Two histopathological patterns of postinflammatory hyperpigmentation: epidermal and dermal.

BACKGROUND: Postinflammatory hyperpigmentation (PIH) commonly occurs, but the histopathological features are not well characterized. METHODS: A total of 21 PIH patients' medical charts were reviewed. Punch biopsies from lesional and perilesional normal skin were performed. Sections were stained with hematoxylin-eosin, Fontana-Masson, NKI/beteb, microphthalmia-associated transcription factor (MITF), CD68, c-kit, factor XIIIa, MMP-2 and MMP-9. RESULTS: Fontana-Masson-stained sections suggested two obvious PIH groups: epidermal (13 cases) and dermal (8 cases) pigmentation. The epidermal pigment group had increased epidermal basal pigmentation. The dermal pigment group had marked pigmentation within the upper dermis and decreased epidermal pigmentation. More intense perivascular lymphocytic infiltration was observed in the dermal pigment group. NKI/beteb levels were increased in lesional skin in both groups. The numbers of MITF+ melanocytes were not different between lesional and perilesional normal skin in either group. The expression of CD68 and c-kit was significantly higher in the dermis of lesional skin than in normal skin in the dermal pigment group. MMP-2 expression was upregulated in lesional skin in both groups. CONCLUSION: PIH patients can be classified into two histopathological groups: epidermal and dermal pigmentation. The dermal pigment group showed decreased levels of epidermal pigmentation. This study provides histopathological information that can improve the treatment of PIH.

A comparative study on hulled adlay and unhulled adlay through evaluation of their LPS-induced anti-inflammatory effects, and isolation of pure compounds.

Coicis semen (=the hulled seed of Coix lacryma-jobi L. var. ma-yuen (Rom.Caill.) Stapf; Gramineae), commonly known as adlay and Job's tears, is widely used in traditional medicine and as a nutritious food. Bioassay-guided fractionation of the AcOEt fraction of unhulled adlays, using measurement of nitric oxide (NO) production on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells, led to the isolation and identification of two new stereoisomers, (+)-(7'S,8'R,7″S,8″R)-guaiacylglycerol ß-O-4'-dihydrodisinapyl ether (1) and (+)-(7'S,8'R,7″R,8″R)-guaiacylglycerol ß-O-4'-dihydrodisinapyl ether (2), together with six known compounds, 3-8. Compounds 3 and 4 exhibited inhibitory activities on LPS-induced NO production with IC50 values of 1.4 and 3.7 µM, respectively, and suppressed inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expressions in RAW 264.7 macrophage cells. Simple high-performance liquid chromatography with ultraviolet detection (HPLC/UV) was used to compare the AcOEt fraction of unhulled adlays responsible for the anti-inflammatory activity in RAW 264.7 cells and the inactive AcOEt fraction of hulled adlays.

Ultrasonographic features of the skin and subcutis: correlations with the severity of breast cancer-related lymphedema.

PURPOSE: Assessing the severity of breast cancer-related lymphedema (BCRL) requires various clinical tools, yet no standardized methodology is available. Ultrasonography shows promise for diagnosing lymphedema and evaluating its severity. This study explored the clinical utility of ultrasonography in patients with BCRL. METHODS: In this retrospective cross-sectional study, patients with unilateral BCRL were examined. The analyzed data included demographics, lymphedema location, International Society of Lymphology (ISL) stage, surgical history, treatment regimens, and arm circumference. Skin, subcutis, and muscle thicknesses were assessed ultrasonographically at predetermined sites, and the percentage of excess thickness was calculated. Multivariate logistic regression analysis was employed to identify associations between ultrasonographic measurements and advanced lymphedema (ISL 2 or 3). The Lymphedema Quality of Life arm questionnaire was used to evaluate patient-reported outcomes regarding lymphedema and their correlations with ultrasonographic findings. RESULTS: Among 118 patients, 71 were classified as ISL 0-1 and 47 as ISL 2-3. Patients with advanced lymphedema were older, had higher nodal stages, underwent more axillary lymph node dissections, and had higher rates of dominant-arm lymphedema. Multivariate logistic regression revealed significant associations of greater skin thickness (adjusted odds ratio [OR], 4.634; 95% confidence interval [CI], 1.233 to 17.419), subcutis thickness (adjusted OR, 7.741; 95% CI, 1.649 to 36.347), and subcutis echogenicity (adjusted OR, 4.860; 95% CI, 1.517 to 15.566) with advanced lymphedema. Furthermore, greater skin thickness (P=0.016) and subcutis echogenicity (P=0.023) were correlated with appearance-related discomfort. CONCLUSION: Ultrasonographic measurements were significantly associated with advanced lymphedema in BCRL. Ultrasonography represents a valuable diagnostic and severity assessment tool for lymphedema.

A computational framework to in silico screen for drug-induced hepatocellular toxicity.

Drug-induced liver injury (DILI) is the most common trigger for acute liver failure and the leading cause of attrition in drug development. In this study, we developed an in-silico framework to screen drug-induced hepatocellular toxicity (INSIGHT) by integrating the post-treatment transcriptomic data from both rodent models and primary human hepatocytes. We first built an early prediction model using logistic regression with elastic net regularization for 123 compounds and established the INSIGHT framework that can screen for drug-induced hepatotoxicity. The 235 signature genes identified by INSIGHT were involved in metabolism, bile acid synthesis, and stress response pathways. Applying the INSIGHT to an independent transcriptomic dataset treated by 185 compounds predicted that 27 compounds show a high DILI risk, including zoxazolamine and emetine. Further integration with cell image data revealed that predicted DILI compounds can induce abnormal morphological changes in the endoplasmic reticulum (ER) and mitochondrion. Clustering analysis of the treatment-induced transcriptomic changes delineated distinct DILI mechanisms induced by these compounds. Our study presents a computational framework for a mechanistic understanding of long-term liver injury and the prospective prediction of DILI.

UBX-390: A Novel Androgen Receptor Degrader for Therapeutic Intervention in Prostate Cancer.

The androgen receptor (AR) is an attractive target for treating prostate cancer, considering its role in the development and progression of localized and metastatic prostate cancer. The high global mortality burden of prostate cancer, despite medical treatments such as androgen deprivation or AR antagonist therapy, highlights the need to explore alternative strategies. One strategy involves the use of heterobifunctional degraders, also known as proteolysis-targeting chimeras, which are novel small-molecule therapeutics that inhibit amplified or mutated targets. Here, the study reports a novel cereblon-based AR degrader, UBX-390, and demonstrates its superior activity over established AR degraders, such as ARV-110 or ARCC-4, in prostate cancer cells under short- and long-term treatment conditions. UBX-390 suppresses chromatin binding and gene expression of AR and demonstrates substantial efficacy in the degradation of AR mutants in patients with treatment-resistant prostate cancer. UBX-390 is presented as an optimized AR degrader with remarkable potential for treating castration-resistant prostate cancer.

Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models.

Bruton tyrosine kinase (BTK) is an important signaling hub that activates the B-cell receptor (BCR) signaling cascade. BCR activation can contribute to the growth and survival of B-cell lymphoma or leukemia. The inhibition of the BCR signaling pathway is critical for blocking downstream events and treating B-cell lymphomas. Herein, we report potent and orally available proteolysis-targeting chimeras (PROTACs) that target BTK to inactivate BCR signaling. Of the PROTACs tested, UBX-382 showed superior degradation activity for wild-type (WT) and mutant BTK proteins in a single-digit nanomolar range of half-maximal degradation concentration in diffuse large B-cell lymphoma cell line. UBX-382 was effective on 7 out of 8 known BTK mutants in in vitro experiments and was highly effective in inhibiting tumor growth in murine xenograft models harboring WT or C481S mutant BTK-expressing TMD-8 cells over ibrutinib, ARQ-531, and MT-802. Remarkably, oral dosing of UBX-382 for <2 weeks led to complete tumor regression in 3 and 10 mg/kg groups in murine xenograft models. UBX-382 also provoked the cell type-dependent and selective degradation of cereblon neosubstrates in various hematological cancer cells. These results suggest that UBX-382 treatment is a promising therapeutic strategy for B-cell-related blood cancers with improved efficacy and diverse applicability.

Novel herbal medicine LA16001 ameliorates cisplatin-induced anorexia.

Chemotherapy frequently causes anorexia in cancer patients, which has been associated with poor disease prognosis. Several therapeutic strategies for the treatment of chemotherapy­induced anorexia are available; however, their adverse effects limit their clinical use. Herbal medicines have a long history of use for the treatment of various diseases, including cancer, and recent research has demonstrated their safety and efficacy. In the present study, combinations of herbal medicines were designed based on traditional Korean medicine, and their effects were investigated on chemotherapy­induced anorexia. Herbal mixtures were extracted, composed of Atractylodes japonica, Angelica gigas, Astragalus membranaceus, Lonicera japonica Thunb., Taraxacum platycarpum H. Dahlstedt and Prunella vulgaris var. asiatica (Nakai) Hara. The mixtures were termed LCBP­Anocure­16001­3 (LA16001, LA16002, LA16003). A cisplatin­induced anorexic mouse model was used to evaluate the putative effects of the extracts on chemotherapy­induced anorexia. Treatment with LA16001 was revealed to prevent body weight loss, and all three extracts were demonstrated to improve food intake. When the molecular mechanisms underlying the orexigenic effects of LA16001 were investigated, altered expression levels of ghrelin, leptin and interleukin­6 were revealed. Furthermore, LA16001 was reported to induce phosphorylation of Janus kinase 1 and signal transducer and activator of transcription 3. In addition, LA16001 administration increased the number of white blood cells and neutrophils. These results suggested that the herbal formula LA16001 may be able to prevent chemotherapy­induced anorexia and may have potential as a novel therapeutic strategy for the adjuvant treatment of patients with cancer.

Erratum: Neutrophilic Dermatosis Confined to the Lymphedematous Area.

[This corrects the article on p. 411 in vol. 26, PMID: 24966650.].

Daurinol blocks breast and lung cancer metastasis and development by inhibition of focal adhesion kinase (FAK).

FAK overexpression has been reported in diverse primary and metastatic tumor tissues, supporting its pro-tumorigenic and pro-metastatic roles. Therefore, we have developed a neo-treatment strategy using daurinol to effectively treat cancer metastasis. Daurinol blocked cancer cell migration and invasion in vitro and exhibited anti-metastatic activity in an experimental metastasis model of breast and lung cancer. Daurinol selectively inhibited phosphorylation of FAK at Tyr925, Tyr576/577, and Tyr397 sites in a dose- and time-dependent manner. Daurinol effectively suppressed migration and invasion of MDA-MB-231 and A549 cancer cells. These data were associated with inhibition of expression and secretion of invasion factors, including matrix metalloproteinase (MMP) 2, MMP9, and urokinase plasminogen activator (uPA). Consistent with these in vitro results, daurinol (10 mg/kg; Oral gavage) effectively inhibited breast and lung cancer metastasis in a mouse model. In addition, daurinol showed strong suppressive activity of cell survival as revealed by colony formation assays. Analysis of cellular phenotypes revealed that inhibition of FAK phosphorylation in cancer cells limited colony formation, cell migration, and invasion, thereby reducing the cell proliferation rate. Furthermore, daurinol significantly reduced tumor development in 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK)/benzo(a)pyrene (BaP)-treated A/J mice. Our results suggest that daurinol suppresses lung metastasis through inhibition of migration and survival via blockade of FAK activity.

Increased blood flow and vasculature in solar lentigo.

Solar lentigo (SL) is a hallmark of ultraviolet (UV)-induced photoaged skin and growing evidence implicates blood vessels in UV-associated pigmentation. In this study, we investigated whether the vasculatures are modified in SL. Twenty-five women with facial SL were enrolled and colorimetric and blood flow studies were performed. There was a significant increase in erythema which was associated with increased blood flow in the lesional skin compared with perilesional normal skin. Immunohistochemical studies with 24 facial SL biopsies consistently revealed a significant increase in vessel density accompanied by increased levels of vascular endothelial growth factor expression. CD68 immunoreactivity was significantly higher in lesional skin suggesting increased macrophage infiltration in SL. In conclusion, SL is characterized by increased blood flow and vasculature. These findings suggest the possible influence of the characteristics of vasculature on development of SL.

Bilateral iliac and popliteal arterial thrombosis in a child with focal segmental glomerulosclerosis.

Thromboembolic complications (TECs) are clinically important sequelae of nephrotic syndrome (NS). The incidence of TECs in children is approximately 2%-5%. The veins are the most commonly affected sites, particularly the deep veins in the legs, the inferior vena cava, the superior vena cava, and the renal veins. Arterial thrombosis, which is less common, typically occurs in the cerebral, pulmonary, and femoral arteries, and is associated with the use of steroids and diuretics. Popliteal artery thrombosis in children has been described in cases of traumatic dissection, osteochondroma, Mycoplasma pneumoniae infection, and fibromuscular dysplasia. We report of a 33-month-old girl with bilateral iliac and popliteal arterial thrombosis associated with steroid-resistant NS due to focal segmental glomerulosclerosis. Her treatment involved thrombectomy and intravenous heparinization, followed by oral warfarin for 8 months. Herein, we report a rare case of spontaneous iliac and popliteal arterial thrombosis in a young child with NS.

A single nanoparticle-based sensor for hydrogen peroxide (H2O2) via cytochrome c-mediated plasmon resonance energy transfer.

Herein, we report a novel method for H2O2 detection based on a single plasmonic nanoprobe via cytochrome c (Cyt c)-mediated plasmon resonance energy transfer (PRET). Dynamic spectral changes were observed in the fingerprint quenching dip of a single plasmonic nanoprobe in response to changes in the redox state of Cyt c, induced by H2O2. Based on the changes in the spectral profile of the single plasmonic nanoprobe, H2O2 was successfully detected in a wide concentration range from 100 mM to 10 nM, including physiologically relevant micromolar and nanomolar concentrations.

Pleiotrophin inhibits melanogenesis via Erk1/2-MITF signaling in normal human melanocytes.

Pleiotrophin (PTN) is a secreted heparin-binding protein that is involved in various biological functions of cell growth and differentiation. Little is known about the effects of PTN on the melanocyte function and skin pigmentation. In this study, we investigated whether PTN would affect melanogenesis. PTN was expressed in melanocytes and fibroblasts of human skin. Transfection studies revealed that PTN decreased melanogenesis, probably through MITF degradation via Erk1/2 activation in melanocytes. The inhibitory action of PTN in pigmentation was further confirmed in ex vivo cultured skin and in the melanocytes cocultured with fibroblasts. These findings suggest that PTN is a crucial factor for the regulation of melanogenesis in the skin.

Clinical Experience of Interferon Alfa-2a Treatment for Refractory Uveitis in Behçet's Disease.

Behçet's disease (BD) involves multisystem vasculitis of unknown origin. Ocular manifestations of BD mostly include bilateral panuveitis and retinal vasculitis, which are very challenging to treat. Interferon alfa-2a (IFN) has been recently introduced for treating refractory Behçet uveitis, mainly in Germany and Turkey. Nonetheless, there is so far no consensus about the ideal treatment regimen of IFN for Behçet uveitis. We report our experience of IFN treatment in five Korean BD patients with refractory uveitis. All patients complained of oral ulcers; one patient had a positive pathergy test and 2 showed the presence of HLA-B51. Immunosuppressive agents used prior to IFN treatment included cyclosporine and methotrexate. The IFN treatment was commenced with a dose of 6-9 MIU/day for 7 days, adjusted according to individual ocular manifestations, tapered down to 3 MIU three times in a week, and then discontinued. All patients showed positive response to IFN treatment; 50% of them showed complete response without additional major ocular inflammation during the follow-up period. Other BD symptoms also improved after IFN treatment in most cases. After treatment, the relapse rate and the required dose of oral corticosteroid were decreased in most cases, showing a significant steroid-sparing effect. However, the visual acuity was not improved in most cases due to irreversible macular sequelae. Despite the small sample size of this study, we suggest that, in Korean patients, IFN is an effective treatment modality for BD uveitis as was observed in German and Turkish patients.

Photodynamic therapy with ablative carbon dioxide fractional laser for treating Bowen disease.

BACKGROUND: Topical photodynamic therapy (PDT) has been increasingly used to treat malignant skin tumors including the Bowen disease. However, patients could be displeased with the long incubation time required for conventional PDT. OBJECTIVE: We evaluated the efficacy and safety of PDT with a short incubation time of ablative CO2 fractional laser pretreatment for treating Bowen disease. METHODS: Ten patients were included. Just before applying the topical photosensitizer, all lesions were treated with ablative CO2 fractional laser, following the application of methyl aminolevulinate and irradiation with red light (Aktilite CL 128). Histological confirmation, rebiopsy, and clinical assessments were performed. Adverse events were also recorded. RESULTS: Five of the ten (50%) lesions showed a complete response (CR) within three PDT sessions. After four treatment sessions, all lesions except one penile shaft lesion (90%) achieved clinical and histological CR or clinical CR only. The average number of treatments to CR was 3.70±1.70. The treatments showed favorable cosmetic outcomes and no serious adverse events. CONCLUSION: The results suggest that pretreatment with an ablative fractional CO2 laser before PDT has similar treatment efficacy and requires a shorter photosensitizer incubation time compared with the conventional PDT method.

Ultrastructural changes in photorejuvenation induced by photodynamic therapy in a photoaged mouse model.

BACKGROUND: Photoaging is defined as premature aging of the skin induced by ultraviolet (UV) irradiation. Photodynamic therapy (PDT) has been shown to be a non-invasive but effective technique for photoaged skin. OBJECTIVE: We observed histological and ultrastructural changes of photoaging and photorejuvenating effects of 5-aminolevulinic acid (ALA)-PDT in a UV-irradiated mice model. METHODS: A total of 20 mice were divided into a control (group A) group and a UV-irradiated (photoaging) group. The photoaging group was divided according to the following interventions: photoaging only (group B), ALA application only (group C), light-emitting diode (LED) irradiation only (group D), and ALA-PDT with a light dose of 20 J/cm(2) (group E). Serial skin biopsies were performed from day 2 to day 21, and transmission electron microscopic (TEM) studies were performed. RESULTS: After UV irradiation, the amount of dermal collagen fibers decreased, and the quantity of elastotic materials increased. Following ALA-PDT application, the amount of collagen fibers increased from day 2 to day 21 and the increased elastotic materials during the photoaging period were normalized. With TEM, the decreased collagen fibers during photoaging were restored after PDT application. Also, distended dermal fibroblasts with distended endoplasmic reticulum by UV irradiation were normalized after PDT application. CONCLUSION: This study provides histologic evidence of the beneficial effects of ALA-PDT, even in photodamaged skin. ALA-PDT induces deposition of collagen in the dermis, normalizes elastotic materials which were induced by photoaging and may even have a direct effect on the normalization of the morphology of fibroblasts.

Huge Bowen's disease: a pitfall of topical photodynamic therapy.

Bowen's disease (BD) is one of the major histological types of nonmelanoma skin cancer. With challengeable "multiple and large" patches of BD, topical photodynamic therapy (PDT) has been considered as a first-line effective modality for decades. However, there was no general consensus among authors about the definition of "large BD". Herein, we have experienced two cases of huge BD which has over 10 cm in diameter with resistance to topical PDT. Our cases suggest that topical PDT is likely to show a much less satisfactory effect for huge BD than we have expected, and the previously specified indication of topical PDT ("multiple, larger lesion") seems the fallacy of hasty generalization. Therefore, it is required that further cut-off value of size for suitable candidate for topical PDT would be clarified.

Effects of Xanthium stramarium and Psoralea corylifolia Extracts Combined with UVA1 Irradiation on the Cell Proliferation and TGF-ß1 Expression of Keloid Fibroblasts.

BACKGROUND: Xanthium stramarium (XAS) and Psoralea corylifolia (PSC), phototoxic oriental medicinal plants, has been used in traditional medicines in Asian countries. OBJECTIVE: The effects of highly purified XAS or PSC extract combined with ultraviolet A1 (UVA1) irradiation on cell proliferation and transforming growth factor-beta1 (TGF-ß1) expression of the keloid fibroblast were being investigated to define potential therapeutic uses for keloid treatments. METHODS: The keloid fibroblasts were treated with XAS or PSC alone or in the combination with UVA1 irradiation. The cell viability, apoptosis, and expression of TGF-ß1 and collagen I were investigated. RESULTS: XAS and PSC in combination with UVA1 irradiation suppressed cell proliferation and induced apoptosis of keloid fibroblasts. Furthermore, the XAS and PSC in combination with UVA1 irradiation inhibited TGF-ß1 expression and collagen synthesis in keloid fibroblasts. CONCLUSION: These findings may open up the possibility of clinically used XAS or PSC in combination with UVA1 irradiation for keloid treatments.