Inherited and noninherited sources of variation in metastasis and the growth rate of tumors: Implications for tumor evolution and therapy

I have undertaken measurements of the genetic (or inherited) and nongenetic (or noninherited) components of the variability of metastasis formation and tumor diameter doubling time in more than 100 metastatic lines from each of three murine tumors (sarcoma SANH, sarcoma SA4020, and hepatocarcinoma HCA-I) syngeneic to C3Hf/Kam mice. These lines were isolated twice from lung metastases and analysed immediately thereafter to obtain the variance to spontaneous lung metastasis and tumor diameter doubling time. Additional studies utilized cells obtained from within 4 passages of isolation. Under the assumption that no genetic differences in metastasis formation or diameter doubling time existed among the cells of a given line, the variance within a line would estimate nongenetic variation. The variability derived from differences between lines would represent genetic origin. The estimates of the genetic contribution to the variation of metastasis and tumor diameter doubling time were significantly greater than zero, but only in the metastatic lines of tumor SANH was genetic variation the major source of metastatic variability (contributing 53% of the variability). In the tumor cell lines of SA4020 and HCA-I, however, the contribution of nongenetic factors predominated over genetic factors in the variability of the number of metastasis and tumor diameter doubling time. A number of other parameters examined, such as DNA content, karyotype, and selection and variance analysis with passage in vivo, indicated that genetic differences existed within the cell lines and that these differences were probably created by genetic instability. The mean metastatic propensity of the lines may have increased somewhat during their isolation and isotransplantation, but the variance was only slightly affected, if at all. Analysis of the DNA profiles of the metastatic lines of SA4020 and HCA-I revealed differences between these lines and their primary parent tumors, but not among the SANH lines and their parent tumor. Furthermore, there was a direct correlation between the extent of genetic influence on metastasis formation and the ability of the tumor cells to develop resistance to cisplatinum. Thus although nongenetic factors might predominate in contributing to metastasis formation, it is probably genetic variation and genetic instability that cause the progression of tumor cells to a more metastatic phenotype and leads to the emergence of drug resistance. ^

Host factors in metastasis: Direct lysis of bloodborne metastatic tumor cells by murine vascular endothelial cells

During the process of cancer metastasis, the majority of circulating tumor cells arrest in microcapillary beds and then rapidly die. To study whether vascular endothelial cells can directly lyse tumor cells, we isolated vascular endothelial cells by perfusion of lungs from immunocompetent or nude mice. The cells were grown in culture, and then cloned and characterized. Cloned endothelial cells were incubated with several lymphokines and cytokines. Cells incubated with IFN-$\gamma$ and TNF lysed a variety of tumor cells with different metastatic potential. Mouse skin and lung fibroblasts treated with the same cytokines did not. Endothelial cell mediated tumor cell lysis was not due to different binding ability of tumor cells to cytokine treated and untreated endothelial monolayers. Kinetic studies demonstrated that the continuous presence of cytokines in the tumor-endothelial cocultures was necessary to produce maximal lysis of tumor cells. Target cell lysis was not due to the direct effects of IFN-$\gamma$ or TNF, since vascular endothelial cells isolated from the lung of nude mice lysed human melanoma cells that are sensitive or resistant to TNF. Cytokine treated endothelial cells produced a high level of nitric oxide, which is known to be cytotoxic to a variety of target cells. The level of nitric oxide production was directly correlated with the degree of tumor cell lysis. A specific inhibitor of nitric oxide synthesis(N$\sp{\rm G}$-monomethyl-L-arginine), completely inhibited production of nitric oxide and tumor cell lysis. Treatment of cytokine activated endothelial cells with dexamethasone also inhibited tumor cell lysis. This inhibition was independent of tumor-endothelial adhesion but correlated with inhibition of nitric oxide production. Collectively, these results suggest that vascular endothelial cells can directly destory tumor emboli and thus play an active role in the pathogenesis of cancer metastasis. ^

Radiolabeled human monoclonal IgM for intracompartmental cancer therapy

Radioimmunotherapy (RIT) with i.v. administered radiolabeled IgG can selectively irradiate tumor cells in vivo. However, it only provides effective therapy for lymphomas. Intracompartmental RIT with radiolabeled human monoclonal IgM may allow curative treatment of solid tumors by increasing tumor deposition of radioactivity, reducing systemic toxicity and allowing repeated administration. This hypothesis was tested in nude mouse models with IgM radiolabeled with indium-111 $\rm(\sp{111}In)$ or yttrium-90 $\rm(\sp{90}Y).$ The use of two radioisotopes, $\rm\sp{111}In$ for imaging and $\rm\sp{90}Y$ for therapy, allow for more quantitative and cautious development of RIT.^ Radiolabled 2B12, an IgM reactive with human ovarian carcinomas was tested by i.v. and intraperitoneal (i.p.) administration in nude mice bearing i.p. nodules of a human ovarian carcinoma cell line (SKOV3 NMP2). Radiolabeled CR4E8, an IgM reactive with human squamous cell carcinomas was tested by i.v. and intralesional (i.l.) administration in nude mice bearing subcutaneous tumors of a human head and neck squamous cell carcinoma cell line (886). These two models were selected to test proof of concept. Radiolabeled irrelevant IgM (CH-1B9), and $\rm\sp{90}Y$-aggregate served as specificity controls. Biodistribution was performed by excising, weighing and then measuring the radioactivity of tumor and normal organs. Therapy was conducted with i.p. $\rm\sp{90}Y$-labeled 2B12 using both single and fractionated administration and with i.l. $\rm\sp{90}Y$-labeled CR4E8 using single administration. Mice were monitored for tumor response, survival and systemic toxicity.^ Intracompartmental administration of radiolabeled IgM produced immediate high and prolonged tumor deposition of radioactivity with low normal tissue uptake. In contrast, i.v. administration resulted in low tumor, but high liver and spleen uptake. Similar biodistributions were demonstrated for $\rm\sp{111}In$- and $\rm\sp{90}Y$-labeled IgM. Intraperitoneal therapy with $\rm\sp{90}Y$-labeled 2B12 increased survival by approximately 12 days for every 100 $\rm\mu Ci$ of activity without significant toxicity for single (0-300 $\rm\mu Ci)$ and fractionated (150-510 $\rm\mu Ci)$ administration. Intralesional therapy with $\rm\sp{90}Y$-labeled CR4E8 (150-400 $\rm\mu Ci)$ induced prolonged complete regressions. Significant local or systemic toxicity was not observed.^ Intracompartmental RIT with radiolabeled tumor-reactive human monoclonal IgM can selectively irradiate tumor cells. Intracompartmental radiolabled IgM can significantly extend the survival of treated mice with minimal toxicity. It deserves further development as a new cancer therapy. ^

A quality of life subscale for terminally ill cancer patients

A subscale was developed to assess the quality of life of cancer patients with a life expectancy of six months or less. Phase I of this study identified the major concerns of 74 terminally ill cancer patients (19 with breast cancer, 19 with lung cancer, 18 with colorectal cancer, 9 with renal cell cancer, 9 with prostate cancer), 39 family caregivers, and 20 health care professionals. Patients interviewed were being treated at the University of Texas M. D. Anderson Cancer Center or at the Hospice at the Texas Medical Center in Houston. In Phase II, 120 patients (30 with breast cancer, 30 with lung cancer, 30 with colorectal cancer, 15 with prostate cancer, and 15 with renal cell cancer) rated the importance of these concerns for quality of life. Items retained for the subscale were rated as "extremely important" or "very important" by at least 60% of the sample and were reported as being applicable by at least two-thirds of the sample. The 61 concerns that were identified were formatted as a questionnaire for Phase III. In Phase III, 356 patients (89 with breast cancer, 88 with lung cancer, 88 with colorectal cancer, 44 with prostate cancer, and 47 with renal cell cancer) were interviewed to determine the subscale's reliability and sensitivity to change in clinical status. Both factor analysis and item response theory supported the inclusion of the same 35 items for the subscale. Internal consistency reliability was moderate to high for the subscale's domains: spiritual (0.87), existential (0.76), medical care (0.68), symptoms (0.67), social/family (0.66), and emotional (0.61). Test-retest correlation coefficients also were high for the domains: social/family (0.86), emotional (0.83), medical care (0.83), spiritual (0.75), existential (0.75), and symptoms (0.81).^ In addition, concurrent validity was supported by the high correlation between the subscale's symptom domain and symptom items from the European Organization for Research and Treatment of Cancer (EORTC) scale (r = 0.74). Patients' functional status was assessed with the Eastern Cooperative Oncology Group (ECOG) Performance status rating. When ECOG categories were compared to subscale domains, patients who scored lower in functional status had lower scores in the spiritual, existential, social/family, and emotional domains. Patients who scored lower in physical well-being had higher scores in the symptom domain. Patient scores in the medical care domain were similar for each ECOG category. The results of this study support the subscale's use in assessing quality of life and the outcomes of palliative treatment for cancer patients in their last six months of life. ^

Developmental effects of estrogen and PCBs in the reproductive tract of BALB/C mice

Many of the tumorigenic effects that result from neonatal exposure to both natural and synthetic estrogens resemble those found in humans exposed to diethylstilbestrol (DES) in utero. Using this established DES neonatal mouse model, my goal was to investigate long-term molecular and morphological effects of certain polychlorinated biphenyls (PCBs) that are weakly estrogenic in adult mice. Focusing on the cervicovaginal (CV) tract, since this is where tumors develop in the BALB/c mouse, I first assessed the 17β-estradiol (E2) dose-response for expression of lactoferrin (LTF). LTF is a highly inducible estrogen biomarker that is permanently altered in uteri from neonatally treated mice. Treatments were administered via 5 subcutaneous injections beginning within 16 hrs after birth, days 1–5. ^ The ontogeny of LTF expression from mouse CV tracts was determined by examining three different stages of life: pups, immature, and mature mice. Northern RNA analysis and immunohistochemistry showed that neonatal E 2 treatment both increases and decreases LTF expression. Early expression of LTF in the CV tract at all doses occurred in pups. In both immature and adult mice, increased LTF expression was dependent on whether E2 induced ovary-dependent or ovary-independent persistent vaginal cornification. ^ Next, I studied biological responses from neonatally PCB exposed adult mice. As expected, using a neonatal uterine bioassay I showed that 2 ′4′6′-trichloro-4-biphenylol (OH-PCB-30), 2′3′4′ 5-tetrachloro-4-biphenyloI (OH-PCB-61), and OH-PCB-30/61 (50/50 mixture), were estrogenic causing a dose-dependent increase in uterine weight. ^ Long-term effects of OH-PCB 30 [200 μg/pup/day] were most similar to E2 as seen by an increased uterine wet weight in day 50 mice similar to E2 [5 μg/pup/day] (141% and 140% of control, respectively). Another similarity between OH-PCB 30 and E2 neonatally treated mice was found in those sacrificed at 20 months of age. At these same doses CV tract squamous cell carcinoma induction was 43% of E2 treated mice and 47% of OH-PCB 30 treated mice. Differences were noted in adenoaquamous; cell carcinoma development, where 16% of OH-PCB-30 neonatally treated mice developed tumors versus 8% for E2. Based on these results using the neonatal mouse model, I conclude that the OH-PCBs tested are strongly estrogenic and tumorigenic showing dose-response relationships when exposure occurs during development of the reproductive tract in mice. These results may have important implications for risk assessment in determining the effects of xenoestrogens exposure early versus later in life. ^

Tumor immunization strategies for enhancing the graft versus tumor activity of allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) is known to induce a beneficial anti-tumor immune response called graft-versus-tumor (GVT) activity. However, GVT activity is closely associated with graft-versus-host disease (GVHD), a potentially fatal immune response against antigens on normal recipient tissues. The T-cell populations mediating these two processes are often overlapping, but studies have shown that some donor T-cells can be tumor-specific. Therefore, the goal of this study was to develop strategies for preferentially activating donor T-cells capable of mediating GVT activity but not GVHD. The three hypotheses tested were: (1) Pre-transplant immunization of BMT donors with a recipient-derived tumor cell vaccine will induce a relative increase in GVT activity as compared to GVHD. (2) Post-transplant tumor immunization of BMT recipients will enhance GVT activity without exacerbating GVHD. (3) Pre-transplant immunization of BMT donors against a tumor-specific antigen will enhance GVT activity without exacerbating GVHD. ^ To test the first two hypotheses, C3H.SW mice (MHC-matched donors) were immunized with a C57BL/6 (recipient)-derived tumor cell vaccine (leukemia or fibrosarcoma) prior to BMT, or recipients were immunized starting one month after BMT. Both donor and recipient immunization led to a significant increase in GVT activity (enhanced recipient survival and decreased tumor growth). However, donor immunization also increased fatal GVHD, which was at least partially due to activation of alloreactive T-cells recognizing the immunodominant minor histocompatibility antigen B6dom1. GVT immunity following recipient immunization was not associated with an exacerbation of GVHD or a response to B6dom1. ^ To test the third hypothesis, influenza nucleoprotein (NP) was used as a model tumor antigen. C3H.SW donors were immunized against NP prior to BMT, which led to a significant increase in GVT activity. Although recipients were not completely protected against growth of antigen loss variant tumors, there was no increase in GVHD. ^ In conclusion, (1) immunization of allogeneic BMT donors with a recipient-derived tumor cell vaccine substantially increases GVT activity but also exacerbates GVHD, (2) post-transplant tumor immunization of allogeneic BMT recipients significantly increases GVT activity and survival without exacerbating GVHD, and (3) immunization of allogeneic BMT donors against a tumor-specific antigen significantly enhances GVT activity without exacerbating GVHD. ^

Evaluating the impact of vertical integration on health system peformance

Vertical integration is grounded in economic theory as a corporate strategy for reducing cost and enhancing efficiency. There were three purposes for this dissertation. The first was to describe and understand vertical integration theory. The review of the economic theory established vertical integration as a corporate cost reduction strategy in response to environmental, structural and performance dimensions of the market. The second purpose was to examine vertical integration in the context of the health care industry, which has greater complexity, higher instability, and more unstable demand than other industries, although many of the same dimensions of the market supported a vertical integration strategy. Evidence on the performance of health systems after integration revealed mixed results. Because the market continues to be turbulent, hybrid non-owned integration in the form of alliances have increased to over 40% of urban hospitals. The third purpose of the study was to examine the application of vertical integration in health care and evaluate the effects. The case studied was an alliance formed between a community hospital and a tertiary medical center to facilitate vertical integration of oncology services while maintaining effectiveness and preserving access. The economic benefits for 1934 patients were evaluated in the delivery system before and after integration with a more detailed economic analysis of breast, lung, colon/rectal, and non-malignant cases. A regression analysis confirmed the relationship between the independent variables of age, sex, location of services, race, stage of disease, and diagnosis, and the dependent variable, cost. The results of the basic regression model, as well as the regression with first-order interaction terms, were statistically significant. The study shows that vertical integration at an intermediate health care system level has economic benefits. If the pre-integration oncology group had been treated in the post-integration model, the expected cost savings from integration would be 31.5%. Quality indicators used were access to health care services and research treatment protocols, and access was preserved in the integrated model. Using survival as a direct quality outcome measure, the survival of lung cancer patients was statistically the same before and after integration. ^

The role of UV radiation in the development of myeloid malignancy in Rag2 knockout mice

Excessive exposure to the UV radiation present in sunlight can lead to the development of skin cancer in humans. Majority of the UV-induced skin tumors in immune-competent mice are highly antigenic in nature. Additionally, they exhibit a high frequency of mutations in the p53 gene, which arise very early in the course of UV radiation and most of them disappear before the development of skin tumors. ^ Initially, this study was to determine whether UV radiation induces skin tumors much earlier in immune deficient Rag2 knockout mice than in immune-competent mice, and if so, compare their antigenic properties and p53 mutation spectra. However, chronic UV irradiation (10 kJ/m2) induced myeloproliferative disease (MPD) as early as 4 weeks in Rag2 knockout mice instead of skin tumors. Conversely, unirradiated Rag2 knockout mice developed MPD at a low frequency, but the frequency increased with the animal's age. Although the UV-irradiated wild type mice (B6129) developed MPD, its frequency was lower and the occurrence much later than the Rag2 knockout mice. ^ This observation led to our new hypothesis that UV irradiation plays a role in the development of MPD in Rag2 knockout mice. After 4 weeks of UV radiation, both histopathology (myeloid:erythroid ratio, number of blast cells) and flow cytometry (mature myeloid, granulocytes and immature cells) demonstrated an increased number of mice affected with the disease in the UV-irradiated Rag2 knockout group than the other groups. ^ We also investigated the role of cytokines and absence of T and B cells in the development of MPD in the Rag2 knockout mice. Results indicated that IL-3 and IL-3Rα chain expression was upregulated in the spleens of the UV-irradiated Rag2 knockout mice (4 weeks). Reconstitution of the Rag2 knockout mice with T and B cells abrogated the UV-accelerated development of MPD. Both histopathology and flow cytometric analysis (mature myeloid cells, granulocytes) showed a decrease in the number of mice affected with the disease in the UV-irradiated, reconstituted group rather than any other group. In summary, this study provides the first experimental evidence that exposure to UV irradiation can lead to the development of MPD in immune deficient mice. ^

Preclinical evaluation of proteasome inhibition for the treatment of prostate cancer

Prostatic carcinoma is the most prevalent cancer detected in men. Bortezomib is the first proteasome inhibitor to undergo clinical trials for several forms of cancer. Although we know this class of agent preferentially kills cancer cells, our knowledge of proteasome inhibition mechanisms of induced death is far from complete. We investigated the effects of bortezomib on the LNCaP-Pro5 (Pro5) and PC-3-Pro4 (Pro4) human prostatic adenocarcinoma cells lines. We showed a reduction in proliferation and an increase in DNA fragmentation, caspase 3 activity, and cell surface phosphatidyl serine exposure. The bortezomib-treated tumors from both cell lines were dramatically reduced, and apoptosis was induced. There was also a reduction in proliferation in the treated tumors from both cells lines. We looked at changes in the levels of the proangiogenic factors VEGF, IL-8 and bFGF in vitro and in vivo. Although there was a reduction in the levels of VEGF produced by the Pro5 cell line and tumor due to bortezomib, no similar observations were made for the other angiogenic factors or in the Pro4 cells. We investigated the effects of bortezomib on p53 in the Pro5 cell line. Bortezomib induced strong stabilization of p53. It did not promote phosphorylation on serines 15 and 24 and p53 remained bound to its inhibitor, mdm2. Nonetheless, confocal microscopy revealed that bortezomib stimulated p53 translocation to the nucleus and enhanced p53 DNA binding, accumulation of p53-dependant transcripts, and activation of a p53-responsive reporter gene. Furthermore, stable transfectants of LNCaP-Pro5 expressing the p53 inhibitor, HPV-E6, displayed reduced bortezomib-induced p53 activation and cell death. Our data shows bortezomib to induce antitumor effects in the human Pro4 and Pro5 prostatic adenocarcinoma cell lines by the direct induction of apoptosis. The drug also causes a reduction in cell proliferation and mean vessel density while modulating the secretion of proangiogenic factors. Although we show that proteasome inhibition stimulates p53 activation via a novel mechanism in Pro5 cells, it is also toxic to p53 null cells as is seen in the Pro4 line. ^

Community preferences for cancer pain health states

The study's objective was to assess the reliability, acceptability, and concordance of cancer pain health states when using two utility assessment methods—simple rank order (RO) and numerical analogue scale (NAS). Additional aims were to describe the preferences of Hispanic and non-Hispanic community members toward cancer pain health states and identify predictors affecting these preferences. In this descriptive, cross-sectional study, telephone calls were made to a quota sample of 1,387 households that had telephone numbers listed for the Houston and surrounding Harris County area. Subjects (n = 302) within the general population completed a 20 minute telephone interview in their preferred language—English or Spanish. Study respondents assessed six cancer pain health states consisting of three attributes, pain intensity, presence of side effects, and interference with daily function. ^ Overall, the numerical analogue scale (NAS) had better test-retest reliability. Respondents were able to clearly distinguish the worst health state using both methods, but were not able to do so as clearly for less severe health states. Acceptability and subjects' ability to answer questions and complete the survey was high. Missing responses were low across methods for all health states. Concordance in the health state rankings was higher for the most severe health state in the non-Hispanic group, those in fair to poor health, males, and those $30,000 or greater income. Preferences for the less severe health states did not show much variation across methods. No significant predictors for health states were found except for ethnicity for a less severe health state when using the rank order method. ^ We found that the rank order (RO) and numerical analogue scale (NAS) are both robust in ranking the more severe cancer pain health states, e.g., moderate pain with three side effects. This study documents that RO and NAS methods to assess cancer pain preferences through a telephone-based approach among a relative diverse community dwelling, non-patient population for cancer pain health states represented a relatively valid and acceptable approach. ^

14-3-3zeta overexpression in multiple human cancers plays a critical role in cancer progression

14-3-3 is a family of highly conserved and ubiquitously expressed proteins in eukaryotic organisms. 14-3-3 isoforms bind in a phospho-serine/threonine-dependent manner to a host of proteins involved in essential cellular processes including cell cycle, signal transduction and apoptosis. We fortuitously discovered 14-3-3 zeta overexpression in many human primary cancers, such as breast, lung, and sarcoma, and in a majority of cancer cell lines. To determine 14-3-3 zeta involvement in breast cancer progression, we used immunohistochemical analysis to examine 14-3-3 zeta expression in human primary invasive breast carcinomas. High 14-3-3 zeta expression was significantly correlated with poor prognosis of breast cancer patients. Increased expression of 14-3-3 zeta was also significantly correlated with elevated PKB/Akt activation in patient samples. Thus, 14-3-3 zeta is a marker of poor prognosis in breast cancers. Furthermore, up-regulation of 14-3-3 zeta enhanced malignant transformation of cancer cells in vitro. ^ To determine the biological significance of 14-3-3 zeta in human cancers, small interfering RNAs (siRNA) were used to specifically block 14-3-3 zeta expression in cancer cells. 14-3-3 zeta siRNA inhibited cellular proliferation by inducing a G1 arrest associated with up-regulation of p27 KIP1 and p21CIP1 cyclin dependent kinase inhibitors. Reduced 14-3-3 zeta inhibited PKB/Akt activation while stimulating the p38 signaling pathway. Silencing 14-3-3 zeta expression also increased stress-induced apoptosis by caspase activation. Notably, 14-3-3 zeta siRNA inhibited transformation related properties of breast cancer cells in vitro and inhibited tumor progression of breast cancer cells in vivo. 14-3-3 zeta may be a key regulatory factor controlling multiple signaling pathways leading to tumor progression. ^ The data indicate 14-3-3 zeta is a major regulator of cell growth and apoptosis and may play a critical role in the development of multiple cancer types. Hence, blocking 14-3-3 zeta may be a promising therapeutic approach for numerous cancers. ^

Targeted cancer diagnosis with radiolabeled endostatin

Nuclear imaging is used for non-invasive detection, staging and therapeutic monitoring of tumors through the use of radiolabeled probes. Generally, these probes are used for applications in which they provide passive, non-specific information about the target. Therefore, there is a significant need for actively-targeted radioactive probes to provide functional information about the site of interest. This study examined endostatin, an endogenous inhibitor of tumor angiogenesis, which has affinity for tumor vasculature. The major objective of this study was to develop radiolabeled analogues of endostatin through novel chemical and radiochemical syntheses, and to determine their usefulness for tumor imaging using in vitro and in vivo models of vascular, mammary and prostate tumor cells. I hypothesize that this binding will allow for a non-invasive approach to detection of tumor angiogenesis, and such detection can be used for therapeutic monitoring to determine the efficacy of anti-angiogenic therapy. ^ The data showed that endostatin could be successfully conjugated to the bifunctional chelator ethylenedicysteine (EC), and radiolabeled with technetium-99m and gallium-68, providing a unique opportunity to use a single precursor for both nuclear imaging modalities: 99mTc for single photon emission computed tomography and 68Ga for positron emission tomography, respectively. Both radiolabeled analogues showed increased binding as a function of time in human umbilical vein endothelial cells and mammary and prostate tumor cells. Binding could be blocked in a dose-dependent manner by unlabeled endostatin implying the presence of endostatin receptors on both vascular and tumor cells. Animal biodistribution studies demonstrated that both analogues were stable in vivo, showed typical reticuloendothelial and renal excretion and produced favorable absorbed organ doses for application in humans. The imaging data provide evidence that the compounds quantitate tumor volumes with clinically-useful tumor-to-nontumor ratios, and can be used for treatment follow-up to depict changes occurring at the vascular and cellular levels. ^ Two novel endostatin analogues were developed and demonstrated interaction with vascular and tumor cells. Both can be incorporated into existing nuclear imaging platforms allowing for potential wide-spread clinical benefit as well as serving as a diagnostic tool for elucidation of the mechanism of action of endostatin. ^

Activation of dendritic cells from patients with epithelial ovarian cancer

Dendritic cells (DCs) are the most potent antigen-presenting cells for inducing immune responses to tumor cells. Lin−HLA-DR + DC populations in peripheral blood mononuclear cells (PBMCs) and in ascites mononuclear leukocytes (MNLs) of patients with epithelial ovarian cancer (EOC) are phenotypically immature. Lin−HLA-DR + DCs from PBMCs of normal subjects and EOC patients and MNLs from ascites cells of patients were examined for specific cell surface markers or indicators of differentiation or activation. Separating Lin− HLA-DR+ DCs into subsets based on their HLA-DR intensity provided an additional method for identifying the two major lineages of DCs, myeloid and plasmacytoid. The activation potential of these DCs following exposure to the maturation agents CD40 ligand (CD40L) and lipopolysaccharide (LPS) was examined by measurement of IL-12 and IL-10 concentrations in DC culture supernatants in addition to their ability to stimulate allogeneic T cells. DCs from PBMCs of normal subjects and EOC patients and DCs isolated from ascites MNLs of EOC patients were separated into subsets based on CD11c and CD123 cell surface marker expression identifying the major DC types. These subsets were then compared with cells sorted on the basis of HLA-DR intensity. The in vivo behavior of DCs and DC subsets in peripheral blood and ascites following treatment of peritoneal carcinoma patients with the growth factor fins-like tyrosine kinase 3 ligand (Flt3L) was also examined. Increases in proportions and total numbers of DCs from peripheral blood and ascites were associated with increased secretion of IL-12 and IL-10 following in vitro activation of cultured DCs. There were differences between DCs from PBMCs and ascites and between DC subsets in expression of cell surface markers, cytokine profile, and the ability of Lin−HLA-DR + cells to stimulate proliferation of allogeneic T cells from EOC patients. These Lin−HLA-DR+ cells have certain functional properties that suggest that they could have the potential to facilitate an adaptive anti-tumor immune response. ^

Interrelationships between the structural and functional aspects of social relationships, comorbidity and health related quality of life in breast cancer survivors

It is widely acknowledged in theoretical and empirical literature that social relationships, comprising of structural measures (social networks) and functional measures (perceived social support) have an undeniable effect on health outcomes. However, the actual mechanism of this effect has yet to be clearly understood or explicated. In addition, comorbidity is found to adversely affect social relationships and health related quality of life (a valued outcome measure in cancer patients and survivors). ^ This cross sectional study uses selected baseline data (N=3088) from the Women's Healthy Eating and Living (WHEL) study. Lisrel 8.72 was used for the latent variable structural equation modeling. Due to the ordinal nature of the data, Weighted Least Squares (WLS) method of estimation using Asymptotic Distribution Free covariance matrices was chosen for this analysis. The primary exogenous predictor variables are Social Networks and Comorbidity; Perceived Social Support is the endogenous predictor variable. Three dimensions of HRQoL, physical, mental and satisfaction with current quality of life were the outcome variables. ^ This study hypothesizes and tests the mechanism and pathways between comorbidity, social relationships and HRQoL using latent variable structural equation modeling. After testing the measurement models of social networks and perceived social support, a structural model hypothesizing associations between the latent exogenous and endogenous variables was tested. The results of the study after listwise deletion (N=2131) mostly confirmed the hypothesized relationships (TLI, CFI >0.95, RMSEA = 0.05, p=0.15). Comorbidity was adversely associated with all three HRQoL outcomes. Strong ties were negatively associated with perceived social support; social network had a strong positive association with perceived social support, which served as a mediator between social networks and HRQoL. Mental health quality of life was the most adversely affected by the predictor variables. ^ This study is a preliminary look at the integration of structural and functional measures of social relationships, comorbidity and three HRQoL indicators using LVSEM. Developing stronger social networks and forming supportive relationships is beneficial for health outcomes such as HRQoL of cancer survivors. Thus, the medical community treating cancer survivors as well as the survivor's social networks need to be informed and cognizant of these possible relationships. ^

The relationship between risk perception and ethnicity as an explanation for late stage skin cancer diagnosis in Black and Hispanic populations: An analysis using data from the 2005 Health Information and National Trends Survey

Objective. The purpose of this study was to determine the relationship between ethnicity and skin cancer risk perception while controlling for other risk factors: education, gender, age, access to healthcare, family history of skin cancer, fear, and worry. ^ Methods. This study utilized the Health Information National Trends Survey (HINTS) dataset, a nationally representative sample of 5,586 individuals 18 years of age or older. One third of the respondents were chosen at random and asked questions involving skin cancer. Analysis was based on questions that identified skin cancer risk perception, fear of finding skin cancer, and frequency of worry about skin cancer and a variety of sociodemographic factors. ^ Results. Ethnicity had a significant impact on risk perception scores while controlling for other risk factors. Other risk factors that also had a significant impact on risk perception scores included family history of skin cancer, age, and worry. ^