A high-content small molecule screen identifies sensitivity of glioblastoma stem cells to inhibition of polo-like kinase 1

Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults and there are few effective treatments. GBMs contain cells with molecular and cellular characteristics of neural stem cells that drive tumour growth. Here we compare responses of human glioblastoma-derived neural stem (GNS) cells and genetically normal neural stem (NS) cells to a panel of 160 small molecule kinase inhibitors. We used live-cell imaging and high content image analysis tools and identified JNJ-10198409 (J101) as an agent that induces mitotic arrest at prometaphase in GNS cells but not NS cells. Antibody microarrays and kinase profiling suggested that J101 responses are triggered by suppression of the active phosphorylated form of polo-like kinase 1 (Plk1) (phospho T210), with resultant spindle defects and arrest at prometaphase. We found that potent and specific Plk1 inhibitors already in clinical development (BI 2536, BI 6727 and GSK 461364) phenocopied J101 and were selective against GNS cells. Using a porcine brain endothelial cell blood-brain barrier model we also observed that these compounds exhibited greater blood-brain barrier permeability in vitro than J101. Our analysis of mouse mutant NS cells (INK4a/ARF(-/-), or p53(-/-)), as well as the acute genetic deletion of p53 from a conditional p53 floxed NS cell line, suggests that the sensitivity of GNS cells to BI 2536 or J101 may be explained by the lack of a p53-mediated compensatory pathway. Together these data indicate that GBM stem cells are acutely susceptible to proliferative disruption by Plk1 inhibitors and that such agents may have immediate therapeutic value

Presenting a simplified assistant tool for breast cancer diagnosis in mammography to radiologists

This paper proposes a method to simplify a computational model from logistic regression for clinical use without computer. The model was built using human interpreted featrues including some BI-RADS standardized features for diagnosing the malignant masses. It was compared with the diagnosis using only assessment categorization from BI-RADS. The research aims at assisting radiologists to diagnose the malignancy of breast cancer in a way without using automated computer aided diagnosis system

Number of mammography cases read per year is a strong predictor of sensitivity

Early detection of breast cancers affects the 5-year recurrence rates and treatment options for diagnosed patients, and consequently, many countries have instituted nationwide screening programs. This study compared the performance of expert radiologists from Australia and the United States in detection of breast cancer. Forty-one radiologists, 21 from Australia and 20 from the United States, reviewed 30 mammographic cases containing two-view mammograms. Twenty cases had abnormal findings and 10 cases had normal findings. Radiologists were asked to locate malignancies and assign a level of confidence. A jackknife free-response receiver operating characteristic, figure of merit (JAFROC, FOM), inferred receiver operating characteristic, area under curve (ROC, AUC), specificity, sensitivity, and location sensitivity were calculated using Ziltron software and JAFROC v4.1. A Mann-Whitney U test was used to compare the performance of Australian and U.S. radiologists. The results showed that when experience and the number of mammograms read per year were taken into account, the Australian radiologists sampled showed significantly higher sensitivity and location sensitivity (p≤0.001). JAFROC (FOM) and inferred ROC (AUC) analysis showed no difference between the overall performance of the two countries. ROC (AUC) and location sensitivity were higher for the Australian radiologists who read the most cases per year

The mammary hamartoma: appreciation of additional imaging characteristics.

OBJECTIVE: To determine the mammographic and sonographic findings of hamartomas that were not classic on imaging, how pathologists distinguish the hamartoma from benign breast tissue on core samples, and reasons for discrepancies between core and surgical biopsy. METHODS: A retrospective review of all image-recommended core biopsies between 1993 and 2001 was performed. There were 41 cases of hamartomas found on either core or surgical biopsy. The mammographic, sonographic, and pathologic findings were reviewed. RESULTS: Of 41 hamartomas in 38 patients, 18 went on to surgical biopsy. Of these 18 cases, 4 cases of hamartoma on core biopsy were fibroadenoma after excision; 2 cases of hamartoma on core biopsy were confirmed by surgery; and 12 cases of fibrocystic change after core biopsy were hamartoma after surgical biopsy. The 4 cases of fibroadenoma shown at final pathologic examination were excluded from imaging review, leaving 37 cases. In the 20 patients who underwent only core sampling, 23 hamartomas were diagnosed. Seventeen masses were visible on mammography, and 82% were homogeneously dense. Of 36 masses shown on sonography, 86% were uniformly hypoechoic. At histologic examination, only 16% contained fat within the mass. CONCLUSIONS: Hamartomas may appear as homogeneously dense, well-circumscribed masses, varying in appearance from the classically described encapsulated mixed fatty-fibroglandular mass. Pathologists can make the diagnosis of hamartoma without the presence of adipose tissue but may have difficulty in distinguishing the hamartoma from fibrocystic change. However, if there is radiologic-pathologic concordance, further surgical excision is not warranted

In the digital era, architectural distortion remains a challenging radiological task

Aim To compare readers' performance in detecting architectural distortion (AD) compared with other breast cancer types using digital mammography. Materials and methods Forty-one experienced breast screen readers (20 US and 21 Australian) were asked to read a single test set of 30 digitally acquired mammographic cases. Twenty cases had abnormal findings (10 with AD, 10 non-AD) and 10 cases were normal. Each reader was asked to locate and rate any abnormalities. Lesion and case-based performance was assessed. For each collection of readers (US; Australian; combined), jackknife free-response receiver operating characteristic (JAFROC), figure of merit (FOM), and inferred receiver operating characteristic (ROC), area under curve (Az) were calculated using JAFROC v.4.1 software. Readers' sensitivity, location sensitivity, JAFROC, FOM, ROC, Az scores were compared between cases groups using Wilcoxon's signed ranked test statistics. Results For lesion-based analysis, significantly lower location sensitivity (p=0.001) was shown on AD cases compared with non-AD cases for all reader collections. The case-based analysis demonstrated significantly lower ROC Az values (p=0.02) for the first collection of readers, and lower sensitivity for the second collection of readers (p=0.04) and all-readers collection (p=0.008), for AD compared with non-AD cases. Conclusions The current work demonstrates that AD remains a challenging task for readers, even in the digital era