Classification tree analysis of second neoplasms in survivors of childhood cancer

Background  

Reports on childhood cancer survivors estimated cumulative probability of developing secondary neoplasms vary from 3,3% to 25% at 25 years from diagnosis, and the risk of developing another cancer to several times greater than in the general population.     

Familial stenosis of the pulmonary artery branches with a JAG1 mutation.

Although most congenital heart defects are isolated abnormalities of embryonic development, with little genetic contribution, a small number are components of syndromes. In such cases, an accurate diagnosis has important implications for individual prognosis and familial genetic counseling. Alagille syndrome (AGS) is a dominantly inherited multisystem developmental disorder, which primarily affects the liver, heart, eyes, skeleton, and face. In recent years, the identification of the AGS gene has drawn attention to the existence of subclinical carriers, and broadened the spectrum of phenotypical variation associated with this syndrome. The authors present a case of mother and son with benign stenosis of the pulmonary artery branches. Subtle facial aspects suggested the diagnosis of AGS, which was confirmed by molecular analysis. Relevant clinical investigations and diagnostic implications are discussed.     

Computed tomography in gunshot wounds to the neck: Can we predict vascular injury?

The purpose of this study was to evaluate the ability of helical computed tomography (CT) to detect arterial injuries in gunshot wounds to the neck. In a blinded retrospective review, 54 helical CT scans of the cervical spine were evaluated for bullet/bone fragments, subcutaneous air, bullet path, hematoma, spine fractures, and pharyngoesophageal compromise. The distance of fragments to a major vessel was calculated. CT findings that correlated significantly with major arterial injury included the presence of fragments (bullet/bone) close to a major vessel (2.5 mm) and spine fractures. Visualizing fragments <5 mm from a vessel or a transcervical bullet trajectory predicted 12 of 13 major arterial injuries. We conclude that CT clearly depicts anatomic damage. Specific findings, such as the location of fragments and bullet trajectory adjacent to a vessel and spine fractures, indicate a higher probability of vascular damage, thus directing more definitive evaluation.     

Determination of sex and Y chromosome]

Years of speculations about the nature of the elusive testis determining factor (TDF) of the Y chromosome have ended last year. A gene named SRY satisfies many criteria expected of the testis determining gene, and gives us a basis to understand molecular mechanisms of the testis differentiation. The different steps which gave rise to SRY cloning are described.     

Influence of cigarette smoking on pituitary and sex hormone balance in healthy premenopausal women

Plasma gonadotropin FSH and LH, PRL, sex steroids (17-beta E2, E1, and P), SBP binding capacity, and urine estrogens (E1, E2, and E3) were measured in 485 premenopausal healthy women, subdivided according to smoking habits. The aim of the study was to verify if cigarette smoking influences sex hormone balance. Baseline PRL levels were significantly lower (P less than 0.002) in smoker (n = 174) than in nonsmoker (n = 311) women. No difference was found in the other parameters of the two groups, particularly in plasma and urine estrogenic pattern. Our data suggest that smoking directly affects PRL levels by involving the hypothalamic mechanism that regulates PRL secretion.     

Haplotype analysis of the BRCA2 9254delATCAT recurrent mutation in breast/ovarian cancer families from Spain

A frame-shift 9254del5 mutation was independently identified in 12 families, eleven of them with Spanish ancestors, in a BRCA2 screening performed in 841 breast and/or ovarian cancer families and in 339 women with breast cancer diagnosed before the age of 40 at different centers in France and Spain. We sought to analyze in detail the haplotype and founder effects of the 9254del5 and to estimate the time of origin of the mutation. Eight polymorphic microsatellite markers and two BRCA2 polymorphisms were used for the haplotype analyses. The markers were located flanking the BRCA2 gene spanning a region of 6.1 cM. Our results suggest that these families shared a common ancestry with BRCA2 9254del5, which is a founder mutation originating in the Northeast Spanish, with an estimated age of 92 (95% CI 56-141) generations.     

Bcl-x(L)-mediated changes in metabolic pathways of breast cancer cells: from survival in the blood stream to organ-specific metastasis

Bcl-x(L) protein plays a role in breast cancer dormancy, promoting survival of cells in metastatic foci by counteracting the proapoptotic signals in the microenvironment. The aim of this study was to identify phenotypes mediated by Bcl-x(L) in breast cancer cells that enhance in vivo survival of clinical metastases. 435/Bcl-x(L) or 435/Neo human breast cancer cells were injected into the inguinal mammary gland of nude mice, and tumors, metastases in lymph node, lung, and bone, and bloodstream surviving cells were examined. Proteomic analysis identified 17 proteins that were overexpressed (more than twofold) or underexpressed (less than twofold) in metastases. A protein interaction program allowed us to functionally associate peroxiredoxin 3, peroxiredoxin 2, carbonyl reductase 3, and enolase 1, suggesting a role for cellular responses to oxidative stress in metastasis organ selection. The prediction included proteins involved in redox systems, kinase pathways, and the ATP synthase complex. Furthermore, the interaction of redox proteins with enolase 1 suggests a connection between glycolysis and antioxidant pathways, enabling achievement of a high metastatic activity. In conclusion, Bcl-x(L) mediates a phenotype in which redox pathways and glycolysis are coupled to protect breast cancer metastatic cells during transit from the primary tumor to the metastatic state.     

Seven generations of genetic selection for ethanol dependence in mice

An animal model of alcohol dependence is being produced by selecting mice for differences in severity of ethanol withdrawal seizures. Replicate lines of high-dependence (HA), low-dependence (LA), and control (CA) mice are being developed by within-family selection. After seven generations both (replicate) HA and LA lines have separated significantly. Some of the difference between the replicate pairs of HA and LA in the early generations was due to differences in ethanol consumption. This difference in consumption may be attributable to a difference in metabolic rate or activity level rather than to a difference in ethanol preference. Females are more susceptible to seizures than males; this appears to be due partly to their higher consumption of ethanol during treatment.This research was supported in part by Grant AA-03527 from the National Institute of Alcohol Abuse and Alcoholism to the University of Colorado Alcohol Research Center.