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BACKGROUND: Triple negative breast cancer (TNBC), accounting for 15% of all breast cancer cases, was usually considered as the most aggressive subtype. The present study evaluated the prognosis of T1a TNBC and the impact of tumor size on T1 TNBC survival in large-scale population. METHODS: This retrospective study enrolled T1a/T1b/T1c TNBC and HER2(+)/hormone receptor (HoR)(−) patients diagnosed between 2010 to 2012 from the Surveillance, Epidemiology, and End Results database. The following information was extracted for further analyses: demographic variables including age at diagnosis, race, marital status, laterality, histological grade, T/N stage, American Joint Committee on Cancer (AJCC) stage, radiation therapy, survival and cause of death. Kaplan-Meier method and Cox regression were engaged for breast cancer specific survival (BCSS) and overall survival (OS) analyses. RESULTS: In all, the present study enrolled 6,953 TNBC and 2,648 HER2(+)/HoR(−) patients. T1a TNBC which generally omitted adjuvant chemotherapy had worse prognosis than T1a HER2(+)/HoR(−) [BCSS: hazard ratio (HR) 3.23, 95% confidence interval (CI): 1.05–9.09, P=0.03; OS: HR 2.63, 95% CI: 1.25–5.56, P=0.01] and T1b HER2(+)/HoR(−) (BCSS: HR 5.26, 95% CI: 1.61–16.7, P=0.006; OS: HR 3.03, 95% CI: 1.27–7.14, P=0.013) tumors which both were recommended by the National Comprehensive Cancer Network (NCCN) guideline to have chemotherapy. T1a TNBC also showed a trend with poorer prognosis than T1b TNBC, but did not reach statistical significance. CONCLUSIONS: T1a TNBC had the worst prognosis among all small tumors (

Background: Non-alcoholic fatty liver disease (NAFLD) was a common disease and a frequent side effect of endocrine therapy for breast cancer patients. This was the first meta-analysis to investigate the impact of NAFLD on breast cancer survival. Material and Methods: We searched Pubmed, Embase and Cochrane Central Register of Controlled Trials database for relevant studies that investigated the correlation between NAFLD and breast cancer survival. Fixed- and random-effect meta-analyses were conducted according to the heterogeneity of enrolled studies. Subgroup analyses were based on whether NAFLD was induced by Selective-estrogen receptor modulator (SERM) administration. Results: Six cohorts from five studies including 935 NAFLD and 2102 non-NAFLD patients were enrolled. NAFLD was significantly associated with advanced age (p< 0.001), obesity (p< 0.001), lymph node metastasis (p = 0.003), hormone receptor positivity (p < 0.001) and human epidermal growth factor receptor 2 positivity (p = 0.008). NAFLD had no significant impact on disease free survival(DFS) [hazard ratio (HR) 0.95, 95% confidence interval (CI) = 0.48-1.87, p = 0.87] and overall survival (OS) (HR 1.28, 95% CI = 0.59-2.78, p = 0.53). In subgroup analyses, SERM-associated NAFLD showed no significant impact on DFS and OS. Nonetheless, non-SERM-associated NAFLD had a strong prognostic correlation with poor OS (HR 1.92, 95% CI = 1.09-2.06, p = 0.02). Conclusion: NAFLD had no significant impact on breast cancer survival. However, non-SERM-associated NAFLD implied increasing death risk. Future large-scale studies are warranted to further elucidate the correlation between NAFLD and breast cancer prognosis. Keywords: breast cancer; non-alcoholic fatty liver disease; selective estrogen receptor modulator; liver metastasis TABLES Table 1. Characteristics of studies enrolled in meta-analysisStudyCountryDesignNMedian follow-up (month)TNM StageNAFLD AssessmentLiver Metastasis AssessmentClinical EndpointsHormone ReceptorRelationship Between SERM-treatment and NAFLDDuran(2015)TurkeyRC107NAIVContrast-enhanced/ Non-Contrast CTNAOSNANon-SERM-associated NAFLDYan(2017)ChinaRC64664(7-91)I-IIIUSGUSGDFS, OSER+ and/or PR+SERM-associated NAFLDWu(2017)ChinaRC123030.7±24.9 32.4±26.3I-IIIUSGUSG/CT/MRILiver-MFSER/PR+799 ER/PR- 331NAZheng(2015)ChinaRC78576(14-122)I-IIIUSGNADFS, OSER/PR+SERM-associated NAFLDYang(2015) Cohort A*KoreaRC28NAII/IIIUSG/ Non-Contrast CT/ Contrast CTNADFS, OSNANon-SERM-associated NAFLDYang(2015) Cohort B*KoreaRC24NAII/IIIUSG/ Non-Contrast CT/ Contrast CTNADFS, OSNANon-SERM-associated NAFLDRC, retrospective cohort; NA, not available; CT, computed tomography; OS, overall survival; DFS, disease free survival; SERM, selective estrogen receptor modular; USG, ultrasonography; MRI, Magnetic resonance imaging; MFS, metastasis free survival.*Study by Yang et al. included two cohorts Table 2. Correlation Between NAFLD Presence and Clinicopathological FeaturesNAFLD(%)Non-NAFLD(%)P valueAge (years)50397(32.4%)829(67.6)BMI (kg/m2)25320(43.2%)421(56.8%)Tumor Size (mm)5080(30.3%)184(69.7%)LN MetastasisYes540(40.9%)780(59.1%)0.003*No281(36.6%)486(63.4%)MenopausePre153(33.5%)304(66.5%)0.766Post96(32.4%)200(85.9%)ER/PR StatusER/PR +630(34.9%)1173(65.1%) Citation Format: Yu Song, Changjun Wang, Wei Huang, Yidong Zhou, Ziyuan Chen, Hanjiang Zhu, Feng Mao, Yan Lin, Xiaohui Zhang, Songjie Shen, Ying Zhong, Xin Huang, Chang Chen, Qiang Sun. The impact of pre-existed and SERM-induced non-alcoholic fatty liver disease on breast cancer survival: A meta-analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-14.

Background: Non-alcoholic fatty liver disease (NAFLD) is a common disorder and a frequent side effect of endocrine therapy (ET) for breast cancer treatment. This was the first meta-analysis to investigate the impact of NAFLD on breast cancer survival. Material and Methods: We searched Pubmed, Embase and Cochrane Central Register of Controlled Trials database for relevant studies that investigated the correlation between NAFLD and breast cancer survival. Fixed- and random-effect meta-analyses were conducted according to the heterogeneity of enrolled studies. Subgroup analyses were performed based on whether NAFLD was induced by ET administration Results: Eight cohorts from six studies including 3684 breast cancer patients were enrolled. NAFLD was significantly associated with advanced age (p < 0.001), obesity (p < 0.001), lymph node metastases (p = 0.003) and hormone receptor positivity (p < 0.001). NAFLD had no significant impact on disease free survival (DFS) [hazard ratio (HR) 1.07, 95% confidence interval (CI) = 0.64-1.77, p = 0.81] and overall survival (OS) (HR 1.29, 95% CI = 0.68-2.44, p = 0.44). In subgroup analyses, ET-associated NAFLD showed no significant impact on DFS and OS. Nonetheless, non-ET-associated NAFLD had a strong prognostic correlation with poor OS (HR 1.92, 95% CI = 1.09-3.41, p = 0.02). Conclusion: NAFLD had no significant impact on breast cancer survival. However, non-ET-associated NAFLD implied increasing death risk. Future large-scale studies are warranted to further elucidate the correlation between NAFLD and breast cancer prognosis.

This study compared the efficiency for in vitro human skin decontamination using DDGel and RSDL. Experiments were performed using in vitro human skin models, in which skin was mounted onto Flow-Through diffusion cells. The mass of 14-C CEES removed from skin surface after decontamination was quantitated by measuring radioactivity with a liquid scintillation spectrometer. Both decontaminants removed more than 82% of CEES from skin. DDGel skin decontamination significantly reduced toxicant amount when compared to RSDL. Mean CEES remaining in stratum corneum (SC), viable epidermis, dermis, and systemic absorption of DDGel and RSDL were, 0.12 and 0.55% (P

Ying Zou,1,2,* Anna Celli,2,3,* Hanjiang Zhu,2,* Akram Elmahdy,2 Yachao Cao,2 Xiaoying Hui,2 Howard Maibach2 1Skin & Cosmetic Research Department, Shanghai Skin Disease Hospital, Shanghai, People’s Republic of China; 2Department of Dermatology, School of Medicine, University of California San Francisco, San Francisco, CA, USA; 3SanFrancisco Veterans Medical Center, San Francisco, CA, USA *These authors contributed equally to this work Objective: With rapid development of nanotechnology, there is increasing interest in nanoparticle (NP) application and its safety and efficacy on human skin. In this study, we utilized confocal laser scanning microscopy to estimate NP skin penetration.Methods: Three different-sized polystyrene NPs marked with red fluorescence were applied to human skin, and Calcium Green 5N was used as a counterstain. Dimethyl sulfoxide (DMSO) and ethanol were used as alternative vehicles for NPs. Tape stripping was utilized as a barrier-damaged skin model. Skin biopsies dosed with NPs were incubated at 4°C or 37°C for 24hours and imaged using confocal laser scanning microscopy.Results: NPs were localized in the stratum corneum (SC) and hair follicles without penetrating the epidermis/dermis. Barrier alteration with tape stripping and change in incubation temperature did not induce deeper penetration. DMSO enhanced NP SC penetration but ethanol did not.Conclusion: Except with DMSO vehicle, these hydrolyzed polystyrene NPs did not penetrate intact or barrier-damaged human “viable” epidermis. For further clinical relevance, in vivo human skin studies and more sensitive analytic chemical methodology are suggested. Keywords: nanoparticles, skin penetration, stratum corneum, confocal laser scanning microscopy, tape stripping

Clinical Treatment Score post-5 years (CTS5) is a promising prognostic tool to evaluate late recurrence risk for breast cancer. Our study aimed to validate its prognostic value in large-scale population and explore the impact of menopausal and HER2 status on CTS5 model. We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database. Survival analyses were conducted to assess the prognostic value of CTS5 in different breast cancer subgroups in terms of overall survival (OS) and breast cancer specific survival (BCSS) after five years. A total of 23,168 breast cancer patients with positive hormone receptor (HoR) were enrolled. Postmenopausal and premenopausal patients were 13,686 and 9,482, respectively. Taking CTS5 score as a continuous variable, it had significant positive correlation with poor prognosis beyond five years in both postmenopausal and premenopausal subgroups. Nevertheless, for HER2+ postmenopausal patients, the model has less effective prognostic value on long-term BCSS [HR1.177 (95%CI 0.960–1.443), p = 0.117]. Using CTS5 score as a categorical variable, HER2- patients with high-risk level revealed significant poor survival in terms of both BCSS and OS, irrespective of menopausal status. Our study showed the CTS5 model could be a useful prognostic tool for predict long-term survival in HoR+/HER2- patients. And further large-scale studies are warranted to assess its prognostic value for HER2+ patients and develop novel prediction model for late recurrence risk estimation.

Additional file 1.

This in vitro skin study determined absorption, diffusion, and binding rates of four [14C]-labeled nanoparticles (NPs): 12 nm Fe3O4, 32 nm Fe3O4@SiO2, 33 nm SiO2, and 78 nm SiO2 in each layer of human cadaver skin. In vitro microdialysis device and flow-through skin diffusion system were used to measure the binding affinity to the stratum corneum (SC) and permeability into/through skin layer of the four NPs with different physical–chemical properties, respectively, in short (30 min) and/or long (24 hours) exposures. Results show that NP size is an important factor affecting NP percutaneous absorption. The 12 nm Fe3O4 NPs reached the SC and viable epidermis; 32 nm Fe3O4@SiO2 core/shell NPs only reached SC. However, 33 nm and 78 nm silica NPs did not permeate SC. Similar patterns were observed for NP binding affinity to SC and dermatopharmacokinetic analysis using the tape stripping method. The binding affinity determination may be a useful method to efficiently screen skin penetration of NPs.

This study determined ME1111 onychopharmacokinetics and possible topical antifungals' clinical efficacy in human great toenails using an in vitro finite dose model. ME1111 topical formulations in 1, 5, 10 or 15% for 3 days observation and 1, 5 or 10% for 14 days observation, respectively, were used to determine ME1111 penetration rate and transungual kinetics. ME1111 concentrations in the deeper nail (ventral/intermediate layers) and a cotton pad/nail bed, were several orders of magnitude greater than MIC90 and MFC90 for three major dermatophytes. ME1111 concentrations 3 days after a single and 14 days after multiple dosing of 10% formulation were 253 and 7991 μg/g nail, respectively, and superior to those of 8% ciclopirox control. ME1111 concentration (μg equivalent/cm3) in the cotton pad following 10% ME1111 multiple applications increased linearly throughout the 336 h experiment and was significantly greater than that of 8% ciclopirox. Flux rate of ME1111 averaged as 50.9 μg/cm3/day, which was ca. two orders of magnitude greater than the MIC90 values. The novel antifungal ME1111 penetrated well into human nail plate and its concentrations in the deeper nail and cotton pad after application of 10% formulation were significantly greater than those of ciclopirox.

// Changjun Wang 1, * , Bo Pan 1, * , Hanjiang Zhu 2 , Yidong Zhou 1 , Feng Mao 1 , Yan Lin 1 , Qianqian Xu 1 , Qiang Sun 1 1 Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China 2 Department of Dermatology, University of California, San Francisco, CA, USA * These authors have contributed equally to this work Correspondence to: Qiang Sun, email: sunqiangpumch@sina.com Keywords: androgen receptor, breast cancer, triple negative breast cancer, prognostic value, meta-analysis Received: April 12, 2016 Accepted: June 03, 2016 Published: June 21, 2016 ABSTRACT Background: Androgen receptor (AR) is a promising therapeutic target for breast cancer. However, its prognostic value remains controversial in triple negative breast cancer (TNBC). Here we present a meta-analysis to investigate the correlation between AR expression and TNBC prognosis. Results: Thirteen relevant studies with 2826 TNBC patients were included. AR positive rate was 24.4%. AR+ patients tended to have lower tumor grade ( p < 0.001), but more lymph node metastases ( p < 0.01). AR positivity was associated with prolonged disease free survival (HR 0.809, 95% CI = 0.659-0.995, p < 0.05), but had no significant impact on overall survival (HR 1.270, 95% CI=0.904-1.782, p = 0.168). No difference in survival existed between subgroups using different AR or estrogen receptor cutoff values. Materials and methods: Literature search was performed in Pubmed, Embase and Cochrane Central Register of Controlled Trials databases to identify relevant articles on AR and TNBC prognosis. Fixed- and random-effect meta-analyses were conducted based on the heterogeneity of included studies. Heterogeneity and impacts of covariates were further evaluated by subgroup analyses and meta-regression. Conclusion: AR positivity is associated with lower risk of disease recurrence in TNBC. Further clinical studies are warranted to clarify its prognostic role on TNBC recurrence and survival.

Background: Apocrine carcinoma was a rare subtype of breast cancer. Due to its rarity and lack of standardized diagnostic criteria, there was no consensus on its biological behaviors. The present study retrospectively analyzed the Surveillance, Epidemiology, and End Results (SEER) database to clarify the impact of apocrine feature on breast cancer prognosis. Materials and Methods: Patient data for invasive apocrine (aBC), mucinous (mBC) or ductal (IDC) breast cancer between 2010 and 2012 were obtained from SEER program. Kaplan-Meier method and Cox proportion hazard regression were adopted for breast cancer-specific survival (BCSS) and overall survival (OS) analyses. Results: There were totally 306 aBC, 2733 mBC and 120127 IDC enrolled. Compared with IDC, aBC tended to occur in elderly patients with higher histological grade, more triple-negative breast cancer (TNBC) and less radiation therapy. Except univariate analysis revealed aBC had shortened BCSS than mBC (HR 5.020, p< 0.001), neither mBC nor IDC revealed BCSS or OS advantage over aBC. As for TNBC, aBC was associated with prolonged BCSS (univariate: HR 0.329, p = 0.020; multivariate: HR 0.183, p = 0.017) and OS (univariate: HR 0.445, p = 0.028; multivariate: HR 0.338, p = 0.016) over IDC. This finding was consistent with the results for hormone receptor negative breast cancers. Conclusion: aBC had the trend with worse BCSS than mBC and comparable prognosis as IDC. Morphological apocrine features indicated favorable prognosis for TNBC and hormone receptor negative subtype. Future studies were warranted to further evaluate the prognostic value of different histological types. Table 1. Clinicopathological characteristics of patients with aBC and IDCCharacteristicsaBC (N=306)IDC (N=120127)p value cMedian Follow-up (months)(IQR)22.0 (10.0-35.8)21.0 (10.0-33.0)Age (Mean ± SD)60.7 ± 11.357.8 ± 11.8< 0.001RaceWhite225 (73.8%)93483 (78.3%)0.108Black39 (12.8%)13690 (11.5%)Others a41(13.4%)12145 (10.2%)Marital StatusMarried166 (57.2%)70109 (61.4%)0.164Not Married b124 (42.8%)44086 (38.6%)LateralityLeft136 (44.4%)60705 (50.5%)0.038Right170 (55.6%)59410 (49.5%)GradeI19 (6.4%)24345 (20.8%)< 0.001II159 (53.9%)48323 (41.3%)III / IV117 (39.7%)44294 (37.9%)AJCC StageI154 (50.3%)64223 (53.5%)0.334II109 (35.6%)41978 (34.9%)III43 (14.1%)13926 (11.6%)T StageT1187 (61.1%)75070 (62.5%)0.358T289 (29.1%)36385 (30.3%)T319 (6.2%)5755 (4.8%)T411 (3.6%)2917 (2.4%)N StageN0202 (66.0%)81605 (68.0%)0.589N173 (23.9%)28830 (24.0%)N220 (6.5%)6413 (5.3%)N311 (3.6%)3228 (2.7%)Molecular SubtypeHER2-/ER+62 (20.3%)83840 (69.8%)0.001HER2+/ER+27 (8.8%)14194 (11.8%)HER2+/ER-54 (17.6%)6331 (5.3%)Triple Negative163 (53.3%)15762 (13.1%)SurgeryBCS156 (53.1%)67965 (58.5%)0.067Mastectomy138 (46.9%)48214 (41.5%)RadiationYes139 (48.4%)64981 (56.4%)0.008No148 (51.6%)50270 (43.6%) Table 2. Clinicopathological characteristics of patients with aBC and mBCCharacteristicsaBC (N=306)mBC (N=2733)p value cMedian Follow-up (months)(IQR)22.0 (10.0-35.8)21.0 (9.0-34.0)Age (Mean ± SD)60.7 ± 11.362.5 ± 12.30.018RaceWhite225 (73.8%)2050 (75.5%)0.709Black39 (12.8%)342 (12.6%)Others a41(13.4%)322 (11.9%)Marital StatusMarried166 (57.2%)1454 (56.1%)0.756Not Married b124 (42.8%)1138 (43.9%)LateralityLeft136 (44.4%)1397 (51.1%)0.031Right170 (55.6%)1335 (48.9%)GradeI19 (6.4%)1538 (60.7%)< 0.001II159 (53.9%)887 (35.0%)III / IV117 (39.7%)110 (4.3%)AJCC StageI154 (50.3%)1773 (64.9%)< 0.001II109 (35.6%)851 (31.1%)III43 (14.1%)109 (4.0%)T StageT1187 (61.1%)1825 (66.8%)0.002T289 (29.1%)741 (27.1%)T319 (6.2%)136 (5.0%)T411 (3.6%)31 (1.1%)N StageN0202 (66.0%)2465 (90.2%)< 0.001N173 (23.9%)221 (8.1%)N220 (6.5%)33 (1.2%)N311 (3.6%)14 (0.5%)Molecular SubtypeHER2-/ER+62 (20.3%)2544 (93.1%)< 0.001HER2+/ER+27 (8.8%)22 (0.8%)HER2+/ER-54 (17.6%)151 (5.5%)Triple Negative163 (53.3%)16 (0.6%)SurgeryBCS156 (53.1%)1769 (66.3%)< 0.001Mastectomy138 (46.9%)898 (33.7%)RadiationYes139 (48.4%)1473 (55.1%)0.037No148 (51.6%)1201 (44.9%) Table 3. Comparison of BCSS and OS between aBC and IDC by multivariate Cox proportional hazard model according to different molecular subtypesUnivariateMultivariateHazard ratio (95% CI)ap valuebHazard ratio (95% CI)ap valuebAll BCSS1.224 (0.611 - 2.450)0.5680.726 (0.180 - 2.933)0.652OS1.100 (0.624 - 1.939)0.7420.394 (0.098 - 1.585)0.190ER+BCSS2.773 (0.893 - 8.609)0.0661.764 (0.440 - 7.092)0.423OS1.358 (0.438 - 4.214)0.5951.012 (0.253 - 4.049)0.987ER-BCSS0.378 (0.157 - 0.910)0.0240.241 (0.077 - 0.751)0.014OS0.517 (0.268 - 0.995)0.0440.409 (0.194 - 0.864)0.019ER+/HER2-BCSS3.961 (1.275 - 12.30)0.0102.370 (0.590 - 9.524)0.224OS1.912 (0.616 - 5.932)0.2541.370 (0.342 - 5.495)0.656ER+/HER2+ cBCSSNANANANAOSNANANANAER-/HER2+BCSS0.601 (0.084 - 4.287)0.6080.840 (0.117 - 6.061)0.862OS0.854 (0.213 - 3.431)0.8241.120 (0.277 - 4.525)0.874TNBCBCSS0.329 (0.123 - 0.880)0.0200.183 (0.046 - 0.736)0.017OS0.445 (0.212 - 0.935)0.0280.338 (0.140 - 0.816)0.016 Table 4. Comparison of BCSS and OS between aBC and mBC by multivariate Cox proportional hazard model according to different molecular subtypesUnivariateMultivariateHazard ratio (95% CI)ap valuebHazard ratio (95% CI)ap valuebAll BCSS5.020 (2.106 - 11.97) Citation Format: Changjun Wang, Yu Song, Hanjiang Zhu, Yidong Zhou, Feng Mao, Yan Lin, Yanna Zhang, Xiaohui Zhang, Songjie Shen, Ying Zhong, Xin Huang, Qiang Sun. Morphological apocrine and mucinous features of breast carcinoma: Does histology matter for survival? [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-31.

The stratum corneum (SC), a permeable membrane, limits percutaneous penetration. As SC chemical and structural properties responsible for skin barrier function appear depth-related, we conducted an in vitro dermatopharmacokinetic study on intact and adhesive tape-stripped skin samples to clarify whether SC is a homogeneous barrier for chemical transport. SC concentration-thickness profiles were determined for four C-14 labeled model chemicals, panthenol, benzoic acid, paraoxon and butenafine, using the tape-stripping approach. Data analysis with the unsteady-state diffusion equation of Fick's second law permitted a chemical diffusion coefficient in SC. To evaluate the consistency of SC permeability from its surface to lower levels, the skin was tape-stripped five to 10 times to remove the upper cell layers before chemical application, such that diffusion coefficients could be determined from three SC depth levels (0, 5 and 10 tape strips). Results suggested the depth-dependency of SC permeability to panthenol, benzoic acid and butenafine; the diffusion coefficient of panthenol decreased significantly after the first five tape strips and subsequently remained consistent. A progressive increase in diffusion coefficients of benzoic acid and butenafine was observed as tape-stripping levels increased. The removal of superficial SC did not result in a significant difference in the paraoxon diffusion coefficient. For individual chemicals, a variation in the diffusion coefficient from SC surface to deeper layers agreed with the change of the diffusion coefficient over time in intact skin. Characterization of the SC properties contributing to the depth-dependent SC permeability will hopefully provide further insight to skin penetration/decontamination. Copyright © 2016 John Wiley & Sons, Ltd.

Compounds with varying physical and chemical properties may have different affinities to the stratum corneum (SC) and/or its intercellular lipids, keratin protein, and possible water domains. To better understand the mechanism of percutaneous absorption, we utilized 21 carbon-14 labeled chemicals, with wide hydrophilicity (log P = -0.05 to 6.17), and quantified their absorption/adsorption properties for a short incubation time (15 min) with regards to intact SC membrane, delipidized SC membrane and SC lipid. A facile method was developed for SC/lipid absorption, providing a more equivalent procedure and comparable data. SC lipid absorption of chemical solutes positively correlated with the octanol/water partition coefficient (log P). Differences between the percent dose of chemical absorption to intact SC and the total percent dose contributed by the protein and lipid domains suggest the possibility and significance of a water domain. Absorption rate experiments showed a longer lag time for intact SC than for delipidized SC or SC lipid, suggesting that the water domain may delay chemical binding to protein and lipid domains, and may be a factor in the resistance of many chemicals to current decontamination methods. Copyright © 2015 John Wiley & Sons, Ltd.

Negative aromas such as rancid, fusty, winey-vinegary and frozen are sensory attributes of defective virgin olive oil recognized by the International Olive Council. Solid phase microextraction-gas chromatography/mass spectrometery (SPME-GC/MS) was employed to establish a flavour profile for each defective oil. The potential contribution of the identified compounds to the overall aromas of oil samples was assessed by calculating the ratio relative area/odour threshold in air – Relative Area over Threshold (RAOT). The relevant compounds of each defective sensory attributes were suggested: a series of C7-C12 unsaturated aldehydes, such as 2, 4-heptadienal, E-2-nonenal and E-2-octenal, were found to be responsible for rancidity, Z-3-hexenyl acetate and nonanoic acid were related to fusty defects, acetic acid and butyric acid were responsible for winey-vinegary defects, and limonene was found as a relevant compound in frozen oil. Copyright © 2015 John Wiley & Sons, Ltd.

Six chemical warfare agent simulants (trimethyl phosphate, dimethyl adipate, 2-chloroethyl methyl sulfide, diethyl adipate, chloroethyl phenyl sulfide and diethyl sebacate) were studied in in vitro human skin to explore relationship between dermal penetration/absorption and the mechanisms of simulant partitioning between stratum corneum (SC) and water as well as between dermal decontamination gel (DDGel) and water. Both binding affinity to and decontamination of simulants using DDGel were studied. Partition coefficients of six simulants between SC and water (Log PSC/w ) and between DDGel and water (Log PDDGel/w ) were determined. Results showed that DDGel has a similar or higher binding affinity to each simulant compared to SC. The relationship between Log P octanol/water and Log PSC/w as well as between Log P octanol/water and Log PDDGel/w demonstrated that partition coefficient of simulants correlated to their lipophilicity or hydrophilicity. Decontamination efficiency results with DDGel for these simulants were consistent with binding affinity results. Amounts of percentage dose of chemicals in DDGel of trimethyl phosphate, dimethyl adipate, 2-chloroethyl methyl sulfide, diethyl adipate, chloroethyl phenyl sulfide and diethyl sebacate were determined to be 61.15, 85.67, 75.91, 53.53, 89.89 and 76.58, with corresponding amounts absorbed in skin of 0.96, 0.65, 1.68, 0.72, 0.57 and 1.38, respectively. In vitro skin decontamination experiments coupled with a dermal absorption study demonstrated that DDGel can efficiently remove chemicals from skin surface, back-extract from the SC, and significantly reduced chemical penetration into skin or systemic absorption for all six simulants tested. Therefore, DDGel offers a great potential as a NextGen skin Decon platform technology for both military and civilian use.

The volatile profiles of virgin olive oils originating from the USA were first studied: 71 volatile compounds were identified in 21 monovarietal virgin olive oils using solid-phase microextraction–gas chromatography/mass spectrometry, representing 100 % of the headspace composition. Principal component analysis (PCA) allowed for the grouping of olive oils based on geographical origin, and also the distinguishing of olive oil varieties by their relative positions in the group; 17 distinguishable volatile compounds that significantly contributed to the olive oil classification were found to be distributed on a PCA plot according to their sensory attributes. Moreover, the major volatile components were compared among varieties and origins to clarify the genetic and geographic influences. Our results indicate the significant effects of both origin and cultivar on the volatile composition of olive oil as well as the dominant role of the geographic effect compared to the genetic effect on applied samples.

Storage conditions can affect the stability and quality of extra virgin olive oil (EVOO). While many studies have reported the influence of high temperature and light exposure during storage, little is known on the influence of the cold storage. The aim of this study was to evaluate the effect of different storage conditions (25, 4.5 and −27 °C) on the various compositions of EVOO and to determine if cold storage will prolong shelf-life by retarding hydrolysis and oxidation. The changes of quality indices (FFA, PV, and UV) and natural antioxidants such as α-tocopherol and phenolic compounds were evaluated periodically during storage. The characterization and quantification of phenolics were achieved by ultra-performance liquid chromatography—diode array detector (UPLC-DAD). In addition, 1, 2-diacylglycerols (DAGs), pyropheophytin A (PPP) were measured to indicate thermal degradation during storage.

Verifying the authenticity of edible oils is of international concern. A new quality control standard for olive oil has been proposed that relates the ratio of 1,2-diacylglycerol (DAG) to 1,3-DAG to sensory aspects of olive oil. DAGs and their isomers are difficult to quantitate and characterize by Flame Ionization Gas Chromatography (GC-FID) due to the lack of suitable standards. Mass detectors offer the advantage of providing structural detail to the eluding DAG(s), thus removing ambiguity to the identification of both resolved and unresolved DAGs in GC chromatograms. In this study, a GC Electron Ionization Mass Spectrometry (GC-EI-MS) method was developed to determine the fatty acid composition and molecular structure of trimethylsilyl (TMS) derivatized DAGs present in edible oils. Twenty-two species of DAG isomers were identified in refined coconut oil and unrefined olive oil utilizing signature fragment ions, [M-15](+), [M-89](+), [M-RCO2](+), [RCO2+58](+) and [M-RCO2CH2](+). The [M-RCO2CH2](+) ion is considered the key diagnostic ion to distinguish between DAG positional isomers. MS/MS spectra of [M-RCO2](+) and [M-15](+) ions obtained from commercial standards containing both 1,2- and 1,3-DAG isomers were used as a model system to confirm the identification of DAG isomers in natural products. Furthermore, a number of reaction mechanisms are proposed to explain the formation of the most abundant mass fragments of DAGs and their isomers.

Programmed cell death 1 ligand 1 (PD-L1) is a promising therapeutic target for cancer immunotherapy. However, the correlation between PD-L1 and breast cancer survival remains unclear. Here, we present the first meta-analysis to investigate the prognostic value of PD-L1 in breast cancer. We searched Pubmed, Embase, and Cochrane Central Register of Controlled Trials databases for relevant studies evaluating PD-L1 expression and breast cancer survival. Fixed- and random-effect meta-analyses were conducted based on heterogeneity of included studies. Publication bias was evaluated by funnel plot and Begg's test. Overall, nine relevant studies with 8583 patients were included. PD-L1 overexpression was found in 25.8% of breast cancer patients. PD-L1 (+) associated with several high-risk prognostic indicators, such as ductal cancer (p = 0.037), high tumor grade (p = 0.000), ER negativity (p = 0.000), PR negativity (p = 0.000), HER2 positivity (p = 0.001) and aggressive molecular subtypes (HER2-rich and Basal-like p = 0.000). PD-L1 overexpression had no significant impact on metastasis-free survival (HR 0.924, 95% CI = 0.747–1.141, p = 0.462), disease-free survival (HR 1.122, 95% CI = 0.878–1.434, p = 0.357) and overall specific survival (HR 0.837, 95% CI = 0.640–1.093, p = 0.191), but significantly correlated with shortened overall survival (HR 1.573, 95% CI = 1.010–2.451, p = 0.045). PD-L1 overexpression in breast cancer associates with multiple clinicopathological parameters that indicated poor outcome, and may increase the risk for mortality. Further standardization of PD-L1 assessment assay and well-controlled clinical trials are warranted to clarify its prognostic and therapeutic value.

This study evaluated the effects of three vehicles—ethanol (EtOH), isopropyl alcohol (IPA), and isopropyl myristate (IPM)—on stratum corneum (SC) absorption and diffusion of the [14C]-model compounds benzoic acid and butenafine hydrochloride to better understand the transport pathways of chemicals passing through and resident in SC. Following application of topical formulations to human dermatomed skin for 30 min, penetration flux was observed for 24 h post dosing, using an in vitro flow-through skin diffusion system. Skin absorption and penetration was compared to the chemical-SC (intact, delipidized, or SC lipid film) binding levels. A significant vehicle effect was observed for chemical skin penetration and SC absorption. IPA resulted in the greatest levels of intact SC/SC lipid absorption, skin penetration, and total skin absorption/penetration of benzoic acid, followed by IPM and EtOH, respectively. For intact SC absorption and total skin absorption/penetration of butenafine, the vehicle that demonstrated the highest level of sorption/penetration was EtOH, followed by IPA and IPM, respectively. The percent doses of butenafine that were absorbed in SC lipid film and penetrated through skin in 24 h were greatest for IPA, followed by EtOH and IPM, respectively. The vehicle effect was consistent between intact SC absorption and total chemical skin absorption and penetration, as well as SC lipid absorption and chemical penetration through skin, suggesting intercellular transport as a main pathway of skin penetration for model chemicals. These results suggest the potential to predict vehicle effects on skin permeability with simple SC absorption assays. As decontamination was applied 30 min after chemical exposure, significant vehicle effects on chemical SC partitioning and percutaneous penetration also suggest that skin decontamination efficiency is vehicle dependent, and an effective decontamination method should act on chemical solutes in the lipid domain.

Objective Percutaneous absorption of l-ascorbic acid (LAA) is limited due to its high hydrophilicity and low stability. Here, we investigated the effect of post-dosing sonophoresis (329 kHz, 20 mW cm−2) and heat (36°C) on transdermal delivery of LAA. Methods Ultrasound/heat, heat and control treatments were applied on skin surface for 2 and 5 min after topical application of C14-labelled LAA aqueous solution. After 15 min post-exposure, radioactivity was measured in tape-striped stratum corneum (TS-SC), epidermis, dermis and receptor fluid. As Franz diffusion cell model may have different acoustic response than in vivo human tissues, a novel Petri dish model was developed and compared with Franz cell model on the effects of ultrasound/heat treatment on the skin permeability. Results Five-min ultrasound/heat treatment significantly accelerated skin absorption/penetration of LAA; 2-min treatment showed no enhancement effect on Franz diffusion cell model at the end of experiment. The use of Petri dish model significantly increased LAA concentrations in epidermis after 5 min of ultrasound/heat treatment, compared to the results of Franz cell model. Conclusion Combination of ultrasound (329 kHz, 20 mW cm−2) and heat (36°C) significantly enhanced LAA transdermal penetration, when the time of treatment was sufficient (5 min). As Petri dish model was designed to simulate acoustic respond of dense human tissue to ultrasound, the difference between Franz cell and Petri dish models suggests that the enhancement effect of ultrasound/heat on skin penetration in vivo may be greater than that determined on in vitro Franz cell model.

Mutation of p110 alpha-catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA) has high predictive and prognostic values for breast cancer. Hence, there has been a marked interest in detecting and monitoring PIK3CA genotype with non-invasive technique, such as circulating free DNA (cfDNA). However, the diagnostic accuracy of PIK3CA genotyping by cfDNA is still a problem of controversy. Here, we conducted the first meta-analysis to evaluate overall diagnostic performance of cfDNA for PIK3CA mutation detection. Literature search was performed in Pubmed, Embase and Cochrane Central Register of Controlled Trials databases. Seven cohorts from five studies with 247 patients were included. The pooled sensitivity, specificity, positive and negative likelihood ratio, diagnostic odds ratio and area under summary receiver operating characteristic curve were calculated for accuracy evaluation. The pooled sensitivity and specificity were 0.86 (95% confidence interval [CI] 0.32–0.99) and 0.98 (95% CI 0.86–1.00), respectively; the pooled positive and negative likelihood ratio were 42.8 (95% CI 5.1–356.9) and 0.14 (95% CI 0.02–1.34), respectively; diagnostic odds ratio for evaluating the overall diagnostic performance was 300 (95% CI 8–11867); area under summary receiver operating characteristic curve reached 0.99 (95% CI 0.97–0.99). Subgroup analysis with metastatic breast cancer revealed remarkable improvement in diagnostic performance (sensitivity: 0.86–0.91; specificity: 0.98; diagnostic odds ratio: 300–428). This meta-analysis proved that detecting PIK3CA gene mutation by cfDNA has high diagnostic accuracy in breast cancer, especially for metastatic breast cancer. It may serve as a reliable non-invasive assay for detecting and monitoring PIK3CA mutation status in order to deliver personalized and precise treatment.

The stratum corneum (SC), a permeable membrane, limits percutaneous penetration. As SC chemical and structural properties responsible for skin barrier function appear depth-related, we conducted an in vitro dermatopharmacokinetic study on intact and adhesive tape-stripped skin samples to clarify whether SC is a homogeneous barrier for chemical transport. SC concentration-thickness profiles were determined for four C-14 labeled model chemicals, panthenol, benzoic acid, paraoxon and butenafine, using the tape-stripping approach. Data analysis with the unsteady-state diffusion equation of Fick's second law permitted a chemical diffusion coefficient in SC. To evaluate the consistency of SC permeability from its surface to lower levels, the skin was tape-stripped five to 10 times to remove the upper cell layers before chemical application, such that diffusion coefficients could be determined from three SC depth levels (0, 5 and 10 tape strips). Results suggested the depth-dependency of SC permeability to panthenol, benzoic acid and butenafine; the diffusion coefficient of panthenol decreased significantly after the first five tape strips and subsequently remained consistent. A progressive increase in diffusion coefficients of benzoic acid and butenafine was observed as tape-stripping levels increased. The removal of superficial SC did not result in a significant difference in the paraoxon diffusion coefficient. For individual chemicals, a variation in the diffusion coefficient from SC surface to deeper layers agreed with the change of the diffusion coefficient over time in intact skin. Characterization of the SC properties contributing to the depth-dependent SC permeability will hopefully provide further insight to skin penetration/decontamination. Copyright © 2016 John WileySons, Ltd.

Skin decontamination is a primary interventional method used to decrease dermal absorption of hazardous contaminants, including chemical warfare agents, pesticides and industrial pollutants. Soap and water wash, the most common and readily available decontamination system, may enhance percutaneous absorption through the "wash-in effect." To understand better the effect of soap-water wash on percutaneous penetration, and provide insight to improving skin decontamination methods, in vitro human epidermal penetration rates of four C(14) -labeled model chemicals (hydroquinone, clonidine, benzoic acid and paraoxon) were assayed using flow-through diffusion cells. Stratum corneum (SC) absorption rates of these chemicals at various hydration levels (0-295% of the dry SC weights) were determined and compared with the results of the epidermal penetration study to clarify the effect of SC hydration on skin permeability. Results showed accelerated penetration curves of benzoic acid and paraoxon after surface wash at 30 min postdosing. Thirty minutes after washing (60 min postdosing), penetration rates of hydroquinone and benzoic acid decreased due to reduced amounts of chemical on the skin surface and in the SC. At the end of the experiment (90 min postdosing), a soap-water wash resulted in lower hydroquinone penetration, greater paraoxon penetration and similar levels of benzoic acid and clonidine penetration compared to penetration levels in the non-wash groups. The observed wash-in effect agrees with the enhancement effect of SC hydration on the SC chemical absorption rate. These results suggest SC hydration derived from surface wash to be one cause of the wash-in effect. Further, the occurrence of a wash-in effect is dependent on chemical identity and elapsed time between exposure and onset of decontamination. By reducing chemical residue quantity on skin surface and in the SC reservoir, the soap-water wash may decrease the total quantity of chemical absorbed in the long term; however, the more immediate accelerated absorption of chemical toxins, particularly chemical warfare agents, may be lethal. Copyright © 2015 John Wiley & Sons, Ltd.

Compounds with varying physical and chemical properties may have different affinities to the stratum corneum (SC) and/or its intercellular lipids, keratin protein, and possible water domains. To better understand the mechanism of percutaneous absorption, we utilized 21 carbon-14 labeled chemicals, with wide hydrophilicity (log P = -0.05 to 6.17), and quantified their absorption/adsorption properties for a short incubation time (15 min) with regards to intact SC membrane, delipidized SC membrane and SC lipid. A facile method was developed for SC/lipid absorption, providing a more equivalent procedure and comparable data. SC lipid absorption of chemical solutes positively correlated with the octanol/water partition coefficient (log P). Differences between the percent dose of chemical absorption to intact SC and the total percent dose contributed by the protein and lipid domains suggest the possibility and significance of a water domain. Absorption rate experiments showed a longer lag time for intact SC than for delipidized SC or SC lipid, suggesting that the water domain may delay chemical binding to protein and lipid domains, and may be a factor in the resistance of many chemicals to current decontamination methods. Copyright © 2015 John WileySons, Ltd.

Interaction between drug and proteins and lipids in stratum corneum (SC) is an important pharmacokinetic parameter in early steps of absorption. Previous in vivo studies showed that the total amount of compound, regardless of properties, penetrating over a 96 h period could be predicted by the amount present in SC 30 min after application by a linear relationship. Validating this linear relationship through in vitro study would facilitate testing of transdermal drug delivery platforms. We aimed to determine in vitro penetration behavior across SC of humans by determining the relationship between quantity present in SC reservoir 30 min after application with 24 h skin absorption and penetration. In this study, use of the SC reservoir effect to predict absorption and penetration of topical compounds is reaffirmed with in vitro models involving human skin. These results indicate the amount in short-term (30 min) SC reservoir predict long-term (24 h) skin absorption and penetration, as characterized by statistically significant linear relationships determined via regression. This may be explained by the fact that SC is a rate-limiting barrier to percutaneous drug transport. After molecules diffuse through SC barrier, passage into deeper dermal layers and systemic uptake occur relatively quickly. These results enable one to measure quantity in SC reservoir shortly after topical application as a proxy for absorption and penetration over longer periods. With respect to drug development and risk assessment of toxic substances, this may simplify assays attempting to quantitate penetration capacity. Further investigation with a larger range of compounds is needed to clarify the observations recorded here. Copyright © 2015 John Wiley & Sons, Ltd.

The enzymatic and chemical oxidation reaction in olive oil produces many volatile carbonyl compounds that contribute to the complex flavor of olive oil. A novel ultrahigh performance liquid chromatography (UHPLC) method with dynamic headspace sampling and 2,4-dinitrophenylhydrazine (DNPH) derivatization were established to determine the volatile carbonyls in virgin olive oil. Quantification of nine characteristic carbonyls (acetone, hexanal, E-2-hexenal, octanal, E-2-octenal, nonanal, E-2-nonenal, E,E-2,4-nonadienal, and E,E-2,4-decadienal) was achieved using cyclopentanal as an internal standard. This method provides comparable linearity (R(2) = 0.9917-1.0000) and repeatability (less than 7.6% relative standard deviations) with solid phase microextraction gas chromatography (SPME-GC). The relative standard deviations (%RSD) of all applied carbonyl standards were lower than 7.6%. The limits of detection (LOD) and quantification (LOQ) were in the ranges of 1.6-150.1 and 4.8-906.1 μg/kg. The recoveries obtained for olive oil samples were in the range of 81.0-115.3%. To show the potential of this method on the quantification of other volatile carbonyls that were not included in this study, GC-electron ionization mass spectrometry (GC-EI/MS) was employed to identify the derivatized carbonyls (carbonyl (2,4-DNPH) hydrazones) while peak assignments were made on the basis of elution sequences and peak areas. This method provided feasibility of using LC to determine volatile carbonyls in oil matrices, which can be applied to exam the degree of lipid oxidation and evaluate the sensory properties of VOO and other edible oils.