Quantitative Imaging to Assess Tumor Response to Therapy: Common Themes of Measurement,Truth Data,and Error Sources

RATIONALE: Early detection of tumor response to therapy is a key goal. Finding measurement algorithms capable of early detection of tumor response could individualize therapy treatment as well as reduce the cost of bringing new drugs to market. On an individual basis, the urgency arises from the desire to prevent continued treatment of the patient with a high-cost and/or high-risk regimen with no demonstrated individual benefit and rapidly switch the patient to an alternative efficacious therapy for that patient. In the context of bringing new drugs to market, such algorithms could demonstrate efficacy in much smaller populations, which would allow phase 3 trials to achieve statistically significant decisions with fewer subjects in shorter trials. MATERIALS AND METHODS: This consensus-based article describes multiple, image modality-independent means to assess the relative performance of algorithms for measuring tumor change in response to therapy. In this setting, we describe specifically the example of measurement of tumor volume change from anatomic imaging as well as provide an overview of other promising generic analytic methods that can be used to assess change in heterogeneous tumors. To support assessment of the relative performance of algorithms for measuring small tumor change, data sources of truth are required. RESULTS: Very short interval clinical imaging examinations and phantom scans provide known truth for comparative evaluation of algorithms. CONCLUSIONS: For a given category of measurement methods, the algorithm that has the smallest measurement noise and least bias on average will perform best in early detection of true tumor change.     

Oxidative stress in skin fibroblasts cultures from patients with Parkinson's disease

Background  

In the substantia nigra of Parkinson's disease (PD) patients, increased lipid peroxidation, decreased activities of the mitochondrial complex I of the respiratory chain, catalase and glutathione-peroxidase, and decreased levels of reduced glutathione have been reported. These observations suggest that oxidative stress and mitochondrial dysfunction play a role in the neurodegeneration in PD. We assessed enzymatic activities of respiratory chain and other enzymes involved in oxidative processes in skin fibroblasts cultures of patients with PD.     

Lack of germ-line promoter methylation in BRCA1-negative families with familial breast cancer

Hereditary breast cancer accounts for about 10% of breast cancer in the United States, but high-penetrance, germ-line mutations in BRCA1 and BRCA2 are responsible for less than half of these high-risk families. Epigenetic modification of DNA by promoter methylation can result in a potentially heritable epimutation that silences the gene. Using a highly sensitive technique, we assayed the BRCA1 gene for promoter methylation among 41 BRCA1- and BRCA2-negative women whose personal and family histories indicated a high risk of BRCA mutations (median prior likelihood = 60%) using the BRCAPro model. DNA from 19 women who were "true negatives" for BRCA mutations served as controls. We found no evidence for promoter methylation among the high-risk women who tested negative for germ-line BRCA mutations. Thus, epimutation is an unlikely explanation for hereditary breast cancer in women who test negative for BRCA mutations.     

Fetal and maternal transforming growth factor-beta 1 may combine to maintain pregnancy in mice

One of the mysteries of pregnancy is why a mother does not reject her fetuses. Cytokine-modulation of maternal-fetal interactions is likely to be important. However, mice deficient in transforming growth factor-beta1 (TGF beta 1) and other cytokines are able to breed, bringing this hypothesis into question. The phenotype of TGF beta 1 null-mutant mice varies with genetic background. We report here that, in outbred mice, the loss of TGF beta 1-deficient embryos is influenced by the parity of their mother. This is consistent with the loss of mutants being due to immune rejection. An inbred line of TGF beta 1(+/-) mice that supported TGF beta 1-deficient fetuses had high levels of TGF beta 1 in their plasma. Analysis of the amniotic fluids in this line indicated that biologically relevant levels of maternal TGF beta 1 were present in the TGF beta 1(-/-) fetuses. These data are consistent with maternal and fetal TGF beta 1 interacting to maintain pregnancy, within immune-competent mothers.     

The transforming growth factor-betas: multifaceted regulators of the development and maintenance of skeletal muscles,motoneurons and Schwann cells

This review discusses the roles of the transforming growth factor-betas (TGF-betas) as part of a complex network that regulates the development and maintenance of the neuromuscular system. The actions of the TGF-betas often vary depending on which other growth factors are present, making it difficult to extrapolate results from in vitro experiments to the in vivo situation. A new approach has therefore been needed to understand the physiological functions of the TGF-betas. The behaviours (proliferation, fusion, apoptosis) of many of the cells in the neuromuscular system have a complex pattern which varies in space and time. The actions of growth factors in this system can thus be deduced based on how well their pattern of expression correlates with known cellular behaviours. Hypotheses based on this molecular anatomical evidence can then be further tested with genetically modified mice. From this type of evidence, we suggest that: (1) TGF-beta1 is an autocrine regulator of Schwann cells; (2) maternally-derived TGF-beta1 helps to suppress self and maternal immune attack; (3) TGF-beta2 regulates when and where myoblasts fuse to myotubes; (4) motoneuron survival is regulated by multiple sources of TGF-betas, with TGF-beta2 being the more important isoform. The concept of TGF-beta1 as a regulator of secondary myotube formation is not supported by either the location of the TGF-beta1 in developing muscles or by the phenotype of TGF-beta1-/- mice. The review concludes with a discussion of whether all of these of postulated functions can occur independently of each other, within the confines of the neuromuscular system.     

Only the N-Terminal Domain of FtsK Functions in Cell Division

Deletion of ftsK results in the inhibition of cell division, but this inhibition can be reversed by a plasmid carrying only the first ∼17% of ftsK. The division block can be suppressed in most mutants by deletion of dacA, which codes for the d-alanine:d-alanine carboxypeptidase PBP5, or in all mutants by overexpression of ftsN. Overexpression of ftsK inhibits cell division and the formation of FtsZ rings. This division block is not due to the induction of either the SOS or the heat shock regulons.The ftsK gene of Escherichia coli encodes a large protein (1,329 amino acids) which belongs to a family of bacterium- and plasmid-encoded proteins (2), at least some of which are required for DNA transfer between cells (12, 14, 17, 23) or between a mother cell and a spore compartment (24, 25). The FtsK protein is predicted to have an N-terminal domain (of about 200 amino acids) with several (four or five) membrane-spanning α helices, a proline-glutamine-rich region (∼660 amino acids), and a cytoplasmic domain (∼469 amino acids) with a consensus nucleotide-binding pocket (2). Two independent missense mutations (ftsK44 and ftsK3531) cause different single-amino-acid substitutions in the N-terminal domain, resulting in a temperature-dependent block of cell division (2; unpublished data). The division defect in both of these mutants can be suppressed by deletion of the dacA gene, coding for a d-alanine:d-alanine carboxypeptidase (PBP5), and can be complemented by cloned fragments of the wild-type ftsK gene that contain only the first 600 to 700 bp (2; unpublished data). The temperature sensitivity of cells carrying the ftsK44 or ftsK3531 allele is suppressed by plasmids carrying ftsN (17a).The present report describes the effects of disruption, deletion, and overexpression of the ftsK gene. We conclude that only the N-terminal ∼200-amino-acid domain of FtsK is required for cell division and that deletion of the remainder of the protein is not lethal. The ftsK gene is preceded by an SOS-inducible promoter, P_dinH (19, 20), and we show here that overexpression of FtsK blocks cell division in an SfiA-independent manner. It is therefore possible that ftsK overexpression forms part of an SfiA-independent, SOS-inducible division block.     

INTERSPECIFIC RECOGNITION AND DISCRIMINATION BASED UPON OLFACTORY CUES IN NORTHERN SWORDTAILS

Female Xiphophorus montezumae were attracted to olfactory cues from conspecific and heterospecific (X. cortezi and X. nigrensis) males when given a choice between the stimulus and water. When given a choice between conspecific and heterospecific cues, females only demonstrated a strong preference for the conspecific stimulus when it was matched against X. nigrensis. Female X. nigrensis were attracted to olfactory cues from their close relative, X. cortezi, but did not respond to cues from the more distantly related X. montezumae. They preferred the scent of their own males to the olfactory cues of both heterospecific species. Our results indicate that X. cortezi and X. nigrensis share an apomorphic change in some aspect of their olfactory cue-receiver system that is not shared with X. montezumae. We also uncovered an asymmetry in response based on olfactory stimuli in these fishes: X. montezumae is moderately attracted to the cue from X. nigrensis, whereas X. nigrensis does not respond to the cue from X. montezumae at all.     

Linkage analysis of chromosome 1q markers in 136 prostate cancer families. The Cancer Research Campaign/British Prostate Group U.K. Familial Prostate Cancer Study Collaborators.

Prostate cancer shows evidence of familial aggregation, particularly at young ages at diagnosis, but the inherited basis of familial prostate cancer is poorly understood. Smith et al. recently found evidence of linkage to markers on 1q, at a locus designated "HPC1," in 91 families with multiple cases of early-onset prostate cancer. Using both parametric and nonparametric methods, we attempted to confirm this finding, in 60 affected related pairs and in 76 families with three or more cases of prostate cancer, but we found no significant evidence of linkage. The estimated proportion of linked families, under a standard autosomal dominant model, was 4%, with an upper 95% confidence limit of 31%. We conclude that the HPC1 locus is responsible for only a minority of familial prostate cancer cases and that it is likely to be most important in families with at least four cases of the disease.     

HIV-particles in spermatozoa of patients with AIDS and their transfer into the oocyte

By immunocytochemistry and in situ hybridization at the electron microscopy level, and by the PCR technique, we have shown that HIV-1 binds and enters normal sperm; that viral particles, their antigens, and nucleic acid are present in sperm from HIV-1 infected men; and that such sperm can transfer HIV-1 like particles to normal human oocytes. We also present evidence that a galactosylceramide-like compound is present on the sperm membrane and could function as an alternative receptor for HIV.     

Prospects for estimating nucleotide divergence with RAPDs

The technique of random amplification of polymorphic DNA (RAPD), which is simply polymerase chain reaction (PCR) amplification of genomic DNA by a single short oligonucleotide primer, produces complex patterns of anonymous polymorphic DNA fragments. The information provided by these banding patterns has proved to be of great utility for mapping and for verification of identity of bacterial strains. Here we consider whether the degree of similarity of the banding patterns can be used to estimate nucleotide diversity and nucleotide divergence. With haploid data, fragments generated by RAPD-PCR can be treated in a fashion very similar to that for restriction-fragment data. Amplification of diploid samples, on the other hand, requires consideration of the fact that presence of a band is dominant to absence of the band. After describing a method for estimating nucleotide divergence on the basis of diploid samples, we summarize the restrictions and criteria that must be met when RAPD data are used for estimating population genetic parameters.