PLAC1 as a serum biomarker for breast cancer

<div><p>Placental-specific protein 1 (PLAC1) is an X-linked trophoblast gene that is re-expressed in several malignancies, including breast cancer, and is therefore a potential biomarker to follow disease onset and progression. Sera from 117 preoperative/pretreatment breast cancer patients and 51 control subjects, including those with fibrocystic disease, were analyzed for the presence of PLAC1 protein as well as its expression by IHC in tumor biopsies in a subset of subjects. Serum PLAC1 levels exceeded the mean plus one standard deviation (mean+SD) of the level in control subjects in 67% of subjects with ductal carcinoma in situ (DCIS), 67% with HER2⁺ tumors, 73% with triple-negative cancer and 73% with ER⁺/PR⁺ tumors. Greater sensitivity was achieved using the mean+2 SD of control PLAC1 serum values, where the false positive rate was 3% and was exceeded by 38%, 40%, 60% and 43% of subjects with DCIS, HER2⁺, TNBC and ER⁺/PR⁺/HER2^- tumors. PLAC1 was detected in 97% of tumor biopsies, but did not correlate quantitatively with serum levels. There was no significant correlation of serum PLAC1 levels with race, age at diagnosis, body mass index (BMI) or the presence of metastatic disease. It remains to be determined whether PLAC1 serum levels can serve as a diagnostic biomarker for the presence or recurrence of disease post-surgery and/or therapy.</p></div

Immunochemical detection of PLAC1 in tumor biopsies and its correlation with serum PLAC1 levels.

<p><b>A</b>, Examples of PLAC1 detection by IHC in tumor biopsies from subjects with DCIS, ER⁺/PR⁺/HER2^-, HER2⁺ and TNBC. <i>Low</i> levels have less intensity and are more scattered than biopsies with <i>High</i> levels of PLAC1. <b>B</b>, Relationship between serum PLAC1 levels and PLAC1 expression in biopsies from the same patient based on the total number of subjects as indicated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0192106#pone.0192106.t002" target="_blank">Table 2</a>. <i>0</i>, <i>1</i> and <i>2</i> represent negative, low and high staining intensity, respectively, as shown in <b>A</b>.</p

Characteristics of control and cancer patients.

<p>FCD, fibrocystic condition.</p

Serum PLAC1 levels in control and breast cancer subjects.

<p>Shown are serum levels from individual subjects. The mean plus one or two SD of PLAC1 serum levels in control subjects is indicated by the <i>lower</i> and <i>upper red</i> lines, respectively. The <i>inset</i> indicates the data for each subject category. <i>FCD</i>, fibrocystic disease.</p

Serum and biopsy PLAC1 in control and cancer subjects.

<p>Serum and biopsy PLAC1 in control and cancer subjects.</p

Understanding particles emitted from spray and wall-guided gasoline direct injection and flex fuel vehicles operating on ethanol and iso-butanol gasoline blends

<p>Traffic-related pollutants are an ever-growing concern. However, the composition of particle emissions from new vehicle technologies using relevant current and prospective fuel blends is not known. This study tested four current and up-and-coming vehicle technologies with nine fuel blends with various concentrations of ethanol and iso-butanol. Vehicles were driven on both the federal test procedure (FTP) and the unified cycle (UC). Additional tests were conducted under steady-state speed conditions. The vehicle technologies include spray-guided gasoline direct injection (SG-GDI), wall-guided gasoline direct injection (WG-GDI), port-fuel injection flex fuel vehicle (PFI-FFV), and a wall-guided GDI-FFV. The fuels consisted of 10–83% ethanol and 16–55% iso-butanol in gasoline. The composition of soot, water-insoluble mass (WIM), water-soluble organic mass, and water-insoluble organic mass (WIOM), and OM was measured. The majority of emissions over FTP and UC were water-insoluble (>70%), and WIOM contributes mostly to OM. PFIs have lower soot and particulate matter (PM) emissions in comparison to the WG-GDI technology even while increasing the renewable fuel content. SG-GDI technology, which has not penetrated the market, show promise as soot and PM emissions are comparable to PFI vehicles while preserving the GDI fuel economy benefits. The WIM fraction in GDI-FFV consistently increased with increasing ethanol concentration. Lastly, the impact of the future vehicle emissions and traffic pollutants is discussed. SG-GDI technology is found to be a promising sustainable technology to enhance fuel economy and also reduce PM, soot, and WIM emissions.</p> <p>Copyright © 2017 American Association for Aerosol Research</p

DataSheet_1_A Phase I Trial of Dasatinib and Osimertinib in TKI Naïve Patients With Advanced EGFR-Mutant Non-Small-Cell Lung Cancer.pdf

BackgroundOsimertinib is an effective first-line therapy option for EGFR-mutant NSCLC, but virtually all patients develop resistance. CRIPTO, through Src activation, has been implicated in resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. Dasatinib, a Src inhibitor, has shown preclinical synergy with EGFR-TKI therapy.MethodThis is a single-arm phase I/II trial of osimertinib and dasatinib in TKI-naïve advanced EGFR-mutant NSCLC (NCT02954523). A 3 + 3 design was used in the phase I to establish the recommended phase II dose (RP2D). Osimertinib 80 mg QD was combined with dasatinib 70 mg BID (DL2), 50 mg BID (DL1), 70 mg QD (DL-1), and 50 mg QD (DL-2).ResultsTen patients (DL2: 3, DL1: 6, DL -1: 1) were enrolled. 3 (50%) of 6 patients at DL1 experienced a DLT (grade 3 headaches/body pain, neutropenia, rash, one each). Common treatment-related adverse events included pleural effusion (n=10), diarrhea (n=8), rash (n=7), transaminitis (n=7), thrombocytopenia (n=7), and neutropenia (n=7). While the MTD was not determined by protocol-defined DLT criteria, DL-2 was chosen as the RP2D, considering overall tolerability. Nine (90%) patients had a PR, including 1 unconfirmed PR. Median PFS was 19.4 months and median OS 36.1 months. The trial was closed to accrual prematurely due to slow accrual after the approval of osimertinib as first-line therapy.ConclusionsThe combination of dasatinib and osimertinib demonstrated anticancer activity. The treatment was limited by chronic toxicities mainly attributed to dasatinib. To improve the safety and tolerability of Src and EGFR co-inhibition, Src inhibitors with a more favorable safety profile should be utilized in future studies.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT02954523</p

DataSheet_2_A Phase I Trial of Dasatinib and Osimertinib in TKI Naïve Patients With Advanced EGFR-Mutant Non-Small-Cell Lung Cancer.pdf

BackgroundOsimertinib is an effective first-line therapy option for EGFR-mutant NSCLC, but virtually all patients develop resistance. CRIPTO, through Src activation, has been implicated in resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. Dasatinib, a Src inhibitor, has shown preclinical synergy with EGFR-TKI therapy.MethodThis is a single-arm phase I/II trial of osimertinib and dasatinib in TKI-naïve advanced EGFR-mutant NSCLC (NCT02954523). A 3 + 3 design was used in the phase I to establish the recommended phase II dose (RP2D). Osimertinib 80 mg QD was combined with dasatinib 70 mg BID (DL2), 50 mg BID (DL1), 70 mg QD (DL-1), and 50 mg QD (DL-2).ResultsTen patients (DL2: 3, DL1: 6, DL -1: 1) were enrolled. 3 (50%) of 6 patients at DL1 experienced a DLT (grade 3 headaches/body pain, neutropenia, rash, one each). Common treatment-related adverse events included pleural effusion (n=10), diarrhea (n=8), rash (n=7), transaminitis (n=7), thrombocytopenia (n=7), and neutropenia (n=7). While the MTD was not determined by protocol-defined DLT criteria, DL-2 was chosen as the RP2D, considering overall tolerability. Nine (90%) patients had a PR, including 1 unconfirmed PR. Median PFS was 19.4 months and median OS 36.1 months. The trial was closed to accrual prematurely due to slow accrual after the approval of osimertinib as first-line therapy.ConclusionsThe combination of dasatinib and osimertinib demonstrated anticancer activity. The treatment was limited by chronic toxicities mainly attributed to dasatinib. To improve the safety and tolerability of Src and EGFR co-inhibition, Src inhibitors with a more favorable safety profile should be utilized in future studies.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT02954523</p

Effect of Ion Distribution on Conductivity of Block Copolymer Electrolytes

Energy-filtered transmission electron microscopy (EFTEM) was used to determine the distribution of lithium ions in solid polymer electrolytes for lithium batteries. The electrolytes of interest are mixtures of bis(trifluoromethane)sulfonimide lithium salt and symmetric poly(styrene-block-ethylene oxide) copolymers (SEO). In contrast to current solid and liquid electrolytes, the conductivity of SEO/salt mixtures increases with increasing molecular weight of the copolymers. EFTEM results show that the salt is increasingly localized in the middle of the poly(ethylene oxide) (PEO) lamellae as the molecular weight of the copolymers is increased. Calculations of the inhomogeneous local stress field in block copolymer microdomains, modeled using self-consistent field theory, provide a quantitative explanation for this observation. These stresses, which increase with increasing molecular weight, interfere with the ability of PEO chains to coordinate with lithium cations near the walls of the PEO channels where ion mobility is expected to be low