Most Lung and Colon Cancer Susceptibility Genes Are Pair-Wise Linked in Mice, Humans and Rats

Genetic predisposition controlled by susceptibility quantitative trait loci (QTLs) contributes to a large proportion of common cancers. Studies of genetics of cancer susceptibility, however, did not address systematically the relationship between susceptibility to cancers in different organs. We present five sets of data on genetic architecture of colon and lung cancer susceptibility in mice, humans and rats. They collectively show that the majority of genes for colon and lung cancer susceptibility are linked pair-wise and are likely identical or related. Four CcS/Dem recombinant congenic strains, each differing from strain BALB/cHeA by a different small random subset of ±12.5% of genes received from strain STS/A, suggestively show either extreme susceptibility or extreme resistance for both colon and lung tumors, which is unlikely if the two tumors were controlled by independent susceptibility genes. Indeed, susceptibility to lung cancer (Sluc) loci underlying the extreme susceptibility or resistance of such CcS/Dem strains, mapped in 226 (CcS-10×CcS-19)F2 mice, co-localize with susceptibility to colon cancer (Scc) loci. Analysis of additional Sluc loci that were mapped in OcB/Dem strains and Scc loci in CcS/Dem strains, respectively, shows their widespread pair-wise co-localization (P = 0.0036). Finally, the majority of published human and rat colon cancer susceptibility genes map to chromosomal regions homologous to mouse Sluc loci. 12/12 mouse Scc loci, 9/11 human and 5/7 rat colon cancer susceptibility loci are close to a Sluc locus or its homologous site, forming 21 clusters of lung and colon cancer susceptibility genes from one, two or three species. Our data shows that cancer susceptibility QTLs can have much broader biological effects than presently appreciated. It also demonstrates the power of mouse genetics to predict human susceptibility genes. Comparison of molecular mechanisms of susceptibility genes that are organ-specific and those with trans-organ effects can provide a new dimension in understanding individual cancer susceptibility

Predicting a local recurrence after breast-conserving therapy by gene expression profiling

INTRODUCTION: To tailor local treatment in breast cancer patients there is a need for predicting ipsilateral recurrences after breast-conserving therapy. After adequate treatment (excision with free margins and radiotherapy), young age and incompletely excised extensive intraductal component are predictors for local recurrence, but many local recurrences can still not be predicted. Here we have used gene expression profiling by microarray analysis to identify gene expression profiles that can help to predict local recurrence in individual patients. METHODS: By using previously established gene expression profiles with proven value in predicting metastasis-free and overall survival (wound-response signature, 70-gene prognosis profile and hypoxia-induced profile) and training towards an optimal prediction of local recurrences in a training series, we establish a classifier for local recurrence after breast-conserving therapy. RESULTS: Validation of the different gene lists shows that the wound-response signature is able to separate patients with a high (29%) or low (5%) risk of a local recurrence at 10 years (sensitivity 87.5%, specificity 75%). In multivariable analysis the classifier is an independent predictor for local recurrence. CONCLUSION: Our findings indicate that gene expression profiling can identify subgroups of patients at increased risk of developing a local recurrence after breast-conserving therapy

A prospective, randomised and blinded comparison of first shock success of monophasic and biphasic waveforms in out-of-hospital cardiac arrest

Background: Evidence suggests that biphasic waveforms are more effective than monophasic waveforms for defibrillation in out-of-hospital cardiac arrest (OHCA), yet their performance has only been compared in un-blinded studies. Methods and results: We compared the success of biphasic truncated exponential (BTE) and monophasic damped sine (MDS) shocks for defibrillation in OHCA in a prospective, randomised, double blind clinical trial. First responders were equipped with MDS and BTE automated external defibrillators (AEDs) in a random fashion. Patients in ventricular fibrillation (VF) received BTE or MDS first shocks of 200 J. The ECG was recorded for subsequent analysis continuously. The success of the first shock as a primary endpoint was removal of VF and required a return of an organized rhythm for at least two QRS complexes, with an interval of <5 s, within 1 min after the first shock. The secondary endpoint was termination of VF at 5 s. VF was the initial recorded rhythm in 120 patients in OHCA, 51 patients received BTE and 69 received MDS shocks. The success rate of 200 J first shocks was significantly higher for BTE than for MDS shocks, 35/51 (69%) and 31/69 (45%), P = 0.01. In a logistic regression model the odds ratio of success for a BTE shock was 4.01 (95% CI 1.01-10.0), adjusted for baseline cardiopulmonary resuscitation, VF-amplitude and time between collapse and first shock. No difference was found with respect to the secondary endpoint, termination of VF at 5 s (RR 1.07 95% Cl: 0.99 - 1.11) and with respect to survival to hospital discharge (RR 0.73 95% CI: 0.31-1.70). Conclusion: BTE-waveform AEDs provide significantly higher rates of successful defibrillation with return of an organized rhythm in OHCA than MDS waveform AEDs. (C) 2003 Elsevier Ireland Ltd. All rights reserve

Predictors of the rate of decline of residual renal function in incident dialysis patients

BACKGROUND: Residual renal function (RRF) influences morbidity, mortality and quality of life in chronic dialysis patients. Few studies have been published on risk factors for loss of RRF in dialysis patients. These studies were either retrospective, performed in a small number of patients, or estimated GFR without a urine collection. METHODS: We analyzed the decline rates of residual GFR (rGFR) prospectively in 522 incident HD and PD patients who had structured follow-up assessments. GFR was measured as the mean of urea and creatinine clearance, calculated from urine collections. The initial value was obtained 0 to 4 weeks before the start of dialysis. The measurements were repeated 3, 6, and 12 months after the start of dialysis treatment. After logarithmic transformation, differences in rGFR changes over time were analyzed using repeated measurement analysis of variance. RESULTS: Baseline factors that were negatively associated with rGFR at 12 months were a higher diastolic blood pressure (P < 0.001) and a higher urinary protein loss (P < 0.001). Primary kidney disease did not affect rGFR. Averaged over time, PD patients had a higher rGFR (P < 0.001) than HD patients. This relative difference increased over time (P = 0.04). Investigation of possible effects of the dialysis procedure on the decline rate between 0 and three months showed that dialysis hypotension (P = 0.02) contributed to the decline in HD and the presence of episodes with dehydration contributed in PD (P = 0.004). CONCLUSIONS: rGFR is better maintained in PD patients than in HD patients. The associated factors such as a higher diastolic blood pressure, proteinuria, dialysis hypotension and dehydration can either be treated or avoide

Different Genetic Control of Cutaneous and Visceral Disease after Leishmania major Infection in Mice

The mouse strains BALB/cHeA (BALB/c) and STS/A (STS) are susceptible and resistant to Leishmania major-induced disease, respectively. We analyzed this difference using recombinant congenic (RC) BALB/c-c-STS/Dem (CcS/Dem) strains that carry different random subsets of 12.5% genes of the strain STS in a BALB/c background. Previously, testing the resistant strain CcS-5, we found five novel Lmr (Leishmania major response) loci, each associated with a different combination of pathological and immunological reactions. Here we analyze the response of RC strain CcS-16, which is even more susceptible to L. major than BALB/c. In the (CcS-16 × BALB/c)F(2) hybrids we mapped three novel loci that influence cutaneous or visceral pathology. Lmr14 (chromosome 2) controls splenomegaly and hepatomegaly. On the other hand Lmr15 (chromosome 11) determines hepatomegaly only, and Lmr13 (chromosome 18) determines skin lesions only. These data confirm the complex control of L. major-induced pathology, where cutaneous and visceral pathology are controlled by different combinations of genes. It indicates organ-specific control of antiparasite responses. The definition of genes controlling these responses will permit a better understanding of pathways and genetic diversity underlying the different disease phenotypes