Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities.

Clock genes in the skin exhibit day-night changes in expression; however, whether these changes are brought by external light or intrinsic mechanisms is unclear. In this study, we demonstrated that expression of the clock and clock-controlled genes showed robust rhythms in mouse skin under constant dark conditions, whereas these rhythms were completely lost in Cry1/Cry2 knockout mice lacking a molecular clock. At the cellular level, the main oscillatory protein in the mammalian molecular clock, PER2, was expressed in the nuclei of keratinocytes in the epidermis and hair follicles, with expression peaking at CT16 (subjective dusk), 4-8 hours after expression of its mRNA. These expression patterns in the skin stopped after the ablation of the central clock in the suprachiasmatic nucleus (SCN), which was not recovered even in animals housed in 12 hour-light/12 hour-dark conditions. These findings demonstrate that the intrinsic oscillating molecular clock exists in the epidermis, and that signaling from the SCN is essential for the maintenance of the epidermal clock, and cannot be compensated by external light.

Summary Background  Cosmetic camouflage is important for patients with vitiligo vulgaris. However, few studies have investigated its benefit for vitiligo patients. Objectives  To analyze the psychological effects on patients with vitiligo vulgaris by camouflage lessons performed in vitiligo clinics in Kyoto University Hospital and Fukui Red Cross Hospital, Dermatological Life Quality Index (DLQI) questionnaires were collected before and 1 month after camouflage lessons. Patients  Patients with vitiligo vulgaris, who visited our clinics in 2008 and had never experienced camouflage, were enrolled in this study. They took camouflage lessons and continued subsequent self‐camouflage for 1 month. Control patients took no lessons and no camouflage. Results  Camouflage improved the scores of DLQI when compared with those without camouflage (P = 0.005). Camouflage improved DLQI scores from 5.90 to 4.48. In DLQI subcategories, camouflage lessons improved a subcategory of “symptoms and feelings” (P = 0.0037). Conclusions  These data supported the idea that camouflage for patients with vitiligo not only covers the white patches but also improves their quality of life.

POLH mutations were identified in 16 Japanese patients, who were diagnosed, both clinically and at a cellular level, as being of the xeroderma pigmentosum variant type (XPV). While all the patients developed skin cancer with an average onset of the cancer at 45 years, in non-XP Japanese the onset was at over 70 years. All the cell strains from the patients were normal or slightly hypersensitive to UV and most of these showed enhanced UV sensitivity when the post-UV colony formation was performed in the presence of caffeine. Immunoprecipitation analysis with two kinds of anti-POLH protein antibodies revealed that cells from 13 patients did not show the 83 kDa POLH band and that cells from one patient had a faint 83 kDa band. All of these 14 cell strains, without a POLH band or with a weak POLH band, had mutations in the POLH gene. The IP analysis of the POLH protein revealed a very useful method for screening the patients suspected of XPV. Seven mutations in the POLH gene including three novel mutations were identified. Among the mutations detected, 11 alleles out of 28 (39%) were G490T mutations.

Olaparib (AZD2281) is an orally active Poly(ADP‐ribose) polymerase (PARP) inhibitor with favorable antitumor activity in advanced ovarian and breast cancers with BRCA1/2 mutations in Western (USA and European) studies. This Phase I dose‐finding study evaluated the tolerability, pharmacokinetics, PARP inhibitory activity, and antitumor activity of olaparib in Japanese patients with solid tumors. Olaparib was administered as a single‐dose on day 1, followed by twice‐daily dosing for 28 days from 48 h after a single dose. Doses were escalated from 100 mg b.i.d. in successive cohorts, up to a maximum of 400 mg b.i.d. The present study enrolled 12 patients (n = 3, 3, and 6 in 100, 200 and 400‐mg b.i.d. levels, respectively). The most common adverse events were nausea, increased blood creatinine, decreased hematocrit, leukopenia and lymphopenia; dose‐limiting toxicities were not observed up to and including the 400‐mg b.i.d. dose level. Following twice‐daily dosing, olaparib showed no marked increase in exposure at steady state over that expected from the single‐dose pharmacokinetics. PARP‐1 inhibition was observed from the 100‐mg b.i.d. dose level in peripheral blood mononuclear cells from 6 h post‐dose on day 1 during the multiple‐dosing period. A patient with metastatic breast cancer (100 mg b.i.d.) had a partial response for 13 months and four patients (two each in the 200 and 400‐mg b.i.d. levels) had stable disease >8 weeks. Olaparib was well tolerated up to the 400‐mg b.i.d. dose in Japanese patients with solid tumors. Preliminary evidence of antitumor activity was observed. (Cancer Sci 2012; 103: 504–509)

The Guidelines for the Treatment of Acne Vulgaris of the Japanese Dermatological Association was first published in Japanese in 2008 and revised in 2016 and 2017. These guidelines (GL) indicate the standard acne treatments in Japan and address pharmaceutical drugs and treatments applicable or in use in Japan. In these GL, the strength of the recommendation is based on clinical evidences as well as availability in Japanese medical institutions. In the 2016 and 2017 GL, some of the clinical questions were revised, and other questions were added in accordance with approval of topical medicines containing benzoyl peroxide (BPO). Rather than monotherapies of antibiotics, the 2017 GL more strongly recommend combination therapies, especially fixed-dose combination gels including BPO in the aspects of pharmacological actions and compliance in the acute inflammatory phase to achieve earlier and better improvements. The 2017 GL also indicate to limit the antimicrobial treatments for the acute inflammatory phase up to approximately 3 months and recommend BPO, adapalene, and a fixed-dose combination gel of 0.1% adapalene and 2.5% BPO for the maintenance phase to avoid the emergence of antimicrobial-resistant Propionibacterium acnes. The 2017 GL also discuss rosacea, which requires discrimination from acne and a different treatment plan.

Background:We evaluated the efficacy of aprepitant plus granisetron and an increased dose of dexamethasone in selected patients undergoing moderately emetogenic chemotherapy (MEC).Methods:Nondrinking women <70 years undergoing MEC were randomly assigned to aprepitant (day 1, 125 mg; days 2 and 3, 80 mg) or placebo. Dexamethasone on days 1–3 was 12, 4, and 4 mg with aprepitant and 20, 8, and 8 mg with placebo. The primary end point was complete response (CR; no emesis or rescue therapy) during 120 h of the first cycle. Logistic regression analysis was performed to identify predictors of overall CR.Results:Of the 94 patients enrolled, 91 were assessable. Most received carboplatin-based chemotherapy. In the aprepitant (n=45) and placebo (n=46) groups, the overall, acute (day 1), and delayed (days 2–5) CR rates were 62% and 52%, 98% and 96%, and 62% and 52%, respectively. Although not statistically significant, the overall CR rate was 10% higher in the aprepitant group. Both regimens were well tolerated. On multivariate analysis, advanced ovarian cancer (OR, 0.26 (0.10–0.72)) was independently associated with a lower CR.Conclusion:Even with an increased dose of dexamethasone, aprepitant seemed more effective than placebo in these selected patients undergoing MEC; however, delayed phase management remains a significant problem.

Tumor-infiltrating lymphocytes (TILs) have been reported as a prognostic factor in various cancers and are a promising target for immunotherapy. To investigate whether TILs have any impact on the prognosis of angiosarcoma patients, 55 non-treated patients (40 patients at stage 1 with cutaneous localized tumors, 4 patients at stage 2 with lymph node metastases and 11 patients at stage 3 with distant metastases) with angiosarcoma were evaluated retrospectively by immunohistochemistry stained CD4, CD8, FOXP3 and Ki67. The Kaplan-Meier method was used to estimate overall survival with patients at stage 1. Survival differences were analyzed by the log-rank test. Patients with higher numbers of CD8 1 TILs in their primary tumors survived significantly longer compared with patients with lower values. Moreover, the number of CD8 in TILs was positively correlated with a distant metastasis-free period. The total number of primary TILs (CD4 plus CD8) and CD8 1 primary TILs of stage 3 patients with distant metastases was positively correlated with their overall survival. To evaluate whether CD8 1 effector T cells are activated or differentiated, flow cytometric analysis of peripheral blood mononuclear cells (PBMC) was performed. The percentages of CD8 1 T cells producing IFN-c in PBMC were significantly higher in patients with angiosarcoma (n 5 10) compared not only with that of healthy controls (n 5 20) but also patients with advanced melanoma (n 5 11). These results suggest that anti-tumor immunity is clinically relevant in angiosarcoma.