during spermatogenesis in mice.

Tesmin is a testis-specific protein. Four mouse tesmin cDNAs so far reported encode a testis-specific, metallothionein-like, 30-kDa protein (tesmin-30). An antibody against tesmin-30, however, detected a protein of 60 kDa (tesmin-60) from the mouse testis. To resolve the relationship between the two, the immunoprecipitated native tesmin-60 was sequenced. The result indicated that tesmin-30 is not full-length but is part of the C-terminal half of tesmin-60. The full-length cDNA (2.2 kilobases [kb]) encoding tesmin-60 (475 amino acid residues) and its genomic DNA (23 kb) were cloned and sequenced. A search of databases indicated that tesmin is a member of the CXC-hinge-CXC family. Immunohistochemistry indicated that tesmin exhibits dynamic subcellular localization changes during spermatogenesis. Before meiosis, it was localized in the cytoplasm of early to late spermatocytes and then translocated into the nucleus just before meiotic division. After meiosis, it appeared in spermatids, starting from the acrosomal vesicles, moving to the nuclear membrane and then to the caudal end as the spermatids elongated, and finally relocating into the cytoplasm. Oxidative stress by cobalt chloride, as well as by diethylmaleate, induced both premature translocation of tesmin from the cytoplasm to the nucleus and apoptotic signals in spermatocytes. The persistent existence of tesmin and its temporally and spatially dynamic localization suggest that tesmin is involved in multiple stages of spermatogenesis and spermiogenesis, possibly during sperm maturation and/or morphogenesis.