Faculty Publications

Selection of a dominant follicle that will ovulate likely occurs by activation of cell survival pathways and suppression of death-promoting pathways in a mechanism involving FSH and its cognate receptor (FSHR). A yeast two-hybrid screen of an ovarian cDNA library was employed to identify potential interacting partners with human FSHR intracellular loops 1 and 2. Among eight cDNA clones identified in the screen, APPL1 (adaptor protein containing PH domain, PTB domain, and leucine zipper motif; also known as APPL or DIP13alpha) was chosen for further analysis. APPL1 appears to coimmunoprecipitate with FSHR in HEK 293 cells stably expressing FSHR (293/FSHR cells), confirming APPL1 as a potential FSHR-interacting partner. The phosphorylation status of members of the phosphatidylinositol-3-kinase (P13K)/Akt signaling pathway was also examined because of the proposed role of APPL1 in the antiapoptotic P13K/Akt pathway. FOXO1a, also referred to as forkhead homologue in rhabdomyosar! coma, is a downstream effector in the pathway and tightly linked to expression of proapoptotic genes. FOXO1a, but not the upstream kinase Akt, is rapidly phosphorylated, and FOXO1 a is thereby inactivated when 293/FSHR cells are treated with FSH. In addition, FSHR coimmunoprecipitates with Akt. The identification of APPL1 as a potential interactor with FSHR and the finding that FOXO1a is phosphorylated in response to FSH provide a possible link between FSH and P13K/Akt signaling, which may help to delineate a survival mechanism whereby FSH selects the dominant follicle to survive.

Background: Several studies have reported that the risk of breast cancer decreases with increasing duration of breast-feeding. Whether breast-feeding is associated with a reduced risk of hereditary breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations is currently unknown. Methods: We conducted a case-control study of women with deleterious mutations in either the BRCA1 or the BRCA2 gene. Study participants, drawn from an international cohort, were matched on the basis of BRCA mutation (BRCA1 [n = 685] or BRCA2 [n = 2801), year of birth ( 2 years), and country of residence. The study involved 965 case subjects diagnosed with breast cancer and 965 control subjects who had no history of breast or ovarian cancer. Information on pregnancies and breast-feeding practices was derived from a questionnaire administered to the women during the course of genetic counseling. Conditional logistic regression analyses were used to estimate odds ratios (ORs) for the risk of breast cancer. All statistical tests were two-sided. Results: Among women with BRCA1 mutations, the mean total duration of breast-feeding was statistically significantly shorter for case subjects than for control subjects (6.0 versus 8.7 months, respectively; mean difference = 2.7 months, 95% confidence interval [CI] = 1.4 to 4.0; P<.001). The total duration of breast-feeding was associated with a reduced risk of breast cancer (for each month of breast-feeding, OR = 0.98, 95% CI = 0.97 to 0.99; P-trend <.001)- Women with BRCA1 mutations who breast-fed for more than 1year were less likely to have breast cancer than those who never breast-fed (OR = 0.55, 95% CI = 0.38 to 0.80; P =.001), although no such association was seen for BRCA2 (OR = 0.95, 95% CI = 0.56 to 1.59; P =.83). Conclusions: Women with deleterious BRCA1mutations who breast-fed for a cumulative total of more than 1year had a statistically significantly reduced risk of breast cancer.

BACKGROUND. The efficacy of energy conservation and activity management (ECAM) for fatigue reduction and maintenance of functional performance has never been evaluated in adults with cancer who are undergoing treatment. METHODS. A randomized clinical trial compared an ECAM intervention with a control intervention focused on nutrition. Individuals initiating chemotherapy, radiotherapy, or concurrent therapy for cancer were randomized to receive either the semistructured ECAM intervention (n = 200) or the control intervention (n = 196). Participants in each group participated in 3 telephone sessions with an oncology nurse during the first 5 weeks of treatment. Data on fatigue and limitation of functioning were obtained before cancer treatment and at two follow-up points that coincided with times of high fatigue for each type of treatment. The outcomes of interest included perception of fatigue and functional performance. RESULTS. A repeated-measures analysis of covariance using the type of cancer treatment as a covariate revealed a significant study group-by-time interaction indicating that the ECAM group experienced a greater decrease in fatigue over time compared with the control group (F-2,F-544 = 4.5; P = 0.01). The intervention was not associated with changes in overall functional performance. CONCLUSIONS. individuals who received the ECAM intervention derived a modest but significant benefit from it. To achieve a more robust clinical benefit from the intervention, it may be necessary to manage other key symptoms in addition to fatigue. Research is needed to examine symptom clusters or combinations associated with negative outcomes as well as combination strategies for symptom management. (C) 2004 American Cancer Society.

S-Adenosylmethionine decarboxylase (AdoMetDC) is a pyruvoyl cofactor-dependent enzyme that participates in polyamine biosynthesis. AdoMetDC from the Archaea Methanococcus jannaschii is a prototype for a recently discovered class that is not homologous to the eucaryotic enzymes or to a distinct group of microbial enzymes. M. jannaschii AdoMetDC has a Km of 95 microm and the turnover number (kcat) of 0.0075 s(-1) at pH 7.5 and 22 degrees C. The turnover number increased approximately 38-fold at a more physiological temperature of 80 degrees C. AdoMetDC was inactivated by treatment with the imine reductant NaCNBH3 only in the presence of substrate. Mass spectrometry of the inactivated protein showed modification solely of the pyruvoyl-containing subunit, with a mass increase corresponding to reduction of a Schiff base adduct with decarboxylated AdoMet. The presteady state time course of the AdoMetDC reaction revealed a burst of product formation; thus, a step after CO2 formation is rate-limiting in turnover. Comparable D2O kinetic isotope effects of were seen on the first turnover (1.9) and on kcat/Km (1.6); there was not a significant D2O isotope effect on kcat, suggesting that product release is rate-limiting in turnover. The pH dependence of the steady state rate showed participation of acid and basic groups with pK values of 5.3 and 8.2 for kcat and 6.5 and 8.3 for kcat/Km, respectively. The competitive inhibitor methylglyoxal bis(guanylhydrazone) binds at a single site per (alphabeta) heterodimer. UV spectroscopic studies show that methylglyoxal bis(guanylhydrazone) binds as the dication with a 23 microm dissociation constant. Studies with substrate analogs show a high specificity for AdoMet.

Background: Ductal lavage has the potential to detect cancer by sampling breast epithelium in asymptomatic high-risk women. To assess the utility of ductal lavage as a cancer diagnostic test, we investigated the association between ductal lavage cytologic findings and histologic findings in women with known breast cancer undergoing mastectomy. Methods: Ductal lavage was performed in the operating room before mastectomy on 44 breasts from 32 women with known cancer and on eight breasts from seven women undergoing prophylactic mastectomy, two with occult malignancy. If the ductal lavage sample from one or more ducts contained enough epithelial cells for a cytologic diagnosis, lavaged ducts were injected with a mixture of colored dye, gelatin, and a radiographic contrast compound after mastectomy, and breast tissue was radiographed and sectioned. Histologic findings in ducts with and without dye were recorded. Associations between cytologic results and histologic results were e xamined by univariate and multivariable analyses. Results: At least one duct was lavaged in 36 breasts (mean = 1.4 ducts per breast); all histologic and cytologic procedures were completed in 28 breasts and in 39 ducts. Markedly atypical or malignant cytology was found in five cancer-containing breasts. In 39 ducts with complete cytologic and histologic data and when marked atypia or malignant cells defined a positive cytologic test, sensitivity was 43% (95% confidence interval [CI] = 23% to 72%), specificity was 96% (95% CI = 86% to 100%), and accuracy was 77% (95% CI = 63 % to 89 %). When mild or marked atypia or malignant cells defined a positive cytologic test, sensitivity was 79% (95% CI = 57% to 96%), specificity was 64% (95% CI 46% to 83%), and accuracy was 69% (95% CI = 55% to 83%). When all 31 cytologically evaluable breasts were analyzed, sensitivity was 17% (95% CI = 7% to 35%), specificity was 100 % (95 % CI = 5 % to 100 %), and accuracy was 19% (95% CI = 9% to 38%). Conclusion: In breasts with cancer, ductal lavage appears to hav e low sensitivity and high specificity for cancer detection, possibly because cancer-containing ducts fail to yield fluid or have benign or mildly atypical cytology.

Polymorphisms in genes that encode for metabolic enzymes have been associated with variations in enzyme activity between individuals. Such variations could be associated with differences in individual exposure to carcinogens that are metabolized by these genes. In this study, we examine the association between polymorphisms in several metabolic genes and the consumption of tobacco in a large sample of healthy individuals. The database of the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens was used. All the individuals who were controls from the case-control studies included in the data set with information on smoking habits and on genetic polymorphisms were selected (n = 20,938). Sufficient information was available on the following genes that are involved in the metabolism of tobacco smoke constituents: CYPIAI, GSTMI, GSTTI, NAT2 and GSTPI. None of the tested genes was clearly associated with smoking behavior. Information on smoking ! dose, available for a subset of subjects, showed no effect of metabolic gene polymorphisms on the amount of smoking. No association between polymorphisms in the genes studied and tobacco consumption was observed; therefore, no effect of these genes on smoking behavior should be expected. (C) 2004 Wiley-Liss, Inc.

Several studies have found millisecond protein folding reactions to be controlled by the viscosity of the solvent: Reducing the viscosity allows folding to accelerate. In the limit of very low solvent viscosity, however, one expects a different behavior. Internal interactions, occurring within the solvent-excluded interior of a compact molecule, should impose a solvent-independent upper limit to folding speed once the bulk diffusional motions become sufficiently rapid. Why has this not been observed? We have studied the effect of solvent viscosity on the folding of cytochrome c from a highly compact, late-stage intermediate configuration. Although the folding rate accelerates as the viscosity declines, it tends toward a finite limiting value similar to10(5) s(-1) as the viscosity tends toward zero. This limiting rate is independent of the cosolutes used to adjust solvent friction. Therefore, interactions within the interior of a compact denatured polypeptide can limit the fo lding rate, but the limiting time scale is very fast. It is only observable when the solvent-controlled stages of folding are exceedingly rapid or else absent. Interestingly, we find a very strong temperature dependence in these "internal friction"-controlled dynamics, indicating a large energy scale for the interactions that govern reconfiguration within compact, near-native states of a protein.

(from the journal abstract) This longitudinal study examined the relation between life stress and basic beliefs about self-worth and the benevolence and meaningfulness of the world among mothers of children undergoing bone marrow transplantation (BMT). One hundred mothers completed study measures during the child's hospitalization for BMT and 1 year later. Prior trauma and recent negative events were associated with basic beliefs during hospitalization and also with changes in basic beliefs in the subsequent year, with distress mediating some of these relations. Findings also demonstrated relations between basic beliefs and physical and mental functioning. However, each basic belief exhibited different relations with study variables, suggesting the need to investigate them separately. (PsycINFO Database Record (c) 2004 APA, all rights reserved).

(from the journal abstract) Background: This longitudinal study investigated the course and predictors of benefit finding among 144 mothers of children undergoing hematopoietic stem cell transplantation (HSCT), a severely stressful and life-threatening medical procedure. Purpose: Children's medical risk and mothers' dispositional optimism and Sociodemographic resources were examined as predictors of benefit finding. The association between benefit finding and mothers' psychosocial adaptation was also investigated. Methods: Assessments occurred during hospitalization for HSCT (Time 1 [T1]) and 6 months later (Time 2 [T2]). Results: Hierarchical multiple regression analyses revealed that predictors of benefit finding differed systematically across assessments, with optimism and medical risk predicting benefit finding at both time points but Sociodemographic resources predicting only 72 benefit finding. Benefit finding did not predict psychosocial adaptation until optimism was considered as a moderator of their relation: T1 benefit finding was positively associated with 72 adaptation only for mothers high in optimism. Conclusions: The need for longitudinal research on posttrauma adaptation and the utility of considering the natural history of the trauma are discussed. (PsycINFO Database Record (c) 2004 APA, all rights reserved).

Imatinib mesylate is a selective inhibitor of a few tyrosine kinases including KIT, and it is the first effective treatment for gastrointestinal stromal tumors (GISTs). We monitored the serum levels of KIT, KIT ligand (stem cell factor, SCIF), and the vascular endothelial growth factor (VEGF) in patients with advanced GISTs treated with imatinib in a prospective randomized trial. Patients with GISTs (n = 66) had elevated pretreatment serum KIT and VEGF levels as compared with controls (median, 292 AU/mL [409 ng/mL] vs 238 AU/mL [333 ng/mL], P = .037; and median, 303 pg/mL vs 190 pg/mL, P = .013, respectively), but lower levels of SCIF (median, 645 pg/mL vs 950 pg/mL; P less than or equal to .0001). After 1 and 6 months of imatinib treatment the average serum KIT levels decreased 31% and 52% from pretreatment levels, whereas SCIF levels increased 11% and 33%, respectively. Serum VEGF levels decreased during treatment in responding patients. The median serum SCF/KIT ratio increased with treatment duration, and was 7.7-fold higher after 12 months of treatment than at baseline (range, 3.1-259-fold). A high serum SCF/KIT ratio may increase SCF-induced cell signaling with prolonged imatinib treatment, at the time when imatinib treatment is withdrawn, and in patients whose GIST has wild-type receptors. (C) 2004 by The American Society of Hematology. Addresses: Univ Helsinki, Cent Hosp, Dept Oncol, FIN-00029 Helsinki, Finland; Novartis Oncol, Basel, Switzerland; Oregon Hlth Sci Univ, Inst Canc, Portland, OR 97201 USA; Portland Vet Affairs Med Ctr, Portland, OR USA; Fox Chase Canc Ctr, Philadelphia, PA 19111 USA; Dana Farber Canc Inst, Boston, MA 02115 USA; Harvard Univ, Ctr Canc, Boston, MA 02115 USA