Faculty Bibliography

PURPOSE: We investigated the factors that influenced urinary symptoms in the first 10 years after prostate brachytherapy. MATERIALS AND METHODS: A total of 1,932 men were treated with prostate brachytherapy alone or with external beam irradiation and followed a mean of 6.8 years. The influence of pretreatment American Urological Association symptom score (7 or less, 8 to 19, 20 or greater), external beam radiotherapy, (125)I or (103)Pd, biological effective dose, age, prostate size and hormone therapy on the change in American Urological Association symptom score (11,491) was compared. RESULTS: The mean change from initial score (7.4) was 11.4, 5.5, 3.3, 2.7, 1.5, 1.2, 1, 1, 1, 1, 1.3 and 1.4 points at 3, 6 months and 1 to 10 years, respectively (p <0.001). Factors that resulted in a greater increase in urinary symptoms at year 1 were low pretreatment score (p <0.001), no hormonal therapy (p <0.001), younger age (p = 0.046) and higher biological effective dose (p = 0.025). At 10 years patients with an initial score of 20 or greater had an average decrease of 11 points compared to a decrease of 0.9 for an initial score of 8 to 19 and an increase of 2.7 for an initial score of 7 or less (p <0.001). On linear regression the scores at 1 year were influenced by initial score (p <0.001), biological effective dose (p = 0.022), prostate size (p <0.001) and hormonal therapy (p = 0.009). At 10 years only the pretreatment score remained significant (p <0.001). CONCLUSIONS: There is minimal change in mean American Urological Association symptom score (1.4 points) 10 years after prostate brachytherapy. Patients presenting with high initial scores have the greatest improvement from baseline. Biological effective dose, external beam radiotherapy, hormonal therapy, isotope, patient age and prostate size do not appear to influence long-term urinary symptoms.

PURPOSE: Gastrointestinal cancers frequently exhibit mutational activation of the Ras/MAPK pathway, which is implicated in resistance to ionizing radiation (IR) and chemotherapy. Concurrent radiotherapy and 5-fluorouracil (5-FU) based chemotherapy is commonly used for treatment of gastrointestinal malignancies. We previously reported radiosensitization with selumetinib, an inhibitor of MEK1/2. The purpose of the current study was to evaluate if selumetinib could enhance radiosensitivity induced by 5-FU. EXPERIMENTAL DESIGN: Clonogenic survival assays were carried out with the HT29 (colorectal), HCT116 (colorectal), and MiaPaca-2 (pancreatic) cell lines using pre-IR treatment with selumetinib, 5-FU and 5-FU+selumetinib. Cell proliferation was determined using a tetrazolium conversion assay. Mitotic catastrophe and DNA repair were analyzed using immunocytochemistry. Flow cytometry was used to analyze cell cycle and apoptosis. Growth delay was used to determine effects of 5-FU+selumetinib on in vivo tumor radiosensitivity. RESULTS: Pre-IR treatment with 5-FU+selumetinib significantly decreased clonogenic survival compared with either agent alone. Dose modifying factors at a surviving fraction of 0.1 for 5-FU+selumetinib was 1.78, 1.52, and 1.3 for HT29, HCT116, and MiaPaca-2, respectively. Cell proliferation was decreased by treatment with selumetinib+5-FU as compared with single agent treatment regardless of treatment sequencing. Enhancement of 5-FU cytotoxicity and 5-FU mediated radiosensitization with selumetinib treatment was accompanied by an increase in mitotic catastrophe and apoptosis, and reductions in Stat3 phosphorylation and survivin expression. In vivo, an additive growth delay was observed with 5-FU+selumetinib+3Gy versus 5-FU+3Gy and selumetinib alone. CONCLUSION: These data suggest that selumetinib can be used with 5-FU to augment radiation response.

Polyoma virus middle T antigen (PyVmT) is a powerful viral oncogene; however, the mechanisms of PyVmT activation are poorly understood. The insulin-like growth factor I receptor (IGF-IR) and the insulin receptor (IR) are known to be implicated in the development of many cancers. Furthermore, PyVmT-overexpressing mouse mammary carcinoma Met-1 cells are highly responsive to IGF-I and insulin. Herein, we demonstrate that PyVmT physically interacts with IGF-IR and IR in Met-1 cells. Insulin and IGF-I increase association of the IR and IGF-IR with PyVmT, enhance tyrosine phosphorylation of PyVmT and augment the recruitment of Src and PLCgamma(1) to PyVmT. This is accompanied by robust and sustained phosphorylation of Akt and ERK1/2, which are implicated in both PyVmT and IGF-IR/IR signalling. Both ligands significantly increase proliferation, survival, migration and invasion of Met-1 cells. Furthermore, orthotopic inoculation of Met-1 cells with shRNAmir-mediated knockdown of IR or IGF-IR fails to initiate tumour growth in recipient mice. In conclusion, our data indicate that the physical and functional interaction between PyVmT and cellular receptor tyrosine kinases, including IR and IGF-IR, is critical for PyVmT activation and tumour initiation. These results also provide a novel mechanism for oncogene activation in the host cell.

Disruption of endoplasmic reticulum (ER) homeostasis causes accumulation of unfolded and misfolded proteins in the ER, triggering the ER stress response, which can eventually lead to apoptosis when ER dysfunction is severe or prolonged. Here we demonstrate that human MCF-7 breast cancer cells, as well as murine NIH/3T3 fibroblasts, are rescued from ER stress-initiated apoptosis by insulin-like growth factor-I (IGF-I). IGF-I significantly augments the adaptive capacity of the ER by enhancing compensatory mechanisms such as the IRE1 alpha-, PERK- and ATF6-mediated arms of ER stress signalling. During ER stress, IGF-I stimulates translational recovery and induces expression of the key molecular chaperone protein Grp78/BiP, thereby enhancing the folding capacity of the ER and promoting recovery from ER stress. We also demonstrate that the antiapoptotic activity of IGF-I during ER stress may be mediated by a novel, as yet unidentified, signalling pathway(s). Application of signal transduction inhibitors of MEK (U1026), PI3K (LY294002 and wortmannin), JNK (SP600125), p38 (SB203580), protein kinases A and C (H-89 and staurosporine) and STAT3 (Stattic) does not prevent IGF-I-mediated protection from ER stress-induced apoptosis. Taken together, these data demonstrate that IGF-I protects against ER stress-induced apoptosis by increasing adaptive mechanisms through enhancement of ER stress-signalling pathways, thereby restoring ER homeostasis and preventing apoptosis.

The study set out to examine the predictive effects of patients' emotional distress and their relationships with their health care providers on satisfaction with obstetric services in high-risk pregnancies. Participants were 104 pregnant women with a history of recurrent losses, fetal demise, previous or current fetal genetic abnormality, advanced maternal age, or obstetric or medical complications of the present pregnancy. Self-report measures of emotional distress and the quality of their relationships with their medical provider were administered. Hierarchical multiple regression analyses were conducted to assess the predictive effect of these variables on satisfaction with services. Provision of information, constructive communication, and good relationships predicted elevated satisfaction with health services. Provision of information also buffered against the adverse effect of emotional distress on satisfaction with health services. These findings elucidate the central role of provider patient interaction, particularly as it is related to provision of information, in high-risk pregnancy.