Malignant pleural mesothelioma (MPM) is an aggressive cancer that occurs more frequently in men, but is associated with longer survival in women. Insight into the survival advantage of female ...patients may advance the molecular understanding of MPM and identify therapeutic interventions that will improve the prognosis for all MPM patients. In this study, we performed whole-genome sequencing of tumor specimens from 10 MPM patients and matched control samples to identify potential driver mutations underlying MPM. We identified molecular differences associated with gender and histology. Specifically, single-nucleotide variants of BAP1 were observed in 21% of cases, with lower mutation rates observed in sarcomatoid MPM (P < 0.001). Chromosome 22q loss was more frequently associated with the epithelioid than that nonepitheliod histology (P = 0.037), whereas CDKN2A deletions occurred more frequently in nonepithelioid subtypes among men (P = 0.021) and were correlated with shorter overall survival for the entire cohort (P = 0.002) and for men (P = 0.012). Furthermore, women were more likely to harbor TP53 mutations (P = 0.004). Novel mutations were found in genes associated with the integrin-linked kinase pathway, including MYH9 and RHOA. Moreover, expression levels of BAP1, MYH9, and RHOA were significantly higher in nonepithelioid tumors, and were associated with significant reduction in survival of the entire cohort and across gender subgroups. Collectively, our findings indicate that diverse mechanisms highly related to gender and histology appear to drive MPM.
To develop a standardized approach for molecular diagnostics, we used the gene expression ratio bioinformatic technique to design a molecular signature to diagnose malignant pleural mesothelioma ...(MPM) from among other potentially confounding diagnoses and differentiate the epithelioid from the sarcomatoid histologic subtype of MPM. In addition, we searched for pathways relevant in MPM in comparison with other related cancers to identify unique molecular features in MPM.
We conducted microarray analysis on 113 specimens including MPMs and a spectrum of tumors and benign tissues comprising the differential diagnosis of MPM. We generated a sequential combination of binary gene expression ratio tests able to discriminate MPM from other thoracic malignancies. We compared this method with other bioinformatic tools and validated this signature in an independent set of 170 samples. Functional enrichment analysis was conducted to identify differentially expressed probes.
A sequential combination of gene expression ratio tests was the best molecular approach to distinguish MPM from all the other samples. Bioinformatic and molecular validations showed that the sequential gene ratio tests were able to identify the MPM samples with high sensitivity and specificity. In addition, the gene ratio technique was able to differentiate the epithelioid from the sarcomatoid type of MPM. Novel genes and pathways specifically activated in MPM were identified.
New clinically relevant molecular tests have been generated using a small number of genes to accurately distinguish MPMs from other thoracic samples, supporting our hypothesis that the gene expression ratio approach could be a useful tool in the differential diagnosis of cancers.
The most widely used histochemical marker of apoptosis (in situend labeling, TUNEL) detects both apoptotic and necrotic cells and evaluates only late stages of apoptosis. Hence, a specific and ...sensitive cellular marker of apoptosis is needed to determine the role of apoptotic death in biology and pathology. The present study describes a novel immunohistochemical procedure for the staining of apoptotic cells using a monoclonal antibody (MAb) to single-stranded DNA. This MAb stained all cells with the morphology typical of apoptosis in etoposide-treated HL-60, MOLT-4, and R9 cell cultures, in which apoptosis was accompanied by high, moderate, and low levels of internucleosomal DNA fragmentation, respectively. TUNEL stained all apoptotic cells in HL-60 cultures, nearly 60% of apoptotic cells in MOLT-4 cultures, and only 14% of apoptotic cells in R9 cultures. Apoptotic R9 cells, which progressed into secondary necrosis, retained MAb staining and became TUNEL-positive. Necrotic cells in MOLT-4 cultures treated with sodium azide were stained by TUNEL, but were negative for MAb staining. All floating cells at a late stage of apoptosis in MDA-MB-468 cultures treated with cisplatin were stained by both MAb and TUNEL. However, among adherent cells in the early stages of apoptosis, MAb stained nearly 20 times more cells than TUNEL. In histological sections of human tumor xenografts, MAb detected clusters of apoptotic cells in viable tumor tissue, but did not stain cells in areas of central ischemic necrosis. In contrast, TUNEL stained nuclei in necrotic areas. Thus, MAb to single-stranded DNA is a specific and sensitive cellular marker of apoptosis, which differentiates between apoptosis and necrosis and detects cells in the early stages of apoptosis.
Precise quantitation of apoptotic cells in solid tumors is necessary to determine the role of apoptosis in cancer growth, prognosis, and treatment. In this study, the intensity of apoptotic death was ...determined in 91 breast carcinomas with a novel cellular marker of apoptosis based on the staining of histological sections with a monoclonal antibody (MAb) to single-stranded DNA. Staining of apoptotic cells with the MAb reflected the decreased thermal stability of DNA induced by the digestion of nuclear proteins, as demonstrated by the elimination of staining in sections reconstituted with histones before heating. The high sensitivity and specificity of apoptosis analysis with the MAb is based on the central role of protease activation in the mechanism and control of apoptosis. Apoptotic indexes (AIs) in breast carcinomas ranged between 0 and 46%. Most of the carcinomas had relatively low AIs, whereas 29 cases were classified as carcinomas with intensive apoptosis (AI >/= 10%). The high level of apoptotic cell death was associated with negative immunostaining for bcl-2 protein, the loss of estrogen and progesterone receptors, high proportion of cells in S-phase, and increased risk of lymph node metastases. There was no correlation between AI and tumor size or p53 immunostaining. Lymph node metastases were detected in 59% of patients with high levels of apoptosis in primary carcinomas and in only 21% of patients with AIs below 10% in primary carcinomas. Thus, the high sensitivity of the MAb assay made it possible to identify a subset of breast carcinomas with intensive apoptosis and markers of poor prognosis. These results demonstrate that the measurement of apoptosis in breast carcinomas provides valuable prognostic information.
Probe station for testing of ALICE silicon drift detectors Humanic, T.J; Kotov, I.V; Piemonte, C ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
10/2003, Letnik:
512, Številka:
1
Journal Article
Recenzirano
Large area,
7.25
cm×8.76
cm
silicon drift detectors have been developed and are in production for the ALICE experiment at LHC. An active area of the detector of more than
50
cm
2
imposes high demands ...on the quality of processing and raw material. Automated testing procedures have been developed to test detectors before mounting them on the ladders. Probe stations for ALICE SDD testing were designed and built at INFN, Trieste and Ohio State University (OSU). Testing procedures, detector selection criteria and some details of the OSU probe station design are discussed.
The STAR Silicon Vertex Tracker: A large area Silicon Drift Detector Bellwied, R.; Beuttenmuller, R.; Caines, H. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
03/2003, Letnik:
499, Številka:
2
Journal Article
Recenzirano
The Solenoidal Tracker At RHIC-Silicon Vertex Tracker (STAR-SVT) is a three-barrel microvertex detector based upon silicon drift detector (SDD) technology. As designed for the STAR-SVT, (SDDs) are ...capable of providing unambiguous two-dimensional hit position measurements with resolutions on the order of
20
μm
in each coordinate. In addition, a high-resolution energy loss measurement in the three layers of the SVT enables good particle identification. We describe features of the design of the STAR-SVT SDDs and electronics that are motivated by such characteristics. We also detail the mechanical structure, assembly procedures, and performance characteristics of the completed device.
Breast cancer cells are relatively resistant to the induction of apoptosis (AP) and drug regimens which readily activate apoptotic death, may enhance the antitumor effect. Rapid and intensive ...induction of apoptosis was observed in estrogen receptor positive and negative breast cancer cell cultures treated with tamoxifen (TMX) combined with the calmodulin antagonists trifluoperazine (TFP) or W7. TMX (1–5μM) alone or calmodulin antagonists alone did not induce apoptosis. Importantly, intensive apoptosis was also induced by TMX and TFP in the cells obtained from primary human breast carcinomas. Inhibition of the Ca
2+ calmodulin signaling pathway is an effective way to activate apoptotic death in epithelial cells. Combination of TMX with non-toxic calmodulin inhibitors may increase the preventive and therapeutic effects of TMX.
INPOL – the Indiana University Neutron Polarimeter Palarczyk, M; Rapaport, J; Hautala, C ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
01/2001, Letnik:
457, Številka:
1
Journal Article
Recenzirano
We describe the upgraded time-of-flight facility at the Indiana University Cyclotron which has been used to measure the polarization transfer induced in
(
p
→
,
n
→
)
reactions at intermediate ...energies,
E
p=100–200 MeV. The Indiana Neutron POLarimeter (INPOL) is able to measure simultaneously two orthogonal neutron spin polarizations induced in charge exchange reactions with polarized proton beams oriented in each of the three spin states, normal (
N
→
), sideways (
S
→
) and longitudinal (
L
→
).
The intensity of post-treatment melanoma patient follow-up varies widely among physicians. We investigated whether physician age accounts for the observed variation in surveillance intensity among ...plastic surgeons. A custom-designed questionnaire was mailed to USA and non-USA surgeons, all of whom were members of the American Society of Plastic and Reconstructive Surgeons. Subjects were asked how they use 14 specific follow-up modalities during years 1-5 and 10 following primary treatment for patients with cutaneous melanoma. Repeated-measures analysis of variance was used to compare practice patterns by TNM stage, year post-surgery, and age. Of the 3,032 questionnaires mailed, 1,142 (38%) were returned. Of those returned, 395 (35%) were evaluable. Non-evaluability was usually due to lack of melanoma patient follow-up in surgeons' practices. Follow-up strategies for most of the 14 modalities were highly correlated across TNM stages and years post-surgery, as expected. The pattern of testing varied significantly by surgeon age for 3 modalities (complete blood count, liver function tests, and chest X-ray), but the variation was quite small. We concluded that the post-treatment surveillance practice patterns of ASPRS members caring for patients with cutaneous melanoma vary only marginally with physician age. Continuing medical education could account for this observation.
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