The therapeutic responsiveness of genetically defined tumors expressing or devoid of the p53 tumor suppressor gene was compared in immunocompromised mice. Tumors expressing the p53 gene contained a high proportion of apoptotic cells and typically regressed after treatment with gamma radiation or adriamycin. In contrast, p53-deficient tumors treated with the same regimens continued to enlarge and contained few apoptotic cells. Acquired mutations in p53 were associated with both treatment resistance and relapse in p53-expressing tumors. These results establish that defects in apoptosis, here caused by the inactivation of p53, can produce treatment-resistant tumors and suggest that p53 status may be an important determinant of tumor response to therapy.

The presence of large number of false lesion classification on segmented brain MR images is a major problem in the accurate determination of lesion volumes in multiple sclerosis (MS) brains. In order to minimize the false lesion classifications, a strategy that combines parametric and nonparametric techniques is developed and implemented. This approach uses the information from the proton density (PD)-and T2-weighted and fluid attenuation inversion recovery (FLAIR) images. This strategy involves CSF and lesion classification using the Parzen window classifier. Image processing, morphological operations and ratio maps of PD and T2 weighted images are used for minimizing false positives. Contextual information is exploited for minimizing the false negative lesion classifications using hidden Markov random field -expectation maximization (HMRF-EM) algorithm. Lesions are delineated using fuzzy connectivity. The performance of this algorithm is quantitatively evaluated on 23 MS patients. Similarity index, percentages of over, under and correctestimations of lesions are computed by spatially comparing the results of present procedure with expert manual segmentation. The automated processing scheme detected 80% of the manually segmented lesions in the case of low-lesion load and 93% of the lesions in those cases with high lesion load.

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Tensor based morphometry (TBM) was applied to determine the atrophy of deep gray matter (DGM) structures in 88 relapsing multiple sclerosis (MS) patients. For group analysis of atrophy, an unbiased atlas was constructed from 20 normal brains. The MS brain images were co-registered with the unbiased atlas using a symmetric inverse consistent nonlinear registration. These studies demonstrate significant atrophy of thalamus, caudate nucleus, and putamen even at a modest clinical disability, as assessed by the expanded disability status score (EDSS). A significant correlation between atrophy and EDSS was observed for different DGM structures: (thalamus: r = −0.51, p = 3.85×10 −7 ; caudate nucleus: r = −0.43, p = 2.35×10 −5 ; putamen: r = −0.36, p = 6.12×10 −6 ). Atrophy of these structures also correlated with 1) T2 hyperintense lesion volumes (thalamus: r = −0.56, p = 9.96×10 −9 ; caudate nucleus: r = −0.31, p = 3.10×10 −3 ; putamen: r = −0.50, p = 6.06×10 −7 ), 2) T1 hypointense lesion volumes (thalamus: r = −0.61, p = 2.29×10 −10 ; caudate nucleus: r = −0.35, p = 9.51×10 −4 ; putamen: r = −0.43, p = 3.51×10 −5 ), and 3) normalized CSF volume (thalamus: r = −0.66, p = 3.55×10 −12 ; caudate nucleus: r = −0.52, p = 2.31×10 −7 , and putamen: r = −0.66, p = 2.13×10 −12 ). More severe atrophy was observed mainly in thalamus at higher EDSS. These studies appear to suggest a link between the white matter damage and DGM atrophy in MS.

Most mammalian genes will soon be characterized as cDNA sequences with little information about their function. To utilize this sequence information for large-scale functional studies, a gene trap retrovirus shuttle vector has been developed to disrupt genes expressed in murine embryonic stem (ES) cells. A library of mutant clones was isolated, and regions of genomic DNA adjacent to 400 independent provirus inserts were cloned and sequenced. The flanking sequences, designated 'promoter-proximal sequence tags', or PSTs, identified 63 specific genes and anonymous cDNAs disrupted as a result of virus integration. The efficiency of tagged sequence mutagenesis suggests that many of the 10,000-20,000 genes expressed in ES cells can be targeted, providing defined mutations for the analysis of gene functions in vivo. In addition, PSTs provide the first expressed sequence tags derived from genomic DNA, and define gene features such as exon boundaries and promoters that are missing from cDNA sequences.