Dextran sulfate sodium (DSS)-induced murine colitis represents an experimental model for human inflammatory bowel disease. The aim of this study was to screen various inbred strains of mice for genetically determined differences in susceptibility to DSS-induced colitis. Mice of strains C3H/HeJ, C3H/HeJBir, C57BL/6J, DBA/2J, NOD/LtJ, NOD/LtSz- Prkdcscid/Prkdcscid , 129/SvPas, NON/LtJ, and NON.NOD- H2g7 were fed 3.5% DSS in drinking water for 5 days and necropsied 16 days later. Ceca and colons were scored for histological lesions based on severity, ulceration, hyperplasia, and area involved. Image analysis was used to quantitate the proportion of cecum ulcerated. Histological examination revealed significant differences among inbred strains for all parameters scored. In both cecum and colon, C3H/HeJ and a recently selected substrain, C3H/HeJBir, were highly DSS susceptible. NOD/LtJ, an autoimmune-prone strain, and NOD/LtSz- Prkdcscid/Prkdcscid , a stock with multiple defects in innate and adoptive immunity, were also highly DSS susceptible. NON/LtJ, a strain closely related to NOD, was quite DSS resistant. The major histocompatibility (MHC) haplotype of NOD mice ( H2g7 ), a major component of the NOD autoimmune susceptibility, was not crucial in determining DSS susceptibility, since NON mice congenic for this MHC haplotype retained resistance. C57BL/6J, 129/SvPas, and DBA/2J mice showed various degrees of susceptibility, depending upon the anatomical site. A greater male susceptibility to DSS-induced colonic but not cecal lesions was observed. In summary, this study demonstrates major differences in genetic susceptibility to DSS-induced colitis among inbred strains of mice. Knowledge of these strain differences in genetic responsiveness to acute inflammatory stress in the large intestine will permit design of genetic crosses to elucidate the genes involved.

Colitic lesions are much more severe in C3H͞HeJBir (C3H) than C57BL͞6J (B6) mice after 10 backcrosses of a disrupted interleukin-10 (Il10) gene. This study identified cytokine deficiency-induced colitis susceptibility (Cdcs) modifiers by using quantitative trait locus (QTL) analysis. A segregating F2 population (n ‫؍‬ 408) of IL-10-deficient mice was genotyped and necropsied at 6 weeks of age. A major C3H-derived colitogenic QTL (Cdcs1) on chromosome (Chr.) 3 contributed to lesions in both cecum [logarithm of odds ratio (LOD) ‫؍‬ 14.6)] and colon (LOD ‫؍‬ 26.5) as well as colitis-related phenotypes such as spleen͞body weight ratio, mesenteric lymph node͞body weight ratio, and secretory IgA levels. Evidence for other C3H QTL on Chr. 1 (Cdcs2) and Chr. 2 (Cdcs3) was obtained. Cdcs1 interacted epistatically or contributed additively with loci on other chromosomes. The resistant B6 background also contributed colitogenic QTL: Cdcs4 (Chr. 8), Cdcs5 (Chr. 17, MHC), and Cdcs6 (Chr. 18). Epistatic interactions between B6 QTL on Chr. 8 and 18 contributing to cecum hyperplasia were particularly striking. In conclusion, a colitogenic susceptibility QTL on Chr. 3 has been shown to exacerbate colitis in combination with modifiers contributed from both parental genomes. The complex nature of interactions among loci in this mouse model system, coupled with separate deleterious contributions from both parental strains, illustrates why detection of human inflammatory bowel disease linkages has proven to be so difficult. A human ortholog of the Chr. 3 QTL, if one exists, would map to Chr. 4q or 1p.

Purpose-The aims of this study were to determine outcomes for patients with inflammatory breast cancer (IBC) treated with multimodality therapy, to identify factors associated with locoregional recurrence, and to determine which patients may benefit from radiation dose escalation. Results-The 192 patients who were able to complete the planned course of chemotherapy, mastectomy, and postmastectomy radiation had significantly better outcomes than the 64 patients who did not. The respective 5-year outcome rates were: locoregional control (84% vs. 51%), distant metastasis-free survival (47% vs. 20%), and overall survival (51% vs. 24%) (p < 0.0001 for all comparisons). Univariate factors significantly associated with locoregional control in the patients who completed plan treatment were response to neoadjuvant chemotherapy, surgical margin status, number of involved lymph nodes, and use of taxanes. Increasing the total chest-wall dose of postmastectomy radiation from 60 Gy to 66 Gy significantly improved locoregional control for patients who experienced less than a partial response to chemotherapy, patients with positive, close, or unknown margins, and patients <45 years of age. Methods and Materials-WeConclusions-Patients with IBC who are able to complete treatment with chemotherapy, mastectomy, and postmastectomy radiation have a high probability of locoregional control.

Severity of inflammatory bowel disease in IL-10 gene-targeted mice is in part determined by genetic background. In the current study, a targeted IL-10 gene was transferred into the C3H/HeJBir substrain, known to exhibit high T-cell and B-cell responses to enteric flora, and to be highly sensitive to colitigenic stress. IL-10-deficient C3H/HeJBir mice developed early onset colitis in contrast to IL-10-deficient C57BL/6J congenic mice. Histopathologic analysis of disease in C3H/HeJBir.Il10-/- and C57BL/6J.Il10-/- mice showed significant differences at all ages studied. Hybrids of these congenic strains (F1.Il10-/-) were produced to study the mode of inheritance as well as subphenotypes that correlated with histopathology. Lesions in F1 mice were intermediate between parental strains. C3H-contributed subphenotypes that correlated best with histopathology were peripheral blood granulocyte percentage, serum amyloid A concentration, spleen weight/body weight ratio, and mesenteric lymph node weight/ body weight ratio. Neither enhanced humoral immunity (secretory IgA, anti-Escherichia coli cellular membrane Ig) characteristic of C3H/HeJBir, nor T-cell percentages in peripheral blood correlated as well. This study represents a necessary step in elucidating murine genetic modifiers controlling colitis sensitivity.

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Abbreviations & Acronyms BMI = body mass index CAD = coronary artery disease CPM = clinical prediction models NA = not available PSA = prostate-specific antigen RT = radiation therapy Objectives: To develop clinical prediction models estimating the probability of maintaining erections adequate for intercourse 2 years after prostate cancer treatment, based on pretreatment characteristics. Methods: Study participants consisted of prostate cancer patients with localized disease and functional erections before undergoing surgery (n = 536) or radiation therapy (n = 240) at a single USA institution. Baseline patient-and treatment-related data were collected from a clinical database and through chart review. Erectile function at 2 years post-treatment was prospectively assessed through a self-administered single-item measure. Multivariate logistic regression using backward selection was used to derive clinical prediction models to predict erectile function at 2 years for surgery and radiation therapy patients; the models were internally validated using bootstrapping methods. Results: The final prediction model for surgery patients included the predictor variables of age, body mass index, smoking, diabetes, hypertension and nerve-sparing procedures, whereas the model for radiation therapy patients included hypertension, risk category and radiation technique. The new models showed acceptable calibration and discrimination: c-statistic = 0.71 (95% confidence interval 0.68-0.76) for surgery and 0.66 (95% confidence interval 0.61-0.74) for radiation therapy models. Conclusions: New clinical prediction models based on patient and treatment characteristics show promising accuracy in predicting erectile function at 2 years in patients treated with surgery and radiation for localized prostate cancer. More work is required to confirm and validate these models in different patient populations.